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.

Restoration of postictal cortical activity after electroconvulsive therapy relates to recovery of orientation in person, place, and time.

BACKGROUND: Most patients show temporary impairments in clinical orientation after electroconvulsive therapy (ECT)-induced seizures. It is unclear how postictal reorientation relates to electroencephalography (EEG) restoration. This relationship may provide additional measures to quantify postictal recovery and shed light on neurophysiological aspects of reorientation after ECT. METHODS: We analyzed prospectively collected clinical and continuous ictal and postictal EEG data from ECT patients. Postictal EEG restoration up to 1 h was estimated by the evolution of the normalized alpha-delta ratio (ADR). Times to reorientation in the cognitive domains of person, place, and time were assessed postictally. In each cognitive domain, a linear mixed model was fitted to investigate the relationships between time to reorientation and postictal EEG restoration. RESULTS: In total, 272 pairs of ictal-postictal EEG and reorientation times of 32 patients were included. In all domains, longer time to reorientation was associated with slower postictal EEG recovery. Longer seizure duration and postictal administration of midazolam were related to longer time to reorientation in all domains. At 1-hour post-seizure, most patients were clinically reoriented, while their EEG had only partly restored. CONCLUSIONS: We show a relationship between postictal EEG restoration and clinical reorientation after ECT-induced seizures. EEG was more sensitive than reorientation time in all domains to detect postictal recovery beyond 1-hour post-seizure. Our findings indicate that clinical reorientation probably depends on gradual cortical synaptic recovery, with longer seizure duration leading to longer postsynaptic suppression after ECT seizures.

Sex differences in clot, vessel and tissue characteristics in patients with a large vessel occlusion treated with endovascular thrombectomy.

INTRODUCTION: To improve our understanding of the relatively poor outcome after endovascular treatment (EVT) in women we assessed possible sex differences in baseline neuroimaging characteristics of acute ischemic stroke patients with large anterior vessel occlusion (LVO). PATIENTS AND METHODS: We included all consecutive patients from the MR CLEAN Registry who underwent EVT between 2014 and 2017. On baseline non-contrast CT and CT angiography, we assessed clot location and clot burden score (CBS), vessel characteristics (presence of atherosclerosis, tortuosity, size, and collateral status), and tissue characteristics with the Alberta Stroke Program Early Computed Tomography Score (ASPECTS). Radiological outcome was assessed with the extended thrombolysis in cerebral infarction score (eTICI) and functional outcome with the modified Rankin Scale score (mRS) at 90 days. Sex-differences were assessed with multivariable regression analyses with adjustments for possible confounders. RESULTS: 3180 patients were included (median age 72 years, 48% women). Clots in women were less often located in the intracranial internal carotid artery (ICA) (25%vs 28%, odds ratio (OR) 0.85;95% confidence interval: 0.73-1.00). CBS was similar between sexes (median 6, IQR 4-8). Intracranial (aOR 0.73;95% CI:0.62-0.87) and extracranial (aOR 0.64;95% CI:0.43-0.95) atherosclerosis was less prevalent in women. Vessel tortuosity was more frequent in women in the cervical ICA (aOR 1.89;95% CI:1.39-2.57) and women more often had severe elongation of the aortic arch (aOR 1.38;95% CI:1.00-1.91). ICA radius was smaller in women (2.3vs 2.5 mm, mean difference 0.22;95% CI:0.09-0.35) while M1 radius was essentially equal (1.6vs 1.7 mm, mean difference 0.09;95% CI:-0.02-0.21). Women had better collateral status (⩾50% filling in 62%vs 53% in men, aOR 1.48;95% CI:1.29-1.70). Finally, ASPECT scores were equal between women and men (median 9 in both sexes, IQR 8-10vs 9-10). Reperfusion rates were similar between women and men (acOR 0.94;95% CI:0.83-1.07). However, women less often reached functional independence than men (34%vs 46%, aOR 0.68;95% CI:0.53-0.86). DISCUSSION AND CONCLUSION: On baseline imaging of this Dutch Registry, men and women with LVO mainly differ in vessel characteristics such as atherosclerotic burden, extracranial vessel tortuosity, and collateral status. These sex differences do not result in different reperfusion rates and are, therefore, not likely to explain the worse functional outcome in women after EVT.

Cognitive screening and rehabilitation after cardiac arrest: only a few hurdles to take.

Dutch and European guidelines recommend systematic screening for cognitive and emotional impairments in cardiac arrest survivors. We aimed to clarify opinions on cognitive screening and rehabilitation, identify barriers and facilitators for implementation in the Netherlands, and arrive at recommendations in this field. We conducted 22 semi-structured interviews with various stakeholders using the Tailored Implementation in Chronic Diseases checklist. There is broad-based acknowledgement of the relevance of cognitive impairment and a positive attitude regarding early cognitive screening among health professionals and patients. Barriers to implementation include a lack of practical recommendations on how, where and when to screen, insufficient knowledge of cognitive consequences of cardiac arrest, insufficient collaboration and knowledge sharing among different specialties within hospitals, insufficient resources, and insufficient evidence of the effectiveness of screening and therapy to justify financial compensation. Most of the identified barriers to implementation are solvable: national guidelines need practical recommendations and knowledge gaps among healthcare workers can be bridged by in-hospital collaboration. Fulfilling these requirements should be sufficient for the implementation of simple screening and tailored advice. More extensive cognitive rehabilitation therapy needs stronger evidence of efficacy in order to warrant stronger guideline recommendations and financial reimbursement.

Changes in postictal cerebral perfusion are related to the duration of electroconvulsive therapy-induced seizures.

OBJECTIVE: Postictal symptoms may result from cerebral hypoperfusion, which is possibly a consequence of seizure-induced vasoconstriction. Longer seizures have previously been shown to cause more severe postictal hypoperfusion in rats and epilepsy patients. We studied cerebral perfusion after generalized seizures elicited by electroconvulsive therapy (ECT) and its relation to seizure duration. METHODS: Patients with a major depressive episode who underwent ECT were included. During treatment, 21-channel continuous electroencephalogram (EEG) was recorded. Arterial spin labeling magnetic resonance imaging scans were acquired before the ECT course (baseline) and approximately 1 h after an ECT-induced seizure (postictal) to quantify global and regional gray matter cerebral blood flow (CBF). Seizure duration was assessed from the period of epileptiform discharges on the EEG. Healthy controls were scanned twice to assess test-retest variability. We performed hypothesis-driven Bayesian analyses to study the relation between global and regional perfusion changes and seizure duration. RESULTS: Twenty-four patients and 27 healthy controls were included. Changes in postictal global and regional CBF were correlated with seizure duration. In patients with longer seizure durations, global decrease in CBF reached values up to 28 mL/100 g/min. Regional reductions in CBF were most prominent in the inferior frontal gyrus, cingulate gyrus, and insula (up to 35 mL/100 g/min). In patients with shorter seizures, global and regional perfusion increased (up to 20 mL/100 g/min). These perfusion changes were larger than changes observed in healthy controls, with a maximum median global CBF increase of 12 mL/100 g/min and a maximum median global CBF decrease of 20 mL/100 g/min. SIGNIFICANCE: Seizure duration is a key factor determining postictal perfusion changes. In future studies, seizure duration needs to be considered as a confounding factor due to its opposite effect on postictal perfusion.

Additional predictive value of optic nerve sheath diameter for neurological prognosis after cardiac arrest: a prospective cohort study.

BACKGROUND: The goal is to estimate the additional value of ultrasonographic optic nerve sheath diameter (ONSD) measurement on days 1-3, on top of electroencephalography (EEG), pupillary light reflexes (PLR), and somatosensory evoked potentials (SSEP), for neurological outcome prediction of comatose cardiac arrest patients. We performed a prospective longitudinal cohort study in adult comatose patients after cardiac arrest. ONSD was measured on days 1-3 using ultrasound. Continuous EEG, PLR, and SSEP were acquired as standard care. Poor outcome was defined as cerebral performance categories 3-5 at 3-6 months. Logistic regression models were created for outcome prediction based on the established predictors with and without ONSD. Additional predictive value was assessed by increase in sensitivity for poor (at 100% specificity) and good outcome (at 90% specificity). RESULTS: We included 100 patients, 54 with poor outcome. Mean ONSD did not differ significantly between patients with good and poor outcome. Sensitivity for predicting poor outcome increased by adding ONSD to EEG and SSEP from 25% to 41% in all patients and from 27% to 50% after exclusion of patients with non-neurological death. CONCLUSIONS: ONSD on days 1-3 after cardiac arrest holds potential to add to neurological outcome prediction. TRIAL REGISTRATION: clinicaltrials.gov, NCT04084054. Registered 10 September 2019, https://www. CLINICALTRIALS: gov/study/NCT04084054 .

Cortical excitation/inhibition ratios in patients with major depression treated with electroconvulsive therapy: an EEG analysis.

Electroconvulsive therapy (ECT) is an effective treatment for major depression, but its working mechanisms are poorly understood. Modulation of excitation/inhibition (E/I) ratios may be a driving factor. Here, we estimate cortical E/I ratios in depressed patients and study whether these ratios change over the course of ECT in relation to clinical effectiveness. Five-minute resting-state electroencephalography (EEG) recordings of 28 depressed patients were recorded before and after their ECT course. Using a novel method based on critical dynamics, functional E/I (fE/I) ratios in the frequency range of 0.5-30 Hz were estimated in frequency bins of 1 Hz for the whole brain and for pre-defined brain regions. Change in Hamilton Depression Rating Scale (HDRS) score was used to estimate clinical effectiveness. To account for test-retest variability, repeated EEG recordings from an independent sample of 31 healthy controls (HC) were included. At baseline, no differences in whole brain and regional fE/I ratios were found between patients and HC. At group level, whole brain and regional fE/I ratios did not change over the ECT course. However, in responders, frontal fE/I ratios in the frequencies 12-28 Hz increased significantly (pFDR < 0.05 [FDR = false discovery rate]) over the ECT course. In non-responders and HC, no changes occurred over time. In this sample, frontal fE/I ratios increased over the ECT course in relation to treatment response. Modulation of frontal fE/I ratios may be an important mechanism of action of ECT.

Effects of oral anticoagulation in people with atrial fibrillation after spontaneous intracranial haemorrhage (COCROACH): prospective, individual participant data meta-analysis of randomised trials.

BACKGROUND: The safety and efficacy of oral anticoagulation for prevention of major adverse cardiovascular events in people with atrial fibrillation and spontaneous intracranial haemorrhage are uncertain. We planned to estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation. METHODS: In this prospective meta-analysis, we searched bibliographic databases and trial registries using the strategies of a Cochrane systematic review (CD012144) on June 23, 2023. We included clinical trials if they were registered, randomised, and included participants with spontaneous intracranial haemorrhage and atrial fibrillation who were assigned to either start long-term use of any oral anticoagulant agent or avoid oral anticoagulation (ie, placebo, open control, another antithrombotic agent, or another intervention for the prevention of major adverse cardiovascular events). We assessed eligible trials using the Cochrane Risk of Bias tool. We sought data for individual participants who had not opted out of data sharing from chief investigators of completed trials, pending completion of ongoing trials in 2028. The primary outcome was any stroke or cardiovascular death. We used individual participant data to construct a Cox regression model of the time to the first occurrence of outcome events during follow-up in the intention-to-treat dataset supplied by each trial, followed by meta-analysis using a fixed-effect inverse-variance model to generate a pooled estimate of the hazard ratio (HR) with 95% CI. This study is registered with PROSPERO, CRD42021246133. FINDINGS: We identified four eligible trials; three were restricted to participants with atrial fibrillation and intracranial haemorrhage (SoSTART [NCT03153150], with 203 participants) or intracerebral haemorrhage (APACHE-AF [NCT02565693], with 101 participants, and NASPAF-ICH [NCT02998905], with 30 participants), and one included a subgroup of participants with previous intracranial haemorrhage (ELDERCARE-AF [NCT02801669], with 80 participants). After excluding two participants who opted out of data sharing, we included 412 participants (310 [75%] aged 75 years or older, 249 [60%] with CHA2DS2-VASc score ≤4, and 163 [40%] with CHA2DS2-VASc score >4). The intervention was a direct oral anticoagulant in 209 (99%) of 212 participants who were assigned to start oral anticoagulation, and the comparator was antiplatelet monotherapy in 67 (33%) of 200 participants assigned to avoid oral anticoagulation. The primary outcome of any stroke or cardiovascular death occurred in 29 (14%) of 212 participants who started oral anticoagulation versus 43 (22%) of 200 who avoided oral anticoagulation (pooled HR 0·68 [95% CI 0·42-1·10]; I2=0%). Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events (nine [4%] of 212 vs 38 [19%] of 200; pooled HR 0·27 [95% CI 0·13-0·56]; I2=0%). There was no significant increase in haemorrhagic major adverse cardiovascular events (15 [7%] of 212 vs nine [5%] of 200; pooled HR 1·80 [95% CI 0·77-4·21]; I2=0%), death from any cause (38 [18%] of 212 vs 29 [15%] of 200; 1·29 [0·78-2·11]; I2=50%), or death or dependence after 1 year (78 [53%] of 147 vs 74 [51%] of 145; pooled odds ratio 1·12 [95% CI 0·70-1·79]; I2=0%). INTERPRETATION: For people with atrial fibrillation and intracranial haemorrhage, oral anticoagulation had uncertain effects on the risk of any stroke or cardiovascular death (both overall and in subgroups), haemorrhagic major adverse cardiovascular events, and functional outcome. Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events, which can inform clinical practice. These findings should encourage recruitment to, and completion of, ongoing trials. FUNDING: British Heart Foundation.

The International Cardiac Arrest Research Consortium Electroencephalography Database.

OBJECTIVES: To develop the International Cardiac Arrest Research (I-CARE), a harmonized multicenter clinical and electroencephalography database for acute hypoxic-ischemic brain injury research involving patients with cardiac arrest. DESIGN: Multicenter cohort, partly prospective and partly retrospective. SETTING: Seven academic or teaching hospitals from the United States and Europe. PATIENTS: Individuals 16 years old or older who were comatose after return of spontaneous circulation following a cardiac arrest who had continuous electroencephalography monitoring were included. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: Clinical and electroencephalography data were harmonized and stored in a common Waveform Database-compatible format. Automated spike frequency, background continuity, and artifact detection on electroencephalography were calculated with 10-second resolution and summarized hourly. Neurologic outcome was determined at 3-6 months using the best Cerebral Performance Category (CPC) scale. This database includes clinical data and 56,676 hours (3.9 terabytes) of continuous electroencephalography data for 1,020 patients. Most patients died ( n = 603, 59%), 48 (5%) had severe neurologic disability (CPC 3 or 4), and 369 (36%) had good functional recovery (CPC 1-2). There is significant variability in mean electroencephalography recording duration depending on the neurologic outcome (range, 53-102 hr for CPC 1 and CPC 4, respectively). Epileptiform activity averaging 1 Hz or more in frequency for at least 1 hour was seen in 258 patients (25%) (19% for CPC 1-2 and 29% for CPC 3-5). Burst suppression was observed for at least 1 hour in 207 (56%) and 635 (97%) patients with CPC 1-2 and CPC 3-5, respectively. CONCLUSIONS: The I-CARE consortium electroencephalography database provides a comprehensive real-world clinical and electroencephalography dataset for neurophysiology research of comatose patients after cardiac arrest. This dataset covers the spectrum of abnormal electroencephalography patterns after cardiac arrest, including epileptiform patterns and those in the ictal-interictal continuum.

Evidence of rTMS for Motor or Cognitive Stroke Recovery: Hype or Hope?

BACKGROUND: Evidence of efficacy of repetitive transcranial magnetic stimulation (rTMS) for stroke recovery is hampered by an unexplained variability of reported effect sizes and an insufficient understanding of mechanisms of action. We aimed to (1) briefly summarize evidence of efficacy, (2) identify critical factors to explain the reported variation in effects, and (3) provide mechanism-based recommendations for future trials. METHODS: We performed a systematic review of the literature according to Cochrane and PRISMA Protocols. We included trials with ≥10 patients per treatment group. We classified outcome measures according to the International Classification of Functioning, Disability, and Health. Meta-analysis was done when at least 3 trials were reported on the same construct. In case of significant summary effect sizes with significant heterogeneity, we used sensitivity analyses to test for correlations and differences between found individual effect sizes and possible effect modifiers such as patient-, repetitive transcranial magnetic stimulation-, and trial characteristics. RESULTS: We included 57 articles (N=2595). Funnel plots showed no publication bias. We found significant effect sizes at the level of body function (upper limb synergies, muscle strength, language functioning, global cognitive functioning, visual/spatial inattention) with repetitive transcranial magnetic stimulation within or beyond 3 months after stroke. We also found significant effect sizes at the level of activities. We found no subgroup differences or significant correlations between individual summary effect sizes and any tested possible effect modifier. CONCLUSIONS: Repetitive transcranial magnetic stimulation holds the potential to benefit a range of motor and cognitive outcomes after stroke, but the evidence of efficacy is challenged by unexplained heterogeneity across many small sampled trials. We propose large trials with the collection of individual patient data on baseline severity and brain network integrity with sufficiently powered subgroup analyses, as well as protocolized time-locked training of the target behavior. Additional neurophysiological and biomechanical data may help in understanding mechanisms and identifying biomarkers of treatment efficacy. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: CRD42022300330.

The International Cardiac Arrest Research (I-CARE) Consortium Electroencephalography Database.

Objective: To develop a harmonized multicenter clinical and electroencephalography (EEG) database for acute hypoxic-ischemic brain injury research involving patients with cardiac arrest. Design: Multicenter cohort, partly prospective and partly retrospective. Setting: Seven academic or teaching hospitals from the U.S. and Europe. Patients: Individuals aged 16 or older who were comatose after return of spontaneous circulation following a cardiac arrest who had continuous EEG monitoring were included. Interventions: not applicable. Measurements and Main Results: Clinical and EEG data were harmonized and stored in a common Waveform Database (WFDB)-compatible format. Automated spike frequency, background continuity, and artifact detection on EEG were calculated with 10 second resolution and summarized hourly. Neurological outcome was determined at 3-6 months using the best Cerebral Performance Category (CPC) scale. This database includes clinical and 56,676 hours (3.9 TB) of continuous EEG data for 1,020 patients. Most patients died (N=603, 59%), 48 (5%) had severe neurological disability (CPC 3 or 4), and 369 (36%) had good functional recovery (CPC 1-2). There is significant variability in mean EEG recording duration depending on the neurological outcome (range 53-102h for CPC 1 and CPC 4, respectively). Epileptiform activity averaging 1 Hz or more in frequency for at least one hour was seen in 258 (25%) patients (19% for CPC 1-2 and 29% for CPC 3-5). Burst suppression was observed for at least one hour in 207 (56%) and 635 (97%) patients with CPC 1-2 and CPC 3-5, respectively. Conclusions: The International Cardiac Arrest Research (I-CARE) consortium database provides a comprehensive real-world clinical and EEG dataset for neurophysiology research of comatose patients after cardiac arrest. This dataset covers the spectrum of abnormal EEG patterns after cardiac arrest, including epileptiform patterns and those in the ictal-interictal continuum.

Handling missing values in the analysis of between-hospital differences in ordinal and dichotomous outcomes: a simulation study.

Missing data are frequently encountered in registries that are used to compare performance across hospitals. The most appropriate method for handling missing data when analysing differences in outcomes between hospitals with a generalised linear mixed model is unclear. We aimed to compare methods for handling missing data when comparing hospitals on ordinal and dichotomous outcomes. We performed a simulation study using data from the Multicentre Randomised Controlled Trial of Endovascular Treatment for Acute Ischaemic Stroke in the Netherlands (MR CLEAN) Registry, a prospective cohort study in 17 hospitals performing endovascular therapy for ischaemic stroke in the Netherlands. The investigated methods for handling missing data, both case-mix adjustment variables and outcomes, were complete case analysis, single imputation, multiple imputation, single imputation with deletion of imputed outcomes and multiple imputation with deletion of imputed outcomes. Data were generated as missing completely at random (MCAR), missing at random and missing not at random (MNAR) in three scenarios: (1) 10% missing data in case-mix and outcome; (2) 40% missing data in case-mix and outcome; and (3) 40% missing data in case-mix and outcome with varying degree of missing data among hospitals. Bias and reliability of the methods were compared on the mean squared error (MSE, a summary measure combining bias and reliability) relative to the hospital effect estimates from the complete reference data set. For both the ordinal outcome (ie, the modified Rankin Scale) and a common dichotomised version thereof, all methods of handling missing data were biased, likely due to shrinkage of the random effects. The MSE of all methods was on average lowest under MCAR and with fewer missing data, and highest with more missing data and under MNAR. The 'multiple imputation, then deletion' method had the lowest MSE for both outcomes under all simulated patterns of missing data. Thus, when estimating hospital effects on ordinal and dichotomous outcomes in the presence of missing data, the least biased and most reliable method to handle these missing data is 'multiple imputation, then deletion'.

Neurophysiology State Dynamics Underlying Acute Neurologic Recovery After Cardiac Arrest.

BACKGROUND AND OBJECTIVES: Epileptiform activity and burst suppression are neurophysiology signatures reflective of severe brain injury after cardiac arrest. We aimed to delineate the evolution of coma neurophysiology feature ensembles associated with recovery from coma after cardiac arrest. METHODS: Adults in acute coma after cardiac arrest were included in a retrospective database involving 7 hospitals. The combination of 3 quantitative EEG features (burst suppression ratio [BSup], spike frequency [SpF], and Shannon entropy [En]) was used to define 5 distinct neurophysiology states: epileptiform high entropy (EHE: SpF ≥4 per minute and En ≥5); epileptiform low entropy (ELE: SpF ≥4 per minute and <5 En); nonepileptiform high entropy (NEHE: SpF <4 per minute and ≥5 En); nonepileptiform low entropy (NELE: SpF <4 per minute and <5 En), and burst suppression (BSup ≥50% and SpF <4 per minute). State transitions were measured at consecutive 6-hour blocks between 6 and 84 hours after return of spontaneous circulation. Good neurologic outcome was defined as best cerebral performance category 1-2 at 3-6 months. RESULTS: One thousand thirty-eight individuals were included (50,224 hours of EEG), and 373 (36%) had good outcome. Individuals with EHE state had a 29% rate of good outcome, while those with ELE had 11%. Transitions out of an EHE or BSup state to an NEHE state were associated with good outcome (45% and 20%, respectively). No individuals with ELE state lasting >15 hours had good recovery. DISCUSSION: Transition to high entropy states is associated with an increased likelihood of good outcome despite preceding epileptiform or burst suppression states. High entropy may reflect mechanisms of resilience to hypoxic-ischemic brain injury.

Value of EEG in outcome prediction of hypoxic-ischemic brain injury in the ICU: A narrative review.

Prognostication of comatose patients after cardiac arrest aims to identify patients with a large probability of favourable or unfavouble outcome, usually within the first week after the event. Electroencephalography (EEG) is a technique that is increasingly used for this purpose and has many advantages, such as its non-invasive nature and the possibility to monitor the evolution of brain function over time. At the same time, use of EEG in a critical care environment faces a number of challenges. This narrative review describes the current role and future applications of EEG for outcome prediction of comatose patients with postanoxic encephalopathy.

Neuronal Responses to Ischemia: Scoping Review of Insights from Human-Derived In Vitro Models.

Translation of neuroprotective treatment effects from experimental animal models to patients with cerebral ischemia has been challenging. Since pathophysiological processes may vary across species, an experimental model to clarify human-specific neuronal pathomechanisms may help. We conducted a scoping review of the literature on human neuronal in vitro models that have been used to study neuronal responses to ischemia or hypoxia, the parts of the pathophysiological cascade that have been investigated in those models, and evidence on effects of interventions. We included 147 studies on four different human neuronal models. The majority of the studies (132/147) was conducted in SH-SY5Y cells, which is a cancerous cell line derived from a single neuroblastoma patient. Of these, 119/132 used undifferentiated SH-SY5Y cells, that lack many neuronal characteristics. Two studies used healthy human induced pluripotent stem cell derived neuronal networks. Most studies used microscopic measures and established hypoxia induced cell death, oxidative stress, or inflammation. Only one study investigated the effect of hypoxia on neuronal network functionality using micro-electrode arrays. Treatment targets included oxidative stress, inflammation, cell death, and neuronal network stimulation. We discuss (dis)advantages of the various model systems and propose future perspectives for research into human neuronal responses to ischemia or hypoxia.

Cognition, emotional state, and quality of life of survivors after cardiac arrest with rhythmic and periodic EEG patterns.

AIM: Rhythmic and periodic patterns (RPPs) on the electroencephalogram (EEG) in comatose patients after cardiac arrest have been associated with high case fatality rates. A good neurological outcome according to the Cerebral Performance Categories (CPC) has been reported in up to 10% of cases. Data on cognitive, emotional, and quality of life outcomes are lacking. We aimed to provide insight into these outcomes at one-year follow-up. METHODS: We assessed outcome of surviving comatose patients after cardiac arrest with RPPs included in the 'treatment of electroencephalographic status epilepticus after cardiopulmonary resuscitation' (TELSTAR) trial at one-year follow-up, including the CPC for functional neurological outcome, a cognitive assessment, the hospital anxiety and depression scale (HADS) for emotional outcomes, and the 36-item short-form health survey (SF-36) for quality of life. Cognitive impairment was defined as a score of more than 1.5 SD below the mean on ≥ 2 (sub)tests within a cognitive domain. RESULTS: Fourteen patients were included (median age 58 years, 21% female), of whom 13 had a cognitive impairment. Eleven of 14 were impaired in memory, 9/14 in executive functioning, and 7/14 in attention. The median scores on the HADS and SF-36 were all worse than expected. Based on the CPC alone, 8/14 had a good outcome (CPC 1-2). CONCLUSION: Nearly all cardiac arrest survivors with RPPs during the comatose state have cognitive impairments at one-year follow-up. The incidence of anxiety and depression symptoms seem relatively high and quality of life relatively poor, despite 'good' outcomes according to the CPC.

Preservation of thalamocortical circuitry is essential for good recovery after cardiac arrest.

Continuous electroencephalographam (EEG) monitoring contributes to prediction of neurological outcome in comatose cardiac arrest survivors. While the phenomenology of EEG abnormalities in postanoxic encephalopathy is well known, the pathophysiology, especially the presumed role of selective synaptic failure, is less understood. To further this understanding, we estimate biophysical model parameters from the EEG power spectra from individual patients with a good or poor recovery from a postanoxic encephalopathy. This biophysical model includes intracortical, intrathalamic, and corticothalamic synaptic strengths, as well as synaptic time constants and axonal conduction delays. We used continuous EEG measurements from hundred comatose patients recorded during the first 48 h postcardiac arrest, 50 with a poor neurological outcome [cerebral performance category ( CPC = 5 ) ] and 50 with a good neurological outcome ( CPC = 1 ). We only included patients that developed (dis-)continuous EEG activity within 48 h postcardiac arrest. For patients with a good outcome, we observed an initial relative excitation in the corticothalamic loop and corticothalamic propagation that subsequently evolved towards values observed in healthy controls. For patients with a poor outcome, we observed an initial increase in the cortical excitation-inhibition ratio, increased relative inhibition in the corticothalamic loop, delayed corticothalamic propagation of neuronal activity, and severely prolonged synaptic time constants that did not return to physiological values. We conclude that the abnormal EEG evolution in patients with a poor neurological recovery after cardiac arrest may result from persistent and selective synaptic failure that includes corticothalamic circuitry and also delayed corticothalamic propagation.

Endovascular treatment versus no endovascular treatment after 6-24 h in patients with ischaemic stroke and collateral flow on CT angiography (MR CLEAN-LATE) in the Netherlands: a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial.

BACKGROUND: Endovascular treatment for anterior circulation ischaemic stroke is effective and safe within a 6 h window. MR CLEAN-LATE aimed to assess efficacy and safety of endovascular treatment for patients treated in the late window (6-24 h from symptom onset or last seen well) selected on the basis of the presence of collateral flow on CT angiography (CTA). METHODS: MR CLEAN-LATE was a multicentre, open-label, blinded-endpoint, randomised, controlled, phase 3 trial done in 18 stroke intervention centres in the Netherlands. Patients aged 18 years or older with ischaemic stroke, presenting in the late window with an anterior circulation large-vessel occlusion and collateral flow on CTA, and a neurological deficit score of at least 2 on the National Institutes of Health Stroke Scale were included. Patients who were eligible for late-window endovascular treatment were treated according to national guidelines (based on clinical and perfusion imaging criteria derived from the DAWN and DEFUSE-3 trials) and excluded from MR CLEAN-LATE enrolment. Patients were randomly assigned (1:1) to receive endovascular treatment or no endovascular treatment (control), in addition to best medical treatment. Randomisation was web based, with block sizes ranging from eight to 20, and stratified by centre. The primary outcome was the modified Rankin Scale (mRS) score at 90 days after randomisation. Safety outcomes included all-cause mortality at 90 days after randomisation and symptomatic intracranial haemorrhage. All randomly assigned patients who provided deferred consent or died before consent could be obtained comprised the modified intention-to-treat population, in which the primary and safety outcomes were assessed. Analyses were adjusted for predefined confounders. Treatment effect was estimated with ordinal logistic regression and reported as an adjusted common odds ratio (OR) with a 95% CI. This trial was registered with the ISRCTN, ISRCTN19922220. FINDINGS: Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned, and 502 (94%) patients provided deferred consent or died before consent was obtained (255 in the endovascular treatment group and 247 in the control group; 261 [52%] females). The median mRS score at 90 days was lower in the endovascular treatment group than in the control group (3 [IQR 2-5] vs 4 [2-6]), and we observed a shift towards better outcomes on the mRS for the endovascular treatment group (adjusted common OR 1·67 [95% CI 1·20-2·32]). All-cause mortality did not differ significantly between groups (62 [24%] of 255 patients vs 74 [30%] of 247 patients; adjusted OR 0·72 [95% CI 0·44-1·18]). Symptomatic intracranial haemorrhage occurred more often in the endovascular treatment group than in the control group (17 [7%] vs four [2%]; adjusted OR 4·59 [95% CI 1·49-14·10]). INTERPRETATION: In this study, endovascular treatment was efficacious and safe for patients with ischaemic stroke caused by an anterior circulation large-vessel occlusion who presented 6-24 h from onset or last seen well, and who were selected on the basis of the presence of collateral flow on CTA. Selection of patients for endovascular treatment in the late window could be primarily based on the presence of collateral flow. FUNDING: Collaboration for New Treatments of Acute Stroke consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.

Timing and causes of death after endovascular thrombectomy in patients with acute ischemic stroke.

Introduction: Endovascular thrombectomy (EVT) increases the chance of good functional outcome after ischemic stroke caused by a large vessel occlusion, but the risk of death in the first 90 days is still considerable. We assessed the causes, timing and risk factors of death after EVT to aid future studies aiming to reduce mortality. Patients and methods: We used data from the MR CLEAN Registry, a prospective, multicenter, observational cohort study of patients treated with EVT in the Netherlands between March 2014, and November 2017. We assessed causes and timing of death and risk factors for death in the first 90 days after treatment. Causes and timing of death were determined by reviewing serious adverse event forms, discharge letters, or other written clinical information. Risk factors for death were determined with multivariable logistic regression. Results: Of 3180 patients treated with EVT, 863 (27.1%) died in the first 90 days. The most common causes of death were pneumonia (215 patients, 26.2%), intracranial hemorrhage (142 patients, 17.3%), withdrawal of life-sustaining treatment because of the initial stroke (110 patients, 13.4%) and space-occupying edema (101 patients, 12.3%). In total, 448 patients (52% of all deaths) died in the first week, with intracranial hemorrhage as most frequent cause. The strongest risk factors for death were hyperglycemia and functional dependency before the stroke and severe neurological deficit at 24-48 h after treatment. Discussion and conclusion: When EVT fails to decrease the initial neurological deficit, strategies to prevent complications like pneumonia and intracranial hemorrhage after EVT could improve survival, as these are often the cause of death.