Twelve controversial questions in aneurysmal subarachnoid hemorrhage / Doce preguntas controvertidas en hemorragia subaracnoidea aneursmática

Critical care management of aneurysmal subarachnoid hemorrhage (aSAH) remains a major challenge. Despite the recent publication of guidelines from the American Heart Association/American Stroke Association and the Neurocritical Care Society, there are many controversial questions in the intensive care unit (ICU) management of this population. The authors provide an analysis of common issues in the ICU and provide guidance on the daily management of this specific population of neurocritical care patients. (AU)

El manejo en la unidad de cuidados intensivos (UCI) de los pacientes con hemorragia subaracnoidea aneurismática continua siendo un reto. A pesar de la publicación de las guías de la American Heart Association/American Stroke Association y la Neurocritical Care Society todavía existen muchos aspectos controvertidos en el manejo de esta población en la UCI. Los autores proporcionan un detenido análisis de los problemas habituales en la UCI y proporcionan recomendaciones en el manejo diario de esta población específica de pacientes neurocríticos. (AU)

Pharmacological Inhibition of Epidermal Growth Factor Receptor Prevents Intracranial Aneurysm Rupture by Reducing Endoplasmic Reticulum Stress.

BACKGROUND: Multiple pathways and factors are involved in the rupture of intracranial aneurysms. The EGFR (epidermal growth factor receptor) has been shown to mediate inflammatory vascular diseases, including atherosclerosis and aortic aneurysm. However, the role of EGFR in mediating intracranial aneurysm rupture and its underlying mechanisms have yet to be determined. Emerging evidence indicates that endoplasmic reticulum (ER) stress might be the link between EGFR activation and the resultant inflammation. ER stress is strongly implicated in inflammation and apoptosis of vascular smooth muscle cells, both of which are key components of the pathophysiology of aneurysm rupture. Therefore, we hypothesized that EGFR activation promotes aneurysmal rupture by inducing ER stress. METHODS: Using a preclinical mouse model of intracranial aneurysm, we examined the potential roles of EGFR and ER stress in developing aneurysmal rupture. RESULTS: Pharmacological inhibition of EGFR markedly decreased the rupture rate of intracranial aneurysms without altering the formation rate. EGFR inhibition also significantly reduced the mRNA (messenger RNA) expression levels of ER-stress markers and inflammatory cytokines in cerebral arteries. Similarly, ER-stress inhibition also significantly decreased the rupture rate. In contrast, ER-stress induction nullified the protective effect of EGFR inhibition on aneurysm rupture. CONCLUSIONS: Our data suggest that EGFR activation is an upstream event that contributes to aneurysm rupture via the induction of ER stress. Pharmacological inhibition of EGFR or downstream ER stress may be a promising therapeutic strategy for preventing aneurysm rupture and subarachnoid hemorrhage.

Does the use of oral contraceptives or hormone replacement therapy offer protection against the formation or rupture of intracranial aneurysms in women?: a systematic review and meta-analysis.

OBJECTIVE: The aim of this study was to carry out a systematic review of the literature with meta-analysis to evaluate the effect of using oral contraceptive and hormone replacement therapy as a protective factor in the formation of intracranial aneurysms and subarachnoid hemorrhage. METHODS: This is a systematic review of the literature with meta-analysis, using PubMed and Embase as databases and the PRISMA method. Case-control and cohort studies published until December 2022 were included in this review. RESULTS: Four studies were included in this review; three of which were eligible for meta-analysis. Regarding the use of oral contraceptive and the development of subarachnoid hemorrhage, there was a lower risk of aneurysm rupture with an odds ratio 0.65 (confidence interval 0.5-0.85). In the analysis of patients using hormone replacement therapy and developing subarachnoid hemorrhage, there was also a lower risk of aneurysm rupture with an OR 0.54 (CI 0.39-0.74). Only one article analyzed the formation of intracranial aneurysm and the use of hormone replacement therapy and oral contraceptive, and there was a protective effect with the use of these medications. oral contraceptive: OR 2.1 (CI 1.2-3.8) and hormone replacement therapy: OR 3.1 (CI 1.5-6.2). CONCLUSION: The use of hormone replacement therapy and oral contraceptive has a protective effect in intracranial aneurysm rupture and formation.

Suppression of MALAT1 alleviates neurocyte apoptosis and reactive oxygen species production through the miR-499-5p/SOX6 axis in subarachnoid hemorrhage.

Subarachnoid hemorrhage (SAH), a common devastating cerebrovascular accident, is a great threat to human health and life. Exploration of the potential therapeutic target of SAH is urgently needed. Previous studies showed that long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes cell apoptosis in various diseases, while its role in SAH remains unclear. In our study, we established a mouse model of SAH and used the oxyhemoglobin (OxyHb) to induce neuronal injury in vitro. Interestingly, MALAT1 was found upregulated in brain tissues of SAH mice and OxyHb-stimulated neurons. In addition, knockdown of MALAT1 attenuated apoptosis and decreased reactive oxygen species (ROS) production in OxyHb-stimulated neurons. Mechanistically, we demonstrated that MALAT1 bound with miR-499-5p. Furthermore, our findings indicated that miR-499-5p bound to SOX6 3' untranslated region (UTR) and negatively regulated SOX6 mRNA and protein levels. Rescue assays suggested that SOX6 overexpression counteracted the effects of MALAT1 knockdown on neurocyte apoptosis, and ROS production in OxyHb-stimulated neurons. The in vivo assays indicated that knockdown of MALAT1 improved brain injury of SAH mice. Our study demonstrates that silencing of MALAT1 alleviates neurocyte apoptosis and reduces ROS production through the miR-499-5p/SOX6 axis after SAH injury.

Microsurgery versus embolization: different risk factors for short- and long- term outcomes of patients with ruptured aneurysms

Purpose: To evaluate the risk factors for poor outcomes after surgical and endovascular treatment of aneurysmal subarachnoid hemorrhage (aSAH). Methods: Patients with ≥ 18-years of age and aSAH were included, while patients who died within 12 h of admission or lost follow-up were excluded. All participants underwent standardized clinical and radiological assessment on admission and were reassessed at discharge and at 6-months follow-up using the Glasgow Outcome Scale (GOS). Results: Death at discharge was associated with female gender, anterior communication artery (ACoA) aneurysm location and presence of atherosclerotic plaque in the surgical group, and with age in the endovascular group. Both groups had clinical condition on follow-up associated with mFisher score on admission and hypertension. GOS on follow-up was also associated with presence of atherosclerotic plaque and multiple aneurysms in surgical group, and with age in endovascular group. Conclusions: Subjects treated surgically are prone to unfavorable outcomes if atherosclerotic plaques and multiple aneurysms are present. In patients with endovascular treatment, age was the main predictor of clinical outcome.

Tranexamic acid for subarachnoid hemorrhage: A systematic review and meta-analysis.

BACKGROUND: The efficacy of tranexamic acid for subarachnoid hemorrhage remains controversial. Thus, we conduct this meta-analysis to explore the efficacy of tranexamic acid for subarachnoid hemorrhage. METHODS: PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systematically searched. Randomized controlled trials (RCTs) assessing the effect of tranexamic acid on subarachnoid hemorrhage were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. This meta-analysis was performed using the random-effect model. RESULTS: Five RCTs and 2359 patients were included in the meta-analysis. Overall, compared with control intervention for subarachnoid hemorrhage, tranexamic acid was associated with significantly reduced risk of rebleeding (Odd ratio [OR] =0.62; 95% confidence interval [CI] =0.41 to 0.93; P = 0.02), but had no influence on mortality (OR = 0.94; 95% CI = 0.75 to 1.18; P = 0.61), poor outcome (OR = 0.95; 95% CI = 0.61 to 1.48; P = 0.82), hydrocephalus (OR = 1.17; 95% CI = 0.94 to 1.46; P = 0.17) or delayed cerebral ischemia (OR = 1.26; 95% CI = 0.78 to 2.04; P = 0.34). CONCLUSIONS: Tranexamic acid may be effective to reduce the risk of rebleeding in patients with subarachnoid hemorrhage.

Warning Signs in the Era of Unruptured Intracranial Aneurysms: Report on 2 Cases of Fatal Aneurysmal Hemorrhage.

INTRODUCTION: The timing of treatment remains unresolved for patients with unruptured intracranial aneurysms (UIAs) and headaches, particularly when the pain is short term, localized, and related to the aneurysm site. We lack evidence to support the notion that when a headache accompanies an aneurysm, it elevates the risk of rupture. RESULTS: We describe 2 cases of fatal subarachnoid hemorrhage in patients with a history of headache and known aneurysms. Both of these patients had good indications for treatment: a young age and an aneurysm >7 mm, and both were qualified for elective surgery. However, both patients died of fatal aneurysm ruptures before the planned surgery. CONCLUSION: These cases suggested that treatment should be started as soon as possible, when a UIA is diagnosed based on a short-term period of severe headaches or when a UIA is observed and then severe headaches appear. There is no straightforward guideline for treatment timing in these patients. However, in this era of UIAs, the significance of sentinel headaches should be reevaluated. Given the incidence of headaches in the general population and the very low risk of aneurysm rupture, there may be a tendency to neglect the role of headache as a possible warning sign.

Ultra-Early Induction of General Anesthesia for Reducing Rebleeding Rates in Patients with Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: Rebleeding of aneurysmal subarachnoid hemorrhage (aSAH) is one of the significant risk factors for poor clinical outcome. The rebleeding risk is the highest during the acute phase with an approximate rebleeding rate of 9-17% within the first 24 h. Theoretically, general anesthesia can stabilize a patient's vital signs; however, its effectiveness as initial management for preventing post-aSAH rebleeding remains unclear. The purpose of this study was to determine the feasibility and safety of ultra-early general anesthesia induction for reducing the rebleeding rates among patients with aSAH. MATERIALS AND METHODS: We retrospectively evaluated patients with aSAH who were admitted to our department between January 2013 and December 2019. All the patients underwent ultra-early general anesthesia induction as initial management regardless of their severity. We evaluated the rebleeding rate before definitive treatment, factors influencing rebleeding, and general anesthesia complications. RESULTS: We included 191 patients with two-third of them having a poor clinical grade (World Federation of Neurological Society [WFNS] grade IV or V). The median duration from admission to general anesthesia induction was 22 min. Rebleeding before definitive treatment occurred in nine patients (4.7%). There were significant differences in the Glasgow Coma Scale score (p = 0.047), WFNS grade (p = 0.02), and dissecting aneurysm (p <0.001) between the rebleeding and non-rebleeding patients. There were no cases of unsuccessful tracheal intubation or rebleeding during general anesthesia induction. CONCLUSION: Ultra-early general anesthesia induction could be performed safely in patients with aSAH, regardless of the WFNS grade; moreover, it resulted in lower rebleeding rate than that reported in previous epidemiological reports.

The combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats.

Diabetics have a higher risk of developing cerebral vasospasms (CVSP) after subarachnoid hemorrhagic stroke than non-diabetics. Serotonin (5-HT) is one of the key vasoconstrictors released in the hemorrhagic blood and an important contributor to the etiology of CVSP. The combination of the ryanodine receptor blocker dantrolene and the Ca2+ channel blocker nimodipine significantly reduces phenylephrine (PHE)-induced vascular contraction in both diabetic and nondiabetic rats, but the effectiveness of this drug combination in reducing 5-HT-induced contraction is unknown. Dose-response curves for the 5-HT-induced contraction (from 0.1 nM to 100 µM) were performed on aortic rings from diabetic and non-diabetic rats after a 30-min incubation period with dantrolene, nimodipine, and both drugs in combination. In diabetic rats, 10 µM of dantrolene alone failed to reduce 5-HT-induced maximal contraction (Emax), but 50 µM reduced this parameter by 34% (n = 7, p < 0.05). In non-diabetic rats, by contrast, dantrolene did not modify the vascular response to 5-HT. 50 nM of nimodipine alone, however, reduced this parameter by 57% in diabetic rats (n = 10, p < 0.05), and by 34% in non-diabetic rats (n = 10, p < 0.05). In addition, concomitant administration of dantrolene and nimodipine reduced vascular reactivity to a similar extent in both diabetic (~ 60% reduction, n = 10, p < 0.05) and non-diabetic rats (~ 70% reduction, n = 10, p < 0.05). Moreover, the combination of nimodipine with the higher concentration of dantrolene significantly increased the EC50 values for the 5-HT-induced contraction curves in both diabetics (from 10.31 ± 1.17 µM to 19.26 ± 2.82; n = 10, p < 0.05) and non-diabetic rats (5.93 ± 0.54 µM to 15.80 ± 3.24; n = 10, p < 0.05). These results suggest that simultaneous administration of dantrolene and nimodipine has a synergistic effect in reducing 5-HT-induced vascular contraction under both diabetic and non-diabetic conditions. If our findings with rats are applicable to humans, concomitant administration of these drugs may represent a promising alternative for the management of CVSP in both diabetics and non-diabetics.

MerTK inhibits the activation of the NLRP3 inflammasome after subarachnoid hemorrhage by inducing autophagy.

The NLR family pyrin domain-containing 3 (NLRP3) multiprotein complex is associated with neuroinflammation and poor prognosis after subarachnoid hemorrhage (SAH). Accumulating evidence shows that Mer tyrosine kinase (MerTK) alleviates inflammatory responses via a negative feedback mechanism. However, the contribution and function of MerTK in SAH remain to be determined. In this study, we explored the role of MerTK during microglial NLRP3 inflammasome activation and evaluated its contribution to the outcome of SAH in mice. Activating MerTK with growth arrest-specific 6 (Gas6) alleviated brain edema, neuronal degeneration and neurological deficits after SAH by regulating neuroinflammation. Gas6 did not change the mRNA levels of Nlrp3 or Casp1 but decreased the protein expression of NLRP3, cleaved caspase1 (p20), interleukin-1ß and interleukin-18. Furthermore, Gas6 increased the expression of Beclin1, the ratio of LC3-II/LC3-I and the level of autophagic flux. Inhibiting autophagy with 3-MA reversed the inhibition of NLRP3 inflammasome activation and diminished the neuroprotective effects of Gas6. Thus, MerTK activation may exert protective effects by limiting neuroinflammation and promoting neurological recovery after SAH via autophagy induction.

MiR-706 alleviates white matter injury via downregulating PKCα/MST1/NF-κB pathway after subarachnoid hemorrhage in mice.

Increasing numbers of patients with spontaneous subarachnoid hemorrhage(SAH) who recover from surgery and intensive care management still live with cognitive impairment after discharge, indicating the importance of white matter injury at the acute stage of SAH. In the present study, standard endovascular perforation was employed to establish an SAH mouse model, and a microRNA (miRNA) chip was used to analyze the changes in gene expression in white matter tissue after SAH. The data indicate that 17 miRNAs were downregulated, including miR-706, miR-669a-5p, miR-669p-5p, miR-7116-5p and miR-195a-3p, while 13 miRNAs were upregulated, including miR-6907-5p, miR-5135, miR-6982-5p, miR-668-5p, miR-8119. Strikingly, miR-706 was significantly downregulated with the highest fold change. Further experiments confirmed that miR-706 could alleviate white matter injury and improve neurological behavior, at least partially by inhibiting the PKCα/MST1/NF-κB pathway and the release of inflammatory cytokines. These results might provide a deeper understanding of the pathophysiological processes in white matter after SAH, as well as potential therapeutic strategies for the translational research.

Neuroprotective Effects of Early Brain Injury after Subarachnoid Hemorrhage in Rats by Calcium Channel Mediating Hydrogen Sulfide.

The present study explored the modulating apoptosis effect of hydrogen sulfide (H2S) in subarachnoid hemorrhage (SAH) rats and its exact mechanism. A rat SAH model established by intravascular puncturing was used for the present study. After giving NaHS (donor of H2S), an L-type calcium channel opener (Bay K8644), or a calcium channel agonist (nifedipine), the neurological function of the rats, associated pathological changes, and expression of apoptosis-related proteins (Bcl-2, Bax, and caspase-3) and microtubule-associated protein (MAP-2) were examined. The concentration of H2S and expression of cystathionine beta synthase in the hippocampus changed upon early brain injury (EBI) after SAH. Compared with the SAH group, the neurological function of the rats and microstructure observed by electron microscopy were better in the SAH + NaHS group and SAH + Bay K8644 group. It was observed that apoptosis was more obvious in the SAH group than in the control group and was alleviated in the SAH + NaHS group. Furthermore, the alleviating effect of NaHS was partially weakened by nifedipine, indicating that the effect of anti-apoptosis in H2S might be correlated with the calcium channel. The expression of Bax and caspase-3 was elevated, while the expression of Bcl-2 decreased in the SAH group but improved in the SAH + NaHS and SAH + Bay K8644 group. Compared with the SAH + NaHS group, the expression of pro-apoptotic proteins was higher in the SAH + NaHS + nifedipine group. Therefore, upon EBI following SAH, the H2S system plays an important neurological protective effect by modulating the function of the L-type calcium channel and inhibiting apoptosis.

Relationship between aspirin use and subarachnoid hemorrhage: A systematic Review and meta-analysis.

BACKGROUND: Aspirin has been associated with a decreasing risk of subarachnoid hemorrhage due to its anti-inflammatory mechanism of action and potential protective properties against aneurysm growth. OBJECTIVE: To determine the association between aneurysmal subarachnoid hemorrhage and aspirin use. METHODS: A systematic review of the literature and a meta-analysis were performed across the PubMed database. The following keywords were used: "aspirin, acetylsalicylic acid, 2-acetyloxy-benzoic acid, ruptured intracranial aneurysm, aneurysmal subarachnoid hemorrhage, spontaneous subarachnoid hemorrhage, intracerebral hemorrhage, spontaneous aneurysmal hemorrhage, spontaneous intracerebral bleeding". Studies that were performed with animals or analyzed patients with traumatic brain injury were excluded. A total of five studies were included in our meta-analysis, with a total of 19,222 patients evaluated. Statistical analysis was performed to determine the association between the use of aspirin and the risk of subarachnoid hemorrhage. RESULTS: Aspirin use reduce the risk of subarachnoid hemorrhage (odds ratio [OR] 0.51, 95 % confidence interval [CI] 0.34-0.76). CONCLUSION: Although some previous studies suggested that aspirin may potentially reduce the risk of subarachnoid hemorrhage, our meta-analysis found an association between the reduction of risk of aneurysmal subarachnoid hemorrhage.

Mast Cell Promotes the Development of Intracranial Aneurysm Rupture.

BACKGROUND AND PURPOSE: Inflammation has emerged as a key component of the pathophysiology of intracranial aneurysms. Mast cells have been detected in human intracranial aneurysm tissues, and their presence was associated with intramural microhemorrhage and wall degeneration. We hypothesized that mast cells play a critical role in the development of aneurysmal rupture, and that mast cells can be used as a therapeutic target for the prevention of aneurysm rupture. METHODS: Intracranial aneurysms were induced in adult mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Aneurysm formation and rupture were assessed over 3 weeks. Roles of mast cells were assessed using a mast cell stabilizer (cromolyn), a mast cell activator (C48/80), and mice that are genetically lacking mature mast cells (KitW-sh/W-sh mice). RESULTS: Pharmacological stabilization of mast cells with cromolyn markedly decreased the rupture rate of aneurysms (80% versus 19%, n=10 versus n =16) without affecting the aneurysm formation. The activation of mast cells with C48/80 significantly increased the rupture rate of aneurysms (25% versus 100%, n=4 versus n=5) without affecting the overall rate of aneurysm formation. Furthermore, the genetic deficiency of mast cells significantly prevented aneurysm rupture (80% versus 25%, n=10 versus n=8, wild-type versus KitW-sh/W-sh mice). CONCLUSIONS: These results suggest that mast cells play a key role in promoting aneurysm rupture but not formation. Stabilizers of mast cells may have a potential therapeutic value in preventing intracranial aneurysm rupture in patients.

Unfavorable Outcome After Good Grade Aneurysmal Subarachnoid Hemorrhage: Exploratory Analysis.

OBJECTIVE: Patients with good-grade aneurysmal subarachnoid hemorrhage (aSAH) are thought to recover well, yet some do not. This work sought to identify predictors of unfavorable functional outcome after good-grade aSAH. METHODS: We performed a post-hoc analysis of the CONSCIOUS-1 trial. Patients with World Federation of Neurosurgical Societies grades I or II aSAH were included. The primary outcome was unfavorable functional outcome (defined as a modified Rankin Scale score >2) at 12 weeks. Parametric and nonparametric testing were used as appropriate. Variables were classified as modifiable or nonmodifiable, depending on whether they were present at patient admission. Stepwise logistic regression models were created for modifiable and nonmodifiable predictors of outcome. Independent predictors in the respective multivariate analyses were combined into a final multivariate regression model. RESULTS: We included 301 patients, 67 of whom (22%) had an unfavorable outcome. Of the nonmodifiable predictors, higher admission systolic blood pressure (P = 0.002) and female sex (P = 0.011) were independently associated with unfavorable outcome. Potentially modifiable independent predictors of outcome were delayed cerebral ischemia (P = 0.039), higher maximum temperature (0.036), suffering a respiratory system complication (P = 0.004), and suffering an intracranial hemorrhagic complication (P = 0.022). All variables found to be independently predictive of poor outcome in their respective models retained statistical significance in the combined multivariate analysis. CONCLUSIONS: About 1 in 5 good-grade aSAH patients enrolled in CONSCIOUS-1 suffered an unfavorable functional outcome. Admission systolic blood pressure, female sex, hyperthermia, delayed cerebral ischemia, respiratory complications, and intracranial hemorrhagic complications may be predictive of outcome.

ß-Caryophyllene Liposomes Attenuate Neurovascular Unit Damage After Subarachnoid Hemorrhage in Rats.

This study was conducted to prepare ß-caryophyllene loaded liposomes (BCP-LP) and investigated their effects on neurovascular unit (NVU) damage after subarachnoid hemorrhage (SAH) in rats. A blood injection into the pre-chiasmatic cistern was used to achieve SAH. BCP-LP were prepared, characterized and administrated to rats with SAH. The prepared BCP-LP were spherical with a size distribution of approximately 189.3 nm and Zeta potential of - 13.9 mV. Neurological scoring, the balance beam test, cerebral blood flow monitoring, brain edema and biochemical analyses were applied to evaluate the effects of BCP-LP on rat NVU damage after SAH. The results demonstrated that BCP-LP treatment improved neurological function disorder, balance ability and cerebral blood perfusion in rats. Brain edema detection and blood-brain barrier permeability detection revealed that BCP-LP could reduce brain edema and promote repairment of blood-brain barrier after SAH. Using the western blot experiments, we demonstrated that BCP-LP attenuated the loss of tight junction proteins Occludin and Zonula occludens-1, inhibit the high expression of VEGFR-2 and GFAP, and promote the repair of laminin. These results demonstrate the protective effect BCP-LP exert in the NVU after SAH in rats, and supports the use of BCP-LP for future study and therapy of SAH.

Association Between Aspirin Use and Risk of Aneurysmal Subarachnoid Hemorrhage: A Meta-analysis.

OBJECTIVE: To assess the association between aspirin use and risk of aneurysmal subarachnoid hemorrhage (aSAH). METHODS: A systematic search was performed in various databases updated on October 22, 2019. The heterogeneity test was performed for each outcome variable. Random-effect model and fixed-effect model were respectively conducted according to the heterogeneity statistics. Trial sequential analysis was used to control random errors. RESULTS: Ten studies involving 1,107,616 patients were involved in this meta-analysis. No significant association was shown between aspirin users and non-aspirin users regarding the risk of aSAH (odds ratio [OR]: 0.981, 95% confidential interval [CI]: 0.773-1.312, P = 0.897]. The results of subgroup analyses indicated that the risk of aSAH was notably associated with a short-term use of aspirin (<3 months) (OR: 1.697, 95% CI: 1.175-2.452, P = 0.005), but not aspirin use for 3-12 months (OR: 1.026, 95% CI: 0.609-1.730, P = 0.922), 1-3 years (OR: 0.942, 95% CI: 0.660-1.346, P = 0.744), >3 years (OR: 0.892, 95% CI: 0.573-1.389, P = 0.612), ≤2 times per week (OR: 0.857, 95% CI: 0.560-1.313, P = 0.479), ≥3 times per week (OR: 1.104, 95% CI: 0.555-2.193, P = 0.778) and former use (OR: 1.029, 95% CI: 0.482-2.196, P = 0.941). CONCLUSIONS: A short-term use of aspirin (<3 months) is associated with an elevated risk of aSAH, whereas the role of its long-term use in either decreasing or increasing the risk of aSAH still requires well-designed, large-scale randomized control trials for verification.

Update of the ULtra-early TRranexamic Acid after Subarachnoid Hemorrhage (ULTRA) trial: statistical analysis plan.

BACKGROUND: Recurrent bleeding from an intracranial aneurysm after subarachnoid hemorrhage (SAH) is associated with unfavorable outcome. Recurrent bleeding before aneurysm occlusion can be performed occurs in up to one in five patients and most often happens within the first 6 h after the primary hemorrhage. Reducing the rate of recurrent bleeding could be a major factor in improving clinical outcome after SAH. Tranexamic acid (TXA) reduces the risk of recurrent bleeding but has thus far not been shown to improve functional outcome, probably because of a higher risk of delayed cerebral ischemia (DCI). To reduce the risk of ultraearly recurrent bleeding, TXA should be administered as soon as possible after diagnosis and before transportation to a tertiary care center. If TXA is administered for a short duration (i.e., < 24 h), it may not increase the risk of DCI. The aim of this paper is to present in detail the statistical analysis plan (SAP) of the ULTRA trial (ULtra-early TRranexamic Acid after Subarachnoid Hemorrhage), which is currently enrolling patients and investigating whether ultraearly and short-term TXA treatment in patients with aneurysmal SAH improves clinical outcome at 6 months. METHODS/DESIGN: The ULTRA trial is a multicenter, prospective, randomized, open, blinded endpoint, parallel-group trial currently ongoing at 8 tertiary care centers and 16 of their referral centers in the Netherlands. Participants are randomized to standard care or to receive TXA at a loading dose of 1 g, immediately followed by 1 g every 8 h for a maximum of 24 h, in addition to standard care, as soon as SAH is diagnosed. In the TXA group, TXA administration is stopped immediately prior to treatment (coil or clip) of the causative aneurysm. Primary outcome is the modified Rankin Scale (mRS) score at 6 months after SAH, dichotomized into good (mRS 0-3) and poor (mRS 4-6) outcomes, assessed blind to treatment allocation. Secondary outcomes include case fatalities at 30 days and at 6 months and causes of poor clinical outcome. Safety outcomes are recurrent bleeding, DCI, hydrocephalus, per-procedural complications, and other complications such as infections occurring during hospitalization. Data analyses will be according to this prespecified SAP. TRIAL REGISTRATION: Netherlands Trial Register, NTR3272. Registered on 25 January 2012. ClinicalTrials.gov, NCT02684812. Registered on 17 February 2016.

Intra-arterial Administration of Verapamil for the Prevention and Treatment of Cerebral Angiospasm.

From 2013 to 2017, at the Burdenko Institute of Neurosurgery, intra-arterial verapamil for treatment of cerebral vasospasm following intracranial hemorrhage after aneurysm rupture was administered to 35 patients (total 75 procedures). The age is from 8 to 77 years. All ruptured aneurysms were treated: in 26 cases with open approach-clipping-and in 9 cases with endovascular occlusion. The procedure was carried out from 0 to 11 days after the operation. Severity of spasm was assessed by angiography and TCDU. Efficacy of the administration was assessed by TCDU 1 h after the procedure and by clinical evaluation of the patient's condition. The dose of verapamil was 15-50 mg (on average 40 mg) per procedure/per carotid pool and depended on the data of TCDU and clinical and radiological picture. The procedure was performed repeatedly (1-5 times) according to the indications and depending on the patient's condition, with an interval of 24 h. The procedure was effective as a preventive measure for care of patients in the initial stage of cerebral ischemia and was ineffective with a formed focus of ischemia. Endovascular administration of verapamil for treatment of cerebral vasospasm is a safe technique which positively affects the overall recovery of such patients.

Clinical relevance of short-term follow-up of unruptured intracranial aneurysms.

OBJECTIVE: Unruptured intracranial aneurysms are common incidental findings on brain imaging. Short-term follow-up for conservatively treated aneurysms is routinely performed in most cerebrovascular centers, although its clinical relevance remains unclear. In this study, the authors assessed the extent of growth as well as the rupture risk during short-term follow-up of conservatively treated unruptured intracranial aneurysms. In addition, the influence of patient-specific and aneurysm-specific factors on growth and rupture risk was investigated. METHODS: The authors queried their prospective institutional neurovascular registry to identify patients with unruptured intracranial aneurysms and short-term follow-up imaging, defined as follow-up MRA and/or CTA within 3 months to 2 years after initial diagnosis. Medical records and questionnaires were used to acquire baseline information. The authors measured aneurysm size at baseline and at follow-up to detect growth. Rupture was defined as a CT scan-proven and/or CSF-proven subarachnoid hemorrhage (SAH). RESULTS: A total of 206 consecutive patients with 267 conservatively managed unruptured aneurysms underwent short-term follow-up at the authors' center. Seven aneurysms (2.6%) enlarged during a median follow-up duration of 1 year (range 0.3-2.0 years). One aneurysm (0.4%) ruptured 10 months after initial discovery. Statistically significant risk factors for growth or rupture were autosomal-dominant polycystic kidney disease (RR 8.3, 95% CI 2.0-34.7), aspect ratio > 1.6 or size ratio > 3 (RR 10.8, 95% CI 2.2-52.2), and initial size ≥ 7 mm (RR 10.7, 95% CI 2.7-42.8). CONCLUSIONS: Significant growth of unruptured intracranial aneurysms may occur in a small proportion of patients during short-term follow-up. As aneurysm growth is associated with an increased risk of rupture, the authors advocate that short-term follow-up is clinically relevant and has an important role in reducing the risk of a potential SAH.