A Randomized Trial of Enteral Glutamine for Treatment of Burn Injuries.

BACKGROUND: Glutamine is thought to have beneficial effects on the metabolic and stress response to severe injury. Clinical trials involving patients with burns and other critically ill patients have shown conflicting results regarding the benefits and risks of glutamine supplementation. METHODS: In a double-blind, randomized, placebo-controlled trial, we assigned patients with deep second- or third-degree burns (affecting ≥10% to ≥20% of total body-surface area, depending on age) within 72 hours after hospital admission to receive 0.5 g per kilogram of body weight per day of enterally delivered glutamine or placebo. Trial agents were given every 4 hours through a feeding tube or three or four times a day by mouth until 7 days after the last skin grafting procedure, discharge from the acute care unit, or 3 months after admission, whichever came first. The primary outcome was the time to discharge alive from the hospital, with data censored at 90 days. We calculated subdistribution hazard ratios for discharge alive, which took into account death as a competing risk. RESULTS: A total of 1209 patients with severe burns (mean burn size, 33% of total body-surface area) underwent randomization, and 1200 were included in the analysis (596 patients in the glutamine group and 604 in the placebo group). The median time to discharge alive from the hospital was 40 days (interquartile range, 24 to 87) in the glutamine group and 38 days (interquartile range, 22 to 75) in the placebo group (subdistribution hazard ratio for discharge alive, 0.91; 95% confidence interval [CI], 0.80 to 1.04; P = 0.17). Mortality at 6 months was 17.2% in the glutamine group and 16.2% in the placebo group (hazard ratio for death, 1.06; 95% CI, 0.80 to 1.41). No substantial between-group differences in serious adverse events were observed. CONCLUSIONS: In patients with severe burns, supplemental glutamine did not reduce the time to discharge alive from the hospital. (Funded by the U.S. Department of Defense and the Canadian Institutes of Health Research; RE-ENERGIZE ClinicalTrials.gov number, NCT00985205.).

Evidence of unrestrained beta-cell proliferation and neogenesis in a patient with hyperinsulinemic hypoglycemia after gastric bypass surgery.

Hyperinsulinemic hypoglycemia syndrome (HIHG) is a rare complication of roux-en-Y gastric bypass surgery. The pathology is associated with an excessive function of pancreatic beta-cells, and requires pancreas resection in patients that are recalcitrant to nutritional and pharmacological interventions. The exact prevalence is not clearly understood and the underlying mechanisms not yet fully characterized. We herein sought to perform histological and molecular examination of pancreatic sections obtained from a patient who developed HIHG as a complication of gastric bypass compared to 3 weight-matched controls. We studied markers of cellular replication and beta-cell differentiation by immunohistochemistry and immunofluorescence. HIHG after gastric bypass was characterized by a profound increase in beta-cell mass. Cellular proliferation was increased in islets and ducts compared to controls, suggesting unrestrained proliferation in HIHG. We also detected beta-cell differentiation markers in duct cells and occasional duct cells displaying both insulin and glucagon immunoreactivity. These histological observations suggest that beta-cell differentiation from ductal progenitor cells could also underly beta-cell mass expansion in HIHG. Altogether, our results can be construed to demonstrate that HIHG after gastric bypass is characterized by abnormal beta-cell mass expansion, resulting from both unrestrained beta-cell replication and neogenesis.

A RandomizEd trial of ENtERal Glutamine to minimIZE thermal injury (The RE-ENERGIZE Trial): a clinical trial protocol.

BACKGROUND: Burn injury represents a significant public health problem worldwide. More than in any other injury, the inflammation and catabolism associated with severe burns can exacerbate nutrient deficiencies resulting in impaired immune function and increased risk of developing infection, organ dysfunction and death. Consequently, over the last few decades numerous trials have evaluated the impact of different nutritional strategies in severe burn injury. Glutamine is of particular interest, as it appears vital for a number of key stress-response pathways in serious illness. The purpose of the current manuscript is to provide the rationale and protocol for a large clinical trial of supplemental enteral glutamine in 2700 severe burn-injured patients. METHODS: We propose a multicentre, double-blind, pragmatic, randomized, clinical trial involving 80 tertiary intensive care unit (ICU) burn centres worldwide. We aim to enrol patients with deep second- and/or third-degree burns at moderate or high risk for death. We will exclude patients admitted > 72 h before screening and patients with advanced liver and kidney disease. The study intervention consists of enteral glutamine 0.5 g/kg/day vs. isocaloric maltodextran control delivered enterally. Primary outcome will be six-month mortality. Key secondary outcomes include time to discharge alive from hospital, ICU and hospital mortality, length of stay and health-related quality of life at six months. SIGNIFICANCE: This study will be the first large international multicentre trial examining the effects of glutamine in burn patients. Negative or positive, the results of this trial will inform the clinical practice of burns care worldwide.Clinicaltrials.gov ID #NCT00985205.

Enteral glutamine supplementation in critically ill patients: a systematic review and meta-analysis.

INTRODUCTION: Glutamine (GLN) has been suggested to have a beneficial influence on outcomes of critically ill patients. However, recent large-scale trials have suggested harm associated with GLN supplementation. Recently, systematic reviews on the use of parenteral GLN have been published; however, less information is available on the role of enteral GLN. Therefore, the aim of this systematic review was to study the effects of enteral GLN supplementation in patients with critical illness. METHODS: We identified randomized controlled trials conducted from 1980 to 2014 with enterally administered GLN in adult critically ill patients. Studies of parenteral GLN only or combined enteral-parenteral GLN were excluded. The methodological quality of studies was scored, and trial data were statistically combined. We examined a priori the treatment effects in subgroups of trials of burn and trauma patients. RESULTS: A total of 11 studies involving 1079 adult critically ill patients and enteral GLN supplementation were identified. Enteral GLN supplementation was not associated with a reduction of hospital mortality (risk ratio [RR] 0.94, 95% confidence interval [CI] 0.65-1.36; p = 0.74), infectious complications (RR 0.93, 95% CI 0.79-1.10; p = 0.39) or stay in the intensive care unit (weighted mean difference [WMD] -1.36 days, 95% CI -5.51 to 2.78; p = 0.52). However, there was a significant reduction in hospital stay (WMD 4.73 days, 95% CI -8.53 to -0.90; p = 0.02). In the subset of studies of patients with burns, enteral GLN supplementation was associated with significant reductions in hospital mortality (RR 0.19, 95% 0.06-0.67; p = 0.010) and hospital stay (WMD -9.16, 95% CI -15.06 to -3.26; p = 0.002). There was no effect in trauma patients. CONCLUSIONS: Enteral GLN supplementation does not confer significant clinical benefit in critically ill patients, with the exception of reduced hospital stay. There may be a significant benefit in patients with burns, but data are sparse and larger randomized trials are warranted to confirm this effect.

Contribution of the lean body mass to insulin resistance in postmenopausal women with visceral obesity: a Monet study.

Some insulin-resistant obese postmenopausal (PM) women are characterized by an android body fat distribution type and higher levels of lean body mass (LBM) compared to insulin-sensitive obese PM women. This study investigates the independent contribution of LBM to the detrimental effect of visceral fat (VF) levels on the metabolic profile. One hundred and three PM women (age: 58.0+/-4.9 years) were studied and categorized in four groups on the basis of their VF (higher vs. lower) and lean BMI (LBMI=LBM (kg)/height (m2); higher vs. lower). Measures included: fasting lipids, glucose homeostasis (by euglycemic/hyperinsulinemic clamp technique and 2-h oral glucose tolerance test (OGTT)), C-reactive protein (CRP) levels, fat distribution (by computed tomography (CT) scan), and body composition (by dual-energy X-ray absorptiometry). Women in the higher VF/higher LBMI group had lower glucose disposal and higher plasma insulin levels compared to the other groups. They also had higher plasma CRP levels than the women in the lower VF/lower LBMI group. VF was independently associated with insulin levels, measures of glucose disposal, and CRP levels (P<0.05). LBMI was also independently associated with insulin levels, glucose disposal, and CRP levels (P<0.05). Finally, significant interactions were observed between LBMI and VF levels for insulin levels during the OGTT and measures of glucose disposal (P<0.05). In conclusion, VF and LBMI are both independently associated with alterations in glucose homeostasis and CRP levels. The contribution of VF to insulin resistance seems to be exacerbated by increased LBM in PM women.

Relationship between the metabolic syndrome and physical activity energy expenditure: a MONET study.

The purpose of this cross-sectional study was to examine the association between the metabolic syndrome (MetS) and physical activity energy expenditure (PAEE) in overweight and obese sedentary postmenopausal women. The study population consisted of 137 overweight and obese sedentary postmenopausal women (age, 57.7 +/- 4.8 years; BMI, 32.4 +/- 4.6 kg.m(-2)). Subjects had the MetS if 3 out of the following 5 criteria were met: visceral fat > 130 cm2, high-density lipoprotein (HDL) cholesterol < 1.29 mmol.L(-1), fasting triglycerides > or = 1.7 mmol.L(-1), blood pressure > or = 130/85 mmHg, and fasting glucose > or =5.6 mmol.L(-1). We measured (i) body composition (by dual-energy X-ray absorptiometry); (ii) visceral fat (by computed tomography); (iii) insulin sensitivity (using the hyperinsulinemic-euglycemic clamp); (iv) plasma lipids, fasting glucose, and insulin, as well as 2 h glucose during an oral glucose tolerance test; (v) resting blood pressure; (vi) peak oxygen consumption (VO2 peak); (vii) PAEE (using doubly labeled water); and (viii) lower-body muscle strength (using weight-training equipment). Forty-two women (30.7%) had the MetS in our cohort. Individuals without the MetS had significantly higher levels of PAEE (962 +/- 296 vs. 837 +/- 271 kcal.d(-1); p < 0.05), VO2 peak (18.2 +/- 3.0 vs. 16.7 +/- 3.2 mL.min(-1).kg(-1); p < 0.05), and insulin sensitivity, as well as significantly lower levels of 2 h glucose and central lean body mass. No differences in total energy expenditure, resting metabolic rate, and muscle strength between groups were observed. Logistic regression analysis showed that 2 h glucose (odds ratio (OR): 1.50 (95% CI 1.17-1.92)), central lean body mass (OR: 1.17 (95% CI 1.05-1.31)), and PAEE (OR: 0.998 (95% CI 0.997-1.000)), but not VO2 peak and (or) muscle strength, were independent predictors of the MetS. Lower levels of PAEE and higher levels of 2 h glucose, as well as central lean body mass, are independent determinants of the MetS in our cohort of overweight and obese postmenopausal women.

Metabolic syndrome in three ethnic groups using current definitions.

According to two current definitions, the prevalence of the metabolic syndrome (MetS) among black Haitians of Montreal was <20%, 30%-36% in Algonquin Indians of Quebec, and >45% in Mexicans of Oaxaca (all aged 35-60 y). Although phenotypes were different, high triglycerides and fasting dysglycemia were good predictors of MetS in all three groups using both definitions. The international cut-offs for abdominal obesity were not predictive of MetS in the Haitian subjects.

Relationship between insulin sensitivity and the triglyceride-HDL-C ratio in overweight and obese postmenopausal women: a MONET study.

The objective of this cross-sectional study was to examine the relationship between the triglyceride-HDL-cholesterol ratio (TG:HDL-C) and insulin sensitivity in overweight and obese sedentary postmenopausal women. The study population consisted of 131 non-diabetic overweight and obese sedentary postmenopausal women (age; 57.7+/-5.0 y; body mass index (BMI), 32.2+/-4.3 kg/m2). Subjects were characterized by dividing the entire cohort into tertiles based on the TG:HDL-C (T1<0.86 vs. T2=0.86 to 1.35 vs. T3>1.35, respectively). We measured (i) insulin sensitivity (using the hyperinsulinenic-euglycemic clamp and homeostasis model assessment (HOMA)), (ii) body composition (using dual-energy X-ray absorptiometry), (iii) visceral fat (using computed tomography), (iv) plasma lipids, C-reactive protein, 2 h glucose concentration during an oral glucose tolerance test (2 h glucose), as well as fasting glucose and insulin, (v) peak oxygen consumption, and (vi) lower-body muscle strength (using weight training equipment). Significant correlations were observed between the TG:HDL-C and the hyperinsulinemic-euglycemic clamp (r=-0.45; p<0.0001), as well as with HOMA (r=0.42; p<0.0001). Moreover, the TG:HDL-C significantly correlated with lean body mass, visceral fat, 2 h glucose, C-reactive protein, and muscle strength. Stepwise regression analysis showed that the TG:HDL-C explained 16.4% of the variation in glucose disposal in our cohort, which accounted for the greatest source of unique variance. Other independent predictors of glucose disposal were 2 h glucose (10.1%), C-reactive protein (CRP; 7.6%), and peak oxygen consumption (5.8%), collectively (including the TG:HDL-C) explaining 39.9% of the unique variance. In addition, the TG:HDL-C was the second predictor for HOMA, accounting for 11.7% of the variation. High levels of insulin sensitivity were associated with low levels of the TG:HDL-C. In addition, the TG:HDL-C was a predictor for glucose disposal rates and HOMA values in our cohort of overweight and obese postmenopausal women.

Differential effect of burn injury on fibroblasts from wounds and normal skin.

BACKGROUND: Although there are well-recognized fluctuations in the systemic concentration of cytokines and growth factors after burn injuries, the effect on wound-healing potential in patients is not well understood. The objective of this study was to characterize the proliferation rate and response of wound and dermal fibroblasts to cytokines in burn patients compared with normal subjects. METHODS: Polyvinyl alcohol sponges were implanted subcutaneously in normal subjects and burn patients soon after admission. Sponges were removed for wound fibroblast explantation after 12 days. At the same time, a small piece of skin was excised for dermal fibroblast explantation. Fibroblast proliferation was then quantified after exposure to 10% fetal bovine serum, 1% fetal bovine serum, interleukin-1, transforming growth factor-beta1, or interferon-alpha2b. RESULTS: Normal subjects' dermal fibroblasts (n = 7) exposed to 10% fetal bovine serum showed significantly increased proliferation relative to normal subjects' wound fibroblasts (n = 3) (p < 0.0005), burn patients' dermal fibroblasts (n = 5) (p < 0.05), and burn patients' wound fibroblasts (n = 5) (p < 0.0001). Burn patients' dermal fibroblast proliferation was also significantly augmented relative to burn patients' wound fibroblasts (p < 0.005); however, there was no significant difference between the two wound fibroblast types. Proliferation of burn subjects' fibroblasts was significantly enhanced with the addition of interleukin-1 and significantly decreased for dermal fibroblasts with interferon-alpha2b. A significant elevation of proliferation with transforming growth factor-beta1 was seen only with burn patients' dermal fibroblasts. CONCLUSIONS: The data suggest that systemic mediators markedly alter the proliferation potential of dermal fibroblasts but not of wound fibroblasts. However, the wound environment substantially alters both the proliferation rate and the responsiveness of fibroblasts to cytokines. Thus, the data support the value of using wound fibroblasts during preliminary in vitro experiments to investigate wound-healing modification by cytokine manipulation.

Ethnic differences in body composition and other markers of cardiovascular disease risk: study in matched Haitian and White subjects from Quebec.

OBJECTIVES: People of African descent may be at greater risk of metabolic syndrome (MS) compared with whites. We examined the associations among MS markers, body composition, and resting metabolic rate (RMR) in black Haitians and in white subjects living in Quebec, Canada. RESEARCH METHODS AND PROCEDURES: Forty randomly selected Haitians were matched with 40 white subjects for age, sex, and BMI. Glycemic status and insulin resistance were assessed based on a 3-hour glucose tolerance test. Blood lipids, blood pressure, abdominal fat (computed tomography), and waist circumference (WC) were measured. RMR was estimated by indirect calorimetry. RESULTS: Triglycerides were significantly correlated with blood pressure only in Haitians and with the area under the curve for insulin only in whites. Haitians had significantly (p < 0.05) lower triglycerides and higher high-density lipoprotein-cholesterol concentrations but higher blood pressure than whites at any given WC value. General linear models showed that Haitians had less visceral adipose tissue than whites for the same WC. RMR was lower among Haitians for any given value of BMI or WC than in whites. Also, WC was more strongly associated with glucose area under the curve and to log-homeostasis model assessment in white than in Haitian subjects. DISCUSSION: The MS may be ethnospecific in its features and etiology. The standard anthropometric indices of obesity may not be as effective in populations of African descent compared with whites, unless appropriate cut-off values are defined.

Corticosterone binding globulin regulation and thymus changes after thermal injury in mice.

Thermal injury is extremely stressful, and data characterizing the systemic endocrine stress response to this injury are sparse. The objective of this study was to measure the effects of thermal injury on mice on corticosterone (Cort) levels in relation with corticosteroid-binding globulin (CBG) and thymus cell populations. The endocrine stress response was determined by measuring total Cort, free Cort, CBG binding capacity, liver CBG mRNA, and circulating CBG levels at 1, 2, 5, and 10 days postburn. Thymus cell populations were also analyzed. After thermal injury, a rapid increase of total Cort was observed in the first 48 h. This was associated with a decrease of hepatic CBG mRNA, protein levels, and binding capacity. Percentage of free Cort in the burn group peaked at day 2 postburn with a dramatic (+500%) increase. This correlated with a significant decrease of thymus cellularity (50% less). Phenotypic analyses showed that corticosensitive cells were significantly altered. After treatment (5 days), both endocrine and immune parameters returned to control levels. Our results demonstrate that, after a thermal injury, CBG is mainly responsible for Cort's action on corticosensitive immune cells.

Burn injury induces a change in T cell homeostasis affecting preferentially CD4+ T cells.

Burn injuries are known to be associated with altered immune functions, resulting in decreased resistance to subsequent infection. In the present study, we determined the in vivo changes in T cell homeostasis following burn injury. Two groups of mice were used: a sham-burn group receiving buprenorphine as an analgesic and a burn group receiving buprenorphine and subjected to burn injury on 20% of the total body surface area. Results showed an important decrease in splenocytes following burn injury. This decrease persisted for 5 days and was followed, at day 10, by a 63% increase in number of cells. In vivo cell proliferation, as determined by the incorporation of 5-bromo-2'-dexoxyuridine, showed a significant increase of cycling splenocytes between days 2 and 10 after burn injury. The percentage of CD4+ and CD8+ T cells in the spleen was altered for 10 days after thermal injury. Analysis of naive (CD62Lhigh CD44low) and effector/memory (CD62Llow CD44high) T cells showed a percent decrease, independent of the expression of CD4 or CD8 molecules. However, early activation markers, such as CD69+, were expressed only on CD4+ T cells after a number of days following injury. Even with an activated phenotype, 10 days post-burn injury, CD4+ naive T cells significantly increased spontaneous apoptosis, detected by using a fluorescent DNA-binding agent 7-amino-actinomycin D. CD8+ T lymphocytes did not express early activation markers and were more resistant to apoptosis. Using purified T cells, we have shown unresponsiveness at day 10. Overall, these results demonstrate that mechanisms of T cell homeostasis were perturbed following burn injury. However, after 10 days, this perturbation persisted only in CD4+ T cells.

Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine supplements: a prospective, controlled, randomized clinical trial.

OBJECTIVE: Enteral glutamine supplements have been shown to reduce infectious morbidity in trauma patients, but their effect on burn patients is not known. The objective of this study was to measure the impact of enteral glutamine supplementation on infectious morbidity, length of care, and the immune system in burn patients. DESIGN: Double-blinded, randomized clinical trial. SETTING: Burn center. PATIENTS: Forty-five adults with severe burns. INTERVENTIONS: Patients were randomized to receive either glutamine or an isonitrogenous control mixture until complete healing occurred. Length of care, incidence of positive blood culture, and mortality were recorded. Phagocytosis by circulating polymorphonuclear cells was measured every 3 days. MEASUREMENTS AND MAIN RESULTS: Patient characteristics were similar in both groups. Four patients were excluded from the analysis, because three of them died within 72 hrs and the fourth could not receive enteral nutrition and amino acid supplements for the first 10 days. Of the remaining 41 patients, length of care in the survivors was not different between groups (0.9 vs. 1.0 days/percent total body surface area for glutamine vs. control, respectively), positive blood culture was three times more frequent in control than in glutamine treatment (4.3 vs. 1.2 days/patient, p <.05), and Pseudomonas aeruginosa was detected in six patients on control and zero on glutamine (p <.05). Phagocytosis by polymorphonuclear cells was not different between groups. Mortality rate was significantly lower in glutamine than in control: intention to treat, two vs. 12 (p <.05); per protocol analysis, zero vs. eight (p <.01). CONCLUSIONS: Enteral glutamine supplementation in adult burn patients reduces blood infection by a factor of three, prevents bacteremia with P. aeruginosa, and may decrease mortality rate. It has no effect on level of consciousness and does not appear to influence phagocytosis by circulating polymorphonuclear cells.

Acute phase modulation of systemic insulin-like growth factor-1 and its binding proteins after major burn injuries.

OBJECTIVES: To provide a detailed, sequential analysis of insulin-like growth factor-1 and its binding proteins in adults during the acute phase after a major burn injury. DESIGN: Descriptive, repeated measurements for quantitation and characterization of insulin-like growth factor-1 and its binding proteins in adult burn survivors. SETTING: Burn center in a university hospital. PATIENTS: A total of 17 severely burned (>15% total body-surface area burned) adult patients. INTERVENTIONS: Venous blood was collected twice a day for 10 days and centrifuged, and the sera were stored at -80 degrees C until analysis. A series of 340 serum samples were analyzed by radioimmunoassay to determine the circulating concentration of insulin-like growth factor-1 and its major binding proteins (insulin-like growth factor-binding protein), by Western ligand blotting. To better understand the changes seen in systemic insulin-like growth factor-binding protein-3 levels by Western ligand blotting, a proteolysis assay was performed. MEASUREMENTS AND MAIN RESULTS: Insulin-like growth factor-1 levels were reduced from day 0 and correlated with insulin-like growth factor-binding protein-1 and -2 (p <.01), but not insulin-like growth factor-binding protein-3 and -4. Insulin-like growth factor-binding protein-3 was decreased relative to normal on day 0, declined further until day 3, and began recovering by day 6, but returned to only 35% of normal by day 10. Insulin-like growth factor-binding protein-1 and -2 were increased relative to normal and remained increased throughout the 10-day period. Insulin-like growth factor-binding protein-4 concentrations, however, were similar to normal at day 1 but gradually increased over time. Burn serum incubated with recombinant human glycosylated iodine-125 insulin-like growth factor-binding protein-3 did not demonstrate any proteolysis, although proteolysis of nonglycosylated iodine-125 insulin-like growth factor-binding protein-3 reached levels of approximately 40%. CONCLUSIONS: Insulin-like growth factor-binding protein-3 proteolysis does not seem to be the mechanism by which systemic insulin-like growth factor-1 levels are reduced in major burn survivors. In vitro proteolysis of recombinant human glycosylated and nonglycosylated iodine-125 insulin-like growth factor-binding protein-3 does not reflect the in vivo situation in major burn survivors.