Parenteral Glutamine Supplementation

The majority of clinical studies of parenteral glutamine in critically ill patients are small or also include noncritical patients. A summary of key clinical studies is presented in Table 14.3. Prior recommendation for using intravenous glutamine supplementation in critically ill patients (Heyland et al. 2003) was based mainly on two single-center studies. In one of the first studies of parenteral glutamine supplementation, 84 patients admitted to a general ICU with an Acute Physiological and Chronic Health Evaluation (APACHE) II score of >11 were randomized in a double-blind fashion to receive TPN with or without glutamine supplementation. Patients who received glutamine supplementation had significantly lower 6-month mortality than those who did not (33% vs. 57%), with the major cause of death in both groups being multisystem organ failure (Griffiths et al. 1997). Interestingly, this difference in mortality occurred late, as survival curves in the two groups were similar at 20 days. In another study, 144 ICU patients were

TABLE 14.3

Select Key Trials of Parenteral Glutamine Supplementation in Critical Illness

randomized to receive either supplementation with parenteral Ala-Gln or no supplementation, but only 95 patients who completed 5 days of nutritional support were analyzed (Goeters et al. 2002). There was no difference between the groups in ICU or hospital mortality, but in a subgroup of 68 patients who stayed in the ICU at least 9 days, 6-month mortality was lower in the glutamine supplemented group.

In the last few years, three large trials of parenteral glutamine supplementation have been published. The Scandinavian glutamine trial (Wernerman et al. 2011) was a multicenter trial of 413 ICU patients receiving either parenteral or enteral nutrition who were randomized to also receive either parenteral Ala-Gln or placebo. In the per-protocol but not the intention-to-treat analysis, ICU mortality was improved with glutamine supplementation; however, there was no difference in 6-month mortality. In the SIGNET trial (Andrews et al. 2011), 502 ICU patients were randomized to either glutamine-supplemented TPN or standard TPN. Glutamine supplementation had no effect on the incidence of new infections or mortality. A systematic review of parenteral glutamine trials that included these two trials found that parenteral glutamine was associated with only a trend toward reduction in mortality (RR = 0.88, p = 0.10) and a trend toward a reduction in infectious complications (RR 0.86, p = 0.09) (Dhaliwal et al. 2014). As a result of the weaker overall effect after the addition of these two trials, the Canadian Clinical Practice Guidelines downgraded its recommendation for parenteral glutamine in critically ill patients in 2013. Therefore, the current recommendation states that parenteral glutamine supplementation should be considered in critically ill patients, rather than strongly recommended (Dhaliwal et al. 2014).

The REDOX study was a very large multicenter study in 40 ICUs, which randomized 1223 critically ill patients with multiorgan failure and on mechanical ventilation to receive either a combination of parenteral and enteral glutamine supplementation or placebo (Heyland et al.

2013). Contrary to the hypothesis, there was actually a trend toward increased 28-day mortality (32.4% in patients who received glutamine vs. 27.2% in patients who did not receive glutamine, p = 0.05) as well as a significantly increased in-hospital and 6-month mortality in patients who received glutamine compared to those who did not. The REDOX authors subsequently conducted a post hoc analysis in an attempt to identify potential subgroups of patients that might benefit from glutamine supplementation, but there was no subgroup that was associated with a positive treatment effect (Heyland et al. 2015). However, the greatest potential for harm was found in patients with renal dysfunction, and approximately one-third of included patients had renal dysfunction at baseline.