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Diabetes and smoking are known risk factors for cataract development. In this study, we evaluated the effect of nicotine on the progression of cataracts in a type 1 diabetic rat model. Diabetes was induced in Sprague-Dawley rats by a single injection of 65 mg/kg streptozotocin. Daily nicotine injections were administered subcutaneously. Forty-five rats were divided into groups of diabetics with and without nicotine treatment and controls with and without nicotine treatment. Progression of lens opacity was monitored using a slit lamp biomicroscope and scores were assigned. To assess whether systemic inflammation played a role in mediating cataractogenesis, we studied serum levels of eotaxin, IL-6, and IL-4. The levels of the measured cytokines increased significantly in nicotine-treated and untreated diabetic animals versus controls and demonstrated a positive trend in the nicotine-treated diabetic rats. Our data suggest the presence of a synergistic relationship between nicotine and diabetes that accelerated cataract formation via inflammatory mediators.

Severe thermal injury induces inflammatory and hypermetabolic responses that are associated with morbidity and mortality. However, it is not well-documented whether the causes of burns affect inflammation, hypermetabolism, and morbidity. The aim of the present study was to determine whether there is a difference in degree of inflammation, hypermetabolism, endocrine and acute-phase response, and clinical outcome between pediatric patients with scald and flame burns.None.Children with burns requiring surgical intervention were enrolled in this cohort study and divided into two groups, scald or flame burn. In a second assignment, we analyzed the study populations in representative subgroups containing individuals with third-degree burns of 40% to 60% total body surface area. We determined clinical outcomes, resting energy expenditures, cytokine profiles, acute-phase proteins, constitutive proteins, and hormone panels. Statistical analysis was evaluated by analysis of variance, Student's t test corrected with the Bonferroni post hoc test, and the propensity score. Statistical significance was set at p.05. A total of 912 patients were identified. Six hundred seventy-four had a flame burn and 238 had a scald burn. There was a significant difference (p.05) in burn size (flame, 48% ± 23%; scald, 40% ± 21%), third-degree burn (flame, 39% ± 27%; scald 22% ± 25%), age (flame, 8 ± 5 yrs; scald, 3 ± 3 yrs), and mortality between groups. Propensity analysis confirmed the type of burn as a significant risk factor for morbidity and mortality. Subanalysis conducted in a representative patient group suffering from 40% to 60% burn total body surface area revealed that flame burns lead to significantly increased hypermetabolic, inflammatory, and acute-phase responses when compared to scald burns (p.05). The frequency of sepsis was 3% in the scald burn group, while it was 14% in the flame group (p.001). Multiorgan failure occurred in 14% of the scald patients, while it occurred in 17% of flame patients. The mortality in patients suffering from a scald burn was 3% compared to 6% in the flame-burned group (p.05).The type of burn affects hypermetabolism, inflammation, acute-phase responses, and mortality postburn.

Burn injury leads to vast changes in both metabolic and inflammatory responses and is associated with increased morbidity and mortality. Insulin resistance (IR) and hyperglycemia are major components of the hypermetabolic response found in burn-injured patients and subsequently contribute to adverse outcomes. Studies have shown that increased systemic retinol binding protein (RBP) levels are associated with IR and hyperinflammation in diabetic and obese patients. The aim of this study was to determine RBP profiles and to test the hypothesis that elevated RBP levels are associated with both IR and the inflammatory response in burned patients.RBP was measured in 372 patients during the acute stay postburn. Patients' demographics, glucose levels, and insulin administration were recorded. Cytokines, hormones, plasma proteins, and organ markers were measured. The average of all measurements of RBP (2.1 mg/dL) was used to divide patients into high and low groups. Statistical analysis was performed by Student t test. Statistical significance was accepted at P.05.Fifty-one patients (high group) had elevated RBP levels during acute hospitalization and demonstrated a significant higher incidence of multiorgan failure, sepsis, and mortality (P.05). Moreover, in the high group, a significant increase of IR, inflammatory cytokines, and catabolic and organ-specific markers were detected (P.05).Increased RBP levels postburn correlate with increased IR, inflammatory and catabolic responses, incidence of multiorgan failure, and mortality. RBP may be a novel biomarker to monitor these detrimental responses postburn.

In the treatment of burns, patients' own skin is the preferred material to cover burn wounds, resulting in the need to create a donor site wound. Enhancement of healing of the donor site wound would be beneficial in burn patients. Insulin, an anabolic agent, is used routinely to treat hyperglycemia after injury. We investigated whether intensive insulin treatment increases fractional synthesis rate (FSR) of the donor site wound protein and decreases the length of hospitalization normalized for total body surface area burned (LOS/TBSA).FSR of the donor site wound protein was measured in pediatric patients randomized to control (n = 13) and insulin (n = 10) treatments. Depending on the postoperative day when the tracer study was done, studies were divided into "early" (days5) and "late" (days ≥ 5) periods.FSR of the donor site wound protein was greater in the insulin group at the "early" period of wound healing (control vs insulin, 8.2 ± 3.8 vs 13.1 ± 6.9% per day; P.05); but not at the "late" (control vs insulin, 19.7 ± 4.6 vs 16.6 ± 4.0% per day; P.05). Despite these differences, LOS/TBSA was not decreased in the insulin group. Correlation analyses demonstrated that, independent of the treatment regimen, FSR positively correlated (P.05) with time after creation of the donor site and negatively correlated (P.05) with LOS/TBSA.Insulin treatment increased FSR of the donor site wound protein in the early period of wound healing; FSR correlated with LOS/TBSA independent of the treatment regimen.

Few publications recognize acute pancreatitis as a complication after large burns, consequently the incidence and outcome acute pancreatitis after burn in children is not well defined. The aim of this study was to determine the incidence, morbidity, and mortality relating to acute pancreatitis in a pediatric burn population and to correlate clinical diagnosis with autopsy findings to determine the incidence of unrecognized pancreatitis. Records of 2699 patients with acute burns were reviewed. Acute pancreatitis was defined as abdominal pain and/or feeding intolerance in addition to a three-fold elevation of amylase and/or lipase. One-hundred twenty-seven burned children served as the control cohort. To assess the presence of autopsy confirmed AP in pediatric burn patients, we evaluated autopsy reports of 78 children who died from burns, looking for reported evidence of pancreatic inflammation, and fat/parenchymal necrosis. Our data show that acute pancreatitis in children has a low incidence after burn. The study included 2699 patients of which 13 were suffering acute pancreatitis (13/2699 = 0.05%). Mortality is significantly higher for the acute pancreatitis group vs. the control group, p < 0.05. Autopsy reports established 11 of 78 patients with evidence of pancreatitis, resulting in an incidence of 0.17% for pancreatitis at autopsy. Although it has low incidence, acute pancreatitis is associated with increased mortality in severely burned pediatric patients, which underlines the importance of increased vigilance in the evaluation and treatment of pancreatitis in burned children.

Hyperglycemia is a common pathophysiological phenomenon in burn and critically ill patients. During the early phases of postburn, hyperglycemia is due to an increased rate of glucose appearance along with an impaired tissue extraction of glucose leading to an increase of glucose and lactate1, 2 associated with impaired insulin receptor signaling and endoplasmic reticulum stress.3–5 The clinical relevance of hyperglycemia after a severe burn was shown in recent studies in which the authors showed that burn patients with poor glucose control had a significantly higher incidence of bacteremia/fungemia and mortality.6–8 These data indicate that hyperglycemia, associated with insulin resistance, represents a significant clinical problem in burn patients similar to insulin resistance in critically ill patients. Tight euglycemic control as published by van den Berghe and colleagues9 changed ICU practice. They showed that insulin administered to maintain glucose at levels below 110 mg/dl decreased morbidity and mortality in surgically critically ill patients and morbidity in medically critically ill patients.10 In another study, the authors showed that tight euglycemic control improved mortality in pediatric ICU patients11 and insulin given during the acute phase not only improved acute hospital outcomes but also improved long-term rehabilitation and social reintegration of critically ill patients over a period of 1 year12, 13, indicating the advantage of insulin therapy. Various unicenter and multicenter studies followed the Leuven trials to determine whether tight euglycemic control, in fact, improves outcomes of critically ill, septic, trauma, and medical patients. Results of these studies were mixed with some showing a benefit with the use of euglycemic control14, 15, while others failed to show improved outcomes; in contrast, some of these studies even demonstrated detrimental effects associated with tight euglycemic control and a dramatically increase in the incidence of hypoglycemia.16 A large multicenter trial was initiated: the NICE SUGAR trial, which failed to show beneficial outcome for critically ill patients with intensive insulin therapy17. This trial on the other hand delineated risks and problems associated with tight euglycemic therapy. Given all these controversial findings, current recommendations which glucose range should be targeted, are now based on opinions and not on scientific evidence. We, therefore, designed this trial in severely burned patients to answer the question which glucose levels are associated with improved morbidity and mortality. We hypothesized that hypoglycemia as well as hyperglycemia are detrimental for severely thermally injured patient outcome and that an ideal glucose range exists that is associated with improved morbidity and mortality.

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". 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", CINC-1, CINC-2, and MCP-1, whereas KX reduced CINC-2 and increased IL-6 levels. Meanwhile, PEN reduced levels of IL-1" and MCP-1, and CO2 reduced CINC-2 and MCP-1. In addition,decapitation after KX, PEN, or CO2 decreased IL-1" 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.

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:Atotalof239severelyburnedpediatricpatientswithburns over greater than 30% of their total body surface area were randomized (block randomization 1:3) to intensive insulin treatment (n 5 60) or control (n 5 179). Measurements and Main Results: Demographics, clinical outcomes, sepsis,glucosemetabolism,organfunction,andinflammatory,acutephase, and hypermetabolic responses were determined. Demographics were similar in both groups. Intensive insulin treatment significantly decreased the incidence of infections and sepsis comparedwithcontrols(P ,0.05).Furthermore,intensiveinsulintherapy improved organ function as indicated by improved serum markers, DENVER2scores,andultrasound(P ,0.05). Intensiveinsulintherapy alleviatedpost-burninsulinresistanceandthevastcatabolicresponse ofthebody(P ,0.05).Intensiveinsulintreatmentdampenedinflammatoryandacute-phaseresponsesbydeceasingIL-6andacute-phase proteins compared with controls (P , 0.05). Mortality was 4% in the intensive insulin therapy group and 11% in the control group (P 5 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).

Increased catecholamine (CA) levels after severe burn are associated with stress, inflammation, hypermetabolism, and impaired immune function. The CA secretion profiles in burned patients are not well described. Mechanisms, duration, and extent of CA surge are unknown. The purpose of this large unicenter study was to evaluate the extent and magnitude of CA surge after severe burn in pediatric patients. Patients admitted between 1996 and 2008 were enrolled in this study. Twenty-four-hour urine collections were performed during acute hospitalization and up to 2 years postburn. Results from the samples collected from 12 normal, healthy volunteers were compared with the data from the burned patients. Relevant demographic and clinical information was obtained from medical records. Student t-test and one-way ANOVA were used to analyze the data where appropriate. Significance was accepted at P0.05. Four hundred thirteen patients were enrolled in this study; 17 patients died during acute hospitalization. Burn caused a marked stress and inflammatory response, indicated by massive tachycardia and elevated proinflammatory cytokines. In burned patients, CA levels are consistently and significantly modulated after burn when compared with the levels in normal, healthy volunteers. Catecholamine levels were significantly higher in boys compared with girls, correlated with burn size in burns greater than 40%, and were increased in older children. There were differences over time in survivors versus nonsurvivors, with CA levels significantly higher in nonsurvivors at two time points. Inflammatory cytokines show a similar profile during the study period. Our study gives clinicians a useful insight into the extent and magnitude of CA elevation to better design treatment strategies.

Neuronal nitric oxide synthase is critically involved in the pathogenesis of acute lung injury resulting from combined burn and smoke inhalation injury. We hypothesized that 7-nitroindazole, a selective neuronal nitric oxide synthase inhibitor, blocks central molecular mechanisms involved in the pathophysiology of this double-hit insult. Twenty-five adult ewes were surgically prepared and randomly allocated to 1) an uninjured, untreated sham group ( n = 7), 2) an injured control group with no treatment ( n = 7), 3) an injury group treated with 7-nitroindazole from 1-h postinjury to the remainder of the 24-h study period ( n = 7), or 4) a sham-operated group subjected only to 7-nitroindazole to judge the effects in health. The combination injury was associated with twofold increased activity of neuronal nitric oxide synthase and oxidative/nitrosative stress, as indicated by significant increases in plasma nitrate/nitrite concentrations, 3-nitrotyrosine (an indicator of peroxynitrite formation), and malondialdehyde lung tissue content. The presence of systemic inflammation was evidenced by twofold, sixfold, and threefold increases in poly(ADP-ribose) polymerase, IL-8, and myeloperoxidase lung tissue concentrations, respectively (each P < 0.05 vs. sham). These molecular changes were linked to tissue damage, airway obstruction, and pulmonary shunting with deteriorated gas exchange. 7-Nitroindazole blocked, or at least attenuated, all these pathological changes. Our findings suggest 1) that nitric oxide formation derived from increased neuronal nitric oxide synthase activity represents a pivotal reactive agent in the patho-physiology of combined burn and smoke inhalation injury and 2) that selective neuronal nitric oxide synthase inhibition represents a goal-directed approach to attenuate the degree of injury.

Insulin resistance with its associated hyperglycemias represents one significant contributor to mortality in burned patients. A variety of cellular stress-signaling pathways are activated as a consequence of burn. A key player in the cellular stress response is the endoplasmic reticulum (ER). Here, we investigated a possible role for ER-stress pathways in the progression of insulin function dysregulation post-burn. Rats received a 60% TBSA thermal injury and a laparotomy was performed at 24, 72 and 192 h post-burn. Liver was harvested before and 1 min after insulin injection (1 IU/kg) into the portal vein and expression patterns of various proteins known to be involved in insulin and ER-stress signaling were determined by Western blotting. mRNA expression of Glucose-6-Phosphatase (G-6-P) and Glucokinase (GK) were determined by RT-PCR and fasting serum glucose and insulin levels by standard enzymatic and ELISA techniques, respectively. Insulin resistance indicated by increased glucose and insulin levels occurred starting 24 h post-burn. Burn injury resulted in activation of ER stress pathways, reflected by significantly increased accumulation of phospho-PERK and phosphor-IRE-1 leading to an elevation of phospho-JNK and serine phosphorylation of IRS-1 post-burn. Insulin administration caused a significant increase in tyrosine phosphorylation of IRS-1 leading to activation of the PI3K/Akt pathway in normal liver. Post-burn tyrosine phosphorylation of IRS-1 was significantly impaired associated with an inactivation of signaling molecules acting downstream of IRS-1 leading to significantly elevated transcription of G-6-P and significantly decreased mRNA expression of GK. Activation of ER-stress signaling cascades may explain metabolic abnormalities involving insulin action following burn.

Children suffering severe burns develop progressive vitamin D deficiency because of inability of burned skin to produce normal quantities of vitamin D(3) and lack of vitamin D supplementation on discharge. Our study was designed to determine whether a daily supplement of a standard multivitamin tablet containing vitamin D(2) 400 IU (10 microg) for 6 months would raise serum levels of 25-hydroxyvitamin D [25(OH)D] to normal. We recruited eight burned children, ages 5-18, whose families were deemed reliable by the research staff. These children were given a daily multivitamin tablet in the hospital for 3 months in the presence of a member of the research staff and then given the remainder at home. At 6 months, the subjects returned for measurements of serum levels of 25(OH)D,1,25-dihydroxyvitamin D [1,25(OH)(2)D], intact parathyroid hormone (iPTH), Ca, P, albumin, and total protein as well as bone mass by dual energy X-ray absorptiometry. Serum 25(OH)D levels were compared to a group of seven age-matched burned children studied at an earlier date without the vitamin supplement but with the same method of determination of 25(OH)D at 6 months post-burn. In addition, the chewable vitamins were analyzed for vitamin D(2) content by high performance liquid chromatography. Serum concentration of 25(OH)D was 21 +/- 11(SD) ng/ml (sufficient range 30-100) with only one of the eight children having a value in the sufficient range. In comparison, the unsupplemented burn patients had mean serum 25(OH)D level of 16 +/- 7, P = 0.33 versus supplemented. Serum levels of 1,25(OH)(2)D, iPTH, Ca, P, albumin, and total protein were all normal in the supplemented group. Vitamin D(2) content of the chewable tablets after being saponified and extracted was 460 +/- 20 IU. Bone mineral content of the total body and lumbar spine, as well as lumbar spine bone density, failed to increase as expected in the supplemented group. No correlations were found between serum 25(OH)D levels and age, length of stay, percent body surface area burn or third-degree burn. Supplementation of burned children with a standard multivitamin tablet stated to contain 400 IU of vitamin D(2) failed to correct the vitamin D insufficiency.

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 >or=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 (Delta females: 5+/-4% vs. Delta 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. Language: en

OBJECTIVE We hypothesized that nitric oxide derived from the neuronal nitric oxide synthase (NOS) is responsible for much of the injury resulting from skin burn and smoke inhalation. Therefore, we aimed to examine the effects of selective neuronal NOS inhibition on cardiopulmonary functions and cellular injury in sheep with acute respiratory distress syndrome secondary to combined burn and smoke inhalation injury. DESIGN Prospective, randomized, controlled laboratory experiment. SETTING Investigational intensive care unit. SUBJECTS A total of 22 chronically instrumented adult ewes. INTERVENTIONS Sheep were randomly assigned to either healthy controls (sham), injured controls (40% third-degree flame burn; 48 breaths of cotton smoke), or an injury group treated with the specific neuronal NOS inhibitor 7-nitroindazole (1 mg x kg(-1) x hr(-1)) from 1 hr postinjury to the end of the 48-hr study period. Hypoxic pulmonary vasoconstriction was assessed as decrease in left pulmonary blood flow in response to single-lung hypoxic challenges (100% nitrogen) at baseline, 24 hrs, and 48 hrs. MEASUREMENTS AND MAIN RESULTS The combination injury contributed to a approximately 90% loss of hypoxic pulmonary vasoconstriction and was associated with significant pulmonary shunting and death of one animal. The increase in nitrate/nitrite plasma levels in injured controls (12 hrs: 17 +/- 2 vs. 6 +/- 1 microM in sham animals; p < .001) was linked to increases in inducible NOS messenger RNA and 3-nitrotyrosine formation in lung tissue (48 hrs: 22 +/- 1 vs. 0.8 +/- 0.3 nM in sham animals; p < .001). 7-Nitroindazole treatment prevented the injury-associated changes in inducible NOS messenger RNA, nitrate/nitrite, and 3-nitrotyrosine, thereby attenuating the loss of hypoxic pulmonary vasoconstriction and improving gas exchange. In addition, 7-nitroindazole decreased lung tissue concentrations of hemoxygenase-1 and ameliorated myocardial depression, airway obstruction, pulmonary edema, ventilatory pressures, and histopathologic changes seen in injured controls. CONCLUSIONS The present study provides evidence that neuronal NOS-derived nitric oxide plays a pivotal role in the pathogenesis of acute respiratory distress syndrome resulting from combined burn and smoke inhalation injury.

OBJECTIVE. The aim of this study was to identify contributors to morbidity and death in severely burned patients METHODS. A total of 188 severely burned pediatric patients were divided into 3 age groups (0–3.9 years, 4–9.9 years, and 10–18 years of age). Resting energy expenditure was measured through oxygen consumption, body composition through dual-energy x-ray absorptiometry, liver size and cardiac function through ultrasonography, and levels of inflammatory markers, hormones, and acute-phase proteins through laboratory chemistry assays. RESULTS. Resting energy expenditure was highest in the 10- to 18-year-old group, followed by the 4- to 9.9-year-old group, and was lowest in the 0- to 3.9-year-old group. Children 0 to 3.9 years of age maintained lean body mass and body weight during acute hospitalization, whereas children >4 years of age lost body weight and lean body mass. The inflammatory cytokine profile showed no differences between the 3 age groups, whereas liver size increased significantly in the 10- to 18-year-old group and was lowest in the 0- to 3.9-year-old group. Acute-phase protein and cortisol levels were significantly decreased in the toddler group, compared with the older children. Cardiac data indicated increased cardiac work and impaired function in the toddler group, compared with the other 2 age groups. CONCLUSIONS. Increased mortality rates for young children are associated with increased cardiac work and impaired cardiac function but not with the inflammatory and hypermetabolic responses.

Objective and Summary Background Data: Postbum 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.

This is a large cohort analysis in severely burned pediatric children to determine whether C-reactive protein (CRP) can be used as a predictor for severe infection or sepsis. Nine-hundred eighteen pediatric burn patients were enrolled in this study. CRP values were measured throughout acute hospitalization and for up to 6 months postburn. Demographic data, incidence of infection, surgical interventions and other relevant clinical information was compiled from medical records. We performed an extensive literature search to identify models that other groups have developed to determine the effects of CRP levels postburn to assess the value of these parameters as predictors of sepsis or severe infection. Statistical analysis was performed using ANOVA and regression analysis where appropriate. Three-hundred fifteen female and 603 male pediatric patients were enrolled in this study. Average total body surface area (TBSA) burn was 45±23%, with full thickness burn over 32±27% TBSA, and patients were 7±6 years old. CRP values significantly correlated with burn size, survival and gender. Significantly higher levels of CRP were found in large burns, in non-survivors, and in females, p

Hyperglycemia and inflammation are hallmarks of burn injury. In this study, we used a rat model of hyperglycemia and burn injury to investigate the effects of hyperglycemia on inflammatory responses in the liver. Hyperglycemia was induced in male Sprague-Dawley rats with streptozotocin (STZ) (35–40 mg/kg), followed by a 60% third-degree scald burn injury. Cytokine levels (by multiplex, in cytosolic liver extracts), hormones (by enzyme-linked immunosorbent assay (ELISA), in serum), nuclear factor (NF)-κB protein deoxyribonucleic acid (DNA) binding (by ELISA, in nuclear liver extracts) and liver functional panel (using VetScan, in serum) were measured at different time points up to 7 d after burn injury. Blood glucose significantly increased after burn injury in both groups with different temporal patterns. Hyperglycemic rats were capable of endogenous insulin secretion, which was enhanced significantly versus controls 12 h after burn injury. DNA binding data of liver nuclear extracts showed a robust and significant activation of the noncanonical NF-κB pathway in the hyperglycemic versus control burn animals, including increased NF-κB–inducing kinase expression (p < 0.05). Liver acute-phase proteins and cytokine expression were increased, whereas secretion of constitutive proteins was decreased after burn injury in hyperglycemic versus control animals (p < 0.05). These results indicate that burn injury to the skin rapidly activated canonical and noncanonical NF-κB pathways in the liver. Robust activation of the NF-κB noncanonical pathway was associated with increased expression of inflammatory markers and acute-phase proteins, and impaired glucose metabolism. Hyperglycemia is detrimental to burn outcome by augmenting inflammation mediated by hepatic noncanonical NF-κB pathway activation.

Background Hypercortisolemia has been suggested as a primary hormonal mediator of whole-body catabolism following severe burn injury. Ketoconazole, an anti-fungal agent, inhibits cortisol synthesis. We, therefore, studied the effect of ketoconazole on post-burn cortisol levels and the hyper-catabolic response in a prospective randomized trial (block randomization 2:1). Methodology/Principal Findings Fifty-five severely burned pediatric patients with >30% total body surface area (TBSA) burns were enrolled in this trial. Patients were randomized to receive standard care plus either placebo (controls, n = 38) or ketoconazole (n = 23). Demographics, clinical data, serum hormone levels, serum cytokine expression profiles, organ function, hypermetabolism measures, muscle protein synthesis, incidence of wound infection sepsis, and body composition were obtained throughout the acute hospital course. Statistical analysis was performed using Fisher’s exact test, Student’s t-test, and parametric and non-parametric two-way repeated measures analysis of variance where applicable. Patients were similar in demographics, age, and TBSA burned. Ketoconazole effectively blocked cortisol production, as indicated by normalization of the 8-fold elevation in urine cortisol levels [F(1, 376) = 85.34, p

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, Student's t-test with Bonferroni correction where appropriate with significance accepted at p

We recently showed that mechanisms of protein turnover in skeletal muscle are unresponsive to amino acid (AA) infusion in severely burned pediatric patients at 6 months postinjury. In the current study, we evaluated whether oxandrolone treatment affects mechanisms of protein turnover in skeletal muscle and whole-body protein breakdown in pediatric burn patients 6 months postinjury.At the time of admission, patients were randomized to control or oxandrolone treatments. The treatment regimens were continued until 6 months postinjury, at which time patients (n = 26) underwent study with a stable isotope tracer infusion to measure muscle and whole-body protein turnover.Protein kinetics in leg muscle were expressed in nmol/min per 100 mL leg volume (mean ± SE). During AA infusion, rates of protein synthesis in leg muscle were increased (P.05) in both groups (basal vs AA: control, 51 ± 8 vs 86 ± 21; oxandrolone, 56 ± 7 vs 96 ± 12). In the control group, there was also a simultaneous increase in breakdown (basal vs AA: 65 ± 10 vs 89 ± 25), which resulted in no change in the net balance of leg muscle protein (basal vs AA: -15 ± 4 vs -2 ± 10). In the oxandrolone group, protein breakdown did not change (basal vs AA: 80 ± 12 vs 77 ± 9), leading to increased net balance (basal vs AA: -24 ± 7 vs 19 ± 7; P.05). Protein breakdown at the whole-body level was not different between the groups.Long-term oxandrolone treatment increased net deposition of leg muscle protein during AA infusion by attenuating protein breakdown, but did not affect whole-body protein breakdown.

Acute lung injury secondary to smoke inhalation is a major source of morbidity and mortality in burn patients. We tested the hypothesis that nebulized epinephrine would ameliorate pulmonary dysfunction secondary to acute lung injury by reducing airway hyperemia and edema formation and mediating bronchodilatation in an established, large animal model of inhalation injury.Prospective, controlled, randomized trial.University research laboratory.Twenty-four chronically instrumented, adult, female sheep.Following baseline measurements, the animals were allocated to a sham-injured group (n = 5), an injured and saline-treated group (n = 6), or an injured group treated with 4 mg of nebulized epinephrine every 4 hrs (n = 6). Inhalation injury was induced by 48 breaths of cotton smoke. The dose of epinephrine was derived from dose finding experiments (n = 7 sheep).The injury induced significant increases in airway blood flows, bronchial wet/dry weight ratio, airway obstruction scores, ventilatory pressures, and lung malondialdehyde content, and contributed to severe pulmonary dysfunction as evidenced by a significant decline in Pao₂/Fio₂ ratio and increase in pulmonary shunt fraction. Nebulization of epinephrine significantly reduced tracheal and main bronchial blood flows, ventilatory pressures, and lung malondialdehyde content. The treatment was further associated with significant improvements of Pao₂/FIO₂ ratio and pulmonary shunting.Nebulization of epinephrine reduces airway blood flow and attenuates pulmonary dysfunction in sheep subjected to severe smoke inhalation injury. Future studies will have to improve the understanding of the underlying pathomechanisms and identify the optimal dosing for the treatment of patients with this injury.

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.

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.

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.

The acute hypermetabolic response post-burn is associated with insulin resistance and hyperglycemia, significantly contributing to adverse outcome of these patients.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.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.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 P0.05.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 (P0.05). Glucose values were significantly augmented for 6 months post-burn (P0.05), associated with significant increases in serum C-peptide and insulin that remained significantly increased for 36 months compared to nonburned children (P0.05). 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.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.

To improve clinical outcome and to determine new treatment options, we studied the pathophysiologic response postburn in a large prospective, single center, clinical trial.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.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.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%); P0.05. 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; P0.05. Cardiac function was compromised immediately after burn and remained abnormal up to discharge; P0.05. 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.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.

OBJECTIVE Recombinant human growth hormone (rhGH) is a salutary modulator of posttraumatic metabolic responses. However, rhGH administration is associated with deleterious side effects, such as hyperglycemia, increased free fatty acids, and triglycerides, which limit its use. Administration of beta-blocker attenuates cardiac work and resting energy expenditure after severe thermal injury and improves fat metabolism and insulin sensitivity. Therefore, the combination of rhGH plus propranolol appears ideal. The aim of the present study was to determine whether rhGH plus propranolol improves hypermetabolism and the inflammatory and acute phase response after severe burn without causing adverse side effects. DESIGN Prospective randomized control trial. SETTING Shriners Hospitals for Children. PATIENTS Fifteen pediatric patients with burns > 40% total body surface area, 0.1-16 yrs of age, admitted within 7 days after burn. Fifteen children were matched for burn size, age, gender, inhalation injury, and infection and served as controls. INTERVENTIONS Patients in the experimental group received rhGH (0.2 mg/kg/day) and propranolol (to decrease heart rate by 15%) for > or = 15 days. MEASUREMENTS AND MAIN RESULTS Outcome measurements included resting energy expenditure, body composition, acute phase proteins, and cytokines. Both cohorts were similar in age, burn size, gender, and accompanying injuries. Percent predicted resting energy expenditure significantly decreased in patients receiving rhGH/propranolol (Delta -5% +/- 8%) compared with controls (Delta +35% +/- 20%) (p < .05). rhGH/propranolol administration significantly decreased serum C-reactive protein, cortisone, aspartate aminotransferase, alanine aminotransferase, free fatty acids, interleukin-6, interleukin-8, and macrophage inflammatory protein-1beta when compared with controls, while growth hormone/propranolol increased serum insulin-like growth factor-I, insulin-like growth factor binding protein-3, growth hormone, prealbumin, and interleukin-7 when compared with placebo (p < .05). CONCLUSIONS rhGH in combination with propranolol attenuates hypermetabolism and inflammation without the adverse side effects found with rhGH therapy alone.

Methicillin-resistant Staphylococcus aureus (MRSA)-related pneumonia and/or sepsis are a frequent serious menace. The aim of the study was to establish a standardized and reproducible model of MRSA-induced septic pneumonia to evaluate new therapies. Sheep were operatively prepared for chronic study. After 5 days' recovery, tracheostomy was performed under anesthesia, and smoke injury was induced by inhalation of cotton smoke (48 breaths

Introduction Severe 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. Methods Primary 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, Student's t-test and Kaplan-Meier for survival where applicable. Significance was accepted as P < 0.05. Results Five-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). Conclusions Sepsis 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.

Background Increased 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. Methods Pediatric burned patients were divided into four burn size groups: 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. Results One hundred and eighty-nine pediatric patients of similar age and gender distribution were included in the study (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). Conclusion Morbidity 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.

Introduction Intensive 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.