Outcome Of Subarachnoid Hemorrhage Research Articles

Genetically proxied liability to migraine and risk of intracranial aneurysm and subarachnoid hemorrhage.

Observational studies have reported inconsistent relationships between migraine and the risk of intracranial aneurysm and subarachnoid hemorrhage (SAH). To determine whether genetic liability to migraine is associated with risk of intracranial aneurysm and aneurysmal SAH. This study was designed as a two-sample Mendelian randomization (MR) analysis. Genetic associations with migraine were obtained from a large-scale meta-analysis of five population and clinic-based genome-wide association studies of migraine (102,084 cases and 771,257 controls of European ancestry). Genetic associations with intracranial aneurysm and SAH were obtained from a meta-analysis of 22 population-based genome-wide association studies (7495 cases and 71,934 controls of European ancestry). Findings were corroborated by sensitivity analyses and replicated in an independent sample of combined cases of intracranial aneurysm and SAH (3529 cases and 234,948 controls of Asian ancestry from the Biobank Japan and China Kadoorie Biobanks). In secondary analyses, we investigated the outcomes of extracranial aneurysm in the FinnGen and UK Biobank cohorts (up to 7466 combined cases of thoracic and abdominal aortic aneurysm). Genetic liability to migraine was associated with increased risk of the combined outcome of unruptured intracranial aneurysm and SAH (odds ratio [OR] of outcome per doubling in migraine liability 1.19, 95% confidence interval [CI] 1.06-1.35; p = 0.005). This finding was replicated in an independent sample (OR 1.15, 95% CI 1.02-1.30; p = 0.027), and there were similar associations across the component outcomes of unruptured intracranial aneurysm (OR 1.20, 95% CI 1.01-1.42; p = 0.035) and SAH (OR 1.18, 95% 1.04-1.33; p = 0.008). These findings were consistent in sensitivity analyses robust to violations of the MR assumptions. In reverse MR analyses, genetic liability to intracranial aneurysm was not associated with migraine (OR 1.03, 95% CI 0.99-1.07; p = 0.141). In a secondary analysis, there were similar associations of genetic liability to migraine with all forms of aortic aneurysm (OR for combined thoracic and aortic aneurysm 1.18, 95% CI 1.10-1.27; p = 8.49 × 10-6). Genetic liability to migraine was associated with increased risk of intracranial and extracranial aneurysms, supporting a causal relationship between liability to migraine and these traits. Further work is needed to identify the biological mechanisms and clinical relevance of these findings.

Therapeutic utility of Perfluorocarbon Oxygent in limiting the severity of subarachnoid hemorrhage in mice

Subarachnoid hemorrhage (SAH) is the deadliest form of hemorrhagic stroke; however, effective therapies are still lacking. Perfluorocarbons (PFCs) are lipid emulsion particles with great flexibility and their much smaller size as compared to red blood cells (RBCs) allows them to flow more efficiently within the blood circulation. Due to their ability to carry oxygen, a specific PFC-based emulsion, PFC-Oxygent, has been used as a blood substitute; however, its role in cerebral blood flow regulation is unknown. Adult C57BL/6 wildtype male mice were subjected to an endovascular perforation model of SAH followed by an intravenous (i.v.) injection of 9 ml/kg PFC-Oxygent or no treatment at 5 h after SAH. At 48 h after SAH, functional and anatomical outcomes were assessed. We found that SAH resulted in significant neurologic and motor deficits which were prevented by PFC-Oxygent treatment. We found that SAH-induced vasospasm, reduced RBC deformability, and augmented endothelial dysfunction were also restricted by PFC-Oxygent treatment. Moreover, mitochondrial activity and fusion proteins were also markedly decreased as assessed by oxidative phosphorylation (OXPHOS) after SAH. Interestingly, PFC-Oxygent treatment brought the mitochondrial activity close to the basal level. Moreover, SAH attenuated the level of phosphorylated AMP-activated protein kinase (pAMPK), whereas PFC treatment improved pAMPK levels. These data show the beneficial effects of PFC-Oxygent in limiting the severity of SAH. Further studies are needed to fully understand the mechanism through which PFC-Oxygent exerts its beneficial effects in limiting SAH severity.

Cerebrospinal fluid red blood cells and total protein are associated with clinical outcome in spontaneous subarachnoid hemorrhage.

Prognostication in patients with spontaneous subarachnoid hemorrhage (SAH) can be challenging. The aim of this study was to assess whether cerebrospinal fluid (CSF) red blood cell (RBC) count and total protein (TP) concentration are associated with SAH prognosis. Patients with SAH treated at the neurological intensive care unit (ICU) in Innsbruck were included in this real-world, observational study. Longitudinal CSF samples were collected as part of routine diagnostics. RBC count and CSF TP at the time of admission (RBCfirst, TPfirst), in Week 1 (RBCDays1-7, TPDays1-7), Week 2 (RBCDays8-14, TPDays8-14), and Week 3 or thereafter (RBCDay>14, TPDay>14), the highest detected value (RBChighest, TPhighest), as well as the RBC count adjusted for disease duration (RBCadjusted) were assessed. Primary outcomes were good functional outcome after 3 months, defined as modified Rankin scale score ≤2 and ICU survival. A total of 183 SAH patients with a female predominance (69%), a median (interquartile range [IQR]) age of 60 (50-70) years and median (IQR) Hunt and Hess score of 4 (3-5) were included. Multivariable analyses revealed that lower values of RBCfirst, RBCadjusted, RBChighest, TPfirst and TPhighest were associated with good functional outcome and hospital survival. Lower TP concentrations in Weeks 1, 2 and 3 were associated with good functional outcome, and in Weeks 1 and 2 with ICU survival. Early RBC measurements (Week 1) were associated with good functional outcome and ICU survival. Low CSF RBC counts and TP concentrations were associated with good functional outcome and ICU survival in a real-world cohort of SAH patients requiring external ventricular drainage.

Age-Related Differences in Clinical Characteristics and Outcomes of Aneurysmal Subarachnoid Hemorrhage: A Retrospective Study of 657 Patients

Aneurysmal subarachnoid hemorrhage (aSAH) has an incidence of 6-7 per 100,000 person-years. Despite advancements in treatment, 26% of patients die, and 19% remain dependent post-hemorrhage. Long-term neuropsychological sequelae affect about half of the survivors, significantly impacting their quality of life. This study aims to assess aSAH characteristics and identify predictive factors of clinical outcomes in young patients. A retrospective study analyzed 657 aSAH patients treated at two South Korean medical centers from January 2011 to December 2023. Data on demographics, comorbidities, smoking history, clinical grades, aneurysm size and location, and outcomes were collected. Outcomes were classified using the modified Rankin Scale (mRS), with scores ≤2 indicating good outcomes. The cohort included 233 men and 424 women (male-to-female ratio 1:1.8). Most patients were middle-aged (74.4%), followed by young (16.7%) and old (8.8%) groups. Young patients exhibited male predominance (56.8%), lower hypertension (12.7%) and diabetes (1.8%) rates, and higher smoking rates (39.6%). Older patients had higher hypertension (44.6%) and diabetes (23.3%) rates, and were predominantly female (69.1%). Aneurysms in young patients were smaller (p=0.04). Multivariate analysis identified poor Hunt-Hess grade, permanent cerebral infarction, and aneurysmal recurrence or rebleeding as predictors of poor outcomes in young patients. Middle-aged patients had additional predictors, including diabetes and hydrocephalus. In older patients, only poor Hunt-Hess grade was significant. Young aSAH patients exhibit distinct characteristics and prognostic factors compared to older patients. Despite higher post-operative complications, young patients generally have better outcomes, emphasizing the need for age-specific management strategies in aSAH.

Impact of intracranial atherosclerosis burden on vasospasm risk and outcomes in aneurysmal subarachnoid hemorrhage

BackgroundCerebral vasospasm is a well-known complication after aneurysmal subarachnoid hemorrhage (aSAH) and occurs more commonly in younger patients. We hypothesized that intracranial atherosclerosis, which is seen predominantly in older patients, affects vasospasm risk. We sought to determine association between intracranial atherosclerosis burden with vasospasm and outcomes in aSAH. MethodsWe retrospectively reviewed a cohort of consecutive patients with aSAH admitted to a Comprehensive Stroke Center between 2016 and 2023. Intracranial atherosclerosis burden was quantified by using modified Woodcock (MW) score on CT angiograms. Vasospasm was defined based on transcranial Doppler (TCD) criteria. Poor outcome was defined as 3-month modified Rankin Scale 3–6. ResultsWe reviewed 392 patients and included 302 (mean age 56.8 years [SD 13.3], 65 % female and 70 % white) in the final analysis. MW scores were measured with excellent intra-rater and inter-rater reliability (Cohen's kappa coefficient 0.9 and 0.83 respectively) ranging from 0 to 3 (mean 0.59, SD 0.83) with higher scores in older patients (beta coefficient 0.019, 95 % CI 0.009–0.028; p < 0.001). Higher MW calcification score was associated with lower risk of vasospasm (OR 0.52 per point increase, 95 % CI 0.36–0.78; p = 0.001). There was an inverse correlation between MW scores and severity of vasospasm (beta coefficient −0.29, 95 % CI −0.48, −0.1; p = 0.003). However, MW score was not independently associated with poor functional outcome (p = 0.62). ConclusionsIntracranial atherosclerosis is a potential mechanism for lower TCD-based vasospasm in older patients with aSAH; however, it may not impact functional outcomes. Larger prospective studies are needed to confirm our findings.

Quantification of blood and CSF volume to predict outcome after aneurysmal subarachnoid hemorrhage

This study aimed to describe the relationship between blood and CSF volumes in different compartments on baseline CT after aSAH, assess if they independently predict long-term outcome, and explore their interaction with age. CT scans from patients participating in a prospective multicenter randomized controlled trial of patients with aSAH were segmented for blood and CSF volumes. The primary outcomes were the mRS, and the Subarachnoid Hemorrhage Outcome Tool (SAHOT) at day 28 and 180. Univariate regressions were conducted to identify significant predictors of poor outcomes, followed by principal component analysis to explore correlations between imaging variables and WFNS. A multivariate predictive model was then developed and optimized using stepwise regression. CT scans from 97 patients with a median delay from symptom onset of 271 min (131–547) were analyzed. Univariate analysis showed only WFNS, and total blood volume (TBV) were significant predictors of both short and long-term outcome with WFNS more predictive of mRS and TBV more predictive of SAHOT. Principal component analysis showed strong dependencies between the imaging predictors. Multivariate ordinal regression showed models with WFNS alone were most predictive of day 180 mRS and models with TBV alone were most predictive of SAHOT. TBV was the most significant measured imaging predictor of poor long-term outcome after aSAH. All these imaging predictors are correlated, however, and may have multiple complex interactions necessitating larger datasets to detect if they provide any additional predictive value for long-term outcome.

Association of dynamic changes in arterial partial pressure of carbon dioxide with neurological outcomes in aneurysmal subarachnoid hemorrhage

BackgroundCerebral blood flow (CBF) is closely regulated by carbon dioxide (CO2). In patients with aneurysmal subarachnoid hemorrhage (aSAH), abnormal arterial partial pressure of CO2 (PaCO2) might deteriorate brain injuries. Nevertheless, the impact of dynamic PaCO2 fluctuations on neurological outcomes in aSAH patients has not been extensively studied. Our study aimed to investigate the association between dynamic PaCO2 levels and unfavorable neurological outcomes in aSAH patients. MethodsIn this retrospective observational study, we consecutively enrolled 159 aSAH patients from December 2019 to July 2021. Arterial blood gas measurements within 10 days after intensive care unit (ICU) admission for each patient were recorded to calculate the time-weighted average (TWA)-PaCO2, an indicator representing the dynamic changes in PaCO2 levels. For the association between TWA-PaCO2 levels and unfavorable neurological outcomes in aSAH patients, multivariable logistic analysis was used to explore TWA-PaCO2 levels as categorical variables, and restricted cubic spline (RCS) was used to explore TWA-PaCO2 levels as continuous variables. ResultsIn multivariable logistic analysis, after adjusting confounders, when TWA-PaCO2 35–45 mmHg was as a reference, TWA-PaCO2 < 35 mmHg (odds ratio [OR] 2.15, 95 % confidence interval [CI] 0.83–5.55, P = 0.113) and TWA-PaCO2 > 45 mmHg (OR 8.31, 95 % CI 0.72–96.14, P = 0.090) were not independently associated with unfavorable neurological outcomes (modified Rankin score of 3–6). The RCS shows a “U” shape curve between TWA-PaCO2 levels and unfavorable neurological outcomes, with a nonlinear P-value of 0.023. The lowest ORs of unfavorable neurological outcomes were within PaCO2 32.8–38.1 mmHg. ConclusionsBoth lower and higher PaCO2 levels are harmful to aSAH patients. PaCO2 in the range of 32.8–38.1 mmHg is associated with lowest unfavorable neurological outcomes.

The relationship between intraoperative surrogates of vascular stiffness, cerebral aneurysms, and surgical outcomes

ObjectiveIncreased arterial stiffness has been linked to aneurysm formation in the systemic and cerebral circulations, though the role played by arterial stiffness in the cerebral vasculature continues to be refined. This study assesses whether intraoperative surrogates of arterial stiffness differ between patients with cerebral aneurysms and controls, and the extend that these indices relate to outcomes following open surgical treatment. MethodsWe evaluated patients in a prospectively maintained database who underwent cerebral aneurysm surgery, and compared them to controls without cerebral aneurysms. Arterial stiffness was estimated using the intraoperative ambulatory arterial stiffness index (AASI) and average pulse pressure (PP). ResultsWe analyzed 214 cerebral aneurysm patients and 234 controls. Patients in the aneurysm group were predominantly female and had a higher incidence of hypertension, diabetes mellitus, and vascular disease. They also demonstrate elevated AASI and average PP. When stratified by the occurrence of subarachnoid hemorrhage (SAH) or unfavorable neurological outcome, the AASI and average PP were not highly associated with the occurrence of SAH but were highly associated with unfavorable neurological outcomes. After multivariable analysis, both the AASI and average PP were no longer associated with unfavorable neurological outcomes, however elevated age, strongly linked with arterial stiffness, became a key predictive variable. ConclusionReadily obtained intraoperative surrogates of arterial stiffening demonstrates its presence in those with cerebral aneurysm disease and the extent that it does it may meaningfully direct their clinical course. However, multivariable analysis demonstrates limitations of using arterial stiffness measures to predict clinical outcomes.

Prevalence, trends, and outcomes of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage in the USA.

Cerebral infarction remains an important cause of death or disability in patients with aneurysmal subarachnoid hemorrhage (SAH). The prevalence, trends, and outcomes of cerebral infarction in patients with aneurysmal SAH at a national level are not known. We identified the proportion of patients who develop cerebral infarction (ascertained using validated methodology) among patients with aneurysmal SAH and annual trends using the Nationwide Inpatient Sample (NIS) from 2016 to 2021. We analyzed the effect of cerebral infarction on in-hospital mortality, routine discharge without palliative care (based on discharge disposition), poor outcome defined by the NIS SAH outcome measure, and length and costs of hospitalization after adjusting for potential confounders. A total of 35,305 (53.6%) patients developed cerebral infarction among 65,840 patients with aneurysmal SAH over a 6-year period. There was a trend toward an increase in the proportion of patients who developed cerebral infarction from 51.5% in 2016 to 56.1% in 2021 (p trend p<.001). Routine discharge was significantly lower (30.5% vs. 37.8%, odds ratio [OR] 0.82, 95% confidence interval [CI] 0.75-0.89, p<.001), and poor outcome defined by NIS-SAH outcome measure was significantly higher among patients with cerebral infarction compared with those without cerebral infarction (67.4% vs. 59.3%, OR 1.29, 95% CI 1.18-1.40, p<.001). There was no difference in in-hospital mortality (13.0% vs. 13.6%, OR 0.94, 95% CI 0.85-1.05, p =.30). The length of stay (median 18 days [interquartile range [IQR] 13-25] vs. 14 days [IQR 9-20]), coefficient 3.04, 95% CI 2.44-3.52 and hospitalization cost (median $96,823vs. $71,311, coefficient 22,320, 95% CI 20,053-24,587) were significantly higher among patients who developed cerebral infarction compared with those who did not develop cerebral infarction. Cerebral infarction was seen in 54% of the patients with a trend toward an increase in the affected proportion of patients with aneurysmal SAH. Patients with cerebral infarction had higher rates of adverse outcomes and required higher resources during hospitalization.

Comprehensive Management and Clinical Outcomes in Subarachnoid Hemorrhage: A Case Report

Comprehensive Management and Clinical Outcomes in Subarachnoid Hemorrhage: A Case Report

High Plasma D-Dimer Levels Correlate with Ictal Infarction and Poor Outcomes in Spontaneous Subarachnoid Hemorrhage

Early brain injury is the leading cause of poor outcomes in spontaneous subarachnoid hemorrhage (sSAH). Plasma D-dimer levels and acute cerebral ischemia have been highlighted as relevant findings in early brain injury; however, their correlation has not been substantially investigated. This retrospective, single-center cohort study was conducted at a tertiary emergency medical center from January 2004 to June 2022. Consecutive patients with sSAH who presented within 12hours of ictus and underwent magnetic resonance imaging within 3days were included. We assessed the correlation of plasma D-dimer levels with acute ischemic lesions detected on the diffusion-weighted imageing and the clinical characteristics. Among 402 eligible patients (mean age, 63.5years; 62.7% women; median time from onset to arrival, 45.5minutes), 140 (34.8%) had acute ischemic lesions. Higher plasma D-dimer levels linearly correlated with worse neurological grades, more severe SAH on initial computed tomography, acute ischemic lesions, and poor outcomes, except for patients with neurogenic stunned myocardium. In the multivariate analysis, acute ischemic lesions were significantly associated with worse neurological grades, higher plasma D-dimer levels, bilateral loss of light reaction, and advanced age. The receiver operating characteristic curve analysis showed D-dimer levels as excellent predictors for acute ischemic lesions (area under the curve, 0.897; cut-off value, 5.7μg/mL; P<0.0001) and unfavorable outcomes (area under the curve, 0.786; cut-off value, 4.0μg/mL; P<0.0001). High plasma D-dimer levels correlated with the appearance of acute ischemic lesions on diffusion-weighted imaging and were dose-dependently associated with worse neurological grades, more severe hemorrhage, and worse outcomes.

The potential of disulfiram as a drug to improve the prognosis after the onset of subarachnoid hemorrhage

Subarachnoid hemorrhage due to rupture of intracranial aneurysms has a poor outcome, making this disease being the social problem. Inflammation evoked by the increase in intracranial pressure and the clot in the subarachnoid space after the onset of SAH exacerbates neuronal death and vasospasm, resulting in the poor outcome and severe aftereffects. Here, FROUNT mediates CCR2 and CCR5 signaling as an intracellular molecule binding to these chemoattractant receptors which facilitate the migration of inflammatory cells, such as macrophages, in situ to trigger inflammation there. Animal model of subarachnoid hemorrhage was established in rats through intrathecal injection of autologous blood. The effect of the FROUNT inhibitor, disulfiram, on survival rate, neuronal death in hippocampus or vasospasm was then examined. The intrathecal administration of disulfiram significantly suppressed the infiltration of CD68-positive macrophages and myeloperoxidase-positive neutrophils toward the clot in the cistern in situ. In this condition, disulfiram ameliorated the death of animals after the onset of subarachnoid hemorrhage in rats. In addition, disulfiram suppressed both the two major events after subarachnoid hemorrhage, the neuronal death in hippocampus and vasospasm. The pharmacological inhibition of CCR2 and CCR5 signaling by disulfiram could thus be the therapeutic strategy to improve the outcome of subarachnoid hemorrhage.

Pitfalls of single-study external validation illustrated with a model predicting functional outcome after aneurysmal subarachnoid hemorrhage

BackgroundPrediction models are often externally validated with data from a single study or cohort. However, the interpretation of performance estimates obtained with single-study external validation is not as straightforward as assumed. We aimed to illustrate this by conducting a large number of external validations of a prediction model for functional outcome in subarachnoid hemorrhage (SAH) patients.MethodsWe used data from the Subarachnoid Hemorrhage International Trialists (SAHIT) data repository (n = 11,931, 14 studies) to refit the SAHIT model for predicting a dichotomous functional outcome (favorable versus unfavorable), with the (extended) Glasgow Outcome Scale or modified Rankin Scale score, at a minimum of three months after discharge. We performed leave-one-cluster-out cross-validation to mimic the process of multiple single-study external validations. Each study represented one cluster. In each of these validations, we assessed discrimination with Harrell’s c-statistic and calibration with calibration plots, the intercepts, and the slopes. We used random effects meta-analysis to obtain the (reference) mean performance estimates and between-study heterogeneity (I2-statistic). The influence of case-mix variation on discriminative performance was assessed with the model-based c-statistic and we fitted a “membership model” to obtain a gross estimate of transportability.ResultsAcross 14 single-study external validations, model performance was highly variable. The mean c-statistic was 0.74 (95%CI 0.70–0.78, range 0.52–0.84, I2 = 0.92), the mean intercept was -0.06 (95%CI -0.37–0.24, range -1.40–0.75, I2 = 0.97), and the mean slope was 0.96 (95%CI 0.78–1.13, range 0.53–1.31, I2 = 0.90). The decrease in discriminative performance was attributable to case-mix variation, between-study heterogeneity, or a combination of both. Incidentally, we observed poor generalizability or transportability of the model.ConclusionsWe demonstrate two potential pitfalls in the interpretation of model performance with single-study external validation. With single-study external validation. (1) model performance is highly variable and depends on the choice of validation data and (2) no insight is provided into generalizability or transportability of the model that is needed to guide local implementation. As such, a single single-study external validation can easily be misinterpreted and lead to a false appreciation of the clinical prediction model. Cross-validation is better equipped to address these pitfalls.

Outcome of Aneurysmal Subarachnoid Hemorrhage Not Altered With Transatlantic Airplane Transfer: A Bicentric Matched Case-control Study.

It is recommended that ruptured cerebral aneurysms are treated in a high-volume center within 72 hours of ictus. We assessed the impact of long-distance aeromedical evacuation in patients presenting aSAH. This case-control study compared patients with aneurysmal subarachnoid hemorrhage (aSAH) who had a 6750km air transfer from Guadeloupe (a Caribbean island) to Paris, France, for neurointerventional management in a tertiary center with a matched cohort from Paris region treated in the same center over a 10-year period (2010 to 2019). The 2 populations were matched on age, sex, World Federation of Neurological Surgeons score, and Fisher score. The primary outcome was a 1-year modified Rankin Scale score ≤3. Secondary outcomes included time from diagnosis to securing aneurysm, 1-year mortality, and a cost analysis. Among 128 consecutive aSAH transferred from Guadeloupe, 93 were matched with 93 patients from the Paris area. The proportion of patients with 1-year modified Rankin Scale ≤3 (75% vs 82%, respectively; P= 0.5) and 1-year mortality (18% vs 14%, respectively; P= 0.2) was similar in the Guadeloupe and Paris groups. The median (interquartile range: Q1, Q3) time from diagnosis to securing the aneurysm was higher in the patients from Guadeloupe than those from Paris (48 [30, 63] h vs 23 [12, 24] h, respectively; P< 0.001). Guadeloupean patients received mechanical ventilation (58% vs 38%; P< 0.001) and external ventricular drainage (55% vs 39%; P= 0.005) more often than those from Paris. The additional cost of treating a Guadeloupe patient in Paris was estimated at 7580 Euros or 17% of the estimated cost in Guadeloupe. Long-distance aeromedical evacuation of patients with aSAH from Guadeloupe to Paris resulted in a 25-hour increase in time to aneurysm coiling embolization time but did not impact 1-year functional outcomes or mortality.

A Randomised Controlled Trial of SFX-01 After Subarachnoid Haemorrhage - The SAS Study.

SFX-01 is a novel drug for clinical delivery of sulforaphane (SFN). SFN is a potent nuclear factor erythroid 2-related factor 2 activator that reduces inflammation and oxidation, improving outcomes after subarachnoid haemorrhage (SAH) in animal models. This was a multi-centre, double-blind, placebo-controlled, parallel-group randomised clinical trial to evaluate the safety, pharmacokinetics and efficacy of 28days of SFX-01 300mg BD in patients aged 18-80 with spontaneous SAH and high blood load on CT. Primary outcomes were (1) safety, (2) plasma and CSF SFN and metabolite levels and (3) vasospasm on transcranial doppler ultrasound. Secondary outcomes included CSF haptoglobin and malondialdehyde and clinical outcome on the modified Rankin Scale (mRS) and SAH outcome tool (SAHOT). A total of 105 patients were randomised (54 SFX-01, 51 placebo). There were no differences in adverse events other than nausea (9 SFX-01 (16.7%), 1 placebo (2.0%)). SFN, SFN-glutathione and SFN-N-acetyl-cysteine AUClast were 16.2, 277 and 415h × ng/ml. Plasma SFN was higher in GSTT1 null individuals (t = 2.40, p = 0.023). CSF levels were low with many samples below the lower limit of quantification and predicted by the CSF/serum albumin ratio (R2 = 0.182, p = 0.039). There was no difference in CSF haptoglobin (1.981 95%CI 0.992-3.786, p = 0.052) or malondialdehyde (1.12 95%CI 0.7477-1.687, p = 0.572) or middle cerebral artery flow velocity (1.04 95%CI 0.903-1.211, p = 0.545) or functional outcome (mRS 1.647 95%CI 0.721-3.821, p = 0.237, SAHOT 1.082 95%CI 0.464-2.525, p = 0.855). SFX-01 is safe and effective for the delivery of SFN in acutely unwell patients. SFN penetrated CSF less than expected and did not reduce large vessel vasospasm or improve outcome. Trial registration: NCT02614742 clinicaltrials.gov.

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

Whether 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. A total of 472 patients admitted within 72h 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). Compared 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). Women 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.

Impact of thyroid hormone replacement therapy on the course and functional outcome of aneurysmal subarachnoid hemorrhage

BackgroundThyroid hormones were reported to exert neuroprotective effects after ischemic stroke by reducing the burden of brain injury and promoting post-ischemic brain remodeling.ObjectiveWe aimed to analyze the value of thyroid hormone replacement therapy (THRT) due to pre-existing hypothyroidism on the clinical course and outcome of aneurysmal subarachnoid hemorrhage (SAH).MethodsSAH individuals treated between January 2003 and June 2016 were included. Data on baseline characteristics of patients and SAH, adverse events and functional outcome of SAH were recorded. Study endpoints were cerebral infarction, in-hospital mortality and unfavorable outcome at 6 months. Associations were adjusted for outcome-relevant confounders.Results109 (11%) of 995 individuals had THRT before SAH. Risk of intracranial pressure- or vasospasm-related cerebrovascular events was inversely associated with presence of THRT (p = 0.047). In multivariate analysis, THRT was independently associated with lower risk of cerebral infarction (adjusted odds ratio [aOR] = 0.64, 95% confidence interval [CI] = 0.41–0.99, p = 0.045) and unfavorable outcome (aOR = 0.50, 95% CI = 0.28–0.89, p = 0.018), but not with in-hospital mortality (aOR = 0.69, 95% CI = 0.38–1.26, p = 0.227).ConclusionSAH patients with THRT show lower burden of ischemia-relevant cerebrovascular events and more favorable outcome. Further experimental and clinical studies are required to confirm our results and elaborate the mechanistic background of the effect of THRT on course and outcome of SAH.

Association of Fluid Balance and Hemoglobin Decline With Neurological Outcome After Aneurysmal Subarachnoid Hemorrhage.

To explore the relationship between fluid balance and hemoglobin decline with secondary infarctions and neurologic outcome in aneurysmal subarachnoid hemorrhage (aSAH) patients. Secondary analysis of the Earlydrain trial, a prospective randomized controlled study investigating prophylactic lumbar drain use in aSAH patients. Patients with aSAH treated in ICUs at 19 tertiary hospitals in Germany, Switzerland, and Canada. From January 2011 to January 2016, 287 patients were enrolled in the Earlydrain trial. Only files with complete information on both daily hemoglobin and balance values were used, leaving 237 patients for analysis. Investigation of fluid balance management and hemoglobin levels during the initial 8 days post-aSAH to establish thresholds for unfavorable outcomes and assess their impact on secondary infarctions and 6-month neurologic outcome on the modified Rankin Scale (mRS). Patients with unfavorable outcome after 6 months (mRS > 2) showed greater hemoglobin decline and increased cumulative fluid balance. A significant inverse relationship existed between fluid balance and hemoglobin decline. Thresholds for unfavorable outcome were 10.4 g/dL hemoglobin and 4894 mL cumulative fluid balance in the first 8 days. In multivariable analysis, fluid balance, but not fluid intake, remained significantly associated with unfavorable outcome, while the influence of hemoglobin lessened. Fluid balance but not hemoglobin related to secondary infarctions, with the effect being significant after inverse probability of treatment weighting. Transfusion was associated with unfavorable outcomes. Increased fluid balance influences hemoglobin decline through hemodilution. Fluid overload, rather than a slight decrease in hemoglobin levels, appears to be the primary factor contributing to poor outcomes in aSAH patients. The results suggest aiming for euvolemia and that a modest hemoglobin decline may be tolerated. It may be advisable to adopt a restrictive approach to transfusions, as they can potentially have a negative effect on outcome.

GPR30 alleviated subarachnoid hemorrhage-induced blood-brain barrier dysfunction by activating the PI3K/Akt and Nrf2/HO-1 pathways.

The blood-brain barrier (BBB) plays a critical role in the development and outcome of subarachnoid hemorrhage (SAH). This study focuses on the potential mechanism by which G-protein-coupled estrogen receptor 30 (GPR30) affects the BBB after SAH. A rat SAH model was established using an intravascular perforation approach. G1 (GPR30 agonist) was administered to investigate the mechanism of BBB damage after SAH. Brain water content, Western blotting, Evans blue leakage, and immunofluorescence staining were performed. Brain microvascular endothelial cells were induced by hemin to establish SAH model in vitro. By adding LY294002 [a phosphatidylinositol 3-kinase (PI3K) blocker] and zinc protoporphyrin IX (ZnPP IX) [a heme oxygenase 1 (HO-1) antagonist], the mechanism of improving BBB integrity through the activation of GPR30 was studied. In vivo, GPR30 activation improved BBB disruption, as evidenced by decreased cerebral edema, downregulated albumin expression, and reduced extravasation of Evans blue and IgG after G1 administration in SAH rats. Moreover, SAH downregulated the levels of tight junction (TJ) proteins, whereas treatment with G1 reversed the effect of SAH. The protective effect of G1 on BBB integrity in vitro was consistent with that in vivo, as evidenced by G1 reducing the impact of hemin on transendothelial electrical resistance (TEER) value, dextran diffusivity, and TJ protein levels in brain microvascular endothelial cells. In addition, G1 activated the PI3K/ protein kinase B (Akt) and nuclear factor erythroid 2-related factor 2 (Nrf2)/HO-1 pathways both in vivo and in vitro. Furthermore, the administration of LY294002 and ZnPP IX partially reversed the protective effect of G1 on BBB integrity in hemin-stimulated cells. We demonstrated that the activation of GPR30, at least partly through the PI3K/Akt and Nrf2/HO-1 pathways, alleviated BBB damage both in vivo and in vitro. This study introduced a novel therapeutic approach for protecting the BBB after SAH.NEW & NOTEWORTHY The PI3K/Akt and Nrf2/HO-1 pathways might be potential mechanisms by which GPR30 protected the integrity of the BBB in SAH models. Therefore, treatment of SAH with GPR30 activator might be a promising therapeutic strategy.

Incidence of Rebleed Following Cerebrospinal Fluid (CSF) Drainage in Poor Grade Subarachnoid Hemorrhage: An Institutional Experience.

The outcome of poor grade subarachnoid hemorrhage (SAH) is dismal. Some of these patients need cerebrospinal fluid (CSF) drainage procedure for the hydrocephalus and intraventricular hemorrhage (IVH) which may precipitate rebleeding. However, aneurysmal rebleed following CSF drainage procedure is controversial. Our study aimed at analyzing the effect of CSF drainage procedure on aneurysmal rebleeding. We retrospectively analyzed the records of all the consecutive patients diagnosed with poor grade aneurysmal SAH over three year period. Patients initially requiring either external ventricular drainage (EVD) or lumbar drain (LD) were included in the study group, and the rest (not requiring drainage) were included in the control group. Rebleeding was confirmed on computed tomography. The factors affecting rebleeding were analyzed. Overall 194 patients with poor grade SAH were enrolled in the study (91 males: 103 females; mean age: 50.6 years). The study group had 91 patients (83 EVD and 8 LD) while 103 patients were in the control group. Posterior circulation aneurysms, poor grade SAH, hydrocephalus, and IVH were more common in the study group P < 0.001. The rebleeding rate was 7.6% in the study group and 8.7% in the control group. On univariate analysis size >1 cm, multiplicity, multilobularity, vasospasm, and CSF drainage were significant risk factors for rebleeding (P < 0.001). On multivariate analysis aneurysm size >1 cm, CSF overdrainage >250 ml/day were significantly associated with risk of rebleeding. Ventricular drainage is essential to relieve acute hydrocephalus and drain IVH in SAH and we found no significant association between CSF drainage and rebleeding. However, rapid overdrainage of CSF can lead to aneurysm rupture, hence controlled controlled CSF drainage should be undertaken.