Publication

• Title: 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
• Acronym: MetaPlus
• Year: 2014
• Journal published in: JAMA
• Citation: van Zanten ARH, 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;312(5):514-524.

Context & Rationale

• Background

  • Nosocomial infections are common during prolonged mechanical ventilation and are associated with longer ICU stays, higher costs, and worse outcomes.
  • “Immune-modulating” or “pharmaconutrition” enteral formulas (typically combining glutamine, omega-3 fatty acids, and antioxidants) were used in some ICUs on the basis of heterogeneous earlier trial signals suggesting fewer infections.
  • By the time of MetaPlus design, there was substantial uncertainty about generalisability of earlier signals (often surgical cohorts) to mixed ICU populations and concern that combining multiple pharmaconutrients could produce unexpected harms.
• Research Question/Hypothesis

  • Does an immune-modulating, high-protein enteral formula reduce the incidence of ICU-acquired nosocomial infection compared with an iso-caloric, standard high-protein formula in mechanically ventilated critically ill adults?
  • Hypothesis: immune-modulating high-protein enteral nutrition would reduce new infections acquired in ICU.
• Why This Matters

  • Enteral nutrition is ubiquitous in critical care; even modest benefit or harm from a commonly used formula has large population-level impact.
  • A rigorously blinded pragmatic comparison against a high-protein, iso-caloric control was needed to separate nutrient “signal” from confounding by general nutrition adequacy.
  • Safety, not only efficacy, was clinically pivotal given the biological plausibility of immunomodulation causing harm in some phenotypes of critical illness.

Design & Methods

• Research Question: In mechanically ventilated ICU adults expected to need enteral tube feeding for ≥72 hours, does an immune-modulating high-protein enteral formula (glutamine + omega-3 fatty acids + antioxidant micronutrients) reduce the incidence of new ICU-acquired infections versus an iso-caloric, standard high-protein formula?
• Study Type: Randomised, double-blind, multicentre, international (14 ICUs across The Netherlands, Germany, France, and Belgium), parallel-group trial (February 2010 to April 2012) in mixed medical/surgical/trauma intensive care settings.
• Population:
  • Setting: Adult ICUs; enrolment required early enteral nutrition, with study product started within the first 48 hours of ICU admission.
  • Inclusion: ICU patients expected to be mechanically ventilated for at least 72 hours and expected to require enteral tube feeding for at least 72 hours.
  • Key exclusions (examples): Severe organ failure at start of nutritional support (SOFA >12 within 24 hours); contraindication to enteral nutrition (e.g., severe/refractory shock requiring escalating vasopressors, bowel obstruction/ischaemia/infarction); pregnancy; morbid obesity (BMI >40); planned or current selective digestive decontamination/selective oral decontamination; need for specialised enteral formula (e.g., hepatic/renal/diabetes formula); recent enteral/parenteral supplementation with omega-3 fatty acids, selenium, vitamin E, or glutamine.
  • Randomisation strata: Stratified by participating site and by patient type (medical vs surgical vs trauma ICU admission category).
• Intervention:
  • Immune-modulating high-protein enteral nutrition (IMHP): Iso-caloric high-protein tube feed enriched with glutamine, omega-3 fatty acids, and antioxidant micronutrients.
  • Composition (per 1500 mL): 1920 kcal; 112.5 g protein (20% as alanyl-glutamine dipeptide); total glutamine 30 g; EPA + DHA 7.5 g; vitamin C 690 mg; vitamin E 266 mg; selenium 285 μg; zinc 30 mg; carbohydrate 141 g; fat 96 g; fibre 22.5 g.
  • Delivery: Enteral tube feeding per unit routine with guidance to progress early enteral nutrition to a maximum of 25 kcal/kg/day (cap 2500 kcal/day); study product continued during ICU stay up to a maximum of 28 days.
• Comparison:
  • Standard high-protein enteral nutrition (HP): Iso-caloric high-protein tube feed without immune-modulating enrichment.
  • Composition (per 1500 mL): 1920 kcal; 112.5 g protein; total glutamine 9 g; EPA + DHA 0 g; vitamin C 195 mg; vitamin E 23 mg; selenium 113 μg; zinc 23 mg; carbohydrate 231 g; fat 55.5 g; fibre 22.5 g.
  • Co-interventions: Supplemental parenteral nutrition permitted; limited complementary feeding allowed (with restrictions on additional glutamine/omega-3/selenium/vitamin E exposure).
• Blinding: Double-blind; study products packaged identically and labelled with allocation codes known only to the manufacturer; clinicians, patients, investigators, and outcome assessors were blinded.
• Statistics: A total of 300 patients were required to detect a 12.5% absolute reduction in new infections (from 25% to 12.5%) with 80% power at the 5% significance level; primary analyses were intention-to-treat, with a prespecified per-protocol analysis and prespecified subgroup analyses (including by patient type).
• Follow-Up Period: Infections assessed during ICU stay; additional outcomes included ICU/hospital endpoints and survival follow-up to 6 months after randomisation.

Key Results

This trial was not stopped early.

• Despite biological separation (increased plasma glutamine/selenium/vitamins and omega-3 fatty acid ratios), IMHP did not reduce ICU-acquired infections (53% vs 52%; P=.96).
• A concerning late signal emerged: 6-month mortality was higher in medical patients (54% vs 35%; P=.04) and in the adjusted time-to-event model (HR 1.57; 95% CI 1.03 to 2.39; P=.04), despite no early mortality difference.
• Serious adverse events were similar (25.7% vs 25.5%; P=.975); glycaemic trajectories differed (time to glucose ≤113.5 mg/dL: 24.2 vs 35.1 hours; P=.02).

Internal Validity

• Randomisation and allocation: Central computer-generated allocation, stratified by site and patient type with fixed block size of 4; allocation concealment maintained via manufacturer-held codes and identical packaging.
• Dropout / exclusions: 301 patients randomised (152 IMHP; 149 HP); all received the allocated product; 6-month vital status was not obtained for 2 patients in each group (transfer), but primary outcome ascertainment occurred during ICU stay.
• Performance and detection bias: Double-blinding reduces differential co-intervention and ascertainment bias; all-cause mortality objective; infection ascertainment used prespecified definitions but still depends on clinical sampling and diagnostic thresholds.
• Protocol adherence and delivery: Study product started early (median 31 [21–41] vs 30 [22–39] hours after ICU admission) and continued for a median 12 [7–19] vs 13 [8–19] days.
• Baseline characteristics: Groups were comparable in measured severity and phenotype (e.g., APACHE II 20 [16–26] vs 19 [16–25]; SOFA 8 [6–10] vs 8 [6–10]; medical 41% vs 40%; antibiotic use at baseline 73% vs 75%).
• Heterogeneity: Mixed ICU case-mix with prespecified patient-type strata; the mortality signal was concentrated in the medical stratum rather than consistent across strata.
• Timing: Intervention delivered within the anticipated early window; this is a plausible timeframe for immune-modulation to influence early infection risk.
• Dose and separation of the variable of interest:
  • Planned compositional separation (per 1500 mL): glutamine 30 g (IMHP) vs 9 g (HP); EPA+DHA 7.5 g vs 0 g; vitamin C 690 mg vs 195 mg; vitamin E 266 mg vs 23 mg; selenium 285 μg vs 113 μg; carbohydrate 141 g vs 231 g; fat 96 g vs 55.5 g.
  • Delivered nutrition (median per ICU day): volume 899 (544–1352) mL (IMHP) vs 1027 (674–1500) mL (HP); energy 1151 (696–1730) vs 1315 (863–1919) kcal/day; protein 67 (41–101) vs 77 (50–112) g/day.
  • Biochemical separation (baseline to day 4, mean change): plasma glutamine +1.1 vs +0.4 mg/dL; selenium +11.0 vs −2.3 μg/L; vitamin E +3.6 vs −0.4 mg/dL; vitamin C +5.6 vs −1.6 mg/dL; (EPA+DHA):LCP ratio +3.4% vs +0.4%.
• Adjunctive therapy use: Supplemental parenteral nutrition was used in 15% (IMHP) vs 13% (HP); concomitant non-study enteral feeding was uncommon (5% vs 1%).
• Outcome assessment: Infections were categorised using standard definitions and then classified as confirmed or probable after investigator review; mortality endpoints were robust and clinically unambiguous.
• Statistical rigour: The primary analysis was intention-to-treat; the power calculation assumed a large absolute risk reduction (12.5%) which, if incorrect, limits ability to exclude smaller benefits or harms for the primary endpoint.

Conclusion on Internal Validity: Overall, internal validity appears moderate-to-strong given robust allocation concealment, double-blinding, minimal loss to follow-up, and biochemical evidence of intervention separation; confidence is tempered by modest between-group differences in delivered energy/protein and the inherent subjectivity of infection diagnosis compared with mortality.

External Validity

• Population representativeness: Adults in mixed European ICUs with anticipated prolonged ventilation and enteral nutrition needs; baseline severity was moderate (SOFA ~8) and very severe organ failure was excluded (SOFA >12).
• Key exclusions with generalisability implications: Severe/refractory shock and other contraindications to enteral feeding; morbid obesity (BMI >40); planned/selective digestive decontamination; requirement for disease-specific enteral formulas (e.g., hepatic/renal/diabetes formulations).
• Applicability across systems: Findings translate best to similar high-resource ICUs with early enteral feeding capability and access to high-protein formulas; they may be less applicable where feeding is initiated later, where SDD is routine, or where the excluded phenotypes (severe organ failure, burns, bariatric populations) are common.
• Intervention feasibility: Both study feeds were commercially manufacturable, protocol-light, and implemented within routine ICU feeding workflows, supporting pragmatic external applicability where products exist.

Conclusion on External Validity: Generalisability is moderate: results apply to a broad, but not universal, ventilated ICU population, with meaningful limitations for the sickest patients (SOFA >12), for settings using SDD, and for specific subgroups not represented (major burns/complex gut failure).

Strengths & Limitations

• Strengths:
  • Double-blind, randomised, international multicentre design with allocation concealment.
  • Appropriate active comparator (iso-caloric, high-protein control) limiting confounding by general nutrition adequacy.
  • Clinically meaningful primary endpoint (ICU-acquired infection) and objective mortality follow-up to 6 months.
  • Demonstrated biological separation in target nutrients (glutamine, selenium, vitamins, omega-3 ratios), supporting adequate exposure.
• Limitations:
  • Power calculation assumed a large absolute reduction in infections (12.5%); the trial cannot exclude smaller but clinically relevant effects.
  • Infection outcomes, while protocol-defined, are less objective than mortality and depend on clinical investigation thresholds.
  • Between-group differences in delivered volume/energy/protein (HP group received higher medians per ICU day) may dilute or confound attribution to pharmaconutrients.
  • Combined intervention (glutamine + omega-3 + antioxidants) prevents identification of which component(s) drive benefit or harm signals.
  • Industry provided study products and reimbursed participating sites; sponsor involvement in manuscript drafting was reported, increasing the importance of transparency and independent replication.

Interpretation & Why It Matters

• Clinical practice

  Routine use of immune-modulating high-protein formulas in unselected mechanically ventilated ICU patients is not supported: infection rates were unchanged and no early mortality benefit was observed.
• Safety and phenotype

  A late harm signal (higher 6-month mortality in medical patients and in adjusted survival modelling) shifts the burden of proof toward safety in medical ICU populations and argues against empirical pharmaconutrition “bundles”.
• Trial design implications

  MetaPlus illustrates the methodological challenge of multi-nutrient interventions in complex syndromes: future studies may need biological enrichment (e.g., deficiency-based inclusion), single-component testing, and phenotype-specific hypotheses to avoid conflating heterogeneous effects.

Controversies & Other Evidence

• The accompanying editorial interpreted MetaPlus as demonstrating limited benefit of immunonutrition in critical illness and emphasised the potential for harm, particularly given the observed late mortality signal in medical patients and the broader uncertainty around pharmaconutrient bundles in heterogeneous ICU populations.¹
• Correspondence highlighted that the trial was powered for a large infection reduction and was not designed to detect mortality differences, urging caution with interpretation of subgroup mortality findings; the authors’ reply acknowledged the power issue while reiterating concern regarding the medical subgroup signal.²³
• A post hoc safety analysis reported that the excess 6-month mortality in medical patients persisted after adjustment (HR 2.52; 95% CI 1.36 to 4.78; P=0.004) and found an association between early rise in plasma (EPA+DHA)/LCF ratio and 6-month mortality (HR 1.18; 95% CI 1.02 to 1.35; P=0.021), suggesting (but not proving) a plausible mechanistic link to omega-3 exposure.⁴
• A systematic review/meta-analysis of enteral glutamine supplementation in critically ill patients (including MetaPlus) found no significant effect on mortality (RR 1.01; 95% CI 0.86 to 1.19), infectious complications (RR 0.88; 95% CI 0.75 to 1.03), ICU length of stay (mean difference 0.28 days; 95% CI −1.21 to 1.78), or ventilator days (mean difference 0.22 days; 95% CI −0.48 to 0.92), and concluded that routine enteral glutamine could not be supported by the available evidence.⁵
• The most recent ESPEN practical ICU nutrition guideline recommends that additional enteral glutamine should not be administered in ICU patients except in those with burns or trauma (strong consensus), aligning with a conservative interpretation of MetaPlus and the broader pharmaconutrition literature.⁶

Summary

• In 301 mechanically ventilated adults across 14 European ICUs, an immune-modulating high-protein enteral formula (glutamine + omega-3 + antioxidants) did not reduce ICU-acquired infections versus an iso-caloric standard high-protein formula (53% vs 52%; P=.96).
• There was no difference in ICU, hospital, or 28-day mortality; 6-month mortality was numerically higher overall (35% vs 29%; P=.21) and significantly higher in medical patients (54% vs 35%; P=.04), with an adjusted model suggesting increased hazard (HR 1.57; 95% CI 1.03 to 2.39; P=.04).
• Biochemical separation confirmed exposure (greater increases in plasma glutamine, selenium, vitamins, and omega-3 fatty acid ratios in the intervention group), yet without clinical infection benefit.
• Serious adverse events were similar (25.7% vs 25.5%; P=.975), but the late mortality signal drove subsequent debate and cautious interpretation.
• Subsequent analyses and contemporary guidelines support avoiding routine pharmaconutrient-enriched enteral formulas (particularly glutamine-containing) in general ICU populations, especially medical patients.

Overall Takeaway

MetaPlus is a landmark nutrition trial because it tested a widely adopted “immune-modulating” enteral strategy in a rigorous, double-blind, active-comparator design and found no reduction in nosocomial infection. More importantly, it raised credible concern for late harm in medical ICU patients, helping to shift critical care nutrition away from routine multi-nutrient pharmaconutrition bundles and toward phenotype- and evidence-aligned supplementation.

Bibliography

• 1.Rice TW. Immunonutrition in critical illness: limited benefit, potential harm. JAMA. 2014;312(5):490-491.
• 2.Buijs N, van Leeuwen PAM. Standard vs enriched high-protein enteral nutrition in the ICU. JAMA. 2014;312(21):2288.
• 3.van Zanten ARH, Hofman Z. Standard vs enriched high-protein enteral nutrition in the ICU. JAMA. 2014;312(21):2288.
• 4.Hofman Z, van Zanten ARH. Glutamine, fish oil and antioxidants in critical illness: MetaPlus trial post hoc safety analysis. Ann Intensive Care. 2016;6:119.
• 5.van Zanten ARH, Dhaliwal R, Garrel D, Heyland DK. Enteral glutamine supplementation in critically ill patients: a systematic review and meta-analysis. Crit Care. 2015;19:294.
• 6.Singer P, Reintam Blaser A, Berger MM, Calder PC, Casaer M, Hiesmayr M, et al. ESPEN practical and partially revised guideline: clinical nutrition in the intensive care unit. Clin Nutr. 2023;42(9):1671-1689.