Detecting genetic predisposition for complicated clinical outcomes after burn injury.

Sepsis, septic shock and organ failure are common among patients with moderate to severe burns. The inability of demographic and clinical factors to identify patients at high risk for such complications suggests that genetic variation may influence clinical outcome. Moreover, the genetic predisposition to death from infection has been estimated to be greater than for cardiovascular disease or cancer . While it is widely accepted that genetic factors influence many complex disease processes, controversy has emerged regarding the most appropriate methods for detection and even the validity of many published allelic associations . This article will review the few studies of genetic predisposition that have been conducted in the setting of burn injury, then discuss some of the obstacles and potential approaches for the discovery of additional allelic associations.

TLR4 and TNF-alpha polymorphisms are associated with an increased risk for severe sepsis following burn injury.

CONTEXT: Sepsis, organ failure, and shock remain common among patients with moderate to severe burn injuries. The inability of clinical factors to identify at-risk patients suggests that genetic variation may influence the risk for serious infection and the outcome from severe injury. OBJECTIVE: Resolution of genetic variants associated with severe sepsis following burn injury. PATIENTS: A total of 159 patients with burns > or =20% of their total body surface area or any smoke inhalation injury without significant non-burn related trauma (injury severity score (ISS)> or =16), traumatic or anoxic brain injury, or spinal cord injury and who survived more than 48 h post-admission. METHODS: Candidate single nucleotide polymorphisms (SNPs) within bacterial recognition (TLR4 +896, CD14 -159) and inflammatory response (TNF-alpha -308, IL-1beta -31, IL-6 -174) loci were evaluated for association with increased risk for severe sepsis (sepsis plus organ dysfunction or septic shock) and mortality. RESULTS: After adjustment for age, full-thickness burn size, ethnicity, and gender, carriage of the TLR4 +896 G-allele imparted at least a 1.8-fold increased risk of developing severe sepsis following a burn injury, relative to AA homozygotes (adjusted odds ratio (aOR) 6.4; 95% confidence interval (CI) 1.8 to 23.2). Carriage of the TNF-alpha -308 A-allele imparted a similarly increased risk, relative to GG homozygotes (aOR = 4.5; 95% CI 1.7 to 12.0). None of the SNPs examined were significantly associated with mortality. CONCLUSIONS: The TLR4 +896 and TNF-alpha -308 polymorphisms were significantly associated with an increased risk for severe sepsis following burn trauma.

Sentinel lymph node biopsy identifies occult nodal metastases in patients with Marjolin's ulcer.

Since Marjolin's description, the management of burn scar carcinoma has remained controversial. A multitude of options and recommendations exist for the management of both primary lesions and regional nodal metastasis. This work reviews six cases of Marjolin's ulcer staged using sentinel lymph node biopsy. All primary lesions were confirmed to be squamous cell carcinoma and occurred a median of 29.5 years after burn. No patient had clinically detectable lymphadenopathy. In all cases, preoperative lymphoscintigraphy successfully identified a single draining regional nodal basin. Subsequent intraoperative lymphatic mapping/sentinel lymph node (SLN) biopsy was successful in five of six cases (83%). A successful intraoperative lymphatic mapping/SLN biopsy was defined as the identification of blue (uptake of isosulfan blue dye) or "hot" (uptake of radiolabeled sulfur colloid as measured with a handheld gamma counter) node(s) and subsequent excision. Four of five SLN biopsies identified previously occult nodal metastasis. SLN biopsy represents a minimally invasive and accurate staging procedure for Marjolin's ulcer.

Serial measurements increase the accuracy of laser Doppler assessment of burn wounds.

Traditional methods of judging burn depth by clinical evaluation of the wound based on appearance and sensation remain in wide use but are subject to individual variation by examiner. In addition to the clinical difficulties with burn wound management, observer dependency of wound assessment complicates clinical trials of burn wound therapy. A laser Doppler flowmeter with a multichannel probe was used to measure burn wound perfusion as a tool to predict wound outcome. Serial measurement with laser Doppler flowmetry had an 88% specificity and a positive predictive value of 81% for identifying nonhealing wounds. These results suggest that laser Doppler flowmetry is a potentially useful tool for burn wound assessment.

A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century.

Toxic epidermal necrolysis (TEN) is a potentially fatal disorder that involves large areas of skin desquamation. Patients with TEN are often referred to burn centers for expert wound management and comprehensive care. The purpose of this study was to define the presenting characteristics and treatment of TEN before and after admission to regional burn centers and to evaluate the efficacy of burn center treatment for this disorder. A retrospective multicenter chart review was completed for patients admitted with TEN to 15 burn centers from 1995 to 2000. Charts were reviewed for patient characteristics, non-burn hospital and burn center treatment, and outcome. A total of 199 patients were admitted. Patients had a mean age of 47 years, mean 67.7% total body surface area skin slough, and mean Acute Physiology and Chronic Health Evaluation (APACHE II) score of 10. Sixty-four patients died, for a mortality rate of 32%. Mortality increased to 51% for patients transferred to a burn center more than one week after onset of disease. Burn centers and non-burn hospitals differed in their use of enteral nutrition (70 vs 12%, respectively, P < 0.05), prophylactic antibiotics (22 vs 37.9%, P < 0.05), corticosteroid use (22 vs 51%, P < 0.05), and wound management. Age, body surface area involvement, APACHE II score, complications, and parenteral nutrition before transfer correlated with increased mortality. The treatment of TEN differs markedly between burn centers and non-burn centers. Early transport to a burn unit is warranted to improve patient outcome.

Differential activation of coronary and pulmonary endothelial cells by thermal injury.

Remote organ dysfunction during resuscitation of severe thermal injury is characterized by early, transient pulmonary insufficiency and cardiac contractile dysfunction. Thermal injury is typified by profound systemic alterations of endothelial immunological, vasoactive, and barrier functions. The unique location of this ubiquitous, fragile monolayer makes it vulnerable to circulating serum factors created at remote cutaneous wounds. We examined endothelial "activation" in 2 distinct cell types, human coronary and pulmonary endothelial cells (EC), after severe thermal injury. By using human serum isolated at specific times after thermal injury ("early" [2 h post-burn] or "late" [26 h post-burn]), the endothelial release of vasoactive mediators, ICAM-1 expression, and monolayer permeability were assessed in vitro. Early burn serum enhanced coronary EC vasoconstrictor (ET-1) release and ICAM expression, inhibited vasodilator (PGI2) release, but had no effect on permeability. Conversely, under similar conditions, pulmonary EC PGI2 release and permeability were enhanced, ET-1 release was diminished, but ICAM was unaffected. Late burn serum enhanced vasodilator (NO) release and permeability to albumin in both coronary and pulmonary EC, whereas ET-1 release was inhibited. Under these conditions, only pulmonary ICAM expression was significantly enhanced. These data suggest that human endothelium isolated from divergent vascular beds are activated by burn injury in a unique manner for time post-burn and vascular site of cell origin.

Objective estimates of the incidence and consequences of multiple organ dysfunction and sepsis after burn trauma.

BACKGROUND: Organ dysfunction and sepsis are frequent after major burn trauma, represent quantifiable consequences of the systemic response to injury, and may be important end points by which to measure treatment effectiveness. However, standard and widely applied methods for their measurement have not been applied to burn trauma victims. Therefore, the purpose of this study was to quantify these complications after burn trauma. METHODS: Patients with > or = 20% total body surface area burns admitted to a single center were prospectively enrolled. Standard sepsis criteria and multiple organ dysfunction (MOD) scores for the pulmonary, renal, cardiovascular, hepatic, and hematologic systems were determined. The incidence and risk factors for severe MOD (cumulative MOD score > or = 6) and severe sepsis were determined. The relationships between these complications and mortality and resource utilization were examined by univariate and multivariate analyses. RESULTS: A total of 85 patients were enrolled over 1 year. Severe MOD developed in 24 (28%) and severe sepsis or septic shock developed in 12 (14%). Both were associated with increasing age and burn size and were more likely to occur in men. Most patients who developed severe MOD or severe sepsis survived (71% and 67%, respectively), and both were associated with longer intensive care unit stays and duration of mechanical ventilation. CONCLUSION: According to simple and objective scoring systems, severe MOD and severe sepsis/septic shock are both related to burn size, age, and male sex. Both are related to intensive care unit length of stay and duration of mechanical ventilation.

An evaluation of risk factors for mortality after burn trauma and the identification of gender-dependent differences in outcomes.

BACKGROUND: The primary objective of this study was to determine an objective method for estimating the risk of mortality after burn trauma, and secondarily, to evaluate the relationship between gender and mortality, in the setting of a quantifiable inflammatory stimulus. Previously reported estimates of mortality risk after burn trauma may no longer be applicable, given the overall reduction in case-fatality rates after burn trauma. We expect that future advances in burn trauma research will require careful and ongoing quantification of mortality risk factors to measure the importance of newly identified factors and to determine the impact of new therapies. Conflicting clinical reports regarding the impact of gender on survival after sepsis and critical illness may in part, be from different study designs, patient samples, or failure to adequately control for additional factors contributing to the development ofsepsis and mortality. STUDY DESIGN: Data from the prospectively maintained burn registry for patients admitted to the Parkland Memorial Hospital burn unit between January 1, 1989 and December 31, 1998 were analyzed. Logistic regression was used to generate estimates of the probability of death in half of the study sample, and this model was validated on the second half of the sample. Risk factors evaluated for their relationship with mortality were: age, inhalation injury, burn size, body mass (weight), preexisting medical conditions, nonburn injuries, and gender. RESULTS: Of 4,927 patients, 5.3% died. The best model for estimating mortality included the percent of total body surface area burned; the percent of full-thickness burn size; the presence of an inhalation injury; age categories of: < 30 years, 30 to 59 years, > or = 60 years; and gender. The risk of death was approximately two-fold higher in women aged 30 to 59 years compared with men of the same age. CONCLUSIONS: We have provided a detailed method for estimating the risk of mortality after burn trauma, based on a large, contemporary cohort of patients. These estimates were validated on a second sample and proved to predict mortality accurately. We have identified an increased mortality risk in women of 30 to 59 years of age.

American Burn Association/Shriners Hospitals for Children burn outcomes questionnaire: construction and psychometric properties.

To develop a standardized, practical, self-administered questionnaire to monitor pediatric patients with burns and to evaluate the effectiveness of comprehensive pediatric burn management treatments, a group of experts generated a set of items to measure relevant burn outcomes. Children between the ages of 5 and 18 years were assessed in a cross-sectional study. Both parent and adolescent responses were obtained from children 11 to 18 years old. The internal reliability of final scales ranged from 0.82 to 0.93 among parents and from 0.75 to 0.92 among adolescents. Mean differences between parent and adolescent were small; the greatest difference occurred in the appearance subscale. Parental scales showed evidence of validity and potential for sensitivity to change. In an effort to support the construct validity of the new scales, they were compared with the Child Health Questionnaire and related to each other in clinically sensible ways. These burn outcomes scales reliably and validly assess function in patients with burns, and the scales have been developed in such a way that they are likely to be sensitive to change over time.

Cardiovascular effect of 7.5% sodium chloride-dextran infusion after thermal injury.

HYPOTHESIS: Clinical study can help determine the safety and cardiovascular and systemic effects of an early infusion of 7.5% sodium chloride in 6% dextran-70 (hypertonic saline-dextran-70 [HSD]) given as an adjuvant to a standard resuscitation with lactated Ringer (RL) solution following severe thermal injury. DESIGN: Prospective clinical study. SETTING: Intensive care unit of tertiary referral burn care center. PATIENTS: Eighteen patients with thermal injury over more than 35% of the total body surface area (TBSA) (range, 36%-71%) were studied. INTERVENTIONS: Eight patients (mean +/- SEM, 48.2% +/- 2% TBSA) received a 4-mL/kg HSD infusion approximately 3.5 hours (range, 1.5-5.0 hours) after thermal injury in addition to routine RL resuscitation. Ten patients (46.0% +/- 6% TBSA) received RL resuscitation alone. MAIN OUTCOME MEASURES: Pulmonary artery catheters were employed to monitor cardiac function, while hemodynamic, metabolic, and biochemical measurements were taken for 24 hours. RESULTS: Serum troponin I levels, while detectable in all patients, were significantly lower after HSD compared with RL alone (mean +/- SEM, 0.45 +/- 0.32 vs 1.35 +/- 0.35 microg/L at 8 hours, 0.88 +/- 0.55 vs 2.21 +/- 0.35 microg/L at 12 hours). While cardiac output increased proportionately between 4 and 24 hours in both groups (from 5.79 +/- 0.8 to 9.45 +/- 1.1 L/min [mean +/- SEM] for HSD vs from 5.4 +/- 0.4 to 9.46 +/- 1.22 L/min for RL), filling pressure (central venous pressure and pulmonary capillary wedge pressure) remained low for 12 hours after HSD infusion (P = .048). Total fluid requirements at 8 hours (2.76 +/- 0.7 mL/kg per each 1% TBSA burned [mean +/- SEM] for HSD vs 2.67 +/- 0.24 mL/kg per each 1% TBSA burned for RL) and 24 hours (6.11 +/- 4.4 vs 6.76 +/- 0.75 mL/kg per each 1% TBSA burned) were similar. Blood pressure remained unchanged, and serum sodium levels did not exceed 150 +/- 2 mmol/L (mean +/- SD) in either group. CONCLUSIONS: The absence of deleterious hemodynamic or metabolic side effects following HSD infusion in patients with major thermal injury confirms the safety of this resuscitation strategy. Postburn cardiac dysfunction was demonstrated in all burn patients through the use of cardiospecific serum markers and pulmonary artery catheter monitoring. Early administration of HSD after a severe thermal injury may reduce burn-related cardiac dysfunction, but it had no effect on the volume of resuscitation or serum biochemistry values.

Thermal injury alters endothelial vasoconstrictor and vasodilator response to endotoxin.

BACKGROUND: The unique location of the endothelium makes it vulnerable to injury from circulating factors created at remote wounds. In this study, we examined the effect of a sequential burn and lipopolysaccharide (LPS) challenge on endothelial function in vitro. METHODS: Human umbilical vein endothelial cells treated with 20% human serum isolated from burn patients (>40% total burn surface area) at 2 and 24 hours postinjury. Cultures were subsequently treated with Escherichia coli LPS:0111:B4 (0.10-100ng/mL). Endothelin-1 (ET-1), 6-ketoPGF1a, and NO2/NO3 were detected by using specific enzyme immunoassays. RESULTS: Burn serum did not alter endothelial ET-1, PGI2, or NO secretion compared with Control serum. LPS significantly enhanced 6-ketoPGF1a (54,242+/-14,466 pg/10(6) cells) and NO2/ NO3 (723+/-210 microM) secretion, but not ET-1 compared with Control serum alone (3,878+/-963 and 219+/-110). Burn serum pretreatment significantly enhanced the ET-1 response to LPS (303+/-36 pg/10(6) cells vs. 193+/-47). The 6-ketoPGF1a (16,509+/-3,785) and NO2/NO3 (354+/-98) responses to Burn/LPS were significantly diminished compared with Control/LPS. Although this level of 6-ketoPGF1a was elevated compared with Control alone (7,518+/-2,299), NO2/NO3 was unchanged (significance at p < 0.05). CONCLUSION: Thermal injury may prime remote endothelium and alter the response to a septic focus with an enhanced vasoconstrictor (ET-1) and diminished vasodilator (PGI2/NO) response, a situation that may contribute to postburn distal organ injury.

Traumatic wound care.

The scope and importance of traumatic wound care, assessment, debridement, pre and postoperative management, and subsequent skin care during the course of treatment cannot be over-emphasized, and indeed, are the most important considerations for functional and cosmetic outcome. Care begins in the emergent phase and continues through acute and convalescent phases. Efforts are directed at methods and techniques which prevent infection, facilitate wound healing, promote comfort, and at the same time, maintain optimal function and minimize deformities.

Evaluation of troponin-I as an indicator of cardiac dysfunction after thermal injury.

BACKGROUND: Biochemical serum markers commonly used to assess human cardiac injury (creatinine phosphokinase, creatine phosphokinase-MB) have been shown to have diminished specificity for detection of cardiac injury in the setting of burn-related soft-tissue and skeletal muscle injury. Laboratory studies have demonstrated that severe cutaneous thermal injury is associated with cardiac contractile dysfunction and a corresponding elevation in serum cardiac troponin-I (cTn-I) in several species. METHODS: Twenty-three patients admitted to a tertiary care burn referral center were evaluated. Patients were monitored with pulmonary artery catheters, and creatinine phosphokinase, creatine phosphokinase-MB, and cTn-I levels were determined for 24 hours. Using a database, 6,722 burn patients were reviewed to determine the incidence of preexisting cardiac disease and postburn cardiac complications. RESULTS: All patients had persistent sinus tachycardia (>115 beats per minute) without obvious electrical anomalies. All patients centrally monitored with a pulmonary artery catheter (n=20) maintained a cardiac index of greater than 3.0 L x min(-1) x m(-2) x cTn-I was present (>0.3 ng/mL) within 3.0 hours and elevated (>0.55 ng/mL) at 24 hours for all burns of more than 18% total body surface area. Historically, although only 5% of all admissions manifest acute postburn cardiac complications, 94% of these patients presented with preexisting heart disease. CONCLUSION: Severe thermal injury was associated with a mild elevation in serum troponin-I; however, this did not correlate with overt cardiac morbidity or mortality. Postburn elevation of cTn-I suggested that a subtle degree of cardiac injury was present after a severe thermal injury despite hyperdynamic cardiac function during resuscitation.

Tracheostomy in the young pediatric burn patient.

OBJECTIVE: To evaluate the incidence of complications in comparison with the benefits of tracheostomy in young pediatric burn patients (newborn to 3 years old). DESIGN: Retrospective survey. SETTING: Tertiary care burn center. PATIENTS: A total of 1549 consecutive pediatric burn patients, of whom 180 were intubated. INTERVENTIONS: Tracheostomy was performed in 76 children. MAIN OUTCOME MEASURES: Duration of mechanical ventilation, mortality, respiratory complications, airway complications, and condition of the airway at discharge from the hospital. RESULTS: Seventy-six patients required tracheostomy. Their mean burn size was 34% total body surface area and mean length of stay in the hospital was 56 days. There were no perioperative complications. Eight patients (10%) could not be decannulated because of airway obstruction. Five of these outgrew their obstruction, 2 required surgery, and 1 continues to be evaluated for laryngeal reconstruction. CONCLUSION: Pediatric tracheostomy can be performed safely with no perioperative complications and acceptable chronic morbidity.

Toxic epidermal necrolysis.

Toxic epidermal necrolysis (TEN) is a poorly understood and devastating condition. It is usually diagnosed in a primary care setting. Treatment of severe cases by burn care personnel is usually by referral. In this review, we report excessive mortality rates associated with prolonged use of systemic steroid therapy and delayed referral (more than 1 week from diagnosis). Forty-four consecutive patients admitted to a regional burn center with the diagnosis of TEN over a 14-year period, (0.7% of all admissions) were included. Precipitating factors were identified in 30 cases. Twenty-one patients had known prehospital allergy conditions directly related to the inciting agent. The mean age of this population was 44.9 years, and the mean total body surface area (TBSA) injury was 52.4%. Eighty-four and one-half percent of all patients with TEN were admitted to the ICU. Twenty-four patients required ventilator support. Overall mortality rate was 36%. Nonsurviving patients had a mean age of 61.6 years, compared to 35.3 years for survivors. Nonsurvivors had a mean TBSA of 64.4%, survivors had a mean TBSA of 44%. TEN, although a nonthermal injury, is best managed by personnel experienced in the care of severe thermal injuries. Despite the availability of this expertise, delayed transfer of severe presentations continues to contribute to exceptionally high morbidity and mortality rates.

A multicenter clinical trial of a biosynthetic skin replacement, Dermagraft-TC, compared with cryopreserved human cadaver skin for temporary coverage of excised burn wounds.

This multicenter study compared the use of a biosynthetic human skin substitute with frozen human cadaver allograft for the temporary closure of excised burn wounds. Dermagraft-TC (Advanced Tissue Sciences, Inc.) (DG-TC) consists of a synthetic material onto which human neonatal fibroblasts are cultured. Burn wounds in 66 patients with a mean age of 36 years and a mean burn size of 44% total body surface area (28% total body surface area full-thickness) were surgically excised. Two comparable sites, each approximately 1% total body surface area in size, were randomized to receive either DG-TC or allograft. Both sites were then treated in the same manner. When clinically indicated (> 5 days after application) both skin replacements were removed, and the wound beds were evaluated and prepared for grafting. DG-TC was equivalent or superior to allograft with regard to autograft take at postautograft day 14. DG-TC was also easier to remove, had no epidermal slough, and resulted in less bleeding than did allograft while maintaining an adequate wound bed. Overall satisfaction was better with DG-TC.

The 1996 Clinical Research award. Use of a pneumatonometer in burn scar assessment.

The evaluation of wound outcome after burn injury is a challenging problem in the performance of clinical trials evaluating potential impact on wound healing and scar formation. The purpose of this study was to determine whether an ocular tonometer could be adapted to provide an objective measurement of scar compliance. A pneumatonometer was used to perform measurements of cutaneous compliance at 8 anatomic areas (14 separate sites) on each of 17 normal volunteers and on 59 burn scars. Comparison of different anatomic sites showed there to be significant differences in the cutaneous compliance of different areas. The aggregate compliance of the burn scars in all sites was less than that of the control sites. These results indicate that the pneumatonometer can discern differences in the compliance of normal skin and differences between normal skin and scar and suggest that it may be a useful tool in the objective assessment of scar formation.

Alcohol, drug intoxication, or both at the time of burn injury as a predictor of complications and mortality in hospitalized patients with burns.

The objective of this study was to characterize the association between drug and alcohol intoxication at the time of injury and subsequent complications and mortality in hospitalized patients with burns. A computerized burn database was used to analyze data on 3047 consecutive adult (21 to 75 years) hospitalized patients with burns admitted between January 1982 and August 1994. Data for intoxicated (by history, blood alcohol content, or positive drug screen) and nonintoxicated patients were compared. The same analysis was also conducted on 429 consecutive adolescent patients with burns (ages 14 to 20 years) admitted during the same time period. The incidence of intoxication at the time of burn was 6.9%. No significant differences in age, sex, race, or burn size were noted. Intoxicated patients had a higher incidence of associated injuries. Skin graft loss, cellulitis, donor site conversion, hypotension, and pneumonia were more common in the intoxicated group. They also had more intensive care unit admissions, ventilator days, operations, transfusions, and total hospital days. Intoxicated patients had a lower mortality (7.1%) than patients in the control group (10.9%). Intoxication at the time of burn injury is an important predictor of complications in adult patients with burns.

Early assessment of pediatric burn wounds by laser Doppler flowmetry.

Evaluation of burn wound depth in pediatric patients is often difficult. A Laser Doppler Flowmeter with a temperature-controlled multichannel probe was used to measure burn wound perfusion as a tool to predict wound outcome. The average perfusion levels for wounds that healed spontaneously in fewer than 21 days was significantly higher than the average perfusion levels for wounds that required excision and grafting or were not healed by day 21 after burn injury. Laser Doppler Flowmetry showed high positive predictive values for "nonhealing" wounds on postburn days 1, 2, and 3. These results suggest that Laser Doppler Flowmetry is a useful tool for burn wound assessment in pediatric patients.