Neuroprotective Treatment of Postanoxic Encephalopathy: A Review of Clinical Evidence

Abstract

Postanoxic encephalopathy is the key determinant of death or disability after successful cardiopulmonary resuscitation. Animal studies have provided proof-of-principle evidence of efficacy of divergent classes of neuroprotective treatments to promote brain recovery. However, apart from targeted temperature management (TTM), neuroprotective treatments are not included in current care of patients with postanoxic encephalopathy after cardiac arrest. We aimed to review the clinical evidence of efficacy of neuroprotective strategies to improve recovery of comatose patients after cardiac arrest and to propose future directions. We performed a systematic search of the literature to identify prospective, comparative clinical trials on interventions to improve neurological outcome of comatose patients after cardiac arrest. We included 53 studies on 21 interventions. None showed unequivocal benefit. TTM at 33 or 36°C and adrenaline (epinephrine) are studied most, followed by xenon, erythropoietin, and calcium antagonists. Lack of efficacy is associated with heterogeneity of patient groups and limited specificity of outcome measures. Ongoing and future trials will benefit from systematic collection of measures of baseline encephalopathy and sufficiently powered predefined subgroup analyses. Outcome measurement should include comprehensive neuropsychological follow-up, to show treatment effects that are not detectable by gross measures of functional recovery. To enhance translation from animal models to patients, studies under experimental conditions should adhere to strict methodological and publication guidelines.

Keywords: cerebral ischaemia; hypoxic ischaemic brain injury; post-cardiac arrest syndrome; postanoxic coma; resuscitation.

Figure 1

Overview of used search strategy.

Figure 2

Neuroprotective studies directed at improvement of neurological outcome after cardiac arrest. An overview of the included studies in this review. The darker the box, the larger the amount of included studies on that topic. Barb indicates barbiturates; Ca²⁺, calcium antagonists; CO₂, carbon dioxide; Cycl, cyclosporine; Adr, adrenaline; EPO, erythropoietin; Exe, exenatide; Gcd, glucocorticoid; Gluc, glucose; HT, hypothermia; Mg²⁺, magnesium; MAP, mean arterial pressure; NaHCO₃, sodium bicarbonate; NO, Sodium nitrite; O2, oxygen; PA, prophylactic antibiotics; Q10, coenzyme Q10; Sed, sedation; SPH, scopolamine and penehyclidine hydrochloride; Thromb, thrombolysis; Xe, xenon.

Figure 3

Schematic overview of pathophysiology of brain damage in the first 72 h after cardiac arrest. Each step can lead to direct or delayed neuronal cell death. The numbers indicate the presumed point of action of the discussed neuroprotective treatments. (1) Calcium antagonists: Nimodipine, Flunarizine, Lidoflazine. Mitigating mitochondrial damage: Cyclosporine, Coenzyme Q10. (2) Preventing acidosis: Sodium bicarbonate. (3) Glutamate antagonism: Noble gases, Exenatide, Scopolamine, and penehyclidine hydrochloride, Magnesium. (4) Antioxidants: Preventing hyperoxia, Sodium nitrite. (5) Anti-inflammation: Erythropoietin, Glucocorticoids. (6) Optimizing cerebral perfusion: Adrenaline, Mild hypocapnia, High mean arterial pressure, Thrombolysis. (1–6) Pan-inhibition: Hypothermia. Not indicated by a number: Decreasing cerebral metabolism: Barbiturates. Supportive therapies: Sedation, Glucose regulation, Prophylactic antibiotics. Na/K, sodium/potassium; Ca, calcium.

Figure 4

Cerebral Performance Category (CPC) compared to extended Glasgow Outcome Scale (GOS-E). CPC 1-2 and GOS-E 5-8 are considered good neurological outcome.