Felicia N. Williams

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.

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.

The Hypermetabolic Response to Burn Injury and Interventions to Modify this Response

Severe burn injury is followed by a profound hypermetabolic response that persists up to 24 months after injury. It is mediated by up to 50-fold elevations in plasma catecholamines, cortisol, and inflammatory cells that lead to whole-body catabolism, elevated resting energy expenditures, and multiorgan dysfunction. All of these metabolic and physiologic derangements prevent full rehabilitation and acclimatization of burn survivors back into society. Modulation of the response by early excision and grafting of burn wounds, thermoregulation, early and continuous enteral feeding with high-protein high-carbohydrate feedings, and pharmacologic treatments have markedly decreased morbidity.

Long-term propranolol use in severely burned pediatric patients: A randomized controlled study

Objective:To determine the safety and efficacy of propranolol given for 1 year on cardiac function, resting energy expenditure, and body composition in a prospective, randomized, single-center, controlled study in pediatric patients with large burns. Background:Severe burns trigger a hypermetabolic response that persists for up to 2 years postburn. Propranolol given for 1 month postburn blunts this response. Whether propranolol administration for 1 year after injury provides a continued benefit is currently unclear. Methods:One-hundred seventy-nine pediatric patients with more than 30% total body surface area burns were randomized to control (n = 89) or 4 mg/kg/d propranolol (n = 90) for 12 months postburn. Changes in resting energy expenditure, cardiac function, and body composition were measured acutely at 3, 6, 9, and 12 months postburn. Statistical analyses included techniques that adjusted for non-normality, repeated-measures, and regression analyses. P < 0.05 was considered significant. Results:Long-term propranolol treatment significantly reduced the percentage of the predicted heart rate and percentage of the predicted resting energy expenditure, decreased accumulation of central mass and central fat, prevented bone loss, and improved lean body mass accretion. There were very few adverse effects from the dose of propranolol used. Conclusions:Propranolol treatment for 12 months after thermal injury, ameliorates the hyperdynamic, hypermetabolic, hypercatabolic, and osteopenic responses in pediatric patients. This study is registered at clinicaltrials.gov: NCT00675714.

Modulation of the hypermetabolic response to trauma: temperature, nutrition, and drugs.

Severe burn injury is associated with a profound hypermetabolic, hypercatabolic response proportional to the original size of the injury, which persists for 1 to 2 years postburn.1,2 The response is characterized by supraphysiologic metabolic rates, hyperdynamic circulation, constitutive protein fat and bone catabolism, blunted growth, insulin resistance, and increased risk for infection1–5 (Figs. 1 to ​to33). Figure 1 Physiologic and metabolic changes post severe burn injury. Demonstrates changes in resting energy expenditure, stress hormones (epinephrine), cardiac function (cardiac output), gender hormones (testosterone), cytokines (interleukin-6) and changes in body ... Figure 3 Effects of metabolic dysfunction postburn. Cuthbertson6 originally described a stress response to fractures characterized by an “ebb” phase, with a decrease in tissue perfusion and a decrease in metabolism. This is followed by a “flow” phase—starting 3 to 5 days postinjury—which is characterized by an increase in metabolic rate and hyperdynamic circulation. If left untreated, physiologic exhaustion and death can result.7–10 Severe burns exhibit the most dramatic hypermetabolic stress response of any injury. This article reports our single institution’s experience during the past decade, in >1,000 patients with burns of >40% of their total body surface area (TBSA), delineating the magnitude of the metabolic and catabolic responses to major burn injury. Serially performed randomized prospective clinical studies using common methods are described, demonstrating the efficacy of interventions to mitigate the hypermetabolic response: the effects of early excision and grafting, environmental thermoregulation, early continuous enteral feeding with a high-carbohydrate, high-protein diet, use of anabolic agents (growth hormone, insulin-like growth factor-1 [IGF-1], with insulin-like growth factor binding protein-3 [IGFBP-3], insulin, oxandrolone), the anticatabolic agent (propranolol), and use of therapeutic exercise are compared. This article describes the destructive aspects of the hypermetabolic response and strategies implemented during the last decade to modulate this response, which have improved burn care, survival, and quality of life in burn patients. It is hoped that these strategies might also be applicable to the larger populations of patients who have undergone other forms of injury, including large elective operations.

Changes in Cardiac Physiology After Severe Burn Injury

Cardiac stress, mediated by increased catecholamines, is the hallmark of severe burn injury typified by marked tachycardia, increased myocardial oxygen consumption, and increased cardiac output (CO). It remains one of the main determinants of survival in large burns. Currently, it is unknown for how long cardiac stress persists after a severe injury. Therefore, the aim of this study was to determine the extent and duration of cardiac stress after a severe burn. To determine persistence of cardiac alteration, the authors determined cardiac parameters of all surviving patients with burns ≥40% TBSA from 1998 to 2008. One hundred ninety-four patients were included in this study. Heart rate, mean arterial pressure, CO, stroke volume, cardiac index, and ejection fractions were measured at regular intervals from admission up to 2 years after injury. Rate pressure product was calculated as a correlate of myocardial oxygen consumption. All values were compared with normal nonburned children to validate the findings. Statistical analysis was performed using log transformed analysis of variance with Bonferroni correction and Students t-test, where applicable. Heart rate, CO, cardiac index, and rate pressure product remained significantly increased in burned children for up to 2 years when compared with normal ranges (P < .05), indicating vastly increased cardiac stress. Ejection fraction was within normal limits for 2 years. Cardiac stress persists for at least 2 years postburn, and the authors suggest that attenuation of these detrimental responses may improve long-term morbidity.

Effects of exercise training on resting energy expenditure and lean mass during pediatric burn rehabilitation.

Severe burns cause profound hormonal and metabolic disturbances resulting in hypermetabolism, reflected in extreme elevation of resting energy expenditure (REE) and extensive skeletal muscle catabolism. Aerobic and resistive exercise programs during rehabilitation have shown substantial benefits, although whether such training potentially exacerbates basal metabolism is unknown. Therefore, the effects of exercise training on REE during the rehabilitation of severely burned pediatric patients were examined. Children with 40% total body surface area burns and greater were enrolled at admission to the burn intensive care unit to participate in a 12-week, hospital-based exercise program (EX) or a home-based standard of care program (SOC), commencing 6 months after injury. Twenty-one patients (aged 7–17 years) were enrolled and randomized to SOC (n = 10) or EX (n = 11). Age, sex, and total body surface area burned were similar. Mean change (±standard deviation) in REE, normalized to individual lean body mass, was almost negligible between SOC and EX group patients (SOC, 0.03 ± 17.40% vs EX, 0.01 ± 26.38%). A significant increase in lean body mass was found for EX patients (SOC, 2.06 ± 3.17% vs EX, 8.75 ± 5.65%; P = .004), which persisted when normalized to height (SOC, 0.70 ± 2.39% vs EX, 6.14 ± 6.46%; P = .02). Peak torque also improved significantly more in EX patients (SOC, 12.29 ± 16.49% vs EX, 54.31 ± 44.25%; P = .02), reflecting improved strength. Exercise training significantly enhanced lean mass and strength, without observed exacerbation of postburn hypermetabolism. Therefore, the use of exercise conditioning as a safe and effective component of pediatric burn rehabilitation is advocated.

PROPRANOLOL DECREASES CARDIAC WORK IN A DOSE- DEPENDENT MANNER IN SEVERELY BURNED CHILDREN

BACKGROUND Severe burn is followed by profound cardiac stress. Propranolol, a nonselective β(1,) β(2)-receptor antagonist, decreases cardiac stress, but little is known about the dose necessary to cause optimal effect. Thus, the aim of this study was to determine in a large, prospective, randomized, controlled trial the dose of propranolol that would decrease heart rate ≥15% of admission heart rate and improve cardiac function. Four-hundred six patients with burns >30% total body surface area were enrolled and randomized to receive standard care (controls; n = 235) or standard care plus propranolol (n = 171). METHODS Dose-response and drug kinetics of propranolol were performed. Heart rate and mean arterial pressure (MAP) were measured continuously. Cardiac output (CO), cardiac index, stroke volume, rate-pressure product, and cardiac work (CW) were determined at regular intervals. Statistical analysis was performed using analysis of variance with Tukey and Bonferroni corrections and the Student t test when applicable. Significance was accepted at P < .05. RESULTS Propranolol given initially at 1 mg/kg per day decreased heart rate by 15% compared with control patients, but was increased to 4 mg/kg per day within the first 10 days to sustain treatment benefits (P < .05). Propranolol decreased CO, rate-pressure product, and CW without deleterious effects on MAP. The effective plasma drug concentrations were achieved in 30 minutes, and the half-life was 4 hours. CONCLUSION The data suggest that propranolol is an efficacious modulator of the postburn cardiac response when given at a dose of 4 mg/kg per day, and decreases and sustains heart rate 15% below admission heart rate.

The use of exenatide in severely burned pediatric patients

IntroductionIntensive insulin treatment (IIT) has been shown to improve outcomes post-burn in severely burnt patients. However, it increases the incidence of hypoglycemia and is associated with risks and complications. We hypothesized that exenatide would decrease plasma glucose levels post-burn to levels similar to those achieved with IIT, and reduce the amount of exogenous insulin administered.MethodsThis open-label study included 24 severely burned pediatric patients. Six were randomized to receive exenatide, and 18 received IIT during acute hospitalization (block randomization). Exenatide and insulin were administered to maintain glucose levels between 80 and 140 mg/dl. We determined 6 AM, daily average, maximum and minimum glucose levels. Variability was determined using mean amplitude of glucose excursions (MAGE) and percentage of coefficient of variability. The amount of administered insulin was compared in both groups.ResultsGlucose values and variability were similar in both groups: Daily average was 130 ± 28 mg/dl in the intervention group and 138 ± 25 mg/dl in the control group (P = 0.31), MAGE 41 ± 6 vs. 45 ± 12 (respectively). However, administered insulin was significantly lower in the exenatide group than in the IIT group: 22 ± 14 IU patients/day in the intervention group and 76 ± 11 IU patients/day in the control group (P = 0.01). The incidence rate of hypoglycemia was similar in both groups (0.38 events/patient-month).ConclusionsPatients receiving exenatide received significantly lower amounts of exogenous insulin to control plasma glucose levels. Exenatide was well tolerated and potentially represents a novel agent to attenuate hyperglycemia in the critical care setting.Trial registrationNCT00673309.

Glucose control in severely thermally injured pediatric patients: What glucose range should be the target?

Objective:To determine which glucose levels are associated with improved morbidity and mortality in thermally injured patients. Summary background data:Tight euglycemic control was rapidly implemented in intensive care units around the world, but there is increasing evidence that tight euglycemic control is associated with detrimental outcomes. Currently, no study exists that indicates which glucose range should be targeted. Methods:Two-hundred and eight severely burned pediatric patients with burns over 30% of their total body surface area were included in this trial. Several statistical models were used to determine the daily average and 6 am glucose target that were associated with improved morbidity and mortality. Patients were then divided into good glucose controlled and poor glucose controlled patients and demographics, clinical outcomes, infection, sepsis, inflammatory, and hypermetabolic responses were determined. Results:Statistical modeling showed that hyperglycemia is a strong predictor of adverse hospital outcome and that daily 6 am glucose level of 130 mg/dL and daily average glucose levels of 140 mg/dL are associated with improved morbidity and mortality postburn. When patients were divided into good glucose control and poor glucose control, we found that patients with glucose levels of 130 mg/dL exert attenuated hypermetabolic and inflammatory responses, as well as significantly lower incidence of infections, sepsis, and mortality compared with patients with poor glucose control, P < 0.05. Conclusions:Given the controversy over glucose range, glucose target, and risks and detrimental outcomes associated with hypoglycemia we suggest that in severely burned patients blood glucose of 130 mg/dL should be targeted.