Patrick J. Coppler, David J. Gagnon, Katharyn L. Flickinger, Jonathan Elmer, Clifton W. Callaway, Francis X. Guyette, Ankur Doshi, Alexis Steinberg, Cameron Dezfulian, Ari L. Moskowitz, Michael Donnino, Teresa L May, David B Seder, Jon C. Rittenberger
Clin Exp Emerg Med 2024;11(2):205-212. Published online January 29, 2024
Objective We hypothesized that the administration of amantadine would increase awakening of comatose patients resuscitated from cardiac arrest. Methods We performed a prospective, randomized, controlled pilot trial, randomizing subjects to amantadine 100 mg twice daily or placebo for up to 7 days. The study drug was administered between 72 and 120 hours after resuscitation and patients with absent N20 cortical responses, early cerebral edema, or ongoing malignant electroencephalography patterns were excluded. Our primary outcome was awakening, defined as following two-step commands, within 28 days of cardiac arrest. Secondary outcomes included length of stay, awakening, time to awakening, and neurologic outcome measured by Cerebral Performance Category at hospital discharge. We compared the proportion of subjects awakening and hospital survival using Fisher exact tests and time to awakening and hospital length of stay using Wilcoxon rank sum tests. Results After 2 years, we stopped the study due to slow enrollment and lapse of funding. We enrolled 14 subjects (12% of goal enrollment), seven in the amantadine group and seven in the placebo group. The proportion of patients who awakened within 28 days after cardiac arrest did not differ between amantadine (n=2, 28.6%) and placebo groups (n=3, 42.9%; P>0.99). There were no differences in secondary outcomes. Study medication was stopped in three subjects (21.4%). Adverse events included a recurrence of seizures (n=2; 14.3%), both of which occurred in the placebo group.
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Targeted temperature management with mild hypothermia (TTM-hypothermia; 32–34 °C) is a treatment strategy for adult patients who are comatose after cardiac arrest. Robust preclinical data support the beneficial effects of hypothermia beginning within 4 hours of reperfusion and maintained during the several days of postreperfusion brain dysregulation. TTM-hypothermia increased survival and functional recovery after adult cardiac arrest in several trials and in realworld implementation studies. TTM-hypothermia also benefits neonates with hypoxic-ischemic brain injury. However, larger and methodologically more rigorous adult trials do not detect benefit. Reasons for inconsistency of adult trials include the difficulty delivering differential treatment between randomized groups within 4 hours and the use of shorter durations of treatment. Furthermore, adult trials enrolled populations that vary in illness severity and brain injury, with individual trials enriched for higher or lower illness severity. There are interactions between illness severity and treatment effect. Current data indicate that TTM-hypothermia implemented quickly for adult patients after cardiac arrest, may benefit select patients at risk of severe brain injury but not benefit other patients. More data are needed on how to identify treatment-responsive patients and on how to titrate the timing and duration of TTM-hypothermia.
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