Cooling after Cardiac Arrest: Conclusively Favorable, or Equivocally Studied?

Abstract & Commentary

Abstract 1

Source: The Hypothermia after Cardiac Arrest Study Group. Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest. N Engl J Med 2002;346: 549-556.

Laboratory studies suggest that hypothermia induced shortly after the restoration of spontaneous circulation may improve neurologic outcome. Conclusive human studies are lacking. This study originates in Austria from attempts to determine whether mild, systemic hypothermia increases the rate of neurologic recovery after resuscitation from cardiac arrest due to ventricular fibrillation. The study was a multi-center trial with blinded assessment of the outcome of patients who had been resuscitated after cardiac arrest due to ventricular fibrillation. These patients were randomly assigned to undergo therapeutic hypothermia (target temperature, 32°-34°C, measured in the bladder) over a period of 24 hours or to receive standard treatment without hypothermia.

The authors state that both groups received similar intensive care treatment based on standard critical care protocols. Despite random assignation, 19% of patients in the control group had diabetes vs. 8% in the hypothermia group; and 43% of the control group had coronary artery disease, compared to 32% of the hypothermia group. The hypothermia group also received intravenous fentanyl, midazolam, and pancuronium during the hypothermia phase, but no mention is made of a similar drip for the control group. The primary end point was a favorable neurologic outcome within six months of cardiac arrest; secondary end points were mortality within six months and the rate of complications within seven days. Six-month neurological recovery was better in the hypothermia group. Seventy-five of the 136 patients in the hypothermia group (55%) had a favorable neurologic outcome, compared with 54 of 137 (39%) in the normothermia group (risk ratio [RR], 1.40; 95% confidence interval [CI], 1.08-1.81). Mortality at six months was 41% in the hypothermia group (56 of 137 patients died), as compared with 55% in the normothermia group (76 of 138 patients; RR, 0.74; 95% CI, 0.58-0.95). The complication rate did not differ significantly between the two groups. In patients who successfully have been resuscitated after cardiac arrest due to ventricular fibrillation, therapeutic mild hypothermia increased the rate of a favorable neurologic outcome and reduced mortality.

Abstract 2

Source: Bernard SA, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557-563.

This Australian study used a randomized, controlled trial to compare the effects of moderate hypothermia and normothermia in patients who remained unconscious after resuscitation from out-of-hospital cardiac arrest. Randomly assigned study subjects were treated with hypothermia (with the core body temperature reduced to 33°C within two 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.

The demographic characteristics of the 77 patients in the study were similar in the both groups. Twenty-one of the 43 patients treated with hypothermia (49%) survived and were discharged home or to a rehabilitation facility. In comparison, nine of the 34 treated with normothermia (26%) achieved the same end point. This difference was statistically significant, although not robustly so (p = 0.046). Interestingly, the normothermia group died more often (23 of 34, or 68%) when compared to the hypothermia group (22 of 43, or 51%). The authors performed an adjustment for base-line differences in age and time from collapse to the return of spontaneous circulation and determined that the odds ratio for a good outcome with hypothermia as compared with normothermia was 5.25 (95% CI, 1.47-18.76; 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. The authors conclude that treatment with moderate hypothermia appears to improve outcomes in patients with coma after resuscitation from out-of-hospital cardiac arrest.

Commentary by Richard J. Hamilton, MD, FAAEM, ABMT

Previous studies have found induced hypothermia to have no protective effect in acute brain injury, leading to prolonged hospital stays and complications.1 These two new studies examine this novel therapy for a protective neurologic effect in cardiac arrest. The Austrian study follows the authors’ earlier publication of a successful feasibility study.2 The results of both of these studies seem to indicate that hypothermia protects the cerebral circulation, and this very well may be the case. However, the first study is too flawed to provide conclusive support to that theory. First of all, many more of the patients in the control group had diabetes and coronary artery disease—apparently despite the randomization. The morbidity and mortality associated with these conditions could account for the outcome difference. Second, if hypothermia preserves central nervous system function, I would expect an improvement in neurologic outcome early in the patient’s course—within a week, rather than within six months.

The Australian study does a better job of controlling demographic variables, although there were more women in the treatment group. The study found a difference in a rather soft end point—discharge to home or rehabilitation center. In fact, the normothermia group died more often than the hypothermia group. This may have less to do with neurologic outcome and more to do with a positive cardiologic benefit. In other words, could the elevated systemic vascular resistance and lower cardiac index have had a salutary effect on cardiac survival? Only further study will tell.

It’s my opinion that hypothermia may have some benefit, but it may not necessarily be due to the lowered temperature. The authors are to be commended on a tremendous effort to bring this study to fruition through the institutional review process and coordinating the efforts of so many practitioners. Both groups have identified the limitations in their studies, and their effort may help us understand the effect of hypothermia, who benefits from this intervention, and why.

Dr. Hamilton, Associate Professor of Emergency Medicine, Program Director, Emergency Medicine, MCP Hahnemann University, Philadelphia, PA, is on the Editorial Board of Emergency Medicine Alert.

References

1. Clifton GL, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med 2001;344:556-563.

2. Zeiner A, et al. Mild resuscitative hypothermia to improve neurological outcome after cardiac arrest. A clinical feasibility trial. Hypothermia After Cardiac Arrest (HACA) Study Group. Stroke 2000;31:86-94