John L. Hunt

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.

The risk factors and time course of sepsis and organ dysfunction after burn trauma

BACKGROUND Sepsis and organ dysfunction are common and likely contribute to death after burn trauma. We sought to define relationships between sepsis, severe multiple organ dysfunction (MOD), and death after burn trauma. METHODS Adults with > or = 20% total body surface area burns were prospectively enrolled. Information regarding infection, severity of sepsis, and organ failure was collected daily. Risk factors (e.g., age, burn size, shock) were analyzed for their association with severe MOD, complicated sepsis, and death. We characterized the temporal relationship between organ failure and sepsis. RESULTS Of 175 patients, 27% developed severe MOD, 17% developed complicated sepsis, and 22% died. Full-thickness burn size, age, and inhalation injury were associated with MOD, sepsis, and death. Infection preceded MOD in 83% of patients with both. A base deficit of > or = 6 mEq/L at 24 hours after injury was associated with death. CONCLUSION When it occurs, severe MOD is usually preceded by infection. In addition, an elevated base deficit at 24 hours and septic shock are the most important factors associated with and possibly contributing to death after burn trauma.

Quantitative proteome analysis of human plasma following in vivo lypopolysaccharide administration using 16O/18O labeling and the accurate mass and time tag approach

Identification of novel diagnostic or therapeutic biomarkers from human blood plasma would benefit significantly from quantitative measurements of the proteome constituents over a range of physiological conditions. Herein we describe an initial demonstration of proteome-wide quantitative analysis of human plasma. The approach utilizes postdigestion trypsin-catalyzed 16O/18O peptide labeling, two-dimensional LC-FTICR mass spectrometry, and the accurate mass and time (AMT) tag strategy to identify and quantify peptides/proteins from complex samples. A peptide accurate mass and LC elution time AMT tag data base was initially generated using MS/MS following extensive multidimensional LC separations to provide the basis for subsequent peptide identifications. The AMT tag data base contains >8,000 putative identified peptides, providing 938 confident plasma protein identifications. The quantitative approach was applied without depletion of high abundance proteins for comparative analyses of plasma samples from an individual prior to and 9 h after lipopolysaccharide (LPS) administration. Accurate quantification of changes in protein abundance was demonstrated by both 1:1 labeling of control plasma and the comparison between the plasma samples following LPS administration. A total of 429 distinct plasma proteins were quantified from the comparative analyses, and the protein abundances for 25 proteins, including several known inflammatory response mediators, were observed to change significantly following LPS administration.

TLR4 and TNF-α 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 ⩾20% of their total body surface area or any smoke inhalation injury without significant non-burn related trauma (injury severity score (ISS)⩾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-α −308, IL-1β −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-α −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-α −308 polymorphisms were significantly associated with an increased risk for severe sepsis following burn trauma.

High Dynamic Range Characterization of the Trauma Patient Plasma Proteome

Although human plasma represents an attractive sample for disease biomarker discovery, the extreme complexity and large dynamic range in protein concentrations present significant challenges for characterization, candidate biomarker discovery, and validation. Herein we describe a strategy that combines immunoaffinity subtraction and subsequent chemical fractionation based on cysteinyl peptide and N-glycopeptide captures with two-dimensional LC-MS/MS to increase the dynamic range of analysis for plasma. Application of this “divide-and-conquer” strategy to trauma patient plasma significantly improved the overall dynamic range of detection and resulted in confident identification of 22,267 unique peptides from four different peptide populations (cysteinyl peptides, non-cysteinyl peptides, N-glycopeptides, and non-glycopeptides) that covered 3654 different proteins with 1494 proteins identified by multiple peptides. Numerous low abundance proteins were identified, exemplified by 78 “classic” cytokines and cytokine receptors and by 136 human cell differentiation molecules. Additionally a total of 2910 different N-glycopeptides that correspond to 662 N-glycoproteins and 1553 N-glycosylation sites were identified. A panel of the proteins identified in this study is known to be involved in inflammation and immune responses. This study established an extensive reference protein database for trauma patients that provides a foundation for future high throughput quantitative plasma proteomic studies designed to elucidate the mechanisms that underlie systemic inflammatory responses.

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 pathophysiology of acute electric injuries

Results of the present investigation indicate that an electric burn is simply a thermal injury. The tissue damage associated with an electric injury occurs when electric energy is converted to thermal energy or heat. An electric burn is self limiting: once the current arcs, no further skin and muscle damage is possible because amperage falls to zero. Tissue temperature is the critical factor in determining the magnitude of tissue injury before the current arcs. With the exception of skin resistance, resistances of individual tissues seem not relevant to amount of tissue damage in electric injuries. Living tissue acts as a volume conductor; once skin resistance has been overcome all internal tissue resistance, with the exception of bone, is negligible to current flow. In the present study the volume of tissue traversed by the electric current was more closely related to the extent of tissue injury than the internal resistance of the individual tissues. Muscle injury occurred at the time of initial thermal insult and progressive or de novo muscle necrosis was not seen in this model.

Fiberoptic bronchoscopy in acute inhalation injury

Fiberoptic bronchoscopy proved to be a simple, safe, and accurate method of diagnosing acute inhalation injury. Both the anatomic level and the severity of large airway injury were easily identified. The identification of a supraglottic and infraglottic component to inhalation injury was not only helpful in determining the appropriate therapy but also in predicting ultimate pulmonary complications. When bronchoscopy was used in conjunction with the 133Xenon scintiphotoscan, both large and small airway injuries could be identified. The only clinical situation where bronchoscopy failed to identify an inhalation injury was in the immediate postburn period if the patient wasin hypovolemic shock. In this particular clinical circumstance the characteristic mucosal alterations may be absent; yet if bronchoscopy is performed after hypovolemic shock has been corrected, mucosal changes characteristic of inhalation injury will be seen.

Electrical Injuries: A 20-Year Review

Electrical injuries continue to present problems with devastating complications and long-term socioeconomic impact. The purpose of this study is to review one institutions experience with electrical injuries. From 1982 to 2002, there were 700 electric injury admissions. A computerized burn registry was used for data collection and analysis. Of these injuries, 263 were high voltage (> or =1000 V), 143 were low voltage (<1000 V), 277 were electric arc flash burns, and 17 were lightning injuries. Mortality was highest in the lightning strikes (17.6%) compared with the high voltage (5.3%) and low voltage (2.8%) injuries, and mortality was least in electric arc injuries without passage of current through the patient (1.1%). Complications were most common in the high-voltage group. Mean length of stay was longest in this group (18.9 +/- 1.4 days), and the patients in this group also required the most operations (3 +/- 0.2). Work-related activity was responsible for the majority of these high-voltage injuries, with the most common occupations being linemen and electricians. These patients tended to be younger men in the prime of their working lives. Electrical injuries continue to make up an important subgroup of patients admitted to burn centers. High-voltage injuries in particular have far reaching social and economic impact largely because of the patient population at greatest risk, that is, younger men at the height of their earning potential. Injury prevention, although appropriate, remains difficult in this group because of occupation-related risk.

Child abuse by burning--an index of suspicion

Although general awareness of child abuse is increasing, abuse by burning is often unrecognized. Seventy-one consecutive children admitted with inflicted burns were studied. Mean age was 1.8 yrs and mean burn size was 13.5%. Mean length of stay was 18.9 days. Scalds (83% from tap water) were the most frequent cause of injury. An immersion pattern was present in 59%; six patients had a classic forced immersion injury. Fourteen children had nonburn trauma. Four patients died: all had tap water immersion burns. Inflicted burns are usually manifested by characteristic patterns of injury, which must be correlated with the given history. When compared with accidentally burned children, abused children were significantly younger, had longer hospital stays, and had a higher mortality. A team approach to child abuse with the addition of a specially trained group is important to insure prompt recognition, more objective appraisals, and further followup.