Multimodal monitoring to guide neurosurgical intervention in high-grade aneurysmal subarachnoid hemorrhage: illustrative case.

BACKGROUND: Multimodal monitoring to guide medical intervention in high-grade aneurysmal subarachnoid hemorrhage (aSAH) is well described. Multimodal monitoring to guide surgical intervention in high-grade aSAH has been less studied. OBSERVATIONS: Intracranial pressure (ICP), brain lactate to pyruvate ratio (L/P ratio), and brain parenchymal oxygen tension (pO2) were used as surrogates for clinical status in a comatose man after high-grade aSAH. Acute changes in ICP, L/P ratio, and pO2 were used to identify brain injury from both malignant cerebral edema and delayed cerebral ischemia, respectively, and decompressive hemicraniectomy with clot evacuation and intraarterial nimodipine were used to treat these conditions. The patient showed marked improvement in multimodal parameters following each intervention and eventually recovered to a modified Rankin score of 2. LESSONS: In patients with a limited neurological examination due to severe acute brain injury in the setting of aSAH, multimodal monitoring can be used to guide surgical treatment. With prompt, aggressive, maximal medical and surgical interventions, otherwise healthy individuals may retain the capacity for close to full recovery from seemingly catastrophic aSAH.

Posterior communicating artery injury and symptomatic vasospasm after high-energy blunt head injury: illustrative case.

BACKGROUND: Most of the published literature pertaining to blunt traumatic cerebrovascular injury (BCVI) is focused on extracranial arterial injury. Studies of intracranial arterial injury are relatively uncommon. OBSERVATIONS: The clinical course of a patient who sustained an injury to the right posterior communicating artery followed by infarction due to vasospasm after severe traumatic brain injury is presented, along with a focused literature review. LESSONS: Intracranial BCVI is uncommon, and this report may serve to raise awareness of BCVI management and the importance of recognizing symptomatic vasospasm due to BCVI.

Predictors of the development of takotsubo cardiomyopathy in aneurysmal subarachnoid hemorrhage and outcomes in patients with intra-aortic balloon pumps.

OBJECTIVE: Takotsubo cardiomyopathy (TC) in patients with aneurysmal subarachnoid hemorrhage (aSAH) is associated with high morbidity and mortality. Previous studies have shown that female patients presenting with a poor clinical grade are at the greatest risk for developing TC. Intra-aortic balloon pumps (IABPs) are known to support cardiac function in severe cases of TC, and they may aid in the treatment of vasospasm in these patients. In this study, the authors investigated risk factors for developing TC in the setting of aSAH and outcomes among patients requiring IABPs. METHODS: The authors retrospectively reviewed the records of 1096 patients who had presented to their institution with aSAH. Four hundred five of these patients were originally enrolled in the Barrow Ruptured Aneurysm Trial, and an additional 691 patients from a subsequent prospectively maintained aSAH database were analyzed. Medical records were reviewed for the presence of TC according to the modified Mayo Clinic criteria. Outcomes were determined at the last follow-up, with a poor outcome defined as a modified Rankin Scale (mRS) score > 2. RESULTS: TC was identified in 26 patients with aSAH. Stepwise multivariate logistic regression analysis identified female sex (OR 8.2, p = 0.005), Hunt and Hess grade > III (OR 7.6, p < 0.001), aneurysm size > 7 mm (OR 3, p = 0.011), and clinical vasospasm (OR 2.9, p = 0.037) as risk factors for developing TC in the setting of aSAH. TC patients, even with IABP placement, had higher rates of poor outcomes (77% vs 47% with an mRS score > 2, p = 0.004) and mortality at the last follow-up (27% vs 11%, p = 0.018) than the non-TC patients. However, aggressive intra-arterial endovascular treatment for vasospasm was associated with good outcomes in the TC patients versus nonaggressive treatment (100% with mRS ≤ 2 at last follow-up vs 53% with mRS > 2, p = 0.040). CONCLUSIONS: TC after aSAH tends to occur in female patients with large aneurysms, poor clinical grades, and clinical vasospasm. These patients have significantly higher rates of poor neurological outcomes, even with the placement of an IABP. However, aggressive intra-arterial endovascular therapy in select patients with vasospasm may improve outcome.

Whole blood levels of S1PR4 mRNA associated with cerebral vasospasm after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: The authors sought to identify mRNA biomarkers of cerebral vasospasm in whole blood of patients suffering from aneurysmal subarachnoid hemorrhage (aSAH). METHODS: A prospective transcriptomic study for vasospasm was conducted in whole blood samples of 44 aSAH patients who developed (VSP+ group, n = 22) or did not develop (VSP- group, n = 22) vasospasm. Samples from all patients were profiled for 21,460 mRNA probes using the Illumina Human HT12v4.0 array. Differential statistical analysis was performed using a linear mixed model. RESULTS: Levels of sphingosine-1-phosphate receptor 4 (S1PR4) mRNA were significantly higher (p = 8.03 × 10-6) at presentation in patients who developed vasospasm after aSAH than in patients who did not. CONCLUSIONS: The results, which are consistent with findings of previous experimental investigations conducted in animal models, support the role of S1PR4 and its ligand, sphingosine-1-phosphate (S1P), in arterial-associated vasoconstriction, which suggests that S1PR4 could be used as a biomarker for cerebral vasospasm in aSAH patients.

Patterns of care for ruptured aneurysms of the middle cerebral artery: analysis of a Swiss national database (Swiss SOS).

OBJECTIVE: The objective of this study was to determine patterns of care and outcomes in ruptured intracranial aneurysms (IAs) of the middle cerebral artery (MCA) in a contemporary national cohort. METHODS: The authors conducted a retrospective analysis of prospective data from a nationwide multicenter registry of all aneurysmal subarachnoid hemorrhage (aSAH) cases admitted to a tertiary care neurosurgical department in Switzerland in the years 2009-2015 (Swiss Study on Aneurysmal Subarachnoid Hemorrhage [Swiss SOS]). Patterns of care and outcomes at discharge and the 1-year follow-up in MCA aneurysm (MCAA) patients were analyzed and compared with those in a control group of patients with IAs in locations other than the MCA (non-MCAA patients). Independent predictors of a favorable outcome (modified Rankin Scale score ≤ 3) were identified, and their effect size was determined. RESULTS: Among 1866 consecutive aSAH patients, 413 (22.1%) harbored an MCAA. These MCAA patients presented with higher World Federation of Neurosurgical Societies grades (p = 0.007), showed a higher rate of concomitant intracerebral hemorrhage (ICH; 41.9% vs 16.7%, p < 0.001), and experienced delayed cerebral ischemia (DCI) more frequently (38.9% vs 29.4%, p = 0.001) than non-MCAA patients. After adjustment for confounders, patients with MCAA were as likely as non-MCAA patients to experience DCI (aOR 1.04, 95% CI 0.74-1.45, p = 0.830). Surgical treatment was the dominant treatment modality in MCAA patients and at a significantly higher rate than in non-MCAA patients (81.7% vs 36.7%, p < 0.001). An MCAA location was a strong independent predictor of surgical treatment (aOR 8.49, 95% CI 5.89-12.25, p < 0.001), despite statistical adjustment for variables traditionally associated with surgical treatment, such as (space-occupying) ICH (aOR 1.73, 95% CI 1.23-2.45, p = 0.002). Even though MCAA patients were less likely to die during the acute hospitalization (aOR 0.52, 0.30-0.91, p = 0.022), their rate of a favorable outcome was lower at discharge than that in non-MCAA patients (55.7% vs 63.7%, p = 0.003). At the 1-year follow-up, 68.5% and 69.6% of MCAA and non-MCAA patients, respectively, had a favorable outcome (p = 0.676). CONCLUSIONS: Microsurgical occlusion remains the predominant treatment choice for about 80% of ruptured MCAAs in a European industrialized country. Although patients with MCAAs presented with worse admission grades and greater rates of concomitant ICH, in-hospital mortality was lower and long-term disability was comparable to those in patients with non-MCAA.

Cerebrospinal fluid macrophage migration inhibitory factor: a potential predictor of cerebral vasospasm and clinical outcome after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: In patients with aneurysmal subarachnoid hemorrhage (aSAH), poor outcomes have been shown to be correlated with subsequent cerebral vasospasm (CV) and delayed cerebral ischemia (DCI). The identification of novel biomarkers may aid in the prediction of which patients are vulnerable to developing vasospasm, cerebral ischemia, and neurological deterioration. METHODS: In this prospective clinical study at North Shore University Hospital, patients with aSAH or normal pressure hydrocephalus (NPH) with external ventricular drains were enrolled. The concentration of macrophage migration inhibitory factor (MIF) in CSF was assessed for correlation with CV or DCI, the primary outcome measures. RESULTS: Twenty-five patients were enrolled in the aSAH group and 9 were enrolled in the NPH group. There was a significant increase in aggregate CSF MIF concentration in patients with aSAH versus those with NPH (24.4 ± 19.2 vs 2.3 ± 1.1 ng/ml, p < 0.0002). Incidence of the day of peak MIF concentration significantly correlated with the onset of clinical vasospasm (rho = 0.778, p < 0.0010). MIF concentrations were significantly elevated in patients with versus those without evidence of DCI (18.7 ± 4.93 vs 8.86 ± 1.28 ng/ml, respectively, p < 0.0025). There was a significant difference in MIF concentrations between patients with infection versus those without infection (16.43 ± 4.21 vs 8.5 ± 1.22 ng/ml, respectively, p < 0.0119). CONCLUSIONS: Preliminary evidence from this study suggests that CSF concentrations of MIF are correlated with CV and DCI. These results, however, could be confounded in the presence of clinical infection. A study with a larger patient sample size is necessary to corroborate these findings.

Decrease of blood flow velocity in the middle cerebral artery after stellate ganglion block following aneurysmal subarachnoid hemorrhage: a potential vasospasm treatment?

OBJECTIVE: Cerebral vasospasm (CV) is a delayed, sustained contraction of the cerebral arteries that tends to occur 3-14 days after aneurysmal subarachnoid hemorrhage (aSAH) from a ruptured aneurysm. Vasospasm potentially leads to delayed cerebral ischemia, and despite medical treatment, 1 of 3 patients suffer a persistent neurological deficit. Bedside transcranial Doppler (TCD) ultrasonography is used to indirectly detect CV through recognition of an increase in cerebral blood flow velocity (CBFV). The present study aimed to use TCD ultrasonography to monitor how CBFV changes on both the ipsi- and contralateral sides of the brain in the first 24 hours after patients have received a stellate ganglion block (SGB) to treat CV that persists despite maximum standard therapy. METHODS: The data were culled from records of patients treated between 2013 and 2017. Patients were included if an SGB was administered following aSAH, whose CBFV was ≥ 120 cm/sec and who had either a focal neurological deficit or reduced consciousness despite having received medical treatment and blood pressure management. The SGB was performed on the side where the highest CBFV had been recorded with 8-10 ml ropivacaine 0.2%. The patient's CBFV was reassessed after 2 and 24 hours. RESULTS: Thirty-seven patients (male/female ratio 18:19), age 17-70 years (mean age 49.9 ± 11.1), who harbored 13 clipped and 22 coiled aneurysms (1 patient received both a coil and a clip, and 3 patients had 3 untreated aneurysms) had at least one SGB. Patients received up to 4 SGBs, and thus the study comprised a total of 76 SGBs.After the first SGB, CBFV decreased in 80.5% of patients after 2 hours, from a mean of 160.3 ± 28.2 cm/sec to 127.5 ± 34.3 cm/sec (p < 0.001), and it further decreased in 63.4% after 24 hours to 137.2 ± 38.2 cm/sec (p = 0.007). A similar significant effect was found for the subsequent SGB. Adding clonidine showed no significant effect on either the onset or the duration of the SGB. Contralateral middle cerebral artery (MCA) blood flow was not reduced by the SGB. CONCLUSIONS: To the authors' knowledge, this is the largest study on the effects of administering an SGB to aSAH patients after aneurysm rupture. The data showed a significant reduction in ipsilateral CBFV (MCA 20.5%) after SGB, lasting in about two-thirds of cases for over 24 hours with no major complications resulting from the SGB.

Between-center and between-country differences in outcome after aneurysmal subarachnoid hemorrhage in the Subarachnoid Hemorrhage International Trialists (SAHIT) repository.

OBJECTIVE: Differences in clinical outcomes between centers and countries may reflect variation in patient characteristics, diagnostic and therapeutic policies, or quality of care. The purpose of this study was to investigate the presence and magnitude of between-center and between-country differences in outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: The authors analyzed data from 5972 aSAH patients enrolled in randomized clinical trials of 3 different treatments from the Subarachnoid Hemorrhage International Trialists (SAHIT) repository, including data from 179 centers and 20 countries. They used random effects logistic regression adjusted for patient characteristics and timing of aneurysm treatment to estimate between-center and between-country differences in unfavorable outcome, defined as a Glasgow Outcome Scale score of 1-3 (severe disability, vegetative state, or death) or modified Rankin Scale score of 4-6 (moderately severe disability, severe disability, or death) at 3 months. Between-center and between-country differences were quantified with the median odds ratio (MOR), which can be interpreted as the ratio of odds of unfavorable outcome between a typical high-risk and a typical low-risk center or country. RESULTS: The proportion of patients with unfavorable outcome was 27% (n = 1599). The authors found substantial between-center differences (MOR 1.26, 95% CI 1.16-1.52), which could not be explained by patient characteristics and timing of aneurysm treatment (adjusted MOR 1.21, 95% CI 1.11-1.44). They observed no between-country differences (adjusted MOR 1.13, 95% CI 1.00-1.40). CONCLUSIONS: Clinical outcomes after aSAH differ between centers. These differences could not be explained by patient characteristics or timing of aneurysm treatment. Further research is needed to confirm the presence of differences in outcome after aSAH between hospitals in more recent data and to investigate potential causes.

Assessment of tissue permeability by early CT perfusion as a surrogate parameter for early brain injury after subarachnoid hemorrhage.

OBJECTIVE: The severity of early brain injury (EBI) after aneurysmal subarachnoid hemorrhage (aSAH) correlates with delayed cerebral ischemia (DCI) and outcome. A disruption of the blood-brain barrier is part of EBI pathophysiology. The aim of this study was to assess tissue permeability (PMB) by CT perfusion (CTP) in the acute phase after aSAH and its impact on DCI and outcome. METHODS: CTP was performed on day 3 after aSAH. Qualitative and quantitative analyses of all CTP parameters, including PMB, were performed. The areas with increased PMB were documented. The value of an early PMB increase as a predictor of DCI and outcome according to the modified Rankin Scale (mRS) grade 3 to 24 months after aSAH was assessed. Possible associations of increased PMB with the Subarachnoid Hemorrhage Early Brain Edema Score (SEBES) and with early perfusion deficits, as radiographic EBI markers, were evaluated. RESULTS: A total of 69 patients were enrolled in the study. An increased PMB on early CTP was detected in 10.1% (7/69) of all patients. A favorable outcome (mRS grade ≤ 2) occurred in 40.6% (28/69) of all patients. DCI was detected in 25% (17/69) of all patients. An increased PMB was a predictor of DCI (logistic regression, p = 0.03) but not of outcome (logistic regression, p = 0.40). The detection of increased PMB predicted DCI with a sensitivity of 25%, a specificity of 94%, a positive predictive value of 57%, and a negative predictive value of 79% (chi-square test p = 0.03). Early perfusion deficits were seen in 68.1% (47/69) of the patients, a finding that correlated with DCI (p = 0.005) but not with the outcome. No correlation was found between the SEBES and increased PMB. CONCLUSIONS: Changes in PMB can be detected by early CTP after aSAH, which correlates with DCI. Future studies are needed to evaluate the time course of PMB changes and their interaction with therapeutic measures.

Rebleeding drives poor outcome in aneurysmal subarachnoid hemorrhage independent of delayed cerebral ischemia: a propensity-score matched cohort study.

OBJECTIVE: Delayed cerebral ischemia (DCI) and aneurysm rebleeding contribute to morbidity and mortality in aneurysmal subarachnoid hemorrhage (aSAH); however, the relationship between their impacts on overall functional outcome is incompletely understood. METHODS: The authors conducted a cohort study of all aSAH during the study period from 2001 to 2016. Primary end points were overall functional outcome and ischemic aSAH sequelae, defined as delayed cerebral ischemia (DCI), DCI with infarction, symptomatic vasospasm (SV), and global cerebral edema (GCE). Outcomes were compared between the rebleed and nonrebleed cohorts overall and after propensity-score matching (PSM) for risk factors and treatment modality. Univariate and multivariate ordered logistic regression analyses for functional outcomes were performed in the PSM cohort to identify predictors of poor outcome. RESULTS: Four hundred fifty-five aSAH cases admitted within 24 hours of aneurysm rupture were included, of which 411 (90%) experienced initial aneurysm ruptures only, while 44 (10%) had clinically confirmed rebleeding. In the overall cohort, rebleeding was associated with significantly worse functional outcome, longer intensive care unit length of stay (LOS), and GCE (all p < 0.01); treatment modality, overall LOS, DCI, DCI with infarction, and SV were nonsignificant. In the PSM analysis of 43 matched rebleed and 43 matched nonrebleed cases, only poor functional outcome and GCE remained significantly associated with rebleeding (p < 0.01 and p = 0.02, respectively). Multivariate regression identified that both rebleeding (HR 21.5, p < 0.01) and DCI (HR 10.1, p = 0.01) independently predicted poor functional outcome. CONCLUSIONS: Rebleeding and DCI after aSAH are highly morbid and potentially deadly events after aSAH, which appear to have independent negative impacts on overall functional outcome. Early rebleeding did not significantly affect the risk of delayed ischemic complications.

Acute kidney injury after aneurysmal subarachnoid hemorrhage and its effect on patient outcome: an exploratory analysis.

OBJECTIVE: Acute kidney injury (AKI) is associated with death in critically ill patients, but this complication has not been well characterized after aneurysmal subarachnoid hemorrhage (aSAH). The purpose of this study was to determine the incidence of AKI after aSAH and to identify risk factors for renal dysfunction. Secondary objectives were to examine what effect AKI has on patient mortality and functional outcome at 12 weeks post-aSAH. METHODS: The authors performed a post hoc analysis of the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial data set (clinical trial registration no.: NCT00111085, https://clinicaltrials.gov). The primary outcome of interest was the development of AKI, which was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. Secondary outcomes of interest were death and a modified Rankin Scale score greater than 2 at 12 weeks post-aSAH. Propensity score matching was used to assess for a significant treatment effect related to clazosentan administration and AKI. Univariate analysis, locally weighted scatterplot smoothing (LOWESS) curves, and stepwise logistic regression models were used to evaluate for associations between baseline or disease-related characteristics and study outcomes. RESULTS: One hundred fifty-six (38%) of the 413 patients enrolled in the CONSCIOUS-1 trial developed AKI during their ICU stay. A history of hypertension (p < 0.001) and the number of nephrotoxic medications administered (p = 0.029) were independent predictors of AKI on multivariate analysis. AKI was an independent predictor of death (p = 0.028) but not a poor functional outcome (p = 0.21) on multivariate testing. Unresolved renal dysfunction was the strongest independent predictor of death in this cohort (p < 0.001). CONCLUSIONS: AKI is a common complication following aSAH. Patients with premorbid hypertension and those treated with nephrotoxic medications may be at greater risk for renal dysfunction. AKI appears to confer an increased probability of death after aSAH.

Genetic basis of intracranial aneurysm formation and rupture: clinical implications in the postgenomic era.

OBJECTIVE: Despite the prevalence and impact of intracranial aneurysms (IAs), the molecular basis of their pathogenesis remains largely unknown. Moreover, there is a dearth of clinically validated biomarkers to efficiently screen patients with IAs and prognosticate risk for rupture. The aim of this study was to survey the literature to systematically identify the spectrum of genetic aberrations that have been identified in IA formation and risk of rupture. METHODS: A literature search was performed using the Medical Subject Headings (MeSH) system of databases including PubMed, EMBASE, and Google Scholar. Relevant studies that reported on genetic analyses of IAs, rupture risk, and long-term outcomes were included in the qualitative analysis. RESULTS: A total of 114 studies were reviewed and 65 were included in the qualitative synthesis. There are several well-established mendelian syndromes that confer risk to IAs, with variable frequency. Linkage analyses, genome-wide association studies, candidate gene studies, and exome sequencing identify several recurrent polymorphic variants at candidate loci, and genes associated with the risk of aneurysm formation and rupture, including ANRIL (CDKN2B-AS1, 9p21), ARGHEF17 (11q13), ELN (7q11), SERPINA3 (14q32), and SOX17 (8q11). In addition, polymorphisms in eNOS/NOS3 (7q36) may serve as predictive markers for outcomes following intracranial aneurysm rupture. Genetic aberrations identified to date converge on posited molecular mechanisms involved in vascular remodeling, with strong implications for an associated immune-mediated inflammatory response. CONCLUSIONS: Comprehensive studies of IA formation and rupture have identified candidate risk variants and loci; however, further genome-wide analyses are needed to identify high-confidence genetic aberrations. The literature supports a role for several risk loci in aneurysm formation and rupture with putative candidate genes. A thorough understanding of the genetic basis governing risk of IA development and the resultant aneurysmal subarachnoid hemorrhage may aid in screening, clinical management, and risk stratification of these patients, and it may also enable identification of putative mechanisms for future drug development.

Flow-induced, inflammation-mediated arterial wall remodeling in the formation and progression of intracranial aneurysms.

OBJECTIVE: Unruptured intracranial aneurysms (UIAs) are relatively common lesions that may cause devastating intracranial hemorrhage, thus producing considerable suffering and anxiety in those affected by the disease or an increased likelihood of developing it. Advances in the knowledge of the pathobiology behind intracranial aneurysm (IA) formation, progression, and rupture have led to preclinical testing of drug therapies that would prevent IA formation or progression. In parallel, novel biologically based diagnostic tools to estimate rupture risk are approaching clinical use. Arterial wall remodeling, triggered by flow and intramural stresses and mediated by inflammation, is relevant to both. METHODS: This review discusses the basis of flow-driven vessel remodeling and translates that knowledge to the observations made on the mechanisms of IA initiation and progression on studies using animal models of induced IA formation, study of human IA tissue samples, and study of patient-derived computational fluid dynamics models. RESULTS: Blood flow conditions leading to high wall shear stress (WSS) activate proinflammatory signaling in endothelial cells that recruits macrophages to the site exposed to high WSS, especially through macrophage chemoattractant protein 1 (MCP1). This macrophage infiltration leads to protease expression, which disrupts the internal elastic lamina and collagen matrix, leading to focal outward bulging of the wall and IA initiation. For the IA to grow, collagen remodeling and smooth muscle cell (SMC) proliferation are essential, because the fact that collagen does not distend much prevents the passive dilation of a focal weakness to a sizable IA. Chronic macrophage infiltration of the IA wall promotes this SMC-mediated growth and is a potential target for drug therapy. Once the IA wall grows, it is subjected to changes in wall tension and flow conditions as a result of the change in geometry and has to remodel accordingly to avoid rupture. Flow affects this remodeling process. CONCLUSIONS: Flow triggers an inflammatory reaction that predisposes the arterial wall to IA initiation and growth and affects the associated remodeling of the UIA wall. This chronic inflammation is a putative target for drug therapy that would stabilize UIAs or prevent UIA formation. Moreover, once this coupling between IA wall remodeling and flow is understood, data from patient-specific flow models can be gathered as part of the diagnostic workup and utilized to improve risk assessment for UIA initiation, progression, and eventual rupture.

Neutrophil-to-lymphocyte ratio as an independent predictor for unfavorable functional outcome in aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Stroke-associated immunosuppression and inflammation are increasingly recognized as factors triggering infections and thus potentially influencing outcome after stroke. Several studies have demonstrated that elevated neutrophil-to-lymphocyte ratio (NLR) is a significant predictor of adverse outcomes for patients with ischemic stroke or intracerebral hemorrhage. Thus far, in patients with subarachnoid hemorrhage the association between NLR and outcome is insufficiently established. The authors sought to investigate the association between NLR on admission and functional outcome in aneurysmal subarachnoid hemorrhage (aSAH). METHODS: This observational study included all consecutive aSAH patients admitted to a German tertiary center over a 5-year period (2008-2012). Data regarding patient demographics and clinical, laboratory, and in-hospital measures, as well as neuroradiological data, were retrieved from institutional databases. Functional outcome was assessed at 3 and 12 months using the modified Rankin Scale (mRS) score and categorized into favorable (mRS score 0-2) and unfavorable (mRS score 3-6). Patients' radiological and laboratory characteristics were compared between aSAH patients with favorable and those with unfavorable outcome at 3 months. In addition, multivariate analysis was conducted to investigate parameters independently associated with favorable outcome. Receiver operating characteristic (ROC) curve analysis was undertaken to identify the best cutoff for NLR to discriminate between favorable and unfavorable outcome in these patients. To account for imbalances in baseline characteristics, propensity score matching was carried out to assess the influence of NLR on outcome measures. RESULTS: Overall, 319 patients with aSAH were included. Patients with unfavorable outcome at 3 months were older, had worse clinical status on admission (Glasgow Coma Scale score and Hunt and Hess grade), greater amount of subarachnoidal and intraventricular hemorrhage (modified Fisher Scale grade and Graeb score), and higher rates of infectious complications (pneumonia and sepsis). A significantly higher NLR on admission was observed in patients with unfavorable outcome according to mRS score (median [IQR] NLR 5.8 [3.0-10.0] for mRS score 0-2 vs NLR 8.3 [4.5-12.6] for mRS score 3-6; p < 0.001). After adjustments, NLR on admission remained a significant predictor for unfavorable outcome in SAH patients (OR [95% CI] 1.014 [1.001-1.027]; p = 0.028). In ROC analysis, an NLR of 7.05 was identified as the best cutoff value to discriminate between favorable and unfavorable outcome (area under the curve = 0.614, p < 0.001, Youden's index = 0.211; mRS score 3-6: 94/153 [61.4%] for NLR ≥ 7.05 vs 67/166 [40.4%] for NLR < 7.05; p < 0.001). Subanalysis of patients with NLR levels ≥ 7.05 vs < 7.05, performed using 2 propensity score-matched cohorts (n = 133 patients in each group), revealed an increased proportion of patients with unfavorable functional outcome at 3 months in patients with NLR ≥ 7.05 (mRS score 3-6 at 3 months: NLR ≥ 7.05 82/133 [61.7%] vs NLR < 7.05 62/133 [46.6%]; p = 0.014), yet without differences in mortality at 3 months (NLR ≥ 7.05 37/133 [27.8%] vs NLR < 7.05 27/133 [20.3%]; p = 0.131). CONCLUSIONS: Among aSAH patients, NLR represents an independent parameter associated with unfavorable functional outcome. Whether the impact of NLR on functional outcome is related to preexisting comorbidities or represents independent causal relationships in the context of stroke-associated immunosuppression should be investigated in future studies.

Assessment of lipoprotein-associated phospholipase A2 level and its changes in the early stages as predictors of delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVE: The relationship between lipoprotein-associated phospholipase A2 (Lp-PLA2) and various cardiovascular and cerebrovascular diseases is inconsistent. However, the connection between Lp-PLA2 level and delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) remains unclear. The objective of this study was to investigate the relationships between the Lp-PLA2 levels in the early stages of aSAH and the occurrence of DCI. METHODS: The authors evaluated 114 patients with aSAH who were enrolled into a prospective observational cohort study. Serum Lp-PLA2 level at admission (D0), on the first morning (D1), and on the second morning of hospitalization (D2) were determined using commercial enzyme-linked immunosorbent assay kits. The relationship between Lp-PLA2 levels and DCI was analyzed. RESULTS: Forty-three patients with aSAH (37.72%) experienced DCI. Mean serum Lp-PLA2 level decreased from 183.06 ± 61.36 µg/L at D0 (D0 vs D1, p = 0.303), to 175.32 ± 51.49 µg/L at D1 and 167.24 ± 54.10 µg/L at D2 (D0 vs D2, p = 0.040). The Lp-PLA2 level changes (D0-D1 and D0-D2) were comparable between patients with and without DCI. Multivariate model analysis revealed Lp-PLA2 level (D0) > 200 µg/L was a more significant factor of DCI compared with Lp-PLA2 (D1) and Lp-PLA2 (D2), and was a strong predictor of DCI (odds ratio [OR] 6.24, 95% confidence interval [CI] 2.05-18.94, p = 0.001) after controlling for World Federation of Neurosurgical Societies (WFNS) grade (OR 3.35, 95% CI 1.18-9.51, p = 0.023) and modified Fisher grade (OR 6.07, 95% CI 2.03-18.14, p = 0.001). WFNS grade (area under the curve [AUC] = 0.792), modified Fisher grade (AUC = 0.731), and Lp-PLA2 level (D0; AUC = 0.710) were all strong predictors of DCI. The predictive powers of WFNS grade, modified Fisher grade, and Lp-PLA2 (D0) were comparable (WFNS grade vs Lp-PLA2: p = 0.233; modified Fisher grade vs Lp-PLA2: p = 0.771). The poor-grade patients with Lp-PLA2 (D0) > 200 µg/L had significantly worse DCI survival rate than poor-grade patients with Lp-PLA2 (D0) ≤ 200 µg/L (p < 0.001). CONCLUSIONS: The serum level of Lp-PLA2 was significantly elevated in patients with DCI, and decreased within the first 2 days after admission. Lp-PLA2 in the early stages of aSAH might be a novel predictive biomarker for the occurrence of DCI.

In vitro and in vivo testing of a novel local nicardipine delivery system to the brain: a preclinical study.

OBJECTIVE: The management of patients with aneurysmal subarachnoid hemorrhage (aSAH) remains a highly demanding challenge in critical care medicine. Despite all efforts, the calcium channel antagonist nimodipine remains the only drug approved for improving outcomes after aSAH. However, in its current form of application, it provides less than optimal efficacy and causes dose-limiting hypotension in a substantial number of patients. Here, the authors tested in vitro the release dynamics of a novel formulation of the calcium channel blocker nicardipine and in vivo local tolerance and tissue reaction using a chronic cranial window model in mice. METHODS: To characterize the release kinetics in vitro, dissolution experiments were performed using artificial cerebrospinal fluid over a time period of 21 days. The excipients used in this formulation (NicaPlant) for sustained nicardipine release are a mixture of two completely degradable polymers. A chronic cranial window in C57BL/6 mice was prepared, and NicaPlant slices were placed in proximity to the exposed cerebral vasculature. Epifluorescence video microscopy was performed right after implantation and on days 3 and 7 after surgery. Vessel diameter of the arteries and veins, vessel permeability, vessel configuration, and leukocyte-endothelial cell interaction were quantified by computer-assisted analysis. Immunofluorescence staining was performed to analyze inflammatory reactions and neuronal alterations. RESULTS: In vitro the nicardipine release profile showed an almost linear curve with about 80% release at day 15 and full release at day 21. In vivo epifluorescence video microscopy showed a significantly higher arterial vessel diameter in the NicaPlant group due to vessel dilatation (21.6 ± 2.6 µm vs 17.8 ± 1.5 µm in controls, p < 0.01) confirming vasoactivity of the implant, whereas the venous diameter was not affected. Vessel dilatation did not have any influence on the vessel permeability measured by contrast extravasation of the fluorescent dye in epifluorescence microscopy. Further, an increased leukocyte-endothelial cell interaction due to the implant could not be detected. Histological analysis did not show any microglial activation or accumulation. No structural neuronal changes were observed. CONCLUSIONS: NicaPlant provides continuous in vitro release of nicardipine over a 3-week observation period. In vivo testing confirmed vasoactivity and lack of toxicity. The local application of this novel nicardipine delivery system to the subarachnoid space is a promising tool to improve patient outcomes while avoiding systemic side effects.

Terminal spreading depolarizations causing electrocortical silencing prior to clinical brain death: case report.

The authors report on a 57-year-old woman in whom progression to brain death occurred on day 9 after aneurysmal subarachnoid hemorrhage without evidence of significant brain edema or vasospasm. Neuromonitoring demonstrated that brain death was preceded by a series of cortical spreading depolarizations that occurred in association with progressive hypoxic episodes. The depolarizations induced final electrical silence in the cortex and ended with a terminal depolarization that persisted > 7 hours. To the authors' knowledge, this is the first report of terminal spreading depolarization in the human brain prior to clinical brain death and major cardiopulmonary failure.

Nationwide analysis of hospital-to-hospital transfer in patients with aneurysmal subarachnoid hemorrhage requiring aneurysm repair.

OBJECTIVEAneurysmal subarachnoid hemorrhage (aSAH) has devastating consequences. The association between higher institutional volumes and improved outcomes for aSAH patients has been studied extensively. However, the literature exploring patterns of transfer in this context is sparse. Expansion of the endovascular workforce has raised concerns about the decentralization of care, reduced institutional volumes, and worsened patient outcomes. In this paper, the authors explored various patient and hospital factors associated with the transfer of aSAH patients by using a nationally representative database.METHODSThe 2013 and 2014 years of the National Inpatient Sample (NIS) were used to define an observational cohort of patients with ruptured brain aneurysms. The initial search identified patients with SAH (ICD-9-CM 430). Those with concomitant codes suggesting trauma or other intracranial vascular abnormalities were excluded. Finally, the patients who had not undergone a subsequent procedure to repair an intracranial aneurysm were excluded. These criteria yielded a cohort of 4373 patients, 1379 of whom had undergone microsurgical clip ligation and 2994 of whom had undergone endovascular repair. The outcome of interest was transfer status, and the NIS data element TRAN_IN was used to define this state. Multiple explanatory variables were identified, including age, sex, primary payer, median household income by zip code, race, hospital size, hospital control, hospital teaching status, and hospital location. These variables were evaluated using descriptive statistics, bivariate correlation analysis, and multivariable logistic regression modeling to determine their relationship with transfer status.RESULTSPatients with aSAH who were treated in an urban teaching hospital had higher odds of being a transfer (OR 2.15, 95% CI 1.71-2.72) than the patients in urban nonteaching hospitals. White patients were more likely to be transfer patients than were any of the other racial groups (p < 0.0001). Moreover, patients who lived in the highest-income zip codes were less likely to be transferred than the patients in the lowest income quartile (OR 0.78, 95% CI 0.64-0.95). Repair type (clip vs coil) and primary payer were not associated with transfer status.CONCLUSIONSA relatively high percentage of patients with aSAH are transferred between acute care hospitals. Race and income were associated with transfer status. White patients are more likely to be transferred than other races. Patients from zip codes with the highest income transferred at lower rates than those from the lowest income quartile. Transfer patients were preferentially sent to urban teaching hospitals. The modality of aneurysm treatment was not associated with transfer status.

Riskier-than-expected occlusive treatment of ruptured posterior communicating artery aneurysms: treatment and outcome of 620 consecutive patients.

OBJECTIVE: Occlusive treatment of posterior communicating artery (PCoA) aneurysms has been seen as a fairly uncomplicated procedure. The objective here was to determine the radiological and clinical outcome of patients after PCoA aneurysm rupture and treatment and to evaluate the risk factors for impaired outcome. METHODS: In a retrospective clinical follow-up study, data were collected from 620 consecutive patients who had been treated for ruptured PCoA aneurysms at a single center between 1980 and 2014. The follow-up was a minimum of 1 year after treatment or until death. RESULTS: Of the 620 patients, 83% were treated with microsurgical clipping, 8% with endovascular coiling, 2% with the two procedures combined, 1% with indirect surgical methods, and 6% with conservative methods. The most common procedural complications were treatment-related brain infarctions (15%). The occurrence of artery occlusions (10% microsurgical, 8% endovascular) was higher than expected. Most patients made a good recovery at 1 year after aneurysmal subarachnoid hemorrhage (modified Rankin Scale [mRS] score 0-2: 386 patients [62%]). A fairly small proportion of patients were left severely disabled (mRS score 4-5: 27 patients [4%]). Among all patients, 20% died during the 1st year. Independent risk factors for an unfavorable outcome, according to the multivariable analysis, were poor preoperative clinical condition, intracerebral or subdural hematoma due to aneurysm rupture, age over 65 years, artery occlusion on postoperative angiography, occlusive treatment-related ischemia, delayed cerebral vasospasm, and hydrocephalus requiring a shunt. CONCLUSIONS: Even though most patients made a good recovery after PCoA aneurysm rupture and treatment during the 1st year, the occlusive treatment-related complications were higher than expected and caused morbidity even among initially good-grade patients. Occlusive treatment of ruptured PCoA aneurysms seems to be a high-risk procedure, even in a high-volume neurovascular center.

Significance of fluctuations in serum sodium levels following aneurysmal subarachnoid hemorrhage: an exploratory analysis.

OBJECTIVE: Fluctuations in patient serum sodium levels are common after aneurysmal subarachnoid hemorrhage (aSAH), but their effect on patient outcome is not well described in the literature. The goal of this work was to better characterize the relationship between fluctuations in serum sodium levels, outcome, and the development of delayed cerebral ischemia (DCI) after aSAH. METHODS: The authors performed a post hoc analysis of data from the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage (CONSCIOUS-1) trial. Patients had their serum sodium values recorded daily for 14 days post-aSAH. Average and average absolute daily differences in sodium levels were calculated for each patient based on 3 reference points: admission sodium levels, a normal sodium level (defined as 140 mmol/L), and the previous day's sodium level. These variables were also calculated for the classic "vasospasm window" (days 3-12) post-aSAH. A stepwise logistic regression model, locally weighted scatterplot smoothing curves, and receiver operator characteristic curve analysis were used to evaluate the relationship between alterations in serum sodium levels and clinical outcome or the development of DCI after aSAH. Poor outcome was defined as a modified Rankin Scale (mRS) score of > 2 at 3 months. RESULTS: The average daily difference in sodium values from baseline (p < 0.001), average daily difference from a normal sodium level (p < 0.001), average absolute daily difference from a normal sodium level (p = 0.015), and average absolute daily difference from the previous day's sodium level (p = 0.017) were significant predictors of poor outcome in a stepwise multivariate regression model. There was a trend toward significance for average absolute daily difference from admission sodium levels during the vasospasm window as an independent predictor of DCI (p = 0.052). There was no difference in the predictive capacity for DCI when sodium fluctuations from post-aSAH days 1-14 were compared with those from the classic vasospasm window (days 3-12). CONCLUSIONS: Fluctuations in serum sodium levels may play a role in clinical outcome and the development of DCI after aSAH. The timing of these fluctuations appears to have no significant effect on the development of DCI.