Ronald P. Mlcak

Pathophysiologic response to severe burn injury.

Objective:To improve clinical outcome and to determine new treatment options, we studied the pathophysiologic response postburn in a large prospective, single center, clinical trial. Summary Background Data:A severe burn injury leads to marked hypermetabolism and catabolism, which are associated with morbidity and mortality. The underlying pathophysiology and the correlations between humoral changes and organ function have not been well delineated. Methods:Two hundred forty-two severely burned pediatric patients [>30% total body surface area (TBSA)], who received no anabolic drugs, were enrolled in this study. Demographics, clinical data, serum hormones, serum cytokine expression profile, organ function, hypermetabolism, muscle protein synthesis, incidence of wound infection sepsis, and body composition were obtained throughout acute hospital course. Results:Average age was 8 ± 0.2 years, and average burn size was 56 ± 1% TBSA with 43 ± 1% third-degree TBSA. All patients were markedly hypermetabolic throughout acute hospital stay and had significant muscle protein loss as demonstrated by a negative muscle protein net balance (−0.05% ± 0.007 nmol/100 mL leg/min) and loss of lean body mass (LBM) (−4.1% ± 1.9%); P < 0.05. Patients lost 3% ± 1% of their bone mineral content (BMC) and 2 ± 1% of their bone mineral density (BMD). Serum proteome analysis demonstrated profound alterations immediately postburn, which remained abnormal throughout acute hospital stay; P < 0.05. Cardiac function was compromised immediately after burn and remained abnormal up to discharge; P < 0.05. Insulin resistance appeared during the first week postburn and persisted until discharge. Patients were hyperinflammatory with marked changes in IL-8, MCP-1, and IL-6, which were associated with 2.5 ± 0.2 infections and 17% sepsis. Conclusions:In this large prospective clinical trial, we delineated the complexity of the postburn pathophysiologic response and conclude that the postburn response is profound, occurring in a timely manner, with derangements that are greater and more protracted than previously thought.

Determinants of Skeletal Muscle Catabolism After Severe Burn

ObjectiveTo determine which patient factors affect the degree of catabolism after severe burn. Summary Background DataCatabolism is associated with severe burn and leads to erosion of lean mass, impaired wound healing, and delayed rehabilitation. MethodsFrom 1996 to 1999, 151 stable-isotope protein kinetic studies were performed in 102 pediatric and 21 adult subjects burned over 20–99.5% of their total body surface area (TBSA). Patient demographics, burn characteristics, and hospital course variables were correlated with the net balance of skeletal muscle protein synthesis and breakdown across the leg. Data were analyzed sequentially and cumulatively through univariate and cross-sectional multiple regression. ResultsIncreasing age, weight, and delay in definitive surgical treatment predict increased catabolism (P < .05). Body surface area burned increased catabolism until 40% TBSA was reached; catabolism did not consistently increase thereafter. Resting energy expenditure and sepsis were also strong predictors of net protein catabolism. Among factors that did not significantly correlate were burn type, pneumonia, wound contamination, and time after burn. From these results, the authors also infer that gross muscle mass correlates independently with protein wasting after burn. ConclusionsHeavier, more muscular subjects, and subjects whose definitive surgical treatment is delayed are at the greatest risk for excess catabolism after burn. Sepsis and excessive hypermetabolism are also associated with protein catabolism.

Long-Term Persistance of the Pathophysiologic Response to Severe Burn Injury

Background Main contributors to adverse outcomes in severely burned pediatric patients are profound and complex metabolic changes in response to the initial injury. It is currently unknown how long these conditions persist beyond the acute phase post-injury. The aim of the present study was to examine the persistence of abnormalities of various clinical parameters commonly utilized to assess the degree hypermetabolic and inflammatory alterations in severely burned children for up to three years post-burn to identify patient specific therapeutic needs and interventions. Methodology/Principal Findings Patients: Nine-hundred seventy-seven severely burned pediatric patients with burns over 30% of the total body surface admitted to our institution between 1998 and 2008 were enrolled in this study and compared to a cohort non-burned, non-injured children. Demographics and clinical outcomes, hypermetabolism, body composition, organ function, inflammatory and acute phase responses were determined at admission and subsequent regular intervals for up to 36 months post-burn. Statistical analysis was performed using One-way ANOVA, Students t-test with Bonferroni correction where appropriate with significance accepted at p<0.05. Resting energy expenditure, body composition, metabolic markers, cardiac and organ function clearly demonstrated that burn caused profound alterations for up to three years post-burn demonstrating marked and prolonged hypermetabolism, p<0.05. Along with increased hypermetabolism, significant elevation of cortisol, catecholamines, cytokines, and acute phase proteins indicate that burn patients are in a hyperinflammatory state for up to three years post-burn p<0.05. Conclusions Severe burn injury leads to a much more profound and prolonged hypermetabolic and hyperinflammatory response than previously shown. Given the tremendous adverse events associated with the hypermetabolic and hyperinflamamtory responses, we now identified treatment needs for severely burned patients for a much more prolonged time.

Burn size determines the inflammatory and hypermetabolic response

BackgroundIncreased burn size leads to increased mortality of burned patients. Whether mortality is due to inflammation, hypermetabolism or other pathophysiologic contributing factors is not entirely determined. The purpose of the present study was to determine in a large prospective clinical trial whether different burn sizes are associated with differences in inflammation, body composition, protein synthesis, or organ function.MethodsPediatric burned patients were divided into four burn size groups: <40% total body surface area (TBSA) burn, 40–59% TBSA burn, 60–79% TBSA burn, and >80% TBSA burn. Demographic and clinical data, hypermetabolism, the inflammatory response, body composition, the muscle protein net balance, serum and urine hormones and proteins, and cardiac function and changes in liver size were determined.ResultsOne hundred and eighty-nine pediatric patients of similar age and gender distribution were included in the study (<40% TBSA burn, n = 43; 40–59% TBSA burn, n = 79; 60–79% TBSA burn, n = 46; >80% TBSA burn, n = 21). Patients with larger burns had more operations, a greater incidence of infections and sepsis, and higher mortality rates compared with the other groups (P < 0.05). The percentage predicted resting energy expenditure was highest in the >80% TBSA group, followed by the 60–79% TBSA burn group (P < 0.05). Children with >80% burns lost the most body weight, lean body mass, muscle protein and bone mineral content (P < 0.05). The urine cortisol concentration was highest in the 80–99% and 60–79% TBSA burn groups, associated with significant myocardial depression and increased change in liver size (P < 0.05). The cytokine profile showed distinct differences in expression of IL-8, TNF, IL-6, IL-12p70, monocyte chemoattractant protein-1 and granulocyte–macrophage colony-stimulating factor (P < 0.05).ConclusionMorbidity and mortality in burned patients is burn size dependent, starts at a 60% TBSA burn and is due to an increased hypermetabolic and inflammatory reaction, along with impaired cardiac function.

Reduction in Mortality in Pediatric Patients with Inhalation Injury with Aerosolized Heparin/acetylcystine Therapy

Smoke-inhalation injury causes a destruction of the ciliated epithelium that lines the tracheobronchial tree. Casts produced from these cells, polymorphonuclear leukocytes and mucus, can cause upper-airway obstruction, contributing to pulmonary failure. We have reported that a combination of aerosolized heparin and a mucolytic agent, N-acetylcystine [corrected], can ameliorate cast formation and reduce pulmonary failure secondary to smoke inhalation. In this study, 90 consecutive pediatric patients between 1985 and 1995 who had bronchoscopically diagnosed inhalation injury requiring ventilatory support were studied. Forty-three children admitted between 1985 and 1989 acted as controls. Forty-seven children admitted between 1990 and 1994 received 5000 units of heparin and 3 ml of a 20% solution of N-acetylcystine [corrected] aerosolized every 4 hours the first 7 days after the injury. All patients were extubated when they were able to maintain spontaneously a PaO2/FIO2 ratio of more than 400. The number of patients requiring reintubation for successive pulmonary failure was recorded, as was mortality. The results indicate a significant decrease in reintubation rates, in incidence of atelectasis, and in mortality for patients treated with the regimen of heparin and N-acetylcystine [corrected] when compared with controls. Heparin/N-acetylcystine [corrected] nebulization in children with massive burn injury and smoke-inhalation injury results in a significant decrease in incidence of reintubation for progressive pulmonary failure and a reduction in mortality.

Energy Expenditure and Caloric Balance After Burn: Increased Feeding Leads to Fat Rather Than Lean Mass Accretion

ObjectiveResting energy expenditure (REE) is commonly measured in critical illness to determine caloric “demands” and thus nutritive needs. Summary Background DataThe purpose of this study was to 1) determine whether REE is associated with clinical outcomes and 2) determine whether an optimal caloric delivery rate based on REE exists to offset erosion of lean mass after burn. MethodsFrom 1995 to 2001, REE was measured by indirect calorimetry in 250 survivors of 10 to 99%TBSA burns. Caloric intake and REE were correlated with muscle protein catabolism, length of stay, ventilator dependence, sepsis, and mortality. From 1998 to 2000, 42 patients (>60%TBSA burns) received continuous enteral nutrition at a spectrum of caloric balance between 1.0x REE kcal/d –1.8x REE kcal/d. Serial body composition was measured by dual energy x-ray absorptiometry. Lean mass, fat mass, morbidity, and mortality were determined. ResultsREE/predicted basal metabolic rate correlated directly with burn size, sepsis, ventilator dependence, and muscle protein catabolism (P < .05). Declining REE correlated with mortality (P < .05). 2) Erosion of lean body mass was not attenuated by increased caloric balance, however, fat mass increased with caloric supply (P < .05). ConclusionIn surviving burned patients, caloric delivery beyond 1.2 × REE results in increased fat mass without changes in lean body mass. Declining energy expenditure appears to be a harbinger of mortality in severely burned patients.

Effects of early excision and aggressive enteral feeding on hypermetabolism, catabolism, and sepsis after severe burn.

BACKGROUND Severe burn induces a systemic hypermetabolic response, which includes increased energy expenditure, protein catabolism, and diminished immunity. We hypothesized that early burn excision and aggressive enteral feeding diminish hypermetabolism. METHODS Forty-six burned children were enrolled into a cohort analytic study. Cohorts were segregated according to time from burn to transfer to our institution for excision, grafting, and nutritional support. No subject had undergone wound excision or continuous nutritional support before transfer. Resting energy expenditure, skeletal muscle protein kinetics, the degree of bacterial colonization from quantitative cultures, and the incidence of burn sepsis were measured as outcome variables. RESULTS Early, aggressive treatment did not decrease energy expenditure; however, it did markedly attenuate muscle protein catabolism when compared with delay in aggressive treatment. Wound colonization and sepsis were diminished in the early treatment group as well. CONCLUSION Early excision and concurrent aggressive feeding attenuate muscle catabolism and improve infectious outcomes after burn.

Browning of Subcutaneous White Adipose Tissue in Humans after Severe Adrenergic Stress

Since the presence of brown adipose tissue (BAT) was confirmed in adult humans, BAT has become a therapeutic target for obesity and insulin resistance. We examined whether human subcutaneous white adipose tissue (sWAT) can adopt a BAT-like phenotype using a clinical model of prolonged and severe adrenergic stress. sWAT samples were collected from severely burned and healthy individuals. A subset of burn victims were prospectively followed during their acute hospitalization. Browning of sWAT was determined by the presence of multilocular adipocytes, uncoupling protein 1 (UCP1), and increased mitochondrial density and respiratory capacity. Multilocular UCP1-positive adipocytes were found in sWAT samples from burn patients. UCP1 mRNA, mitochondrial density, and leak respiratory capacity in sWAT increased after burn trauma. Our data demonstrate that human sWAT can transform from an energy-storing to an energy-dissipating tissue, which opens new research avenues in our quest to prevent and treat obesity and its metabolic complications.

Gender differences in pediatric burn patients: does it make a difference?

Objective:There is evidence that females have a better outcome in intensive care units (ICUs) when compared with males. The aim of the present study was to compare hospital course and physiologic markers between severely burned pediatric females and males. Summary Background Data:One-hundred eighty-nine children sustaining a ≥40% total body surface area burn were divided into females (n = 76) and males (n = 113). Methods:Patient demographics, clinical parameters, and mortality were noted. Muscle protein synthesis was determined by stable isotope technique. Resting energy expenditure (REE) was measured by indirect calorimetry and body composition by dual x-ray absorptiometry. Serum hormones, proteins, and cytokines were determined. Cardiac function and liver size were determined by repeated ultrasound measurements. Results:There were no significant differences between females and males for mortality, demographics, burn size, nutritional intake, or concomitant injuries. ICU stay was in females: 29±3 days whereas the stay in males was 38±3 days, P < 0.05. Females had a significant attenuated loss in muscle protein net balance (females: −0.028±0.001% vs. males: −0.05±0.007%) and an increase in lean body mass (Δ females: 5±4% vs. Δ males: −1±3%), P < 0.05. Percent-predicted REE was significantly decreased in females compared with males, P < 0.05. Systemic inflammatory markers and stress hormone levels were significantly decreased in females, P < 0.05. Cardiac and liver dysfunction were significantly attenuated in females compared with males, P < 0.05. Conclusions:Female burned patients exert an attenuated inflammatory and hypermetabolic response compared with males. This decrease is reflected in improved muscle protein net balance and preservation of lean body mass, which are associated with shortened hospital stay.

Longitudinal assessment of Integra in primary burn management: a randomized pediatric clinical trial.

Background:Early excision with autograft-allograft closure is standard in severe burn management. Cadaver skin is associated with risks such as antigenicity, infection, and limited availability and shelf life. Previous studies have shown that Integra is safe to use in burns of <20% total body surface area. However, the suitability of its use in large burns (>50% total body surface area), its effects on postburn hypermetabolism, and the long-term cosmetic and functional results have not yet been evaluated. Materials and Methods:Twenty children with an average burn size of 73 ± 15% total body surface area (71 ± 15% full-thickness burn) were randomized to be treated with either Integra or with autograft-allograft technique. Outcome measures such as length of hospital stay, mortality, incidence of infection and sepsis, acute phase protein levels, and muscle fractional synthetic rate were compared between and within groups during the acute stay (admission to discharge). Outcome measures such as resting energy expenditure, body composition data (measured by dual-energy radiograph absorptiometry), cardiac function indexes, and number of reconstructive procedures were compared during acute hospital stay and at long-term follow-up (up to 2 yrs postinjury). Scar evaluation was performed at long-term follow-up. Results:There were no significant differences between Integra and controls in burn size (70 ± 5% vs. 74 ± 4% total body surface area), mortality (40% vs. 30%), and length of stay (41 ± 4 vs. 39 ± 4 days). In the short term, resting energy expenditure significantly decreased (p < .01), and serum levels of constitutive proteins significantly increased (p < .03) in the Integra group compared with controls. Long-term follow-up revealed a significant increase in bone mineral content and density (24 months postburn, p < .05), as well as improved scarring in terms of height, thickness, vascularity, and pigmentation (12 months and 18–24 months, p < .01) in the Integra group. Conclusion:Integra can be used for immediate wound coverage in children with severe burns without the associated risks of cadaver skin.