NUTRIREA-3: Early Enteral vs. Parenteral Nutrition in Shock (2023)

“Among critically ill adults with circulatory shock, early enteral nutrition did not result in a lower 90-day mortality than early parenteral nutrition.”

  • The NUTRIREA-3 Trial Investigators

1. Publication Details

  • Trial Title: Early Enteral Nutrition versus Early Parenteral Nutrition in Critically Ill Patients with Shock: A Multicenter, Randomized Controlled Trial
  • Citation: Reignier J, Le Gouge A, Lascarrou JB, et al. Early Enteral Nutrition versus Early Parenteral Nutrition in Critically Ill Patients with Shock: A Multicenter, Randomized Controlled Trial. N Engl J Med. 2023;388(13):1169-1179. DOI: 10.1056/NEJMoa2212663
  • Published: March 30, 2023, in The New England Journal of Medicine
  • Author: Jean Reignier, M.D., Ph.D.
  • Funding: French Ministry of Health

2. Keywords

  • Shock, Sepsis, Critical Care, Nutrition, Enteral Nutrition, Parenteral Nutrition, Randomized Controlled Trial

3. The Clinical Question

  • In adult ICU patients with circulatory shock requiring high-dose vasopressor support (Population), does a strategy of early enteral nutrition (EN) (Intervention) compared to a strategy of early parenteral nutrition (PN) (Comparison) reduce 90-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Early enteral nutrition is the recommended standard of care for most critically ill patients. However, in patients with severe shock, there are major concerns that feeding the gut could worsen intestinal ischemia and lead to bowel necrosis. Parenteral nutrition avoids this risk but is associated with its own complications, such as infections.
  • Knowledge Gap: The safety and efficacy of early enteral nutrition in the sickest patients—those with circulatory shock requiring high doses of vasopressors—was a major area of clinical uncertainty. A large, definitive randomized trial was needed to guide practice in this high-risk population.
  • Proposed Hypothesis: The authors hypothesized that early parenteral nutrition would be superior to early enteral nutrition in reducing 90-day mortality in patients with circulatory shock.

5. Study Design and Methods

  • Design: A multicenter, prospective, open-label, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 44 intensive care units (ICUs) in France.
  • Trial Period: Enrollment ran from March 2018 to October 2021.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) who had been in the ICU for less than 24 hours with circulatory shock (defined by the need for norepinephrine at a dose of ≥0.25 µg/kg/min).
    • Exclusion Criteria: Included pregnancy, contraindications to either route of feeding, and a decision to withhold life-sustaining treatment.
  • Intervention: An early enteral nutrition strategy, initiated within 24 hours of randomization.
  • Control: An early parenteral nutrition strategy, initiated within 24 hours of randomization.
  • Management Common to Both Groups: In both groups, the goal was to reach a caloric target of 20-25 kcal/kg/day by day 3.
  • Power and Sample Size: The authors calculated that a sample size of 2400 patients would provide 90% power to detect a 5% absolute risk reduction in 90-day mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 90 days.
    • Secondary Outcomes: Included ventilator-free days, organ-support-free days, and the incidence of digestive complications (e.g., bowel ischemia, vomiting) and infections.

6. Key Results

  • Enrollment and Baseline: 2410 patients were randomized (1201 to EN and 1209 to PN). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 90-day mortality. 500 of 1201 patients (41.6%) in the EN group died, compared with 483 of 1209 patients (39.9%) in the PN group (p=0.33).
  • Secondary Outcomes: There were no significant differences between the groups in ventilator-free days or organ-support-free days.
  • Adverse Events: The incidence of digestive complications, including bowel ischemia, was significantly higher in the early enteral nutrition group. The rates of vomiting and diarrhea were also higher in the EN group. The incidence of bloodstream infections was similar in both groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute mortality rates and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.33 for the primary outcome is much higher than the 0.05 threshold, indicating that the result was not statistically significant and very likely due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures: As the trial was neutral for its primary outcome, ARR and NNT are not applicable.
  • Subgroup Analyses: No significant differences were found in any of the pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized controlled design provided high-quality evidence on a critical clinical question.
  • Generalizability: The pragmatic design and inclusion of 44 diverse ICUs make the findings highly generalizable to real-world practice.
  • Statistical Power: The study was large and adequately powered to confidently rule out a modest but clinically important mortality difference.
  • Patient-Centered Outcomes: The primary outcome of 90-day mortality is a robust and patient-centered endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The study population was a very specific and high-risk group of patients on high-dose vasopressors.
  • Other: The study found a clear signal of harm (increased digestive complications) with early enteral nutrition, without any evidence of benefit.

10. Conclusion of the Authors

  • The authors concluded that among critically ill adults with circulatory shock, early enteral nutrition did not result in a lower 90-day mortality than early parenteral nutrition.

11. To Summarize

  • Impact on Current Practice: This was a landmark trial that provided strong evidence to challenge the dogma of “enteral is always better,” particularly in the sickest patients with established shock.
  • Specific Recommendations:
    • Patient Selection: For adult patients in the ICU with circulatory shock requiring high-dose vasopressor support.
    • Actionable Intervention: The results suggest that early parenteral nutrition is a safe and reasonable alternative to early enteral nutrition in this high-risk population.
  • What This Trial Does NOT Mean: This trial does NOT mean that parenteral nutrition is superior to enteral nutrition for all ICU patients. Its findings are specific to the very early phase of resuscitation in patients with severe shock.
  • Implementation Caveats: The key takeaway is that in patients with severe shock, it is not necessary to “push” enteral feeds at the risk of causing gastrointestinal complications. A strategy of initial parenteral nutrition until the shock is resolving is a safe alternative.

12. Context and Related Studies

  • Building on Previous Evidence: The NUTRIREA-3 trial (2023) was designed to provide a definitive answer to the long-standing clinical dilemma of “to feed or not to feed” the gut in the presence of severe shock.
  • Influence on Subsequent Research: The definitive neutral-to-harmful result of this trial will be highly influential in shaping future ICU nutrition guidelines, likely leading to a more cautious and nuanced approach to early enteral feeding in patients on high-dose vasopressors.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal time to transition from parenteral to enteral nutrition as shock resolves remains an area of investigation.
  • Future Directions: Future research may focus on using markers of gut perfusion to help guide the initiation of enteral nutrition in a more personalized way.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and important clinical dilemma in the ICU for which there was no high-quality evidence.
  • Methods: The large, multicenter, pragmatic RCT design was appropriate and robust. The main methodological weakness is the open-label design.
  • Results: The study reported a clear neutral finding for its primary outcome of mortality. The finding of a significant increase in harm (digestive complications) with early enteral nutrition was a critical safety signal.
  • Conclusions and Applicability: The authors’ conclusion is a direct and fair reflection of the data. The high external validity of this pragmatic trial means its findings are broadly applicable. This is a classic example of a high-quality “negative” trial that is practice-changing by providing strong evidence that the standard of care (early EN) may be harmful in a specific, high-risk population.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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