EDEN: Trophic vs. Full Enteral Feeding in Acute Lung Injury (2012)

“Among patients with acute lung injury, there was no significant difference in the number of ventilator-free days with initial trophic enteral nutrition compared with initial full enteral nutrition.”

  • The EDEN Investigators and the ARDS Network

1. Publication Details

  • Trial Title: Initial Trophic vs Full Enteral Feeding in Patients With Acute Lung Injury: The EDEN Randomized Trial
  • Citation: The National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network. Initial trophic vs full enteral feeding in patients with acute lung injury: the EDEN randomized trial. JAMA. 2012;307(8):795-803. DOI: 10.1001/jama.2012.137
  • Published: February 22, 2012, in The Journal of the American Medical Association (JAMA)
  • Author: The National Heart, Lung, and Blood Institute (NHLBI) ARDS Clinical Trials Network
  • Funding: The National Heart, Lung, and Blood Institute (NHLBI).

2. Keywords

  • Acute Lung Injury, ARDS, Enteral Nutrition, Trophic Feeding, Hypocaloric Feeding, Critical Care, Randomized Controlled Trial

3. The Clinical Question

  • In adult patients with acute lung injury (ALI) requiring mechanical ventilation (Population), does an initial strategy of trophic enteral nutrition (Intervention) compared to a strategy of initial full enteral nutrition (Comparison) affect the number of ventilator-free days at 28 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Providing early enteral nutrition to critically ill patients was known to be beneficial. However, many patients, particularly those with ARDS, have poor gastrointestinal motility and often do not tolerate feeding at full goal rates, leading to frequent interruptions and complications like high gastric residual volumes.
  • Knowledge Gap: It was unknown if a strategy of “trophic” or “trickle” feeding (providing a very small amount of nutrition to maintain gut integrity without trying to meet full caloric needs) for the first several days would be a safe and effective alternative to attempting full feeding, potentially reducing gastrointestinal complications without worsening clinical outcomes.
  • Proposed Hypothesis: The authors hypothesized that there would be no significant difference in the number of ventilator-free days between a strategy of initial trophic feeding and initial full feeding.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 44 hospitals in the ARDS Network in the United States.
  • Trial Period: Enrollment ran from January 2008 to April 2011.
  • Population:
    • Inclusion Criteria: Adult patients intubated and mechanically ventilated with acute lung injury (ALI), defined by a PaO2:FiO2 ratio of ≤300.
    • Exclusion Criteria: Included pregnancy, contraindications to enteral feeding, and severe malnutrition at baseline.
  • Intervention: A trophic feeding strategy, where patients received enteral nutrition at a very low rate (approximately 10-20 mL/hr, providing ~25% of goal calories) for the first 6 days.
  • Control: A full feeding strategy, where enteral nutrition was advanced as quickly as possible to meet the full caloric goal.
  • Management Common to Both Groups: All patients were managed with a low tidal volume ventilation strategy. After day 6, both groups were advanced to full goal-rate feeding as tolerated.
  • Power and Sample Size: The authors calculated that a sample size of 1000 patients would provide 88% power to detect a 2.5-day difference in ventilator-free days. (Power is a study’s ability to find a real difference between treatments if one truly exists; 80-90% is considered standard).
  • Outcomes:
    • Primary Outcome: The number of ventilator-free days to day 28.
    • Secondary Outcomes: Included 60-day mortality, incidence of infectious complications, and measures of gastrointestinal intolerance (e.g., high gastric residual volumes, vomiting).

6. Key Results

  • Enrollment and Baseline: 1000 patients were randomized (508 to trophic feeding and 492 to full feeding). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in the primary outcome. The mean number of ventilator-free days was 14.9 in the trophic-feeding group and 15.0 in the full-feeding group (p=0.92).
  • Secondary Outcomes: There was no significant difference in 60-day mortality (22.2% in the trophic group vs. 21.5% in the full-feeding group).
  • Adverse Events: Patients in the trophic-feeding group had significantly less gastrointestinal intolerance, with lower rates of high gastric residual volumes and less use of prokinetic agents.

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 Wilcoxon rank-sum test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the mean number of ventilator-free days between the two groups.
  • Key Statistic(s) Reported: The key statistics were the mean ventilator-free days and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.92 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, 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 an important clinical question.
  • Generalizability: The pragmatic design and inclusion of 44 diverse hospitals make the findings highly generalizable to a broad population of patients with ARDS.
  • Statistical Power: The study was large and adequately powered to confidently rule out a clinically important difference between the two strategies.
  • Patient-Centered Outcomes: The primary outcome of ventilator-free days is a robust and patient-centered composite outcome.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The study population was generally well-nourished at baseline and specifically excluded patients with severe malnutrition. The findings may not be applicable to this high-risk group.
  • Other: The study only evaluated the first 6 days of nutrition; the optimal strategy beyond this period was not addressed.

10. Conclusion of the Authors

  • The authors concluded that in patients with acute lung injury, an initial strategy of trophic enteral nutrition for up to 6 days is as effective as a strategy of initial full enteral nutrition with respect to ventilator-free days and 60-day mortality.

11. To Summarize

  • Impact on Current Practice: This was a practice-changing trial that provided strong evidence that “less is more” in the early phase of nutritional support for ARDS. It provided reassurance that it is safe to underfeed patients for the first week of their illness.
  • Specific Recommendations:
    • Patient Selection: For adult patients with ARDS requiring mechanical ventilation who are not severely malnourished at baseline.
    • Actionable Intervention: An initial strategy of trophic enteral feeding (e.g., 10-20 mL/hr) for the first 6 days is a safe and acceptable alternative to aggressive attempts at full feeding.
  • 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 ARDS, providing full caloric support is not superior to providing a minimal amount of enteral nutrition.
  • 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 EDEN trial (2012) was designed to provide a definitive answer to the “trophic vs. full” feeding debate, which had been a major area of clinical uncertainty.
  • Influence on Subsequent Research: The findings of this trial, along with the EPaNIC trial (2011) which showed harm with early parenteral nutrition, have been highly influential in shaping modern ICU nutrition guidelines, which now broadly support a more conservative, permissive underfeeding approach in the first week 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. The ideal timing to transition from trophic to full feeding is also not fully defined.
  • 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 practical clinical dilemma in the ICU.
  • Methods: The large, multicenter RCT design was appropriate and robust. The main methodological weakness is the open-label design. The exclusion of severely malnourished patients is a key factor in interpreting the applicability of the results.
  • Results: The study reported a clear neutral finding for its primary outcome and for mortality. The finding of less gastrointestinal intolerance in the trophic feeding group was a clinically important secondary outcome.
  • 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 to the majority of well-nourished patients with ARDS. This is a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence that a less aggressive and simpler strategy is not inferior to a more complex one.

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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