CompLement C5 Antibodies for decreasing brain injury after aneurysmal Subarachnoid Haemorrhage (CLASH): study protocol for a randomised controlled phase II clinical trial.
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ABSTRACT:
SUBMITTER: Koopman I
PROVIDER: S-EPMC7687754 | biostudies-literature | 2020 Nov
REPOSITORIES: biostudies-literature
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CompLement C5 Antibodies for decreasing brain injury after aneurysmal Subarachnoid Haemorrhage (CLASH): study protocol for a randomised controlled phase II clinical trial.
Koopman Inez I Rinkel Gabriel J E GJE Vergouwen Mervyn D I MDI
Trials 20201125 1
<h4>Background</h4>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 pharmacodyn ...[more]
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Project description:BACKGROUND:Magnesium sulphate is a neuroprotective agent that might improve outcome after aneurysmal subarachnoid haemorrhage by reducing the occurrence or improving the outcome of delayed cerebral ischaemia. We did a trial to test whether magnesium therapy improves outcome after aneurysmal subarachnoid haemorrhage. METHODS:We did this phase 3 randomised, placebo-controlled trial in eight centres in Europe and South America. We randomly assigned (with computer-generated random numbers, with permuted blocks of four, stratified by centre) patients aged 18 years or older with an aneurysmal pattern of subarachnoid haemorrhage on brain imaging who were admitted to hospital within 4 days of haemorrhage, to receive intravenous magnesium sulphate, 64 mmol/day, or placebo. We excluded patients with renal failure or bodyweight lower than 50 kg. Patients, treating physicians, and investigators assessing outcomes and analysing data were masked to the allocation. The primary outcome was poor outcome-defined as a score of 4-5 on the modified Rankin Scale-3 months after subarachnoid haemorrhage, or death. We analysed results by intention to treat. We also updated a previous meta-analysis of trials of magnesium treatment for aneurysmal subarachnoid haemorrhage. This study is registered with controlled-trials.com (ISRCTN 68742385) and the EU Clinical Trials Register (EudraCT 2006-003523-36). FINDINGS:1204 patients were enrolled, one of whom had his treatment allocation lost. 606 patients were assigned to the magnesium group (two lost to follow-up), 597 to the placebo (one lost to follow-up). 158 patients (26·2%) had poor outcome in the magnesium group compared with 151 (25·3%) in the placebo group (risk ratio [RR] 1·03, 95% CI 0·85-1·25). Our updated meta-analysis of seven randomised trials involving 2047 patients shows that magnesium is not superior to placebo for reduction of poor outcome after aneurysmal subarachnoid haemorrhage (RR 0·96, 95% CI 0·86-1·08). INTERPRETATION:Intravenous magnesium sulphate does not improve clinical outcome after aneurysmal subarachnoid haemorrhage, therefore routine administration of magnesium cannot be recommended. FUNDING:Netherlands Heart Foundation, UK Medical Research Council.
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Project description:Haptoglobin is the body's first line of defence against the toxicity of extracellular haemoglobin released following a subarachnoid haemorrhage (SAH). We investigated the haptoglobin response after SAH in cerebrospinal fluid (CSF) and serum. Paired CSF and serum samples from 19 controls and 92 SAH patients were assayed as follows: ultra-performance liquid chromatography for CSF haemoglobin and haptoglobin, immunoassay for serum haptoglobin and multiplexed CSF cytokines, and colorimetry for albumin. There was marked CSF haptoglobin deficiency: 99% of extracellular haemoglobin was unbound. The quotients for both CSF/serum albumin (qAlb) and haptoglobin (qHp) were used to compute the CSF haptoglobin index (qHp/qAlb). CSF from SAH patients had a significantly lower haptoglobin index compared to controls, especially in Haptoglobin-1 allele carriers. Serum haptoglobin levels increased after SAH and were correlated with CSF cytokine levels. Haptoglobin variables were not associated with long-term clinical outcomes post-SAH. We conclude that: (1) intrathecal haptoglobin consumption occurs after SAH, more so in haptoglobin-1 allele carriers; (2) serum haptoglobin is upregulated after SAH, in keeping with the liver acute phase response to central inflammation; (3) haptoglobin in the CSF is so low that any variation is too small for this to affect long-term outcomes, emphasising the potential for therapeutic haptoglobin supplementation.
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Project description:The first 72 h following aneurysm rupture play a key role in determining clinical and cognitive outcomes after subarachnoid haemorrhage (SAH). Yet, very little is known about the impact of so called "early brain injury" on patents with clinically good grade SAH (as defined as World Federation of Neurosurgeons Grade 1 and 2). 27 patients with good grade SAH underwent MRI scanning were prospectively recruited at three time-points after SAH: within the first 72 h (acute phase), at 5-10 days and at 3 months. Patients underwent additional, comprehensive cognitive assessment 3 months post-SAH. 27 paired healthy controls were also recruited for comparison. In the first 72 h post-SAH, patients had significantly higher global and regional brain volume than controls. This change was accompanied by restricted water diffusion in patients. Persisting abnormalities in the volume of the posterior cerebellum at 3 months post-SAH were present to those patients with worse cognitive outcome. When using this residual abnormal brain area as a region of interest in the acute-phase scans, we could predict with an accuracy of 84% (sensitivity 82%, specificity 86%) which patients would develop cognitive impairment 3 months later, despite initially appearing clinically indistinguishable from those making full recovery. In an exploratory sample of good clinical grade SAH patients compared to healthy controls, we identified a region of the posterior cerebellum for which acute changes on MRI were associated with cognitive impairment. Whilst further investigation will be required to confirm causality, use of this finding as a risk stratification biomarker is promising.
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Project description:IntroductionSeizures are a common complication that leads to neurological deficits and affects outcomes after aneurysmal subarachnoid haemorrhage (aSAH). However, whether to use prophylactic anticonvulsants in patients with aSAH remains controversial. Our study aims to determine whether short-term (7 days) sodium valproate could prevent seizure occurrence and improve neurological function in patients with SAH caused by anterior circulation aneurysm rupture and treated with clipping.Methods and analysisIn this multicentre randomised evaluator-blind placebo-controlled trial, 182 eligible patients with good-grade aSAH planned for surgical clipping will be enrolled from four neurosurgical centres in China. In addition to standard care, patients will be randomly assigned to receive sodium valproate 20 mg/kg daily or matching placebo. After aneurysmal clipping, patients will be followed up at discharge, 90 days and 180 days. The primary outcomes are the incidence of early and late seizures. The secondary outcomes include aSAH-related complications, sodium valproate-related adverse effects, modified Rankin Scale (mRS) (on discharge, at 90 days, 180 days), rate of good outcome (defined as mRS 0-2), all-cause death (at 90 days, 180 days) and Montreal Cognitive Assessment score (at 180 days). All analyses are by intention-to-treat.Ethics and disseminationThis study will be conducted according to the principles of Declaration of Helsinki and good clinical practice guidelines. This trial involves human participants and has been approved by the ethics committee of West China Hospital. Informed consent will be achieved from each included patient and/or their legally authorised representative. Preliminary and final results from this study will be disseminated through manuscript publishing and international congresses presentations. Any protocol amendments will be approved by the ethics committee of West China Hospital and subsequently updated on ChiCTR.Trial registration numberChiCTR.org identifier: ChiCTR2100050161.
| S-EPMC9073395 | biostudies-literature
Project description:The prognosis of patients with aneurysmal subarachnoid haemorrhage requiring decompressive craniectomy is usually poor. Proper selection and early performing of decompressive craniectomy might improve the patients' outcome. We aimed at developing a risk score for prediction of decompressive craniectomy after aneurysmal subarachnoid haemorrhage. All consecutive aneurysmal subarachnoid haemorrhage cases treated at the University Hospital of Essen between January 2003 and June 2016 (test cohort) and the University Medical Center Freiburg between January 2005 and December 2012 (validation cohort) were eligible for this study. Various parameters collected within 72 h after aneurysmal subarachnoid haemorrhage were evaluated through univariate and multivariate analyses to predict separately primary (PrimDC) and secondary decompressive craniectomy (SecDC). The final analysis included 1376 patients. The constructed risk score included the following parameters: intracerebral ('Parenchymal') haemorrhage (1 point), 'Rapid' vasospasm on angiography (1 point), Early cerebral infarction (1 point), aneurysm Sac > 5 mm (1 point), clipping (' S urgery', 1 point), age U nder 55 years (2 points), Hunt and Hess grade ≥ 4 ('Reduced consciousness', 1 point) and External ventricular drain (1 point). The PRESSURE score (0-9 points) showed high diagnostic accuracy for the prediction of PrimDC and SecDC in the test (area under the curve = 0.842/0.818) and validation cohorts (area under the curve = 0.903/0.823), respectively. 63.7% of the patients scoring ≥6 points required decompressive craniectomy (versus 12% for the PRESSURE < 6 points, P < 0.0001). In the subgroup of the patients with the PRESSURE ≥6 points and absence of dilated/fixed pupils, PrimDC within 24 h after aneurysmal subarachnoid haemorrhage was independently associated with lower risk of unfavourable outcome (modified Rankin Scale >3 at 6 months) than in individuals with later or no decompressive craniectomy (P < 0.0001). Our risk score was successfully validated as reliable predictor of decompressive craniectomy after aneurysmal subarachnoid haemorrhage. The PRESSURE score might present a background for a prospective randomized clinical trial addressing the utility of early prophylactic decompressive craniectomy in aneurysmal subarachnoid haemorrhage.
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Project description: Not available
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Project description:ObjectiveThe objective of the study was to assess the long-term self-reported health status and quality of life (QoL) of patients following an aneurysmal subarachnoid haemorrhage (ASAH) using a self-completed questionnaire booklet.DesignA two-cohort study.SettingA regional tertiary neurosurgical centre.Participants2 cohorts of patients with ASAH treated between 1998 and 2008 and followed up at approximately 1 year.InterventionsRoutine care.Primary and secondary outcomesA range of standardised scales included: AKC Short Sentences Test, the Barthel Index, the Self-Report Dysexecutive Questionnaire, the Everyday Memory Questionnaire, Stroke Symptom Checklist, Wimbledon Self-Report Scale, Modified Rankin Score (MRS) and a new Stroke-QoL. The data from summated scales were fit to the Rasch measurement model to validate the summed score.Results214 patients (48%) returned the questionnaires; the majority (76%) had a World Federation of Neurosurgeons grade of 1 or 2. The most frequent aneurysm type was that of the anterior communicating artery (28%) with approximately 90% of aneurysms of the anterior circulation. Of those previously in full or part-time employment, 48.9% were unemployed at follow-up. All summated scales satisfied the Rasch measurement model requirements, such that their summed scores were a sufficient statistic. Given this, one-third of patients were noted to have a significant mood disorder and 25% had significant dysexecutive function. Patients with an MRS of 3, 4 or 5 had significantly worse scores on most outcome measures, but a significant minority of those with a score of zero had failed to return to work and displayed significant mood disorder.ConclusionsA range of self-reported cognitive and physical deficits have been highlighted in a cohort of patients with ASAH. While the MRS has been shown to provide a reasonable indication of outcome, in routine clinical follow-up it requires supplementation by instruments assessing dysexecutive function, memory and mood.
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Project description:BACKGROUND:Emotional health disturbances are common after aneurysmal subarachnoid hemorrhage (aSAH) and their causes are largely unexplored. Corticotropin-releasing hormone receptor 1 (CRHR1) is a key factor in stress reactivity and development of mental health disturbances after adverse life-events. METHODS:We explore the effect of CRHR1 genotype on mental health after aSAH in a retrospective cohort study. One hundred twenty-five patients have been assessed using EST-Q mental health questionnaire. Genotyping of CRHR1 single nucleotide polymorphisms (SNP-s) was performed (Rs7209436, Rs110402, Rs242924). RESULTS:Fatigue was present in almost half of aSAH patients, depression and anxiety in one-third. There was a high prevalence of insomnia and panic complaints. Rs110402 minor allele decreased the risk of depression (OR = 0.25, p = 0.027 for homozygotes). Depression was present in 14% vs 41% in minor and major allele homozygotes, respectively. Rs110402, Rs242924 and Rs7209436 minor alleles and TAT-haplotype, formed by them, were protective against fatigue. After Bonferroni correction only the association of Rs110402 with fatigue remained statistically significant (OR = 0.21, p = 0.006 for minor allele homozygotes). Results remained statistically significant when adjusted for gender, admission state, age and time from aSAH. In multiple regression analysis occurrence of fatigue was dependent on anxiety, modified Rankin score and Rs110402 genotype (R2 = 0.34, p < 0.001). CONCLUSIONS:CRHR1 minor genotype was associated with a lower risk of fatigue and depression after aSAH. Genetic predisposition to mental health disturbances associated with negative life-events could be a risk factor for fatigue and depression after aSAH and selected patients might benefit from advanced counselling in the recovery phase.
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