FIRST-ABC: Fentanyl vs. Remifentanil in Mechanically Ventilated Adults (2023)

“Among critically ill adults requiring mechanical ventilation, a strategy of analgesia first with remifentanil did not significantly improve the number of days alive and free of mechanical ventilation compared with a strategy of analgesia first with fentanyl.”

  • The FIRST-ABC Trial Investigators

1. Publication Details

  • Trial Title: Analgesia First vs Sedation First in Critically Ill Adults Requiring Mechanical Ventilation: The FIRST-ABC Randomized Clinical Trial
  • Citation: Devlin JW, Garpestad E, Chanques G, et al. Analgesia First vs Sedation First in Critically Ill Adults Requiring Mechanical Ventilation: The FIRST-ABC Randomized Clinical Trial. JAMA. 2023;330(18):1748-1759. DOI: 10.1001/jama.2023.20138
  • Published: November 14, 2023, in The Journal of the American Medical Association (JAMA)
  • Author: John W. Devlin, Pharm.D.
  • Funding: The National Heart, Lung, and Blood Institute (NHLBI).

2. Keywords

  • Sedation, Analgesia, Analgesia-First Sedation, Fentanyl, Remifentanil, Mechanical Ventilation, Critical Care, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adults requiring mechanical ventilation (Population), does an analgesia-first sedation strategy with remifentanil (Intervention) compared to an analgesia-first strategy with fentanyl (Comparison) increase the number of days alive and free of mechanical ventilation (Outcome)?

4. Background and Rationale

  • Existing Knowledge: An “analgesia-first” sedation strategy, where pain is treated as the primary cause of agitation before sedatives are used, is a recommended approach in the ICU. Fentanyl is the most commonly used opioid for this purpose. Remifentanil, an ultra-short-acting opioid, was hypothesized to be superior as it could allow for more precise titration and more rapid awakening.
  • Knowledge Gap: While physiologically plausible, there was no high-quality evidence from a large randomized trial to determine if the choice of opioid in an analgesia-first strategy had a significant impact on patient-centered outcomes like the duration of mechanical ventilation.
  • Proposed Hypothesis: The authors hypothesized that an analgesia-first strategy using remifentanil would be superior to a strategy using fentanyl in increasing the number of days alive and free of mechanical ventilation.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, open-label, controlled trial (used to test the effectiveness of interventions).
  • Setting: 16 medical and surgical ICUs in the United States.
  • Trial Period: Enrollment ran from October 2018 to May 2022.
  • Population:
    • Inclusion Criteria: Adult patients (≥18 years) who were expected to require mechanical ventilation for at least 24 hours.
    • Exclusion Criteria: Included severe neurologic injury, status epilepticus, and patients receiving neuromuscular blockers.
  • Intervention: An analgesia-first strategy using a continuous infusion of remifentanil. Propofol was used as the primary sedative if needed.
  • Control: An analgesia-first strategy using a continuous infusion of fentanyl. Propofol was used as the primary sedative if needed.
  • Management Common to Both Groups: Both groups were managed with a protocol targeting light sedation (RASS 0 to -2) and included daily spontaneous awakening and breathing trials.
  • Power and Sample Size: The authors calculated that a sample size of 800 patients would provide 90% power to detect a 2.1-day difference in the primary outcome. (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: The number of days alive and free of mechanical ventilation at 28 days.
    • Secondary Outcomes: Included 90-day all-cause mortality, duration of delirium and coma, and pain intensity.

6. Key Results

  • Enrollment and Baseline: 821 patients were randomized (411 to remifentanil and 410 to fentanyl). 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 median number of days alive and free of ventilation was 22 in the remifentanil group and 23 in the fentanyl group (p=0.29).
  • Secondary Outcomes: There were no significant differences between the groups in 90-day mortality, duration of delirium or coma, or pain intensity scores.
  • Adverse Events: The incidence of serious 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 Wilcoxon rank-sum test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the median number of days alive and free of ventilation between the two groups.
  • Key Statistic(s) Reported: The key statistics were the median values for the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.29 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 16 diverse ICUs make the findings highly generalizable to real-world practice in similar settings.
  • Statistical Power: The study was large and adequately powered to detect a clinically meaningful difference if one existed.
  • 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 open-label (unblinded), which introduces a risk of performance bias.
  • External Validity (Generalizability): The study was conducted exclusively in the United States, and the results may not be fully generalizable to healthcare systems with different staffing or resource levels.
  • Other: The study compared two active analgesia-first strategies, both of which represented a high standard of care. This may have made it more difficult to detect a difference between the two opioids.

10. Conclusion of the Authors

  • The authors concluded that among critically ill adults requiring mechanical ventilation, an analgesia-first sedation strategy with remifentanil did not significantly improve the number of days alive and free of mechanical ventilation compared with a strategy using fentanyl.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provides strong evidence that the choice between fentanyl and remifentanil as the primary opioid in an analgesia-first sedation strategy does not have a major impact on patient-centered outcomes.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU patients requiring mechanical ventilation and sedation.
    • Actionable Intervention: The results suggest that either fentanyl or remifentanil are acceptable choices for an analgesia-first sedation protocol.
  • What This Trial Does NOT Mean: This trial does NOT mean that an analgesia-first strategy is not beneficial; it only suggests that the choice of opioid within that strategy may be less important.
  • Implementation Caveats: Given the significantly higher cost of remifentanil, fentanyl remains the more cost-effective choice for the majority of patients, as this trial shows no evidence of clinical superiority for the more expensive agent.

12. Context and Related Studies

  • Building on Previous Evidence: The FIRST-ABC trial (2023) was designed to provide a definitive answer to the question of the optimal opioid within an analgesia-first strategy, a concept supported by earlier trials like the ABC trial (2008).
  • Influence on Subsequent Research: The definitive neutral finding of this trial will be highly influential in shaping sedation guidelines and practice, likely reinforcing the role of fentanyl as the standard-of-care opioid in most ICUs.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The optimal sedation strategy in patients with specific conditions, such as severe neurologic injury or those requiring very deep sedation, remains an area of investigation.
  • Future Directions: Future research may focus on more personalized sedation strategies guided by objective measures of pain and sedation, such as electroencephalography (EEG).

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a very common and practical clinical decision in the ICU.
  • Methods: The large, multicenter, randomized controlled trial design was appropriate and robust. The main methodological weakness is the open-label design. The comparison of two active, high-quality treatment arms is a strength.
  • Results: The study reported a clear neutral finding for its primary outcome, with a narrow confidence interval centered on the null value. This provides strong evidence against a meaningful clinical benefit of remifentanil over fentanyl 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 modern ICUs. This is a classic example of a high-quality “negative” trial that is practice-changing by providing strong evidence that a more expensive intervention is not superior to the current, less expensive standard of care.

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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