Bernard et al: Therapeutic Hypothermia after Cardiac Arrest (2002)

“In this randomized, controlled trial, we found that the induction of mild hypothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest of presumed cardiac cause increased the proportion of patients who had a favorable neurologic outcome and were discharged home or to a rehabilitation facility.”

  • Stephen A. Bernard, M.B., B.S., et al.

1. Publication Details

  • Trial Title: Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia
  • Citation: Bernard SA, Gray TW, Buist MD, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346(8):557-563. DOI: 10.1056/NEJMoa003289
  • Published: February 21, 2002, in The New England Journal of Medicine
  • Author: Stephen A. Bernard, M.B., B.S.
  • Funding: The National Heart Foundation of Australia; and others.

2. Keywords

  • Cardiac Arrest, Therapeutic Hypothermia, Targeted Temperature Management, Neurologic Outcome, Resuscitation, Randomized Controlled Trial

3. The Clinical Question

  • In comatose adult patients successfully resuscitated from out-of-hospital cardiac arrest (Population), does therapeutic mild hypothermia (Intervention) compared to standard normothermia (Comparison) increase the proportion of patients with a favorable neurologic outcome (discharge home or to a rehabilitation facility) (Outcome)?

4. Background and Rationale

  • Existing Knowledge: Anoxic brain injury is the primary cause of death and disability in patients who are successfully resuscitated from cardiac arrest. Animal studies had suggested that inducing hypothermia after a period of cerebral ischemia could reduce the extent of brain injury.
  • Knowledge Gap: At the time, there was no definitive clinical evidence from human randomized trials to support the use of therapeutic hypothermia in this patient population.
  • Proposed Hypothesis: The authors hypothesized that mild therapeutic hypothermia would improve the rate of good neurologic outcomes in comatose survivors of out-of-hospital cardiac arrest.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, controlled trial (used to test the effectiveness of interventions).
  • Setting: 4 emergency departments in Melbourne, Australia.
  • Trial Period: Enrollment ran from June 1996 to December 1999.
  • Population:
    • Inclusion Criteria: Adult patients who remained comatose after resuscitation from an out-of-hospital cardiac arrest of presumed cardiac origin.
    • Exclusion Criteria: Included cardiogenic shock, pregnancy, and a core temperature of less than 30°C on admission.
  • Intervention: Patients were cooled to a target temperature of 33°C for 12 hours using ice packs applied in the field and in the emergency department.
  • Control: Patients received standard care with a goal of normothermia.
  • Management Common to Both Groups: All patients received standard post-cardiac arrest care.
  • Power and Sample Size: The authors calculated that a sample size of 77 patients would be required to have 80% power to detect a 30% absolute difference in the rate of favorable outcomes. (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: Survival with a sufficiently good neurologic outcome to be discharged to home or a rehabilitation facility.
    • Secondary Outcomes: Included mortality and complications.

6. Key Results

  • Enrollment and Baseline: 77 patients were randomized (43 to hypothermia and 34 to normothermia). The groups were well-matched at baseline.
  • Trial Status: The trial was completed as planned.
  • Primary Outcome: A significantly higher proportion of patients in the hypothermia group had a favorable neurologic outcome. 21 of 43 patients (49%) in the hypothermia group had a good outcome, compared with 9 of 34 patients (26%) in the normothermia group (p=0.046).
  • Secondary Outcomes: Mortality was also lower in the hypothermia group (51% vs. 68%), but this difference was not statistically significant (p=0.145).
  • Adverse Events: The incidence of complications was similar between the two 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 patients with a favorable outcome between the two groups.
  • Key Statistic(s) Reported: The key statistics were the absolute rates of favorable outcome and the associated P-value.
  • Interpretation of Key Statistic(s):
    • P-value: The p-value of 0.046 is just below the 0.05 threshold, indicating the result is statistically significant and unlikely to be due to chance (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Reduction (ARR) (for the adverse outcome of poor neurologic recovery):
      • Formula: ARR = (Risk of Poor Outcome in Control Group) – (Risk of Poor Outcome in Intervention Group)
      • Calculation: ARR = (100% – 26%) – (100% – 49%) = 74% – 51% = 23%.
      • Clinical Meaning: For every 100 patients treated with hypothermia, about 23 additional patients were saved from a poor neurologic outcome.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.23 = 4.3, which is rounded down to 4.
      • Clinical Meaning: You would need to treat only 4 patients with therapeutic hypothermia to achieve one additional favorable neurologic outcome.
  • Subgroup Analyses: Not a major feature of this publication.

8. Strengths of the Study

  • Study Design and Conduct: The randomized, controlled design was a major strength for its time and provided a high level of evidence.
  • Generalizability: The pragmatic approach of initiating cooling in the field with simple ice packs is highly generalizable.
  • Patient-Centered Outcomes: The primary outcome of functional status at discharge is a highly relevant and patient-centered outcome.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias. The sample size was very small, which makes the results less precise and more susceptible to the play of chance.
  • External Validity (Generalizability): The study included patients with any initial rhythm, but the majority had ventricular fibrillation, so the results are most applicable to this group.
  • Other: The primary outcome was assessed at hospital discharge, not at a longer-term follow-up like 6 months.

10. Conclusion of the Authors

  • In comatose survivors of out-of-hospital cardiac arrest, induced hypothermia was associated with an improved rate of favorable neurologic outcomes.

11. To Summarize

  • Impact on Current Practice: This trial, along with the concurrent HACA trial, provided the foundational evidence for therapeutic hypothermia, transforming it from an experimental concept into a standard of care for post-cardiac arrest management worldwide.
  • Specific Recommendations:
    • Patient Selection: For adult patients who are comatose after resuscitation from an out-of-hospital cardiac arrest.
    • Actionable Intervention: Initiate cooling to a target temperature of 33°C.
    • Expected Benefit: This intervention can be expected to result in one additional patient having a good neurologic recovery for every 4 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that hypothermia is a magic bullet. The overall mortality and rate of poor outcomes were still high in both groups.
  • Implementation Caveats: The use of simple ice packs is a feasible method for inducing hypothermia.

12. Context and Related Studies

  • Building on Previous Evidence: The Bernard et al. trial (2002) was one of two landmark trials published in the same issue of NEJM that established the benefit of therapeutic hypothermia. The other was the larger HACA trial (2002) which showed similar results in a more select population.
  • Influence on Subsequent Research: The positive findings of this trial led to the widespread adoption of therapeutic hypothermia. However, it also raised new questions. The subsequent, larger TTM trial (2013) later challenged the optimal temperature target, finding no difference between cooling to 33°C and a more conservative strategy of simply preventing fever (targeting 36°C).

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial did not determine the optimal target temperature, duration of cooling, or rewarming strategy.
  • Future Directions: The results of this trial spurred a decade of research into optimizing post-cardiac arrest care, culminating in trials like the TTM (2013) and TTM2 (2021) which have further refined our approach to temperature management.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, addressing a critical unmet need in post-resuscitation care.
  • Methods: The RCT design was appropriate. The main methodological weaknesses are the lack of blinding and the very small sample size, which makes the results less precise than those of the larger HACA trial.
  • Results: The study reported a large and clinically significant effect size (NNT of 4). The result was statistically significant, but the small sample size is a major consideration when interpreting the strength of this finding.
  • Conclusions and Applicability: The authors’ conclusion is supported by their data. The fact that their findings were consistent with the larger, concurrent HACA trial greatly strengthened the overall evidence for therapeutic hypothermia. The pragmatic nature of the intervention (using ice packs) made its findings highly applicable.

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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