PEDIATRIC BURNS
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PEDIATRIC BURNS
Edited By
BRADLEY J. PHILLIPS, MD
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Copyright Cambria Press 2012. Editor: Bradley J. Phillips, M.D. Director, Burn Program Director, Surgical Critical Care Associate Director, Trauma Surgery Swedish Medical Center: Level 1 Trauma—Adult & Pediatric Injury Phillips Surgical, PC: from tragedy … Hope! Burn-Trauma-ICU & Emergency Surgery 499 E. Hampden Rd: Suite 380 Englewood, CO 80113 Office: 303-788-5300 Fax: 303-788-5363 Email: [emailprotected] All rights reserved Printed in the United States of America No part of this publication may be reproduced, stored in or introduced into a retrieval system, or transmitted, in any form, or by any means (electronic, mechanical, photocopying, recording, or otherwise), without the prior permission of the publisher. Requests for permission should be directed to: [emailprotected], or mailed to: Cambria Press 20 Northpointe Parkway, Suite 188 Amherst, NY 14228 ISBN: 978-1-60497-696-0 Library of Congress Cataloging-in-Publication Data Pediatric burns / edited by Bradley Phillips. p. ; cm. Includes bibliographical references and index. ISBN 978-1-60497-696-0 1. Burns and scalds in children. I. Phillips, Bradley. [DNLM: 1. Burns. 2. Adolescent. 3. Child. 4. Infant. WO 704 P371 2010] RD96.4.P42 2010 617.1’10083—dc22 2010006665
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To my parents
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TABLE OF CONTENTS
Acknowledgment
ix
Introduction
xi
Chapter 1: Historical Perspective and the Development of Modern Burn Care
1
Chapter 2: Principles of Pediatric Burn Injury
14
Chapter 3: Epidemiology and Economics of Pediatric Burns
28
Chapter 4: Skin: Structure, Development, and Healing
44
Chapter 5: Etiology of Immune Dysfunction in Thermal Injuries
69
Chapter 6: Burn Pathophysiology
77
Chapter 7: Pediatric Burn Resuscitation
96
Chapter 8: Burn Critical Care
117
Chapter 9: Common Pitfalls of Pediatric Burn Care
131
Chapter 10: Anesthesia for Pediatric Burn Patients
141
Chapter 11: Acute Burn Excision
160
Chapter 12: Blood Transfusion in Children with Burn Injury
165
Chapter 13: Infections in Patients with Severe Burns: Diagnostic and Management Approach
176
Chapter 14: Fungal Infections
187
Chapter 15: Inhalation Injury
205
Chapter 16: Metabolic Response to Burns
215
Chapter 17: Changes to the Hypothalamic-Pituitary-Adrenal Axis in Burns and Use of Steroids
230
Chapter 18: Hypermetabolism and Anabolic Agent Use in Pediatric Burn Patients
252
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Chapter 19: Scald Burns
262
Chapter 20: Electrical Burns and Rhabdomyolysis
277
Chapter 21: Caustic Ingestions
287
Chapter 22: Burn-Related Child Abuse
310
Chapter 23: Pediatric Burn Injury: A Neurosurgery Perspective
319
Chapter 24: Rehabilitation of the Pediatric Burn Patient
325
Chapter 25: Pain Management in the Burned Child
352
Chapter 26: The Psychology of Pediatric Burn Pain
374
Chapter 27: Psychosocial Aspects of Pediatric Burn Care
393
Chapter 28: Outpatient Management of Pediatric Burn Patients
406
Chapter 29: Pediatric Burn Care in Rural Environments
412
Chapter 30: Pediatric Burns in Developing Countries
425
Chapter 31: Care of the Hospitalised Paediatric Burn Patient: A Perspective from the United Kingdom
439
Chapter 32: The Surgical Treatment of Acute Burns: The Viennese Concept
463
Chapter 33: Pediatric Burns: A Global Perspective
469
Chapter 34: Pediatric Burns in War Environments
477
Chapter 35: Disaster Management: Implications for Pediatric Burn Patients
484
Chapter 36: Burns Research and the Forgotten Trauma of Childhood
490
Chapter 37: Long-Term Outcomes After Burn Injury in Children
504
Index
507
viii
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ACKNOWLEDGMENTS I would like to deeply thank and acknowledge Dr. Ronald Hunt and Dr. Richard Dennis; their guidance helped a young student learn the art of medicine. Throughout my career, I have had many teachers and mentors––three who stand out in terms of my burn experience are Dr. David Herndon, Dr. David Greenhalgh, and, of course, Dr. Robert Sheridan. I owe each of these gentlemen more than they realize and I hope that this book will be accepted as some small form of payment. All of us that treat injured children are motivated by these physicians, day in and day out. This book exists because of the work of many: the authors, the reviewers, and the publishing staff. I want to especially thank each of the chapter authors––in our busy, hectic world they have taken the time to help put this textbook together. I would also like to thank Ms. Amy Halm for all of her time and dedication to this project. With the dynamic support of Cambria Press, Inc. this book is now in your hands and I will ask of you one favor: to help us create hope from tragedy…
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we shall not warmly nor gently embrace the manifestations of burn injury for she is the devil’s haunt she is the invading crusader she is the omnipresent masquerade and as such, we must strike at her very heart we must attack her cascading armies and drive them to the gates of hell we must stand and defend the very weak—lifting them up in loving arms we are tasked to keep guard—a constant vigil every minute, every hour, every day until the battle is won these deeds, at all costs, I say for the price of failure is death so let us not pause in doubt or fear let us push forward into the darkness and hunt for her hidden truths if our work is just, our acts are bold, our efforts are courageous, then we shall overcome we shall and we must
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INTRODUCTION The practice of pediatric burns is a dynamic and ever evolving field. Many aspects of care are unique to this patient population and the delivery of care is a challenge even for the most experienced medical team. It is in this framework that we have composed Pediatric Burns: a comprehensive guide for the diagnosis, treatment and follow up of the burned child from Time Zero through Long-term Rehabilitation. Mindful of the complexities of burn injuries themselves, with the many divergent causes, as well as, the social and psychological harm associated with severe burn wounds, we have endeavored to create this text for the medical professional involved in attaining the most positive outcome possible for the patient and his or her family.
THE STUDY OF PEDIATRIC BURNS: TEXTBOOK AND RELATED LEARNING MATERIAL This project describes the most advanced practices in use throughout the world in every type of burn wound category, providing clear descriptions of treatment methods from every discipline’s perspective. Contributors represent practitioners from a wide variety of backgrounds, locations and cultures, all with a common goal: to ensure the healthiest and most highly functioning young burn survivors possible.
THE REALITY AND SEVERITY OF THE PEDIATRIC BURN In the United States alone, burns are the third leading cause of death among children 0 to 14 years of age. In addition, each year greater than 125,000 children suffer serious burn injuries, with a disturbing percentage of those through abuse. Yet the number of specialized burn centers in the U.S. is not near enough to be in proximity or even accessible to the majority of these patients. The situation is even worse in most other regions of the world. Therefore, it is critical that we reach as many caregivers as possible with the information contained in these pages, as treatment of burn injuries has undergone dramatic changes over time in every area, from surgical procedures to respiratory and fluid resuscitation and even nourishment and metabolic support. The ability to recognize and react appropriately to pediatric injury can greatly affect the outcome and prognosis, up to and including the patient’s future quality of life.
THE NEED FOR SPECIALIZATION A seriously burned child requires an immediate, unique and complex order of care from a myriad of disciplines if survival and full functional recovery are to be achieved. When we remember that serious burn injuries are trauma cases first, a comprehensive understanding of these injuries is called for. First responders who can recognize, assess, and take rapid and correct actions in a serious burn case can greatly impact patient survivability until handoff to the ER and surgical team. This project is an important resource for medical students interested in pursuing a specialty of pediatrics or burns, as well as current practitioners or those in the study of family practice, emergency medicine, surgery and critical care. Surgical and critical care nurses and allied health professionals in respiratory, physical and occupational therapy, psychology and social work will benefit from learning about the comprehensive nature of treatment of the burn-injured child. Clinic and hospital administrators will have a greater appreciation of the specialized equipment and expertise required to deliver optimal care to this most vulnerable patient population after reading this book.
FROM TRAGEDY….HOPE Pediatric Burns is a multi-authored volume that is solely dedicated to providing a comprehensive roadmap to caregivers involved in treating and rehabilitating a child with a serious burn injury. It is my hope that this work will have a profound effect on the lives of young burn survivors and their families. –Bradley J. Phillips
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PEDIATRIC BURNS
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1
C H A P T E R
O N E
HISTORICAL PERSPECTIVE AND THE DEVELOPMENT OF MODERN BURN CARE LEOPOLDO C. CANCIO, MD, FACS COLONEL, MEDICAL CORPS, US ARMY, US ARMY INSTITUTE OF SURGICAL RESEARCH BASIL A. PRUITT JR, MD, FACS CLINICAL PROFESSOR OF SURGERY, UNIVERSITY OF TEXAS HEALTH SCIENCES CENTER AT SAN ANTONIO The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or Department of Defense.
c. d. e. f.
OUTLINE 1. Introduction 2. Organizational Landmarks a. The World Wars and Fire Disasters b. Organization of the Burn Unit c. National and International Burn Associations
3. Milestones in Research and Clinical Care a. Fluid Resuscitation b. The Burn Wound: Topical Treatment
1 1 1 2 3
4. 5. 6. 7. 8.
The Burn Wound: Surgical Treatment Inhalation Injury Metabolism and Nutrition Rehabilitation
Conclusion Key Points Acknowledgments Table References
6 7 7 8
8 8 9 9 9
3 3 5
INTRODUCTION Before WWII and the creation of specialized units for the care of thermally injured patients, deep burns in excess of 30% were almost invariably fatal1; the pathophysiology of death following thermal injury was misunderstood, and effective options for resuscitation, wound care, and surgical closure did not exist. What conditions made possible the extraordinary revolution of the last 60 years? Answering this question is important in order to continue to progress in addressing the unsolved problems in burn care and to make our most lifesaving advances available to the rest of the world.
or surgical technique has been more important than the burn center concept itself, which involves the institutional commitment to excellence in research, teaching, and clinical care. Several landmarks in the history of the burn center are provided in the Table. The first burn hospital was established in 1843 by James Syme in Edinburgh, who felt that mixing burn and other surgical patients would represent “the highest degree of culpable recklessness.” Subsequently, space was created in a former workshop. Five years later, however, the burn patients were transferred in order to accommodate an increased number of patients from railway and other accidents.2
ORGANIZATIONAL LANDMARKS
The World Wars and Fire Disasters
Of the various innovations which led to the marked reduction in postburn mortality of the last 60 years, no technology
Subsequent developments in burn care, as in trauma care generally, were clearly given impetus by the world wars
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and civilian fire disasters.3-5 In 1916, Sir Harold Gillies, who is recognized as the founder of modern plastic surgery, returned from service in France during WWI to establish the first plastic and oral-maxillofacial surgery service in the United Kingdom, treating combat casualties, including burn patients, at Cambridge Military Hospital, Aldershot. Gillies proceeded to develop forward-deployed units during WWII to care for patients with burns and other injuries meriting plastic surgical attention.6 His cousin, Archibald McIndoe, became consultant in plastic surgery to the Air Ministry and established a burn hospital at East Grinstead during the Battle of Britain in 1940. One of McIndoe’s most important contributions was his recognition of the need for a social support system for burn survivors, which was provided for these airmen not only by their own “Guinea Pig Club,” but also by hospital staff and local townspeople. McIndoe condemned the use of tannic acid for topical wound care, defined the need for early rehabilitation, and developed techniques for facial reconstruction based on experience with 600 patients with severe facial burns.7,8 He later recalled his state of mind upon embarking on this uncharted path: “A good, competent surgeon, experienced, yes…but when I looked at a burned boy for the first time and saw I must replace his eyelids, God came down my right arm.”9 Even though no dedicated burn unit was employed for the care of US combat casualties during WWII, that conflict nonetheless accelerated the development of burn care in the United States, just as in England. The Japanese attack on Pearl Harbor generated several hundred burn casualties,10 propelled the United States into war, and was followed in January 1942 by a National Research Council symposium on burns, with the initiation of several research programs in burn care. Two such federally funded programs were in place at the Massachusetts General Hospital (MGH) (in burn and complex wound infections and in the physiology of burns) when, on November 28, 1942, a fire at the Cocoanut Grove nightclub in Boston killed 492 of approximately 1000 occupants.11 One hundred fourteen patients arrived at MGH within a 2-hour period, of whom 39 survived to be admitted to a special casualty ward which remained open till December 13. The hospital course of these 39 patients was carefully documented, and although MGH did not establish a permanent burn unit at the time, these observations (which ranged from fluid resuscitation and management of inhalation injury to social work and rehabilitation) formed a foundation for subsequent research.12 Dr Chester Keefer, who supervised the US national program to evaluate penicillin, released enough of the new drug to Dr Champ Lyons, a young surgeon at Massachusetts General Hospital, to treat 13 of the 39 burn patients.13 Dr Lyons authored the microbiology chapter in the Cocoanut Grove
burns monograph, in which he remarked on the benign nature of the burn wounds of patients who received penicillin.14 In the spring of 1943, Dr Lyons became a major in the US Army’s Surgical Consultants and began a study of penicillin in the treatment of soldiers with complicated orthopedic injuries at the Bushnell General Hospital in Brigham, Utah.15 In June 1943, a second clinical unit to study penicillin was established at Halloran General Hospital on Staten Island, New York. Dr Lyons was placed in charge of the Wound Unit’s study of penicillin, in the course of which 209 combat casualties were treated with the new drug. After completing the studies at Halloran General Hospital, Lyons was reassigned to the Surgical Consultants Division, a new addition to the Army Medical Department. He served as surgical infections and wound management consultant in the Mediterranean theater of operations, where he continued to refine methods of penicillin usage.15 In 1947, the Wound Unit was relocated from Staten Island to Fort Sam Houston, Texas, and renamed the Surgical Research Unit (SRU).16 In this unit, patients with infected burns and other infected wounds were treated on a special ward at Brooke General Hospital.17 Two years later (1949), due to growing concerns about the possibility of nuclear war with the Soviet Union and recognition (based on experience in Japan) that such a war could generate thousands of burn survivors, the SRU established the nation’s second burn unit and refocused its research effort from the evaluation and use of antibiotics to the treatment of burns.18
Organization of the Burn Unit The organization and subsequent development of the SRU was one of the US Army’s most important contributions to burn care. Under a single commander and within a small organization separate from the host military, hospital surgeons, physicians, basic scientists, therapists, nurses, enlisted medics, and support personnel were brought together. The members of this prototypical multidisciplinary burn team had one objective: to improve patient outcomes by conducting integrated basic and clinical research. That is, they sought to take problems from the clinic to the laboratory, where models of injury were developed and the solutions were then transferred back to the clinic and applied to patient care. Along with a growing number of civilian burn units, the SRU (later the US Army Institute of Surgical Research, USAISR) made numerous contributions, several of which are discussed later. Also critical for improving care in the United States was the unit’s commitment to training surgeons, many of whom became directors of civilian burn centers.19-21 Finally, designation of the unit as a single destination for all US military burn casualties, as
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T HE DE VE L OP M E NT OF M ODE R N B U R N C A R E well as for civilians in the region, provided a constant and sufficient number of patients during both war and peace. Another major factor in the development of burn care in the United States was the decision on July 4, 1962, by the Shriners Hospitals for Crippled Children to privately fund the construction and operation of 3 pediatric burn units. The center in Galveston, Texas, opened in 1963 under Dr Curtis Artz as chief of staff; the unit in Cincinnati, Ohio, in 1964 under Dr Bruce Macmillan; and the unit in Boston, Massachusetts in 1964 under Dr Oliver Cope. Other dedicated facilities were constructed from through 196in the late 1960s. Similar to the USAISR, they became centers of excellence in care, teaching, and research.22-24 The period of most rapid growth in the number of burn units in the United States occurred during the decade 19701979, in which the number of units tripled.23 One hundred fifty units were open in 1979, with a mean of 11 beds each. By 2007, the number of units had decreased to 125, but there was a slight increase in the mean number of beds, to 14. Currently, this translates to a ratio of 1 burn unit per 2.5 million people in the United States.25 Possible future trends involve a further decrease in the number of burn units, with a concomitant increase in the number of beds per burn unit and increased regionalization of care.26
National and International Burn Associations The exponential growth in the number of burn professionals led to a series of National Burn Seminars (1959-1967), followed by creation of the American Burn Association (ABA) in 1968. A noteworthy aspect of the ABA has been its inclusion of representatives of all specialties involved in the care of burn patients, that is, all members of the multidisciplinary team. Abroad, similar national (eg, British Burn Association, 1968) and international (eg, International Society for Burn Injuries, 1965; European Burns Association, 1981)27,28 organizations were formed. In addition to sponsoring an annual meeting for burn care professionals, the ABA has played an increasing role in carrying out several functions of national importance. These functions have included education, disaster planning, promulgation of standards, and collection of data. Educational efforts include publication of the Journal of Burn Care and Research and sponsorship of the Advanced Burn Life Support course (formerly managed by the Nebraska Burn Institute). The ABA supports research primarily via its newly formed Multicenter Trials Group, which, since 2001, has contributed several publications to the field.29,30 The organization represents its members before Congress, for example, by advocating safe sleepwear for children, firesafe cigarettes, appropriate payment for burn care services,
and timely qualification of burn survivors for Social Security disability. With respect to disaster planning, the USAISR and the ABA collaborated during Gulf War I in 1991 and then again during Operation Iraqi Freedom in 2003 to determine, on a daily basis, the number of available beds at burn centers across the country in case of a mass casualty event.31,32 The relevance of this system to civilian disaster planning led to its continuation by the ABA along with the US Department of Health and Human Services. Disasters such as the World Trade Center attacks in 200133 and the Station nightclub fire of 200334 further highlighted the need for regional and national burn disaster plans. The ABA has made such planning a priority, as have several regional burn organizations.35-37 The ABA publishes a continuing series of clinical practice guidelines to address various issues in burn care.38 The organization’s verification committee, which began work in 1992, plays an indispensable role in both promulgating a standard of care for burn center operation as well as providing burn centers with individualized guidance to assist them in achieving that standard.25,39 Finally, the National Burn Repository, which began collecting data in 1991, provides data for research and enables the setting of performance benchmarks.40
MILESTONES IN RESEARCH AND CLINICAL CARE The creation of specialized centers dedicated to integrated clinical and laboratory research in burns and to excellence in clinical care and teaching made possible a series of changes in patient management which markedly reduced postburn mortality.
Fluid Resuscitation The first milestone was an understanding of the pathophysiology of burn shock and the development of fluid resuscitation formulae. In the early 20th century, it was commonly believed that early postburn deaths were caused by “toxemia.” According to this view, the eschar released a toxic substance or substances into the circulation, which caused death. Topical treatment of the burn wound was directed at “tanning” the eschar in an effort to prevent the release of this toxin (see following). The toxemia theory also inspired the rebirth of therapeutic bleeding in the form of partial exchange transfusion: Should a patient be admitted after the toxaemia has developed…we have practiced exsanguination transfusion. In the adult we have made no attempt to
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completely exsanguinate the patient, and in the child we have removed about 20 c.c. per lb. body weight.41 Fluid resuscitation, by contrast, was rarely practiced before WWII. In 1945 the Medical Research Council of the United Kingdom reviewed 1200 admissions from 1937 through 1941 to the Glasgow Royal Infirmary and discovered that one-half of deaths occurred within the first 24 hours and 72 percent within 3 days. Only 4 patients received intravenous plasma or serum.7 Similarly, Artz and Fox found that the “majority” of burn patients in this era died from inadequate or inappropriate fluid replacement.18 Three developments formed the foundation for the method of burn resuscitation used today. First, Underhill, writing in 1930 about his experiences following the Rialto Theatre fire in New Haven, Connecticut, of 1921, argued that the toxemia theory was “an obstruction.” Rather, anhydremia, or loss of water from the blood, magnified “the circulatory deficiency” (ie, shock). “The thick, sticky blood… finds great difficulty in passing through the capillaries…the tissues in general suffer from inadequate oxygenation… the heart pumps only a portion of its normal volume.” Tissue damage and inflammation caused increased capillary permeability and loss of plasma-like fluid. This was manifested by an increase in hemoglobin, which could also be used as an index of resuscitation. Therapy should consist of intravenous, oral, subcutaneous, and/or rectal infusions of saline solutions, at a rate not to exceed 1.5 liters per hour.42 Second, Blalock in 1931 demonstrated that thermal injury in unresuscitated dogs caused loss of over half of the total plasma volume as interstitial edema fluid. He concluded that “fluid loss probably is the initiating factor in the decline of blood pressure”—not toxemia. He also revealed the protein content of edema fluid to be almost as high as that of blood. Interestingly, he did not (at that time) propose that these fluid losses be replaced, but incorrectly speculated that tannic acid and other escharotics might effect a reduction in fluid loss rates.43 The third major contribution was the demonstration that plasma, now available in sufficient quantities for clinical use, could be used to resuscitate burn patients when guided by burn-size-based formulae to estimate plasma dose. Use of plasma for burn resuscitation was described by several authors after 193944-46; consistent with Underhill’s recommendations, complex formulae based on frequent determinations of the hematocrit or hemoglobin were used to adjust the infusion rate. Mass production of plasma was begun by the Blood for Britain program under Dr Charles Drew et al. in August 1940.47 As a consequence, plasma was used in the treatment of the approximately 300 thermally injured casualties admitted to the US Naval Hospital Pearl
Harbor following the Japanese attack.10 At the National Research Council meeting of January 7, 1942, chaired by I. S. Ravdin, Harkins proposed for far-forward military use (where laboratory facilities for calculation of the hematocrit were not available) the first formula for resuscitation based on burn size, known as the first aid formula. Fifty ml of plasma were to be given per percent total body surface area burned (TBSA), “in divided doses.”46,48 Later, he defined a more rapid initial rate of infusion—one-third of the estimated volume given in the first 2 hours, one-third in the next 4 hours, and one-third in the next 6 hours.49 It should be noted that this volume is considerably less than would be recommended by later formulae. After the Cocoanut Grove fire, Cope and Rhinelander reported giving plasma to all but 10 of the 39 patients admitted to MGH. In a fortuitous modification of the NRC formula, [f]or each 10 percent of the body surface involved, it was planned to give 500 cc. in the first 24 hours. Because the plasma delivered by the Blood Bank during the first 36 hours was diluted with an equal volume of physiologic saline solution, the patient was to receive 1000 cc. for each 10 per cent burned. The plasma dosage was modified subsequently on the basis of repeated hematocrit and serum protein determinations.50 In Cope and Moore’s follow-up paper of 1947, a further refinement called the surface area formula is described: 75 ml of plasma and 75 ml of isotonic crystalloid solution per TBSA, with one-half given over the first 8 hours and one-half over the second 16 hours. The urine output was to be used as the primary index of resuscitation.51 Subsequent refinements of this basic concept included the following: • Evans formula: incorporation of body weight; colloid 1 ml/kg/TBSA and crystalloid 1 ml/kg/ TBSA52 • Brooke formula: decrease in colloid content to 0.5 ml/kg/TBSA, with crystalloid 1.5 ml/kg/ TBSA; replacement of plasma with 5% albumin due to risk of hepatitis53 • Parkland formula: elimination of colloid; increase in crystalloid to 4 ml/kg/TBSA54 • Modified Brooke formula: elimination of colloid during first 24 hours; crystalloid 2 ml/kg/TBSA55 The net effect of this effort was the virtual elimination of postburn renal failure during the early 1950s and a reduction in burn shock as the cause of postburn death by approximately 13%. Currently, the hazards of over-resuscitation (extremity and abdominal compartment syndromes, airway and pulmonary edema, progression of wound depth)56
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T HE DE VE L OP M E NT OF M ODE R N B U R N C A R E mandate a continued search for an approach to resuscitation which reduces the rate of edema formation.
The Burn Wound: Topical Treatment In 1954, Liedberg and colleagues at the SRU noted that effective fluid resuscitation now kept many patients with greater than 50% TBSA burns alive past the 2-day mark, only to succumb later. Whereas previous authors had attributed these delayed deaths to “toxemia” or “exhaustion,” the presence of positive blood cultures, particularly in patients with large full-thickness burns, pointed at bacteremia of burn wound origin as the cause of death. This hypothesis was confirmed in the animal model of invasive pseudomonal burn wound infection developed by Walker and Mason.57,58 At that time, however, no effective topical therapy had been identified.59 Early descriptions of treatment of wounds are found in ancient Egyptian papyri. Several agents are recommended for the topical treatment of burns in the Ebers papyrus (1550 BC), ranging from boiled, ground goat dung in fermenting yeast, to copper filings and honey, to rubbing a frog warmed in oil on the wound.60 Hippocrates (460-377 BC), whose influence permeated Western medicine for more than 5 centuries, mentioned several topical agents for the treatment of burns and seemed to favor old hog seam (lard) mixed with any or all of several other agents such as wax, bitumen and resin, and wine. Topical treatment was little changed in the 9th and 10th centuries, when Rhazes (850-932), the most famous Arabian physician of that time, proposed treating burns more gently by application of cold water or egg yolk in attar of roses. He is also credited with being the first to write about the use of animal gut for ligatures in operations. In the next century, Avicenna (Ibn Sina, 980-1037) is said to have recommended ice water for the treatment of burns. That treatment achieved no popularity in ancient times, but has elicited renewed interest in recent years.61 The application of various topical agents to the burn wound was continued by surgeons throughout the Middle Ages and Renaissance, with the stature of the physician, rather than data, determining the force of the recommendation. Ambroise Paré (1510-1590) is credited with a comparative trial showing that treatment with mashed onion and salt improved the healing of burns compared to an unspecified “control” substance. William Clowes and Richard Wiseman, the leading British surgeons of the 16th and 17th centuries, respectively, were also proponents of the onion treatment of fresh burns, as was Fabricius Hildanus in Germany.61,62 A less irritating agent, carron oil, a 50/50 mixture of lime water and linseed oil, was widely used in topical dressings in the 18th and 19th centuries.61
The topical application of silver nitrate was initially, in concentrated form (lapis infernalis), used to remove granulation tissue from slow-healing burns and to produce a crust on the surface of fresh burns. Silver at that concentration caused severe pain in partial-thickness injuries and could, by itself, cause tissue necrosis. Johann Nepomuk Rust (1775-1840), a surgeon in the Prussian army, was an early advocate of dilute silver nitrate solution (0.2%) for the immediate treatment of burn wounds.63 Unfortunately, a single application of the dilute solution of silver nitrate could not affect long-term control of microbial proliferation. Consequently, that use of silver nitrate did not win general acceptance. In the colonial years of the United Sates, American physicians commonly traveled to Europe and England to “complete” their medical education. Consequently, burn care mirrored that practiced in Europe. In 1684, Dr Stafford of London gave Governor John Winthrop of Plymouth Colony a detailed recipe for the preparation of an ointment containing “rine of Eelder, Ssambucus, Ssempervive, and Mmosse” boiled in oil, to which was added barrow’s grease (lard from castrated male hogs). At the end of the 18th century, Mr John Vinal of Boston reported the beneficial effects of electricity on his burned thumb, and near the midpoint of the 19th century, Dr Samuel W. Francis described his invention of a glass glove which was used for continuous lime water irrigation of burns on extremities. In the very next year, Dr George Derby of Boston reported on the use of finely powdered dry earth for the successful treatment of burns of the leg and feet.64 Throughout the remainder of the 19th century and during the early years of the 20th century, topical therapy of burn wounds changed little, with a wide variety of agents preferred by individual surgeons, without evidence of clinical effectiveness. In 1925, E. C. Davidson described the topical application of tannic acid to bind toxins and coagulate damaged tissue. The tannic acid treatment achieved transient popularity, but findings such as liver damage, impaired distal circulation (when used on the hands), and failure to reduce plasma losses, to prevent subeschar infection, or to improve patient survival led to its abandonment by the early 1940s.22 The triple-dye treatment (gentian violet, acriflavine, and brilliant green) of Aldrich had similarly transient popularity due to a lack of effect on patient outcome.22 With the development of antimicrobial agents such as sulfonamides and other antibiotics in the 1930s and 1940s, it was only a matter of time until effective topical burn wound chemotherapy was developed. Initial trials of penicillin cream by Leonard Colebrook at the Birmingham Accident Hospital Burns Unit were frustrated by the rapid development of microbial resistance, and an early trial of
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sulfadiazine by Fraser Gurd in Canada was foiled by its low solubility and renal toxicity.64 In the mid-1960s, Sulfamylon® (mafenide acetate) burn cream was developed by Moncrief and colleagues at the US Army Institute of Surgical Research, at the same time as the effectiveness of 0.5% silver nitrate soaks in controlling burn wound infection was confirmed by Moyer and Monafo.65-68 Silver sulfadiazine was subsequently developed by Dr Charles Fox to combine the advantages of a sulfonamide and the silver ion, while minimizing the complications of both.69 Those three agents, along with the recently developed silver-impregnated fabrics,70 are the most commonly employed chemotherapeutic antimicrobials used in modern burn wound care. Effective topical therapy resulted in a dramatic reduction in invasive gram-negative burn wound infection (burn wound sepsis) as a cause of death (from 59% to 10% of deaths), and in postburn mortality.65
The Burn Wound: Surgical Treatment Originally, the surgical treatment of burn wounds, if performed, was limited to contracture release and reconstruction after the wound had healed by scar formation. In patients with larger wounds or burns of functional areas, this was wholly unsatisfactory. The creation of burn units committed to care for these patients led to the development of more effective techniques for wound closure. Artz noted that one should “wait until natural sequestration has occurred and a good granulating barrier has formed beneath the eschar…After removing the eschar…skin grafting should be performed as soon as the granulating surface is properly prepared.”71 Debridement to the point of bleeding or pain during daily immersion hydrotherapy (Hubbard tanks) was used to facilitate separation of the eschar.72 Then, cadaver cutaneous allografts (homografts) were often used to prepare the granulating wound bed for autografting.73 In patients with larger (>50% TBSA) burns and in the absence of topical antimicrobials, this cautious approach did not prevent death from invasive burn wound infection, leading some to propose a more radical solution: primary excision of the burn wound. Surgeons at the SRU suggested that a “heroic” practice of early excision, starting postburn day 4, should be considered for patients with large burns. This would reduce the “large pabulum” of dead tissue available for microbial proliferation, while immediate coverage with a combination of autograft and cadaver allograft would further protect the wound.59 Several authors during the 1950s and 1960s demonstrated the feasibility of this approach, but without an improvement in mortality.74 In 1968, Janzekovic described the technique of tangential primary excision of the burn wound with immediate grafting; operating in postwar Yugoslavia, she recalled
that “a barber’s razor sharpened on a strap was the pearl among our instruments.”75,76 In a retrospective study, Tompkins et al. reported an improvement in mortality attributed to excision over the course of 1974 through 1984.77 McManus and colleagues compared patients with burn size >30% TBSA who underwent excision with those who did not from 1983 through 1985. Unfortunately, an improvement in mortality could not be attributed to excision due to the presence of preexisting organ failure precluding surgery in many unexcised patients. However, only 6 of the 93 patients (6.5%) who died in this study had invasive bacterial burn wound infection, whereas 54 of the 93 (58%) developed pneumonia—indicating a shift from wound to nonwound infections.78 In McManus’ study, excision was performed a mean of 13.5 days postburn. By contrast, Herndon et al. at Galveston implemented a method of excision within 48 to 72 hours of admission, which relied on widely meshed (4:1) autograft covered by allograft. In a small study of children from 1977 through 1981, these authors noted a decrease in length of stay, but not in mortality with this technique.79 From 1982 through 1985, adults were randomized to undergo early excision versus excision after eschar separation 3 weeks later. Young adults without inhalation injury and with burns >30% TBSA showed an improvement in mortality.80 A recent meta-analysis found a decrease in mortality but an increase in blood use in early excision patients without inhalation injury.81 Despite the limitations of prior studies, early excision is performed today in most US burn centers; however, controversy remains about the definition of “early” and the feasibility of performing radical, total excision during one operation, especially in adults. For patients with the largest wounds and limited donor sites, new methods of temporary and permanent closure have been sought. Burke and Yannas developed the first successful dermal regeneration template (Integra®), composed of a dermal analog (collagen and chondroitin-6-sulfate) and a temporary epidermal analog (Silastic).82 Cultured epidermal autografts provide material for wound closure for patients with the most extensive burns, although the cost is high and final take rates are variable.83,84 The ultimate goal of an off-the-shelf bilaminar product for permanent wound closure, with a take rate similar to that of cutaneous autografts, has not yet been achieved.
Inhalation Injury Improvements in fluid resuscitation and wound care refocused attention on inhalation injury. Although the term “acute respiratory distress syndrome” (ARDS) was first applied to post-traumatic pulmonary failure in 1967,85
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T HE DE VE L OP M E NT OF M ODE R N B U R N C A R E direct injury to the lung parenchyma by inhalation of toxic gases such as chlorine and phosgene was recognized during WWI. This injury featured “pulmonary oedema, rupture of the pulmonary alveoli and concentration of the blood, with increased viscosity and a tendency to thrombosis.” Treatment included oxygen and (for patients with deep cyanosis) venesection of as much as 400 ml of blood.86 The potential of indoor fire disasters to cause rapid, early death by asphyxia or inhalation injury was demonstrated by the Cleveland Clinic fire of 1929. This fire, started by ignition of highly flammable X-ray film, claimed 125 lives. Most of the deaths have been attributed to inhalation of carbon monoxide, hydrogen cyanide, and nitrogen oxides.87 Those caring for the Cocoanut Grove victims were aware of that earlier experience and noted that the majority of patients arriving at MGH who did not survive to admission had elevated carbon monoxide levels. A sense of the situation can be gleaned from this description: “The first clue to the high incidence of pulmonary burns was afforded by the number who died within the first few minutes after reaching the hospital. They were very cyanotic, comatose or restless, and had severe upper respiratory damage.”88 From this description, it appears likely that some patients died with airway obstruction. In the patients surviving to admission, these authors provided a classic description of smoke inhalation injury. Severe upper respiratory and laryngeal edema mandated “radical therapy” in 5 patients, namely endotracheal intubation followed by immediate tracheotomy. Oxygen was provided via tent or transtracheal catheter. Those surviving this initial phase developed diffuse bronchiolitis, bronchial plugging, and alveolar collapse.88 Further improvements in the care of patients with inhalation injury required the development of positive-pressure mechanical ventilators. In the course of thoracic trauma research in North Africa during WWII, Brewer, Burbank, and colleagues of the Second Auxiliary Surgical Group (with the support of theater consultant surgeon Colonel Churchill) delivered oxygen via mask along with an intermittent, hand-operated positive airway pressure device to casualties with “wet lung of trauma.”89,90 Dr Forrest Bird, V. R. Bennett, and J. Emerson built mechanical positivepressure ventilators towards the end of WWII, all inspired by technology developed during the war to deliver oxygen to pilots flying at high altitudes.91 The availability of these and similar machines, as well as the Scandinavian polio epidemic of 1952, spurred the creation of intensive care units (ICUs).92 At the USAISR and several other centers, burn ICUs were located within the burn unit under the direction of surgeons who ensured continuity of care and clinical research.
Once accurate diagnosis of inhalation injury by bronchoscopy and xenon-133 lung scanning became available, it became apparent that these patients were at increased risk of pneumonia and death.93 Large animal models were developed and the pathophysiology of the injury was defined.94 Unlike ARDS as a result of mechanical trauma or alveolar injury due to inhalation of chemical warfare agents, smoke inhalation injury was found to damage the small airways, with resultant ventilation-perfusion mismatch, bronchiolar obstruction, and pneumonia.95,96 This injury process featured activation of the inflammatory cascade, which in animal models was amenable to modulation by various anti-inflammatory agents. However, the most effective interventions to date are those directly aimed at maintaining small airway patency and avoiding injurious forms of mechanical ventilation. These include use of high-frequency percussive ventilation with the Volumetric Diffusive Respiration (VDR-4®) ventilator developed by Bird and delivery of heparin by nebulization.97,98
Metabolism and Nutrition Bradford Cannon described the nutritional management of survivors of the Cocoanut Grove fire: “All patients were given a high protein and high vitamin diet…it was necessary to feed [one patient] by stomach tube with supplemental daily intravenous amogen, glucose, and vitamins.”99 But it soon became apparent that survivors of major thermal injury evidenced a hypermetabolic, hypercatabolic state which continued at least until wounds were closed and often resulted in severe loss of lean body mass. Cope and colleagues reported measurements of metabolic rate up to 180% of normal in the early postburn period and recognized a relationship between wound size and metabolic rate.100 Wilmore and colleagues identified the role of catecholamines as mediators of the postburn hypermetabolic state.101 They further documented that the burn patient is internally warm and not externally cold, and that hypermetabolism is wound-directed, as evidenced by elevated blood flow to the burn wound.102-104 Consequently, the metabolic needs of the burn patient should be met rather than suppressed. Earlier (1971), Wilmore et al. demonstrated the feasibility of providing massive amounts of calories by a combination of intravenous and enteral alimentation.105 Curreri published the first burn-specific formula for estimating caloric requirements: calories/day = 25(wt in kg) + 40(TBSA).106 However, the provision of adequate calories and nitrogen failed to arrest hypermetabolism and reduced, but did not eliminate, erosion of lean body mass in these patients. Three approaches have recently been taken to address this problem: the use of anabolic steroids such as oxandrolone,29
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the use of propranolol,107 and the use of insulin,108 insulinlike growth factor,109 or human growth hormone.110
Rehabilitation As postburn mortality decreased, the problems encountered by burn survivors, particularly those with deep and extensive injuries, became paramount.111 The scientific study of the occupational, physical, and psychosocial rehabilitation of the thermally injured patient is a relatively young field. The Cocoanut Grove monograph briefly states that 6 patients with dorsal hand burns who had been splinted in extension were referred to the Physical Therapy Department after completion of surface healing.112 In the 1950s, Moncrief began rehabilitation soon after admission and resumed it 8 to 10 days after skin grafting.113,114 The advent of heat-malleable plastic (thermoplastic) material made it possible to fabricate increasingly complex and effective positioning devices.115 This was followed by the introduction of pressure to treat hypertrophic scars and the development of customized pressure garments.116 Others reduced or eliminated the delay between skin grafting and ambulation, without deleterious effects on graft take.117,118 In brief, burn rehabilitation is no longer viewed as a “phase” which begins after completion of wound healing, but as a highly specialized process which must begin immediately upon patient admission and often continues for 24 or more months. A recent review noted a need for more research in this area, to include prevention and management of hypertrophic scarring and contractures, pain management, posttraumatic stress disorder, affective disorders, and bodyimage problems.119
CONCLUSION The 1910 edition of the Encyclopedia Britannica stated that death “almost invariably” results when one-third or more of the TBSA is burned.1 For young adults, the 20th century in the West featured an extraordinary diminution in the lethal-area 50% (LA50—that burn size which is lethal for 50% of a given cohort of patients), from 43% TBSA in 1945 through 1957 to 82% in 1987 through 1991.21 At the Galveston Shriners’ Burn Center, the mortality rate in children with 96-100% TBSA burns during 1982 through 1996 was only 69%. This led the authors to conclude that “prompt intravenous access and resuscitation, aggressive operative therapy, and the avoidance of sepsis and organ failure by meticulous critical care should enable any child with almost any burn size to live.” At that hospital120 and others providing comprehensive long-term psychosocial and physical rehabilitation,121 follow-up data indicate that
young survivors of massive thermal injury can experience reasonably well-adjusted lives. No one intervention was solely responsible for these improvements; rather, it is the combined effects of fluid resuscitation, wound care, infection control, inhalation injury management, nutritional support, and aggressive rehabilitation. All these interventions, however, were directed in a coordinated fashion at correcting what Burke called “the fundamental defects of burn injury—the destruction of skin and its immediate physiologic effects.”1 This revolution has been possible only because of integrated clinical and laboratory research, carried out by multidisciplinary teams in specialized centers supported by generous public and private funding. New challenges remain—in maintaining and expanding adequate numbers of fully trained nurses, therapists, and physicians,122 in caring for the most severely injured, in facilitating their return to a successful role in society, and in translating the most effective of these advances to that large portion of the world which has not yet adopted them.
KEY POINTS • Civilian fire disasters and military conflicts focused attention on the burn problem and motivated the creation of a new type of specialized care facility: the burn unit. The success of these units depends on multidisciplinary teams engaged in closely integrated laboratory and translational research and evidence-based clinical care. • Postburn shock is primarily caused by loss of fluid similar to plasma from the blood into the interstitium (edema formation). Fluid resuscitation formulae were developed based on the recognition that these losses are proportional to burn size. • Before the development of effective topical antimicrobials, invasive gram-negative burn wound infection was the leading cause of postburn death. The commonly used topical agents are mafenide acetate or some form of the silver cation (silver sulfadiazine, silver-impregnated dressings). • Early excision and grafting of deep partial and full-thickness burn wounds has become the standard of care for burn patients. • Inhalation injury increases postburn mortality. Effective therapies include not only gentle mechanical ventilation, but also those which maintain small airway patency. • Thermal injury causes hypermetabolism and hypercatabolism, which persist to some degree
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T HE DE VE L OP M E NT OF M ODE R N B U R N C A R E long after the wound is closed. Caloric requirements are roughly proportional to the burn size. • Effective rehabilitation must begin immediately upon admission and must be directed at minimizing disability from hypertrophic scarring, contracture, and deconditioning. • Particularly in children and young adults, striking improvements in postburn survival call into question the notion of futile care and refocus attention on long-term psychosocial rehabilitation.
1962: Shriners Hospitals set up three burn units for children in the United States22 1959–1967: National burn seminars are held in the United
States127 1965: International Society for Burn Injuries is founded27 1968: British Burn Association and American Burn Association (ABA) are founded 1974: Burns Including Thermal Injury (later, Burns) begins publication 1980: Journal of Burn Care and Rehabilitation (later, Jour-
nal of Burn Care and Research) begins publication
ACKNOWLEDGMENTS
1991: ABA and American College of Surgeons Committee on Trauma begin verification of US burn centers
The authors gratefully acknowledge the support of Ms Gerri Trumbo, USAISR librarian.
1991: ABA creates the National Burn Repository database
TABLE 1. Organizational landmarks in the history of modern burn care. 1843: Syme establishes first burn hospital in Edinburgh2 1884: Burn patients admitted to a special ward at the Glas-
gow Royal Infirmary7 1915: Sir Harold Gillies sets up the first plastics and oral-
maxillofacial unit in the United Kingdom at Cambridge Military Hospital, Aldershot6 1940: During the Battle of Britain, Archibald McIndoe in-
augurates a Royal Air Force burn unit at East Grinstead7 1941: Japanese attack on Pearl Harbor marks entry of
United States into WWII and tests US military burn care capabilities10
2003: US Army Institute of Surgical Research and ABA reinstitute a national burn-bed reporting system developed during Operation Desert Storm to support combat operations in Iraq and other crises32
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93. Shirani KZ, Pruitt BA Jr, Mason AD Jr. The influence of
muscle protein synthesis by long-term insulin infusion in severely burned patients. Ann Surg. 1995; 222: 283–297.
Reversal of catabolism by beta-blockade after severe burns. N Engl J Med. 2001; 345: 1223–1229.
inhalation injury and pneumonia on burn mortality. Ann Surg. 1987; 205: 82–87.
109. Cioffi WG, Gore DC, Rue LW III, et al. Insulin-like growth
94. Shimazu T, Yukioka T, Hubbard GB, Langlinais PC, Mason
factor-1 lowers protein oxidation in patients with thermal injury. Ann Surg. 1994; 220: 310–319.
AD Jr, Pruitt BA Jr. A dose-responsive model of smoke inhalation injury. Severity-related alteration in cardiopulmonary function. Ann Surg. 1987; 206: 89–98.
110. Herndon DN, Hawkins HK, Nguyen TT, Pierre E, Cox R,
95. Shimazu T, Yukioka T, Ikeuchi H, Mason AD Jr, Wagner PD, Pruitt BA Jr. Ventilation-perfusion alterations after smoke inhalation injury in an ovine model. J Appl Physiol. 1996; 81: 2250–2259.
111. Pereira C, Murphy K, Herndon D. Outcome measures in
96. Cancio LC, Batchinsky AI, Dubick MA, et al. Inhalation injury: pathophysiology and clinical care. Proceedings of a symposium conducted at the Trauma Institute of San Antonio, San Antonio, TX, USA on 28 March 2006. Burns. 2007; 33: 681–692.
Barrow RE. Characterization of growth hormone enhanced donor site healing in patients with large cutaneous burns. Ann Surg. 1995; 221: 649–659. burn care. Is mortality dead? Burns. 2004; 30: 761–771. 112. Watkins AL. A note on physical therapy. In: Aub JC, Beecher
HK, Cannon B, et al., eds. Management of the Cocoanut Grove Burns at the Massachusetts General Hospital. Philadelphia: JB Lippincott; 1943: 111–114. 113. Moncrief JA. Complications of burns. Ann Surg. 1958;
97. Cioffi WG Jr, Rue LW III, Graves TA, McManus WF, Mason
147: 443–475.
AD Jr, Pruitt BA Jr. Prophylactic use of high-frequency percussive ventilation in patients with inhalation injury. Ann Surg. 1991; 213: 575–582.
114. Moncrief JA. Third degree burns of the dorsum of the hand.
98. Desai MH, Mlcak R, Richardson J, Nichols R, Herndon DN. Reduction in mortality in pediatric patients with inhalation injury with aerosolized heparin/N-acetylcystine therapy. J Burn Care Rehabil. 1998; 19: 210–212.
treatment of the acutely burned child: preliminary report. Am J Occup Ther. 1969; 23: 57–61.
99. Cannon B. Procedures in rehabilitation of the severely burned.
Am J Surg. 1958; 96: 535–544. 115. Willis B. The use of Orthoplast isoprene splints in the
116. Larson DL, Abston S, Evans EB, Dobrkovsky M, Linares
HA. Techniques for decreasing scar formation and contractures in the burned patient. J Trauma. 1971; 11: 807–823.
In: Aub JC, Beecher HK, Cannon B, et al., eds. Management of the Cocoanut Grove Burns at the Massachusetts General Hospital. Philadelphia: JB Lippincott; 1943: 103–110.
117. Schmitt MA, French L, Kalil ET. How soon is safe?
100. Cope O, Nardi GL, Quijano M, Rovit RL, Stanbury JB, Wight A. Metabolic rate and thyroid function following acute thermal trauma in man. Ann Surg. 1953; 137: 165–174.
118. Burnsworth B, Krob MJ, Langer-Schnepp M. Immediate
101. Wilmore DW, Long JM, Mason AD Jr, Skreen RW, Pruitt BA Jr. Catecholamines: mediators of the hypermetabolic response to thermal injury. Ann Surg. 1974; 180: 653–669.
119. Esselman PC, Magyar-Russell G, Fauerbach JA. Burn
Ambulation of the patient with burns after lower-extremity skin grafting. J Burn Care Rehabil. 1991; 12: 33–37. ambulation of patients with lower-extremity grafts. J Burn Care Rehabil. 1992; 13: 89–92. rehabilitation: state of the science. Am J Phys Med Rehabil. 2006; 85: 383–413.
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T HE DE VE L OP M E NT OF M ODE R N B U R N C A R E 120. Wolf SE, Rose JK, Desai MH, Mileski JP, Barrow RE, Herndon DN. Mortality determinants in massive pediatric burns. An analysis of 103 children with > or = 80% TBSA burns (> or = 70% full-thickness). Ann Surg. 1997; 225: 554–569.
124. Lawrence JC. Some aspects of burns and burns research at
121. Sheridan RL, Hinson MI, Liang MH, et al. Long-term
outcome of children surviving massive burns. JAMA. 2000; 283: 69–73.
Services, Office of the Surgeon General of the Air Force, Headquarters, U.S. Air Force. Washington, DC: US Air Force; November 27, 1951.
Birmingham Accident Hospital 1944–93: A. B. Wallace Memorial Lecture, 1994. Burns. 1995; 21: 403–413. 125. Maxwell E. Memorandum from Director of Professional
122. Gamelli RL. Who will follow? J Burn Care Res. 2006; 27:
126. Cancio LC, Pruitt BA Jr. Management of mass casualty burn
1–7.
disasters. Int J Disaster Med. 2004; 2: 114–129.
123. Artz CP. Historical aspects of burn management. Surg Clin
127. Baxter CR. Before the American Burn Association. J Burn
North Am. 1970; 50: 1193–1200.
Care Rehabil. 1993; 14: 228–229.
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2
C H A P T E R
T W O
PRINCIPLES OF PEDIATRIC BURN INJURY ALICE LEUNG, MD, AND
BRADLEY J. PHILLIPS, MD
OUTLINE 1. Introduction 2. Pathophysiology 3. Burn Management a. Triage Outpatient Care Inpatient Care Pre-hospital Preparation b. Emergent Airway—Upper Airway Injury Breathing—Lower Airway Injury Circulation Fluids Temperature Secondary Assessment Tetanus
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INTRODUCTION Over 250,000 children suffer from burn injuries each year, accounting for one-third of all burns in the United States.1 Thirty thousand of these patients sustain injuries that require admission to a hospital.2 In the last 25 years, pediatric mortality has decreased through improved resuscitation and aggressive operative treatment. However, burn injuries are still the fifth leading cause of death in pediatric patients and are estimated to cost society $2.3 billion each year.3,4 Burn injuries are ubiquitous, affecting every age, class, and ethnicity. Toddlers are most at risk for injury, as their newly gained mobility and ability to explore their environment outpace their cognitive development and sense of danger.5 In all age groups, males are 50% to 100% more likely to be burned than females. The majority of pediatric
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c. Acute Phase Operative Management Sepsis Antibiotics/Antifungals Nutrition and Metabolism d. Rehabilitation and Reintegration Hypertrophic Scarring Contracture Heterotopic Ossification Leukoderma Psychological Follow-Up
4. Key Points 5. Figures and Tables 6. References
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burns are scald injuries, followed by flame injuries. Chemical and electrical injuries occur less frequently; these burns tend to be small, involving less than 10% of the body. One of the greatest dangers in caring for pediatric burn patients is underestimation of the severity of the injury, both by physicians and by families. The presence of an inhalation injury in children younger than 4 years is associated with a poor prognosis. Even small burns in the absence of inhalation in infants have been known to be fatal.6 Although death from burn injury can result from burn shock in the immediate postinjury period, it is more commonly due to septic complications such as pneumonia, respiratory distress syndrome, and multisystem organ failure.7 The best outcome for patients with large burns is achieved by referral to the multidisciplinary setting of specialized burn centers. The first line of care is often given by emergency medical services, pediatricians, and emergency department
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P R INC IP L E S OF P E DIAT R IC B UR N I N J U RY physicians. It is essential that patients be properly triaged for care. Smaller burns should be treated as outpatients, while referral of more significant injuries to multidisciplinary burn centers is necessary to optimize patient care. In order to treat patients effectively, all health care providers should have a general understanding of burn physiology and care.
PATHOPHYSIOLOGY The skin is the largest organ in the human body, providing structural support, immunity, and regulation of heat and water loss.3 It is comprised of 3 layers: epidermis, dermis, and subcutaneous tissue. The epidermis is comprised of avascular sheets of keratinocytes. The basal layer of the epithelium continues to replicate as the superficial layers are constantly exfoliated. The epidermis acts as a mechanical barrier to infection by preventing invasion of bacteria. The dermis is more physiologically active and can be divided into 2 layers. The papillary dermis interdigitates with the epidermis, supplying the avascular layer with nutrients and oxygen. The reticular dermis is rich in collagen and elastin, giving skin its strength and elasticity.8 This strong reticular layer is embedded with hair follicles, nerves, sebaceous glands, and sweat glands. Once a thermal injury is sustained, it can be separated into 3 zones: (1) the zone of coagulation, (2) the zone of stasis, and (3) the zone of hyperemia. The zone of coagulation is characterized by severe injury with irreversible damage. This area of devitalized tissue is surrounded by the zone of stasis, which sustains lesser injury but demonstrates significant inflammation and impaired vasculature. The outermost zone of hyperemia exhibits vasodilation and increased blood flow. Injury to this area is reversible and typically resolves in 7 to 10 days.8,9 The boundaries of these zones are dynamic and affected by management. The zone of coagulation may continue to expand in the setting of impaired blood supply. These wounds are at risk of deepening in the setting of hypovolemia, hypotension, catecholamine-induced vasoconstriction, and infection. The best-case scenario is for the zone of coagulation to remain stable while the zone of hyperemia ingresses, replacing the zone of stasis.8 Appropriate fluid resuscitation in the first 24 to 48 hours is the best means of avoiding worsening of wounds.3 Determining the extent of damage in a burn injury is based on the depth and the total body surface area involved. The actual thickness of skin will vary between different patients and different sites of the body. Therefore, wound depth is described relative to the layer of skin injured rather than as a numeric measurement. Knowing the remaining
layer of uninjured skin provides insight on the wound’s ability to spontaneously heal versus the need for surgical intervention. Many tools have been developed in recent years to help assess the depth of injury, including dyes, laser Doppler, and thermography.3,10 However, these methods are expensive and often not readily accessible in the daily care of patients. The depth of a wound remains primarily a clinical diagnosis, taking into account the physical examination and mechanism of injury. The preferred nomenclature divides the depth of burn injury into 4 classes: (1) superficial, (2) superficial partial thickness, (3) deep partial thickness, and (4) full thickness. A superficial burn involves only the epidermis and is characterized by erythema and edema in the absence of blistering and desquamation. Superficial burns heal spontaneously in days and are commonly seen in sunburns. Both superficial partial-thickness and deep partialthickness burns involve the entire epidermis and a portion of the dermis.1 These wounds are commonly seen in scald and flash burns.1 Superficial partial-thickness injuries are contained within the papillary dermis, while deep partialthickness injuries extend into the reticular dermis. Both wounds are characterized by pain and fluid-filled blisters. Debridement of superficial partial-thickness wounds will expose moist, pink tissue which blanches with pressure. These wounds will reepithelialize from retained epithelial islands and dermal appendages. They can be expected to heal within 7 to 28 days with minimal scarring.1 Deep partial-thickness injuries destroy the epithelial interstices of the papillary dermis along with a greater proportion of the vasculature. The surface of these wounds will appear drier and will be slower to blanch with digital pressure on exam. If uncomplicated by infection, deep partial-thickness wounds can spontaneously heal in 3 to 8 weeks from the wound edges and remnant dermal appendages.1,3 The protracted course of healing renders these deeper wounds prone to complications, such as hypertrophy and pigment changes.3,11 The epidermis and dermis are completely destroyed in full-thickness injuries. These burns will not heal spontaneously due to destruction of dermal appendages. Full-thickness burns are leathery, insensate, and fail to blanch, corresponding to destruction of elastin fibers, nerve endings, and vasculature of the dermis.1 Full-thickness burns are seen in flame, grease, and solid contact injuries. They are associated with multiple complications, such as acute renal failure, hyperkalemia, rhabdomyolysis, myoglobinuria, and compartment syndrome.8 The other major factor in defining the extent of damage is determining the total body surface area (TBSA) involved. Calculation of the TBSA includes all partial-thickness and full-thickness burns, with the exclusion of superficial
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injuries.11 Due to the highly variable body proportions in the pediatric population, the commonly used “rule of nines” in adult burn management is not applicable without significant modification. An alternative method to estimate the area involved, referred to as the “rule of palms,” uses the patient’s hand as an internal control. The surface area of one side of the patient’s hand, including the fingers, is equal to 1% of the TBSA. This palm estimate is particularly useful with injuries that present with a splattered or blotchy distribution. A more precise calculation of the TBSA involves the use of an age-appropriate Lund-Browder chart (Table 1).1 In particular, emergency medical services and the emergency department may find the modified “rule of nines” and the palm estimate very helpful. In these circumstances, the TBSA is used for triage purposes and serves only as a marker of the extent of injury. Upon admission to a burn center or intensive care setting, the TBSA will influence initial resuscitation and management until the Lund-Browder chart is utilized for a more accurate assessment.8
BURN MANAGEMENT History should be obtained from the patient, the patient’s caregivers, and the responding emergency medical services, if applicable. The mechanism of injury as well as the temperature of the agent and duration of contact should be determined. The surrounding circumstances should be documented very carefully, as up to 20% of pediatric burns are a result of negligence or abuse.12 Health care providers should be alert and aware of the warning signs of abuse, such as an inconsistent or changing history, an unexplained delay in seeking medical attention, and treatment being sought by an unrelated adult (Table 2).8
Triage
moist environment conducive to wound healing and to help with pain control. The wound can then be covered with a nonadherent dry dressing. The patient’s pain should be sufficiently controlled with oral medications to permit dressing changes and regular use of the affected areas. In addition to patient education, physical therapy should be considered, particularly if the injury crosses a joint.2
Inpatient Care The American Burn Association has recommended guidelines for admission or transfer to a burn center. All children with a burn greater than 10% TBSA or with involvement of an area of functional importance should be immediately admitted for care.11 Other cutaneous injuries requiring admission, which may be more significant than initially appreciated, are chemical and electrical burns and the presence of inhalation injury. Pediatric patients initially treated in a facility without qualified caregivers should be transferred to a burn center specializing in pediatric care. The child may require intubation prior to transportation and should be covered in dry, sterile sheets to maintain body temperature.12
Pre-hospital Preparation In preparing for the patient’s arrival, the room should be warmed to 31.5ºC ± 0.7ºC and equipped with warming blankets.12 The materials necessary for airway management and intravenous access should be readily available, as well as large volumes of warm intravenous fluids. All personnel should be gowned, gloved, and masked to protect themselves and the patient.8 Burn management can be divided into 3 phases (Figure 1): (1) emergent, (2) acute, and (3) rehabilitation and reintegration.
Outpatient Care
Emergent
Outpatient care of a pediatric burn is preferable whenever possible. Management of smaller burns (TBSA less than 10%) in the normal home environment provides a less traumatic as well as a more cost-effective means of providing care, to the benefit of both the patient and society. In order to permit outpatient care, the patient must be able to maintain oral nutrition and hydration, and the family must be able to manage appropriate wound care.1 The caregiver should be reliable and should demonstrate wound care competence prior to discharge.9 Daily care involves washing the wound with a mild detergent in warm water and providing gentle debridement with a wet washcloth. A thin layer of topical antimicrobials, such as silvadene or bacitracin, should be applied to the affected area in order to maintain a
The goal of the emergent phase in pediatric burn management is to stop the injury process and stabilize the patient. Health care providers should follow the pediatric advanced life support and advanced trauma life support protocols, attending to the patient’s airway, breathing, and circulation. Adequate fluid resuscitation and maintenance of core body temperature are also very important throughout the management of a pediatric burn.
Airway—Upper Airway Injury Airway obstruction occurs with injury to the soft tissues of the head, face, and neck, including the upper airway. The upper airway is defined as the oropharynx above the glottis
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P R INC IP L E S OF P E DIAT R IC B UR N I N J U RY and is typically injured from direct heat to the mucosa. This injury responds with formation of edema within 45 to 60 minutes. Patients with inhalation injury may initially present with a patent airway but can rapidly deteriorate within 12 to 24 hours of injury as edema peaks from aggressive fluid resuscitation. Some warning signs of exposure to high heat include singed nasal hairs and facial burns.1 Common signs of a compromised airway include progressive hoarseness, stridor or inspiratory grunting, and increased respiratory rate and work of breathing. Providers should continue to monitor the patient’s airway throughout the emergent phase, with a low threshold for intubation in burn patients. Upon any sign of a deteriorating airway, an endotracheal tube should be placed, as delay in securing the airway can lead to a difficult and potentially dangerous emergent intubation. Edema can be minimized by elevating the head of the bed 20º to 30º and typically resolves in 2 to 3 days12; thus, tracheostomy is typically not required.1 Particular care must be taken to properly secure the endotracheal tube once placement is confirmed. Failure to secure the tube may be disastrous due to the difficulty of reintubation in the setting of massive edema. The tube may be secured carefully with umbilical tape, but the surrounding skin must be monitored regularly for signs of pressure necrosis.1
Breathing—Lower Airway Injury Lower airway inhalation injuries (defined as injury below the glottis, including the lung parenchyma) greatly increase the severity of the burn. Lower airway injuries are the result of smoke inhalation, usually within an enclosed space, such as a house fire. The inhalation of smoke results in exposure of the terminal bronchioalveolar tree to chemical irritants. With the notable exception of steam injuries, lower airway injuries are not a result of direct thermal injury, since the upper airway dissipates the energy prior to exposure to the lower airway.8 Pediatric patients become disoriented easily and may hide rather than making an attempt to escape from an enclosed space.13 Young children in particular are at high risk of inhalation injury due to relative immobility and lack of situational awareness.7 The diagnosis of lower airway injury in pediatric patients is typically clinical. Visualization of subglottic structures via bronchoscopy requires an internal diameter of at least 8.0 mm and can be technically demanding in small children. Any patient who presents with a history of being involved in an enclosed space fire, loss of consciousness, or change in mental status should be presumed to have some degree of inhalation injury and closely monitored. These injuries may occur in the absence of cutaneous damage and may present with dyspnea, rales and rhonchi, and carbonaceous sputum.8
These signs and symptoms typically develop within 24 to 48 hours of the initial insult.1 The treatment of lower airway injuries is mainly supportive.14 Bronchodilators may be useful in treating bronchospasm caused by aerosolized irritants. Mechanical ventilation with positive end expiratory pressure may be necessary in the event of a declining respiratory status. Permissive hypercapnia is allowed in patients with inhalation injury as long as the pH remains above 7.20.12 Meticulous pulmonary toilet plays an important role, particularly in younger children, where the small diameter of pediatric endotracheal tubes can result in an increased risk of obstruction by secretions as well as wound exudates and topical wound care agents.1 Systemic poisoning caused by inhaled toxins, frequently carbon monoxide and cyanide, is also very common. Carbon monoxide poisoning is the leading cause of death at the scene of a fire.8 This toxin binds over 200 times more efficiently to hemoglobin than oxygen does, thereby impairing oxygen uptake and delivery to tissues.13 Patients can present with headaches, dizziness, nausea, and seizures. A high clinical suspicion is required based on the history and mechanism of injury. Pulse oxymetry will be unreliable in carbon monoxide poisoning, as hemoglobin will be detected in its bound form. Treatment with high-flow oxygen via a nonrebreather mask is initiated while blood carboxyhemoglobin levels are measured to confirm the diagnosis. Treatment is continued until carboxyhemaglobin is less than 10% total hemoglobin.8 Cyanide poisoning is associated with incomplete combustion of nitrogenous materials such as silks and polyesters.15 The severity of poisoning is directly related to the extent of smoke exposure and results in metabolic acidosis. Patients with cyanide poisoning present with nonspecific symptoms such as nausea, tachypnea, and changes in mentation. Unfortunately, treatment is limited and the patient is notably unresponsive to supplemental oxygen.3 There is no available widespread testing method, and patients are typically diagnosed postmortem.8
Circulation Predictable hemodynamic changes occur following severe burn injury. The patient exhibits an elevated cardiac output and decreased total peripheral resistance, making assessment of intravascular volume difficult.12 Intravenous access is very important in patient management. In large burns, 2 large-bore peripheral IVs are required.1 Obtaining access may be difficult secondary to distribution of the burn, edema, and reluctance to penetrate burned skin. Though not ideal, access may be obtained through areas of burn injury, followed by venous cut-downs and intraosseous access.
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Once acquired, lines should be secured by sutures, as exudative fluid will not permit adhesive tapes and edema will render wraps impractical.1
Fluids Though the skin’s gross appearance may be deceptively intact, burn injuries have 5 to 10 times the evaporative loss of normal skin. In smaller burns, patients are able to maintain hydration with oral fluids or with a combination of oral fluids supplemented with low volumes of intravenous fluids.3 Patients with burns involving greater than 15% TBSA have substantial exudative and evaporative fluid loss and require intravenous fluid resuscitation.8 Different factors, such as electrical or chemical injury, may lead to higher than expected fluid requirements. Inhalation injury is known to increase resuscitation requirements by up to 50%.8 Large burn injuries will cause systemic physiologic changes which exacerbate intravascular loss. Inflammatory mediators are released from the wound and lead to significant capillary leak. Fluid is able to escape the intravascular space and migrate into the interstitium. Capillary permeability peaks 18 hours following injury, and maximum edema is observed at 48 hours.9 The use of colloid as resuscitation fluid is controversial and generally not recommended in the first 24 hours. Extravasation of colloid during the initial resuscitation period is thought to prolong edema secondary to capillary leak. Instead, colloid use in resuscitation should be reserved for persistent hypotension or to possibly prevent overresuscitation in patients who manifest a less than ideal response to crystalloids.3 Beyond the first 24 hours, colloid may be given regularly in order to supplement the disproportionate protein loss observed in pediatric patients. Initial resuscitation may be calculated based on a number of formulae, such as the Parkland formula and the Galveston formula (Figure 2).16 In addition to the resuscitation volume, maintenance fluids must be added and will constitute a greater proportion of the fluid delivered to patients relative to adults.1 The goal of resuscitation is adequate end organ perfusion, which can be evaluated by a combination of clinical and laboratory findings. A Foley catheter, rather than diapers or urine bags, should be placed to more accurately monitor hourly urine output in order to evaluate fluid resuscitation. Appropriate goals are 1 cc to 1.5 cc urine/hour in children and 1.5 cc to 2.0 cc urine/hour in infants. In the event that urine output does not respond to resuscitation after substantial amounts of crystalloid fluids, such as lactated Ringers solution, a transesophageal echo or pulmonary artery catheter may be invaluable to determine intravascular fluid status. Resuscitation efforts can be evaluated based on vital signs, peripheral temperature, capillary refill, and level of mentation.
Lab values such as hematocrit, base deficit, central venous pressure, and lactate levels may be helpful in evaluating tissue perfusion and should be monitored regularly throughout the emergent phase. Although certain injuries will require more fluid than calculated by the resuscitation formula, health care providers must be cognizant of possible overresuscitation. Complications of excessive resuscitation include pulmonary edema, electrolyte imbalances, and prolific third spacing. Electrolyte imbalance is commonly seen in conjunction with the massive cellular damage of a significant burn injury. Specifically, hyponatremia can occur, while hypovolemia and the generous use of albumin may lead to hyperkalemia. Large fluctuations of sodium in the pediatric population can lead to seizures, cerebral edema, herniation, and central pontine myelinosis,3,12,17 which are all associated with increased mortality. Such significant electrolyte fluctuations may be prevented by close monitoring. Continued third spacing of excess fluid from overresuscitation can result in abdominal compartment syndrome. This complication should be considered when bladder pressure, acting as a marker for abdominal pressure, exceeds 30 mmHg (thus overcoming capillary filling pressures).18 Abdominal compartment syndrome may be relieved by reducing intravenous fluids or by performing a paracentesis or decompressive laparotomy. Diuretics are inappropriate in the setting of acute burns. Infants and small children younger than 2 years and with a weight less than 20 kg require the addition of glucose to their resuscitative fluids since they have sparse glycogen stores and are susceptible to hypoglycemia.1,12,18 Their glucose should be monitored hourly during the initial resuscitation period and replaced as necessary.
Temperature Temperature dysregulation is a hallmark of burn injury, with a tendency towards hypothermia. A subnormal body temperature should be minimized, as it leads to coagulation dysfunction and is associated with increased mortality. The use of warm intravenous fluids, particularly during resuscitation, when large volumes are used, can help maintain core body temperature.1 The ambient temperature in the intensive care setting and operating room should be kept warm in order to decrease radiant heat loss through large, hyperemic burns.8
Secondary Assessment Though the temptation is to immediately address a burn injury, a systemic head-to-toe evaluation should be performed. Any potentially life-threatening injury should be addressed before wound management is initiated.
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P R INC IP L E S OF P E DIAT R IC B UR N I N J U RY Head and Neurological—A change in mental status or loss of consciousness is an indication for a head CT scan in order to evaluate for accompanying intracranial trauma. Other causes to be considered include intoxication, hypoxia, hypotension, and inhalation injury. Eyes and Ears—In the event of facial involvement, an ophthalmology consultation should be obtained early, as a delayed evaluation will be difficult with advancing facial edema. A fluorescein exam to evaluate the cornea is helpful to evaluate for subtle eye injuries. External ear burns should be debrided and treated with mafenide acetate to prevent suppurative chondritis. Chest—The patient’s ability to ventilate should be reevaluated during the secondary survey, particularly with a deep, circumferential injury. Full-thickness burns will result in an inelastic eschar which restricts the chest wall’s ability to rise with inspiration. Signs of respiratory distress and elevated peak airway pressures will be seen with decreased chest compliance. An escharotomy, in which incisions through the eschar to healthy tissue are made along the flanks and below the costal margins, allows the anterior chest wall to dissociate from the posterior chest wall and abdomen.19 This results in relieving the constriction and improving the patient’s respiratory status. Extremities—Deep circumferential burns to the limbs may cause a complication similar to that described above. The leathery eschar constricts the underlying soft tissue as subcutaneous structures proceed to swell with aggressive fluid resuscitation and systemic inflammation. This constriction results in an increase in compartment pressure. When the pressure exceeds 25 mmHg to 30 mmHg, capillary filling pressure is overcome and tissue becomes hypoperfused. This hypoperfusion can lead to limb ischemia, functional disability, and amputation.3 The injured limb should be kept at the level of the heart to maintain optimal mean arterial pressure while limiting dependent pooling.12 Early findings of compartment syndrome include pain on stretching, a tense limb, palpable pulses, brisk capillary refill, and paresthesia.19 Once the syndrome develops, treatment via escharotomy to release constriction is indicated.3 Warm ischemia leads to soft tissue death within 2 to 3 hours, allowing escharotomies to be performed in the controlled environment of an operating room. The incision should be performed with electrocautery to minimize blood loss and should follow the proceeding guidelines: avoid named nerves, preserve longitudinal veins, and avoid crossing joints in straight lines to minimize future contractures.19 Abdomen—The patient should be evaluated for associated injuries, particularly in the setting of excess fluid requirements and rapidly decreasing hematocrit levels. Abdominal fluid and pressure should be monitored in efforts to
avoid massive overresuscitation. With sympathetic activity decreasing splanchnic flow, the patient should be initiated on H2 antagonist prophylaxis to prevent Curling’s ulcers of the gastroduodenum. Since burn patients are also prone to swallowing air and gastric dilation, a nasogastric tube should be placed to decompress the stomach during the emergent phase.12
Tetanus As open wounds, burn injuries are vulnerable to tetanus infection.8 If the patient’s immune status is unknown, he or she should receive active immunization with injection of tetanus toxoid. If the patient is not immunized, passive immunization in the form of antitetanus immunoglobulin should be administered in addition to tetanus toxoid.20
Acute Phase The goal of the acute phase is to cover the wound in order to decrease water vapor loss, prevent desiccation, and aid in pain control and bacterial inhibition.20 Complications seen during this period include wound infection, sepsis, pulmonary insufficiency, and multisystem organ failure.2 Pain control throughout this phase is very important in order to minimize trauma and additional stress. Doseappropriate intravenous morphine, oral acetaminophen, and acetaminophen with codeine are commonly used in pediatric burn management. Similar to other pediatric medications, these analgesics should be dosed by weight.21 Morphine IV: 0.1-0.2 mg/kg/dose Q2-4 hr PRN (max. dose: 15 mg/dose). Oxycodone PO: 0.05-0.15 mg/kg/dose Q4-6 hr PRN (max. dose: 5 mg/dose). Acetaminophen PO: 10-15 mg/kg/dose Q4-6 hr PRN (max. dose: 90 mg/kg/24 hr). Extended-release oxycodone can help with pain control in older children. Conscious sedation with the use of ketamine is helpful during procedures such as extensive dressing changes.9 Intact blisters of partial-thickness wounds are managed by using firm, sweeping motions with warm saline-soaked gauze to unroof and debride them. The wounds are then treated with topical antimicrobials and covered with dry, nonadherent dressings. Bacitracin is commonly used and has coverage against some gram-positive bacteria. Its primary function is to maintain a moist environment conducive to healing. Silvadene is an agent which has a broader spectrum of antimicrobial coverage, including gram-positive and gramnegative bacteria and fungi. However, as an opaque white
19
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cream, Silvadene renders wound assessment more difficult between dressing changes. The most common adverse drug reaction of Silvadene is self-limited leukocytosis, but other potential complications include anaphylaxis and kernicturus. Its use should be avoided in patients with known sulfa allergies and children younger than 2 years. Mafenide acetate, a carbonic anhydrase inhibitor with good penetration of devitalized tissue and cartilage, is commonly used on the tip of the nose and ears. It covers a broad range of gram-positive and gram-negative bacteria, pseudomonas, and some anaerobes. Broader use of mafenide acetate in pediatrics is generally limited due to pain associated with its application.3 With the increased antibiotic resistance seen with hospital-acquired infections, the choice of topical antimicrobials for wound management is becoming increasingly important. The provider must choose a regimen which meets the patient’s tolerance of dressing changes and appropriately covers the specific pathogens identified.22
Operative Management Early excision and grafting of burn wounds is a key component in the management of burns. Epinephrine (0.5 μg/ml) is used as tumescence during excision and helps control blood loss. The use of epinephrine decreases typical blood loss of 3.5% to 5% total blood volume per percent of TBSA excised by up to 80%.17 Excision within 48 hours of injury has been shown to be effective in improving care and decreasing mortality.17,23 In addition, patients display decreased risk of infection, decreased antibiotic requirements, and improved long-term outcomes, such as reduced hypertrophic scarring. Patients are also able to leave the hospital earlier, and the cost of care as a whole is minimized.23 There are many options for coverage once the wound is excised, including autograft, allograft, xenograft, and a number of synthetic coverings. The standard of care for definitive coverage is autograft in the form of split-thickness skin graft (STSG). The grafts are harvested from an unburned area using a pneumatic-powered dermatome at a thickness of 0.010 inch to 0.012 inch. The scalp is a good harvest site in children because of its ability to reepithelialize very quickly. Repeated harvesting of donor sites for wound coverage may be allowed as necessary once healing occurs. STSGs are typically meshed 1:1 or 2:1 in order to protect wounds. Besides permitting drainage of fluid from the wound bed to maximize graft viability, meshing also allows for the possibility of graft expansion. STSGs may be placed as sheets over cosmetically or functionally important areas such as the face and hands. Sheet grafts are pie-holed using a knife in order to allow drainage of exudates during the immediate postoperative period. Meshing at ratios greater than 1:1 permits the graft to cover a larger area. Ratios of
up to 3:1 and 4:1 are commonly used for coverage of large wounds. Greater ratios are uncommon secondary to fragility of the grafts and the greater distance epithelial cells must migrate to facilitate full wound coverage. Even with substantial meshing, there may be insufficient uninjured skin available for full burn coverage. These patients benefit from cultured epithelial autografts to aid in definitive coverage. Within the first few days of care, a healthy sample of the patient’s skin is taken and sent for cell culture. The cultured epithelial cells are then applied to the patient’s excised wounds. Some surgeons use the cultured epithelial cells in conjunction with STSG meshed with large expansion ratios, such as 8:1, to encourage reepithelialization of the mesh interstices. Cultured epithelial autografts are capable of organizing into epidermal structures within weeks and allow for coverage of extensive open wounds.24 Allograft and xenograft may be used as temporary biologic dressings for excised burns. These wound coverings act as physical barriers to infection, limit fluid loss, and decrease the inflammatory response.25 Temporary coverage of the wound is capable of promoting dermal regeneration of the wound bed in preparation for definitive coverage with autograft. Even though these biologic dressings are chemically treated to reduce immunogenicity, they will still be rejected within days to weeks.26 Alternative nonimmunogenic synthetic dressings, such as Biobrane and Integra, have been developed in recent years. Biobrane is a porous mesh of nylon filaments embedded with type I collagen which is covered with a layer of silicone. The collagen fibers adhere to the wound bed and allow for improved migration of epithelial cells. The pores allow leakage of exudates and reciprocal passage of topical antimicrobials down to the wound. Integra is another synthetic bilayer commonly used in the coverage of complex burn wounds. The chondroitin sulfate layer serves as a dermal regeneration template and is protected by a silastic membrane. Once the Integra becomes vascularized, the superficial silastic layer is removed and replaced with a thin STSG.26
Sepsis With the loss of an important barrier for infection, burn patients are at high risk of developing infection and sepsis. The use of elevated temperature as a marker for sepsis is unreliable in pediatric burn patients since these children are often febrile in the absence of infection secondary to the release of inflammatory mediators.20 A heightened suspicion of sepsis is warranted if the patient becomes toxic, hypotensive, thrombocytopenic, leukocytic, or experiences a change in mental status.27 In the context of these signs and symptoms, the patient’s wound should be examined and a pan-culture, including blood, sputum, and urine, should be
20
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P R INC IP L E S OF P E DIAT R IC B UR N I N J U RY obtained. Quantitative cultures of the wound are useful to differentiate infection from colonization. Broad-spectrum antibiotic coverage should be started immediately and continued until culture sensitivities can further direct treatment. If no infection is found, then antibiotics may be stopped after 48 to 72 hours to avoid overuse of broad-spectrum antibiotics. Preventative protocols, such as the scheduled rotation of central venous catheters, also help to reduce the prevalence of sepsis.20
Antibiotics/Antifungals There is no role for systemic antibiotic prophylaxis in burn care. Antibiotics should only be initiated to treat known or suspected infections and continued as directed by culture sensitivities.12 Prudent, sensitivity-driven antibiotic use is important in limiting antibiotic resistance in a population very prone to sepsis and infection. Fungal wound infections are very common in large burns and typically occur at day 16 following injury.28 Because these infections are associated with a very high mortality rate, oral prophylaxis with antifungal agents is appropriate and has been shown to decrease the incidence of fungal infections.29
Nutrition and Metabolism Patients with large burns experience a hypercatabolic state over an extended period, well beyond their initial injury.30 This state is characterized by increased insulin resistance, gluconeogenesis, and protein catabolism.3 In injuries involving greater than 40% TBSA, a patient’s resting energy expenditure is 150% to 200% higher than normal.31 In these large burns, patients can lose up to 25% of their preburn body weight by the third week following their injury.32 The effects of hypercatabolism include loss of lean body mass and growth delay for up to 2 years.25 As bone mineral density is chronically lower in children with severe burns, these patients have an increased lifelong risk of osteoporosis. The goal of nutrition and metabolism in the acute phase is to maintain preadmission weight, which may be difficult to assess initially due to fluctuations in fluid status. Laboratory findings are also unreliable in the acute phase and cannot be used in the evaluation of nutritional status. Hypoalbuminemia is expected acutely as the liver shifts production in favor of acute phase reactants such as C-reactive protein.33 Early excision of injured tissue helps to decrease catabolism, presumably by removing a major source of inflammatory mediators. Early initiation of nutrition is an important component in counteracting catabolism.34 Delays in initiating nutritional support have been shown to exacerbate catabolism, impair wound healing, and increase the risk of infection.8 Therefore, a nasogastric tube should be placed early
in order to begin a high caloric diet with carbohydrates as the main source of calories. Early enteral feeding has also been shown to maintain the gut barrier, prevent gut atrophy, and potentially decrease enterogenic infections. Care should be taken to avoid overfeeding, which can lead to hepatic dysfunction, hyperglycemia, and increased carbon dioxide production. When initiating enteral feedings in the acute phase, patients should be monitored for hypotension, splanchnic hypoperfusion, and intestinal necrosis.30 Therapy, in addition to nutrition, can help to attenuate lean body mass loss. While aerobic exercise is effective for older children in maintaining lean body mass, muscle strength, and power, it has limited use in infants and toddlers.31 Anabolic agents have also been shown to benefit pediatric burn patients. Oxandrolone given orally twice daily at a dose of 0.1 mg/kg will increase protein synthesis and decrease loss of lean body mass. Insulin supplementation can help overcome burn-induced insulin resistance. When titrated between 400 mU/ml and 900 mU/ml to control blood glucose levels for 7 days, patients demonstrate improved healing time and increased muscle protein synthesis.31 Catabolism-blocking agents can also be useful in these patients. Propanolol, a beta blocker, can attenuate the stressinduced hypermetabolism. When titrated to decrease the patient’s baseline heart rate by 20% for several weeks, beta blockade is able to decrease excess thermogenesis, tachycardia, cardiac work, and superphysiologic resting energy expenditure.35
Rehabilitation and Reintegration Improved resuscitation, along with early excision and grafting, permits most pediatric patients to survive deep burns. Currently, even a child with a large burn of up to 60% TBSA may be expected to survive with appropriate care in a specialized burn center.36 With more severely burned children surviving their injuries, the focus has shifted to improving their quality of life.37 The morbidity of these burns is significant and includes common complications such as scarring, contraction, and weakness from loss of muscle. The ultimate goal of this phase is to facilitate psychological and functional recovery, and is best accomplished in the multidisciplinary setting of a specialized burn center.
Hypertrophic Scarring Hypertrophic scarring is a common complication of burns and occurs most often in deep dermal burns that are left to heal spontaneously over a protracted period of greater than 3 weeks.1 Hypertrophic areas have an exaggerated inflammatory response which stimulates excess growth
21
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of collagen fibers. These scars typically form in areas of high elasticity and tension, such as the lower face, anterior chest, and submental triangle.2 The formation of these scars peaks at 3 to 6 months. The course of each scar will vary, but most will partially resolve in 12 to 18 months as the scar matures, becoming softer and flatter with decreased hyperemia.7 Hypertrophy is also associated with significant pruritus, which can be difficult to treat and very distressing to the patient. The first line of therapy for pruritus includes oral antihistamines and emollient creams.38 Keloid scars are another complication, with a similar appearance to hypertrophic scarring. However, they continue to expand beyond the original borders of the injury and occur more often in darker-pigmented patients.2 The treatment of hypertrophic and keloid scars begins conservatively with the application of pressure garments. These garments apply 24 mmHg of pressure to the scar and help remodel collagen fibers.2 Patients who are at risk of developing scars or who show early signs of hypertrophy should be fitted for these garments as soon as wounds are closed and the majority of edema has resolved. In order to be effective, the garments must be worn 23 hours each day for months.39 The greatest challenge in using these garments in pediatric care is compliance, particularly in adolescents. If the garments produce insufficient results, steroid injections may also be helpful. Steroid therapy requires many injections spaced 1 cm apart with 1 mg triamcinolone/site. This treatment can be effective but may lead to hypopigmentation, atrophy, telangiectasia, and recurrence of scarring.2 Scars which are unresponsive to conservative treatment and cause a functional deficit or undue stress to the patient are referred to a reconstructive surgeon for management. Multiple options exist, including dermabrasion and release of tension using transposition flaps such as Z-plasties.
Contracture Contractures occur when hypertrophic scarring develops across joints.36 This predisposition of hypertrophy in areas of tension is worsened by the tendency of patients to assume a flexed position in order to help alleviate pain. Over time, the scar matures and effectively tethers the joint as it becomes thicker and tighter.2 If left immobile, the underlying muscles and tendons become shortened with subsequent capsular contraction.12 The best treatment for contractures is to continue range-of-motion exercises. Occupational and physical therapy should follow the patient to ensure appropriate use of the area and recommend exercises to help regain range of motion. Pediatric burns in areas of functional importance should be closely followed to monitor for contractures. Since the scar does not grow or stretch proportionately as the child develops, there is the potential for contractures to
occur even years after the burn.2 Early treatment of these contractures focuses on prevention with use of pressure garments and splinting. In patients who may have developed mild to moderate contractures, serial splinting can be effective. With severe contractures or those unresponsive to splinting, contracture release may be planned by a burn or reconstructive surgeon.2
Heterotopic Ossification Heterotopic ossification is an uncommon complication of burns where normal bone forms ectopically in soft tissue via calcium deposition. This dilemma occurs most commonly following deep burns of the elbow, followed by the shoulder, hip, knee, and forearm. The patient will present with pain, edema, and decreased range of motion of the affected joint.40 Diagnosis is confirmed radiographically. Because conservative treatment is unlikely to help resolve this complication, surgical intervention is often necessary once ossification begins to limit function and activities of daily living.
Leukoderma Hypopigmentation, or leukoderma, is a very common sequela of burn injury, particularly in patients with darker skin pigmentation. This complication has no functional deficit, but may need to be addressed for psychological or cosmetic reasons. Treatment can be provided by a plastic and reconstructive surgeon who may restore more normative pigmentation through dermabrasion and regrafting of the affected area.2
Psychological Severe burns can remove a child from a normal home and school environment for weeks to months.36 Regardless of the size of the burn injury, the severity is not directly correlated with the psychological impact of the injury.36 Therefore, consultation with a child-life specialist is very important with every pediatric burn in helping to normalize the patient’s care. The ability of the family to cope and the presence of other psychological issues are better predictors of the impact of injury, particularly in young children. Care must be taken to minimize additional trauma during management of the burn by suitable pain and anxiety control. Providers should also be aware of the possibility of post-traumatic stress disorder in pediatric burn patients. During this phase of burn management, health care providers should inquire about hypervigilance, nightmares, and chronic fearfulness.2 Early referral to a counselor is helpful in managing this disorder. The development of acute stress and post-traumatic stress disorder is strongly associated with the actions of caregivers and their projection
22
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P R INC IP L E S OF P E DIAT R IC B UR N I N J U RY onto their charges.41 Depending on the patient’s age and stage of development, family counseling may be an appropriate option as well.
KEY POINTS • Determination of the extent of burn injury is based on depth and total body surface area (TBSA) involvement. • Extent of the burn injury is based on the temperature and duration of contact with the offending agent. • Burn management should always begin with PALS and ATLS protocols, along with specific management of fluid resuscitation and temperature maintenance. • Early excision and grafting is imperative in optimizing patient outcomes from significant burns. • Physical therapy with early range of motion and exercise will improve long-term outcome. • Continued follow-up for years with the patient and his or her family with a multidisciplinary burn center improves long-term rehabilitation and reintegration.
Follow-Up Patients suffering from burns have a better prognosis when consistent, long-term follow-up and early integration occurs.6 A multidisciplinary team can help provide physical and occupational therapy, scar management, reconstructive surgery, and family support.32 A significant burn is often a life-changing event for the patient as well as for his or her family. Health care providers must involve family in their children’s management as early as possible since a functional family and early reintegration are key components of a good prognosis.42 Severe burns are no longer synonymous with a poor quality of life, and it is our responsibility to make it a priority to help return these children to normal, meaningful, and productive lives.
TABLE 1 The Lund and Browder Chart, Calculating the Percent Total Body Surface Area Involved in Burn Injury
Head
Neck
Chest
Right: Upper Arm
Left: Upper Arm
Right: Forearm
Left: Forearm
Right: Hand
Newborn
1 Year Old
5 Years Old
10 Years Old
15 Years Old
Anterior
9.5
8.5
6.5
5.5
4.5
Posterior
9.5
8.5
6.5
5.5
4.5
Anterior
1
1
1
1
1
Posterior
1
1
1
1
1
Anterior
13
13
13
13
13
Posterior
13
13
13
13
13
Anterior
2
2
2
2
2
Posterior
2
2
2
2
2
Anterior
2
2
2
2
2
Posterior
2
2
2
2
2
Anterior
1.5
1.5
1.5
1.5
1.5
Posterior
1.5
1.5
1.5
1.5
1.5
Anterior
1.5
1.5
1.5
1.5
1.5
Posterior
1.5
1.5
1.5
1.5
1.5
Anterior
1.25
1.25
1.25
1.25
1.25
Posterior
1.25
1.25
1.25
1.25
1.25
continued on next page
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BURNS TABLE 1 (continued) Newborn
1 Year Old
5 Years Old
10 Years Old
15 Years Old
Anterior
1.25
1.25
1.25
1.25
1.25
Posterior
1.25
1.25
1.25
1.25
1.25
Perineum
1
1
1
1
1
Right: Buttock
2.5
2.5
2.5
2.5
2.5
Left: Buttock
2.5
2.5
2.5
2.5
2.5
Anterior
2.75
3.25
4
4.5
4.5
Posterior
2.75
3.25
4
4.5
4.5
Anterior
2.75
3.25
4
4.5
4.5
Posterior
2.75
3.25
4
4.5
4.5
Anterior
2.5
2.5
2.75
3
3.25
Posterior
2.5
2.5
2.75
3
3.25
Anterior
2.5
2.5
2.75
3
3.25
Posterior
2.5
2.5
2.75
3
3.25
Anterior
1.75
1.75
1.75
1.75
1.75
Posterior
1.75
1.75
1.75
1.75
1.75
Anterior
1.75
1.75
1.75
1.75
1.75
Posterior
1.75
1.75
1.75
1.75
1.75
Left: Hand
Right: Thigh
Left: Thigh
Right: Calf
Left: Calf
Right: Foot
Left: Foot
SUM - TBSA
TABLE 2 Common signs of child abuse in pediatric patients sustaining thermal injury. Signs of Child Abuse • Delay in seeking medical treatment • Changing reports of how injury was sustained • Injury inconsistent with reported mechanism • Clean line of demarcation in injury • Injury to buttocks, ankles, wrist, palms, soles • Other injuries present (fractures, bruises, healed burns) • Multiple hospitalizations
24
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P R INC IP L E S OF P E DIAT R IC B UR N I N J U RY FIGURE 1 The phases of thermal injury care, consisting of preparatory, emergent, acute, and rehabilitation and reintegration.
FIGURE 2 The Parkland formula and the Galveston formula, calculating the amount of fluid required for resuscitation.
Parkland formula: 4cc/kg/percent TBSA burned Initial 8 hrs: 1/2 of the fluid administered Following 16 hrs: Remaining 1/2 fluid administered
Galveston formula: Initial 24 hrs: 5000 cc LR/m2 TBSA burned + 2000 cc LR/m2 BSA (D5W for total BSA component in children > 2 years old is recommended) Initial 8 hrs: 1/2 of the fluid administered Following 16 hrs: Remaining 1/2 fluid administered Following 24 hours: 3750 cc/m2 TBSA burned + 1500 cc LR/m2 BSA 25
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3
C H A P T E R
T H R E E
EPIDEMIOLOGY AND ECONOMICS OF PEDIATRIC BURNS BRUCE CHUNG, MD, STEVEN A. KAHN, MD, UNIVERSITY OF ROCHESTER SCHOOL OF MEDICINE, ROCHESTER, NY DEPARTMENT OF SURGERY DIVISION OF BURN, ACUTE CARE, AND TRAUMA SURGERY AND
CHRISTOPHER W. LENTZ, MD, FACS, FCCM, UNIVERSITY OF NEW MEXICO HEALTH SCIENCES CENTER DEPARTMENT OF SURGERY, DIVISION OF GENERAL SURGERY, ALBUQUERQUE, NM
4. Child Abuse
OUTLINE 1. Introduction 2. Epidemiology 3. Burn Etiologies a. b. c. d. e.
Scalds Contact Burns House Fires and Fire-Related Injuries Fireworks Burns Electrical Burns
28 28 29 29 30 31 31 32
INTRODUCTION Studying the distribution of disease and the factors that affect the health and illness of the population are increasingly important aspects in medicine. Careful compilation of medical data through local databases and national registries can help determine problematic trends. The pediatric population is a target of significant preventive medicine strategies, including bicycle helmets, car seats, and poison control. Epidemiology allows us to appropriately apply these preventative measures. More attention has also been placed on preventing burn injuries. Burn injury is an important cause of morbidity in North America. The pediatric population and the elderly are at higher risks for burns. More so than in many other diseases or injuries, pediatric burn injury is a highly preventable injury. Initiatives and programs have been established to
Phillips, Bradley_3.indd 28
5. 6. 7. 8. 9. 10.
32
a. Risk Factors for Burns
32
Burn Prevention Burn Economics Summary and Conclusion Key Points Figures and Tables References
33 35 35 36 37 42
decrease the number of burn injuries through fire prevention, smoke alarm use, hot tap water temperature control, and increasing the general public awareness. By understanding the epidemiology of pediatric burn injury, we can better understand the risk factors for burn injury, identify specific and more cost-effective targets of prevention, reduce morbidity and mortality, and provide more effective methods for therapy, health care delivery, and resource utilization.
EPIDEMIOLOGY Burns are a significant cause of injury and one of the leading causes of death in the pediatric population. According to the Centers for Disease Control and Prevention, burn injury is the third most common cause of death in patients aged between 0 and 14 years. This number tapers off in the older
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EP ID E M IOL OGY AND E C ONOM IC S OF P E DIAT RI C B U R N S pediatric population, and overall is the seventh most common cause of death between the ages of 0 and 18.1 In 2004, data from the CDC reported 9339 total deaths from unintentional injuries in the pediatric population. Of these, burns and fires accounted for 5.7% of deaths, behind only motor vehicle accidents and drowning. In the pediatric population, burn injury accounts for 4.7%, 5.8%, 2.2%, and 0.5% mortality in the age groups of 0 to 4 years, 5 to 9 years, 10 to 14 years, and 15 to 18 years, respectively. The number of deaths from burns decreases with age in the pediatric population. In contrast, burn injury is only the sixth leading cause of unintentional death and is not within the top 20 causes of deaths in the overall population, accounting for only 0.1% of total deaths in 2004.1 In 2006, the CDC reported 9036931 nonfatal injuries in people between the ages of 0 and 18 years. Fire and burn injury accounted for 128182 incidents and represented 1.4% of total injuries. Between the ages of 1 to 4 years, fire and burn injury accounted for 2.6% of injuries, and between the ages of 5 to 9 years, 10 to 14 years, and 15 to 18 years, they accounted for 1.1%, 0.7%, and 1.1% of injuries, respectively. The incidence for fire and burn injury across all age groups is 1.4%.1 Although the incidence between all age groups and in the 0- to 18-year-old group is almost equal, there is a higher mortality in the pediatric population.1 Overall, the number of deaths and incidents from fire and burn injury has been decreasing (Figures 1 and 2). In 1981, the CDC reported that of 15702 deaths in children younger than 19 years (Figure 3), fire and burn injury accounted for 1349, or 8.6% of these deaths. In 1990, of 11807 deaths, fire and burn injury accounted for 953, or 8.1% of deaths, and in 2000 there were 9778 deaths, of which 629, or 6.4%, were due to fire and burn injury. Over the 19-year period, burn-related mortality decreased by 53.4%, exceeding the decrease in overall mortality of 37.7%.1 The American Burn Association also maintains a database of patients hospitalized in burn centers, the National Burn Repository. Between 1997 and 2007, there were 181836 burn patients treated in US burn centers. Patients from the ages of 0 to 20 years accounted for 51211, or 32% of burn admissions.2 The most common causes of burn injury requiring admission were scalds and flames. Scalds accounted for nearly 28% of burn injury in 0- to 20-year-olds, while flames accounted for 18% of injuries. Flame injury is the more common etiology after the age of 5, and it is rare in children under the age of 2 (4.3%). In the 0- to 2-year age group, the second leading cause of injury after scalds is contact burns, accounting for 19% (of injuries in that age group.2 Reported incidence of burns from the CDC and National Burn Repository emphasize the importance of burn injury in the pediatric population. Although the number of burns
has decreased from decade to decade, burns remain an important target for preventative medicine. Pediatric burn admissions vary according to availability of resources, cultural differences, and medical practice. There are a growing number of specialized burn care centers, but the majority of burn injuries are minor and can usually be managed on an outpatient basis.3 Minor burn injuries are usually evaluated in emergency departments and urgent care clinics and followed with primary care physicians.
BURN ETIOLOGIES By understanding the causes and reasons for burn injury, we are able to more accurately prevent burn injury and identify better targets for prevention. The main causes of burns are scalds, contact/thermal burns, fire and fire-related injuries, fireworks-related injuries, and electrical injuries. Each cause has its own specific risk factors and age predominance. Understanding these risk factors is important for reducing the incidence of burn injuries and developing prevention strategies for specific target age groups. The American Burn Association recognized the importance of a age-specific stratification of the etiology of burns in children. Looking at the pediatric population as a whole does not give an accurate picture of the cause of childhood burns (figure 5 A)2. Prior to 2007, the National Burn Repository (NBR) reported burn etiology in ages 0–2, 2–5 and 5–20. This stratification was not sufficient to study the etiology of thermal injury in a developing pediatric population since it was recognized that the cause of the burn was age dependent. The current stratifications reported by the NBR in children are ages 0–1, 1–2, 2–5, 5–16 and 16–20.2 This finer analysis will permit a better method of analyzing thermal injury in the dynamic development of children. As demonstrated, the incidence of scalds and contacts decrease with age and the incidence of fire and fire-related burns increasess (Figures 5B–5F).
Scalds Scald burns account for the majority of burn injuries in the pediatric age group, accounting for 30% to 50% of injuries.4,5,6 Scald burns are of particular importance in patients aged from 0 to 5 years. An average of 8 children with scald burns die each year, with a majority of deaths occurring in children younger than 4 years.7 The majority of scald burns occur when hot water is pulled from a pot off an elevated surface or when a container of hot water is overturned or spilled. The greatest risk comes to children younger than 2 years, with scalds accounting for nearly 65% of burn injuries in that age group. Two main injury patterns account for 52% of scalds. These injuries most commonly occur when a child reaches
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up and pulls down a pot from an elevated surface such as a stove or when a child grabs, overturns, or spills a pot onto himself or herself.8 Another significant cause of scalds in patients younger than 15 months occurs when another person spills or splashes hot liquid on the child, accounting for 28% of scald injuries.8 Males are more prone to scald injuries, accounting for 58% of scald incidents.5,9,10 The majority of scald injuries are treated and released without a hospital admission.7 Injuries that require hospitalization involve higher percentage of total surface area burned or deeper burns. While scald burns are usually due to hot water pulled from an elevated surface, another significant cause of scald burns is hot tap water scalds. Hot tap water scalds account for nearly 25% of scald injuries and tend to be more severe and have a larger total body surface area burned compared to spills. Due to these factors, hot tap water scalds are associated with a higher hospitalization and mortality rate than other scald burns.11,12 Up to 39% of tap water scalds involve a body surface area of at least 25%, and nearly one-third of these patients require hospitalizations. In addition, the occurrence of tap water scalds is more frequent in younger children, in which 88% of tap water scalds occurred by age 5.12 A survey of hot-water temperature in household bathtubs showed a mean of 142ºF, with a range from 90ºF to 168ºF.12 It has been shown that temperatures greater than 120ºF can result in significant burns.13 Temperatures at 140ºF or higher can increase the risk of full-thickness burns if skin is exposed for more than 30 seconds.13 In infants, this time is reduced to as little as 1 second (Table 1). Careful attention to the temperature of tap water should be taken to prevent tap water scalds. Surveys have demonstrated that very few people understand at what temperature a hot water heater should be set to prevent burn injury. This ignorance even extends to pediatric health care providers; 12 of 32 pediatric practitioners surveyed at one institution recommended that water heater temperatures be set above 130ºF.12 It is unclear whether their recommendations were related to insufficient knowledge of burn prevention tactics or whether they had some other reason to justify their decision (for example, risks of incubating Legionella at lower temperatures). Water at 130ºF can cause significant burn injury.13 A possible explanation for a higher incidence of deeper scald injuries in children is that young children have thinner skin that sustains damage more quickly and at a lower temperature. Due to their age and development, children also have less awareness and coordination and lack the ability to react quickly to avoid a burn.14,15 By nature, children are inquisitive and explore their environment through touch. They often learn to extend their hands to grab things, including pulling down pots filled with hot water. Because of their short stature, they are less aware of the contents in a
pot or container that they pull down. In conjunction with the lack of a coordinated muscular system, they lack fine motor skills, making children at higher risk for scalds. Some hot tap water scalds occur when an infant’s caretaker fills a bathtub with hot water, not realizing that the water is too hot. In addition, he or she might leave the infant in a tub filled with hot water if there is a distraction in a different room or area, such as a telephone call or a cry for help from other persons. There are a high number of tap water scalds in toddlers/preschool ages when curiosity or abuse results in the child becoming trapped in hot water and unable to escape.12
Contact Burns Contact burns account for the second most common burn injury in young children. Among hospitalized burn victims, they accounted for 26% of injuries in children aged 0 to 1 years and 24% in children aged 1 to -2 years. This number decreases to 17% in ages 2 to 5, and 9% in ages 5 to 16.2 The majority of contact burns occur from household appliances, including clothing irons, hair straighteners, hair curlers, stove tops, and room heaters. Contact burns are usually well defined, linear, and affect a small total body surface area. Nevertheless, due to the high temperature of some of these appliances, contact burns can often result in severe injury. Hot irons are a frequent offending agent. In the resting position, the hot surface is exposed, leaving it open to injury. One study revealed that the mean age of patients with thermal injury from a hot iron was 24 months, with children between 1 and 2 years most at risk for contact burn with a hot iron.16 Males were again more likely to be burned than females.16,17 Hair straighteners are an increasing cause of contact burn. Unlike an iron, hair straighteners have two hot surfaces that can heat up to 220ºC, or 428ºF. The resting and cooling positions leave the hot surfaces exposed and vulnerable to contact. Because of the two surfaces, they often cause thermal injury in two areas of the body.18 Injuries from hot appliances typically result in small burns. The total body surface area injury from contact burns averages 2.1%. Burn injury via this mechanism is usually partial thickness; however, children are vulnerable to fullthickness burns with prolonged contact.17 Due to the severity of the injury, up to 36% of contact burns from hot appliances require surgical intervention.19 The hands and fingers are the most frequent areas of injury. Children aged between 1 and 2 years are at most risk for a contact injury from a hot item. Learning to ambulate, they need to steady themselves against stationary objects. One of these stationary objects may happen to be a hot appliance. Young children in their “exploratory years” are extremely curious. In addition, this age group is more
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EP ID E M IOL OGY AND E C ONOM IC S OF P E DIAT RI C B U R N S ambulatory than the infant group but less aware of dangerous items than older children are. The combination of mobility and lack of awareness makes children aged 1 to 2 years more able to encounter and more vulnerable to injury from hot items such as irons, hair straighteners, and radiators. They also cannot react or withdraw as quickly to avoid serious burns. This is also demonstrated by the most injured area of the body from contact burns, the palm. Spending time in the kitchen with a parent who is preparing a meal places the child in an environment with hot objects that can cause injury.
clothing has decreased the incidence of clothing ignition.24 Legislation related to fire prevention and children’s clothing is discussed in more detail in the “Burn Prevention” section of this chapter. Children are at higher risk for house fire injury for several reasons. First, they are more likely to play with fire. Second, they lack the comprehension for the potential dangers of playing with fire. Third, they are unable to react as well when circumstances are out of control and are unable to plan an escape. Lastly, although they may be aware of a fire, they often depend on others for escape.25
House Fires and Fire-Related Injuries
Fireworks Burns
House fires account for approximately 3000 deaths and 17000 injuries a year in the United States.20 Overall, house fires are the third leading cause of fatal home injuries.21 Children under age 5 have double the risk of adults of death after injury in a house fire.22 In 2003, residential fire-related injuries accounted for 261 deaths, representing 7.4% of all mortality between the ages of 0 and 4 years.23 Although not as common as scalds and contact burns, fire and fire-related injury remain a leading cause of mortality in children. Of all mechanisms of burn injury, fire-related injury results in the highest mortality rates.6 Fire and fire-related injury accounted for 40% of burn hospital admissions between 1997 and 2007 and 18% of pediatric burn admissions.2 Unlike scalds and contact burns, burn injury from fires increases with age. Approximately 4% of admissions due to fire are for children younger than 2 years, and this increases to 18% in patients aged 2 to 5 years and 36% in patients aged 5 to 20 years. Males also tend to be at higher risk for fire-related injuries than females.2 Only 5% of house fires are due to fire-play by children. However, up to 42% of fire-related injuries are due to fireplay by children, including playing with matches or lighters. The majority of house fires are due to cigarette smoking, which accounts for over 50% of causes. Fires that start in the living room or bedroom are almost twice as likely to result in injury compared to fires started in the kitchen or other parts of the house. Clothing ignition often occurs in the setting of fire and in flame injury. The number of pediatric burn injuries from clothing ignition is declining, but it remains a significant cause of mortality due to the thickness of the burn and the higher percentage of total body surface area burned as a result. The incidence for clothing ignition has decreased dramatically with the use of fire-resistant and flame-retardant fibers for clothing. Among these fire-resistant materials are polyester and other synthetic materials. Cotton and many natural fibers, on the other hand, have been shown to burn quite readily and quickly. The use of more snug and tighter-fitting
Burns from fireworks occur with less frequency than other types of burns. There were approximately 10800 people treated for fireworks-related injury in the United States in 2005, with only 4 mortalities.26 This figure is slightly lower than an estimated 12600 people treated for fireworksrelated injury in 1994. Children represent more than half of these patients.27 Approximately 60% of fireworks-related injuries are burns, primarily from sparklers and firecrackers. Sparklers, popular among younger children, caused 20% of injuries. They were more prevalent in younger children, causing 46%, 25%, 15%, and 11% of burns in children aged 0 to 4, 5 to 9, 10 to 14, and 15 to 19 years, respectively. Firecrackers had a higher cause of injury in the older age groups, accounting for 24%, 34%, 32%, and 25% in those same age groups.28 Also causing significant injury were aerial devices (ie, bottle rockets or Roman candles), often causing injuries other than burns, such as eye injuries. The individual responsible for lighting the firework is most likely to sustain injury. However, bystanders are still at significant risk, with at least 22% of children sustaining injury from fireworks as bystanders. In addition, there is an overwhelmingly high rate of injury with fireworks in males, with males accounting for 77% of all fireworks-related injuries.26 The common sites of burns with fireworks are the hands, fingers, and eyes. The majority of fireworks-related burns are second degree, representing 37% of all injuries. Firstdegree burns occurred in 19% of injuries and third-degree in only 4% of incidents. The large part of fireworks injuries occur between June 18 and July 18, with 60% to 80% of injuries recorded around the Fourth of July. Over the last 15 years, there has been a steady decline in fireworks-related injuries in children.26 The majority of fireworks-related injuries do not require hospital admission. Greater than 90% are treated and discharged from the emergency department, and only 5% to 7% require hospitalization.26
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Electrical Burns Electrical injuries are rare in children, accounting for only 1.1% of burn injuries between 1997 and 2007.2 The incidence of electrical injury increases with age, accounting for 0.5%, 0.8%, 2%, 2.1%, and 2.6% of all electrical injuries occurring in the age groups of 0 to 1, 1 to 2, 2 to 5, 5 to 16 and 16 to 20 years, respectively. Electrical injuries can be divided in two categories, low voltage (1000 volts, e.g., or lighting strikes). The most common causes of electrical injuries are direct contact with electrical cords, up to 48%, or with faulty electrical appliances, 26%. Inserting a metal object into an electrical outlet accounts for approximately 18% of electrical burns.29 Although the occurrence of electrical injuries is relatively low, up to 61% of electrical injuries require skin grafting. The most common areas affected by electrical injury are the hands, feet, and skull. These body parts represent areas of source and ground contact points. Younger children also have been linked to cord biting, causing burn injury around the oral orifice.30 Cord biting has been shown to have a higher incidence in the Canadian population, up to 6%, but remains a concern regardless of geographic differences.31 Males are more likely to have electrical injuries than females, with figures as high as 70%.30 The greatest number of deaths from electrical injury occurred in older children, while, the majority of less severe injuries occurred in the younger population (0–4 years). Nonfatal electrical injuries tend to be caused by low-voltage current from household electrical outlets. In one study, most of the low-voltage injuries were minor, requiring minimal treatment.31 Injury from lightning strikes represents only a fraction, or approximately 1%, of all electrical injuries. However, lightning strikes are not required to be reported, and the number of injuries or deaths may be underestimated. Lightning strikes tend to be high voltage and account for a higher percentage of mortality. Nearly 25% of deaths secondary to electrical burns in children are due to lightning strikes. A report between 1980 and 1995 found mortality from lightning strikes to be greatest between patients aged 15 to 19 years. There is a high male prevalence of lightning strikes, with as much as 7 times the rate of that of females.32,33 This mechanism of injury tends to occur in areas where thunderstorms are more prevalent: the South, the Rockies, and the Ohio and the Mississippi river valleys.33
CHILD ABUSE Abuse remains a significant cause of injury to children although it represents a completely preventable injury. The number of child abuse–related burns is underestimated but
may represent a significant fraction of burn injuries. Up to 20% to 30% of children with burn injury have evidence suggestive of abuse, neglect, or failure to thrive or have an old burn injury detectable on admission or in old records.12,34 Burns caused by abuse are considered to be more indicative of premeditated attacks than other cases of abuse. Other violent acts are thought to be more spontaneous, as a result of and as a response to acts of anger, passion, or aggression. Risk factors include single-parent families and parental drug abuse, and delay in seeking health care may be a sign of child abuse.35 Ethnicity and social class have not been found to correlate with the incidence of child abuse. Abuse also has been found to be twice more common in males than in females. In cases of child abuse involving scalds, injuries usually include bilateral limbs or an isolated buttocks burn, have a clear tide mark, and exhibit symmetrical lesions.36 Also indicative of abuse are scald injuries with stocking or glove patterns and a uniform thickness of burn. Splash marks are typically absent in abuse cases. One study revealed that burns inflicted by abuse had a higher mortality than accidental burns, required higher frequency of skin grafting, and had more intensive care admissions.37
Risk Factors for Burns Studies have shown a strong correlation between different socioeconomic classes, available health care resources, and mortality. The mortality from all injuries in children has been shown to be highest in the lowest socioeconomic class. Injuries from burns and fires also show a strong correlation among different socioeconomic classes. A large-scale study evaluating burn injuries in the pediatric population in 2000 from the Healthcare Cost and Utilization Project Kids’ Inpatient Database showed a significant difference in age, race, and income in the number of children requiring admission to hospitals following burn injuries.6 Children younger than 2 years were more likely to require hospitalizations and were also more likely to be nonwhite. Risks of burn-related injuries were higher in Hispanics and blacks (Figure 6). Children living in areas of high poverty rates, single-parent families, and families with lower incomes also had a higher rate of burn injuries.38,39,40 The education level of the parents was also a significant factor in determining burns in children. Parents, whether one or both parents, with an education level higher than high school displayed a decreased risk for burns in children. Interestingly, the education of the father was less of a factor than that of the mother.33 Children living in crowded housing and areas where housing was more closely grouped together were also at higher risk for burn injury. This may be a reflection of the economic status of the family and the likelihood that
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EP ID E M IOL OGY AND E C ONOM IC S OF P E DIAT RI C B U R N S burns occurred more frequently in urban areas than in rural areas.40 Protective factors for burns include families with a living room in the house, ownership of the house, and higher education of the parents. These are also indicators that higher socioeconomic status plays a role.40 Many families with scald injuries in children were single-parent homes with little supervision. Families that did not have running water were at higher risks for scalds.40 As previously mentioned, contact burns are frequently due to irons, hair straighteners, and heaters. There is a higher incidence of contact burns in lower-income, single-parent, and single-child households.41 In lower-income housing, it has been shown that many families do not use elevated ironing tables and often improvise by ironing on floors or tables, leaving hot irons exposed in easily accessible areas. In most cases, contact burns from irons and other appliances are often due to carelessness and neglect, with the parents unaware of the dangers from these hot appliances. This is especially true in single-child households, where many burns have been attributed to parental inexperience.40 House fire has been well studied due to the high morbidity and mortality of the related injury. House fires are commonly due to smoking, fire-play, arson, faulty electrical wiring, and heating equipment. One study revealed that at higher risk are houses built between the 1950s and 1960s, low-income families, and homes without smoke detectors. Families earning the lowest median income, less than $20000 a year, had an incidence of 9.9 injuries per 100000 compared to an incidence of only 2.3 injuries per 100000 people in families earning an income between $40000 and $60000. Families earning the lowest median income also had almost 150% higher incidence of house fires.42 Residents of central urban areas as well as rural areas were at higher risk for injury in a house fire. In addition, people living in the southern United States had a higher risk of house fire–related mortality.43 The risk of house fire injury is also greatly increased in nonwhite populations, especially in African American, Native American, and Hispanic populations. These groups tend to live in homes that are associated with a higher risk of fire-related injuries and fatalities, including mobile homes and apartment complexes. Mobile homes and apartment complexes fall in a category of homes that have been shown to be at higher risks for fire-related deaths. They have fewer exits, fewer windows, and oftentimes, out-of-date heating systems. Smoke detectors have been highly linked to preventing fatal house fires. Smoke alarms have decreased the number of deaths by up to 60%. Nonwhite populations have been shown to have a lower rate of functional smoke detector use. This also has contributed to the higher risk of fire-related
injury in the nonwhite population. The protective effects of smoke alarms also depend on the cause of the house fire. In cases where fire-play was the cause of the house fire, smoke detectors did not show any difference in protection from injuries or fatalities. In all other causes, smoke detectors have been associated with a decrease in house-fire related injuries.44 Smoking and alcohol abuse are significant risk factors for house fires. Studies have found careless smoking to be responsible for a significant percentage of house fire–related deaths. Tobacco-related fires usually start with ignition of bedding or furniture when someone falls asleep while smoking. Alcohol intoxication is frequently associated with these fires.45 The greatest risk from fireworks-related injuries comes from lack of adult supervision. In more than 50% of cases, there was a lack of supervision possibly leading to inappropriate handling of fireworks. Recent studies, however, have also found that increased adult supervision may not prevent injury in children.46
BURN PREVENTION Burn injury is a highly preventable injury, especially in the pediatric population (Figure 7), as up to 64% of burns result from accidents. Improvements in survival from burns have been made over the last several decades due to advances in medical management, surgical intervention, nutrition, and resuscitation. The most effective way to improve survival, however, is likely through prevention of burn injuries. A large amount of resources have been invested into prevention and education. The fire service, fire companies, American Burn Association, and individual burn centers have been primarily responsible for fire prevention. One of the most widely publicized, effective measures is the “stop, drop, and roll” fire safety technique. Some other methods involve active programs promoting the use of smoke detectors and carbon monoxide detectors. However, more educational programs and public awareness are being distributed through media outlets other than fire services. A joint effort by the media, health care services, educational services, and fire services would make a greater impact on public awareness and prevent unnecessary burn injury. Currently, two major classes of burn prevention are utilized. Primary prevention involves preventing the event from occurring, whereas secondary prevention focuses on supportive therapy and reducing disability after the event.47 Both active and passive prevention strategies exist as well. Passive prevention includes approaches that do not depend on individuals for prevention. Instead, standards and techniques
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that remove the human factor are implemented. Automobile airbags fall into the passive category. Active prevention requires behavioral adjustments and efforts by individuals to reduce the risks of danger. An example of active prevention is the use of seatbelts to reduce serious injury in car accidents. Active prevention measures are more difficult to implement due to the compliance and cooperation of the people involved. For pediatric burn prevention, compliance depends on both children and parents. In many cases, children are too young to comprehend the subject matter, and it is often difficult to persuade parents to approach matters differently. Successful prevention of burn injuries relies on well-structured implementation of both passive and active prevention measures. One of the best examples of burn prevention includes the use of smoke detectors. The use of smoke detectors has decreased house fire–related injuries significantly and has arguably had the greatest impact on reducing fire-related mortality. One study estimated a decrease in mortality by 60%. Smoke detectors have been shown to reduce the risk of fire death by 13%.48 Smoke detector giveaway programs have decreased the number of house fire-related injuries in high-risk populations. In addition, it has been found that giving away smoke detectors in high-risk communities is the most effective and cost-efficient measure to reach highrisk populations and reduce injury.49 Although the use of smoke detectors has decreased the number of house fire-related injuries, it has been found that many households do not have functional smoke detectors. One study found that about 71% of households polled reported having a functional smoke detector. However, when the households were physically surveyed, only 49% of houses had functional smoke detectors.50 This finding points to the importance of campaigns to educate people about testing their smoke detectors and changing the batteries regularly, a program often led by fire services. Although passive prevention with smoke detectors has been shown to be quite effective, education programs to reach children through schools, primary care physician office visits, and other community arenas are also important. These programs have been shown to be effective in increasing the knowledge about the dangers of fire and the importance of formulating escape plans.51,52 Efforts to reduce scald burns have included campaigns to educate the public about the dangers of scalds and ways to minimize exposure to hot water. Installation of water heater temperature regulators has also been evaluated. For tap water scalds, educational programs have not been shown to be effective.53 Prevention programs utilizing both an educational component as well as installation of water heater temperature regulators that limit water temperatures to 120ºF have been shown to be effective.54,55 Legislative
measures to require water heater temperatures to be preset at lower temperatures have decreased the number of injuries and the total body surface area burned when an injury does occur. Furthermore, these measures reduced mortality, length of hospital stay, and the number of surgical interventions required after thermal injury.56 Contact burns from hot irons are a preventable source of burns. The development of an “iron shoe” cooling device may help to dissipate heat and prevent contact burns. One such device uses a silicone polymer that shields the iron from the edges and surfaces of the iron and decreases the temperature of the iron from over 200°C to under 50°C. A prototype has been created and tested at our institution but has yet to be distributed to consumers. This device has potential to be an inexpensive method for preventing contact burns from irons.57 Measures to reduce firework injuries include educational campaigns as well as legislative interventions. States that have banned certain fireworks have seen a reduction in fireworks-related burns.58 Programs to increase awareness of fireworks-related burns also need to be effective, abundant, and publicized during Fourth of July celebrations, when fireworks-related burns most commonly occur.26 Other successful programs to reduce fire-related injuries include the implementation of child-safe lighters and legislative measures to use fire-resistant materials in clothing. The use of fire-resistant and flame-retardant materials has led to a decline in the number of sleepwear-related burn injuries. Legislation in 1972 required that children’s pajamas be made of flame-resistant materials, which resulted in an almost zero incidence of sleepwear-related burns. However, this was overturned in 1996 by the Consumer Product Safety Commission (CPSC). Since this policy reversal, recent surveys have shown that sleepwear-related burn injuries have increased by 157%.59 Currently, the American Burn Association and several members of Congress are attempting to reenact legislation to require usage of fire-resistant and flame-retardant material in children’s sleepwear. Currently the CPSC recommends that child sleepwear (for children greater than 9 months old) be either flame resistant or made of snug-fitting cotton.60 Cotton is widely regarded as more comfortable than flame-retardant fabrics of the past, and snug-fitting clothes are less likely to hang and ignite. Time will tell whether this clothing strategy is effective.60 Future prevention programs should target the high-risk population. These include communities with a high number of low-income families, single-parent families, and a nonwhite population. Early and frequent educational programs for children are also important. In summary, burn prevention strategies involve primary, secondary, passive, and active techniques. When these preventative measures are backed by legislation, injuries are more effectively reduced.
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BURN ECONOMICS Fire and burn injuries represent a significant burden to medical costs. Burns can have long-term impact on victims, including ongoing medical bills for follow-up care, rehabilitation, and scar revisions. Significant emotional stress and psychological trauma can also result from burn injury. The visible effects and scars from burns can be emotionally damaging, which may add up to extensive costs in clothing, make-up, and other cosmetic interventions. By evaluating the cost of burn injuries, decisions about health care resources and distribution can be better made. There is increasing pressure to reduce costs from insurance companies, thirdparty payers, and hospital administration. Fire and burn injuries are estimated to cost over $2.1 billion annually in children younger than 19 years.61 In the year 2000, the total charges for burn-associated hospitalizations totaled $211772700. The mean charge for each hospitalization was approximately $21800, with a median of $7700. Charges for individual hospitalizations ranged from $25 to $985951. However, approximately 10% of patients accrued more than $47300 of total charges.6 The extent of injury was associated with the length of stay and the expenses of hospitalization. First-degree injuries were associated with a shorter length of stay, 2.1 days, and a smaller total charge, $5430. As the injury became larger, the total charge increased dramatically. Second-degree burns had a length of stay of 4.1 days, totaling $11200, while thirddegree burns had a mean length of stay of 11.7 days, with a mean charge of $43900.6 The same associations were also made with the percent total body surface area burned. The smaller the total body surface area burned, the shorter the length of stay and the lower the cost of the hospitalization. A burn less than 10% total body surface area had a mean hospitalization of 4.9 days with a charge of $13900.6 Burns greater than 40% total body surface had a mean length of stay greater than 5 times that and charges more than 10 times that of a burn less than 10% total body surface area. The total charge for hospitalizations did not show any difference between gender, race, or hospital location.6 Patients that had minor burn injuries and were seen in the emergency department had an average hospital charge of $1185.62 These patients had a mean total body surface area burned of 5.4%. Patients with minor burns seen in an outpatient burn clinic had an average total charge of $691 with a mean total surface area burned of 7.2%.59 These statistics may represent a higher cost in the emergency department due to treatment time, laboratory tests, radiologic tests, and other diagnostic tests. Most of these tests may be unnecessary
and superfluous expenses. Pharmacy represents one of the higher charges incurred to patients when visiting an outpatient burn clinic. There was a 76% greater charge for pharmacy services compared to that for patients seen in the emergency department.59 Specialized burn centers are larger and have higher staffing and a higher level of technology. These centers have better patient outcomes and survival despite treating sicker patients and more severe burns.63 However, specialized burn centers typically have higher costs. The mean cost per patient in one study was $32033. The mean cost per hospital day was $477.64 Factors that affected the total charge included timing of surgery and interventions. Early surgical interventions for severe burns reduced total charge. The importance of analyzing burn economics is to provide better understanding for decisions for distribution of health care resources. Pressures to reduce health care costs are increasing. Specialized burn centers provide a higher level of care that has been shown to improve patient outcomes. Despite the high cost of hospitalization in specialized burn centers, they are a necessary resource to improve patient survival and allow patients to have a more productive life following their injury. Although many communities depend on emergency departments for burn care, minor burn injuries may be better treated through outpatient burn clinics. Such clinics have lower total charge while reducing unnecessary diagnostic tests and reserving health care resources. Data would suggest that more money and time should be placed into implementing outpatient burn clinics to reduce total expenses.
SUMMARY AND CONCLUSION Burn injury remains a significant burden in the pediatric population and is a large public health concern. It is one of the leading causes of injury and death in children, utilizing a significant amount of health care resources. Through the study of epidemiology, burn providers can identify and control health problems in the population. After problems are identified, steps can be taken to decrease the incidence and mortality of burns, improve the quality of life of burn victims, and allocate health care resources to more effectively to treat burns. The current system creates enormous pressures for health care to be more efficient and less costly. Understanding the causes and risk factors for burns will determine better, targeted areas of prevention and treatment. Continued emphasis on tabulating patient factors and outcomes is needed to further the evolution of health care and burn treatment. This includes improving modes of health care delivery, improving resource allocation, and minimizing excessive and unnecessary health care dollars.
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Prevention of burns remains a public health goal. The first step to decreasing the amount of burn injuries is prevention. Increasing public awareness and education has seen mixed results. In the future, better methods may utilize both passive and active preventative measures as well as legislation to reduce risks for burn injuries.
KEY POINTS • Epidemiology is a key component in medicine that helps to understand ways to prevent disease, reduce mortality, and improve patient outcomes. The etiology of thermal injury in pediatric patients is age dependent and prevention strategies need to target specific age groups in children. • Burn and fire-related injuries are leading causes of injury and deaths in the pediatric population. They are the third leading cause of unintentional deaths in children younger than 14 years, only behind motor vehicle accidents and drownings. • Scalds and fire-related burns comprise most of the burns in children. • Scalds make up over 60% of burns in children younger than 2. The largest risk factors for scalds are children younger than 2, nonwhite families, and single-parent families. • Scald burns are usually due to children pulling containers and pots filled with hot liquid from an elevated surface, splashes, and bathtubs filled with hot tap water. • Contact thermal burns occur from exposure to irons, curling irons, hair straighteners, and stove tops. They often cause deeper burns due to the high temperatures that these appliances can reach. • House fires do not occur as frequently as scalds or contact burns but are responsible for a higher mortality rate. • Most house fires are due to cigarette use and children playing with fire. • Fifty percent of fireworks-related burns are seen in children and occur mostly during the month surrounding the Fourth of July.
• Sparklers and firecrackers account for the majority of injuries. Sparklers cause more burn injuries in children younger than 5 years, while firecrackers are responsible for the majority of burns in the remaining pediatric age groups. • Electrical injuries account for only a small portion of overall injuries and are due to contact with faulty electrical cords or to inserting metal objects into electrical outlets. • Lightning injuries are rare but are responsible for nearly a quarter of deaths in electrical burns in children. • Child abuse is a significant cause of burn injury in the pediatric population. Suspicious attributes include stocking and glove scald patterns with a uniform burn thickness, isolated buttocks burns, and symmetrical lesions. • Risk factors for burns include low-income families, single-parent families, and nonwhite families. A poor maternal education also places children at higher risk for burns. • Smoke detectors have reduced house fire injuries significantly. Families and communities without smoke detectors are at higher risks for house fire–related injuries. • Prevention is a key component to limiting burn injury. A large number of resources have been placed towards burn prevention, including educational programs, smoke alarm giveaways, limiting firework sales, hot water heater temperature regulators, child-safe lighters, and fire-resistant fibers. • The most effective prevention campaigns involve both active and passive prevention techniques. The combination of techniques should be applied towards future prevention programs where applicable. • Burn injury consumes a large share of health expenses, and expenditures for health charges total $2.1 billion per year. • Specialized burn centers, although more expensive, increase survival and patient quality of life. Outpatient clinics are less costly than emergency department visits and provide adequate and comparable care.
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EP ID E M IOL OGY AND E C ONOM IC S OF P E DIAT RI C B U R N S
FIGURES AND TABLES
Number of Unintentional Burn Injuries
FIGURE 1 Number of unintentional burns in children aged 0 to 19 years from 2000–2006.
Number of Unintentional Burns in Children 0 - 19 Years 180000
160000
140000
120000 2000
2001
2002
2003
2004
2005
2006
Year
Source. Data extrapolated from CDC WISQARS database for nonfatal injuries 2006.
FIGURE 2 Deaths from burn injuries in children aged 0 to 19 years from 1981 to 2004.
Deaths from Burn Injuries in Children 0-19 Years Number of Deaths
2000 1500 1000 500 0 1984
1988
1992
1996
2000
2004
Year Source. Data extrapolated from CDC WISQARS database for fatal injuries.
37
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FIGURE 3 Number of burns in age groups 0 to 4, 5 to 9, 10 to 14, and 15 to 19 years in 2006.
Number of Burns per Age in 2006
Number of Burns
80000 60000 40000 20000 0 0-4
5-9
10 - 14
15- 19
Age Source. Data extrapolated from CDC WISQARS database for nonfatal injuries 2006.
FIGURE 4 Graph of incidence of burns by age and gender.
Source. Data from NBR 2007.
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EP ID E M IOL OGY AND E C ONOM IC S OF P E DIAT RI C B U R N S FIGURE 5A Burn etiologies in children from birth to 20 years, 1997–2007.
FIGURE 5B Burn etiologies in children from birth to 0.9 years, 1997–2007.
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BURNS FIGURE 6 Ethnicity/race of burn patients.
Other Unknown 3% 7%
Asian 2%
Native American 1%
Hispanic 11% White 59%
Black 17%
Source. Data from NBR 2007.
FIGURE 7 Categories of circumstances of burn injuries. Suspected Assualt/Abuse 1.7% Accident, Unspecified 4.3%
Suspected Child Abuse 1.3% Suspected Self Inflicted 1.3%
Accident, Recreation 4.8% Other 6.7%
Accident, Work Related 15.8% Accident, Non-Work Related 64.2%
Source. Data from NBR 2007.
40
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EP ID E M IOL OGY AND E C ONOM IC S OF P E DIAT RI C B U R N S FIGURE 8 Categories of injury site. Residential Institution 1.3%
Public Building 2.4%
Farm 0.7% Mine/Quarry 0.0%
Recreation and Sport 4.3%
Other Specified Place 5.4% Home 41.7%
Industrial 7.0%
Unspecified 14.7% Street/Highway 22.4% Source. Data from NBR 2007.
TABLE 1 Time exposure for second- and third-degree scald burns for various water temperatures. Time to Second-Degree Time to Third-Degree Burns Burns
Temp ºC
Temp ºF
40
104
100 min
167 min
45
113
2 min
8 min
50
122
11 sec
20 sec
55
131
2 sec
5 sec
60
140
instant
1 sec
65
149
instant
instant
70
158
instant
instant
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REFERENCES 1. Data Collected from queries to WISQARS Injury Mortality
Reports, 1999–2006 (http://webappa.cdc.gov/sasweb/ncipc/ mortrate10_sy.html) National Center for Injury and Prevention and Control, Atlanta,GA. 2. National Burn Repository Report 2007, Dataset 4.0, American
Burn Association, Chicago, IL, 2007. 3. Carlsson A, Uden G, Hakansson A, Karlsson ED. Burn injuries
in small children, a population-based study in Sweden. J Clin Nurs. 2006; 15(2): 129–134. 4. Smith EI. The epidemiology of burns: the cause and control of
burns in children. Pediatrics. 1969; 44: 821. 5. Safe Kids Worldwide. Burn and Scalds Safety. Washington,
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GA. Healthcare resource utilization and epidemiology of pediatric burn-associated hospitalizations, United States, 2000. J Burn Care Res. 2007; 28(6): 811–826. 7. Washington State Childhood Injury Report. Fire and Burn.
Washington State Department of Health, Olympia, WA, November 2004. 8. Drago DA. Kitchen scalds and thermal burns in children five years and younger. Pediatrics. 2005; 115(1): 10–16. 9. Banco L, Lapidus G, Zavoski R, Braddock M. Burn injuries
among children in an urban emergency department. Pediatr Emerg Care. 1994; 10(2): 98–101. 10. Quayle KS, Wick NA, Gnauck KA, Schootman M, Jaffe DM. Description of Missouri children who suffer burn injuries. Inj Prev. 2000; 6(4): 255–258. 11. McLoughlin E, McGuire A. The causes, cost, and prevention of childhood burn injuries. Am J Dis Child. 1990; 144(6): 677–683. 12. Feldman KW, Schaller RT, Feldman JA, McMillon M. Tap water scald burns in children. 1997. Inj Prev. 1998; 4(3): 238–242. 13. Moritz AR, Henriques FC. Studies of thermal injury: the relative importance of time and surface temperature in the causation of cutaneous burns. Am J Pathol. 1947; 23: 695. 14. Katcher ML. Scald burns from hot tap water. JAMA. 1981; 246(11): 1219–1222. 15. American Burn Association. Scald injury prevention educator’s guide. http://www.ameriburn.org/Preven/ScaldInjuryEducator’s Guide.pdf., American Burn Association, Chicago, IL, 2010. 16. Gaffney P. The domestic iron. A danger to young children. J Accid Emerg Med. 2000; 17(3): 199–200. 17. Qazi K, Gerson LW, Christopher NC, Kessler E, Ida N. Curling iron-related injuries presenting to US emergency departments. Acad Emerg Med. 2001; 8(4): 395–397. 18. Duncan RA, Waterston S, Beattie TF, Stewart K. Contact burns from hair straighteners: a new hazard in the home. Emerg Med J. 2006; 23(3): e21. 19. Alden NE, Rabbitts A, Yurt RW. Contact burns: is further prevention necessary? J Burn Care Res. 2006; 27(4): 472–475.
20. Federal Emergency Management Agency. Fire in the United States 1987–1996. 11th ed. Emmitsburg, MD: National Fire Data Center, United States Fire Administrator and FEMA (produced by TriData Corporation, Arlington, VA); 1999. 21. Runyan CW, Bangdiwala SI, Linzer MA, Sacks JJ, Butts J. Risk factors for fatal residential fires. N Engl J Med. 1992; 327(12): 859–863. 22. Safe Kids Worldwide. Fire Safety. Washington, DC: SKW; 2007. 23. Pressley JC, Barlow B, Kendig T, Paneth-Pollak R. Twenty-year trends in fatal injuries to very young children: the persistence of racial disparities. Pediatrics. 2007; 119(4): e875–e884. 24. Warda L, Tenenbein M, Moffatt ME. House fire injury prevention update. Part II. A review of the effectiveness of preventive interventions. Inj Prev. 1999; 5(3): 217–225. 25. Squires T, Busuttil A. Can child fatalities in house fires be
prevented? Inj Prev. 1996; 2(2): 109–113. 26. Greene MA, Joholske J. 2005 fireworks annual report; fireworks-related deaths, emergency department treated injuries, and enforcement activities during 2005. Washington, DC: US Consumer Product Safety Commission; 2006. 27. Smith GA, Knapp JF, Barnett TM, Shields BJ. The rockets’ red glare, the bombs bursting in air: fireworks-related injuries to children. Pediatrics. 1996; 98(1): 1–9. 28. Witsaman RJ, Comstock RD, Smith GA. Pediatric fireworks-
related injuries in the United States: 1990–2003. Pediatrics. 2006; 118(1): 296–303. 29. Lui P, Tildsley J, Fritsche M, Kimble RM. Electrical burns in children. J Burns and Surg Wound Care. 2003; 2: 8. 30. Rabban JT, Blair JA, Rosen CL, Adler JN, Sheridan RL. Mechanisms of pediatric electrical injury. New implications for product safety and injury prevention. Arch Pediatr Adolesc Med. 1997; 151(7): 696–700. 31. Nguyen BH, MacKay M, Bailey B, Klassen TP. Epidemiology of electrical and lightning related deaths and injuries among Canadian children and youth. Inj Prev. 2004; 10(2): 122–124. 32. Lightning-associated deaths—United States 1980–1995. MMWR. 1998; 47: 391–394. 33. Lopez RE, Holle RL. Demographics of lightning casualties. Semin Neurol. 1995; 15(3): 286–295. 34. Rosenberg NM, Marino D. Frequency of suspected abuse/ neglect in burn patients. Pediatr Emerg Care. 1989; 5(4): 219–221. 35. Chester DL, Jose RM, Aldlyami E, King H, Moiemen NS. Non-accidental burns in children—are we neglecting neglect? Burns. 2006; 32(2): 222–228. 36. Yeoh C, Nixon JW, Dickson W, Kemp A, Sibert JR. Patterns of scald injuries. Arch Dis Child. 1994; 71(2): 156–158. 37. Andronicus M, Oates RK, Peat J, Spalding S, Martin H. Nonaccidental burns in children. Burns. 1998; 24(6): 552–558.
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EP ID E M IOL OGY AND E C ONOM IC S OF P E DIAT RI C B U R N S 38. Simon PA, Baron RC. Age as a risk factor for burn injury requiring hospitalization during early childhood. Arch Pediatr Adolesc Med. 1994; 148(4): 394–397.
52. Eckelt K, Fannon M, Blades B, Munster AM. A successful burn prevention program in elementary schools. J Burn Care Rehabil. 1985; 6(6): 509–510.
39. Karr CJ, Rivara FP, Cummings P. Severe injury among Hispanic and non-Hispanic white children in Washington state. Public Health Rep. 2005; 120(1): 19–24.
53. Spallek M, Nixon J, Bain C, et al. Scald prevention campaigns: do they work? J Burn Care Res. 2007; 28(2): 328–333.
factors for burns in children: crowding, poverty, and poor maternal education. Inj Prev. 2002; 8(1): 38–41.
54. Han RK, Ungar WJ, Macarthur C. Cost-effectiveness analysis of a proposed public health legislative/educational strategy to reduce tap water scald injuries in children. Inj Prev. 2007; 13(4): 248–253.
41. Scholer SJ, Hickson GB, Mitchel EF Jr, Ray WA. Predictors of mortality from fires in young children. Pediatrics. 1998; 101(5): E12.
55. Cagle KM, Davis JW, Dominic W, Gonzales W. Results of a focused scald-prevention program. J Burn Care Res. 2006; 27(6): 859–863.
42. Istre GR, McCoy MA, Osborn L, Barnard JJ, Bolton A.
Deaths and injuries from house fires. N Engl J Med. 2001; 344(25): 1911–1916.
56. Erdmann TC, Feldman KW, Rivara FP, Heimbach DM, Wall HA. Tap water burn prevention: the effect of legislation. Pediatrics. 1991; 88(3): 572–577.
43. Warda L, Tenenbein M, Moffatt ME. House fire injury prevention update. Part II. A review of the effectiveness of preventive interventions. Inj Prev. 1999; 5(3): 217–225.
57. Beers R, Anthamattan M, Reid D, Kahn S, Lentz C. Development of a safety device for preventing clothing iron contact burns. J Burn Care Res. 2009; 30(1): 70–76.
44. Istre GR, McCoy M, Carlin DK, McClain J. Residential fire
58. Berger LR, Kalishman S, Rivara FP. Injuries from fireworks. Pediatrics. 1985; 75(5): 877–882.
40. Delgado J, Ramirez-Cardich ME, Gilman RH, et al. Risk
related deaths and injuries among children: fireplay, smoke alarms, and prevention. Inj Prev. 2002; 8(2): 128–132. 45. Barillo DJ, Goode R. Fire fatality study: demographics of fire
victims. Burns. 1996; 22(2): 85–88. 46. Baker SP. Childhood injuries: the community approach to
prevention. J Public Health Policy. 1981; 2(3): 235–246. 47. Hunt JL, Arnoldo BD, Purdue GF. Prevention of burn injuries. In: Herndon DN, ed. Total Burn Care. 3rd ed. Philadelphia: Saunders Elsevier; 2007: 33–42.
59. American Burn Association. Key legislative and policy issues. http://www.ameriburn.org/advocacy_safechildrenssleepwear.php. American Burn Association, Chicago IL, 2000. 60. US Consumer Product Safety Commission. NEWS from CPSC, New labels on children’s sleepware alert parents to fire dangers, Washington, DC, 2000, http://www.cpsc.gov/cpscpub/ prerel/prhtml00/00129.html.
48. DiGuiseppi C, Roberts I, Li L. Smoke alarm ownership and house fire death rates in children. J Epidemiol Community Health. 1998; 52(11): 760–761.
61. Miller TR, Finkelstein AE, Zaloshnja E, Hendrie D. The cost of child and adolescent injuries and the savings from prevention. In: Liller KD, ed. Injury Prevention for Children and Adolescents: Research, Practice, and Advocacy. Washington, DC: American Public Health Association; 2006; 10–16.
49. Douglas MR, Mallonee S, Istre GR. Comparison of community based smoke detector distribution methods in an urban community. Inj Prev. 1998; 4(1): 28–32.
62. Kagan RJ, Warden GD. Care of minor burn injuries: an analysis of burn clinic and emergency room charges. J Burn Care Rehabil. 2001; 22(5): 337–340.
50. Douglas MR, Mallonee S, Istre GR. Estimating the proportion of homes with functioning smoke alarms: a comparison of telephone survey and household survey results. Am J Public Health. 1999; 89(7): 1112–1114.
63. Pacella SJ, Butz DA, Comstock MC, Harkins DR, Kuzon WM Jr, Taheri PA. Hospital volume outcome and discharge disposition of burn patients. Plast Reconstr Surg. 2006; 117(4): 1296–1305; discussion 306–307.
51. Varas R, Carbone R, Hammond JS. A one-hour burn prevention
64. Sanchez JL, Pereperez SB, Bastida JL, Martinez MM. Cost-
program for grade school children: its approach and success. J Burn Care Rehabil. 1988; 9(1): 69–71.
utility analysis applied to the treatment of burn patients in a specialized center. Arch Surg. 2007; 142(1): 50–57; discussion 57.
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4
C H A P T E R
F O U R
SKIN: STRUCTURE, DEVELOPMENT, AND HEALING NAVEED SAQIB, MD, DEPARTMENT OF SURGERY SECTION OF BURNS TRAUMA, UNIVERSITY OF NEW MEXICO HSC ALBUQUERQUE, NM
AND
THOMAS R. HOWDIESHELL, MD, PROFESSOR OF SURGERY, DEPARTMENT OF SURGERY SECTION OF BURNS AND TRAUMA, UNIVERSITY OF NEW MEXICO HSC, ALBUQUERQUE, NM
OUTLINE 1. Introduction 2. Skin Structure a. b. c. d. e. f. g. h. i. j.
Overview The Keratinocyte Layers of the Epidermis Nonkeratinocytes of the Epidermis Dermal-Epidermal Junction The Dermis Cutaneous Vasculature Cutaneous Lymphatics Nerves and Receptors Skin Appendages
3. Development of Skin a. Overview b. Insights From Fetal Wound Healing Inflammation Reepithelialization Angiogenesis Extracellular Matrix Growth Factors Fibroblasts and Myofibroblasts Developmental Genes
Cornified Envelope Biology of Vernix
44 45
a. b. c. d. e. f.
Phases Inflammation Epithelialization Granulation Tissue Formation Neovascularization Wound Contraction and Extracellular Matrix Reorganization g. Epithelial-Mesenchymal Transition (EMT) and Endothelial-Mesenchymal Transition (EndMT) Concepts
45 45 46 47 48 48 50 51 51 51
52 52 53 53 54 54 54 55 55 55
INTRODUCTION Great improvements have been achieved over the past few decades to reduce morbidity and mortality related to burn injuries. Increasingly aggressive surgical approaches with early tangential excision and wound closure probably represent the most significant change in recent years, leading to improvement in mortality rates of burn victims at a substantially lower cost.1,2,3 Early burn wound closure reduces the
Phillips, Bradley_4.indd 44
4. Normal Wound Healing
5. Abnormal Wound Healing
6. 7. 8. 9.
56 56
56 56 56 57 57 58
58
59
59
a. Introduction b. Keloid Versus Hypertrophic Scar c. Pathogenesis
59 59 60
Bench To Bedside Conclusion Key Points References
61 61 62 62
infectious complications and shortens hospital stay. Faster healing decreases the severity of hypertrophic scarring, joint contractures, and joint stiffness and promotes quicker rehabilitation.4 Therefore, a comprehensive and evolving knowledge of wound healing is of major importance to the survival and clinical outcome of burn patients. Human skin is a complex structure with unusual functional diversity. Topologically, the skin is continuous with the lung and intestinal epithelia. Whereas the lung and gut
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S KIN: S T R UC T UR E , DE VE L OP M E NT, AND H E A L I N G are commonly viewed as exchange surfaces for gasses and nutrients, the skin is more commonly considered a barrier.5,6 The concept of an integumental barrier emphasizes the role of the skin as a protective boundary between the organism and a potentially hostile environment. This protective role is evident at birth as the fetus abruptly transitions from the warm, wet, sterile, and protected milieu to a cold, dry, microbe-laden world filled with physical, chemical, and mechanical dangers. Focusing only on the barrier properties of the skin, however, de-emphasizes the important role of the skin in social communication, perception, and behavioral interactions. The skin, as the surface of the organism, is both a cellular and molecular structure as well as a perceptual and psychological interface.7 This dual functionality befits a true boundary and must be kept in mind to fully appreciate the dynamic organization of the skin and its close kinship with the nervous system. The skin also provides the physical scaffold that defines the form of the animal. Due to the action of the somatic musculature, a vertebrate’s body continually changes shape, which is difficult in a dry, terrestrial environment. A wide variety of strategies have been devised by different animals to cope with the exigencies of different habitats.8 Arthropods have a largely inflexible body surface, covered with an exoskeleton. Many vertebrates, such as amphibians, live on land but are confined to humid or wet microhabitats. Reptiles and fish have a skin surface covered predominantly with scales, birds have evolved feathers, and most mammals are covered with a protective mantle of fur. Among primates, humans are unique in possessing a nonfurred skin with a thick, stratified interfollicular epidermis and a welldeveloped stratum corneum.9,10 The question of the presumptive advantage of losing a protective and insulating coat of fur has long intrigued evolutionary biologists and physical anthropologists.11 Three of the most distinctive physical features distinguished among human beings are a nonfurred skin surface; a large, versatile, highly organized brain; and opposable thumbs. The close embryologic connection between the epidermis and the brain (both are ectodermal derivatives) supports the contention that these peculiar structural aspects of human development have coevolved. We have often overlooked the direct participation of the skin in higher-level functions such as perception and behavioral interactions.12 Cutaneous attributes form the basis for many readily observed biologic distinctions, including age, race, and gender, as well as multiple overlapping sociocultural characteristics, including tattooing, cosmetics, and tanning. Much of the complex structure of skin can be explained in terms of the function of its component cells, cellular organelles, and biochemical composition. This broad image
has resulted from the application of immunology, biochemistry, physiology, transgenic models, biophysics, and molecular biology, often used in combination with various forms of microscopy.
SKIN STRUCTURE Overview The epidermis is a continually renewing, stratified squamous epithelium that keratinizes and gives rise to derivative structures (sebaceous glands, nails, hair follicles, and sweat glands) called appendages. The epidermis is approximately 0.4 mm to 1.5 mm in thickness, as compared to the 1.5 mm to 4 mm full-thickness skin. The majority of cells in the epidermis are keratinocytes that are organized into 4 layers named for either their position or a structural property of the cells. Viable cells move outwardly from the basal layer to form layers of progressively more differentiated cells; terminally differentiated keratinocytes are found in the stratum corneum. Intercalated among the keratinocytes at various levels in the epidermis are the immigrant cells—melanocytes, Langerhans cells, and Merkel cells. Melanocytes and Langerhans cells migrate into the epidermis during embryonic development, while Merkel cells probably differentiate in situ. Other cells, such as lymphocytes, are transient inhabitants of the epidermis and are extremely sparse in normal skin. The epidermis rests on and is attached to a basal lamina that separates epidermis and dermis and mediates their attachment. There are many regional variations in the structural properties of the epidermis and its appendages; some are apparent grossly, such as thickness, comparing palm with flexor forearm, while other regional differences are microscopic.13
The Keratinocyte The keratinocyte is an ectodermally derived cell that constitutes at least 80% of the epidermal cells. All keratinocytes contain cytoplasmic keratin intermediate filaments in their cytoplasm and form desmosomes or modified desmosomal junctions with adjacent cells. Other features of keratinocytes depend upon their location within the epidermis.14 Keratin filaments are a hallmark of the keratinocyte and other epithelial cells. Predominantly, they serve a structural (cytoskeletal) role in the cells. More than 30 different keratins, approximately 20 epithelial and 10 hair keratins, all within a range of 40 kDa to 70 kDa molecular mass, have been identified in epithelial cells, cataloged, and assigned a number. The keratins are separated into acidic (type I, cytokeratins K10 to K20) and basic to neutral (type II, cytokeratins K1 to K9) subfamilies based on their isoelectric points,
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immunoreactivity, and sequence homologies with type I and type II wool keratins.15,16 Keratins assemble into filaments both within cells and when reconstituted in vitro as obligate heteropolymers, meaning that a member of each family (acidic and basic) must be coexpressed in order to form the filament structure. The coexpression of specific keratin pairs is dependent on cell type, tissue type, developmental stage, differentiation stage, and disease condition. Thus, understanding how keratin expression is regulated provides insight into epidermal differentiation.17,18
Layers of the Epidermis The basal layer, or stratum germinativum, contains mitotically active, columnar-shaped keratinocytes that attach to the basement membrane zone and give rise to cells of the more superficial epidermal layers. Basal cells contain a large nucleus with typical housekeeping organelles, including Golgi, rough endoplasmic reticulum, mitochondria, lysosomes, and ribosomes. In addition, there are membrane-bound vacuoles that contain pigmented melanosomes transferred from melanocytes by phagocytosis.19 The keratin filaments in basal cells are in fine bundles organized around the nucleus, and they insert into desmosomes and hemidesmosomes. The K5 and K14 pair of keratins are expressed in the basal layer of the epidermis and other stratifying epithelia. Other keratins are expressed in small subpopulations of basal keratinocytes, including K15 and K19, which are associated with putative stem cells.20,21 Microfilaments (actin, myosin, and α-actinin) and microtubules are other cytoskeletal elements present in basal cells. Some of the microfilamentous components of the cytoskeleton are also important links with the external environment via their association with the integrin receptors present on basal keratinocytes. Integrins are a large family of cell surface molecules involved in cell-cell and cell-matrix interactions, including adhesion and initiation of terminal differentiation.22 Based on cell kinetic studies, 3 populations coexist within the basal layer: stem cells, transient amplifying cells, and postmitotic cells. Functional evidence for the existence of long-lived epidermal stem cells comes from both in vivo and in vitro studies.23,24 Because epidermal cells isolated from small biopsy specimens can be expanded in tissue culture and can be used to reconstitute sufficient epidermis to cover the entire skin surface of burn patients, such a starting population must contain long-lived stem cells with extensive proliferative potential. The tissue localization of putative epidermal stem cells has been based in part on stem cell characteristics defined in other self-renewing systems, such as bone marrow and fetal
liver. Under stable conditions, stem cells cycle slowly; only under conditions requiring more extensive proliferative activity, such as during wound healing or after exposure to exogenous growth factors, do stem cells undergo multiple, rapid cell divisions. A large amount of data supports the existence of multipotent epidermal stem cells within the bulge region of the hair follicle based on these traits. Additional evidence suggests that a subpopulation of surface epidermal basal cells also possesses stem cell characteristics.25,26,27 The second type of basal cell, the transient amplifying cells of the stratum germinativum, arise as a subset of daughter cells produced by the infrequent division of stem cells. These transient amplifying cells provide the bulk of the cell divisions needed for stable self-renewal and are the most common cells in the basal compartment. After undergoing several cell divisions, these cells give rise to the third class of epidermal basal cells, the postmitotic cells. It is the postmitotic cells that undergo terminal differentiation, detaching from the basal lamina and migrating superficially, ultimately differentiating into a corneocyte. In humans, the normal transit time for a basal cell, from the time it detaches from the basal layer to the time it enters the stratum corneum, is at least 14 days. Transit through the stratum corneum and desquamation requires another 14 days.28,29 These 3 functional classes of epidermal basal cells (stem cells, transient amplifying cells, and postmitotic cells) are difficult to distinguish in situ based solely on morphology or protein expression. The term “epidermal proliferative unit” has been used to describe vertical columns of progressively differentiating cells in the epidermis.30 The shape, structure, and subcellular properties of spinous cells correlate with their position within the midepidermis. They are named for the spinelike appearance of the cell margins in histologic sections. Suprabasal spinous cells are polyhedral in shape and have a rounded nucleus. Cells of the upper spinous layers are larger, more flattened, and contain organelles called lamellar granules. The cells of all spinous layers contain large and conspicuous bundles of keratin filaments. As in basal cells, the filaments are organized concentrically around the nucleus and insert into desmosomes peripherally.31 The “spines” of spinous cells are the abundant desmosomes, calcium-dependent cell surface modifications that promote adhesion of epidermal cells and resistance to mechanical stresses. The molecular components of the desmosome have been well characterized.32 Within each cell there is a desmosomal plaque associated with the internal surface of the plasma membrane. It is composed of 6 polypeptides: plakoglobin, desmoplakins I and II, keratocalmin, desmoyokin, and band 6 protein. Transmembrane glycoproteins of the cadherin family provide the adhesive properties
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S KIN: S T R UC T UR E , DE VE L OP M E NT, AND H E A L I N G on the external surface or core of the desmosome. These glycoproteins include desmogleins 1 and 3 and desmocollins I and II. The extracellular domains of these proteins form part of the core. The intracellular domains insert into the plaque, linking them to the intermediate filament (keratin) cytoskeleton. E-cadherins, which are characteristic of adherens junctions, are associated with actin filaments via interaction with the catenins and may regulate the organization of adherens junctions and influence epidermal stratification. The differences in the proteins in the 2 types of cell attachment structures may be related to specific requirements for the adherens junction-actin relationship, as compared with the association of the desmosome proteins and keratin intermediate filaments.33,34,35 Lamellar granules deliver precursors of stratum corneum lipids into the intercellular space. The granules are first evident in the cytoplasm of the upper spinous cells, even though the primary site of their activity is at the granular-cornified layer interface.36 They are 0.2 μm to 0.3 μm in diameter, membrane-bound, secretory organelles that contain a series of alternating thick and thin lamellae; these are folded sheets or disklike or liposomelike structures. Lamellar granules contain glycoproteins, glycolipids, phospholipids, free sterols, and a number of acid hydrolases, including lipases, proteases, acid phosphatase, and glycosidases. Glucosylceramides, the precursors to ceramides and the dominant component of the stratum corneum lipids, are found in lamellar granules. The enzymes indicate that lamellar granules are a type of lysosome with characteristics of both secretory granules and liposomes. Roles for the lamellar granule in providing the epidermal lipids responsible for the barrier properties of the stratum corneum, the synthesis and storage of cholesterol, and the adhesion/desquamation of cornified cells have been hypothesized.37,38 The granular layer is characterized by the buildup of components necessary to the process of programmed cell death and the formation of a superficial water-impermeable barrier.39 The typical cytoplasmic organelles associated with an active synthetic metabolism are still evident within cells of the stratum granulosum, but the most apparent structures within these cells are the basophilic, keratohyalin granules. Keratohyalin granules are composed primarily of an electron-dense protein, profilaggrin, and keratin intermediate filaments. Loricrin, a protein of the cornified cell envelope, is also found within the keratohyalin granule.40 Other protein markers of keratinization are components of the cornified cell envelope (CE), a 7 nm- to 15 nm-thick dense protein layer deposited beneath the plasma membrane of cornified cells. Proteins of the CE constitute a significant fraction of the protein in the granular cell and are rendered insoluble by cross-linking via disulfide bonds and
(γ-glutamyl) lysine isopeptide bonds formed by transglutaminases. Involucrin, keratolinin, loricrin, small proline-rich proteins, the serine protease inhibitor elafin (SKALP), filaggrin linker-segment peptide, and envoplakin have all been found as components of the CE.41 The granular cell not only synthesizes, modifies, and/ or cross-links new proteins involved in keratization, it also plays a role in its own programmed destruction. This occurs during the abrupt transition from a granular cell to a terminally differentiated cornified cell. The change involves the loss of the nucleus and virtually all of the cellular contents, with the exception of the keratin filaments and filaggrin matrix.42 Complete transition from a granular to a cornified cell is accompanied by a 45% to 85% loss in dry weight. The layers of resultant cornified, or horny, cells provide mechanical protection to the skin and a barrier to water loss and permeation of soluble substances from the environment. The stratum corneum barrier is formed by a 2-component system of lipid-depleted protein-enriched corneocytes surrounded by a continuous extracellular lipid matrix. The flattened, polyhedral-shaped cell is the largest cell of the epidermis. Its shape and surface features are adapted to maintain the integrity of the stratum corneum yet allow for desquamation. High molecular mass keratins stabilized by intermolecular disulfide bonds account for up to 80% of the cornified cell. The remainder of the cell content appears to be an electron-dense matrix material, probably filaggrin, surrounding the filaments. The nucleus is lost from normal stratum corneum cells, but it persists in incompletely keratinized cells, as seen in psoriasis. Remnants of organelles, especially profiles of membranes and melanin pigment, are occasionally present within the normal cell.43,44 A rigid CE borders the outer stratum corneum cells. The stratum corneum cell retains some metabolic functions and thus is not the inert covering it has been previously considered.45
Nonkeratinocytes of the Epidermis The melanocyte is a dendritic, pigment-synthesizing cell derived from neural crest that is confined mainly to the basal layer.46 In postnatal skin, the cell body of the melanocyte often extends toward the dermis below the level of the basal cell, but always superior to the lamina densa. Melanocyte processes contact keratinocytes in basal and more superficial layers but do not form junctions with them at any level. Melanocytes are recognized light microscopically by their palestaining cytoplasm, ovoid nucleus, and the intrinsic color of the pigment-containing melanosomes. Differentiation of the melanocyte correlates with the acquisition of its primary functions: melanogenesis, arborization, and transfer of pigment to keratinocytes.47,48 The melanosome is the distinctive organelle
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of the melanocyte. It is resolved at the ultrastructural level as an ovoid, membrane-bound structure within which a series of receptor-mediated, hormone-stimulated, enzyme-catalyzed reactions produce melanin.49 There are important organizational relationships and functional interactions between keratinocytes and melanocytes that the melanocyte depends on for differentiation and function.50 Approximately 36 basal and suprabasal keratinocytes are thought to coexist functionally with each melanocyte in an epidermal-melanin unit, an organizational system that is mimicked in vitro when the 2 cell types are co-cultured. Within this aggregate, melanocytes transfer pigment to associated keratinocytes. As a result, pigment is distributed throughout the basal layer and, to a lesser extent, the more superficial layers, where it protects the skin by absorbing and scattering potentially harmful radiation.51 Merkel cells are slow-adapting, type I mechanoreceptors located in sites of high tactile sensitivity. They are present among basal keratinocytes in particular regions of the body.52 Merkel cells receive stimuli as keratinocytes are deformed and respond by secretion of chemical transmitters. They are found both in hairy skin and in the glabrous skin of the digits, lips, regions of the oral cavity, and the outer root sheath of the hair follicle. In some of these sites, they are assembled in specialized structures called tactile discs or touch domes. Like other nonkeratinocytes, Merkel cells have a pale-staining cytoplasm. The nucleus is lobulated, and the margins of cells project cytoplasmic “spines” toward keratinocytes.53 Merkel cells make synaptic contacts with nerve endings to form the Merkel cell-neurite complex. New evidence suggests that Merkel cells are the mechanoreceptors while the nerve terminals transduce the transient phase. The morphology of the contacting membranes of both the Merkel cell and neurite is similar to the presynaptic and postsynaptic modifications that are characteristic of a synapse. Moreover, the presence of neurotransmitterlike substances in the dense core granules suggests that the Merkel cell is the receptor that transmits a stimulus to the neurite via a chemical synapse.54 Langerhans cells are bone marrow–derived, antigenprocessing, and antigen-presenting cells that are involved in a variety of T cell responses.55 The Langerhans cell is not unique to the epidermis: it is found in other squamous epithelia, including the oral cavity, esophagus, and vagina; in lymphoid organs such as the spleen, thymus, and lymph node; and in the normal dermis.56 Langerhans cells migrate from the bone marrow to the circulation into the epidermis early in embryonic development and continue to repopulate the epidermis throughout life.56 Langerhans cells are the primary cells in the epidermis responsible for the recognition, uptake, processing, and presentation of soluble antigen and haptens to sensitized T lymphocytes and
are implicated in the pathologic mechanisms underlying allergic contact dermatitis, cutaneous leishmaniasis, and human immunodeficiency virus infection.57
Dermal-Epidermal Junction The dermal-epidermal junction (DEJ) is a basement membrane zone that forms an interface between the epidermis and dermis. The major function of the DEJ is to attach the epidermis and dermis to each other and to provide resistance against external sheering forces. It serves as a support for the epidermis, determines the polarity of growth, directs the organization of the cytoskeleton and basal cells, provides developmental signals, and serves as a semi-penetrable barrier. The structures of the DEJ are almost entirely products of basal keratinocytes, with minor contributions from dermal fibroblasts.26,58 The DEJ can be subdivided into 3 supramolecular networks: the hemidesmosome-anchoring filament complex, the basement membrane itself, and the anchoring fibrils. The localization of antigens, determination of composition, and the known affinities of matrix molecules present in the basement membrane zone for other matrix molecules (laminin and type IV collagen) are the basis for the structural models of this region of the skin and define its function and physical properties. The subdivisions coincide with areas of weakness that can result in dermal-epidermal separation under circumstances of physical stress, genetic disease, an autoimmune process, or trauma.59 The hemidesmosome-anchoring filament complex binds basal keratinocytes to the basement membrane. The importance of these structures and molecules in maintaining the integrity of the skin can be surmised from inherited and acquired disorders of the skin in which they are either destroyed, altered, or absent, thereby resulting in dermalepidermal separation.59 A similar, although more superficial blistering within the plane of the basal epidermal layer, occurs in patients with the various forms of epidermolysis bullosa simplex caused by mutations in genes that code for the K5 and/or K14 basal cell keratins or other structural proteins specific for this layer.59
The Dermis The dermis is an integrated system of fibrous, filamentous, and amorphous connective tissue that accommodates nerve and vascular networks, epidermally derived appendages, fibroblasts, macrophages, mast cells, and other blood-borne cells, including lymphocytes, plasma cells, and leukocytes, that enter the dermis in response to various stimuli. Dermis makes up the bulk of the skin and provides its pliability, elasticity, and tensile strength. It protects the body from
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S KIN: S T R UC T UR E , DE VE L OP M E NT, AND H E A L I N G mechanical injury, binds water, aids in thermal regulation, and includes receptors of sensory stimuli. The dermis interacts with the epidermis in maintaining the properties of both tissues, collaborates during development in the morphogenesis of the DEJ and epidermal appendages (teeth, nails, sebaceous structures, and sweat glands), and interacts in repairing and remodeling the skin as wounds are healed.60 Collagen and elastic connective tissue are the main types of fibrous connective tissue of the dermis. Collagen is the major dermal constituent. It accounts for approximately 75% of the dry weight of the skin and provides both tensile strength and elasticity. The periodically banded, interstitial collagens (types I, III, and V) account for the greatest proportion of the collagen in the adult dermis. Approximately 80% to 90% of the collagen is type I collagen, and 8% to 12% is type III collagen. Type V collagen, although less than 5%, co-distributes and assembles into fibrils with both types I and III collagen, in which it is believed to assist in regulating fibril diameter. Type V collagen is polymorphic in structure (granules, filaments) and has been immunolocalized primarily to the papillary dermis and the matrix surrounding basement membranes of vessels, nerves, epidermal appendages, and at the DEJ.61 Type IV collagen of the skin is confined to the basal lamina of the DEJ vessels and epidermal appendages.61 The elastic connective tissue is a complex macromolecular mesh, assembled in a continuous network that extends from the lamina densa of the DEJ throughout the dermis and into the connective tissue of the hypodermis. Its organization and importance in the dermis is best appreciated when examining samples of skin that have been digested to remove the collagen and other structures of the dermis but retain the extraordinarily stable elastic fibers. Elastic fibers return the skin to its normal configuration after being stretched or deformed. Elastic fibers are also present in the walls of cutaneous blood vessels and lymphatics and in the sheaths of hair follicles. By dry weight, elastic connective tissue accounts for approximately 4% of the dermal matrix protein.62,63 Elastic fibers have microfibrillar and amorphous matrix components. Several glycoproteins have been identified as constituents of the microfibrils. Among the most characterized of these molecules is fibrillin, a 350 kDa molecule. Mutations in fibrillin have been identified in patients with Marfan’s syndrome, an inherited connective tissue disease in which patients frequently die of aneurysm of the aorta.63 Several filamentous or amorphous matrix components are present in the dermis between the fibrous matrix elements, associated with the fibers themselves, organized on the surface of cells and in basement membranes. Proteoglycans (PG) and glycosaminoglycans (GAG) are the molecules of the “ground substance” that surrounds and embeds the fibrous components. They account for up to 0.2% dry
weight of the dermis. PGs are unusually large molecules (100–2500 kDa) consisting of a core protein that is specific for the molecule and that determines which GAGs will be incorporated into the molecule. Hyaluronic acid usually binds to the core protein. The PGs/GAGs can bind up to 1000 times their own volume and thus regulate the waterbinding capabilities of the dermis and influence dermal volume and compressibility; they also bind growth factors and link cells with the fibrillar and filamentous matrix, thereby influencing proliferation, differentiation, tissue repair, and morphogenesis. They are components of basement membranes and are present on surfaces of mesenchymal and epithelial cells.64,65 The major PGs in the adult dermis are chondroitin sulfates/dermatan sulfates (biglycan, decorin, versican), heparan sulfate proteoglycans, and chondroitin-6 sulfate proteoglycans.65 Fibronectin (in the matrix), laminin (restricted to basement membranes), thrombospondin, vitronectin, and tenascin are glycoproteins found in the dermis, and like the PGs/ GAGs, they interact with other matrix components and with cells through specific integrin receptors.66,67 As a consequence of their binding to other glycoproteins, collagen and elastic fibers, PGs, and cells, glycoproteins are involved in cell attachment (adhesion), migration, spreading in vitro, morphogenesis (epithelial-mesenchymal interactions), and differentiation.68 Fibronectin is an insoluble, filamentous glycoprotein synthesized in the skin by both epithelial and mesenchymal cells; it ensheaths collagen fiber bundles and the elastic network, is associated with basal laminae, and appears on the surface of cells, where it is bound to the cell through 1 of multiple integrin receptors that mediate cell-matrix adhesion. Fibronectin also binds platelets to collagen, is found in fibrin-fibrinogen complexes, and plays a role in organizing the extracellular matrix.69 The dermis is organized into papillary and reticular regions; the distinction of the 2 zones is based largely on their differences in connective tissue organization, cell density, and nerve and vascular patterns.70 Subdivisions of each of these regions are more or less apparent in mature skin, depending upon the individual. The papillary dermis is proximal to the epidermis, molds to its contours, and is usually no more than twice its thickness. The reticular dermis is the dominant region of the dermis and of the skin as a whole. A horizontal plane of vessels, the subpapillary plexus, marks the boundary between the papillary and reticular dermis. The deep boundary between the dermis and the hypodermis is defined by the transition from fibrous to adipose connective tissue.71 The papillary dermis is characterized by small bundles of small-diameter collagen fibrils and elastic fibers. Mature elastic fibers are usually not found in the normal papillary
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dermis. The papillary dermis also has a high density of fibroblasts that proliferate more rapidly, have a higher rate of metabolic activity, and synthesize different species of PGs as compared to those of the reticular dermis. Capillaries extending from the subpapillary plexus project toward the epidermis within the dermal papillae, fingerlike projections of papillary dermis that interdigitate with the rete pegs that project from the epidermis into the dermis.72 The reticular dermis is composed primarily of large-diameter collagen fibrils organized into large, interwoven fiber bundles. Fibroblasts, macrophages, and mast cells are regular residents of the dermis. They are found in greatest density in normal skin in the papillary region and surrounding vessels of the subpapillary plexus, but they also reside in the reticular dermis, where they are found in the interstices between collagen fiber bundles. Small numbers of lymphocytes collect around blood vessels in normal skin, and at a site of inflammation, lymphocytes and other leukocytes from the blood are prominent. Pericytes and veil cells ensheath the walls of blood vessels, and Schwann cells encompass nerve fibers.73 The fibroblast is a mesenchymally derived cell that migrates through the tissue and is responsible for the synthesis and degradation of fibrous and nonfibrous connective tissue matrix proteins and a number of soluble factors.74 Most commonly, the function of fibroblasts is to provide a structural extracellular matrix framework as well as to promote interaction between epidermis and dermis by the synthesis of soluble factors.60 The same fibroblast is capable of synthesizing more than 1 type of matrix protein simultaneously. The morphology of the fibroblast often suggests active synthetic activity; the cytoplasm includes multiple profiles of dilated rough endoplasmic reticulum and typically more than 1 Golgi complex.75 The monocytes, macrophages, and dermal dendrocytes are a heterogeneous collection of cells that constitute the mononuclear phagocytic system of cells in the skin. Macrophages have an expansive list of functions. They are phagocytic; they process and present antigen to immunocompetent lymphoid cells; they are microbicidal (through the production of lysozyme, peroxide, and superoxide), tumoricidal, secretory (growth factors, cytokines, and other immunomodulary molecules), and hematopoietic; and they are involved in coagulation, atherogenesis, wound healing, and tissue remodeling.73,76 Mast cells are specialized secretory cells distributed in connective tissue throughout the body, typically at sites adjacent to the interface of an organ and the environment. In the skin, mast cells are present in greatest density in the papillary dermis, near the DEJ, in sheaths of epidermal appendages, and around blood vessels and nerves of the subpapillary plexus.77 The surface of dermal mast cells is modified by microvilli, and like fibroblasts, they are coated
with fibronectin, which probably assists in securing the cells within the connective tissue matrix. Mast cells originate in the bone marrow from CD34 stem cells. Mast cell proliferation depends on the c-kit receptor and its ligand, SCF (stem cell factor).78 Like basophils, mast cells also contain metachromatic granules and stores of histamines; both cells synthesize eosinophilic chemotactic factor and have IgE antibodies bound to their plasma membranes. Mast cells synthesize an impressive repertoire of mediators. Some of them are preformed and stored in the granules. Histamine, heparin, tryptase, chymase, carboxypeptidase, neutrophil chemotatctic factor, and eosinophilic chemotactic factor of anaphylaxis are organized in the predominantly proteoglycan milieu of the granule in a manner that is suggested to retain enzymes in an inactive state prior to release.77 The mast cell synthesizes and releases other molecules without storage, including a number of growth factors, cytokines (IL-1, IL-3, IL-4, IL-5, GM-CSF, and TNF-α), leukotrienes, and platelet-activating factors. Lysosomal granules in the cells contain acid hydrolases that degrade GAGs, PGs, and complex glycolipids intracellularly. Several additional enzymes are present in both the lysosomal and the secretory granules. These may be important in initiating the repair of damaged tissue and/or may help in degrading foreign material.78 The dendrocyte is a stellate, or sometimes spindleshaped, highly phagocytic mixed connective tissue cell in the dermis of normal skin. Dermal dendrocytes are not specialized fibroblasts, but rather represent a subset of antigenpresenting macrophages or a distinct lineage that originates in the bone marrow. Similar to many other bone marrow– derived cells, dermal dendrocytes express factor XIIIa and the HLe-1 (CD45) antigen, and they lack typical markers of the fibroblastic cell (Te-7).79 These cells are particularly abundant in the papillary dermis and upper reticular dermis, frequently in the proximity of vessels of the subpapillary dermis. Dermal dendrocytes are also present around vessels in the reticular dermis and in the subcutaneous fat. The number of dermal dendrocytes is elevated in fetal, infant, photoaged, and select pathologic adult skin and in association with sites of angiogenesis. Dermal dendrocytes are immunologically competent cells that function as effector cells in the afferent limb of an immune response.80
Cutaneous Vasculature The dermal microvascular unit represents an intricate assemblage of cells responsible not only for cutaneous nutrition but also for immune cell trafficking, regulation of vessel tone, and local hemostasis. The dermal microvasculature is divided into 2 important strata. First, the superficial vascular plexus defines the boundary between the papillary
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S KIN: S T R UC T UR E , DE VE L OP M E NT, AND H E A L I N G and reticular dermis and extends within an adventitial mantle to envelop adnexal structures. This subpapillary plexus forms a layer of anastomosing arterioles and venules in close approximation to the overlying epidermis and is normally surrounded by other cellular components of the dermal microvascular unit. Small capillary loops emanate from the superficial vascular plexus and extend into each dermal papilla. The capillaries that are present throughout the dermis, but especially in the papillary dermis, are composed of a layer of endothelial cells surrounded by an incomplete layer of pericytes. The second plexus, the deep vascular plexus, is connected to the first by vertically oriented reticular dermal vessels and separates the reticular dermis from the subcutaneous fat. Many of these vessels are of larger caliber and communicate with branches that extend within fibrous septa that separate lobules of underlying subcutaneous fat.81,82 A special vascular structure, the glomus, is located within the reticular dermis in certain areas. Glomus formations occur most abundantly in the pads and nail beds of the fingers and toes, but also on the volar aspect of the hands and feet, in the skin of the ears, and in the center of the face. The glomus is concerned with temperature regulation. It represents a special arteriovenous shunt that, without the interposition of capillaries, connects an arteriole and a venule. When open, these shunts cause a great increase in blood flow in the area.83
Cutaneous Lymphatics The lymph channels of the skin are important in regulating pressure of the interstitial fluid by resorption of fluid released from vessels and in clearing the tissue of cells, proteins, lipids, bacteria, and degraded substances. Lymph flow within the skin depends upon movements of the tissue caused by arterial pulsations and larger-scale muscle contractions and movement of the body. Bicuspid-like valves within the lymphatic vessels may help prevent backflow and stasis of fluid in the vessels.84 The lymph capillaries drain into a horizontal plexus of larger lymph vessels located deep in the subpapillary venous plexus. Lymph vessels can be distinguished from blood vessels in the same position by a larger luminal diameter (often difficult to see in their normally collapsed state in the skin) and thinner wall that consists of an endothelium, discontinuous basal lamina, and elastic fibers.84
receptors of touch, pain, temperature, itch, and mechanical stimuli. The density and types of receptors are regionally variable and specific, thus accounting for the variation in acuity at different sites of the body. Receptors are particularly dense in hairless areas such as the areola, labia, and glans penis. Sympathetic motor fibers are co-distributed with the sensory nerves in the dermis until they branch to innervate the sweat glands, vascular smooth muscle, arrector pili muscle of the hair follicles, and sebaceous glands.85 The skin is innervated by large, myelinated cutaneous branches of musculocutaneous nerves that arise segmentally from spinal nerves. Small branches that enter the deep dermis are surrounded by an epineurial sheath; perineurial and endoneurial sheaths and Schwann cells envelop fiber bundles and individual fibers, respectively. The pattern of nerve fibers in the skin is similar to the vascular patterns. Nerve fibers form a deep plexus, then ascend to a superficial, subpapillary plexus.86 The sensory nerves, in general, supply the skin segmentally (dermatomes), but the boundaries are imprecise and there is overlapping innervation to any given area. Autonomic innervation does not follow exactly the same pattern because the postganglionic fibers distributed in the skin originate in sympathetic chain ganglia where preganglionic fibers of several different spinal nerves synapse.85 Free nerve endings are the most widespread and undoubtedly the most important sensory receptors of the body. In humans, they are always ensheathed by Schwann cells and a basal lamina. Free nerve endings are particularly common in the papillary dermis just beneath the epidermis, and the basal lamina of the fiber may merge with the lamina densa of the basement membrane zone.86 Corpuscular receptors have a capsule and an inner core and contain both neural and nonneural components. The capsule is a continuation of the perineurium, and the core includes preterminal and terminal portions of the fiber surrounded by laminated wrappings of Schwann cells. The Meissner’s corpuscle is an elongated or ovoid mechanoreceptor located in the dermal papilla of digital skin and oriented vertically toward the epidermal surface. The Pacinian corpuscle lies in the deep dermis and subcutaneous tissue of skin that covers weight-bearing surfaces of the body. Pacinian corpuscles serve as rapidly adapting mechanoreceptors responding to vibrational stimuli.87,88
Skin Appendages Nerves and Receptors The nerve networks of the skin contain somatic sensory and autonomic fibers. The sensory fibers alone (free nerve endings) or in conjunction with specialized structures (corpuscular receptors) function at every point of the body as
The hair follicle, with its hair in longitudinal section, consists of 3 parts: the lower portion, extending from the base of the follicle to the insertion of the arrector pili muscle; the middle portion, or isthmus, a rather short section, extending from the insertion of the arrector pili to the entrance
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of the sebaceous duct; and the upper portion, or infundibulum, extending from the entrance of the sebaceous duct to the follicular orifice. The lower portion of the hair follicle is composed of 5 major portions: the dermal hair papilla; the hair matrix; the hair, consisting inward to outward of medulla, cortex, and hair cuticle; the inner root sheath, consisting inward to outward of inner root sheath cuticle, Huxley layer, and Henle layer; and the outer root sheath.89 It has been proposed that stem cells lie in a specialized region of the hair follicle outer root sheath (ORS) known as the bulge, and are ultimately responsible for replenishing the differentiated cells of the interfollicular epidermis in addition to generating all the hair lineages.90 The bulge lies beneath the sebaceous gland at the point of insertion of the arrector pili muscle. Communication with the underlying dermis plays an important role in regulating epidermal differentiation, with specialized mesenchymal cells of the dermal papilla at the base of the hair follicle providing the best-characterized microenvironment (often referred to as a niche) both in vivo and in vitro. Growth and differentiation of postnatal hair follicles are controlled by reciprocal interactions between the dermal papilla and the cells of the hair matrix.91,92 In human epidermis of non-hair-bearing skin, basal cells that are not actively cycling and that express several putative stem cell markers are found in clusters that have a specific topology with respect to the underlying connective tissue.93 The stem cell clusters are surrounded by basal cells that are actively cycling and express markers of transient amplifying cells, and it is from within this latter compartment that cells committed to terminal differentiation move into the layers above.94 Sebaceous glands are an appendage of the hair follicle, located above the bulge and arrector pili muscle and just below the hair shaft orifice at the skin surface. Sebaceous gland progenitor cells emerge near the conclusion of embryogenesis, but the gland does not mature until just after birth. The main role of the gland is to generate terminally differentiated sebocytes, which produce lipids and sebum. When sebocytes disintegrate, they release these oils into the hair canal for lubrication and protection against bacterial infections. Sebaceous gland homeostasis necessitates a progenitor population of cells that gives rise to a continual flux of proliferating, differentiating, and, finally, dead cells that are lost through the hair canal.95 The apocrine glands differ from eccrine glands in origin, distribution, size, and mode of secretion. The eccrine glands primarily serve in the regulation of heat, and the apocrine glands represent scent glands. Eccrine glands are present everywhere in the human skin; however, they are absent in areas of modified skin that lack all cutaneous appendages,
that is, the vermillion border of the lips, the nail beds, the labia minora, the glans penis, and the inner aspect of the prepuce. They are found in greatest abundance on the palms and soles and in the axillae. The eccrine sweat gland is engineered for temperature regulation. With approximately 3 million glands in the human integument weighing 35 μg per gland, the average human boasts about 100 g of eccrine glands capable of producing a maximum of approximately 1.8 L of sweat per hour.96 Apocrine glands are encountered in only a few areas: in the axillae, in the anogenital region, as modified glands in the external ear canal (ceruminous glands), in the eyelid (Moll’s glands), and in the breast (mammary glands). Occasionally, a few apocrine glands are found on the face, in the scalp, and on the abdomen; they usually are small and nonfunctional. Apocrine glands develop their secretory portion and become functional only at puberty. The reason for apocrine secretion in humans remains an enigma, although it may simply be an evolutionary vestige (musk glands of the deer and scent glands of the skunk are modified apocrinetype structures).97 The nail unit is a region of specialized keratinization of practical importance, since dermatoses, infections, and neoplasms may affect this site, prompting histologic sampling. The nail unit has 6 main components: (1) the nail matrix, which gives rise to the nail plate; (2) the nail plate; (3) the cuticular system, consisting of the dorsal component, or cuticle, and the distal component, or hyponichium; (4) the nail bed, which includes the dermis and underlying bone and soft tissue beneath the nail plate; (5) an anchoring system of ligaments between bone and matrix proximally and between grooves distally; and (6) the nail folds proximally, laterally, and distally.98
DEVELOPMENT OF SKIN Overview Significant advances in the understanding of the molecular processes responsible for the development of the skin have been made over the last several years. Such advances have significantly broadened our knowledge of wound healing and increased our understanding of the clinicopathologic correlation among inherited disorders of the skin, allowing for the early diagnosis and treatment of such diseases.99 Conceptually, fetal skin development can be divided into 3 distinct but temporally overlapping stages, those of specification, morphogenesis, and differentiation. These stages roughly correspond to the embryonic period (0–60 days), the early fetal period (2–5 months), and the late fetal period (5–9 months) of development. The earliest stage, specification, refers to the process by which the ectoderm lateral
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S KIN: S T R UC T UR E , DE VE L OP M E NT, AND H E A L I N G to the neural plate is committed to become epidermis and subsets of mesenchymal and neural crest cells are committed to form the dermis. It is at this time that patterning of the future layers and specialized structures of the skin occurs, often via a combination of gradients of proteins and cell-cell signals. The second stage, morphogenesis, is the process by which these committed tissues begin to form their specialized structures, including epidermal stratification, epidermal appendage formation, subdivision between the dermis and subcutis, and vascular formation. The last stage, differentiation, denotes the process by which these specialized tissues further develop and assume their mature forms.100 After gastrulation, the embryo surface emerges as a single layer of neuroectoderm, which will ultimately specify the nervous system and skin epithelium. At the crossroads of this decision is Wnt signaling, which blocks the ability of ectoderm to respond to fibroblast growth factors (FGFs). In the absence of FGF signaling, the cells express bone morphogenetic proteins (BMPs) and become fated to develop into epidermis. Conversely, the acquisition of neural fate arises when, in the absence of a Wnt signal, the ectoderm is able to receive and translate activating cues by FGFs, which then attenuate BMP signaling through inhibitory cues. The embryonic epidermis that results consists of a single layer of multipotent epithelial cells. It is covered by a transient protective layer of tightly connected squamous endodermislike cells, known as periderm, which is shed once the epidermis has stratified and differentiated.101,102
Insights From Fetal Wound Healing In mature skin, wound repair typically begins with hemostasis and inflammation. This is followed by a proliferative phase, with reepithelialization, angiogenesis, and collagen production, and ends with the generation of a permanent scar. However, animal studies and clinical observations have shown that a different type of healing occurs in fetal skin in the first 2 trimesters of development. In early fetal skin, wounds exhibit a unique pattern of wound healing leading to regeneration. Notably, repair in the fetus takes place with little or no inflammation, faster reepithelialization, and no scarring.103 Insights into regenerative healing may provide information about how to accelerate postnatal wound healing as well as how to improve healing from a cosmetic standpoint. Future research directions include identification of the molecular controls responsible for scarless healing, with the intention that this new information will lead to improved therapeutic strategies for wound healing.104 As experimental studies have demonstrated, it is evident that fetal wounds heal differently depending upon the gestational age of the fetus. In the first and second trimesters of development, fetal skin undergoes rapid healing with
little or no inflammation and no scarring. Scarless healing in early fetal skin is a form of regeneration, with renewal of skin appendages such as hair follicles and sebaceous glands in addition to the restoration of a normal dermal matrix and no scar. Near the third trimester, a transition period occurs. At this point, the skin begins to lose its ability to regenerate and instead undergoes fibrotic healing similar to that in postnatal skin.105 Pathology reports and basic research studies have shown that scarless healing occurs in fetal skin until around 22 weeks to 24 weeks of gestation in the human fetus.106 The uterine environment in which fetal wounds heal is unique, with amniotic fluid surrounding the healing wounds. Originally, this warm and sterile amniotic fluid, rich in growth factors and extracellular matrix components, was considered imperative for the scarless fetal healing process. Although it has been suggested that the sterile nature of amniotic fluid and anti-inflammatory factors that it contains may help facilitate noninflammatory, scarless healing, the amniotic fluid environment is not required for this process.107 Studies utilizing the developing opossum indicate that amniotic fluid is not essential for scarless healing. In this marsupial model, offspring develop in a pouch instead of a uterine environment, but the developmental process in the pouch resembles the in utero development of a mammalian fetus with scarless healing.108 Transplantation studies have also been used to investigate the importance of amniotic fluid in scarless tissue repair. Studies in sheep have shown that wounds made in adult skin or late gestational fetal skin transplanted onto fetal lambs heal with a scar; therefore, skin beyond the transition to fibrotic healing continues to heal with a scar even if repair takes place in a fetal environment. In addition, early human fetal skin transplanted subcutaneously in nude mice heals without a scar after wounding, demonstrating that scarless healing in fetal skin is independent of amniotic fluid or perfusion by fetal serum.103
Inflammation One of the first distinguishing characteristics of scarless fetal healing identified was a lack of inflammation. A diminished inflammatory response in scarless fetal wounds has been demonstrated repeatedly in many different models of fetal wound healing.109,110 The presence of inflammation during repair is believed to contribute to the transition from scarless to fibrotic healing in fetal skin because a significant inflammatory response to injury does not manifest until the third trimester, when the skin begins to heal with a scar.104,108 Inducing inflammation with killed or live bacteria, chemical agents, or various mediators of inflammation, including cytokines, growth factors, and prostaglandins, in early fetal
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wounds results in the formation of a scar, when normally these wounds would have healed without a scar.111,112 Once the idea that minimal inflammation defined scarless fetal repair was accepted, studies focused on characterizing the specific inflammatory cell types that were missing and determining the mechanisms of reduced inflammation. Virtually all the cells involved in acute inflammation respond differently to injury in early fetal skin, including platelets, neutrophils, macrophages, and lymphocytes.113
Reepithelialization Martin et al, who conducted numerous studies on fetal wound reepithelialization, identified fundamental differences in the mechanics of reepithelialization in embryonic wounds. Although adult wounds have been shown to reepithelialize through extension of lamellipodia followed by epidermal cells at the wound edge crawling over the wound bed, embryonic wounds exhibit no signs of lamellipodia or filopodial extensions. Instead, epidermal cells at the edge of wounds in both chick and mouse embryos assemble an actin cable that contracts like a purse string to close the wound.114,115
Angiogenesis Angiogenesis, the process of new blood vessel growth, is a key element of the proliferative phase of healing in adult wounds. Until recently, no studies quantitatively comparing angiogenesis in early and late fetal wounds were available. Whitby and Ferguson reported a noticeable lack of neovascularization in fetal mouse wounds compared to adult wounds with immunostaining for collagen IV and laminin, both of which stain endothelial basement membranes.116 In addition, in a rat model of fetal wound healing, investigators observed angiogenesis in day 19 fetal wounds but not in day 16 wounds.117 Several proangiogenic factors have been found to be absent or present at lower levels in scarless wounds versus scar-forming wounds, including basic fibroblast growth factor (bFGF), transforming growth factor β1 (TGF-β1), platelet-derived growth factor (PDGF), and prostaglandin E2 (PG E2).118,119 It has also been shown that the addition of substances capable of inducing angiogenesis in early fetal wounds (TGF-β1, PDGF, PGE2, and hyaluronidase) causes scar formation.120,121
Extracellular Matrix The most obvious difference between fetal and adult skin healing is the lack of dermal scar tissue formation. Instead of reducing a scar with a significantly altered extracellular matrix (ECM), fetal skin has the unique ability to lay down
new ECM with a composition and arrangement similar to normal, unwounded skin, complete with the regeneration of hair follicles and other appendages.122 One of the first differences identified in the ECM of fetal wounds is the presence of high levels of glycosaminoglycans (GAGs). Glycosaminoglycans are polysaccharides comprised of repeating acidic and basic disaccharides found at high levels in connective tissues. Important GAGs in the skin include chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, and hyaluronic acid (HA).123 Many initial fetal wound healing studies focused on one particular GAG, hyaluronic acid, which appears to be present at the highest levels in fetal wounds. Hyaluronic acid can influence the structure, assembly, and hydration of the ECM and appears to support cell growth and migration, especially during development. Amniotic fluid has high levels of HA, especially earlier in gestation; high levels of hyaluronic acid stimulating activity (HASA), a factor that promotes HA deposition, also are present in amniotic fluid.124,125 Fetal wounds also have less of the HA degrading enzyme hyaluronidase than adult wounds. Together, the high levels of HA and HASA, combined with low levels of hyaluronidase, are thought to be responsible for the persistent high levels of HA in fetal wounds.126 Collagen production obviously differs between scarless and scar-forming fetal wounds. In the first and second trimesters of development, fetal skin is capable of healing wounds with newly formed collagen in a fine reticular or basket-weave pattern identical to normal skin. This type of collagen network allows for regeneration rather than scar formation and is distinctly different from the thick, disorganized, parallel bundles of collagen that make up scar tissue.127 During normal adult wound repair, extensive ECM remodeling leads to collagen reorganization and formation of a mature scar. The remodeling process consists of both the production and the degradation of collagen and other ECM components; a relative imbalance in this process by either an abnormally high production of collagen or inadequate degradation could result in excessive scarring. According to a review of the subject, matrix metalloproteases (MMPs) and tissue inhibitors of the proteolytic activity of MMPs (TIMPs) are key to maintaining the appropriate balance between matrix production and degradation.128 Bullard et al used immunochemistry to examine MMP levels in a model of subcutaneous transplantation of human fetal skin in immunodeficient mice and reported higher levels of MMP-1 (interstitial collagenase), MMP-2 (gelatinase A), and MMP-3 (stromelysin-1) in midgestation human fetal skin compared to adult skin. In addition, the authors showed that adding TGF-β reduced MMP levels in fetal skin.129 More recently, mRNA levels of a panel of MMPs and TIMPs were
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S KIN: S T R UC T UR E , DE VE L OP M E NT, AND H E A L I N G determined using scarless and fibrotic fetal wound healing in rat skin. Dang et al showed that scarless fetal wounds express MMP-1, MMP-9 (gelatinase B), and MMP-14 (membrane type 1 MMP) more quickly or at higher levels than fibrotic fetal wounds.130
Growth Factors Several growth factors with profibrotic properties have been studied in fetal wound healing. Many of the published fetal wound–healing experiments have focused on TGF-β family members because this family of proteins has been shown to have a defined role in fibrosis.131 Differences in TGF-β expression, with lower levels and rapid clearance of TGF-β1 and TGF-β2 during scarless fetal repair compared to fibrotic healing, have been demonstrated repeatedly. In particular, reduced expression of TGF-β1 in early fetal wounds has been confirmed in incisional and excisional wounds in murine, rat, and human skin. The consistency of these findings in several diverse models suggests that minimal TGF-β1 expression in response to injury is a conserved response in early fetal skin.132 Numerous studies demonstrate that adding TGF-β causes a fibrotic healing response in early fetal skin that would normally heal scarlessly or without fibrosis, further solidifying a role for TGF-β and scar formation. The TGF-β3 isoform, which has antifibrotic effects in adult wounds, is reportedly higher in non-scarring fetal wounds. In addition, TGF-β receptors, TGF-βRI, and TGF-βRII are present at lower levels in scarless fetal wounds than in fibrotic wounds.133,134
Fibroblasts and Myofibroblasts The fibroblast is the primary cell type responsible for determining whether scarless or fibrotic healing will occur; therefore, regenerative fetal healing must ultimately depend on the ability of fetal fibroblasts to produce and arrange new collagen and other ECM components in similar quantities, ratios, and arrangements to unwounded skin. These characteristics appear to be unique to early gestation fetal fibroblasts because skin fibroblasts past the transition period lose the ability to make normal ECM in response to wounding. The critical role of the fetal fibroblast in scarless healing has been highlighted by Lorenz et al.135 Human fetal skin retains the ability to heal scarlessly when transplanted subcutaneously in nude mice but heals with a scar when transplanted as a cutaneous graft. Utilizing antibodies specific for either mouse or human collagen types I and III, the authors demonstrated that the healed dermis in scarless, subcutaneous grafts was made up of human collagen. The collagen contained within the newly formed dermis of
the subcutaneous graft wounds was assessed histologically and found to be arranged in a reticular pattern similar to unwounded skin. The collagen in these scarless wounds was identified as human collagen and as such must have been produced by the human fetal fibroblasts. Conversely, the new matrix in cutaneous grafts that healed with a scar consisted of mouse collagen, suggesting that the murine adult fibroblasts, not the human fetal fibroblasts, were involved in the production of scar tissue. These studies underscore the unique ability of fetal fibroblasts to facilitate scarless healing in the fetus.135 Aside from normal fibroblasts, myofibroblasts, specialized contractile fibroblasts, also can contribute to wound repair. These cells express alpha smooth muscle actin (α-SMA) and are characterized using transmission electron microscopy by a well-developed rough endoplasmic reticulum, nuclei with irregular borders, secretory vesicles denoting active collagen synthesis, and organized microfilament bundles.136 In fetal wounds, myofibroblast numbers appear to correlate with fibrotic healing. Studies in sheep have indicated that myofibroblasts are absent in early scarless fetal wounds but are present during healing at later stages, when permanent scarring occurs.137 A lack of myofibroblasts has been reported in wounded mouse embryos. In addition, adding TGF-β1 to early fetal rabbit wounds induces fibrosis and increases the number of α-SMA-positive myofibroblasts in the wounds, further supporting the association of myofibroblasts with scar formation in fetal wounds.138,139
Developmental Genes A few studies have explored the potential involvement of developmental genes in scarless healing. The bone morphogenetic proteins (BMPs) belong to one family of developmental growth factors involved in skin and hair follicle development. Stelnicki et al demonstrated BMP-2 expression in the epidermis and developing hair follicles of human fetal skin. When exogenous BMP-2 was added to fetal lamb wounds, epidermal growth was augmented and the number of hair follicles and other skin appendages increased. However, fibroblast number and fibrosis also increased.140 Stelnicki et al also found differential regulation of 2 homeobox genes, PRX-2 and HOXB-13, in a model of scarless fetal repair. Expression of PRX-2 was induced during scarless fetal wound healing, in contrast to adult wounds that displayed no increase in expression. In addition, expression of HOXB-13 was reduced during fetal wound healing compared to unwounded skin or adult wounds. Subsequent studies from the same group showed that deletion of the PRX-2 gene altered in vitro wound-healing parameters of fetal but not adult skin fibroblasts, which may have implications for the regulation of scarless healing.141
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The Wnt signaling pathway also is known to be important for skin and hair follicle development. Recently, Colwell et al showed that Wnt-4 is expressed at higher levels in uninjured fetal skin than in postnatal skin. However, Wnt-4 expression increased during the healing of both fetal and postnatal wounds, suggesting that Wnt-4 is not likely to be an important mediator of scar tissue formation.142
Cornified Envelope During the latter part of gestation, epithelial surfaces at environmental interfaces undergo structural and functional changes, including synthesis of complex proteolipid materials. The stratum corneum is generally formed after 23 to 24 weeks of gestation. The formation of a barrier to water loss and infection is a sine qua non for survival in the extrauterine environment. Of note, synthesis and secretion of epidermal barrier lipids occurs in the form of lamellar bodies. This process is similar to that occurring over a parallel time frame in the developing lung.143 The barrier lipids in the epidermis, unlike the lung, are generally devoid of phospholipids and consist primarily of free fatty acids, cholesterol, and ceramides.5 Covalent cross-linking of structural proteins and ceramides results in formation of a highly insoluble cornified envelope, typical of the mature mammalian stratum corneum.45 The cornified envelope, while only 10 nm to 15 nm thick and of uniform density, is highly insoluble, secondary to cross-linking by intracellular transglutaminases.144
Biology of Vernix The development of epidermal barrier function has many similarities to surfactant production and lung development. Both the epidermal keratinocyte and the type 2 alveolar cell are lipid-synthesizing cells that secrete barrier lipids in the form of lamellar bodies. Both interface with a gaseous environment under similar hormonal control at similar periods of development. There is a clear analogy between the mechanisms by which the lung develops a functionally mature epithelial surface ready for air adaptation and those by which the skin surface matures under total aqueous conditions for terrestrial adaptation to a dry environment. An unanswered question in epidermal biology, however, is by which mechanism the epidermal barrier forms under conditions of total aqueous emersion. Prolonged exposure of the skin surface to water in adults is harmful.145 Sebaceous glands are found in the skin of all mammals except whales and porpoises.146 The primary function is the excretion of sebum, which is a complex mixture of relatively nonpolar lipids, most of which are synthesized de novo by the glands.147 In newborn infants, sebaceous glands are well formed, hyperplastic, and macroscopically visible
over certain body areas. The surge in sebaceous gland activity during the last trimester of pregnancy leads to production of a thick, lipid-rich, hydrophobic film (the vernix caseosa) overlying the developing stratum corneum.148 The amniotic fluid becomes turbid during the last trimester of pregnancy. In vitro, the addition of physiologically relevant amounts of pulmonary surfactant leads to emulsification and release of immobilized vernix. This finding is consistent with a mechanism by which vernix is progressively released from the skin surface after formation of an intact stratum corneum under the influence of lung-derived surfactant within the amniotic fluid. The fetus subsequently swallows the detached vernix. Measurements of the amino acids of vernix have demonstrated that it is rich in glutamine, a known trophic factor for the developing gut. Further work is required to establish the degree to which epithelial surfaces “cross-talk” in preparation for birth.149,150
NORMAL WOUND HEALING Phases Wound healing is a dynamic, interactive process involving soluble mediators, blood cells, extracellular matrix, and parenchymal and stem cells. Wound healing has 3 phases— inflammation, proliferation, and maturation—that overlap in time. During the first 4 to 5 days after closing an incision, little change in wound strength is noted. During this time, inflammatory cells invade the incision, so it is called the inflammatory or lag phase. After this period, there is a rapid increase in collagen content in the incision that is associated with a rapid increase in tensile strength. This phase is called the proliferative or collagen phase. Two key events occur during this phase, the deposition of the ECM and the ingrowth of new vessels. Finally, there is a prolonged phase where the incision continues to gain strength (up to approximately 80% of the original skin) but there is no increase in collagen content. Also during this maturation phase, the wound tends to become less cellular and vascular until a quiescent scar is formed.151
Inflammation Tissue injury causes the disruption of blood vessels and extravasation of blood constituents. The blood clot reestablishes hemostasis and provides a provisional extracellular matrix for cell migration. Platelets not only facilitate the formation of a hemostatic plug but also secrete several mediators of wound healing, such as PDGF, that attract and activate macrophages and fibroblasts.152 However, in the absence of hemorrhage, platelets are not essential to wound healing. Numerous vasoactive mediators and
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S KIN: S T R UC T UR E , DE VE L OP M E NT, AND H E A L I N G chemotactic factors are generated by the coagulation and activated-complement pathways and by injured or activated parenchymal cells. These substances recruit inflammatory leucocytes to the site of injury.153 Infiltrating neutrophils cleanse the wound area of foreign particles and bacteria and are then extruded with the eschar or phagocytosed by macrophages. In response to specific chemoattractants, such as fragments of extracellular-matrix protein, TGF-β, and monocyte chemoattractant protein 1 (MCP-1), monocytes also infiltrate the wound site and become activated macrophages that release growth factors such as PDGF and vascular endothelial growth factor (VEGF), which initiate the formation of granulation tissue. Macrophages bind to specific proteins of the extracellular matrix by their integrin receptors, an action that stimulates phagocytosis of microorganisms and fragments of extracellular matrix by the macrophages.154 Adherence to the extracellular matrix also stimulates monocytes to undergo metamorphosis into inflammatory or reparative macrophages. Adherence induces monocytes and macrophages to express colony-stimulating factor 1 (CSF-1), a cytokine necessary for the survival of monocytes and macrophages; tumor necrosis factor α (TNF-α), a potent inflammatory cytokine; and PDGF, a potent chemoattractant and mitogen for fibroblasts. Other important cytokines expressed by monocytes and macrophages are transforming growth factor α (TGF-α), interleukin-1 (IL-1), TGF-β, and insulin-like growth factor 1 (IGF-1).155 The monocytederived and macrophage-derived growth factors are almost certainly necessary for the initiation and propagation of new tissue formation in wounds, because macrophage-depleted animals have defective wound repair.156 Thus, macrophages appear to have a pivotal role in the transition between inflammation and repair.157
Epithelialization When exposed to physical trauma and chemical assaults, the epidermis must protect itself, which it does by producing copious amounts of cytoplasmic heteropolymers, known as intermediate filaments, that are composed of keratin proteins. As cells exit from the basal layer and begin their journey to the skin surface, they switch from the expression of keratins K5 and K14 to K1 and K10. This switch was discovered more than 25 years ago and remains the most reliable indication that an epidermal cell has undergone a commitment to terminally differentiate.158 The first suprabasal cells are known as spinous cells, reflecting their cytoskeleton of K1/K10 filament bundles connected to robust cellcell junctions known as desmosomes. These connections provide a cohesive, integrative mechanical framework across and within stacks of epithelial sheets. K6, K16, and
K17 are also expressed suprabasally, but only in hyperproliferative situations such as wound healing. This keratin network not only remodels the cytoskeleton for migration but also regulates cell growth through binding to adaptor protein 14–3–3σ and stimulating Akt/mTOR (mammalian target of rapamycin) signaling.159 As spinous cells progress to the granular layer, they produce electron-dense keratohyalin granules packed with the protein profilaggrin, which, when processed, bundles keratin intermediate filaments even more to generate large macrofibrillar cables. In addition, cornified envelope proteins, which are rich in glutamine and lysine residues, are synthesized and deposited under the plasma membrane of the granular cells. When the cells become permeabilized to calcium, they activate transglutaminase, generating γ-glutamyl ε-lysine cross-links to create an indestructible proteinaceous sac to hold the keratin macrofibrils. The final steps of terminal differentiation involve the destruction of cellular organelles, including the nucleus, and the extrusion of lipid bilayers, packaged in lamellar granules, onto the scaffold of the cornified envelope. The dead stratum corneum cells create an impenetrable seal that is continually replenished as inner layer cells move outwards and are sloughed from the skin surface.160
Granulation Tissue Formation New stroma, often called granulation tissue, begins to invade the wound space approximately 4 days after injury. Numerous new capillaries endow the new stroma with its granular appearance. Macrophages, fibroblasts, and blood vessels move into the wound space at the same time.161 Macrophages provide a continuing source of growth factors necessary to stimulate fibroplasia and angiogenesis, the fibroblasts produce the new extracellular matrix necessary to support cell ingrowth, and blood vessels carry oxygen and nutrients necessary to sustain cell metabolism. Growth factors, especially PDGF and TGF-β1, in concert with the extracellular matrix molecules, presumably stimulate fibroblasts of the tissue around the wound to proliferate, express appropriate integrin receptors, and migrate into the wound space.162 The structural molecules of newly formed extracellular matrix, termed the provisional matrix, contribute to the formation of granulation tissue by providing a scaffold or conduit for cell migration. These molecules include fibrin, fibronectin, and hyaluronic acid. In fact, the appearance of fibronectin and the appropriate integrin receptors that bind fibronectin, fibrin, or both on fibroblasts appears to be the rate-limiting step in the formation of granulation tissue.163 The fibroblasts are responsible for the synthesis, deposition, and remodeling of the extracellular matrix.
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Conversely, the extracellular matrix can have a positive or negative effect on the ability of fibroblasts to synthesize, deposit, remodel, and generally interact with the extracellular matrix.162 After migrating into wounds, fibroblasts commence the synthesis of extracellular matrix. The provisional extracellular matrix is gradually replaced with a collagenous matrix, perhaps as a result of the action of TGF-β1.164 Once an abundant collagen matrix has been deposited in the wound, the fibroblasts stop producing collagen and the fibroblast-rich granulation tissue is replaced by a relatively acellular scar. Cells in the wound undergo apoptosis triggered by unknown signals. Dysregulation of these processes occurs in fibrotic disorders such as keloid formation and scleroderma.165
Neovascularization Adult neovascularization has traditionally been thought to be limited to angiogenesis, which can be defined as the sprouting of vessels from preexisting endothelial cells. Prior research has shown that this process is mediated by the release of angiogenic growth factors such as VEGF, PDGF, nitric oxide (NO), and FGF. These factors initiate local changes, including vasodilatation and increased vascular permeability, the activation of resident endothelial cells, and the degradation of the basement membrane. These cytokines/growth factors also stimulate endothelial cell migration and proliferation and the formation of capillary sprouts that ultimately lead to restored perfusion.166 Progenitor cells have been identified in adult bone marrow cells that possess the ability to replace resident cells throughout the human body.167 Tissues in which bone marrow–derived stem cells have been identified include liver, brain, heart, and skeletal muscle.168 While the contribution of progenitor cells is variable, it is becoming increasingly clear that wound healing in adults occurs by both differentiated resident cells and the recruitment of cells from the circulation.169 New blood vessel growth (neovascularization) is a process currently being reevaluated in light of recent advances in progenitor biology. With the identification of circulating endothelial progenitor cells (EPCs), neovascularization is now believed to occur via 2 possible mechanisms: the sprouting of preexisting resident endothelial cells (angiogenesis) or the recruitment of bone marrow–derived EPCs (vasculogenesis).170 The participation of EPCs has been well documented in a number of conditions requiring neovascularization, including peripheral vascular disease, myocardial ischemia, stroke, retinopathy, tumor growth, and wound healing.171,172 This has led to the examination of EPC transplantation in the treatment of ischemic conditions. Since human trials have already been initiated to investigate the
therapeutic and diagnostic utility of EPCs, it is important that their mechanism of action be more fully understood.173 It has been previously reported that EPCs are mobilized from bone marrow into circulation, home to sites of ischemia, undergo in situ differentiation, and ultimately participate in the formation of new blood vessels. This EPC mobilization cascade starts with peripheral hypoxia-induced tissue release of VEGF and subsequent activation of bone marrow stromal nitric oxide synthase (NOS), resulting in increased bone marrow NO levels. In this process, eNOS is essential in the bone marrow microenvironment, and increases in bone marrow NO levels result in mobilization of EPCs from bone marrow niches to circulation, ultimately allowing for their participation in tissue-level vasculogenesis in wound healing. At tissue level, EPC recruitment depends on ischemia-induced upregulation of stromal cell-derived factor-1α (SDF-1α). Impairments in eNOS function have been reported with hyperglycemia, insulin resistance, and in peripheral tissue from diabetic patients.174,175,176
Wound Contraction and Extracellular Matrix Reorganization Wound contraction involves a complex and superbly orchestrated interaction of cells, extracellular matrix, and cytokines. During the second week of healing, fibroblasts assume a myofibroblast phenotype characterized by large bundles of actin-containing microfilaments along the cytoplasmic face of the plasma membrane of the cells and by cell-cell and cell-matrix linkages.177 The appearance of the myofibroblast corresponds with the commencement of connective tissue compaction and the contraction of the wound. The contraction probably requires stimulation by TGF β-1 or β-2 and PDGF, attachment of fibroblasts to the collagen matrix through integrin receptors, and cross-links between individual bundles of collagen.178,179 Collagen remodeling during the transition from granulation tissue to scar is dependent on continued synthesis and catabolism of collagen at a low rate. The degradation of collagen in the wound is controlled by several proteolytic enzymes, termed matrix metalloproteases, which are secreted by macrophages, epidermal cells, and endothelial cells as well as fibroblasts.180 The various phases of wound repair rely on distinct combinations of matrix metalloproteases and tissue inhibitors of metalloproteases (TIMPs).181 Wounds gain only about 20% of their final strength in the first 3 weeks, during which time fibrillar collagen has accumulated relatively rapidly and has been remodeled by contraction of the wound. Thereafter, the rate at which wounds gain tensile strength is slow, reflecting a much slower rate of accumulation of collagen and, more importantly, collagen remodeling with the formation of larger
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S KIN: S T R UC T UR E , DE VE L OP M E NT, AND H E A L I N G collagen bundles and an increase in the number of intermolecular crosslinks.182 Nevertheless, wounds never attain the same breaking strength (the tension at which skin breaks) as uninjured skin. At maximal strength, a scar is only 70% to 80% as strong as normal skin.183
Epithelial-Mesenchymal Transition (EMT) and Endothelial-Mesenchymal Transition (EndMT) Concepts Cell phenotype is the result of the dynamic equilibrium state reached between a cell’s transcription and transduction machinery and the local environment. Cell phenotype transitions involving modulation of cell-cell adhesion occur during both physiological and pathological states. Epithelial cell subpopulations actively downregulate cellcell adhesion systems during embryogenesis and wound healing and leave their “local neighborhood” to move into new microenvironments where they eventually differentiate into distinct cell types.184 Reepithelialization of cutaneous wounds involves extensive modulation of keratinocyte adhesion and motility. Intermediate filaments retract from keratinocyte surfaces, desmosomes and hemidesmosomes associated with these intermediate filaments are disrupted, partial or complete dissolution of the basement membrane occurs, and keratinocytes lose polarity.185 These changes are accompanied by profound alterations in the actin-based cytoskeleton and occur concomitantly with an increase in migratory activity. In the final stages of reepithelialization, reversion to the differentiated epithelial phenotype occurs with formation of stable intercellular and cell-substrate contacts. The events taking place during wound reepithelialization are reminiscent of the developmental process of epithelial-mesenchymal transition (EMT). EMT is a dramatic phenotypic alteration characterized by transformation of anchored epithelial cells into migratory fibroblastlike individualized cells. EMT involves complete dissociation of intercellular adhesion structures (adherens junctions and desmosomes), cell elongation, and reorganization of the cytoskeleton.184 The Snail family of zinc finger transcription factors, including Snail and Slug, is involved in EMT during development. Slug was first described as a transcription factor expressed in cells undergoing EMT during gastrulation and neural crest emergence in chicken.186 Both Snail and Slug induce EMT-like changes when overexpressed in epithelial cell lines, and both repress E-cadherin, a key molecule in cell adhesion, at the transcriptional level in vitro. Reepithelialization in the adult skin shares some features with EMT, such as modulation of the cytokeratin network, marked remodeling of cell-cell adhesion structures, and the emergence of cell motility.187
Traditionally, adult fibroblasts are considered to be derived directly from embryonic mesenchymal cells and to increase in number slowly as a result of the proliferation of resident fibroblasts.188 However, recent studies in organs such as the kidney, lung, and liver and in metastatic tumors have shown that during fibrosis, in addition to the proliferation of resident fibroblasts, bone marrow–derived fibroblasts and epithelial cells contribute to fibroblast accumulation through EMT.189 Endothelial-mesenchymal transition (EndMT) is a form of EMT that occurs during the embryonic development of the heart. The mesenchymal cells that form the atrioventricular cushion, the primordia of the valves and septa of the adult heart, are derived from the endocardium by EndMT. Both EMT and EndMT appear to be important molecular mechanisms involved in wound healing.190
ABNORMAL WOUND HEALING Introduction For decades, hypertrophic scarring, contraction, and pigment abnormalities have altered the future for children and adults after thermal injury. The hard, raised, red and itchy scars, inelastic wounds, and hyperpigmented and hypopigmented scars are devastating to physical and psychosocial outcomes. The specific causes remain essentially unknown, and at present, prevention and treatment are symptomatic and marginal at best.191 Hypertrophic scarring after deep partial-thickness and full-thickness wounds is common. A review of the English literature on the prevalence of hypertrophic scarring reveals that children, young adults, and people with darker, more pigmented skin are particularly vulnerable, and in this subpopulation, the prevalence is as high as 75%.192 Hypertrophic scarring is devastating and can result in disfigurement and scarring that affects quality of life, which in turn can lead to a lowered self-esteem, social isolation, prejudicial societal reactions, and job discrimination. Scarring also has profound rehabilitation consequences, including loss of function, impairment, disability, and difficulties pursuing recreational and vocational pursuits.193,194
Keloid Versus Hypertrophic Scar Keloids and hypertrophic scars are separate clinical and histochemical entities. Clinically, hypertrophic scars remain within the confines of the original scar border, whereas keloids invade adjacent normal dermis. Hypertrophic scars generally arise within 4 weeks, grow intensely for several months, and then regress. In contrast, keloids may appear later, following the initial scar,
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and then gradually proliferate indefinitely. Although both keloids and hypertrophic scars have increased fibroblast density, only keloids have increased fibroblast proliferation rates. Collagen fibers in keloids are larger, thicker, and more wavy than those found in hypertrophic or normal scars and assume a random orientation, whereas those in hypertrophic scars orient parallel to the epidermal surface. Enzyme concentrations, such as alanine transaminase and metabolic activities marked by adenosine triphosphate, are elevated in keloids compared with normal scar tissue and hypertrophic scars. Fibroblasts isolated from keloid and hypertrophic scar tissue exhibit increased gene transcription of α-I procollagen. However, the increased mRNA concentration is compensated at the posttranscriptional level in hypertrophic scars, but not in keloids. The posttranscriptional difference results in an increased ratio of type I to type III collagen found in keloids, but not in hypertrophic scars.195–200
Pathogenesis Numerous hypotheses have been proposed for keloid formation and growth. The exuberant scar tissue found in keloids has been attributed to augmented growth factor activity (TGF-β and PDGF) and alterations in extracellular matrix (fibronectin, hyaluronic acid, and biglycan).201 TGF-β and PDGF are growth factors normally produced during the proliferative phase of wound healing and whose activities are most significantly abnormal in keloids. Keloid fibroblasts have heightened sensitivity to and dysfunctional regulation of TGF-β. Areas of enhanced proliferation and collagen deposition within keloid tissue have distinctly elevated levels of TGF-β. Similarly, keloid fibroblasts have 4-fold to 5-fold increased levels of PDGF receptor, and the growth-stimulatory effects are synergistic with TGF-β.202 The components of the extracellular matrix regulate growth factor activity. The extracellular matrix of keloids is abnormal, with elevated levels of fibronectin and certain proteoglycans and decreased levels of hyaluronic acid.203 Fibronectin and hyaluronic acid are proteins expressed during normal wound healing, and their dysfunctional regulation in keloids contributes to the fibrotic phenotype. Biglycan and decorin are proteoglycans that bind collagen fibrils and influence collagen architecture. Keloids have aberrant production of these proteoglycans, resulting in disorganized extracellular matrix and collagen architecture.204 Epithelial-mesenchymal interactions likely play a fundamental role in keloid pathogenesis. Studies using keratinocyte-fibroblast in vitro co-culture systems have revealed that keloid keratinocytes can induce the keloid phenotype
in normal fibroblasts. Furthermore, histologic changes in the epidermis of abnormal scars in vivo correlate with dermal fibroblast activity.205 Proliferative pathways active in fetal cells and disabled in the adult possibly reemerge in the keloid. Unlike normal adult skin fibroblasts, fetal and keloid tissue can survive and proliferate in vitro in a reduced serum environment.206 Hypoxia detected in keloid tissue has been reported to trigger the release of angiogenic growth factors, spurring endothelial proliferation, delayed wound maturation, and increased collagen production by fibroblasts. The hypoxia appears to be caused by endothelial overgrowth, partially to fully occluding the microvessel lumens in the keloids.207,208 Abnormal regulation of the collagen equilibrium leads to the characteristic physical appearance of a keloid, the large collagenous mass that distinguishes it from normal scar. Collagen content in keloids is elevated compared with normal tissue or scar tissue. Light and electron microscopic studies demonstrate that collagen in keloids is disorganized compared with normal skin. The collagen bundles are thicker and more wavy, and the keloids contain hallmark “collagen nodules” at the microstructural level. The ratio of type I to type III collagen is increased significantly in keloids compared with normal skin or scar, and this difference results from control at both the pretranscriptional and posttranscriptional levels.209 Keloid fibroblasts have a greater capacity to proliferate because of a lower threshold to enter S phase and produce more collagen in an autonomous fashion.210 Matrix metalloproteases and their inhibitors (TIMPs) play a major role in keloid formation. Collagen is degraded by collagenase produced in fibroblasts and in inflammatory cells. Enzymes that inhibit or degrade collagenase exert an additional level of collagen regulation. Concentrations of collagenase inhibitors, alpha-globulins and plasminogen activator inhibitor-1, are consistently elevated in both in vitro and in vivo keloid samples, whereas levels of degradive enzymes are frequently decreased. Steroid-treated and irradiated keloids exhibit a decrease in collagenase inhibitors and an increase in apoptosis in fibroblasts, leading to normalization of net collagen levels.211,212 Furthermore, matrix metalloprotease activity differs between keloid and normal fibroblasts, and these differences appear to directly affect phenotype. Because collagen predominates in the phenotypic appearance of keloids, collagen metabolism and particularly modulation of matrix metalloproteases serve as valuable targets of therapeutic intervention.213 An inherited abnormal immune response to dermal injury may cause keloid formation, as keloids are associated with particular human leukocyte antigen subtypes. Keloids tend to occur in darker-skinned individuals, and familial tendencies suggest a polygeneic inheritance pattern. However,
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S KIN: S T R UC T UR E , DE VE L OP M E NT, AND H E A L I N G darker complexion does not correlate directly with a higher rate of keloid formation, as seen in a study of 175 Malaysian keloid patients.214 A genetic influence is probably directed through an immune phenotype. Studies suggest association of group A blood type and human leukocyte antigen B14, B21, BW35, DR5, and DQW3 in patients with a keloid diatheses.215 Patients who develop keloids have a disproportionately high incidence of allergic diathesis and elevated levels of serum immunoglobin E. Multiple reports have found trends in patterns of serum complement, immunoglobin G, and immunoglobin M levels in patients with keloids, suggesting a systemic immune state genetically predisposed to keloid formation.216 Keloid formation has been considered an autoimmune connective tissue disease. Circulating non-complement-fixing antifibroblast antibodies bind to fibroblasts and stimulate proliferation and collagen production, similar to antithyroid antibodies in Hashimoto’s thyroiditis. Keloids have been found associated with a number of other genetic connective tissue diseases, including Ehlers-Danlos syndrome, progeria, and scleroderma.217 Keloids can arise from an immune reaction to sebum. Dermal injury exposes the pilosebaceous unit to systemic circulation, and in individuals who retain T lymphocytes sensitive to sebum, a cell-mediated immune response is initiated.218 Release of cytokines, in particular interleukins and TGF-β, stimulates mast cell chemotaxis and fibroblast production of collagen. As the keloid expands, further pilosebaceous units on the advancing border are disrupted and the process propagates. Keloids preferentially occur on anatomical sites with high concentrations of sebaceous glands, such as the chest wall, shoulder, and pubic area, and rarely occur on anatomical sites lacking sebaceous glands, such as the palm and the sole. The sebum reaction hypothesis explains why an individual with 2 otherwise identical incisions could develop 1 keloid and 1 normal scar.219 The sebum reaction hypothesis also explains why only human beings, the only mammals with true sebaceous glands, are affected by keloid scarring. Patients with keloids demonstrate a positive skin reaction to intradermal sebum antigen and tend to have a greater resultant weal size than patients without a keloid diathesis. Furthermore, keloids can form following immunization with autologous skin, and a sebum vaccine can successfully desensitize select patients from keloid recurrence following excision.220 The success of radiation therapy and steroids in the treatment of keloids, the former reducing sebum production and the latter inhibiting local lymphocyte activity, is consistent with a sebum reaction as the cause.221 It has been speculated that ablation of the pilosebaceous unit before elective surgical excision may provide prophylaxis against the later formation of keloids.219
BENCH TO BEDSIDE Skin grafts have long been considered the standard for coverage of extensive soft-tissue defects such as burns and chronic wounds. However, autologous donor skin can be scarce, especially in large surface area burns. This has led to the development of alternative methods for wound coverage through tissue engineering of artificial skin.222 Although much research has been performed, artificial skin equivalents have yet to demonstrate comparable clinical results to autologous skin grafts. One of the reasons for this is that the artificial skin lacks an intrinsic blood supply, whereas autologous skin has an extensive microvasculature consisting of, depending on thickness, a subpapillary dermal plexus and ascending capillary loops to the dermal papillae.223,224 Attempts to enhance the process of angiogenesis using various growth factors such as VEGF have yielded an increase in survival and differentiation of endothelial cells in vitro and in vivo, but have not resulted in the production of a true vascularized construct.225,226 With the development of tissue-engineered skin replacements, the process of skin graft revascularization has become particularly relevant. The repeated failure of fabricated skin replacements to adequately revascularize has led to renewed efforts to definitively comprehend the process of autologous skin graft revascularization to tailor the creation of appropriate artificial skin equivalents.227 Early studies of skin graft revascularization suggested an early and direct connection between host and graft vessels (inosculation), before which graft survival was dependent on the process of inbibition (fluid absorption).228 Recent research by Gurtner et al using transgenic rodent technology suggests that the potential mechanism of skin graft neovascularization occurs by means of an ordered process of recipient vascular ingrowth mirrored by donor vascular regression, eventually resulting in reconnection (inosculation) of the 2 separate vascular networks and restoration of circulatory continuity229. In addition, they demonstrated that postnatal vasculogenesis contributes to vascular growth and remodeling in a skin graft model, with up to 20% of new blood vessels formed from bone marrow–derived endothelial progenitor cells. This mechanism provides valuable insight into potential strategies for improving clinical success of larger composite grafts and tissue-engineered constructs.229
CONCLUSION Technologies for various molecular analyses (such as genomics, proteomics, transgenic mice), systems for sustained topical delivery (such as polymers and adenovirus vectors), major advances in tissue engineering (such
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as human skin engineering, cellular matrices, and bone marrow–derived cell therapy), novel discoveries of disease molecular pathogenesis from studies of patient biopsies and animal models, and developments in molecular targeting (in areas such as antisense oligonucleotides, siRNA, antibodies, and small molecules), coupled with breakthroughs in stem cell research, hold the promise of a bright future in wound-healing research. One of the major remaining steps is the integration of these resources into a coordinated effort to make the technology developed at the bench available to burn patients at the bedside.
KEY POINTS • Skin structures: epidermal-dermal junction, cutaneous vasculature, lymphatics, nerves, and appendages. • Skin development including insights from fetal wound healing. • Phases of normal wound healing. • Abnormal wound healing to include keloid and hypertrophic scar pathogenesis. • Current research and promise of the future.
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fetal wound transforming growth factor-beta regulation correlates with collagen organization. Am J Pathol. 2003; 163(6): 2459. the effector cell of scarless fetal skin repair. Plast Reconstr Surg. 1995; 96(6): 1251. 136. Longaker MT, Burd DA, Gown AM, et al. Midgestational
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164. Clark RAF, Nielsen LD, Welch MP, et al. Collagen matrices
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cell trafficking is regulated by hypoxic gradients through H1F-1 induction of SDF-1. Nat Med. 2004; 10: 858. 176. Du XL, Edelstein D, Dimmeler S, et al. Hyperglycemia inhibits endothelial nitric oxide synthase activity by post-translational modification at the Akt site. J Clin Invest. 2001; 108: 1341. 177. Welch MP, Odland GF, Clark RAF. Temporal relationships of F-actin bundle formation, collagen and fibronectin matrix assembly, and fibronectin receptor expression to wound contraction. J Cell Biol. 1990; 110: 133. 178. Montesano R, Orci L. Transforming growth factor-β stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. Proc Natl Acad Sci U S A. 1988; 85: 4894. 179. Chiro JA, Chan BMC, Roswit WT, et al. Integrin α2β1 (VLA-2) mediates reorganization and contraction of collagen matrices by human cells. Cell. 1991; 67: 403. 180. Mignatti P, Rifkin DB, Welgus HG, et al. Proteinases and tissue remodeling. In: Clark RAF, ed. The Molecular and Cellular Biology of Wound Repair. 2nd ed. New York: Plenum Press; 1996: 171–194. 181. Madlener M, Parks WC, Werner S. Matrix metalloproteinases (MMPs) and their physiological inhibitors (TIMPs) are
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201. Pierce GF, Tarpley JE, Yanagihara D, et al. Platelet-derived
growth factor (BB homodimer), transforming growth factorbeta 1, and basic fibroblast growth factor in dermal wound healing: neovessel and matrix formation and cessation of repair. Am J Pathol. 1992; 140: 1375. 202. Younai S, Venters G, Vu S, et al. Role of growth factors in scar contraction: an in vitro analysis. Ann Plast Surg. 1996; 36: 495. 203. Kischer CW, Wagner HN Jr., Pindur J, et al. Increased fibronectin production by cell lines from hypertrophic scar and keloid. Connect Tissue Res. 1989; 23: 279. 204. Hunzelmann N, Anders S, Solberg S, et al. Co-ordinate induction of collagen type I and biglycan expression in keloids. Br J Dermatol. 1996; 135: 394. 205. Andriessen MP, Niessen FB, Van de Kerkhof PC, et al. Hypertrophic scarring is associated with epidermal abnormalities: An immunohistochemical study. J Pathol. 1998; 186: 192. 206. Russell SB, Trupin KM, Rodriguez-Eaton S, et al. Reduced growth-factor requirement of keloid-derived fibroblasts may account for tumor growth. Proc Natl Acad Sci U S A. 1988; 85: 587. 207. Kischer CW. The microvessels in hypertrophic scars, keloids, and related lesions: a review. J Submicrosc Cytol Pathol. 1992; 24: 281. 208. Kischer CW, Thies AC, Chvapil M. Perivascular myofibroblasts and microvascular occlusion in hypertrophic scars and keloids. Hum Pathol. 1982; 13: 819. 209. Younai S, Nichter LS, Wellisz T, et al. Modulation of collagen synthesis by transforming growth factor-beta in keloid and hypertrophic scar fibroblasts. Ann Plast Surg. 1994; 33: 148. 210. Nakaoka H, Miyauchi S, Miki Y. Proliferating activity of dermal fibroblasts in keloids and hypertrophic scars. Acta Derm Venereol. 1995; 75: 102. 211. Luo S, Benathan M, Raffoul W, et al. Abnormal balance between proliferation and apoptotic cell death in fibroblasts derived from keloid lesions. Plast Reconstr Surg. 2001; 107: 87. 212. Tuan TL, Zhu JY, Sun B, et al. Elevated levels of plasminogen activator inhibitor-1 may account for the altered fibrinolysis by keloid fibroblasts. J Invest Dermatol. 1996; 106: 1007. 213. Uchida G, Yoshimura K, Kitano Y, et al. Tretinoin reverses upregulation of matrix metalloproteinase-13 in human keloidderived fibroblasts. Exp Dermatol. 2003; 12: 35. 214. Alhady SM, Sivanantharajah K. Keloids in various races: a review of 175 cases. Plast Reconstr Surg. 1969; 44: 564. 215. Castagnoli C, Peruccio D, Stella M, et al. The HLA-DR beta 16 allogenotype constitutes a risk factor for hypertrophic scarring. Hum Immunol. 1990; 29: 229. 216. Placik OJ, Lewis VL Jr. Immunologic associations of keloids. Surg Gynecol Obstet. 1992; 175: 185. 217. Kazeem AA. The immunological aspects of keloid tumor formation. J Surg Oncol. 1988; 38: 16. 218. Fong EP, Bay BH. Keloids: the sebum hypothesis revisited. Med Hypotheses. 2002; 58: 264. 219. Fong EP, Chye LT, Tan WT. Keloids: time to dispel the myths? Plast Reconstr Surg. 1999; 104: 1199.
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5
C H A P T E R
F I V E
ETIOLOGY OF IMMUNE DYSFUNCTION IN THERMAL INJURIES DAIZHI PENG, MD, PHD, PROFESSOR OF SURGERY, DEPUTY DIRECTOR, INSTITUTE OF BURN RESEARCH, SOUTHWEST HOSPITAL, STATE KEY LABORATORY OF TRAUMA, BURNS AND COMBINED INJURY, THE THIRD MILITARY MEDICAL UNIVERSITY, CHONGQING, PR CHINA WENHUA HUANG, MD, PROFESSOR OF CLINICAL IMMUNOLOGY, INSTITUTE OF BURN RESEARCH, SOUTHWEST HOSPITAL, STATE KEY LABORATORY OF TRAUMA, BURNS AND COMBINED INJURY, THE THIRD MILITARY MEDICAL UNIVERSITY, CHONGQING, PR CHINA
OUTLINE 1. 2. 3. 4. 5. 6.
Introduction Stress Reaction Injured Tissues Ischemia and Hypoxia Bacteria and Their Components Nutritional Deficits
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INTRODUCTION The skin is the largest organ of the body, consisting of epidermal and dermal layers. As the main target tissue of thermal injuries, it provides a formidable, and yet vulnerable, physical barrier. The epidermis consists of keratinocytes, Langerhans cells, intraepidermal lymphocytes, and melanocytes. The dermis contains capillaries and a variety of immune cells, including dendritic cells, macrophages, and dermal lymphocytes.1–3 Comprising a mechanical barrier, the keratinocytes secrete or express a number of cytokines, chemokines, and other bioactive molecules, such as interleukin-1, macrophage inflammatory protein 3α (MIP-3α, CCL20), antimicrobial peptides, and receptor activator of NF-B ligand (RANKL).3–6 RANKL overexpression in keratinocytes results in functional alterations of epidermal dendritic cells and systemic increases of regulatory CD4+ and CD25+ T cells.5 Langerhans cells are attracted to the epidermis from the circulation by CCL20.2 Langerhans and dermal dendritic cells act as antigen-presenting cells to initiate the adaptive immune response in the skin.1,2
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7. Therapeutic Medicines and Host Factors 8. Conclusion 9. Key points 10. Acknowledgments 11. Figure 12. References
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Most of the skin-associated lymphocytes are CD8+ cells with γδ T cell receptors (TCR).7 Therefore, the skin, being the largest innate immune organ, plays an important role in local inherent and adaptive immunities of the host immune system.1–7 Since burn injury directly destroys the skin, the balance between the body and environment is ultimately disturbed. Despite significant advances in intensive care technology and antibiotic administration, infections and multiple organ failure are still the most common lethal complications of major burn patients.8–11 Thermal injury causes not only local changes of the skin wound but also systemic pathophysiological disorders of various systems.12–15 The immunological consequences following severe thermal injury are an important component of the systemic responses of the host. For nearly five decades it has been recognized that burn injury causes marked alterations of immune function, resulting in life-threatening systemic infections, tissue damage, and even death.16–18 Extensive and deep burns have widespread and profound impact on the various cells and molecules of the innate and adaptive immune systems.13–21
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The initial response to a severe burn injury is hyperinflammation, often referred to clinically as the systemic inflammatory response syndrome (SIRS). The function of innate immune cells, such as neutrophils, is suppressed during this period.18–22 The adaptive immune response after burn injury begins with slightly increased lymphocyte activity and immunoglobulin responses, then converts to marked immunodepression of T and B lymphocytes.23–26 Obviously, both innate and adaptive immunity have increased or depressed functions and variable amounts of different cells and molecules throughout the postburn period. The general characteristics of postburn immune dysfunction are a hyperinflammatory and hypoimmune response for the innate and adaptive immunities, respectively.19,21 The main clinical outcomes of postburn immune dysfunction include tissue damage18,22 and increased susceptibility to opportunistic pathogens caused by uncontrolled inflammation and suppressed adaptive immunity.14,17,20 Furthermore, severely burned patients are predisposed to multiple organ damage and infection leading to increased mortality. In order to decrease the morbidity of these lethal complications, the mechanism of postburn immune dysfunction has been studied at both the cellular and molecular level.27,28,29 However, restoration of immune dysfunction after burn injury has been a difficult task due to the complicated and sophisticated interactions among the immune cells and molecules within the immune system. Stress, massive necrotic tissue, shock, infection, malnutrition, and other events sequentially appear in burn patients.8,10,15,16,20,23 Subsequently, seriously burned patients undergo various therapeutic procedures, administration of medications, and surgical manipulations.9,22 Based on etiologic considerations, all of these clinically relevant factors alter the microenvironment of the immune cells and molecules in which they reside, finally causing postburn immune dysfunction. In this chapter, we summarize recent advances of the above-mentioned factors in order to gain a greater understanding of the pathogenesis of this immune dysfunction. More attention should be paid to the immunologic effects of these factors in order to better improve immune function in the comprehensive treatment of seriously burned patients.
STRESS REACTION Complex interactions between the neuroendocrine and immune systems exist. The neuroendocrine system plays a predominant role in the regulation of immune responses, particularly during times of stress. It is well known that the hypothalamus controls the immune functions of the body via the hypothalamic-pituitary-adrenal (HPA) axis.31 Recently, it has been shown that the afferent and efferent vagus
nerve fibers have proinflammatory and anti-inflammatory effects, respectively. Neurotransmitters, neuropeptides, and stress hormones released by the activated autonomic nervous system and HPA axis act on the immune system.32 Various stressors, including wound pain, necrotic tissue, shock, infection, and surgical procedures, can stimulate the neuroendocrine system and elicit stress reactions directed at neutralizing the initial insult to the body. Ample evidence exists regarding the influence of elevated levels of catecholamines, glucocorticoids, and ß-endorphins on spontaneous and mitogen-stimulated lymphocyte proliferation after injury or in vitro coculture.23,33,34 Corticosteroids are also responsible for thymus atrophy and thymocyte apoptosis.23,34,35 Thermal injury with sepsis is associated with both increased monocytopoiesis and increased release of LPS-stimulated macrophage cytokines. These actions are partly mediated by sympathetic activation and increased nerve-stimulated release of norepinephrine from the bone marrow.36
INJURED TISSUES Thermal injury involves the skin and underlying tissues, as well as the lungs when inhalation injury occurs. Immediately after thermal injury, viable tissue in the zone of stasis surrounds heat-coagulated tissue in the center of the burn wound.12 The necrotic and apoptotic tissues caused by heat energy are the major pathogenic factors involved in postburn immune dysfunction. The injured tissues release large numbers of tissue thromboplastin, activated Factor XII, and denatured proteins. The extrinsic and intrinsic blood coagulation systems and complement system are directly activated,18,37,38 followed thereafter by the fibrinolytic and kinin systems. Consequently, inflammatory mediators are generated as products of the activated components from these four systems.37 The injured tissues robustly produce and/or release vasoactive amines and lipid mediators as well as proinflammatory and chemotaxtic cytokines such as histamine, platelet-activated factor (PAF), arachidonic acid products, tumor necrotic factor-α (TNF-α), and interleukin 8.37 The dead and dying cells in necrotic and apoptotic tissues release components of various cellular structures, particularly from the nucleus.39,40 Recently, both host chromosomal high-mobility group box 1 protein (HMGB1) and genomic DNA are thought to trigger an inflammatory response.39,40 From our experiments, we have observed that the elevated level of serum HMGB1 in scalded rats partially contributes to the direct release of dead or necrotic cells from the burn wound (D.P., W.H., unpublished data). These mediators not only initiate the local inflammatory response of thermally injured tissues but are also involved in the inflammation and tissue edema of remote organs when the
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ETIOLOGY OF IM M UNE DYS F UNC T ION IN T HE R M AL I N J U R I E S burn injury is severe enough.37 It has been experimentally proven that inhalation injury affecting one side of lung can induce edema of the other lung as well. Eschar toxin from a burn wound causes inhibition of mitochondrial respiratory function in hepatocytes, eliciting a stronger immunosuppressive effect on antibody formation and cell-mediated immunity than that of lipopolysaccharide (LPS).41,42 The subeschar fluid from burned patients also inhibits lymphocyte proliferation.43 In addition, the extent of burn injury profoundly impacts patient immune status by causing suppressed splenic T-cell proliferation.44 Therefore, burn wounds are not only well recognized as a main source of inflammatory mediators which initiate the hyperinflammatory response, but are also an important arsenal of immunosuppressive substances that induce the hypoimmune response after burns.
ISCHEMIA AND HYPOXIA Burn trauma produces significant fluid shifts that in turn reduce cardiac output and tissue perfusion. Fluid resuscitation restores peripheral perfusion and increases oxygen delivery to previously hypoperfused tissue. While persistent tissue ischemia and hypoxia after burn injury can result in cell death, volume resuscitation may also exacerbate tissue injury by producing oxygen free radicals during reperfusion. Cell death and oxygen free radicals can subsequently initiate tissue inflammation. Hypoxia increases the TNF-α production of monocytes from healthy volunteers, whereas enhanced production of IL-1 and IL-6 only occurs after transient hypoxia and reoxygenation of monocytes.45 Systemic hypoxia induces the microvascular inflammatory response mediated by mast cells.46 Hypoxia also reduces the mitogen-stimulated proliferation and IL-2 and interferon-γ (IFN-γ) release of T cells, but not mitogen-stimulated B cell proliferation.47 Burn trauma upregulates inflammatory cytokine synthesis of IL-1β, IL-6, and TNF-α by parenchymal cells of other tissues such as cardiomyocytes.48 These results provide strong support to the idea that ischemia and hypoxia in lymphoid and other tissues during burn shock and volume resuscitation play a critical role in postburn immune dysfunction.
BACTERIA AND THEIR COMPONENTS Severe burn patients are particularly vulnerable to wound contamination, bacterial colonization, wound sepsis, and systemic infection.8 There is extensive evidence from animal studies that translocation of bacteria and LPS from the intestine to intestinal lymph nodes, liver, and circulation occur in certain circumstances, such as severe burns, hemorrhagic shock, and malnutrition.49 The ability
of pathogens to cause serious inflammation is due to the effects of their structural components acting upon the innate immune system of the host. These include bacterial DNA, proteins (exotoxin and hemolysin), flagella, pili, and LPS from gram-negative bacteria and teichoic acid, lipoteichoic acid, and peptidoglycan from grampositive bacteria.50–52 These components are released when bacterial cells are destroyed during their spontaneous growth and subsequently activate the immune cells, inducing vigorous production of inflammatory mediators by binding the relevant pattern recognition receptors on the surface of these cells.53 The release of bacterial DNA molecules is obviously influenced by the different classes and dosages of antibiotics.52 LPS stimulates the monocytes and macrophages to produce considerable inflammatory cytokines (TNF-α, IL-1, IL-6, IL-8, and HMGB1, a DNA-binding cytokine), anti-inflammatory mediators (IL-10, IL-13, IL-14, transforming growth factor ß [TGF-ß], and nitric oxide [NO]), and breakdown products of arachidonic acid (prostaglandin [PG] E2 and I2, thromboxane [TX] A2 and B2, and leukotrience [LT] C4, D4, and E4 ).37,39,50 LPS also activates components of the complement system and allows them to split into fragments such as C5a, C3a, and C567. Furthermore, LPS enhances glucocorticoid release from the adrenal glands. These factors, including IL-10, TGF-β, NO, and PGE2, have immunosuppressive activities and contribute to the inhibitory effect of LPS on the adaptive immune response. The synergistic effect between bacterial DNA and LPS makes the diverse immunological consequences of LPS more powerful.51 Burn victims with infection exhibit high levels of circulating cytokines such as TNF-α, IL-6, IL-8[55], and HMGB1. The bacterial quorum sensing system is particularly involved in the induction of cytokine expression during Pseudomonas aeruginosa infections of burn wounds.55
NUTRITIONAL DEFICITS The stress-induced metabolic alterations after burn injury lead to protein-calorie/protein malnutrition, which, along with micronutrient deficits, can induce immune function depression.56 Furthermore, the hypermetabolism triggered from burn injury leads to specific nutrient deficits such as glutamine and arginine.57–59 Glutamine and arginine are semidispensable amino acids with a number of beneficial effects on the immune response. The nutritional deficits which occur during burn injury contribute to the pathogenesis of alterations in both innate and adaptive immune defenses. It is generally accepted that high-protein diets improve immunologic functions and decrease infectious complications.
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THERAPEUTIC MEDICINES AND HOST FACTORS Most burn patients require opiate analgesics for treatment of pain associated with the initial injury and postinjury procedures such as wound debridement and dressing changes. Severe burn patients often need blood transfusions due to extensive volume resuscitation and procedures such as escharectomy. Antibiotics are routinely used for the prophylaxis and treatment of infection in major burn patients. It is well documented that opiates, blood transfusions, antimicrobial agents, and the type of fluid used for resuscitation have profound immunomodulatory effects.60–63 A number of host factors can also impact immune functional parameters following burn injury, including age, gender, and genetic background.64–67 All of the above therapy-associated regimens and other factors can contribute to the development of immune dysfunction under a variety of circumstances following thermal injury.
CONCLUSION Severe burns directly cause extensive skin degeneration and necrosis and also induce a series of significant systemic responses, such as stress, ischemia and reperfusion, infection, and hypermetabolism. These factors, along with some of the relevant therapies used for the treatment of such patients, cause changes in the microenvironment surrounding the immune cells and immune molecules and also play critical roles in the pathogenesis of immune dysfunction after burns (Figure 1). Postburn immune dysfunction involves a number of cells and molecules not only in the immune system but in other systems as well. Attempting to modulate immune function by choosing appropriate target cells or molecules to decrease the degree of tissue damage and infection is a difficult task. According to the etiologic analysis of postburn immune dysfunction, efforts for improving immune dysfunction after burn injury have occurred at the global and integral level against pathogenic factors. These measures include amelioration of the stress reaction, prompt eschar excision for reducing release of biological factors or toxins from necrotic wound tissues, rapid fluid resuscitation for ameliorating ischemia and hypoxia, adequate antimicrobial chemotherapy with powerful bactericidal effects and less release of microbial components, and enteral nutritional supplementation combined with immunonutrients, prebiotics, and metabolically
relevant hormones such as growth hormone and insulinlike growth factor I.68 The effect of these clinically relevant factors upon immune functions should be carefully considered during the treatment of major burn patients. The future comprehensive therapeutic protocol for massively burned patients should be updated with consideration of the advances in basic and clinical research in the field of immunology.
KEY POINTS • The skin is the largest innate immune organ of the body and also the main target tissue of thermal insults. • Burn injury results in marked immune dysfunction, that predisposes patients to multiple organ damage and infection leading to increased mortality in seriously burned patients. • Burn wounds are well recognized as a main storage of inflammatory mediators as well as an important arsenal of immunosuppressive substances. • Ischemia and hypoxia in lymphoid and other tissues during burn shock and volume resuscitation play a critical role in the postburn immune dysfunction. • Bacteria and their components from the gut and wounds following burns cause serious inflammation and have the inhibitory effects on the adaptive immune response. • The nutritional deficits, various stressors, medications and patient-associated factors contribute to the development of immune dysfunction under a variety of circumstances following thermal injury. • The effect of these clinically relevant factors upon the immune functions should be comprehensively considered during the treatment of massive burn patients for a higher survival rate.
ACKNOWLEDGMENTS This review article was supported by grants from the National Natural Science Foundation of China (Grand Program, No. 39290700-01), National Key Basic Research and Development Project of China (973 Project) (No. 2005CB522605), and National High Technology Research and Development Project of China (863 Project) ( No. 2006AA02A121).
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FIGURE
FIGURE 1 Etiologic factors of postburn immune dysfunction.
BURNS
Shock
TISSUE INJURY Coagulation
Neuromediators Hormones
Ischemia Hypoxia
Necrosis
Stasis Apoptosis
Infection
Hypermetabolism
Congestion Edema
Pathogens & Their Components
Macronutrient Deficits Micronutrient Deficits
Denatured Proteins Constitutive Components Release
Host Factors: Age Gender Genetic Background Health Status Concomitant Injury
ALTERED MICROENVIRONMENT
ಹಹ
Therapeutic Factors: Anaesthesia Fluid Resuscitation Antimicrobial Agents Surgical Procedures Blood Transfusion ಹಹ
IMMUNE CELLS & MOLECULES IMMUNE DYSFUNCTION
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Stress
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function after burn injury and lipopolysaccharide exposure: single-cell contraction analysis and cytokine secretion profile. Shock. 2006; 25(2): 176–183. 49. Kane TD, Alexander JW, Johannigman JA. The detection of microbial DNA in the blood: a sensitive method for diagnosing bacteremia and/or bacterial translocation in surgical patients. Ann Surg. 1998; 227(1): 1–9. 50. de Haas CJ, van Leeuwen EM, van Bommel T, Verhoef J, van Kessel KP, van Strijp JA. Serum amyloid P component bound to gram-negative bacteria prevents lipopolysaccharide-mediated classical pathway complement activation. Infect Immun. 2000; 68(4): 1753–1759. 51. Gao JJ, Xue Q, Papasian CJ, Morrison DC. Bacterial DNA and lipopolysaccharide induce synergistic production of TNFalpha through a post-transcriptional mechanism. J Immunol. 2001; 166(11): 6855–6860.
52. Peng D, Guymon CH, McManus AT, Xiao GX. Release of DNA from Pseudomonas aerugisona in vitro during spontaneous growth and treatment with ciprofloxacin. Chin J Surg. 2005; 43(3): 178–181. 53. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003; 21: 335–376. 54. Yamada Y, Endo S, Inada K. Plasma cytokine levels in patients with severe burn injury—with reference to the relationship between infection and prognosis. Burns.1996; 22(8): 587–593. 55. Rumbaugh KP, Hamood AN, Griswold JA. Cytokine induction by the P. aeruginosa quorum sensing system during thermal injury. J Surg Res. 2004; 116(1): 137–144. 56. Peng D. The effect of nutrition support on the modulation of immune disturbance after burns. Chin J Burns. 2006; 22(6): 401–404. 57. Jeschke MG, Herndon DN, Ebener C, Barrow RE, Jauch KW. Nutritional intervention high in vitamins, protein, amino acids, and omega3 fatty acids improves protein metabolism during the hypermetabolic state after thermal injury. Arch Surg. 2001; 136(11): 1301–1306. 58. Wang S, Li A. Gut-derived hypermetabolism after burns. Chin
J Burns. 2001; 17(4): 200–201. 59. Wischmeyer PE, Lynch J, Liedel J, et al. Glutamine administration reduces gram-negative bacteremia in severely burned patients: a prospective, randomized, double-blind trial versus isonitrogenous control. Crit Care Med. 2001; 29(11): 2075–2080. 60. Alexander M, Daniel T, Chaudry IH, Schwacha MG. Opiate analgesics contribute to the development of post-injury immunosuppression. J Surg Res. 2005; 129(1): 161–168. 61. Winslow GA, Shelby J, Nelson EW, Saffle JR. Influence of allogeneic blood transfusion on natural killer cell activity in burninjured mice. J Burn Care Rehabil. 1996; 17(2): 117–123. 62. Nau R, Eiffert H. Modulation of release of proinflammatory
bacterial compounds by antibacterials: potential impact on course of inflammation and outcome in sepsis and meningitis. Clin Microbiol Rev. 2002; 15(1): 95–110. 63. Horton JW, Maass DL, White DJ. Hypertonic saline dextran after burn injury decreases inflammatory cytokine responses to subsequent pneumonia-related sepsis. Am J Physiol Heart Circ Physiol. 2006; 290(4): H1642–H1650. 64. Choudhry MA, Plackett TP, Schilling EM, Faunce DE, Gamelli RL, Kovacs EJ. Advanced age negatively influences mesenteric lymph node T cell responses after burn injury. Immunol Lett. 2003; 86(2): 177–182. 65. Gregory MS, Duffner LA, Faunce DE, Kovacs EJ. Estrogen mediates the sex difference in post-burn immunosuppression. J Endocrinol. 2000; 164(2): 129–138. 66. Schwacha MG, Holland LT, Chaudry IH, Messina JL. Genetic variability in the immune-inflammatory response after major burn injury. Shock. 2005; 23(2): 123–128.
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6
C H A P T E R
S I X
BURN PATHOPHYSIOLOGY TODD F. HUZAR, MD, UNITED STATES ARMY INSTITUTE OF SURGICAL RESEARCH EDWARD MALIN IV, MD, UNITED STATES ARMY INSTITUTE OF SURGICAL RESEARCH STEVEN E. WOLF, MD, FACS, DEPARTMENT OF SURGERY, UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER—SAN ANTONIO
OUTLINE 1. 2. 3. 4. 5. 6. 7.
Introduction Burn Depth Burn Size Immune System Local Changes Systemic Response Hypermetabolism in Children 8. Effects on the Renal System
9. 77 78 79 79 79 81 82 83
INTRODUCTION Injuries are common in the pediatric population and are associated with dramatic morbidity and mortality. In fact, unintentional injuries are a leading cause of injury and death among children. Historically, fires have been catastrophic to both health and home. In 2007, there were an estimated 1.6 million fires, causing over 17000 injuries and nearly 3500 deaths.1 Death from fire and burn injuries was the second leading cause of nontransportation and unintentional fatalities in children 15 years of age and younger. Approximately 80% of all pediatric burns are unintentional, while the other 20% are associated with abuse or neglect.2 Death and injury from fire primarily affect children aged 4 years and younger.3 These children face an increased risk in a fire because they are still somewhat dependent on others for their safety. Sadly enough, many of these children perish in their own homes because they are incapable of understanding the need to escape or how to do so quickly. In 2004, the National Fire Incident Reporting System (NFIRS) and the National Fire Protection Association (NFPA) found that 2007 children suffered thermal injuries, with 44% of burns and 50% of fire deaths occurring in the 4 years and younger age group.3
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10. 11. 12. 13. 14. 15. 16. 17. 18.
Effects on the Gastrointestinal System Inhalation Injury Bacteremia/Sepsis Electrical Burns Chemical Burns Cold Injuries Conclusion Key Points Tables References
84 85 86 87 88 89 89 89 90 91
Small children should not be considered small adults. Young children are physiologically different compared to adults and even older children and often do not tolerate thermal injury well. Their thinner skin results in much deeper burns than in older children, and they are also more susceptible to the effects of smoke, which is associated with 48% of the fatalities found in children under the age of 15 years.3 In addition, even small burns in children often require formal fluid resuscitation and more volume (cc/kg/ TBSA) compared to adults with similar sized burns. Scald burns are common in children and account for nearly 60% to 80% of burn injuries occurring worldwide.4,5 In the United States, scalds are the leading cause of burns in children and account for approximately 65% of burns to children under the age of 5 years.6 In fact, children aged 5 years and under have a risk of scald injury 3 to 4 times that of any other age group.7 Hot tap water is associated with roughly 25% of all scald burns seen in children, which tend to be rather severe due to high temperatures causing deeper burns than other agents.7 Feldman and others demonstrated that hot water scalds burn a larger body surface area, create more fullthickness injury, have a higher incidence of postburn scarring, and carry a higher mortality rate than other forms of scalds.8
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Epidemiological studies have shown that children are vulnerable to the effects of thermal and nonthermal injury. However, most research involving the pathophysiology of burns has been reported in the adult literature. Interestingly, despite their differences, children exhibit many of the same physiologic, inflammatory, and immunological responses as adults.
BURN DEPTH The skin is the largest organ in the body and is composed of 2 layers: epidermis and dermis. The thickness of the epidermis varies depending on the region of the body (thin eyelids and thick soles). The dermis constitutes the majority of skin’s thickness, which varies depending on age, gender, and location.9 In addition to management of thermoregulation, the skin functions as a protective layer against fluid and electrolyte loss, infection, and exposure to radiant energy. The epidermis is the superficial portion of skin, composed of 5 different layers. The innermost basal layer is composed of immature and undifferentiated keratinocytes (ectodermal origin). It takes approximately 2 to 4 weeks for keratinocytes to move from the basal layer to the stratum corneum, which is the most superficial and protective layer of the epidermis.10,11 Other cell types present within the epidermis which serve to filter out ultraviolet light and phagocytize invading microorganisms are melanocytes and Langerhans cells, respectively. One of the more unique characteristics of the epidermis is its ability to regenerate from keratinocytes lining the dermal appendages and edges of the wound. The dermis, on the other hand, is a thick (2–4 mm) layer of highly vascularized and innervated cells of mesodermal origin.12 The dermis is composed of a papillary (superficial) and reticular (deeper) layer. The bulk of the dermis is made up of collagen fibers that are secreted by fibroblasts. Fiber orientation in the extracellular matrix allows for stretching and tensile strength.13 The dermis contains adnexal structures (ie, sweat glands, hair follicles) that extend through the upper layers of the epidermis and supply reepithelializing keratinocytes after injury. Both the dermis and epidermis receive their blood supply from a dermal plexus of capillary vessels and the endothelial lining, which also secrete mediators of inflammation. These mediators regulate local and systemic inflammatory responses.14 An abundance of sensory nerves are present in the dermal layer, and after injury they mediate pain and itching and influence local inflammation and wound healing.15 The major mechanisms of burns in children include thermal, chemical, and electrical injuries. Thermal injury is the most common form and occurs from excessive temperatures causing direct damage to skin and its underlying
structures.6,16 Injuries can result from direct contact with fire or an open flame, scalding from liquids, and contact with a superheated object causing coagulation necrosis of the skin and its elements. The depth of the burn varies according to the source of thermal injury and duration of exposure to the offending agent. A chemical burn occurs from exposure to an alkali or acid and can be lethal due to the possibility of systemic absorption of the chemical as well as the depth/extent of the injury. The severity of the burn depends on the concentration and type of chemical in addition to the duration and degree of exposure.17 Damage is created by direct injury to the cellular membranes and transfer of heat by chemical reactions within the skin. Chemical burns are initially difficult to assess because absorption can take hours to days before tissue damage is complete.6 Although cutaneous chemical burns are uncommon in children, their risk for accidental ingestion of such compounds is greater. Children are particularly vulnerable to electrical injuries in the household. Common injuries emanate from chewing on electrical cords and inserting metallic objects into electric sockets. Many of these injuries result from low-voltage electricity and cause small cutaneous burns; however, in the case of oral commissure burns, they have devastating complications, such as risk for late contractures.18 Injury to the skin is mediated by direct injury to the cell membranes and generation of heat due to differences in resistance of the body’s tissues. The depth to which burns damage the skin and underlying tissues varies depending on the injurious agent. Some of the factors that can affect the depth of a burn should be mentioned. Medical personnel should consider the age of the patient in relation to the cause of an injury, because children under the age of 2 years have thinner skin than adults and thus suffer deeper burns in a relative sense.6 The location of the burn itself may affect the depth due to variations in skin thickness by body region.7 Additionally, the mechanism of the burn and duration of exposure to the injurious agent have significant impact on depth.19 Burn depth can be defined as the amount of tissue destroyed by heat, chemicals, or electricity.20 Historically, burns have been classified as first, second, and third degree. Subsequently, a newer method was developed which is more accurate in classifying burn wound depth by describing the actual anatomic thickness of injured skin (Table 1). Superficial burns (formerly first-degree) are confined only to the outer epidermal layers of skin. Since only the epidermis is injured, there is no disruption of skin integrity. These burns are characterized by pain and erythema without blistering or any open wounds. Pain from these burns is generated by injury to nerve endings found in the epidermis. A common cause of superficial burns is ultraviolet
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B UR N PAT HOP HY S I O L O G Y radiation (eg, sunburn). These injuries typically heal rapidly (< 1 week) without any scarring. Second-degree or partial-thickness burns destroy the epidermis and also injure part of the dermis, including dermal appendages. They do not extend through the entire depth of the dermis. Partial-thickness burns can be further divided into 2 categories depending on the depth of dermal injury. Superficial partial-thickness burns destroy the entire epidermis as well as the upper portion of the dermis. Although the dermal skin appendages are damaged, many of them survive and participate in reepithelialization. Blisters are secondary to injury to the dermal capillaries and allow leakage of plasma that then separates the destroyed epidermis from the basement membrane. These blisters weep inflammatory fluid that contributes to further volume loss. Wounds tend to be bright red to mottled in appearance and wet to touch, with blisters as described. Pain can be quite severe in this particular type of burn due to exposure of dermal nerve endings to air.15 Fortunately, these wounds tend to heal spontaneously in 1 to 2 weeks with minimal scarring. Deep partial-thickness burns are of greater concern since they involve complete destruction of the epidermis and a majority of the dermis. Such severe dermal damage leaves few dermal appendages intact, which diminishes the ability to heal spontaneously. Wounds are described as dark red to yellowish-white in color and slightly moist, and they minimally blanch to pressure. There is decreased sensation to pinprick, although the perception to deep pressure may remain intact.7 Blisters do not usually occur since close adherence between destroyed tissue and viable dermis prevents edema fluid from separating the epidermis from the dermis. Pain is minimal due to destruction of pain fibers in the dermis. Compromised blood flow to areas with deep partial-thickness burns allows for increased risk of infection and wound conversion to full-thickness injury. Excision and grafting is commonly warranted to expedite wound repair in these patients since healing can be delayed for months. Furthermore, the risk for development of hypertrophic scarring increases with nonoperative management. Third-degree or full-thickness burns involve injury to the epidermis, dermis, and the underlying subcutaneous tissue. These wounds appear to be charred or white in color, dry, leathery, and insensate and contain thrombosed blood vessels that are visible through the burnt tissue. Necrotic skin (eschar) is a potent stimulator of the inflammatory response and is excellent pabulum for bacterial and fungal growth. Full-thickness burns do not heal spontaneously due to destruction of the dermis and are at high risk of hypertrophic scarring if allowed to heal by contraction. The inflammatory response is attenuated when early excision and grafting of full-thickness burns is performed. Subdermal
burns, once called fourth-degree, occur with severe thermal injury and extend through subcutaneous tissue into connective tissue, muscle, and even bone. As expected, they present a significant challenge for even the most experienced burn surgeons.
BURN SIZE Proper sizing of burns assists with estimating the extent of injury. More importantly, it helps with determining the amount of fluid resuscitation required for patients with burn shock. Burn size is expressed as a percentage of total body surface area (%TBSA). When determining %TBSA, first-degree burns are not included in the tabulation. Adults can be initially mapped using the “rule of nines,” which assigns certain percentages to different areas of the body.21 However, this schema is inappropriate for use in children because the head and neck comprise a larger percentage of body surface area, with a smaller portion of body surface area encompassing the lower extremities. In 1944, Lund and Browder devised a new mapping system for children which took into account these differences in body proportions relative to age.22 Most pediatric burn centers now employ a modified version of the Lund-Browder charting system (Table 2). This system can be difficult when mapping children with scald burns due to their noncontiguous nature.23 Nagel et al described another method for measuring difficult burns by estimating the hand surface of a child (1–13 years of age) to approximate a 1% TBSA.23
IMMUNE SYSTEM Thermal and nonthermal burns to human tissue can have deleterious local and systemic effects on the immune system depending on the mechanism of injury, duration of contact, and associated secondary injuries. The immune system’s response to burns has been extensively studied in the adult population. For various reasons, the pediatric literature is not as prolific. The unique qualities of the pediatric patient which will affect their response to burn injury include a discrepancy of body surface area (BSA) versus weight compared to adults, as well as the baseline hypermetabolic state seen in younger patients. Even though the pediatric literature has fewer entries on the subject, the overall response of the child’s immune system to burns appears to be relatively similar to that of an adult.
LOCAL CHANGES Burns cause pathophysiologic changes in skin that can be characterized by the effects of the heat source in combination
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with acute inflammatory changes caused by the injury.24 The mechanism by which burns cause injury is through coagulative necrosis of the epidermis and underlying deeper skin structures. The depth of injury is dependent on the substance’s temperature, duration of exposure, and its specific heat (eg, grease burns cause more extensive damage compared to hot water burns at the same temperature and duration). The extent of exposure will dictate if the injury is limited locally or whether a systemic response is elicited. Burns greater than 10% total body surface area (TBSA) are more likely to produce a systemic response which is affected by immunoinflammatory factors, causing a dysfunction of the immune system. The disruption of immune function is proportional to the degree of burn injury. The 2 layers of skin act as a “heat sink” to decrease the transfer of thermal energy to the underlying vital structures. Because of immediate changes in capacitance and temperature transmission, injury is mainly confined superficially. Sensory fibers in the skin sense changes in body surface temperature, leading to secretion of locally acting vasoactive mediators, which then cause vasodilation of dermal blood vessels in an attempt to dissipate thermal energy.19 Injury to the skin and its structures from thermal energy releases acute inflammatory mediators from the injured cells and initiates the inflammatory response.25 After the thermal insult, inflammatory cells begin to demarginate from the bloodstream and migrate into the burned tissues. Large numbers of neutrophils are found within the dermis in the first few hours after superficial thermal injury, peak within 24 hours, and slowly retreat from the dermis in 72 hours.26 However, deeper burns cause prolonged sequestration of neutrophils due to obliteration of vessels in the upper dermis and damage to deeper vessels.27 Neutrophils are partly responsible for ischemic reperfusion injury due to release of free oxygen radicals. These then cause endothelial cell damage by increasing capillary permeability and provoking denaturation and fragmenting of collagen and extracellular matrix components.28,29 Lymphocytes and macrophages begin to accumulate in the superficial burn at approximately 12 hours, but have not been found in deeper dermal burns.30 Although the combination of inflammatory cells and mediators causes significant damage to the tissues in the thermally injured area, the inflammatory response can be seen throughout the entire human body. The local tissue environment is overwhelmed with vasoactive mediators due to the combined effects of the local inflammatory response and release from injured cells. Substances such as cytokines, bradykinin, histamine, and arachidonic acid derivatives damage the capillaries and interstitium as a prelude to the formation of massive tissue edema.25 Changes in the derivatives of Starling forces
create favorable pressure gradients for capillary leakage of intravascular volume.31,32 These forces result in loss of intravascular volume along capillary beds and produce an increased capacity of the interstitial space.33 The formation of edema is relatively quick for smaller burns; however, the overall amount of edema fluid is less in larger burns, since large losses of intravascular volume lead to decreased blood flow to burned tissue and cause less edema formation.34 Additionally, both formation and resorption of edema fluid occur faster in partial-thickness burns compared to fullthickness burns. This phenomenon is due to the greater vascular perfusion and larger number of intact lymphatics seen in partial-thickness burns.25 Edema formation is decreased in deep thermal burns due to diminished vascular perfusion and limited resolution of formed edema secondary to damaged lymphatics.35 In 1953, Jackson described 3 concentric zones of thermal injury.36 The innermost zone is that of coagulation, where cellular death occurs from direct tissue damage. In severe burns, it represents nonviable cells with no identifiable functioning vasculature. The middle area is the zone of stasis, containing a mixture of viable and nonviable cells with variable blood flow secondary to vasoconstriction, leading to ischemia. It is believed that thromboxane A2 is the cause of decreased blood flow in this zone.25 Survival of cells in this zone is dependent upon adequate blood flow, prevention of infection, and prevention of desiccation, all of which could contribute to conversion of this zone to an area similar to the zone of coagulation.37 The outermost area of injury is the zone of hyperemia, which is completely viable and shows signs of vasodilation due to inflammatory mediators. Discoloration of skin helps to delineate this area from noninjured tissue. This zone will usually recover and heal as long as hypotension and burn wound infection are avoided.38 Changes of the microvasculature in the tissues surrounding the burn can cause extension of burn wound necrosis that can convert partial-thickness injuries to fullthickness burns.39 Additional factors involved in the body’s response to local tissue trauma involve degranulation of mast cells that release multiple biologically active mediators, specifically histamine.40 Vasodilation and vasoconstrictive factors both contribute to advancement of tissue damage due to an influx of inflammatory mediators and a decrease of perfusion, respectively. These vasoactive substances help mediate the flow of excess fluid into the interstitium. Consequently, histamine and its stimulation of xanthine oxidase produce an abundance of oxygen radicals, which results in more tissue damage and systemic consequences. If the burn is severe enough, the circulation of vasoactive substances, along with the decrease in intravascular volume, leads to the systemic process of “burn shock.”
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B UR N PAT HOP HY S I O L O G Y Animal research has broadened our understanding of histamine receptors and their role in regulating local edema after burn trauma. In one study comparing the function of histamine receptors on cellular permeability, H1, H2, and H3 receptors were not proven to be “important actors in the regulation of vascular patency permeability.”41 The clinical use of antihistamines in the treatment of edema has not provided much success either. Several other vasoactive substances have been implicated in the systemic formation of hemodynamic alterations and have also contributed to the local effects of increased capillary permeability. These circulatory factors include serotonin, thromboxanes (TXA—from platelet activation), components of complement activation, products of arachidonic acid breakdown, bradykinin, and cortisol, as well as others.26,42 Regardless of the mechanism, insult and destruction of the skin’s protective characteristics exposes the underlying tissue to a local inflammatory response. Furthermore, the extent of the injury determines the nature and degree of the systemic response.
SYSTEMIC RESPONSE The immune response elicited by burns involves a complex physiologic patchwork of proinflammatory reactions. Homeostasis of the existing immunoinflammatory and hematological systems are disrupted after a severe burn injury. The combination of cytokine release, activation of the complement system (C3a, C5a), platelet activation and the coagulation cascade, release of endothelial vasoactive substances (bradykinin, NO), influx of TXA and other byproducts of arachidonic acid, response of the immune system to endotoxin, and the production of oxygen radicals all play a role in the clinical effects.19 The baseline status of the patient dictates the effectiveness of his or her response; however, most children do not suffer from the same maladies of chronicity as the adult population. The systemic response to severe burns can manifest in many ways. Clinically, the patient can exhibit signs of the systemic inflammatory response syndrome (SIRS). When there is a concomitant source of infection, sepsis can be diagnosed. Septic shock is described when factors contribute to the development of cardiovascular collapse. As the severity of the burn increases, so does the incidence of acute lung injury, renal failure, and multiple organ dysfunction syndrome (MODS), leading to increased morbidity and mortality.43,44 At the time of the injury, upregulation of macrophages initiates a cascade of cytokine release (eg, IL-1, IL-2, IL-6, IL-8, IL-10, TNF-α, TGF-β, and IFN-γ) and lymphocyte activation.45 The corresponding cascade of
immunoinflammatory mediators leads to immune dysfunction, with a resultant decreased resistance to infection, hemodynamic instability and shock, acute lung injury, and multiorgan failure.46 Over the last 2 decades, many studies have examined the role of cytokines with respect to trauma and burns. Stimulation of macrophages under these circumstances causes a release of proinflammatory cytokines not normally circulating in healthy patients. Significantly elevated levels of IL-1, IL-6, IL-8, and TNF-α have been measured in severely injured patients who also developed sepsis.47,48,49 These cytokines were also associated with a higher incidence of mortality. Deitch described a “two-hit” phenomenon which illustrates the effects of thermal injury on the immune system. The initial hit from a cutaneous burn primes the immune system to abnormally express proinflammatory factors and consequent anti-inflammatory mediators. Elevation of both leads to an inadequate response to a second insult, for example, wound infection. This is associated with a robust hypermetabolic state equipped with producing hemodynamic instability and further tissue injury.50 Research continues to explore the clinical applications in utilizing inflammatory and biological markers for the identification of sepsis. In a recent analysis of burn patients suffering from SIRS, sepsis, severe sepsis, or septic shock, the authors explored the utility of various laboratory values— C-reactive protein, WBC count, and procalcitonin—in diagnosing sepsis. The results revealed the presence of elevated procalcitonin levels in septic patients, which were superior to CRP or WBC in predicting sepsis.51 An earlier retrospective study had also reported procalcitonin to have diagnostic value in evaluating for sepsis.52 As prevention of sepsis and its early diagnosis are essential to the management of the severely burned patient, these conflicting studies reveal some of the challenges in establishing clear standards for monitoring the immunoinflammatory process. Burn shock is the outcome of multiple factors characterized by the innate inflammatory response to severe injury. The roles of macrophages and the subsequent cascade of increasing cytokines contribute to instability of the body’s homeostasis. As inadequate perfusion continues, additional local and systemic mediators further worsen the structure of microvascular permeability, causing a leak into the interstitial or “third” space. Oxygen radicals have been postulated to contribute to this process. Oxidative damage due to overproduction of oxygen radicals and its toxic effects have been implicated in “the local and distant pathophysiological events observed after burn.”53 The use of antioxidants such as vitamin C, vitamin E, and melatonin may have some clinical role in managing the toxic effects of free radicals— though no definitive consensus has been reached on their
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use in treating burns.54,55 Some animal studies have even considered the use of induced hypothyroidism for managing the systemic response and resultant organ failure in severe burns.56 In severely burned patients with a significant systemic response, the mainstay of treatment is fluid resuscitation in order to maximize end-organ perfusion. An untoward consequence of high-volume crystalloid infusion can be intra-abdominal hypertension (IAH), with bladder pressures exceeding 25 mmHg.57,58 Complications associated with abdominal compartment syndrome include elevated peak airway pressures, oliguria, and potential bowel ischemia. When decompressive laparotomy is required for severe cases of IAH, the patient’s overall mortality is significantly increased. Some studies have demonstrated the use of colloids to be protective against the development of IAH.59,60 Regardless of the type of fluid chosen, the effects of the initial resuscitation should be monitored closely.
HYPERMETABOLISM IN CHILDREN The human body is highly susceptible to injury that has effects both physically and metabolically. While there is a broad spectrum of injury we can endure, burns have one of the most severe impacts. Burns can scar physically and severely alter our metabolic capacity. Burn victims undergo intense hypermetabolic and catabolic states for weeks to months, and in extreme cases, these alterations can last for 1 to 2 years.61 Patients who are severely burned undergo a metabolic response initially characterized by a short, hypodynamic state after the initial injury. A hypermetabolic state ensues, with a hyperdynamic circulation delineated by increased body temperature, glycolysis, proteolysis, lipolysis, and futile substrate cycling.62 These hypermetabolic patients undergo a significant reduction in lean body mass, muscle weakness, immunodepression, and poor wound healing. Consequently, metabolism enters the “ebb” or shock phase, consisting of decreased blood pressure, cardiac output, body temperature, and oxygen consumption.63 The ebb phase lasts for 12 to 24 hours and can be best described as depression of metabolic activity seen in early injury, including burns. Response to injury involves large increases in circulating levels of both catecholamines and vasopressin, with the level of response dependent on the severity of the injury.64 Increased catecholamine activity in these patients leads to elevated levels of glucagon, which inhibits secretion of insulin, resulting in hyperglycemia. Due to relative insulin resistance, tissues which rely on glucose as a fuel must instead draw on whatever energy sources are available. The hypodynamic/hypovolemic state created by a
severe burn causes increased vasopressin levels, leading to water retention. In addition, the renin-angiotensin system is activated in order to maintain intravascular volume, which tends to become rapidly diminished in severely burned patients. After a period of time, metabolism enters the “flow” phase, characterized by hypermetabolism, increased cardiac output, increased urinary nitrogen losses, altered glucose metabolism, and accelerated tissue catabolism. Hypermetabolism can be defined as an increase in the basal metabolic rate above the predicted normal level. Thus, the overall increase in oxygen consumption, which can be related to the severity of the burn, occurs from elevations in both heart rate and myocardial contractility (cardiac output) in an attempt to deliver the optimal supply of energy and substrates to the burn wound at the expense of other tissues.65 The hypermetabolic or “flow” phase lasts from 9 to 12 months following a severe burn. The intensity of the catabolic state in these patients depends on the percentage of total body surface area burned. The resting metabolic rate in burn patients increases in a curvilinear fashion, dependent upon the %TBSA.66 During this hypermetabolic phase, patients lose significant amounts of lean body mass, with even a 10% to 15% loss leading to increased infection rates and marked delays in wound healing.57 The loss of lean mass directly results in muscle weakness, which can cause prolonged mechanical ventilation, diminished cough reflexes, and increased difficulty with ambulating proteinmalnourished patients.67 A severe burn causes an imbalance between anabolism and catabolism by increasing the plasma levels of catecholamines. The surge in catecholamine levels directly increases levels of glucagon as compared to the already lower levels of insulin.68 This difference in the glucagon to insulin ratio favors release of amino acids from skeletal muscle, which become a fuel in this hypermetabolic state.57 Additionally, studies have shown that burn patients oxidize amino acids 50% faster than nonburn patients due to hypermetabolism. Another major metabolic disturbance caused by severe burns is the inability to utilize body fat stores for energy. During starvation, the body is normally able to utilize lipids as fuel and create a “protein sparing” effect. However, thermal injury inhibits fat utilization, and skeletal muscle subsequently undergoes proteolysis to meet the nitrogen needs of burn patients.69 Negative net protein balance can be further enhanced by the development of sepsis, leaving open wounds, uncontrolled hyperglycemia, insulin resistance, and severe hypermetabolism.70,71 In studies by Gore et al and Flakoll et al, hyperglycemic patients tended to have increased rates of muscle protein
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B UR N PAT HOP HY S I O L O G Y breakdown.72,73 Insulin use in hyperglycemic burn patients acts as a muscle protein anabolic agent.74 Thomas et al showed that burned children started on low-dose insulin infusions (9–10 units/hr) experience substantial muscle anabolism.75 Furthermore, the use of glucose coupled with insulin in burn patients can preserve body mass, reverse nitrogen balance, and retain energy stores, but unfortunately does not alter the hypermetabolic state.76 Patients with extensive burns can lose up to 25% of their premorbid body weight in the first 3 weeks due to flow phase hypermetabolism. Increased rates of catabolism seen in burn patients can be associated with larger percentage TBSA burns, heavier admission weights, and longer periods of time to primary wound excision and grafting. Early excision and grafting performed within the first 48 to 72 hours can decrease the metabolic rate by nearly 40%. In addition, patients started on enteral nutrition which delivers adequate amounts of kilocalories proportionate to their body weight and TBSA burned will have a diminished overall hypermetabolic status; however, early feeding and adequate calories do not abolish the hypermetabolic state. Enteral nutritional support is preferable to parenteral formulations due to the increased mortality, impaired liver function, and reduced immunocompetence seen with parenteral feeding.53 In many burn units, resting energy expenditure (REE) is estimated using the Harris-Benedict equation, which incorporates gender, age, weight, and height. The equations are REE (males) = 10 × weight (kg) + 6.25 × height (cm) – 5 × age (y) + 5; REE (females) = 10 × weight (kg) + 6.25 × height (cm) – 5 × age (y) – 161.77 Another method of determining REE is indirect calorimetry, which measures actual oxygen consumption and carbon dioxide production to derive energy utilization. Burns can cause severe and prolonged metabolic disturbances that can last up to a year after the initial injury. The persistent and profound catabolism from this hypermetabolic state hampers rehabilitation efforts and delays the patient’s return to a meaningful, functional life.78 Although many anabolic strategies are employed to limit loss of lean body mass, the simplest and most effective is early burn excision and grafting of the wound. Other modalities used in an attempt to augment the tide of catabolism include beta blockers (propranolol), growth hormone, and synthetic testosterone analogues (ie, oxandrolone). The use of beta blockers began from the belief that the most effective way of treating the catabolic state is by inhibiting catecholamines, catabolism of skeletal muscle, and the overall increase in basal energy expenditure. By blocking beta adrenergic receptors, there is a decrease in
thermogenesis, tachycardia, cardiac work, and resting energy expenditure. Barret et al found that long-term use of propranolol in burn patients (at doses reducing the heart rate by approximately 20%) was found to decrease overall cardiac work and decrease fatty infiltration of the liver.79 Another study revealed that propranolol diminishes wasting of skeletal-muscle protein and raises lean body mass after major burns by causing enhanced intracellular recycling of free amino acids used in protein synthesis.80 Another drug used to augment the body’s response to burn injury is growth hormone, which has been found to be useful in reducing wound healing at skin graft donor sites by nearly 25% and to improve the quality of wound healing with no increase in scar formation. The use of recombinant growth hormone has been shown to be extremely effective in children by increasing lean body mass, vertical bone growth, and bone mineral content even after being discontinued for years. Growth hormone also attenuates the initial acute response to thermal injuries and improves albumin production by the liver.81 Growth hormone is not without its own side effects, specifically hyperglycemia, which can lead to increased morbidity and mortality.82 Oxandrolone, a steroid analogue which is 1/20 the strength of testosterone, has been used in burn patients. Studies of its use in young males with burn injury have shown a 2-fold improvement in protein synthetic insufficiency and a 2-fold decrease in protein breakdown.83 At a dose of 0.1 mg/kg twice daily, oxandrolone was found to improve muscle protein metabolism in burn patients by enhancing the efficiency of protein synthesis. In 2003, Demling and De Santi showed that patients receiving oxandrolone and adequate nutrition regained weight and lean mass 2 to 3 times faster than with nutrition alone. At a 6-month follow up, these patients maintained their body weight and lean body mass.84
EFFECTS ON THE RENAL SYSTEM Severe burns have been implicated in causing a broad spectrum of local and widespread negative effects on the body. Acute renal failure secondary to burns is a well-known complication associated with portending a worse prognosis.85 The incidence of this devastating complication has been noted in the literature to range from 1% to 30% of admitted patients, but its presence has an associated mortality of 70% to 100%.86,87 Acute renal failure has a multitude of definitions, but ours involves a sudden decrease in the glomerular filtration rate due to either intrinsic kidney disease or changes in intrarenal hemodynamics.88 Diminished renal function leads to accumulation of cellular waste products (eg, urea, creatinine, and potassium) in the bloodstream, which can subsequently cause their own significant complications.
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Burn patients are unique in their susceptibility to acute renal failure at 2 points during the postburn period: early and late. Early renal failure can occur immediately after a severe burn secondary to decreases in renal perfusion due to hypovolemia or damage from intravascular pigments (eg, hemoglobin or myoglobin) that deposit in and occlude the renal tubules.89 Hypovolemia from burn shock occurs as a consequence of excessive fluid loss from burn wounds, depletion of intravascular volume secondary to fluid shifts, and decreases in cardiac output from circulating vasogenic mediators.83,84 Most importantly, delays in the initiation of aggressive fluid resuscitation may aggravate the profound hypovolemia due to the previously mentioned causes, and together lead to renal hypoperfusion and injury.90 A study by Jeschke et al illustrated this point by showing that aggressive fluid resuscitation started within the first 2 hours after a burn injury in children resulted in significant improvement in the survival of patients with acute renal failure.83 Extensive depletion of intravascular volume and burn stress leads to a significant release in catecholamines and other stress hormones (eg, vasopressin and aldosterone). As a result, vasoconstriction and changes in regional blood flow to the kidneys occurs, which further exacerbates renal hypoperfusion.85,91 The thermal cutaneous injury is thought to be the source of mediators that enhance the effects of stress-induced hormones. Many authors have proposed that cytokines (eg, interleukin-6, tumor necrosis factor) released from the burn wound itself interact with circulating stressinduced hormones and promote continuously unopposed vasoconstriction of the renal vasculature. Consequently, this event increases the chances of developing acute renal injury.92,93 The late form of acute renal failure is mainly attributed to systemic sepsis and manifests approximately 2 weeks after a burn. Severe sepsis and associated multiorgan failure associated with elevated levels of cytokines and other proinflammatory mediators can lead to increased vascular permeability and renal tissue damage.83 Even the treatment of clinical sepsis can be a culprit in the initiation of late renal failure. For example, nephrotoxic antibiotics such as aminoglycosides can increase the risk of renal failure in septic burn patients.94 The combination of sepsis and renal failure predicts a rather poor prognosis.83,84 As time progresses, it is hoped that advances in the management of acute renal failure will lead to decreases in morbidity and mortality. For now, early initiation of fluid resuscitation and aggressive management of sepsis can possibly spare burned children the added insult of renal failure and its dismal prognosis.
EFFECTS ON THE GASTROINTESTINAL SYSTEM A child exposed to a severe burn (> 20% TBSA) is at risk for developing secondary organ involvement, especially with the gastrointestinal tract, either directly or indirectly. In children, the accidental ingestion of caustic chemicals can have deleterious effects on the gastrointestinal system, ranging from minor oral cavity ulceration to full-thickness necrosis and perforation. Stress ulceration associated with burns was first described in the mid-eighteenth century by Curling, and its incidence has prompted the widespread use of prophylactic medications.95 Another complex process which exists in the severely burned child is the extent of the external insult and its treatment influencing secondary injury to the intestine and further exacerbating the body’s systemic response to the trauma. The literature has sought to determine the etiology of gastrointestinal injury in burns and the clinical implications as related to sepsis. A phenomenon in which the mucosa of the gastrointestinal tract atrophies as result of a burn has been described. In animal studies, the intestinal weight of rats with burn trauma has been compared to those without such wounds. Injured animals were shown to have about 20% less intestinal weight than the control group secondary to a decrease in mucosa.96 Additional studies examining the effects of burns on the gastrointestinal tract have further elucidated this process by proving disruption of the normal homeostatic balance of cell death and proliferation. Despite increased cell proliferation after scalding injury, the gut epithelium of mice revealed an overall decrease in cell number due to the overwhelming presence of diffuse apoptosis.97 Follow-up studies showed this increase in cell death was less likely a result of hypoperfusion in mesenteric vessels and more likely secondary to the systemic inflammatory response after a severe burn.98 The clinical implications of gastrointestinal damage are quite significant when considering the development of burn sepsis. Some have demonstrated gut-derived sepsis may be directly related to an increase in gut permeability with paracellular translocation of gram-negative bacteria and release of endotoxin. Based on the fact that the extent of the burn directly correlates with the degree of permeability, a gutlymph theory has evolved, describing a leaky gut that spills inflammatory factors into the lymphatic channels rather than the portal system.99,100,101 In studies examining the effects of severe injury, it has been postulated that the process of lymphatic drainage of these inflammatory mediators via the thoracic duct may also contribute to shock-induced acute lung injury.102 Life-threatening sepsis can be attributed to many factors related to gastrointestinal injury: (1) microbial load and
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B UR N PAT HOP HY S I O L O G Y virulence, (2) status of the gut barrier, and (3) magnitude of the host’s immunoinflammatory response.103 Early enteral feeding has been speculated to be one of the ways to ameliorate the injurious systemic response to burns and also fortify the gastrointestinal tract’s mucosal layer.104 Gastrointestinal problems, including gastrointestinal bleeding, Curling ulcers, pancreatitis, superior mesenteric artery syndrome, acalculous cholecystitis, intestinal necrosis, and paralytic ileus105 are well-recognized complications associated with burns. Paralytic ileus and enteral feeding intolerance are often seen in burn patients as a prequel to the onset of sepsis; however, the exact etiology of these 2 conditions is unknown.106 Tokyay et al and Reines et al showed that elevated thromboxane A2 levels in sepsis cause significant mesenteric vasoconstriction that limits mesenteric blood flow.107,108 Decreased mesenteric perfusion possibly causes the intestinal neuroendocrine system to slow peristalsis, leading to ileus/feeding intolerance; malperfusion can directly alter mucosal fluid resorption, producing diarrhea.106 Enteral feeding intolerance is an entity which should be monitored closely, as it may be the only early clinical sign of sepsis.
INHALATION INJURY Inhalation injury was first recognized in the first century AD in prisoners who were exposed to wood smoke as a method of execution. However, injury from smoke inhalation did not receive much public or scientific attention until the infamous Cocoanut Grove fire of 1942 occurred, killing 491 people.109 Many of the victims of this fire suffered severe inhalation injury secondary to being trapped in an oxygendeprived, confined space. Following this tragedy, there was a significant amount of research into the pathophysiology of inhalation injury. Smoke inhalation has been found to be associated with 20% to 30% of major burns and increases the overall morbidity and mortality in severely burned patients.110,111 Studies have shown that inhalation injury is an important contributor to mortality when also considering percentage of total body surface area involved and patient age.112 The lethality of smoke inhalation is due to the combination of its components (eg, particulate matter and gases) affecting different levels of the respiratory tract. The composition of smoke depends on the type of combustible material and the room’s oxygen content.113 Some of the more dangerous gases found in smoke include sulfur dioxide, carbon monoxide, phosgene, acrolein, ammonia, hydrogen chloride, and hydrogen cyanide, all of which have different effects locally in the lungs and systemically.103 Smoke inhalation has been found to have devastating effects on both the upper and lower airways.
The oropharynx and upper airways suffer the brunt of the heat from inhaled gases, with most of the large particulate matter trapped in the nasopharynx and oropharynx. Hot, inspired gases are rapidly cooled by the moist and well-vascularized mucosal surfaces of the mouth, tongue, and oropharynx. The exchange of thermal energy into these tissues causes rapid mucosal swelling as well as increased transvascular fluid migration due to higher flow of lymph fluid and blood into the injured mucosa.114 As the injury progresses, cytokines released in response to tissue injury further compound airway swelling to the point that the airway begins to narrow. This then leads to a decreased ability to move air and secretions, which can ultimately result in asphyxiation.115 Prophylactic intubation should be considered in patients with upper airway injury to prevent airway loss and the need for an emergency airway. Intubation, however, may itself cause further damage to the tracheal mucosa and even result in laryngeal injury.116 The action of the oropharynx and upper airways as a “heat sink” protects the lower airways from thermal injury; however, steam can bypass this cooling mechanism due to its greater heat-carrying capacity compared to “dry” smoke.117 The inhaled steam remains “hot” and easily proceeds to the lower airways, where it causes blistering. Eventual sloughing of the bronchial mucosa leading to an intense inflammatory response with subsequent parenchymal damage is seen. This group of patients is at higher risk for the development of ARDS and pneumonia than those with smoke-related inhalation injuries.118 Injuries from steam inhalation occur with less frequency in the pediatric population than in adults because this occurs more often in job-related incidents. As smoke begins to percolate down the tracheobronchial tree, a mixture of particulate matter and toxins attack the ciliated, columnar epithelium, causing local vasodilation mediated by leukotrienes, histamine, neural neuropeptides, and nitric oxide (produced by nitric oxide synthase).103,119 The effect of this rapid vasodilation is necrosis of the ciliated epithelium that precipitates separation from the tracheobronchial wall.120 Simultaneously, smoke-borne toxins cause a massive release of inflammatory mediators that may lead to severe bronchoconstriction such that spontaneous breathing or mechanical ventilation may be extremely difficult.121 The combination of damaged epithelium and increased flow of lymph and blood results in transudation of large amounts of protein-rich fluid from “leaky” capillaries into the airways. This transudative/exudative proteinaceous fluid mixes with inflammatory cells and sloughed-off tracheobronchial epithelium to form soft, bronchial casts.122 In a few hours, these casts solidify and cause obstruction of small-caliber and medium-caliber airways, along with alveoli.105,123 The formation of these obstructive casts is
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not uniform and can affect different segments of the lung. Bronchial casts cause distal airway atelectasis, precipitating ventilation/perfusion mismatch due to hypoventilation.103 In normal lungs, hypoventilation causes hypoxic vasoconstriction of blood vessels in underventilated segments and shunts blood away from these areas, thus preventing ventilation/perfusion mismatching. However, circulating inflammatory mediators (eg, nitric oxide, a vasodilator) inhibit this mechanism and lead to continuous perfusion of these segments, which results in poor oxygenation of blood and eventual hypoxemia.124 Mechanically ventilated patients may suffer a combination of barotrauma/volutrauma to nonoccluded pulmonary segments secondary to increased airway pressures from the ventilator attempting to overcome airway occlusion from these casts.125 The alveolus is the final stop in the pathway of destruction for smoke and its components. Gases and particulate matter directly damage the epithelial lining of the alveoli, while obstructive bronchial casts and sequelae of the inflammatory response cause indirect injury to these fragile structures. Particulate matter entering the alveolus activates pulmonary macrophages, which phagocytize debris and subsequently release oxygen free radicals (eg, superoxide) and lysozymes that injure both the macrophage and surrounding alveolar epithelium.103 Pulmonary macrophages consequently lyse, releasing cytokines and proinflammatory mediators that enter the circulation and attract neutrophils into the alveoli, causing epithelial damage and further propagating the systemic inflammatory response.126 Neutrophils secrete enzymes (eg, elastase, oxygen radicals) that cause disruption of the capillary endothelial junctions, allowing protein-rich plasma to enter the alveoli.102 Plasma within the alveoli begins to clot as a result of the procoagulant nature of pulmonary epithelium; this causes dissolution of surfactant and eventual atelectasis of affected pulmonary segments.127 As one would expect, pneumonia and ARDS are common complications of parenchymal injury and increase mortality in patients with severe inhalation injury. A common and deadly component of smoke is carbon monoxide (CO). It is a product of incomplete combustion of many fuels commonly found in homes, including wood, paper, and cotton.128 The toxic effect of carbon monoxide is mediated by its ability to bind to hemoglobin and make it unavailable for oxygen transport.129 Since carbon monoxide’s affinity for hemoglobin is 230 to 270 times greater than that of oxygen,130 small concentrations of carbon monoxide give rise to high carboxyhemoglobin levels. This causes a left shift of the oxygen-hemoglobin curve and decreases the availability for oxygen to dissociate at the capillary level for a given partial pressure of oxygen.131 The overall effect of carbon monoxide poisoning
is profound hypoxemia manifesting as cardiac and central nervous system symptoms, including coma, seizures, dysrhythmias, myocardial ischaemia, and hypotension.132,133 Carbon monoxide also binds to intracellular cytochromes, which leads to electron transport chain dysfunction and finally, direct injury at the cellular level.134 Also of great concern is carbon monoxide exposure to a fetus, which is more detrimental due to fetal hemoglobin’s greater affinity for CO compared to adult hemoglobin. As a result, CO could cause more profound effects at lower concentrations.135 Carbon monoxide poisoning can have long-term side effects such as psychiatric disorders and a fatal demyelination syndrome; however, longitudinal studies in the pediatric population are limited.136,137,138
BACTEREMIA/SEPSIS Skin provides a natural mechanical barrier to microbial invasion. In the event of a disruption in the skin’s protective quality, as in a burn, the body is at risk for systemic infection. The consequences of bacteremia and subsequent sepsis can be minimized with aggressive resuscitation and timely treatment of burn wounds with early debridement. The pathogens responsible for bacteremia are vast and can often be identified based on the mode of exposure (ie, pulmonary, urinary, gastrointestinal, etc).139 Disruption of the skin’s protective nature leads to penetration and exposure of normally sterile tissue space to bacteria, fungi, and viruses; the same process occurs to the mucosal lining of the respiratory tract in inhalation injury. The presence of necrotic tissue planes inhibits the effectiveness of innate antimicrobial responses. The issue of gut translocation has led to more speculation than confirmation regarding its contribution to bacteremia. The burn patient’s physiologic status often masks the normal response to infection (eg, tachycardia, fever, leukocytosis, etc). These signs are also seen in most trauma patients; additionally, the pediatric burn patient’s baseline hypermetabolic state provides an additional challenge in determining whether an infection is present. Important signs of systemic infection and sepsis such as hypotension, mental status changes, fluid sequestration, oliguria, and organ failure become more significant signals in light of the above discussion. Therefore, early detection and diagnosis with prompt treatment are essential in the management of bacteremia. In burn patients, sepsis usually precedes the development of multiple organ failure.39 Even in the most severe cases of pediatric burn injury, early treatment with excision and grafting can minimize morbidity and mortality.140,141 Other contributors to bacteremia include central line catheters, endotracheal tubes, disruption of the blood-brain barrier, urinary drainage tubes, and body cavity drains.
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ELECTRICAL BURNS The US Consumer Product Safety Commission estimates that 4000 injuries associated with electric extension cords are treated in emergency departments each year. Half of these injuries involving young children resulted in burns to the mouth.142 An additional 1000 children are injured secondary to electrocution after inserting an object into an electrical receptacle.143 The pediatric population is particularly susceptible to injuries in the household, especially those which occur by exposure to electrical current. The effects of these often preventable injuries can vary from minor trauma to even death. For the clinician, it is helpful to understand the effects of electrical exposure on the body in order to completely manage the sequelae of such injuries. The sources of electrical injury can vary widely: oral or hand contact, insertion of an object into an electrical outlet, direct contact with an industrial or household appliance, contact with high-voltage current secondary to an electrically charged rail, and contact with a high-powered wire while climbing a tree.144 Young children are often exposed to electrical injury from biting electrical cords or placing objects into electrical outlets; however, older children are more frequently exposed to high-voltage injuries from power lines while climbing trees or utility poles.145,146 Regardless of the mechanism, children experiencing electrical injuries can suffer devastating and disfiguring injuries. Electrical injury can be divided into 2 categories: lowvoltage and high-voltage. Low voltage is typically classified as energy less than 1000 volts (V) (eg, household current is 110V to 230V), and high voltage is considered greater than 1000V (eg, high-tension lines possess greater than 100000V and lightning strikes can exceed 10 million volts).147 Block et al described 4 ways that electrical energy can cause injury: (1) direct injury to the electrical system of the heart, resulting in dysrhythmias; (2) blunt injury from high voltage strikes (eg, lightning), leading to falls; (3) transformation of electrical energy to thermal energy, causing cutaneous burns; and (4) electroporation in highvoltage injuries allowing formation of pores in the cell membrane, leading to cellular disruption and causing death without direct thermal insult.148 One of the reasons why electrical injury is so devastating is because of the variety of ways in which tissue damage can occur. Burns secondary to an electrical current often begin at the point of contact and travel through the path of least resistance along nerves, muscle, and blood vessels.149 In electrical exposure, some claim that high-resistance tissues (eg, skin, bone, and fat) develop larger elevations in temperature and undergo coagulative necrosis, causing damage that is not visible by the naked eye.150 However, because the duration of current is miniscule (in nanoseconds), it is
difficult to justify this alone as the cause of injury. Skin has a wide range of electrical resistance, which can be altered by its external moisture content. For example, it has been demonstrated that dry skin has a higher resistance to electrical current compared to moist skin, and this results in a greater degree of superficial injury while more of the deeper structures are spared. On the other hand, less resistance is encountered with moist skin, which allows electrical current to easily reach deeper layers, causing injury to both those structures and internal organs.147 Injury from an electrical source has a wide variety of sequelae, and the amount of physiologic damage correlates with the current/voltage that flows through the body. Electricity can affect a majority of the body’s organs, including the lungs, heart, central nervous system, and musculoskeletal system. The respiratory drive can become dysfunctional due to inhibition of the central nervous system, paralysis of the respiratory muscles, or cardiac arrest from an electrical shock; however, damage to the parenchyma is not commonplace.150 The functions of the heart and brain can easily be disrupted since they rely on electrical impulses. As current makes its way through the heart it can cause arrhythmias, conduction abnormalities, and direct myocardial injury. Ventricular fibrillation is the most common arrhythmia seen in low alternating current (AC) voltage injuries. Higher rates of asystole are seen in patients receiving shocks from high AC voltage and direct current.151,154 Sudden death is a direct complication of both these arrhythmias. Children rarely suffer from postelectrical injury arrhythmias; however, nonspecific ST segment/T wave abnormalities associated with premature ventricular and junctional complexes can be seen on an EKG.145,152 Alternating current has been noted to cause sinus bradycardia and high-degree atrioventricular blockade by directly damaging the sinoatrial (SA) and atrioventricular (AV) nodes, respectively.153 Direct injury to the myocardium has also been reported in the literature and is possibly due to conversion of electrical current to thermal energy or electroporation.154 As electrical current traverses the body, it travels through nerves and can damage both the peripheral and central nervous systems. Sensory deficits, memory loss, muscle paralysis, loss of consciousness, cerebral infarction, cerebral hemorrhage, and respiratory arrest can occur as a result of severe electrical shocks.155 The musculoskeletal system can also be adversely affected. There have been reports of fractured bones and joint dislocations secondary to tetanic muscle contractions.156 Muscle is also damaged from the conversion of electrical energy to thermal energy causing rhabdomyolysis and pigmenturia that can lead to subsequent renal failure. Electrothermal injury has been well documented in the literature. In one of the earliest studies on the effects of
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electricity in animals, the pathophysiology of this type of burn was tested. The study examined the effects of alternating current at different voltage levels on the tissues of mongrel dogs and rats. Low-voltage exposure resulted in a superficial burn, while higher voltages translated into more extensive deep tissue and muscle injury. The relationship between temperature and amperage helped explain the extent of tissue damage. Small areas of electrical exposure translated into high electrical current and therefore a greater concentration of damage. Additional factors contributing to the degree of injury were linked to derivatives of Ohm’s law, which relates the ratio of voltage to amperage as it is equal to resistance. The study found that as amperage increased, resistance of the tissue decreased to a point where “a rapid climb in amperage coincided with the complete breakdown of skin resistance.”157 Overall, the “general effects vary from a minimal tingling to that of death, depending on the type of current, frequency, duration, the pathway of the current and the amount of current.”158 The clinical implications of these findings help describe the injuries sustained by children. A child who bites an electrical cord or inserts a pen into an electrical socket will most likely suffer from severe localized tissue injury. On the other hand, exposure of electrical energy to a broader surface, such as the back, will have greater dispersion of the current with less tissue injury; however, the effects on other organ systems may result in more severe damage and even death. It should be noted that either mechanism of electrical exposure can result in cardiac complications. In the United States, households are powered with alternating current, which is considered more dangerous than direct current. Exposure to alternating current can cause repetitive muscle contractions, which can lead to sudden cardiac death secondary to ventricular fibrillation (more commonly in adults than children).148,159 On the other hand, direct current affects muscle by creating a synchronous, forceful contraction which is able to throw the victim away from the electrical source, thus causing additional nonthermal trauma.150 In addition, disruption of the electrical impulses that travel through the nervous system by electrical injury can lead to possible paralysis and subsequent respiratory arrest. All these factors contribute to the exceptionally dangerous nature of this form of injury.
CHEMICAL BURNS Chemical burns result from exposure to acid, alkali, or organic (hydrocarbon) compounds. The means of exposure can occur by direct contact through skin, ingestion, or inhalation. Factors involved in determining the extent of injury include the amount and concentration of a substance, its toxicity, the mechanism of injury, and the duration of
exposure. Tissue destruction from these nonthermal burns will persist until the offending chemical has been removed or neutralized. Acids produce coagulation of the surrounding tissue. By the process of hydrolysis, proteins precipitate into the extracellular space. Alkali burns are often more extensive, causing liquefactive necrosis and disruption of tissue planes. Most chemical burns of this nature result in full-thickness tissue damage. The lipid-soluble characteristics of organic solutions complicate the management of these exposures, as chemical absorption can lead to systemic toxicity.160 In the example of hydrocarbons (eg, gasoline), the consequences of exposure can vary from a simple cutaneous burn to multiorgan failure from a more devastating systemic toxicity.161 Also, it is possible that activation of some chemicals when exposed to tissue may cause an exothermic reaction resulting in thermal injury as well. Most chemical burns can be managed with local wound care; however, a severe and extensive exposure can lead to a systemic response, as described previously in this chapter. In the event of an inhalation injury, early identification of the toxin and mechanism of exposure will be essential in the management of these patients. For example, the inhalation of ammonia within a confined space can have both short-term effects on the patient’s respiratory status as well as producing long-standing parenchymal injury to the lung tissue. If a child ingests a toxin, the effects on the upper gastrointestinal (GI) system can range from mild erythema to perforation with contamination of the mediastinum. The management of this injury should be tailored to identifying the degree of injury and its location along the GI tract. The toxicity of the chemical is the key to understanding the extent of tissue damage. If a systemic response is clinically evident, the liver and kidney will be particularly affected as the body attempts to cleanse itself of the toxin. Despite the presence of millions of different chemicals in the world in general, the pediatric patients’ exposure to these substances occurs more often in their own homes. The presence of household cleaners and solutions supplies ample opportunity for unintended exposures to young children. In a retrospective analysis of children ingesting caustic substances, the majority of chemicals were alkali in nature, resulting in 87% of the identified esophageal burns.162 Despite the type of toxin, the initial treatment to topical exposure remains the same: immediate removal of the substance, either by brushing away excess powder and/or by thoroughly lavaging the area with several liters of fluid.163 The goal is to neutralize the chemical by returning physiologic pH to the affected tissue in order to minimize denaturation of the cell’s protein matrix. In the event of inhalation of chemicals, continuous monitoring in an ICU setting and possible early intubation are the mainstays to
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COLD INJURIES Exposure to cold temperatures has similar effects on tissue as compared to thermal injury. The principles remain the same in that the degree and extent of tissue injury is related to the temperature (ie, the lower the temperature the more tissue damage) and the duration of exposure. In the case of frostbite, the extremities, especially the fingers and toes, are particularly susceptible to injury. The mechanism of frostbite injury is a 2-hit phenomenon. The first hit causes direct cellular damage due to decreased tissue temperatures. As tissues reach freezing temperatures, ice crystals form within the extracellular spaces and cause structural damage to the cell membranes.164 The resultant membrane damage results in intracellular dehydration due to changes in the electrochemical/osmotic gradient allowing free water to flow out of cells. Severe alterations in the concentrations of intracellular electrolytes can lead to cell death. Declining tissue temperature produces a precipitation of intracellular ice crystals that will eventually expand, destroying the cell.165 In addition, alterations in blood flow to the skin due to tissue cooling result in cycles of alternating vasoconstriction and vasodilation, causing partial freezing and thawing that further enhances cellular damage.166,167 The second hit is due to progressive dermal ischemia that is related to the repeated “freeze/thaw” cycles releasing a variety of inflammatory mediators (eg, prostaglandins, thromboxanes, bradykinin, and histamine). Consequently, significant endothelial injury, tissue edema, cessation of dermal blood flow, and eventual skin necrosis occurs.164 The damaged tissue can be graded according to its appearance by the following classification: first-degree— white, hard plaque; second-degree—clear fluid, superficial blisters; third-degree—purple fluid, deep blisters, and discolored skin; and fourth-degree—necrotic tissue.145 The management and treatment of these injuries focuses on rapidly rewarming the tissue, maintaining aggressive wound care with debridement of nonviable tissue (if needed), and minimizing systemic effects.
CONCLUSION The pathophysiology of thermal and nonthermal burn injuries in the pediatric population is still not completely understood. In burn trauma, the complex balance of immunologic, hematological, and inflammatory systems is disrupted as the normally protective tissue planes in the body are destroyed. The mechanism of the injury and the duration of the exposure help dictate the extent of the burn. The key components to evaluating a burn are the following: establishing an accurate extent of the injury, understanding the local and systemic effects of burns, and recognizing the presence of secondary organ injury. The immunoinflammatory response to burn trauma will affect the patient’s treatment and recovery. Much of the research on the immunoinflammatory system over the last 2 decades has helped to shed some light into this response. Inflammatory substances have been shown to play a major role in the local and systemic effects; however, more research is needed in these areas in order to transform the science into clinical application.
KEY POINTS • It is important for clinicians to understand the pathophysiology of burn injury when evaluating and treating pediatric burn patients. • The severity of the injury can be measured by calculating the burn size, identifying the mechanism of injury and duration of exposure, and accounting for associated comorbidities. • Mortality and morbidity are directly related to the severity of the injury. • The immunoinflammatory system can produce both a local and a systemic response, which in turn can have deleterious effects on the body’s organ systems—severe burns can lead to multiple organ dysfunction syndrome and death. • More research on pediatric burns is required to further improve care in this population.
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TABLES TABLE 1 Descriptions of burn depth. Burn Type
Definition
Physical Signs
Superficial (First-Degree)
Injury only to the epidermis
Skin is pink or slightly reddish, dry with no blister formation, mildly painful to touch.
Partial-Thickness (Second-Degree) 1. Injury to the epidermis and upper 1/3 of dermis 2. Injury to the epidermis, majority of dermis, and skin appendages
1. Superficial 2. Deep
Injury to epidermis, dermis, and subcutaneous tissue
Full-Thickness (Third-Degree)
1. Skin is bright red or mottled in color; presence of bullae/blisters, wet and weeping; blanches when touched; extremely painful to touch or with air movement. 2. Skin is dark red to whitish/yellowish; ruptured bullae and minimal moisture; less painful to touch compared to superficial partial-thickness burn; decreased sensation to pinprick, but intact to deep pressure. Skin is charred or white in color with dry texture and leathery feel; thrombosed vessels visible through eschar; nonblanching and nonpainful; insensate to touch.
TABLE 2 Body area versus appropriate body surface area percentage in pediatric patients. Area
Birth to 1 Year
1–4 Years
5–9 Years
10–14 Years
15 Years
Head
19%
17%
13%
11%
9%
Neck
2%
2%
2%
2%
2%
Anterior Trunk
13%
13%
13%
13%
13%
Posterior Trunk
13%
13%
13%
13%
13%
2.5% each buttock
2.5% each buttock
2.5% each buttock
2.5% each buttock
2.5% each buttock
Buttock (Left or Right)
1%
1%
1%
1%
1%
Upper Arm (Left or Right)
4% each upper arm
4% each upper arm
4% each upper arm
4% each upper arm
4% each upper arm
Lower Arm (Left or Right)
3% each lower arm
3% each lower arm
3% each lower arm
3% each lower arm
3% each lower arm
Hand (Left or Right)
2.5% each hand
2.5% each hand
2.5% each hand
2.5% each hand
2.5% each hand
Thigh (Left or Right)
5.5% each thigh
6.5% each thigh
8% each thigh
8.5% each thigh
9% each thigh
Leg (Left or Right)
5% each leg
5% each leg
5.5% each leg
6% each leg
6.5% each leg
Foot (Left or Right)
3.5% each foot
3.5% each foot
3.5% each foot
3.5% each foot
3.5% each foot
Genitalia
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97. Ramzy PI, Wolf SE, Irtun O, Hart DW, Thompson JC, Herndon DN. Gut epithelial apoptosis after severe burn: effects of gut hypoperfusion. J Am Coll Surg. 2000; 190(3): 281–283.
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liver in severely burned pediatric patients: autopsy findings and clinical implications. J Trauma. 2001; 51: 736–739. 80. Herndon DN, Hart DW, Wolf SE, Chinkes DL, Wolfe RR. Reversal of catabolism by beta-blockade after severe burns. N Eng J Med. 2001; 345: 1223–1229.
98. Wolf SE, Ikeda H, Matin S, Debroy MA, Rajaraman S, Herndon DN. Cutaneous burn increases apoptosis in the gut epithelium of mice. J Am Coll Surg. 1999; 188(1): 10–16. 99. Othman M, Aguero R, Lin H. Alterations in intestinal microbial flora and human disease. Gastroenterology. 2008; 24(1): 11–16.
81. Jeschke MG, Barrow RE, Herndon DN. Recombinant human growth hormone treatment in pediatric burn patients and its role during the hepatic acute phase response. Crit Care Med. 2000; 28: 1578–1584.
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hormone treatment in pediatric burns: a safe therapeutic response. Ann Surg. 1998; 228: 439–448. 83. Ferrando AA, Sheffield-Moore M, Wolf SE, Herndon DN,
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85. Holm C, Hörbrand F, von Donnersmarck GH, Mühlbauer W. Acute renal failure in severely burned patients. Burns. 1999; 25(2): 171–178.
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conservative versus early excision. Ann Surg. 1989; 209: 547–553.
gastrointestinal tract in the development of burn sepsis. Plast Reconstr Surg. 1992; 90(3): 524–531. nutrition support for burn injuries. Cochrane Database of Systematic Reviews. Issue 3, Art. No.: CD005489. The Cochrane Library. http://www.cochrane.org/reviews. Jul 19, 2006. 105. Pruitt BA Jr. Complications of thermal injury. Clin Plast
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Effects of thromboxane synthetase inhibition on postburn mesenteric vascular resistance and the rate of bacterial translocation in a chronic porcine model. Surg Gynecol Obstet. 1992; 174: 125– 132. 108. Reines HD, Halushka PV, Cook JA. Plasma thromboxane
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93. Rodriguez JL, Miller CO, Garner WL, et al. Correlation of the local and systemic cytokine response with clinical outcome following thermal injury. J Trauma. 1993; 34: 684–694.
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131. Roughton FJ, Darling RC. The effect of carbon monoxide on
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pulmonary pathophysiology associated with inhalation injury. Resuscitation. 1986; 14: 43–59. 115. Herndon DN, Traber DL, Traber LD. The effect of resuscitation on inhalation injury. Surgery. 1986; 100: 248–251. 116. Calhoun KH, Deskin RW, Garza C, et al. Long-term airway
sequelae in a pediatric burn population. Laryngoscope. 1988; 98: 721–725.
baric oxygen in suspected carbon monoxide poisoning. JAMA. 1981; 264: 2478–2481. the oxyhemoglobin dissociation curve. Am J Physiol. 1944; 141: 17–31. 132. Colburn RF, Mayers LB. Myglobin O2 tension determined
from measurement of carboxymyoglobin in skeletal muscle. Am J Physiol. 1973; 220: 66–74. 133. Cancio LC. Current concepts in the pathophysiology and
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carbon monoxide hypoxia in the rat brain. J Clin Invest. 1992; 90: 1193–1199.
117. Merrel P, Mayo D. Inhalation injury in the burn patient. Critical Care Nurs Clin North Am. 2004; 16: 27–38.
135. Longo LD, Hill EP. Carbon monoxide uptake and elimin-
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ducible nitric oxide synthase (iNOS) inhibition on smoke inhalation injury in sheep. Shock. 2000; 13: 261–266. 120. Linares HA, Herndon DN, Traber DL. Sequence of morpho-
logic events in experimental smoke inhalation. J Burn Care Rehabil. 1989; 10: 27–37. 121. Traber DL, Herndon DN, Stein MD, et al. The pulmonary lesion of smoke inhalation in the ovine model. Circ Shock. 1986; 18: 311–323.
136. Parrish RA. Smoke inhalation and carbon monoxide poison-
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122. Herndon DN, Traber DL, Niehaus GD, et al. The pathophysiology of smoke inhalation in a sheep model. J Trauma. 1984; 24: 1044–1051.
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123. Cox RA, Burke AS, Soejima K, et al. Airway obstruction in
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sheep with burn and smoke inhalation injuries. Am J Respir Cell Mol Biol. 2003; 29(3, pt 1): 295–302.
142. Consumer Product Safety Commission. http://www.cpsc.
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144. Rabban JT, Blair JA, Rosen CL, Adler JN, Sheridan RL.
Treatment of the seriously burned infant. J Burn Care Rehabil. 1998; 19(2): 115–118. atric patient with burns. J Burn Care Rehabil. 1993; 14(1): 3–8.
gov/cpscpub/pubs/524.html. Sept 15, 2008 Mechanisms of pediatric electrical injury: new implications for product safety and injury prevention. Arch Pediatr Adolesc Med. 1997; 151(7): 696–700.
126. Youn YK, Lalonde C, Demling R. Oxidants and the pathophysiology of burn and smoke inhalation injury. Free Radic Biol Med. 1992; 12: 409–415.
145. Celik A, Ergün O, Ozok G. Pediatric electrical injuries: a
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7
C H A P T E R
S E V E N
PEDIATRIC BURN RESUSCITATION BRADLEY J. PHILLIPS, MD
OUTLINE 1. Introduction a. General Incidence and Mortality Figures b. Early Studies in Brief c. Development of Resuscitation Formulas d. Colloid e. Hypertonic Saline f. Endpoints g. Overresuscitation and Complications
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2. General Goals and Objectives 3. Burn Shock Resuscitation
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a. Pathophysiology in Brief b. Resuscitating the Burned Child Isotonic Crystalloid Hypertonic Saline
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INTRODUCTION General Incidence and Mortality Figures In the year 2000, an estimated 10000 children younger than the age of 18 years were hospitalized with burn-associated injuries in the United States.1 Although the majority of pediatric burn patients survive and go on to lead healthy, productive lives, deaths from fire and burn-related injuries are still the second leading cause of unintentional death for 1- to 9-year-olds and the third leading cause for African American 10- to 19-year-olds.2 Male pediatric burn patients considerably outnumber female patients,1 and African Americans are disproportionately affected in the 1-to9-year-old age group.2 Most importantly, children under the age of 4 years continue to have a 2 to 2.7 higher risk of mortality (dependent upon age) as a result of burn-related injuries compared to older children.3 However, data from the National Burn Repository for the years 1995 to 20054
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Colloid Alternatives to Albumin or Plasma The Very Young Patient Inhalation Injury in Children Abdominal Compartment Syndrome c. Choice of Fluids and Formulas Baxter–Parkland Cincinnati Galveston d. Vasopressors, Hemodynamics, and Adjunctive Measures e. Failure of Resuscitation: Now What?
4. Fluid Replacement Following The Resuscitation Phase 5. Conclusion 6. Key Points 7. References
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show a mortality rate of about 1.5%, which is about less than half the typical rate for the years 1982 to 1985.5 This significant achievement is in part due to improvements in burn shock resuscitation and an aggressive approach to overall care, including intensivist-directed protocols.
Early Studies in Brief The first 48 hours of treating a pediatric burn patient are by far the most critical due to burn-induced hypovolemic shock and vascular compartmental imbalance. The extensive fluid loss that starts within minutes of the injury was first recognized by Underhill,6 who in 1921 studied the victims of the Rialto Theater fire in New Haven, Connecticut. This concept was also understood by Cope, the senior surgeon at Massachusetts General Hospital, who, with assistance from Moore, his resident, treated many of the burn victims from the 1942 Cocoanut Grove nightclub fire in Boston. Their subsequent research led to an approach in which fluid was given to combat the consequences of the
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P E DIAT R IC B UR N R E S US C I TAT I O N fast-developing edema and loss of intravascular volume.7 A team led by Evans et al8 from the Medical College of Richmond, however, was the first to report a simple surface area/weight-based formula that utilized a 1:1 ratio of intravenous electrolytes (crystalloid) and colloids (highmolecular-weight materials, such as proteins or dextrans) to guide resuscitation; this combination was then titrated to individual needs based upon urine output and hemoglobin concentration. The Evans formula, as it became known, was quickly revised by researchers at the Brooke Army Medical Center in San Antonio to include Ringer’s lactate solution (the Brooke formula).9 In part this was due to a recognition that metabolic acidosis played a role in burn shock and that adding sodium bicarbonate helped correct the base deficit.
Development of Resuscitation Formulas Based upon differing schools of thought, a number of resuscitation formulas and various methods for calculating their infusion rate were published from the 1950s to the 1970s. One of the most highly debated points was (and is) the use of colloid. A key study conducted by Baxter and Shires in 1968,10 which employed radioisotope dilution techniques, demonstrated that the composition of edema fluid in early postburn wounds was isotonic with respect to plasma and that the protein concentrations in the two compartments were essentially similar. This led to the authors’ conclusion that adding protein during resuscitation was futile because it simply escaped into the interstitial space, which was the primary reason why the formula that Baxter11 later developed was colloid-free. This approach became known as the Parkland formula, named after the Parkland Hospital in Dallas, Texas, where Baxter practiced; at present, it is the most commonly used formula in the United States. The Baxter-Parkland formula uses lactated Ringer’s solution and is infused at a rate of 4 mL/kg/percent of burn area for the first 24 hours of resuscitation, with one half administered in the first 8 hours. A review conducted by Baxter12 of 516 children under the age of 12 years admitted during the years 1973 to 1977 indicated that only 2% exceeded the guideline of 4 ± 0.3 mL, although the deviation rate for adults was 30%. In this review, resuscitation endpoints were urine output (>40 mL/hour) and cardiac output. Interestingly, only 4 deaths occurred in this pediatric group: all had burns exceeding 50% of TBSA (total body surface area), all were younger than 3 years, and all experienced a delay of 3 to 6 hours in resuscitation. In their review of 177 children under the age of 13 years, conducted at the Intermountain Burn Center in Salt Lake City, Utah (1978-1985), Merrell et al13 also employed the Parkland formula, modified to include basal fluid requirements.
Interestingly, their intravenous infusion rates were titrated to a urinary endpoint of 1 mL/kg/h. Clinical assessment included serum electrolyte levels and hematocrit, supported by data from urinary catheters, arterial lines, and at times CVP (central venous pressure) catheters. Children who required twice the predicted amount of crystalloid were switched to hypertonic lactated Ringer’s solution (180-230 mEq/sodium/L), and exchange transfusion at 1.5 times the patient’s calculated blood volume was initiated in unresponsive patients. In this study, resuscitation volumes for children versus adults were reversed compared to the study of Baxter,12 with an average of 5.80 mL/kg/% BSA (burn surface area). Early mortality rate was 7% versus 15% for the final mortality rate. Two points emerge from a comparison of these studies: (1) considerably higher resuscitation volumes were reported by Merrell et al, and (2) the mortality rates were much higher in the study of Merrell et al13 compared to that of Baxter,12 although not out of line with previously reported studies.14,15 In addition, based upon regression analysis, Merrell et al13 were among the first to question the long-held idea that the higher surface area to body weight ratio in children was responsible for the increased resuscitation volumes. The higher resuscitation volumes reported by Merrell et al13 also caused the investigators at the US Army Institute of Surgical Research to initiate a retrospective study of their patients.16 This group utilized the modified Brooke formula, which is composed of lactated Ringer’s solution at 3 mL /kg/percent of burn area—less than the Parkland formula— titrated to 1 ml/kg/h urine output. The formula was administered in the same manner as Parkland, although the calculation of maintenance fluid requirements was different. Even though the mean age of patients was much younger (2.2 years vs. 4 years), the injuries were more severe in terms of % BSA (41.7% vs. 27.3%), mean full-thickness percentage was greater (23.7% vs. 12.6%), and the associated inhalation injury rate was much higher (21% vs. 12%), the results demonstrated that the mean resuscitation volume was 3.91 mL/kg/percent of burn area, only a 30% excess compared to a 45% excess for Merrell et al.13 Do these results mean that groups of patients at different facilities were overresuscitated or underresuscitated with regard to volume compared to other groups? This is not an easy question to answer, but it is a key point, because the problem of overresuscitation has become increasingly frequent since the 1980s. Some investigators believe that more aggressive endpoints and inotropic treatment are the major causes, as exemplified by a recent study that randomized patients to 1 of 2 possible treatments.17 In this trial, the control group was resuscitated with the Baxter-Parkland formula (4 mL/kg/percent of burn area; 5.6 mL/kg/percent of burn area in cases of verified inhalation injury) using conventional endpoints (minimum urine output 0.5 mL
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/kg/h, mean arterial pressure >70 mmHg, and central venous pressure >2 cm H2O above PEEP [positive end-expiratory pressure]). In the experimental group, the endpoint goals were an intrathoracic blood volume index (ITBV) >800 mL/m2 and a cardiac index >3.5 L/min/m2. Although the mean age of the patients was 41.3 years, clearly marking this study as an adult investigation, the mean resuscitation volume during the first 24 hours of the control group almost matched the predicted volume based upon the Baxter formula (16.2 L vs. 16.0 L). However, the experimental group received 27.1 L. Mortality rates were slightly higher in the control group compared to the experimental group (40% vs. 32%). The message from this study seems to be that more aggressive endpoints may account for excessive crystalloid resuscitation, but even more importantly, may not confer a significant benefit when the risks of overresuscitation are taken into account. This point will be further discussed in the context of burn pathophysiology.
Colloid Not all burn specialists agree with just using the Parkland or modified Brooke formula to resuscitate pediatric burn patients during the first 24 hours. For example, the group at the Shriner’s Burns Institute in Galveston by the late 1970s added both glucose and colloid to the basic lactated Ringer’s solution (47.5 g/L glucose, 12.5 g/L albumin); significant amounts of antacids (Maalox, 30 mL/m2 body surface area) were also given orally or through a nasogastric tube.18 In this small study of 30 children, no mortality occurred as result of the treatment, although 17% later died of infectious complications. In addition, there was no reported overresuscitation, although this is hard to judge due to the presentation of the data and the fact that relatively vague endpoints were used. The effect of adding colloid to the resuscitation formula was investigated on dogs by the same group to test the hypothesis that colloid added early after a burn could decrease the amount of plasma lost to interstitial spaces.19 The results demonstrated that fluid loss 6 hours postburn was much higher when only lactated Ringer’s solution was used compared to adding 5% albumin. The fluid loss was also inversely proportional to the amount of albumin administered. Furthermore, the severely depressed cardiac output that occurs after a burn was modestly increased relative to the output 2 hours postburn in proportion to the amount of albumin given. Hematocrit values were also much more normal in the group of dogs given albumin (likely a reflection of dilution in the LR group). The conclusion of these experiments—in agreement with previous observations and experiments—seemed to confirm the concept that adding colloid to the resuscitation approach decreased the amount of fluid escaping to the extravascular space.
Demling’s group,20 based in Boston, agreed with the general principle of adding colloid, but their experiments suggested that adding colloid was not helpful until recovery of membrane semipermeability began. Moreover, they favored the use of dextrans because of higher colloid osmotic pressure and lower expense compared to albumin. In fact, in a sheep model, using CVP and pulmonary wedge pressure (PWP) as endpoints, one group was resuscitated with lactated Ringer’s solution commencing 2 hours postburn, while the experimental group received a 10% solution of low-molecular-weight dextran in saline. The findings were unequivocal: the control group required a resuscitation volume of 75 mL/kg while the experimental group required only 35 mL/kg, with mean urine outputs of 65 mL/ kg and 40 mL/kg, respectively. The net fluid requirements translated to 3.5 mL/kg/% TBSA and 1.5 mL/kg/% TBSA, respectively. By the mid-1980s, therefore, it should have been clear that adding colloids to the resuscitation approach— for example, 12 hours postburn—was a more effective method than just using isotonic crystalloid. Why did this not happen? Principally for 2 reasons: first, there was no evidence that adding colloid improved outcomes in terms of mortality—indeed, to the contrary, a meta-analysis conducted by Schierhout and Roberts21 later showed that colloid administration was associated with an increase in mortality in critically ill patients (however, the majority of these were not burn patients); and second, a movement to use hypertonic saline had gained support.
Hypertonic Saline Based on earlier work, Monafo et al22 published a key paper in 1973 which appeared to demonstrate that the use of hypertonic saline (240-300 mEq of sodium) could substantially reduce the amount of fluid necessary to resuscitate a patient while providing the same overall sodium load. The concept was a simple one: reduce the shift of intravascular water into extracellular spaces by increasing the osmolality of the plasma. One of the additional benefits was thought to be an increase in urine output because the kidneys are required to deal with a higher osmotic work load. Although Monafo et al22 were unable to observe a benefit with pediatric patients, Caldwell and Bowser23 undertook a prospective study to determine if this was truly the case. Although a small study (N = 37) comparing the use of hypertonic saline (experimental) against lactated Ringer’s solution (control), the authors reported that despite a 38% greater water load received by the control group, the cumulative urine volume was not significantly greater until 48 hours postburn (2.1 vs. 1.2 mL/kg/percent burn). Monafo et al24 then published a subsequent study in
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P E DIAT R IC B UR N R E S US C I TAT I O N 1984 that involved 74 patients with a greater burn injury (mean 63% TBSA) and a high percentage of inhalation injury (47%). Again, patients treated with hypertonic saline required significantly less fluid (44% less than a control group treated with lactated Ringer’s solution). Water and sodium load requirements generally increased in concert with larger burns, although the correlation was poor. Patients older than 60 years required significantly higher water and sodium loads, although the authors reported no excess requirements regarding inhalation injury. Factors that accounted for the high mortality rate (42%) included advanced age and inhalation injury. While there was a significant difference between water and sodium loads required by survivors and nonsurvivors, there was no significant correlation between the amount of sodium administered in the resuscitation fluid and outcome, which used urine output as the endpoint and mortality rate as outcome. Gunn et al25 also studied adult burn patients using hypertonic lactated saline (HLS) and lactated Ringer’s solutions (LR), although the study was smaller (N = 51) and the mean burned area was much smaller (23%). However, the investigators did not observe any significant difference in any of the parameters measured, except for differences in pulmonary artery wedge pressure (PAWP) and stroke volume index. What is also noteworthy in this trial is that patients received colloid (fresh frozen plasma) to maintain a serum albumin over 2 g/dL. In addition, many patients were given enteral feeding support during the first 24 hours. Since no mortality data were reported, it is difficult to correlate the resuscitation procedures with outcomes and compare this approach to other studies. Resuscitation volumes were 5.4 mL/kg/percent burn for both groups, which is much higher compared to other literature values of the time for HTS treatment, and ought to have been lower if the plasma given actually had a substantial impact. In conclusion, this was one of the first papers to report “disappointing” results with HTS. In 1995, Huang et al26 published an alarming report showing that resuscitation with HTS was associated with a 2-fold increase in mortality rate compared to patients resuscitated with LR. This was attributed in part to a 4-fold increase in renal failure. Moreover, while total resuscitation volumes were lower during the first 24 hours in the HTS group compared to the 2 LR groups, after 48 hours cumulative fluid loads were similar and total sodium load was higher in the hypertonic saline group. The results of this study were unexpected given the outcomes of previous investigations, but in reality, no one had attempted such a rigorous examination of outcomes before. It had been known for some time that the consequences of hypernatremia could be devastating, even when guidelines restricting plasma sodium levels to less than 160 mEq/L
were followed.24,25 In particular, subarachnoid and subdural hemorrhages were known risks associated with hypernatremia.27 Moreover, correcting hypernatremia too quickly carries attendant penalties.28,29 Despite minor deviations compared to previous hypertonic saline resuscitation protocols, the ensuing debate did not find any major flaws with the study, and the paper today remains a cautionary tale for all who still use HTS in resuscitating burn patients. Perhaps the most illuminating item to come from this investigation is that in hypovolemic patients, HTS infusions per se do not cause the kidney to increase its output, as will be discussed in a later section of this chapter.
Endpoints Prior to the late 1980s, clinicians principally used urinary and cardiac output parameters as their primary endpoints for resuscitation of burn patients during the first 48 hours, augmented by vital signs and mental status. However, a few practitioners had gained experience with invasive cardiac monitoring in difficult cases, and a key series was published by Dries and Waxman in 1991.30 This review of 14 patients documented fluid challenges during resuscitation (boluses of fluid given within 30 minutes, varying from 0.5 L to 2 L) by observing urine output as well as hemodynamic and oxygen transport variables obtained from flow-directed, balloon-tip pulmonary artery catheters (PACs) and cardiac output parameters acquired by using the thermodilution technique. All the patients were critically ill, and 9 patients died of sepsis after the first 48 hours. After fluid challenge, both cardiac index (CI) and oxygen delivery (DO2) increased, and in half of the patients, VO2 (oxygen consumption) increased concurrently with fluid challenge, although changes in this parameter were not detected by vital signs or urine output. These findings suggested that in some patients, an apparently acceptable set of vital signs and urine output masked an inadequate plasma volume to meet increased oxygen and metabolic demands. In other words, a tissue oxygen deficit occurred in 50% of the patients—this was recognized only by invasive monitoring and would have gone unnoticed using traditional endpoints. Thus in theory, these authors suggested that invasive monitoring allows titration of resuscitation volumes, infusing additional volume in cases of tissue oxygen deficit, but minimizing volume in those cases in which it is not needed, thus potentially decreasing the edema. Against these new endpoints, however, must be weighed the attendant risks that invasive monitoring brings, especially in the young neonate or infant. Similar invasive monitoring trials had been going on in the field of severe trauma, based on earlier work by Shoemaker and others.31,32 For example, Fleming et al33 conducted a randomized controlled trial (RCT) enrolling patients into
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either a control group (resuscitation guided by vital signs, hemoglobin levels, CVP, wedge pressure, and urine output) or an experimental group in which resuscitation was guided by achieving a DO2 target of 670 mL/min/m2, a VO2 target of 166 mL/min/m2, and a CI of 4.52 L/min within 24 hours of admission and maintaining these goals through the first 48 hours of resuscitation. The mortality rates were 23% for the experimental group and 44% for the control group, which was not statistically significant. However, for the 47 study patients that had more severe blood loss (3-10 L), the difference was more pronounced: 18% vs. 44%. Furthermore, in the 27 patients that reached supranormal values within 24 hours, the mortality rate (15%) was significantly lower compared to those patients who took longer to reach the targeted values (54%). Interestingly, mean cardiac and oxygen transport parameters for the control and experimental groups started diverging 8 hours postadmission. These results encouraged similar studies to be undertaken in the field of burn resuscitation. For example, Schiller et al34 undertook a retrospective review of patient records from 1990 to 1994 and divided them into 3 groups: (1) 53 patients for whom hyperdynamic circulatory endpoints were utilized by employing a PAC during 1992-1993 (index group); (2) a match-paired group of 33 patients in which traditional endpoints were utilized during 1990-1991 (control group); and (3) a third group of 30 patients designated as a protocol group, in which a written resuscitation protocol was utilized that incorporated lessons learned from previous experiences prior to 1994 following an aggressive series of oxygen transport and hemodynamic endpoints. Mortality steadily decreased over the time period studied, and the incidence of resuscitation failure and associated death significantly decreased during the same time period. Mortality rates were 48% for the control group, 32% for the index group, and 10% for the protocol group, despite comparable BSAs, age, and inhalation injuries. Resuscitation volumes for the control group were close to that predicted by the Parkland formula, whereas volumes for the other groups were much higher. The authors concluded that “resuscitation of burn victims to a higher circulatory standard improves microcirculatory flow, tissue perfusion, and tissue organization, thereby protecting organ function.”34(p14) Despite these and other encouraging studies, many clinicians were far from being persuaded that invasive monitoring, particularly that which required PACs, was the wave of the future, especially when the study of Connors et al35 was published in JAMA in 1996.36,37 Using case-matching analysis, Connors et al35 found that patients with a PAC had an increased 30-day mortality (OR 1.24, 95% CI: 1.03-1.49; OR = odds ratio, CI = confidence interval). Moreover, the mean cost per hospital stay was $49300 with a PAC and
$35700 without it. This was a large (N = 5735), wellconducted study whose results were surprising, in part because no other study had so vividly demonstrated such a lack of cost-benefit, and there were no ready explanations for the increased mortality. However, while this study raised the alarm concerning PACs, it did not impede advances in the search for less invasive and more elegant approaches to setting aggressive goals for burn resuscitation endpoints. One such approach is ITBV: intrathoracic blood volumes. ITBV has most recently been measured by the transpulmonary double-indicator dilution (TPID) technique, which employs a CV catheter and an arterial fiberoptic thermistor catheter inserted into the femoral artery.38 TPID utilizes both temperature and dye dilution principles to obtain a variety of cardiac parameters,39 and includes the possibility to calculate extravascular lung water (EVLW), which can offer an accurate estimate of interstitial water in the lung. A fair correlation between ITBV and CI was obtained (R2 = 0.445) in an observational study of 24 burn patients, although the correlation between ITBV and DO2 was poor (R2 = 0.247), and there was no correlation between CVP and CI or DO2. However, the correlation between ITBV and DO2 did permit optimization of oxygen delivery, although the end result was a substantially larger resuscitation volume compared to the predicted volumes using the Parkland formula. Importantly, ITBV-guided resuscitation allowed preload restoration and peripheral oxygen delivery within 24 hours. EVLW did not increase in parallel with ITBV, suggesting, as other studies had found,40,41 that pulmonary complications are less associated with crystalloid resuscitation per se than with sepsis or pulmonary capillary permeability. A more recent investigation has also studied the relationship between CVP and total circulating blood volume index (TBVI) during burn resuscitation,42 its authors concluding that CVP is more influenced by external pressures, such as intra-abdominal pressure, rather than TBVI, and is not a good endpoint for resuscitation. On the other hand, TBVI correlated well with cardiac output and stroke volume (R2 = 0.550, R2 = 0.606, respectively).
Overresuscitation and Complications In recent years, a trend to much higher resuscitation volumes than was originally intended by Baxter has become apparent.43,44 This phenomenon has been termed fluid creep by Pruitt.45 Its origin is likely to be multifactorial and is probably caused by more aggressive endpoints and a higher use of opiates and other analgesics (which blunt systemic responses).46 One consequence of these aggregate phenomena is a rise in the incidence of abdominal compartment syndromes. In 1995, Greenhalgh and Warden47 highlighted
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P E DIAT R IC B UR N R E S US C I TAT I O N this problem for the first time in burn patients by measuring the intra-abdominal pressure (IAP) in 30 children with large burns. They found that patients who had 1 or more measurements exceeding 30 mmHg during the monitoring period had (1) significantly larger burns, (2) an increase in septic episodes, and (3) a higher mortality rate. However, they also noted that relatively simple interventions, or even laparotomy (in order to relieve intra-abdominal pressure), could be instituted with good outcomes. In 2005, O’Mara et al48 reported the results of a randomized controlled trial (RCT) that was conducted to determine if the use of colloid (fresh frozen plasma, 75 mL/kg, titrated against urine output 0.5-1 mL/kg/h) and lactated Ringer’s solutions (2 L over 24 hours) (experimental group) could lower intra-abdominal pressure in comparison to utilization of the Parkland formula in adult burn resuscitation. The results were startling: the mean IAP for the control group was 10.6 mm Hg vs. 26.5 mm Hg for the experimental group, and while 2 patients in the experimental group developed IAPs > 25 mm Hg, only 1 patient in the control group maintained an IAP of < 25 mm Hg. In addition, the control group required 24% more fluid than the experimental group. Mortality was 27% in the control group and 19% in the experimental group. Although this was a small trial in terms of numbers (N = 15 for the control group, N = 16 in the experimental group), and thus little emphasis should be placed on the difference between mortality rates, the study unequivocally showed a relationship between IAP and resuscitation volume. Although many other studies have confirmed this relationship, we do not know if excessive fluid is the only cause of ACS (abdominal compartmental syndrome). However, it is clear that should IAP rise above a certain critical level (most authors agree > 25 mm Hg), swift intervention should take place to ensure that ACS does not develop.
GENERAL GOALS AND OBJECTIVES Children are more sensitive than adults in regard to resuscitation, and since their physiological reserve is less, resuscitation must be more precise. The general goals for resuscitation during the first 48 hours are to attain correct vascular volume, maintain tissue perfusion, and improve acid-base balance—all goals to be achieved without exacerbating postburn edema, evidenced at the extreme by development of ACS. Addressing the oxygen deficit and restoring cardiac parameters to preburn levels are also important goals, although often these cannot be achieved within the first 48 hours due to physiological limitations. As discussed earlier, how these goals are achieved is still a matter for debate since many options are viable. The classic endpoint for children weighing < 30 kg is still a urine
output of 1 mL/kg/hour, as was reiterated at the State of the Science meeting in 2006,49 although in practice, a range of 1.0 to 1.5 mL/kg/hour is acceptable for the first 24 hours, provided that there are no concurrent signs of underresuscitation or overresuscitation.16 Children approaching 50 kg in weight, however, are better served using adult endpoints. For the first several hours, urine output should be checked every 15 minutes. Should other endpoints besides urinary output be utilized in resuscitation of children with severe burns? Given that invasive monitoring has not been validated in adults with regard to improved mortality either in burns or trauma,50,51 this approach should be reserved for more serious cases. Pham et al52 recently conducted a review of invasive monitoring in adults using the grading scheme of Sackett.53 The level of evidence was mostly Class V. Their recommendation (grade level A) was to not use a preloaddriven strategy, nor to use invasive monitoring in general unless special circumstances warrant. In children, most providers use femoral or internal jugular triple lumen catheters to monitor CVP and oxygen parameters rather than pulmonary artery catheters. In addition, since children have significant cardiopulmonary reserve and reflex tachycardia is frequently present, mental clarity, pulse pressures, arterial blood gases, distal extremity color, capillary refill, and body temperature, as well as the modified Glasgow coma scale when appropriate, should all be assessed to further guide resuscitation.56 In parallel to trauma studies, burn studies57-60 have also shown that monitoring serum base deficit and lactate can provide additional information regarding the generalized state of burn shock. Although there is some dispute whether plasma lactate is a better predictor of outcome compared to base deficit, serial measurements of either of these variables seem to be superior to gastric tonometry61 as a means of assessing burn-induced metabolic acidosis. Several factors must also be considered when resuscitating children, since they will impact the methods by which goals are achieved: BSA percentage, presence of inhalation injury, electrolyte infusion rates, glycogen reserves, and time since the burn was inflicted. In terms of burned surface area, children are more at risk compared to adults. For example, in this age group, intravenous resuscitation is commonly required for burns with a surface area of 10% to 20%.12,13,62 Children also require greater resuscitation volumes compared to adults because of larger maintenance volumes resulting from a higher surface to weight ratio.13,16,63-65 Intravenous boluses should be avoided (if possible) during the resuscitation phase, since this method likely aggravates the escape of fluid into the extravascular space. If venous access is initially
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compromised, bone marrow compartments in the anterior tibial plateau, medial malleolus, anterior iliac crest, and distal femur can be safely infused for children up to 8 years of age using a gravity drip, provided the bone is sufficiently soft for needle penetration (ie, intraosseus infusion).56,66 After decompression of the stomach,67 enteral nutrition should be established as soon as possible. This is particularly important for children with high TBSAs given the associated metabolic demands. Such feeding can prevent upper gastrointestinal bleeding, obviate the need for antacids, and may assist in preventing subsequent infection.68 Although vomiting is always a risk factor in children, administration of antiemetics can be used to help facilitate overall management.69 Various formulas are available for determination of caloric needs for different age groups and TBSA percentages.70-72 One overriding important message that has remained constant, despite the various formulas or fluids utilized, is this: fluid resuscitation and the restoration of intravascular volume should not be delayed. This might seem obvious, but one study demonstrated that the incidence of sepsis, renal failure, and mortality was significantly higher in burned children receiving fluid resuscitation 2 or more hours after the burn injury (P < .0001).73
BURN SHOCK RESUSCITATION Pathophysiology in Brief Although the pathophysiology of burn shock is covered in a later chapter, a short summary will help provide the basic understanding for fluid resuscitation and why some of its aspects are still contentious. Burn injury comprises hypovolemic shock as well as direct injury at the cellular level. Although heat is responsible for most of the damage in burned tissue, the effects in cells distal to the burn are mediated by a host of entities, including histamine, bradykinin, vasoactive amines, hormones, prostaglandins, leukotrienes, and neutrophils. Oxidative damage, including the release of lipid peroxidation products, results in endothelial cell damage, the most critical aspect of which is increased capillary permeability.74 Matrix elements, such as collagen and hyaluronic acid,75,76 are also degraded by pro-oxidants, which could be one cause of the negative interstitial pressure encountered.74 Thus, treatment with antioxidants ought to reduce the edema associated with the burn, and many studies have reported such results, the most intriguing of which has been the use of high doses of vitamin C.77 The vasoconstriction induced by thromboxane TXA2, which is partly responsible for the ischemic flow in affected tissues, coupled with
the local vasodilation initiated by PGI2, also potentiate the resultant edema.74 The vascular changes brought about by these mediators can be best understood through the Starling equation, which governs fluid movement in the capillary bed:74 Q = Kf (Pcap – Pi) + σ (πp – πi) in which Q represents the fluid filtration rate that peaks 1 to 2 hours after the burn; Kf is the capillary filtration coefficient, which increases 2 to 3 times because of the burn injury; Pcap is the capillary hydrostatic pressure, which typically increases from 24 mmHg to 48 mmHg postburn; Pi is the interstitial hydrostatic pressure, which changes from a slightly negative pressure to a much stronger one, chiefly as a result of collagen/hyaluronic acid degradation producing many osmotically active fragments; σ is the reflection coefficient, a measure of semipermeability of the capillary membrane, which is reduced postburn; and (πp – πi) represents the plasma colloid gradient (oncotic gradient), which opposes the hydrostatic gradient (Pcap – Pi) and approaches zero postburn. Overall, the changes in the Starling equation are thus: ↑
Kf
[increases]
↑↑
(Pcap – Pi)
[dramatically increases]
→0
σ (πp – πi)
[becomes negligible]
These changes cause the net fluid filtration rate (Q) to vastly increase. However, another factor, the interstitial compliance—a measure of how much pressure is required to change the volume of the interstitial space—dramatically increases as a result of damage to the mechanical (helical coiling) properties of the interstitial protein matrices. In other words, the initial edema makes it far easier for more edema to occur in the interstitial space. Finally, the lymphatic system has to drain the excess fluid from the interstitium, but is typically overwhelmed by the huge increases in flow rate. In addition, if dermal and subdermal lymphatics are damaged, this further decreases the ability of the lymphatic system to cope effectively. The time course of edema formation following a partialthickness burn is shown in Figure 3. As a rule, full-thickness burns cause less local edema (and slower-developing edema) than partial-thickness burns due to less vascular perfusion.78,79 However, burns that destroy dermal lymphatics are likely to prolong the edema. Thus, the dynamics of the edema change in parallel with the type of burn and the amount of burn area as a result of differing changes in the elements of the Starling equation. Appreciating the changes that govern capillary and interstitial dynamics is helpful in
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P E DIAT R IC B UR N R E S US C I TAT I O N comprehending the limitations of colloid addition during resuscitation. Other important cellular changes that result from a severe burn include cell membrane depolarization, which is associated with an influx of sodium and water. This event seems to be mediated by at least one type of shock factor80 and is likely related to burn-related inhibition of Na-K-ATPase81,82 as well as calcium transport changes,783 both of which seem to decrease cardiac function. There is also evidence that caspases, which are intracellular cysteine proteases involved in programmed cell death (apoptosis), provide a pivotal role in the disruption of homeostasis.84 This body of evidence should give some pause to those that believe cardiac function can be completely restored through aggressive fluid resuscitation and inotropic support alone. The acidosis that develops as a consequence of a severe burn has always been deemed an indicator of oxygen deficit, but this might not be entirely true; rather, it might be a consequence of increased glucose flux.85 We do know that energy expenditure increases postburn and that there is a limitation to oxidative phosphorylation. However, there is preliminary evidence to suggest that the rate of glucose oxidation is not the limiting step, which indicates that another unidentified mechanism is at work.86 These results imply that the increase in serum lactate is not entirely a result of oxygen deficit, and thus lactate levels should not primarily drive oxygen demand goals, although they should help in following overall perfusion status.
in favor of normal saline; bicarbonate should then be used in place of the lactate, or Plasmalyte B can be started, taking care to ensure that metabolic alkalosis does not occur. More effective replacements for lactate have been tested in hemorrhagic shock resuscitation, such as betahydroxybutyrate87 and the L isomer of lactate (commercial lactated Ringer’s solutions are racemic),88 but this is still of question in the burn community. The rationale for testing such replacements is that racemic LR solutions can provoke inflammatory responses (ie, increase neutrophilic oxidative bursts), especially when large volumes are infused. Plasmalyte B is another commonly used resuscitation fluid that more closely approximates plasma (sodium 140 mmol/L, chloride 98 mmol/L, potassium 5 mmol/L, bicarbonate 50 mmol/L), but since published trials of this fluid versus LR in burn resuscitations have taken place, its costeffectiveness and overall utility are in doubt. During fluid resuscitation with LR, it is also vital to monitor electrolytes to ensure that sodium and potassium plasma concentrations do not reach dangerously low or high concentrations. Typically, hypernatremia develops if fluid underresuscitation or sepsis occurs, although other causes are possible.89 Hyponatremia is less common during the first 48 hours, but may be observed between the third and fifth day postburn, and is commonly due to overresuscitation;12 however, its cause must be established before correcting it.
Hypertonic Saline Resuscitating the Burned Child Isotonic Crystalloid As was noted earlier, lactated Ringer’s solution has become the base crystalloid for resuscitation fluids. It is composed of 130 mmol/L of sodium, 109 mmol/L of chloride, 28 mmol/L lactate, 4 mmol/L of potassium, and 1.5 mmol/L of calcium (sodium chloride 0.6%, sodium lactate 0.31%, potassium chloride 0.03%, calcium chloride 0.015%), which is slightly different to the Hartman’s solution that is commonly used in the United Kingdom (sodium chloride 0.6%, sodium lactate 0.25%, potassium chloride 0.04%, calcium chloride 0.027%). LR is isotonic with respect to plasma but also contains lactate, which is ultimately metabolized in the liver, effectively producing bicarbonate, and thus partially counteracts the metabolic acidosis induced by the burn. This bicarbonate formation is temporary, though, and through the enzymatic action of carbonic anhydrase, an equilibrium will tend to be maintained, thus forming more CO2 and worsening the acidosis over time. If liver impairment is known prior to fluid resuscitation or discovered during resuscitation, LR should be immediately discontinued
Research regarding the use of hypertonic saline since the publication of the safety study of Huang et al26 has been divided into animal experiments and human investigations. Several small experiments have been conducted on sheep, rats, and mice to compare various aspects of fluid resuscitation. Kinsky et al90 compared the use of 7.5% saline and 6% dextran (HSD) versus LR in sheep and found that fluid requirements in the HSD group were 22% of the LR group, the water content of various organs was less in the HSD group, and plasma colloid osmotic pressure was 3 mm Hg to 5 mm Hg higher in the HSD group. Chen et al,91 using mice, compared hypertonic to various hypotonic saline solutions and concluded that hypertonic saline (HTS) stimulated the toll-like receptors of inflammatory cells, which is an important measure of the host’s response in bacterial challenge. Using rats, Kien et al92 compared HTS to LR and confirmed the resuscitation volume ratios observed by Kinsky et al90 and discovered that the HTS group had better cardiac and organ tissue perfusion compared to the LR group. Finally, Milner et al93 compared HTS to LR in sheep and reported similar results to Kinsky et al90 and Kien et al.92 Although positive in outlook regarding the case for HTS,
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one criticism of these and other animal experiments is that the time course has been too short to determine whether the differential in observed fluid requirements is maintained over the long term. A small study comparing fluid resuscitation in burned adults (N = 18, percentage TBSA > 35%) using an HTS bolus in conjunction with LR versus LR alone found little differences between most parameters with the exception of troponin I levels, which were significantly lower in the HTS bolus group, suggesting that cardiac dysfunction was not as severe in this group.94 This was an interesting finding not previously seen in human studies, and could have a potential application, although we have no information in regard to mortality in burns patients using this method of HTS infusion. A Japanese study that compared HTS versus LR in the resuscitation of burned adults (N = 36, percentage BSA > 40%) showed a significant resuscitation volume difference (3.1 mL/24 h/kg/% TBSA vs. 5.2 mL/24 h/kg/% TBSA) over the first 24 hours, but primarily investigated IAP, demonstrating a consistently lower bladder pressure in the HTS group but a consistently higher abdominal perfusion pressure.95 The interpretation of these results suggested that the HTS group had a lower risk of developing ACS, which is consistent with the premise that higher resuscitation volumes do increase the chance that ACS might develop. Pham et al52 analyzed several prospective clinical studies of hypertonic saline resuscitation and determined that the level of evidence was mostly Class I and Class II. Their recommendation (grade level B) was that this technique should only be used by experienced burn physicians and that close monitoring of plasma sodium is required. In 2004, the Cochrane group updated their latest findings with regard to burn resuscitation, comparing near isotonic crystalloid to hypertonic crystalloid.100 Their meta-analysis reported that the pooled relative risk of mortality for resuscitation using HTS was 1.49 (95% CI: 0.56-3.95), which is lower than that reported by Huang et al,26 but still elevated. Although the authors were conservative in their conclusion, the results suggest that resuscitation based upon HTS does carry a substantial increased risk of mortality compared to standard LR treatment. If this is so, by what mechanism could HTS cause mortality to rise? For many years, it was thought that the increased levels of ADH (antidiuretic hormone) observed after major burns constituted a syndrome of inappropriate ADH secretion. However, in 1991, Cioffi et al101 demonstrated that this concept was incorrect because the increased renal perfusion did not relate to total blood volume, which is the neuronal set point (a factor not measured prior to this study, and which was found to be relatively low). As Huang et al26 have pointed out, hypovolemia and increased serum osmolality
further stimulate ADH release, but likely depress ANP (antinatriuretic peptide). In addition, following a severe burn, aldosterone levels are mildly elevated, aggravating sodium retention in the plasma. Consequently, serum sodium and osmolality can remain persistently elevated while urine output is significantly decreased, sometimes to the point of renal failure. This might be the “danger point” in some patients. Summarizing, it is clear that while resuscitation using hypertonic saline may have some advantages on the battlefield and in mass casualty events,87 the LR approach is preferable in burn units unless there are some specific concerns that might justify the increased risks, such as very high TBSA burns or failure to resuscitate with isotonic saline.
Colloid The rationale for using any kind of colloid has always centered on the concept that its addition to the plasma of burn patients will exert an oncotic force and perhaps ameliorate the oncotic gradient (πp – πi), which in burn patients tends to drastically decrease as the reflection coefficient, a measure of the semipermeability of the capillary membranes, worsens. Biochemically speaking, adding colloids will only help if a significant fraction of the oncotically active biomolecules are retained on the plasma side of the capillary membrane. Further, this concept only applies to partial-thickness burns and uninjured surrounding tissue, not full-thickness burns where the capillaries are quickly occluded.74 While the burn itself was originally thought to be responsible for the change in the reflection coefficient, we now know that inflammatory mediators also contribute toward the alteration, thus opening the door to the possibility that if we can control the mediators, we may be able restore the permeability characteristics of the membrane more quickly. The evidence to date suggests that until approximately 8 to 12 hours postburn, it is not worthwhile to add plasma or albumin to the fluid resuscitation regimen because the molecular size of albumin is too small in relation to the enlarged pore sizes of the semipermeable membrane.74,102,103 In addition, early addition of albumin may increase the risk of bacterial translocation in the GI tract, thus inviting sepsis complications.104 However, dextrans may be employed at a slightly earlier time because of their higher molecular size. The meta-analysis of Schierhout and Roberts published in 1998,21 which examined mortality rates in crystalloid versus colloid resuscitation in critically ill patients, had a chilling effect on the use of colloids in burn resuscitation, especially in the United Kingdom.105 Based upon 4 studies, the analysis showed a pooled RR of 1.21 (95% CI: 0.881.66) in regard to mortality.21 Ten years later, with more data, a different picture emerged for resuscitated critically
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P E DIAT R IC B UR N R E S US C I TAT I O N ill patients106: (1) for colloid versus crystalloid resuscitation using albumin or plasma, the pooled RR was 1.01 (95% CI: 0.92-1.10); (2) for dextran versus crystalloid, the pooled RR was 1.24 (95% CI: 0.94-1.65); (3) for hydroxyethyl starch versus crystalloid, the pooled RR was 1.05 (95% CI: 0.63-1.75); (4) for modified gelatin versus crystalloid, the pooled RR was 0.91 (95% CI: 0.49-1.72); and (5) for colloid (dextran) plus hypertonic crystalloid versus isotonic crystalloid, the pooled RR was 0.88 (95% CI: 0.74-1.05). Although the burn care community has yet to comment on this recent meta-analysis, some tentative conclusions can be drawn. First, the use of plasma or albumin does not appear to pose a substantial risk of excess mortality. Second, the use of dextran appears to affect the mortality rate substantially, depending on how it is combined with other fluids. Finally, the majority of patients utilized in this metaanalysis were not burn patients, so these results should be applied with caution. Based upon these findings, if a decision to use colloid is made, the options with the least question marks are plasma, albumin, or modified gelatin. The practice of using plasma in burn resuscitation dates back to the original Evans and Brooke formulas, which incorporate plasma at the specified colloid addition rate of 1 mL/kg/% TBSA. However, the use of plasma has not been systematically studied in humans via large clinical trials, although there is a wealth of animal and human case series data. For example, Du et al107 conducted a small RCT to test the outcome of crystalloid plasma versus fresh frozen plasma (FFP), but extrapolation of the promising results to a general statement of the efficacy of plasma addition is difficult because of the small numbers involved. Reconstituted dried plasma and plasma protein fractions were in common use in the United Kingdom in the 1980s and 1990s (Mount Vernon, Muir, and Barclay formulas),108-110 and FFP is still employed in some burn centers as an adjunct to resuscitation with crystalloid due to the expense of and shortages of albumin. Albumin has been used as an adjunct to crystalloid fluid resuscitation since it became commercially available in the early 1950s. Following the early studies we have already described,18,19 Goodwin et al conducted a burn resuscitation RCT in which young adults either received LR (N = 39; TBSA = 48%) or LR + 2.5% albumin (N = 40; TBSA = 53%) for the first 24 hours.111 In the second 24 hours, plasma volume was replaced by colloid equivalent to plasma at a rate of 0.3 to 0.5 ml/kg body weight/% BSA. This was a welldesigned study that evaluated cardiac functions and EVLW. The authors concluded that there were no differences in the cardiac parameters studied but a significant difference in the accumulation of EVLW over several days, with more water accumulating in the albumin-treated group. In comparison, an experiment conducted in sheep a few years later
using several protocols, including LR and LR plus albumin, showed a clear advantage for the albumin-treated group.112 In any case, modern studies continue to demonstrate a lack of superior long-term outcome (eg, multiple organ dysfunction scores113) when comparing crystalloid plus albumin versus crystalloid-alone resuscitation. Further, long-term administration of albumin, even to reverse clinical hypoalbuminemia, does not appear to confer any advantages in previously healthy children receiving adequate nutrition.114 If albumin is selected, the amount of 5% albumin infusion required can be based upon the simple formula of 0.5 mL/kg/% TBSA or a more graduated approach in which more albumin is used (0.3 to 0.5 mL/kg/% TBSA) to match the amount of burned surface area (30 % to ≥ 70%).115 As early as 1995, a university hospital consortium using Delphi techniques produced a series of guidelines on the use of albumin,116 which for burn resuscitation was phrased thus: Fluid resuscitation should be initiated with crystalloid solutions. If crystalloid resuscitation exceeds 4L in adults 18 to 26 hours postburn, and burns cover more than 30% of the patient’s body surface area, non-protein colloids may be added. If non-protein colloids are contraindicated, albumin may be used. This trend toward less usage of albumin was accentuated in the United Kingdom following a series of meta-analyses published by the Cochrane group which led to an interesting discussion in the Journal of Critical Care concerning the use of albumin in critically ill patients.117,118 Predictably, the issue continues to simmer. A recent case-controlled study published in 2007, for example, showed that albumin administered to burn patients with a TSBA ≥ 20% who were more ill compared to the control group (higher inhalation injury rate, higher initial serum lactate, and longer time to achieve resuscitation endpoint) was protective in a multivariate mode of mortality (OR: 0.27; 95% CI: 0.07-0.97).119 This was a surprising result compared to the meta-analysis of Perel and Roberts.106 Another factor is that the true incidence of excess mortality related to the product itself likely has steadily decreased over the last 20 years because manufacturing impurities have been progressively eliminated.120 In their evidence-based review of colloid resuscitation, Pham et al52 listed 6 trials with Class I or Class II evidence, summing up the trials by suggesting that use of colloid can decrease total volume requirements, but that if it is employed, it should be given late in the first 24 hours (recommendation grade A). Again, it should be pointed out that none of these trials have demonstrated superior long-term outcome.
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Alternatives to Albumin or Plasma Other colloids have been tested in burn resuscitation, primarily dextrans, which are polymerized high-molecularweight glucose chains. However, the vast majority of experiments have been animal-based. As described previously, Murphy et al94 conducted a small RCT testing hypertonic saline plus Dextran 70 (HSD) versus crystalloid, but since no data regarding long-term outcome were reported, conclusions regarding mortality cannot be drawn. Interestingly, one experiment conducted in sheep suggested that the volume-sparing effect produced by HSD is dependent on the dose, dosing interval, and infusion rate—that is, a continuously infused dose does not provide a prolonged reduction in volume resuscitation.123 A single-dose approach was also utilized by Murphy et al.94 Hydroxyethyl starch (HES) has also been tested in both animals and humans. Early studies demonstrated that this material seemed equivalent to plasma or albumin, but the nature of the experimental design precluded exact conclusions.124 A more recent and larger Chinese study also concluded that HES could partially substitute for plasma (patients were randomized to HES or plasma), and no adverse effects were reported.125 However, it should be stressed that we still do not have any long-term outcome data using this material. Gelatin has not yet been used in burn resuscitation, although the mortality data associated with its use in trauma is favorable.106 Based upon his research and that of others, Demling74 believes that colloids can only affect the edema situation in nonburned tissue, and that clinicians might further investigate antioxidants in lieu of using colloid. As with much other clinical science, the question of benefit using colloids during the critical phase of burn resuscitation will have to await answers from RCTs that employ reasonably large numbers.
via gastric feeding tubes was also provided within 24 hours postburn. Anabolic agents, such as growth hormone or steroids, were not given, although the judicious use of these entities to improve healing rates is a longer-term question worthy of more research.127 Fluid losses in very young children are proportionately higher compared to older children, and most formulas will often miscalculate how much fluid should be given.56 Based on the “rule of nines” for this age group (head: 19; body: 32; arms: 9.5 each; legs: 15 each), or preferably a nomogram, resuscitation should be accomplished by first calculating surface area. The Galveston approach uses a formula of 5000 mL/m2 of BSA plus 2000 mL/m2 BSA during the first 24 hours postburn, with half of the volume given during the first 8 hours.18,56 The next 24 hours should employ 3750 mL/m2 of BSA plus 1500 mL/m2 of BSA for maintenance requirements. Another vital requirement is to start fluid resuscitation as soon as possible, since delays of an hour or more can mean the difference between survival and death. Caloric needs are also an important consideration because very young children do not have sufficient glycogen stores to meet the metabolic demands imposed by burns during the first 24 hours. Enteral feeding should be started as soon as possible. Milk is well tolerated by young children, although its low sodium content may need to be compensated for with sodium supplementation56 since urinary sodium losses can be substantial. Although resuscitation goals for very young children are generally the same as for older children, any decision to use invasive hemodynamic monitoring must be carefully thought out, weighing the risks against benefits. While such monitoring is helpful at times, other, more indirect techniques, such as echo-Doppler devices,128 may be useful in more severe cases.
Inhalation Injury in Children The Very Young Patient The very young burn patient, typically aged 4 years or younger, deserves special consideration because, as mentioned previously, this age group is considered to be high risk in regard to mortality.3 In a recent review of children admitted to a burn unit in Boston, 26 out of 1537 (1.7%) had all 3 risk factors that the authors identified as problematic: young age, inhalation injury, and large burns.126 The authors reported not starting colloid administration until 18 to 24 hours postburn and using 5% albumin in LR at a dose of 0.5 to 0.7 mL/kg/percent burn for 24 hours “after the leak seals.” In addition, supplemental albumin was given at a rate of 1 to 2 g/kg/day if serum albumin fell below 1 g/dL or below 1.5 g/dL in the presence of pulmonary dysfunction or enteral feeding intolerance. Enteral nutritional support
Inhalation injury is always a significant risk for mortality regardless of age or burn size, and if not recognized can lead to pulmonary failure. Therefore, children involved in any kind of flame injury should be promptly assessed. A large study (N = 12010) of children aged 1 to 14 years discharged from hospitals in 4 populous states after treatment for burns showed an incidence of 5.1% for inhalation injury.129 Incidence of inhalation injury in children tends to increase in respect to age due to the nature of the burn injury (scalds are more common in younger children); a longitudinal study reported by Ryan et al found more than a doubling of the incidence of inhalation injury in an age group of 11 to 20 years compared to 1 to 10 years (19.0% vs. 8.1%).130 Adding inhalation injury to a burn increases mortality by a factor of 5 to 9.131,132
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P E DIAT R IC B UR N R E S US C I TAT I O N The pathophysiology of inhalation injury has been described and will be a focus of another chapter. However, a recent study found that there were no increased levels of proinflammatory cytokines, indicating that inhalation injury in addition to a burn injury does not seem to augment the systemic inflammatory response.133 An alternate hypothesis advanced by the same authors suggested that immunocompromise and immunodysfunction might be involved. Intubation is required in many cases. A retrospective study of patients with smoke inhalation injury found that intubation was positively and significantly correlated with findings of soot in the oral cavity, facial burns, body burns, and fiberoptic laryngoscopic findings of edema in the true and false vocal cords.134 However, the authors also discovered that classic symptoms of smoke inhalation—stridor, hoarseness, drooling, and dysphagia—had no correlation with intubation. Other signs that inhalation injury has occurred include carbonaceous sputum, abnormal mental status (agitation or stupor), respiratory distress, or elevated carboxyhemoglobin (> 10%).135 Controversies continue over airway management. When required, the ideal intubation uses an endotracheal tube, aided by bronchoscopy if needed. If this fails, tracheostomy should be performed between the second and third cervical ring,56 since cricothyroidotomy for children under 12 years of age is not recommended.136 A study of 38 children with an average BSA of 54%, of whom 63% had an inhalation injury and a tracheostomy performed, showed that tracheostomy was a safe procedure that resulted in improved ventilator management.137 In terms of pharmacological management, one study has shown that administration of heparin (5000 units) and 3 mL of a 20% solution of N-acetylcystine aerosolized every 4 hours the first 7 days after the injury can ameliorate casts produced from destroyed ciliated epithelial cells and reduce pulmonary failure secondary to smoke inhalation.138 Experiments in sheep utilizing nebulized albuterol to mitigate the results of inhalation injury by improving airway clearance and decreased fluid flux (lower pause and peak inspiratory pressures, decreased pulmonary transvascular fluid flux, significantly higher PaO2/FiO2 ratio, and decreased shunt fraction at 48 hours postburn) have also been sufficiently promising.139 However, in most centers this approach is still of question. In terms of fluid requirements, it was always observed that inhalation injury increased fluid requirements.140-142 However, a recent study conducted by Klein et al143 that employed a more sophisticated regression analysis showed that this was not necessarily true. Rather, increased fluid requirements seem to be linked with intubation and ventilation need. As the vast majority of pediatric patients with inhalation injury are likely to be intubated and placed
on a ventilator, it is not surprising that inhalation injury has become thought of as predictive of increased fluid requirements. In practical terms, despite conventional approaches and higher infusion formulas (eg, 6 ml/kg/% TBSA), there does not seem to be evidence to support an a priori adjustment of fluid rates in the setting of inhalation injury.
Abdominal Compartment Syndrome In the general burn population, about 1% of all patients develop ACS,144 although Ivy et al report that it is a common problem in patients with TBSAs of 70% or more145; other studies suggest that its incidence rapidly increases with percentage of burned surface area, although this is not the only factor. The issue of abdominal compartment syndrome has not been thoroughly discussed in the literature with regard to children. Case studies demonstrate that compartmental syndromes can appear within several hours of a burn injury, but also may be delayed several days.47 Aggressive intervention is vital because intra-abdominal hypertension (IAH) can swiftly prove fatal, with mortality rates of 50% to 60%.47,144 Early signs that can alert the clinician to the possibility of ACS include an unexplained drop in urine output associated with lack of response to volume loading, unexplained increases in peak inspiratory pressures, or decreases in cardiac performance. One simple way to estimate the intraabdominal pressure is by attaching a pressure monitor to the Foley catheter.47 If the bladder pressure is ≥ 30 mm Hg, a laparotomy should be immediately considered. Other specific indications reported by Ivy et al145 (in adults) to start checking bladder pressures include (1) attainment of a fluid volume of 250 ml/kg body weight, and (2) peak inspiratory pressure exceeding 40 cm of water. Oda et al146 noted similar results to the study of Ivy et al145 and suggested that 300 ml/kg body weight (in the first 24 hours) and 70% BSA were the thresholds for developing ACS in adults. Ivy et al145 also define intra-abdominal hypertension as a bladder pressure > 25 mm Hg and point out that IAH is far more manageable than ACS. Thus the range in bladder pressure of 25 mm Hg to 30 mm Hg seems to be critical. Zak147 has commented that abdominal ultrasounds and plain film abdominal and chest radiographs can be also useful in detecting the presence of ACS and reminds emergency room personnel that even “minor household accidents” in very young children, particularly with erythrematous but as yet nonblistered skin, can later develop ACS if not properly managed. Although Oda et al95 reported that during burn resuscitation of adults the development of ACS was far less when using hypertonic lactated Ringer’s solution, there is a paucity of data in children on which to base such a fluid resuscitation strategy. It also remains unknown whether it
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would benefit a child to switch to such a fluid if the child started developing IAH.
Choice of Fluids and Formulas To date, there is no level I or level II evidence to support a single crystalloid-based resuscitation strategy52; as such, it seems that if resuscitation is conducted in a timely and efficient manner, the exact choice of fluids or the specific formula used may be less important than the overall clinical picture of organ perfusion. All formulas and protocols should be viewed as general “starting points” and placed in context with endpoint goals. Children with more severe burns and/or inhalation injuries will likely require more fluid compared to children with less severe burns or no inhalation injuries; this should be remembered at the bedside in order to avoid either underresuscitation or overresuscitation. Some of the more common formulas used in the United States are shown in Table 4, and 3 specific formulas will be reviewed in more detail.
Baxter-Parkland In the United States, Ireland, and the United Kingdom, Parkland is the most commonly used formula.148,149 However, surveys in the United States have found that practices at many burn units vary according to the experience of the director and experience gathered at the unit for many years.148 Although many institutions consistently hold to the Parkland formula for the first 24 hours, there is considerable variation in regard to the second 24 hours, which reflects different ideas and practice methods. As noted previously, in the last 2 decades, actual resuscitation volumes have often exceeded calculated requirements by a large margin,150 and many clinicians have been rightly concerned about this trend, particularly with regard to complications such as ACS. However, provided that endpoints have been properly defined and followed, this large gap between observed and calculated fluid requirement should not dominate assessment in the first 24 hours. There is also some evidence to show that burn patients transferred to burn units from other outside hospitals in rural areas tended to be overresuscitated for small burns and underresuscitated for larger burns because of inaccurate estimation of burned area.151 The former problem may not have major consequences, but the latter is far more serious. Maintenance fluids to replace insensible losses of water and salts in children can be calculated based on a straightforward approach—that is, the “4:2:1” (4 mL/kg for the first 10 kg of body weight; 2 mL/kg for the next 11-20 kg; and 1 mL/kg for weight above 20 kg).
Maintenance requirements can be met by intravenous infusion and/or enteral feedings. In many centers, the second 24-hour period features the addition of colloid, although the permissible range is large and is adjusted according to the preferences of the burn unit. Within 48 hours, most children should be well resuscitated, and the process then shifts to the maintenance phase and protein replacement phase.
Cincinnati The major difference between the Parkland formula and the Cincinnati approach is that maintenance fluid volumes are calculated using actual body surface area. Originally in Cincinnati, maintenance levels in the first 24 hours were calculated using a formula of 1500 mL/m2, but a newer formula has been added to account for evaporative water losses.62 A further difference from Parkland is that colloid is added at the rate of 20% of calculated plasma volume during the second 24-hour period. In very young children and in children with massive burns and/or severe inhalation injury, Warden have recommended the use of modified hypertonic saline (LR + 50 mEq sodium bicarbonate) for the first 8 hours as a means of reducing the fluid load and correcting for the more severe metabolic acidosis. After 8 hours, such patients are then given LR for 8 hours, and finally 5% albumin in LR for the final 8 hours of the first 24-hour period.62
Galveston The Galveston approach to calculating fluid requirements for burn resuscitation is also different than others. It employs a formula based upon the area of burned skin (5000 mL/m2 of burn) and maintenance based on body surface area (2000 mL/m2). In addition, albumin is added to maintain a serum albumin greater than 2.5 g/dL by using a solution consisting of 50 mL of 25% human serum albumin (12.5 g) added to 950 mL LR.152 This seems to be a fundamental difference in opinion between the shrines in the application of colloid in the first 24 hours. For example, the Cincinnati approach does not espouse colloid addition during the first 24 hours because their researchers determined that addition of albumin to maintain a serum albumin level of 1.5 to 2.5 g/dL or 2.5 to 3.5 g/dL made no difference in outcome.113
Vasopressors, Hemodynamics, and Adjunctive Measures The use of inotropic or hemodynamic support has not been systematically studied in the burn literature, and the
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P E DIAT R IC B UR N R E S US C I TAT I O N scattered results that do exist have been contradictory. For example, one study in sheep (60% BSA, full-thickness burn) demonstrated no advantage in outcome by using dobutamine,153 whereas a small study of adults (N = 9) indicated that dobutamine infusions (5 μg/kg/min) given after the PAWP reached 15 mm Hg improved cardiac output parameters.54 Other human studies of burn patients have also been supportive of dobutamine use: inotropic support with dobutamine and careful titration of volume infusion according to end-diastolic volumes improved hemodynamics, as demonstrated by significant increases in right ventricular ejection fractions in all patients without any changes in mean arterial pressures, urine output, or oxygenation.154 In younger children, large-scale fluid resuscitation may cause a relative state of right-sided heart failure which can be improved with dobutamine. Given that the study of inotropic/hemodynamic support has been far more extensive in the general sepsis/shock literature, and the supposition that it is reasonable to assume that conclusions from this body of literature are somewhat relevant to burn resuscitation, several guidelines have recently been proposed as part of evidence-based reviews. First, vasopressor preference is norepinephrine or dopamine to maintain an initial target of mean arterial pressure ≥ 65 mm Hg. Second, dobutamine inotropic therapy is useful when cardiac output remains low despite fluid resuscitation and combined inotropic/vasopressor therapy. Both these recommendations are strong, but the quality of evidence for them is low (grade C).155,156 Other ideas for adjunctive therapy have also been advanced and some tested, including vitamin C therapy. It is likely that as we better understand the mediation of burn injury through signaling and inflammatory mediators, more precise adjunct therapy, including inotropic support, will be forthcoming.
Failure of Resuscitation: Now What? Assessing resuscitation is a continual process throughout the first 48 hours, given that approximately 13% of all patients die because of resuscitation failure.157 Whereas a successful resuscitation will likely become apparent during this period (and can be predicted with good accuracy), it is extremely difficult to predict those patients that have a high risk of mortality based on standard variables.158 If resuscitation is not successful, there are 3 general causes: (1) overresuscitation with respect to fluid volume, (2) underresuscitation, and (3) other etiologies. Overresuscitation means that too much fluid has been infused, and several problems may be encountered. Klein et al143 examined outcome and amount of fluid administration using both odds ratio and the equation [(fluids received – fluids predicted)/fluids predicted x 100] to define
3 categories: ≤ predicted; 0 to 25% of predicted; and > 25 % predicted. The authors found that using odd ratios, there was a significant increased risk of developing ARDS, pneumonia, bloodstream infections, multiple organ failure, and death with increasing fluid requirements. Use of the equation and adjusting for patient and injury characteristics, a logistical regression analysis also showed that when the measured infused volume was > 25 % of predicted volume, there was a trend (nonsignificant difference) toward increased risk of adverse outcome, including death. However, dichotomizing patients based on a 250 mL/kg of fluid received parameter145 resulted in predictions that were more similar to odd ratios. Although there have been several investigations examining outcomes in relation to fluid amount given during resuscitation, the study of Klein et al143 is probably one of the most illuminative and suggests that the benchmark figure of 250 mL/kg of fluid received devised by Ivy et al145 is a useful indicator that overresuscitation has occurred. If overresuscitation is suspected, the development of compartmental syndromes should be first confirmed or denied by measuring bladder pressure and treating excessive pressure accordingly, as has been previously described. In addition, intraocular pressure should be measured, as excessive pressure in the eye can be devastating. Sullivan et al158 recommend lateral canthotomy in cases in which IOP exceeds 30 mm Hg. If overresuscitation is suspected as the cause of resuscitation failure, in experienced centers, consideration should be given to switching to HTS treatment to minimize further fluid addition. In extreme cases, the use of plasma exchange as a means to combat resuscitation failure in burn patients could be initiated. Warden et al159 reported that in resuscitation failure, defined as reaching twice the fluid requirements predicted by the Parkland formula as well as persistent metabolic acidosis and arterial hypotension and no improvement after switching to HTS, plasma exchange was successful in 16 out of 17 patients. This process involved a continuous blood cell separator and rejection of platelet-poor plasma fractions and addition of 1.5 times the calculated blood volume with type-specific fresh frozen plasma. Similar results were documented by Stratta et al,160 who studied children, and Schnarrs et al,161 who studied both adolescent children and adults. A small RCT was conducted by Kravitz et al162 to test the outcome of crystalloid versus plasma exchange in burned adults, but the numbers were too small to draw any substantive conclusions despite promising results. A few centers are having anecdotal success employing continuous renal replacement therapy (CRRT) in this setting, although formal investigation is lacking. Failure due to underresuscitation is rarer but can happen in patients in which the burned surface area is high (eg, > 70%),
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especially when inhalation injury is present and/or the burned child is very young. When one compares fluid requirements according to a particular formula and compares this figure against fluids administered, it is possible to have met the formula requirements and yet still have underresuscitated the child because burn surface area and/ or severity of injury may have been underestimated or mistakes were made in calculations.163 Therefore, how does one recognize underresuscitation? There is no single parameter that will provide an answer. Rather, several clinical markers may provide clues: insufficient urine output (eg, < 1.0–1.5 ml/kg/hour), very low cardiovascular indices, or a generalized delay in initiating resuscitation.164 If underresuscitation is suspected, the immediate response should be to increase the rate of fluid infusion, using additional small boluses if required. A switch to another formula may also be beneficial, especially one that bases fluid requirements on burn area, is more generous with fluid maintenance requirements, or uses colloid. If overresuscitation or underresuscitation has been ruled out and resuscitation failure is apparent (eg, respiratory distress [PaO2/FiO2 ≤ 200 mm Hg], CVP > 10 mm Hg, or urine output < 1 mL/kg/h164), other etiologies are likely. One recent study has determined that failure to maintain a patent airway was the third most common cause of death in pediatric burn patients165; since this cause is preventable, a reassessment of the child’s oxygenation status should quickly reveal whether this is the case. Another study has indicated that depressed ventricular function (left ventricular stroke work index of 19.9 g/m/m2; normal 44–68 19.9 g/m/m2) is common in children unresponsive to resuscitation but can be compensated for with the initiation of inotropes and vasopressors.164 In younger children, clinically important right-sided heart failure can be seen on a transient basis, which further impedes efforts toward restoring global perfusion; in this setting, low-dose dobutamine may play a role by improving inotropy, as well as the microcirculatory flow via peripheral vasodilation. In an emergency, plasma exchange may be successful when resuscitation failure is due to excessive levels of inflammatory mediators or severe metabolic acidosis. But severe lung injury, which Gore et al165 have identified as the most common cause of death, is still the greatest single challenge, and various modes of progressive mechanical support can be employed, including and up to extracorporeal membrane oxygenation (ECMO).
FLUID REPLACEMENT FOLLOWING THE RESUSCITATION PHASE Successful resuscitations are usually complete within the first 48 hours following the burn injury. Once resuscitated,
patients will only need maintenance fluid and enteral support until their burns have been treated, either with excision and grafting or conventional wound care. A switchover from intravenous infusion to complete enteral feeding is possible 1 to 4 days after the burn depending on the percent TBSA and other injuries. However, a few other considerations are needed. First, if colloid has not been given, protein replacement may be required and the level of serum albumin can be used as a guide, with supplementation advised if the level is below 2 to 2.5 g/dL. Second, if a hypertonic saline approach was employed, more free water may be needed to reduce any hyperosmolar state induced. Potassium and magnesium supplementation are commonly required, and close monitoring (and control) of blood glucose should be undertaken.
CONCLUSION Burn injuries in children—even severe burns—can successfully be treated provided resuscitation is properly accomplished. Successful resuscitation also leads to fewer complications, such as organ dysfunction and sepsis. Although many different formulas can be employed during the resuscitation phase, in the last 2 decades there has been a tendency to use much higher volumes than calculated. This “fluid creep” can have serious consequences, especially in regard to the development of abdominal compartment syndrome. Mistakes in calculating fluid requirements from formulas or incorrectly estimating burn areas can also lead to underresuscitation or overresuscitation. Regardless of the fluid or formula chosen, starting fluid resuscitation as soon as possible is the key to successful resuscitation and outcome. There is no consensus regarding the type of fluid (or formula) to be used in pediatric burn resuscitation. Most approaches use isotonic crystalloid, although some cases may benefit from hypertonic saline solutions if appropriate precautions are taken. The use of colloid is still controversial, with no demonstrated benefit in long-term outcome, although recent work indicates that judicious use may not adversely affect mortality rates. If colloid is chosen, plasma, albumin, or gelatin are the safest approaches to take. Proper attention to endpoint titration rather than adhering to rigid parameters tends to lead to better resuscitation. Although classical endpoints such as urine output and cardiac indices are still important, other invasive means of assessing pulmonary or cardiovascular parameters should be used when there is uncertainty in assessment or in more severe cases. However, the decision to use invasive devices must always be balanced against risk engendered by their usage.
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P E DIAT R IC B UR N R E S US C I TAT I O N The use of adjunctive measures to support hemodynamics is encouraged, but should be conservative in approach. On the other hand, employing antioxidants, such as vitamin C, seems to be a safe and promising adjunct; it is likely that many more novel adjunctive treatments will be developed as research continues into better comprehension of the burn injury at the cellular level. Perhaps the most important message of all is that there should be no grounds to refuse treatment to a badly burned child simply because of the nature of the injuries; even children with 98% TBSA injuries and inhalation injury have survived to lead productive lives.
• Underresuscitation may occur in patients with high (>70%) BSA and/or inhalation injury; hypertonic saline fluids may have a role to play in these patients. • In cases of resuscitation failure when underresuscitation or overresuscitation is not obvious, consider hypertonic saline use or even plasma exchange. • Inhalation injuries require swift evaluation and frequently intubation or even tracheostomy.
REFERENCES KEY POINTS • There is no evidence that one particular formula is better than another; starting fluid resuscitation without delay is more critical than the formula chosen. • Isotonic crystalloid formulas are most commonly used during the first 24 hours of burn resuscitation. • In children, adequate maintenance volumes must be added to the resuscitation formulas. • Hypertonic saline-based approaches should be reserved for those cases that may benefit (signs of overresuscitation, more severe injuries). • The use of colloids is optional, but if chosen, should not be started until 8 to 12 hours postburn. • The colloids with the least risk are plasma, albumin, and gelatin. • If colloids are not given during resuscitation, plasma protein replacement will be necessary in some children. • Start enteral feeding as soon as the child can tolerate it—often within hours of the injury. • Be mindful of caloric requirements, especially in high BSA cases. • Ensure that burned areas are estimated and formulas calculated correctly; mistakes in calculations can be very harmful. • Resuscitate by means of endpoint titration. • Classical endpoints such as urine output and cardiac output still remain the most useful; however, invasive monitoring can be employed in more severe cases where hemodynamic monitoring provides additional information. • Watch out for overresuscitation. • Overresuscitation can lead to the development of compartment syndromes or even intra-abdominal hypertension, which is often fatal if not aggressively treated.
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BURN CRITICAL CARE ROB SHERIDAN, MD, BURN SURGERY SERVICE, SHRINERS HOSPITAL FOR CHILDREN, BOSTON, MA
6. Common Complications in the Burn ICU
OUTLINE 1. Introduction 2. Management Strategy 3. Burn Physiology as It Applies to Critical Care a. Physiology of the Resuscitation Period b. Postresuscitation Physiology
4. Intensive Care Unit Admission and Resuscitation a. Admission Evaluation b. Initial Resuscitation
5. Burn Intensive Care Issues by System a. Neurologic Issues in the Burn ICU b. Pulmonary Issues in the Burn ICU Inhalation Injury Carbon Monoxide Poisoning c. Gastrointestinal Issues in the Burn ICU d. Nutritional Support in the Burn ICU e. Infectious Disease Issues in the Burn ICU f. Combined Burns and Trauma in the Burn ICU g. Rehabilitation in the Burn ICU
117 117 118 118 118
118 118 119
119 119 120 120 120 121 121 122
7. 8. 9. 10.
Conclusion Key Points Tables References
123 123 123 123 124 124 124 124 124 125
125 125 126 130
122 123
INTRODUCTION The probability of survival and the quality of life for burned children has substantially improved over the years. This is largely the result of surgical maneuvers that change the natural history of burns by identification and excision of deep wounds and biologic closure of generated wounds before uncontrolled sepsis and systemic inflammation occur. However, in order to be successful, these physiologically stressful operations, and the burn resuscitation that usually precedes them, require sophisticated critical care management. Although many components of critical care in general apply to burn patients, this
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a. Neurologic Complications in the Burn ICU b. Cardiovascular Complications in the Burn ICU c. Pulmonary Complications in the Burn ICU d. Hematologic Complications in the Burn ICU e. Otologic Complications in the Burn ICU f. Enteric Complications in the Burn ICU g. Ophthalmic Complications in the Burn ICU h. Renal/Adrenal and Genitourinary Complications in the Burn ICU i. Musculoskeletal Complications in the Burn ICU
chapter will attempt to concisely summarize those critical care issues which are unique to the burn population.
MANAGEMENT STRATEGY Organizing the overall care of patients with large burns can be difficult, and is therefore best divided into phases.1 One such organizational plan is outlined in Table 1. During the initial evaluation and resuscitation phase, which typically occurs from days 0 through 3, the patient and injury are thoroughly evaluated, associated injuries and comorbid conditions are identified, and an accurate individualized
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fluid resuscitation is carried out. During the second phase, the natural history of burns is changed by identification, excision, and biologic closure of deep wounds. In patients with larger wounds, this may require a series of staged operations during the first 3 to 7 days after injury. During the third phase of definitive wound closure, temporary coverages are replaced with autograft, and acute reconstruction of the hands, face, genitals, and feet are completed. The final stage of care is rehabilitation and reconstruction, which involves ranging, splinting, and antideformity positioning. In actual practice, this phase begins during resuscitation, but becomes increasingly involved and time-consuming towards the end of the acute hospital stay. In patients with serious injuries, this phase of care may continue for years after discharge and include scar management, reconstructive surgery, and emotional recovery.
BURN PHYSIOLOGY AS IT APPLIES TO CRITICAL CARE A unique and important aspect of caring for seriously burned children in the intensive care unit involves recognition of a predictable sequence of major physiologic changes (Table 2), which should be anticipated and accurately supported to optimize outcome. These changes were described by Cuthbertson as the “ebb” and “flow” phases of injury.2 The ebb phase describes the period in the first 24 hours following injury, characterized by a hypodynamic state which is addressed with fluid resuscitation. The physiology of the postresuscitation period, or flow phase, describes the subsequent development of high cardiac output, reduced peripheral resistance, fever, and muscle catabolism. This hypermetabolic phase is profound in patients with large burns and will persist until well after wound closure. The increased need for nutritional support in this latter phase has major implications for burned patients.3 This period can be significantly exaggerated by delayed wound closure and sepsis.
Physiology of the Resuscitation Period After sustaining serious burns, patients develop a diffuse capillary leak that is relatively unique to this population. This is thought to be secondary to a poorly described group of wound-released mediators which results in extravasation of fluids, electrolytes, and even moderate-sized colloid molecules into the interstitial tissues for a number of hours after injury. The clinical consequence of this physiology is the need for fluid resuscitation. A variety of body-size-and-burnsize-based resuscitation formulas have been developed over the past several decades to address this problem. However,
all are inherently inaccurate, as multiple other variables can affect the degree and duration of this leak, including delays in resuscitation, inhalation injury, and the depth and vapor transmission characteristics of the wound. No formula accurately predicts volume requirements in all patients, and unfortunately, inaccurate resuscitation is associated with substantial morbidity. Therefore, burn resuscitation is ideally guided by hourly reevaluation of resuscitation endpoints, with formulas serving only to help determine initial volume infusion rates and roughly predict overall volume requirements.
Postresuscitation Physiology After a successful resuscitation, the diffuse capillary leak predictably abates and fluid needs abruptly decline 18 to 24 hours after injury. Over the next 2 or 3 days, a systemic inflammatory state evolves which is manifested clinically by a hyperdynamic circulation, fever, and increased protein catabolism. The etiology of this physiology is also poorly characterized but is felt to be driven by a combination of cortisol, catecholamines, glucagon, and bacteria and their by-products from the wound as well as a compromised gastrointestinal barrier, pain, and evaporative temperature loss. The clinical consequences during this phase involve cachexia and compromised wound healing if adequate nutritional support is not provided. Other important considerations are control of environmental temperature, prompt removal of nonviable tissue with physiologic wound closure, and management of pain and anxiety. Although these maneuvers will reduce the degree of systemic inflammation and hypermetabolism, there is no known method by which this physiology can be eliminated.
INTENSIVE CARE UNIT ADMISSION AND RESUSCITATION Burn patients should be approached as having sustained potential multiple traumas. Their evaluation should follow guidelines established by the advanced trauma life support (ATLS) course of the American College of Surgeons Committee on Trauma.4 In many if not most cases, burn patients will not be completely evaluated for trauma prior to their arrival in the intensive care unit. This need for a thorough evaluation and tertiary survey is an important consideration during initial care in the ICU.
Admission Evaluation A special point of emphasis regarding the primary survey of burn patients includes airway evaluation and control. Progressive mucosal edema can compromise airway patency
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B UR N C R IT I C A L C A R E over the first few postinjury hours, especially in young children. The safety and control of the airway should be evaluated as soon as burn patients arrive in the ICU. Swelling of the face, tongue, or neck or the presence of soot in the airway should prompt concern. A large surface burn in conjunction with these findings can portend rapid airway compromise. Facial and airway edema can make the burned child challenging to intubate. If the child’s airway is edematous and appears likely to be difficult, requesting extra help is advisable prior to initiating intubation efforts. Proper tube security is critical since inadvertent extubation in the patient with a burned, swollen face and airway is potentially lethal. A harness system using umbilical ties is one method of proven efficacy. Secure, reliable vascular access is also an essential component of the initial evaluation. In children with significant burns, this usually requires central venous access. In an emergent situation, intraosseous access is a useful bridge, although it is important to confirm proper placement of these lines in order to avoid infusion into soft tissues. A number of burn-specific issues which commonly arise during the secondary survey of burn patients should be considered during the admission of seriously burned children to the ICU (Table 3).
Initial Resuscitation Shortly after the burn injury, wound-released mediators are absorbed into the systemic circulation, leading to stresstriggered and pain-triggered hormonal release. These changes drive a diffuse loss of capillary integrity and secondary extravasation of fluids, electrolytes, and moderatesized colloid molecules. Increased permeability is seen in children whose resuscitation has been delayed or who have suffered inhalation injury. A number of burn resuscitation formulas based on body size and burn extent have evolved over the past 40 years to assist in estimating the fluid needs of these patients. However, since other variables that impact fluid needs are not considered, all the formulas are inherently inaccurate. The modified Brooke is a common consensus resuscitation formula (Table 4). Although somewhat controversial, many centers practice early colloid administration to reduce overall volume needs and reduce edema. Burn resuscitation should be guided by hourly reevaluation of resuscitation endpoints (Table 5). At any point during resuscitation, the total 24-hour volume can be predicted based on the known volume infused and the current rate of infusion. If this number exceeds 6 ml/kg/% burn/24 h, it is likely that the resuscitation is not proceeding optimally. At this point one can consider the use of low-dose dopamine, colloid administration, echocardiography, or placement of a pulmonary artery catheter to gather additional information regarding the adequacy of ventricular filling and myocardial contractility.
BURN INTENSIVE CARE ISSUES BY SYSTEM As care in the intensive care unit proceeds, multiple burnspecific issues can be expected. ICU length of stay for burn patients is typically longer compared to those associated with most other disease processes, as children undergo the trial of staged wound closure.
Neurologic Issues in the Burn ICU Neurologic issues that should be addressed on a regular basis include management of pain and anxiety, the exposed globe, and peripheral neuropathies. Significant pain and anxiety accompany virtually all burn injuries and can have adverse short-term and long-term physiologic and psychological consequences. Post-traumatic stress syndrome is described in approximately a third of patients surviving serious burns.5 In the past, suboptimal control of predictable injury-related pain and treatment-related pain and anxiety was very common. This is a legacy that the current generation of burn intensivists endeavors to correct. Given the rapid development of opiate and benzodiazepine tolerance in patients with serious burns, as well as the fear of respiratory depression, addiction, and litigation, significant undermedication in this unique population of patients with severe pain has resulted, along with an often protracted need for intensive care.6 However, addiction is rare, and medication requirements typically rapidly decrease after wound closure, particularly in children. Successful management is facilitated by organized pharmacological guidelines.7 Selected nonpharmacological measures can be useful adjuncts to pain control, but opiate and benzodiazepine synergy remains the cornerstone at this time. In children with deep facial burns and large surface burns, intraocular hypertension can occur because of retrobulbar (with generalized) edema in the setting of a noncompliant deeply burned face. When detected, this should be addressed with lateral canthotomy to reduce intraocular pressure and decrease the chance of visual loss. Progressive contraction of the burned eyelids and periocular skin can cause exposure of the globe. This predictably results in desiccation, which is followed by keratitis, ulceration, and globe-threatening infection. To address these issues, frequent lubrication with hourly application of ocular lubricants suffices in most situations. If this is inadequate and keratitis develops, acute lid release is indicated. Tarsorrhaphy is rarely adequate treatment and can damage the lids, as the power of contraction will often cause tarsorrhaphy sutures to pull through.
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Peripheral neuropathies occur in critically ill children in the burn intensive care unit because of direct thermal damage to peripheral nerves, metabolic derangements associated with critical illness, or secondary to pressure from positioning or splinting. With careful attention to prompt decompression of tight compartments and proper positioning and splint fitting, many peripheral neuropathies can be avoided. Diligent monitoring of extremity perfusion with prompt escharotomy and/or fasciotomy will avoid the morbidity of constricting eschar and missed compartment syndromes. Properly applied and fitting splints will avoid pressure-induced neuropathies. Careful positioning of deeply sedated or anesthetized patients will prevent traction and pressure injuries.
Pulmonary Issues in the Burn ICU Pulmonary issues often dominate the critical care needs of children with burns. These include airway control, inhalation injury, pulmonary infection, respiratory failure, and in some, carbon monoxide intoxication. The highest priority, the “most important vital sign,” is security of the airway. Security of the endotracheal tube or tracheostomy should be regularly evaluated and verified. The unit staff should be equipped to deal with sudden airway emergencies. Indications for intubation include impending or established airway edema, respiratory failure, and in some patients, the need for frequent trips to the operating room. Inhalation injury alone, in the absence of complications such as airway obstruction, pneumonia, or respiratory failure, is not an indication for intubation.
Inhalation Injury Inhalation injury is a clinical diagnosis based on a history of closed space exposure presence of burned nasal hairs, and carbonaceous sputum. Fiberoptic bronchoscopy facilitates diagnosis in equivocal cases, may help document laryngeal edema, and can also be useful when making decisions regarding preemptive intubation for evolving upper airway edema. Inhalation injury is commonly associated with five issues in the intensive care unit: initial large airway obstruction and bronchospasm, followed later by small airway obstruction, infection, and respiratory failure. Initially, facial and oropharyngeal edema leads to acute upper airway obstruction, which is more common in smaller children. When anticipated, intubation in this setting is often not emergent, allowing for carefully performed procedures with proper staff and equipment. Bronchospasm caused by aerosolized irritants is a common occurrence in the first 24 to 48 hours, especially in young children. Although it usually responds well to inhaled beta-2
adrenergic agonists, children will occasionally require intravenous bronchodilators such as terbutaline or lowdose epinephrine infusions. Steroids can be useful in rare instances of recalcitrant bronchospasm. If mechanical ventilatory support is necessary, it is important to use ventilation techniques that minimize auto-PEEP in order to avoid an otherwise common and difficult complication. In the later phases of care, small airway obstruction may develop as necrotic endobronchial debris sloughs, and the ciliary clearance mechanism is usually simultaneously impaired. Small airway obstruction is followed by pulmonary infection (pneumonia or tracheobronchitis) in approximately 30% to 50% of children with inhalation injury.8 Differentiating between pneumonia and tracheobronchitis (purulent infection of the denuded tracheobronchial tree) is difficult, but the difference is generally not important. Any patient with inhalation injury who develops newly purulent sputum, fever, and impaired gas exchange is likely to have pulmonary infection and should probably be treated with pulmonary toilet and antibiotics adjusted to sputum gram stain and culture.9 Pulmonary toilet is particularly important because inhalation injury to bronchial mucosa greatly impairs mucocilliary clearance. In most cases, shorter antibiotic courses combined with pulmonary toilet are effective therapy. Since small endotracheal tubes can become suddenly occluded, it is important to be prepared to evaluate acute deterioration of intubated children with inhalation injury (Table 6). In older children with larger endotracheal tubes, therapeutic bronchoscopy can help maintain clearance of more distal airways. Respiratory failure in burn patients is managed as for other etiologies. Patients generally do well with a pressurelimited ventilation strategy based on permissive hypercapnia.10 Even if fluid balance is accurate and pulmonary toilet vigorous, some children will fail with this approach and may need to be considered for innovative methods of support, such as extracorporeal support or inhaled nitric oxide.9 Some patients, especially those with extensive burns and generalized systemic inflammation, will develop ARDS in the absence of infection. These children should be managed with ventilatory strategies that limit inflating pressures. When instituting a strategy of permissive hypercapnia, it is useful to remember that topical sulfamylon is a carbonic anhydrase inhibitor which can limit the ability of the kidneys to generate bicarbonate.
Carbon Monoxide Poisoning Carbon monoxide (CO) exposures are not uncommon in structural fires. By binding heme-containing enzymes, notably hemoglobin and the cytochromes, carbon monoxide causes a deficiency of both oxygen delivery and utilization,
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B UR N C R IT I C A L C A R E resulting in cellular hypoxia. There may also be other associated cellular damage due to lipid peroxidation, although this is less well described. It has been reported that a small percentage of patients with serious CO exposures may develop delayed neurologic sequelae. Although cyanide has been detected in some patients with inhalation injury, it is rapidly metabolized and very rarely a cause for concern. Therefore, routine treatment with amyl nitrate and sodium thiosulfate is not justified unless uncorrectable acidosis raises unusual suspicion of severe exposure. Differentiating serious CO exposures from obtundation due to hypoxia, alcohol, drugs, head injury, or hypotension can be difficult. The issue of whether hyperbaric oxygen may improve the prognosis of those suffering serious isolated CO exposures remains controversial. Rather, the practical question is, when the resource is available, which CO-exposed patients should be treated with hyperbaric oxygen versus 100% normobaric oxygen for 6 hours.8 Hyperbaric oxygen (HBO) treatments vary, but an exposure to 3 atmospheres for 90 minutes, with 3 10-minute “air breaks,” is typical. Especially in monoplace chambers, patient access and monitoring are compromised, so unstable patients are often not good candidates. Relative contraindications include wheezing or air trapping, which increases the risk of pneumothorax, and high fever, due to the increased risk of seizures. Before HBO treatment is begun, endotracheal tube balloons should be filled with saline to avoid balloon compression and associated air leaks, and the possibility of occult pneumothorax from central line placement should be reasonably excluded. Myringotomies are required in unconscious patients. Since there is data both supporting and refuting the utility of HBO in treating CO exposures, each patient should be considered individually with documentation of thoughtful judgment.
Gastrointestinal Issues in the Burn ICU Gut failure has a number of presentations common in patients with serious burns. Varieties of gut failure include both solid and hollow organ dysfunctions. Perhaps the most commonly affected solid organ is the liver, which is manifested in 3 basic forms: early transaminase elevations, cholestasis, and hepatic synthetic failure. It is very common for patients with large burns to develop transaminase elevations in the first days after injury. This is thought to be secondary to early splanchnic ischemia and hepatocellular injury. It usually resolves in the days following successful resuscitation and is rarely associated with synthetic dysfunction. Cholestasis commonly accompanies septic episodes later in the course of burn care and can be differentiated from obstructive phenomena by ultrasound.
Successful treatment requires identification and eradication of the often distant septic focus. Hepatic synthetic failure can occur if septic foci are not identified and controlled. Both cholestasis and hepatic synthetic dysfunction are occasionally caused by overfeeding via the parenteral route, with secondary fatty infiltration. However, cholestasis leading to synthetic failure can also be characteristic of endstage organ dysfunction. Rising hepatocellular chemistries and associated synthetic dysfunction are a cause of great concern. Pancreatitis is occasionally seen, usually as a complication of splanchnic ischemia during resuscitation. It presents with enteral feeding intolerance, ileus, and upper abdominal pain. Laboratory findings include amylase and lipase elevations. Rarely, progression to hemorrhagic pancreatitis occurs.12 Most patients will tolerate enteral postpyloric feedings if carefully monitored, although some may require temporary parenteral support. Burn patients demonstrate a propensity for a remarkable ulcer diathesis (Curling’s ulcers) that historically was a common cause of death due to perforation, peritonitis, or bleeding. It seems likely that this is secondary to reduced splanchnic flow. Prophylactic treatment is advisable in most children with serious burns until physiologic wound closure is accomplished and patients are tolerating tube feedings. Cholecystitis is rarely seen in children, although it should be sought (generally by ultrasound) in the setting of obstructive chemistries and upper abdominal pain. Bedside drainage is possible in critically ill patients.13 Enteral dysfunction in the form of ileus commonly accompanies septic episodes and generally resolves with identification and treatment of the septic focus. Rare children will develop significant enteral ischemia associated with resuscitation failure or severe unremitting sepsis. Initially this will present as ileus but can progress to abdominal distension and recalcitrant septic shock. It is a common autopsy finding in burn patients.14 Varieties of infectious colitis, most commonly Clostridium difficile, are occasionally seen in the burn unit. This usually presents as diarrhea but can progress to colonic dilatation and necrosis. Diagnosis is by stool titer, and effective treatment includes enteral administration of metronidazole or vancomycin. Finally, diarrhea is common in the burn unit and is commonly an artifact of hyperosmolar enteral feedings, but infectious etiologies must be excluded.
Nutritional Support in the Burn ICU Hypermetabolic burn patients become rapidly catabolic without nutritional support.14 The optimal route of feeding is enteral. Most children will tolerate intragastric continuous tube feedings beginning at a low rate during resuscitation
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and advanced as tolerated. Initially, a sump nasogastric tube can be used to monitor gastric residuals and help determine feeding tolerance. Subsequently, soft-weighted tubes can be placed. Postpyloric feedings are better tolerated by some patients, particularly if gastric motility is compromised. It is important to ensure that an ileus is not present when administering postpyloric feedings. Monitoring abdominal distention and bowel sounds is important. Parenteral nutrition can be initiated if tube feedings are not tolerated. Whether feeding parenterally or enterally, it is prudent to monitor and control serum glucose. The hormonal milieu after burns predisposes even healthy children to hyperglycemia. It has been shown that persistent hyperglycemia can contribute to negative outcomes.15 Insulin infusions can be helpful in this regard, but they must be used cautiously and in conjunction with close monitoring as well as specific unit policies and procedures in order to avoid the dangerous consequences of hypoglycemia. Both underfeeding and overfeeding have adverse sequelae. Underfeeding results in muscle catabolism and immune compromise. Overfeeding results in fatty liver infiltration and excessive CO2 production. Nutritional support should be designed to meet individual needs. A large number of formulas have been developed to predict individual requirements, but they vary widely in their predictions. The current consensus suggests that in most children, protein needs are about 2.5 gm/kg/day and caloric needs are between 1.5 and 1.7 times the calculated basal metabolic rate (BMR), or 1.3 to 1.5 times measured resting energy expenditure (REE). BMR is generally calculated from equations such as the Harris-Benedict equation, whereas REE is generally measured by indirect calorimetry. Physical examination, quality of wound healing, and nitrogen balance can be used to clinically monitor the adequacy of nutritional support over the long course of a burn hospitalization.
Infectious Disease Issues in the Burn ICU The most effective way of minimizing sepsis in burn patients is through prompt excision and closure of their wounds, but topical agents are helpful in slowing the inevitable development of infection in deep wounds. Common topical wound agents relatively unique to the burn ICU environment have critical care implications. Mafenide acetate as an 11% cream or a 5% aqueous solution may be painful upon application but has excellent eschar penetration and a broad antibacterial spectrum. It is absorbed systemically and is a moderately strong carbonic anhydrase inhibitor, compromising renal bicarbonate production. Aqueous silver nitrate as a 0.5% solution is painless on application, with a broad antibacterial and antifungal spectrum. It does not penetrate thick eschar
well and tends to leach electrolytes, contributing to hyponatremia and hypokalemia. If silver sulfadiazine is used as the topical agent, trans-eschar free water losses can be very high, and serum sodium should be closely monitored. It is tempting to overuse antibiotics in critically ill burn patients. However, antibiotics are two-edged swords. Hypermetabolic burn patients are routinely moderately febrile, so this sign is insensitive in its association with infection. When unexpected high fever develops, a complete physical exam should be performed, lines inspected for infection, wounds evaluated for sepsis, supportive labs and radiographs taken, and cultures of blood, urine, and sputum sent. If no clear focus of infection is seen and the child appears unstable, hypotensive, or with very high fever or leukocytosis, empiric broad-spectrum antibiotic administration is a reasonable precaution pending return of culture data. If no focus of infection is documented, antibiotics can be stopped after a 48-hour to 72-hour course. Reflexive prolonged antibiotic administration for moderate fever in this setting may lead to development of resistant organisms. Burn patients referred after receiving care in outside facilities may bring with them not only their wounds but also resistant organisms unique to the referring institution. Relatively rigid infection control practices should be a routine part of care in all burn units to minimize the occurrence of cross-infection. Although it is probably not possible to completely eliminate this problem in real life, universal precautions and compulsive hand washing will go a long way toward minimizing it.
Combined Burns and Trauma in the Burn ICU Children with combined burns and trauma present unique challenges to the burn ICU team. Typically, these patients present as management conflicts when the priorities of the burn struggle with those of the nonburn traumatic injuries. Thoughtful judgment is required in every case and is facilitated by clear identification of the conflict. A common scenario involves children with burns and head injury or anoxic injury who must have cerebral edema controlled during resuscitation. However, placing intracranial pressure monitors through burns increases the risk of infection. While every case is unique, a reasonable compromise often includes very tightly controlled resuscitation with short-term placement of indicated pressure monitors under proper precautions and antibiotic coverage. Children with blunt chest injuries and overlying burns may require chest tubes which traverse burned areas and increase the risk of empyema. Moreover, tubes may be difficult to secure and the tracts may not close well at the time of removal. One approach might involve use of a long subcutaneous tunnel
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B UR N C R IT I C A L C A R E to reduce trouble closing the tract and timely tube removal to reduce the chance of empyema. Children with blunt or penetrating abdominal injury and burns may have their visceral injuries masked and thereby detected late. Furthermore, there is a higher incidence of wound dehiscence when operating through a burned abdominal wall. While every case is different, liberal use of imaging will detect otherwise occult injuries when the mechanism of injury is consistent with abdominal trauma. In those requiring operative intervention, one can consider placing retention sutures after laparotomy. Children with simultaneous fractures may have fracture management compromised by an overlying burn. Although internal fixation through burned skin is not an optimal option, many burned and fractured extremities can be managed with external fixation followed by prompt wound excision and closure.
Rehabilitation in the Burn ICU Rehabilitation efforts should ideally begin during resuscitation and continue, as much as is practical, during critical illness. Both physical and occupational therapists should be involved, initially with twice-daily passive ranging of joints and static antideformity positioning to prevent the otherwise inevitable development of contractures. Therapists should be informed of the sequence of planned operations in order to modify therapy to support these procedures. Therapists should be encouraged to range patients under anesthesia and to use this valuable time to fabricate custom splints. These efforts during the acute period will pay great dividends later in the hospitalization.
COMMON COMPLICATIONS IN THE BURN ICU Successful management of complications in the burn ICU is facilitated by a high index of suspicion. Management of patients with serious injuries often requires that a series of complications are successfully addressed as the wound is progressively closed. Compulsive attention to changes in the patient’s clinical status will facilitate early detection and successful intervention.
Neurologic Complications in the Burn ICU Transient delirium occurs in as many as 30% of children at some point during their hospitalization.16 Immediate care involves elimination and/or management of hypoxia, metabolic disturbances, or structural injuries. In some children this will require neuroimaging. Seizures are occasionally seen as
the result of hyponatremia or as a consequence of too-rapid weaning of benzodiazepines. They are generally prevented or managed with correction of these issues. Peripheral nerve injuries can be discovered late in the course of therapy. They are usually a consequence of direct thermal injury, compression from compartment syndrome or overlying inelastic eschar, metabolic disturbances, or improper splinting techniques. In most children, these resolve or improve with supportive therapy, although liberal decompression, careful positioning, and splinting will minimize their occurrence.
Cardiovascular Complications in the Burn ICU Serious cardiovascular complications are rare. Intravascular infections, including endocarditis and suppurative thrombophlebitis, present with fever and recurrent bacteremia without signs of local infection. Examination of peripheral and central intravenous sites and use of ultrasound facilitate diagnosis. While infected peripheral veins can be excised, the treatment of infected central venous clots or endocarditis usually requires protracted antibiotic therapy with judicious use of long-term anticoagulation. Hypertension occurs in up to 20% of recovering seriously burned children and is generally well managed with beta-adrenergic blockers. As venous thromboembolic complications are surprisingly infrequent in children with serious burns, routine prophylaxis is not currently standard-of-care. However, this practice is controversial in older children and adults, and many facilities have guidelines for formal prophylaxis. We recommend this be individualized to both the patient and program. Iatrogenic catheter insertion complications, such as vascular lacerations, are minimized by careful technique and should occur infrequently.17
Pulmonary Complications in the Burn ICU Pulmonary complications are common, particularly in children with inhalation injury. Up to 50% of children with serious inhalation injuries will develop pneumonia, which is frequently successfully managed with pulmonary toilet and focused antibiotics.18 Respiratory failure may occur early in the absence of infection secondary to inhalation of noxious chemicals or later in the course secondary to sepsis or pneumonia. Lung protective ventilation strategies can facilitate recovery and minimize further complications. Some children will require innovative methods of support.19 Finally, children will occasionally present with carbon monoxide intoxication, which is usually well managed with 6 hours of 100% oxygen. Some children may benefit from hyperbaric oxygen treatment, but this therapy is not without risk and should be considered on a case-by-case basis.
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Hematologic Complications in the Burn ICU Neutropenia can be seen in two settings. In the first days after resuscitation, some children will develop worrisome neutropenia in the absence of infection. If the absolute neutrophil count is concerning, this is usually managed with prophylactic antibiotics. Later, neutropenia can occur with sepsis and is especially worrisome. Often the harbinger of sepsis, thromobcytopenia is a particularly concerning development. Disseminated intravascular coagulation also frequently accompanies uncontrolled sepsis and should prompt preemptive antibiotic therapy and focused investigation for a septic focus. Global immunologic deficits are associated with serious burns and can contribute to a high rate of infectious complications.
Otologic Complications in the Burn ICU
to ileus and hemorrhagic pancreatitis. It reflects another manifestation of splanchnic flow deficits early and sepsisinduced organ failures later in the hospital course. Sepsis without localizing signs but with rising cholestatic chemistries can be suggestive of acalculous cholecystitis. It can be diagnosed by examination and ultrasound and managed with antibiotics, percutaneous cholecystostomy, or surgery. Gastroduodenal ulceration, also related to splanchnic flow deficits that impair mucosal defenses, is common, but is prevented in most patients with routine use of proton pump inhibitors, histamine receptor blockers, or antacids. Intestinal ischemia and infarction is secondary to inadequate resuscitation, sepsis, or as a late-stage manifestation of multiorgan failure.
Ophthalmic Complications in the Burn ICU
Denuded cartilage is susceptible to auricular chondritis secondary to bacterial invasion. This can result in rapid loss of viable cartilage and severe aesthetic deformity. It can often be prevented by routine use of topical mafenide acetate on all burned ears, as this agent will penetrate the underlying relatively avascular cartilage. Sinusitis and otitis media can complicate transnasal instrumentation with endotracheal and enteral tubes. When this occurs, drainage of these spaces can be restored by relocation of tubes. Infections are treated with antibiotics and topical decongestants. Rarely, surgical drainage is needed. Many children who require prolonged airway access may experience such complications as nasal alar and septal necrosis, vocal cord erosions and ulcerations, tracheal stenosis, and tracheoesophageal and tracheo-innominate artery fistulae. All these complications are minimized by frequent attention to tube position and cuff pressures, avoidance of oversized tubes, and regular inspection of tube-securing straps and devices.
Acute intraocular hypertension can occur during resuscitation if the face has been deeply burned and there is a large overall surface burn causing diffuse, retrobulbar edema.20 In worrisome circumstances, it can be quickly diagnosed by tonometry and treated by lateral canthotomy, a bedside procedure. Ectropia results from contraction of burned tissues around the eye. This can occur surprisingly rapidly during the first weeks after injury if the face has been burned and will result in exposure of the globe. This will predictably lead to keratitis and desiccation of the globe, which can cause ulceration and perforation. In order to prevent this very serious complication, modest exposure can be managed with topical ophthalmic lubricants. More severe exposure, however, should prompt acute lid release. Tarsorrhaphy is rarely helpful as the force of contraction will pull out tarsorrhaphy sutures. Children with Toxic Epidermal Necrolysis (TENS) can develop symblepharon, or scarring of the lid to the denuded conjunctiva. This can be minimized through daily examinations and mechanical adhesion disruption.
Enteric Complications in the Burn ICU
Renal/Adrenal and Genitourinary Complications in the Burn ICU
Early hepatic dysfunction is usually secondary to splanchnic ischemia and results in transient transaminase elevations. It is extremely common during resuscitation from large burns and resolves after resuscitation. Hepatic failure which develops later in a patient’s course is usually a late-stage manifestation of sepsis and multiorgan failure. It begins with elevation of cholestatic chemistries and progresses to coagulopathy and synthetic failure. Pancreatitis which begins with elevations of amylase and lipase can lead
Renal complications include both early and delayed renal insufficiency.21 Early acute renal failure follows inadequate perfusion during resuscitation or is a consequence of myoglobinuria. Late renal failure can be seen as a complication of sepsis, multiorgan failure, or the use of nephrotoxic agents. In most children, management with careful fluid and electrolyte support suffices. Occasional patients will require transient continuous or intermittent renal replacement therapy. Survivors rarely need long-term dialysis.
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B UR N C R IT I C A L C A R E Acute adrenal insufficiency rarely occurs in children secondary to hemorrhage into the gland.22 It presents with cryptic hypotension, fevers, hyponatremia, and hyperkalemia. The electrolyte abnormalities may be obscured by electrolyte replacement therapy. Screening is performed by obtaining a random cortisol level, and diagnosis is confirmed by ACTH stimulation testing. Therapy involves glucocorticoid replacement, which can usually be tapered in most patients during the recovery period. Urinary tract infections are minimized by using bladder catheters only when absolutely necessary. Such infections are treated with focused antibiotics. Children with even severe perineal and genital burns do not generally require colonic diversion or catheterization. Candida cystitis is usually seen in those with bladder catheters who have undergone treatment with broad-spectrum antibiotics. Changing the catheter and Amphotericin irrigation are generally successful. If infections are recurrent, the upper urinary tracts should be screened with ultrasound.
Musculoskeletal Complications in the Burn ICU Exposed bone is common in severe burn injuries. In many children, small areas can be debrided with a powered bit until viable cortical bone is reached and subsequently allowed to granulate. Vacuum-assisted dressings can speed
granulation of many of these wounds until autografts can be done. Some children will need local or distant flaps. Simultaneously fractured and burned extremities are best immobilized with external fixators while overlying burns are grafted. Heterotopic ossification develops weeks after injury, especially in deeply burned elbows. Most patients respond to physical therapy, but some require excision of heterotopic bone to achieve full function. Unusual pain with passive motion during ranging in the burn ICU should prompt radiographic investigation.
CONCLUSION Seriously burned children require a high level of skill and attention from the multidisciplinary critical care team in order to achieve favorable outcomes. However, survival is not the only consideration. Thoughtful, coordinated efforts in the ICU enhance both survival and the quality of ultimate recovery of children suffering serious burns.
KEY POINTS • Intensive Care is an essential element of acute burn management. • An organized, systematic approach to these complex patients facilitates good outcomes.
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TABLES TABLE 1 Phases of burn care. Phase
Objectives
Time Period
Initial Evaluation and Resuscitation
Accurate fluid resuscitation and thorough evaluation
0–72 hours
Initial Wound Excision and Biologic Closure
Exactly identify and remove all full-thickness wounds and achieve biologic closure
Days 1–7
Definitive Wound Closure
Replace temporary with definitive covers and close small complex wounds
Day 7–Week 6
Rehabilitation, Reconstruction, and Reintegration
Initially to maintain range and reduce edema, subsequently to strengthen and facilitate return to home, work, school
Day 1 through discharge
TABLE 2 Predictable physiologic changes in burn patients. Period
Physiologic Changes
Clinical Implications
Resuscitation Period (days 0 to 3)
Massive capillary leak
Closely monitor fluid resuscitation
Postresuscitation Period (day 3 until 95% definitive wound closure)
Hyperdynamic and catabolic state with high risk of infection
Remove and close wounds to avoid sepsis; nutritional support is essential
Recovery Period (95% wound closure until one year after injury)
Continued catabolic state and risk of nonwound septic events
Accurate nutritional support essential; anticipate and treat complications
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B UR N C R IT I C A L C A R E TABLE 3 Burn-specific issues in the secondary survey. HISTORY
1. Important points include the mechanism of injury, closed space exposure, extrication time, delay in seeking attention, fluid given during transport, and prior illnesses and injuries.
HEENT
1. The globes should be examined and the corneal epithelium stained with fluorescein before adnexal swelling makes examination difficult. Adnexal swelling provides excellent coverage and protection of the globe during the first days after injury. Tarsorrhaphy is virtually never indicated acutely. 2. Corneal epithelial loss can be overt, giving a clouded appearance to the cornea, but is more often subtle, requiring fluorescein staining for documentation. Topical ophthalmic antibiotics constitute optimal initial treatment. 3. Very deep burns of the face in association with diffuse and retrobulbar edema can cause intraocular hypertension. This should be checked in this setting, and if pressures are elevated, lateral canthotomy should be performed. 4. Signs of airway involvement include perioral and intraoral burns or carbonaceous material and progressive hoarseness. 5. Hot liquid can be aspirated in conjunction with a facial scald injury and can result in acute airway compromise requiring urgent intubation. 6. Endotracheal tube security is crucial and is best maintained with an umbilical tape harness, rather than adhesive tape, on the burned face.
NECK
1. The radiographic evaluation is driven by the mechanism of injury. 2. Rarely, in patients with very deep burns, neck escharotomies are needed to facilitate venous drainage of the head.
CARDIAC
1. The cardiac rhythm should be monitored for 24 to 72 hours in those with electrical injury. 2. Although elderly patients may develop transient atrial fibrillation if modestly overresuscitated, significant dysrhythmias are unusual if intravascular volume and oxygenation are adequately supported. 3. Those with a prior history of myocardial infarction may reinfarct with the hemodynamic stress associated with the injury and should be appropriately monitored.
PULMONARY
1. Ensure inflating pressures are less than 40 cm H2O by performing chest escharotomies when needed. 2. Severe inhalation injury may lead to slough of endobronchial mucosa and thick bronchial secretions that can occlude the endotracheal tube; one should be prepared for sudden endotracheal tube occlusions.
VASCULAR
1. The perfusion of burned extremities should be vigilantly monitored by serial examinations. Indications for escharotomy include decreasing temperature, increasing consistency, slowed capillary refill, and diminished Doppler flow in the digital vessels. One should not wait until flow in named vessels is compromised to decompress the extremity. 2. Fasciotomy is indicated after electrical injury or deep thermal injury when distal flow is compromised on clinical examination. Compartment pressures can be helpful, but clinically worrisome extremities should be decompressed regardless of compartment pressure readings.
ABDOMEN
1. Nasogastric tubes should be in place and their function verified, particularly prior to air transport in unpressurized helicopters. 2. An inappropriate resuscitative volume requirement may be a sign of an occult intra-abdominal injury. 3. Torso escharotomies may be required to facilitate ventilation in the presence of deep circumferential abdominal wall burns. 4. Immediate ulcer prophylaxis with histamine receptor blockers and antacids is indicated in all patients with serious burns. (continued on next page)
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GENITOURINARY
1. Bladder catheterization facilitates using urinary output as a resuscitation endpoint and is appropriate in all who require a fluid resuscitation. 2. It is important to ensure that the foreskin is reduced over the bladder catheter after insertion, as progressive swelling may otherwise result in paraphimosis.
NEUROLOGIC
1. An early neurologic evaluation is important, as the patient’s sensorium is often progressively compromised by medication or hemodynamic instability during the hours after injury. This may require CT scanning in those with a mechanism of injury consistent with head trauma. 2. Patients who require neuromuscular blockade for transport should also receive adequate sedation and analgesia.
EXTREMITIES
1. Extremities that are at risk for ischemia, particularly those with circumferential thermal burns or those with electrical injury, should be promptly decompressed by escharotomy and/or fasciotomy when clinical examination reveals increasing consistency, decreasing temperature, and diminished Doppler flow in digital vessels. Limbs at risk should be dressed so they can be frequently examined. 2. The need for escharotomy usually becomes evident during the early hours of resuscitation. Many escharotomies can be delayed until transport has been effected if transport times will not extend beyond 6 hours postinjury. 3. Burned extremities should be elevated and splinted in a position of function.
WOUND
1. Wounds, although often underestimated in depth and overestimated in size on initial examination, should be evaluated for size, depth, and the presence of circumferential components.
LABORATORY
1. Arterial blood gas analysis is important when airway compromise or inhalation injury is present. 2. A normal admission carboxyhemoglobin concentration does not eliminate the possibility of a significant exposure, as the half-life of carboxyhemoglobin is 30 to 40 minutes in those effectively ventilated with 100% oxygen. 3. Baseline hemoglobin and electrolytes can be helpful later during resuscitation. 4. Urinalysis for occult blood should be sent in those with deep thermal injuries or electrical injuries.
RADIOGRAPH
1. The radiographic evaluation is driven by the mechanism of injury and the need to document placement of supportive cannulae.
ELECTRIC
1. Monitor cardiac rhythm in high-voltage (greater than 1000 volt) or intermediate-voltage (greater that 220 volt) exposures for 24 to 72 hours. 2. Low-voltage and intermediate-voltage exposures can cause locally destructive injuries, but uncommonly result in systemic sequelae. 3. After high-voltage exposures, delayed neurologic and ocular sequelae can occur, so a carefully documented neurologic and ocular examination is an important part of the initial assessment. 4. Injured extremities should be serially evaluated for intracompartmental edema and promptly decompressed when it develops. 5. Bladder catheters should be placed in all patients suffering high-voltage exposure to document the presence or absence of pigmenturia. This is treated adequately with volume loading in most patients.
CHEMICAL
1. Irrigate wounds with tap water for at least 30 minutes. Irrigate the globe with isotonic crystalloid solution. Blepharospasm may require ocular anesthetic administration. 2. Exposures to hydrofluoric acid may be complicated by life-threatening hypocalcemia, particularly exposures to concentrated or anhydrous solutions. Such patients should have serum calcium closely monitored and supplemented. Subeschar injection of 10% calcium gluconate solution is appropriate after exposure to highly concentrated or anhydrous solutions.
TAR
1. Tar should be initially cooled with tap water irrigation and later removed with a lipophilic solvent.
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B UR N C R IT I C A L C A R E TABLE 4 A consensus resuscitation formula. FIRST 24 HOURS
Adults and Children > 20 kg: Ringer’s Lactate: 2-4 cc/kg/%burn/24 h (first half in first 8 hours) Colloid*: none, but many practitioners would advise 5% albumin at 1 x maintenance rate if burn is over 30% TBSA Children < 20 kg: Ringer’s Lactate: 2-3 cc/kg/%burn/24 h (first half in first 8 hours) Ringer’s Lactate with 5% Dextrose: maintenance rate (approximately 4 cc/kg/h for the first 10 kg, 2 cc/kg/h for the next 10 kg, and 1 cc/kg/h for weight over 20 kg) Colloid*: none, but many practitioners would advise 5% albumin at 1 x maintenance rate if burn is over 30% TBSA
SECOND 24 HOURS All patients: Crystalloid: To maintain urine output, commonly requiring approximately 1.5 x maintenance rate. If silver nitrate is used, sodium leeching will mandate continued isotonic crystalloid. If other topical is used, free water requirement is significant. Serum sodium should be monitored closely. Nutritional support should begin, ideally by the enteral route. Colloid* (5% albumin in Ringer’s lactate to maintain serum albumin at or above 2.0 gm/dl): 0%–30% burn:
none
30%–50% burn:
0.3 cc/kg/%burn/24 h
50%–70% burn:
0.4 cc/kg/%burn/24 h
70%–100% burn:
0.5 cc/kg/%burn/24 h
* The role of colloid is an area of controversy. Check with the program to which the patient will be referred for its recommendations. This author routinely administers 5% albumin at a maintenance rate to patients with burns over 40% of the body surface.
TABLE 5 Age-specific resuscitation endpoints. Sensorium: arousable and comfortable Temperature: warm centrally and peripherally Systolic Blood Pressure: for infants, 60 mmHg systolic; for older children, 70 to 90 plus 2 x age in years mmHg; for adults, mean arterial pressure over 60 mmHg Pulse: 80-180 per minute (age dependent) Urine Output: 0.5-1 cc/kg/h (glucose negative) Base Deficit: less than 2
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REFERENCES 1. Sheridan RL. Burn care: results of technical and organizational
progress. JAMA Contemp Update. 2003: 290(6): 719–722. 2. Cuthbertson D. The physiology of convalescence after injury.
Br Med Bull. 1945; 3: 96–102. 3. Jeschke MG, Mlcak RP, Finnerty CC, et al. Burn size deter-
14. Prelack K, Dwyer J, Dallal GE, et al. Growth deceleration and restoration after serious burn injury. J Burn Care Res. 2007; 28(2): 262–268. 15. Hemmila MR, Taddonio MA, Arbabi S, Maggio PM, Wahl WL. Intensive insulin therapy is associated with reduced infectious complications in burn patients. Surgery. 2008; 144(4): 629– 635.
mines the inflammatory and hypermetabolic response. Crit Care. 2007; 11(4): R90.
16. Ilechukwu ST. Psychiatry of the medically ill in the burn unit. Psychiatr Clin North Am. 2002; 25(1): 129–147.
4. Kennedy D, Gentleman D. The ATLS course, a survey of 228
17. Sheridan RL, Weber JM. Mechanical and infectious complications of pediatric central venous cannulation: lessons learned from a 10-year experience placing over 1000 central venous catheters in children. J Burn Care Res. 2006; 27(5): 713–718.
ATLS providers. Emerg Med J. 2001; 18(1): 55–58. 5. Stoddard FJ, Ronfeldt H, Kagan J, et al. Young burned chil-
dren: the course of acute stress and physiological and behavioral responses. Am J Psychiatry. 2006; 163(6): 1084–1090. 6. Saxe G, Stoddard F, Courtney D, et al. Relationship between
18. Edelman DA, Khan N, Kempf K, White MT. Pneumonia after inhalation injury. J Burn Care Res. 2007; 28(2): 241–246.
acute morphine and the course of PTSD in children with burns. J Am Acad Child Adolesc Psychiatry. 2001; 40(8): 915–921.
19. Sheridan RL, Hess D. Inhaled nitric oxide in inhalation injury. J Burn Care Res. 2009; 30(1): 162–164.
7. Sheridan RL, Hinson M, Blanquierre M, et al. Development of
20. Sullivan SR, Ahmadi AJ, Singh CN, et al. Elevated orbital pressure: another untoward effect of massive resuscitation after burn injury. J Trauma. 2006; 60(1): 72–76.
a pediatric burn pain and anxiety management program. J Burn Care Rehabil. 1997; 18: 455–459. 8. Mlcak RP, Suman OE, Herndon DN. Respiratory management
of inhalation injury. Burns. 2007; 33(1): 2–13. 9. Pham TN, Neff MJ, Simmons JM, Gibran NS, Heimbach DM,
Klein MB. The clinical pulmonary infection score poorly predicts pneumonia in patients with burns. J Burn Care Res. 2007; 28(1): 76–79. 10. Hollingsed TC, Saffle JR, Barton RG, Craft WB, Morris SE. Etiology and consequences of respiratory failure in thermally injured patients. Am J Surg. 1993; 166(6): 592–596, discussion 596–597. 11. Sheridan RL, Shank ES. Hyperbaric oxygen treatment: a brief
21. Steinvall I, Bak Z, Sjoberg F. Acute kidney injury is common, parallels organ dysfunction or failure, and carries appreciable mortality in patients with major burns: a prospective exploratory cohort study. Crit Care. 2008; 12(5): R124. 22. Reiff DA, Harkins CL, McGwin G Jr, Cross JM, Rue LW III. Risk factors associated with adrenal insufficiency in severely injured burn patients. J Burn Care Res. 2007; 28(6): 854–858. 23. Rosenkrantz K, Sheridan RL. Management of the burned trauma patient: balancing conflicting priorities. Burns. 2002; 28(7): 665–669.
12. Ryan CM, Sheridan RL, Schoenfeld DA, Warshaw AL, Tompkins RG. Postburn pancreatitis. Ann Surg. 1995; 222(2): 163–170.
24. Neugebauer CT, Serghiou M, Herndon DN, Suman OE. Effects of a 12-week rehabilitation program with music & exercise groups on range of motion in young children with severe burns. J Burn Care Res. 2008; 29(6): 939–948.
13. Sheridan RL, Ryan CM, Lee MJ, Mueller PR, Tompkins RG. Percutaneous cholecystostomy in the critically ill burn patient. J Trauma. 1995; 38: 248–251.
25. Sheridan RL, Hinson, MM, Liang MM, Mulligan JL, Ryan CM, Tompkins RG. Long-term outcome of children surviving massive burns. JAMA. 2000; 283(1): 69–73.
overview of a controversial topic. J Trauma. 1999; 47(2): 426–435.
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C H A P T E R
N I N E
COMMON PITFALLS OF PEDIATRIC BURN CARE J. KEVIN BAILEY, MD, FACS, ASSISTANT PROFESSOR OF SURGERY, UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE; STAFF SURGEON, SHRINERS HOSPITALS FOR CHILDREN; ASSOCIATE DIRECTOR, UNIVERSITY HOSPITAL BURN CENTER; CINCINNATI, OH RICHARD J. KAGAN, MD, FACS, PROFESSOR OF SURGERY, UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE; CHIEF OF STAFF, SHRINERS HOSPITALS FOR CHILDREN; DIRECTOR, UNIVERSITY HOSPITAL BURN CENTER; CINCINNATI, OH PETRA WARNER, MD, FACS, ASSOCIATE PROFESSOR OF SURGERY, UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE; ASSISTANT CHIEF OF STAFF, SHRINERS HOSPITALS FOR CHILDREN; CINCINNATI, OH
OUTLINE 1. Introduction 131 2. Pitfalls of Initial Care and Resuscitation (the Emergent Setting) 131 3. Pitfalls During the Secondary Exam 133
INTRODUCTION In the majority of cases, treatment of acute thermal injury is relatively straightforward, particularly with pediatric injuries. However, the relative resilience of children may lead to a false sense of security. This patient population can tolerate a degree of less-than-optimal management up until the point of disaster. Therefore, avoiding these pitfalls is clearly preferable in order to minimize morbidity and mortality.
PITFALLS OF INITIAL CARE AND RESUSCITATION (THE EMERGENT SETTING) The initial step in evaluation and management of any emergent patient care dilemma is security of the airway.
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4. Pitfalls During the Initial Resuscitation and Early Definitive Care 5. Conclusion 6. Key Points 7. Figures 8. References
135 136 136 136 139
The foremost question is “Does the patient have a patent airway?” followed by “If so, will the patient be able to maintain the airway, and for how long?” A stepwise approach should allow for timely treatment and avoidance of airway emergencies. Patency of the airway in the emergent setting is assessed similar to nonburn scenarios. If the child’s level of consciousness is markedly depressed or if there are concerns regarding the ability of the patient to protect his or her airway, then intubation is indicated.1 Simultaneously, the patient should be assessed for audible breathing, such as stridor or wheezing. The presence of stridor is relatively infrequent, but in cases of inhalation injury, it is a specific sign.2, 3 In cases of stridor which indicate impending airway loss, plans should turn towards immediate intubation. When maintainability of the airway is in question or there is evidence of impending respiratory failure, consultation
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with the definitive burn care team should be sought if possible. Otherwise, it is prudent to proceed with definitive airway management rather than risk the possibility of dealing with an emergent situation. The unique anatomic differences of the pediatric airway are critical to keep in mind when assessing and managing airway, breathing, and ventilation issues in children. The shorter tracheal length, larger tongue size, and the more anterior/superior location of the glottic opening are key points to remember when attempting intubation in children. Because the pediatric epiglottis is less cartilaginous, use of a straight laryngoscope blade may facilitate intubation. The quality of the voice and some gauge of the ability to move air into and out of the lungs can be assessed with interrogation of the patient. Clearly, this may be slightly less fruitful in nonverbal patients. The assessment can then quickly proceed to evaluation of the general effort involved in air exchange. Important elements of the examination include evidence of tachypnea, retractions, or use of accessory muscles. Without preexisting respiratory disease, such as asthma, these findings suggest inhalation injury until proven otherwise.2 The sense of urgency should be tempered by the fact that progression of respiratory failure is usually observable over a period of hours. The pitfall can occur from failure to recognize the potential for disaster and not maintaining a vigilant posture. During assessment of the patient’s breathing, the physician should also obtain a sense of the size of the burn and the circumstances surrounding the injury. With burns greater than 30% total body surface area (TBSA) in children, significant swelling will be expected. The edema may eventually lead to a disproportionately larger decrease in the cross-sectional area of the child’s trachea compared to adults. At this point, the astute physician must balance the competing needs of the patient—assessment of the relative size of the burn, the possible need for intubation, and the pressing urgency to avoid hypothermia. Historic factors may weigh in the decision as well, such as mechanism of injury (entrapment in a burning building), preexisting medical disease, or polytrauma. It is noteworthy to discuss the problems encountered in securing the airway of a child who has suffered facial burns. Tape will not adhere to the moist wound bed incurred from partial-thickness burns, to eschar, or to areas treated with topical antibiotic ointment. However, a number of commercial devices are available which function well. Alternate strategies include the use of twill tape secured around the head, although care must be taken to guard against pressure on the oral commisures or ears (particularly as swelling occurs). A second method is to apply adhesive tape to the endotracheal tube and then simply staple the tape to the
face.4 Although this strategy has little drawback in cases of full-thickness burns, one must use caution in cases of partial-thickness burns in order to avoid scarring from the staples themselves (Figure 1). If facial burns are not clearly full thickness, then staples should be replaced in 3 to 5 days. Following confirmation of a secure airway, attention is then directed towards assessment of breathing. Supplemental oxygen should be administered in all cases, since the addition of oxygen not only addresses hypoxia, but is also the first-line treatment for carbon monoxide (CO) toxicity. If the possibility of CO poisoning is raised, then hyperbaric oxygen therapy (HBO) may be suggested by a member of the initial care team. In critically burned patients, however, hyperbaric oxygen treatment is not indicated for 2 reasons. First, any potential efficacy of treatment must be weighed against the increased risk created by isolating the patient from the full support of the burn care team.5 Moreover, if transfer is indicated, then definitive care may be delayed. Secondly, despite several studies regarding use of HBO for carbon monoxide poisoning, its efficacy remains uncertain.6 Suffice it to say, the decision regarding HBO therapy should be deferred to the burn surgeon. The next issue involved in the initial care of a burned child will be obtaining intravenous access. Any burn greater than 10% TBSA in a child should suggest the possible need for ongoing fluid administration/resuscitation.7 In addition, IV access is often necessary for administration of analgesics. In children, initial access can be peripheral, central, or intraosseous (IO). During the acute burn injury, collapsed vessels due to hypovolemia can make intravenous access difficult. In this scenario, intraosseous access should be considered. Recent amendment of the PALS (Pediatric Advanced Life Support) guidelines now has no age restrictions for intraosseous line placement. The only clinical contraindications are suspected tibial fracture or traumatic disruption of the venous return proximal to the site of IO insertion. If IO access is not an option, rehydration can be initiated with a feeding tube until intravenous access is obtained. In general, guidelines for the choice of access follow those elaborated by the American College of Surgeons (ACS), the Advanced Trauma Life Support® (ATLS®).1 In the emergent setting, peripheral access would be the first choice, followed by central access via the femoral vein, although the internal jugular and subclavian vessels are also options. Additional areas of access include the scalp vein or a saphenous vein cutdown. A temporary alternative route for IV access in the neonate involves catheterization of the umbilical artery or vein. Central line placement in a child under the age of 5 years can be daunting due to the small
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C OM M ON P IT FAL L S OF P E DIAT R IC B U R N C A R E vessel sizes; however, the technique is essentially identical to that used in adults. With the availability of ultrasound technology, it is probably worth noting the growing emphasis of this technique; not only has its use been recently encouraged by the American College of Surgeons,8 but it has been shown to decrease complications rates.9 It also offers the opportunity to more effectively monitor the procedure during training, as the instructor can hold the ultrasound probe for the trainee and track the course of the needle’s point as it moves through the soft tissue. Given the greater benefits of utilizing ultrasound compared to the risks of performing a blind procedure, along with support from the ACS, Leapfrog Group for Patient Safety, and insurance companies, it is likely that this technique will become the standard of care for placement of central lines in the near future. Invariably, once intravenous access is gained, the next potential pitfall will present itself. The question will be raised as some variant of “What fluids do you want and how fast do you want to run them?” Essentially, the options fall into the broad choices of “too fast,” “too slow,” and “just right.” “Just right” is the most tempting. Every practitioner has at least a vague recollection of the Parkland formula. However, in order to calculate the appropriate volume of fluid to administer, the size of the burn must be estimated. The pitfall occurs by exposing the patient for assessment of the burn wound and the distraction of the burn team by the injury. This is then followed by a period in which the calculations for an estimation of the fluid rate occur, which will then be taken as gospel until the patient reaches definitive care. Meanwhile, the team is still working on the “ABC’s” of trauma care.1 So, “just right” comes at the risk of rushing assessment of the injury, exposing the patient to hypothermia an additional time (as there will be a thorough head-to-toe evaluation with the secondary exam), and the potential for erroneous estimation that will remain in place until a fresh set of eyes reassesses the situation. Key in management is to remember that the patient is first a trauma patient, then a burn patient. Once the trauma workup has been completed, assessment of the burn can be performed. While trying to determine the exact extent of burn injury and its associated depth, significant time can pass, thus increasing the time of exposure and subsequent risk of hypothermia. Multiple authors have remarked on the disparity between the initial estimation and the final determination of burn size in the burn unit.10, 11 Much of this difference probably arises from the approach of estimating burn size too early in the course of care. Given the immediate sense of urgency, alternate solutions for fluid management include arbitrary boluses of crystalloid. And, in fact, ATLS and PALS both support this method in their algorithms; however, PALS
categorizes burn shock as “hypovolemic,” and this oversimplification of the pathophysiology can lead to the somewhat common approach of recommending successive boluses of 10 ml/kg to 20 ml/kg.12 Rather, the challenge of burn shock management is probably more akin to that of septic shock. As such, fluid administration must be somewhat judicious, and treatment may sometimes necessitate the careful use of vasopressors, as in sepsis.13, 14 One must remember that there may be a price to be paid for overaggressive fluid administration, which is often not evident in the emergency room.15, 16 An alternative strategy to consider is the following: for infants, order isotonic intravenous fluids (e.g., lactated Ringer’s) at a rate of 125 ml/hr; for children, begin IVF at a rate of 250 ml/hr; and for teens, begin at 500 ml/hr.17 This strategy will accomplish several objectives. First, once IV access is obtained, it will quickly answer the question of fluids, and the resuscitation team can maintain their focus on the orderly evaluation and care of the trauma patient. Examination of the child should remain deliberate and organized, hopefully decreasing the time of exposure and risk of hypothermia. Secondly, if there are significant differences between this arbitrary rate and that derived from the Parkland formula, then the relative excess or deficiency of fluid will have been given for a short time (perhaps 15 minutes to an hour). Thus, this strategy avoids bolus therapy and potential overresuscitation. Finally, because the fluid administration rate is temporary, the rate will need to be confirmed and adjusted by monitoring urine output. This method emphasizes the need to continuously reassess the volume status of the patient and avoids the pitfall of trying to use algebra (the Parkland formula) to solve a calculus problem (the rate of flow out of the intravascular space due to the injury, or third spacing). Ultimately, even in the burn center, the key is to frequently adjust the rate of fluid administration to achieve adequate resuscitation as judged by adequate urine output and other indices of tissue perfusion.
PITFALLS DURING THE SECONDARY EXAM As resuscitation begins and evaluation of the patient progresses, a more detailed examination of the patient is conducted by the team. At this point, the goal is 2-fold. First, all injuries need to be appreciated and the severity of each injury assessed.14 This may require the team to deliberately ignore the burn injury for a brief period of time in order to focus specifically on the possibility of missed injuries. Secondly, the circumstances regarding the history of the injury can be sought at this point. These details are of particular importance when there is any possibility of abuse. It is worth noting and documenting
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details of the events so that any changes in the reported history can be clearly tracked. Although it would seem relatively simple, a word of caution is warranted. When seeking and documenting a clear history, one must avoid inferring information and introducing bias—particularly in cases of possible abuse. Fortunately, missed injuries concomitant with thermal injuries are rare. This is probably due to a number of reasons. First, in order to sustain blunt or penetrating injuries with burns, the patient is usually a victim of an explosion, fall, or motor vehicle collision. In such cases, first responders alert emergency care teams fairly predictably. Consequently, there is a search for injury patterns common to the mechanism. For example, patients burned in motor vehicle collisions are more prone to blunt trauma, and the emergency room team has experience with motor vehicle collision injury patterns. The challenge occurs when the medical team or patient becomes distracted by the injury; when the patient is the victim of an unwitnessed accident (e.g., the patient is presumed to have walked out of an open front door instead of falling through the broken second-story window) or assault (where fire was started in an attempt to cover up evidence or cause harm in addition to penetrating trauma); or when initial circumstances are not clearly communicated (the presence of an explosion with significant concussive force) (Figure 2). In general, the larger the burn injury, the more distracting it is for both the patient and the care team. ATLS® lists burns as distracting injuries, so that the physical exam alone is insufficient to detect intra-abdominal injuries. Just as any other type of grotesque traumatic injury (amputated limb, severe facial trauma, or gross soft tissue loss) may divert the care team, so, too, can a burn. Therefore, attention may be prematurely focused on the more obvious injury (the burn) and transfer arranged without obtaining a full history or fully examining a patient. A penetrating injury may be completely overlooked by this omission. Part of the reluctance to complete the exam may stem from a concern of causing more pain by moving the patient or manipulating burned skin. However, this is a necessary discomfort in any case where the existence of additional injury is uncertain. At this point, a more concerted effort to quantify the burn can occur. Numerous methods have been devised to estimate the size of a burn. The 3 most useful tools are the “rule of nines,” the Lund-Browder chart, and the “rule of palms.” Each requires some knowledge of the tool and its correct use. The rule of nines divides the body into regions which have a percentage of the total body surface somewhere close to a multiple of 9.18 The Lund-Browder chart and its derivations divide the body into smaller regions with
the intent of arriving at a more precise percentage of the burned area (Figure 3).19 The rule of palms essentially states that the patient’s palm (exclusive of the fingers and thumb) is equal to about one-half of a percent of the total body surface area, or that the entire palmar surface of the hand and fingers approximates 1% of the patient’s total body surface area.20 There are numerous reports regarding the discrepancy in estimation of burn size between the emergency department and burn centers. The differences result from unappreciated burns, areas erroneously thought burned (perhaps covered by soot), and misapplication of the tools. Burns are somewhat dynamic in that blisters develop over time and wounds change as the patient progresses through the medical system. It is also probably unwise to expect burn patients to be cleaned (potentiating hypothermia) in the emergency department. However, there is merit to emphasizing that with both the rule of nines and the LundBrowder chart, the areas circumscribed on the chart can be divided further. For example, if only one-third of the anterior torso is burned, then the area involved would approximate one-third of 18% (or 6%) rather than rounding up to 18% as the estimated area of involvement. In addition, if the estimation is conducted during the secondary exam, there may be less urgency to force more gross approximations. Finally, it should be emphasized again that if adjustments are made to the intravenous fluid administration rate based on the patient’s response, then any gross errors in estimation of burn size or estimated fluid needs will be mitigated. There are additional elements of the secondary exam that are important. First, the patient’s immunization history should be obtained, and if doubt exists, confirmed later. Burns are tetanus-prone wounds, which warrant appropriate prophylaxis. Second, the condition of the eyes should be documented with facial burns since the incidence of corneal abrasion may be as high as 13% in such patients.21 Specific evidence of corneal abrasion or conjunctival irritation should be sought, such as foreign body sensation or photophobia. If the patient cannot supply appropriate responses, or if any uncertainty exists, then fluorescein examination of the cornea is indicated. This is particularly important in victims with extensive or severe facial burns, as the rapid development of periorbital edema may preclude an adequate exam for days. If there is evidence of ocular trauma, then consultation from an ophthalmologist should be sought early in order to afford the consultant the ability to examine the patient. Finally, neuromuscular function of the extremities should be specifically examined and thoroughly documented. This information is vital in assessing for clinical evidence of
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C OM M ON P IT FAL L S OF P E DIAT R IC B U R N C A R E compartment syndrome, which can develop insidiously and generally is not present during the time a patient is in the emergency department (during the first few hours after injury). Therefore, it can be a pitfall of resuscitation during the first 24 to 36 hours.
PITFALLS DURING THE INITIAL RESUSCITATION AND EARLY DEFINITIVE CARE As care of the burned child progresses through the first 24 to 48 hours, a concerted effort to minimize the amount of fluid given should be maintained. Details regarding the experimental and clinical evidence supporting a judicious and systematic approach to resuscitation are explored elsewhere in this textbook. It is worthwhile to echo the concerns, as there is evidence of morbidity induced by “overresuscitation.” The complications associated with greater volumes of resuscitative fluid include the development of pulmonary edema, abdominal compartment syndrome, and compartment syndromes of the extremities. The development of a compartment syndrome has the potential to greatly increase the morbidity of a thermal injury. The pressure threshold at which ischemia develops has been debated for a number of years. Experimental work in animals has demonstrated that normal muscle metabolism requires a perfusion pressure (the difference between the mean arterial pressure and compartment pressure) of 30 mmHg in normal muscle and 40 mmHg in moderately injured muscle.22 Deep-tissue ischemia results from tissue pressures exceeding capillary perfusion pressure (conservatively estimated as 30 mmHg).23 As tissue edema develops beneath the eschar (or deep dermal burns) and fascia of the extremities, one or the other layer may become restrictive enough to prevent any further change in the volume of the muscular compartments. At this point, further development of edema is hypothesized to result in increased compartment pressures. Regardless of the exact mechanism, management is relatively straightforward. The most important component in the management of compartment syndrome is diagnosis. If a patient can accurately report pain with passive stretch of the muscle group, pain at rest (deep muscular pain), or paresthesias, then this is sufficient cause for objective confirmation. If a patient cannot reliably report neurological symptoms, then a screening examination looking for evidence of pain with passive motion at the joints and increased firmness of the compartment can be done. However, it is a pitfall to rely solely on these maneuvers. Furthermore, the mere presence of pulses (either by palpation or Doppler) should not be
accepted as evidence that a compartment syndrome is not present. The muscle of entire compartments may die even if a palpable pulse is present more distally on the extremity (Figure 4). Finally, it is possible to miss the window of increased pain, which may only last for approximately 1 hour.24 Measurement of compartment pressures is the most reliable, objective measure to predict the development of a compartment syndrome. Available methods for measurement include the use of a Stryker® device or simply using an 18-gauge needle attached to a pressure monitor, as found at the bedside of most modern critical care rooms. Pressures of 30mm Hg or greater are considered elevated. Once there is evidence of elevated pressures, intervention is guided by the clinical situation. If there is overlying eschar or deeply burned skin, then an escharotomy should be performed expeditiously. Once completed, the physician must document that the pressure has been adequately released by repeated measurement of the compartment. If compartment hypertension has been inadequately treated, then an appropriate fasciotomy should be considered. Admittedly, there is some debate as to whether an absolute pressure should be used as the sole indication for fasciotomy or if the difference between the diastolic blood pressure (or mean arterial pressure) and the compartment pressure should be used. In our experience, children who have elevated compartment pressures after escharotomy are victims of large burns, have large fluid requirements, and usually have circumferential third-degree burns of the extremities. The need to avoid the pitfall of a missed compartment syndrome in this group more than outweighs any small potential benefit of trying to avoid a fasciotomy. Few outcomes are more disheartening than saving a child from the mortality of a large burn, only to realize the most morbid injury is a missed compartment syndrome—possibly requiring amputation of the extremity. A fasciotomy performed for questionable indications is preferable to the consequences that might occur by delaying treatment while awaiting absolute diagnostic certainty. With respect to avoidable morbidity, the burn surgeon treating the child and coordinating care should also avoid the pitfall of allowing consultants to make conservative care decisions without being challenged. For example, an orthopedic surgeon may advise against operative fixation of a fracture. The rationale may involve unfamiliarity with improved outcomes from burn injury in recent years, so that a child with a large burn and associated injuries may erroneously be judged to have a low chance of survival. Furthermore, the decision may be based on a desire to avoid infection of hardware, in which case the burn surgeon may
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be able to redouble efforts to excise all full-thickness burns in a timely manner and thus allow for propitious fixation. This is greatly preferable to delaying specialty treatment that might have better results with earlier intervention.
the benefits of early consultation with staff at a burn center verified by the American Burn Association.
KEY POINTS
CONCLUSION As in other forms of trauma, the key to expert burn care is adherence to a systematic approach that seeks to minimize the chances of avoidable or missed injuries. The fundamental elements include strong consideration of early respiratory support (especially in cases of suspected inhalation injury), deliberate avoidance of tunnel vision focused only on the cutaneous injury, and cautious administration of resuscitative fluid, with sensitivity to the consequences of overly vigorous resuscitation. Finally, it is worth noting
• Initial care of the trauma/burn patient should follow guidelines established by the American College of Surgeons’ program, ATLS®. • Care should be exercised to avoid overresuscitation, particularly avoiding fluid boluses unless the patient is hypotensive. • A focused search for associated injuries may require deliberately ignoring the burn wound for a short time, while avoiding hypothermia. • Missed compartment syndrome is the most debilitating preventable complication of burn injury, and avoidance requires vigilance on the part of the entire team.
FIGURES FIGURE 1 In cases where facial burns are involved, it can be particularly challenging to effectively secure endotracheal tubes. One alternative is to use adhesive tape, and then secure the tape to the patient with staples. In areas of the face not involved with full-thickness burn, the staples can be replaced every few days to avoid scarring.
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C OM M ON P IT FAL L S OF P E DIAT R IC B U R N C A R E FIGURE 2 A graphic reminder that burn patients are trauma patients and subject to the same pitfall of missed injury. A young man ignited acetylene when he tried to start his car. The condition of the vehicle and injury circumstances were incompletely communicated, such that associated injuries––pulmonary contusion, three fractured ribs, and vague abdominal pain—were not initially addressed in the emergency department.
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FIGURE 3 Example of Lund-Browder chart. Advantage of this type of diagram is more precise documentation of extent of injury and geometric pattern.
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C OM M ON P IT FAL L S OF P E DIAT R IC B U R N C A R E FIGURE 4 Unfortunate example of missed compartment syndrome of anterior compartment (note remarkable difference between necrotic muscle in the most superior portion of the photograph and viable muscle running parallel in the more inferior portion of the field). This photograph is of an unburned extremity, with the most likely contributor being an aggressive fluid resuscitation.
REFERENCES
6. Juurlink DN, Buckley N, Stanbrook MB, Isbister GK, Bennett
tors. 7th ed. Chicago: American College of Surgeons; 2004.
M, McGuigan MA. Hyperbaric oxygen for carbon monoxide poisoning. Cochrane Database Syst Rev. 2005; (1): CD002041. DOI: 10.1002/14651858.cd002041.pub2.
2. Clark WR, Bonaventura M, Myers W. Smoke inhalation and
7. Merrell SW, Saffle JR, Sullivan JJ, Navar PD, Kravitz M,
airway management at a regional burn unit: 1974–1983. Part I: diagnosis and consequences of smoke inhalation. J Burn Care Rehabil. 1989; 10: 52–62.
8. Statement on recommendations for uniform use of real-time ul-
1. Trauma ACoSCo. Advanced Trauma Life Support® for Doc-
3. Madnani DD, Steele NP, de Vries E. Factors that predict the
need for intubation in patients with smoke inhalation injury. Ear Nose Throat J. 2006; 85: 278–280. 4. McCall JE, Cahill TJ. Respiratory care of the burn patient.
J Burn Care Rehabil. 2005; 26: 200–206. 5. Grube BJ, Marvin JA, Heimbach DM. Therapeutic hyperbaric
oxygen: help or hindrance in burn patients with carbon monoxide poisoning? J Burn Care Rehabil. 1988; 9: 249–252.
Warden GD. Fluid resuscitation in thermally injured children. Am J Surg. 1986; 152: 664–669. trasound guidance for placement of central venous catheters. Bull Am Coll Surg. 2008; 93: 35–36. 9. Leyvi G, Taylor DG, Reith E, Wasnick JD. Utility of ultrasound-
guided central venous cannulation in pediatric surgical patients: a clinical series. Paediatr Anaesth. 2005; 15: 953–958. 10. Collis N, Smith G, Fenton OM. Accuracy of burn size estimation and subsequent fluid resuscitation prior to arrival at the Yorkshire Regional Burns Unit. A three year retrospective study. Burns. 1999; 25: 345–351.
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11. Freiburg C, Igneri P, Sartorelli K, Rogers F. Effects of differences in percent total body surface area estimation on fluid resuscitation of transferred burn patients. J Burn Care Res. 2007; 28: 42–48.
18. Knaysi GA, Crikelair GF, Cosman B. The rule of nines: its history and accuracy. Plast Reconstr Surg. 1968; 41: 560–563. 19. Lund C, Browder NC. The estimation of areas of burns. Surg
12. Ralston M, Gonzales L, Fuchs S, Simon W, et al. Pediatric
Gynecol Obstet. 1944; 79: 352–358.
Advanced Life Support. Dallas, TX: American Heart Association; 2006.
20. Nagel TR, Schunk JE. Using the hand to estimate the
13. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis
surface area of a burn in children. Pediatr Emerg Care. 1997; 13: 254–255.
Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008; 36: 296–327.
21. Lipshy KA, Wheeler WE, Denning DE. Ophthalmic thermal injuries. Am Surg. 1996; 62: 481–483.
14. White CE, Renz EM. Advances in surgical care: management of severe burn injury. Crit Care Med. 2008; 36: S318–S324.
22. Heppenstall RB, Sapega AA, Scott R, et al. The compartment syndrome. An experimental and clinical study of muscular energy metabolism using phosphorus nuclear magnetic resonance spectroscopy. Clin Orthop Relat Res. 1988; 226: 138–55.
15. Pruitt BA Jr. Protection from excessive resuscitation: “pushing the pendulum back.” J Trauma. 2000; 49: 567–568. 16. Klein MB, Hayden D, Elson C, et al. The association between fluid administration and outcome following major burn: a multicenter study. Ann Surg. 2007; 245: 622–628. 17. Cancio LC, Mozingo DW, Pruitt BA Jr. Administering effective emergency care for severe thermal injuries. J Crit Illn. 1977; 12: 85–95.
23. Musgrave DS, Mendelson SA. Pediatric orthopedic trauma: principles in management. Crit Care Med. 2002; 30: S431–S443. 24. Whitesides TE, Heckman MM. Acute compartment syndrome: update on diagnosis and treatment. J Am Acad Orthop Surg. 1996; 4: 209–218.
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10
C H A P T E R
T E N
ANESTHESIA FOR PEDIATRIC BURN PATIENTS CHRISTINA FIDKOWSKI, MD, MASSACHUSETTS GENERAL HOSPITAL, AND GENNADIY FUZAYLOV, MD, HARVARD MEDICAL SCHOOL
OUTLINE 1. Introduction 2. Relevant Pathophysiology a. Cardiovascular b. Pulmonary Direct Pulmonary Injury Carbon Monoxide Poisoning Cyanide Toxicity Indirect Pulmonary Injury c. Renal d. Endocrine and Metabolic e. Hepatic d. Hematologic e. Gastrointestinal f. Neurologic
3. Relevant Pharmacology a. b. c. d.
Inhalational Anesthetic Agents Intravenous Anesthetic Agents Neuromuscular Blockers Antibiotics
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INTRODUCTION Major burn injuries are a significant cause of morbidity and mortality in many pediatric patients. Serious morbidity is more common than mortality. In the United States, pediatric burn injuries generate medical costs exceeding 2 billion dollars per year.1 The majority of burns are due to thermal injuries, either from contact with hot liquids or vapors, from fires, or from direct contact with hot surfaces.1 Electrical burns usually cause tissue destruction by direct thermal damage and associated injuries. For chemical burns, the degree of injury depends on the chemical, its concentration, and the duration of exposure. Burn injury is characterized by depth of the burn, total body surface area (TBSA) involved, and the presence or absence of inhalational injury. The characterization of burn
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e. Opioids f. Opioid Adjuncts Ketamine Alpha-2 Agonists g. Benzodiazepines
4. Anesthetic Management for Acute Burn Procedures a. Preoperative Assessment and Management b. Monitoring and Access c. Airway Management d. Induction and Maintenance e. Fluid Management f. Temperature Regulation
5. Anesthetic Management for Reconstructive Procedures 6. Pain Management 7. Conclusion 8. Tables 9. References
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depth is shown in Table 1. First-degree and superficial second-degree burns heal spontaneously, while deep seconddegree, third-degree, and fourth-degree burns require excision and grafting surgery. The TBSA is approximated by the rule of nines in adults, as shown in Figure 1. This rule, however, does not accurately approximate TBSA in children because a child’s head size is disproportionately larger than the body as compared to an adult. An approximation of TBSA in children of various ages is shown in Figure 1. The definition of a major burn injury as classified by depth, TBSA, and the location of burn injury is shown in Table 2.2 It is important to note that severe burns in infants and neonates occur with a smaller TBSA burn injury due to immaturity of the organ systems and the subsequent difficulty maintaining homeostasis.3 The prognosis following burn injury is determined by age, size
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and depth of the burn, associated injuries, and preexisting disease. Pediatric burn patients present many anesthetic challenges, such as difficult airways, difficult vascular access, fluid and electrolyte imbalances, altered temperature regulation, sepsis, cardiovascular instability, and increased requirements of muscle relaxants and opioids. The anesthesia provider participates in the care of these critically ill pediatric patients with the initial resuscitation, intraoperative management, intensive care management, and pain control. The relevant pathophysiologic and pharmacologic changes from burn injury as well as guidelines for intraoperative management and pain control are discussed in this chapter.
RELEVANT PATHOPHYSIOLOGY The skin serves as a barrier to protect the host from infection as well as from heat and fluid losses. The destruction of this protective barrier by burn injury leads to infection and altered heat and fluid regulation. Children are particularly prone to these alterations because of their high surface area to volume ratio as compared to adults. A major burn injury not only destroys the protective skin layer but also leads to the release of local and systemic mediators that produce systemic hypermetabolism and immunosuppression. These mediators also cause localized and systemic capillary leak with resultant edema. Local mediators include prostaglandins, leukotrienes, bradykinin, nitric oxide, histamine, and oxygen free radicals.4 Systemic mediators include interleukin (IL) 1, IL-6, IL-8, IL-10, and tumor necrosis factor α (TNF-α).4 The resultant hypermetabolism from systemic mediators begins within the first 3 to 5 days after thermal injury and continues for an extended period of time, up to many months postinjury.5 The degree of hypermetabolism increases with an increase in burn size.6 Females over the age of 3 years appear to have a decreased hypermetabolic response compared to their male counterparts.7 Along with the hypermetabolism associated with major thermal injury, pathophysiologic changes occur in all organ systems. Generally, these alterations only occur in the setting of a severe burn injury. The changes which are relevant to the anesthetic management of burn-injured patients are discussed below and summarized in Table 3.
Cardiovascular The acute phase of a burn injury starts immediately after the injury and resolves within 24 to 48 hours postinjury. During this time, patients have a transiently decreased cardiac output due to depressed myocardial function, increased
blood viscosity, and increased systemic vascular resistance from the release of vasoactive substances. Initially, patients develop burn shock primarily due to hypovolemia from the loss of intravascular volume to extravascular edema. Persistent hypovolemia and burn shock subsequently result in decreased tissue perfusion. This state of shock is treated with adequate fluid resuscitation to maintain urine output greater than 1 mL/kg/h.8 Patients with severe burns may develop overt ventricular failure6 and may benefit from inotropic support with dobutamine or dopamine. Placement of a pulmonary artery catheter may also be helpful to tailor therapy.9 A systemic inflammatory response is seen around 3 to 5 days postinjury (the second phase of burn injury) as patients become hypermetabolic. As a result, their cardiac output increases and systemic vascular resistance decreases, which allows for increased blood flow to organs and tissues. Clinically, patients may develop persistent tachycardia and systemic hypertension.
Pulmonary Altered pulmonary physiology results from both direct and indirect injury. Direct pulmonary injury occurs from the inhalation of flames, smoke, or toxic gases. Inhalational injury causes tissue edema with potential airway obstruction that may lead to respiratory distress. Carbon monoxide poisoning and cyanide toxicity can also contribute to respiratory compromise. Indirect causes of pulmonary compromise include systemic mediator–induced pulmonary hypertension, pulmonary edema, and decreased chest wall compliance from circumferential burns.
Direct Pulmonary Injury Direct pulmonary injury results from both thermal and chemical irritation.10,11,12 Because the respiratory tract is an efficient heat exchanger, only the upper respiratory tract is affected by direct thermal injury. Direct injury to the upper respiratory tract results in edema and mucosal sloughing, which can eventually lead to airway obstruction. Damage to both the upper and lower respiratory tracts occurs by chemical irritation from products of combustion, such as oxides of nitrogen and sulfur, aldehydes, and hydrochloric acid. Injury to the lower respiratory tract results in inactivation of surfactant and the formation of interstitial edema. Clinically, the patient may develop bronchospasm, pulmonary edema, decreased pulmonary compliance, and ventilationperfusion mismatch. Inhalational burn injury is suggested by singed nasal hairs, carbonaceous secretions, sooty sputum, respiratory distress, wheezing, and facial burns. The diagnosis of upper airway
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ANE S T HE S IA F OR P E DIAT R IC B UR N PAT I E N T S injury is made by direct visualization using fiberoptic bronchoscopy. Xenon scanning and transthoracic thermal dilution techniques to calculate extravascular lung water may be used to determine the extent of parenchymal injury.12 The treatment for inhalational injury is ventilatory support. Treatment should be aggressive with early intervention since children can deteriorate more quickly than adults. If inhalational injury is suspected, the airway should be immediately secured by endotracheal intubation since edema formation during the first 24 to 72 hours postinjury could compromise the airway. This statement is especially pertinent in children because of their smaller airway diameters. Since resistance is indirectly proportional to the diameter to the fourth power, even a small amount of mucosal edema will cause a significant increase in airway resistance. Pharmacologic treatment options include bronchodilators, racemic epinephrine, aerosolized n-acetylcysteine, and/or aerosolized heparin.12 There appears to be no longterm benefit of treatment with corticosteroids.13
Carbon Monoxide Poisoning Carbon monoxide poisoning should be suspected in any patient with inhalational injury or with burns from open fires. Carbon monoxide binds to heme-containing proteins such as hemoglobin, cytochromes, and myoglobin.14 The affinity of carbon monoxide for hemoglobin is 200 times stronger than that of oxygen. Carbon monoxide not only displaces oxygen from hemoglobin but also shifts the oxygen dissociation curve to the left. As a result, tissue oxygen delivery is decreased. The binding of carbon monoxide to cytochromes decreases cellular metabolism and tissue oxygenation. The binding of carbon monoxide to myoglobin decreases oxygen tension in cardiac and skeletal muscles, which can lead to cardiac dysfunction and rhabdomyolysis. The diagnosis of carbon monoxide poisoning is confirmed by carboxy-hemoglobin levels and cooximetry.14 The presence of carboxy-hemoglobin adversely affects the accuracy of conventional 2-wavelength pulse oximetry, which results in falsely high readings. The carboxyhemoglobin level is dependent on both the concentration and duration of exposure. Normal carboxy-hemoglobin levels are in the range of 1% to 3%. Typically, patients with a level less than 20% present with mild symptoms such as nausea and headache.14 Levels greater than 60% to 70% are often fatal due to coma, seizure, or cardiopulmonary arrest.14 Treatment should not be delayed if there is a high suspicion of carbon monoxide poisoning. The mainstay of treatment is exposure to high concentrations
of inspired oxygen. The half-life of carboxy-hemoglobin is 240 to 320 minutes when breathing room air but decreases to 40 to 80 minutes when breathing 100% oxygen.14 While treatment with hyperbaric oxygen is controversial, it can be considered for patients with a history of loss of consciousness, neurologic sequela, metabolic acidosis, or cardiopulmonary compromise or for patients at the extremes of age. The half-life of carboxy-hemoglobin decreases to 20 minutes when breathing 100% oxygen at 2.5 to 3 atmospheres.
Cyanide Toxicity Clinicians should be suspicious of cyanide toxicity when patients present with inhalational injury. Patients are exposed to cyanide during open fires involving nitrogencontaining plastics. Cyanide binds to cytochrome oxidase and impairs tissue oxygenation by converting intracellular aerobic metabolism to anaerobic metabolism.15,16 Since cyanide levels cannot be obtained in a timely manner, it is not practical to await test results prior to commencing treatment. Therefore, other signs, such as an elevated venous oxygen level and lactic acidosis that does not improve with oxygen administration, are suggestive of cyanide toxicity.15 Initial treatment consists of 100% oxygen and supportive measures. Cyanide is metabolized slowly by the liver to the nontoxic thiocyanate. The administration of sodium thiosulfate, which serves as a sulfate donor, increases this conversion. The administration of nitrites such as amyl nitrite and sodium nitrite increases the amount of methemoglobin, which competes for cyanide binding from cytochrome oxidase. The induction of methemoglobin may be dangerous with inhalational injuries because of coexisting carboxy-hemoglobin. Young children are particularly sensitive to nitrite administration since fetal hemoglobin more easily converts to methemoglobin and since children have lower levels of methemoglobin reductase in comparison to adults. A recently approved antidote for cyanide toxicity in the United States is hydroxocobalamin, a precursor to vitamin B12.16 The cobalt moiety of hydroxocobalamin readily binds intracellular cyanide to form the nontoxic cyanocobalamin (vitamin B12). This treatment may be more advantageous in children with smoke inhalation since it does not induce methemoglobinemia and has a rapid onset of action.
Indirect Pulmonary Injury Pulmonary injury can occur with severe burns in the absence of inhalational injury.17 During the initial 24 to 72 hours postinjury, hypoproteinemia and decreased plasma oncotic pressure contribute to pulmonary edema
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formation. Additionally, inflammatory mediators such as TNF-α contribute to increased pulmonary capillary permeability. Clinically, the patient may develop tachypnea, dyspnea, and pneumonia as a result of increased pulmonary vascular resistance, interstitial edema, and decreased pulmonary compliance. Aggressive management of this pulmonary dysfunction with early endotracheal intubation or tracheostomy and mechanical ventilation is appropriate.
Renal In the acute phase of burn injury, the glomerular filtration rate is decreased due to a combination of decreased cardiac output and increased vascular tone from circulating catecholamines, vasopressin, and renin-angiotensin-aldosterone.18 During the hypermetabolic phase, glomerular filtration increases due to increased cardiac output, but tubular dysfunction may occur. As a result, the exact effect on renal function and creatinine clearance is variable among patients. Burn-injured patients, particularly those with electrical or crush injuries, are at risk for myoglobin release from damaged muscle cells. The subsequent myoglobinuria can lead to tubular damage and renal dysfunction.
Endocrine and Metabolic After the acute phase of burn injury, there is a massive release of stress hormones, which include catecholamines, antidiuretic hormone, renin, angiotensin, aldosterone, glucagon, and cortisol.19,20,21 The amount of stress hormones released increases with the TBSA of burn injury.22 This milieu of circulating stress hormones drives the hypermetabolic state that manifests clinically with increases in resting energy expenditure, core body temperature, muscle catabolism, lipolysis, glucolysis, futile substrate cycling, and insulin resistance.19,20,21 While it was initially thought that this hypermetabolic state subsided with wound closure, there is evidence that it persists for at least 9 to 12 months postinjury. For children with greater than 40% TBSA burns, resting energy expenditure is 179% that of normal controls 1 week postinjury. This rate decreases to 153% at the time of wound closure and gradually declines to 115% at 12 months postinjury.23 Current efforts are focused on attenuating this hypermetabolic response.19,20,21 Nonpharmacologic methods of decreasing hypermetabolism include early excision and wound closure, aggressive treatment of sepsis, high protein and carbohydrate enteral feeds, environmental temperature elevation, and a resistive exercise program. Pharmacologic agents that may attenuate hypermetabolism include anabolic proteins (growth hormone, insulinlike growth factor, and insulin), anabolic steroids (oxandrolone), and catecholamine
antagonists (propranolol). Insulin,24 oxandrolone,25,26,27,28 and propranolol29 are the most cost-effective pharmacologic treatments. Although the beneficial effects of these agents are not definitively established, they appear to be useful in certain circumstances. In addition to hypermetabolism from stress hormone release, other endocrine derangements include decreased levels of thyroid hormones (T3 and T4) and vitamin D.30,31 Hypovitaminosis D is secondary to acquired hypoparathyroidism in burn-injured children.32 The resultant hypocalcemia and hypomagnesemia should be aggressively treated to prevent adverse cardiovascular effects such as hypotension and dysrhythmias.
Hepatic During the acute phase of burn injury, the liver is subjected to hypoperfusion from hypovolemia and depressed cardiac output. Hypoperfusion, along with ischemia-reperfusion injury and circulating inflammatory cytokines, leads to hepatic cell apoptosis.33 Elevated levels of liver enzymes such as ALT, AST, and bilirubin are suggestive of this hepatic injury. These enzymes are elevated immediately postburn and typically return to normal within 2 to 6 weeks postinjury. Persistent or severe hepatic dysfunction is associated with worse outcomes. Hepatic enlargement occurs due to intrahepatic fat and edema. There is also a decrease in the intrinsic hepatic proteins albumin and transferrin, as well as an increase in acute phase reactants, haptoglobin, C-reactive protein, and complement. These changes can persist for up to 6 to 12 months postinjury.
Hematologic During the acute phase of injury, systemic edema causes hemoconcentration with a resultant increased hematocrit and increased blood viscosity. After the initial resuscitation, patients develop anemia from a combination of dilution from resuscitation, blood loss at wound sites, and hemolysis from heat-damaged erythrocytes.34 In the absence of other illness, patients can tolerate a low hematocrit (20%–25% range); however, in severely burn-injured children, a higher hematocrit may be desirable due to persistent blood loss. After burn injury, thrombocytopenia occurs due to platelet aggregation at wound sites and damaged microvasculature. The body responds by increasing production of clotting factors, which leads to the development of a hypercoagulable state and may give rise to disseminated intravascular coagulation (DIC). Generally, patients do not require platelet transfusion.
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Gastrointestinal The gastrointestinal tract is also susceptible to damage from hypoperfusion, ischemia-reperfusion injury, and circulating inflammatory mediators. Specifically, the intestinal mucosal barrier is easily damaged and becomes permeable to bacteria and endotoxins.35 There is evidence that early enteral nutrition minimizes mucosal damage, decreases endotoxinemia, and reduces TNF-α levels.35,36 Burn-injured patients are at risk for developing gastric and duodenal stress ulcers, referred to as Curling’s ulcers, which may lead to gastrointestinal bleeding.2 Prophylactic treatment with H2-antagonists or proton pump inhibitors may be beneficial. These patients can also develop acute enterocolitis with resultant abdominal distention, hypotension, and bloody diarrhea. Additionally, severely burned patients can develop adynamic ileus and may benefit from gastric decompression. Acalculous cholecystitis can develop during the second and third week postinjury.
Neurologic Burn encephalopathy is described in the literature as a syndrome that includes hallucination, personality change, delirium, seizure, and coma. One study of 140 burn-injured children reports 20 cases of burn encephalopathy.37 The most common causes of encephalopathy in that study are hypoxia followed by sepsis, hyponatremia, hypovolemia, and cortical vein thrombosis. Hypoxic neurologic insult results in a 33% chance of permanent cognitive deficits.38 Another source of neurologic derangement is cerebral edema and elevated intracranial pressure, which are shown to occur during days 1 through 3 postinjury.39 Hypertensive encephalopathy with resultant seizures is shown to occur in 7% of hypertensive pediatric burn patients.40 The incidence of seizures in burn patients is roughly 1.5%, and risk factors include hyponatremia, a history of epilepsy, hypoxia, sepsis, and drug effects.41 Patients with electrical burns are at risk for developing direct neurologic injury. Depending on the entry and exit sites of the electrical current, paraplegia and quadriplegia from spinal cord damage are described in the literature.42,43 Direct brain injury can also occur.44
RELEVANT PHARMACOLOGY Burn injury results in altered pharmacokinetics of many anesthetic drugs due to changes in the volume of distribution, protein binding, and metabolism.45 The volume of distribution increases with the increased extracellular volume due to capillary leak. The free fraction of drug is altered with increased α1-acid glycoprotein and decreased albu-
min concentrations. Drug clearance is also altered by the metabolic derangements of burn injury. Specifically, during the acute phase (24-48 hours), decreased cardiac output and hypoperfusion to the liver and kidneys can result in decreased drug clearance. During the hypermetabolic phase (> 48 hours), renal and hepatic clearance increases. In addition to altered pharmacokinetics, burn physiology causes alterations in drug receptors that affect the pharmacodynamics of some anesthetic agents, such as the neuromuscular blockers.46 The pharmacology of anesthetic agents relevant to the management of burn-injured patients is discussed below.
Inhalational Anesthetic Agents Potent inhalational anesthetic agents, which include halothane, isoflurane, sevoflurane, and desflurane, can be used for the induction and/or maintenance of general anesthesia. Children have an increased requirement of inhalational agents as compared to adults. The requirement of inhalational agents peaks in infants aged between 1 and 6 months and decreases through adulthood.47 All potent inhalational agents have cardio-depressant properties that may not be tolerated by burn patients with hemodynamic compromise. Halothane is a safe and effective agent that is classically used in pediatric anesthesia because it enables a rapid inhalational induction without airway irritation.47 However, the use of halothane in patients who require hemodynamic support, have metabolic or respiratory acidosis, or receive epinephrine-containing tumescent solutions may lead to further cardiac depression and arrhythmias. Although halothane hepatitis is reported in adult populations, pediatric burn patients do not appear to be at risk for this disease.48 Isoflurane has fewer cardio-depressant properties compared to halothane; however, it does not allow for a rapid inhalational induction. Sevoflurane also has decreased cardiodepressant properties compared to halothane and is suitable for inhalational inductions due to its rapid onset, pleasant smell, and low airway irritability. Desflurane provides a rapid induction and emergence; however, it is a potent airway irritant and should not be used for inhalational inductions. Nitrous oxide is a weak inhalational anesthetic agent and potent analgesic with minimal respiratory and cardiac depressant effects; therefore, it is a suitable adjunct to other anesthetic agents.
Intravenous Anesthetic Agents Thiopental, propofol, and ketamine are intravenous agents that can be used in pediatric burn patients for the induction and maintenance of anesthesia. Thiopental is
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a barbiturate with cardio-depressant properties that may lead to hypotension in hemodynamically unstable patients. The pharmacology of thiopental is altered in burn patients such that higher doses even up to 1 year postinjury may be required.49 Propofol is a sedative-hypnotic agent that also possesses cardio-depressant properties. These 2 agents can be safely used in burn patients when the dose is titrated to effect. Ketamine, an N-methyl-D-aspartate (NMDA) antagonist, does not have respiratory depressant properties. Its cardio-depressant properties are typically balanced by its sympathomimetic effect; therefore, it may be more suitable for induction and maintenance of anesthesia in unstable patients. However, caution is warranted when using this agent for patients with a high sympathetic tone, as its cardio-depressant properties will become more prominent.
Neuromuscular Blockers Burn injury causes an upregulation of extrajunctional nicotinic acetylcholine receptors (AChRs) in the muscle membrane.46 These extrajunctional receptors are mainly immature, with an altered response to ligand binding. This proliferation of immature receptors, which occurs within 48 to 72 hours after a burn injury, places the patient at risk for hyperkalemia from succinylcholine. Resistance to nondepolarizing muscle relaxants also occurs due to these receptor changes.46,50 Because of its rapid onset and short duration of effect, the depolarizing relaxant succinylcholine is often used for rapid sequence intubations or airway emergencies. While use of succinylcholine during the first 24 to 48 hours after burn injury is acceptable, it should be avoided after that time.50 The upregulation of extrajunctional AChRs allows for a larger efflux of potassium from the intracellular to the extracellular space. Additionally, the immature receptors remain open longer, which also allows a larger efflux of potassium from the cell. It is hypothesized that once wounds are healed and functional mobility is regained, the patient is no longer at risk for lethal hyperkalemia.50 Since conversion back to normal pharmacodynamics can take 1 to 2 years, succinylcholine should be avoided during that time. Burn patients develop resistance to nondepolarizing muscle relaxants approximately 48 to 72 hours after injury due to AChR changes.50 As a result, these drugs have a prolonged time to onset of effect and a shorter duration of action. This phenomenon is shown clinically with the steroidal nondepolarizing relaxants vecuronium and rocuronium.51,52 Dose escalation of rocuronium to 0.9 mg/kg or 1.2 mg/kg prolongs its duration of action and decreases the time to onset, which may make it a suitable alternative
to succinylcholine for urgent intubations.52 With the exception of atracurium and cisatracurium, which are metabolized by Hoffman elimination in the plasma, the nondepolarizing relaxants undergo renal and hepatic clearance, which can be significantly altered in burn patients based on their renal and hepatic function.46
Antibiotics The pharmacokinetics of many classes of antibiotics are altered in burn patients.53 Aminoglycosides are shown to have a larger volume of distribution and an increased clearance, which may require elevated dosages at more frequent intervals.54 β-lactams also have an increased volume of distribution and an increased clearance.55,56 Vancomycin and the carbapenem imipenem are shown to have altered clearance that correlates with creatinine clearance.53,57 The pharmacokinetics of the quinolone levofloxacin in burn patients is shown not to differ significantly from that of normal controls.58 These studies also demonstrate large intrapatient and interpatient variability. Because of the unpredictable nature of antibiotic pharmacokinetics, certain antibiotic levels should be monitored. More specifically, intraoperative antibiotic dosing regimens may need to be altered to ensure adequate prophylaxis.56
Opioids Patients with burn injury typically require large amounts of opioids for pain control. A morphine infusion is commonly used to control baseline pain. Initial pharmacokinetic studies of morphine in burn patients showed a decreased clearance, a decreased half-life, and a decreased volume of distribution.59 More recent studies reveal morphine clearance in burned patients is the same, if not slightly increased, compared to that of nonburned patients.60,61 Therefore, large morphine requirements are likely due to severe pain or pharmacodynamic changes. Doses of morphine should be adjusted based on clinical needs. A recent study of bolus dose fentanyl in burn patients demonstrates an increased clearance and increased volume of distribution.62 This finding is consistent with the larger fentanyl doses that are needed to achieve the same clinical effect.
Opioid Adjuncts Ketamine Since burn patients require high doses of opioid analgesics, which are associated with undesirable side effects such as gastrointestinal dysmotility and respiratory depression,
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ANE S T HE S IA F OR P E DIAT R IC B UR N PAT I E N T S opioid adjuncts are sometimes necessary for pain control. Ketamine, an NMDA antagonist, produces dissociative amnesia, analgesia, and sedation without hemodynamic or respiratory depression.63 Oral and intramuscular ketamine are both shown to be effective for painful bedside procedures in pediatric burn patients.64,65 In a case report, longterm intravenous ketamine is shown to be an effective opioid adjunct in a pediatric burn patient without tolerance or psychomimetic side effects.66
Alpha-2 Agonists Alpha-2 (α2) agonists are also used as opioid adjuncts in pediatric burn patients.67 The α2-agonists act at the locus caeruleus to modulate pain perception. Potential side effects of these agents include hypotension and bradycardia. Clonidine is used orally and epidurally as an analgesic adjunct. Case reports show that clonidine reduces opioid requirements in both adult and pediatric burn patients.68,69 In comparison to clonidine, dexmedetomidine (Precedex) is a newer α2-agonist that is 8 times more selective for α2 receptors than for α1 receptors. A recent retrospective study of pediatric burn patients shows that dexmedetomidine infusions in conjunction with opioids provide adequate analgesia when opioid infusions alone were inadequate.70 Since dexmedetomidine has a relatively short half-life (2 hours), it is easily titrated during continuous infusions.
Benzodiazepines Benzodiazepines are sedative-hypnotic agents that act by potentiating the inhibitory action of gamma-aminobutyric acid (GABA) receptors. Parenteral benzodiazepines, such as diazepam, lorazepam, and midazolam, are used as anxiolytics. The clearance of diazepam is decreased in burn-injured children,71 whereas that of lorazepam is increased.72 While the clearance of midazolam is decreased in critically ill pediatric patients, its elimination half-life during continuous infusions is significantly shorter than that of other benzodiazepines. As a result, midazolam infusions are readily titratable and useful in the management of ventilated pediatric burn patients.73
ANESTHETIC MANAGEMENT FOR ACUTE BURN PROCEDURES The management of pediatric burn patients provides challenges for the anesthesiologist. In the acute phase of injury, attention must be paid to the patients’ physiologic and pharmacologic changes described above. These patients are often critically ill with hemodynamic and respiratory
compromise; however, operative management cannot be delayed since procedures such as excision and grafting are the only treatment for their illness. General principles for the anesthetic management of these patients are described in the literature and summarized below.2,74,75,76,77
Preoperative Assessment and Management The preoperative assessment of a burn patient begins with an evaluation of the type of burn and the extent and depth of the burn, as well as any associated injuries. Patients with minor burns and a TBSA less than 10% typically do not require formal resuscitation, whereas those with major burns, with a TBSA greater than 30%, develop the systemic physiologic changes described above and require resuscitation. Patients with burn injury between these extremes require resuscitation but do not develop the systemic physiologic changes. The patient’s medical history should be reviewed, as significant medical illness may merit more aggressive treatment and resuscitation even with minor burns. A review of previous anesthetic records is useful since these patients undergo frequent trips to the operating room. The patient’s current physiologic state is determined by assessing the patient’s present hemodynamics and/or pressor requirements, pulmonary compliance and ventilator settings, and volume status and urine output. The physical exam should include a thorough airway evaluation, as many of these patients have distorted anatomy and are potential difficult intubations. Even if the patient is already intubated, the airway should be evaluated, as there may be a requirement for reintubation due to a ventilation leak around the endotracheal tube or an accidental extubation. The size and location of intravenous access and invasive monitoring is also noted on physical exam. Because these patients have high metabolic demands, enteral nutrition should be continued as long as possible preoperatively.78 Parenteral nutrition can be continued intraoperatively. Burn patients do not have evidence of delayed gastric emptying; therefore, stopping clear liquids 2 hours preoperatively or discontinuing enteral feeds 1 to 2 hours preoperatively is adequate.79 See Table 4 for traditional preoperative NPO guidelines. Traditional preoperative fasting is waived for burn patients receiving continuous enteral tube feeds since this practice is not associated with increased morbidity or increased risk of aspiration in these patients.80 For enteral feeds, the nasogastric tube is suctioned preoperatively and left open to gravity intraoperatively to minimize the risk of aspiration. Laboratory studies, including complete blood count, electrolytes, coagulation studies, and BUN/creatinine,
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should be noted. Special emphasis should be placed on correcting any acid-base disturbances during the acute phase. If a blood bank sample is not current, one should be sent prior to the operation. A chest radiograph should be obtained in patients suspected of smoke inhalation. The positioning of central access is also evaluated with the chest radiograph. In the presence of carbon monoxide poisoning, the pulse oximeter may overestimate the saturation of hemoglobin; therefore, a carboxyhemoglobin level or co-oximetry should be used to assess the degree of carbon monoxide poisoning and guide treatment. Upon completion of the initial assessment, the anesthetic plan is reviewed with the parent and informed consent is obtained. At that point, the patient is ready for transport to the operating room. Transport to the operating room requires the presence of at least 1 if not 2 skilled anesthesia providers. A transport monitor is utilized to monitor the electrocardiogram (EKG), blood pressure, and oxygen saturation. If the patient is intubated, an oxygen supply as well as an ambu bag or transport ventilator must be available. A PEEP valve should be used if the patient requires PEEP to maintain oxygenation. During transport, resuscitation medications and emergency airway equipment should be available.
Monitoring and Access Monitors for burn surgery include the ASA standard monitors for general anesthesia (Table 5). Many patients have large areas of burn injury, which may make standard monitor placement difficult. Large thorax burns may necessitate creative, nonstandard-surface electrode placement for EKG monitoring. Esophageal EKG monitoring is another option.81 Peripheral pulse oximetry monitoring may be unreliable with extensive burn injury, hypoperfusion, or hypothermia. Alternative sites of probe placement include the ear lobe, buccal mucosa, tongue, and esophagus.82,83,84 Blood pressure is monitored either invasively or noninvasively. Invasive blood pressure monitoring is advantageous if the extremities are injured or if large fluid shifts or blood loss are expected. End-tidal carbon dioxide monitoring allows for assessment of adequate ventilation given the increased carbon dioxide production from hypermetabolism. If the patient has pulmonary injury, an arteriolaralveolar gradient may be present; therefore, arterial carbon dioxide measurements may be more appropriate than endtidal carbon dioxide measurements for assessment of the adequacy of ventilation. Temperature should be monitored given the propensity for heat loss. Invasive central venous pressure monitoring along with urine output measurements provide insight into the patient’s volume status.
Obtaining intravascular access can be challenging in burn patients. Large-bore peripheral intravenous lines are ideal for fluid replacement, especially with the large blood loss from excision and grafting surgery. Multilumen central catheters are satisfactory for drug infusions but may not be adequate for rapid fluid replacement given their high resistance. The femoral vein is our preferred site for central access. The subclavian vein and internal jugular vein are our second and third choices, respectively. Ideally, intravenous and intra-arterial access should be placed through noninjured tissue. If intravenous access cannot be obtained and the child needs access emergently for fluid resuscitation or medications, intraosseous access can be obtained rapidly in the anterior medial tibia, distal femur, or sternum as a temporary measure.85 Complications from intraosseous access, such as osteomyelitis, are rare (~0.6%).86
Airway Management Pediatric airway anatomy differs from that of an adult, as shown in Table 6.87 Laryngoscopy may be more difficult in a child due to a relatively large tongue which is difficult to manipulate, a relatively high glottic opening that is difficult to visualize, and an angled epiglottis that is difficult to lift during laryngoscopy. Passing the endotracheal tube through the glottic opening may be difficult since the opening is not perpendicular to the trachea. As the narrowest part of the pediatric airway is at the level of the cricoid cartilage, an endotracheal tube may be too large even if it passes easily through the vocal cords. These anatomical airway differences are most notable during infancy and gradually disappear as the child ages. Because of these airway differences, straight laryngoscope blades are more effective in pediatric patients. A summary of suggested laryngoscope blades and endotracheal tube sizes for children of various ages is shown in Table 7. Securing the airway in a pediatric burn patient is challenging. Within the first 24 hours, succinylcholine is safe to use. Previously, the standard practice in pediatric patients was to place uncuffed endotracheal tubes to prevent mucosal damage. However, recent evidence suggests that low-pressure, high-volume cuffed endotracheal tubes should be used.88 Patients who have suffered inhalational injury may develop decreased compliance, which requires higher ventilatory pressures that can cause leaks around uncuffed tubes. Most patients presenting to the operating room during the acute phase will already have a secured airway, either an endotracheal tube or a tracheostomy. In those instances, the airway should be adequately secured prior to positioning the patient on the operating room table to prevent unintentional dislodgement.
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ANE S T HE S IA F OR P E DIAT R IC B UR N PAT I E N T S In the acute phase, patients may have facial and airway edema that distorts the normal airway anatomy. In addition, patients may have limited neck mobility and mouth opening. All pediatric burn patients with face, neck, or upper chest injuries should be approached as potentially difficult airways. A thorough preoperative assessment should be performed, with a plan for securing the airway. Adequate instruments, such as laryngeal mask airways (LMAs), lighted stylets, fiberoptic bronchoscopes, and a surgeon capable of performing an emergent surgical airway, should be readily available. An organized approach to evaluate the airway is to consider securing the airway through the nose, mouth, or trachea while the patient is awake, sedated, or anesthetized. If the patient has severe craniofacial abnormalities which suggest difficult mask ventilation, securing the airway while the patient is awake may be prudent. However, this option is only practical for older and cooperative patients. Awake nasal or oral intubations are performed with adequate local anesthetic to suppress airway reflexes. To secure the airway under sedation, agents such as ketamine (0.5-2 mg/kg) or dexmedetomidine (0.5-1 mcg/kg over 10 minutes followed by 0.2-0.7 mcg/kg/h) are used to ensure that respiratory depression does not occur. To secure the airway under general anesthesia, either an inhalational or an intravenous induction can be used as long as the patient is spontaneously ventilating until a definitive airway can be established. The approach to the airway through the nose includes blind nasal intubation, which is reserved for extreme emergencies, and fiberoptic guided nasal intubation. The approach to the airway through the mouth includes direct laryngoscopy with endotracheal intubation, lighted stylet blind oral-tracheal intubation, bougie-guided endotracheal intubation under direct vision, fiberoptic intubation, and LMA insertion. The approach to securing the airway through the trachea includes emergent and elective surgical airways. If both oral and nasal intubation techniques are viable options, we prefer oral intubation since the nasal route carries a risk of sinus infection. Additionally, we prefer oral intubation over early tracheostomy. Although early tracheostomy is shown to be safe and efficacious in pediatric burn patients,89 we choose a more conservative approach to minimize tracheostomy site infections and pulmonary infections.
Induction and Maintenance The choice of anesthetic agents for a burn patient depends on the patient’s current condition and the anesthesia provider’s preference. Prior to induction, the patient should
be adequately fluid resuscitated to prevent hemodynamic compromise with the anesthetic agents. If the patient is not already intubated, either an inhalational induction with halothane or sevoflurane or an intravenous induction with ketamine, thiopental, or propofol are good options. The dose ranges of intravenous anesthetic agents suitable for inducing general anesthesia are shown in Table 8. It is possible to induce the child prior to transfer to the operating room table to minimize pain and discomfort if his or her airway does not appear difficult. Maintenance of anesthesia is accomplished with potent inhalational agents, a nitrous-narcotic technique, or a total intravenous anesthetic (TIVA). Patients in the acute phase of their injury may be too hemodynamically unstable to tolerate potent inhalational agents; therefore, the nitrousnarcotic technique with or without ketamine supplementation might be preferred. With the latter technique, muscle relaxants might be required to prevent movement due to spinal cord reflexes. Regardless of which induction or maintenance agents are chosen, all medications should be titrated to effect since these patients demonstrate altered physiology. The anesthesia provider should also be aware of the pharmacologic changes discussed above, such as resistance to nondepolarizing muscle relaxants and requirements of higher narcotic doses.
Fluid Management Large intraoperative fluid losses are predictable during major burn surgeries. Not only are there insensible evaporative losses from the burn wounds, but there is also the potential for massive blood loss from excised wounds and donor sites. There is limited data to approximate the amount of blood loss during excision and grafting procedures. Expected blood loss increases each day postinjury as the wound becomes more hyperemic. An estimation of blood loss during excision and grafting surgery based on the number of days postinjury is shown in Table 9.90 The amount of blood loss is greater for tangential excisions as compared to fascial excisions and is approximated as 4 ml/cm2 and 1.5 ml/ cm2, respectively.77 Blood loss is also greater in infected wounds. Since these numbers are only approximations of blood loss, frequent hematocrit and hemoglobin measurements are necessary to determine blood loss for each individual patient. While burn surgery has the reputation for massive blood loss, current surgical practice is aimed at reducing blood loss.91 Such measures include infiltration with vasoconstrictors, limb tourniquets, compressive dressings, electrocautery, and maintaining euthermia. While large-volume
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infiltration with tumescent solutions containing vasoconstrictors is beneficial for minimizing blood loss, there is potential for systemic absorption with resultant fluid overload.92 We limit the amount of tumescent solution, which contains 2 mcg/mL to 3 mcg/mL epinephrine, to 10 mL/kg to 40 mL/kg. While there is no current data to predict the amount of systemic absorption from tumescent solution, there is evidence that burn patients have altered body fluid water composition. In the acute setting, extracellular water is increased while intracellular water is decreased.93 With these alterations in fluid balance, the patient’s volume status should be monitored closely perioperatively. In addition to blood loss, patients also have insensible fluid losses. During the initial resuscitation phase, fluid replacement is approximated by the Parkland formula, which is 4 mL/(kg x % BSA burned), in addition to standard maintenance fluids. When the patient has been adequately resuscitated prior to coming to the operating room, fluid replacement is best guided by indicators of organ perfusion, such as urine output, acid-base status, central venous pressure, blood pressure, and arterial pressure waveforms. Intraoperative fluid losses are initially replaced with crystalloid and colloid solutions. We prefer colloid, in the form of 5% albumin, instead of crystalloid for fluid replacement. Packed red cell transfusions may be appropriate based on the patient’s starting hemoglobin, estimated blood loss, and lowest tolerable hemoglobin. If the patient has received multiple units of red cells, the additional transfusion of coagulation factors may be warranted.
Temperature Regulation Burn patients are at great risk for intraoperative heat loss due to lack of an intact skin layer. In comparison to adults, pediatric patients are at a higher risk for intraoperative heat loss due to their larger surface area to volume ratio. When these patients become hypothermic, their metabolism increases heat production.94 As a result, metabolic energy is diverted from other areas, such as wound healing. Therefore, one must take care to prevent intraoperative heat loss in these patients, even if these measures result in the operating room becoming uncomfortably warm. Heat loss occurs by 4 mechanisms: radiation, convection, conduction, and evaporation. Radiation heat loss is the transfer of electromagnetic radiation from a warm patient to the cooler surrounding objects. Convective heat loss is the transfer of heat to cool air as it flows over the body surface. Conductive heat loss is the direct transfer of heat to objects in contact with the body surface. Evaporative heat loss is the transfer of heat to vaporize liquid water on the body surface. For a nude adult in a room at ambient
temperature, heat losses from radiation, convection, conduction, and evaporation are approximately 60%, 12%, 3%, and 25%, respectively.95 With loss of the dry protective skin barrier, evaporative losses become more significant in burn patients. Heat loss can be minimized intraoperatively by many different interventions. Radiation heat loss is diminished by warming the operating room to decrease the temperature gradient between the patient and surroundings, by using heat lamps, and by placing reflective barriers such as mylar over the patient. Convective heat loss is minimized by warming the operating room, while conductive heat loss is reduced by placing the patient on warming blankets or other insulated materials. Evaporative heat loss is limited by covering the patient with impermeable materials such as plastic sheets or by humidifying anesthetic gases. Other methods to minimize heat loss include intravenous fluid and blood warmers and forced-air warming blankets to maintain euthermia.
ANESTHETIC MANAGEMENT FOR RECONSTRUCTIVE PROCEDURES Burn patients often return to the operating room multiple times for reconstructive procedures, such as scar revisions, reexcisions, and grafting. At the time of these reconstructive procedures, the primary wound is healed. Therefore, the patient may no longer exhibit the extreme physiologic and pharmacologic changes. Controversy remains as to when these patients are no longer susceptible to hyperkalemia from succinylcholine. A reasonable guideline is that once the wounds are healed and the patient is mobile, the patient is no longer susceptible to hyperkalemia.46 The anesthetic management for these procedures is similar to that for other plastic surgical operations. Since these patients typically undergo multiple reconstructive procedures, the preoperative assessment should focus on major changes in health since the last anesthetic and a careful airway evaluation. The previous anesthetic records should be reviewed to gain information on previous airway management and opioid requirements. Since these procedures are elective, the patient should be appropriately fasted, as shown in Table 4. Since these patients undergo multiple anesthetics for reconstructive procedures, anxiolysis may be required prior to entering the operating room. Examples of premedication for younger children who do not have intravenous access include oral midazolam, oral or intramuscular ketamine, and oral clonidine. Older children who have intravenous access can benefit from intravenous benzodiazepines or
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ANE S T HE S IA F OR P E DIAT R IC B UR N PAT I E N T S opioids. Appropriate dose ranges for these agents are shown in Table 10. Reconstructive procedures typically do not result in large amounts of blood loss or extensive fluid shifts. Therefore, a single peripheral intravenous line and standard ASA monitors for general anesthesia are adequate. Since the patient’s primary wounds are healed, excessive fluid or heat loss is less of a concern. Fluid replacement should be based on maintenance fluid requirements. Temperature can be monitored, with warming blankets used as needed. The choice of anesthetic is based on the surgical procedure. Minor surgical procedures such as suture removal can be performed with sedation. Ketamine may provide adequate analgesia and sedation for such procedures. A general anesthetic may be required for more invasive procedures. The choice of induction, either inhalational or intravenous, is made partially based on the patient’s age and preference. The aim of this practice is to make the experience as pleasant as possible so that the child will not shy away when it is time for a repeat procedure. After induction, the airway is secured. Based on the surgical location and procedure duration, an LMA is often adequate for securing the airway. If the patient has face or neck contractures, scar tissue may distort the airway, resulting in fixed flexion abnormalities and limited mouth opening. Severe neck contractures can limit placement of an LMA, in which case, the upside-down intubating LMA technique is an effective alternative.96,97 If an LMA is not adequate, use of adjunctive airway equipment such as a fiberoptic bronchoscope or lighted stylet may be necessary. In extreme cases, a surgical neck release may be required prior to induction of anesthesia. Surgical neck release prior to intubation is performed with either local or general anesthesia with spontaneous mask ventilation.98 In an extreme case of craniofacial deformity, extracorporeal membrane oxygenation (ECMO) is described in a case report as a bridge to securing the airway until neck release could be performed.99 Maintenance of anesthesia is performed with either potent inhalational agents, a nitrous-narcotic technique, or a total intravenous anesthetic per the anesthesia provider’s preference. Emergence from anesthesia should be focused on patient comfort and adequate analgesia. These patients have a tendency to develop opioid tolerance, so these agents should be titrated to clinical effect. Throughout the entire perioperative period, attention should be paid to the patient’s comfort and anxiolysis. One example of providing pain-free care is using local anesthetics prior to intravenous placement. While there is concern for adverse psychological outcome from multiple general anesthetics, there appears to be no evidence of adverse psychological impact provided that adequate precautions are taken, such as premedication as needed.100
PAIN MANAGEMENT The ability to assess and treat pain in pediatric patients can be challenging, especially since younger children are not able to directly communicate their pain levels. Burn pain is a combination of background pain, procedure-related pain, and postoperative pain. Guidelines for the management of pain in pediatric burn patients are described in the literature.101,102 Background pain is the constant and variable pain from the burn injury itself. From our experience, this pain is proportional to the size of the thermal injury. While background pain from smaller TBSA burns may be controlled with intermittent boluses of opioids, pain control for larger TBSA burns may require opioid infusions. For a bolus dose, we typically start with 0.1 mg/kg/dose morphine every 2 hours as needed for pain control. Morphine infusions are started at 0.05 mg/kg/h for nonintubated patients and at 1 mg/kg/h for intubated patients. These patients do develop tolerance to opioids; therefore, doses should be reassessed frequently and titrated to patient comfort. In order to minimize the escalation of opioid doses, other agents can be used as analgesic adjuncts. Acetaminophen, either oral or rectal, is one such opioid adjunct for pain control.103 A ketamine infusion is also shown to be an effective analgesic adjunct.66 For intubated patients, we use ketamine infusions at a rate of 0.5 to 3 mg/kg/h. We also use dexmedetomidine infusions starting at 0.5 mcg/kg/h, with titration up to a maximum of 2.5 mcg/kg/h. Other factors, such as anxiety and pruritis, contribute to pain perception; therefore, treatment of these factors can better control the patient’s pain. Benzodiazepines, such as oral or intravenous lorazepam (0.05 mg/kg/dose up to 1-2 mg/dose) or intravenous midazolam (0.02-0.04 mg/kg/ dose) are effective in treating anxiety. Based on the patient’s needs, a midazolam infusion can be started at 0.01 to 0.02 mg/kg/h for nonintubated patients and at 0.05 to 1 mg/kg/h for intubated patients. Pruritis is effectively treated with oral or intravenous diphenhydramine (1.25 mg/kg/dose up to 25-50 mg/dose) or with oral hydroxyzine (0.5 mg/kg/ dose up to 25 mg/dose). Burn patients also experience pain with procedures such as dressing changes. Background pain should be adequately controlled in order to have effective control of procedural pain. Procedure-related pain is controlled with additional boluses of opioids, benzodiazepines, and/or ketamine (0.5-2 mg/kg/dose). As an adjunct to opioids, postoperative pain can be managed with regional anesthetic techniques. Choices of regional anesthesia for postoperative pain control in pediatric patients include epidural anesthesia via the caudal, lumbar, or thoracic approach and peripheral nerve blocks.104
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While a case report of epidural anesthesia for a burned child is reported in the literature, there is limited data on the efficacy of this technique in pediatric burn patients.105 Similarly, there is limited data on the use of peripheral nerve blocks for postoperative pain control in this population. A case report demonstrates the use of 2 continuous nerve blocks, axillary and sciatic, for postoperative pain control in a 3-year-old burned child.106 Both continuous and single-shot fascia iliaca compartment blocks are efficacious in the treatment of donor site pain in the adult burn population.107,108 A fascia iliaca compartment block is also shown to decrease pain from femur fractures in pediatric patients.109 Therefore, this block may be beneficial in the pediatric burn population. While regional anesthesia techniques offer benefits for pain control, we typically do not use these techniques. For severe burns in the acute setting, it may be difficult to find sites for regional anesthesia that are free from burn injury. Additionally, regional techniques may not reliably provide analgesia during the many weeks in which excision and grafting procedures are performed. In the reconstructive phase, most operations are superficial plastic surgical procedures that do not require aggressive pain control postoperatively. Therefore, the benefits of regional anesthesia techniques may not outweigh the risks. Another form of regional anesthesia is the intraoperative use of a dilute local anesthetic tumescent solution with epinephrine. In a prospective study of 30 children with less than 20% TBSA burn who received intraoperative dilute lidocaine tumescent solution, 80% did not require supplemental analgesics and 20% required only supplemental acetaminophen in the first 24 hours postoperatively.110 It is essential to use dilute local anesthetics in the tumescent solution so that the
total dose remains under the toxic dose limit of 7 to 10 mg/ kg. Interestingly, systemic toxicity is less likely to occur in the burn population since the free fraction of local anesthetics is decreased due to increased levels of α1-glycoprotein. Regardless of the agents and/or techniques used for pain control in pediatric burn patients, attention must be paid to the alterations in pharmacokinetics and pharmacodynamics. Specific examples of these alterations include tolerance to opioids and the decreased plasma free fraction of local anesthetics. Therefore, pain medications should be titrated to clinical effect.
CONCLUSION Pediatric burn patients provide significant challenges to the anesthesia provider. In order to provide safe and effective care for these patients, attention must be paid to the physiologic and pharmacologic changes that occur with burn injury. While attention to the technical details of airway management, fluid resuscitation, and temperature regulation are important, one must not overlook the importance of analgesia and patient comfort for these critically ill children. Following these principles will lead to a successful anesthetic.
Acknowledgments The authors wish to thank Nishan Goudsouzian, MD, Hemanth Baboolal, MD, and David Moss, MD, of the Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, MA, USA, for their review of this chapter.
TABLES TABLE 1 Depth of burn injury. First Degree
Epidermis
Second Degree Superficial Deep
Epidermis and superficial dermis Epidermis and deep dermis
Third Degree
Epidermis and full-thickness dermis
Fourth Degree
Fascia, muscle, and bone
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ANE S T HE S IA F OR P E DIAT R IC B UR N PAT I E N T S TABLE 2 Definition of major burn injury. Greater than 10% TBSA of third-degree burns Greater than 25% TBSA of second-degree burns Greater than 20% TBSA of second-degree burns in infants and neonates Burn injuries involving the face, hands, feet, or perineum Inhalational burn injuries Chemical or electrical burns
TABLE 3 Pathophysiologic changes from burn injury. Early
Late
Cardiovascular
↓ Cardiac output ↑ Systemic vascular resistance Hypovolemia
↑ Cardiac output Tachycardia Systemic hypertension
Pulmonary
Airway obstruction and edema Carbon monoxide poisoning Cyanide toxicity Pulmonary edema
Chest wall restriction Tracheal stenosis Infection
Renal
↓ Glomerular filtration rate Myoglobinuria
↑ Glomerular filtration rate ↑ Tubular dysfunction ↑ Metabolic rate ↑ Core body temperature ↑ Muscle catabolism ↑ Lipolysis ↑ Glucolysis ↑ Futile substrate cycling ↑ Insulin resistance ↓ Thyroid hormones ↓ Vitamin D ↓ Parathyroid hormone
Endocrine and Metabolic
Hepatic
↓ Perfusion Hepatic apoptosis with ↑ AST, ALT, bilirubin ↑ Intrahepatic fat and edema
↑ Perfusion ↑ Metabolism
Hematologic
Hemoconcentration Hemolysis Thrombocytopenia
Anemia
Gastrointestinal
↓ Perfusion with mucosal damage Endotoxinemia
Stress ulcers Adynamic ileus Acalculous cholecystitis
Neurologic
↑ Cerebral edema ↑ Intracranial pressure
Hallucination Personality change Delirium Seizure Coma
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TABLE 4 Preoperative NPO guidelines for pediatric patients accepted at MGH. Clear liquids
2 hours
Breast milk
4 hours
Infant formula
6 hours
Nonhuman milk
6 hours
Light meal (crackers or dry toast)
6 hours
Solids
8 hours
TABLE 5 ASA standards for basic anesthetic monitoring for general anesthesia. Oxygenation
Measurement of oxygen concentration in inspired gas Quantitative measurement of blood oxygenation Ability to assess patient color
Ventilation
Qualitative assessment by chest wall excursion or breath sounds Quantitative assessment by expired carbon dioxide and volume of expired gas Continual end-tidal carbon dioxide measurement by capnography, capnometry, or spectroscopy System alarm to signal disconnection from mechanical ventilator
Circulation
Continuous electrocardiogram Arterial blood pressure and heart rate determinations every 5 minutes At least one of the following: palpation of pulse, auscultation of heart sounds, intra-arterial pulse tracing, ultrasound peripheral pulse monitoring, or pulse plethysmography or oximetry
Temperature
Monitoring of temperature for anticipated changes in body temperature
TABLE 6 Anatomical differences of the pediatric airway as compared to the adult airway. Relatively large head in comparison to body size Relatively large tongue in comparison to other airway structures Prominent tonsils and adenoids Presence of deciduous teeth that can be loose Narrow nasal passages Larynx that lies higher in the neck—at the level of C3-C4 in infancy Long, narrow, and angulated epiglottis in infancy Vocal cords have a lower attachment anteriorly than posteriorly in infancy Cricoid cartilage is the narrowest portion of airway in infancy Short, narrow, and posteriorly angulated trachea in infancy Narrow airway diameters Relatively floppy pharyngeal muscles that are more sensitive to laryngospasm
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ANE S T HE S IA F OR P E DIAT R IC B UR N PAT I E N T S TABLE 7 Suggested laryngoscope blades and endotracheal tube sizes for pediatric patients. Laryngoscope Blades
Endotracheal Tube Sizes
Premature and term neonate
Miller 0
2.5–3.0
Neonate to 9 months
Miller 0–1
3.5
9 to 24 months
Miller 1, Wis-Hipple 1.5
4.0–4.5
2 to 5 years
Miller 1–1.5, Macintosh 1
4 + [Age(years) / 4]
5 to 12 years
Miller 2, Macintosh 2
4 + [Age(years) / 4]
Adolescent to adult
Miller 2, Macintosh 3
7.0–7.5
TABLE 8 Induction doses for commonly used intravenous anesthetic agents. Ketamine
1–2 mg/kg
Thiopental
5–8 mg/kg
Propofol
2.5–3.5 mg/kg
TABLE 9 Prediction of blood loss during excision and grafting. TBSA > 30% 0–1 days postinjury 2–16 days postinjury > 16 days postinjury
0.41 mL blood loss/cm2 excised 0.72 mL blood loss/cm2 excised 0.49 mL blood loss/cm2 excised
TBSA < 30% Anytime postinjury
1.2 mL blood loss/cm2 excised
TABLE 10 Doses for commonly used premedication agents. Midazolam
IV: 0.02-0.1 mg/kg PO: 0.25-0.75 mg/kg
Fentanyl
IV: 1-4 mcg/kg
Ketamine
PO: 3-6 mg/kg IM: 2-10 mg/kg
Clonidine
PO: 2-4 mcg/kg
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C H A P T E R
E L E V E N
ACUTE BURN EXCISION ROB SHERIDAN, MD, BURN SURGERY SERVICE, SHRINERS HOSPITAL FOR CHILDREN, BOSTON, MA
OUTLINE 1. Acute Burn Excision 2. The Operating Room Environment 3. Wound Evaluation 4. Determination of Need and Timing of Operation
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ACUTE BURN EXCISION At the heart of the past few decades’ revolution in burn care is early excision and biologic closure of deep burn wounds.1 Historically, deep burns were allowed to liquefy and separate over a period of weeks, leaving granulating wounds that might be autografted in those who survived the accompanying systemic infection and inflammation. In the 1970s and 1980s, the concept of early excision of deep burns prior to the development of local and systemic infection evolved due to the hard work of a number of important clinicianinvestigators caring for burn patients. The techniques have subsequently matured, but we owe these earlier pioneers a great debt of gratitude, as do our current patients.
THE OPERATING ROOM ENVIRONMENT Excision and biologic closure of burn wounds is conceptually simple but can be quite hazardous to patients if not prudently practiced. The operating room environment is a critical consideration.2 This begins with transport to and from the operating room, which must be carefully planned and attended by experienced personnel.3 Particular attention is required to avoid dislodgement of airway and vascular access devices. In order to maintain the child’s body temperature, a careful but brisk transport is optimal to minimize the
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5. Techniques of Burn Wound Excision 6. Techniques to Minimize Blood Loss 7. Graft Stabilization and Care 8. Donor Site Management 9. Conclusion 10. References
162 163 163 163 163 164
complications associated with disruption of access devices and hypothermia. The operating room environment must be carefully controlled, particularly with regards to heating capability if operations of any magnitude are to be successfully performed in critically injured children with large burns. Intraoperative hypothermia leads to acidosis, poor peripheral perfusion, and coagulopathy.4 If the operating room can be adequately heated, this complication should essentially never occur. In addition, all intravenous and topical fluids should be warmed. Operating room personnel should become accustomed to any discomfort associated with extreme operating room temperatures. Constant, respectful communication between surgical, nursing, and anesthesia personnel is essential5 in order to ensure the child’s critical care proceeds smoothly throughout the operation. Anesthesia should be familiar with the operative plan so fluid and blood needs can be planned accordingly. The level of stimulation changes substantially during burn cases, increasing rapidly during donor skin procurement. This, as well as the possibility of substantial blood loss, should be anticipated by the anesthesia team. The surgeon should frequently inform those assisting with the operation of current and future events as well. Burn operations often require relative extremes of positioning, as no surface is immune to thermal injury. In
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AC UT E B UR N E X C I S I O N addition to added heating circuits, burn operating rooms are ideally equipped with positioning aids such as overhead suspension systems. A number of devices, such as an overheat track system, are available and can substantially reduce operative time.
WOUND EVALUATION Appropriate intraoperative decisions regarding burn excision assume an ability to accurately determine burn depth, or more importantly, to determine the likelihood that a burn will heal.6 In general, only burns of deep seconddegree or deeper are excised and grafted. As superficial second-degree burns will heal in most patients within 3 weeks, they are for the most part left alone (sometimes assisted with topical agents or membrane dressings). Superficial second-degree burns tend to be moist and painful. Deep second-degree and third-degree burns tend to be leathery, dry, insensate, depressed, and waxy or leathery. Fourth-degree burns involve subcutaneous tissue, tendon, or bone and can have a charred appearance. It can sometimes be difficult, even for an experienced examiner, to accurately determine burn depth on initial examination. As a general rule, burns are often underestimated in depth initially.7 In the operating room, a very light pass with a handheld dermatome over a representative area can give useful guidance, with viable superficial dermis identified by fine capillary bleeding. Many investigators have attempted to develop tools to assist the surgeon in determining which areas will not heal and will require excision. Unfortunately, none have met with wide success. Therefore, the eye of an experienced examiner remains the standard of burn-depth evaluation and provides the most reliable basis for operative decision making. In situations of mixed-depth injury, time spent in thoughtful planning before the initial excision will speed overall operative time and reduce intraoperative physiologic stress to the patient.
DETERMINATION OF NEED AND TIMING OF OPERATION Injuries vary in the physiologic threat they present to an injured child, and this is the principal consideration when deciding upon the need for and timing of operative intervention. In otherwise healthy children, the physiologic threat presented by the injury is primarily a function of injury size more than depth.8 Children with deep dermal or full-thickness burns involving more than perhaps 20% of the body surface are at risk for the rapid development
of wound infection and subsequently systemic infection, which is best avoided by early excision. When children have large burns of indeterminate depth, it is often prudent to excise those areas that appear deep, acknowledging that subsequent excision may be required. In such cases, when it is unclear whether a substantial amount of wound will need excision and grafting, the operating room provides an optimal environment in which to assess wound depth. Quite often, children will present with small indeterminate-depth wounds, most often from scalding injuries. Initially, many are best managed nonoperatively while wounds evolve and depth becomes more clear.9 Generally, wounds are ideally left alone if capable of healing in less than 3 weeks since they are unlikely to become hypertrophic. A common approach to these small mixeddepth wounds is to treat them with topical therapy for approximately 3 to 5 days. During this period, wound depth becomes apparent, and it is usually quite clear which, if any, components of the wound need to be excised and grafted. Often, this can be accomplished in the outpatient setting. In this way, all grafts, donor sites, and second-degree burns can be healed within 3 weeks. Children with small but obviously full-thickness burns, commonly from contact injuries, are best served by early operative intervention. Children with large mixed-depth burns greater than 20% of the body surface often benefit from a more aggressive surgical approach, as the injury size alone presents a physiological threat. Ideally, full-thickness components are excised and closed before wound colonization and systemic inflammation occur. The operative goal is to identify, excise, and close all full-thickness components. In those with very large burns, perhaps greater than 40%, this may require serial operations. In these children, temporary biologic closure can be achieved with human allograft, Integra®, or other temporary membranes. These wounds can subsequently be definitively closed with autograft when donor sites have healed or patients are more stable. The definition of “early” in “early excision” is often debated. Most would probably agree that “early” is prior to the occurrence of local infection and systemic inflammation. Many practitioners define “early” as within 1 to 7 days after injury. The primary advantage of waiting toward the end of this window is that burn wounds have evolved to the point that intraoperative decision making is easier since burn depth is clearer and the level of viable excision is more reliably appreciated. However, in the hands of experienced practitioners, where children are well monitored and supported, excision and closure within hours of injury can be safely and effectively performed.10
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A final, relatively common issue is the child who presents with a smaller injury complicated by localized wound sepsis. The important decision in this situation is whether excision is needed to facilitate control of infection. This is generally advisable with full-thickness burns. If burns are partial thickness, most cases of simple cellulitis can be effectively treated with topical antimicrobials and systemic antibiotics.11
TECHNIQUES OF BURN WOUND EXCISION Superficial wounds deemed likely to heal should not be excised. They need only be cleansed and treated with topical medications or temporary biologic dressings to prevent desiccation and minimize superinfection. Scattered reports have advocated very superficial excisions of such wounds, but there are no data that convincingly support this potentially morbid and expensive practice. Although topical proteolytic enzymes may have a limited role in superficial injuries, it is unclear if this practice improves on the results obtained by supportive care only. After initial decompression is assured via escharotomy and/or fasciotomy, acute burns are generally addressed operatively in 1 of 5 ways, which vary with the depth of the wounds and the clinical status of the patient. These include sharp debridement of loose devitalized tissue, layered deep dermal excision, layered excision to viable subcutaneous fat, fascial excision, or subfascial excision. Layered excision to viable deep dermis is a proper approach to deep second-degree burns which are unlikely to heal in less than 3 weeks. Although they may eventually heal, such wounds frequently become very hypertrophic and pruritic, particularly where skin is thin and has few appendages, such as the upper inner thigh or arm. If too superficial a burn is managed by mid-dermal excision followed by sheet grafting, bothersome sub-graft cyst formation commonly occurs as viable skin appendages lose their natural drainage. Dermal excisions are best reserved for those situations where it is evident that the bulk of the dermis is not viable. Layered deep dermal excisions can be done with hand-held dermatomes or with dermatomes powered by electricity or compressed nitrogen. Deep dermal excisions can be associated with substantial capillary bleeding, so it is important to use techniques to minimize blood loss, including subeschar dilute epinephrine clysis and exsanguination with proximal tourniquet inflation on extremities.12 Perhaps the most useful technique is careful planning, including delineation of surgical margins, followed by swift excision. Layered excision to viable subcutaneous fat is a useful technique in full-thickness cutaneous burns. When successfully applied, this method normalizes subsequent contour, appearance, and function. There is less bleeding than in deep
dermal excision because of reduced capillary density. The conventional wisdom that fat accepts grafts less reliably is probably not true. Rather, it may be more difficult to appreciate the viability of fat, and the bed tolerates desiccation poorly because of the reduced capillary density. Careful evaluation of the wound bed while minimizing open interstices results in reliably good graft take in most situations. These excisions can also be done with hand-held or powered dermatomes. Coverage of a well-excised subcutaneous bed with sheet grafts or minimally expanded meshed grafts usually produces excellent results. It is essential that grafts conform to the many small irregularities in beds of subcutaneous fat and that fat is not left exposed to desiccate. Widely meshed grafts do poorly on beds of subcutaneous fat. Fascial excisions are not often required, having been more commonly done in the early years of acute excisional burn surgery. However, they are indicated if burns involve subcutaneous fat. Some patients with massive full-thickness burns seem best served with fascial excisions to minimize the chance of autograft loss on beds of subcutaneous fat. Also, some fragile elderly patients may be candidates for fascial excision as this technique minimizes blood loss and provides a highly reliable bed for autograft coverage. The disadvantage of major contour deformity must be considered. Fascial excision seems best performed with traction and coagulating electrocautery, which provides excellent hemostasis and a well-defined wound bed. The electrocautery plume can be substantial but can be minimized with high-efficiency suction devices, many of which are incorporated into the electrocautery hand-piece. Subfascial excision of devitalized deep tissue is required in high-voltage injury, soft-tissue trauma, or occasionally in very deep thermal burns. Muscle compartments can be explored through standard fasciotomy incisions, allowing simultaneous decompression and debridement. Vacuumassisted closure devices can be useful in preparing such wounds for grafting. Local or distant flaps may be used in other wounds. Definitive closure of such complex wounds can be difficult, and closure should be addressed on a caseby-case basis. Throughout the operative event, the patient’s condition should be continuously monitored and evaluated. Constant communication between the surgical and anesthetic teams is required to maintain optimal physiologic stability in acute burn operations of the magnitude done today. In particular, hypothermia must be anticipated and prevented, as loss of temperature control risks coagulopathy and instability that will compromise the operative event. This is best achieved by heating the operating room, as the degree of patient exposure needed often renders other devices to maintain temperature ineffective.
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TECHNIQUES TO MINIMIZE BLOOD LOSS Acute burn excisions have a reputation for creating substantial blood loss, largely secondary to use of bleeding as the primary indicator of wound bed viability during excision. Estimates in the range of 3.5% to 5% of the blood volume for every 1% of the body surface excised have been published.13 Other ways to determine viability of the bed during wound excision include bright, moist, yellow fat patent small blood vessels, absence of thrombosis of small vessels, and lack of extravascular hemoglobin staining. Accurate identification of tissue viability without the presence of free bleeding is an acquired skill that is difficult to master or maintain if these operations are not performed on a regular basis. Intraoperative bleeding can be substantially reduced by planning careful excision prior to incision, use of proximal pneumatic tourniquets for extremity excisions, use of subeschar dilute epinephrine clysis for torso and head excisions, use of coagulating electrocautery for fascial excision, and maintaining intraoperative normothermia.14 Further, less blood loss occurs when layered excisions are briskly performed in the first days following injury, when wounds are less hyperemic. Moreover, clear planning of excision margins using a variety of hand-held, gas-powered, or electric dermatomes can also facilitate the procedure. Fascial excisions using traction and coagulating electrocautery result in less blood loss. Maintenance of patient normothermia during large-burn operations may require operating room temperatures of 90°F to 120°F.
GRAFT STABILIZATION AND CARE Although methods of graft stabilization vary, all need to eliminate shear between grafts and underlying wounds, prevent desiccation and colonization of interstices, and minimize blood and serous collections beneath grafts. Ideally, postoperative dressings minimize the degree to which patients must be immobilized after surgery, allowing physical therapy and rehabilitation to continue as much as possible. Even though some of these techniques are timeconsuming, it is time well spent if graft take is improved and postoperative immobility is minimized. On most extremities, simple but very carefully applied gauze wraps which avoid causing distal ischemia suffice. On the anterior torso, moderately tightly stretched mesh can be secured over grafts, resulting in excellent fixation and minimal bulk. On the posterior torso, grafts can be stabilized with multi-ply layered gauze secured to the underlying soft tissues. This technique is suitable for extensive meshed grafts and also allows application of topical
agents.15 Furthermore, prone positioning is not required and therapy can continue immediately after surgery. Standard tie-over dressings are suitable for small grafts in a wide variety of locations. Ideally, nonabsorbable sutures and staples are used judiciously, as removal can be timeconsuming and painful. Carefully constructed and applied operative dressings as well as judicious use of tissue glues are excellent substitutes which minimize the need for these devices.
DONOR SITE MANAGEMENT Donor sites can be dressed by open or closed techniques. Open techniques include any nonocclusive dressing, such as fine-mesh gauze or Vaseline-impregnated dressings. Open management is forgiving of donor site colonization and fluid collections. The major disadvantage is the significant and predictable discomfort that occurs for the first few days until the dressing dries and forms a scablike barrier over the wound. Closed techniques include a wide variety of occlusive membranes and hydrocolloid dressings. The major advantage of this style of donor site management is a significant reduction in pain when they perform as hoped. The primary disadvantage is a relative inability to tolerate fluid collections and wound colonization. When this occurs, commonly in larger and posterior donors, membranes often need to be unroofed or removed, which itself can be unpleasant and uncomfortable. In posterior and/or large donor sites, open donor site management seems more practical, anticipating and pharmacologically treating the predictable pain with techniques such as injection of long-acting anesthetics prior to emergence from anesthesia. For small anterior donor sites, closed management can be quite successful. Scalp donor sites in young children should be harvested relatively thin to minimize donor alopecia and transplantation of scalp hair.
CONCLUSION Most of the progress in burn care over the past 30 years has been a direct result of advances in the operative approach to acute burn wounds. Important adjuncts have included advances in blood banking and anesthetic techniques, but the core change has been early identification and excision of deep wounds prior to the development of sepsis and systemic inflammation. These operations, however, can be physiologically stressful to the point where more harm than good can occur unless careful planning and meticulous technique are diligently practiced. When we approach acute burn excisions with such care and consideration, our patients accrue major benefits.
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REFERENCES
8. Klein GL, Herndon DN. Burns. Pediatr Rev. 2004; 25(12):
1. Sheridan RL. Burn care: results of technical and organizational
9. Desai MH, Rutan RL, Herndon DN. Conservative treatment
progress. JAMA Contemp Update. 2003; 290(6): 719–722. 2. Sheridan RL. Comprehensive management of burns. Curr
of scald burns is superior to early excision. J Burn Care Rehabil. 1991; 12(5): 482–484.
Probl Surg. 2001; 38(9): 641–756.
10. Barret JP, Herndon DN. Modulation of inflammatory and
3. Beckmann U, Gillies DM, Berenholtz SM, Wu AW, Pronovost
catabolic responses in severely burned children by early burn wound excision in the first 24 hours. Arch Surg. 2003; 138(2): 127–132.
P. Incidents relating to the intra-hospital transfer of critically ill patients. An analysis of the reports submitted to the Australian Incident Monitoring Study in Intensive Care. Intensive Care Med. 2004; 30(8): 1579–1585. 4. Inaba K, Teixeira PG, Rhee P, et al. Mortality impact of
hypothermia after cavitary explorations in trauma. World J Surg. 2009; 33(4): 864–869. 5. Elks KN, Riley RH. A survey of anaesthetists’ perspectives of
communication in the operating suite. Anaesth Intensive Care. 2009; 37(1): 108–111. 6. Heimbach D, Engrav L, Grube B, Marvin J. Burn depth: a
review. World J Surg. 1992; 16: 10–15. 7. Sheridan RL. Evaluating and managing burn wounds. Dermatol
Nurs. 2000; 12(1): 17–31.
411–417.
11. Sheridan RL. Sepsis in pediatric burn patients. Pediatr Crit
Care Med. 2005; 6(3): S112–S119. 12. Sheridan RL, Szyfelbein SK. Staged high-dose epinephrine
clysis is safe and effective in extensive tangential burn excisions in children. Burns. 1999; 25: 745–748. 13. Housinger TA, Lang D, Warden GD. A prospective study of blood loss with excisional therapy in pediatric burn patients. J Trauma. 1993; 34: 262–263. 14. White CE, Renz EM. Advances in surgical care: management of severe burn injury. Crit Care Med. 2008; 36(7)(suppl): S318–S324. 15. Sheridan RL, Behringer GE, Ryan CM, et al. Effective postoperative protection for grafted posterior surfaces: the quilted dressing. J Burn Care Rehabil. 1995; 16: 607–609.
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C H A P T E R
T W E L V E
BLOOD TRANSFUSION IN CHILDREN WITH BURN INJURY TINA L. PALMIERI, MD, FACS, FCCM, SHRINERS HOSPITAL FOR CHILDREN, NORTHERN CALIFORNIA, AND THE UNIVERSITY OF CALIFORNIA DAVIS, SACRAMENTO, CA
8. Specific Component Therapy Considerations
OUTLINE 1. Introduction 2. History of Blood Transfusion 3. Hematologic and Physiologic Differences Between Children and Adults a. Physical Characteristics of Children
4. Metabolic Consequences and Risks of Blood Transfusion in Children 5. Infectious Disease Transmission 6. Incompatibility/Immunologic Factors 7. Determining How and When to Transfuse a Child a. Coagulopathy of Transfusion
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Red Cell Transfusions Red Cell Transfusion and Burns Platelet Transfusions Fresh Frozen Plasma Cryoprecipitate and Factor Concentrates f. Erythropoietin
9. Decreasing Intraoperative Blood Loss in Burn Surgery 10. Conclusions 11. Table 12. References
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INTRODUCTION Anemia is a common occurrence in critically ill patients, with approximately 25% receiving a blood transfusion.1 Anemia is also frequent after major burn injury, which results in prolonged critical illness and hospitalization. Postburn hemolysis, surgical blood loss, the hypermetabolic state, sepsis, and decreased red cell production all contribute to postburn anemia. Children with major burn injury are no exception; approximately 25% of these children receive a blood transfusion.2 Because every transfusion is associated with both risks and benefits, it is important to understand the history, salutary effects, and risks of transfusion for both adults and children with burns. Knowledge of the physiologic and anatomic differences between children and adults with respect to response to injury will help guide the
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decision-making process regarding blood transfusion. The goal of this chapter is to provide the burn practitioner with a fundamental knowledge base for transfusion in burned children based on patient physiology and blood product characteristics.
HISTORY OF BLOOD TRANSFUSION Many of our current transfusion practices are rooted in the historical development of blood transfusion as a therapeutic modality. Appreciation of the implications of this procedure requires a thorough understanding of how current blood transfusion practices were developed. Although the technique is relatively simple, the use of blood transfusion in clinical practice has been widely employed for less than 100 years.3 Blood-letting as a therapeutic modality
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can be traced back to Hippocrates in 430 BC; however, the infusion of blood was delayed for several reasons. First, both the Romans and Greeks held to the humoral theory, which maintained that all living beings consisted of the balance of 4 elements: black bile, blood, phlegm, and yellow bile.4 Illness was due to an imbalance of these elements, which could be corrected with proper diet and environmental alterations. Second, the physiology of circulation, which is the crux of transfusion medicine, needed to be recognized. Blood circulation physiology was first reported by William Harvey in 1628. This laid the groundwork for further advances in transfusion therapy. The first blood transfusion experiments were conducted in the 1650s by members of the Oxford Experimental Philosophy Club, which consisted of such preeminent scientists as Robert Boyle, Thomas Willis, Christopher Wren, and Robert Hook. Wren demonstrated that substances injected intravenously could yield systemic effects. In 1666, Richard Lower successfully transfused blood from one dog to another venisected dog. Jean Denis, professor of philosophy and mathematics at Montpellier in France, began the practice of transfusion of blood from calves and lambs into humans, usually for the treatment of mental disorders.5 Although this became popularized in Europe, others were not successful with interspecies blood transfusion in humans. Subsequently, blood transfusion fell into disfavor by the end of the century due to its high mortality rate. The pioneer of modern blood transfusion therapy is James Blundell (1790–1878), an obstetrician at Gary’s and St Thomas’ hospitals in London.6 Dr Blundell is credited with identifying 2 key concepts: (1) blood transfusion needs to occur between 2 members within the same species, and (2) blood transfusion requires specialized and appropriate medical equipment. Before applying these principles in people, Dr Blundell demonstrated through multiple canine experiments that intraspecies (ie, dog to dog) transfusion could be successful. He also demonstrated that interspecies (human to dog) transfusion was not feasible, a great accomplishment given that the concept of antibodies had not yet been introduced. Dr Blundell reported 10 successful human-to-human blood transfusions, primarily in postpartum hemorrhage, between 1818 and 1829.7 He published these findings in the Lancet and retired 5 years later.8 However, the adoption of this concept was slow, and by 1849 only 44 individuals had received blood transfusions. The consistent success of blood transfusion in humans required further elucidation of the A, B, O, and ABO blood groups. Karl Landsteiner (1868–1943), an assistant in the Pathological-Anatomical Institute in Vienna, described clumping of red cells when serum of one individual was added to others. He attributed this reaction to an immunologic response and consequently reported 3 different blood
groups in 1901. Although his work went unrecognized until the 1920s, he was eventually awarded the Nobel Prize in 1930. Multiple investigators developed different blood group categories, and it was not until the 1937 Congress of the International Society of Blood Transfusion that the ABO terminology was universally adopted.3 Twenty-five years later, other blood group antigens were identified, including Rhesus antibodies. Interestingly, the systems used to designate blood antigens are derived from the first patient described with the syndrome, rather than the investigator. Examples include the Kell system (infant with hematologic disease), Duffy (named after patient Joseph Duffy), and Kidd (named after a child of Mrs. Kidd with hematologic disease of the newborn).9 Once the major blood antigens were identified, the next challenge facing the widespread application of blood transfusion in clinical practice was to prevent blood coagulation during transfusion. In March 1908, Alexis Carrel (18731948) was the first physician to partially solve this problem when he successfully anastomosed the left radial artery of a father with a vein in the leg of his infant. When the transfusion was judged to be complete, Dr Carrel tied off both the artery and vein.10 Both father and infant survived. This practice had several limitations, not the least of which was the inability to judge the volume of blood transfused, as well as the loss of the donor’s vessel for further blood donation. It became clear that an anticoagulant needed to be added to donated blood to prevent clot formation. Richard Lewinsohn of Mount Sinai Hospital in New York performed a series of experiments which demonstrated that a 0.2% solution of sodium citrate was effective in preventing blood from clotting without causing systemic toxicity.11 Later studies of dextrose and phosphate led to the current practice of using a citrate-phosphate-dextrose (CPD) solution to store blood safely for up to 28 days.12 The advent of World War I brought further advances in blood transfusion medicine. As it was not practical to bring blood donors to the front lines, a blood bank needed to be formed. The first blood bank was established in 1937 by Bernard Fantus at Cook County Hospital in Chicago.13 The Second World War reinforced the need for blood banks as well as for fractionated blood products. Edwin Cohn, a professor at Harvard, isolated fractions of plasma (including albumin, fibrinogen, and immunoglobulin) by using serial additions of ethyl alcohol.14 Cryoprecipitate was developed by Judith Pool in 1964 from the insoluble fraction of fresh quick-frozen plasma.15 The use of blood and blood products has expanded markedly since the initial transfusion experiments. Each year in the United States approximately 50% of children hospitalized in an intensive care unit receive a blood transfusion.16,17 The use of fresh frozen plasma (FFP) has
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B LOOD T R ANS F US ION IN C HIL DR E N WIT H B URN I N J U RY also increased steadily in the United States in the past 20 years. In 1979, one unit of FFP was transfused for every 6.6 units of packed red blood cells (PRBC), while in 2001, one FFP was transfused for every 3.6 units PRBC.18 The ratio of FFP to PRBC continues to increase, especially in military medicine.
HEMATOLOGIC AND PHYSIOLOGIC DIFFERENCES BETWEEN CHILDREN AND ADULTS Children and adults differ both in their physiology and in their response to injury and illness. These differences influence both the timing and volume of transfusion. Rational administration of blood and blood products in children relies on an understanding of basic pediatric cardiovascular physiology.
Physical Characteristics of Children Children differ from adults with respect to cardiac physiology and function. For example, children have a higher resting heart rate than adults. The normal resting heart rate for a newborn infant is 100 to 160 beats per minute. This decreases to 70 to 120 beats per minute for children aged 1 to 10 years. After 10 years, the normal heart rate of a child approaches the adult norm of 60 to 100 beats per minute. Cardiac function also differs with age. Unlike an adult, the newborn’s myocardium operates at near-maximum function at baseline. Therefore, a newborn may have difficulty increasing cardiac output to compensate for decreased oxygen carrying capacity.19 In other words, infants cannot increase cardiac contractility to augment cardiac output; instead, they tend to increase heart rate. It is far more difficult for a burned child who already has tachycardia due to burn hypermetabolism to increase cardiac output by further raising heart rate. Infants with a burn may subsequently develop heart failure due to the increased metabolic demands of their injury.20 In addition, decreased oxygen delivery capacity could result in myocardial ischemia in the newborn or very young infant. This may partly account for the increased mortality of burned children younger than 2 years.21 Despite being physically smaller than adults, children have a greater blood volume per unit mass. The mean blood volume for a child is 70 mL/kg, while the entire intravascular volume of an adult is 7% of total body weight. The increased blood volume per unit mass in children results in higher oxygen consumption and an elevated cardiac output per unit blood volume than adults.22,23 This higher oxygen consumption can result in the need for greater oxygen delivery during times of critical illness, which can be ameliorated only by a blood transfusion.
Normal hemoglobin levels are also age-dependent. A child’s normal hemoglobin reaches its nadir of 11.2 g/dL at approximately 2 to 3 months of age24 (Table 1). Fetal hemoglobin, which decreases red blood cell life span from 120 to 90 days and shifts the oxygen-hemoglobin dissociation curve to the left, also plays a role in oxygen delivery in infants. Although fetal hemoglobin comprises 70% of hemoglobin at birth, only a fraction remains at 6 months of age.25,26 In addition, critically ill infants with sepsis or polytrauma have a decreased production of erythropoietin in response to hypoxia or anemia.27 Finally, children have a higher metabolic rate than adults, a difference that is exacerbated after burn injury.
METABOLIC CONSEQUENCES AND RISKS OF BLOOD TRANSFUSION IN CHILDREN Because children have a higher blood transfusion unit per volume ratio, they are at higher risk for metabolic perturbations after blood transfusion due to both the properties of red blood cells and the substrates used to help preserve red blood cells. These risks include hypocalcemia, hyperkalemia, hypomagnesemia, hypothermia, acidosis, and oxygen-hemoglobin dissociation curve shifts. Ionized calcium is an important cofactor in many aspects of the coagulation cascade, as well as for myocardial contractility in the infant.28 Hypocalcemia poses a greater risk to the neonate since the reduced sarcoplasmic reticulum in neonate myocardium makes cardiac contractility and relaxation dependent on ionized calcium concentration. The mechanism of action of citrate, which is used in blood storage, is to chelate calcium to prevent clot formation. As a result, transfusion can result in hypocalcemia. The degree of hypocalcemia is dependent on several factors, including the type of blood product transfused, the rate of the transfusion, and hepatic function.29,30 Transfusion of whole blood and FFP results in the highest risk for development of hypocalcemia due to the higher concentration of citrate per unit volume. Hypocalcemia has been demonstrated following FFP administration during massive resuscitation in burns.31 Decreasing the rate of blood transfusion to less than 1 mL/kg/min may ameliorate this hypocalcemic effect. Hypocalcemia can be corrected with either calcium chloride (5–10 mg/kg) or calcium gluconate (15–30 mg/kg). Calcium should never be administered through the same line as blood, as it may result in clot formation. Hypomagnesemia may also occur after massive transfusion due to citrate toxicity. Because magnesium stabilizes resting membrane potential, hypomagnesemia may result in a life-threatening arrhythmia. If ventricular fibrillation or ventricular tachycardia refractory to calcium administration
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occurs after transfusion, intravenous magnesium sulfate in a dose of 25 to 50 mg/kg may be helpful. Hyperkalemia has been implicated as a cause of cardiac arrest in children and infants during intraoperative transfusion of large amounts of blood products and during exchange transfusions.32,33 Children with small blood volumes are at particularly high risk for hyperkalemia. The blood components with the highest levels of potassium include whole blood, irradiated units, and units nearing expiration (ie, “old blood”).34,35 Methods to decrease the risk of hyperkalemic cardiac arrest include using PRBC < 7 days old, avoiding whole blood in small infants, and washing erythrocytes. Large blood volumes infused rapidly can result in life-threatening arrhythmias.32,35 Administration of calcium can help to resolve these arrhythmias by opposing the electrophysiologic effects of hyperkalemia; however, additional measures to lower serum potassium, such as glucose, insulin, albuterol, and Kayexalate, need to be administered to definitively resolve hyperkalemia. Acidosis may also occur after blood transfusion. Stored blood cells initially undergo aerobic metabolism, but eventually anaerobic metabolism develops and increases lactic acid. The greatest risk for developing life-threatening acidosis occurs during rapid transfusion for massive blood loss in a hypovolemic patient. In the setting of burn injury, this is most likely to occur during extensive excision of the burn wound. Frequent measurement of acid/base status during burn excision and grafting will allow treatment of metabolic acidosis. Several days after a massive transfusion, it is not unusual for patients to develop metabolic alkalosis from metabolism of citrate in the blood products previously administered. Hypothermia after blood transfusion in children requires special note. Children, due to their large surface area to body ratio, are predisposed to heat loss. Children with burn injury, due to loss of skin integrity, open wounds, and exposed tissue, are at an even higher risk for hypothermia. This increases oxygen consumption, exacerbates coagulopathy, and increases mortality.36,37 The use of blood warmers during transfusion may decrease the incidence of hypothermia, as will maintenance of a warm operating room environment.
INFECTIOUS DISEASE TRANSMISSION Although the incidence of infectious disease transmission via blood transfusion is now lower than that for metabolic or immunologic complications, it remains an important consideration for children requiring blood transfusion.38 Parents in particular are extremely concerned about the transmission of hepatitis and human immunodeficiency virus (HIV). Current blood screening tests include hepatitis B surface and core antigen, hepatitis C virus (HCV) antibody, HIV-1
and HIV-2 antibody, human T-lymphotrophic virus (HTLV) types I and II antibody, and nucleic acid amplification testing for HIV-1, HCV, syphilis, and West Nile virus. In addition to these commonly tested viral infections, bacteria can also infect blood products. The incidence of bacterial contamination is highest for platelets.39,40,41 The incidence of infection from blood transfusion includes hepatitis C (1/1,600,000), hepatitis A (1/1,000,000), hepatitis B (1/220,000), HIV (1/1,900,000), bacterial contamination of blood (1/500,000), and blood type mismatch (1/14,000).42 Other potential infections that could be transmitted via transfusion but are not tested for include HTLV, West Nile virus, babesiosis, Chagas disease, Lyme disease, malaria, Creutzfeldt-Jakob disease, and severe acute respiratory syndrome (SARS).
INCOMPATIBILITY/IMMUNOLOGIC FACTORS Acute hemolytic reactions generally occur when ABO incompatibility results in immunologic destruction of red cells. Despite the careful application of compatibility testing, these reactions continue to occur. Clerical error remains the leading cause of blood mismatch transfusion reactions. It is particularly important for 2 medical professionals to check the unit with both the blood bank paperwork and the patient’s arm band in order to verify that the correct unit is truly intended for that patient. Strict adherence to transfusion protocols is important to avoid this iatrogenic complication. Acute hemolytic reactions can also occur due to serologic incompatibilities of minor antigens not detected by current screening techniques. Fortunately, anaphylactic reactions rarely occur. Transfusion-related graft versus host reaction, in which lymphocytes in the transfused blood cause host cell destruction, occurs primarily in immunocompromised patients.43,44 This condition can also happen primarily in premature infants or children with rapid acute blood loss, cardiopulmonary bypass, cancer, or severe systemic illness.45 Thus, children with burn injury are at risk for this complication since they are immunosuppressed and often receive large volumes of blood in the operating room. Transfusion-related graft-versus-host disease can be minimized by using irradiated units, which effectively decreases the lymphocyte count. However, potassium levels must be monitored closely since irradiated blood has a higher potassium concentration. Acute transfusion reactions are not infrequent in children. A recent study in a pediatric intensive care unit reported a 1.6% rate of acute transfusion reactions in 2500 transfusions, with 15% being immediately life-threatening.46 Transfusion-related acute lung injury (TRALI), the onset
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B LOOD T R ANS F US ION IN C HIL DR E N WIT H B URN I N J U RY of pulmonary insufficiency within 6 hours of transfusion, is estimated to occur in approximately 1 in every 5000 units transfused.47 Children need to be monitored closely for these complications.
DETERMINING HOW AND WHEN TO TRANSFUSE A CHILD The blood volume of a child varies with age and weight, which impacts how much blood a child should receive during acute blood loss. The highest blood volume per unit weight is for a premature infant, at 90 to 100 mL/kg, while the lowest is for a very obese child, at 65 mL/kg. A term infant has a blood volume of 80 to 90 mL/kg until the age of 3 months, after which the total blood volume drops to 70 mL/kg.48 The lower total blood volume of an infant relative to an adult is an important consideration in determining the amount of blood to give a child. During massive blood loss (defined as blood loss greater than 1 blood volume) in a child without preexisting anemia, the blood loss at which transfusion should be started (maximal allowable blood loss, or MABL) can be calculated from the following formula: MABL = [(Hctstart – Hcttarget)/Hctstart] x EBV where EBV is estimated blood volume, Hcttarget is hematocrit goal, and Hctstart is starting hematocrit. In theory, blood loss to the level of MABL can be replaced by either crystalloid or colloid, with blood transfusion reserved for larger losses. Since the hematocrit in packed RBCs averages 70%, approximately 0.5 ml of packed RBCs should be transfused for each milliliter of blood loss beyond the MABL. Although this formula is attractive, it is merely an estimate and must be applied with caution. This formula can be problematic in the burned child, who has elevated red cell destruction and decreased red cell production. In general, during burn excision, a child loses 5% of his or her blood volume per percent burn excised on the face and 2% of his or her blood volume per percent burn excised on other areas.49 Thus, an infant undergoing burn excision of the entire head could potentially lose 18% (body surface area of head) x 5 ml/% (blood volume lost per percent excision of head), which is 90% of the child’s total blood volume. Adequate amounts of blood products should be ordered and readily available prior to the onset of surgery.
Coagulopathy of Transfusion Massive blood transfusion may result in coagulopathy due to a variety of reasons. First, thrombocytopenia may be caused by dilution of platelets during transfusion. In general,
a patient will lose 40% of the starting platelet count in the first blood volume lost, with loss of an additional 20% of the initial count at the second blood volume.50 A preoperative platelet count measurement can be particularly valuable in this regard, especially in major burn excision cases. A child with sepsis and thrombocytopenia is more likely to require platelets than a child with a high or normal platelet count. The second cause of coagulopathy during massive blood transfusion is depletion of clotting factors. Currently, packed red blood cells (PRBC) are the predominant form of red cell transfusion in the United States. Since 80% of the coagulation factors have been separated from packed RBCs, clotting factor deficiency will occur at approximately 1 blood volume.50 If whole blood is used, all clotting factors except labile factors V and VIII will be transfused at normal levels. Thus, coagulation abnormalities tend to occur later (>3 blood volumes) when using whole blood.51
SPECIFIC COMPONENT THERAPY CONSIDERATIONS Red Cell Transfusions PRBC transfusion is used to augment hemodynamic status in more than 3 million patients per year, and an estimated 11 million units of PRBCs are transfused every year in the United States.52 Approximately one-quarter of patients in the intensive care unit receive blood transfusions to ameliorate the effects of anemia.53 Although PRBC transfusion has many beneficial effects, it is not without complications. Commonly cited adverse effects include infection, pulmonary edema, immune suppression, and microcirculatory alterations.54 Blood transfusion has been associated with increased risk of nosocomial infections in the critically ill, including patients with burn injury.55,56 Increased complications, including death, after transfusion have been associated with older and nonleukoreduced blood.57-59 Several methods have been advocated to reduce the complication rate of PRBC transfusion. In particular, some have advocated the use of “young” packed red blood cells (ie, less than 2 weeks after donation). After 15 days, stored red blood cells undergo a variety of morphologic and functional changes, including decreased deformability, depletion of 2,3-diphosphoglycerate, decreased ability to offload oxygen, reduction in adenosine triphosphate, loss of endogenous red blood cell antioxidants, and red cell sludging.60 In addition, leukoreduction of packed red blood cells has been proposed as a possible method of decreasing the adverse outcomes after PRBC transfusion. Since the white blood cells present in both PRBC and platelet preparations can result in immunologic and physiologic dysfunction in
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the recipient,61,62 reduction of leukocytes may mitigate these alterations. Traditionally, blood has been transfused in both adults and children to maintain a hemoglobin level of at least 10 g/dL or hematocrit of 30%, to assure “optimal” oxygen delivery. However, the Transfusion Requirements in Critical Care (TRICC) study, a multicenter, prospective, randomized study of ICU patients, challenges this standard.63 A total of 838 patients were randomized to receive blood transfusion based on a liberal (maintain hemoglobin 10–12 g/dL) versus a restrictive (maintain hemoglobin 7–8 g/dL) strategy. The restrictive strategy was found to be at least as effective as the liberal strategy in critically ill patients. Parameters such as in-hospital mortality, cardiac complications, and organ dysfunction were lower in the restrictive group. A similar study performed in children by many of the same investigators found that a restrictive transfusion policy could also be applied in children without increasing the incidence of adverse outcomes.64 These findings are especially relevant since numerous studies have documented increased mortality and infection rates in children and adults receiving blood transfusions.65,66,67
Red Cell Transfusion and Burns The previously performed randomized trials evaluating blood transfusion practices have limited applicability to the burn population, since patients were excluded if they had a drop in hemoglobin of 3 g/dL or had ongoing blood loss. In the acute resuscitative phase, burn patients often have a significant reduction in hemoglobin due to ongoing blood loss (other trauma, escharotomies), hemodilution, or hemolysis. Neither study indicated whether or not burn patients were included. Of the 838 patients enrolled in the adult study, only 165 comprised the trauma category, and in the pediatric study, only 93 patients were in the surgery group, of which burn injury would have been a minor component. Hence, an adequate sample size to determine the outcome of a restrictive strategy in children with burn injury did not exist. Finally, the effects of a restrictive strategy on wound healing or infection were not assessed. Both of these variables are major considerations in children with burns. Data on the ideal blood transfusion threshold in burns remain limited. In one study by Sittig and Deitch, a total of 14 patients admitted to a burn center during a 6-month interval were transfused if their hemoglobin level was < 6.0 g/dL.68 The outcomes of patients with > 20% total body surface area (TBSA) burns or patients requiring excision and grafting of > 10% TBSA were retrospectively compared to a matched group of 38 patients treated the previous year using a nonrestrictive policy (hemoglobin maintained above
9.5–10 g/dL). No differences existed in hospital length of stay. The patients treated with the traditional strategy received 3.5 times more blood than their restrictive counterparts. A more recent study evaluating the blood transfusion practices of 21 burn centers throughout the United States reported that for patients with burn injury >20% TBSA, mortality was related to age, TBSA burn, inhalation injury, the number of units of blood transfused in the burn intensive care unit, and the total number of units transfused.69 The infection rate was also influenced by the number of blood transfusions: each transfusion increased the risk of infection by 11%. Thus, there appears to be an association between the volume of blood transfused with both infection and mortality. The data for blood transfusions in burned children are limited primarily to single-center retrospective observational studies. Several studies have demonstrated that children are more likely to develop sepsis and/or infection if they receive a larger number of blood products.2,70 In addition, these studies demonstrate that more complications occur in children receiving a greater number of blood transfusions. Hence, packed red blood cell transfusions should be administered judiciously. To date, the “optimal” transfusion threshold has not been defined for children with burn injury. The use of whole blood transfusion after injury increased due to several reports of improved outcomes in soldiers with severe hemorrhage and burn injury during military conflicts.71,72 A single case series report on the use of reconstituted whole blood during early burn excision in 20 children reported no increased risk of infectious episodes or coagulopathy during near-total-body burn excision.73 Although intriguing, neither of these studies is prospective nor adequately powered to draw meaningful conclusions regarding the use of whole blood in burned children.
Platelet Transfusions Platelets, which are produced in the bone marrow and destroyed by the spleen, have an average lifespan of 9 to 10 days. They are obtained in 1 of 2 ways: the first method involves centrifugation of whole blood into platelet-rich plasma, which is again centrifuged to obtain platelets. In the second method, dubbed apheresis or plasmapheresis, blood is taken from a single donor, run through an apheresis unit (which separates the blood via centrifugation), and all components except for platelets are returned to the donor. The resulting apheresis unit has 6 times the number of platelets as whole blood and can be stored at room temperature for up to 5 days.74 Platelets play an important role in coagulation. However, the administration of platelets also carries multiple risks.75 One study cited a 30% incidence of a transfusion
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B LOOD T R ANS F US ION IN C HIL DR E N WIT H B URN I N J U RY reaction from platelets compared to 6.8% for red blood cells.76 The age of the blood product is a predominant factor increasing the incidence of transfusion reaction: the older the blood product, the greater the risk. Platelets also have the highest bacterial contamination rate of all blood products. In patients who have active bleeding or are in need of surgical intervention, such as children with burn injury, the platelet count should be greater than 50,000/μL at the beginning of the procedure.77
Fresh Frozen Plasma Fresh frozen plasma (FFP) is perhaps the most commonly used plasma product to correct clotting factor abnormalities.78 In general, FFP administration is indicated in patients with factor XI deficiency, active bleeding with an INR of > 2, and patients with disseminated intravascular coagulation (DIC). Children with major burn injury frequently develop clotting abnormalities as well. Shortly after burn injury, a consumptive coagulopathy, together with microangiopathic destruction of red blood cells, occurs.78,79 This results in anemia, thrombocytopenia, and coagulopathy. In addition, sepsis can result in DIC and a decreased platelet count.80 Although FFP transfusion has traditionally been advocated for documented clotting abnormalities, studies of massive transfusion from the military have suggested improved survival if FFP is administered in a 1:1 ratio with packed red blood cells during times of massive blood loss.81 The use of this strategy in children with burns has not been fully assessed.
Cryoprecipitate and Factor Concentrates Cryoprecipitate, rich in factor VIII, factor XIII, fibrinogen, and von Willebrand factor, is created by freezing and then slowly thawing plasma. The components of cryoprecipitate are more highly concentrated than in fresh frozen plasma; hence, a smaller volume is needed. A 10 to 15 mL bag of cryoprecipitate contains approximately 200 mg of fibrinogen.77 The smaller volume needed to replete factors may be important for children, who have smaller blood volumes than adults and are less likely to tolerate large fluid volumes. Recombinant factor VIIa (rFVIIa), originally developed to treat bleeding in patients with hemophilia, has also been used in the setting of massive hemorrhage. In critically ill patients, rFVIIa has been used successfully in a variety of disorders, including massively transfused trauma patients, cardiopulmonary bypass, liver injury or transplantation, and uncontrolled gastrointestinal hemorrhage.82,83,84 rFVIIa decreases prothrombin time and improves hemostasis in
adults. Several papers describing the use of rFVIIa in burn excision and grafting have suggested that it may decrease the blood loss associated with burn wound excision.85,86 However, the routine use of rFVIIa in burn excision cannot be recommended at this time.
Erythropoietin One method of potentially decreasing the need for red blood cell transfusion is the use of recombinant human erythropoietin (rHuEPO). In patients with responsive progenitor cells and adequate iron stores, rHuEPO may stimulate increased erythropoiesis. Several studies have reported the use of rHuEPO in critically ill patients. One prospective randomized study demonstrated a 10% decrease in allogeneic blood transfusion in critically ill patients receiving rHuEPO.87 Its use in burns may be problematic due to the decreased iron stores and red cell production as well as the increased red cell destruction after burn injury. One prospective study of rHuEPO in burns showed no difference in the development of postburn anemia or transfusion requirements.88 However, this study was probably underpowered to detect significant differences between groups with respect to mortality.
DECREASING INTRAOPERATIVE BLOOD LOSS IN BURN SURGERY Several simple techniques can be employed to decrease major blood loss due to massive excision of burn wounds. First, early excision has been demonstrated to reduce the blood loss associated with burn surgery.89 This may be due in part to the effects of vasoactive mediators and edema associated with the early phases of burn injury. In addition, the neovascularization that accompanies wound healing will be far less extensive in the first few days postinjury. Other methods reported to decrease blood loss during burn excision include the use of limb tourniquets, subcutaneous tumescence or topical placement of vasoconstrictors, topical application of thrombin or fibrin, dermabrasion, and a 2-stage operative technique (burn excision 1 day, skin harvest and grafting the next).90,91,92 Children in particular are well suited to the 2-stage approach, as it limits operating room time and the development of hypothermia, thus enabling massive early excision to be performed safely.
CONCLUSIONS Children with burn injuries pose challenges in multiple areas, including the use of blood transfusions. Age-related
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differences between adults and children impact the decision for transfusion. The indications for transfusion, type of transfusion, volume of transfusion, and potential side effects need to be scrutinized for every child with a burn injury in order
to maximize the efficacy and minimize the complications associated with blood transfusion. Furthermore, minimizing blood loss during burn care treatment may decrease transfusion requirements and improve patient outcomes.
TABLE TABLE 1 Normal infant hemoglobin levels. Age
Hemoglobin (g/dL)
Birth
19.3
2 weeks
16.6
1 month
13.9
3 months
11.2
4 months
12.2
6 months
12.5
1 year
12.5
9 years
13.5
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70. Jeschke MG, Chinkes DL, Finnerty CC, et al. Blood transfusions are associated with increased risk for development of sepsis in severely burned pediatric patients. Crit Care Med. 2007; 35: 579–583. 71. Spinella PC. Warm fresh whole blood transfusion for severe hemorrhage: U.S. military and potential civilian applications. Crit Care Med. 2008; 36: S340–S345. 72. Repine TB, Perkins JG, Kauvar DS, et al. The use of fresh whole
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74. www.aabb.org/Content/About_Blood /Facts_About_Blood_ and_Blood_Banking. Accessed September 10, 2008.
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leukoreduced blood transfusion on infection risk following injury: a randomized controlled trial. Shock. 2006; 26: 342–347. 60. Raghavan M, Marik PE. Anemia, allogenic blood transfusion, and immunomodulation in the critically ill. Chest. 2005; 127: 295–307. 61. Bordin JO, Heddle NM, Blajchman MA. Biologic effects of leukocytes present in transfused cellular blood products. Blood. 1994; 84: 1703–1721. 62. Jensen LS, Kissmeyer-Nielsen P, Wolff B, et al. Randomised
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13
C H A P T E R
T H I R T E E N
INFECTIONS IN PATIENTS WITH SEVERE BURNS: DIAGNOSTIC AND MANAGEMENT APPROACH JONATHAN M. ZENILMAN, MD, PROFESSOR OF MEDICINE, DIVISION OF INFECTIOUS DISEASES, JOHNS HOPKINS BAYVIEW MEDICAL CENTER, BALTIMORE, MD
OUTLINE 1. Introduction 2. Microbiology of Burn Sepsis 3. Differentiating Sepsis From Burn-Induced SIRS 4. Burn Wound Infection
176 176 178 178
a. Burn Impetigo b. Burn Wound Cellulitis c. Invasive Burn Wound Infection
178 178 178
5. The Diagnostic Challenge of Differentiating Wound Colonization Versus Infection
179
a. Quantitative Cultures b. Pulmonary Issues c. Toxic Shock Syndrome in Burns
179 179 179
INTRODUCTION In the United States and other developed countries, aggressive resuscitation of patients with severe burns and rapid transport to specialized regional burn centers have essentially eliminated early hospital mortality. The major cause of death after the acute admission phase is sepsis, typically caused by nosocomially acquired organisms that are frequently resistant to multiple antimicrobials. Even if patients with burn injuries have few or no concurrent illnesses, they are nonetheless susceptible to infection because of large wound exposure, prolonged hospital stays, and use of invasive monitoring devices. The incidence of infection in burn patients is high.1 Palmieri et al reviewed 199 patients with toxic epidermal necrolysis at 15 major burn centers between 1995 and 2000 and found an overall mortality of 32%.2 Sepsis accounted for the majority of early deaths in 33% of patients. In an additional
Phillips, Bradley_13.indd 176
d. Infectious Complications in the Head and Neck e. Nosocomial Infections in Burns f. Noninfectious Masqueraders
6. Principles of Diagnosis and Treatment 7. Clinical Strategies and Approach to Specific Problems a. b. c. d. e.
Surveillance Cultures Management Strategies Special Circumstances Prevention of Burn Infections Isolation and Infection Control
8. Table 9. References
180 180 180
181 181 181 181 182 182 183
184 185
33%, multisystem organ failure primarily attributable to sepsis was the immediate cause. Weber et al reported on a series of children (< 18 years old) seen between 1996 and 2000 and found that the incidence of serious invasive infection for patients with > 30% body surface area (BSA) burns was 55 out of 60 (92%).3 De Macedo et al4 reviewed 252 unselected burn patients in Brazil between 2001 and 2002 and described a sepsis rate of 19% during hospitalization.
MICROBIOLOGY OF BURN SEPSIS The microbiology of burn wound infections and burn sepsis has changed dramatically over the past 25 years. In the 1960s and 1970s, burn wound cellulitis and impetigo was common, caused largely by gram-positive organisms, especially streptococci and staphylococci. With the evolution of silvercontaining and more effective antibacterial dressings,5,6,7 Pseudomonas and other hospital-acquired gram-negatives
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INF E C T IONS IN PAT IE NT S WIT H S E VE R E B U R N S became the predominant organism. Pseudomonas is particularly well suited to establish wound infection because it easily forms biofilms on wound surfaces and has a natural reservoir in water, which is widely used for burn wound irrigation. Between 1997 and 2002, the Chandigarh, India Burn Center found Pseudomonas to be the most common isolate, followed by Staphylococcus and Acinetobacter.8 Our results at the Hopkins Center were essentially similar, except for staphylococci being more common due to line infections. Evolution of Pseudomonas strains resistant to multiple antibiotics, including the carbapenems, has also evolved as a major problem in many centers.9–11 In most cases, the burn surface is initially sterile because of the thermal injury. However, subsequent interventions may result in inoculation of unusual organisms. For example, if a patient was immediately immersed in nonenvironmental water sources (such as a pond or river), the array of possible microorganisms can be expansive. It is therefore important to obtain a detailed history of postinjury events from the patient, family, and first responders. Absent unusual environmental exposures, the microbial evolution is typically from normal skin flora, primarily gram-positive cocci. Gram-negative organisms become more prevalent as the individual becomes colonized. The surface microbiology in 51 patients with a mean BSA burn of 23% who were hospitalized for at least 3 weeks was evaluated by Erol et al.17 Gram-positive cocci, predominantly Staphylococcus species, were most prevalent on admission, but the flora shifted to Pseudomonas and other gram-negatives within a week after admission. Since 2000, Acinetobacter has become a major pathogen, which is highly problematic because of its propensity to acquire multiple resistance determinants and therefore develop resistance to nearly all antibiotic classes.9,12-16,18 These organisms are found in the environment and water sources and are particularly well suited to the biofilm environment which develops in patients with large BSA burns. Acinetobacter is frequently isolated from burn patients and severely injured/trauma patients who have long exposures to broad-spectrum antimicrobials. Despite these concerns, clinical experience has shown that the organism is not as virulent as other pyogenic bacteria.19,20 However, differentiation of colonization from invasive disease can be extremely difficult in such critically ill patients. Davis et al from the US Army reported on patients with multidrugresistant Acinetobacter infections from Iraq during 2003 through 2005, including 18 with osteomyelitis, 2 with burn infections, and 3 with deep wound infections.21 Because the organism can be found on numerous fomites in the ICU setting,22 it has been difficult to eradicate even with aggressive infection-control measures.
Besides Acinetobacter, enteric bacteria with multiple resistance determinants are increasingly encountered. Three emerging groups of particular concern are • Pseudomonas and Serratia. These classical nosocomial organisms share the ability to acquire or evolve resistant determinants under antibiotic pressure. Pseudomonas expresses a variety of toxins and is the most common cause of invasive local infections in burn centers. • Organisms with extended spectrum beta-lactamases (ESBL).9,23 These are organisms with plasmids which encode beta-lactamases that have the capability of hydrolyzing second-generation and third-generation cephalosporins. There are over 100 types of ESBL that have been identified in the literature. These organisms are especially concerning from an infection-control perspective because the plasmids can potentially be transferred to other bacteria via conjugation. • Klebsiella pneumoniae carbapenemase (KPC). Because this newly emergent organism encodes enzymes which hydrolyze carbapenems24,25 such as meropenem and imipenem, it affords relatively few treatment options. In contrast to Acinetobacter, these organisms have been associated with as much as a 3-fold increase in mortality compared to other patients with bacteremia. Whether this is due to intrinsic pathogenicity or whether infection is a surrogate for more severe illness remains to be elucidated. Fungal infections are a feared complication in severely injured patients with prolonged hospital stays.1,26 Cochran reported on 44 patients with an average 49% BSA burn and Candida infection (defined as either candidemia or positive cultures from > 2 body sites). Patients with Candida received an average of 72 days of systemic antibiotics, while controls only had 36 days. Moreover, patients with multiple sites of Candida were more likely to receive broad-spectrum antibiotics. In intensive care settings, aggressive antimicrobial parsimony and fluconazole prophylaxis27 have reduced candidemia as a nosocomial infection. Morbidity, and especially mortality, from fungal infections is increasingly due to filamentous fungi (molds), especially Fusariaum, Aspergillus, and Zygomeces species.1,28,29 These organisms have a particular predilection for areas of necrotic tissue and almost exclusively occur in patients on prolonged courses of broad-spectrum antibiotics. Diagnosis is often difficult, and careful examination of the tissue during dressing changes is critical. Mortality from these infections can reach over 50%.
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DIFFERENTIATING SEPSIS FROM BURN-INDUCED SIRS Sepsis and inflammation due to thermal injury can cause the systemic inflammatory response syndrome (SIRS). The American Burn Association (ABA) consensus statement on burns and SIRS succinctly summarized the problem:30
between bacteremia and the clinical signs of either fever or leukocytosis. SIRS independently induces an inflammatory response which can result in fever, leukocytosis, or other signs of inflammation. Hypothermia is commonly encountered in patients with large BSA burns because of loss of skin thermoregulation.
BURN WOUND INFECTION Burn patients lose their primary barrier to microorganism invasion so they are constantly and chronically exposed to the environment. In response to this exposure, inflammatory mediators that change the baseline metabolic profile of the burn patient are continuously released. The baseline temperature is reset to about 38.5°C, and tachycardia and tachypnea persist for months.… The current definition of SIRS was created by a consensus conference of critical care and trauma physicians more than a decade ago. SIRS is considered to be present when a patient demonstrates 2 or more of the following: • Temperature above 38°C or below 36°C • Heart rate > 90 beats per minute (bpm) or > 2 SD above age-specific norms (85% age-adjusted maximum heart rate) • Respiratory rate > 20 breaths per minute or maintenance of PaCO2 < 32 mm Hg. (children > 2 SD above age-specific norms) • WBC count > 12000/mm3 or < 4000/mm3, or left shift defined as > 10% bands Clinically differentiating sepsis in burn patients from burnassociated SIRS is not possible, as both have similar presentations. However, sepsis should always be suspected whenever there is an acute change in a patient’s status. Other factors suggesting sepsis include • • • • • •
hyperglycemia and insulin resistance thrombocytopenia abdominal distension enteral feeding intolerance diarrhea acute renal failure
A substantial clinical issue surrounding sepsis is the lack of reliability of the classical clinical markers. A study conducted by the US Army Burn Center evaluating 591 blood cultures from 129 patients with severe burns demonstrated that fever and hypothermia are neither sensitive nor specific as a predictor of bacteremia.31 Similarly, a study conducted by Keen et al32 between 1993 and 1997 at the Salt Lake City Burn Center found no relationship
Burn wound infection has been classified into 3 major categories representing stages in the evolution of the burn wound. These consensus definitions have recently been extensively reviewed by Church et al1 and modified for children by Upperman et al.33,34
Burn Impetigo Primary impetigo can also be seen in patients with partialthickness burns, particularly of the scalp, and is often associated with Staphylococcus aureus and Streptococcus pyogenes. In hospitalized patients, impetigo involves loss of epithelium from a previously reepithelialized surface, such as grafted burns, partial-thickness burns allowed to close by secondary intention, or healed donor sites. Burn wound impetigo is not related to inadequate excision of the burn, mechanical disruption of the graft, or hematoma formation. Aggressive management is required with appropriate antibiotics in order to avoid graft failure.
Burn Wound Cellulitis Burn wound cellulitis is a spreading dermal infection in uninjured skin around a burn wound or donor site, characterized by erythema, tenderness, and induration with an advancing border. It is commonly caused by S pyogenes, and the diagnosis is usually based on clinical examination, as cultures are difficult to obtain.35 In children, toxic shock syndrome needs to be a concern, as this may be their initial presentation. In hospitalized patients, streptococcal infections are much less common, as gram-negative rods and staphylococci are more typical. Gram-negative rods that produce exotoxins, such as Pseudomonas, are particularly prone to cause burn wound cellulitis. Candida is also a pathogen in patients who have had prolonged courses of antimicrobials, and may be particularly problematic at venous access sites.
Invasive Burn Wound Infection Invasive burn wound infection involves invasion of subcutaneous fascia, muscle, or healthy tissue beneath a wound
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INF E C T IONS IN PAT IE NT S WIT H S E VE R E B U R N S from colonization/infection of overlying eschar. Its incidence is proportional to burn wound size, BSA involvement, and length of time before full coverage. Such patients are usually systemically toxic, with bacteremia and hypotension. The controversy regarding establishing a diagnosis of invasive burn wound infection is discussed in the following section. Since current surgical practice involves early, aggressive excision of burns, invasive infection usually occurs after debridement and is almost always due to gramnegative nosocomial pathogens. Clinical signs of invasive infection in the setting of a toxic patient include a change in the wound’s appearance, such as hemorrhage, change in color, drainage, and liquefactive necrosis. In patients who have had recent skin grafts, development of a dusky appearance and separation of the graft is usually the first indication of invasive wound infection. Similarly, underlying infection in patients with allograft should be suspected if discharge is present or if there is clear separation of the allograft from the underlying tissue. Definite invasive burn wound infection is heralded by a change in wound appearance with punctate hemorrhages or rapid liquefaction, systemic toxicity, and positive blood cultures.
THE DIAGNOSTIC CHALLENGE OF DIFFERENTIATING WOUND COLONIZATION VERSUS INFECTION As all patients with severe burns become colonized with gram-negative organisms and clinical signs of invasive infection are difficult to discern in these very critically ill patients, determining true infection versus colonization remains challenging. Furthermore, there are no accurate, sensitive, or specific clinical features which can assist clinicians with the decision to initiate antibiotic therapy.
Quantitative Cultures Starting in the late 1960s, obtaining tissue biopsy specimens for histological examination and quantitative wound cultures of burns became widely used.7,36,37 Diagnostic criteria included histological evidence of bacterial invasion beyond the burn eschar and bacteriological criteria of 104 to 105 organisms per gram of tissue. These empirically derived criteria were established during the period before burn excision became the standard of care. Since then, these criteria have been challenged as being overly empiric. Danilla evaluated38 concordance between 1443 pairs of superficial and quantitative cultures and found mixed results.38 Steer and colleagues collected 69 paired biopsy samples from 47 patients and found that there was no relationship between
clinical outcome and bacterial counts obtained either by biopsy or by total white cell count.39,40 From an operational standpoint, quantitative cultures are expensive and involve tissue excision biopsies and complex processing by the clinical microbiology lab. Moreover, results from quantitative cultures using standard bacteriological techniques are typically not available for 3 to 4 days. By this time, the patient’s status may have dramatically changed. Because of these problems, some experts, such as Mayhall, have questioned the utility of the procedure.5 The issue of quantitative culture needs to be revisited for the following reasons: • The studies which developed the technique were all performed in the clinical era before aggressive surgical excision, where the tissue culture was often burn eschar. • There are critical clinical questions in learning how to differentiate colonization versus invasive infection, which can be answered by the use of animal models and molecular techniques. • Development of newer, rapid quantitative molecular techniques can substantially shorten the turnaround time from days to hours.
Pulmonary Issues In patients with inhalation injury, pneumonia or tracheobronchitis occurs in approximately 30% of patients.1,41,42 In our center, we have discovered upper respiratory flora are rapidly replaced with staphylococcal species (including methicillin-resistant S aureus, or MRSA) and gram-negative rods. Therefore, vigorous pulmonary toilet is critical, even early in the clinical course. Clinical signs of pulmonary infection may be subtle due to aggressive resuscitation efforts, large fluid shifts, and potential underlying diseases. In addition, trauma and high transfusion requirements in some cases may predispose to acute respiratory distress syndrome (ARDS), which can be very difficult to differentiate from pneumonia.
Toxic Shock Syndrome in Burns Toxic shock syndrome (TSS) is a burn complication almost exclusively seen in children.43,44 TSS should be suspected when there is a sudden unexplained clinical deterioration with findings of fever, poor perfusion, hyponatremia, lymphopenia, and coagulopathy. Mucositis and a macular erythematous rash may be seen on intact skin and mucosal areas. The burn wound itself does not have a characteristic appearance, and the actual burn injury may be minor. Multiple organisms have been implicated in expressing the
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TSS-associated toxins, including Group A Streptococcus, S aureus, and some Pseudomonas and Klebsiella strains. Young and Thornton43 have proposed that children are susceptible to burn TSS because • loss of protective skin barrier allows entry of the organisms • there is functional immunosuppression • the burn wound provides an ideal environment for toxin production • pyrexia favors toxin production • interstitial edema and disruption of surface and vascular clearance mechanisms are present • the prevalence of antibodies to TSS toxin are directly proportional to age, which explains why burn TSS is almost never seen in adults
Infectious Complications in the Head and Neck In burns to the head, neck, and scalp, careful evaluation of the mucous membranes, eyes, ears, and surrounding structures should be performed early,41,42 as formation of edema can interfere with pertinent findings. The eyes should be promptly evaluated by an ophthalmologist, preferably with fluorescein staining. Careful attention is required throughout the hospital course for development of keratitis, which can be catastrophic if caused by organisms such as Pseudomonas. Similarly, burns of the external ear and nose, especially in younger patients, can be complicated by suppurative chondritis. Topical prophylaxis of the eyes with antimicrobial-containing drops which provide high local concentrations and application of topical silver or mafenide acetate to the cartilaginous surfaces largely prevents these complications.
Nosocomial Infections in Burns Patients with severe burns often require hospitalization for prolonged periods, with long-term indwelling vascular access devices, urinary catheters, and endotracheal tubes. They are thus susceptible to the complications related to these interventions. Catheter-associated BSI rates for burn intensive care units (ICUs) enrolled in the CDC’s National Nosocomial Infections Surveillance (NNIS) System from January 1995 to June 2002 were 8.8 per 1000 central venous catheter (CVC) days, compared with pooled mean rates of 7.4 for pediatric ICUs, 7.9 for trauma ICUs, and 5.2 for surgical ICUs. These estimates include both the adult and pediatric burn population.45 The incidence of all complications is
higher in patients with larger BSA burns, as demonstrated from a recent study in 2005, which reported blood stream infection at 4.9 episodes per 1000 days, ventilator-associated pneumonia at 11.4 episodes per 1000 days, and urinary tract infections at 13.2 cases per 1000 days.46 Often overlooked complications of intubation include otitis and sinusitis, which should always be kept in mind when evaluating patients with suspected sepsis. Bloodstream infections due to S aureus, particularly MRSA, have increased. In our current environment, these infections are typically nosocomially acquired and related to indwelling lines rather than to the burn wound itself. MRSA now accounts for up to 70% of all staphylococci isolated in the United States and has become highly virulent.47,48,49 Endocarditis due to these organisms is a particular concern, as they have a predilection for endocardial tissue. A case series of burn patients with endocarditis has demonstrated that those with staphylococcal bacteremia are particularly susceptible, with an appreciable increase in mortality. Current recommendations for staphylococcal bacteremia include treatment for a minimum of 4 weeks unless endocarditis can be conclusively ruled out. All patients who remain hospitalized for prolonged periods and are exposed to broad-spectrum antibiotics are at increased risk for Clostridium difficile colitis.50,51 This is less of an issue in the pediatric population than in adults, but can still cause appreciable morbidity and mortality. Prevention of C difficile colitis involves aggressive antimicrobial management, minimizing antibiotic exposure, and strict infection control measures. Clinically, C difficile colitis should be suspected in any patient with diarrhea and leukocytosis. Diagnosis requires identification of the toxin by cytotoxic assay. Empiric therapy with orally administered metronidazole or vancomycin should be initiated and continued for 10 to 14 days if the diagnosis is confirmed.
Noninfectious Masqueraders Acute hypotension in critically ill patients can also be caused by underlying noninfectious medical conditions. Critically ill patients, and burn patients in particular, may not necessarily manifest any symptoms, and diseases with cutaneous manifestations may not be evident because of the burn injury. In particular, the clinician should be attuned to • Hypovolemia. Insensate fluid losses can be enormous, and fluid management, even in the most closely monitored circumstances, may be inadequate. Burn patients with SIRS-induced fever and hypovolemia can be misdiagnosed with sepsis and even septic shock.
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INF E C T IONS IN PAT IE NT S WIT H S E VE R E B U R N S • Endocrinopathies. Hypothyroidism and hypoadrenalism may result in hypotension and cardiovascular lability, including low cardiac output. In particular, patients without prior disease who have minimal thyroid or adrenal function can be tipped into crisis by the extreme metabolic demands of a burn injury. Clinicians should have a low threshold for evaluating the thyroid and adrenal axis. • Hyperthyroidism/Thyroid Storm. This will present with persistent tachycardia, fever, and leukocytosis. Thyroid storm can be precipitated in patients with underlying hyperthyroidism who suffer a major injury. Patients exhibiting persistent tachycardia even after euvolemia is achieved should be suspected of manifesting thyroid dysfunction.
PRINCIPLES OF DIAGNOSIS AND TREATMENT The approach to managing infections in burn patients is predicated on the following principles: • In the majority of cases, pediatric burn patients have minimal underlying disease and can manifest a robust inflammatory response. • Surveillance cultures are obtained to identify existing organisms in case the patient becomes clinically septic. Treatment decisions, however, are not based on surveillance cultures alone. • Patients with major BSA injuries will have a prolonged hospitalization and are susceptible to infection because of interruption of the skin barrier and multiple invasive devices. • Antimicrobials, and especially broad-spectrum drugs, are critical for treating documented or highly suspected infection. Prolonged courses of these drugs will subsequently result in selection of antimicrobial-resistant organisms, predilection to fungal infection, and complications such as C difficile. Therefore, the shortest course of therapy should be used. • Since patients will be colonized with multiple organisms, the decision to treat an infection should not be based solely on a culture that shows organisms. Rather, clinical indicators of infection need to be present as well. • Differentiating SIRS from infection can be difficult, especially early in the patient’s course. Furthermore, fever and leukocytosis have poor
predictive value for sepsis. The likelihood of infection is low in patients with fever and leukocytosis if the following are not present: • hypotension • infiltrate on chest X-ray (for intubated patients) • clinical diagnosis of invasive wound infection • Empiric treatment for burn infection or sepsis often involves use of broad-spectrum antimicrobials. Therapy should be “trimmed and tailored” to be as narrow spectrum as possible once an etiological diagnosis is made. • With the exception of staphylococcal bacteremia, there is no prescribed time course for treatment. Once a removable source is debrided or drained, then antimicrobials can be discontinued 24 to 48 hours afterwards. Gram-negative bacteremia should be treated with courses of therapy for 5 to 7 days after documented clearance, assuming that all removable sources have been addressed.
CLINICAL STRATEGIES AND APPROACH TO SPECIFIC PROBLEMS Patients admitted to any burn facility should receive tetanus prophylaxis. Burn management, including excision, debridement, and coverage, is the most important aspect of infection prevention and management. Patients admitted to the ICU who are intubated or expected to have prolonged stays for multiple excisions should be considered for fluconazole prophylaxis.27
Surveillance Cultures Cultures of skin and other suspicious sites should be performed on admission to the facility in order to ascertain what organisms are colonizing the host skin, such as MRSA. This is particularly important if there are postburn environmental exposures or if the burn itself was related to water exposure (scald) where waterborne organisms may be involved. Biweekly surveillance cultures should be obtained in intubated patients (tracheal aspirates) and from burn wound sites, preferably by swab after debridement. As noted above, the utility of quantitative cultures for clinical decision making is controversial.
Management Strategies Days 1 to 3 of hospitalization. During the early hospitalization, infectious complications of burns are rare. Nearly
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all episodes of fever and leukocytosis during this time are due to burn-induced SIRS. Antimicrobials should not be administered unless there is a clear indication of sepsis. Days 4 to 7 of hospitalization. During this period, discriminating burn-induced SIRS from infectious complications is difficult. In our experience, most infections during this period are caused by community-acquired organisms, although there is substantial local variation. Infections due to complications from indwelling catheters begin to arise. Appropriate cultures should be obtained, and regimens with effectiveness against Pseudomonas and resistant staphylococci should be initiated. Initial regimens used in our center include • vancomycin + piperacillin/tazobactam • vancomycin + ceftazidime • vancomycin + cefipime Vancomycin can be discontinued if cultures do not reveal staphylococci within 48 hours. After obtaining cultures, it is necessary to ensure they are monitored. In our experience, over half of such cultures indicate sensitive organisms such as gram-negative enterics. In these cases, we recommend changing antibiotic coverage to the narrowest coverage possible in order to reduce the pressure for selection of more resistant organisms. For example, if blood or fluid cultures grow Escherichia coli–sensitive to first-generation cephalosporins, we would reduce coverage to maximal dose cefazolin. Second- and third-generation cephalosporin drugs such as cefotetan, ceftriaxone, or ampicillin/clavulanate are appropriate if the organisms’ susceptibility is demonstrated. After day 7 of hospitalization. At this point in time, burn-induced SIRS becomes less relevant, although increases in temperature and leukocytosis following debridement are more common. Colonization of the burn wound by nosocomial gram-negative organisms is nearly universal. Treatment for infection should be initiated if there are systemic signs of persistent fever (> 39°C), episodes of hypotension, or evidence of burn wound infection, such as indications of burn wound cellulitis or invasive burn wound infection or skin graft failure. Management strategies should include source control, particularly excision of wound surfaces that are clinically infected. After cultures are obtained from all sources, empiric antimicrobials should be initiated. Our practice is to initiate treatment with a carbapenem, such as imipenem, meropenem, or doripenem, in combination with vancomycin. Treatment should be guided by knowledge of the surveillance wound or other source cultures if results are < 24 hours old. As above, reducing coverage to the narrowest regimen as soon as is appropriate is highly encouraged.
Special Circumstances Surgical prophylaxis. As standard surgical prophylaxis regimens predebridement are relatively ineffective against most burn-associated pathogens, such practice is not generally advised. Intubated patients with inhalation injury. Inhalation injury produces an inflammatory response, especially if caustic substances are involved. We do not routinely recommend antimicrobial prophylaxis, but prefer close observation. After initial stabilization, daily Gram stains and sputum cultures of tracheal aspirates are recommended. In > 80% of patients who remain intubated, tracheitis or tracheobronchitis will occur, typically due to S aureus at days 5 to 7. This should be treated with a short course of antimicrobials (5-7 days) guided by susceptibility reports. Bacteremia. When bacteremia is documented, all indwelling intravascular catheters should be changed, if feasible. Since burn patients often have very poor vascular access, if changing access sites is not possible, then the catheters should be changed over guidewires. Some data suggests lower rates of infection with silver-impregnated catheters. Staphylococcal bacteremia. S aureus is a highly invasive organism which is particularly prone to cause metastatic infection and involve the endocardium.52 Echocardiography, preferably trans-esophageal echocardiography, should be performed in all cases of staphylococcal bacteremia. In patients who remain bacteremic after 24 hours of therapy, occult abscesses and additional sources of infection should be considered; this includes careful physical examination and tomographic scanning of the chest, abdomen, and pelvis. Pneumonia. Pneumonia in critically ill hospitalized patients should be managed using protocols for ventilatorassociated pneumonia. Empiric antimicrobials should be included in such protocols as well. Pseudomonas wound infection. Burn patients are particularly at risk for wound infection due to Pseudomonas. These should be aggressively treated with local debridement and systemic antimicrobial therapy. Dual therapy with aminoglycoside and beta-lactam combinations is not indicated in most cases.53-55 However, deterioration of renal function should prompt reevaluation and potential discontinuation.
Prevention of Burn Infections The pathogenesis of burn infections is clearly related to disruption of the surface epithelium, which allows access of microorganisms. Early excision, aggressive debridement of necrotic tissue, and rapid progress towards grafting is
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INF E C T IONS IN PAT IE NT S WIT H S E VE R E B U R N S critical. However, these steps take time, especially in patients with extensive injuries. Topical dressings.56,57 Topical dressings are used ubiquitously, and silver-containing dressings have been largely credited with reducing morbidity and mortality from burn sepsis since the 1960s. Silver sulfadiazine is a widely used agent with excellent broad-spectrum activity which is used in the United States for second- and third-degree burns. Its silver ions bind to nucleic acids of individual microorganisms and release sulfadiazine, which poisons the microbe’s metabolism. The major complication of silver-containing dressings is silverinduced leukopenia. Although this can occur at any time, it is typically seen within the first week of use and manifests as a progressive decrease in the leukocyte count. Thought to be due to bone marrow suppression, it is reversible with discontinuation of silver-containing dressings. In severe cases of leukopenia, use of Neupogen as a temporizing measure can be considered if leukocyte counts are < 1000. Mafenide acetate (Sulfamylon) has predominantly bacteriostatic activity against gram-negative bacteria, including Pseudomonas, as well as anaerobes such as Clostridium. There is little activity against gram-positive organisms such as S aureus or fungi. Mafenide is indicated for bacterial invasion of second- and third-degree wounds. Because of its high soft tissue and cartilage penetration, it is particularly useful in settings where underlying tissue may be involved, such as deep burns, or in burns overlying cartilaginous areas, such as the ear or nose. Although resistance to mafenide is rare, it needs to be used with care because it is painful on application and has been associated with impaired wound healing. Patients with large burns are at
risk for metabolic acidosis since the drug is an inhibitor of carbonic anhydrase. Bacitracin/neomycin/polymyxin B is frequently used for superficial burn wounds, but can be employed as a second-line dressing in patients who have experienced adverse effects to silver or mafenide. It has antimicrobial activity against gram-positive bacteria; the addition of neomycin and polymyxin B bolsters gram-negative coverage.
Isolation and Infection Control58 In an ideal setting, all patients would have 1:1 nursing and implementation of barrier contact precautions. Since this is not feasible, standard precautions, which include aggressive compliance monitoring for hand washing, checklist procedures for insertion and maintenance of catheters and other invasive devices, and scrupulous attention to respiratory hygiene and wound care, should be followed when caring for all patients with burn injury. Pediatric burn patients should also have policies restricting the presence of nonwashable toys such as stuffed animals and cloth objects, which can harbor large numbers of bacteria and can be difficult to disinfect. Toys should be nonporous and washable, designated for individual patient use, and thoroughly disinfected after use and before being given to another child. Paper items, such as storybooks and coloring books, should always be designated for singlepatient use and should be disposed of if they become grossly contaminated or when the child is discharged. In summary, burn infections in pediatric patients cause substantial morbidity and mortality. The menu of organisms involved is diverse, and treatment can be complex.
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TABLE TABLE 1 Microorganisms causing invasive burn wound infections. Gram-positive Organisms Streptococcus pyogenes Staphylococcus aureus Methicillin-resistant S aureus Enterococcus species Vancomycin-resistant enterococci Gram-negative Organisms Pseudomonas aeruginosa Escherichia coli and other entericsi Klebsiella pneumoniae Serratia marcescens Enterobacter species Proteus species Acinetobacter species Bacteroides species MDR-resistant Species MDR-Acinetobacter MDR-Serratia MDR-Pseudomonas ESBL-Enterobacter KPC-Klebsiella Fungi Candida species Aspergillus species Fusarium species Alternaria species Rhizopus species Mucor species Dosing Recommendations (Maximal Dosing for Suspected Sepsis in Burns) Amikacin: 5 mg/kg first dose; subsequent 5 to 7.5 mg/kg every 8 hours; adjust dose to maintain trough 2 to 5 µg/ml Cefipime: 50 mg/kg every 8 hours Ceftazidime: 50 mg/kg every 8 hours Imipenem: 25 mg/kg every 6 hours Meropenem: 20 mg/kg every 8 hours Piperacillin/Tazobactam: 100 mg (piperacillin) every 8 hours up to maximal adult dose Vancomycin: 15 mg/kg every 6 hours—dose by level
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26. Cochran A, Morris SE, Edelman LS, Saffle JR. Systemic
Candida infection in burn patients: a case-control study of management patterns and outcomes. Surg Infect (Larchmt). 2002; 3: 367–374. 27. Pelz RK, Hendrix CW, Swoboda SM, et al. Double-blind
placebo-controlled trial of fluconazole to prevent candidal infections in critically ill surgical patients. Ann Surg. 2001; 233: 542–548. 28. Murray CK, Loo FL, Hospenthal DR, et al. Incidence of systemic fungal infection and related mortality following severe burns. Burns. 2008; 34: 1108–1112. 29. Ribes JA, Vanover-Sams CL, Baker DJ. Zygomycetes in human disease. Clin Microbiol Rev. 2000; 13: 236–301. 30. Greenhalgh DG, Saffle JR, Holmes JH IV, et al. American
Burn Association consensus conference to define sepsis and infection in burns. J Burn Care Res. 2007; 28: 776–790. 31. Murray CK, Hoffmaster RM, Schmit DR, Hospenthal DR, Ward JA, Cancio LC, Wolf SE. Evaluation of white blood cell count, neutrophil percentage, and elevated temperature as predictors of bloodstream infection in burn patients. Arch Surg. 2007 Jul; 142(7): 639–642. 32. Keen A, Knoblock L, Edelman L, Saffle J. Effective limitation
of blood culture use in the burn unit. J Burn Care Rehabil. 2002; 23: 183–189. 33. Upperman JS, Sheridan RL. Pediatric trauma susceptibility to sepsis. Pediatr Crit Care Med. 2005; 6: S108–S111.
Engl J Med. 2008; 358: 1271–1281.
34. Upperman JS, Sheridan RL, Marshall J. Pediatric surgical site and soft tissue infections. Pediatr Crit Care Med. 2005; 6: S36–S41.
17. Erol S, Altoparlak U, Akcay MN, Celebi F, Parlak M. Changes of microbial flora and wound colonization in burned patients. Burns. 2004; 30: 357–361.
35. Edwards-Jones V, Greenwood JE; Manchester Burns Research Group. What’s new in burn microbiology? James Laing Memorial Prize Essay 2000. Burns. 2003; 29: 15–24.
16. Munoz-Price LS, Weinstein RA. Acinetobacter infection. N
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36. Robson MC, Heggers JP. Bacterial quantification of open wounds. Mil Med. 1969; 134: 19–24.
bloodstream infections in US intensive care units, 1997–2007. JAMA. 2009; 301: 727–736.
37. Robson MC, Heggers JP. Delayed wound closure based on bacterial counts. J Surg Oncol. 1970; 2: 379–383.
49. Klevens RM, Morrison MA, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA. 2007; 298: 1763–1771.
38. Danilla S, Andrades P, Gomez ME, et al. Concordance between qualitative and quantitative cultures in burned patients. Analysis of 2886 cultures. Burns. 2005; 31: 967–971. 39. Steer JA, Papini RP, Wilson AP, McGrouther DA, Parkhouse N. Quantitative microbiology in the management of burn patients. II. Relationship between bacterial counts obtained by burn wound biopsy culture and surface alginate swab culture, with clinical outcome following burn surgery and change of dressings. Burns. 1996; 22: 177–181. 40. Steer JA, Papini RP, Wilson AP, McGrouther DA, Parkhouse
N. Quantitative microbiology in the management of burn patients. I. Correlation between quantitative and qualitative burn wound biopsy culture and surface alginate swab culture. Burns. 1996; 22: 173–176. 41. Sheridan RL. Burns. Crit Care Med. 2002; 30: S500–S514. 42. Sheridan RL. Comprehensive treatment of burns. Curr Probl
Surg. 2001; 38: 657–756. 43. Young AE, Thornton KL. Toxic shock syndrome in burns: diagnosis and management. Arch Dis Child Educ Pract Ed. 2007; 92: ep97–ep100. 44. White MC, Thornton K, Young AE. Early diagnosis and treatment of toxic shock syndrome in paediatric burns. Burns. 2005; 31: 193–197. 45. Weber J, McManus A; Nursing Committee of the International
Society for Burn Injuries. Infection control in burn patients. Burns. 2004; 30: A16–A24. 46. Wisplinghoff H, Bischoff T, Tallent SM, Seifert H, Wenzel RP, Edmond MB. Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis. 2004; 39: 309–317. 47. Daum RS. Clinical practice. Skin and soft-tissue infections
caused by methicillin-resistant Staphylococcus aureus. N Engl J Med. 2007; 357: 380–390. 48. Burton DC, Edwards JR, Horan TC, Jernigan JA, Fridkin SK.
Methicillin-resistant Staphylococcus aureus central line-associated
50. Rice LB. The Maxwell Finland lecture: for the duration-rational
antibiotic administration in an era of antimicrobial resistance and Clostridium difficile. Clin Infect Dis. 2008; 46: 491–496. 51. Owens RC Jr, Donskey CJ, Gaynes RP, Loo VG, Muto CA. Antimicrobial-associated risk factors for Clostridium difficile infection. Clin Infect Dis. 2008; 46(suppl 1): S19–S31. 52. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis:
diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005; 111: e394–e434. 53. Magnotti LJ, Schroeppel TJ, Clement LP, et al. Efficacy of monotherapy in the treatment of Pseudomonas ventilatorassociated pneumonia in patients with trauma. J Trauma. 2009; 66: 8,1052, discussion 1058–1059. 54. Paul M, Silbiger I, Grozinsky S, Soares-Weiser K, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactamaminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev. 2006; 1: CD003344. 55. Goverman J, Weber JM, Keaney TJ, Sheridan RL. Intravenous colistin for the treatment of multi-drug resistant, gram-negative infection in the pediatric burn population. J Burn Care Res. 2007; 28: 421–426. 56. Patel PP, Vasquez SA, Granick MS, Rhee ST. Topical antimicrobials in pediatric burn wound management. J Craniofac Surg. 2008; 19: 913–922. 57. D’Avignon LC, Saffle JR, Chung KK, Cancio LC. Prevention and management of infections associated with burns in the combat casualty. J Trauma. 2008; 64: S277–S286. 58. Weber J, McManus A; Nursing Committee of the International Society for Burn Injuries. Infection control in burn patients. Burns. 2004; 30: A16–A24.
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14
C H A P T E R
F O U R T E E N
FUNGAL INFECTIONS BRADLEY J. PHILLIPS, MD MARISSA CARTER, PHD
OUTLINE 1. Introduction a. Incidence of Fungal Infections in Burn Patients b. Trends in the Last 40 Years
2. Pathophysiology a. b. c. d.
Candida Aspergillus Fusarium Other Fungal Infections
3. Diagnosis a. Clinical Signs b. Laboratory and Culture Tests c. Making the Diagnosis
4. Treatment
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INTRODUCTION Fungal infections are always a source of concern in burn patients due to their underlying dysfunctional immune system, particularly when the burned area is extensive (> 60% TBSA—total body surface area). Besides the issue of immunocompetence, other sources of infection, including central venous lines, urinary catheters, prolonged mechanical ventilation, and broad-spectrum antibiotics, make burn patients one of the highest at-risk groups for invasive infection.1,2 While newer antifungal agents have added to the armory available for clinicians to combat infection, certain fungal species still present problems, and the possibility of drug resistance must be borne in mind. An appreciation of the problem is best attained by examining both the past and current incidence of fungal infection as well as ascertaining trends from the data over the last 40 years. However, since pediatric-specific evidence is sparse in terms of fungal burn infection, we will try to draw lessons from the adult literature whenever possible.
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a. b. c. d. e. f. g. h.
Considerations Amphotericin B Nystatin 5-fluorocytosine The Azoles The Echinocandins Drug Interactions Specific Recommendations
5. Special Topics a. Risk Factors b. Prophylaxis c. Eliminating Sources of Fungal Infection
6. Conclusion 7. Key Points 8. References
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Incidence of Fungal Infections in Burn Patients When assessing fungal infections over the past few decades in order to draw meaningful conclusions, one has to appreciate the progress of scientific technique. In this case, this translates to understanding that the characterization methods used today were less sophisticated 30 years ago. Furthermore, management of bacterial and fungal infections was different in terms of available options, and this in turn affected both the incidence and type of infection reported.
Reports Prior to 1986 MacMillan et al3 were among the first to publish data on candidiasis in burn patients based on a data collection period from 1964 through 1971. Of their 427 patients, 63.5% had at least one positive Candida culture, and 54.6% had positive cultures on more than one occasion. Candida albicans was the most common species isolated (43%). Although the
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Candida organism was cultured from wounds in 58.6% of patients, 12% of positive cultures were obtained from urine, 11% from stools, and 9% from intravenous catheters. Of the 22 patients who developed Candida septicemia, 14 died (64%). A follow-up study by the same group at the Shriners Burns Institute in Cincinnati revealed that of 12 patients diagnosed with candidemia who had burns >30% TBSA, 5 patients had infections from C albicans and 7 patients’ infections were from C tropicalis.4 In the United Kingdom, Kidson and Lowbury5 reported a 12.9% incidence of positive Candida cultures from wound isolates in 922 burn patients over a period of 2 years during the mid- to late 1970s. Of these cultures, 69% were due to C albicans, 12% to C parapsilosis, 5% to C stellatoidea, 4% each to C krusei and C pseudotropicalis, and 2% to C tropicalis. The authors also noted a positive association between percentage of TBSA burned and the appearance of positive cultures. Their explanation for the lower rate of positive Candida cultures compared to MacMillan et al3 was due to a lower proportion of severely burned patients. In 1979, Stone et al6 reported the first study on Aspergillus infection in burn patients for the period 1963 through 1977, calculating an incidence rate of 0.5%. The authors also noted a much higher average TBSA burned (54%) and percentage of full-thickness injury (42%) in these patients compared to the general burn patient population. From an epidemiological viewpoint, the Aspergillus infections were episodic in 13 of the 18 cases, with the first outbreak involving 6 patients due to colonized air-conditioning ducts and filters in the burn unit. Although a maintenance cleaning schedule was initiated, new filters were still not available several years later. Therefore, the old filters were cleaned in situ, which resulted in an immediate cluster of 4 separate wound colonizations with the organism. Although this study was not the first to investigate the source of fungal infections, it remains a vivid illustration of the importance of maintaining good hygiene in burn units. The experience of Spebar and Pruitt7 in regard to candidiasis in the burned patient at the US Army Institute of Surgical Research at Fort Sam Houston, Texas, which spanned a time period from 1973 through 1978, was similar to previous reports.3,5 Of the 1513 patients admitted for treatment, 521 (34.4%) had positive fungal cultures, and 86.7% of these patients were positive for Candida. While only 36 patients developed burn wound infection, 75% of these patients had candidemia, with a mortality rate for the entire group (36 patients) of 92%. The higher mortality rate was initially ascribed to the prolonged time (1 week) required to identify Candida in blood cultures and the delay in initiating amphotericin B treatment. However, the authors also pointed out that the invasive phase was invariably caused by an episode of bacterial sepsis, hemorrhage, or
hypotension that permitted existing colonization to expand out of control.
1986 through 1995 In their review of patients with thermal burns during 1984 and 1985, Pensler et al8 noted an increased incidence of fungal sepsis with a mortality rate of 32%. Furthermore, they found that capricious use of broad-spectrum antibiotics aggravated the establishment of sepsis after wound colonization by fungi. Similar to previous studies, Desai et al9 reported that 31.8% of their burn patients had a positive Candida culture during hospitalization. However, they observed a trend toward earlier Candida septicemia, which was ascribed to early, repeated surgical interventions, large transfusions, and more widespread use of broad-spectrum antibiotics in massively burned, immunosuppressed patients. Prevention, early detection, and aggressive treatment of candidiasis were promoted by Prasad et al,10 who reported lower overall culture rates (13.5%), but higher rates of mortality (54%). However, these authors also reported that death in the majority of cases was due to bacterial septicemia or multiple organ failure (MOF). Similar positive Candida rates were reported in a much smaller study, but with much lower sepsis and mortality rates.11 During the mid- to late 1980s, there was a surge in the use of nystatin. By 1983, Desai and Herndon12 reported the incidence of Candida burn wound infection had been steadily increasing at the Shriners Burns Institute in Galveston, Texas. This resulted in a change of practice in late 1984 to oral nystatin use (“swish and swallow”) as well as for wound treatment. According to the authors of this study, this resulted in an order of magnitude decrease in Candida cultures and also eliminated cases of Candida-related septicemia. An extension of this study, in which burn patients admitted from 1980 through 1984 served as case controls versus patients admitted from 1985 through 1990 who were treated with nystatin, seemed to confirm these findings. A reduction in Candida colonization from 26.6% to 15.6% and a reduction in Candida sepsis rate from 3.3% to 0% was observed, as well as a reduction in patients with infection from 5.7% to 1.6%.13 Dubé et al14 also reported a reduction in Candida-positive cultures in burn patients from 15.5% to 10.5% as a result of the institution of nystatin therapy. However, the introduction of nystatin into the burn environment also resulted in a shift of Candida species, with a predominance of nystatin-resistant C rugosa. Characterization of Candida isolates during this period of time showed small to moderate differences from previously reported results3-5: C albicans 72.6%; C tropicalis 9.7%; C parapsilosis 5.3%; multiple Candida species 11.5% (pediatric patients)15; and C albicans 75%; C parapsilosis 13%;
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F UNGAL IN F E C T I O N S C tropicalis 6%; C glabrata 6% (adults).16 A serotype/biotype analysis also revealed significant differences between burn and nonburn populations regarding metabolism (ability to utilize citrate). It further suggested that the partial -57 C albicans biotype might be either more common or more virulent compared to other biotypes.15 A follow-up review from 1979 through 1989 at the US Army Institute of Surgical Research revealed a rate of fungal wound infection of 6.7%,17 with a mortality rate of 75% for this group of patients. While the rate of bacterial infections decreased during this period, the fungal infection rate remained steady. Although the causative agent of the infections could not be identified in many cases, the majority were caused by Aspergillus and Fusarium (68%), followed by Candida species (18%), Mucor and Rhizopus (9.1%), and Microspora and Alternaria species (each causing < 5% of infections). This pattern of infection was quite different from those reported by other studies. The authors also commented that, in their opinion, a previous study12 which claimed that nystatin was effective against candidal infections was flawed due to diagnostic and procedural issues. A preference for amphotericin B, in combination with other antifungal agents, was noted by Becker et al.17 Another study conducted over 3¼ years on the management of Candida septicemia in burn patients reported a combined rate of bacterial/fungal infection of 6.9%, with almost one-third of these patients having positive blood cultures for Candida.18 The species breakdown was C albicans 48%; C parapsilosis 28%; and C tropicalis 14%, with multiple species causing 10% of Candida infections. The Candida colonization rates reported over 5 years in a pediatric investigation during a similar time frame were 14.4%, but only 12% of these children developed candidemia.19 A mortality rate of 24% was recorded, despite administration of nystatin (enteral), amphotericin B, and other antifungal drugs. The proportions of Candida species were similar to the study of Still et al.18 Furthermore, the researchers demonstrated that recovery of fungal organisms at multiple sites was associated with candidemia.
Penicillium, Fusarium, and Zygomycetes spp were more commonly found in burn wards compared to control sites, and were also isolated from patients. This indicates that dissemination of fungi from wounds to surroundings and reintroduction into patients was probably occurring. A Brazilian investigation of patients (N = 203) with a mean TBSA burn of 15% conducted from February 2004 to February 2005 sampled wounds and cultured fungal organisms 4 times over a period of 1 month.21 Approximately 12% of patients had a positive culture from the first swab, with C tropicalis and C parapsilosis accounting for the majority of organisms; however, by the time of the second swab, C tropicalis was dominant. The relatively high incidence of C tropicalis was considered alarming, as the species was not considered commensal and was nearly always associated with deep fungal infections. Interestingly, a similarly sized Indian study (N = 220) demonstrated a much higher colonization rate (63%) and a different prevalence of Candida species: C albicans (45%), C tropicalis (33%), C glabrata (13.5%), C parapsilosis (4%), C krusei (2.8%), and C kefyr (1.8%).22 The most recent study of fungal infection, which comprised 15 institutions and 6918 burn patients over the period 2003-2004, indicated an overall infection rate of 6.3% for patients admitted for acute burns.2 Of those with a positive fungal infection, Candida was documented in 85.3% of patients, Aspergillus in 13.1%, unspecified yeast infections in 21.5%, other types of molds in 9.0%, and unidentified fungal species in 1.4%. Interestingly, 26.7% of patients had more than one organism cultured, with wounds, respiratory, urine, and blood being the most common sites of infection. The overall mortality rate in culture-positive patients was 13.3%, but was higher (21.2%) for the subgroup in which systematic antifungal treatment was instituted. The mortality rate was 11.6% for candidal infection, 25% for Aspergillus, and 41% for molds. This disturbing result for molds translated into an odds ratio (OR) of 11.99 in regard to mortality.
Trends in the Last 40 Years 1996 Onward To a large extent, the fungal species that cause burn wound infections are a reflection of their presence in the immediate environment. An Iraqi study documented that of 132 patients, 21.2% developed a fungal infection, and all except 1 were coinfected with bacterial species. Aspergillus was the most common fungal organism (53%), followed by Candida (31%)—of which C krusei and C tropicalis were the most common species—then Penicillium spp and Zygomycetes spp (8% each).21 Although A Niger was the most common isolate in patients and burn care units, A terreus,
Since the introduction of broad-spectrum antibiotics and better care, there is no doubt that the incidence of bacterial wound infections has substantially decreased. While fungal infections were considered more of a nuisance prior to 1970, the advent of effective topical antibiotics, such as mafenide acetate, had serious consequences. Subsequently, fungal colonization of burn wounds became a serious problem during the 1970s and 1980s, with as many as 85% of patients affected.2,23 Moreover, the change in the prevalence of fungal species, part of which may have resulted from the widespread use of nystatin, has presented challenging
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problems. The explanation for these observations is complex and is best understood by the interaction of fungi with changing drug patterns and practices as well as environments. In addition, the appearance of high-risk populations with compromised immune systems has had an impact on the prevalence of fungal infection.24 Although candidemia rates in acute, nonburn clinical settings rose during the 1980s and appeared to peak with a downward trend in the last few years,24-26 a similar trend in burn units does not appear to have happened. Rather, although infection rates in most burn units rose during the 1970s and 1980s but declined thereafter, such rates appear to be holding steady around 5% to 8% for the last 10 to 15 years (with some exceptions reported of lower or higher rates). Also of concern is the appearance of other Candida spp, such as C tropicalis, C parapsilosis, C glabrata, and C krusei, whose increase in prevalence has in some instances caused treatment problems due to drug resistance. The most important statistic, however, is the mortality rate from fungal wound infections. This appears to have remained unchanged in recent years despite the introduction of newer antifungal agents, such as the echinocandins.27 Again, this is not a universal experience in all burn units, which may represent different practices, such as more aggressive treatment or prophylaxis, that are more effective in their settings. In the future, the challenge for burn specialists will be learning and incorporating techniques that effectively reduce colonization, infection, and mortality from fungal species.
PATHOPHYSIOLOGY Candida Even though more than 200 species of Candida are known, 99% of cases seen in the burn unit will be confined to about half a dozen species. Although most fungi are dimorphous, existing in the yeast and mycelial or filamentous hyphae form and switching from the filamentous to yeast form in the body, Candida is an exception. Instead, it propagates in the yeast form in the environment, then reproduces as blastospores in the body, which elongate and stick together to produce hyphae and pseudohyphae (a combination of yeast and filamentous forms). Most Candida species are commensal inhabitants of skin as well as the mucosal membranes of the respiratory, gastrointestinal, and genitourinary tracts. Many Candida species have been isolated from the environment as well. Thus, in burn patients, who have compromised immune systems, colonization normally proceeds from an endogenous source. However, several studies have demonstrated that infection
from exogenous sources does occur in hospital settings, even in specialized units where scrupulous hygiene is practiced.26 This further emphasizes the susceptibility of burn patients to fungal infections, especially those whose percentage of TBSA burned is high. For example, a French study that utilized random amplified polymorphic DNA as a typing method to track C albicans in a burn unit found that some profiles of isolates showed a particular geographic pattern within the unit, suggesting room-to-room transmission.28 The possibility of C albicans transmission at the Shriners Burns Institute in Cincinnati, Ohio, was also raised from the finding that 20 out of 96 pediatric patients over a 3-year period possessed the same serotype and biotype.29 Although the detailed biochemical pathophysiology of Candida infection is beyond the scope of this chapter, there are some important findings worth detailing in the context of burn wounds. Early work in animal models subjected to thermal injury suggested the virulence of C albicans strains was related to their ability to generate proteases. For example, proteinase augmentation of burned mice challenged with the low-virulence MY 1044 strain increased the mortality rate, whereas proteinase inhibition treatment of burned mice challenged with the high-virulence strain MY 1044 decreased it.30 Both in vivo and in vitro studies also demonstrated that growth of the organism was related to its ability to project proteases into the surrounding environment and thus provide a source of amino acids from nearby proteins.31 Degradation of immunoglobulins or activation of the kininogen-kinin cascade system would further lower the immune response to fungal growth. More recent work has focused on the synthesis, characterization, and substrate definition of these proteases in terms of understanding the virulence of different C albicans strains as well as other Candida species. In the chapter discussing the hypothalamic-pituitaryadrenal axis, it was noted that suppression of type 1 Th cells occurs following thermal injury while the Th2 response is enhanced, and this shift favors C albicans infection. For example, Kobayashi et al32 demonstrated that when SCID mice were inoculated with peripheral blood lymphocytes (PBLs) from burned patients, there was no resistance to infection. However, when PBLs were depleted of CD30+ cells, the mice survived infection. CD30 is a surface antigen and member of the tumor necrosis factor receptor superfamily whose high serum concentration is found in several type 2 Th–related disorders and immune-mediated diseases, including rheumatoid arthritis. It appears to have a counter-regulatory function during chronic inflammation. More recent work has also demonstrated that soluble, T-cell-derived antigen binding molecules (TABMs) are another group of immunoproteins
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F UNGAL IN F E C T I O N S associated with type 1 Th cell suppression, cell-mediated immunity. In a study that characterized C albicans mannan-specific production (mannan is a polysaccharide) in patients who had invasive candidiasis, fungal colonization, or no colonization and healthy patients,33 it was determined that the TABM specific to C albicans mannan was highest in patients with invasive candidiasis. Thus, it has been conjectured that the yeast form is recognized by dendritic cells (DCs) via toll-like receptor 4 (TLR4), which leads to candidal growth restriction and a type 1 Th response. However, in burn patients with cell-mediated immune response depression, the transition to the hyphal form is encouraged, with TLR2-mediated DC activation leading to T regulatory cell upregulation and invasive infection. Of interest is that growth of Candida spp in burn wounds is often inhibited by the presence of other bacteria. Gupta et al34 demonstrated that Pseudomonas spp inhibit the growth of Candida spp in burn patients 8 to 10 days postburn with TBSA burns varying from 15% to 90%. Previous in vitro studies35 had suggested that Pseudomonas can form biofilms on Candida cells, thus killing them. This apparent toxicity, which is probably related to sterol metabolism, only affects the filamentous and not the yeast form due to differences in cell wall composition. Depending on geographic location, the most common candidal species after C albicans likely to be present in burn wounds are C parapsilosis, C tropicalis, and C glabrata. Candida parapsilosis is common in infections associated with central lines and patients receiving TPN.36 Although infections associated with this species are generally less virulent, invasive infection and death are possible with involvement of the respiratory system.37 Resistance to amphotericin B37 and 5-fluorocytosine38 has been reported, and a recent examination of the susceptibility of the organism to 9371 isolates showed that resistance to fluconazole also occurred. However, concern regarding resistance to voriconazole or the echinocandins appeared unwarranted.39 While C tropicalis has been considered an important cause of candidemia in patients with leukemia and other hematopoetic malignancies, as well as those who have undergone bone marrow transplantation, its mortality rate is comparable to C albicans.40 Thus, it is not considered a major threat to burn units, even though its prevalence has been increasing. The prevalence of C glabrata, formerly known as Torulopsis glabrata, has also been increasing, with some concern regarding its resistance to fluconazole. Generally, it is not considered any more virulent than C albicans; it is commonly found in immunocompromised patients and patients with uncontrolled diabetes, and is often associated with diabetic renal infection. On the other hand, C kruzei, which is commonly associated with hematology-oncology services, has an intrinsic resistance to ketoconazole and fluconazole. It is also less susceptible to
other antifungals, although response to the echinocandins so far has been excellent.41
Aspergillus As with Candida, more than 200 species of Aspergillus are known, but in general burn units typically see infection due to 3 or 4 species, with A fumigatus, A niger, A terreus, and A flavus most commonly identified. In comparison to Candida, Aspergillus spp produce thin, septate hyphae of approximately the same diameter, with acute branching angles of approximately 45º. The incidence of invasive aspergillosis has been increasing and carries a high mortality rate. Therefore, Aspergillus filamentous fungal infections in wounds should be considered life threatening. For example, Stone et al6 reported a mortality rate of 78% in 18 burn patients with documented Aspergillus infection and recommended amputation of a single extremity in which infection was localized in order to improve the patient’s prognosis. Recently, Murray et al42 attempted to determine the relationship between fungal elements discovered at autopsy and mortality. While they noted that Aspergillus and Candida were the most frequently recovered fungi, Aspergillus was recovered in 13 of the 14 cases in which fungal infection was identified as an attributed cause of death. The implication is that Aspergillus has a greater propensity for directly causing mortality. Ballard et al2 also reported a 12-fold increase in mortality when finding Aspergillus or other mold at any infection site. In addition, the authors considered the fact that slightly less than half of the mold and Aspergillus cultures reported in their review were from patients who were not receiving systemic treatment. Both these studies imply that prompt aggressive treatment is not being undertaken in some burn units. Delineating the pathobiology of Aspergillus infections has been challenging. One recent study suggests that in A fumigatus, gliotoxin, a cytotoxic secondary metabolite produced by the organism, appears to induce apoptotic cell death by activating the proapoptotic Bcl-2 gene family member Bak. This elicits generation of reactive oxygen species, mitochondrial release of apoptogenic factors, and caspase-3 activation.43 In essence, the toxin causes otherwise healthy cells to prematurely die. Another line of research suggests that the virulence of Aspergillus spp depends on its ability to acquire iron, either by using reductive iron assimilation (RIA) or by employing siderophore-assisted iron uptake44 (siderophores are low-molecular-mass, ferric-iron-specific chelators). Because effectively combating aspergillosis with the current antifungal agents is difficult, prevention of extracellular siderophore biosynthesis via novel inhibitors, which leads to reduced virulence, looks to be a promising avenue.
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Fusarium Fusarium is another organism that has been reported periodically in both case series45,46 and review studies17,21 of fungal infections in burn patients. Although the incidence of colonization and infection is less than Aspergillus, progression to invasive or disseminated infections is often fatal. Infection is possible in healthy, immunocompetent patients but is usually localized, often to limbs, and rarely fatal; however, when significant comorbid factors are present, such as chronic renal failure, ischemic heart disease, or diabetes, the risk of mortality increases.47 Four Fusarium species are commonly pathogenic in humans: F solani, F oxysporum, F verticilliodes, and F proliferatum; F solani has been determined to be the most virulent in a murine model,48 but due to the paucity of data, it is undetermined whether this is the case in humans. Several mycotoxins are produced by Fusarium spp, including fumonisin B1, produced by F verticillioides in corn, which targets the liver and kidneys. A recent study also demonstrated that it induces expression of TNFα, IFNγ, and IL-12 in mouse liver, and that macrophages and liver epithelial cells interact in response to fumonisin B1 to augment cytokine expression.49 The trichothenes inhibit eukaryotic protein synthesis, depress cell-mediated immunity and the humoral response to T-dependent antigens, and increase the susceptibility to candidiasis and cryptococcosis; these actions are mediated primarily via lymphocytes.50 Given the impaired immune response and problems with protein biosynthesis observed in burn patients, it can be readily appreciated why these toxins are so deadly.
Other Fungal Infections It has been noted that previously rare fungal infections started to appear in the 1980s and continue to appear more frequently in burn units. For example, Becker et al reported the presence of both Mucor and Rhizopus spp in patients with disseminated fungal disease during the period 1979 through 1989.17 While there are likely several factors contributing to this situation, the largest has been, and continues to be, the increase in the immunocompromised population, including HIV patients or organ transplant recipients.26,51 It can then be conjectured that these “rare” fungi become more established in the environment of acute and long-term care facilities caring for these patients, and thus chances for opportunistic infection are enhanced. Again, it should be stressed that these types of fungal infections are normally absent in immunocompetent individuals, but patients with severe burns are more vulnerable to developing significant infections from these organisms. Zygomycosis is an acute inflammation of the soft tissues, often associated with fungal invasion of the vasculature.
The zygomycete organisms commonly responsible, Rhizopus, Mucor, and Absidia spp, are ubiquitous in the environment. They produce a cottonlike growth on decaying vegetable matter or bread, which is composed of wide, ribbonlike, aseptate (hyphae or spore cells that lack cross-walls) hyaline hyphae with wide or right-angle branching.52 With proper sectioning and staining, this morphology enables a relative easy distinction under the microscope between these species and other filamentous fungi which have pseudohyphae, such as Aspergillus and Candida species. Transmission of these zygomycetes has been linked to spore-contaminated adhesive bandages,53 catheter sites, electrodes, and contaminated surgical equipment or air-conditioner filters, but can also occur via the respiratory tract.52 Typically, the infection site is cutaneous in burn patients, but cases of rhinocerebral mucormycosis, in which infection is initiated in the sinal or palate mucosa and progresses to the retro-orbital area and brain via the facial nerves, blood vessels, or cartilage, have occurred. For example, Stern and Kagan54 reported the case of a 62-year-old diabetic male who had 29% TBSA burn injury after being involved in an airplane crash. Although successfully resuscitated, he later died of a massive cerebral vascular accident (CVA) with necrosis of the right temporal, right frontal, and parietal lobes. An autopsy and histopathological examination of the affected tissues revealed the presence of zygomycetal organisms. Another case involving ischemic necrosis of the upper extremities in a patient caused by invasive mucormycosis following soil contamination of severe burn wounds also highlights the aggressive measures that must be taken following diagnosis if the patient is to survive.55 The most recent review of the literature involving cutaneous mucormycosis indicated a mortality rate of 31%.56 Ballard et al2 recorded a mortality rate of 28% due to molds. Horvath et al27 also noted that 30% of fungal wound infections had Mucor-like morphology—a high percentage— and using regression analysis determined that patients older than 40 years were the most vulnerable in terms of mortality. However, these authors also showed that mortality increased with decreasing age below 20 years, with infants predicted to have a mortality rate of nearly 10%. Absidia corymbifera, which can invade intact skin by using proteolytic enzymes, has also been reported in burn patients. This organism also exemplifies the difficulty in treating such cases, as it possesses a propensity for growth via the vasculature.57
DIAGNOSIS Clinical Signs The diagnosis of fungal infections is always difficult due to the variety of presenting clinical signs as well as the common finding that symptoms may not occur until the
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F UNGAL IN F E C T I O N S infection is well advanced. Moreover, uniform criteria for diagnosis are lacking.2 Although colonization by Candida spp has been found to precede invasive sepsis, in 80% of patients this had no effect on their clinical course.7 Thus, in some cases, an overtaxed immune system will tip the balance towards a critical event and cause an infection to propagate from a colonization site. Generally, manifestations of candidemia include pyelonephritis, peritonitis, arthritis, hepatosplenic abscesses, pneumonitis, myositis, macronodular skin lesions, osteomyelitis, endophthalmitis, meningitis, and/or multiorgan involvement.26 However, the progression from infection to invasive fungemia affects different organs according to the route of infection. For example, translocation from the gut will likely involve the liver and splenic tissues, whereas infection from a central line will often lead to endocarditis and renal problems. Patients with candidemia or disseminated infection will also develop fever and leukocytosis (leukocyte count typically above 15 x 109/L) unless they are taking immunosuppressive medications. Candidemia is most likely to occur 2 to 7 weeks postburn.58 Fever also tends to be constant (101ºF to 105ºF, 24.1ºC to 26.3ºC) rather than variable, as is often observed with many bacterial infections. Fungemia-induced fever should not be confused with the metabolically related increase in temperature often seen for the first several days postburn in children. Another clue to the presence of candidiasis may be irresolution of a chronic episode of gram-negative sepsis.58 When Candida is suspected, clinicians should also consult the risk factors associated with candidemia, which are described in a later section, as such factors can be informative. Depending upon the age of a child and severity of infection, Malassezia yeast spp may induce temperature instability, bradycardia, thrombocytopenia, respiratory distress, or merely fever with mild illness.26 Although candidiasis is a very serious condition in a severely burned child, early recognition of Aspergillus or zygomycetes infections is more critical, as they carry a poorer prognosis once dissemination occurs. The classical route for aspergillosis is the respiratory tract through inhalation of fungal conida,26 but in burned children this is unlikely unless an inhalation injury is present.2 Early symptoms of invasive pulmonary aspergillosis include cough, fever, hemoptysis, and hypoxia, with variable chest radiographic changes.24 Of note, one-third of patients may be asymptomatic. Aspergillosis in the majority of pediatric burn patients is initially cutaneous. The first clinical presentation begins with erythrematous fluctuant nodules or plaques that progress to necrosis and/or eschar formation in a burn wound.59 When changes in the character of a wound surface suddenly change—notably, swelling, induration, and tenderness accompanied by fever—cutaneous aspergillosis should
be added to the list of “usual suspects.”60 Generally, erythema and induration appear when the site of infection is an intravenous catheter, followed by progressive necrosis that develops radially.60 In a case study of 5 adults and 1 child with primary cutaneous aspergillosis, the diagnosis was made at approximately 6 weeks postburn.59 Absolute neutrophil (polymorphonuclear cells) count in these patients was depressed (mean: 1058 per μL), but not classified as neutropenia. Although half of these patients were successfully treated, the remainder developed invasive aspergillosis and died. Typically, cutaneous aspergillosis develops 10 to 35 days postburn in patients with burns of 50% to 60% TBSA, but it can still occur even when burn wounds are nearly healed. For example, Williams et al61 reported that a 4-year-old female with an 80% TBSA scald burn was treated successfully, even though she had multiple positive blood cultures for gram-positive and gram-negative organisms. Prior to discharge, however, she suddenly developed fulminant gram-negative sepsis thought to be unrelated to the healed scald. While this episode was also well managed, small, dark, necrotic ulcers started to extensively appear over the scalded area. Despite intensive antifungal treatment, fascial excision of involved tissue, and coverage with Integra, she developed MOF and died. This case study is an extremely unusual illustration of Koebner’s phenomenon—the development of lesions in previously normal skin that has been internally or externally traumatized. Another case study documented the very rare development of aspergillosis in the GI tract.62 Fusarium infections can initiate in the skin, respiratory tract, extremities, eyes, GI tract, or the peritoneum.47 Skin infections usually present as ulceration. In one case of Fusarium infection involving an adult male with a 73% TBSA hot grease scald injury, the process started with colonization of the wound 30 days postburn and progressed to fulminant, disseminated infection within 1 week to the thighs, legs, and thence to the feet, groin, and abdomen.46 Disseminated, reddish, elevated boils infiltrated with Fusarium also appeared on his arms in the terminal phase. Despite attempts to halt the infection with below-the-knee amputations and aggressive antifungal treatment, he subsequently died. While some Mucor infections are likely to manifest symptoms similar to cutaneous aspergillosis (central, black necrotic eschars surrounded by a margin of red to purple edematous cellulitis54), pulmonary, rhinocerebral, rhino-orbital, and gastrointestinal cases are possible.52 Gastrointestinal manifestations include abdominal pain with hepatic abscesses, necrotic stomach wall ulcerations, diarrhea, paralytic ileus, and appendiceal masses. The diagnosis of rhinocerebral mucormycosis is difficult, although CT scans may assist in defining soft tissue abnormalities. Magnetic resonance
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imaging, however, is superior in demonstrating intracranial complications caused by fungal invasion.54 Trichosporon spp normally cause superficial infections of the hair shaft known as white piedra. It can also cause bloodstream infections in burn patients, resulting in endocarditis or peritonitis if dialysis is being performed.26 In addition, wounds may be infected with results similar to aspergillosis.
Laboratory and Culture Tests Culturing fungal species is still an art which can be difficult in many instances, particularly when infections are due to more than one species. Moreover, as resources at some burn units may be limited, there are 3 important questions which a burn clinician should address: (1) Under what circumstances is it appropriate to culture fluids or tissues from a patient? (2) From what fluids or tissues should biopsies or swabs be taken? (3) How should the results be utilized? Although some burn units have policies regarding routine fungal cultures, at a minimum, cultures should be obtained when (1) the patient is judged to be at high risk for a fungal infection, or (2) when suspicion is high that a fungal infection may be present. In the first instance, sampling should commence at least 1 week after burn injury, since this is the beginning of the fungal infection “envelope,” unless there is already suspicion of an infection. Risks of infection may also change during the course of burn treatment and should therefore be frequently reevaluated. As we have previously seen, an individual who is progressing well can develop a defining event, or series of events, that may predispose him or her to infection. Such events include, but may not be limited to, bacterial sepsis; prolonged, extensive, and multiple surgeries involving debridement or excision; development of compartment syndromes or respiratory distress; or hypotensive episodes. What constitutes “high suspicion”? Any prolonged fever accompanied by leukocytosis which is not explainable by bacterial infection is one possibility; another is a suspected or confirmed bacterial infection that fails to resolve after appropriate antibiotic treatment. In addition, appearance of any of the clinical signs or symptoms that have already been described, and which cannot be explained by other factors, should alert the clinician to the possibility of fungal infection. There is a considerable difference between colonization and infection of a wound. Fungal colonization is not uncommon and usually goes unrecognized; generally, it is defined as observation of fungal elements in the burn eschar without penetration to the level of viable tissue. Fungal infection, on the other hand, has been defined as fungal invasion into viable tissue below the eschar.64 Moreover, in terms of quantitative colony-forming culture analysis (defined as
log10 colony-forming units per gram of disrupted tissue), Horvath et al27 highlighted the finding that infection, but not colonization, is independently associated with higher mortality. However, colonization may be an important finding in a high-risk patient who warrants early presumptive treatment to prevent infection. In addition, if resources permit, obtaining wound swabs on a periodic basis (for example, every 1 to 3 years) can help identify shifts in fungal colonization patterns that may be reflective of changes in the burn unit environment. Swabs of the wound or other affected tissues are the most important sites to sample; blood, urine, and sputum cultures may also be helpful in confirmation of infection. However, results of cultures from such specimens by themselves can be misleading either because of contamination, especially from Candida, or because of failure to grow cultures, such as zygomycetes, even though fungi may be present.52 In general, attempting to culture fungi from cerebrospinal fluid (CSF) specimens is not recommended64; in the case of meningitis, the combined use of the cryptococcal antigen test and bacterial cultures of CSF can replace routine fungal cultures of CSF, unless experience in the burn unit suggests that fungal pathogens other than Cryptococcus and Candida remain important causes of meningitis. When equipment or devices, such as catheters, are suspected as the source of a fungal infection (eg, intravenous site infection), a swab of the surface should also be taken. Newer techniques, such as real-time PCR (polymerase chain reaction), are beginning to make inroads as an adjunct to the classical fungal culture methods.66 In particular, Aspergillus spp have been targeted because of their high morbidity and mortality. Compared to current ELISA tests for galactomannan and tests for (1→3)-β-D-glucan, the results of one PCR test were available 2.8 and 6.5 days earlier than the other tests, with a sensitivity of 79% vs 58% and 67%, and a specificity of 92% vs 97% and 84%, respectively, for the other tests.67 However, such PCR tests are limited because most are only targeted toward one particular species. PCR tests targeted toward Candida identification are focused on the 6 or 7 most common species.66 The initial results have been promising, but it will most likely be at least another decade before such tests are commonly available. Ultimately, the approach could be combined with array (“chip”) technology to allow simultaneous detection of many fungal species. Currently, many of the laboratories used by burn units only identify genera, rather than individual species of fungi. This approach is still helpful since it can differentiate between Candida, Aspergillus, or zygomycetes infection. More sophisticated analysis allows for species identification, which can aid in tailoring empirical treatment based on clinical suspicion alone. In interpreting results, it is important to keep in mind the definitions of infection
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F UNGAL IN F E C T I O N S and consider laboratory findings in the context of clinical findings. For example, an isolated urine sample positive for Candida does not necessarily mean that an infection is present. On the other hand, positive findings of a given fungal genus or species from multiple samples can assure the clinician that an infection is present and must be addressed.
Making the Diagnosis Making a diagnosis of fungal infection or fungal involvement requiring action is challenging because (1) if there is an infection, treatment should be initiated without waiting for culture or laboratory tests, (2) giving a patient antifungal treatment is not without risk, and (3) equivocal culture results are not helpful. For high-risk patients who have been already started on prophylactic antifungal agents, suspicion regarding a possible infection suggests the situation is likely to be serious. However, for lower-risk patients, there is no consensus on how to proceed. Ballard et al2 expressed concern, based on their review of 2114 burn patients, that almost half of the cultures positive for molds or Aspergillus were from patients in whom systemic antifungal treatment had not been initiated. Should this result be interpreted as laxness by the attending clinicians or as their inability to judge whether an infection was really present given the clinical signs and symptoms (if any) that were present? In terms of interpreting equivocal culture results, Ballard et al2 also encapsulate the dilemma faced in burn units with such questions as “Do positive blood cultures, or cultures of mold or Aspergillus, mandate treatment? When can cultures of Candida from urine or sputum be ignored?” At this time, the best advice is to allow the patient’s status to guide therapeutic decisions. Where strong suspicion has been elicited regarding infection, it is wiser to begin empirical therapy given that the risks involved in instituting antifungal treatment far outweigh those posed by infection. Moreover, while antifungal treatment can always be discontinued if unwarranted, one cannot gain the time lost from delayed treatment if a serious infection is present.
TREATMENT
In general, the treatment of fungal infections relies upon a combination of debridement or more extensive excision of infected tissue where necessary (including amputation of extremities in life-threatening situations), surgical drainage, and systemic antifungal therapy. Removal of catheters and/or prosthetics may also be necessary if these are implicated in the infection. There are 4 indications for administration of antifungal agents: (1) prophylaxis in the case of high-risk patients, (2) early presumptive treatment in the case of documented fungal colonization in which the risk and consequences of developing an invasive or disseminating infection are judged serious, (3) topical therapy for localized infection, and (4) systematic therapy for invasive infection or situations to prevent invasive fungemia.67 Empirical treatment (ie, treatment without obtaining a culture) should be initiated whenever patients have 3 or more of the following risk factors: (1) 1 or more weeks of antibiotic therapy (2) immunosuppression (prior condition or laboratory tests indicating it is present) (3) long-term intravenous catheters (4) violation of the GI tract (5) intra-abdominal abscesses (6) prolonged hospitalization (ie, several weeks) (7) SIRS or multisystem organ failure Empirical treatment should generally utilize the most effective agents until such time as culture results can provide more definitive information that might allow a more tailored response. For example, intravenous fluconazole (800 mg/day as a loading dose) can be started, followed by 400 mg/day for 7 days (IV). Renal failure patients should be treated according to their creatinine clearance: (1) > 50 mL/min—400 mg/day; (2) 20 to 50 mL/min— 200 mg/day; and (3) 10 to 20 mL/min—100 mg/day. For patients undergoing dialysis, administering 400 mg after dialysis is recommended. In the following sections, some of the major trials of different antifungal agents are described, along with a consensus of use against different fungal infections when available.
Considerations Although many case reports and studies have been published over the years regarding antifungal treatments for burn patients, all the efficacy studies of antifungal agents (eg, randomized controlled trials—RCTs) have been conducted in patients with other diseases or conditions. That is not to say the results of such trials are inapplicable, but rather that they should be interpreted with caution since the course of a Candida infection in a severely burned patient is not identical to that in a patient with HIV or cancer.
Amphotericin B Amphotericin B (amp B) is a polyene that has been used for several decades to treat fungal infections and is regarded as the “gold standard” drug against which newer agents are compared. It has a broad spectrum of activity, although its efficacy against C lusitaniae, C guillermondi, A terreus, and Scedosporium spp is limited.24 Currently, it is considered a “second-line” drug due to its potential toxicity and side effects and is often used as a back-up when newer first-line
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drugs fail to resolve an infection. For example, in a recent expert panel consensus,25 17 out of 20 experts would choose a regimen of amp B in Candida infections if fluconazole treatment had already been tried, even if the patient was stable. Side effects observed in 50% to 90% of cases include fever, chills, nausea, vomiting, and hypotension. More serious adverse effects include nephrotoxicity or are infusionrelated. Amp B’s nephrotoxic effects are potentiated by a high dosage and/or long duration, as well as other nephrotoxic drugs and diuretics. Alternate-day dosing, combinations with 5-fluorocytosine (at lower doses), and continuous infusion have all been attempted to moderate toxicity,24 but the newer lipid-formulated versions (liposome) appear to be the most promising. Although case reports from the early 1970s indicated that amp B was generally successful at clearing Candida infections from the blood, most patients subsequently died3,4; our opinion is that treatment was given too late to be effective. More recent RCTs comparing conventional amp B against its liposomal formulation suggest that timely treatment is effective. For example, a 1999 neutropenic sepsis RCT (empirical antifungal therapy for patients with persistent fever following antibacterial treatment) showed a 90% survival rate for the conventional amp B group vs 93% for the liposomal amp B group after 1 week. Moreover, fewer proven breakthrough fungal infections occurred in the liposomal amp B group.69 Most importantly, significantly fewer adverse events and side effects occurred in the liposomal amp B group compared to the conventional amp B group. However, a more recent RCT tested a high-loading dose regimen (10 mg/day) of liposomal amp B against a standard dose (3 mg/day), followed by 3 mg/day for 2 weeks in patients with definite or presumed invasive/mold aspergillosis. No benefit was demonstrated in regard to higher dosing, with respective survival rates of 59% and 72% after 12 weeks.70 Three liposomal amp B formulations are currently available: ABLC-Abelcet, ABCD-Amphocil, and L-AmBAmBisome. While a meta-analysis indicated that such formulations can reduce all-cause mortality for invasive fungal infections by 30% compared to conventional amp B, there appears to be no difference regarding efficacy between the 3 formulations.71 The overall NNT (number needed to treat) figure calculated when using liposomal formulations of amp B (versus conventional amp B) to prevent 1 death was 31, which indicates little difference in effects. However, further RCTs72,73 have revealed differences in tolerability of the formulations; combined adverse events were lowest with L-AmB (12%), intermediate with ABLC (32%), and highest with ABCD (41%).24
Nystatin Nystatin is a polyene that was brought into use during the mid-1950s for topical treatment of fungal infections and was found to be effective in treating Histoplasma and Cryptococcus infections as well. In the 1960s, burn units began employing it against Candida strains. Because of its limited solubility in water as well as serious side effects of nephrotoxicity and hemolytic toxicity when used parenterally, it is used in topical ointment form or taken as an oral suspension. Like other polyene macrolides, it acts by binding ergosterol, the primary fungal steroid, in the cell walls of fungi, causing formation of pores and apoptosis. During the 1970s and 1980s, nystatin use was common in many burn units, either as a topical agent in conjunction with amphotericin B in cases of aspergillosis or Candida, or as prophylaxis in high-risk patients to prevent candidiasis by using the so-called “swish and swallow” technique.6,11,12 However, besides issues of patient compliance, there were doubts of its efficacy. The case series of Heggers et al74 suggested some efficacy when nystatin was used as a topical agent in combination with antimicrobial drugs. The case control design of Desai et al, which tested use of “swish and swallow” prophylactic nystatin, was more convincing, with a reduction of Candida colonization from 26.7% to 15.6%, Candida infection from 21.3% to 10.0%, and sepsis from 12.2% to 0%. 13 While the experience of Dubé et al14 was similar to that of Heggers et al,74 the authors raised the suggestion of topical nystatin use increasing fungemias and colonization caused by nystatin-resistant, amphotericin B–susceptible C rugosa. In 1999, Barret et al75 reported the cases of 4 severely burned children in which excision of fungi-affected tissue, as well as use of amphotericin B and other agents, proved ineffective against Fusarium and Aspergillus angioinvasive infections. In order to save lives, they treated wounds with topical nystatin powder at 6 x 106 units/g, which was found to eradicate invasive clusters of fungi in deep wound tissues. A recent RCT tested prophylactic fluconazole (200 μg/ day) against nystatin suspension (6,000,000 IU/day) to prevent fungal infections in patients with leukemia undergoing remission induction chemotherapy.76 The results showed that fluconazole was more successful in preventing fungal infections (68% of the fluconazole-treated patients vs 47% of the nystatin-treated patients, P = .03). The result of this clinical trial (and others) is one reason why nystatin is not routinely used as prophylaxis in current burn unit practice. However, some burn units choose to add the drug to other agents to prevent wound infection. Moreover, as Barret et al75 have shown, its use may have some utility in Fusarium, Aspergillus, or infections due to rarer fungi in cases in which newer antifungal agents have limited activity.
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5-fluorocytosine 5-fluorocytosine (flucytosine) is a fluorinated analog of cytosine that is deamidated intrafungally to 5-fluorouracil, which is subsequently phosphorylated and incorporated into fungal RNA, inhibiting protein synthesis. In addition, it is converted to 5-fluorodeoxyuridine-monophosphate, which inhibits fungal DNA synthesis. In the treatment of fungal infections in burn patients, flucytosine has not been used extensively due to its relatively weak antifungal activity.14 Moreover, some fungi can become rapidly resistant to the drug when used alone.24 As a result, it must always be used in combination with other antifungal agents. In combination with amphotericin B, it may be particularly useful in meningitis and endocarditis caused by Candida species.77
The Azoles The azoles include the imidazoles, ketoconazole and miconazole, and the triazoles, itraconazole, fluconazole, and voriconazole. The latter 2 azoles have constituted the mainstay of systemic antifungal treatment, largely because of their efficacy and lower toxicity compared to amphotericin B, and will thus be examined in terms of their efficacy. Many trials involving fluconazole have been conducted, particularly in regard to cancer. Many of these studies have been ignored, however, in part because the “treatment model” is less applicable to burn patients and because several trials had major design flaws.78 Instead, we shall focus on broader-applicability trials. Several early RCTs79-81 of fluconazole versus amphotericin B for treatment of candidemia were designed as noninferiority trials, meaning they were designed to show equivalency. In strict terms, while at least 2 trials79,80 might have been underpowered in our opinion, overall, they did show that fluconazole was an excellent substitute for amphotericin B, given that much data was missing regarding evaluability of the trials. Another trial revealed that the addition of amphotericin B to fluconazole appeared to improve outcomes, even though it was too underpowered to demonstrate this conclusion statistically.82 However, the use of fluconazole in preventing fungal infections in critically ill patients was less unambiguous, with one trial83 suggesting a positive benefit in regard to Candida infection and the other suggesting no benefit.84 A 2-cohort study of 99 and 38 patients, respectively, also buttressed the findings of the Schuster et al RCT.84 Furthermore, they suggested that, in concert with previous findings, broad use of prophylactic fluconazole in ICUs was increasing both the incidence of fluconazoleresistant Candida organisms as well as bacterial resistance of other microorganisms toward broad-spectrum antibiotics.85 In addition, before the second trial84 was conducted,
a consensus conference on candidal infection had already unanimously recommended that antifungal prophylaxis not be given on a routine basis.25 We would agree and suggest that prophylaxis be undertaken only in high-risk, severely burned patients. Voriconazole is a second-generation azole, and several trials were conducted to determine its efficacy compared to amphotericin B, or to a sequence of amphotericin B followed by fluconazole. Both the RCTs conducted by Walsh et al86 and Herbrecht et al87 suffered major problems. In the first instance, the outcome of the trial clearly showed that voriconazole was inferior to liposomal amphotericin B by composite endpoint. However, the claimed significant reduction in breakthrough infections disappeared when infections arbitrarily excluded from analysis were included.78 The second trial,87 which followed treatment for invasive aspergillosis, suffered from protocol design flaws that did not include premedication (steroids) to prevent infusion-related adverse events or the addition of fluid and electrolytes to minimize nephrotoxicity in the amphotericin B arm. Most importantly, the duration of treatments was vastly different, with a median duration of 77 days for the voriconazole group and 10 days for the amphotericin B group. This factor alone renders comparison between the groups meaningless. The third RCT, which compared voriconazole against a short course of amphotericin B (average duration 4 days) followed by fluconazole to treat candidemia,88 also failed to show unequivocal equivalency, because although the outcomes were equivalent at 12 weeks according to the analysis protocol, they were not at the last available follow-up. The incidence of adverse events related to administration of voriconazole appears to be less than for amphotericin B. They include visual disturbances (6%-45%), rashes, Stevens Johnson syndrome, toxic epidermal necrolysis, pancreatitis, hepatitis, and jaundice.87,89,90 In addition, because voriconazole is metabolized via the cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4, the potential for drug interactions is high. Therefore, monitoring liver function and serum levels of the drug where possible, as well as adjusting dosages with coadministration of other medications, is required.24,89 Posaconazole has a broad spectrum of activity akin to voriconazole, but the latter is available only in oral form. In an RCT comparing posaconazole against fluconazole and itraconazole as prophylactic treatment to prevent fungal infection in patients undergoing chemotherapy, posaconazole demonstrated superior results in regard to proven or probable invasive fungal infections (2% vs 8% in the fluconazole/itraconazole groups).91 Survival rates were significantly better in the posaconazole group, but serious adverse events possibly or probably related to treatment were also
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significantly higher in this group. Thus far, this drug has not been widely studied in burn patients. Although it appears to be a promising candidate for treating invasive infections, it should probably be reserved for salvage therapy in refractory or resistant infections or used as an alternative agent in zygomycosis, fusariosis, cryptococcal meningitis, coccidioidomycosis, or histoplasmosis until more data are available.92 Several other azoles, including isavuconazole, ravuconazole, and albaconazole, are in various phases of clinical testing, and data on these drugs should be available in the near future. Albaconazole in particular has shown very potent activity against species of Candida, Cryptococcus, and Aspergillus.93
The Echinocandins Caspofungin, micafungin, and anidulafungin are lipopeptides that block the synthesis of glucan in the cell wall and are the result of several decades of research to find lowtoxicity compounds in the echinocandin group. Due to low oral bioavailability, they must be given intravenously. Several RCTs have tested the efficacy of the echinocandins. Mora-Duarte et al94 conducted a double-blind trial of intravenous caspofungin against amphotericin B for the treatment of invasive candidiasis (N = 239). Successful outcomes were demonstrated in 73% of the caspofungin patients vs 62% in the amphotericin B group (ITT analysis, after therapy). Moreover, a significant difference in outcomes was noted in the per protocol analysis both after the end of therapy and 6 to 8 weeks after treatment. The results showed that caspofungin was at least as effective as amphotericin B, while causing significantly fewer adverse events. A similar but much larger trial (N = 1095) using caspofungin and liposomal amphotericin B to empirically treat patients with persistent fever and neutropenia confirmed the noninferiority of caspofungin (33.9% success rate vs 33.7% for amphotericin B) as well as a lower incidence of adverse events.95 Concerns arose regarding the fact that the first trial did not employ fluconazole (the preferred drug of choice at the time) rather than amphotericin B as the drug that should have been compared against caspofungin.96 Subsequently, a RCT comparing anidulafungin against fluconazole in the treatment of patients with invasive candidiasis (N = 245) was undertaken.97 In the modified ITT analysis, successful outcomes after the end of therapy and at a 2-week follow-up showed a significant difference in favor of anidulafungin (74% vs 57%, and 65% vs 49%, respectively), but were not significantly different after 6 weeks. Adverse events were generally similar, and the Kaplan-Meier estimates of survival showed a nonsignificant trend in favor of anidulafungin. Micafungin (low and high dosages of 100 mg and 150 mg daily) was also tested against caspofungin (70 mg, then 50 mg daily) for treatment of candidemia and other
forms of invasive candidiasis in a large trial (N = 595).98 Successful outcomes were recorded in 76.4% of the lowdose micafungin group, 71.4% in the high-dose micafungin group, and 72.3% in the caspofungin group. Again, adverse events were similar across all groups. The results of these trials suggest that the echinocandins are at least as efficacious in treating candidiasis as fluconazole; they may be superior under certain circumstances, but this will need to be confirmed with more data.
Drug Interactions The interactions between amphotericin B and other drugs have not been studied as extensively as for the azoles, but in general, other nephrotoxic drugs, such as aminoglycosides, cidofovir, or foscarnet, should be avoided. In addition, amphotericin B has the potential to induce potassium depletion, which may increase digitalis toxicity or enhance the curariform effect of skeletal muscle relaxants. Many of these effects, including the nephrotoxicity of amphotericin B, can be avoided through careful monitoring and the addition of fluids and electrolytes. If flucytosine is used, caution must be employed with concomitant administration of myelosuppressive drugs, since cytarabine can reduce levels of flucytosine.24 Because triazoles inhibit a number of CYP isoenzymes, major drug-drug interactions will occur if a patient receives any other drugs metabolized by these enzymes in the liver.99 Both itraconazole and voriconazole have the greatest potential in this regard, while fluconazole and posaconazole have less potential.99,100 Animal data and small case reports indicate that concentrations of caspofungin in the blood can be reduced by rifampicin after prompting an initial rise, whereas cyclosporin can cause a sustained elevation in caspofungin levels.24 Increases in caspofungin clearance have also been noted when given concurrently with carbamazepine, dexamethasone, efavirenz, nelfinavir, nevirapine, or phenytoin. In these instances, increasing the dosage of caspofungin may be required.101 Furthermore, caspofungin can cause reduced blood concentrations of tacrolimus, and thus monitoring of tacrolimus levels is advised.
Specific Recommendations As iterated at the beginning of this section, empirical treatment with fluconazole can be instituted while awaiting results of cultures. However, once identification of the genus or species has been accomplished, more refined treatment can begin. This does not preclude interim changes if the patient is not responding to fluconazole. It is useful to begin by understanding the spectrum of activity of the antifungal agent classes and the specific
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F UNGAL IN F E C T I O N S species in which resistance has been observed. If a Candida species is confirmed as being responsible for the infection, treatment changes are appropriate for certain species. For example, if C glabrata is confirmed, asking the laboratory to conduct an MIC study is warranted: a continuing dosage of 400 mg/day of fluconazole is appropriate for an MIC of < 16, but values of 16 to 32 may indicate doubling the dosage to 800 mg/day; values > 32 suggests switching to an alternative treatment, such as amphotericin B at 0.5 to 1.0 mg/ kg per day, would be beneficial. If C krusei is confirmed, treatment should be changed to 1 of the echinocandins, voriconazole, or amphotericin B. Finally, if endocarditis, meningitis, or endophthalmitis is present with a definite Candida infection, adding flucytosine may be of benefit.77 If infection with Cryptococcus neoformans is confirmed, fluconazole therapy should be maintained since it demonstrates good activity against this organism.99 Proven Aspergillus infections are best treated with caspofungin or amphotericin B, respectively, although amphotericin B should not be used in cases of infection due to A terreus.24,63 Infections due to Fusarium or Scedosporium spp are best treated with voriconazole or posaconazole.24 Zygomycete infections are usually treated with liposomal variants of amphotericin B, although posaconazole may be a good alternative, despite the fact that it is only currently available in oral form.100 It should also be remembered that amphotericin B has inconsistent activity against Trichosporon species and Pseudallescheria boydi63; in the latter case, voriconazole is appropriate, whereas in the former case, a combination of high-dosage fluconazole and amphotericin B may be the best strategy at this time.102 Since consensus guidelines regarding treatment of fungal infections in burn patients are lacking, management of such infections is largely influenced by local practice. As has been demonstrated, fungal infection patterns can differ considerably between burn units. Therefore, a comprehensive history of such infections in each unit can provide valuable information in terms of predicting the probability of infections due to certain species, the appearance of resistance to certain antifungal agents, and successful management options in difficult cases.
SPECIAL TOPICS Risk Factors Candidemia is the most studied model in terms of determining risk factors for fungal infection. Unfortunately, no published studies have specifically examined the burn patient population. In a case control study of 30 cancer patients and 58 controls, Karabinis et al determined that positive peripheral cultures for Candida spp, central catheterization, and neutropenia were the principal risk factors from
a multivariate logistic model.103 A similarly designed study of 48 patients with leukemia (and 48 controls) revealed the following major risk factors from the logistic regression model: presence of a central line, bladder catheter, administration of 2 or more antibiotics, uremia, transfer from another hospital, diarrhea, and candiduria.104 Conversely, prior surgical procedures reduced the odds of acquiring a candidal infection by a factor of 10, which implies that surgical patients receiving such treatments were protected to some extent. A larger case-control study (N = 88 for each arm) of hospital-acquired candidemia found that, from a multivariate analysis, the number of antibiotics administered prior to infection, isolation of Candida species from areas other than blood, prior hemodialysis, and prior use of a Hickman catheter were the major risk factors.105 A large prospective cohort study that tracked the development of candidal bloodstream infections in a SICU for > 48 hours over a 2-year period, however, found that prior surgery, acute renal failure, parenteral nutrition, and the presence of a triple lumen catheter were major risk factors in patients who underwent surgery.106 Ballard et al,2 specifically studying burn patients, reported the incidence of many of the risk factors identified from these studies, indicating that the presence of catheters and central lines, systemic use of antibiotics, and need for ventilatory support were the most common occurrences. Reviewing all these studies together, the 3 likely factors predisposing toward Candida infections are high utilization of antibiotics, the presence of catheters, and total parenteral nutrition. In addition, hyperglycemia (> 180 mg/dL) and possibly APACHE scores should be considered as additional factors in the development of any type of fungal infection.107 Perhaps the best approach to encompassing use of risk factors in defining a high-risk population who will require prophylactic antifungal agents after completing resuscitation is to compile a short in-house list and define vulnerable patients as those who have 3 or more risk factors, such as were outlined at the beginning of the treatment section.
Prophylaxis The decision whether to empirically administer antifungal agents to patients at high risk of developing a fungal infection, and what drugs should be used, is not an easy one, even when addressing candidemia.25 In addition to defining the high-risk patient, such factors as the presence of diabetes, the percentage of burned total body surface area, degree of immunosuppression, and age must be considered. Part of the problem is lack of an inherently safe antifungal agent which can cover all possibilities. Fluconazole is reasonably effective against some Candida species, but not all, and overuse may lead to increasing resistance in the burn unit. Moreover, fluconazole is ineffective against most molds.
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Low prophylactic doses of amphotericin B have been utilized in neutropenic bone marrow transplant recipients to prevent aspergillosis in units where Aspergillus infections are common, but this strategy remains controversial.107 Likewise, investigators have published findings on the prophylactic use of itraconazole and ketoconazole, but there is no agreement whether this is effective. What would be useful are case control studies investigating prophylaxis in high-risk burn patients in regard to incidence of infection, outcomes, and mortality. However, until these studies are performed, the decision to institute prophylaxis will remain in the hands of burn unit policies, guided by local patterns and prior experience.
Eliminating Sources of Fungal Infection As has been discussed earlier, many episodes of fungal infection can be traced to the presence of specific fungal organisms in the environment or to patient-caregiver interactions. Although one cannot eliminate all sources of fungal infections—for example, many candidal sources originate from within the body—there are several practices that can minimize infection and certainly prevent nosocomial outbreaks. First and foremost is hygiene. Poor hygiene and crosscontamination from within units or personnel adjacent to burn units are frequently cited as sources of infection that can be eliminated or certainly minimized. Both the biotyping analysis conducted by Neely et al15 and the study of Mousa et al20 offer insight into the mechanism of in-house transmission between patients and suggest that regular decontamination of units may pay dividends, particularly if clusters of infections are observed. Routine, careful cleaning of airconditioning filters can also hinder dissemination of fungi. Since structural changes to burn units or adjacent facilities can also cause airborne transportation of fungi, provision for monitoring the environment should be undertaken during these renovations. Instruments, catheters, and other surgical supplies can also be occasionally contaminated, either in an “as received” condition from the manufacturer or during use. Monitoring the frequency and site of fungal infections, as well as noting the species responsible for infections from month to month, can also provide valuable clues in regard to sources of infection. Clusters of cases should be promptly investigated, as such occurrences may signify an ongoing transmission that is beyond the “normal” background.
CONCLUSION Since the introduction of broad-spectrum antibiotics in burn units, the incidence of fungal infections has increased, although the overall rate seems to have stabilized in recent
years. However, the incidence of candidal infections due to other species besides C Albicans has increased, as has resistance to the most popular antifungal agent, fluconazole. Moreover, the incidence of aspergillosis and infections due to other fungi, such as zygomycetes, is becoming more common. This has increased difficulty in both diagnosis and treatment. Diagnosis still relies heavily on clinical suspicion since laboratory cultures take several days to process. Such results can subsequently be used to refine empirical treatment with fluconazole. Due to the high morbidity and mortality of fungal infections, suspected or probable infections should be treated immediately, especially in high-risk patients, as delays in instituting treatment can prove fatal. Although the introduction of fluconazole, voriconazole, posaconazole, and caspofungin has shifted the role of amphotericin B to second-line and salvage use, it will still continue to be used for the treatment of zygomycetes infections until more data on posaconazole are available. As relevant data and consensus on prophylaxis, diagnosis, and treatment in the burn patient population are lacking, management of fungal infections will depend on local experience for the foreseeable future. Data suggest that paying particular attention to hygiene, changes in the environment, catheters, and central lines, as well as classifying the risk of patients upon admission to burn units, will all assist in the challenging process of reducing fungal infections and their significant consequences.
KEY POINTS • Although the current incidence of fungal infections is approximately 6% to 7%, the proportion of noncandidal infections is probably around 40%, with high (proportional) rates of mold and Aspergillus infections reported in some burn units. • For candidal infection, the mortality rate is approximately 10% to 15%, but mortality rates are much higher for Aspergillus and molds (25%– 40%). • A substantial proportion of Candida infections today are due to species other than C albicans. Both C glabrata and C krusei are increasingly resistant to fluconazole and require a switch to amphotericin B or one of the echinocandins. • Once rare, infections due to zygomycetes, Trichosporon, and other molds and yeasts are becoming more common, in part due to the rise in immunocompromised populations. • Diagnosis should be made on clinical suspicion; culture of patient isolates can confirm infection
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and help refine subsequent treatment, but treatment should not await culture results. Any prolonged fever that is not due to bacterial infection, confirmed bacterial infection unresolved by antibiotics, or appearance of other clinical signs/symptoms that cannot be explained by other causes should cause the clinician to consider fungal infection as a possibility. Candida infections are often preceded by a major event that temporarily destabilizes the patient’s condition—for example, surgery, sepsis from bacterial infection, or extensive antibiotic therapy. Drug-drug interactions are very important when azoles are used and require careful management and monitoring; such interactions are less important for the polyenes and echinocandins. Aspergillus infections are best treated with caspofungin; amphotericin B does not have activity against A terreus. Infections due to Fusarium or Scedosporium are best treated with voriconazole or posaconazole. Zygomycete infections are usually treated with liposomal variants of amphotericin B, although posaconazole may be a satisfactory alternative. Voriconazole is appropriate for P boydi infections, while a combination of high-dosage fluconazole and amphotericin B is recommended for Trichosporon infections. Burn patients should be classified as high risk or low risk upon admission to the burn unit. There is no consensus or strong evidence that prophylaxis with fluconazole or amphotericin B reduces the incidence of fungal infections in high-risk patients, but in severely burned patients there may be circumstances in which possible benefits outweigh the risks.
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antifungal agent. Clin Infect Dis. 2003; 36: 630–637. 89. Vehreschild JJ, Böhme A, Reichert D, et al. Treatment of invasive fungal infections in clinical practice: a multi-centre survey on customary dosing, treatment indications, efficacy and safety of voriconazole. Int J Hematol. 2008; 87: 126–131. 90. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole
vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. New Engl J Med. 2007; 356: 348–359. 91. Rachwalski EJ, Wieczorkiewicz JT, Scheetz MH. Posaconazole:
an oral triazole with an extended spectrum of activity (October) (CE) [published online ahead of print August 19, 2008]. Ann Pharmacother. 2008; 42(10): 1429–1438. DOI: 10.1345/ aph.1L005. 92. Pasqualotto AC, Denning DW. New and emerging treatments
97. Pappas PG, Rotstein CM, Betts RF, et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis. 2007; 45: 883–893. 98. Chen SCA, Sorrell TC. Antifungal agents. Med J. 2007; 187: 404–409. 99. Torres HA, Hachem RY, Chemaly RF, et al. Posaconazole: a broad-spectrum triazole antifungal. Lancet Infect Dis. 2005; 5: 775–785. 100. Denning DW. Echinocandin antifungal drugs. Lancet. 2003;
362: 1142–1151. 101. Cawley MJ, Braxton GR, Haith LR, Reilly KJ, Guilday
RE, Patton ML. Trichosporon beigelii infection: experience in a regional burn center. Burns. 2000; 26: 483–486. 102. Karabinis A, Hill C, Leclercq B, Tancrède C, Baume D,
for fungal infections. J Antimicrob Chemother. 2008; 61(suppl 1): i19–i30.
Andremont A. Risk factors for candidemia in cancer patients: a case-control study. J Clin Microbiol. 1988; 26: 429–432.
93. Mora-Duarte J, Bette R, Rotstein C, et al. Comparison of
103. Wey SB, Mori M, Pfaller MA, Woolson RF, Wenzel RP. Risk
caspofungin and amphotericin B for invasive candidiasis. New Engl J Med. 2002; 347: 2020–2029.
factors for hospital-acquired candidemia. A matched case-control study. Arch Intern Med. 1989; 149: 2349–2353.
94. Walsh TJ, Teppler H, Donowitz GR, et al. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. New Engl J Med. 2004; 351: 1391–1402.
104. Blumberg HM, Jarvis WR, Soucie JM, et al. Risk factors
95. Brown AL, Greig JR. Caspofungin versus amphotericin B for invasive candidiasis. New Engl J Med. 2003; 348: 1287.
105. Tufano F. Focus on risk factors for fungal infections in ICU
96. Reboli AC, Rotstein C, Pappas PG, et al. Anidulafungin versus fluconazole for invasive candidiasis. New Engl J Med. 2007; 356; 2472–2482.
106. Perfect JR, Klotman ME, Gilbert CC, et al. Prophylactic
for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. Clin Infect Dis. 2001; 33: 177–186. patients. Minerva Anestesiol. 2002; 68: 269–272. intravenous amphotericin B in neutropenic autologous bone marrow transplant recipients. J Infect Dis. 1992; 165: 891–897.
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F I F T E E N
INHALATION INJURY TISHA K FUJII, DO STEVEN J. SCHWARTZ, MD, ASSISTANT PROFESSOR OF ANESTHESIOLOGY, ADULT CRITICAL CARE AND SURGERY JOHNS HOPKINS HOSPITAL BRADLEY J. PHILLIPS, MD
OUTLINE 1. 2. 3. 4.
Introduction Pathophysiology Clinical Presentation Initial Evaluation and Management
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Diagnostic Tools Carbon Monoxide Cyanide Experimental Therapies Conclusion References
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INTRODUCTION Although children are less likely than adults to suffer from inhalation injury, smoke inhalation nonetheless remains a serious and life-threatening problem. Young children are particularly vulnerable to smoke and other toxins because they are less likely to escape a confined space and because they have a higher minute ventilation and lower physiological reserve compared to teens and adults. In addition, relatively smaller airways may be more severely affected by airway edema and obstructing material. Inhaled toxins cause one of the most critical injuries following a thermal insult—the syndrome of “inhalation injury.” The supraglottic region can be injured by both thermal and chemical components, whereas tracheobronchial and parenchymal injuries more commonly occur as a result of direct chemical damage. Inhalation injury is implicated in approximately 50% of all deaths from burn injury and has therefore become one of the most frequent causes of death. Early hypoxemia contributes to over 50% of smoke inhalation deaths, with carbon monoxide intoxication accounting for as many as 80% of fatalities.1 While progress has been made in improving the care and outcomes for burn patients, inhalation injury continues
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5. 6. 7. 8. 9. 10.
to challenge clinicians. Some reasons for the lack of formal data and studies in this area include the difficulty for a single center to perform a randomized, controlled, prospective trial as well as a lack of specific definitions and diagnostic criteria of the syndrome. A panel of experts at the Inhalation Consensus Conference evaluated the major unresolved issues regarding inhalation injury.1 Research priorities were ranked for both adults and children. Many topics were similar for both populations, with the need for diagnostic and grading criteria and Beta-2 agonist nebulizer therapy serving as the 2 top priorities. However, research into heparinized nebulizer therapy was considered the third most important topic in the pediatric population.1 Over time, the development of advanced pediatric burn care has led to the formation of specialized units and teams who recognize the unique physiology of and needs in caring for critically ill children. Approaching the pediatric population as comprising children and not merely small adults can prove critical to preventing therapeutic errors that can result in disastrous iatrogenic complications. Since studies regarding many aspects of inhalation injury in children are lacking, Palmieri et al conducted a retrospective review of children (0-18 years) admitted to 1 of 4 burn centers with a diagnosis of inhalation
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injury between 1997 and 2007.2 Data were gathered for 3 categories: demographics, injury characteristics, and hospital course. Inhalation injury was primarily diagnosed by bronchoscopy (71%), followed by clinical exam/ history (25%) and elevated carboxyhemoglobin levels (4%). A total of 850 patients were admitted during the study period; the mean age was 7 to 9 years +/- 0.2, with a preponderance of males. The mean TBSA burned was 48.6% +/- 0.9. Although the time from injury to admission was shorter in nonsurvivors (2.8 hrs +/- 0.6 vs 4.4 hrs +/- 0.4), they suffered more full-thickness burns (61.9%TBSA +/- 2.3%TBSA vs 35.4 +/- 1.0), had larger TBSA burns (68.5% +/- 1.9 vs 44.6% +/- 0.9), and spent more time on the ventilator. Significant differences in the group of nonsurvivors were seen with regard to burn size (P < .001), full-thickness burns (P < .001), and shorter hospital length of stay (LOS) (P < .001). The majority of nonsurvivors succumbed to respiratory dysfunction (36%), followed by sepsis (22%), multisystem organ failure (11%), and anoxic injury (11%). In conclusion, the major factors associated with increased mortality in pediatric patients suffering an inhalation injury were TBSA burned and fullthickness burns. In this review, mortality was 16%, and death occurred approximately 3 weeks following the initial injury. Although this was a retrospective study, it provides insight into the features that may assist clinicians with the difficult task of recognizing factors in inhalation injury which contribute to increased mortality.2
PATHOPHYSIOLOGY Injury to the tracheobronchial system is principally chemical in nature, as heat is primarily dispersed in the upper airways; direct thermal damage to the distal bronchi is seen only on occasion. Inhalants are classified as irritants, asphyxiates, or systemic toxins. Irritants such as ammonia, chlorine, sulfur dioxide, and carbon monoxide cause extensive cell injury within the respiratory tract. Every fire is unique with regards to the damage sustained to the respiratory system by the involvement of different chemicals and materials. For instance, combustion of cellulose, nylon, wool, silk, asphalt, and polyurethane increase the risk of hydrogen cyanide poisoning. Hydrogen cyanide, sulfide, and hydrocarbons are examples of asphyxiates which interrupt the delivery of oxygen to the tissues. Systemic toxins, meanwhile, can be absorbed through the respiratory endothelium. Damage correlates with the particular inhalants’ chemical activity, size, solubility, temperature, and the duration and concentration of exposure. Upper airway injuries tend to be caused by more irritating, water-soluble, larger particles, whereas substances of smaller size and lower water solubility cause alveolar and parenchymal injury. Although gasoline self-extinguishes
when the oxygen concentration falls below 15%, other substances may continue to undergo thermal decomposition and further decrease ambient oxygen tension. Hypoxemia can result from a decrease in inspired oxygen concentration at the scene of injury, a mechanical inability of gas exchange because of airway obstruction or parenchymal pulmonary disease, or the inhibition of oxygen delivery and tissue use by toxins. Although early hypoxemia contributes to mortality from smoke inhalation, it is the presence of multiorgan dysfunction, a common sequela of hypoxia, which leads to a substantial increase in morbidity and mortality. The immediate physiological response to smoke inhalation is a significant increase in bronchial blood flow and pulmonary lymph flow.3,4,5,6 Heat from a thermal insult initially denatures protein and leads to complement activation.3,7,8 This subsequently sets off a cascade of events involving histamine release, conversion of xanthine oxidase, and production of oxygen-derived free radicals.3,7,9,10,11,12 As a result, increased permeability to protein and elevated microvascular pressure cause the characteristic formation of edema seen in this type of injury. The lymph content in this situation is similar to serum, thus indicating that permeability at the capillary level is markedly increased. The resulting edema is associated with an increase in neutrophils, postulated to be the primary mediators of pulmonary damage through release of proteases and free radicals, which can produce conjugated dienes via lipid peroxidation.3,13,14,15 High concentrations of conjugated dienes present in pulmonary lymph fluid after inhalation injury support this theory.3,16,17,18 Besides edema formation, another hallmark of inhalation injury is the separation of ciliated epithelial cells from the basement membrane, followed by the formation of exudate within the bronchi.19,20 This protein-rich exudate eventually coalesces to form fibrin casts which can be difficult to clear with standard airway suction techniques. Oftentimes, bronchoscopic removal is necessary. These casts also contribute to barotrauma within localized areas of the lung by producing a “ball-valve” effect. During inspiration, airway diameter increases and air flows past the cast into the distal airways; when the diameter decreases during expiration, the cast effectively occludes the airway, thereby preventing inhaled air from escaping. The subsequent increase in volume leads to localized elevations in pressure that are associated with numerous complications, including pneumothorax and decreased lung compliance. The full extent of airway compromise may not be evident until 12 to 24 hours after the initial injury. For patients with extensive surface burns, chest wall restriction may occur because of eschar formation. Reflexive bronchoconstriction can further exacerbate this obstructive
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INHAL AT IO N I N J U RY process. Both inspiratory and expiratory resistance can be increased with premature closure of tertiary bronchi leading to hyperinflation and air trapping. Surfactant production and activity are both impaired, which worsens alveolar collapse and segmental atelectasis. Low-pressure pulmonary edema seems to also play an important role in the development of lung injury from smoke inhalation. Damage to the alveolar-capillary membrane increases permeability, with ensuing intravascular leakage into the pulmonary interstitium. Eventually, increased lymphatic flow exacerbates alveolar edema. Loss of compliance, further atelectasis, and increasing edema can result in severe ventilation-perfusion mismatch and hypoxemia. Pulmonary insufficiency related to inhalation injury can be broadly categorized as the result of thermal or chemical damage to the epithelial surfaces of the intrathoracic and extrathoracic airways. Pneumonia can then cause a secondary insult, sometimes days after the initial injury, leading to further cytotoxic damage. Accumulation of airway debris occurs due to impaired function of the cilia and the inflammatory cascade, which initiates neutrophil activation and leads to the destruction of alveolar-based macrophages and subsequent proliferation of bacteria. Overt respiratory failure with acute respiratory distress syndrome (ARDS) can develop at any time during this process. Ascertaining whether respiratory insufficiency is due to direct pulmonary injury or is the result of extensive metabolic, hemodynamic, and subsequent infectious complications related to the loss of integument surface can be challenging.
CLINICAL PRESENTATION The clinical presentation of inhalation victims can range from mild to severe. In most cases, the presentation of a person injured in a fire is obvious. When the patient is unable to provide a history, further details of the event and additional information can often be obtained from witnesses and first providers. Patients with inhalation injury may present with various airway and pulmonary symptoms. A strong suspicion of smoke inhalation should be raised with signs of singed facial hair or eyebrows, eye irritations, facial burns, and soot marks. Patients presenting with shortness of breath, hoarseness, cough, hemoptysis, or facial burns should be admitted for observation. If tachypnea, rhonchi, wheezes, rales, or production of carbonaceous sputum are also present, then admission to a monitored unit is more appropriate. It is imperative to recognize that it may take several hours for upper airway swelling to develop. In general, facial burns, hoarseness, stridor, carbonaceous sputum, or upper airway injury with mucosal lesions identified upon oral examination are indications to promptly perform intubation. Symptoms
indicative of lower respiratory tract injury include tachypnea, dyspnea, cough, decreased breath sounds, wheezing, rales, rhonchi, and chest wall retractions. Cyanosis is an unreliable marker of underlying hypoxemia because of the bright-red (“cherry-pink”) color imparted to the skin with elevated carboxyhemoglobin levels. Red retinal veins resulting from elevated venous oxyhemoglobin saturation may be noted on fundoscopic examination. Neurologic injury, which may not be immediately evident, can occur from hypoxemia either at the time of injury or from pulmonary dysfunction. In the burned child, fear, pain, and obtundation from inadequate perfusion may cloud the clinical picture. Performing serial examinations with repeated assessments may improve one’s ability to follow sensory changes and help guide initial resuscitation and stabilization. Victims who have not lost consciousness and with a normal neurologic examination on admission almost always recover without need for treatment beyond the administration of supplemental oxygen. Cyanide toxicity should be suspected in a child whose sensorium remains clouded despite oxygen therapy. The presence of coma following exposure to fire is nearly always indicative of carbon monoxide (CO) poisoning and should be promptly treated with 100% oxygen for at least 4 hours. Although cardiovascular injury itself is usually not a focus in inhalation injury, complex cardiovascular changes with surface burns may coexist with smoke inhalation. Heart rate, capillary refill, warmth of unburned extremities, and blood pressure should be promptly evaluated at presentation and closely followed during the initial stabilization. Carbon monoxide poisoning should be suspected in young people with healthy hearts who demonstrate ischemic changes on an EKG. Narrowed pulse pressure may indicate inadequate volume resuscitation and should necessitate reevaluation of a patient’s perfusion and fluid requirements. A low blood pressure is invariably a late finding of volume loss.
INITIAL EVALUATION AND MANAGEMENT The first priority when assessing a patient with a potential inhalation injury is to assess the airway and determine the need for intubation. Signs of partial obstruction, such as hoarseness, stridor, and expiratory wheezes, suggest a significant risk of progression to complete obstruction.21 A study by Rue et al in 1995 revealed that up to 80% of patients with inhalation injury required endotracheal intubation for inhalation injury, even if only for short-term airway management.22 In general, the indications for intubation in patients with inhalation injury are no different from general guidelines. The benefits of securing the airway with endotracheal intubation include provision of a secure airway, facilitating pulmonary toilet (suctioning, bronchodilator
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administration, etc), and addressing oxygenation and ventilation issues in a more direct fashion. As with all medical interventions, endotracheal intubation is not without risks, which include barotrauma, anatomical damage, increased risk of ventilator-associated pneumonia, tracheobronchitis, tracheomalacia, subglottic stenosis, and innominate or esophageal fistula formation. Until further studies are designed to answer the question of which patients might benefit from intubation, each patient must continue to be assessed individually. Once patients have been intubated, the clinician must decide which mode of mechanical ventilatory support to institute. This becomes particularly relevant when dealing with patients who are significantly hypoxemic or who meet criteria for acute lung injury (ALI) or ARDS. While the ARDSnet study in 2000 has changed the way such patients are now managed (lung protective strategy utilizing low tidal volumes and maintaining low plateau pressures), it remains unclear how the results of these studies can or should be applied to children with inhalation injury. Highfrequency oscillatory ventilation (HFOV), commonly used in neonates with ARDS, has been attempted in critically ill patients with ARDS as well, usually as a rescue therapy. Even though HFOV has been shown to consistently improve oxygenation, studies thus far have not revealed a consistency with improved outcomes. Specifically in burn patients, HFOV studies thus far include one animal experiment, a pediatric case report, and unpublished data from 19 adult burn patients with inhalation injury. HFOV is essentially a form of lung protective mechanical ventilation, which utilizes small tidal volumes at high frequencies (3-15 Hz), along with sustained high mean arterial pressures (30-40 cm H2O). Concerns of HFOV include (1) small airway obstruction due to edema/spasm and sloughing of mucosal carbonaceous debris; (2) trouble managing gas trapping and hypercapnea; (3) difficulty instituting adequate pulmonary toilet and other modalities (bronchodilators); and (4) consideration that ARDS due to inhalation injury may produce different pathophysiologic changes as compared to other diseases.23 Understandably, questions remain as to the utility of HFOV in burns, whether instituted as a rescue therapy or as an earlier approach. Of note, high-frequency percussive ventilation has shown proven benefit when instituted immediately following smoke inhalation.24-26 However, further studies are required to determine the exact role of this unique ventilatory modality. As with all patients, obtaining a complete medical history is important. The presence of underlying lung disease,
including simple asthma, can make a child more susceptible to airway irritation. It is valuable to remember that a child and an adult simultaneously exposed to smoke inhalation can present with notably different disease severity. Pediatric patients have an increased minute ventilation and a smaller body size compared to adults, which may increase toxin exposure. Children may also become disoriented more easily than adults, thus delaying escape from a poisonous environment and prolonging exposure. When documenting the history, it is important to explore the duration of exposure and, if possible, the actual toxins of exposure to help determine toxicity. A description of the mechanism of injury should include the location (ie, closed space) as well. With a smoky fire, any victim trapped in an enclosed space or exhibiting neurologic symptoms should receive 100% oxygen with a tight-fitting mask for at least 4 hours. Carbon monoxide, a colorless, odorless gas, is a major component of the smoke produced by incomplete combustion of carbon-containing compounds, such as wood, coal, and gasoline. A significant carbon monoxide exposure can occur even in the absence of flames, as with malfunctioning domestic equipment (eg, poorly ventilated space heaters, cooking gas) and exposure to automobile exhaust fumes, either from a suicide attempt (not uncommon amongst teenagers) or accidentally, from poor ventilation. A complete physical examination should be performed as soon as possible, with careful inspection of the mouth and pharynx. Although copious mucus production and carbonaceous sputum are signs of inhalation injury, their absence does not rule out the diagnosis. In addition to carboxyhemoglobin (CO-Hb) levels, arterial blood gases should be drawn on anyone with suspected smoke poisoning in order to more accurately assess oxygenation. One of the earliest indicators of pulmonary compromise is an abnormal PaO2 to FIO2 ratio (the P/F ratio). A normal ratio is 400 to 500, whereas patients with respiratory insufficiency may demonstrate a ratio of less than 300 (eg, a PaO2 of less than 120 with a FIO2 of 0.40). A ratio of less than 250 is an indication for vigorous respiratory support rather than merely increasing the inspired oxygen concentration. Once a patient is admitted to the burn unit, a standard approach to monitoring and further management should be followed. All patients should have continuous pulse oximetry. Cutaneous pulse oximetry uses a dual-wavelength technique of light refractance to measure hemoglobin saturation. Because it is falsely elevated by CO-Hb, all patients should have direct measurements of carboxyhemoglobin and oxyhemoglobin. Once the CO-Hb level has reached the reference range, pulse oximetry can be relied upon. All patients should have arterial blood gases drawn upon admission and as necessary thereafter, because CO-oximetry (arterial blood) uses a 4-wavelength technique of light
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INHAL AT IO N I N J U RY refractance which allows accurate measurements of carboxyhemoglobin, oxyhemoglobin, deoxyhemoglobin, and methemoglobin. However, arterial oxygen tension does not accurately reflect the degree of carbon monoxide poisoning or cellular hypoxia. The PaO2 level reflects the oxygen dissolved in blood that is not altered by the hemoglobin-bound carbon monoxide. Since dissolved oxygen makes up only a small fraction of arterial oxygen content, a PaO2 level within the reference range may lead to a serious underestimation of oxygen delivery and the associated degree of hypoxia at the cellular level. Most blood gas machines calculate the oxygen saturation based on the PaO2 level. Nonetheless, ABG measurements are useful to assess the adequacy of pulmonary gas exchange. Although the presence of a PaO2 level within the reference range may not exclude significant tissue hypoxia due to the effects of carbon monoxide, the presence of a low PaO2 (< 60 mm Hg) or hypercarbia (PaCO2 level of 50 mm Hg or greater) is indicative of significant respiratory insufficiency. The workup should also include basic chemistry and complete blood counts in order to correct and follow underlying electrolyte imbalances and aid in fluid management.
DIAGNOSTIC TOOLS Inhalation injury is often suspected with a clinical history of exposure to smoke in a closed space, facial burns, singed nasal hair, hoarseness, wheezing, and carbonaceous sputum. As useful as these signs and symptoms or a suggestive history may be for identifying inhalation injury, they all possess poor sensitivity and specificity. A routine chest radiograph is also insensitive in diagnosing inhalation injury but may be useful as a baseline measure in the event of clinical deterioration. In addition, computed tomography has a limited role in diagnosis, though it may help delineate such pathology as atelectasis, effusions, consolidation, or the presence of a pneumothorax. Therefore, more definitive methods, such as bronchoscopy and xenon 133 (133Xe) scanning, which are more than 90% accurate in determining the presence of inhalation injury, should be employed. The fiberoptic bronchoscope, perhaps the most useful and successful modality, allows direct visualization of the supraglottic airway and tracheobronchial tree.21 Bronchoscopic examination of the airway at the bedside (avoiding the need to transport critically ill patients) is usually sufficient to identify airway edema and inflammatory changes of the tracheal mucosa, such as hyperemia, mucosal ulceration, and sloughing. These findings, together with the clinical manifestations, can usually verify the presence of inhalation injury. Bronchoscopy can also be helpful in assisting with intubation during situations where
a difficult airway may be encountered. Complications of bronchoscopy are rare but include pneumothorax, infection, hypoxemia, arrhythmias, and death. Nonetheless, studies have determined that such complications are quite infrequent and the benefits usually outweigh the risks.3,27,28,29 At this time, bronchoscopy remains the gold standard for diagnosing inhalation injury, even though it has limitations in identifying the full extent of pulmonary parenchymal damage. Bronchoscopic findings, however, do not correlate with clinical severity but are an objective measurement of initial exposure. Ventilation scanning with 133Xe reveals areas of the lung that retain isotope 90 seconds after IV injection, thus indicating segmental airway obstruction. Although infrequently utilized for diagnosing inhalation injury, it may be valuable as an adjunctive modality in those cases where high clinical suspicion remains in the setting of an unremarkable bronchoscopic examination. It has been shown that utilizing both techniques produces 93% accuracy in the diagnosis of smoke inhalation.3
CARBON MONOXIDE Carbon monoxide intoxication is a particularly serious consequence of smoke inhalation and may account for up to 80% of fatalities. As such, carboxyhemoglobin level should be measured in all patients. Elevated levels or any clinical symptoms of CO poisoning are presumptive evidence of poisoning. In very smoky fires, CO-Hb levels of 40% to 50% may be reached after only 2 to 3 minutes of exposure. Neurologic dysfunction of carbon monoxide poisoning is classified into 2 syndromes: (1) persistent neurologic sequelae, which may improve over time, and (2) delayed neurologic sequelae, which occur after an initial period of improvement.30 Up to one-third of patients with significant carbon monoxide exposure will develop long-term neurologic deficits. Carbon monoxide binds to iron-containing compounds such as hemoglobin and cytochromes. Compared to molecular oxygen, CO possesses a much higher affinity (210 times as much) for the binding site on the hemoglobin moiety.30 By causing a leftward shift of the oxyhemoglobin dissociation curve, a diminished amount of oxygen is off-loaded at the cellular level. Administering 100% oxygen decreases the elimination half-life of carbon monoxide, which is dependent on oxygen tension. It should be kept in mind that smokers may have baseline CO levels up to 5% to 10% and therefore may experience worsening symptoms for the same level of exposure as nonsmokers. Also, blood carboxyhemoglobin levels may underestimate the degree of CO intoxication because of oxygen administration before arrival to the hospital. Unfortunately,
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low or normal levels do not rule out inhalation injuries, nor do they indicate the severity of poisoning or assist with determining treatment or prognosis.31 Victims who remain comatose once CO-Hb levels have returned to normal carry a poor prognosis. The use of nomograms to extrapolate levels to the time of rescue has been shown to provide greater prognostic value. Factors that contribute to the extent of injury include the duration of exposure, concentration of CO, and premorbid condition of the victim.32 The symptoms in relation to carboxyhemoglobin concentration are as follows:3,33,34 • Carboxyhemoglobin level of 0%–10% -Usually asymptomatic • Carboxyhemoglobin level of 10%–20% -Mild headache, atypical dyspnea • Carboxyhemoglobin level of 20%–30% -Throbbing headache, impaired concentration • Carboxyhemoglobin level of 30%–40% -Severe headache, impaired thinking • Carboxyhemoglobin level of 40%–50% -Confusion, lethargy, syncope • Carboxyhemoglobin level of 50%–60% -Respiratory failure, seizures • Carboxyhemoglobin level > 70% -Coma, death Initial management of suspected CO toxicity includes supportive care and 100% oxygen. The basis for supplemental oxygen administration is the decreased half-life from 90 minutes (room air) to 20 to 30 minutes (high-flow O2).35 Although enthusiasts for hyperbaric oxygen treatment (HBOT) consider it a standard of care for CO poisoning, many physicians are skeptical. Several trials have been performed exploring the effects of hyperbaric therapy on CO poisoning; of the 7 randomized controlled trials, 4 did not find HBO beneficial in terms of improving neurologic sequelae, 2 reported a benefit, and 1 did not state outcomes.32 Furthermore, when associated with a major burn injury, transport to a hyperbaric chamber may delay definitive burn care. One must also weigh the benefit with such possible complications as emesis, seizures, eustachian tube occlusion, aspiration, agitation requiring restraints or sedation, hypotension, tension pneumothorax, and cardiac arrhythmia or arrest. A recent retrospective study by Hampson et al 36 has revisited the question of HBOT in carbon monoxide poisoning. The records of 1505 patients with acute CO poisoning from 1978 through 2005 who received HBOT were reviewed. This study revealed a mortality rate similar to that previously reported, at 2.6%. Factors associated with increased mortality included decreased level of consciousness, fire as the source of CO, carboxyhemoglobin level, presence of endotracheal intubation during
HBOT, and severe metabolic acidosis. In a follow-up paper for the same group of patients, Hampson et al determined an increased risk of long-term mortality in adult survivors of acute carbon monoxide poisoning who were treated with HBOT.37 While these results do not definitively answer questions, they do provide a basis for further investigation. The issue of whether, and at what time in the progression of CO poisoning, HBOT is of value will undoubtedly continue to be studied and debated.
CYANIDE Approximately one-third of patients with smoke inhalation from domestic fires will be exposed to cyanide (CN). Although laboratory confirmation may be delayed, CN levels should be sent at time of admission, even though the clinical significance of such levels is unknown. Persistent neurologic dysfunction unresponsive to supplemental oxygen, cardiac dysfunction, hypoxemia, unexplained metabolic acidosis, and severe lactic acidosis, particularly in the presence of high mixed venous oxygen saturation, are indicative of CN intoxication. Moreover, the unique odor of bitter almonds has been described with CN toxicity as well.3,38,39 CN causes tissue asphyxiation through inhibition of intracellular cytochrome oxidase. CN blocks the final step in oxidative phosphorylation and prevents mitochondrial oxygen use. Affected cells convert to anaerobic metabolism, and lactic acidosis ensues. The central nervous system (CNS) and the myocardium are most sensitive to cellular hypoxia. The CNS reacts to low concentrations of CN by inducing tachypnea and clinically apparent hyperventilation, which increases further exposure. Death is subsequently due to respiratory center paralysis. In a setting consistent with potential CN exposure, one should consider instituting specific empiric therapy while awaiting laboratory confirmation of the diagnosis. Therapy with CN antidotes versus aggressive supportive care remains controversial. The basis for treatment is to oxidize hemoglobin to methehemoglobin, which preferentially binds CN to form cyanmethemoglobin. This then dissociates and is metabolized by hepatic mitochondria to thiocyanate, which is excreted in the urine.40 Since amyl nitrate or sodium nitrate can both cause cardiac irritability and hypotension, their use should be carefully considered in an often hypovolemic burn patient.
EXPERIMENTAL THERAPIES Antithrombin (AT) III is a serine protease inhibitor produced in the liver which complexes with and inhibits
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INHAL AT IO N I N J U RY thrombin activity. Besides being a major physiologic anticoagulant, it also possesses anti-inflammatory properties. Studies thus far have primarily focused on AT for congenital AT III deficiency, sepsis, and DIC. Thermal injury is a type of acquired AT deficiency due to multiple factors. The deficiency is usually seen postburn days 1 through 5 and is an independent predictor of length of stay and mortality.41 Studies in burn patients have been performed, and there is promise in the potential of AT for improving outcomes in thermal injury (perhaps inhalation injury as well); however, further research is required in order to determine whether this will provide clinicians with another option in the challenging treatment of such patients. Tocopherols are scavengers of reactive oxygen and nitrogen species. Large burns are associated with significant tissue oxidation and alpha tocopherol depletion. In addition, studies in animals have shown depletion of liver stores of vitamin E with skin and lung injury.42 Morita et al subsequently studied nebulized and oral tocopherol in an animal model and discovered they were both effective in reducing the associated pathophysiologic responses of burns and smoke inhalation.43,44 These studies provide interesting thoughts into the use of tocopherol for patients suffering burn and inhalation injury; however, once again, further studies are necessary before any recommendations can be made. Since smoke inhalation injury is characterized by inflammation with oxidative damage, interest in the possible beneficial effects of vitamin C is increasing. In 2000 Tanaka et al performed a clinical trial of severely burned patients who were given high-dose vitamin C during resuscitation.45 Thirty-seven patients with an average > 30% TBSA burn received either placebo or 66 mg/kg/h vitamin C for 24 hours. No differences in heart rate, blood pressure, base deficit, central venous pressure, or urine output were noted. Although the resuscitation volume after 24 hours was 40% lower in the vitamin C group, there was no difference in mortality. Of note is that 73% of these patients were diagnosed with inhalation injury by bronchoscopy at admission, with an equal distribution in both groups. There was no difference in PEEP or FIO2 requirements in the first 96 hours, although a significant difference in PaO2/FIO2 was noted from 18 through 96 hours, as well in as the number of ventilator days.45 A study by Dubick et al from San Antonio revealed similar findings in a 40% TBSA burn sheep model comparing placebo versus highdose vitamin C (10 gm/first 500 cc resuscitation volume, followed by a 15 mg/kg infusion x 48 hours), with a 40% decrease in total fluid requirements noted.46 Another study exploring the effects of vitamin C on smoke inhalation injury in 42 dogs by Jiang showed a reduction in extravascular lung water volume, PVR, carboxemia, hypoxia, and acidosis.47 More impressive was the reduction in mortality
from 47.6% in the control group to 19.1% for the treatment group. Unfortunately, this study was only available in abstract form and utilized a treatment cocktail that included other substances. Therefore, conclusions are difficult to ascertain, and the role of vitamin C in inhalation injury remains elusive at this time.47,48 Steroids have been studied for years in the treatment of ARDS due to their anti-inflammatory effects. Concerns regarding the risks, such as infections, hypothalamic axis dysfunction, neuromuscular dysfunction, and osteoporosis, however, have tempered enthusiasm for their use. Despite multiple studies, steroids have not consistently proven beneficial in patients with ARDS. However, hope springs eternal, and proponents of steroid therapy continue to advocate their use. A recent systemic review and meta-analysis reexplored the controversy of whether corticosteroids are beneficial in acute lung injury and ARDS.49 Five cohort studies and 4 randomized, controlled trials revealed a trend toward improvement in ventilator-free days, ICU stay, PaO2/FIO2, multiple organ dysfunction syndrome and lung injury scores, and mortality, without an increase in any significant complications. The authors concluded that these findings suggest a benefit of steroids in such patients, although confirmation is required by further studies.49 Research involving steroids for inhalation injury has thus far been disappointing, and further research is necessary before any conclusions can be drawn. The characteristic finding of alveolar fibrin deposition in ALI/ARDS is also seen in burn patients. Fibrin contributes to ventilation perfusion mismatch, atelectasis (through inhibition of surfactant), and attraction of inflammatory cells to the injury site. As such, anticoagulants have been theorized to possibly play a role in the pathophysiology of smoke inhalation. A study by Enkhbaatar et al revealed that an aerosolized fibrinolytic agent (tPA) improved pulmonary function in an ovine model of ALI following inhalation injury.50 In 1988, Brown et al first reported on aerosolized heparin with and without dimethyl sulfoxide (DMSO) for smoke-inhalation-induced ALI in an ovine model. Decreased mortality was seen with heparin, and the effects were potentiated with the addition of DMSO.51 A study by Murakami et al in 2003 of smoke inhalation in an ovine model revealed heparin nebulization to be beneficial;52 however, another similar study of ARDS from smoke inhalation did not show any benefit with regards to improvement in pulmonary function. These findings were explained by the presence of decreased antithrombin levels in the bronchoalveolar lavage (BAL) of animals with ARDS.53 In children with massive burns and inhalation injury, Desai et al in 1998 found that nebulized heparin along with aerosolized N-acetylcysteine significantly reduced the rates of reintubation, atelectasis, and mortality.54 Thus far, the potential
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benefits of heparin for inhalation injury have been limited to animal and single-center studies. As with most other promising treatments, further studies need to be performed to better understand the effects before any recommendations can be postulated. Inhaled nitric oxide (INO) is utilized as a treatment modality for pulmonary hypertension, particularly in neonates. It is also indicated for hypoxemic respiratory failure in newborns. INO is a potent, short-acting pulmonary vasodilator which increases cyclic guanosine monophosphate in smooth muscle. Risks associated with its use include methemoglobinemia and rebound hypoxemia after discontinuation. Use of INO in animal models with smoke inhalation revealed decreased pulmonary hypertension associated with inhalation injury, with variable effects regarding improvement of pulmonary shunting. Human studies include 2 adult and 1 children single-institution series that included patients with large burns and inhalation injury with respiratory failure. These studies demonstrated increased PaO2/ FIO2 in two-thirds of patients, with a marginal improvement in the oxygenation ratio in the remainder of patients. Responses were usually seen within 60 minutes at doses of 20 ppm. No complications were reported, and survival was more common in those who demonstrated increases in the PaO2/FIO2 ratio.55,56,57 A 2007 BMJ meta-analysis showed no survival benefit of INO in critically ill patients with oxygenation failure, despite an improvement in oxygenation.58 With respect to burn patients with inhalation injury, INO improved oxygenation in some patients at doses of 5 to 20 ppm. This has prompted consideration for use in those patients who have otherwise failed conventional measures. Until further studies can explore the effects of INO for this population, no conclusions can be drawn. Currently, the management and treatment for inhalation injuries is primarily supportive. The effort to develop new strategies and techniques continues to expand and includes areas of research into systemic as well as local response to thermal injuries. The core to such research is a better understanding of the basic but complex pathophysiology of the body’s response to this type of presentation as well as the way in which the respiratory system responds. Much of the emphasis is placed on trying different methods of ventilatory support, focusing on improving ways to oxygenate and ventilate the child. The challenge involves optimizing these parameters while maintaining low airway pressures to minimize barotrauma. Methods such as HFPV and airway pressure release ventilation (APRV) appear to recruit alveoli and allow efficient gas exchange while simultaneously using lower peak airway pressures when compared to conventional mechanical ventilation.59 For severe respiratory failure, extracorporeal membrane oxygenation (ECMO) has been used in
both the pediatric and adult population.60 Another new and experimental technique called arteriovenous carbon dioxide removal (AVCO2R) utilizes an extracorporeal membrane gas exchanger to remove CO2 while oxygen diffuses across the native alveoli by low-frequency positive-pressure ventilation.61 This method has been shown to significantly reduce ventilatory requirements and improve arterial blood pH levels.62 As overall patient survival continues to improve, pulmonary function as the child grows and develops is another challenge. In one study, hyperreactive airways along with inflammatory changes in the bronchial mucosa and elevated inflammatory cytokines have been shown to last up to 6 months, even with normal pulmonary function tests.63 Other studies have shown development of restrictive and obstructive patterns on pulmonary function testing, with no appreciable return to normal lung function.64 Still, further studies have revealed that children are quite resilient and exhibit a relatively good functional status, albeit with higher respiratory rates; moreover, some adults have shown no evidence of exercise compromise or any alteration in function post–inhalation injury.65 Determining survival from inhalation injuries and returning to premorbid functioning is dependent on further investigation involving trials of newer agents and novel ventilatory strategies.
CONCLUSION The presence of smoke inhalation substantially increases morbidity and mortality of burn patients. Despite significant advances in overall care, the specific management of inhalation injury remains supportive. Furthermore, direct treatments remain elusive, partly due to the complexities involved in balancing a lung protective strategy with the risks of causing damage to at-risk pulmonary tissue. To further complicate matters, there are the multiple confounding factors commonly encountered in burn patients, such as infection, sepsis, and the hypermetabolic response. The long-term outcome of children with inhalation injury is unknown with regards to general health measures, quality of life, physiological effects, and social adaptation. Small case studies comprise the majority of data on longterm pulmonary function after exposure. The available literature reveals that airway obstruction may occur for a prolonged period of time following smoke inhalation and that the extent of obstruction is proportional to the amount inhaled.66 In particular, the effects on children are concerning since lung development continues until midchildhood. Until further studies are designed to determine the long-term physical and psychosocial effects of inhalation injury, caregivers must continue to strive for the best possible outcomes to allow these children to live happy and productive lives.
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