Glutamine supplementation of parenteral nutrition in critically ill patients

The role of glutamine in critically ill patients is debatable. Canadian CPGs 2009 recommended that when TPN is prescribed to critically ill patients, parenteral nutrition supplemented with glutamine where available is strongly recommended. However, in a recent update (2013), the committee downgraded the recommendation for IV glutamine to "should be considered". They also strongly recommend that glutamine NOT be used in critically ill patients with multi-organ failure. There are also insufficient data to generate recommendations for intravenous glutamine in critically ill patients receiving enteral nutrition. Below is the 2013 discussion:
 

It was noted that with the addition of 11 new trials (Tian 2006, Zhang 2007  Ozgultekin 2008, Yang 2008, Eroglu 2009, Perez-Barcena 2010, Andrews 2011, Cekman 2011, Grau 2011, Wernerman 2011 & Ziegler 2012), there were weaker signals for a reduction in overall mortality and  infectious complications and yet a strong treatment effect of IV supplemented glutamine on hospital mortality and ICU and hospital length of stay remained. It was further noted that a few large scale multicenter randomized trials of IV glutamine had failed to demonstrate a convincing positive effect (Andrews 2011, Wernerman 2011, Ziegler 2012).

 

Recent important paper: REDOXs study by the Canadian Critical Care Trials Group. New Engl J Med, 2013, 368:1489-1497.

A Randomized Trial of Glutamine and Antioxidants in Critically Ill Patients. 

Background

Critically ill patients have considerable oxidative stress. Glutamine and antioxidant supplementation may offer therapeutic benefit, although current data are conflicting.

Methods

In this blinded 2-by-2 factorial trial, we randomly assigned 1223 critically ill adults in 40 intensive care units (ICUs) in Canada, the United States, and Europe who had multiorgan failure and were receiving mechanical ventilation to receive supplements of glutamine, antioxidants, both, or placebo. Supplements were started within 24 hours after admission to the ICU and were provided both intravenously and enterally. The primary outcome was 28-day mortality. Because of the interim-analysis plan, a P value of less than 0.044 at the final analysis was considered to indicate statistical significance.

Results

There was a trend toward increased mortality at 28 days among patients who received glutamine as compared with those who did not receive glutamine (32.4% vs. 27.2%; adjusted odds ratio, 1.28; 95% confidence interval [CI], 1.00 to 1.64; P=0.05). In-hospital mortality and mortality at 6 months were significantly higher among those who received glutamine than among those who did not. Glutamine had no effect on rates of organ failure or infectious complications. Antioxidants had no effect on 28-day mortality (30.8%, vs. 28.8% with no antioxidants; adjusted odds ratio, 1.09; 95% CI, 0.86 to 1.40; P=0.48) or any other secondary end point. There were no differences among the groups with respect to serious adverse events (P=0.83).

Conclusions

Early provision of glutamine or antioxidants did not improve clinical outcomes, and glutamine was associated with an increase in mortality among critically ill patients with multiorgan failure.

 

 Comment: Possible reasons for the different results to previous studies offered by the authors include;

 

1. In this study, combined  enteral and parenteral high doses of glutamine were used in critically ill patients with multi-organ failure. Other studies excluded this group of patients.

2. However, it was felt that the results of this 1223 patient multicentre trial, which suggested a significant safety concern, could not be ignored.

3. Previous studies were smaller and less methodologically robust.

4. The treatment was initiated within 24-hours ICU admission, while other studies used it later.

5. Most patients in this study were enterally fed, other studies they were mainly parenteral nutrition.

 

In summary it appears in ventilated patients with shock/multi-organ dysfunction, the use of early antioxidants is of no benefit, and glutamine may be harmful. Is that enough to close the book on this?

I totally agree with this, since in managing our ICU patients, most of our patients will have more than 2 organ failure and  those with MOF are the ones who carry high mortality. I am not keen to supplement my patients with glutamine either enterally or parenterally.

 

                                                                      xoxoxoxoxoxoxo

 

The earlier study of interest was published in BMJ in 2011 by Andrews et al i.e. SIGNET trial (Scottish Intensive care Glutamine or seleNium Evaluative Trial).

Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients

 

Objective To determine whether inclusion of glutamine, selenium, or both in a standard isonitrogenous, isocaloric preparation of parenteral nutrition influenced new infections and mortality among critically ill patients.

 

Design Randomised, double blinded, factorial, controlled trial.

Setting Level 2 and 3 (or combined) critical care units in Scotland. All 22 units were invited, and 10 participated.

Participants 502 adults in intensive care units and high dependency units for ≥48 hours, with gastrointestinal failure and requiring parenteral nutrition.

Interventions Parenteral glutamine (20.2 g/day) or selenium (500 μg/day), or both, for up to seven days.

Main outcome measures Primary outcomes were participants with new infections in the first 14 days and mortality. An intention to treat analysis and a prespecified analysis of patients who received ≥5 days of the trial intervention are presented. Secondary outcomes included critical care unit and acute hospital lengths of stay, days of antibiotic use, and modified SOFA (Sepsis-related Organ Failure Assessment) score.

Results Selenium supplementation did not significantly affect patients developing a new infection (126/251 v 139/251, odds ratio 0.81 (95% CI 0.57 to 1.15)), except for those who had received ≥5 days of supplementation (odds ratio 0.53 (0.30 to 0.93)). There was no overall effect of glutamine on new infections (134/250 v 131/252, odds ratio 1.07 (0.75 to 1.53)), even if patients received ≥5 days of supplementation (odds ratio 0.99 (0.56 to 1.75)). Six month mortality was not significantly different for selenium (107/251 v 114/251, odds ratio 0.89 (0.62 to 1.29)) or glutamine (115/250 v 106/252, 1.18 (0.82 to 1.70)). Length of stay, days of antibiotic use, and modified SOFA score were not significantly affected by selenium or glutamine supplementation.

Conclusions The primary (intention to treat) analysis showed no effect on new infections or on mortality when parenteral nutrition was supplemented with glutamine or selenium. Patients who received parenteral nutrition supplemented with selenium for ≥5 days did show a reduction in new infections. This finding requires confirmation.