IMPROVE: Early vs. Delayed Enteral Nutrition in Critical Illness (2013)

“In critically ill patients with relative contraindications to early enteral nutrition, initiating early parenteral nutrition was not associated with a lower 28-day mortality rate than a strategy of delayed enteral nutrition.”

  • The IMPROVE Study Group

1. Publication Details

  • Trial Title: Early Enteral Nutrition in Critically Ill Patients With Known Preexisting Malnutrition: A Randomized Controlled Trial
  • Citation: Doig GS, Simpson F, Sweetman EA, et al. Early parenteral nutrition in critically ill patients with short-term relative contraindications to early enteral nutrition: a randomized controlled trial. JAMA. 2013;309(20):2130-2138. DOI: 10.1001/jama.2013.5124
  • Published: May 22, 2013, in The Journal of the American Medical Association (JAMA)
  • Author: Gordon S. Doig, Ph.D.
  • Funding: Australian National Health and Medical Research Council.

2. Keywords

  • Critical Care, Nutrition, Parenteral Nutrition, Enteral Nutrition, Malnutrition, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adult patients with a short-term contraindication to early enteral nutrition (Population), does a strategy of early parenteral nutrition (PN) (Intervention) compared to standard care (delayed enteral nutrition) (Comparison) reduce 60-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: While early enteral nutrition (EN) is the preferred method of feeding in the ICU, many critically ill patients have contraindications (e.g., postoperative ileus, shock) that delay its initiation. This often leads to significant caloric deficits in the first week of illness.
  • Knowledge Gap: It was a major clinical question whether these patients would benefit from “bridging” this nutritional gap with early parenteral nutrition (PN). The potential benefits of providing calories had to be weighed against the known risks of PN, such as infection and metabolic complications.
  • Proposed Hypothesis: The authors hypothesized that a strategy of early PN would be superior to standard care (waiting for EN to be feasible) in reducing 60-day mortality.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 31 intensive care units (ICUs) in Australia and New Zealand.
  • Trial Period: Enrollment ran from November 2006 to June 2011.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU who had a relative contraindication to early enteral nutrition and were expected to remain in the ICU for at least 3 days.
    • Exclusion Criteria: Included patients with an absolute contraindication to PN or those who were severely malnourished at baseline.
  • Intervention: Patients received early parenteral nutrition, initiated within 24 hours of ICU admission, to meet 100% of their estimated caloric needs.
  • Control: Patients received standard care, which consisted of intravenous 5% dextrose and waiting until enteral nutrition was deemed feasible by the clinical team.
  • Management Common to Both Groups: In both groups, enteral nutrition was initiated as soon as it was considered safe by the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 1300 patients would provide 80% power to detect a 6.5% absolute risk reduction in 60-day mortality. (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: All-cause mortality at 60 days.
    • Secondary Outcomes: Included 90-day mortality, infection rates, and duration of organ support.

6. Key Results

  • Enrollment and Baseline: 1372 patients were randomized (686 to early PN and 686 to standard care). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 60-day mortality. 149 of 673 patients (22.1%) in the early-PN group died, compared with 142 of 670 patients (21.2%) in the standard-care group (p=0.68).
  • Secondary Outcomes: There were no significant differences between the groups in 90-day mortality, infection rates, or duration of organ support.
  • Adverse Events: The incidence of adverse events 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 0.68 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 31 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 60-day mortality is a robust and patient-centered endpoint.

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 duration of PN in the intervention group was relatively short (median of 2 days), as many patients quickly became eligible for enteral nutrition.

10. Conclusion of the Authors

  • The authors concluded that among critically ill adults with a relative contraindication to early enteral nutrition, the administration of early parenteral nutrition was not associated with a lower 60-day mortality rate than standard care.

11. To Summarize

  • Impact on Current Practice: This was an important “negative” trial that provided strong evidence against the routine use of early “bridging” parenteral nutrition in a general ICU population. It supported a more patient approach to initiating nutrition in patients with contraindications to EN.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients who have a temporary contraindication to early enteral nutrition.
    • Actionable Intervention: The results do not support the routine initiation of early parenteral nutrition in this population. A strategy of providing standard intravenous fluids and waiting for enteral nutrition to become feasible is a safe and acceptable approach.
  • What This Trial Does NOT Mean: This trial does NOT mean that parenteral nutrition is never indicated. It only argues against its routine, early use in patients who are expected to start enteral feeding within a few days.
  • Implementation Caveats: The findings of this trial support a more conservative approach to initiating parenteral nutrition in the ICU.

12. Context and Related Studies

  • Building on Previous Evidence: The IMPROVE trial (2013) added to the body of evidence from other major nutrition trials like EPaNIC (2011) and EDEN (2012), which also supported a more conservative, “permissive underfeeding” approach in the first week of critical illness.
  • Influence on Subsequent Research: The consistent neutral-to-harmful findings of these large trials have been highly influential in shaping modern ICU nutrition guidelines, which now strongly recommend against the routine use of early parenteral nutrition in patients who are not severely malnourished.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal nutritional strategy for patients with pre-existing severe malnutrition, or for those in whom enteral nutrition is contraindicated for a prolonged period (>7 days), remains an area of investigation.
  • Future Directions: Future research is focused on identifying which specific subgroups of patients might benefit from earlier or more aggressive nutritional support, and on the optimal protein dose in critical illness.

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, randomized controlled trial 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 and all major secondary outcomes.
  • 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 another classic example of a high-quality “negative” trial that was practice-changing by providing strong evidence that a more aggressive and expensive intervention is not superior to a simpler, more conservative approach.

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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