Naomi E Jones*
Daren K Heyland*†
MD FRCPC MSc
*Department of Community Health and Epidemiology
†Department of Medicine
*Clinical Evaluation Research Unit
Kingston General Hospital
Intensive care units (ICUs) manage patients with acute life-threatening disorders. These patients experience a degree of hyperinflammation, cellular immune dysfunction and oxidative stress. As a result of this metabolic response to critical illness and an inability to feed orally, patients can rapidly develop nutrient deficiencies. Such deficiencies are common among ICU patients and are associated with an increased risk of developing infectious complications, organ failure and death.(1–4)
Consequently, over the last few decades numerous experimental studies have investigated the efficacy of supplemention with key “disease-modulating” nutrients such as glutamine, arginine, omega-3 fatty acids and antioxidants. The strongest evidence to date suggests that, of these nutrients, glutamine and antioxidants may be associated with a survival advantage.
The amino acid glutamine has many essential metabolic functions. It plays a central role in nitrogen transport within the body, is a fuel for rapidly dividing cells (particularly lymphocytes and enterocytes) and is a precursor to glutathione. Under normal physiological conditions, glutamine is synthesised in sufficient amounts by the skeletal muscle and therefore is considered non-essential. It has been hypothesised that glutamine may become a conditionally essential amino acid in patients with catabolic disease, as studies have shown that glutamine levels drop during critical illness.(5)
To examine the relationship between glutamine supplementation and clinical outcomes in critically ill patients, we conducted a meta-analysis of existing randomised trials.(6,7) A total of 13 studies of glutamine-supplemented enteral or parenteral nutrition were identified.
When the results of all these trials were aggregated we observed a significant reduction in mortality (risk ratio 0.75, 95% CI 0.59–0.96, p = 0.02), a significant reduction in infectious complications (RR 0.79, 95 % CI 0.63–0.98, p = 0.04) and a significant reduction in length of stay (weighted mean difference in days -4.50, 95% CI -8.28–0.72, p = 0.02) in critically ill patients. In a subgroup analysis, a greater treatment effect was observed in studies of parenterally administered glutamine (RR 0.67, 95% CI 0.48–0.92, p = 0.01) compared with studies of enteral glutamine (RR 0.80, 95% CI 0.45–1.43, p = 0.46).
Antioxidants are part of a complex endogenous defence system designed to protect tissues from the damaging effects of oxidative stress caused by excessive amounts of reactive oxygen species (ROS) and reactive nitrogen-oxygen species (RNOS). Evidence is growing that oxidative stress is central to the underlying pathophysiology of critical illness, especially the development of organ failure. In critically ill patients there are reduced stores of antioxidants. This has been associated with an increase in free-radical generation, an augmentation of the systemic inflammatory response, subsequent cell injury, increased morbidity and even higher mortality.(2,3,8)
We conducted a systematic review to examine whether a strategy of supplementing critically ill patients with antioxidant nutrients improves survival.(7,9) We identified 13 articles, most of which studied the effects of selenium either alone or in combination with other trace elements and vitamins, while others looked at the effects of zinc and vitamins A, C and E.
When the results of all the trials were aggregated, overall, antioxidants were associated with a significant reduction in mortality (RR 0.69, 95% CI 0.59–0.82, p < 0.0001) but had no effect on infectious complications (RR 0.90, 95% CI 0.65–1.24, p = 0.51). In a subgroup analysis, we observed that selenium supplementation, either alone or in combination with other antioxidants, may be associated with a significant reduction in mortality (RR 0.73, 95% CI 0.53–0.99, p = 0.04), while non-selenium antioxidants had no effect on mortality (RR 0.73, 95% CI 0.41–1.29, p = 0.3).
Recommendations for clinical practice
Based on these meta-analyses of glutamine and antioxidant supplementation, the Canadian Clinical Practice Guidelines for Nutrition Support in Mechanically Ventilated Critically Ill Adult Patients made the following recommendations:(7,10)
- Enteral glutamine should be considered in burn and trauma patients. There is insufficient data to support routine use of enteral glutamine in other critically ill patients.
- When parenteral nutrition is prescribed to critically ill patients, parenteral supplementation with glutamine, where available, is recommended. There are insufficient data to generate recommendations for intravenous glutamine in critically ill patients who are receiving enteral nutrition.
- The use of supplemental combined vitamins and trace elements should be considered in critically ill patients.
- The use of intravenous/parenteral nutrition selenium supplementation, alone or in combination with other antioxidants, should be considered in critically ill patients.
The strength of inferences that can be made from existing studies is limited by the small number of trials of variable methodological quality.
The optimum dose of glutamine or antioxidant supplementation is unknown. In addition, further research is required to define the optimal combination of antioxidants with or without glutamine. To investigate the maximum tolerable dose of these nutrients, we completed a single-centre, open-label, dose-escalating study involving 28 critically-ill patients.(11)
We discovered that as we escalated the dose of glutamine to an optimal 0.35 g/kg/day parenterally plus 30 g/day enterally, and dose of selenium to 500 μg/day parenterally plus 300 μg/day enterally, we observed a greater reduction in markers of oxidative stress, greater preservation of glutathione levels and improvement in an indirect marker of mitochondrial function with no apparent adverse effect on organ function.
The results of this dosing study suggest that glutamine and antioxidant supplementation at high doses is safe and efficacious.
It appears that glutamine and antioxidants, particularly when administered parenterally at high doses, may be associated with a significant reduction in mortality in critically ill patients. Existing data suggest that glutamine and antioxidant supplementation is not harmful, yet more evidence is required to establish benefit, particularly in enterally fed patients.
Consequently, the results of these meta-analyses are more hypothesis-generating than hypothesis-confirming. We are currently conducting the Reducing Deaths due to OXidative Stress (REDOXS©) study − a large, multicentre, double-blind, randomised trial to examine the effect of supplemental glutamine and antioxidants on the morbidity and mortality of 1,200 critically ill patients. The methodologically strong and innovative study design will enable us to reliably answer these unresolved questions.(12)
1. Oudemans-van Straaten HM, Bosman RJ, Treskes M, et al. Plasma glutamine depletion and patient outcome in acute ICU admissions. Intensive Care Med 2001;27:84-90.
2. Metnitz PGH, Bartens C, Fischer M, et al. Antioxidant status in patients with acute respiratory distress syndrome. Intensive Care Med 1999;25:180-5.
3. Goode HF, Cowley HC, Walker BE, et al. Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction. Crit Care Med 1995;23(4):646-51.
4. Forceville X, Vitoux D, Gauzilt R, et al.
Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients. Crit Care Med 1998;26:1536-44.
5. Planas M, Schwartz S, Arbos MA, et al. Plasma glutamine levels in septic patients.
J Parenter Enteral Nutr 1993;17:299-300.
6. Novak F, Heyland DK, Avenell A, et al. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med 2002;30(9):2022-9.
7. Critical Care Connections. Critical Care Nutrition. Kingston ON; CCC: 2007. Available at:
8. Quasim T, McMillan DC, Talwar D, et al. Lower concentrations of carotenoids in the critically ill patient are related to a systemic inflammatory response and increased lipid peroxidation. Clin Nutr 2003;22:459-62.
9. Heyland DK, Dhaliwal R, Suchner U, et al.
Antioxidant nutrients: a systematic review of vitamins and trace elements in the critically ill patient.
Intensive Care Med 2005;31:327-37.
10. Heyland DK, Dhaliwal R, Drover JW, et al.
Canadian clinical practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients.
J Parenter Enteral Nutr 2003;27(5):355-73.
11. Heyland DK, Dhaliwal R, Day A, et al. Optimizing the dose of glutamine dipeptides and antioxidants in critically ill patients: a phase I dose-finding study. J Parenter Enteral Nutr 2007;31(2):109-18.
12. Dhaliwal R, Heyland DK, Day A, et al. Reducing Deaths due to OXidative Stress: the REDOXS© study. Rationale and study design for a randomized trial of glutamine and antioxidant supplementation in critically ill patients. Proc Nutr Soc 2006;65(3):250-63.
Critical Care Nutrition
An organisation dedicated to improving the practice of nutrition therapies in the critical care setting. Useful online resources include recent publications, presentations, clinical practice guidelines, tools and training kits
29th European Society of Enteral and Parenteral Nutrition (ESPEN) Congress,
Prague, Czech Republic, 8–11 September 2007
Clinical Nutrition Week 2008, American Society of Parenteral and Enteral Nutrition (ASPEN)
10–13 February 2008