Glutamine supplementation to critically ill patients?

Critical Care, Mar 2014

Jan Wernerman

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Glutamine supplementation to critically ill patients?

Wernerman Critical Care Glutamine supplementation to critically ill patients? 0 Department of Anesthesia and Intensive Care Medicine, Karolinska University Hospital, Huddinge , Stockholm , Sweden - Introduction A recent study (Reducing Deaths due to Oxidative Stress, REDOXS) reported harm in critically ill patients who received glutamine supplementation [1]. This is in contrast to a number of earlier studies reporting beneficial effects or failing to demonstrate any effect [2], [3]. Naturally, this finding raises a number of questions, which are not answered by combining all existing studies into a large meta-analysis. This overview will discuss existing clinical data, including dosing and selection of patients. In addition, suggested mechanisms will be discussed from a clinical perspective. Finally, possibilities for future research will be outlined. Rationale for supplementation The background to the suggestion that critically ill patients should receive glutamine supplementation is that plasma glutamine concentration at intensive care unit (ICU) admission is an independent predictor of an unfavorable outcome [4], [5]. Empirically, a plasma concentration of 420 μmol/l has repeatedly been reported as a cut-off for a low plasma glutamine concentration associated with a higher risk of mortality in adults [4], [5]. In principle, the same effect applies in critically ill pediatric patients, but here the low mortality rates have not made it possible to demonstrate a mortality disadvantage, although a morbidity disadvantage has been reported [6]. Approximately one third of ICU admissions are consistently found to have a low plasma glutamine concentration, and this is independent from conventional risk-scoring [1], [4]–[6]. In a study from Stockholm, the mortality associated with a low ICU admission glutamine concentration was to a large extent due to the post-ICU mortality within 6 months from ICU admission [5]. In addition to the predictive value of a low plasma glutamine concentration at ICU admission for an unfavorable outcome, there seem to be a similar prediction also for high plasma glutamine concentrations at admission [5]. This group of patients, however, is much smaller, and the evidence for this prediction is mostly in form of case series. It has been reported that acute liver failure is quite often associated with high or very high plasma glutamine concentrations [7]. Chronic liver insufficiency and acute-on-chronic liver failure are not accompanied by high plasma glutamine concentrations. In single cases, it has been observed that terminal patients with multiple organ failure (not necessarily including advanced liver failure) have very high plasma glutamine concentrations. One can speculate that this observation may relate to impaired cellular integrity in general. In parallel to the association between a low plasma glutamine and an unfavorable outcome, there is an extensive literature about the essential role of glutamine in a number of experimental systems, including whole animals. Cell division demands an increase in nucleotide production, and glutamine is a main precursor for this type of synthesis. Cell culture media usually contain a much higher free glutamine concentration than does human plasma, and lowering of glutamine concentration in cell culture media is associated with a lower rate of cell division. Many cultured cells prefer glutamine over glucose as their main energy source, and imposing stressful events to the cell culture is reported to enhance the preference for glutamine over glucose as energy substrate. In tissues and whole animals, it is the rapidly replicating cells that seem to be particularly dependent on glutamine availability. Enterocytes in the gastrointestinal tract and immune-competent cells are reported to be particularly sensitive to glutamine depletion. Histological changes and bacterial translocation in the gut occur when there is glutamine shortage, and provision of glutamine can reverse this effect. Similarly, for immune-competent cells, markers of immune function deteriorate during glutamine shortage, to return back to normal upon restoration of glutamine availability. Targets for supplementation With this background, the suggestion that glutamine shortage should be compensated for by supplementation is not far-fetched and consequently a number of clinical studies have been performed, mainly in critically ill patients. Behind the suggestion to supplement there are two different philosophies: To substitute a deficiency or to administer a pharmacological agent (pharmaconutrition). It is recommended that these two philosophies be separated because the target for treatment is different in the two cases. To supplement to normal levels would mean adding supplementation in order to reach normal plasma concentrations, or normal availability in tissues if more invasive monitoring is possible. To administer a pharmaconutrition agent on the other hand, would mean that (...truncated)


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Jan Wernerman. Glutamine supplementation to critically ill patients?, Critical Care, 2014, pp. 214, 18, DOI: 10.1186/cc13781