Simpson F, Doig GS. The relative effectiveness of practice change interventions in overcoming common barriers to change: a survey of 14 hospitals with experience implementing evidence-based guidelines. J Eval Clin Pract. 2007 Oct;13(5):709-15
AIMS AND OBJECTIVES: Changing practice to reflect current best evidence can be costly and time-consuming. The purpose of this survey was to determine the optimal combination of practice change interventions needed to overcome barriers to practice change commonly encountered in the intensive care unit (ICU). DESIGN: A survey instrument delivered by mail with email follow-up reminders. SETTING: Fourteen hospitals throughout Australia and New Zealand. SUBJECTS: Individuals responsible for implementing an evidence-based guideline for nutritional support in the ICU. SURVEY: Practice change interventions were ranked in order of effectiveness and barriers to change were ranked in order of how frequently they were encountered. RESULTS: A response rate of 100% was achieved. Interventions traditionally regarded as strong (academic detailing, active reminders) were ranked higher than those traditionally regarded as moderate (audit and feedback), or weak (posters, mouse mats). The high ranks of the site initiation visit (educational outreach, modest) and in-servicing (didactic lectures, weak) were unexpected, as was the relatively low rank of educationally influential, peer-nominated opinion leaders. Four hospitals reported the same doctor-related barrier as 'most common' and the remaining 10 hospitals reported three different doctor-related barriers, two nursing-related barriers and three organizational barriers as most common. CONCLUSIONS: When designing a multifaceted, multi-centre change strategy, the selection of individual practice change interventions should be based on: (1) an assessment of available resources; (2) recognition of the importance of different types of barriers to different sites; (3) the potential for combinations of interventions to have a synergistic effect on practice change, and (4) the potential for combinations of interventions to actually reduce workload.

Luiking YC, Deutz NE. Exogenous arginine in sepsis. Crit Care Med. 2007 Sep;35(9 Suppl):S557-63.
Sepsis is a severe condition in critically ill patients and is considered an arginine deficiency state. The rationale for arginine deficiency in sepsis is mainly based on the reduced arginine levels in sepsis that are associated with the specific changes in arginine metabolism related to endothelial dysfunction, severe catabolism, and worse outcome. Exogenous arginine supplementation in sepsis shows controversial results with only limited data in humans and variable results in animal models of sepsis. Since in these studies the severity of sepsis varies but also the route, timing, and dose of arginine, it is difficult to draw a definitive conclusion for sepsis in general without considering the influence of these factors. Enhanced nitric oxide production in sepsis is related to suggested detrimental effects on hemodynamic instability and enhanced oxidative stress. Potential mechanisms for beneficial effects of exogenous arginine in sepsis include enhanced (protein) metabolism, improved microcirculation and organ function, effects on immune function and antibacterial effects, improved gut function, and an antioxidant role of arginine. We recently performed a study indicating that arginine can be given to septic patients without major effects on hemodynamics, suggesting that more studies can be conducted on the effects of arginine supplementation in septic patients.

Vermeulen MA, van de Poll MC, Ligthart-Melis GC, Dejong CH, van den Tol MP, Boelens PG, van Leeuwen PA. Specific amino acids in the critically ill patient – exogenous glutamine/arginine: a common denominator? Crit Care Med. 2007 Sep;35(9 Suppl):S568-76.
OBJECTIVE: Glutamine and arginine are both used as nutritional supplements in critically ill patients. Although glutamine has been shown to be beneficial for the metabolically stressed patient, considerations about arginine supplementation are not unanimously determined. Our aim is to review the current knowledge on the possible interplay between glutamine and arginine generation in the stressed patient and to elaborate on whether these amino acids may function as a common denominator. Because glutamine can be given by the parenteral and enteral routes, possible different actions on the metabolic fate (e.g., generation of citrulline) with both routes are analyzed. DATA SOURCE: A summary of data on the clinical effect of glutamine and arginine metabolism is given, incorporating data on glutamine and arginine supplementation. Differences between the route of administration, parenteral or enteral, and the molecular form of supplied glutamine, free or as dipeptide, on citrulline generation by the gut and production of arginine are discussed. RESULTS: Glutamine and arginine influence similar organ systems; however, they differ in their targets. For example, glutamine serves as fuel for the immune cells, increases human leukocyte antigen-DR expression on monocytes, enhances neutrophil phagocytosis, and increases heat shock protein expression. Arginine affects the immune system by stimulating direct or indirect proliferation of immune cells. This indirect effect is possibly mediated by nitric oxide, which also enhances macrophage cytotoxicity. Furthermore, glutamine serves as a precursor for the de novo production of arginine through the citrulline-arginine pathway. Glutamine has shown to be beneficial in the surgical and critically ill patient, whereas arginine supplementation is still under debate. The route of glutamine administration (parenteral or enteral) determines the effect on citrulline and on the de novo arginine generation. There is a marked difference between the administration of free glutamine and dipeptide enterally or parenterally. Splanchnic extraction of the hydrolyzed glutamine in mice when administering the dipeptide enterally is higher compared with administering free glutamine from the enteral site. In patients, splanchnic extraction of the dipeptide given enterally is 100% when comparing supplementation of the dipeptide intravenously. CONCLUSIONS: The beneficial effects of free glutamine or dipeptide may depend on the route of administration but also on the metabolic fate of amino acids generated (e.g., citrulline, arginine). Glutamine serves as a substrate for de novo citrulline and arginine synthesis. More research needs to be done to establish the direct clinical relevance of the different metabolic pathways. Future perspectives might include combining enteral and parenteral routes of administrating free glutamine or dipeptide.

Bongers T, Griffiths RD< McArdle A. Exogenous glutamine: the clinical evidence. Crit Care Med. 2007 Sep;35(9 Suppl):S545-52
We know that critically ill patients suffering from undernutrition with a limited nutritional reserve have a poorer outcome. Furthermore, having a low body mass index has been shown to be an independent predictor of excess mortality in multiple organ failure. Therefore, nutritional support has gained increasing interest in critical illness with the hope of preventing or attenuating the effects of malnutrition. A negative nitrogen balance is the characteristic metabolic feature in critical illness, with the major protein loss derived from skeletal muscle. In particular, glutamine concentrations are rapidly reduced in plasma and muscle.Over the last 20 yrs or so, increasing evidence is emerging to support the use of glutamine supplementation in critical illness. Clinical trials have found a mortality and morbidity advantage with glutamine supplementation. The advantage appears to be greater the more glutamine is given and greater again when given parenterally. Various modes of action have been postulated. Glutamine seems to have an effect on the immune system, antioxidant status, glucose metabolism, and heat shock protein response. However, the benefit of exogenous glutamine on morbidity and mortality is not universally accepted. This review critically appraises the current clinical evidence regarding glutamine supplementation in critical illness.

Barbul A. Uliyargoli A. Use of exogenous arginine in multiple organ dysfunction syndrome and sepsis. Crit Care Med. 2007; Sep;35(9 Suppl): S564-7.
Given the multiple biological, metabolic, and pharmacologic effects of supplemental arginine, much effort has been devoted to defining its role in numerous clinical conditions. Herein, we review the multiple pathways of arginine metabolism with its various enzyme systems; the effect of arginine on nutrition, healing, and immune system; and its clinical use. Sepsis has been postulated to be an arginine-deficient state and/or a syndrome with elevated levels of nitric oxide. So-called immunonutritional formulations containing various nutritional components have been used most often, yet the effects often are attributed to arginine alone. Such conclusions led to guidelines recommending against the use of arginine-supplemented diets in critically ill patients. While caution in the face of a lack of evidence for benefit in sepsis is commended, well-defined studies examining arginine monotherapy in the context of full nutritional support should be carried out so as to define the possible clinical uses of arginine in critically ill and septic patients.