Paul E. Wischmeyer

Glutamine administration reduces Gram-negative bacteremia in severely burned patients: a prospective, randomized, double-blind trial versus isonitrogenous control.

Objective To determine the effect of intravenous glutamine supplementation vs. an isonitrogenous control on infectious morbidity in severely burned patients. Previous clinical studies in seriously ill patients suggest a beneficial effect of glutamine on infectious morbidity, but no trials have examined possible clinical benefits in severely burned patients. Design Prospective, double-blind, randomized trial. Setting Burn intensive care unit of a university hospital. Patients Twenty-six severe burn patients with total burn surface area of 25% to 90% and presence of full-thickness burns. Patients were evaluated for occurrence of bacteremia and antibiotic use during the first 30 days of their burn unit admission. Nutritional status and overall inflammation were also measured. Intervention Either intravenous glutamine or an isonitrogenous control amino acid solution was administered as a continuous infusion during burn intensive care unit stay. Measurements and Main Results The incidence of Gram-negative bacteremia was significantly reduced in the glutamine-supplemented group (8%) vs. control (43%;p < .04). No difference was seen in the incidence of Gram-positive bacteremia or fungemia. Average number of positive blood cultures, antibiotic usage, and mortality rates also were reduced but did not reach statistical significance. Significant improvements in serum transferrin and prealbumin were observed in glutamine-supplemented patients at 14 days after burn injury (p < .01 and .04, respectively). C-reactive protein was also significantly reduced at 14 days after burn injury in the glutamine group (p < .01). Conclusions Significantly fewer bacteremic episodes with Gram-negative organisms occurred in the glutamine-supplemented patients. Glutamine supplementation improved measures of nutrition and decreased measures of overall inflammation. In addition, a trend toward lower mortality rate, decreased overall bacteremia incidence, and antibiotic usage in the glutamine group was observed. Glutamine’s beneficial effects may be a result of improved gut integrity or immune function, but the precise mechanism of glutamine’s protection is unknown.

Prevention of chemotherapy and radiation toxicity with glutamine

GOALS OF THE WORK Malignancy produces a state of physiologic stress that is characterized by a relative deficiency of glutamine, a condition that is further exacerbated by the effects of cancer treatment. Glutamine deficiency may impact on normal tissue tolerance to antitumor treatment, and may lead to dose reductions and compromised treatment outcome. Providing supplemental glutamine during cancer treatment has the potential to abrogate treatment-related toxicity. We reviewed the available data on the use of glutamine to decrease the incidence and severity of adverse effects due to chemotherapy and/or radiation in cancer patients. METHODS We performed a search of the MEDLINE database during the time period 1980-2003, and reviewed the English language literature of both human and animal studies pertaining to the use of glutamine in subjects with cancer. We also manually searched the bibliographies of published articles for relevant references. MAIN RESULTS The available evidence suggests that glutamine supplementation may decrease the incidence and/or severity of chemotherapy-associated mucositis, irinotecan-associated diarrhea, paclitaxel-induced neuropathy, hepatic veno-occlusive disease in the setting of high dose chemotherapy and stem cell transplantation, and the cardiotoxicity that accompanies anthracycline use. Oral glutamine supplementation may enhance the therapeutic index by protecting normal tissues from, and sensitizing tumor cells to chemotherapy and radiation-related injury. CONCLUSIONS The role of glutamine in the prevention of chemotherapy and radiation-induced toxicity is evolving. Glutamine supplementation is inexpensive and it may reduce the incidence of gastrointestinal, neurologic, and possibly cardiac complications of cancer therapy. Further studies, particularly placebo-controlled phase III trials, are needed to define its role in chemotherapy-induced toxicity.

Perioperative Use of Arginine-supplemented Diets: A Systematic Review of the Evidence

g p t t c d A d Infections are the most frequent cause of morbidity after surgery and up to 54% of all hospital-acquired infections occur in high-risk surgical populations. Infections result in rolongation of hospital stay and increased health care osts by up to

Glutamine reduces cytokine release, organ damage, and mortality in a rat model of endotoxemia

10 billion per year in the United States lone. Multifaceted efforts to prevent infection are an essential component of any surgical practice. Surgical stress predisposes patients to immune dysfunction, placing them at higher risk of infection, risks that are increased even more if the patient is malnourished before surgical insult. Various nutrient and nutritional strategies ave been studied to evaluate their effect on immune function nd clinical outcomes. One pharmaconutrient that has been he center of much debate in the literature is arginine and rginine-supplemented nutritional formulas. Arginine is an mino acid involved in multiple metabolic processes. It is a recursor of the formation of polyamines and hydroxyproine, which is important for connective tissue repair, and is he precursor for the formation of nitric oxide, an imporant signaling molecule. In addition to these vital roles, arginine is an essential metabolic substrate for immune cells and required for normal lymphocyte function. Arginine deficiency after surgical stress was reported more than 30 years ago, although the mechanisms behind this have until recently remained unknown. More than 20 years ago, supraphysiologic concentrations of arginine were added to the diets of critically ill and surgical patients. These diets were aimed at “enhancing immune function” and also contained increased amounts of omega-3 fatty acids, nucleotides, and other nutrients. These nutrients

GLUTAMINE PREVENTS ACTIVATION OF NF-kappaB AND STRESS KINASE PATHWAYS, ATTENUATES INFLAMMATORY CYTOKINE RELEASE, AND PREVENTS ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) FOLLOWING SEPSIS.

Clinical trials have demonstrated that glutamine (GLN) supplementation can decrease infectious morbidity and improve survival in a number of settings of critical illness. The mechanism of this protection remains unclear. The objective of this study was to evaluate the effect of GLN on cytokine release, organ injury, and survival from endotoxin-induced septic shock. Endotoxemia was induced in Male Sprague-Dawley rats by intravenous administration of 5 mg/kg Escherichia coli lipopolysaccharide (LPS). Concomitantly, animals were fluid resuscitated with a lactated ringers (LR) solution and given GLN (0.75 g/kg i.v.) or LR alone. Blood samples were obtained at multiple time points post-LPS injury for cytokine analysis. Survival rates were monitored for 72 h. Organ injury was evaluated in a separate set of animals via pathologic exam of tissues harvested 6 h post-LPS injury. A single dose of GLN significantly attenuated the release of TNF-alpha at 2 h (P < 0.005) and IL-1 beta at 4 h (P < 0.0001). This attenuation of cytokine release was associated with a significant decrease in mortality (P < 0.003). Pathologic exam demonstrated significant protection of both lung and small bowel tissue by GLN. Blood gas values 6-h post-LPS injury showed increased PaO2 and bicarbonate concentration in GLN treated animals. These data indicate that GLN can significantly attenuate pro-inflammatory cytokine release, protect against end-organ damage, and decrease mortality from endotoxemia. GLN confers protection even when administered at the onset of endotoxemia, rather then as pre-treatment. Thus, one explanation for the clinical benefits observed from GLN-supplementation may be related to the attenuation of pro-inflammatory cytokines.

Glutamine attenuates tumor necrosis factor-α release and enhances heat shock protein 72 in human peripheral blood mononuclear cells

Glutamine (GLN) has been shown to attenuate cytokine release from LPS-stimulated human peripheral blood mononuclear cells; however, the in vivo antiinflammatory effect of GLN in polymicrobial sepsis and ARDS is unknown. This study evaluates the effect of GLN on inflammatory cytokine release and the pathways that may mediate antiinflammatory effects of GLN in the lung. Either 0.75 g/kg of GLN or saline placebo (SP) was administered to male rats 1 h after cecal ligation and puncture (CLP). NF-κB activation, IKBα degradation, phosphorylation of p38 MAPK, ERK, and MKP-1 expression were evaluated in lung tissue 6 h post-CLP. Lung tissue iNOS and eNOS, TNF-α, IL-6, and IL-18 cytokines were assayed. Last, lung histopathology for occurrence of ARDS and survival were examined. GLN given 1 h postsepsis led to inhibition of lung tissue NF-κB activation (P < 0.001 vs. SP), attenuated degradation of IKBα, and inhibited phosphorylation of p38 MAPK, and ERK, pathways critical for cytokine release. GLN treatment increased MKP-1 peptide expression and significantly attenuated TNF-α and IL-6 6 h after CLP. IL-18 was attenuated by GLN at multiple time points post-CLP. Further, GLN abrogated increases in lung iNOS expression and enhanced lung eNOS postsepsis. Finally, GLN prevented the histopathologic appearance of ARDS after sepsis and significantly improved survival. These data reveal that GLN exerts an antiinflammatory effect in sepsis that may be mediated via attenuation of multiple pathways of inflammation such as NF-κB, p38 MAPK, ERK, and MKP-1. GLN also showed an inhibition of increases in iNOS expression. The antiinflammatory effect of GLN was associated with attenuation of ARDS and mortality.

Distance of Cecum Ligated Influences Mortality, Tumor Necrosis Factor-Alpha and Interleukin-6 Expression following Cecal Ligation and Puncture in the Rat

OBJECTIVE Overexpression of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) can contribute to multiple organ dysfunction syndrome and septic shock in critically ill patients. We previously found that glutamine (GLN) can attenuate cytokine expression, induce heat shock protein 72 (HSP 72), and protect against endotoxin-induced mortality and organ injury in an in vivo rat model. However, data on the effect of GLN on direct attenuation of cytokine release and HSP 72 expression in human peripheral blood polymorphonuclear cells (PBMCs) is lacking. METHODS In this study, we assessed the effect of GLN on TNF-alpha and HSP 72 expression in human PBMCs. After treating with various doses of GLN, human PBMCs were stimulated with lipopolysaccharide (LPS). TNF-alpha release was analyzed via enzyme-linked immunosorbent assay and HSP 72 via western blot. RESULTS GLN at doses greater than 4 mM decreased TNF-alpha release at 4 and 24 h after LPS stimulation. Sublethal heating of PBMCs before LPS also markedly decreased TNF-alpha after LPS. Doses of GLN greater than 2 to 4 mM led to an increase in HSP 72 expression after LPS. CONCLUSION These results indicate that GLN, which may improve outcomes in critically ill patients, can directly attenuate pro-inflammatory cytokine release in PBMCs. This effect may be related to enhanced HSP 72 expression.

Metabolic and nutritional support of critically ill patients: consensus and controversies

Background/Aim: A mainstay of laboratory research into new therapies for sepsis has been the cecal ligation and puncture (CLP) model in rodents. Previous data indicate that the number of punctures made in the cecum and needle size utilized are primary determinants of mortality. Despite this, variability exists in mortality from this model, even when needle size is held constant. The aim of the present study was to evaluate the influence of the length of cecum ligated, independent of needle size, as a determinant of mortality. Materials and Methods: We evaluated this by ligating various cecal lengths in male Sprague-Dawley rats. A double puncture was then made with a 20-gauge needle, and mortality was analyzed. Plasma TNF-α and IL-6 expression was assessed at 6 h. Animals received no antibiotics, were not fasted, and fluid resuscitation was administered. Results: We determined that mortality does not begin to occur until a distance of >5% of cecal length is ligated. Further, our findings indicate that in this model, 90–100% mortality occurs 4 days following CLP when a distance of >30% is ligated. TNF-α and IL-6 expression is markedly increased with increasing length of cecum ligated. Conclusions: Our data demonstrate that the length of cecum ligated is a major determinant of mortality in the CLP model of sepsis. These findings indicate that investigators must rigorously control the distance of the cecum ligated in order to generate consistent mortality and inflammation data when utilizing the CLP model in rats. Further, the mortality from this model can be adjusted to fit the individual needs of a particular experiment.

A survey of propofol abuse in academic anesthesia programs.

The results of recent large-scale clinical trials have led us to review our understanding of the metabolic response to stress and the most appropriate means of managing nutrition in critically ill patients. This review presents an update in this field, identifying and discussing a number of areas for which consensus has been reached and others where controversy remains and presenting areas for future research. We discuss optimal calorie and protein intake, the incidence and management of re-feeding syndrome, the role of gastric residual volume monitoring, the place of supplemental parenteral nutrition when enteral feeding is deemed insufficient, the role of indirect calorimetry, and potential indications for several pharmaconutrients.

Glutamine: mode of action in critical illness.

BACKGROUND:Although propofol has not traditionally been considered a drug of abuse, subanesthetic doses may have an abuse potential. We used this survey to assess prevalence and outcome of propofol abuse in academic anesthesiology programs. METHODS:E-mail surveys were sent to the 126 academic anesthesiology training programs in the United States. RESULTS:The survey response rate was 100%. One or more incidents of propofol abuse or diversion in the past 10 yr were reported by 18% of departments. The observed incidence of propofol abuse was 10 per 10,000 anesthesia providers per decade, a fivefold increase from previous surveys of propofol abuse (P = 0.005). Of the 25 reported individuals abusing propofol, 7 died as a result of the propofol abuse (28%), 6 of whom were residents. There was no established system to control or monitor propofol as is done with opioids at 71% of programs. There was an association between lack of control of propofol (e.g., pharmacy accounting) at the time of abuse and incidence of abuse at the program (P = 0.048). CONCLUSIONS:Propofol abuse in academic anesthesiology likely has increased over the last 10 yr. Much of the mortality is in residents. Most programs have no pharmacy accounting or control of propofol stocks. This may be of concern, given that all programs reporting deaths from propofol abuse were centers in which there was no pharmacy accounting for the drug.