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Original Investigation | Caring for the Critically Ill Patient

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

Arthur R. H. van Zanten, MD, PhD1; François Sztark, MD, PhD2; Udo X. Kaisers, MD, PhD3; Siegfried Zielmann, MD, PhD4; Thomas W. Felbinger, MD, PhD5; Armin R. Sablotzki, MD, PhD6; Jan J. De Waele, MD, PhD7; Jean-François Timsit, MD, PhD8; Marina L. H. Honing, MD, PhD9; Didier Keh, MD10; Jean-Louis Vincent, MD, PhD11; Jean-Fabien Zazzo, MD, PhD12; Harvey B. M. Fijn, MD1; Laurent Petit, MD, PhD2; Jean-Charles Preiser, MD, PhD11; Peter J. van Horssen, PhD13; Zandrie Hofman, MSc13
[+] Author Affiliations
1Gelderse Vallei Hospital, Ede, the Netherlands
2Groupe Hôpital Pellegrin – CHU Bordeaux, Bordeaux, France
3Universitätsklinikum Leipzig, Germany
4Heinrich-Braun-Klinikum, Zwickau, Germany
5Klinikum Neuperlach, Munich, Germany
6Klinikum St Georg, Leipzig, Germany
7Ghent University Hospital, Ghent, Belgium
8Hôpital Universitaire Albert Michallon, Grenoble, France
9Medisch Centrum Alkmaar, Alkmaar, the Netherlands
10Charité Universitätsmedizin Berlin, Germany
11Erasme University Hospital, Université libre de Bruxelles, Brussels, Belgium
12Hôpital Antoine-Béclère, Clamart, France
13Nutricia Advanced Medical Nutrition, Nutricia Research, Utrecht, the Netherlands
JAMA. 2014;312(5):514-524. doi:10.1001/jama.2014.7698.
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Importance  Enteral administration of immune-modulating nutrients (eg, glutamine, omega-3 fatty acids, selenium, and antioxidants) has been suggested to reduce infections and improve recovery from critical illness. However, controversy exists on the use of immune-modulating enteral nutrition, reflected by lack of consensus in guidelines.

Objective  To determine whether high-protein enteral nutrition enriched with immune-modulating nutrients (IMHP) reduces the incidence of infections compared with standard high-protein enteral nutrition (HP) in mechanically ventilated critically ill patients.

Design, Setting, and Participants  The MetaPlus study, a randomized, double-blind, multicenter trial, was conducted from February 2010 through April 2012 including a 6-month follow-up period in 14 intensive care units (ICUs) in the Netherlands, Germany, France, and Belgium. A total of 301 adult patients who were expected to be ventilated for more than 72 hours and to require enteral nutrition for more than 72 hours were randomized to the IMHP (n = 152) or HP (n = 149) group and included in an intention-to-treat analysis, performed for the total population as well as predefined medical, surgical, and trauma subpopulations.

Interventions  High-protein enteral nutrition enriched with immune-modulating nutrients vs standard high-protein enteral nutrition, initiated within 48 hours of ICU admission and continued during the ICU stay for a maximum of 28 days.

Main Outcomes and Measures  The primary outcome measure was incidence of new infections according to the Centers for Disease Control and Prevention (CDC) definitions. Secondary end points included mortality, Sequential Organ Failure Assessment (SOFA) scores, mechanical ventilation duration, ICU and hospital lengths of stay, and subtypes of infections according CDC definitions.

Results  There were no statistically significant differences in incidence of new infections between the groups: 53% (95% CI, 44%-61%) in the IMHP group vs 52% (95% CI, 44%-61%) in the HP group (P = .96). No statistically significant differences were observed in other end points, except for a higher 6-month mortality rate in the medical subgroup: 54% (95% CI, 40%-67%) in the IMHP group vs 35% (95% CI, 22%-49%) in the HP group (P = .04), with a hazard ratio of 1.57 (95% CI, 1.03-2.39; P = .04) for 6-month mortality adjusted for age and Acute Physiology and Chronic Health Evaluation II score comparing the groups.

Conclusions and Relevance  Among adult patients breathing with the aid of mechanical ventilation in the ICU, IMHP compared with HP 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 IMHP nutrients in these patients.

Trial Registration  trialregister.nl Identifier: NTR2181.

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Study Flow of Patients in the MetaPlus Trial

The investigators and clinicians prescreened patients for potential eligibility based on medical records of patients. The informed consent procedure and subsequently the screening were only initiated if a patient seemed to be eligible. Data on the numbers of patients prescreened are not available.

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