2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage: A Guideline From the American Heart Association/American Stroke Association.

AIM: The "2023 Guideline for the Management of Patients With Aneurysmal Subarachnoid Hemorrhage" replaces the 2012 "Guidelines for the Management of Aneurysmal Subarachnoid Hemorrhage." The 2023 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with aneurysmal subarachnoid hemorrhage. METHODS: A comprehensive search for literature published since the 2012 guideline, derived from research principally involving human subjects, published in English, and indexed in MEDLINE, PubMed, Cochrane Library, and other selected databases relevant to this guideline, was conducted between March 2022 and June 2022. In addition, the guideline writing group reviewed documents on related subject matter previously published by the American Heart Association. Newer studies published between July 2022 and November 2022 that affected recommendation content, Class of Recommendation, or Level of Evidence were included if appropriate. Structure: Aneurysmal subarachnoid hemorrhage is a significant global public health threat and a severely morbid and often deadly condition. The 2023 aneurysmal subarachnoid hemorrhage guideline provides recommendations based on current evidence for the treatment of these patients. The recommendations present an evidence-based approach to preventing, diagnosing, and managing patients with aneurysmal subarachnoid hemorrhage, with the intent to improve quality of care and align with patients' and their families' and caregivers' interests. Many recommendations from the previous aneurysmal subarachnoid hemorrhage guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.

The Clinical Impact of Recent Methamphetamine Exposure in Aneurysmal Subarachnoid Patients.

Background: Methamphetamines (MA) are a frequently used drug class with potent sympathomimetic properties that can affect cerebral vasculature. Conflicting reports in literature exist about the effect of exposure to MA on vasospasm risk and clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH). This study aimed to characterize the impact of recent MA use on the timing, severity and features of vasospasm in aneurysmal subarachnoid as well as neurological outcomes. Methods: We retrospectively screened 441 consecutive patients admitted to a tertiary care hospital with a diagnosis of SAH who underwent at least one cerebral digital subtraction angiogram (DSA). Patients were excluded if no urinary toxicology screen was performed within 24 hours of admission, if there was a diagnosis of non-aneurysmal SAH, or if ictus was greater than 72 hours from hospital admission. Vasospasm characteristics were collected from DSA and transcranial doppler (TCD) studies and demographic as well as clinical outcome data was abstracted from the chart. Results: 129 patients were included and 24 tested positive for MA. Among the 312 excluded patients, 281 did not have a urinary toxicology screen and 31 had a non-aneurysmal pattern of SAH or ictus occurring greater than 72 hours from hospital admission. No significant differences were found in respect to patient age, sex, or admission Hunt and Hess Score or Modified Fisher Scale based on MA use. There was no difference in the severity of vasospasm or time to peak severity using either TCD or DSA criteria on multivariate analysis. Aneurysms were more likely to be in the anterior circulation for both groups, however the MA cohort experienced less vasospasm involving the anterior circulation and more isolated posterior circulation vasospasm. There was no difference in delayed cerebral ischemia (DCI) incidence, length of ICU stay, need for ventriculoperitoneal shunt placement, functional outcome at discharge or hospital mortality. Interpretation: Recent MA use was not associated with worse vasospasm severity, time to vasospasm, or DCI in aSAH patients. Further investigations about localized MA effects in the posterior circulation and impact on long-term functional outcomes are warranted.

Intracranial Hemorrhage Rate and Lesion Burden in Patients With Familial Cerebral Cavernous Malformation.

Background Familial cerebral cavernous alformation (CCM) is an autosomal dominant disease caused by mutations in KRIT1, CCM2, or PDCD10. Cases typically present with multiple lesions, strong family history, and neurological symptoms, including seizures, headaches, or other deficits. Intracranial hemorrhage (ICH) is a severe manifestation of CCM, which can lead to death or long-term neurological deficits. Few studies have reported ICH rates and risk factors in familial CCM. We report ICH rates and assess whether CCM lesion burden, a disease severity marker, is associated with risk of symptomatic ICH during follow-up in a well-characterized cohort of familial CCM cases. Methods and Results We studied 386 patients with familial CCM with follow-up data enrolled in the Brain Vascular Malformation Consortium CCM Project. We estimated symptomatic ICH rates overall and stratified by history of ICH before enrollment. CCM lesion burden (total lesion count and large lesion size) assessed at baseline enrollment was tested for association with increased risk of subsequent ICH during follow-up using Cox regression models adjusted for history of ICH before enrollment, age, sex, and family structure and stratified on recruitment site. The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient-years (95% CI, 1.9-4.1). Those with ICH before enrollment had a follow-up ICH rate of 4.5 per 100 patient-years (95% CI, 2.6-8.1) compared with 2.0 per 100 patient-years (95% CI, 1.3-3.5) in those without (P=0.042). Total lesion count was associated with increased risk of ICH during follow-up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10-1.71], P=0.006). The symptomatic ICH rate for familial CCM cases was 2.8 per 100 patient-years (95% CI, 1.9-4.1). Those with ICH before enrollment had a follow-up ICH rate of 4.5 per 100 patient-years (95% CI, 2.6-8.1) compared with 2.0 per 100 patient-years (95% CI, 1.3-3.5) in those without (P=0.042). Total lesion count was associated with increased risk of ICH during follow-up (hazard ratio [HR], 1.37 per doubling of total lesion count [95% CI, 1.10-1.71], P=0.006). Conclusions Patients with familial CCM with prior history of an ICH event are at higher risk for rehemorrhage during follow-up. In addition, total CCM lesion burden is significantly associated with increased risk of subsequent symptomatic ICH; hence lesion burden may be an important predictor of patient outcome and aid patient risk stratification.

Intracranial Aneurysm Classifier Using Phenotypic Factors: An International Pooled Analysis.

Intracranial aneurysms (IAs) are usually asymptomatic with a low risk of rupture, but consequences of aneurysmal subarachnoid hemorrhage (aSAH) are severe. Identifying IAs at risk of rupture has important clinical and socio-economic consequences. The goal of this study was to assess the effect of patient and IA characteristics on the likelihood of IA being diagnosed incidentally versus ruptured. Patients were recruited at 21 international centers. Seven phenotypic patient characteristics and three IA characteristics were recorded. The analyzed cohort included 7992 patients. Multivariate analysis demonstrated that: (1) IA location is the strongest factor associated with IA rupture status at diagnosis; (2) Risk factor awareness (hypertension, smoking) increases the likelihood of being diagnosed with unruptured IA; (3) Patients with ruptured IAs in high-risk locations tend to be older, and their IAs are smaller; (4) Smokers with ruptured IAs tend to be younger, and their IAs are larger; (5) Female patients with ruptured IAs tend to be older, and their IAs are smaller; (6) IA size and age at rupture correlate. The assessment of associations regarding patient and IA characteristics with IA rupture allows us to refine IA disease models and provide data to develop risk instruments for clinicians to support personalized decision-making.

Geometric and Morphologic Features of Ruptured Intracranial Aneurysms Associated with Methamphetamine Use.

BACKGROUND: Methamphetamine (MA) use is associated with poor outcomes after aneurysmal subarachnoid hemorrhage (aSAH). MA exerts both hemodynamic and inflammatory effects, but whether these manifest with altered intracranial aneurysm (IA) remodeling is unknown. The objective of this study was to compare IA geometric and morphologic features in patients with and without MA detected on urine toxicology (Utox) at presentation. METHODS: We retrospectively reviewed 160 consecutive patients with SAH and Utox at time of admission. Geometric-morphologic IA characteristics were assessed by blinded neuroradiologists. Studied features were maximum sac diameter, location, size, ellipsoid volume, aspect ratio, size ratio, volume: neck ratio, dome: neck ratio, bottleneck factor, morphology (saccular, fusiform/dissecting, blister, mycotic), and presence of bleb, vasculopathy, or additional unruptured IA. RESULTS: Of 139/160 patients with aSAH, 23/139 (16.5%) were Utox MA+. There was no difference in aneurysm subtype frequency, presence of bleb, vasculopathy, or presence of an additional (unruptured) aneurysm with a trend toward posterior circulation location and higher Hunt and Hess grade (P = 0.09 for both) in the MA+ group. Maximum IA sac diameter, ellipsoid volume, dome-neck ratio, and size ratio were similar between groups. Only the aspect ratio (AR) differed between groups (MA+ = 2.20 vs. MA- = 1.74, P = 0.02). The AR remained a significant predictor of Utox MA+ in a multiple logistic regression analysis (odds ratio 1.87, 95% confidence interval 1.06-3.39). CONCLUSIONS: Active use of methamphetamine is independently associated with larger AR in patients with ruptured IA. This may indicate hazardous remodeling due to hemodynamic and/or inflammatory changes.

Endovascular Therapy for Intracranial Giant Cell Arteritis : Systematic Review, Technical Considerations and the Effect of Intra-arterial Calcium Channel Blockers.

BACKGROUND: Giant cell arteritis (GCA) is a systemic vasculitis that may cause ischemic stroke. Rarely, GCA can present with aggressive intracranial stenoses, which are refractory to medical therapy. Endovascular treatment (EVT) is a possible rescue strategy to prevent ischemic complications in intracranial GCA but the safety and efficacy of EVT in this setting are not well-described. METHODS: A systematic literature review was performed to identify case reports and series with individual patient-level data describing EVT for intracranial GCA. The clinical course, therapeutic considerations, and technique of seven endovascular treatments in a single patient from the authors' experience are presented. RESULTS: The literature review identified 9 reports of 19 treatments, including percutaneous transluminal angioplasty (PTA) with or without stenting, in 14 patients (mean age 69.6 ± 6.3 years). Out of 12 patients 8 (66.7%) with sufficient data had > 1 pre-existing cardiovascular risk factor. All patients had infarction on MRI while on glucocorticoids and 7/14 (50%) progressed despite adjuvant immunosuppressive agents. Treatment was PTA alone in 15/19 (78.9%) cases and PTA + stent in 4/19 (21.1%). Repeat treatments were performed in 4/14 (28.6%) of patients (PTA-only). Non-flow limiting dissection was reported in 2/19 (10.5%) of treatments. The indications, technical details, and results of PTA are discussed in a single illustrative case. We report the novel use of intra-arterial calcium channel blocker infusion (verapamil) as adjuvant to PTA and as monotherapy, resulting in immediate improvement in cerebral blood flow. CONCLUSION: Endovascular treatment, including PTA with or without stenting or calcium channel blocker infusion, may be effective therapies in medically refractory GCA with intracranial stenosis.

Somatic mosaicism in the MAPK pathway in sporadic brain arteriovenous malformation and association with phenotype.

OBJECTIVE: Sporadic brain arteriovenous malformation (BAVM) is a tangled vascular lesion characterized by direct artery-to-vein connections that can cause life-threatening intracerebral hemorrhage (ICH). Recently, somatic mutations in KRAS have been reported in sporadic BAVM, and mutations in other mitogen-activated protein kinase (MAPK) signaling pathway genes have been identified in other vascular malformations. The objectives of this study were to systematically evaluate somatic mutations in MAPK pathway genes in patients with sporadic BAVM lesions and to evaluate the association of somatic mutations with phenotypes of sporadic BAVM severity. METHODS: The authors performed whole-exome sequencing on paired lesion and blood DNA samples from 14 patients with sporadic BAVM, and 295 genes in the MAPK signaling pathway were evaluated to identify genes with somatic mutations in multiple patients with BAVM. Digital droplet polymerase chain reaction was used to validate KRAS G12V and G12D mutations and to assay an additional 56 BAVM samples. RESULTS: The authors identified a total of 24 candidate BAVM-associated somatic variants in 11 MAPK pathway genes. The previously identified KRAS G12V and G12D mutations were the only recurrent mutations. Overall, somatic KRAS G12V was present in 14.5% of BAVM lesions and G12D was present in 31.9%. The authors did not detect a significant association between the presence or allelic burden of KRAS mutation and three BAVM phenotypes: lesion size (maximum diameter), age at diagnosis, and age at ICH. CONCLUSIONS: The authors confirmed the high prevalence of somatic KRAS mutations in sporadic BAVM lesions and identified several candidate somatic variants in other MAPK pathway genes. These somatic variants may contribute to understanding of the etiology of sporadic BAVM and the clinical characteristics of patients with this condition.

Proceedings of the First Curing Coma Campaign NIH Symposium: Challenging the Future of Research for Coma and Disorders of Consciousness.

Coma and disorders of consciousness (DoC) are highly prevalent and constitute a burden for patients, families, and society worldwide. As part of the Curing Coma Campaign, the Neurocritical Care Society partnered with the National Institutes of Health to organize a symposium bringing together experts from all over the world to develop research targets for DoC. The conference was structured along six domains: (1) defining endotype/phenotypes, (2) biomarkers, (3) proof-of-concept clinical trials, (4) neuroprognostication, (5) long-term recovery, and (6) large datasets. This proceedings paper presents actionable research targets based on the presentations and discussions that occurred at the conference. We summarize the background, main research gaps, overall goals, the panel discussion of the approach, limitations and challenges, and deliverables that were identified.

Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation.

Brain arteriovenous malformations (bAVMs) are relatively rare, although their potential for secondary intracranial haemorrhage (ICH) makes their diagnosis and management essential to the community. Currently, invasive therapies (surgical resection, stereotactic radiosurgery and endovascular embolisation) are the only interventions that offer a reduction in ICH risk. There is no designated medical therapy for bAVM, although there is growing animal and human evidence supporting a role for bevacizumab to reduce the size of AVMs. In this single-arm pilot study, two patients with large bAVMs (deemed unresectable by an interdisciplinary team) received bevacizumab 5 mg/kg every 2 weeks for 12 weeks. Due to limitations of external funding, the intended sample size of 10 participants was not reached. Primary outcome measure was change in bAVM volume from baseline at 26 and 52 weeks. No change in bAVM volume was observed 26 or 52 weeks after bevacizumab treatment. No clinically important adverse events were observed during the 52-week study period. There were no observed instances of ICH. Sera vascular endothelial growth factor levels were reduced at 26 weeks and returned to baseline at 52 weeks. This pilot study is the first to test bevacizumab for patients with bAVMs. Bevacizumab therapy was well tolerated in both subjects. No radiographic changes were observed over the 52-week study period. Subsequent larger clinical trials are in order to assess for dose-dependent efficacy and rarer adverse drug effects. Trial registration number: NCT02314377.

International Practice Variability in Treatment of Aneurysmal Subarachnoid Hemorrhage.

Prior research suggests substantial between-center differences in functional outcome following aneurysmal subarachnoid hemorrhage (aSAH). One hypothesis is that these differences are due to practice variability. To characterize practice variability, we sent a survey to 230 centers, of which 145 (63%) responded. Survey respondents indicated that an estimated 65% of ruptured aneurysms were treated endovascularly. Sixty-five percent of aneurysms were treated within 24 h of symptom onset, 18% within 24-48 h, and eight percent within 48-72 h. Centers in the United States (US) and Europe (EU) treat aneurysms more often endovascularly (72% and 70% vs. 51%, respectively, US vs. other p < 0.001, and EU vs. other p < 0.01) and more often within 24 h (77% and 64% vs. 46%, respectively, US vs. other p < 0.001, EU vs. other p < 0.01) compared to other centers. Most centers aim for euvolemia (96%) by administrating intravenous fluids to 0 (53%) or +500 mL/day (41%) net fluid balance. Induced hypertension is more often used in US centers (100%) than in EU (87%, p < 0.05) and other centers (81%, p < 0.05), and endovascular therapies for cerebral vasospasm are used more often in US centers than in other centers (91% and 60%, respectively, p < 0.05). We observed significant practice variability in aSAH treatment worldwide. Future comparative effectiveness research studies are needed to investigate how practice variation leads to differences in functional outcome.

Maternal and Fetal Outcomes in Women with Brain Arteriovenous Malformation Rupture during Pregnancy.

BACKGROUND: Sporadic brain arteriovenous malformations (BAVM) are a major cause of hemorrhagic stroke in younger persons. Prior studies have reported contradictory results regarding the risk of hemorrhage during pregnancy, and there are no standard guidelines for the management of pregnant women who present with BAVM rupture. The purpose of this study is to describe maternal and fetal outcomes and treatment strategies in patients with BAVM hemorrhage during pregnancy. METHODS: We performed a retrospective review of the University of California, San Francisco Brain AVM Project database for female patients who were pregnant at the time of BAVM hemorrhage between 2000 and 2017. Clinical and angiographic characteristics at presentation, BAVM treatment, and maternal outcomes using modified Rankin scale (mRS) score at presentation and 2-year follow-up were recorded. Fetal outcomes were abstracted from medical records and maternal reports. RESULTS: Sixteen patients presented with BAVM hemorrhage during pregnancy, 81% (n = 13) of whom were in their second or third trimester. Three patients (19%) who were in their first trimester terminated or miscarried pregnancy prior to BAVM intervention. Of the remaining 13 patients, 77% (n = 10) received emergent BAVM treatment at time of hemorrhage prior to delivery, and 85% of patients achieved BAVM obliteration and good maternal outcomes (mRS 0-2) at 2-year follow-up. All patients had uncomplicated deliveries (69% cesarean and 23% vaginal) with no reports of postnatal cognitive or developmental delays in infants at 2-year follow-up. CONCLUSIONS: Our study shows good long-term maternal and fetal outcomes in ruptured BAVM patients presenting during pregnancy, the majority who received BAVM interventional treatment prior to delivery.

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

NEWTON-2 Cisternal (Nimodipine Microparticles to Enhance Recovery While Reducing Toxicity After Subarachnoid Hemorrhage): A Phase 2, Multicenter, Randomized, Open-Label Safety Study of Intracisternal EG-1962 in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: A sustained release microparticle formulation of nimodipine (EG-1962) was developed for treatment of patients with aneurysmal subarachnoid hemorrhage (aSAH). OBJECTIVE: To assess safety, tolerability, and pharmacokinetics of intracisternal EG-1962 in an open-label, randomized, phase 2 study of up to 12 subjects. METHODS: Subjects were World Federation of Neurological Surgeons grades 1 to 2, modified Fisher grades 2 to 4, and underwent aneurysm clipping within 48 h of aSAH. EG-1962, containing 600 mg nimodipine, was administered into the basal cisterns. Outcome on the extended Glasgow Outcome Scale (eGOS), pharmacokinetics, delayed cerebral ischemia and infarction, rescue therapy, and safety were evaluated. RESULTS: The study was halted when a phase 3 study of intraventricular EG-1962 stopped because that study was unlikely to meet its primary endpoint. Six subjects were randomized (5 EG-1962 and 1 oral nimodipine). After 90-d follow-up, favorable outcome on the eGOS occurred in 1 of 5 EG-1962 and in the single oral nimodipine patient. Four EG-1962 and the oral nimodipine subject had angiographic vasospasm. One EG-1962 subject had delayed cerebral ischemia, and all subjects with angiographic vasospasm received rescue therapy except 1 EG-1962 patient. One subject treated with EG-1962 developed right internal carotid and middle cerebral artery narrowing 5 mo after placement of EG-1962, leading to occlusion and cerebral infarction. Pharmacokinetics showed similar plasma concentrations of nimodipine in both groups. CONCLUSION: Angiographic vasospasm and unfavorable clinical outcome still occurred after placement of EG-1962. Internal carotid artery narrowing and occlusion after placement of EG-1962 in the basal cisterns has not been reported.

Morphological changes of intracranial pressure quantifies vasodilatory effect of verapamil to treat cerebral vasospasm.

INTRODUCTION: After aneurysmal subarachnoid hemorrhage (SAH), both proximal and distal cerebral vasospasm can contribute to the development of delayed cerebral ischemia. Intra-arterial (IA) vasodilators are a mainstay of treatment for distal arterial vasospasm, but no methods of assessing the efficacy of interventions in real time have been established. OBJECTIVE: To introduce a new method for continuous intraprocedural assessment of endovascular treatment for cerebral vasospasm. METHODS: The premise of our approach was that distal cerebral arterial changes induce a consistent pattern in the morphological changes of intracranial pressure (ICP) pulse. This premise was demonstrated using a published algorithm in previous papers. In this study, we applied the algorithm to calculate the likelihood of cerebral vasodilation (VDI) and cerebral vasoconstriction (VCI) from intraprocedural ICP signals that are synchronized with injection of the IA vasodilator, verapamil. Cerebral blood flow velocities (CBFVs) on bilateral cerebral arteries were studied before and after IA therapy. RESULTS: 192 recordings of patients with SAH were reviewed, and 27 recordings had high-quality ICP waveforms. The VCI was significantly lower after the first verapamil injection (0.47±0.017) than VCI at baseline (0.49±0.020, p<0.001). A larger dose of injected verapamil resulted in a larger and longer VDI increase. CBFV of the middle cerebral artery increases across the days before the injection of verapamil and decreases after IA therapy. CONCLUSION: This study provides preliminary validation of an algorithm for continuous assessment of distal cerebral arterial changes in response to IA vasodilator infusion in patients with vasospasm and aneurysmal SAH.

Intracranial Pressure Monitoring via External Ventricular Drain: Are We Waiting Long Enough Before Recording the Real Value?

BACKGROUND: External ventricular drain (EVD) is a standard approach for both monitoring intracranial pressure (ICP) and draining cerebrospinal fluid (CSF) for patients with subarachnoid hemorrhage. Documenting an accurate ICP value is important to assess the status of the brain, which would require the EVD system to be leveled properly and closed to CSF drainage for an adequate period. It is suggested that a minimum period of 5-minute EVD closure is needed before documenting a true ICP; however, there is no commonly agreed upon standard for documenting ICP. To obtain an insight into how well the intermittent EVD clamping procedure is performed for ICP documentation, we conducted a retrospective analysis of ICP recordings obtained through EVD from 107 patients with subarachnoid hemorrhage. METHODS: The EVD was kept open for continuous CSF drainage and then intermittently closed for ICP documentation. For each EVD closure, mean ICP, standard deviation of ICP, duration of EVD closure, and time interval between 2 adjacent EVD closures were studied. The total number of EVD closures was calculated for each patient. We developed an algorithm to evaluate whether ICP reached a new equilibrium before the EVD was reopened to drainage. The percentage of EVD closures that reach the equilibrium was calculated. RESULTS: The 107 patients had 32 755 EVD closures in total, among which 65.9% instances lasted less than 1 minute and only 16.3% of all the EVD closure episodes lasted longer than 5 minutes. The median duration of each EVD closure was 25 seconds (interquartile range, 10.2 seconds to 2.33 minutes). Only 22.9% of the EVD closures reached ICP equilibrium before EVD reopening. CONCLUSION: A standard guideline and proper training are needed for bedside nurses, and a potential tool that can render ICP trend at a proper scale at bedside would help clinicians correctly document ICP.

mRNA Expression Profiles from Whole Blood Associated with Vasospasm in Patients with Subarachnoid Hemorrhage.

BACKGROUND: Though there are many biomarker studies of plasma and serum in patients with aneurysmal subarachnoid hemorrhage (SAH), few have examined blood cells that might contribute to vasospasm. In this study, we evaluated inflammatory and prothrombotic pathways by examining mRNA expression in whole blood of SAH patients with and without vasospasm. METHODS: Adult SAH patients with vasospasm (n = 29) and without vasospasm (n = 21) were matched for sex, race/ethnicity, and aneurysm treatment method. Diagnosis of vasospasm was made by angiography. mRNA expression was measured by Affymetrix Human Exon 1.0 ST Arrays. SAH patients with vasospasm were compared to those without vasospasm by ANCOVA to identify differential gene, exon, and alternatively spliced transcript expression. Analyses were adjusted for age, batch, and time of blood draw after SAH. RESULTS: At the gene level, there were 259 differentially expressed genes between SAH patients with vasospasm compared to patients without (false discovery rate < 0.05, |fold change| ≥ 1.2). At the exon level, 1210 exons representing 1093 genes were differentially regulated between the two groups (P < 0.005, ≥ 1.2 |fold change|). Principal components analysis segregated SAH patients with and without vasospasm. Signaling pathways for the 1093 vasospasm-related genes included adrenergic, P2Y, ET-1, NO, sildenafil, renin-angiotensin, thrombin, CCR3, CXCR4, MIF, fMLP, PKA, PKC, CRH, PPARα/RXRα, and calcium. Genes predicted to be alternatively spliced included IL23A, RSU1, PAQR6, and TRIP6. CONCLUSIONS: This is the first study to demonstrate that mRNA expression in whole blood distinguishes SAH patients with vasospasm from those without vasospasm and supports a role of coagulation and immune systems in vasospasm.

Standards for Studies of Neurological Prognostication in Comatose Survivors of Cardiac Arrest: A Scientific Statement From the American Heart Association.

Significant improvements have been achieved in cardiac arrest resuscitation and postarrest resuscitation care, but mortality remains high. Most of the poor outcomes and deaths of cardiac arrest survivors have been attributed to widespread brain injury. This brain injury, commonly manifested as a comatose state, is a marker of poor outcome and a major basis for unfavorable neurological prognostication. Accurate prognostication is important to avoid pursuing futile treatments when poor outcome is inevitable but also to avoid an inappropriate withdrawal of life-sustaining treatment in patients who may otherwise have a chance of achieving meaningful neurological recovery. Inaccurate neurological prognostication leading to withdrawal of life-sustaining treatment and deaths may significantly bias clinical studies, leading to failure in detecting the true study outcomes. The American Heart Association Emergency Cardiovascular Care Science Subcommittee organized a writing group composed of adult and pediatric experts from neurology, cardiology, emergency medicine, intensive care medicine, and nursing to review existing neurological prognostication studies, the practice of neurological prognostication, and withdrawal of life-sustaining treatment. The writing group determined that the overall quality of existing neurological prognostication studies is low. As a consequence, the degree of confidence in the predictors and the subsequent outcomes is also low. Therefore, the writing group suggests that neurological prognostication parameters need to be approached as index tests based on relevant neurological functions that are directly related to the functional outcome and contribute to the quality of life of cardiac arrest survivors. Suggestions to improve the quality of adult and pediatric neurological prognostication studies are provided.