HACA: Therapeutic Hypothermia after Cardiac Arrest (2002)

“In patients who have been successfully resuscitated after cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality.”

  • The HACA Study Group

1. Publication Details

  • Trial Title: Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest
  • Citation: The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346:549-556. DOI: 10.1056/NEJMoa012689
  • Published: February 21, 2002, in The New England Journal of Medicine
  • Author: The Hypothermia after Cardiac Arrest (HACA) Study Group
  • Funding: European Union, Austrian Ministry of Science and Transport, and the Austrian Science Foundation.

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 due to ventricular fibrillation (Population), does therapeutic mild hypothermia (Intervention) compared to standard normothermia (Comparison) improve favorable neurologic outcome at 6 months (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 large human trials to support the use of therapeutic hypothermia in this patient population. The potential benefits, risks, and feasibility in a clinical setting were unknown.
  • Proposed Hypothesis: The authors hypothesized that therapeutic mild hypothermia would improve 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: 9 intensive care units (ICUs) in 5 European countries.
  • Trial Period: Enrollment ran from November 1996 to June 2001.
  • Population:
    • Inclusion Criteria: Adult patients (18-75 years) who were comatose after resuscitation from a witnessed, out-of-hospital cardiac arrest caused by ventricular fibrillation or non-perfusing ventricular tachycardia.
    • Exclusion Criteria: Included pregnancy, pre-existing coagulopathy, pre-arrest coma, and persistent cardiogenic shock.
  • Intervention: Patients were cooled to a target temperature of 32°C to 34°C for 24 hours using an external cooling device and ice packs.
  • Control: Patients received standard care with a goal of normothermia (maintaining a normal body temperature).
  • Management Common to Both Groups: All patients received standard post-cardiac arrest care, including mechanical ventilation, sedation, and neuromuscular blockade to prevent shivering.
  • Power and Sample Size: The authors calculated that a sample of 240 patients would be required to have 80% power to detect a 20% absolute difference in the rate of favorable neurologic 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: Favorable neurologic outcome at 6 months, defined as a Cerebral Performance Category (CPC) score of 1 (good recovery) or 2 (moderate disability).
    • Secondary Outcomes: Included mortality at 6 months and the incidence of complications within the first 7 days.

6. Key Results

  • Enrollment and Baseline: 275 patients were randomized (137 to hypothermia and 138 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 at 6 months: 75 of 136 patients (55%) in the hypothermia group vs. 54 of 137 patients (39%) in the normothermia group (p=0.009).
  • Secondary Outcomes: Mortality at 6 months was significantly lower in the hypothermia group (41%) compared to the normothermia group (55%) (p=0.02).
  • Adverse Events: The study monitored for complications such as bleeding, sepsis, and pneumonia. There was no significant difference in the overall rate of complications 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 neurologic outcome between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for favorable neurologic outcome: 1.40 (95% CI, 1.08 to 1.81; P-value: 0.009).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk of Favorable Outcome in Intervention Group) / (Risk of Favorable Outcome in Control Group).
      • Calculation: The paper reports the result as 1.40.
      • Clinical Meaning: The RR of 1.40 means that patients in the hypothermia group were 40% more likely to have a good neurologic outcome compared to the normothermia group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 1.08 to 1.81.
      • Clinical Meaning: Since this entire range is above the line of no effect (1.0), it confirms that the result is statistically significant. Clinically, this means we can be 95% confident that the true benefit of hypothermia is an increase in favorable outcomes of somewhere between 8% and 81%.
    • P-value: The p-value of 0.009 is well 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% – 39%) – (100% – 55%) = 61% – 45% = 16%.
      • Clinical Meaning: For every 100 patients treated with hypothermia, about 16 additional patients were saved from a poor neurologic outcome.
    • Number Needed to Treat (NNT):
      • Formula: NNT = 1 / ARR
      • Calculation: NNT = 1 / 0.16 = 6.25, which is rounded down to 6.
      • Clinical Meaning: You would need to treat 6 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 multicenter, randomized, controlled design was a strength, providing a high level of evidence for a novel therapeutic question.
  • Generalizability: The inclusion of 9 centers across five European countries increases the external validity of the findings compared to a single-center study.
  • Statistical Power: The study was adequately powered and met its planned sample size, increasing confidence in the results.
  • Patient-Centered Outcomes: The primary outcome of neurologic function at 6 months is a robust and highly relevant outcome for patients and their families.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was unblinded, which introduces a risk of performance bias, as clinicians’ knowledge of the treatment could have influenced other aspects of care or prognostication.
  • External Validity (Generalizability): The study had very strict inclusion criteria, focusing only on witnessed, out-of-hospital arrests with an initial rhythm of ventricular fibrillation. Therefore, the results cannot be directly generalized to patients with other arrest rhythms (like asystole) or in-hospital cardiac arrests.
  • Other: The cooling technique used was relatively slow, with the target temperature not being reached until a median of 8 hours after resuscitation.

10. Conclusion of the Authors

  • In comatose survivors of out-of-hospital cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia improves neurologic outcomes and reduces mortality.

11. To Summarize

  • Impact on Current Practice: This trial, along with a concurrent Australian study, 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 a witnessed, out-of-hospital VF cardiac arrest.
    • Actionable Intervention: Initiate cooling to a target temperature of 32-34°C for 24 hours.
    • Expected Benefit: This intervention can be expected to result in one additional patient having a good neurologic recovery for every 6 patients treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that therapeutic hypothermia is a magic bullet, as mortality and poor outcomes were still high. It also does NOT mean that this specific temperature target (32-34°C) is definitively superior to simply preventing fever.
  • Implementation Caveats: Active management of shivering and other physiological effects of hypothermia is required.

12. Context and Related Studies

  • Building on Previous Evidence: The HACA 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 a smaller Australian trial by Bernard et al. (2002) that showed similar results.
  • 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: The HACA trial did not answer whether therapeutic hypothermia is beneficial for patients with non-shockable rhythms (asystole/PEA) or for in-hospital cardiac arrests. It also did not determine the optimal target temperature or duration of cooling.
  • 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 addressed a clinically important area of uncertainty in post-resuscitation care, where anoxic brain injury was a major cause of mortality and morbidity. The study was justified by pre-clinical data suggesting a benefit for hypothermia.
  • Methods: The randomized controlled trial design was appropriate for testing a therapeutic intervention. The strict inclusion criteria (witnessed, VF arrest) created a homogenous patient population, which increased the study’s internal validity and ability to detect a true treatment effect, but limited its external validity. The primary outcome of neurologic function was patient-centered and robust. The main methodological weakness is the lack of blinding, which introduces a risk of performance bias.
  • Results: The study reported a large and clinically significant effect size (NNT of 6), indicating a substantial benefit. The result was statistically significant, with a confidence interval that did not cross the line of no effect, and this finding was consistent across both the primary neurologic outcome and the secondary outcome of mortality.
  • Conclusions and Applicability: The authors’ conclusion is well-supported by the data for the specific population studied. The main consideration for applicability is the trial’s limited external validity; the findings cannot be directly generalized to all cardiac arrest patients (e.g., non-shockable rhythms, in-hospital arrests). The later TTM trial (2013) provided important context, suggesting that the primary benefit may come from aggressively preventing fever rather than from deep hypothermia itself, further refining the applicability of these initial findings.

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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