REVIEW URRENT C OPINION
Glutamine in the intensive care unit Luc Cynober a,b and Jean-Pascal De Bandt a,b
Purpose of review To analyze the recent literature (2011–2013) on glutamine supplementation of parenteral and enteral nutrition in critically ill patients. Potential confounding factors that may explain conflicting results are suggested. Recent findings Some recent, prospective, multicenter trials and two small trials yielded conflicting results that weigh heavily in the conclusions of a recent meta-analysis. Heterogeneity of the patients enrolled (especially in terms of injury severity, age, and basal nutritional status) and difficulties in identifying patients truly in need of glutamine supplementation may explain the discrepancies. Summary Glutamine supplementation has been recognized as beneficial in acutely injured patients. However, recent conflicting results in either ‘real-life conditions’ or very severe situations suggest that its indications need to be more precisely determined. Keywords glutamine, intensive care, metabolism, supplementation
INTRODUCTION Plasma glutamine (GLN), like a number of endogenous substances, is homeostatic by nature, that is, its concentration is roughly constant as a result of an equilibrium between its endogenous production and consumption rates. In healthy conditions, GLN is considered as a nonessential amino acid. However, following injury, GLN consumption increases (in particular by immune cells, the liver, and the kidneys) [1]. Despite an increase in muscle GLN synthesis and release, the response to too longlasting and too severe injury leads to a depletion of GLN pools. This is responsible for morbidity (and perhaps mortality) owing to the numerous roles of this amino acid (e.g. precursor of glutathione, activator of heat-shock protein synthesis, and inhibitor of the synthesis of mediators of the inflammatory responses) [1]. Because of physicochemical constraints (see below for details), GLN is absent from standard parenteral nutrition solutions. Hence, it makes sense to supplement critically ill patients with GLN to avoid a GLN depletion and for the biological properties of this amino acid, of particular importance in ICU patients.
EXPERIMENTAL STUDIES Intestinal failure and subsequent bacterial translocation may be involved in septic shock in ICU www.co-clinicalnutrition.com
patients. Yeh and coworkers [2,3] have performed several studies on the effect of GLN in mice during cecal ligation and puncture (CLP), a recognized model of septicemia. In this model, they evaluated the short-term effects (within 24 h) of a single dose of GLN (as alanyl-glutamine) versus saline on intestinal immunity. They reported a higher percentage of intestinal intraepithelial lymphocyte (IEL) gdTcells, more precisely CD8aaþ TCRabþ IEL, and lower apoptosis of these cells, and a lower level of inflammatory mediators in peritoneal lavage fluid. Of note, the two groups did not receive isonitrogenous support, and the mortality in both groups was unusually low. In addition to these effects on gut immunity, GLN also helps to preserve gut integrity. In a model of experimental endotoxemia in rats, Lehmann et al. [4] showed that intravenous GLN (0.75 g/kg) administered either before or after the
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Department of Clinical Chemistry, Hoˆpitaux Universitaires Paris Centre, AP-HP and bLaboratory of Nutrition Biology EA 4466, Department of Experimental, Metabolic and Clinical Biology, Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cite´, Paris, France Correspondence to Professor Luc Cynober, Service Interhospitalier de Biochimie, Hoˆpitaux Universitaires Paris Centre, 27 rue du Faubourg, Saint-Jacques, 75014 Paris, France. Tel: +33 1 58 41 15 91; fax: +33 1 58 41 15 85; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:98–104 DOI:10.1097/MCO.0000000000000014 Volume 17 Number 1 January 2014
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plasma GLN might result from increased hepatic GLN clearance and is associated with a defective intestinal conversion of GLN into citrulline. This feature might be important because GLN is a potent activator of ureagenesis in the liver [9], and inhibition of its conversion into citrulline in the intestine increases the flux of GLN to the liver. In other words, this impairment could be involved in the high nitrogen loss in sepsis.
KEY POINTS Although a recent meta-analysis supports the indication of glutamine (GLN) supplementation in ICU patients, two large recent clinical trials provided contradictory results. Some methodological limitations and specificities of the patient population studied may explain this contradiction. GLN should be contraindicated in patients with multiple organ failure, especially in those with liver and renal failure.
NUTRITIONAL INTERVENTIONS
An evidence-based decision to supplement should be a GLN plasma level below 420 mmol/l. In our opinion, a GLN level above 700 mmol/l is a clear contraindication.
lipopolysaccharide (LPS) challenge prevented the LPS-induced alterations in intestinal microcirculation. The immunoregulatory properties of GLN are not limited to the gut. In the CLP model in mice, Hu et al. [5] showed that a single GLN administration (0.75 g/kg) also dampened the inflammatory response in other organs, with decreased inflammatory response and oxidative stress in the kidney. This was further illustrated by Hou et al. [6] in a model of acute lung injury induced by intratracheal instillation of endotoxin in male C57BL/6J mice. The animals received either 0.75 g Ala-Gln/kg/day (i.e. 0.46 g GLN/kg/day) or saline by gavage for 9 days. Percentages of regulatory T cells and interleukin-2 levels in bronchoalveolar lavage fluid increased, whereas Th17 cells were suppressed, and the expression of proinflammatory genes in lung tissues decreased in the GLN-treated group. However, although the importance of GLN in promoting gut-barrier function is well established, some data suggest that intestinal GLN metabolism may be impaired in endotoxemia and severe sepsis. In a model of endotoxemia induced in rats by the intraperitoneal injection of LPS, Boutry et al. [7] observed that supplementation with glutamate or GLN failed to restore glutamate, GLN, and citrulline concentrations in plasma and muscle, suggesting a loss of the intestinal capacity for amino acid absorption and metabolism. In humans, Kao et al. [8 ] performed tracer studies in eight patients with severe sepsis and 10 healthy controls. The patients and individuals in the postabsorptive state received primed constant intravenous infusion of 2H2-citrulline and sequential administration of intravenous and enteral 15N-GLN and 13C-leucine. Their results indicate that in the postabsorptive state, the lower &
Scottish Intensive care Glutamine or seleNium Evaluative Trial (SIGNET) is a recent, double-blind, randomized controlled trial (RCT) [10] comparing isonitrogenous and isocaloric parenteral nutrition supplemented with GLN or selenium or both in ICU patients with gastrointestinal failure. In this large (502 patients), multicenter (10 centers) trial, patients received parenteral GLN 20.2 g/day and selenium (500 mg/day) for up to 7 days. There was no effect of GLN (either alone or in combination with selenium) on new infections, mortality, length of stay, or days of antibiotic use. These results are clearly disappointing in the light of those obtained in the previous trials (see the recent meta-analysis [11 ] and below for details) and we need to understand these discrepancies. Most of the previous studies that showed a clear benefit of GLN supplementation were monocentric and concerned rather small groups of homogeneous patients. The large, multicenter SIGNET trial is thus closer to real life and covers a multitude of patients for whom GLN supplementation would be considered. The problem in real life, and so in the SIGNET study, is that patient populations are very heterogeneous. For example, the mean age of patients was 63.8 [14.9 (standard deviation)] years in this study. This means that both rather young adults and much older people were enrolled. Aging brings a number of metabolic and functional changes, and it is uncertain whether GLN supplementation works in the elderly as it may work in young adults. Also, the nutritional status at baseline was very variable, with 27% underweight and 17% obese patients. We do not know what GLN does in obese patients, and we need to question the rationale of providing extra GLN to patients with normal nutritional status. Finally, at baseline, 32% of patients were not receiving any nutrition support and 22% were receiving enteral nutrition. Although some of them are described as presenting gastrointestinal failure, some, presumably, were able to feed themselves or tolerated enteral nutrition; moreover, more than half of the patients received trial parenteral nutrition for less than 5 days. Thus, we
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need to know who these patients were and whether they really required GLN supplementation. The authors addressed most of these issues by subgroup analysis and showed clearly that taking into account nutritional status, age, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, etc., did not change the overall results. Finally, it has been suggested [11 ] that the GLN dosage might have been too low. This might not be so for patients who are underweight. It would have been better if GLN intake had been expressed in g/kg/day and not only in g/day. Considering both older studies in a relatively homogeneous patient population and this ‘real-life’ study, it can be suggested that GLN supplementation is not beneficial for all ICU patients but only for clearly identified subgroups of patients for whom a decrease in GLN availability may be demonstrated. Grau et al. [12] in another prospective, multicenter (12 ICU) RCT in 117 patients compared GLNsupplemented (0.32 g GLN/kg/day as 0.50 g/kg/day alanyl-glutamine) and nonsupplemented isonitrogenous isocaloric total parenteral nutrition. Per protocol statistical analysis in GLN-treated patients showed fewer nosocomial infections per day of mechanical ventilation, fewer urinary infections, and improved insulin sensitivity compared with controls. Improved insulin sensitivity was also found on intention-to-treat analysis. ICU and 6-month mortality and ICU and hospital length of stay were similar in the two groups. Thus, in this multicenter trial, GLN was more efficient than in the SIGNET trial. We note that in the study of Grau et al. [12], patients were more homogeneous in terms of injury severity (APACHE II: 15–23) and age (50–76 years) than in the other trial. Probably as a consequence, global mortality in the ICU was lower (16 and 20% in treated and control patients, respectively) in the study of Grau et al. [12] than in the SIGNET trial [10] (30–37% according to the group). The Scandinavian glutamine trial [13], a multicenter, pragmatic RCT in 413 ICU patients, compared intravenous GLN (0.283 g GLN/kg/day as alanyl-glutamine) and placebo (saline) administered throughout the ICU stay in addition to patients’ enteral or parenteral nutrition. This study was termed ‘pragmatic’ by the authors because there were very few noninclusion criteria. There was no difference in the primary endpoint, that is, the change in Sequential Organ Failure Assessment (SOFA) scores after 7 days of treatment. Concerning the predefined secondary endpoints in patients given GLN supplementation for at least 3 days, ICU mortality was lower, but this was not maintained at 6 months. Although only few &
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details are given, patient needs were adequately covered mainly by enteral nutrition and supplementary parenteral nutrition. The authors acknowledge the lack of statistical power of their study (only 40% of the required number of patients were actually recruited) and noticeable shortcomings that limit the extent of their results: the lack of plasma GLN determination, numerous missing values for important parameters (e.g. SOFA score), and even undefined sex for nine patients. In a small RCT [14], 30 patients admitted to ICU and requiring total parenteral nutrition (TPN) for more than 5 days were randomized to receive either GLN-supplemented TPN (0.34 g GLN/kg/day as 0.5 g/kg/day alanyl-glutamine) or standard GLN-free TPN. There was only a trend for reduced mortality and ICU length of stay. Again, these results may be explained by the very broad heterogeneity of patients enrolled in the study (age 35–95 years, APACHE II 9–44) and the fact that this study was underpowered to address the major outcomes such as mortality. The data from the studies described above were aggregated with those of the previous studies in a meta-analysis of 40 RCTs published between 1994 and 2011, evaluating the effect of exclusively parenteral GLN supplementation [11 ]. Eligible participants were solely adult patients (but in one study) included for major surgery, surgical complication, trauma, burns, pancreatitis, or admission to an ICU. Parenteral GLN (0.13–0.86 g/kg/day) was associated with a significant reduction in infections [relative risk (RR) ¼ 0.83; 95% confidence interval (CI) 0.72–0.95] and length of stay (2.35 days; 95% CI 3.68 to 1.02), but there was no difference in short-term mortality (RR ¼ 0.89; 95% CI 0.77–1.04). The authors underline this absence of reduction in mortality in contrast with the previous metaanalyses, and suggest that the SIGNET study [10] weighs heavily in the results of the analysis. We note that a small meta-analysis specifically addressing burn patients (4 RCTs and 155 patients) [15] showed that GLN supplementation was associated with a significant decrease in Gram-negative bacteremia [odds ratio (OR) ¼ 0.27; 95% CI 0.08– 0.92] and hospital mortality (OR ¼ 0.13; 95% CI 0.03–0.51). In a small, controlled crossover study [16], 30 enterally fed ICU patients received two successive 2-day enteral supplementations with either GLN 30 g/day or isonitrogenous caseinate. These ICU patients were hemodynamically stable, but exhibited a systemic inflammatory response syndrome because of pulmonary infection. Only surrogate markers were measured, that is, oxidative stress markers, cell counts, and plasma proinflammatory &
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and anti-inflammatory cytokines. Very few differences were observed between the groups. As acknowledged by the authors, this could be because of the very short duration of the GLN supplementation (2 days). Heyland et al. [17 ] have conducted the largest prospective RCT on GLN and antioxidant (AOX) supplementation. This international multicenter study included 1223 critically ill patients who had multiple organ failure (MOF) and were receiving mechanical ventilation. Patients were randomized to receive, within 24 h after admission to the ICU, either GLN (0.35 g/kg/day i.v. as 0.50 g alanyl-glutamine and 30 g/kg/day enterally as 42.5 g of alanylglutamine and glycyl-glutamine), a combination of AOXs (selenium 500 mg i.v. and 300 mg enterally; 20 mg of zinc, 10 mg of beta-carotene, 500 mg of vitamin E, and 1500 mg of vitamin C enterally), both GLN and micronutrients, or i.v. and enteral placebo supplements. There was no difference in the overall 28-day mortality, the primary endpoint, between the four groups, but there was a trend toward increased mortality when aggregating patients who received GLN compared with patients who did not (32.4 vs. 27.2%). These results suggest that such supplementation is pointless and may even be harmful in patients most in need of optimal nutritional support. In addition, the patients were selected with few noninclusion criteria (see below for further comments) except in terms of severity (two or more organ failures related to their acute illness), to come close to a ‘real-life’ study (as for the SIGNET study [10]). We believe that this study raises several questions. Its objective was to evaluate the effect of the supplementations in critically ill patients in order to resolve the conflicting results in the recent literature [11 ]. However, the investigators targeted patients with MOF, even though there are almost no data available for such a clinical status, a fact which is recognized in the discussion. The rationale for providing GLN in this setting seems questionable considering that in addition to the intestine, the kidneys and liver play a major role in GLN homeostasis, the equilibrium between these two organs depending on the acid–base status of the patients [9]. In this respect, it would have been very interesting to have data on blood gas and to consider patients with metabolic acidosis separately. In patients with liver and kidney failure, GLN may accumulate and also ammonia, but ammonia was unfortunately not measured. Hyperammonemia in conjunction with an unbalanced low protein diet may be involved in side-effects induced by GLN supplementation [18]. The idea that patients enrolled in this study had an unusual stress-induced &&
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metabolic status is also supported by the fact that in nonsupplemented patients, plasma GLN levels were only moderately decreased or normal and were higher than the values encountered in ICU patients without organ failure. The inclusion of patients with liver and kidney failure explains why some patients (see supplemental material of this study) exhibited overly high and presumably detrimental glutaminemia (i.e. >1000 mmol/l and up to 2500 mmol/l). Such values should be a contraindication to GLN supplementation. Finally, GLN plasma levels have only been analyzed in a subpopulation of patients which may not be representative of all the patients included. Heyland and Dhaliwal [19], by enrolling patients with MOF, probably underestimated the risk of having a large number of patients without hypoglutaminemia. In addition, the statement in the companion editorial [20] that low GLN levels could be merely adaptive, and so need not be corrected, is not only very speculative, but also inappropriate in the circumstances, as there was no hypoglutaminemia in a number of the patients enrolled in this study. The doses of GLN supplements in themselves are also questionable. Whereas selected doses of GLN are in line with the upper limit of the literature, the provision of nearly 65–80 g of GLN represents quite a large nitrogen supplement, resulting in a greatly unbalanced diet (with GLN bringing more than 60% of total nitrogen) [18], in excess of patient needs in a situation of compromised organ function. Second, the level of AOX supplementation seems very high, especially for vitamin E (500 mg/day, i.e. 42 times the normal requirements) and vitamin C (1500 mg/day, i.e. 12.5 times the normal requirements). The sole evidence for the efficacy of such elevated AOX supply comes from the studies in burned patients who have a very specific metabolic status [21]. We must be aware that at such very high intake, AOX may be toxic. We note that among the five AOX added to the diet, only plasma selenium was monitored, whereas the AOX status of the patients, which would have been a good surrogate marker, is unknown. Concerning the nutritional support, we note (see supplementary data of [17 ]) that a significant number of patients received very low calorie and protein supply, if any. Hence, we can suppose that some GLN (and AOX)-supplemented patients received nothing in addition to their GLN (and AOX) supplements. The concept of pharmaconutrition relies on the properties of specific nutrients when they are added to an adequate nutritional support [18]. This was hardly the case for a significant number of patients, and so the results from such patients should have been discarded.
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The broad inclusion criteria mean that the population under study was very heterogeneous. For example, patients with morbid obesity were included (i.e. BMI up to 78.3). Nobody knows what pharmacological doses of GLN and AOX do in ICU patients with morbid obesity, or even what the optimal nutritional support is in such patients in catabolic situations. With greater reason, we know nothing about nutrition in morbidly obese patients with MOF. It does not seem therefore appropriate to include such patients. A separate analysis of the effect of supplementation in this subgroup of patients would have been of major interest. The APACHE II score was also quite heterogeneous (from 6.0 to 51.0). It is logical that a patient with an APACHE II score of 51.0 has low chances of survival with or without GLN and AOX supplementation. Even if patients were stratified for APACHE II score above or below the observed median (i.e. 26), we and others [22] found no evidence in the study for adjustment of the data on the severity score, the presence of shock, and the number of organ failures. Again, a patient suffering from morbid obesity, with cardiogenic shock and MOF involving four organs, is certainly not an ideal individual for investigating the effects of pharmacological doses of GLN and AOX. Last, the authors seem to assume that the properties of GLN and AOX would be additive, allowing the GLN plus AOX-treated patients to be aggregated with the GLN-treated ones. This recalls the immuno-enhancing diet (IED) findings, in which individual pharmaconutrients may be beneficial, whereas their association appears detrimental in severe ICU patients; aggregating individual pharmaconutrient-treated patients and IED-treated ones is thus unsound. This applies even more obviously to the present study: we do not know at the outset whether these two groups can be considered as similar, and so aggregating them may bring out a trend if there are no differences in both primary and secondary endpoints between the groups. In conclusion, we believe that nutrients are not magic bullets even at pharmacological dosages, and it is not surprising that GLN and AOX supplementation in critically ill patients with MOF did not improve their clinical picture, and might even have worsened their state. We have to accept that even the strongest drugs may be ineffective, and that mortality in this subgroup of ICU patients remains extremely high. Hence, in this context, we must keep in mind the principle ‘do not harm’. Finally, the terms ‘with multiple organ failure’ should have appeared in the title of the article, because what has been found certainly does not extend to other ICU patients. 102
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WHAT DO THE RECENT GUIDELINES STATE? Recently, the European Society for Clinical Nutrition and Metabolism (ESPEN) endorsed the recommendations made by three French Medical Societies concerning nutritional therapy in major burns [21]. Concerning the GLN supplementation, it is strongly suggested that supplementation with GLN (or its precursor ornithine a-ketoglutarate) be considered, but with weak agreement among experts. The guidelines state that the GLN dose reported for other critical patients should probably be considered: 0.3 g/kg/day for 5–10 days [21]. In our opinion, this dosage may be insufficient in the case of enteral nutrition because of the large splanchnic extraction of GLN, and 0.4 g/kg/day would probably be better. In addition, severe burn injury is a longlasting insult: patients are hypercatabolic for at least 2–3 weeks and the healing time may be 5 weeks or more. Taking into account the major role of GLN and ornithine a-ketoglutarate (OKG) in the healing process, it makes sense to supplement the diet with GLN or OKG until wound closure. Free GLN utilization is limited in parenteral nutrition because of its poor solubility and stability and to its high osmolarity [1]. Two dipeptides (i.e. alanyl-glutamine and glycyl-glutamine) are available on the market. They present the advantage of being stable in solution, highly soluble, and of rapidly releasing GLN after administration. A very large number of studies have established the safety and efficacy of GLN-containing peptides in various populations of patients, and as a consequence GLN-containing peptides are available worldwide, although not in North America. The underlying reasons for this are unclear, prompting the American Society for Parenteral Nutrition (ASPEN) to publish a position paper [23], advocating the availability of GLN-containing peptide in North America. The ASPEN analysis stresses that parenteral GLN administration is associated with decreased infectious complications, decreased hospital length of stay, and possibility decreased mortality in critically ill patients.
PLASMA GLUTAMINE AS AN INDEPENDENT RISK FACTOR &
Rodas et al. [24 ] evaluated the prevalence of GLN depletion in an observational study in 174 patients hospitalized in a mixed ICU. Low (below 420 mmol/l) or high (above 930 mmol/l) plasma GLN (measured within 24 h after admittance) was associated with 6-month mortality independently of APACHE II or SOFA scores. However, plasma GLN below 400 mmol/l or above 930 mmol/l increased the Volume 17 Number 1 January 2014
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sensitivity of APACHE II score to predict death rate. We note that most of the patients with very high plasma GLN concentrations had acute liver failure: GLN is one of the most potent gluconeogenic and ureogenic amino acids, explaining the role of the liver in its removal.
GLUTAMINE IN THE ICU: WHO NEEDS GLUTAMINE SUPPLY? This question was raised in a recent letter by Gottschalk et al. [25 ]. This issue is of importance because there are two approaches to GLN supplementation. The first considers that GLN is a pharmacological agent regulating numerous functions, and therefore should be provided to any stressed patient. The second considers that GLN supplementation should be reserved for patients who are depleted in GLN. Gottschalk et al. [25 ] retrospectively analyzed data from one of their cohort studies. At the time of randomization, three patients (one GLN supplemented and two controls) exhibited plasma GLN above 700 mmol/l, two of them died. During treatment, seven patients (six GLN supplemented and one control) presented high plasma GLN (above 675 mmol/l), and this was associated with a history of acute right heart failure. The authors claim that in such patients GLN supply may be a toxic burden. However, from these data, it is impossible to distinguish cause from consequence, especially because two control patients died with acute kidney failure. It is reasonable to assume they died from organ failure, which explains high GLN levels (explained by a decrease in GLN utilization by the kidney), and not by high GLN levels per se. The same may apply to patients with temporary high GLN levels who exhibited pulmonary embolism, septic, or cardiac shock. Taking into account all the data discussed above, we can reasonably suggest [13,19] that GLN supplementation should be reserved for patients who have proven hypoglutaminemia at baseline. &
capacity is altered, so GLN should probably not be used in patients with MOF. Clearly, GLN is no magic bullet, and GLN supplementation should be reserved for specifically identified patients with compromised GLN availability. The challenge will be to clearly identify those patients. Finally, the regulatory properties of GLN can only be mobilized if patients are getting adequate nitrogen and energy supplies and if GLN is effectively supplied in appropriate doses (at least 0.2 g GLN/kg/day i.v.). Acknowledgements None. Conflicts of interest L.C. receives honoraria from Nestle´ Clinical Nutrition. Part of EA4466 research is supported by an unrestricted grant from Nestle´ Clinical Nutrition.
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CONCLUSION &
The meta-analysis of Bollhalder et al. [11 ] confirms the interest of GLN supplementation – at least in terms of infectious complications and length of stay. Beyond seemingly discrepant results, the recent literature analyzed highlights several points. First, the underlying rationale for GLN supplementation is that GLN availability decreases in most (but not all) stress situations, and the GLN supply is designed to restore normal plasma GLN. Clearly, dramatically high plasma GLN, like any other amino acid, may be toxic, especially when nitrogen elimination
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Sacks GS. Effect of glutamine-supplemented parenteral nutrition on mortality in critically ill patients. Nutr Clin Pract 2011; 26:44–47. 2. Tung JN, Lee WY, Pai MH, et al. Glutamine modulates CD8aaþ TCRabþ intestinal intraepithelial lymphocyte expression in mice with polymicrobial sepsis. Nutrition 2013; 29:911–917. 3. Lee WY, Hu YM, Ko TL, et al. Glutamine modulates sepsis-induced changes to intestinal intraepithelial gdT lymphocyte expression in mice. Shock 2012; 38:288–293. 4. Lehmann C, Pavlovic D, Zhou J, et al. Intravenous free and dipeptide-bound glutamine maintains intestinal microcirculation in experimental endotoxemia. Nutrition 2012; 28:588–593. 5. Hu YM, Pai MH, Yeh CL, et al. Glutamine administration ameliorates sepsisinduced kidney injury by down regulating the high-mobility group box protein1-mediated pathway in mice. Am J Physiol Renal Physiol 2012; 302:F150– F158. 6. Hou YC, Pai MH, Liu JJ, Yeh SL. Alanyl-glutamine resolves lipopolysaccharide-induced lung injury in mice by modulating the polarization of regulatory T cells and T helper 17 cells. J Nutr Biochem 2013; 24:1555–1563. 7. Boutry C, Matsumoto H, Bos C, et al. Decreased glutamate, glutamine and citrulline concentrations in plasma and muscle in endotoxemia cannot be reversed by glutamate or glutamine supplementation: a primary intestinal defect? Amino Acids 2012; 43:1485–1498. 8. Kao CC, Hsu JW, Bandi V, Jahoor F. Alterations in glutamine metabolism and & its conversion to citrulline in sepsis. Am J Physiol Endocrinol Metab 2013; 304:E1359–E1364. Data presented in this study may be important for a better understanding of the mechanisms of increased nitrogen loss in sepsis. 9. Cynober L. Amino acid metabolism. In: Lennarz WJ, Lane MD, editors. Encyclopedia of biological chemistry. New York: Elsevier; 2013. pp. 91–96. 10. Andrews PJD, Avenell A, Noble DB, et al. Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ 2011; 342:d1542. 11. Bollhalder L, Pfeil AM, Tomonaga Y, Schwenkglenks M. A systematic litera& ture review and meta-analysis of randomized clinical trials of parenteral glutamine supplementation. Clin Nutr 2013; 32:213–223. This meta-analysis seeks to explain why GLN effects on ICU patients are less demonstrative than previously thought in relation to the inclusion of recent multicenter trials. 12. Grau T, Bonet A, Minambres E, et al. The effect of L-alanyl-L-glutamine dipeptide supplemented total parenteral nutrition on infectious morbidity and insulin sensitivity in critically ill patients. Crit Care Med 2011; 39:1263–1268. 13. Wernerman J, Kirketeig T, Andersson B, et al. Scandinavian glutamine trial: a pragmatic multicentre randomised clinical trial of intensive care unit patients. Acta Anaesthesiol Scand 2011; 55:812–818. ¨ . The impact of L-alanyl-L-glutamine dipeptide 14. C ¸ ekmen N, Aydin A, Erdemli O supplemented total parenteral nutrition on clinical outcome in critically patients. e-SPEN 2011; 6:e64–e67.
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Protein, amino acid metabolism and therapy 15. Lin JJ, Chung XJ, Yang CY, Lau HL. A meta-analysis of trials using the intention to treat principle for glutamine supplementation in critically ill patients with burn. Burns 2013; 39:565–570. 16. Cavalcante AAM, Campelo MWS, De Vasconcelos MPP, et al. Enteral nutrition supplemented with L-glutamine in patients with systemic inflammatory response syndrome due to pulmonary infection. Nutrition 2012; 28:397– 402. 17. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of && glutamine and antioxidants in critically ill patients. N Engl J Med 2013; 368:1489–1497. The largest trial on GLN supplementation in ICU patients. However, multiple organ failure is probably not an appropriate indication for GLN supplementation. Also, included patients seem very heterogeneous. 18. Bistrian BR. Glutamine and antioxidants in critically ill patients. N Engl J Med 2013; 369:482. [Letter] 19. Heyland DK, Dhaliwal R. Role of glutamine supplementation in critical illness given the results of the REDOXS study. JPEN J Parenter Enteral Nutr 2013; 37:442–443.
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20. Van den Berghe G. Low glutamine levels during critical illness: adaptive or maladaptive? N Engl J Med 2013; 368:1549–1550. [Letter] 21. Rousseau AF, Losser MR, Ichai C, et al. ESPEN endorsed recommendations: nutritional therapy in major burns. Clin Nutr 2013; 32:497–502. 22. Buijs NB, Vermeulen MAR, Van Leeuwen PAM. Glutamine and antioxidants in critically ill patients [letter]. N Engl J Med 2013; 369:483. [Letter] 23. Vanek VW, Matarese LE, Robinson M, et al. ASPEN position paper: parenteral nutrition glutamine supplementation. Nutr Clin Pract 2011; 26:479–494. 24. Rodas PC, Rooyackers O, Hebert C, et al. Glutamine and glutathione at ICU & admission in relation to outcome. Clin Sci 2012; 122:591–597. This study extends the previous data showing that low plasma GLN is a predictor of mortality in ICU patients. It further shows that high GLN levels are also associated with poor prognosis, probably in relation to liver failure. 25. Gottshalk A, Wempe C, Goeters C. Glutamine in the ICU: who needs supply? & Clin Nutr 2013; 32:668–669. This study shows that high GLN levels are associated with morbi-mortality in ICU patients. GLN should not be supplied in such patients.
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Glutamine in the intensive care unit Luc Cynober a,b and Jean-Pascal De Bandt a,b
Purpose of review To analyze the recent literature (2011–2013) on glutamine supplementation of parenteral and enteral nutrition in critically ill patients. Potential confounding factors that may explain conflicting results are suggested. Recent findings Some recent, prospective, multicenter trials and two small trials yielded conflicting results that weigh heavily in the conclusions of a recent meta-analysis. Heterogeneity of the patients enrolled (especially in terms of injury severity, age, and basal nutritional status) and difficulties in identifying patients truly in need of glutamine supplementation may explain the discrepancies. Summary Glutamine supplementation has been recognized as beneficial in acutely injured patients. However, recent conflicting results in either ‘real-life conditions’ or very severe situations suggest that its indications need to be more precisely determined. Keywords glutamine, intensive care, metabolism, supplementation
INTRODUCTION Plasma glutamine (GLN), like a number of endogenous substances, is homeostatic by nature, that is, its concentration is roughly constant as a result of an equilibrium between its endogenous production and consumption rates. In healthy conditions, GLN is considered as a nonessential amino acid. However, following injury, GLN consumption increases (in particular by immune cells, the liver, and the kidneys) [1]. Despite an increase in muscle GLN synthesis and release, the response to too longlasting and too severe injury leads to a depletion of GLN pools. This is responsible for morbidity (and perhaps mortality) owing to the numerous roles of this amino acid (e.g. precursor of glutathione, activator of heat-shock protein synthesis, and inhibitor of the synthesis of mediators of the inflammatory responses) [1]. Because of physicochemical constraints (see below for details), GLN is absent from standard parenteral nutrition solutions. Hence, it makes sense to supplement critically ill patients with GLN to avoid a GLN depletion and for the biological properties of this amino acid, of particular importance in ICU patients.
EXPERIMENTAL STUDIES Intestinal failure and subsequent bacterial translocation may be involved in septic shock in ICU www.co-clinicalnutrition.com
patients. Yeh and coworkers [2,3] have performed several studies on the effect of GLN in mice during cecal ligation and puncture (CLP), a recognized model of septicemia. In this model, they evaluated the short-term effects (within 24 h) of a single dose of GLN (as alanyl-glutamine) versus saline on intestinal immunity. They reported a higher percentage of intestinal intraepithelial lymphocyte (IEL) gdTcells, more precisely CD8aaþ TCRabþ IEL, and lower apoptosis of these cells, and a lower level of inflammatory mediators in peritoneal lavage fluid. Of note, the two groups did not receive isonitrogenous support, and the mortality in both groups was unusually low. In addition to these effects on gut immunity, GLN also helps to preserve gut integrity. In a model of experimental endotoxemia in rats, Lehmann et al. [4] showed that intravenous GLN (0.75 g/kg) administered either before or after the
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Department of Clinical Chemistry, Hoˆpitaux Universitaires Paris Centre, AP-HP and bLaboratory of Nutrition Biology EA 4466, Department of Experimental, Metabolic and Clinical Biology, Faculty of Pharmacy, Paris Descartes University, Sorbonne Paris Cite´, Paris, France Correspondence to Professor Luc Cynober, Service Interhospitalier de Biochimie, Hoˆpitaux Universitaires Paris Centre, 27 rue du Faubourg, Saint-Jacques, 75014 Paris, France. Tel: +33 1 58 41 15 91; fax: +33 1 58 41 15 85; e-mail: [email protected] Curr Opin Clin Nutr Metab Care 2014, 17:98–104 DOI:10.1097/MCO.0000000000000014 Volume 17 Number 1 January 2014
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plasma GLN might result from increased hepatic GLN clearance and is associated with a defective intestinal conversion of GLN into citrulline. This feature might be important because GLN is a potent activator of ureagenesis in the liver [9], and inhibition of its conversion into citrulline in the intestine increases the flux of GLN to the liver. In other words, this impairment could be involved in the high nitrogen loss in sepsis.
KEY POINTS Although a recent meta-analysis supports the indication of glutamine (GLN) supplementation in ICU patients, two large recent clinical trials provided contradictory results. Some methodological limitations and specificities of the patient population studied may explain this contradiction. GLN should be contraindicated in patients with multiple organ failure, especially in those with liver and renal failure.
NUTRITIONAL INTERVENTIONS
An evidence-based decision to supplement should be a GLN plasma level below 420 mmol/l. In our opinion, a GLN level above 700 mmol/l is a clear contraindication.
lipopolysaccharide (LPS) challenge prevented the LPS-induced alterations in intestinal microcirculation. The immunoregulatory properties of GLN are not limited to the gut. In the CLP model in mice, Hu et al. [5] showed that a single GLN administration (0.75 g/kg) also dampened the inflammatory response in other organs, with decreased inflammatory response and oxidative stress in the kidney. This was further illustrated by Hou et al. [6] in a model of acute lung injury induced by intratracheal instillation of endotoxin in male C57BL/6J mice. The animals received either 0.75 g Ala-Gln/kg/day (i.e. 0.46 g GLN/kg/day) or saline by gavage for 9 days. Percentages of regulatory T cells and interleukin-2 levels in bronchoalveolar lavage fluid increased, whereas Th17 cells were suppressed, and the expression of proinflammatory genes in lung tissues decreased in the GLN-treated group. However, although the importance of GLN in promoting gut-barrier function is well established, some data suggest that intestinal GLN metabolism may be impaired in endotoxemia and severe sepsis. In a model of endotoxemia induced in rats by the intraperitoneal injection of LPS, Boutry et al. [7] observed that supplementation with glutamate or GLN failed to restore glutamate, GLN, and citrulline concentrations in plasma and muscle, suggesting a loss of the intestinal capacity for amino acid absorption and metabolism. In humans, Kao et al. [8 ] performed tracer studies in eight patients with severe sepsis and 10 healthy controls. The patients and individuals in the postabsorptive state received primed constant intravenous infusion of 2H2-citrulline and sequential administration of intravenous and enteral 15N-GLN and 13C-leucine. Their results indicate that in the postabsorptive state, the lower &
Scottish Intensive care Glutamine or seleNium Evaluative Trial (SIGNET) is a recent, double-blind, randomized controlled trial (RCT) [10] comparing isonitrogenous and isocaloric parenteral nutrition supplemented with GLN or selenium or both in ICU patients with gastrointestinal failure. In this large (502 patients), multicenter (10 centers) trial, patients received parenteral GLN 20.2 g/day and selenium (500 mg/day) for up to 7 days. There was no effect of GLN (either alone or in combination with selenium) on new infections, mortality, length of stay, or days of antibiotic use. These results are clearly disappointing in the light of those obtained in the previous trials (see the recent meta-analysis [11 ] and below for details) and we need to understand these discrepancies. Most of the previous studies that showed a clear benefit of GLN supplementation were monocentric and concerned rather small groups of homogeneous patients. The large, multicenter SIGNET trial is thus closer to real life and covers a multitude of patients for whom GLN supplementation would be considered. The problem in real life, and so in the SIGNET study, is that patient populations are very heterogeneous. For example, the mean age of patients was 63.8 [14.9 (standard deviation)] years in this study. This means that both rather young adults and much older people were enrolled. Aging brings a number of metabolic and functional changes, and it is uncertain whether GLN supplementation works in the elderly as it may work in young adults. Also, the nutritional status at baseline was very variable, with 27% underweight and 17% obese patients. We do not know what GLN does in obese patients, and we need to question the rationale of providing extra GLN to patients with normal nutritional status. Finally, at baseline, 32% of patients were not receiving any nutrition support and 22% were receiving enteral nutrition. Although some of them are described as presenting gastrointestinal failure, some, presumably, were able to feed themselves or tolerated enteral nutrition; moreover, more than half of the patients received trial parenteral nutrition for less than 5 days. Thus, we
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need to know who these patients were and whether they really required GLN supplementation. The authors addressed most of these issues by subgroup analysis and showed clearly that taking into account nutritional status, age, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, etc., did not change the overall results. Finally, it has been suggested [11 ] that the GLN dosage might have been too low. This might not be so for patients who are underweight. It would have been better if GLN intake had been expressed in g/kg/day and not only in g/day. Considering both older studies in a relatively homogeneous patient population and this ‘real-life’ study, it can be suggested that GLN supplementation is not beneficial for all ICU patients but only for clearly identified subgroups of patients for whom a decrease in GLN availability may be demonstrated. Grau et al. [12] in another prospective, multicenter (12 ICU) RCT in 117 patients compared GLNsupplemented (0.32 g GLN/kg/day as 0.50 g/kg/day alanyl-glutamine) and nonsupplemented isonitrogenous isocaloric total parenteral nutrition. Per protocol statistical analysis in GLN-treated patients showed fewer nosocomial infections per day of mechanical ventilation, fewer urinary infections, and improved insulin sensitivity compared with controls. Improved insulin sensitivity was also found on intention-to-treat analysis. ICU and 6-month mortality and ICU and hospital length of stay were similar in the two groups. Thus, in this multicenter trial, GLN was more efficient than in the SIGNET trial. We note that in the study of Grau et al. [12], patients were more homogeneous in terms of injury severity (APACHE II: 15–23) and age (50–76 years) than in the other trial. Probably as a consequence, global mortality in the ICU was lower (16 and 20% in treated and control patients, respectively) in the study of Grau et al. [12] than in the SIGNET trial [10] (30–37% according to the group). The Scandinavian glutamine trial [13], a multicenter, pragmatic RCT in 413 ICU patients, compared intravenous GLN (0.283 g GLN/kg/day as alanyl-glutamine) and placebo (saline) administered throughout the ICU stay in addition to patients’ enteral or parenteral nutrition. This study was termed ‘pragmatic’ by the authors because there were very few noninclusion criteria. There was no difference in the primary endpoint, that is, the change in Sequential Organ Failure Assessment (SOFA) scores after 7 days of treatment. Concerning the predefined secondary endpoints in patients given GLN supplementation for at least 3 days, ICU mortality was lower, but this was not maintained at 6 months. Although only few &
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details are given, patient needs were adequately covered mainly by enteral nutrition and supplementary parenteral nutrition. The authors acknowledge the lack of statistical power of their study (only 40% of the required number of patients were actually recruited) and noticeable shortcomings that limit the extent of their results: the lack of plasma GLN determination, numerous missing values for important parameters (e.g. SOFA score), and even undefined sex for nine patients. In a small RCT [14], 30 patients admitted to ICU and requiring total parenteral nutrition (TPN) for more than 5 days were randomized to receive either GLN-supplemented TPN (0.34 g GLN/kg/day as 0.5 g/kg/day alanyl-glutamine) or standard GLN-free TPN. There was only a trend for reduced mortality and ICU length of stay. Again, these results may be explained by the very broad heterogeneity of patients enrolled in the study (age 35–95 years, APACHE II 9–44) and the fact that this study was underpowered to address the major outcomes such as mortality. The data from the studies described above were aggregated with those of the previous studies in a meta-analysis of 40 RCTs published between 1994 and 2011, evaluating the effect of exclusively parenteral GLN supplementation [11 ]. Eligible participants were solely adult patients (but in one study) included for major surgery, surgical complication, trauma, burns, pancreatitis, or admission to an ICU. Parenteral GLN (0.13–0.86 g/kg/day) was associated with a significant reduction in infections [relative risk (RR) ¼ 0.83; 95% confidence interval (CI) 0.72–0.95] and length of stay (2.35 days; 95% CI 3.68 to 1.02), but there was no difference in short-term mortality (RR ¼ 0.89; 95% CI 0.77–1.04). The authors underline this absence of reduction in mortality in contrast with the previous metaanalyses, and suggest that the SIGNET study [10] weighs heavily in the results of the analysis. We note that a small meta-analysis specifically addressing burn patients (4 RCTs and 155 patients) [15] showed that GLN supplementation was associated with a significant decrease in Gram-negative bacteremia [odds ratio (OR) ¼ 0.27; 95% CI 0.08– 0.92] and hospital mortality (OR ¼ 0.13; 95% CI 0.03–0.51). In a small, controlled crossover study [16], 30 enterally fed ICU patients received two successive 2-day enteral supplementations with either GLN 30 g/day or isonitrogenous caseinate. These ICU patients were hemodynamically stable, but exhibited a systemic inflammatory response syndrome because of pulmonary infection. Only surrogate markers were measured, that is, oxidative stress markers, cell counts, and plasma proinflammatory &
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and anti-inflammatory cytokines. Very few differences were observed between the groups. As acknowledged by the authors, this could be because of the very short duration of the GLN supplementation (2 days). Heyland et al. [17 ] have conducted the largest prospective RCT on GLN and antioxidant (AOX) supplementation. This international multicenter study included 1223 critically ill patients who had multiple organ failure (MOF) and were receiving mechanical ventilation. Patients were randomized to receive, within 24 h after admission to the ICU, either GLN (0.35 g/kg/day i.v. as 0.50 g alanyl-glutamine and 30 g/kg/day enterally as 42.5 g of alanylglutamine and glycyl-glutamine), a combination of AOXs (selenium 500 mg i.v. and 300 mg enterally; 20 mg of zinc, 10 mg of beta-carotene, 500 mg of vitamin E, and 1500 mg of vitamin C enterally), both GLN and micronutrients, or i.v. and enteral placebo supplements. There was no difference in the overall 28-day mortality, the primary endpoint, between the four groups, but there was a trend toward increased mortality when aggregating patients who received GLN compared with patients who did not (32.4 vs. 27.2%). These results suggest that such supplementation is pointless and may even be harmful in patients most in need of optimal nutritional support. In addition, the patients were selected with few noninclusion criteria (see below for further comments) except in terms of severity (two or more organ failures related to their acute illness), to come close to a ‘real-life’ study (as for the SIGNET study [10]). We believe that this study raises several questions. Its objective was to evaluate the effect of the supplementations in critically ill patients in order to resolve the conflicting results in the recent literature [11 ]. However, the investigators targeted patients with MOF, even though there are almost no data available for such a clinical status, a fact which is recognized in the discussion. The rationale for providing GLN in this setting seems questionable considering that in addition to the intestine, the kidneys and liver play a major role in GLN homeostasis, the equilibrium between these two organs depending on the acid–base status of the patients [9]. In this respect, it would have been very interesting to have data on blood gas and to consider patients with metabolic acidosis separately. In patients with liver and kidney failure, GLN may accumulate and also ammonia, but ammonia was unfortunately not measured. Hyperammonemia in conjunction with an unbalanced low protein diet may be involved in side-effects induced by GLN supplementation [18]. The idea that patients enrolled in this study had an unusual stress-induced &&
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metabolic status is also supported by the fact that in nonsupplemented patients, plasma GLN levels were only moderately decreased or normal and were higher than the values encountered in ICU patients without organ failure. The inclusion of patients with liver and kidney failure explains why some patients (see supplemental material of this study) exhibited overly high and presumably detrimental glutaminemia (i.e. >1000 mmol/l and up to 2500 mmol/l). Such values should be a contraindication to GLN supplementation. Finally, GLN plasma levels have only been analyzed in a subpopulation of patients which may not be representative of all the patients included. Heyland and Dhaliwal [19], by enrolling patients with MOF, probably underestimated the risk of having a large number of patients without hypoglutaminemia. In addition, the statement in the companion editorial [20] that low GLN levels could be merely adaptive, and so need not be corrected, is not only very speculative, but also inappropriate in the circumstances, as there was no hypoglutaminemia in a number of the patients enrolled in this study. The doses of GLN supplements in themselves are also questionable. Whereas selected doses of GLN are in line with the upper limit of the literature, the provision of nearly 65–80 g of GLN represents quite a large nitrogen supplement, resulting in a greatly unbalanced diet (with GLN bringing more than 60% of total nitrogen) [18], in excess of patient needs in a situation of compromised organ function. Second, the level of AOX supplementation seems very high, especially for vitamin E (500 mg/day, i.e. 42 times the normal requirements) and vitamin C (1500 mg/day, i.e. 12.5 times the normal requirements). The sole evidence for the efficacy of such elevated AOX supply comes from the studies in burned patients who have a very specific metabolic status [21]. We must be aware that at such very high intake, AOX may be toxic. We note that among the five AOX added to the diet, only plasma selenium was monitored, whereas the AOX status of the patients, which would have been a good surrogate marker, is unknown. Concerning the nutritional support, we note (see supplementary data of [17 ]) that a significant number of patients received very low calorie and protein supply, if any. Hence, we can suppose that some GLN (and AOX)-supplemented patients received nothing in addition to their GLN (and AOX) supplements. The concept of pharmaconutrition relies on the properties of specific nutrients when they are added to an adequate nutritional support [18]. This was hardly the case for a significant number of patients, and so the results from such patients should have been discarded.
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The broad inclusion criteria mean that the population under study was very heterogeneous. For example, patients with morbid obesity were included (i.e. BMI up to 78.3). Nobody knows what pharmacological doses of GLN and AOX do in ICU patients with morbid obesity, or even what the optimal nutritional support is in such patients in catabolic situations. With greater reason, we know nothing about nutrition in morbidly obese patients with MOF. It does not seem therefore appropriate to include such patients. A separate analysis of the effect of supplementation in this subgroup of patients would have been of major interest. The APACHE II score was also quite heterogeneous (from 6.0 to 51.0). It is logical that a patient with an APACHE II score of 51.0 has low chances of survival with or without GLN and AOX supplementation. Even if patients were stratified for APACHE II score above or below the observed median (i.e. 26), we and others [22] found no evidence in the study for adjustment of the data on the severity score, the presence of shock, and the number of organ failures. Again, a patient suffering from morbid obesity, with cardiogenic shock and MOF involving four organs, is certainly not an ideal individual for investigating the effects of pharmacological doses of GLN and AOX. Last, the authors seem to assume that the properties of GLN and AOX would be additive, allowing the GLN plus AOX-treated patients to be aggregated with the GLN-treated ones. This recalls the immuno-enhancing diet (IED) findings, in which individual pharmaconutrients may be beneficial, whereas their association appears detrimental in severe ICU patients; aggregating individual pharmaconutrient-treated patients and IED-treated ones is thus unsound. This applies even more obviously to the present study: we do not know at the outset whether these two groups can be considered as similar, and so aggregating them may bring out a trend if there are no differences in both primary and secondary endpoints between the groups. In conclusion, we believe that nutrients are not magic bullets even at pharmacological dosages, and it is not surprising that GLN and AOX supplementation in critically ill patients with MOF did not improve their clinical picture, and might even have worsened their state. We have to accept that even the strongest drugs may be ineffective, and that mortality in this subgroup of ICU patients remains extremely high. Hence, in this context, we must keep in mind the principle ‘do not harm’. Finally, the terms ‘with multiple organ failure’ should have appeared in the title of the article, because what has been found certainly does not extend to other ICU patients. 102
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WHAT DO THE RECENT GUIDELINES STATE? Recently, the European Society for Clinical Nutrition and Metabolism (ESPEN) endorsed the recommendations made by three French Medical Societies concerning nutritional therapy in major burns [21]. Concerning the GLN supplementation, it is strongly suggested that supplementation with GLN (or its precursor ornithine a-ketoglutarate) be considered, but with weak agreement among experts. The guidelines state that the GLN dose reported for other critical patients should probably be considered: 0.3 g/kg/day for 5–10 days [21]. In our opinion, this dosage may be insufficient in the case of enteral nutrition because of the large splanchnic extraction of GLN, and 0.4 g/kg/day would probably be better. In addition, severe burn injury is a longlasting insult: patients are hypercatabolic for at least 2–3 weeks and the healing time may be 5 weeks or more. Taking into account the major role of GLN and ornithine a-ketoglutarate (OKG) in the healing process, it makes sense to supplement the diet with GLN or OKG until wound closure. Free GLN utilization is limited in parenteral nutrition because of its poor solubility and stability and to its high osmolarity [1]. Two dipeptides (i.e. alanyl-glutamine and glycyl-glutamine) are available on the market. They present the advantage of being stable in solution, highly soluble, and of rapidly releasing GLN after administration. A very large number of studies have established the safety and efficacy of GLN-containing peptides in various populations of patients, and as a consequence GLN-containing peptides are available worldwide, although not in North America. The underlying reasons for this are unclear, prompting the American Society for Parenteral Nutrition (ASPEN) to publish a position paper [23], advocating the availability of GLN-containing peptide in North America. The ASPEN analysis stresses that parenteral GLN administration is associated with decreased infectious complications, decreased hospital length of stay, and possibility decreased mortality in critically ill patients.
PLASMA GLUTAMINE AS AN INDEPENDENT RISK FACTOR &
Rodas et al. [24 ] evaluated the prevalence of GLN depletion in an observational study in 174 patients hospitalized in a mixed ICU. Low (below 420 mmol/l) or high (above 930 mmol/l) plasma GLN (measured within 24 h after admittance) was associated with 6-month mortality independently of APACHE II or SOFA scores. However, plasma GLN below 400 mmol/l or above 930 mmol/l increased the Volume 17 Number 1 January 2014
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sensitivity of APACHE II score to predict death rate. We note that most of the patients with very high plasma GLN concentrations had acute liver failure: GLN is one of the most potent gluconeogenic and ureogenic amino acids, explaining the role of the liver in its removal.
GLUTAMINE IN THE ICU: WHO NEEDS GLUTAMINE SUPPLY? This question was raised in a recent letter by Gottschalk et al. [25 ]. This issue is of importance because there are two approaches to GLN supplementation. The first considers that GLN is a pharmacological agent regulating numerous functions, and therefore should be provided to any stressed patient. The second considers that GLN supplementation should be reserved for patients who are depleted in GLN. Gottschalk et al. [25 ] retrospectively analyzed data from one of their cohort studies. At the time of randomization, three patients (one GLN supplemented and two controls) exhibited plasma GLN above 700 mmol/l, two of them died. During treatment, seven patients (six GLN supplemented and one control) presented high plasma GLN (above 675 mmol/l), and this was associated with a history of acute right heart failure. The authors claim that in such patients GLN supply may be a toxic burden. However, from these data, it is impossible to distinguish cause from consequence, especially because two control patients died with acute kidney failure. It is reasonable to assume they died from organ failure, which explains high GLN levels (explained by a decrease in GLN utilization by the kidney), and not by high GLN levels per se. The same may apply to patients with temporary high GLN levels who exhibited pulmonary embolism, septic, or cardiac shock. Taking into account all the data discussed above, we can reasonably suggest [13,19] that GLN supplementation should be reserved for patients who have proven hypoglutaminemia at baseline. &
capacity is altered, so GLN should probably not be used in patients with MOF. Clearly, GLN is no magic bullet, and GLN supplementation should be reserved for specifically identified patients with compromised GLN availability. The challenge will be to clearly identify those patients. Finally, the regulatory properties of GLN can only be mobilized if patients are getting adequate nitrogen and energy supplies and if GLN is effectively supplied in appropriate doses (at least 0.2 g GLN/kg/day i.v.). Acknowledgements None. Conflicts of interest L.C. receives honoraria from Nestle´ Clinical Nutrition. Part of EA4466 research is supported by an unrestricted grant from Nestle´ Clinical Nutrition.
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CONCLUSION &
The meta-analysis of Bollhalder et al. [11 ] confirms the interest of GLN supplementation – at least in terms of infectious complications and length of stay. Beyond seemingly discrepant results, the recent literature analyzed highlights several points. First, the underlying rationale for GLN supplementation is that GLN availability decreases in most (but not all) stress situations, and the GLN supply is designed to restore normal plasma GLN. Clearly, dramatically high plasma GLN, like any other amino acid, may be toxic, especially when nitrogen elimination
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Sacks GS. Effect of glutamine-supplemented parenteral nutrition on mortality in critically ill patients. Nutr Clin Pract 2011; 26:44–47. 2. Tung JN, Lee WY, Pai MH, et al. Glutamine modulates CD8aaþ TCRabþ intestinal intraepithelial lymphocyte expression in mice with polymicrobial sepsis. Nutrition 2013; 29:911–917. 3. Lee WY, Hu YM, Ko TL, et al. Glutamine modulates sepsis-induced changes to intestinal intraepithelial gdT lymphocyte expression in mice. Shock 2012; 38:288–293. 4. Lehmann C, Pavlovic D, Zhou J, et al. Intravenous free and dipeptide-bound glutamine maintains intestinal microcirculation in experimental endotoxemia. Nutrition 2012; 28:588–593. 5. Hu YM, Pai MH, Yeh CL, et al. Glutamine administration ameliorates sepsisinduced kidney injury by down regulating the high-mobility group box protein1-mediated pathway in mice. Am J Physiol Renal Physiol 2012; 302:F150– F158. 6. Hou YC, Pai MH, Liu JJ, Yeh SL. Alanyl-glutamine resolves lipopolysaccharide-induced lung injury in mice by modulating the polarization of regulatory T cells and T helper 17 cells. J Nutr Biochem 2013; 24:1555–1563. 7. Boutry C, Matsumoto H, Bos C, et al. Decreased glutamate, glutamine and citrulline concentrations in plasma and muscle in endotoxemia cannot be reversed by glutamate or glutamine supplementation: a primary intestinal defect? Amino Acids 2012; 43:1485–1498. 8. Kao CC, Hsu JW, Bandi V, Jahoor F. Alterations in glutamine metabolism and & its conversion to citrulline in sepsis. Am J Physiol Endocrinol Metab 2013; 304:E1359–E1364. Data presented in this study may be important for a better understanding of the mechanisms of increased nitrogen loss in sepsis. 9. Cynober L. Amino acid metabolism. In: Lennarz WJ, Lane MD, editors. Encyclopedia of biological chemistry. New York: Elsevier; 2013. pp. 91–96. 10. Andrews PJD, Avenell A, Noble DB, et al. Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ 2011; 342:d1542. 11. Bollhalder L, Pfeil AM, Tomonaga Y, Schwenkglenks M. A systematic litera& ture review and meta-analysis of randomized clinical trials of parenteral glutamine supplementation. Clin Nutr 2013; 32:213–223. This meta-analysis seeks to explain why GLN effects on ICU patients are less demonstrative than previously thought in relation to the inclusion of recent multicenter trials. 12. Grau T, Bonet A, Minambres E, et al. The effect of L-alanyl-L-glutamine dipeptide supplemented total parenteral nutrition on infectious morbidity and insulin sensitivity in critically ill patients. Crit Care Med 2011; 39:1263–1268. 13. Wernerman J, Kirketeig T, Andersson B, et al. Scandinavian glutamine trial: a pragmatic multicentre randomised clinical trial of intensive care unit patients. Acta Anaesthesiol Scand 2011; 55:812–818. ¨ . The impact of L-alanyl-L-glutamine dipeptide 14. C ¸ ekmen N, Aydin A, Erdemli O supplemented total parenteral nutrition on clinical outcome in critically patients. e-SPEN 2011; 6:e64–e67.
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Protein, amino acid metabolism and therapy 15. Lin JJ, Chung XJ, Yang CY, Lau HL. A meta-analysis of trials using the intention to treat principle for glutamine supplementation in critically ill patients with burn. Burns 2013; 39:565–570. 16. Cavalcante AAM, Campelo MWS, De Vasconcelos MPP, et al. Enteral nutrition supplemented with L-glutamine in patients with systemic inflammatory response syndrome due to pulmonary infection. Nutrition 2012; 28:397– 402. 17. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of && glutamine and antioxidants in critically ill patients. N Engl J Med 2013; 368:1489–1497. The largest trial on GLN supplementation in ICU patients. However, multiple organ failure is probably not an appropriate indication for GLN supplementation. Also, included patients seem very heterogeneous. 18. Bistrian BR. Glutamine and antioxidants in critically ill patients. N Engl J Med 2013; 369:482. [Letter] 19. Heyland DK, Dhaliwal R. Role of glutamine supplementation in critical illness given the results of the REDOXS study. JPEN J Parenter Enteral Nutr 2013; 37:442–443.
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20. Van den Berghe G. Low glutamine levels during critical illness: adaptive or maladaptive? N Engl J Med 2013; 368:1549–1550. [Letter] 21. Rousseau AF, Losser MR, Ichai C, et al. ESPEN endorsed recommendations: nutritional therapy in major burns. Clin Nutr 2013; 32:497–502. 22. Buijs NB, Vermeulen MAR, Van Leeuwen PAM. Glutamine and antioxidants in critically ill patients [letter]. N Engl J Med 2013; 369:483. [Letter] 23. Vanek VW, Matarese LE, Robinson M, et al. ASPEN position paper: parenteral nutrition glutamine supplementation. Nutr Clin Pract 2011; 26:479–494. 24. Rodas PC, Rooyackers O, Hebert C, et al. Glutamine and glutathione at ICU & admission in relation to outcome. Clin Sci 2012; 122:591–597. This study extends the previous data showing that low plasma GLN is a predictor of mortality in ICU patients. It further shows that high GLN levels are also associated with poor prognosis, probably in relation to liver failure. 25. Gottshalk A, Wempe C, Goeters C. Glutamine in the ICU: who needs supply? & Clin Nutr 2013; 32:668–669. This study shows that high GLN levels are associated with morbi-mortality in ICU patients. GLN should not be supplied in such patients.
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