Ghrelin for Neuroprotection in Post-Cardiac Arrest Coma: A Randomized Clinical Trial.

Importance: Out-of-hospital cardiac arrest survival rates have markedly risen in the last decades, but neurological outcome only improved marginally. Despite research on more than 20 neuroprotective strategies involving patients in comas after cardiac arrest, none have demonstrated unequivocal evidence of efficacy; however, treatment with acyl-ghrelin has shown improved functional and histological brain recovery in experimental models of cardiac arrest and was safe in a wide variety of human study populations. Objective: To determine safety and potential efficacy of intravenous acyl-ghrelin to improve neurological outcome in patients in a coma after cardiac arrest. Design, Setting, and Participants: A phase 2, double-blind, placebo-controlled, multicenter, randomized clinical trial, Ghrelin Treatment of Comatose Patients After Cardiac Arrest: A Clinical Trial to Promote Cerebral Recovery (GRECO), was conducted between January 18, 2019, and October 17, 2022. Adult patients 18 years or older who were in a comatose state after cardiac arrest were assessed for eligibility; patients were from 3 intensive care units in the Netherlands. Expected death within 48 hours or unfeasibility of treatment initiation within 12 hours were exclusion criteria. Interventions: Patients were randomized to receive intravenous acyl-ghrelin, 600 µg (intervention group), or placebo (control group) within 12 hours after cardiac arrest, continued for 7 days, twice daily, in addition to standard care. Main Outcomes and Measures: Primary outcome was the score on the Cerebral Performance Categories (CPC) scale at 6 months. Safety outcomes included any serious adverse events. Secondary outcomes were mortality and neuron-specific enolase (NSE) levels on days 1 and 3. Results: A total of 783 adult patients in a coma after cardiac arrest were assessed for eligibility, and 160 patients (median [IQR] age, 68 [57-75] years; 120 male [75%]) were enrolled. A total of 81 patients (51%) were assigned to the intervention group, and 79 (49%) were assigned to the control group. The common odds ratio (OR) for any CPC improvement in the intervention group was 1.78 (95% CI, 0.98-3.22; P = .06). This was consistent over all CPC categories. Mean (SD) NSE levels on day 1 after cardiac arrest were significantly lower in the intervention group (34 [6] µg/L vs 56 [13] µg/L; P = .04) and on day 3 (28 [6] µg/L vs 52 [14] µg/L; P = .08). Serious adverse events were comparable in incidence and type between the groups. Mortality was 37% (30 of 81) in the intervention group vs 51% (40 of 79) in the control group (absolute risk reduction, 14%; 95% CI, -2% to 29%; P = .08). Conclusions and Relevance: In patients in a coma after cardiac arrest, intravenous treatment with acyl-ghrelin was safe and potentially effective to improve neurological outcome. Phase 3 trials are needed for conclusive evidence. Trial Registration: Clinicaltrialsregister.eu: EUCTR2018-000005-23-NL.

Myoclonus in comatose patients with electrographic status epilepticus after cardiac arrest: Corresponding EEG patterns, effects of treatment and outcomes.

OBJECTIVE: To clarify the significance of any form of myoclonus in comatose patients after cardiac arrest with rhythmic and periodic EEG patterns (RPPs) by analyzing associations between myoclonus and EEG pattern, response to anti-seizure medication and neurological outcome. DESIGN: Post hoc analysis of the prospective randomized Treatment of ELectroencephalographic STatus Epilepticus After Cardiopulmonary Resuscitation (TELSTAR) trial. SETTING: Eleven ICUs in the Netherlands and Belgium. PATIENTS: One hundred and fifty-seven adult comatose post-cardiac arrest patients with RPPs on continuous EEG monitoring. INTERVENTIONS: Anti-seizure medication vs no anti-seizure medication in addition to standard care. MEASUREMENTS AND MAIN RESULTS: Of 157 patients, 98 (63%) had myoclonus at inclusion. Myoclonus was not associated with one specific RPP type. However, myoclonus was associated with a smaller probability of a continuous EEG background pattern (48% in patients with vs 75% without myoclonus, odds ratio (OR) 0.31; 95% confidence interval (CI) 0.16-0.64) and earlier onset of RPPs (24% vs 9% within 24 hours after cardiac arrest, OR 3.86;95% CI 1.64-9.11). Myoclonus was associated with poor outcome at three months, but not invariably so (poor neurological outcome in 96% vs 82%, p = 0.004). Anti-seizure medication did not improve outcome, regardless of myoclonus presence (6% good outcome in the intervention group vs 2% in the control group, OR 0.33; 95% CI 0.03-3.32). CONCLUSIONS: Myoclonus in comatose patients after cardiac arrest with RPPs is associated with poor outcome and discontinuous or suppressed EEG. However, presence of myoclonus does not interact with the effects of anti-seizure medication and cannot predict a poor outcome without false positives.

Effects of targeted temperature management at 33 °C vs. 36 °C on comatose patients after cardiac arrest stratified by the severity of encephalopathy.

OBJECTIVES: To assess neurological outcome after targeted temperature management (TTM) at 33 °C vs. 36 °C, stratified by the severity of encephalopathy based on EEG-patterns at 12 and 24 h. DESIGN: Post hoc analysis of prospective cohort study. SETTING: Five Dutch Intensive Care units. PATIENTS: 479 adult comatose post-cardiac arrest patients. INTERVENTIONS: TTM at 33 °C (n = 270) or 36 °C (n = 209) and continuous EEG monitoring. MEASUREMENTS AND MAIN RESULTS: Outcome according to the cerebral performance category (CPC) score at 6 months post-cardiac arrest was similar after 33 °C and 36 °C. However, when stratified by the severity of encephalopathy based on EEG-patterns at 12 and 24 h after cardiac arrest, the proportion of good outcome (CPC 1-2) in patients with moderate encephalopathy was significantly larger after TTM at 33 °C (66% vs. 45%; Odds Ratios 2.38, 95% CI = 1.32-4.30; p = 0.004). In contrast, with mild encephalopathy, there was no statistically significant difference in the proportion of patients with good outcome between 33 °C and 36 °C (88% vs. 81%; OR 1.68, 95% CI = 0.65-4.38; p = 0.282). Ordinal regression analysis showed a shift towards higher CPC scores when treated with TTM 33 °C as compared with 36 °C in moderate encephalopathy (cOR 2.39; 95% CI = 1.40-4.08; p = 0.001), but not in mild encephalopathy (cOR 0.81 95% CI = 0.41-1.59; p = 0.537). Adjustment for initial cardiac rhythm and cause of arrest did not change this relationship. CONCLUSIONS: Effects of TTM probably depend on the severity of encephalopathy in comatose patients after cardiac arrest. These results support inclusion of predefined subgroup analyses based on EEG measures of the severity of encephalopathy in future clinical trials.

The Montreal Cognitive Assessment is a valid cognitive screening tool for cardiac arrest survivors.

AIM: The survival rate of out-of-hospital cardiac arrest (OHCA) patients has increased over the past decades. This gives rise to a growing number of patients with hypoxic-ischemic brain damage and cognitive impairment. Currently, cognitive impairment is underdiagnosed in OHCA patients. There is a need for a validated cognitive screening instrument to identify patients with cognitive impairment. This study aimed to examine the diagnostic value of the Montreal Cognitive Assessment (MoCA) in patients after OHCA. METHODS: Survivors (age ≥ 18 years) of OHCA completed the MoCA and a gold standard neuropsychological test battery, including tests for memory, attention, perception, language, reasoning, and executive functioning, at around one year after OHCA. Results of the MoCA are related to the results of the neuropsychological test battery. Analyses of diagnostic accuracy included receiver operating characteristics and calculation of predictive values. RESULTS: We included 54 OHCA survivors (mean age = 57.3, 74% male). The area under the curve (AUC) was 0.8, 95% CI [0.67, 0.93]. The MoCA showed excellent sensitivity of 86%, 95% CI [57, 98] and adequate specificity of 70.0%, 95% CI [53, 83] to detect cognitive impairment at the regular cut-off score of 26. The positive predictive value of the MoCA was 50%, 95% CI [30, 70] and the negative predictive value was 93%, 95% CI [76, 99]. CONCLUSION: This study shows that the MoCA may be a valid cognitive screening instrument for use in the OHCA patient population.

Neuroprotective Treatment of Postanoxic Encephalopathy: A Review of Clinical Evidence.

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.