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Holzer M, et al. "Mild Therapeutic Hypothermia to Improve the Neurologic Outcome After Cardiac Arrest". The New England Journal of Medicine. 2002. 346(8):549-556.
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Clinical Question

In patients with cardiac arrest due to VF or pulseless VT, does mild hypothermia improve neurologic outcomes compared with standard care normothermia?

Bottom Line

Among patients with return of spontaneous circulation after cardiac arrest due to VF or pulseless VT, mild therapeutic hypothermia (32-34° C) improved neurologic outcomes and reduced mortality at six months.

Major Points

Hypoxemic-ischemic brain injury is the most common cause of death in patients after cardiac arrest. Preliminary studies have demonstrated that lowering brain temperature to 32 to 34° C reduces the risk of neurologic injury and improves neurologic outcomes. The 2002 Hypothermia After Cardiac Arrest (HACA) trial randomly assigned 275 patients with return of spontaneous circulation (ROSC) after witnessed cardiac arrest due to VF or pulseless VT to mild therapeutic hypothermia (32 to 34° C) or to standard normothermia. At six months, HACA demonstrated improved neurologic outcomes in the hypothermia group compared to the normothermia group. The authors estimate that six patients would need to be treated with induced hypothermia to prevent one unfavorable neurologic outcome. In addition, therapeutic hypothermia improved survival such that to prevent one death, seven patients would need to be treated with induced hypothermia. A concurrent publication by Benard et al.[1] found a benefit with therapeutic hypothermia for functional outcomes in a similar population.

A 2012 Cochrane review[2] reported that mild hypothermia likely improves survival and neurologic outcome after cardiac arrest. Interestingly, the 2013 TTM trial found no difference between temperature targets of 33° C and 36° C for all-cause mortality or cognitive benefit, calling into question the role of hypothermia rather than simply avoiding hyperthermia in this population.


AHA Post-Cardiac Arrest Care (2010, adapted)[3]

  • Comatose adult patients with ROSC following out-of-hospital VF arrest should be cooled to 32-34°C for 12-24 hours (class I, level B)
  • Comatose adult patients with ROSC after in-hospital arrest of any rhythm or out-of-hospital PEA arrest or asystole can be considered for treatment with induced hypothermia (class IIb, level B)

ACCF/AHA STEMI (2013, adapted)[4]

  • Therapeutic hypothermia for comatose patients with STEMI and out-of-hospital cardiac arrest from VF or pulseless VT (class I, level B)


  • Multicenter, unblinded, parallel-group, randomized, controlled trial
  • N=275
    • Hypothermia group (n=137)
    • Normothermia group (n=138)
  • Setting: 9 centers in 5 European countries
  • Enrollment: 1996-2000 (funding ended)
  • Analysis: Intention-to-treat


Inclusion Criteria

  • Age 18-75 years
  • ROSC after witnessed cardiac arrest, VF or pulseless VT, or presumed cardiac origin of the arrest
  • Estimated interval of 5-15 mins from collapse to first attempt at resuscitation by emergency medical personnel
  • Estimated Interval of ≤60 mins from collapse to ROSC

Exclusion Criteria

  • Temperature <30° C on admission
  • Comatose prior to cardiac arrest due to CNS depressants
  • Pregnancy
  • Response to verbal commands after ROSC and before randomization
  • Evidence of hypotension (MAP <60mmHg) >30 mins after ROSC
  • Evidence of hypoxemia (SaO2 <85%) >15 mins after ROSC
  • Terminal illness prior to cardiac arrest
  • Known preexisting coagulopathy

Baseline Characteristics

Comparisons are hypothermia vs. normothermia.

  • Age: 59 years
  • Male: 77%
  • Diabetes: 8% vs. 19%
  • CAD: 32% vs. 43%
  • Cerebrovascular disease: 8%
  • NYHA class III or IV: 12%
  • Location of arrest:
    • Home: 51%
    • Public place: 37%
    • Other: 12%
  • Witnessed arrest: 99%
  • VF or pulseless VT: 97%
  • Bystander BLS provided: 43 vs. 49%
  • Time between collapse and ROSC: 21-22 mins
  • Total epinephrine dose: 3mg
  • Hypotension after resuscitation: 55% vs. 49%
  • Subsequent nonfatal arrest: 11% vs. 8%
  • Thrombolysis after resuscitation: 19%


  • Randomly assigned to hypothermia or normothermia
  • For hypothermia, goal was to reach target bladder temperature of 32-34° C within 4h after ROSC with external cooling device
    • Median interval between ROSC and initiation of cooling: 105 mins
    • Median interval between ROSC and goal temperature: 8 hrs
  • Temperature maintained at 32-34° C for median 24h from start of cooling, followed by passive rewarming to temperature >36° C over median 8h
  • Sedation: IV midazolam 0.125 mg/kg/hr and fentanyl 0.002 mg/kg/hr; doses adjusted prn for 32h for management of mechanical ventilation
  • Paralysis: pancuronium 0.1 mg/kg q 2 hours for total of 32h to prevent shivering
  • Neurologic outcome assessed using Pittsburgh cerebral performance scale:
    • 1=good recovery, 2=moderate disability, 3=severe disability, 4=vegetative state, 5=death
    • Favorable neurologic outcome: 1=good recovery, 2=moderate disability


Comparisons are hypothermia vs. normothermia.

Primary Outcomes

Favorable neurologic outcome within 6 months
55% vs. 39% (RR 1.40; 95% CI 1.08-1.81; P=0.009)

Secondary Outcomes

6-month mortality
41% vs. 55% (RR 0.74; 95% CI 0.58-0.95; P=0.02)
Rate of complications during first seven days after cardiac arrest
73% vs. 70% (P=0.70)
26% vs. 19%
37% vs 29%
13% vs. 7%
Renal failure
Pulmonary edema
7% vs. 4%
7% vs. 8%
Lethal or long-lasting arrhythmias
36% vs. 32%
Pressure sores


  • Physicians could not be blinded to treatment assignments
  • Only 8% of all patients assessed for eligibility were included in the trial, restricting study population to group of patients with high risk of brain damage. Further studies warranted to determine whether findings extend to patients at lower risk for brain damage and to those with cardiac arrest due to causes other than VF.
  • No report of brainstem reflexes before randomization so unclear if groups were balanced in regards to coma severity[5]
  • Small trial[5]


  • Supported by 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 device.

Further Reading