HACA: Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest

The HACA Study Group. N Engl J Med 2000; 346:549-556

Clinical Question

  • In adults who suffer cardiac arrest due to ventricular fibrillation, does mild hypothermia compared with standard normothermia improve neurological outcome at 6 months?


  • Randomised, controlled trial
  • Blinded assessment of the outcome
  • Computer generated ‘sealed envelope’ randomisation in blocks of 10, stratified by medical centre


  • Nine centres in five European countries
  • March 1996 to January 2001
  • Stopped before full recruitment due to lower than expected enrollment rate and funding shortage


  • Inclusion: 18 – 75 year olds; witnessed cardiac arrest; pulseless VT or VF as initial rhythm.
  • Exclusion: longer than 15 minutes before advanced life support; longer than 60 minutes before ROSC; responsive after ROSC; prolonged hypotension after ROSC (30 minutes at MAP < 60 mmHg); hypoxaemia for more than 15 minutes after ROSC; cardiac arrest after medical support already present
  • 3551 assessed of which 275 randomised


  • 137 patients
  • Induced hypothermia targeting 32–34°C using surface cooling (cold air blanket or ice packs) for 24 hours, followed by passive re-warming
  • Sedation and shiver-management was protocolised: midazolam, fentanyl and pancuronium
    • Median time from ROSC to initiation of cooling was 105 minutes [IQR 61–192]
    • Median time from ROSC to target temperature was 8 hours [IQR 4–16]
    • 12% failed to reach target temperature


  • 128 patients
  • Standard hospital bed with no temperature management
  • Sedation protocol as per intervention arm
    • Diagrammatic data suggests median temperature was 37.5°C or higher from ~12 hours onward


  • Primary outcome: more patients in the hypothermia group were left with good neurological outcomes at six months
      • Good neurological outcome assessed as Pittsburgh Cerebral Performance Categories 1 [no disability] or 2 [mild disability]
      • Bad neurological outcome assessed as P-CPC 3 [severe disability], 4 [persistent vegetative state] or 5 [death]
    • 75 (55%) versus 54 (39%) had favourable neurological outcomes, favouring hypothermia
    • Risk ratio for death in normothermia group was 1.40 (95% CI 1.08–1.81).
    • Number-needed-to-treat was 6 (95% CI 4–25)
    • Secondary outcome: a difference in mortality favoured the hypothermia group

Authors’ Conclusions

  • Among patients in whom spontaneous circulation has been restored after cardiac arrest due to ventricular fibrillation, systemic cooling to a bladder temperature of 32–34°C for 24 hours increases the chance of a favourable neurological outcome, as compared to standard normothermic life support


  • Randomised trial with blinded assessment.
  • First clinical trial testing theory drawn from cohort and animal studies.


  • Narrow inclusion criteria limit generalisability
  • Minor baseline differences between groups, but no change in risk ratio after statistical correction
  • Attending physician not blinded, which may bias toward a positive outcome
  • Blinding of assessing physician not verified, but relatively objective outcome assessment should limit impact of any accidental un-blinding
  • Only 8% of screened patients were included; selection bias cannot be excluded
  • Control group became hyperthermic, which may be harmful. Difference observed could be due to harm of conventional therapy rather than benefit of hypothermic therapy

The Bottom Line

  • In patients who suffer out-of-hospital cardiac arrest due to VT or VF, and where resuscitation efforts are quickly commenced, and when ROSC has been achieved within 1 hour, therapeutic hypothermia targeting 32–34°C will improve the chance of a favourable outcome and should be implemented. The results of this trial now need to be reviewed in light of TTM.


Full text pdf / abstract / doi: 10.1056/NEJMoa012689

Editorial, Commentaries or Blogs


Summary author: @DuncanChambler
Summary date: May 2014
Peer-review editor: @stevemathieu75


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