Safety and pharmacodynamic efficacy of eculizumab in aneurysmal subarachnoid hemorrhage (CLASH): A phase 2a randomized clinical trial.

INTRODUCTION: Complement C5 antibodies reduce brain injury after experimental subarachnoid hemorrhage. PATIENTS AND METHODS: In this randomized, controlled, open-label, phase 2a clinical trial with blinded-outcome assessment, we included adult aneurysmal subarachnoid hemorrhage (aSAH) patients admitted to a tertiary referral center ⩽11 h after ictus. Patients were randomized (1:1) to eculizumab plus care as usual or to care as usual. Eculizumab (1200 mg) was administered <12 h, and on days 3 and 7 after ictus. In the intervention group, all patients received prophylactic antibiotics and, after a protocol amendment, fluconazole if indicated. Primary outcome was C5a concentration in cerebrospinal fluid (CSF) on day 3 after ictus. Safety was monitored during 4 weeks. In each group, 13 patients with CSF assessments were needed to detect a 55% reduction in CSF C5a concentration. RESULTS: From October 2018 to May 2021, we enrolled 31 patients of whom 26 with CSF samples, 13 per group. Median C5a concentration in CSF on day 3 was 251 pg/ml [IQR: 103-402] in the intervention group and 371 pg/ml [IQR: 131-534] in the control group (p = 0.29). Infections occurred in two patients in the intervention group and four patients in the control group. One patient in the intervention group developed a C. albicans meningitis prior to the protocol amendment. DISCUSSION AND CONCLUSION: One dose of eculizumab did not result in a ⩾ 55% decrease in C5a concentration in CSF on day 3 after aSAH. The study did not reveal new safety concerns, except for a C. albicans drain-related infection prior to antifungal monitoring and treatment. TRIAL REGISTRATION: EudraCT 2017-004307-51, https://www.clinicaltrialsregister.eu/.

Glial cell response and microthrombosis in aneurysmal subarachnoid hemorrhage patients: An autopsy study.

Neuroinflammation and microthrombosis may be underlying mechanisms of brain injury after aneurysmal subarachnoid hemorrhage (aSAH), but they have not been studied in relation to each other. In postmortem brain tissue, we investigated neuroinflammation by studying the microglial and astrocyte response in the frontal cortex of 11 aSAH and 10 control patients. In a second study, we investigated the correlation between microthrombosis and microglia by studying the microglial surface area around vessels with and without microthrombosis in the frontal cortex and hippocampus of 8 other aSAH patients. In comparison with controls, we found increased numbers of microglia (mean ± SEM 50 ± 8 vs 20 ± 5 per 0.0026 mm³, p < 0.01), an increased surface area (%) of microglia (mean ± SEM 4.2 ± 0.6 vs 2.2 ± 0.4, p < 0.05), a higher intensity of the astrocytic intermediate filament protein glial fibrillary acidic protein (GFAP) (mean ± SEM 184 ± 28 vs 92 ± 23 arbitrary units, p < 0.05), and an increased GFAP surface area (%) (mean ± SEM 21.2 ± 2.6 vs 10.7 ± 2.1, p < 0.01) in aSAH tissue. Microglia surface area was approximately 40% larger around vessels with microthrombosis than those without microthrombosis (estimated marginal means [95% CI]; 6.1 [5.4-6.9] vs 4.3 [3.6-5.0], p < 0.001). Our results show that the microglial and astrocyte surface areas increased after aSAH and that microthrombosis and microglia are interrelated.

Devastating delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage.

Background: We investigated the proportion of patients in an initial good clinical condition who developed devastating DCI, and aimed to characterize these patients by aneurysm location, blood pressure instability prior to DCI, and the extent of cerebral ischemia. Methods: We included aSAH patients admitted between 2010 and 2021 with a Glasgow Coma Scale of 11 or higher 24 h after aneurysm treatment, who developed devastating DCI, defined as DCI leading to coma for at least 48 h with cerebral infarction on the subsequent scan. Blood pressure instability was defined as nimodipine-induced blood pressure drops, dosage adjustments, or the use of blood pressure drugs before onset of DCI. Descriptive statistics were used to summarize the data. Results: Out of 1,211 consecutive aSAH patients, 617 patients had a good clinical condition after aneurysm treatment of whom 16 (3%) patients [14 (88%) women] were included in this study. Thirteen (81%) patients had an aneurysm in the anterior circulation. Thirteen patients (81%) had blood pressure instability: twelve (75%) had nimodipine-induced blood pressure drops, eleven (69%) received antihypertensive drugs, and 7 (44%) received hypertension induction before onset of DCI. Thirteen (81%) patients had bilateral ischemia, mainly in the anterior circulation (56%). Conclusions: The proportion of aSAH patients with a good clinical condition after aneurysm treatment who develop devastating DCI is small. The vast majority of these patients had blood pressure instability. Future studies are needed to investigate if a reduction in the number and extent of blood pressure fluctuations decreases the incidence of devastating DCI.

Rebleeding After Aneurysmal Subarachnoid Hemorrhage in Two Centers Using Different Blood Pressure Management Strategies.

Background: High systolic blood pressure (SBP) after aneurysmal subarachnoid hemorrhage (aSAH) has been associated with an increased risk of rebleeding. It remains unclear if an SBP lowering strategy before aneurysm treatment decreases this risk without increasing the risk of a delayed cerebral ischemia (DCI). Therefore, we compared the rates of in-hospital rebleeding and DCI among patients with aSAH admitted in two tertiary care centers with different SBP management strategies. Methods: Retrospective cohort study. Consecutive patients from Utrecht and Toulouse admitted within 24 h after the aSAH onset were enrolled. In Toulouse, the target SBP before aneurysm treatment was ≤140 mm Hg, while, in Utrecht, an increased SBP was only treated in extreme situations. We compared SBP levels, the incidence of rebleeding within 24 h after admission, and DCI during hospitalization. Results: We enrolled 373 patients in Utrecht and 149 in Toulouse. The mean SBP on admission was similar but lower in Toulouse 4 h after admission (127.3 ± 17.4 vs. 138. ± 25.7 mmHg; p < 0.0001). After a median delay of 3.7 h (IQR, 2.3-7.4) from admission, 4 patients (3%) in Toulouse vs. 29 (8%) in Utrecht experienced a rebleeding. After adjustment for Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage (PAASH) score, aneurysm size, age, and delay from ictus to admission, the HR was 0.66 (95% CI: 0.23-1.92). Incidence of DCI was 18% in Toulouse and 25% in Utrecht (adjusted OR, 0.68; 95% CI: 0.41-1.11). Conclusion: Our results suggest that an intensive SBP lowering strategy between admission and aneurysm treatment does not decrease the risk of rebleeding and does not increase the risk of DCI compared to a more conservative strategy.

Deferred Consent in an Acute Stroke Trial from a Patient, Proxy, and Physician Perspective: A Cross-Sectional Survey.

BACKGROUND: In some acute care trials, immediate informed consent is not possible, but deferred consent is often considered problematic. We investigated the opinions of patients, proxies, and physicians about deferred consent in an acute stroke trial to gain insight into its acceptability and effects. METHODS: Paper-based surveys were sent to patients who were randomly assigned in the Ultra-early Tranexamic Acid After Subarachnoid Hemorrhage (ULTRA) trial between 2015 and 2018 in two tertiary referral centers and to physicians of centers who agreed or declined to participate. The primary outcome measure was the proportion of respondents who agreed with deferral of consent in the ULTRA trial. Secondary outcomes included respondents' preferred consent procedure for the ULTRA trial, the effect of deferred consent on trust in physicians and scientific research, and the willingness to participate in future research. RESULTS: Eighty-nine of 135 (66%) patients or proxies and 20 of 30 (67%) physicians completed the survey. Of these, 82 of 89 (92%) patients or proxies and 14 of 20 (70%) physicians agreed with deferral of consent in the ULTRA trial. When asked for their preferred consent procedure for the ULTRA trial, 31 of 89 (35%) patients or proxies indicated deferred consent, 15 of 89 (17%) preferred immediate informed consent, and 32 of 89 (36%) had no preference. None of the patients' or proxies' trust in physicians or scientific research had decreased because of the deferred consent procedure. Willingness to participate in future studies remained the same or increased in 84 of 89 (94%) patients or proxies. CONCLUSIONS: A large majority of the surveyed patients and proxies and a somewhat smaller majority of the surveyed physicians agreed with deferred consent in the ULTRA trial. Deferred consent may enable acute care trials in an acceptable manner without decreasing trust in medicine. Future research should investigate factors facilitating the responsible use of deferred consent, such as in-depth interviews, to study the minority of participants who agreed with deferred consent but still preferred immediate informed consent.

CompLement C5 Antibodies for decreasing brain injury after aneurysmal Subarachnoid Haemorrhage (CLASH): study protocol for a randomised controlled phase II clinical trial.

BACKGROUND: The inflammatory response after aneurysmal subarachnoid haemorrhage (aSAH) has been associated with early brain injury, delayed cerebral ischaemia, poor functional outcome, and case fatality. In experimental SAH studies, complement C5 antibodies administered shortly after SAH reduced brain injury with approximately 40%. Complement component C5 may be a new therapeutic target to reduce brain injury and hereby improve the outcome after aSAH. We aim to investigate the pharmacodynamic efficacy and safety of eculizumab (complement C5 antibody) in patients with aSAH. METHODS: A randomised, controlled, open-label, phase II clinical trial with blinded outcome assessment. Eculizumab (1200 mg) is administered intravenously < 12 h, on day 3 and on day 7 after ictus. Patients in the intervention group receive prophylactic antibiotics for 4 weeks, and those with a central line or an external ventricular shunt and a positive fungal or yeast culture also receive prophylactic antifungal therapy for 4 weeks. The primary outcome is C5a concentration in the cerebrospinal fluid (CSF) on day 3 after ictus. Secondary outcomes include the occurrence of adverse events, inflammatory parameters in the blood and CSF, cerebral infarction on magnetic resonance imaging, and clinical and cognitive outcomes. We aim to evaluate 26 patients with CSF assessments, 13 in the intervention group and 13 in the comparator group. To compensate for early case fatality and inability to obtain CSF, we will include 20 patients per group. DISCUSSION: The CLASH trial is the first trial to investigate the pharmacodynamic efficacy and safety of eculizumab in the early phase after aSAH. TRIAL REGISTRATION: Netherlands Trial Register NTR6752 . Registered on 27 October 2017 European Clinical Trials Database (EudraCT) 2017-004307-51.

The course of cerebrospinal fluid parameters ≤ 20 days after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) patients have an inflammatory response in the cerebrospinal fluid (CSF). We determined CSF cell counts, erythrocyte/leukocyte ratio, and glucose- and protein concentrations in patients ≤20 days after aSAH without bacterial meningitis. Such knowledge may help to interpret CSF parameters in patients with an external drain if nosocomial bacterial meningitis or ventriculitis is suspected. METHODS: Patients with aSAH admitted between 2010 and 2017 with at least one CSF sample ≤ 20 days after ictus were included from a prospectively collected database. CSF samples were excluded if the patient used antibiotics or if the CSF culture was positive. We calculated estimated marginal means with 95% confidence intervals (CIs) with linear mixed models for CSF cell counts, glucose- and protein concentrations. RESULTS: We included 209 patients with 306 CSF samples. Highest estimated median leukocyte count was 305 (95%CI:225-412) x10^6/L, and the lowest estimated median erythrocyte/leukocyte ratio was 109 (95%CI:73-163). Estimated mean glucose concentrations remained within the normal range. The estimated median protein concentration decreased from 3.3 g/L (95%CI:2.5-4.2) on day 0 to 1.0 g/L (95%CI:0.8-1.2) on day 14. CONCLUSION: The limits we found for the inflammatory reaction in aSAH patients may help physicians to interpret CSF parameters in aSAH patients with an external CSF drain. Future studies are needed to compare CSF parameters in aSAH patients with and without bacterial meningitis or ventriculitis.

Aneurysm characteristics and risk of rebleeding after subarachnoid haemorrhage.

INTRODUCTION: Knowledge of risk factors for rebleeding after aneurysmal subarachnoid haemorrhage can help tailoring ultra-early aneurysm treatment. Previous studies have identified aneurysm size and various patient-related risk factors for early (≤24 h) rebleeding, but it remains unknown if aneurysm configuration is also a risk factor. We investigated whether irregular shape, aspect- and bottleneck ratio of the aneurysm are independent risk factors for early rebleeding after aneurysmal subarachnoid haemorrhage. PATIENTS AND METHODS: From a prospectively collected institutional database, we investigated data from consecutive aneurysmal subarachnoid haemorrhage patients who were admitted ≤24 h after onset between December 2009 and January 2015. The admission computed tomographic angiogram was used to assess aneurysm size and configuration. With Cox regression, we calculated stepwise-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for irregular shape, aspect ratio ≥1.6 mm and bottleneck ratio ≥1.6 mm. RESULTS: Of 409 included patients, 34 (8%) patients had in-hospital rebleeding ≤24 h after ictus. Irregular shape was an independent risk factor for rebleeding (HR: 3.9, 95% CI: 1.3-11.3) after adjustment for age, sex, PAASH score, aneurysm location, aneurysm size and aspect- and bottleneck ratio. Aspect ratio ≥1.6 mm (HR: 2.3, 95% CI: 0.8-6.5) and bottleneck ratio ≥1.6 mm (HR: 1.7, 95% CI: 0.8-3.6) were associated with an increased risk of rebleeding, but were not independent risk factors after multivariable adjustment. CONCLUSIONS: Irregular shape is an independent risk factor for early rebleeding. However, since the majority of subarachnoid haemorrhage patients have an irregular aneurysm, additional risk factors have to be found for aneurysm treatment prioritisation.

Early skin-to-skin contact for healthy full-term infants after vaginal and caesarean delivery: a qualitative study on clinician perspectives.

AIMS AND OBJECTIVES: This study aims to provide insight into key factors from a clinician's perspective that influence uninterrupted early skin-to-skin contact after vaginal and caesarean delivery of healthy full-term infants. BACKGROUND: Early skin-to-skin contact of healthy full-term infants ideally begins immediately after birth and continues for the first hour or the first breastfeed as recommended by the Baby Friendly Hospital Initiative. However, adoption of early skin-to-skin contact is low in many settings and the barriers that hinder its universal use are not well understood. DESIGN: An exploratory qualitative research design using semi-structured interviews. METHODS: Eleven clinicians were interviewed, including five registered nurses and one medical doctor from the obstetrics and gynaecology unit as well as four registered nurses and one medical doctor from the neonatal intensive care unit. Core topics that were discussed included perceptions on early skin-to-skin contact and facilitating factors and barriers to early skin-to-skin contact after vaginal and caesarean delivery. Interview sessions were recorded, transcribed and analysed using a thematic analysis approach. A coding framework was developed from which subthemes emerged. The overall themes were adopted from Lee et al.'s thematic framework to categorise factors into institutional, familial-level and implementation factors. FINDINGS: Critical institutional factors included inadequate staffing and education of clinicians on early skin-to-skin contact. On a familial level, parental education and motivation were identified as important factors. Barriers to implementation included the absence of a clinical algorithm and unclear definitions for eligible mothers and infants. CONCLUSIONS: Various facilitating factors and barriers to early skin-to-skin contact of healthy full-term infants born via vaginal and caesarean delivery were identified. RELEVANCE TO CLINICAL PRACTICE: Addressing these factors can help to provide a better understanding of clinician perspectives on early skin-to-skin contact and help guide its implementation as standard of care for healthy full-term infants.