Gabriela A. Kulp

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.

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.

Intensive Insulin Therapy in Severely Burned Pediatric Patients: A Prospective Randomized Trial

RATIONALE Hyperglycemia and insulin resistance have been shown to increase morbidity and mortality in severely burned patients, and glycemic control appears essential to improve clinical outcomes. However, to date no prospective randomized study exists that determines whether intensive insulin therapy is associated with improved post-burn morbidity and mortality. OBJECTIVES To determine whether intensive insulin therapy is associated with improved post-burn morbidity. METHODS A total of 239 severely burned pediatric patients with burns over greater than 30% of their total body surface area were randomized (block randomization 1:3) to intensive insulin treatment (n = 60) or control (n = 179). MEASUREMENTS AND MAIN RESULTS Demographics, clinical outcomes, sepsis, glucose metabolism, organ function, and inflammatory, acute-phase, and hypermetabolic responses were determined. Demographics were similar in both groups. Intensive insulin treatment significantly decreased the incidence of infections and sepsis compared with controls (P < 0.05). Furthermore, intensive insulin therapy improved organ function as indicated by improved serum markers, DENVER2 scores, and ultrasound (P < 0.05). Intensive insulin therapy alleviated post-burn insulin resistance and the vast catabolic response of the body (P < 0.05). Intensive insulin treatment dampened inflammatory and acute-phase responses by deceasing IL-6 and acute-phase proteins compared with controls (P < 0.05). Mortality was 4% in the intensive insulin therapy group and 11% in the control group (P = 0.14). CONCLUSIONS In this prospective randomized clinical trial, we showed that intensive insulin therapy improves post-burn morbidity. Clinical trial registered with www.clinicaltrials.gov (NCT00673309).

The leading causes of death after burn injury in a single pediatric burn center

IntroductionSevere thermal injury is characterized by profound morbidity and mortality. Advances in burn and critical care, including early excision and grafting, aggressive resuscitation and advances in antimicrobial therapy have made substantial contributions to decrease morbidity and mortality. Despite these advances, death still occurs. Our aim was to determine the predominant causes of death in burned pediatric patients in order to develop new treatment avenues and future trajectories associated with increased survival.MethodsPrimary causes of death were reviewed from 144 pediatric autopsy reports. Percentages of patients that died from anoxic brain injuries, sepsis, or multi-organ failure were calculated by comparing to the total number of deaths. Data was stratified by time (from 1989 to 1999, and 1999 to 2009), and gender. Statistical analysis was done by chi-squared, Students t-test and Kaplan-Meier for survival where applicable. Significance was accepted as P < 0.05.ResultsFive-thousand two-hundred-sixty patients were admitted after burn injury from July 1989 to June 2009, and of those, 145 patients died after burn injury. Of these patients, 144 patients had an autopsy. The leading causes of death over 20 years were sepsis (47%), respiratory failure (29%), anoxic brain injury (16%), and shock (8%). From 1989 to 1999, sepsis accounted for 35% of deaths but increased to 54% from 1999 to 2009, with a significant increase in the proportion due to antibiotic resistant organisms (P < 0.05).ConclusionsSepsis is the leading cause of death after burn injury. Multiple antibiotic resistant bacteria now account for the bulk of deaths due to sepsis. Further improvement in survival may require improved strategies to deal with this problem.

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.

Abnormal Insulin Sensitivity Persists up to Three Years in Pediatric Patients Post-Burn

CONTEXT The acute hypermetabolic response post-burn is associated with insulin resistance and hyperglycemia, significantly contributing to adverse outcome of these patients. OBJECTIVE The aim of the study was to examine the persistence of abnormalities of various clinical parameters commonly utilized to assess the degree of insulin resistance in severely burned children for up to 3 yr after the burn injury. DESIGN, SETTING AND PATIENTS A total of 194 severely burned pediatric patients, admitted to our institute between 2002 and 2007, were enrolled in this prospective study and compared to a cohort of 95 nonburned, noninjured children. MAIN OUTCOME MEASURES Urinary cortisol, epinephrine, and norepinephrine, serum cytokines, and resting energy requirements were determined at admission and 1, 2, 6, 9, 12, 18, 24, and 36 months post-burn. A 75-g oral glucose tolerance test was performed at similar time points; serum glucose, insulin, and C-peptide were measured; and insulin sensitivity indices, such as ISI Matsuda, homeostasis model assessment, quantitative insulin sensitivity check index, and ISI Cederholm, were calculated. Statistical analysis was performed by ANOVA with Bonferroni correction with significance accepted at P < 0.05. RESULTS Urinary cortisol and catecholamines, serum IL-7, IL-10, IL-12, macrophage inflammatory protein-1b, monocyte chemoattractant protein-1, and resting energy requirements were significantly increased for up to 36 months post-burn (P < 0.05). Glucose values were significantly augmented for 6 months post-burn (P < 0.05), associated with significant increases in serum C-peptide and insulin that remained significantly increased for 36 months compared to nonburned children (P < 0.05). Insulin sensitivity indices, ISI Matsuda, ISI quantitative insulin sensitivity check index, and homeostasis model assessment were abnormal throughout the whole study period, indicating peripheral and whole body insulin resistance. The insulinogenic index displayed physiological values, indicating normal pancreatic beta-cell function. CONCLUSIONS A severe burn is associated with stress-induced insulin resistance that persists not only during the acute phase but also for up to 3 yr post-burn.

The Effect of Oxandrolone on the Endocrinologic, Inflammatory, and Hypermetabolic Responses During the Acute Phase Postburn

Objective and Summary Background Data:Postburn long-term oxandrolone treatment improves hypermetabolism and body composition. The effects of oxandrolone on clinical outcome, body composition, endocrine system, and inflammation during the acute phase postburn in a large prospective randomized single-center trial have not been studied. Methods:Burned children (n = 235) with >40% total body surface area burn were randomized (block randomization 4:1) to receive standard burn care (control, n = 190) or standard burn care plus oxandrolone for at least 7 days (oxandrolone 0.1 mg/kg body weight q.12 hours p.o, n = 45). Clinical parameters, body composition, serum hormones, and cytokine expression profiles were measured throughout acute hospitalization. Statistical analysis was performed by Student t test, or ANOVA followed by Bonferroni correction with significance accepted at P < 0.05. Results:Demographics and clinical data were similar in both groups. Length of intensive care unit stay was significantly decreased in oxandrolone-treated patients (0.48 ± 0.02 days/% burn) compared with controls (0.56 ± 0.02 days/% burn), (P < 0.05). Control patients lost 8 ± 1% of their lean body mass (LBM), whereas oxandrolone-treated patients had preserved LBM (+9 ± 4%), P < 0.05. Oxandrolone significantly increased serum prealbumin, total protein, testosterone, and AST/ALT, whereas it significantly decreased α2-macroglobulin and complement C3, P < 0.05. Oxandrolone did not adversely affect the endocrine and inflammatory response as we found no significant differences in the hormone panels and cytokine expression profiles. Conclusions:In this large prospective, double-blinded, randomized single-center study, oxandrolone shortened length of acute hospital stay, maintained LBM, improved body composition and hepatic protein synthesis while having no adverse effects on the endocrine axis postburn, but was associated with an increase in AST and ALT.

Randomized Controlled Trial to Determine the Efficacy of Long-Term Growth Hormone Treatment in Severely Burned Children

Background:Recovery from a massive burn is characterized by catabolic and hypermetabolic responses that persist up to 2 years and impair rehabilitation and reintegration. The objective of this study was to determine the effects of long-term treatment with recombinant human growth hormone (rhGH) on growth, hypermetabolism, body composition, bone metabolism, cardiac work, and scarring in a large prospective randomized single-center controlled clinical trial in pediatric patients with massive burns. Patients and Methods:A total of 205 pediatric patients with massive burns over 40% total body surface area were prospectively enrolled between 1998 and 2007 (clinicaltrials.gov ID NCT00675714). Patients were randomized to receive either placebo (n = 94) or long-term rhGH at 0.05, 0.1, or 0.2 mg/kg/d (n = 101). Changes in weight, body composition, bone metabolism, cardiac output, resting energy expenditure, hormones, and scar development were measured at patient discharge and at 6, 9, 12, 18, and 24 months postburn. Statistical analysis used Tukey t test or ANOVA followed by Bonferroni correction. Significance was accepted at P < 0.05. Results:RhGH administration markedly improved growth and lean body mass, whereas hypermetabolism was significantly attenuated. Serum growth hormone, insulin-like growth factor-I, and IGFBP-3 was significantly increased, whereas percent body fat content significantly decreased when compared with placebo, P < 0.05. A subset analysis revealed most lean body mass gain in the 0.2 mg/kg group, P < 0.05. Bone mineral content showed an unexpected decrease in the 0.2 mg/kg group, along with a decrease in PTH and increase in osteocalcin levels, P < 0.05. Resting energy expenditure improved with rhGH administration, most markedly in the 0.1 mg/kg/d rhGH group, P < 0.05. Cardiac output was decreased at 12 and 18 months postburn in the rhGH group. Long-term administration of 0.1 and 0.2 mg/kg/d rhGH significantly improved scarring at 12 months postburn, P < 0.05. Conclusion:This large prospective clinical trial showed that long-term treatment with rhGH effectively enhances recovery of severely burned pediatric patients.

Calcium and ER stress mediate hepatic apoptosis after burn injury

A hallmark of the disease state following severe burn injury is decreased liver function, which results in gross metabolic derangements that compromise patient survival. The underlying mechanisms leading to hepatocyte dysfunction after burn are essentially unknown. The aim of the present study was to determine the underlying mechanisms leading to hepatocyte dysfunction and apoptosis after burn. Rats were randomized to either control (no burn) or burn (60% total body surface area burn) and sacrificed at various time-points. Liver was either perfused to isolate primary rat hepatocytes, which were used for in vitro calcium imaging, or liver was harvested and processed for immunohistology, transmission electron microscopy, mitochondrial isolation, mass spectroscopy or Western blotting to determine the hepatic response to burn injury in vivo. We found that thermal injury leads to severely depleted endoplasmic reticulum (ER) calcium stores and consequent elevated cytosolic calcium concentrations in primary hepatocytes in vitro. Burn-induced ER calcium depletion caused depressed hepatocyte responsiveness to signalling molecules that regulate hepatic homeostasis, such as vasopressin and the purinergic agonist ATP. In vivo, thermal injury resulted in activation of the ER stress response and major alterations in mitochondrial structure and function - effects which may be mediated by increased calcium release by inositol 1,4,5-trisphosphate receptors. Our results reveal that thermal injury leads to dramatic hepatic disturbances in calcium homeostasis and resultant ER stress leading to mitochondrial abnormalities contributing to hepatic dysfunction and apoptosis after burn injury.