Aneurysmal Subarachnoid Hemorrhage Research Articles

Sex Differences in Outcome of Aneurysmal Subarachnoid Hemorrhage and Its Relation to Postoperative Cerebral Ischemia

BackgroundWhether there is a sex difference in the outcome of aneurysmal subarachnoid hemorrhage (aSAH) remains controversial, and clarifying the role of women in postoperative cerebral ischemic events can help us to understand its relationship with poor prognosis. Therefore, the purpose of this study was to elucidate the relationship between the three aspects of sex differences, postoperative cerebral ischemia, and poor prognosis after aSAH.MethodsA total of 472 patients admitted within 72 h after aSAH between January 2018 and December 2022 were included. We systematically analyzed the characteristics of sex differences in aSAH and explored the relationship between delayed cerebral ischemia (DCI), surgery-related cerebral infarction (SRCI), and poor prognosis (modified Rankin Scale > 2).ResultsCompared with women, men were in worse condition and had more intracerebral hematoma (p = 0.001) on admission, whereas women were older (p < 0.001) and had more multiple aneurysms (p = 0.002). During hospitalization, men were more likely to experience emergency intubation (p = 0.036) and tracheotomy (p = 0.013). Women achieved functional independence at discharge at a similar rate to men (p = 0.394). Among postoperative complications, the incidence of DCI (22% vs. 12%, p = 0.01) and urinary tract infection (p = 0.022) was significantly higher in women. After adjusting for age, multivariable regression analysis showed that hypertension (odds ratio [OR] 2.139, 95% confidence interval [CI] 1.027–4.457), preoperative rerupture (OR 12.240, 95% CI 1.491–100.458), pulmonary infection (OR 2.297, 95% CI 1.070–4.930), external ventricular drainage placement (OR 4.382, 95% CI 1.550–12.390), bacteremia (OR 14.943, 95% CI 1.412–158.117), SRCI (OR 8.588, 95% CI 4.092–18.023), venous thrombosis (OR 5.283, 95% CI 1.859–15.013), higher modified Fisher grades (p = 0.003), and Hunt–Hess grades (p = 0.035) were associated with poor prognosis, whereas DCI (OR 1.394, 95% CI 0.591–3.292) was not an independent risk factor for poor prognosis. The proportion of patients who fully recovered from cerebral ischemia was higher in the DCI group (p < 0.001) compared with the SRCI group, and more patients were discharged with modified Rankin Scale > 2 in the SRCI group (p = 0.005).ConclusionsWomen have a higher incidence of DCI, but there is no sex difference in outcomes after aSAH, and poor prognosis is associated with worse admission condition and perioperative complications. SRCI is a strong independent risk factor for poor prognosis, whereas DCI is not.

Diagnostic value of transcranial doppler to predict delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

BackgroundTranscranial Doppler (TCD) is a technique to assess blood flow velocity in the cerebral arteries. TCD is frequently used to monitor aneurysmal subarachnoid hemorrhage (aSAH) patients. This study compares TCD-criteria for vasospasm and its association with Delayed Cerebral Ischemia (DCI). An overall score based on flow velocities of various intracranial arteries was developed and evaluated.MethodsA retrospective diagnostic accuracy study was conducted between 1998 and 2017 with 621 patients included. Mean flow velocity (MFV) of the cerebral artery was measured between 2–5 days and between 6–9 days after ictus. Cutoff values from the literature, new cutoff values, and a new composite score (Combined Severity Score) were used to predict DCI. Sensitivity, specificity, and area under the curve (AUC) were determined, and logistic regression analysis was performed.ResultsThe Combined Severity Score showed an AUC 0.64 (95%CI 0.56-.71) at days 2–5, with sensitivity 0.53 and specificity 0.74. The Combined Severity Score had an adjusted Odds Ratio of 3.41 (95CI 1.86–6.32) for DCI. MCA-measurements yielded the highest AUC to detect DCI at day 2–5: AUC 0.65 (95%CI 0.58–0.73). Optimal cutoff MFV of 83 cm/s for MCA resulted in sensitivity 0.73 and specificity 0.50 at days 2–5.ConclusionTCD-monitoring of aSAH patients may be a valuable strategy for DCI risk stratification. Lower cutoff values can be used in the early phase after the ictus (day 2–5) than are commonly used now. The Combined Severity Score incorporating all major cerebral arteries may provide a meaningful contribution to interpreting TCD measurements.

CT perfusion-guided administration of IV milrinone is associated with a reduction in delayed cerebral infarction after subarachnoid hemorrhage

Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid haemorrhage (aSAH) is a singular pathological entity necessitating early diagnostic approaches and both prophylactic and curative interventions. This retrospective before-after study investigates the effects of a management strategy integrating perfusion computed tomography (CTP), vigilant clinical monitoring and standardized systemic administration of milrinone on the occurrence of delayed cerebral infarction (DCIn). The "before"\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\ ext{"before"}}$$\\end{document} period included 277 patients, and the "after"\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\ ext{"after"}}$$\\end{document} one 453. There was a higher prevalence of Modified Fisher score III/IV and more frequent diagnosis of vasospasm in the "after"\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\ ext{"after"}}$$\\end{document} period. Conversely, the occurrence of DCIn was reduced with the "after"\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\ ext{"after"}}$$\\end{document} management strategy (adjusted OR 0.48, 95% CI [0.26; 0.84]). Notably, delayed ischemic neurologic deficits were less prevalent at the time of vasospasm diagnosis (24 vs 11%, p=0.001\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$p=0.001$$\\end{document}), suggesting that CTP facilitated early detection. In patients diagnosed with vasospasm, intravenous milrinone was more frequently administered (80 vs 54%, p<0.001\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$p<0.001$$\\end{document}) and associated with superior hemodynamics. The present study from a large cohort of aSAH patients suggests, for one part, the interest of CTP in early diagnosis of vasospasm and DCI, and for the other the efficacy of CT perfusion-guided systemic administration of milrinone in both preventing and treating DCIn.

Prescribed Drug Use and Aneurysmal Subarachnoid Hemorrhage Incidence: A Drug-Wide Association Study.

Current benefits of invasive intracranial aneurysm treatment to prevent aneurysmal subarachnoid hemorrhage (aSAH) rarely outweigh treatment risks. Most intracranial aneurysms thus remain untreated. Commonly prescribed drugs reducing aSAH incidence may provide leads for drug repurposing. We performed a drug-wide association study (DWAS) to systematically investigate the association between commonly prescribed drugs and aSAH incidence. We defined all aSAH cases between 2000 and 2020 using International Classification of Diseases codes from the Secure Anonymised Information Linkage databank. Each case was matched with 9 controls based on age, sex, and year of database entry. We investigated commonly prescribed drugs (>2% in study population) and defined 3 exposure windows relative to the most recent prescription before index date (i.e., occurrence of aSAH): current (within 3 months), recent (3-12 months), and past (>12 months). A logistic regression model was fitted to compare drug use across these exposure windows vs never use, controlling for age, sex, known aSAH risk factors, and health care utilization. The family-wise error rate was kept at p < 0.05 through Bonferroni correction. We investigated exposure to 205 commonly prescribed drugs between 4,879 aSAH cases (mean age 61.4, 61.2% women) and 43,911 matched controls. We found similar trends for lisinopril and amlodipine, with a decreased aSAH risk for current use (lisinopril odds ratio [OR] 0.63, 95% CI 0.44-0.90, amlodipine OR 0.82, 95% CI 0.65-1.04) and an increased aSAH risk for recent use (lisinopril OR 1.30, 95% CI 0.61-2.78, amlodipine OR 1.61, 95% CI 1.04-2.48). A decreased aSAH risk in current use was also found for simvastatin (OR 0.78, 95% CI 0.64-0.96), metformin (OR 0.58, 95% CI 0.43-0.78), and tamsulosin (OR 0.55, 95% CI 0.32-0.93). By contrast, an increased aSAH risk was found for current use of warfarin (OR 1.35, 95% CI 1.02-1.79), venlafaxine (OR 1.67, 95% CI 1.01-2.75), prochlorperazine (OR 2.15, 95% CI 1.45-3.18), and co-codamol (OR 1.31, 95% CI 1.10-1.56). We identified several drugs associated with aSAH, of which 5 drugs (lisinopril and possibly amlodipine, simvastatin, metformin, and tamsulosin) showed a decreased aSAH risk. Future research should build on these signals to further assess the effectiveness of these drugs in reducing aSAH incidence. This study provides Class III evidence that some commonly prescribed drugs are associated with subsequent development of aSAH.

Ultra-Early and Short-Term Tranexamic Acid Treatment in Patients With Good- and Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

The results of the ULTRA trial showed that ultra-early and short-term treatment with tranexamic acid (TXA) does not improve clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH). Possibly, the lack of a beneficial effect in all patients with aSAH is masked by antagonistic effects of TXA in certain subgroups. In this post hoc subgroup analysis, we investigated the effect of TXA on clinical outcome in patients with good-grade and poor-grade aSAH. The ULTRA trial was a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment. Participants received ultra-early and short-term TXA in addition to usual care or usual care only. This post hoc subgroup analysis included only ULTRA participants with confirmed aSAH and available World Federation of Neurosurgical Societies (WFNS) grade on admission. Patients were categorized into those with good-grade (WFNS 1-3) and poor-grade (WFNS 4-5) aSAH. The primary outcome was clinical outcome assessed by the modified Rankin scale (mRS). Odds ratios (ORs) and adjusted ORs (aORs) with 95% CIs were calculated using ordinal regression analyses. Analyses were performed using the as-treated principle. In all patients with aSAH, no significant effect modification of TXA on clinical outcome was observed for admission WFNS grade (p = 0.10). Of the 812 ULTRA participants, 473 patients had (58%; N = 232 TXA, N = 241 usual care) good-grade and 339 (42%; N = 162 TXA, N = 176 usual care) patients had poor-grade aSAH. In patients with good-grade aSAH, the TXA group had worse clinical outcomes (OR: 0.67, 95% CI 0.48-0.94, aOR 0.68, 95% CI 0.48-0.94) compared with the usual care group. In patients with poor-grade aSAH, clinical outcomes were comparable between treatment groups (OR: 1.04, 95% CI 0.70-1.55, aOR 1.05, 95% CI 0.70-1.56). This post hoc subgroup analysis provides another important argument against the use of TXA treatment in patients with aSAH, by showing worse clinical outcomes in patients with good-grade aSAH treated with TXA and no clinical benefit of TXA in patients with poor-grade aSAH, compared with patients treated with usual care. ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24, 2013). This study provides Class II evidence that tranexamic acid, given for <24 hours within the first 24 hours, does not improve the 6-month outcome in good-grade or poor initial-grade aneurysmal SAH.

Resilience After High-Grade Subarachnoid Hemorrhage: A Prospective Cohort Study on Quality of Life.

Treatment of patients who present with poor clinical condition is often postponed until neurological improvement is observed. Despite previous studies, it is still unclear how survivors perceive their quality of life (QoL). This study aimed to evaluate self-perceived QoL in patients with aneurysmal subarachnoid hemorrhage who present with poor clinical condition, as defined by World Federation of Neurosurgical Societies (WFNS) grades 4 to 5, compared with those who present in more favorable clinical condition (WFNS 1-3). Between 2011 and 2021, 1160 patients with aneurysmal subarachnoid hemorrhage were admitted to the Amsterdam UMC. Among the 845 patients who survived, 537 participated in the QoL questionnaires. Patient characteristics, complications, EQ-5D questionnaires, modified Rankin Scale, and Hospital Anxiety and Depression Scale were analyzed using the nonparametric Mann-Whitney U test for continuous variables or the Pearson χ2 test for categorical variables. Of the 537 responders, 452 (84%) presented with low grade (WFNS 1-3) and 85 (16%) presented with high grade (WFNS 4-5). The high-grade group reported a self-perceived QoL score of 70 (of 100), while the low-grade group reported a score of 75 (P = .12). The mean EQ-5D index value was 0.74 for the high-grade group and 0.81 for the low-grade group (P < .01). In the high-grade group, 61 patients (72%) had a favorable outcome (modified Rankin Scale 0-3) compared with 419 (94%) in the low-grade group (P < .001). High-grade WFNS patients rated their QoL as satisfactory, with only a marginal 5-point difference on a 100-point scale compared with low-grade WFNS patients. In addition, almost three-quarters of high-grade WFNS survivors achieved a favorable outcome. Given that a subset of patients, despite presenting with a poor clinical condition, still achieve a favorable outcome, these findings reinforce our perspective advocating for early and comprehensive treatment.

Diagnostic workup of acute headache and subarachnoid hemorrhage in a Norwegian population: An observational study.

Acute headache may be the primary symptom of subarachnoid hemorrhage (SAH). Recent guidelines suggest that non-contrast computed tomography (CT) is adequate to exclude aneurysmal SAH if performed within 6 h after symptom onset. However, most studies of acute headache including CT, lumbar puncture and SAH are multicenter studies from referral hospitals with highly selected patient populations. The main purpose of this study was to describe the diagnostic properties of head CT and cerebrospinal fluid (CSF) spectrophotometry for detecting SAH in an unselected primary hospital population with acute headache. A retrospective cross-sectional study conducted at a large primary hospital serving roughly 10% of the Norwegian population. Diagnostic workup from consecutive patients evaluated for acute headache in 2009-2020 were collected. All CSF-spectrophotometry reports were standardized and the same CT scanner was used during the study. A total of 3227 patients were included. Median age was 45 years and 63% were women. In total, 170 (5.3% of all acute headache patients) had SAH. Of 3071 CT-negative patients, 2852 (93%) underwent lumbar puncture. Of the CSF reports, 2796 (98%) were negative for xanthochromia. Overall, the rate for detection of aneurysmal SAH by positive xanthochromia was 9 in 2852 cases (3‰). The miss rate for the detection of an aneurysmal SAH with a CT scan within 6 h was 0 and within 12 h 1 in 2852 cases (0.3‰). In acute headache, a CT scan taken within 6 h is practically 100% sensitive for detecting any SAH.

Delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage- areas at risk.

Delayed cerebral ischemia is a major neurological complication of aneurysmal subarachnoid hemorrhage. Its unpredictable course and potentially unfavorable outcome draw attention to clinicians to improve the methods for its prediction, prevention, and diagnosis. The computed tomography perfusion (CTP) technique of the brain is one of the promising methods for revealing brain areas endangered by cerebral vasospasm and delayed cerebral ischemia.

A prognostic model incorporating the albumin-corrected anion gap in patients with aneurysmal subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) patients typically have poor prognoses. The anion gap (AG) has been proven to correlate with mortality in various critically ill patients. However, hypoalbuminemia can lead to underestimations of the true anion gap levels. This study was conducted to verify the prognostic value of single AG and albumin-corrected anion gap (ACAG) among aSAH patients. Significant factors in the univariate logistic regression analysis were included in the multivariate logistic regression analysis to explore the risk factors for mortality in aSAH patients and to confirm the independent relationship between ACAG and mortality. The restricted cubic spline (RCS) was used to visually show the relationship between ACAG level and mortality risk of aSAH patients. The predictive model for mortality was developed by incorporating significant factors into the multivariate logistic regression analysis. The prognostic value of ACAG and the developed model was evaluated by calculating the area under the receiver operating characteristics curve (AUC). Among 710 aSAH patients, a 30-day mortality was observed in 20.3% of the cases. A positive relationship was demonstrated between the ACAG level and mortality in aSAH patients using the RCS curve. The multivariate logistic regression analysis helped discover that only six factors were finally and independently related to mortality of aSAH patients after adjusting for confounding effects, including the Hunt-Hess scale score (p = 0.006), surgical options (p < 0.001), white blood cell count (p < 0.001), serum chloride levels (p = 0.023), ACAG (p = 0.039), and delayed cerebral ischemia (p < 0.001). The AUC values for the AG, albumin, and ACAG in predicting mortality among aSAH patients were 0.606, 0.536, and 0.617, respectively. A logistic regression model, which includes the Hunt-Hess scale score, surgical options, white blood cell count, serum chloride levels, ACAG, and delayed cerebral ischemia, achieved an AUC of 0.911 for predicting mortality. The ACAG is an effective prognostic marker for aSAH patients. A prognostic model incorporating ACAG could help clinicians evaluate the risk of poor outcomes among aSAH patients, thereby facilitating the development of personalized therapeutic strategies.

Nimodipine-associated standard dose reductions and neurologic outcomes after aneurysmal subarachnoid hemorrhage: the era of pharmacogenomics.

Nimodipine, an L-type cerebroselective calcium channel antagonist, is the only drug approved by the US Food and Drug Administration for the neuroprotection of patients with aneurysmal subarachnoid hemorrhage (aSAH). Four randomized, placebo-controlled trials of nimodipine demonstrated clinical improvement over placebo; however, these occurred before precision medicine with pharmacogenomics was readily available. The standard enteral dose of nimodipine recommended after aSAH is 60 mg every 4 h. However, up to 78% of patients with aSAH develop systemic arterial hypotension after taking the drug at the recommended dose, which could theoretically limit its neuroprotective role and worsen cerebral perfusion pressure and cerebral blood flow, particularly when concomitant vasospasm is present. We investigated the association between nimodipine dose changes and clinical outcomes in a consecutive series of 150 patients (mean age, 56 years; 70.7% women) with acute aSAH. We describe the pharmacogenomic relationship of nimodipine dose reduction with clinical outcomes. These results have major implications for future individualized dosing of nimodipine in the era of precision medicine.

Management of Ruptured Intracranial Aneurysm with DVT: Case Report and Brief Review of Literature

AbstractDeep vein thrombosis (DVT) is a known complication of aneurysmal subarachnoid hemorrhage (aSAH), and anticoagulant therapy is crucial for its management. However, in case of a ruptured intracranial aneurysm in a patient of DVT, anticoagulant administration may lead to rebleeding. Anticoagulants are also associated with a risk of hematoma expansion. A systematic approach is required to weigh the risk and benefit ratio while managing such cases. We report the successful management of a 61-year-old female presenting with aSAH and associated DVT who had an intracranial vessel injury during intraoperative clipping of an aneurysm.

Diagnosis and endovascular management of vasospasm after aneurysmal subarachnoid hemorrhage — survey of real-life practices

BackgroundVasospasm and delayed cerebral ischemia (DCI) are the leading causes of morbidity and mortality after intracranial aneurysmal subarachnoid hemorrhage (aSAH). Vasospasm detection, prevention and management, especially endovascular management varies from...

The influence of epigenetic biological age on key complications and outcomes in aneurysmal subarachnoid haemorrhage

BackgroundWe aimed to investigate the association between DNA-methylation biological age (B-age) calculated as age acceleration (ageAcc) and key aneurysmal subarachnoid haemorrhage (aSAH) complications such as vasospasm, delayed cerebral ischaemia (DCI),...

Association Between High Preoperative White Blood Cell-to-Hemoglobin Ratio and Postoperative Symptomatic Cerebral Vasospasm in Patients With Aneurysmal Subarachnoid Hemorrhage.

Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (ASAH) is a serious complication and has a strong relationship with systemic inflammatory responses. Given previously reported relationships between leukocytosis and anemia with ASAH-related cerebral vasospasm, this study examined the association between the preoperative white blood cell-to-hemoglobin ratio (WHR) and postoperative symptomatic cerebral vasospasm (SCV) in patients with ASAH. Demographic, preoperative (comorbidities, ASAH characteristics, laboratory findings), intraoperative (operation and anesthesia), and postoperative (SCV, other neurological complications, clinical course) data were retrospectively analyzed in patients with ASAH who underwent surgical or endovascular treatment of the culprit aneurysm. Patients were divided into high-WHR (n=286) and low-WHR (n=257) groups based on the optimal cutoff value of preoperative WHR (0.74), and stabilized inverse probability weighting was performed between the 2 groups. The predictive power of the WHR and other preoperative systemic inflammatory indices (neutrophil-to-albumin, neutrophil-to-lymphocyte, platelet-to-lymphocyte, platelet-to-neutrophil, platelet-to-white blood cell ratios, and systemic immune-inflammation index) for postoperative SCV was evaluated. Postoperative SCV was more frequent in the high-WHR group than in the low-WHR group before (33.2% vs. 12.8%; P<0.001) and after (29.4% vs. 19.1%; P=0.005) inverse probability weighting. Before weighting, the predictive power for postoperative SCV was the highest for the WHR among the preoperative systematic inflammatory indices investigated (area under receiver operating characteristics curve 0.66, P<0.001). After weighting, preoperative WHR ≥0.74 was independently associated with postoperative SCV (odds ratio 1.76; P=0.006). High preoperative WHR was an independent predictor of postoperative SCV in patients with ASAH.

Impact of premorbid hypertension and renin-angiotensin-aldosterone system inhibitors on the severity of aneurysmal subarachnoid haemorrhage: a multicentre study

BackgroundHypertension is widely acknowledged as a significant contributory factor to the heightened risk of intracranial aneurysm rupture. Nevertheless, the impact of hypertension management on the outcomes subsequent to aneurysmal subarachnoid...

The Difference in Serum Metabolomic Profiles between the Good and Poor Outcome Groups at 3 Months in the Early and Late Phases of Aneurysmal Subarachnoid Hemorrhage.

We aimed to investigate the characteristics of serum metabolomics in aneurysmal subarachnoid hemorrhage patients (aSAH) with different 3-month outcomes (good = modified Rankin score: 0-3 vs. poor = mRS 4-6). We collected serum samples from 46 aSAH patients at 24 (D1) and 168 (D7) hours after injury for analysis by liquid chromatography-mass spectrometry. Ninety-six different metabolites were identified. Groups were compared using multivariate (orthogonal partial least squares discriminant analysis), univariate, and receiving operator characteristic (ROC) methods. We observed a marked decrease in serum homocysteine levels at the late phase (D7) compared to the early phase (D1). At both D1 and D7, mannose and sorbose levels were notably higher, alongside elevated levels of kynurenine (D1) and increased 2-hydroxybutyrate, methyl-galactoside, creatine, xanthosine, p-hydroxyphenylacetate, N-acetylalanine, and N-acetylmethionine (all D7) in the poor outcome group. Conversely, levels of guanidinoacetate (D7) and several amino acids (both D1 and D7) were significantly lower in patients with poor outcomes. Our results indicate significant changes in energy metabolism, shifting towards ketosis and alternative energy sources, both in the early and late phases, even with adequate enteral nutrition, particularly in patients with poor outcomes. The early activation of the kynurenine pathway may also play a role in this process.

Sex differences in risk factor relationships with subarachnoid haemorrhage and intracranial aneurysms: A Mendelian Randomisation study.

The prevalence of intracranial aneurysms (IAs) and incidence of aneurysmal subarachnoid haemorrhage (aSAH) is higher in women than in men. Although several cardiometabolic and lifestyle factors have been related to the risk of IAs or aSAH, it is unclear whether there are sex differences in causal relationships of these risk factors. The aim of this study was to determine sex differences in causal relationships between cardiometabolic and lifestyle factors and risk of aSAH and IA. We conducted a sex-specific two-sample Mendelian randomisation study using summary-level data from genome-wide association studies. We analysed low-density lipoprotein cholesterol, high-density lipoprotein cholesterol [HDL-C], triglycerides, non-HDL-C, total cholesterol, fasting glucose, systolic and diastolic blood pressure, smoking initiation, and alcohol use as exposures, and aSAH and IA (i.e., aSAH and unruptured IA combined) as outcomes. We found statistically significant sex differences in the relationship between genetically proxied non-HDL-C and aSAH risk, with odds ratios (ORs) of 0.72 (95% confidence interval 0.58, 0.88) in women and 1.01 (0.77, 1.31) in men (P-value for sex difference 0.044). Moreover, genetic liability to smoking initiation was related to a statistically significantly higher risk of aSAH in men compared to women (P-value for sex difference 0.007) with ORs of 3.81 (1.93, 7.52) and 1.12 (0.63, 1.99), respectively, and to a statistically significantly higher IA risk in men compared to women (P-value for sex difference 0.036) with ORs of 3.58 (2.04, 6.27) and 1.61 (0.98, 2.64), respectively. In addition, higher genetically proxied systolic and diastolic blood pressure were related to a higher risk of aSAH and IA in both women and men. Higher genetically proxied non-HDL-C was related to a lower risk of aSAH in women compared to men. Moreover, genetic liability to smoking initiation was associated with a higher risk for aSAH and IA in men compared to women. These findings may help improve understanding of sex differences in the development of aSAH and IA.

Automated segmentation of ventricular volumes and subarachnoid hemorrhage from computed tomography images: Evaluation of a rule-based pipeline approach.

Changes in ventricular size, related to brain edema and hydrocephalus, as well as the extent of hemorrhage are associated with adverse outcomes in patients with subarachnoid hemorrhage (SAH). Frequently, these are measured manually using consecutive non-contrast computed tomography scans. Here, we developed a rule-based approach which incorporates both intensity and spatial normalization and utilizes user-defined thresholds and anatomical templates to segment both lateral ventricle (LV) and SAH blood volumes automatically from CT images. The algorithmic segmentations were evaluated against two expert neuroradiologists on representative slices from 20 admission scans from aneurysmal SAH patients. Previous methods have been developed to automate this time-consuming task, but they lack user feedback and are hard to implement due to large-scale data and complex design processes. Our results using automatic ventricular segmentation aligned well with expert reviewers with a median Dice coefficient of 0.81, AUC of 0.91, sensitivity of 81%, and precision of 84%. Automatic segmentation of SAH blood was most reliable near the base of the brain with a median Dice coefficient of 0.51, an AUC of 0.75, precision of 68%, and sensitivity of 50%. Ultimately, we developed a rule-based method that is easily adaptable through user feedback, generates spatially normalized segmentations that are comparable regardless of brain morphology or acquisition conditions, and automatically segments LV with good overall reliability and basal SAH blood with good precision. Our approach could benefit longitudinal studies in patients with SAH by streamlining assessment of edema and hydrocephalus progression, as well as blood resorption.

How many patients do you need? Investigating trial designs for anti-seizure treatment in acute brain injury patients.

Epileptiform activity (EA), including seizures and periodic patterns, worsens outcomes in patients with acute brain injuries (e.g., aneurysmal subarachnoid hemorrhage [aSAH]). Randomized control trials (RCTs) assessing anti-seizure interventions are needed. Due to scant drug efficacy data and ethical reservations with placebo utilization, and complex physiology of acute brain injury, RCTs are lacking or hindered by design constraints. We used a pharmacological model-guided simulator to design and determine the feasibility of RCTs evaluating EA treatment. In a single-center cohort of adults (age >18) with aSAH and EA, we employed a mechanistic pharmacokinetic-pharmacodynamic framework to model treatment response using observational data. We subsequently simulated RCTs for levetiracetam and propofol, each with three treatment arms mirroring clinical practice and an additional placebo arm. Using our framework, we simulated EA trajectories across treatment arms. We predicted discharge modified Rankin Scale as a function of baseline covariates, EA burden, and drug doses using a double machine learning model learned from observational data. Differences in outcomes across arms were used to estimate the required sample size. Sample sizes ranged from 500 for levetiracetam 7 mg/kg versus placebo, to >4000 for levetiracetam 15 versus 7 mg/kg to achieve 80% power (5% type I error). For propofol 1 mg/kg/h versus placebo, 1200 participants were needed. Simulations comparing propofol at varying doses did not reach 80% power even at samples >1200. Our simulations using drug efficacy show sample sizes are infeasible, even for potentially unethical placebo-control trials. We highlight the strength of simulations with observational data to inform the null hypotheses and propose use of this simulation-based RCT paradigm to assess the feasibility of future trials of anti-seizure treatment in acute brain injury.

Early Hydrogen–Oxygen Gas Mixture Inhalation in Patients with Aneurysmal Subarachnoid Hemorrhage (HOMA): study protocol for a randomized controlled trial

BackgroundAneurysmal 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.MethodsEarly Hydrogen–Oxygen Gas Mixture Inhalation 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.DiscussionThe 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 disseminationThe 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 registrationClinicalTrials.gov NCT05282836. Registered on March 16, 2022.