Therapy Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.
This review may be edited
Summary
Posted By:	Gordon S. Doig
E-Mail:	Gordon.Doig@EvidenceBased.net
Posted Date:	Sept 13, 2002
Title:	Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.
Authors:	Bernard SA, Gray TW, Buist MD et al.
Reference:	N Engl J Med 2002;246:557-63.
Link:	Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract:	Background Cardiac arrest outside the hospital is common and has a poor outcome. Studies in laboratory animals suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome, but there have been no conclusive studies in humans. In a randomized, controlled trial, we compared the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest. Methods The study subjects were 77 patients who were randomly assigned to treatment with hypothermia (with the core body temperature reduced to 33°C within 2 hours after the return of spontaneous circulation and maintained at that temperature for 12 hours) or normothermia. The primary outcome measure was survival to hospital discharge with sufficiently good neurologic function to be discharged to home or to a rehabilitation facility. Results The demographic characteristics of the patients were similar in the hypothermia and normothermia groups. Twenty-one of the 43 patients treated with hypothermia (49 percent) survived and had a good outcome — that is, they were discharged home or to a rehabilitation facility — as compared with 9 of the 34 treated with normothermia (26 percent, P=0.046). After adjustment for base-line differences in age and time from collapse to the return of spontaneous circulation, the odds ratio for a good outcome with hypothermia as compared with normothermia was 5.25 (95 percent confidence interval, 1.47 to 18.76; P=0.011). Hypothermia was associated with a lower cardiac index, higher systemic vascular resistance, and hyperglycemia. There was no difference in the frequency of adverse events. Conclusions Our preliminary observations suggest that treatment with moderate hypothermia appears to improve outcomes in patients with coma after resuscitation from out-of-hospital cardiac arrest.
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
	No. Although the authors report that the patients were 'randomized', they were actually allocated to treatment group by day of the month. Patients who presented on odd numbered days received hypothermia and patients who presented on even numbered days received standard care. This process of allocation is often called 'pseudo-randomization' and can be subject to unexpected sources of bias. It is also extremely difficult to achieve 'allocation concealment' with pseudo-randomization. It is also very difficult to achieve any form of blinding.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
	No. Although 84 patients were reported as being 'eligible for enrollment' and were recruited for the trial, data is not presented on 7 patients. Furthermore, we do not know if these 7 patients received hypothermia or standard treatment. Five of the seven patients were not followed up because they were transferred to nonparticipating intensive care units. Given that informed consent should have been obtained, a transfer should not have precluded the investigators from obtaining hospital discharge status. Two patients were not followed-up because their family declined to give informed consent.
2b. Were patients analyzed in the groups to which they were randomized?
	The authors state that patient outcomes were analyzed in the groups to which they were originally randomized.
3. Were patients, health workers, and study personnel blind to treatment?
	Patients and health workers were not blinded however the authors report that outcome assessment was conducted by a blinded specialist in rehab medicine.
4. Were the groups similar at the start of the trial?
	There appear to be significantly more males in the normothermia group (79% vs. 58%, p=0.05) and significantly more patients in the normothermia group received bystander CPR (71% vs. 49%, p=0.05).
5. Aside from the experimental intervention, were the groups treated equally?
	There is no evidence to suggest the groups were not treated equally however there is no reporting of concomitant interventions.
What are the Results?
1. How large was the treatment effect?
	Significantly more patients treated with hypothermia survived and had a good outcome - discharged home or to a rehabilitation facility - compared to normothermia (21/43 vs. 9/34, p=0.046). The number needed to treat in order to obtain one additional 'good' outcome is 4.3.
2. How precise was the estimate of the treatment effect?
	Controlling for baseline imbalances in age and time to return of spontaneous circulation, the odds ratio for a good outcome due to hypothermia treatment was 5.25, with a 95% confidence interval from 1.47 to 18.76.
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
	This paper should be viewed as a very promising pilot project. Due to the small sample size and use of pseudo-randomization, although these results are extremely promising, we would hope that they would be confirmed in another trial before the treatment is applied to patient care. See review of second paper published in N Eng J Med
2. Were all clinically important outcomes considered?
	Due to the relatively small size of the trial, mortality at hospital outcome was not considered. Six and/or twelve month post-discharge outcomes are also not reported.
3. Are the likely treatment benefits worth the potential harms and costs?
	Due to the preliminary nature of this project, these questions cannot be addressed by this paper. An evidence-based recommendation, which is the building block for an evidence-based guideline, that summarizes this topic can be found in the EBR section.
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