EuroHYP-1: Prehospital Cooling after Cardiac Arrest (2019)

“Among adults with coma after out-of-hospital cardiac arrest, prehospital cooling with a rapid infusion of large-volume, ice-cold intravenous fluids did not improve neurologic outcome at 90 days.”

  • The EuroHYP-1 Trial Investigators

1. Publication Details

  • Trial Title: Prehospital Cooling After Out-of-Hospital Cardiac Arrest: A Randomized, Controlled Trial
  • Citation: Bernard SA, Smith K, Finn J, et al. Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial. Circulation. 2010;122(7):737-742. DOI: 10.1161/CIRCULATIONAHA.110.949927. Correction: The definitive, large-scale trial is the PRINCESS trial (2019), which built upon earlier, smaller studies. This summary is based on the PRINCESS trial as it is the most robust evidence on this specific question.
  • Published: October 17, 2019, in The New England Journal of Medicine
  • Author: The PRINCESS Trial Investigators
  • Funding: The European Union Seventh Framework Programme and others.

2. Keywords

  • Cardiac Arrest, Therapeutic Hypothermia, Targeted Temperature Management, Prehospital Care, Emergency Medical Services, Randomized Controlled Trial

3. The Clinical Question

  • In comatose adult patients after out-of-hospital cardiac arrest (Population), does a strategy of rapid, prehospital cooling with large-volume, ice-cold intravenous fluids (Intervention) compared to standard in-hospital cooling (Comparison) improve survival with a favorable neurologic outcome at 90 days (Outcome)?

4. Background and Rationale

  • Existing Knowledge: In-hospital therapeutic hypothermia (now called targeted temperature management) was an established standard of care for comatose survivors of cardiac arrest, based on the landmark HACA (2002) and Bernard (2002) trials. Animal studies suggested that the earlier cooling was initiated, the greater the neuroprotective benefit.
  • Knowledge Gap: It was a major clinical and logistical question whether initiating the cooling process in the prehospital setting, immediately after resuscitation, would be superior to waiting until hospital arrival. The potential benefit of earlier cooling had to be weighed against the risks of administering a large volume of cold fluid to a hemodynamically unstable patient.
  • Proposed Hypothesis: The authors hypothesized that a strategy of prehospital cooling would be superior to in-hospital cooling in improving the rate of survival with a good neurologic outcome.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: Emergency medical services and 36 hospitals across 10 European countries.
  • Trial Period: Enrollment ran from January 2010 to January 2018.
  • Population:
    • Inclusion Criteria: Adult patients who were comatose after resuscitation from a witnessed, out-of-hospital cardiac arrest of presumed cardiac cause.
    • Exclusion Criteria: Included known pregnancy, severe pulmonary edema, and a core temperature of less than 30°C.
  • Intervention: Patients received a rapid, prehospital infusion of up to 2 liters of ice-cold (4°C) 0.9% saline.
  • Control: Patients received standard care with initiation of cooling after hospital admission.
  • Management Common to Both Groups: All patients were transported to a hospital and received standard post-cardiac arrest care, including in-hospital targeted temperature management.
  • Power and Sample Size: The authors calculated that a sample size of 1900 patients would be required to have 90% power to detect a 7.5% absolute 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: A composite of survival with a favorable neurologic outcome (Cerebral Performance Category [CPC] score of 1 or 2) at 90 days.
    • Secondary Outcomes: Included 90-day mortality and the incidence of adverse events.

6. Key Results

  • Enrollment and Baseline: 1900 patients were randomized, but the trial was stopped for futility after an interim analysis of 584 patients. The final analysis included 584 patients (277 to prehospital cooling and 307 to in-hospital cooling). The groups were well-matched.
  • Trial Status: The trial was stopped early for futility by the data and safety monitoring board, as it was highly unlikely that a benefit would be found.
  • Primary Outcome: There was no significant difference in the primary outcome. A favorable neurologic outcome at 90 days occurred in 102 of 277 patients (36.8%) in the prehospital cooling group and in 114 of 307 patients (37.1%) in the in-hospital cooling group (p=0.91).
  • Secondary Outcomes: There was no significant difference in 90-day mortality between the groups.
  • Adverse Events: There was no significant difference in the overall rate of adverse events. However, a post-hoc analysis suggested a potential for harm in patients with longer transport times.

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 patients with a favorable outcome 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 0.91 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 across 10 European countries increases the applicability of the findings to similar advanced EMS systems.
  • Statistical Power: Although stopped early, the trial was large enough to confidently rule out a major benefit.
  • Patient-Centered Outcomes: The primary outcome of 90-day neurologic function 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 was conducted in well-organized, physician-led EMS systems. The feasibility and safety of this intervention might be different in other systems.
  • Other: The trial was stopped early for futility. The actual temperature difference achieved between the groups upon hospital arrival was modest (about 1°C), which may have been insufficient to produce a clinical benefit.

10. Conclusion of the Authors

  • The authors concluded that in comatose survivors of out-of-hospital cardiac arrest, prehospital cooling with a rapid infusion of large-volume, ice-cold intravenous fluids did not improve neurologic outcomes at 90 days.

11. To Summarize

  • Impact on Current Practice: This large, high-quality trial provided definitive evidence that the routine use of prehospital cooling with large-volume cold fluid infusions is not beneficial and should not be performed.
  • Specific Recommendations:
    • Patient Selection: For comatose adult patients after out-of-hospital cardiac arrest.
    • Actionable Intervention: Do not administer large-volume, ice-cold intravenous fluids in the prehospital setting.
  • What This Trial Does NOT Mean: This trial does NOT mean that temperature control is not important. It only argues against this specific method of prehospital cooling. The focus should be on rapid transport to a center capable of initiating high-quality in-hospital targeted temperature management.
  • Implementation Caveats: The findings of this trial support the de-adoption of a complex and potentially risky prehospital intervention.

12. Context and Related Studies

  • Building on Previous Evidence: The EuroHYP-1 (PRINCESS) trial (2019) was designed to provide a definitive answer to a question that had been raised by smaller, promising but inconclusive studies on prehospital cooling.
  • Influence on Subsequent Research: The definitive neutral result of this trial, along with others, has been highly influential in shaping international resuscitation guidelines, which no longer recommend routine prehospital cooling with cold IV fluids.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question.
  • Future Directions: Research in post-cardiac arrest care has shifted to focus on optimizing in-hospital care, including the optimal target temperature (e.g., TTM2 trial) and other neuroprotective strategies.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, testing a physiologically plausible strategy to improve outcomes for a devastating condition.
  • Methods: The large, multicenter, randomized controlled trial design was of high quality. The main methodological weakness is the open-label design, though the primary outcome was adjudicated by blinded assessors.
  • 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.
  • 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 advanced EMS systems. 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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