Mild Hypothermia Benefits Patients Following Cardiac Arrest
Abstracts & Commentary
Synopsis: Two studies in the same issue of the New England Journal of Medicine, one from Europe and one from Australia, show unequivocal improvement in neurologic function with a brief period of mild hypothermia in comatose patients following cardiac arrest.
Sources: Holzer M (for the Hypothermia after Cardiac Arrest Study Group). Mild therapeutic hypothermia to improve neurologic outcome after cardiac arrest. N Engl J Med. 2002;346:549-556; Bernard S, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med. 2002;346:557-563.
Both of these papers describe clinically applicable methods of using hypothermia for treating patients who fail to wake up following cardiac arrest. Both were randomized and succeeded in removing most of the known confounding variables from the control groups; both showed remarkable improvements in outcome as judged by survival and neurological function at 3 to 6 months or hospital discharge. The studies are similar in using noninvasive surface cooling methods, a similar goal for duration of hypothermia (18-24 hours), the same goal for core temperature (32-34°C), and the use of sedation and relaxants for the treatment period. Both studies analyzed their patients on an intention-to-treat basis and found significant benefits of hypothermia. They differed in size of the groups studied (275 vs 77 patients), the outcome measures used (Pittsburgh cerebral-performance categories vs survival to discharge to home or a rehabilitation facility), the method of randomization (block randomization at each institution vs even-odd day of the month), the start of hypothermia (following arrival at the emergency department vs during transport to the emergency department), and the inclusion criteria (any witnessed nonperfusing rhythm vs ventricular fibrillation).
The larger European, multicenter study produced a favorable outcome in 55% (75 out of 136) of the patients treated with hypothermia, as compared to 39% (54 out of 137) in the normothermic group (odds ratio, 1.40, 1.08-1.81). This means that 6 patients must be treated to achieve 1 additional good survivor. The survival at 6 months was also greater following hypothermia, 59% vs. 45%. The hypothermic treatment group did not contain a larger percentage of vegetative individuals. Sepsis was more likely in the hypothermic patients; however, this difference did not reach the level of significance and had no effect on survival.
In the Australian study, 21 (49%) of the patients treated with hypothermia, but only 9 (26%) who were not cooled, were able to care for themselves at discharge (P = .046). There were only 2 patients left severely disabled or unconscious, and both were in the normothermic treatment group. The rest of the difference was due to increased mortality in the normothermic patients. Although the number of patients in this study was small, physiologic variables and confounding conditions were reported and analyzed. As expected, blood pressure, pulse, and cardiac index were lower and SVR was higher during hypothermia. Biochemical differences seen included higher glucose and potassium and a slightly lower pH in the hypothermic patients. Serum creatinine level and creatine phosphokinase (MB) also tended to be higher in these patients. There was no difference in incidence of cardiac arrhythmias, and no patient died from a lethal arrhythmia. Although bleeding and infection have been reported as complications from hypothermia, neither of these was more common in the treatment group. Hemoglobin concentrations, white blood cell counts, and platelet counts were the same. In multivariate analysis, when factors known to influence outcome such as age and time to restoration of spontaneous circulation were taken into account, treatment with hypothermia remained a significant predictor of survival with an odds ratio of 5.25 (95% CI; 1.47-18.76; P = .011).
Comment by Charles G. Durbin, Jr., MD
These reports are important because they suggest that easily applied, mild hypothermia may improve outcome in coma following cardiac arrest. It appears to do so without increasing the number of vegetative individuals. Interest in therapeutic hypothermia increased recently after a report of a small, poorly controlled study demonstrated improved outcome following head injury.1 A larger, prospective study failed to show any improvement in closed-head injured patients,2 and the use of therapeutic hypothermia is not generally recommended in these patients. Earlier, use of more profound levels of hypothermia (28-30°C) following cardiac arrest was associated with many complications including uncontrolled infections, arrhythmias, and bleeding, and no improvement in survival. The current belief is that prevention of hyperthermia is an appropriate goal in brain-injured patients and avoiding fever, especially early following injury, is appropriate.
Ten years ago, it was felt that hypothermia was therapeutic by reducing brain basal metabolism and that a flat EEG was needed to provide brain protection. This metabolic model works well during ischemia, and the use of agents and conditions that produce a flat EEG are associated with improved neurologic outcome following interruption of brain blood flow. This protection needs to occur prior to the insult in order to be effective. It is now recognized that, following brain injury, there is release of excitatory neurotransmitters that can increase the death of brain cells. Agents that reduce the release of these neurotransmitters can improve brain function. Mild hypothermia is one of these treatments. In all animal models tested, mild hypothermia following injury is associated with improved brain survival and less injury. It is logical that this would be true in humans.
The challenge has been to apply hypothermia in a timely fashion without increasing risks. In both of the studies reviewed here, hypothermia was begun shortly after restoration of spontaneous circulation, and core temperature was reduced to the desired level within 8 hours. It is important to note that no patient in the hypothermic treatment group was hyperthermic on arrival at the emergency room. Cooling was begun during transport to the emergency room in both studies.
The optimal duration of hypothermia remains unresolved. The Australian study started rewarming after 12 hours at 32-34°C. Normothermia was achieved in most patients by 24 hours after resuscitation. The European study maintained hypothermia for 24 hours before returning patients to normothermia. It seems that even the shorter period of cooling was effective.
From these studies, it is reasonable to consider inducing mild hypothermia in patients who fail to awaken following return of spontaneous circulation from cardiac arrest. With so few effective treatment options, it is exciting to see such a simple intervention have such a remarkable effect. The ideal candidates would have a reversible, primary arrhythmia as the cause of arrest. In some areas, it may not be practical to begin treatment on transport to the hospital, but certainly this therapy should be easily applied in the hospital setting and in-hospital arrests should be considered for this therapy.
Prevention of shivering was necessary and patients were sedated and paralyzed. This makes neurologic examination impossible. Although cardiac depression and arrhythmia were not limiting factors in these studies, the potential for cardiac compromise must be kept in mind. In addition, bleeding and infection are potential concerns. Further study will be needed to clarify these risks. They do not seem to be limiting at this time and should not prevent use of this intervention.
References
1. Marion DW, et al. Treatment of traumatic brain injury with moderate hypothermia. N Engl J Med. 1997;336: 540-546.
2. Clifton GL, et al. Lack of effect of induction of hypothermia after acute brain injury. N Engl J Med. 2001;344:556-563.
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