Early supplemental glutamine appears to harm rather than benefit critically ill patients who have multiorgan failure, according to a report published online April 18 in the New England Journal of Medicine.

In an international randomized controlled trial, in-hospital mortality and 6-month mortality were significantly increased in patients given intravenous glutamine within 24 hours of presentation to the ICU, compared with those given placebo, said Dr. Daren Heyland of Kingston (Ont.) General Hospital and his associates. A nonsignificant increase was seen in 28-day mortality.

Most of the patients in this study showed no glutamine deficiency at study entry. This observation, together with the primary finding that glutamine therapy may actually be harmful in this setting, "challenges the prevailing concept that glutamine is an essential nutrient that is deficient in critically ill patients and requires immediate supplementation," Dr. Heyland and his colleagues said.

The researchers also assessed whether supplemental antioxidants improved mortality or other outcomes in this study population and found that they did not.

Dr. Heyland and his associates performed this study because glutamine is thought to be rapidly depleted in critical illness and low levels of glutamine have been linked to increased mortality in ICU patients. Metaanalyses of small randomized trials suggested that both glutamine and antioxidant supplementation might improve survival in critically ill patients, but more recent and larger studies failed to confirm such a benefit.

This study included 1,223 consecutive adults who presented to 40 ICUs in the United States, Canada, and Europe during a 6-year period and required mechanical ventilation and had two or more organ failures related to their acute illness. The average patient age was 63 years. Primary diagnoses included cardiovascular, respiratory, gastrointestinal, neurologic, metabolic, and gynecologic disorders as well as sepsis and trauma.

The patients were randomly assigned in a double-blind fashion to receive daily intravenous glutamine, intravenous plus enteral antioxidants, glutamine plus antioxidants, or placebo fluids. The antioxidants included selenium, zinc, beta carotene, vitamin E, and vitamin C.

The primary outcome measure was 28-day mortality. There was a nonsignificant trend toward higher mortality in the patients given glutamine (32.4%) compared with those not given glutamine (27.2%). However, two secondary outcomes – in-hospital mortality and 6-month mortality – both were significantly higher in patients given glutamine than in those not given glutamine. In hospital mortality was 37.2% vs. 31%, respectively; 6-month mortality was 43.7% vs. 37.2%, respectively.

Other secondary outcomes – median time from randomization to ICU discharge and median time to hospital discharge – also were significantly longer for patients who received glutamine (17.1 vs. 13.1 days and 51.1 vs. 40.1 days, respectively), the investigators said (N. Engl. J. Med. 2013 April 18 [doi:10.1056/NEJMoa1212722]).

These results were confirmed in a sensitivity analysis that included only patients who received their assigned intervention for a minimum of 5 days. They also remained the same in several subgroup analyses and in an intention-to-treat analysis.

Glutamine showed no effect on the secondary outcomes of organ failure or infections.

Antioxidants had no significant effect on any outcome, either in the study population as a whole or in any subgroups of patients. "This finding may reflect the true lack of usefulness of antioxidants; alternatively, it may be due to the characteristics of the study population or to the dose and method of administration in this trial," Dr. Heyland and his associates said.

Rates of serious adverse events were similar across all the study groups, but the frequency of excessively high urea levels was greater in patients who received glutamine (13.4%) than in those who did not (4.0%).

There may be several reasons why the findings of this clinical trial are so different from those of previous trials.

The earlier trials were smaller and less methodologically robust, and their results had to be pooled in metaanalyses. Patients in this trial received the highest dose of glutamine currently prescribed for critically ill patients, which is higher than the maximal doses used in previous studies. The agents were administered through both intravenous and enteral routes in this study, while in previous studies the subjects received either exclusively intravenous or exclusively enteral administration.

In addition, "we targeted critically ill patients with multiorgan failure, the majority of whom were in shock, whereas previous studies typically excluded such patients," Dr. Heyland and his colleagues said.

Treatment was initiated within 24 hours of admission to the ICU in this study, but in earlier studies it was given later in the course of critical illness. And finally, most of the patients in this study received enteral nutrition, while those in previous trials received parenteral nutrition.

This study was supported by the Canadian Institutes of Health Research. Fresenius Kabi provided the glutamine supplements and Biosyn provided the selenium to the participating European sites. Dr. Heyland and his associates reported ties to numerous industry sources.

Supplemental glutamine may harm critically ill patients