EPaNIC: Early vs. Late Parenteral Nutrition in Critical Illness (2011)

“Late initiation of parenteral nutrition was associated with a faster recovery and fewer complications, as compared with early initiation.”

  • The EPaNIC Study Investigators

1. Publication Details

  • Trial Title: Early versus Late Parenteral Nutrition in Critically Ill Adults
  • Citation: Casaer MP, Mesotten D, Hermans G, et al. Early versus Late Parenteral Nutrition in Critically Ill Adults. N Engl J Med. 2011;365(6):506-517. DOI: 10.1056/NEJMoa1102662
  • Published: August 11, 2011, in The New England Journal of Medicine
  • Author: Michael P. Casaer, M.D.
  • Funding: The Research Foundation–Flanders (FWO); and others.

2. Keywords

  • Critical Care, Nutrition, Parenteral Nutrition, Enteral Nutrition, Hypocaloric Feeding, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adults for whom enteral nutrition was contraindicated or not tolerated (Population), does a strategy of early parenteral nutrition (PN) (Intervention) compared to a strategy of late PN (Comparison) reduce the length of ICU stay (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Providing adequate nutrition to critically ill patients is a cornerstone of ICU care. When enteral nutrition is not feasible, parenteral nutrition is used. European guidelines at the time recommended initiating supplemental PN within 2 days if enteral feeding was insufficient, while other guidelines suggested waiting longer.
  • Knowledge Gap: The optimal timing to initiate parenteral nutrition was a major area of clinical uncertainty. It was unknown if the benefits of providing early calories with PN outweighed the potential risks, such as infection, metabolic derangement, and potential suppression of autophagy (the body’s cellular “cleanup” process).
  • Proposed Hypothesis: The authors hypothesized that a strategy of late initiation of PN would be inferior to early initiation in terms of the length of ICU stay.

5. Study Design and Methods

  • Design: A large, single-center, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: A single, large tertiary care university hospital in Leuven, Belgium.
  • Trial Period: Enrollment ran from August 2007 to November 2010.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU who were at risk for malnutrition.
    • Exclusion Criteria: Included patients with a very short expected ICU stay (<2 days) or those who were severely malnourished on admission.
  • Intervention: An “early PN” strategy. If patients were not meeting caloric targets with enteral nutrition, supplemental PN was initiated within 48 hours of ICU admission to meet 100% of the goal.
  • Control: A “late PN” strategy. Patients received only intravenous glucose and standard enteral nutrition attempts. PN was withheld until day 8 of the ICU stay if needed.
  • Management Common to Both Groups: All patients were managed with a protocolized approach to enteral nutrition and intensive insulin therapy to maintain tight glycemic control.
  • Power and Sample Size: The authors calculated that a sample size of 4640 patients would provide 80% power to detect a 1-day difference in the length of ICU stay. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80% is the standard accepted level for clinical trials).
  • Outcomes:
    • Primary Outcome: Length of stay in the intensive care unit.
    • Secondary Outcomes: Included in-hospital mortality, incidence of new infections, duration of mechanical ventilation, and total costs of care.

6. Key Results

  • Enrollment and Baseline: 4640 patients were randomized (2312 to early PN and 2328 to late PN). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: Patients in the late-PN group had a significantly shorter median length of ICU stay (3 days vs. 4 days; p=0.02).
  • Secondary Outcomes: The late-PN group had a lower incidence of new infections (22.8% vs. 26.2%; p=0.008), a lower incidence of cholestasis, and a shorter duration of mechanical ventilation. There was no significant difference in in-hospital mortality, but the late-PN group had a significantly lower 90-day mortality rate.
  • Adverse Events: The primary adverse event was a higher rate of infections in the early-PN group.

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 Cox proportional-hazards model.
  • Primary Outcome Analysis: The primary outcome was a time-to-event analysis of time to ICU discharge.
  • Key Statistic(s) Reported: The key statistics were the median lengths of stay and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.02 for the primary outcome of ICU length of stay is below the 0.05 threshold, indicating that the observed difference is statistically significant and unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR) (for new infections):
      • Formula: ARR = (Risk in Control [Early PN] Group) – (Risk in Intervention [Late PN] Group)
      • Calculation: ARR = 26.2% – 22.8% = 3.4%.
      • Clinical Meaning: For every 100 patients managed with a late-PN strategy, about 3-4 new infections were prevented.
    • Number Needed to Treat (NNT) (to prevent one new infection):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.034 = 29.4, which is rounded down to 29.
      • Clinical Meaning: You would need to use a late-PN strategy in 29 patients to prevent one additional new infection.
  • Subgroup Analyses: The benefit of the late-PN strategy was consistent across all pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, randomized, controlled design provided high-quality evidence. The use of strict protocols for all other aspects of care (like glycemic control) is a major strength.
  • Statistical Power: The very large sample size provided excellent statistical power to detect even small differences in outcomes.
  • Patient-Centered Outcomes: The study focused on important patient-centered outcomes like length of stay, infections, and mortality.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The single-center design is a major limitation, as the results may not be applicable to other centers with different patient populations or practices (e.g., less strict glycemic control). The study also excluded severely malnourished patients.
  • Other: The study tested a strategy of supplemental PN. The results do not apply to patients who are receiving no enteral nutrition at all.

10. Conclusion of the Authors

  • The authors concluded that late initiation of parenteral nutrition was associated with a faster recovery and fewer complications as compared with early initiation.

11. To Summarize

  • Impact on Current Practice: This was a landmark, practice-changing trial that provided strong evidence that “less is more” in the early phase of nutritional support. It powerfully challenged the dogma that all critically ill patients must be fed to 100% of their caloric goals as early as possible.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients who are not severely malnourished at baseline.
    • Actionable Intervention: It is safe and may be beneficial to withhold parenteral nutrition for the first week of ICU stay, even if caloric targets are not being met with enteral nutrition.
  • What This Trial Does NOT Mean: This trial does NOT mean that nutrition is unimportant or that patients should be starved. It only suggests that in the acute, inflammatory phase of critical illness, aggressive parenteral feeding is harmful.
  • Implementation Caveats: This strategy may not be appropriate for patients with pre-existing severe malnutrition, who may require earlier and more aggressive nutritional support.

12. Context and Related Studies

  • Building on Previous Evidence: The EPaNIC trial (2011) was one of the key trials that established the concept of “permissive underfeeding” or “trophic” nutrition in the first week of critical illness.
  • Influence on Subsequent Research: The findings of this trial, along with the concurrent EDEN trial (2012) which showed no benefit of early full enteral feeding over trophic feeding, have been highly influential in shaping modern ICU nutrition guidelines, which now broadly support a more conservative approach in the early phase of critical illness for most patients.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal nutritional strategy for patients with pre-existing severe malnutrition remains an important unanswered question.
  • Future Directions: Future research is focused on identifying which specific subgroups of patients (e.g., those with different inflammatory or metabolic profiles) might benefit from earlier or more aggressive nutritional support.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and fundamental aspect of ICU care.
  • Methods: The large, randomized, controlled design was a major strength. However, the single-center, unblinded design is a significant limitation that reduces the external validity of the findings. The highly protocolized nature of all other care at the study center is both a strength (reducing confounding) and a weakness (making it less generalizable).
  • Results: The study reported statistically significant and clinically important benefits for the late-PN strategy across multiple outcomes, including a shorter ICU stay and fewer infections.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by their data. Despite the single-center design, the large sample size and the consistency of the findings with other major nutrition trials (like EDEN) have made this a highly influential study. Its findings are broadly applicable and have been incorporated into international guidelines.

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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