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Glutamine, Fish Oil and Antioxidants in Critical Illness: Metaplus Trial Post Hoc Safety Analysis
Glutamine, Fish Oil and Antioxidants in Critical Illness: Metaplus Trial Post Hoc Safety Analysis
Hofman Z, Swinkels S, van Zanten AR. Ann Intensive Care 2016;6:119
Study Question: In a post hoc analysis of the METAPLUS trial, the investigators considered two questions (1): What is the interaction between immune-modulating high protein (IMHP) enteral feeding versus standard high protein (HP) enteral feeding and in medical versus non-medical patients on 6-month mortality in critically ill patients?; (2) What is the association of baseline plasma levels and changes in immune-modulating nutrient plasma levels and 6-month mortality in critically ill patients?
Study Description: The METAPLUS trial was a prospective, multicenter, randomized, double-blind, controlled, parallel-group trial. The study was conducted in 14 ICUs in four European countries from 2010-2012. Patients randomized to the IMHP group received an enteral tube feed enriched with glutamine, omega-3 fatty acids, selenium, vitamin C, vitamin E, and zinc. Patients were fed according to local practices; however, early enteral feeding up to a target goal of 25 kcal/kg (max 2500 kcal/day) was recommended and continued for up to 28 days. The original study found no statistically significant difference in its primary outcome, development of new infection. However, increased 6-month mortality was noted with the use of IMHP in the medical sub-group in an adjusted analysis (age, APACHE II).
In this post hoc analysis, utilizing Cox proportional hazard regression models, an interaction between treatment type (IMHP vs. HP), type of patient (medical vs. non-medical), gender, age, APACHE II, SOFA score, baseline plasma glutamine, selenium, zinc, and vitamin E concentrations, and baseline plasma (eicosapentaenoic acid + decosahexaenoic acid)/long-chain fatty acid plasma level ratio [epa + dha]/lcf ratio), were assessed. Changes from baseline in plasma concentrations and (epa + dha)/lcf ratio were assessed at study day 4, and study day 8.
Results: The patient type was the only factor that was identified to interact with the type of nutrition. A statistically significant treatment effect was noted among medical patients (HR 2.52; 95% CI 1.36-4.78; p = 0.004), and a non-significant effect in non-medical patients was observed (HR 0.97; 95% CI 0.54-1.74; p = 0.909). There was a statistically significant positive association of change from baseline to day 4 with the (epa + dha)/lcf ratio and 6-month mortality in medical patients (p = 0.016). Changes from baseline to days 4 and 8 were also larger in the IMHP-treated patients for vitamin E and vitamin C, for both medical and non-medical patients (p <0.001).
Conclusion(s): The authors hypothesize that the harmful effect of IMHP compared to HP enteral nutrition in a heterogeneous group of critically ill patients is limited to the medical critically ill patients and is mediated by an early increase in the (epa + dha)/lcf ratio.
Perspective: The findings would appear to support the notion that utilizing immune-modulating enteral feeding provides no benefit in the non-medical population, and is harmful in medical patients. The study group also investigated change from baseline serum concentrations to validate that the observed findings were in fact due to the immune-modulating effects and not other causes, and to identify potential causes of the results observed.