Robert Kraft

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.

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).

Morbidity and survival probability in burn patients in modern burn care

Objective:Characterizing burn sizes that are associated with an increased risk of mortality and morbidity is critical because it would allow identifying patients who might derive the greatest benefit from individualized, experimental, or innovative therapies. Although scores have been established to predict mortality, few data addressing other outcomes exist. The objective of this study was to determine burn sizes that are associated with increased mortality and morbidity after burn. Design and Patients:Burn patients were prospectively enrolled as part of the multicenter prospective cohort study, Inflammation and the Host Response to Injury Glue Grant, with the following inclusion criteria: 0–99 years old, admission within 96 hours after injury, and more than 20% total body surface area burns requiring at least one surgical intervention. Setting:Six major burn centers in North America. Measurements and Main Results:Burn size cutoff values were determined for mortality, burn wound infection (at least two infections), sepsis (as defined by American Burn Association sepsis criteria), pneumonia, acute respiratory distress syndrome, and multiple organ failure (Denver 2 score > 3) for both children (< 16 yr) and adults (16–65 yr). Five hundred seventy-three patients were enrolled, of which 226 patients were children. Twenty-three patients were older than 65 years and were excluded from the cutoff analysis. In children, the cutoff burn size for mortality, sepsis, infection, and multiple organ failure was approximately 60% total body surface area burned. In adults, the cutoff for these outcomes was lower, at approximately 40% total body surface area burned. Conclusions:In the modern burn care setting, adults with over 40% total body surface area burned and children with over 60% total body surface area burned are at high risk for morbidity and mortality, even in highly specialized centers.

Survivors versus nonsurvivors postburn: Differences in inflammatory and hypermetabolic trajectories

Objective:To evaluate whether a panel of common biomedical markers can be utilized as trajectories to determine survival in pediatric burn patients. Background:Despite major advances in clinical care, of the more than 1 million people burned in the United States each year, more than 4500 die as a result of their burn injuries. The ability to predict patient outcome or anticipate clinical trajectories using plasma protein expression would allow personalization of clinical care to optimize the potential for patient survival. Methods:A total of 230 severely burned children with burns exceeding 30% of the total body surface, requiring at least 1 surgical procedure were enrolled in this prospective cohort study. Demographics, clinical outcomes, and inflammatory and acute-phase responses (serum cytokines, hormones, and proteins) were determined at admission and at 11 time points for up to 180 days postburn. Statistical analysis was performed using a 1-way analysis of variance, the Student t test, &khgr;2 test, and Mann-Whitney test where appropriate. Results:Survivors and nonsurvivors exhibited profound differences in critical markers of inflammation and metabolism at each time point. Nonsurvivors had significantly higher serum levels of interleukin (IL)-6, IL-8, granulocyte colony-stimulating factor, monocyte chemoattractant protein-1, C-reactive protein, glucose, insulin, blood urea nitrogen, creatinine, and bilirubin (P < 0.05). Furthermore, nonsurvivors exhibited a vastly increased hypermetabolic response that was associated with increases in organ dysfunction and sepsis when compared with survivors (P < 0.05). Conclusions:Nonsurvivors have different trajectories in inflammatory, metabolic, and acute phase responses allowing differentiation of nonsurvivors from survivors and now possibly allowing novel predictive models to improve and personalize burn outcomes.

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.

Predictive Value of IL-8 for Sepsis and Severe Infections After Burn Injury: A Clinical Study.

ABSTRACT The inflammatory response induced by burn injury contributes to increased incidence of infections, sepsis, organ failure, and mortality. Thus, monitoring postburn inflammation is of paramount importance but, so far, there are no reliable biomarkers available to monitor and/or predict infectious complications after burn. As interleukin 8 (IL-8) is a major mediator for inflammatory responses, the aim of our study was to determine whether IL-8 expression can be used to predict postburn sepsis, infections, and mortality. Plasma cytokines, acute-phase proteins, constitutive proteins, and hormones were analyzed during the first 60 days after injury from 468 pediatric burn patients. Demographics and clinical outcome variables (length of stay, infection, sepsis, multiorgan failure [MOF], and mortality) were recorded. A cutoff level for IL-8 was determined using receiver operating characteristic analysis. Statistical significance is set at P < 0.05. Receiver operating characteristic analysis identified a cutoff level of 234 pg/mL for IL-8 for survival. Patients were grouped according to their average IL-8 levels relative to this cutoff and stratified into high (H) (n = 133) and low (L) (n = 335) groups. In the L group, regression analysis revealed a significant predictive value of IL-8 to percent of total body surface area burned and incidence of MOF (P < 0.001). In the H group, IL-8 levels were able to predict sepsis (P < 0.002). In the H group, elevated IL-8 was associated with increased inflammatory and acute-phase responses compared with the L group (P < 0.05). High levels of IL-8 correlated with increased MOF, sepsis, and mortality. These data suggest that serum levels of IL-8 may be a valid biomarker for monitoring sepsis, infections, and mortality in burn patients.

Insulin protects against hepatic damage postburn.

Burn injury causes hepatic dysfunction associated with endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR). ER stress/UPR leads to hepatic apoptosis and activation of the Jun-N-terminal kinase (JNK) signaling pathway leading to vast metabolic alterations. Insulin has been shown to attenuate hepatic damage and to improve liver function. We therefore hypothesized that insulin administration exerts its effects by attenuating postburn hepatic ER stress and subsequent apoptosis. Male Sprague Dawley rats received a 60% total body surface area (TBSA) burn injury. Animals were randomized to receive saline (controls) or insulin (2.5 IU/kg q. 24 h) and euthanized at 24 and 48 h postburn. Burn injury induced dramatic changes in liver structure and function, including induction of the ER stress response, mitochondrial dysfunction, hepatocyte apoptosis, and up-regulation of inflammatory mediators. Insulin decreased hepatocyte caspase-3 activation and apoptosis significantly at 24 and 48 h postburn. Furthermore, insulin administration decreased ER stress significantly and reversed structural and functional changes in hepatocyte mitochondria. Finally, insulin attenuated the expression of inflammatory mediators IL-6, MCP-1, and CINC-1. Insulin alleviates burn-induced ER stress, hepatocyte apoptosis, mitochondrial abnormalities, and inflammation leading to improved hepatic structure and function significantly. These results support the use of insulin therapy after traumatic injury to improve patient outcomes.

Occurrence of multiorgan dysfunction in pediatric burn patients: Incidence and clinical outcome

Objective:To examine the incidence of single or multiple organ failure postburn and its resultant clinical outcomes during acute hospitalization. Background:Patient outcomes are inherently dependent on intact organ function; however, burn injury affects the structure and function of almost every organ, but especially lung, liver, kidney, and heart. Therefore, single-organ failure and/or multiorgan failure (MOF) are thought to contribute significantly to postburn morbidity and mortality, but to date no large trial examining the effects of MOF on postburn outcomes exists. Methods:Incidence of MOF was monitored in 821 pediatric burn patients during acute hospitalization. Patients were divided into groups on the basis of the incidence of single-organ–specific failure, MOF, and non-MOF. The DENVER2 score was used to assess organ-specific scores for lung, liver, kidney, and heart. The patients demographics, injury characteristics, and outcome parameters were recorded. Results:Respiratory failure has the highest incidence in the early phase of postburn injury and decreases starting 5 days postburn. Cardiac failure was noted to have the highest incidence throughout hospital stay. Incidence of hepatic failure increases with the hospital length of stay and is associated with a high mortality during the late phase of the acute hospital stay. Renal failure has an unexpectedly low incidence but is associated with a high mortality during the first 3 weeks postburn injury. Three or more organ failure is associated with very high mortality. Conclusions:This is the first large study in burn patients to determine the incidence of organ-specific failure and outcome. The results of this study confirmed the expected chronologic incidence of organ-specific failure and yield the long-term mortality from liver and renal failure (NCT00673309).

Impact of anesthesia, analgesia, and euthanasia technique on the inflammatory cytokine profile in a rodent model of severe burn injury.

ABSTRACT Anesthetics used in burn and trauma animal models may be influencing results by modulating inflammatory and acute-phase responses. Accordingly, we determined the effects of various anesthetics, analgesia, and euthanasia techniques in a rodent burn model. Isoflurane (ISO), ketamine-xylazine (KX), or pentobarbital (PEN) with or without buprenorphine were administered before scald-burn in 72 rats that were euthanized without anesthesia by decapitation after 24 h and compared with unburned shams. In a second experiment, 120 rats underwent the same scald-burn injury using KX, and 24 h later were euthanized under anesthesia or carbon dioxide (CO2). In addition, we compared euthanasia by exsanguination with that of decapitation. Serum cytokine levels were determined by an enzyme-linked immunosorbent assay. In the first experiment, ISO was associated with elevation of cytokine-induced neutrophil chemoattractant 2 (CINC-2) and monocyte chemotactic protein 1 (MCP-1), and KX and PEN was associated with elevation of CINC-1, CINC-2, IL-6, and MCP-1. Pentobarbital also decreased IL-1&bgr;. IL-6 increased significantly when ISO or PEN were combined with buprenorphine. In the second experiment, euthanasia performed by exsanguination under ISO was associated with reduced levels of IL-1&bgr;, CINC-1, CINC-2, and MCP-1, whereas KX reduced CINC-2 and increased IL-6 levels. Meanwhile, PEN reduced levels of IL-1&bgr; and MCP-1, and CO2 reduced CINC-2 and MCP-1. In addition, decapitation after KX, PEN, or CO2 decreased IL-1&bgr; and MCP-1, although we found no significant difference between ISO and controls. Euthanasia by exsanguination compared with decapitation using the same agent also led to modulation of several cytokines. Differential expression of inflammatory markers with the use of anesthetics and analgesics should be considered when designing animal studies and interpreting results because these seem to have a significant modulating impact. Our findings indicate that brief anesthesia with ISO immediately before euthanasia by decapitation exerted the least dampening effect on the cytokines measured. Conversely, KX with buprenorphine may offer a better balance during longer procedures to avoid significant modulation. Standardization across all experiments that are compared and awareness of these findings are essential for those investigating the pathophysiology of inflammation in animal models.