September has been very rich with opportunities – our new dietetic interns have started, we are completing details for our fall VASPEN conference, and the hospital seems to have no shortage of admissions even before cold and flu season gets here. We had a last minute change of article for journal club because we wanted to examine the recent publication on glutamine-containing “immunonutrition” in greater detail
van Zanten AR, Sztark F, Kaisers UX, et al. High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition and nosocomial infections in the ICU: a randomized clinical trial. JAMA. 2014 Aug 6;312(5):514-24.
This study was a randomized, double-blind, multicenter trial comparing an EN formula with “immune-modulating nutrients” (glutamine, omega-3 fatty acids, and anti-oxidants) with an isonitrogenous, isocaloric standard EN formula in a mixed ICU population (medical, surgical, trauma, neurologic, cardiac). The formulas were described as high-protein and provided 58.5 gm protein/1000 kcals. The “immune modulating” (IM) formula provided 29% of its protein as alanine-glutamine dipeptide, 39% as wheat hydrolysate and the rest as casein, had additional MCT oil and EPA/DHA, supplemental vitamin C, E, selenium and zinc.
The primary outcome of the study was the incidence of new infections from the start of the EN until discharge from the ICU, or until day 28. Secondary outcomes included number of infections per patient per 100 ICU days, incidence of infection type, mortality (ICU, hospital, discharge, day 28 and 6 months), evolution of SOFA-scores, length of mechanical ventilation, ICU and hospital lengths of stay, blood glucose concentrations, and incidence of hypoglycemia. A per-protocol analysis was performed for the primary end point based on those patients who received at least 50% of the recommended study product during the first 72 hours and subsequently during the ICU stay up to day 28.
Patients were fed up to the target energy requirement of 25 kcal/kg of body weight with a maximum of 2500 kcal/d, for a maximum of 28 days during their ICU stay.
Inclusion and Exclusion Criteria were:
Admitted to one of the 14 participating ICUs, expected to receive mechanical ventilation > 72 hours, require EN within 48 hours after ICU admission that would continue >72 hours.
Sequential Organ Failure Assessment (SOFA) score > 12 between ICU admission and 24 hours after ICU admission or randomization (if randomization occurred <24 hours after ICU admission), BMI > 40, planned to received selective decontamination of the GI tact, pregnancy, contraindication for EN.
A total of 301 patients were randomized and included in the
intention-to-treat analysis. There were no significant differences in the primary outcome of incidence of new infections between groups overall, or between any of the subgroups. There were no significant differences in the mean number of infections per patient, infections per patient per ICU-day, duration of infections, and incidence of specific types of infection in both the intention-to-treat and per-protocol analysis.
There were no significant differences between groups in any of the secondary clinical outcome parameters, except for 6-month mortality in the medical subgroup. ICU, hospital and 28-day mortality were not significantly different between the primary groups or any subgroup. However, the 6-month mortality of the medical subgroup was significantly increased to 54% (95% CI, 40%-67%) in the IM group vs 35% mortality in the HP group (95% CI, 22%-49%; P = 0.04). There were no significant differences in serious adverse events between groups during the study.
“Among adult mechanically ventilated medical, surgical and trauma ICU patients, high-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition did not improve infectious complications or other clinical end points and may be harmful as suggested by increased adjusted mortality at 6 months. These findings do not support the use of high-protein enteral nutrition enriched with immune-modulating nutrients in these patients.”
This study has the strengths of being multi-center and even multi-nation, with randomized and blinded allocation into groups. The EN formulas were isocaloric and even isonitrogenous, but there were differences in macronutrient composition.
The IM formula had MCT oil as well as the EPA/DHA added, so it ended up being a relatively high-fat formula, with approx. 52% of the calories from lipid. Additionally, and perhaps more importantly, the IM formula was not really a high-quality-high-protein formula. Only 41% of the protein in the IM formula was complete protein, with 39% from wheat hydrolysate (lysine-poor) and 20% from alanine-glutamine dipeptide.
If we consider that part of the acute-phase response is to make amino acids available to the liver to synthesize acute-phase proteins necessary for survival, it may be a bad thing to give large amounts of glutamine and alanine, but limited amounts of other potentially necessary amino acids. See our May 2013 e-journal club for another study where the enthusiasm for providing glutamine may have come at the expense of providing critically ill patients adequate complete protein.
We do need to keep in mind, similar to all of the other studies that “shotgun” a number of nutritional factors, that it is possible that some of these supplemental ingredients had positive effects, while some others had negative effects.
It is hard to know what to do with increased mortality at 6 months, but not at the other timepoints, for only one subgroup. There were a large number of secondary endpoints and subgroups analyzed. Once you exceed 7 comparisons there is a 40% likelihood of having a statistical difference by chance, so with the large number of things compared here, it is no surprise something was statistically different. This study was inadequately powered to make strong statements about mortality in a mixed group of ICU patients to begin with. The medical subgroup had an even smaller number of patients, especially with the number that survived beyond 28 days, so there is much more chance that something would be statistically different by chance alone.
Nevertheless, there certainly was nothing from this study to support supplemental glutamine, omega-3 fatty acids and antioxidant micronutrients in a mixed critically ill adult population.
Our Take Home Message (s)
1. Replacing part of the dietary whole protein with glutamine and glutamine-rich incomplete proteins, along with supplemental omega-3 fatty acids and antioxidants did not have any advantages, and may have disadvantages in critically ill patients.
2. Nutrient formulations and supplemental nutrients should be tested in adequately large, randomized, blinded studies before they are given to sick people.
Other News on the UVAHS GI Nutrition Website: (www.ginutrition.virginia.edu):
Upcoming Webinars 2014:–November 18–Feeding the Critically Ill Obese Patient–Joe Krentisky, MS, RD
–December 16–Issues in Long Term Nutrition Support–Carol Parrish, MS, RD
Check out What’s New:
–“Nutrition Support Blog”
Latest Practical Gastroenterology article:
–Phillips W. Coding for Malnutrition in the Adult Patient: What the Physician Needs to Know. Practical Gastroenterology 2014;XXXVIII(9):52.
Joe Krenitsky MS, RD
Carol Rees Parrish MS, RD