Complete Journal Club Article
Holzer M, et al. "Mild Therapeutic Hypothermiato Improve the Neurologic Outcome After Cardiac Arrest". The New England Journal of Medicine. 2002. 346(8):549-556.
PubMed Full text PDF

Clinical Question

Does mild hypothermia improve neurologic outcomes compared with standard care normothermia in patients surviving ventricular fibrillation or pulseless ventricular tachycardic arrest?


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

Major Points

  • Therapeutic Hypothermia, define as deliberate cooling of a patient to 32-33.9°C (90-93F) who has no return of spontaneous neurologic activity after cardiac arrest. The goal is to reduce the repercussion injury to the brain which may be related to free radical formation, micro and macro circulation disruption and protease activation. At therapeutic temperatures the disruption of inflammatory and damaging cascades within the brain are thought to be decreased. [1] 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.[2]
  • The HACA Trial (Hypothermia after Cardiac Arrest) randomized patients after witness Ventricular Fibrillation (VF) and pulseless Ventricular Tachycardia (VT) to 32-34°C Hypothermia. There was a significant patient centered outcome and 6 month mortality decrease in the hypothermia group. A later trial by Bernard et. al. demonstrated similar benefit as did the Cochrane review. The TTM Trial (33°C vs 36°C) found similar mortality and morbidity benefits however 33°C may not confer benefit over 36°C.[1][3][4]
  • Standard care established by the ACCF/AHA 2013 guidelines, recommend therapeutic hypothermia for any comatose patient with a STEMI and out of hospital cardiac arrest from VF or puleless VT[5]
  • Although use of prehospital cooling reduced core temperature by hospital arrival and reduced the time to reach a temperature of 34°C, it did not improve survival or neurological status among patients resuscitated from prehospital VF or those without VF.[6]
  • In comatose children who survived out-of-hospital cardiac arrest, therapeutic hypothermia, as compared with therapeutic normothermia, did not confer a significant benefit in survival with a good functional outcome at 1 year. [7]

Study Design

  • Randomized, Multicenter, unblinded treatment with blinded final outcome assessment.
  • N=275


  • Emergency Department enrollment

Patient Demographics

  • Age: 59 yrs
  • Male: 77%
  • Witnessed arrest: 99%
  • VF or Pulseless VT: 97%
  • Bystander CPR:
    • 49% normothermic group
    • 43% hypothermic group
  • Thrombolysis after resuscitation: 19%
  • Total epinephrine dosing: 3mg
  • Location of cardiac arrest:
    • Home: 51%
    • Public Place: 37%
    • Other: 12%

Inclusion Criteria

  • Witnessed cardiac arrest
  • Ventricular fibrillation or nonperfusing ventricular tachycardia as initial cardiac rhythm
  • Presumed cardiac origin of the arrest
  • Age of 18 to 75 years
  • Estimated interval of 5 to 15 minutes from the patient’s collapse to the first attempt at resuscitation
  • No more than 60 minutes from collapse to restoration of spontaneous circulation

Exclusion Criteria

Patients were excluded if they met any of the following criteria:

  • Tympanic-membrane temperature below 30°C on admission
  • Comatose state before the cardiac arrest due to the administration of drugs that depress the central nervous system
  • Pregnancy
  • Response to verbal commands after ROSC and before randomization
  • Hypotension(mean arterial pressure, less than 60 mm Hg) for more than 30 minutes after ROSC
  • Hypoxemia (arterial oxygen saturation, less than 85 percent) for more than 15 minutes after ROSC
  • Terminal illness that preceded the arrest
  • Factors that made participation in follow-up unlikely
  • Enrollment in another study
  • Cardiac arrest after the arrival of emergency medical personnel
  • Coagulopathy


All patients received the same intensive care and were sedated with midazolam and fentanyl as well as maintained on mechanical ventilation. Pancuronium was used (0.1mg/kg Q2hrs) to reduce shivering.


  • The hypothermia group was cooled to 32°C to 34°C using the TheraKool device in order to reach the target bladder temperature within 4 hours and maintained fro 24hs since the start of the cooling.
  • Passive rewarming occurred at 24hrs to a normothermic temperature >36° C over a median of 8hrs
  • Neurologic outcomes were measured using the Pittsburgh cerebral performance scale.


  • Analysis was performed using the intention to treat principle

Primary Outcome

Favorable neurologic outcome at 6 months:

p value = 0.009
CI 1.08-1.81
RR 1.4

Secondary Outcomes

6-month mortality

p value = 0.02
CI 0.58 - 0.95
RR 0.74

Subgroup analysis

Complication Rate during first seven days after cardiac arrest

  • Normothermia: 70%
  • Hypothermia: 73%

Criticisms & Further Discussion

  • Although there was no blinding for treating physicians the followup for neurologic assessment was blinded
  • Only 8% of all patients assessed for eligibility were included in the trial
  • This trial only established a benefit for the two arrest rhythms of VF and VT with no evidence of PEA
  • Similar ICU care was reported in both groups
  • The TTM Trial found no mortality benefit to the 33°C temperature when compared to a normothermic targeted temperature. Most likely this is due to the fact that both groups were prevented from developing fevers. The more important treatment strategy for hypothermic arrest may be prevention of the development of fever which enhances the harmful repercussion effects on the brain.


  • Grants from Biomedicine and Health Programme (BIOMED 2) implemented under the Fourth RTD Framework Programme of the European Union, Austrian Ministry of Science and Transport, and Austrian Science Foundation.
  • Kinetic Concepts provided TheraKool cooling blanket device

See Also

{{HypothermiaCardiac Arrest Links}}


  1. 1.0 1.1 Arrich J, Holzer M, Herkner H, Müllner M. Hypothermia for neuroprotection in adults after cardiopulmonary resuscitation. Cochrane Database of Systematic Reviews 2009. PMID
  2. The Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549-56
  3. Bernard SA et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557-63
  4. Nielsen N et al. Targeted temperature management at 33°C versus 36°C after cardiac arrest. N Engl J Med Nov 17 2013 doi: 10.1056/NEJMoa1310519
  5. http://www.ncbi.nlm.nih.gov/pubmed/23256913
  6. Kim F et al. Effect of Prehospital Induction of Mild Hypothermia on Survival and Neurological Status Among Adults With Cardiac Arrest A Randomized Clinical Trial. *JAMA Nov 17 2013
  7. Moler FWTherapeutic hypothermia after out-of-hospital cardiac arrest in children.