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Clazosentan, an endothelin receptor antagonist, significantly and dose-dependently reduced angiographic vasospasm after aneurysmal subarachnoid haemorrhage (aSAH). We investigated whether clazosentan reduced vasospasm-related morbidity and all-cause mortality. In this randomised, double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with aSAH secured by surgical clipping to clazosentan (5 mg/h, n=768) or placebo (n=389) for up to 14 days (27 countries, 102 sites, inpatient and outpatient settings) using an interactive web response system. The primary composite endpoint (week 6) included all-cause mortality, vasospasm-related new cerebral infarcts, delayed ischaemic neurological deficit due to vasospasm, and rescue therapy for vasospasm. The main secondary endpoint was dichotomised extended Glasgow outcome scale (GOSE; week 12). This trial is registered with ClinicalTrials.gov, number NCT00558311. In the all-treated dataset, the primary endpoint was met in 161 (21%) of 764 clazosentan-treated patients and 97 (25%) of 383 placebo-treated patients (relative risk reduction 17%, 95% CI −4 to 33; p=0·10). Poor functional outcome (GOSE score ≤4) occurred in 224 (29%) clazosentan-treated patients and 95 (25%) placebo-treated patients (−18%, −45 to 4; p=0·10). Lung complications, anaemia, and hypotension were more common with clazosentan. Mortality (week 12) was 6% in both groups. Clazosentan at 5 mg/h had no significant effect on mortality and vasospasm-related morbidity or functional outcome. Further investigation of patients undergoing endovascular coiling of ruptured aneurysms is needed to fully understand the potential usefulness of clazosentan in patients with aSAH. Actelion Pharmaceuticals.

Background Vasospasms are common in patients presenting with non-traumatic subarachnoid haemorrhage (SAH) and are the main contributor to long-term disability or death in these patients. The key immediate management of vasospasms is the improvement of brain perfusion by the administration of intravenous fluid and vasopressors if needed. Yet, there is no clear recommendation regarding the choice of fluid in this particular patient population. Data suggests a survival benefit using normal saline in patients with TBI; however, its impact on outcomes in patients with SAH is lacking. Thus, the aim of this study is to evaluate whether the use of normal saline reduces clinically relevant vasospasms compared to Ringer’s lactate in patients with SAH. Methods Patients presenting with non-traumatic SAH will be randomised 1:1 to normal saline or Ringer’s lactate group. Blinded study fluid will be used exclusively for resuscitation and maintenance until ICU/IMC discharge or a maximum of 14 days, whichever occurs first. Management of vasospasms and general management of the SAH patient will be according to the clinic standard of care. Primary endpoint is the occurrence of clinically relevant vasospasms. Key secondary outcomes include mortality, severity and treatment of vasospasms, and neurological outcomes at 90 days. Discussion The proposed randomised controlled trial offers a safe, non-invasive way to gain insights about crystalloid fluid choice in SAH patients, with potential to improve outcomes in this critically ill patient group. This study could establish a new gold standard in fluid therapy for neuro-critical care. Trial registration The trial is registered on ClinicalTrials.gov (date of registration 18 June 2021) and on the Swiss National Clinical Trials Portal, SNCTP000004575.

Background Intravenous (IV) milrinone, in combination with induced hypertension, has been proposed as a treatment option for cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH). However, data on its safety and efficacy are scarce. Methods This was a controlled observational study conducted in an academic hospital with prospectively and retrospectively collected data. Consecutive patients with cerebral vasospasm following aSAH and treated with both IV milrinone (0.5 µg/kg/min −1 , as part of a strict protocol) and induced hypertension were compared with a historical control group receiving hypertension alone. Multivariable analyses aimed at minimizing potential biases. We assessed (1) 6-month functional disability (defined as a score between 2 and 6 on the modified Rankin Scale) and vasospasm-related brain infarction, (2) the rate of first-line or rescue endovascular angioplasty for vasospasm, and (3) immediate tolerance to IV milrinone. Results Ninety-four patients were included (41 and 53 in the IV milrinone and the control group, respectively). IV milrinone infusion was independently associated with a lower likelihood of 6-month functional disability (adjusted odds ratio [aOR] = 0.28, 95% confidence interval [CI] = 0.10–0.77]) and vasospasm-related brain infarction (aOR = 0.19, 95% CI 0.04–0.94). Endovascular angioplasty was less frequent in the IV milrinone group (6 [15%] vs. 28 [53%] patients, p  = 0.0001, aOR = 0.12, 95% CI 0.04–0.38). IV milrinone (median duration of infusion, 5 [2–8] days) was prematurely discontinued owing to poor tolerance in 12 patients, mostly ( n  = 10) for “non/hardly-attained induced hypertension” (mean arterial blood pressure < 100 mmHg despite 1.5 µg/kg/min −1 of norepinephrine). However, this event was similarly observed in IV milrinone and control patients ( n  = 10 [24%] vs. n  = 11 [21%], respectively, p  = 0.68). IV milrinone was associated with a higher incidence of polyuria (IV milrinone patients had creatinine clearance of 191 [153–238] ml/min −1 ) and hyponatremia or hypokalemia, whereas arrhythmia, myocardial ischemia, and thrombocytopenia were infrequent. Conclusions Despite its premature discontinuation in 29% of patients as a result of its poor tolerance, IV milrinone was associated with a lower rate of endovascular angioplasty and a positive impact on long-term neurological and radiological outcomes. These preliminary findings encourage the conduction of confirmatory randomized trials.

Microvascular and/or vasospastic anginas are relevant causes of ischemia with no obstructive coronary artery disease (INOCA) in patients after computed tomography coronary angiography (CTCA). Our research has 2 objectives. The first is to undertake a diagnostic study, and the second is to undertake a nested, clinical trial of stratified medicine. A prospective, multicenter, randomized, blinded, sham-controlled trial of stratified medicine (NCT03477890) will be performed. All-comers referred for clinically indicated CTCA for investigation of suspected coronary artery disease (CAD) will be screened in 3 regional centers. Following informed consent, eligible patients with angina symptoms are enrolled before CTCA and remain eligible if CTCA excludes obstructive CAD. Diagnostic study: Invasive coronary angiography involving an interventional diagnostic procedure (IDP) to assess for disease endotypes: (1) angina due to obstructive CAD (fractional flow reserve ≤0.80); (2) microvascular angina (coronary flow reserve <2.0 and/or index of microvascular resistance >25); (3) microvascular angina due to small vessel spasm (acetylcholine); (4) vasospastic angina due to epicardial coronary spasm (acetylcholine); and (5) noncoronary etiology (normal coronary function). The IDP involves direct invasive measurements using a diagnostic coronary guidewire followed by provocation testing with intracoronary acetylcholine. The primary outcome of the diagnostic study is the reclassification of the initial CTCA diagnosis based on the IDP. Stratified medicine trial: Participants are immediately randomized 1:1 in the catheter laboratory to therapy stratified by endotype (intervention group) or not (control group). The primary outcome of the trial is the mean within-subject change in Seattle Angina Questionnaire score at 6 months. Secondary outcomes include safety, feasibility, diagnostic utility (impact on diagnosis and certainty), and clinical utility (impact on treatment and investigations). Health status assessments include quality of life, illness perception, anxiety-depression score, treatment satisfaction, and physical activity. Participants who are not randomized will enter a follow-up registry. Health and economic outcomes in the longer term will be assessed using electronic patient record linkage. CorCTCA will prospectively characterize the prevalence of disease endotypes in INOCA and determine the clinical value of stratified medicine in this population. [Display omitted]

Introduction Stellate ganglion block has been reported to expand cerebral vessels and alleviate vasospasm after aneurysmal subarachnoid hemorrhage. However, the causal relationship between early stellate ganglion block and cerebral vasospasm prevention has not yet been established. The purpose of this study was to explore the effectiveness and safety of early stellate ganglion block as a preventive treatment for cerebral vasospasm and delayed cerebral ischemia. Methods/design This is a single-center, prospective, randomized, controlled, blinded endpoint assessment superiority trial. A total of 228 patients will be randomized within 48 h of aneurysmal subarachnoid hemorrhage onset in a 1:1 ratio into two groups, one group receiving an additional e-SGB and the other group receiving only a camouflaging action before anesthesia induction in the operating room. The primary outcome is the incidence of symptomatic vasospasm within 14 days after aSAH. Further safety and efficacy parameters include the incidence of radiographic vasospasm, new cerebral infarction, postoperative delirium, and complications up to 90 days after surgery; postoperative cerebral hemodynamics; Mini-Mental State Examination score; modified Rankin scale score; and all-cause mortality up to 90 days after surgery. Discussion This is a randomized controlled trial to explore the effectiveness and safety of early stellate ganglion block as a preventive treatment to reduce cerebral vasospasm in patients with aneurysmal subarachnoid hemorrhage. If the results are positive, it may provide a new direction for the prevention and treatment of cerebral vasospasm and delayed cerebral ischemia. Trial registration The study was registered on Clincaltrials.gov on December 13, 2020 (NCT04691271).

BackgroundCerebral vasospasm induced by aneurysmal subarachnoid hemorrhage (aSAH) is a major cause of high morbidity and mortality, for which there is no consistently effective treatment. Cervical spinal cord stimulation (cSCS) has been shown to induce vasodilatation and improve peripheral and cerebral blood flow in both animal and human studies. This pilot study was performed to assess the clinical effect and long-term results of cSCS treatment in aSAH patients.MethodsThis was the first IRB- and US FDA-approved prospective non-randomized non-controlled study comprising of 12 aSAH patients (8 women, 4 men, age range 34–62 years) treated between May and November 2008. All patients underwent up to 2 weeks of cSCS with a single percutaneously implanted 8-contact electrode. Neurological outcomes at discharge and follow-up of up to 13 years and mortality/complications rates were analyzed.ResultsAll 12 aSAH patients underwent cSCS electrode implantation immediately after securing the aneurysm. Patients were stimulated for 10–14 consecutive days starting within 3 days of aneurysm rupture. Angiographic vasospasm occurred in six patients; two patients developed new vasospasm-related neurological symptoms; both recovered completely by discharge time. One patient died from unrelated multi-system failure; the rest were followed up clinically (average, 7.5 years; range, 12–151 months) and angiographically (average, 6.5 years; range, 36–125 months). No delayed ischemic neurological deficits/strokes and no cSCS-related adverse effects were observed.ConclusionsOur short- and long-term data suggest that cSCS is feasible and safe for patients in the acute aSAH settings. Small size of the patient cohort and lack of control do not allow us to conclude whether cSCS is able to prevent cerebral vasospasm, decrease its severity, and improve clinical outcomes in aSAH patients. However, our findings support further clinical trials and development of cSCS as a new concept to prevent and treat cerebral vasospasm.Trial registration.ClinicalTrials.gov NCT00766844, posted on 10/06/2008.

Background Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening neurosurgical emergency with a high mortality rate. Delayed cerebral ischemia (DCI) and cerebral vasospasm (CVS) are delayed products of early brain injury (EBI), which may constitute the principal determinant of an unfavorable patient prognosis. Consequently, the mitigation of DCI and CVS assumes paramount significance in the pursuit of enhanced patient outcomes. However, except for oral nimodipine, there is no effective therapy available in the current guideline. Hence, the exigency arises to proffer novel treatment paradigms. The diversity of hydrogen therapeutic targets has been largely reported in basic research, unveiling its latent capacity to ameliorate EBI in aSAH patients. Methods Early H ydrogen– O xygen Gas M ixture I nhalation in Patients with Aneurysmal Subarachnoid Hemorrhage (HOMA), a single-center, prospective, open-labeled, randomized controlled clinical trial, endeavors to evaluate the efficacy and safety of hydrogen–oxygen gas mixture inhalation therapy in aSAH patients. A cohort of 206 patients will be randomized to either hydrogen–oxygen gas mixture inhalation group (8 h per day, 3 L/min, hydrogen concentration of 67%, oxygen concentration of 33%) or oxygen inhalation group (8 h per day, 3 L/min, oxygen concentration of 33%) within 72 h after aSAH and treated for 7 days in the ICU ward. The primary outcomes are the incidence of DCI and CVS during hospitalization. Discussion The HOMA aims to evaluate the effectiveness of hydrogen–oxygen gas mixture inhalation therapy in preventing DCI or CVS and improving outcomes in aSAH patients. Notably, this is the first large-scale trial of hydrogen therapy in aSAH patients. Given that the Chinese population represents a significant portion of the global population and the increasing incidence of stroke due to aging, optimizing patient care is vital. Given the current challenges in aSAH patient outcomes, initiating more prospective clinical trials is essential. Recent research has shown hydrogen’s therapeutic potential, aligning with EBI in aSAH, driving our exploration of hydrogen therapy’s mechanisms in post-aneurysm rupture damage. Ethics and dissemination The protocol for the HOMA study was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University (KY 2022–020-02). All results of the present study will be published in peer-reviewed journals and presented at relevant conferences. Trial registration ClinicalTrials.gov NCT05282836. Registered on March 16, 2022.

Cerebral vasospasm is a prolonged but reversible narrowing of cerebral arteries beginning days after subarachnoid hemorrhage. Progression to cerebral ischemia is tied mostly to vasospasm severity, and its pathogenesis lies in artery encasement by blood clot, although the complex interactions between hematoma and surrounding structures are not fully understood. The delayed onset of vasospasm provides a potential opportunity for its prevention. It is disappointing that recent randomized, controlled trials did not demonstrate that the endothelin antagonist clazosentan, the cholesterol-lowering agent simvastatin, and the vasodilator magnesium sulfate improve patient outcome. Minimizing ischemia by avoiding inadequate blood volume and pressure, administering the calcium antagonist nimodipine, and intervention with balloon angioplasty, when necessary, constitutes current best management. Over the past two decades, our ability to manage vasospasm has led to a significant decline in patient morbidity and mortality from vasospasm, yet it still remains an important determinant of outcome after aneurysm rupture. Vasospasme cérébral : revue du sujet. Le vasospasme cérébral consiste en un rétrécissement prolongé mais réversible d’une artère cérébrale débutant dans les jours suivant une hémorragie sous-arachnoïdienne (HSA). La progression vers l’ischémie cérébrale est liée surtout à la sévérité du vasospasme et sa pathogenèse est en lien avec le caillot formant une gaine autour de l’artère. Cependant, les interactions complexes entre l’hématome et les structures environnantes demeurent mal connues. Le délai entre l’HSA et le vasospasme fournit une occasion potentielle de prévention. Des essais contrôlés randomisés récents n’ont pas démontré que le clazosentan, un antagoniste de l’endothéline, la simvastatine, un hypocholestérolémiant, ou le sulfate de magnésium, un vasodilatateur, améliorent le résultat chez le patient. Actuellement, le meilleur traitement consiste à minimiser l’ischémie en s’assurant que le volume sanguin et la tension artérielle sont adéquats, en administrant de la nimodipine, un antagoniste du calcium, et en procédant à une angioplastie par ballonnet si nécessaire. Au cours des vingt dernières années, une diminution significative de la morbidité et de la mortalité due au vasospasme a été observée grâce à ces moyens de traitement. Cependant le vasospasme demeure un important déterminant de l’issue chez le patient après la rupture d’un anévrisme cérébral.

Background Systemic inflammatory response syndrome (SIRS) may develop after aneurysmal subarachnoid hemorrhage (SAH). We investigated factors associated with SIRS after SAH, whether SIRS was associated with complications of SAH such as vasospasm, cerebral infarction, and clinical outcome, and whether SIRS could contribute to a difference in outcome between patients treated by endovascular coiling or neurosurgical clipping of the ruptured aneurysm. Methods This was exploratory analysis of 413 patients in the CONSCIOUS-1 study. SIRS was diagnosed if the patient had at least 2 of 4 variables (hypothermia/fever, tachycardia, tachypnea, and leukocytosis/leukopenia) within 4 days of admission. Clinical outcome was measured on the Glasgow outcome scale 3 months after SAH. The relationship between clinical and radiologic variables and SIRS, angiographic vasospasm, delayed ischemic neurologic deficit (DIND), cerebral infarction, vasospasm-related infarction, and clinical outcome were modeled with uni- and multivariable analyses. Results 63% of patients developed SIRS. Many factors were associated with SIRS in univariate analysis, but only poor WFNS grade and pneumonia were independently associated with SIRS in multivariable analysis. SIRS burden (number of SIRS variables per day over the first 4 days) was associated with poor outcome, but not with angiographic vasospasm, DIND, or cerebral infarction. The method of aneurysm treatment was not associated with SIRS. Conclusion SIRS was associated with poor outcome but not angiographic vasospasm, DIND, or cerebral infarction after SAH in the CONSCIOUS-1 data. There was no support for the notion that neurosurgical clipping is associated with a greater risk of SIRS than endovascular coiling.

Subarachnoid hemorrhage (SAH) can lead to devastating neurological outcomes, and there are few pharmacologic treatments available for treating this condition. Both animal and human studies provide evidence of inflammation being a driving force behind the pathology of SAH, leading to both direct brain injury and vasospasm, which in turn leads to ischemic brain injury. Several inflammatory mediators that are elevated after SAH have been studied in detail. While there is promising data indicating that blocking these factors might benefit patients after SAH, there has been little success in clinical trials. One of the key factors that complicates clinical trials of SAH is the variability of the initial injury and subsequent inflammatory response. It is likely that both genetic and environmental factors contribute to the variability of patients’ post-SAH inflammatory response and that this confounds trials of anti-inflammatory therapies. Additionally, systemic inflammation from other conditions that affect patients with SAH could contribute to brain injury and vasospasm after SAH. Continuing work on biomarkers of inflammation after SAH may lead to development of patient-specific anti-inflammatory therapies to improve outcome after SAH.