PREPARE II: IV Fluid Bolus before Tracheal Intubation (2023)

“Among critically ill adults undergoing tracheal intubation, the administration of an intravenous fluid bolus did not significantly decrease the incidence of cardiovascular collapse.”

  • The PREPARE II Investigators and the Pragmatic Critical Care Research Group

1. Publication Details

  • Trial Title: Effect of a Fluid Bolus on Cardiovascular Collapse Among Critically Ill Adults Undergoing Tracheal Intubation (PREPARE II): A Randomised Clinical Trial
  • Citation: Russell DW, Casey JD, Gibbs KW, et al. Effect of a Fluid Bolus on Cardiovascular Collapse Among Critically Ill Adults Undergoing Tracheal Intubation (PREPARE II): A Randomised Clinical Trial. JAMA. 2022;328(3):270–279. DOI: 10.1001/jama.2022.9792
  • Published: July 19, 2022, in The Journal of the American Medical Association (JAMA)
  • Author: David W. Russell, M.D., M.P.H.
  • Funding: The National Heart, Lung, and Blood Institute (NHLBI).

2. Keywords

  • Tracheal Intubation, Cardiovascular Collapse, Hypotension, Fluid Resuscitation, Critical Care, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill adult patients undergoing tracheal intubation (Population), does the administration of a preemptive intravenous fluid bolus (Intervention) compared to no preemptive fluid bolus (Comparison) reduce the incidence of cardiovascular collapse (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Cardiovascular collapse (severe hypotension, cardiac arrest) is a common and life-threatening complication of tracheal intubation in critically ill patients. The combination of sedative induction agents (which cause vasodilation) and positive pressure ventilation (which reduces venous return) can precipitate this collapse.
  • Knowledge Gap: Giving a fluid bolus before intubation to “fill the tank” and buffer against the hemodynamic effects of induction was a very common practice, based on physiological reasoning. However, there was no high-quality evidence from a large randomized trial to determine if this routine practice was actually beneficial or if it could be harmful by contributing to fluid overload.
  • Proposed Hypothesis: The authors hypothesized that a preemptive intravenous fluid bolus would be superior to no fluid bolus in reducing the incidence of cardiovascular collapse during and immediately after tracheal intubation.

5. Study Design and Methods

  • Design: A multicenter, pragmatic, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 11 intensive care units (ICUs) and emergency departments in the United States.
  • Trial Period: Enrollment ran from February 2019 to January 2021.
  • Population:
    • Inclusion Criteria: Critically ill adult patients (≥18 years) undergoing tracheal intubation.
    • Exclusion Criteria: Included patients in cardiac arrest before intubation or those for whom the treating clinician believed a fluid bolus was either mandatory or contraindicated.
  • Intervention: Patients received a 500-mL intravenous bolus of crystalloid fluid (0.9% saline or a balanced solution).
  • Control: Patients received no preemptive fluid bolus.
  • Management Common to Both Groups: All other aspects of the intubation procedure, including the choice of induction agents and vasopressors, were at the discretion of the treating clinicians.
  • Power and Sample Size: The authors calculated that a sample size of 1065 patients would provide 90% power to detect a 5% absolute risk reduction 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: Cardiovascular collapse, defined as a composite of new-onset systolic blood pressure <65 mm Hg, new or increased vasopressor use, or cardiac arrest within the period from induction to 2 minutes after intubation.
    • Secondary Outcomes: Included 28-day mortality, and the number of days alive and free of mechanical ventilation.

6. Key Results

  • Enrollment and Baseline: 1067 patients were randomized (538 to the fluid bolus group and 529 to the no-bolus group). 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. Cardiovascular collapse occurred in 113 of 537 patients (21.0%) in the fluid bolus group and in 96 of 528 patients (18.2%) in the no-bolus group (p=0.25).
  • Secondary Outcomes: There were no significant differences between the groups in 28-day mortality or in the number of ventilator-free days.
  • 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 logistic regression model.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of patients who experienced cardiovascular collapse between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of the primary outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.25 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, pragmatic, randomized design provided high-quality evidence on a common clinical practice.
  • Generalizability: The inclusion of both ICU and emergency department patients from 11 diverse sites makes 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 benefit.
  • Patient-Centered Outcomes: The primary outcome of cardiovascular collapse is a robust and clinically important procedural endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings are highly generalizable to the broad population of critically ill adults undergoing intubation.
  • Other: The study tested a specific 500-mL bolus; it is unknown if a larger volume would have been more effective.

10. Conclusion of the Authors

  • The authors concluded that among critically ill adults undergoing tracheal intubation, a preemptive intravenous fluid bolus did not significantly decrease the incidence of cardiovascular collapse.

11. To Summarize

  • Impact on Current Practice: This was a landmark “negative” trial that provided strong evidence to refute a very common and long-standing practice. It demonstrated that the routine, “one-size-fits-all” administration of a fluid bolus before intubation is not beneficial.
  • Specific Recommendations:
    • Patient Selection: For the broad population of adult ICU and emergency department patients requiring tracheal intubation.
    • Actionable Intervention: Do not routinely administer a preemptive 500-mL fluid bolus before intubation.
  • What This Trial Does NOT Mean: This trial does NOT mean that fluid resuscitation is not important for hypotensive patients. It only argues against the routine prophylactic use of a fluid bolus in all patients, regardless of their fluid status.
  • Implementation Caveats: The key takeaway is that the decision to give a fluid bolus should be individualized based on the patient’s specific physiology and volume status, rather than being a routine part of every intubation.

12. Context and Related Studies

  • Building on Previous Evidence: The PREPARE II trial (2022) was designed to provide a definitive answer to a question that was based on physiological reasoning but lacked high-quality evidence.
  • Influence on Subsequent Research: The definitive neutral result of this trial will be highly influential in shaping airway management guidelines and will likely lead to the de-adoption of this common practice.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear neutral result.
  • Future Directions: The results of this trial will likely shift the focus of research towards other strategies for preventing peri-intubation cardiovascular collapse, such as the optimal choice and dose of induction agents and the preemptive use of vasopressors.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a very common, routine clinical practice that had never been subjected to a rigorous trial.
  • Methods: The large, multicenter, pragmatic RCT design was appropriate and robust. The main methodological weakness is the open-label design, but the primary outcome was a composite of objective endpoints, which mitigates the risk of bias.
  • 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 a routine fluid bolus.
  • 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 a classic example of a high-quality “negative” trial that was profoundly practice-changing by providing strong evidence to stop a common but ineffective therapy.

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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