CALORIES: Early Parenteral vs. Enteral Nutrition in Critical Illness (2014)

“We found no evidence of a difference in 30-day mortality between the parenteral-nutrition group and the enteral-nutrition group. There were also no significant differences in the rates of other clinically important outcomes.”

  • The CALORIES Trial Investigators

1. Publication Details

  • Trial Title: A Randomized Trial of Early Parenteral Nutrition versus Enteral Nutrition in Critically Ill Adults
  • Citation: Harvey SE, Parrott F, Harrison DA, et al. Trial of the route of early nutritional support in critically ill adults. N Engl J Med. 2014;371(18):1673-1684. DOI: 10.1056/NEJMoa1409860
  • Published: October 30, 2014, in The New England Journal of Medicine
  • Author: Sheila E. Harvey, Ph.D.
  • Funding: National Institute for Health Research Health Technology Assessment Programme (UK).

2. Keywords

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

3. The Clinical Question

  • In critically ill adults expected to require nutritional support for at least 3 days (Population), does a strategy of early parenteral nutrition (PN) (Intervention) compared to early enteral nutrition (EN) (Comparison) affect 30-day all-cause mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Providing adequate nutrition to critically ill patients is a cornerstone of ICU care. Enteral nutrition (EN) was generally preferred due to its perceived benefits of maintaining gut integrity and lower cost. However, EN is often interrupted or poorly tolerated, leading to significant caloric deficits. Parenteral nutrition (PN) can reliably deliver calories but is associated with risks like infection and metabolic complications.
  • Knowledge Gap: Despite strong opinions, there was a lack of high-quality evidence from a large, pragmatic randomized trial to determine if one route of early nutritional support was truly superior to the other in terms of patient-centered outcomes.
  • Proposed Hypothesis: The authors hypothesized that there would be no significant difference in 30-day mortality between patients receiving early PN and those receiving early EN.

5. Study Design and Methods

  • Design: A multicenter, pragmatic, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 33 adult general intensive care units (ICUs) in the United Kingdom.
  • Trial Period: Enrollment ran from July 2011 to February 2014.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) admitted to the ICU who were expected to require nutritional support for at least 3 days and in whom both EN and PN were feasible.
    • Exclusion Criteria: Included patients with absolute contraindications to either route of feeding or those with a very poor prognosis.
  • Intervention: Patients were randomized to receive early parenteral nutrition, initiated within 36 hours of ICU admission.
  • Control: Patients were randomized to receive early enteral nutrition, initiated within 36 hours of ICU admission.
  • Management Common to Both Groups: In both groups, the goal was to meet a caloric target of 25 kcal/kg/day. If the assigned route of nutrition was not tolerated, the other route could be used as a supplement or replacement.
  • Power and Sample Size: The authors calculated that a sample size of 2400 patients would provide 90% power to detect a 5.5% absolute risk reduction in 30-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 30 days.
    • Secondary Outcomes: Included duration of organ support, incidence of infections, and length of ICU and hospital stay.

6. Key Results

  • Enrollment and Baseline: 2400 patients were randomized (1200 to PN and 1200 to EN). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: There was no significant difference in 30-day mortality. 393 of 1191 patients (33.0%) in the PN group died, compared with 409 of 1194 patients (34.2%) in the EN group (p=0.57).
  • Secondary Outcomes: There were no significant differences between the groups in any of the secondary outcomes, including the number of infection-free days or the duration of organ support.
  • Adverse Events: The incidence of adverse events was similar in both groups. Patients in the PN group had more episodes of hypoglycemia, while patients in the EN group had more episodes of vomiting.

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: Odds Ratio (OR) for death at 30 days: 0.95 (95% CI, 0.80 to 1.13; P-value: 0.57).
  • Interpretation of Key Statistic(s):
    • Odds Ratio (OR):
      • Formula: Conceptually, OR = (Odds of Death in Intervention Group) / (Odds of Death in Control Group).
      • Calculation: The paper reports the result as 0.95.
      • Clinical Meaning: An OR of 0.95 suggests a non-significant 5% lower odds of death in the PN group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 0.80 to 1.13.
      • Clinical Meaning: Since this range crosses the line of no effect (1.0), it confirms that the result is not statistically significant. Clinically, this means the true effect could range from a 20% benefit to a 13% harm.
    • P-value: The p-value of 0.57 is much higher than the 0.05 threshold, indicating the result is 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, pragmatic, randomized design provided high-quality evidence on a fundamental aspect of ICU care.
  • Generalizability: The inclusion of 33 diverse ICUs and a broad population of critically ill patients makes the findings highly generalizable to real-world practice.
  • Statistical Power: The study was very large and adequately powered to confidently rule out a modest but clinically important mortality difference.
  • Patient-Centered Outcomes: The primary outcome of 30-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 pragmatic design allowed for crossover between groups (e.g., patients in the EN group who were intolerant could receive supplemental PN). This high crossover rate (around 30% in both groups) may have diluted the difference between the strategies.
  • Other: The study did not achieve a large separation in caloric intake between the groups in the first few days, which may have made it more difficult to detect a true difference in outcomes.

10. Conclusion of the Authors

  • In a mixed population of critically ill adults, there was no significant difference in 30-day mortality between a strategy of early nutritional support with parenteral nutrition versus enteral nutrition.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provided strong evidence that the choice of initial nutrition route (enteral vs. parenteral) does not have a major impact on survival in a general ICU population, provided that caloric targets are eventually met.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients requiring nutritional support.
    • Actionable Intervention: The results support the current guideline recommendations to initiate early enteral nutrition when feasible. However, they also provide reassurance that if EN is not tolerated, a switch to or supplementation with PN is a safe and acceptable alternative.
  • What This Trial Does NOT Mean: This trial does NOT mean that parenteral nutrition is superior to enteral nutrition. Given the higher cost and similar outcomes, enteral nutrition remains the preferred first-line strategy.
  • Implementation Caveats: The primary goal of nutritional support should be to provide adequate calories and protein, and the route of administration can be tailored to the individual patient’s tolerance and clinical condition.

12. Context and Related Studies

  • Building on Previous Evidence: The CALORIES trial (2014) was designed to provide a more definitive answer to the “enteral vs. parenteral” debate than previous, smaller studies.
  • Influence on Subsequent Research: The neutral finding of this trial has been influential in shaping international nutrition guidelines, which continue to recommend a “enteral-first” approach but are less dogmatic about avoiding PN when EN is not feasible.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal timing and dose of supplemental PN in patients who are intolerant to EN remains an area of debate.
  • Future Directions: Subsequent research has focused on more nuanced questions, such as the optimal protein dose and the role of specific immunonutrients in different ICU populations.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a fundamental and common aspect of ICU care.
  • Methods: The large, multicenter, pragmatic RCT design was appropriate and robust. The main methodological issue is the high rate of crossover between the groups, which is a feature of a pragmatic design but can make the results harder to interpret as it dilutes the difference between the assigned strategies.
  • Results: The study reported a clear neutral finding for its primary outcome, with a confidence interval that was centered on the null value. This provides strong evidence against a meaningful clinical benefit of one strategy over the other in this population.
  • 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 most general ICUs. The trial provides strong evidence that the focus of nutritional support should be on achieving caloric goals, with the route of administration being a secondary consideration based on patient tolerance.

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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