Acute assessment and management of burn injuries.

Burns are ubiquitous injuries in modern society, with virtually all adults having sustained a burn at some point in their lives. The skin is the largest organ of the body, basically functioning to protect self from non-self. Burn injury to the skin is painful, resource-intensive, and often associated with scarring, contracture formation, and long-term disability. Larger burns are associated with morbidity and mortality disproportionate to their initial appearance. Electrical and chemical burns are less common injuries but are often associated with significant morbidity.

IL-10 polymorphism associated with decreased risk for mortality after burn injury.

OBJECTIVE: Evaluation of single nucleotide polymorphisms (SNPs) in the interleukin-10 promoter (-592 and -819) on risk for death after burn injury. METHODS: Association between the IL-10 SNPs and outcome after burn injury was evaluated in a cohort of 265 patients from Parkland Hospital, Dallas, TX with ≥ 15% TBSA burns without non-burn trauma (ISS ≤ 16), traumatic or anoxic brain injury or spinal cord injury, who survived >48 h under an IRB-approved protocol. Clinical data were collected prospectively and genotyping was conducted by TaqMan assay. Whole blood from 31 healthy volunteers was stimulated with LPS (100 ng/mL) to determine the level of IL-10 expression for each allele by enzyme-linked immunosorbent assay (ELISA). RESULTS: After adjustment for percent total body surface area (TBSA) burned, inhalation injury, age, gender, and race/ethnicity, carriage of ­592A and/or ­819T was significantly associated (P = 0.014) with a decreased risk for death (adjusted odds ratio: 0.404; 95% CI: 0.197-0.829). As the candidate SNPs were in complete linkage disequilibrium, it was not possible to distinguish which allele was associated with decreased mortality risk. Age, inhalation injury, and full-thickness burn size were significantly associated with increased risk for death. In the LPS stimulated blood of healthy controls, carriage of the -592A and/or -819T allele demonstrated a trend for decreased levels of IL-10 (P = 0.079). CONCLUSION: Carriage of the ­592A and/or ­819T allele in the IL-10 promoter appears to reduce the risk for death after burn injury.

Ophthalmic Manifestations of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis and Relation to SCORTEN.

PURPOSE: To evaluate the severity of ocular involvement of patients with Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap, and to investigate the relationship of the SCORTEN (a severity-of-illness score for SJS and TEN based on a minimal set of well-defined variables calculated within 24 hours of admission) with eye disease in this patient population. DESIGN: Retrospective observational case series. METHODS: Charts of all patients admitted to the Parkland Memorial Hospital Burn Center with a preliminary diagnosis of SJS, SJS/TEN overlap, or TEN between 1998 and 2008 were reviewed. Patients were included for study if they met clinical criteria, had positive diagnostic skin biopsy, and had dermatologic and ophthalmologic consultations. Eighty-two patients with a diagnosis of SJS, SJS/TEN overlap, or TEN met inclusion criteria. Ocular manifestations were classified as mild, moderate, or severe. Admission data were used to calculate the SCORTEN. Main outcome measure was the severity of ocular involvement with respect to diagnosis and SCORTEN. RESULTS: Overall, 84% of patients had ocular involvement (71% SJS, 90% TEN, 100% SJS/TEN overlap). There was no difference in the severity of acute ocular complications among groups. While the SCORTEN value did correlate well with mortality rate (correlation coefficient 0.97, P = .005), there was no correlation between the SCORTEN value and severity of eye involvement in the acute setting. There was also no association of any individual diagnosis of SJS/overlap/TEN with the severity of eye involvement, although eye findings are more common in TEN (P = .03). CONCLUSIONS: Ocular damage in the acute setting was more frequent in patients with epidermal detachment >10% of the total body surface area. The SCORTEN value did not correlate with the severity of eye involvement in the acute setting.

Pre-burn center management of the burned airway: do we know enough?

Despite the traditional teaching of early and aggressive airway management in thermally injured patients, paramedics and medical providers outside of burn centers receive little formal training in this difficult skill set. However, the initial airway management of these patients is often performed by these preburn center providers (PBCPs). The purpose of this study was to evaluate the authors' experience with patients intubated by PBCPs and subsequently managed at the authors' center. A retrospective review of a level I burn center database was undertaken. All records of patients arriving intubated were reviewed. From January 1982 to June 2005, 11,143 patients were admitted to the regional burn center; 11.4% (n = 1,272) were intubated before arrival. In this group, mean age was 37.1 years, mean burn size was 35.3% TBSA, and mean length of hospital stay was 27.0 days. Approximately 26.3% were suspected of having an inhalation injury, and this was confirmed by either bronchoscopy or clinical course in 88.6% of this subgroup. Mortality in patients arriving intubated was 30.8%, and these were excluded from the rest of the analysis. In the surviving 879 intubated patients, reasons reported by PBCPs for intubation included "airway swelling" in 34.1%, "prophylaxis" in 27.9%, and "ventilation or oxygenation needs" in 13.2%. Of these patients, 16.3% arrived directly from the scene, with the remainder arriving from another hospital facility. Of all survivors who arrived intubated, 11.9% were extubated on the day of admission, 21.3% were extubated on the first postburn day (PBD), and 8.2% were extubated on the second PBD. No patients who were extubated on PBD1 or PBD2 had to be reintubated. A significant number of burn patients have their initial airway management by PBCPs. Of these, a significant number are extubated soon after arrival at the burn center without adverse sequelae. Rationale for their initial intubation varies, but education is warranted in the prehospital community to reduce unnecessary intubation of the burn patient.

Association of mitochondrial allele 4216C with increased risk for sepsis-related organ dysfunction and shock after burn injury.

Impaired mitochondrial activity has been linked to increased risk for clinical complications after injury. Furthermore, variant mitochondrial alleles have been identified and are thought to result in decreased mitochondrial activity. These include a nonsynonymous mitochondrial polymorphism (T4216C) in the nicotinamide adenine dinucleotide dehydrogenase 1 gene (ND1), encoding a key member of complex I within the electron transport chain, which is found almost exclusively among Caucasians. We hypothesized that burn patients carrying ND1 4216C are less able to generate the cellular energy necessary for an effective immune response and are at increased risk for infectious complications. The association between 4216C and outcome after burn injury was evaluated in a cohort of 175 Caucasian patients admitted to the Parkland Hospital with burns covering greater than or equal to 15% of their total body surface area or greater than or equal to 5% full-thickness burns under an institutional review board-approved protocol. To remove confounding unrelated to burn injury, individuals were excluded if they presented with significant non-burn-related trauma (Injury Severity Score > or =16), traumatic or anoxic brain injury, spinal cord injury, were HIV/AIDS positive, had active malignancy, or survived less than 48 h postadmission. Within this cohort of patients, carriage of the 4216C allele was significantly associated by unadjusted analysis with increased risk for sepsis-related organ dysfunction or septic shock (P = 0.011). After adjustment for full-thickness burn size, inhalation injury, age, and sex, carriage of the 4216C allele was associated with complicated sepsis (adjusted odds ratio = 3.7; 95% confidence interval, 1.5-9.1; P = 0.005), relative to carriers of the T allele.

The diagnosis and management of electrical injuries.

Electrical injuries to the extremity can result in significant local tissue damage and systemic problems. An understanding of the pathophysiology of electrical injuries is critical to the medical and surgical management of patients who sustain these injuries.

Sustained impairments in cutaneous vasodilation and sweating in grafted skin following long-term recovery.

We previously identified impaired cutaneous vasodilation and sweating in grafted skin 5 to 9 months postsurgery. The aim of this investigation was to test the hypothesis that cutaneous vasodilation, but not sweating, is restored as the graft heals. Skin blood flow and sweat rate were assessed from grafted skin and adjacent noninjured skin in three groups of subjects: 5 to 9 months postsurgery (n=13), 2 to 3 years postsurgery (n=13), and 4 to 8 years postsurgery (n=13) during three separate protocols: 1) whole-body heating and cooling, 2) local administration of vasoactive drugs, and 3) local heating and cooling. Cutaneous vasodilation and sweating during whole-body heating were significantly lower (P<.001) in grafted skin when compared with noninjured skin across all groups and demonstrated no improvements with recovery time postsurgery. Maximal endothelial-dependent (acetylcholine) and endothelial-independent (sodium nitroprusside) cutaneous vasodilation remained attenuated (P<.001) in grafted skin up to 4 to 8 years postsurgery, indicating postsynaptic impairments. In grafted skin, cutaneous vasoconstriction during whole-body and local cooling was preserved, whereas vasodilation to local heating was impaired, regardless of the duration postsurgery. Split-thickness skin grafts have impaired cutaneous vasodilation and sweating up to 4 to 8 years postsurgery, thereby limiting the capability of this skin's contribution to thermoregulation during a heats stress. In contrast, grafted skin has preserved vasoconstrictor capacity.

Hydrofluoric acid burns: a 15-year experience.

Hydrofluoric acid (HF) is a strong inorganic acid commonly used in many domestic and industrial settings. It is one of the most common chemical burns encountered in a burn center and frequently engenders controversy in its management. We report our 15 year experience with management of HF burns. We reviewed our experience from 1990 to 2005 for patients admitted with HF burns. Primary treatment was with calcium gluconate gel. Arterial infusion of calcium and fingernail removal were reserved for unrelenting symptoms. There were 7944 acute burn admissions to our center during this study period, 204 of which were chemical burns. HF burns comprised 17% of these chemical burn admissions (35 patients). All were men, with a mean burn size of 2.1 +/- 1.5% (range, 1-6%) and hospital stay of 1.6 +/- 0.7 days (range, 0-3 days). The most common seasonal time of injury was in the summer. Twelve patients (34%) were admitted to the intensive care unit for a total of 14 intensive care unit days, primarily for arterial infusions. Ventilator support was not required in any patient. No electrolyte abnormalities occurred. All burns were either partial thickness or small full thickness with no operative intervention required and no deaths. The upper extremity was most commonly involved (29 patients, 83%). The most common cause was air conditioner cleaner (8 patients, 23%). HF is a common cause of chemical burns. Although hospital admission is usually required for vigorous treatment and pain control, burn size is usually small and does not cause electrolyte abnormalities, significant morbidity, or death.

Heat acclimation of an adult female with a large surface area of grafted skin.

Grafted skin has impaired blood flow and sweating responses necessary for heat dissipation. Heat acclimation improves temperature regulation in healthy individuals, but it is unknown whether heat acclimation improves temperature regulation of individuals with large areas of grafted skin. A 33-year-old woman with 75% total body surface area grafted skin 14 years postinjury performed upright cycling exercise at 45% peak oxygen uptake (50 W) for seven consecutive days in a climatic chamber set to 40 degrees C and 30% relative humidity. The daily goal was for this patient to exercise 90 minutes (with a 5-minute break at minute 45); however, exercise was stopped when an internal temperature (Tc) limit of 39.5 degrees C was reached. The Tc limit was reached during minute 46 of exercise on day 1 of acclimation, but not until minute 65 of exercise on day 7 of acclimation. The increases in Tc and heart rate during the first 45 minutes of exercise (the minimum duration completed for all acclimation bouts) were progressively mitigated with successive days of heat acclimation. Sweat sensitivity (the increase in sweat rate per 1 degrees C increase in Tc) in an area of uninjured skin increased by approximately 30% on acclimation day 7 relative to day 1. Heat acclimation improved thermal tolerance of this patient with a large area of grafted skin, which could increase safety and comfort during thermal stress and/or exercise.

Cutaneous vasoconstriction during whole-body and local cooling in grafted skin five to nine months postsurgery.

The aim of this investigation was to test the hypothesis that skin grafting (5-9 months after surgery) impairs sympathetically mediated cutaneous vasoconstrictor responsiveness. Skin blood flow (laser-Doppler flowmetry) was assessed in grafted skin and adjacent healthy control skin in fourteen subjects (seven male, seven female) during indirect whole-body cooling (ie, cooling the entire body, except the area where skin blood flow was assessed), as well as local cooling (ie, only cooling the area where skin blood flow was assessed). Whole-body cooling was performed by perfusing 5 degrees C water through a water perfusion suit for 3 minutes. Local cooling was performed on a separate visit using a custom Peltier cooling device, which decreased local skin temperature from 39 degrees C to 19 in 5 degrees C decrements in 15-minute stages. Cutaneous vascular conductance (CVC) was calculated from the ratio of skin blood flow to mean arterial pressure. Indirect whole-body cooling decreased CVC from baseline (DeltaCVC) similarly (P = 0.17) between grafted skin (DeltaCVC = -0.23 +/- 0.04 au/mm Hg) and adjacent healthy skin (DeltaCVC = -0.16 +/- 0.02 au/mm Hg). Likewise, decreasing local skin temperature from 39 to 19 degrees C resulted in similar decreases (P = .82) in CVC between grafted skin (DeltaCVC = -1.11 +/- 0.18 au/mm Hg) and adjacent healthy skin (DeltaCVC = -1.06 +/- 0.18 au/mm Hg). Appropriate cutaneous vasoconstriction in grafted skin to both indirect whole-body and local cooling indicates re-innervation of the cutaneous vasoconstrictor system at the graft site. These data suggest that persons with significant skin grafting may have a normal capacity to regulate body temperature during cold exposure by cutaneous vasoconstriction.

Epistatic interactions are critical to gene-association studies: PAI-1 and risk for mortality after burn injury.

Replication of statistically significant associations between single nucleotide polymorphisms (SNPs) and disease phenotypes has been problematic. One reason for conflicting observations may be failure to consider confounding factors, including gene-gene (epistatic) interactions. Our experience with the insertion/deletion polymorphism at -688 in the promoter region of plasminogen activator inhibitor (PAI-1) seems to support this contention and may foreshadow problems for genome-wide association scans, which tend to use unadjusted analytical methodologies. One hundred forty-nine patients with > or =15% total body surface area (TBSA) burns, without significant nonburn-related trauma (injury severity score < or =16), traumatic or anoxic brain injury or spinal cord injury who survived >48 hours postadmission were enrolled under a protocol approved by the UT Southwestern and Parkland Hospital IRBs. Clinical data were collected prospectively and candidate polymorphisms in PAI-1 (-688), toll-like receptor 4 (+896), CD14 (-159), tumor necrosis factor-alpha (-308), and interleukin-6 (-174) were genotyped. The PAI-1 SNP was significantly associated (P-value for trend = 0.036) with risk for death when evaluated in isolation by unadjusted analysis. However, after adjustment for potential confounders using multiple logistic regression, only age, full-thickness burn size, and CD14 genotype (as previously reported) were associated with increased mortality. Genetic association analyses should be adjusted for interactions between multiple SNPs, injury or disease characteristics, and demographic variables. Increasingly sophisticated analytical methods will be required as gene-mapping studies transition from a candidate-gene based approach to genome-wide association scans.

The Parkland formula under fire: is the criticism justified?

Controversy has continued regarding the practicality and accuracy of the Parkland burn formula since its introduction over 35 years ago. The best guide for adequacy of resuscitation is urine output (UOP) per hour. A retrospective study of patients resuscitated with the Parkland formula was conducted to determine the accuracy (calculated vs. actual volume) based on UOP. A review of burn resuscitation from a single institution over 15 years was conducted. The Parkland formula was defined as fluid resuscitation of 3.7 to 4.3 ml/kg/% total body surface area (TBSA) burn in the first 24 hours. Adequate resuscitation was defined as UOP of 0.5 to 1.0 ml/kg/hr. Over-resuscitation was defined as UOP > 1.0 ml/kg/hr. Patients were stratified according to UOP. Burns more than 19% TBSA were included. Electrical burns, trauma, and children (<15 years) were excluded. Four hundred and eighty-three patients were reviewed. Forty-three percent (n = 210) received adequate resuscitation. Forty-eight percent (n = 233) received over-resuscitation. The mean fluid in the adequately and over-resuscitated groups was 5.8 and 6.1 ml/kg/%, respectively (P = .188). Mean TBSA and full thickness burns in the adequately and over-resuscitated groups were 38 and 43%, and 19 and 24%, respectively (P < .05). Inhalation injury was present in 12 and 18% (P = .1). Only 14% of adequately resuscitated and 12% of over-resuscitated patients met Parkland formula criteria. The mean Ivy index in the adequately and over-resuscitated groups was 216 and 259 ml/kg (P < .05). There was no significant difference in complication rates (80 vs. 82%) or mortality (14 vs. 17%). The actual burn resuscitation infrequently met the standard set forth by the Parkland formula. Patients commonly received fluid volumes higher than predicted by the Parkland formula. Emphasis should be placed not on calculated formula volumes, as these should represent the initial resuscitation volume only, but instead on parameters used to guide resuscitation. The Parkland formula only represents a resuscitation "starting" point. The UOP is the important parameter.

American Burn Association consensus conference to define sepsis and infection in burns.

Because of their extensive wounds, burn patients are chronically exposed to inflammatory mediators. Thus, burn patients, by definition, already have "systemic inflammatory response syndrome." Current definitions for sepsis and infection have many criteria (fever, tachycardia, tachypnea, leukocytosis) that are routinely found in patients with extensive burns, making these current definitions less applicable to the burn population. Experts in burn care and research, all members of the American Burn Association, were asked to review the literature and prepare a potential definition on one topic related to sepsis or infection in burn patients. On January 20, 2007, the participants met in Tucson, Arizona to develop consensus for these definitions. After review of the definitions, a summary of the proceedings was prepared. The goal of the consensus conference was to develop and publish standardized definitions for sepsis and infection-related diagnoses in the burn population. Standardized definitions will improve the capability of performing more meaningful multicenter trials among burn centers.

Abdominal compartment syndrome in the severely burned patient.

Scant data exist regarding patient outcome after treatment of abdominal compartment syndrome (ACS) with decompressive laparotomy. This work reviews the outcome of 25 burn patients at a single institution who underwent decompressive laparotomy for treatment of ACS in the periresuscitation period. A computerized burn registry and directed chart review were used for data collection and analysis in this retrospective review. From September 1996, 25 patients underwent decompressive laparotomy after developing ACS. Mean burn size was 65 +/- 19% TBSA. Mean age was 28 +/- 19 years. Twenty-two (88%) died. Myo/ hemoglobinuria was present at admission in eight patients, one of whom survived. Fourteen patients had inhalation injury, of whom two survived. Before decompressive laparotomy, mean bladder pressure and peak inspiratory pressure were 57 +/- 4.2 mm Hg and 41 +/- 2.2 mm Hg, respectively. Mean urine output improved from 28 ml/hr to 90 ml/hr after decompressive laparotomy. The mean Ivy score was 443 +/- 34.95 ml/kg. Development of ACS in burn patients is associated with a high mortality. With development of IAH, therapeutic maneuvers such as sedation and paralysis, escharotomies, or changes in fluid management can be performed in hopes of altering the evolution of intra-abdominal hypertension to ACS. In patients with >40% TBSA burns, bladder pressures should initially be measured every 6 hours. When the Ivy score reaches 200 ml/kg, measure bladder pressures hourly. Decompressive laparotomies should be performed in all patients with ACS if less-invasive maneuvers fail.

Skin grafting impairs postsynaptic cutaneous vasodilator and sweating responses.

This study tested the hypothesis that postsynaptic cutaneous vascular responses to endothelial-dependent and -independent vasodilators, as well as sweat gland function, are impaired in split-thickness grafted skin 5 to 9 months after surgery. Intradermal microdialysis membranes were placed in grafted and adjacent control skin, thereby allowing local delivery of the endothelial-dependent vasodilator, acetylcholine (ACh; 1 x 10(-7) to 1 x 10(-1) M at 10-fold increments) and the endothelial-independent nitric oxide donor, sodium nitroprusside (SNP; 5 x 10(-8) to 5 x 10(-2) M at 10-fold increments). Skin blood flow and sweat rate were simultaneously assessed over the semipermeable portion of the membrane. Cutaneous vascular conductance (CVC) was calculated from the ratio of laser Doppler-derived skin blood flow to mean arterial blood pressure. deltaCVC responses from baseline to these drugs were modeled via nonlinear regression curve fitting to identify the dose of ACh and SNP causing 50% of the maximal vasodilator response (EC50). A rightward shift in the CVC dose response curve for ACh was observed in grafted (EC50 = -2.61 +/- 0.44 log M) compared to adjacent control skin (EC50 = -3.34 +/- 0.46 log M; P = .003), whereas the mean EC50 for SNP was similar between grafted (EC50 = -4.21 +/- 0.94 log M) and adjacent control skin (EC50 = -3.87 +/- 0.65 log M; P = 0.332). Only minimal sweating to exogenous ACh was observed in grafted skin whereas normal sweating was observed in control skin. Increased EC50 and decreased maximal CVC responses to the exogenous administration of ACh suggest impairment of endothelial-dependent cutaneous vasodilator responses in grafted skin 5 to 9 months after surgery. Greatly attenuated sweating responses to ACh suggests either abnormal or an absence of functional sweat glands in the grafted skin.

Impaired cutaneous vasodilation and sweating in grafted skin during whole-body heating.

The aim of this investigation was to identify the consequences of skin grafting on cutaneous vasodilation and sweating in split-thickness grafted skin during indirect whole-body heating 5 to 9 months after surgery. In addition, thermoregulatory function was examined at donor skin sites on a separate day. Skin blood flow and sweat rate (SR) were assessed from both grafted (n = 14) or donor skin (n = 11) and compared with the respective adjacent control skin during indirect whole-body heating. Cutaneous vascular conductance (CVC) was calculated from the ratio of skin blood flow (arbitrary units; au) to mean arterial pressure. Whole-body heating significantly increased internal temperature (37.0 +/- 0.1 degrees C to 37.8 +/- 0.1 degrees C; P < .05). Cutaneous vasodilation (ie, the increase in CVC from baseline, deltaCVC) during whole-body heating was significantly attenuated in grafted skin (deltaCVC = 0.14 +/- 0.15 au/mm Hg) compared with adjacent control skin (deltaCVC = 0.84 +/- 0.11 au/mm Hg; P < .05). Increases in sweat rate (deltaSR) were also significantly lower in grafted skin (deltaSR = 0.08 +/- 0.08 mg/cm2/min) compared with adjacent control skin (deltaSR = 1.16 +/- 0.20 mg/ cm2/min; P < .05). Cutaneous vasodilation and sweating during heating were not significantly different between donor sites (deltaCVC = 0.71 +/- 0.19 au/mm Hg; deltaSR = 1.04 +/- 0.15 mg/cm2/min) and adjacent control skin (deltaCVC = 0.50 +/- 0.10 au/mm Hg; deltaSR = 0.83 +/- 0.17 mg/cm2/min). Greatly attenuated or absence of cutaneous vasodilation and sweating suggests impairment of thermoregulatory function in grafted skin, thereby, diminishing the contribution of this skin to overall temperature control during a heat stress.

Use of high-frequency percussive ventilation in inhalation injuries.

Inhalation injury causes significant morbidity and mortality, accounting for nearly 80% of non-fire-related deaths and affecting nearly 25% of all patients hospitalized with thermal injury. High-frequency percussive ventilation (HFPV) has been reported to decrease both the incidence of pulmonary barotrauma and pneumonia in inhalation injury. It has evolved into a ventilatory modality promoted to rapidly remove airway secretions and improve survival of patients with smoke inhalation injury. From 1997 to 2005, a total of 92 patients with inhalation injury were treated with HFPV. This group was compared with 130 patients treated with conventional mechanical ventilation between 1997 and 2005. The diagnosis of inhalation injury was made on admission, based on the following clinical criteria: injury in a closed space, carbonaceous sputum, and/or positive bronchoscopy (presence of carbonaceous deposits, erythema or ulceration). Both modes of ventilation were begun within 24 hours of injury. Both groups were similar with respect to demographics and injury severity. The mean number of ventilator days, days in the intensive care unit, length of stay, and incidence of pneumonia did not differ significantly between groups. Twenty-six of 92 (28%) patients treated with HFPV, and 56 of 130 with conventional mechanical ventilation (43%) died. There was a significant decrease in both overall morbidity and mortality in the subset of patients with < or = 40% TBSA treated with HFPV. Future randomized, controlled trials are needed to determine the precise role of HFPV in the treatment of inhalation injuries.

Searching for alleles associated with complicated outcomes after burn injury.

Sepsis is a serious and growing health problem among patients admitted to intensive care units. When accompanied by organ failure, sepsis carries a 30-50% case-fatality rate. Although our understanding of burn pathophysiology has grown in recent years, we are still unable to identify accurately patients who are at increased risk for infectious complications and death. Genetic predisposition is likely to explain a portion of this variation. Understanding which genes and allelic variants contribute to disease risk would increase our ability to predict who is at increased risk and intervene accordingly, as well as identify molecular targets for novel and individualized therapies. Several obstacles exist to identification of which specific alleles and loci contribute to patient risk, including achievement of sufficient statistical power, population admixture and epistatic interaction among multiple genes and environmental factors. Although increasing sample size will resolve most, if not all, of these issues, slow patient accrual often makes this solution impractical for a single institution within a reasonable timeframe. This situation is complicated by the fact that traditional analysis methods perform poorly in the face of data sparseness. Identification of risk factors for severe sepsis and death after burn injury will likely require collaborative patient enrollment as well as development of advanced analytical methodologies. While overcoming these obstacles may prove difficult, the effort is warranted, as the ultimate benefit to patients is considerable.

CD14-159 C allele is associated with increased risk of mortality after burn injury.

Although comprehension of postburn pathophysiology has grown in recent years, we are still unable to accurately identify burn patients who are at an increased risk of infectious complications and death. This unexplained variation is likely influenced by heritable factors; the genetic predisposition for death from infection has been estimated as greater than that for cardiovascular disease or cancer. Identify genetic variants associated with increased mortality after burn injury. A total of 233 patients with burns of 15% of total body surface area or greater or smoke inhalation injury who survived more than 48 h after admission and were without significant nonburn-related trauma (injury severity score > or = 16), traumatic or anoxic brain injury, or spinal cord injury. We examined the influence of genotype at five candidate loci (interleukin [IL]-1beta, IL-6, tumor necrosis factor-alpha, toll-like receptor 4, CD14) on mortality risk after burn injury. DNA was isolated from residual blood from laboratory draws and candidate genotypes were determined by real-time polymerase chain reaction using TaqMan probes. Clinical data were prospectively collected into a local, curated database. Allelic associations were analyzed by multivariate logistic regression. After adjustment for age, full-thickness burn size, inhalation injury, ethnicity, and sex, carriage of the CD14-159 C allele imparted at least a 1.3-fold increased risk for death after burn injury, relative to TT homozygotes (adjusted odds ratio, 2.9; 95% confidence interval, 1.3-6.8; P = 0.01). This association was stronger (adjusted odds ratio, 3.3; 95% confidence interval, 1.3-8.4; P = 0.01) when the analysis was conducted only on deaths accompanied by severe sepsis. In addition, a gene dosage effect for increased mortality was apparent for carriage of the CD14-159 C allele (P = 0.006). The gene dosage effect remained when white, Hispanic, or African American patients were analyzed independently, although statistical significance was not achieved in the subgroup analysis. None of the other single nucleotide polymorphisms examined were significantly associated with mortality. These data provide strong evidence that a CD14 promoter allele that is known to impart lower baseline and induced CD14 transcription also affects mortality risk after burn injury. A potential (although untested) mechanism for our observation is that reduced signaling through CD14/toll-like receptor 4 in response to challenge by gram-negative bacteria after burns results in a blunted innate immune response and subsequent increased likelihood for systemic infection and death.