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Best evidence in critical care medicine

Therapeutic hypothermia to improve neurologic outcome after cardiac arrest

Winnipeg, Manitoba

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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.

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Question: Does therapeutic hypothermia improve neurologic outcome in patients who have survived a cardiac arrest with ventricular fibrillation or tachycardia?

Design: Randomized placebo controlled trial. Physicians examining patients six months after randomization were blinded to treatment.

Setting: European emergency and intensive care departments.

Patients: Two hundred and seventy-five patients, 18 to 75 yr old, who survived a witnessed cardiac arrest with an initial rhythm of ventricular fibrillation or ventricular tachycardia. Requirements for inclusion included cardiopulmonary resuscitation initiation within 15 min of arrest and return of circulation within 60 min. Patients were excluded if they responded to verbal stimuli at the time of study entry.

Intervention: All patients were ventilated mechanically, sedated with iv midazolam and fentanyl and paralyzed with pancuronium to prevent shivering. One hundred and thirty-eight patients were randomized to normothermia. One hundred and thirty-seven patients randomized to hypothermia were cooled within four to eight hours using an external cooling device to maintain a bladder temperature between 32 and 34°C for 24 hr.

Main results: Primary outcome was neurologic function six months after the event. Favourable outcomes (Glasgow Pittsburgh cerebral-performance categories 1 or 2, patients who were able to live independently and work at least part-time) were found in 55% of the hypothermic group compared to 39% of the normothermic group (P = 0.009, ARR 16%, NNT 6.3). Six-month mortality was 41% in the hypothermic group which was significantly lower than in the normothermic group with a rate of 55% (P = 0.02, ARR 14%, NNT 7.1).

Conclusions: In selected patients with witnessed cardiac arrest due to a ventricular arrhythmia, induced hypothermia to 32–34°C for 24 hr significantly improves both survival and favourable neurologic outcome.

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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: 557–63.

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Question: Does therapeutic hypothermia improve neurologic outcome in patients who have survived a cardiac arrest with ventricular fibrillation?

Design: Placebo controlled trial, randomized according to the day of the month.

Setting: Hospitals within Melbourne, Australia.

Patients: Seventy-seven patients who were successfully resuscitated after a witnessed or unwitnessed ventricular fibrillation cardiac arrest and remained in a coma. Patients with cardiogenic shock were excluded.

Intervention: All patients were given iv midazolam and vecuronium boluses as needed. The 43 patients randomized to hypothermic treatment were cooled to a core temperature of 33°C for 12 hr after admission using external ice packs. Hypothermia was initiated in the field by the emergency medical services. The 34 patients randomized to normothermia were maintained at a core temperature of 37°C.

Main results: Primary outcome was good neurologic function defined as being discharged home to live independently or to a rehabilitation facility at the end of the hospital stay. Most patients (95%) had a witnessed cardiac arrest. More patients treated with hypothermia had a good neurologic outcome compared to patients receiving normothermia (49% vs 26%, P = 0.0046, ARR 23%, NNT 4.3). This significant difference in outcome occurred even though more patients in the normothermic group received bystander cardiopulmonary resuscitation (71% vs 49%, P = 0.05, ARR 22%, NNT 4.5).

Conclusions: In patients with persistent coma post cardiac arrest due to ventricular fibrillation, induced hypothermia for 12 hr appears to improve neurologic function and decrease mortality.

	Commentary by K. Olafson, M. Selaman and D. Easton

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Anoxic brain injury is a common event following cardiac arrest resulting in significant patient morbidity and mortality, as well as long-term costs to the health care system. Following cardiac arrest the brain becomes depleted of oxygen stores within 20 sec. This is followed by depletion of ATP and glucose stores over the next five minutes, at which time irreversible neuronal damage begins to occur.¹ Injury is also caused by free radical formation, calcium flux across cell membranes, and release of excitatory amino acids.² Paradoxically, further damage occurs with return of spontaneous circulation.³ This reperfusion injury is mediated by free radical formation, calcium shifts and excitatory amino acid release that result in cell damage and death.^2,3

Basic science and animal studies have suggested that mild hypothermia post cardiac arrest may improve both mortality and neurologic outcomes.^1,4 Based on this evidence, hypothermia has been used for several years in the operating room to protect the brain during circulatory arrest and low flow states. In addition, preliminary human studies post cardiac arrest suggested improved neurologic outcome with the use of hypothermia.^4,5 The exact mechanism through which hypothermia aids in neuroprotection is unknown. Animal studies have shown that there are many factors at work. These include decreased cerebral oxygen consumption, and reduced synthesis of neurotransmitters and free radicals.¹

The two well-designed studies summarized above demonstrate that hypothermia increases survival and significantly improves neurologic outcome when applied to patients with anoxic brain injury post cardiac arrest. Despite the relatively small size of these clinical trials and the lack of true randomization in the Bernard et al. study, the benefits demonstrated are so significant that hypothermia should be considered standard of care for selected patients with anoxic brain injury post cardiac arrest. Patients who sustain a witnessed ventricular fibrillation or tachycardia cardiac arrest with return of spontaneous circulation within one hour of initiation of cardiopulmonary resuscitation should be considered for hypothermic therapy. However, hypothermia is not a benign treatment as it can be associated with hemodynamic instability, cardiac arrhythmias and impaired immune response. In the study by Bernard et al., hypothermic patients were more likely to have a lower cardiac index and to require an epinephrine infusion, but these effects were short-lived and did not appear to adversely affect long-term outcome.

Although it is evident that hypothermia post cardiac arrest results in neuroprotection, important questions still remain. We do not know the optimal duration and degree of hypothermia or the optimal rates of cooling and rewarming. These trials included patients who had cardiac arrest secondary to ventricular tachycardia or fibrillation, and it is not known if this therapy can be generalized to patients after an asystole or pulseless electrical activity arrest. Finally, the best mechanism for cooling remains unknown. Further studies are required to conclusively determine the answers to these questions.

	References

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1 Eisenburger P, Sterz F, Holzer M, et al. Therapeutic hypothermia after cardiac arrest. Curr Opin Crit Care 2001; 7: 184–8.[Medline]

2 White BC, Sullivan JM, DeGracia DJ, et al. Brain ischemia and reperfusion: molecular mechanisms of neuronal injury. J Neurol Sci 2000, 179(S1-2): 1–33.[Medline]

3 Vaagenes P, Ginsberg M, Ebmeyer U, et al. Cerebral resuscitation from cardiac arrest: pathophysiologic mechanisms. Crit Care Med 1996; 24(2 Suppl): S57–68.[Medline]

4 Yanagawa Y, Ishihara S, Norio H, et al. Preliminary clinical outcomes study of mild resuscitative hypothermia after out-of-hospital cardiopulmonary arrest. Resuscitation 1998; 39: 61–6.[Medline]

5 Bernard SA, Jones BM, Horne MK. Clinical trial of induced hypothermia in comatose survivors of out-of-hospital cardiac arrest. Ann Emerg Med 1997; 30: 146–53.[Medline]

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