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Emergency Treatment of Severely Burned Pediatric Patients: Current Therapeutic Strategies Gerd G. Gauglitz; David N. Herndon; Marc G. Jeschke

Pediatr Health. 2008;2(6):761-775. ©2008 Future Medicine Ltd. Posted 02/05/2009

Abstract and Introduction

Abstract

Burn trauma represents a devastating injury and remains as one of the leading causes of mortality and morbidity in children. Effective prevention strategies, advances in therapeutic techniques, based on an improved understanding of fluid resuscitation, appropriate infection control and improved treatment of inhalation injury, enhanced wound coverage, better nutritional regimens, advanced support of the hypermetabolic response to injury and improved glucose control, have significantly improved the clinical outcome of this unique patient population over the past years. This article aims to outline the current and emerging therapeutic strategies for the treatment of severely burned pediatric patients in the emergency department or initial phase of the intensive care unit.

Introduction

Burn trauma remains to be a leading cause of mortality and morbidity in children. Over 440,000 children receive medical attention for burn injuries each year in the USA.[1] Children younger than 14 years of age account for nearly half of all emergency department-treated thermal burns.[2] With approximately 1100 children dying of burn-related injuries in the USA every year,[2] severe burns represent the third most common cause of death in the pediatric patient population,[3] and account for a significant number of hospital admissions in the USA.[2,4] The devastating consequences of burns have been recognized by the medical community and significant amounts of resources and research have been dedicated, successfully improving these dismal statistics. Recent reports revealed a dramatic decline in burn-related deaths and hospital admissions in the USA over the last 20 years, mainly resulting from effective prevention strategies, which decreased the number and severity of burns.[5-7] Advances in therapy strategies - based on improved understanding of resuscitation - more appropriate infection control and improved treatment of inhalation injury, enhanced wound coverage and better support of hypermetabolic response to injury, have further improved the clinical outcome of this unique patient population over the past years.

Initial Assessment and Emergency Treatment of the Pediatric Burn Patient

In general, the initial management of the burn patient should be the same as for any other trauma patient, with special attention directed to the airway, breathing, circulation (ABC) and cervical spine immobilization according to the guidelines of the American College of Surgeons Committee on Trauma and the Advanced Trauma Live

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Support Center.[8] The algorithms for trauma evaluation should be diligently applied to the burn patient and the primary survey begins with the ABCs and the establishment of an adequate airway.[9] However, prior to any specific treatment, the patient must be removed from the source of injury and the burning process stopped. Always suspect an inhalation injury and administer 100% oxygen by face mask. As the patient is removed from the source of injury, care must be taken that the rescuer does not become another victim.[6] All care givers should be aware of the possibility that they may be injured by contact with the patient or the patient's clothing. Universal precautions, including wearing gloves, gowns, mask and protective eyewear, should be used whenever there is likely to be contact with blood or body fluids. Burning clothing should be removed as soon as possible to prevent further injury to the patient.[10] Removing all rings, watches, jewelry and belts is critical as they retain heat and can produce a tourniquet-like effect causing vascular ischemia.[11] If water is readily available, it should be poured directly on the burned area, since early cooling can reduce the depth of the burn and reduce pain. However, cooling measures must be used with caution to avoid hypothermia with its clinical sequelae. Ice or ice packs should never be used since they may cause further injury to the skin and induce hypothermia. Initial management of chemical burns consist of removing the saturated clothing, brushing the skin if the agent is a powder and irrigation with copious amounts of water.[11] Irrigation with water should continue from the scene of the accident through the emergency evaluation in the hospital. Efforts to neutralize the chemicals are contraindicated owing to the additional generation of heat, which can contribute to further tissue damage. In addition, the rescuer must be careful not to come into contact with the chemical. Removal of the victim from contact with an electrical current is best accomplished by turning off the current and by utilizing a nonconducting device to separate the victim from the source.[11] The possibility of a spinal cord injury needs to be anticipated in patients who have been involved in an explosion or deceleration accident. Appropriate cervical and thoracolumbal spine stabilization must be accomplished by whatever means necessary, including cervical collars to keep the head immobilized until the condition can be evaluated.

Exposure to heated gases and smoke resulting from the combustion of a variety of materials results in damage to the respiratory tract. Direct heat to the upper airways results in edema formation, which may obstruct the airway. Any stridor, wheezing, hoarseness and/or tachypnea may be a sign of airway compromise. Tracheal tugging, carbonaceous sputum, soot around the patient's airway passages and singed facial or nasal hair may suggest an impending problem and requires immediate attention. As in any trauma, progression to the next step in the primary survey is delayed until a proper airway is established and maintained. Objective measurements of breathing include respiratory rate, respiratory effort, breath sounds and skin color reflect oxygenation.[9,12] A respiratory rate of less than 10 or greater than 60 is a sign of impending respiratory failure.[12] Use of accessory muscles, manifested by supraclavicular, intercostal, subcostal or sternal retractions, as well as the presence of grunting or nasal flaring, indicate increased work of breathing.[9] Auscultation of breath sounds provides a clinicaldetermination of tidal volume. Skin color deteriorates from pink, to pale, to mottled, to blue as hypoxemia progresses.[12] These signs need to be followed throughout the primary survey to avoid respiratory failure. Impaired ventilation and poor oxygenation may be due to smoke inhalation or carbon monoxide intoxication. A total of 100% humidified oxygen administered using a face mask should be given initially to all patients; even no obvious signs of respiratory distress are present. Children with probable respiratory failure should receive aggressive, rapid and definitive airway management. Oral intubation with the largest appropriate endotracheal tube and nasal intubation represent the preferred method for obtaining airway access and should be accomplished early and by the most experienced clinician if impending respiratory failure or ventilatory obstruction is anticipated.[9]

Cardiac assessment in the burned child begins with the assessment of peripheral, followed by the central pulses. Vital signs may be difficult to obtain in the burned victim, especially since burned extremities may impede the ability to obtain a blood pressure reading by a sphygmomanometer (blood pressure cuff). In these situations arterial lines, particularly femoral lines, can be placed to monitor continuous blood pressure readings. To assess for adequate perfusion, the color of skin and capillary refill in nonburned sites can be utilized.

While cardiac dysfunction after severe thermal injury is a well-documented complication, persistent tachycardia postinjury, despite resuscitation efforts, should alert the medical staff to a missed injury. Intravenous access should be established using two large-bore peripheral intravenous catheters, preferably through nonburned viable tissue. If there is no nonburned tissue, then placement of intravenous catheters through burned skin is justified early postburn, when the eschar is still sterile, since delays in resuscitation carry a high mortality.[13] Peripheral, large caliber intravenous catheters provide excellent access and can actually administer greater volumes of fluid owing to a diminished resistance of the catheter secondary to a shorter length. Central venous access may be difficult to establish with the crowding of people around the torso of a newly arrived trauma victim, and also carrys a risk of pneumothorax or an inability to control bleeding from inappropriate placement. In children, it can be particularly difficult to establish intravenous access and the intraosseous route can be used emergently for fluids and medicines. An intraosseous intramedullary catheter can be placed a few fingerbreadths below the tibial tubercle and is highly effective for delivering 180-200 cm3/h of fluid, whereby establishing long-term access. The most serious complication after intraosseous catheterization represents the inadvertent administration of fluid into the muscle compartments, leading to dangerously high pressures. In older children, intraosseous catheterization is more difficult to accomplish and infusion rates are inadequate.




Therefore, if required, a saphenous vein cutdown is the right approach.[14]

Since burn injury may distract the healthcare provider from recognizing a potentially lethal neurologic injury, a rapid neurological survey should be completed. The burn patient should be asked to move their extremities and a Glasgow Coma Score should be assessed to document the patient's level of consciousness. Finally, a nasogastric tube, or an orogastric tube in the intubated patient, should be inserted in all patients with major burns in order to decompress the stomach.[15] Decompression immediately following any major burn is essential to help treat the paralytic ileus often observed postburn,[16] and the trauma patient will often swallow considerable amounts of air to further distend the stomach. In addition, decompression is particularly important for patients who may be transported at high altitudes to a specialized burn center.[15] A urinary catheter should also be placed, not only to decompress the bladder, but also in order to fully evaluate the patient's response to resuscitation.

One of the most important steps is to provide adequate pain control and relieve the patient from pain and stress. Pain medications should be carefully administered to not overdose and induce adverse side effects. In addition, the amount of pain medication should be reasonable and be based on the burn size and subjective pain of the patient.[17] The dosing of pain medication should be according to pediatric guidelines.

Fluid Resuscitation

Severe burn causes significant hemodynamic changes, which must be managed carefully to optimize intravascular volume, maintain end-organ tissue perfusion and maximize oxygen delivery to tissues.[14] Massive fluid shifts after severe burn injury result in the sequestration of fluid in both burned and nonburned tissue.[18] The release of proinflammatory mediators early on postburn, such as histamine, bradykinin and leukotriene, leads to increased microvascular permeability, generalized edema and burn shock, a leading cause for mortality in severely burned patients.[19-21] Therefore, the early and accurate fluid resuscitation of patients with major burns is critical for survival.[13] Calculations of fluid requirements are based on the amount of body surface involved in second- or third-degree burns (not in first-degree burns). The rule-of-nines (Figure 1) is commonly utilized to estimate the body surface area (BSA) burned, but this does have limitations in the pediatric patient population where the head is proportionally larger than the body when compared with the adult. A more accurate assessment can be made of the burn injury, especially in children, by using the Lund and Browder chart, which takes into account changes brought about by growth (Figure 2). Many different fluid-resuscitation formulas have been suggested, each can be used effectively in order to resuscitate a severe burn. The various formulas differ in the amount of crystalloid and colloid given, as well as in the tonicity of the fluid.[14] The American Burn Association (ABA) has recently published practice guidelines on burn-shock resuscitation in order to review the principles of resuscitation after burn injury, including type and rate of fluid administration and the use of adjunct measures. It presents an excellent approach for the initial treatment of burn patients.[22] However, it is important to mention that there is no formula that will accurately predict the volume requirements of the individual patient; all resuscitation formulas are designed to serve as a guide only. The modified Brooke and Parkland formulas,[23] are the most commonly used early resuscitation formulas throughout the world.[24] They use 2-4 ml/kg/% BSA burn of lactated Ringers solution. The calculated needs are for the total fluids to be administered over 24 h.[21] In children, maintenance requirements must be added to the resuscitation formula. For this reason, we recommend the Shriners Burns Hospital-Galveston formula, which calls for an initial resuscitation with 5000 ml/m2 BSA burn/day plus 2000 ml/m2 BSA/day of lactated Ringers solution.[25] For both formulas, the first half is administered within the first 8 h after the burn, and a quarter of each in the next 16 h. Intravascular volume status must be still re-evaluated on a frequent basis during the acute phase. Fluid balance during burn-shock resuscitation is typically measured by an hourly urine output via an indwelling urethral catheter. It has been recommended to maintain a urine output of approximately 0.5 ml/kg/h in adults[26] and between 0.5 and 1.0 ml/kg/h in patients weighing less than 30 kg;[26] however, there have been no clinical studies identifying the optimal hourly urine output to maintain vital organ perfusion during burn-shock resuscitation. Diuretics are generally not indicated during the acute resuscitation period. It is imperative to avoid over-aggressive resuscitation, particularly in small children below the age of 4 years, which may potentially lead to increased extravascular hydrostatic pressure and pulmonary edema.[6] This is especially important in patients who have a concomitant inhalation injury, because they will also have increased pulmonary vascular permeability. Patients with high-voltage electrical burns and crash injuries with myoglobin and/or hemoglobin in the urine have an increased risk of renal tubular obstruction. Therefore, in these patients, sodium bicarbonate should be added to intravenous fluids in order to alkalinize the urine, and urine output should be maintained at 1 and 2 ml/kg/h as long as these pigments are in the urine.[11] The addition of an osmotic diuretic, such as mannitol, may be needed to assist in clearing the urine of these pigments. Since large volumes of fluid and electrolytes are administered both initially and throughout the course of resuscitation, it is important to obtain baseline laboratory measurements of complete blood count, electrolytes, glucose, albumin and acid-base balance.[28] Crystalloid, in particular, lactated Ringer's solution, is the most popular resuscitation fluid currently utilized.[25] Proponents of the use of crystalloid solutions alone for resuscitation report that other solutions, specifically colloids, are not better and are certainly more expensive than crystalloids for maintaining intravascular volume following burn




trauma.[29] Perel and Roberts identified 63 trials comparing colloid and crystalloid fluid resuscitation across a wide variety of clinical conditions and found no improvement in survival when resuscitated with colloids.[30] The use of albumin in burns and critically ill patients has recently been challenged by the Cochrane Central Register of Controlled Trials, which demonstrated no evidence that albumin reduces mortality in this particular patient population when compared with cheaper alternatives, such as saline.[31] Vincent and colleagues demonstrated in a cohort, multicenter, observational study that albumin administration was associated with decreased survival in a population of acutely ill patients when compared with those who did not receive any albumin at any time through out their intensive care unit (ICU) stay. It is worth noting that in this study, albumin-receiving patients were more severely ill than patients who did not receive any albumin.[32] However, most burn surgeons agree that burn patients with very low serum albumin during burn shock may benefit from albumin supplementation to maintain oncotic pressure.[33]

Figure 1.

Estimation of burn size utilizing the rule-of-nines. BSA = Body surface area. Reproduced with permission from [138].




Figure 2.

Estimation of burn size utilizing the Lund and Browder method. Reproduced with permission from [138].

Sepsis

Sepsis is one of the leading causes of morbidity and mortality in critically ill patients.[34] Severely burned patients are markedly susceptible to a variety of infectious complications.[35] There are excellent criteria (fever, tachycardia, tachypnea and leukocytosis) for the diagnosis of infection and sepsis in most patients. However, the standard diagnoses for infection and sepsis do not really apply to burn patients, since these patients, according to the definitions of the ABA Consensus Conference to Define Sepsis and Infection in Burns, already suffer from a systemic inflammatory response syndrome (SIRS) due to their extensive burn wounds.[36] Consequently, experts in the field of burn care and/or research establish definitions and guidelines for the diagnosis and treatments of wound infection and sepsis in burns ( Box 1 ). However, it is important to realize that these definitions are sensitive, but not specific, screening tools that should be primarily used for research purposes, and any direct application to the clinical setting must take into account the dynamic and continuous nature of the sepsis disease process and thestatic and categorical nature of the definitions. In addition, clinical parameters used to define SIRS and organ dysfunction are greatly affected by the normal physiologic changes that occur as children develop.[37] A description of pediatric-specific definitions for SIRS, sepsis, severe sepsis and septic shock based on age-specific risks for invasive infections, age-specific antibiotic treatment recommendations and developmental cardiorespiratory physiologic changes has been recently published by Goldstein and colleagues.[38]




Inhalation Injury

Even though mortality from major burns has significantly decreased during the past 20 years, inhalation injury still constitutes one of the most critical concomitant injuries following thermal insult. Approximately 80% of fire-related deaths result not from burns, but from the inhalation of the toxic products of combustion, and inhalation injury has remained associated with an overall mortality rate of 25-50% when patients require ventilator support for more than 1 week following injury.[39,40] Therefore, the early diagnosis of bronchopulmonary injury is critical for survival and is primarily conducted clinically, based on a history of closed-space exposure, facial burns and carbonaceous debris in mouth, pharynx or sputum.[41] Evidence-based experience on diagnosis of inhalation injury, however, is rare. Chest x-rays are routinely normal until complications, such as infections, have developed. Hence, bronchoscopy of the upper airway should be the standard diagnostic method used on every burn patient. Gamelli and others established a grading system of inhalation injury (0, 1, 2, 3 and 4) derived from findings at initial bronchoscopy and based on Abbreviated Injury Score criteria.[42] Bronchoscopic criteria that areconsistent with inhalation injury included airway edema, inflammation, mucosal necrosis, presence of soot and charring in the airway, tissue sloughing or carbonaceous material in the airway. The treatment of inhalation injury should start immediately with the administration of 100% oxygen administered via a face mask or nasal cannula. Maintenance of the airway is critical. As mentioned previously, if early evidence of upper airway edema is present, early intubation is required because the upper airway edema normally increases over 9-12 h. However, prophylactic intubation without good indication should not be performed.

Advances in ventilator technology and treatment of inhalation injury have resulted in some improvement in mortality. A multicenter, randomized trial in patients with acute lung injury and acute respiratory distress syndrome demonstrated that mechanical ventilation with a lower tidal volume than that traditionally utilized resulted in decreased mortality and increased the number of days without ventilator use.[43] Pruitt's group demonstrated that since the advent of high-frequency ventilation, mortality has decreased to 29% from 41% reported in an earlier study.[44] The management of inhalation injury consists of ventilatory support, aggressive pulmonary toilet, bronchoscopic removal of casts and nebulization therapy.[14] Nebulization therapy can consist of heparin, α-mimetics or polymyxin B and is applied between two- and six-times daily. Pressure-control ventilation with permissive hypercapnia is a useful strategy in the management of these patients, and pCO2 levels of as much as 60 mmHg can be well tolerated if arrived at gradually. Prophylactic antibiotics are not indicated, but imperative with documented lung infections. Clinical diagnosis of pneumonia includes two of the following:[36] chest x-ray revealing a new and persistent infiltrate, consolidation or cavitation; sepsis (as defined in Box 1 ) and/or a recent change in sputum or purulence in the sputum, as well as quantitative culture. Clinical diagnosis can be modified after utilizing microbiologic data into three categories according to the ABA Consensus Conference to Define Sepsis and Infection in Burns.[36] Empiric choices for the treatment of pneumonia prior to culture results should include coverage of methicillin-resistant Staphylococcus aureus and Gram-negative organisms such as Pseudomonas and Klebsiella.[45]

Burn-wound Excision

Methods for handling burn wounds have changed in recent decades and are similar in adults and children. Increasingly aggressive early tangential excision of the burn tissue and early wound closure primarily by skin grafts has led to significant improvement in mortality rates and substantially lower costs in this particular patient population.[14,46-49] Furthermore, early wound closure has been found to be associated with a decreased severity of hypertrophic scarring, joint contractures and stiffness, and promotes quicker rehabilitation.[14,46] Techniques of burn-wound excision have envolved substantially over the past decade. In general, most areas are excised with a hand skin-graft knife or powered dermatome. Sharp excision with a knife or electrocautery is reserved for areas of functional cosmetic importance, such as the hand and face. In partial thickness wounds, an attempt is being made to preserve viable dermis, whereas in full thickness injury, all necrotic and infected tissue must be removed, thus leaving a viable wound bed of either fascia, fat or muscle.[50] The techniques that are mainly utilized are discussed below.

Tangential Excision

This technique was first described by Janzekovic in the 1970s and requires repeated shaving of deep dermal partial thickness burns using a Braithwaite, Watson, Goulian or dermatome set at a depth of 5-10/1000 inches until a viable dermal bed is reached, which is clinically achieved by punctuate bleeding from the dermal wound bed.[50]

Full Thickness Excision




A hand knife, such as the Watson or powered dermatome, is set at at 15-30/1000 inches and serial passes are made excising the full thickness wound. Excision is aided by traction on the excised eschar as it passes through the knife or dermatome. Adequate excision is signaled by a viable bleeding wound bed, which is usually fat.[50]

Fascial Excisison

This technique is reserved for a burn extending down to through the fat into muscle, where the patient presents late with large infected wounds and inpatients with life-threatening invasive fungal infections. It involves surgical excision of the full thickness of the integument, including the subcutaneous fat down to the fascia using Goulian knives and number 11 blades. Unfortunately, fascial excision is mutilating and leaves a permanent contour defect, which is near impossible to reconstruct. Lymphatic channels are excised in this technique and peripheral lymphyedema may develop.[50]

Most patients can be managed with layered excisions that optimize later appearance and function. Published estimates of the amount of bleeding associated with these operations range within 3.5 to 5% of the blood volume for every 1% of the body surface excised.[51,52] The control of blood loss is one of the main determinants for outcome.[53] Therefore, several techniques should be applied to control blood loss. The local application of fibrin or thrombin spray, topical application of epinephrine 1:10000-10001:20000, epinephrine soaked laboratory pads (1:40000) and immediate electrocautery of the blood vessel can control blood loss.[54] The use of a sterilized tourniquet can also limit blood loss.[55] Lastly, pre-excisional tumescence with epinephrine saline can be used on the trunk, back and extremities, but not on the fingers.

Burn-wound Coverage

Following burn-wound excision, it is vital to obtain wound closure. Various biological and synthetic substrates have been employed to replace the injured skin postburn. Autografts from uninjured skin remains the mainstay of treatment for many patients. Since early wound closure using autograft may be difficult when full-thickness burns exceed 40% of total BSA (TBSA), allografts (cadaver skin) frequently serve as substitutes for skin in severely burned patients. While this approach is still commonly used in burn centers throughout the world, it bears considerable risks, including antigenicity, cross-infection as well as limited availability.[56] Xenografts have been used for hundreds of years as temporary replacement for skin loss. Even though these grafts provide a biologically active dermal matrix, the immunologic disparities prevent engraftment and predetermine rejection over time.[57] However, both xenografts and allografts are only a mean of temporary burn-wound cover. True closure can only be achieved with living autografts or isografts. Autologous epithelial cells grown from a single full-thickness skin biopsy have been available for nearly two decades. These cultured epithelial autografts have shown to decrease mortality in massively burned patients in a prospective, controlled trial.[58] Our institution found that cultured epithelial autografts utilized in combination with wide-mesh autograft and allograft overlay in a pediatric patient population with burns of greater than or equal to 90% TBSA to be associated with improved cosmetic results.[59] However, widespread use of cultured autografts has been primarily hampered by poor long-term clinical results, exorbitant costs and fragility and difficult handling of these grafts, which have been consistently reported by different burn units treating deep burns, even when cells were applied on properly prepared wound beds.[57,60,61] Alternatively, dermal analogs have been made available for clinical use in recent years. Integra™ was approved by the US FDA for use in life-threatening burns and has been successfully utilized in immediate and delayed closure of full-thickness burns, leading to a reduction in length of hospital stay, favorable cosmetics and improved functional outcome in a prospective and controlled clinical studies.[62-65] Our group recently conducted a randomized clinical trial utilizing Integra in the management of severe full-thickness burns of 50% or more TBSA in a pediatric patient population comparing it with standard autograft-allograft technique, and found Integra to be associated with attenuated hepatic dysfunction, improved resting energy expenditure and improved aesthetic outcome post-burn.[66] Alloderm™, an acellular human dermal allograft, has been advocated for the management of acute burns. Small clinical series and case reports suggest that Alloderm may be useful in the treatment of acute burns.[67-70] Tissue-engineering technology is advancing rapidly. Fetal constructs have recently been successfully trialed by Hohlfeld and colleagues[71] and the bilaminar skin substitute of Boyce[72] is now routine in clinical use and promise spectacular results.[53] Advances in stem cell culture technology may represent another promising therapeutic approach to deliver cosmetic restoration for burn patients.

Metabolic Response and Nutritional Support

The response to burn injury, known as hypermetabolism, occurs most dramatically following severe burn its modulation constitute an ongoing challenge for successful burn treatment.[73] Increases in oxygen consumption, metabolic rate, urinary nitrogen excretion, lipolysis and weight loss are directly proportional to the size of the burn.[74] Metabolic rates of burned children can dramatically exceed those of other critical care or trauma




patients and cause marked wasting of lean body mass within days after injury.[17] Failure to circumvent the subsequent large energy and protein requirements may result in impaired wound healing, organ dysfunction, susceptibility to infection and death.[75] Thus, adequate nutrition is imperative for the treatment of severely burned patients. Owing to the significant increase in energy expenditure postburn, high-calorie nutritional support was thought to decrease muscle metabolism.[76] However, a randomized, double-blinded, prospective study performed by our group found that aggressive high-calorie feeding with a combination of enteral and parenteral nutrition was associated with increased mortality.[77] Therefore, most authors recommend adequate calorie intake via early enteral feeding and the avoidance of overfeeding to attenuate the catabolic response after injury.[14,17] Different formulations have been developed to address the specific energy requirements of burned adult and pediatric patients.[78-80] In children, formulas based on BSA are more appropriate because of the greater BSA per kilogram. The formulas change with age based on the BSA alterations that occur with growth ( Table 1 ).

Since essential fatty acid deficiency is a well-documented complication in hospital patients receiving long-term nutritional supplements, most ICUs provide a significant amount of caloric requirements as fat.[81] This has been shown to reduce the requirements for carbohydrates and can improve glucose tolerance significantly, which is often altered in the patient postburn.[75] However, several studies demonstrated that increased fat administration may lead to increased complications, including hyperlipidemia, hypoxemia, fatty liver infiltration, higher incidence of infection and higher postoperative mortality rates in the burned patient population.[82-84] We found in a large cohort of severely burned children that patients receiving a low fat/high carbohydrate diet (Vivonex® T.E.N.) displayed a significantly lower incidence of hepatic fatty metamorphosis upon autopsy when compared with milk-fed patients. These patients furthermore displayed a significantly lower incidence of sepsis when compared with children receiving a high-fat diet, demonstrated prolonged survival and had significantly shorter stays in the ICU as well as markedly decreased length of stay in the ICU per percentage in TBSA. Based on these findings, we would recommend that nutritional regimens for the treatment of postburn patients include diets with a significantly reduced proportion of fat as the source of total caloric intake.

In addition, various vitamins, minerals and other micronutrients are required for nutrition following burns. Diminished gastrointestinal absorption, increased urinary losses, altered distribution and altered carrier protein concentrations following severe burn may lead to a deficiency in many micronutrients if not supplemented. These deficiencies in trace elements and vitamins (copper, iron, selenium, zinc and vitamins C and E) have been repeatedly described in major burns since 1960,[85-87] leading to infectious complications, delayed wound healing and stunting in children.[88] However, evidence-based practice guidelines are currently unavailable for the assessment and provision of micronutrients in burn patients. Enhancing trace-element status and antioxidant defenses by selenium, zinc and copper supplementation has been shown to decrease the incidence of nosocomial pneumonia in critically ill, severely burned children in two consecutive, randomized, double-blinded, supplementation trials.[89] Caution should be used to avoid toxicities that can result in gastrointestinal tolerance as well as antagonistic reactions. A complete listing of micronutrients, their functions and supplementation protocols is beyond the scope of this article; excellent reviews are available.[90-92]

Modulation of the Hormonal and Endocrine Response

Severe burn injury leads to significant metabolic alterations, characterized by a hyperdynamic circulatory response associated with increased body temperature, glycolysis, proteolysis, lipolysis and futile substrate cycling.[93-95] These responses are present in all trauma, surgical or critically ill patients, but the severity, length and magnitude is unique for burn patients.[17] Modification of adverse components of the hypermetabolic response, particularly protein catabolism, appears desirable. β-adrenergic blockade, β-adrenergic supplementation, anabolic steroids, recombinant growth hormone and IGF are under active investigation. Various studies have demonstrated the potential beneficial effect of β-blockers in burn patients. In a single-center study, administration of propanolol, a non-selective β1/2-receptor antagonist, in doses that decrease the heart rate by approximately 15 to 20% from baseline values, has been shown to reduce the release of free fatty acids from adipose tissue, decrease hepatic triacylglycerol storage and fat accumulation and reversed muscle protein catabolism.[96-98] In a retrospective study of adult burn patients, the use of β-blockers was associated with decreases in mortality, wound infection rate and wound healing time.[99] Therefore, many burn units recommend β-blockers as the most effective anticatabolic treatment in severely burned patients. Treatment with anabolic agents, such as oxandralone, an analog of testosterone, has been shown to improve muscle protein metabolism through enhanced protein synthesis efficiency[100] and was associated with reduced weight loss and increased donor site wound healing.[101] Wolf and colleagues demonstrated in a prospective, randomized study that the administration of oxandralone 10 mg every 12 h was associated with a decrease in hospital stay[102]. We found in a large prospective, double-blinded, randomized, single-center study, that oxandrolone administered at a dose of 0.1 mg/kg every 12 h to be associated with shortened length of acute hospital stay, maintained lean body mass and improved body composition and hepatic protein synthesis.[103] The use of recombinant human growth hormone in daily subcutaneous doses has been reported to accelerate donor site healing and restore




earlier positive nitrogen balance.[104-106] We found recombinant human growth hormone administered at a dose of 0.05 mg/kg bodyweight for 12 months postburn to significantly improve height, weight, lean body mass, bone mineral content, cardiac function and muscle strength when compared with placebo-treated burn patients.[107] However, Takala and others carried out one prospective, multicenter, double-blind, randomized, placebo-controlled trial involving 247 patients and 285 critically ill patients, and found high doses of growth hormone (0.10 ± 0.02 mg/kg bodyweight) to be associated with increased morbidity and mortality.[108] Others demonstrated that growth hormone treatment was associated with hyperglycemia and insulin resistance.[106,109] IGF-1 has been shown to decrease the metabolic rate postburn and increases whole-body anabolic activity without showing signs of hyperglycemia or insulin resistance.[110]

Glucose Control

One prominent component of the hypermetabolic response postburn is insulin resistance.[111] Stress-induced insulin resistance and its associated hyperglycemia results from both, an increase in hepatic gluconeogenesis and an impaired insulin-mediated glucose transport into skeletal muscle cardiac muscle, and adipose tissue,[112,113] leading to elevated blood glucose levels in association with normal or elevated serum insulin concentrations.[114,115] Both are of serious clinical concern, since hyperglycemia is frequently linked to impaired wound healing, increased number of infectious complications and increased incidence of mortality in those patients.[116-118] Thus, recent studies have focused on elucidating potential treatment options in order to overcome insulin resistance- induced hyperglycemia in the acute period following surgery or medical illness. A recent milestone single-center, randomized study including 1548 patients found that intensive insulin therapy decreased mortality in critically ill patients.[119] Insulin given at doses to maintain blood glucose below 110 mg/dl prevented the incidence of multiorgan failure and, thus, improved clinical outcome and rehabilitation.[119] It is worth noting that the impact of intervention increased with the duration of its application and that a substantial benefit was present with at least 3 days of intensive insulin therapy.[119] Besides saving lives, intensive insulin therapy has shown to prevent several critical illness-associated complications, including the development of critical illness polyneuropathy, blood stream infections, anemia, acute renal failure and hyperbilirubinemia.[119,120] A smaller prospective, randomized, controlled study performed in a predominantly general surgical patient population demonstrated decreased incidence of total nosocomial infections with intensive insulin therapy.[121] However, a recent multicenter, randomized, two-by-two factorial trial including 537 patients with severe sepsis found an increased risk for the development of hypoglycemic events and its associated consequences by a factor of 5-6 in this patient population.[122] Thus, clinical research is currently investigating alternative strategies in order to attenuate trauma-related hyperglycemia utilizing other glucose-lowering drugs that do not cause hypoglycemia as frequently as insulin. Metformin (glucophage), a biguanide, has recently been suggested as an alternative means to correct hyperglycemia in severely injured patients.[123] By inhibiting gluconeogenesis and augmenting peripheral insulin sensitivity, metformin directly counters the two main metabolic processes that underlie injury-induced hyperglycemia.[124-126] In addition, metformin has been rarely associated with hypoglycemic events, thus possibly eliminating this concern associated with the use of exogenous insulin.[127] Experience with metformin in burn patients is limited. In a small, randomized study reported by Gore and colleagues, metformin reduced plasma glucose concentration, decreased endogenous glucose production and accelerated glucose clearance in severely burned patients.[123] A follow-up study investigating the effects of metformin on muscle protein synthesis confirmed these observations, and demonstrated an increased fractional synthetic rate of muscle protein and improvement in net muscle protein balance in metformin-treated patients.[126] Therefore, metformin may - analogous to insulin - have efficacy in critically injured patients as both, an antihyperglycemic and muscle protein anabolic agent. Despite the advantages and potential therapeutic uses, treatment with metformin, or other biguanides, has been associated with lactic acidosis.[127,128] To avoid metformin-associated lactic acidosis, the use of this medication is contraindicated in certain diseases or illnesses in which there is a potential for impaired lactate elimination (hepatic or renal failure) or tissue hypoxia. However, several reports have questioned the causal relationship between metformin and lactic acidosis.[129-131] Several other trials investigating the decrease in postburn hyperglycemia include the use of glucagon-like-peptide-1 and PPAR-γ agonists (e.g., pioglitazone and thioglitazone) or the combination of various antidiabetic drugs.[132]

Long-term Responses

Despite adequate and rapid treatment immediately, postburn injury is associated with long-term consequences. Recent studies demonstrate that inflammation, hypermetabolism, catecholamines and cortisol are increased for up to 3 years postburn [Jeschke MG et al., Unpublished Data]. These data indicate the local and systemic effects of a burn are not limited to the 95% healed stage. A burn continues to plague and impair patients over a prolonged time. The Glue grant group investigated in a recent study the persistence of genomic changes after burn and found that the genome of white blood cells is altered for up 12 months postburn, indicating the profound changes with a burn injury.[133,134] We therefore initiated several studies to determine whether the long-term effects can be alleviated.[17,76,93,100,107] We found that administration of anabolic agents, such as




oxandrolone, growth hormone or propranolol, can improve long-term outcomes. Furthermore, in an unpublished study we found that exercise can tremendously improve strength and rehabilitation of severely burned patients. In summary, a burn is not limited to the acute phase. It is a process that continues over a long time and requires a patient-specific treatment plan in order to improve patient outcome.

Conclusion

Children below the age of 14 years account for approximately 50% of all emergency department-treated thermal burns. With nearly 1100 children dying of burn-related injuries in the USA every year, severe burns still represent the third most common cause of death in the pediatric patient population. However, novel concepts and techniques have been proposed and significantly improved over the past 30 years, resulting in a considerable decline in burn-related deaths and hospital admissions in the USA. The adequate and rapid institution of fluid resuscitation maintains tissue perfusion and prevents organ-system failure. Sepsis is successfully controlled by the early excision of burn wounds and topical antimicrobial agents. Patients suffering from sustained inhalation injury require additional fluid resuscitation, humidified oxygen and, occasionally, ventilatory support. Enteral tube feeding is commenced early in order to control stress ulceration, maintain intestinal mucosal integrity and provide fuel for the resulting hypermetabolic state. β-adrenergic blockade is recommended by many burn units as the most effective anticatabolic treatment. Tight glucose control has been shown to prevent several critical illness-associated complications, including blood stream infections, anemia and acute renal failure. Through the use of aggressive resuscitation, nutritional support, infection control, surgical therapy and early rehabilitation as well as multidisciplinary collaboration, better psychological and physical results can be achieved for burn children.

Future Perspective

Further studies are needed in order to address the primary determinants of death, inhalation injury complications and pneumonia as well as to ameliorate pain and scar formation, which are the persistent sequelae of this thermal injury. Better understanding of the basic mechanisms underlying the metabolic alterations postburn may lead to the development of novel therapeutic options. Centralized care in burn units and multidisciplinary team approaches will advance and extend current therapeutic strategies, thus further improving the prognosis of this unique patient population.

Table 1. Formulas for Estimating Caloric Requirements in Pediatric Burn Patients

Formula Sex/age (years) Equation (daily requirement in kcal) Ref.

WHO Males [133]

0-3 (60.9 × W) - 54

3-10 (22.7 × W) + 495

10-18 (17.5 × W) + 651

Females

0-3 (61.0 × W) - 51

3-10 (22.5 × W) + 499

10-18 (12.2 × W) + 746

RDI 0-6 months 108 × W [134]

6 months-1 year 98 × W

1-3 102 × W

4-10 90 × W

11-14 55 × W




RDI = Recommended Dietary Intake (USA); % TBSAB = Percentage of total body surface area burned; W = Weight (kg).

Box 1. American Burn Association Concensus Definition on Burn Sepsis

SD = Standard deviation. Data taken from [36].

References

Curreri Junior <1 RDA + (15 × % TBSAB) [135]

1-3 RDA + (25 × % TBSAB)

4-15 RDA + (40 × % TBSAB)

Galveston infant 0-1 2100 kcal/m2 + 100 kcal/m2burn [136]

Galveston revised 1-11 2100 kcal/m2 + 100 kcal/m2burn [80]

Galveston adolescent 12+ 2100 kcal/m2 + 100 kcal/m2burn [137]

At least three of the following parameters:

Temperature >38.5 or <36.5°C Progressive tachycardia >90 beats per minute (b.p.m.) in adults or >2 SD above age-specific norms in children Progressive tachypnea >30 b.p.m. in adults or >2 SD above age-specific norms in children White blood cells >12,000 or <4000 in adults or >2SD above age-specific norms in children Refractory hypotension

Thrombocytopenia

Hyperglycemia

Enteral feeding intolerance (residual >150 ml/h in children or two-times feeding rate in adults; diarrhea >2500 ml/day for adults or >400 ml/day in children)

Systolic blood pressure <90 mmHg, mean arterial pressure <70 or a systolic blood pressure decrease >40 mmHg in adults or <2 SD below normal for age in children

Platelet count <100,000/µl in adults, <2 SD below norms in children

Plasma glucose >110 mg/dl or 7.7 mM/l in the absence of diabetes

In addition to:

Pathologic tissue source identified: >105th bacteria on quantitative wound tissue biopsy or microbial invasion on biopsy Bacteremia or fungemia Documented infection as defined by the US CDC




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Pediatric burn patients should be managed initially as trauma patients. Algorithms for trauma evaluation should be diligently applied to the burn patient: airway, breathing, circulation, disability and exposure (ABCDE). Early and accurate fluid resuscitation of patients with major burns is critical for survival. However, over-aggressive resuscitation should be avoided, particularly in small children below the age of 4 years, as it may potentially lead to increased extravascular hydrostatic pressure and pulmonary edema. Early diagnosis of bronchopulmonary injury is critical and is conducted clinically, based on a history of closed-space exposure, facial burns and carbonaceous debris in mouth, pharynx or sputum or via bronchoscopy of the upper airway. Management of inhalation injury consists of ventilatory support, aggressive pulmonary toilet, bronchoscopic removal of casts and nebulization therapy. Increasingly aggressive early tangential excision of the burn tissue and early wound closure primarily by skin grafts has led to significant improvement in mortality rates in burn patients. Adequate calorie via enteral tube feeding should be commenced early to control stress ulceration, maintain intestinal mucosal integrity and provide fuel for the resulting hypermetabolic state. We recommend that nutritional regimens for the treatment of postburn patients include diets with a significantly reduced proportion of fat as the source of total caloric intake. β-adrenergic blockade is recommended by many burn units as the most effective anticatabolic treatment. Anabolic steroids, recombinant growth hormone and IGF are under active investigation. Insulin given at doses to maintain blood glucose below 110 mg/dl has been shown to prevent several critical illness-associated complications, including blood stream infections, anemia and acute renal failure.




Reprint Address

Marc G. Jeschke, Galveston Burns Unit, Shriners Hospitals for Children, 815 Market Street, Galveston, TX 77550, USA. Tel.: +1 409 770 6742; Fax: +1 409 770 6919. E-Mail: [email protected]

Gerd G. Gauglitz,1 David N. Herndon,2 and Marc G. Jeschke3 1Department of Dermatology & Allergology, Ludwig Maximilians University, Munich, Germany 2Shriners Hospitals for Children, Department of Surgery, University Texas Medical Branch, Galveston, TX, USA3Galveston Burns Unit, Shriners Hospital for Children, 815 Market Street, Galveston, TX 77550, USA Disclosure: The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.




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