Pathophysiological processes following subarachnoid hemorrhage (SAH) present survivors of the initial bleeding with a high risk of morbidity and mortality during the course of the disease. As angiographic vasospasm is strongly associated with delayed cerebral ischemia (DCI) and clinical outcome, clinical trials in the last few decades focused on prevention of these angiographic spasms. Despite all efforts, no new pharmacological agents have shown to improve patient outcome. As such, it has become clear that our understanding of the pathophysiology of SAH is incomplete and we need to reevaluate our concepts on the complex pathophysiological process following SAH. Angiographic vasospasm is probably important. However, a unifying theory for the pathophysiological changes following SAH has yet not been described. Some of these changes may be causally connected or present themselves as an epiphenomenon of an associated process. A causal connection between DCI and early brain injury (EBI) would mean that future therapies should address EBI more specifically. If the mechanisms following SAH display no causal pathophysiological connection but are rather evoked by the subarachnoid blood and its degradation production, multiple treatment strategies addressing the different pathophysiological mechanisms are required. The discrepancy between experimental and clinical SAH could be one reason for unsuccessful translational results.

OBJECT Aneurysmal rerupture prior to treatment is a major cause of death and morbidity in aneurysmal subarachnoid hemorrhage. Recognizing risk factors for aneurysmal rebleeding is particularly relevant and might help to identify the aneurysms that benefit from acute treatment. It is uncertain if the size of the aneurysm is related to rebleeding. This meta-analysis was performed to evaluate whether an association could be determined between aneurysm diameter and the rebleeding rate before treatment. Potentially confounding factors such age, aneurysm location, and the presence of hypertension were also evaluated. METHODS The authors systematically searched the PubMed, Embase, and Cochrane databases up to April 3, 2013, for studies of patients with aneurysmal subarachnoid hemorrhage that reported the association between aneurysm diameter and pretreatment aneurysmal rebleeding. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria were used to evaluate study quality. RESULTS Seven studies, representing 2121 patients, were included in the quantitative analysis. The quality of the studies was low in 2 and very low in 5. Almost all of the studies used 10 mm as the cutoff point for size among other classes, and only one used 7 mm. An analysis was performed with this best unifiable cutoff point. Overall rebleeding occurred in 360 (17.0%) of 2121 patients (incidence range, from study to study, 8.7%–28.4%). The rate of rebleeding in small and large aneurysms was 14.0% and 23.6%, respectively. The meta-analysis of the 7 studies revealed that larger size aneurysms were at a higher risk for rebleeding (OR 2.56 [95% CI 1.62–4.06]; p = 0.00; I2 = 60%). The sensitivity analysis did not alter the results. Five of the 7 studies reported data regarding age; 4 studies provided age-adjusted results and identified a persistent relationship between lesion size and the risk of rebleeding. The presence of hypertension was reported in two studies and was more prevalent in patients with rebleeding in one of these. Location (anterior vs posterior circulation) was reported in 5 studies, while in 4 there was no difference in the rebleeding rate. One study identified a lower risk of rebleeding associated with posterior location aneurysms. CONCLUSIONS This meta-analysis showed that aneurysm size is an important risk factor for aneurysmal rebleeding and should be used in the clinical risk assessment of individual patients. The authors' results confirmed the current guidelines and underscored the importance of acute treatment for large ruptured aneurysms.

BACKGROUND AND PURPOSE: Impairment of tissue oxygenation caused by inhomogeneous microscopic blood flow distribution, the so-called capillary transit time heterogeneity, is thought to contribute to delayed cerebral ischemia after aneurysmal SAH but has so far not been systematically evaluated in patients. We hypothesized that heterogeneity of the MTT, derived from CTP parameters, would give insight into the clinical course of patients with aneurysmal SAH and may identify patients at risk of poor outcome. MATERIALS AND METHODS:We retrospectively analyzed the heterogeneity of the MTT using the coefficient of variation in CTP scans from 132 patients. A multivariable logistic regression model was used to model the dichotomized mRS outcome. Linear regression was used to eliminate variables with high linear dependence. T tests were used to compare the means of 2 groups. Furthermore, the time of the maximum coefficient of variation for MTT after bleeding was evaluated for correlation with the mRS after 6 months. RESULTS:On average, each patient underwent 5.3 CTP scans during his or her stay. Patients with high coefficient of variation for MTT presented more often with higher modified Fisher (P ¼ .011) and World Federation of Neurosurgical Societies grades (P ¼ .014). A high coefficient of variation for MTT at days 3-21 after aneurysmal SAH correlated significantly with a worse mRS score after 6 months (P ¼ .016). We found no correlation between the time of the maximum coefficient of variation for MTT after bleeding and the patients' outcomes after 6 months (P ¼ .203).CONCLUSIONS: Heterogeneity of MTT in CTP after aneurysmal SAH correlates with the patients' outcomes. Because the findings are in line with the pathophysiologic concept of the capillary transit time heterogeneity, future studies should seek to verify the coefficient of variation for MTT as a potential imaging biomarker for outcome. ABBREVIATIONS: aSAH ¼ aneurysmal SAH; CTH ¼ capillary transit time heterogeneity; cvMTT ¼ coefficient of variation for MTT; cvMTT-peak ¼ maximum cvMTT after bleeding; DCI ¼ delayed cerebral ischemia; EVD ¼ external ventricular drainage; ICP ¼ intracranial pressure; RTH ¼ relative transit time heterogeneity; Tmax ¼ time-to-maximum; WFNS ¼ World Federation of Neurosurgical Societies

Animal models are established to display the pathophysiological changes following subarachnoid hemorrhage (SAH). The aim of the present study was to determine case fatality in mouse delayed cerebral ischemia (DCI) models, to compare mortality in mouse DCI models to case fatality in human SAH patients, and to identify factors influencing mouse mortality. A systematic search of the PubMed database was performed to identify all studies that assessed mouse DCI models. Mortality rates and predictor variables were extracted and compared to the human case fatality after SAH as previously reported. Predictors for mouse mortality were identified through multivariate analysis. Forty-eight studies were included in the quantitative analysis. The mean overall mortality rate was 21% in mouse DCI models. However, the time period between induction of SAH and evaluation of mortality rates is a significant variable influencing the mortality rate in mouse SAH models. The experimental SAH model was the only significant predictor for mouse mortality after 48 h. In contrast, neither the genetic background nor the anesthetic changed the case fatality rate. Mouse mortality at 24, 48, and 72 h after experimental SAH in DCI models was significantly lower than human case fatality following aneurysmal SAH. The mean overall mortality rate in mouse DCI models is significantly lower than human case fatality following aneurysmal SAH. However, time between SAH induction and evaluation is a significant variable influencing the mortality rate in mouse SAH models. Further analyses will be required to establish whether and to which extent different DCI models affect mortality and reflect human pathophysiology.

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