Incidence Of Delayed Cerebral Ischemia Research Articles

Neutrophils and Neutrophil Extracellular Traps Cause Vascular Occlusion and Delayed Cerebral Ischemia After Subarachnoid Hemorrhage in Mice.

After subarachnoid hemorrhage (SAH), neutrophils are deleterious and contribute to poor outcomes. Neutrophils can produce neutrophil extracellular traps (NETs) after ischemic stroke. Our hypothesis was that, after SAH, neutrophils contribute to delayed cerebral ischemia (DCI) and worse outcomes via cerebrovascular occlusion by NETs. SAH was induced via endovascular perforation, and SAH mice were given either a neutrophil-depleting antibody, a PAD4 (peptidylarginine deiminase 4) inhibitor (to prevent NETosis), DNAse-I (to degrade NETs), or a vehicle control. Mice underwent daily neurological assessment until day 7 and then euthanized for quantification of intravascular brain NETs (iNETs). Subsets of mice were used to quantify neutrophil infiltration, NETosis potential, iNETs, cerebral perfusion, and infarction. In addition, NET markers were assessed in the blood of aneurysmal SAH patients. In mice, SAH led to brain neutrophil infiltration within 24 hours, induced a pro-NETosis phenotype selectively in skull neutrophils, and caused a significant increase in iNETs by day 1, which persisted until at least day 7. Neutrophil depletion significantly reduced iNETs, improving cerebral perfusion, leading to less neurological deficits and less incidence of DCI (16% versus 51.9%). Similarly, PAD4 inhibition reduced iNETs, improved neurological outcome, and reduced incidence of DCI (5% versus 30%), whereas degrading NETs marginally improved outcomes. Patients with aneurysmal SAH who developed DCI had elevated markers of NETs compared with non-DCI patients. After SAH, skull-derived neutrophils are primed for NETosis, and there are persistent brain iNETs, which correlated with delayed deficits. The findings from this study suggest that, after SAH, neutrophils and NETosis are therapeutic targets, which can prevent vascular occlusion by NETs in the brain, thereby lessening the risk of DCI. Finally, NET markers may be biomarkers, which can predict which patients with aneurysmal SAH are at risk for developing DCI.

Abstract WMP112: Neutrophil Extracellular Traps Occlude the Cerebrovasculature Causing Delayed Cerebral Ischemia After Subarachnoid Hemorrhage in Mice

Neutrophils are reported to be critical mediators of to poor outcome after subarachnoid hemorrhage (SAH). Following ischemic stroke, neutrophils cause vascular occlusion via neutrophil extracellular traps (NETs). In this study, our hypothesis was that NETs cause vascular occlusion leading to delayed cerebral ischemia (DCI) and worse outcome after SAH. SAH mice (male and female, young and aged) were administered one of the following: a neutrophil depleting antibody, a PAD4 inhibitor (to prevent NETosis), DNAse-I (to degrade NETs), or a vehicle (control). Mice had neurological assessment daily until day 7 and then were euthanized to quantify the amount of brain vascular NETs. Various subcohorts of mice were used to assess neutrophil propensity to NETose, in vivo formation of NETs via intravital microscopy, and MRI assessment of cerebral perfusion and infarct development. We also examined if NETs were present after SAH in 128 humans by measuring NETs markers via ELISA at 1, 2, 4, 7, and 10 days post-SAH. In mice, SAH induced a pro-NETosis phenotype selectively in skull neutrophils and caused intravascular NETs to be present by day 1 which persisted until at least day 7. Neutrophil depletion reduced NETs, improved cerebral perfusion and neurological outcome, and attenuated the incidence of DCI. Similar findings were observed for PAD4 inhibition. However, degrading NETs only marginally improved outcomes. Aneurysmal SAH patients who developed DCI had elevated markers of NETs compared to non-DCI patients. In conclusion, after SAH, skull-derived neutrophils are primed for NETosis, and neutrophils and NETosis are therapeutic targets to reduce DCI by preventing vascular occlusion by NETs.

Clinical value of serum complement component 1q levels in the prognostic analysis of aneurysmal subarachnoid hemorrhage: a prospective cohort study.

To analyze the relationship between serum complement component 1q (C1q) levels and functional prognosis in patients with aneurysmal subarachnoid hemorrhage (aSAH), and to reveal its clinical value. In this prospective cohort study, we collected clinical data of aSAH patients admitted to the Department of Neurosurgery, Hangzhou First People's Hospital from January 2020 to October 2022. Parameters such as serum C1q levels, Hunt-Hess grade, modified Fisher grade, and the modified Rankin scale (mRS) at 3 months were included for evaluation. Patients were grouped based on the occurrence of delayed cerebral ischemia (DCI). Spearman rank correlation test and Kruskal-Wallis rank sum test were used to analyze the correlation between serum C1q levels, disease severity, and prognosis. Potential risk factors affecting prognosis and the occurrence of DCI were screened through Independent sample t-test or Mann-Whitney U test. Variables with significant differences (p < 0.05) were incorporated into a logistic regression model to identify independent risk factors affecting prognosis and DCI occurrence. Serum C1q levels were plotted as a ROC curve for predicting prognosis and DCI, and the area under the curve was calculated. A total of 107 aSAH patients were analyzed. Serum C1q levels positively correlated with Hunt-Hess grade, modified Fisher grade and mRS (all p < 0.001). Significant differences were observed in C1q levels among different Hunt-Hess grade, mFisher grade and mRS (all p < 0.001). Notably, higher serum C1q levels were seen in the poor prognosis group and DCI group, and correlated with worse prognosis (OR = 36.927, 95%CI 2.003-680.711, p = 0.015), and an increased risk for DCI (OR = 17.334, 95%CI 1.161-258.859, p = 0.039). ROC analysis revealed the significant discriminative power of serum C1q levels for poor prognosis (AUC 0.781; 95%CI 0.673-0.888; p < 0.001) and DCI occurrence (AUC 0.763; 95%CI 0.637-0.888; p < 0.001). Higher C1q levels independently predicted a poor prognosis and DCI with equivalent predictive abilities to Hunt-Hess grade and modified Fisher grade (both p < 0.05). High levels of C1q in the blood is an independent risk factor for poor prognosis and the development of DCI in patients with aSAH. This can more objectively and accurately predict functional outcomes and the incidence of DCI. C1q may have a significant role in the mechanism behind DCI after aSAH.

The impact of perfusion computed tomography on the diagnosis and outcome of delayed cerebral ischemia after subarachnoid hemorrhage.

Delayed cerebral ischemia (DCI) is a preventable cause of poor neurological outcome in aneurysmal subarachnoid hemorrhage (aSAH). Advances in radiological methods, such as cerebral perfusion computed tomography (CTP), could help diagnose DCI earlier and potentially improve outcomes in aSAH. The objective of this study was to assess whether the use of CTP to diagnose DCI early could reduce the risk of infarction related to DCI. Retrospective cohort study of patients in the intensive care unit of Erasme Hospital (Brussels, Belgium) between 2004 and 2021 with aSAH who developed DCI. Patients were classified as: "group 1" - DCI diagnosed based on clinical deterioration or "group 2" - DCI diagnosed using CTP. The primary outcome was the development of infarction unrelated to the initial bleeding or surgery. 211 aSAH patients were diagnosed with DCI during the study period: 139 (66%) in group 1 and 72 (34%) in group 2. In group 1, 109 (78%) patients developed a cerebral infarction, compared to 45 (63%) in group 2 (p = 0.02). The adjusted cumulative incidence of DCI over time was lower in group 2 than in group 1 [hazard ratio 0.65 (95% CI 0.48-0.94); p = 0.02]. The use of CTP to diagnose DCI was not independently associated with mortality or neurological outcome. The use of CTP to diagnose DCI might help reduce the risk of developing cerebral infarction after aSAH, although the impact of such an approach on patient outcomes needs to be further demonstrated.

Effect of an Albumin Infusion Treatment Protocol on Delayed Cerebral Ischemia and Relevant Outcomes in Patients with Subarachnoid Hemorrhage.

An institutional management protocol for patients with subarachnoid hemorrhage (SAH) based on initial cardiac assessment, permissiveness of negative fluid balances, and use of a continuous albumin infusion as the main fluid therapy for the first 5days of the intensive care unit (ICU) stay was implemented at our hospital in 2014. It aimed at achieving and maintaining euvolemia and hemodynamic stability to prevent ischemic events and complications in the ICU by reducing periods of hypovolemia or hemodynamic instability. This study aimed at assessing the effect of the implemented management protocol on the incidence of delayed cerebral ischemia (DCI), mortality, and other relevant outcomes in patients with SAH during ICU stay. We conducted a quasi-experimental study with historical controls based on electronic medical records of adults with SAH admitted to the ICU at a tertiary care university hospital in Cali, Colombia. The patients treated between 2011 and 2014 were the control group, and those treated between 2014 and 2018 were the intervention group. We collected baseline clinical characteristics, cointerventions, occurrence of DCI, vital status after 6months, neurological status after 6months, hydroelectrolytic imbalances, and other SAH complication. Multivariable and sensitivity analyses that controlled for confounding and considered the presence of competing risks were used to adequately estimate the effects of the management protocol. The study was approved by our institutional ethics review board before study start. One hundred eighty-nine patients were included for analysis. The management protocol was associated with a reduced incidence of DCI (hazard ratio 0.52 [95% confidence interval 0.33-0.83] from multivariable subdistribution hazards model) and hyponatremia (relative risk 0.55 [95% confidence interval 0.37-0.80]). The management protocol was not associated with higher hospital or long-term mortality, nor with a higher occurrence of other unfavorable outcomes (pulmonary edema, rebleeding, hydrocephalus, hypernatremia, pneumonia). The intervention group also had lower daily and cumulative administered fluids compared with historic controls (p < 0.0001). A management protocol based on hemodynamically oriented fluid therapy in combination with a continuous albumin infusion as the main fluid during the first 5days of the ICU stay appears beneficial for patients with SAH because it was associated with reduced incidence of DCI and hyponatremia. Proposed mechanisms include improved hemodynamic stability that allows euvolemia and reduces the risk of ischemia, among others.

Microvascular Cerebral Blood Flow Monitoring Detects Response to Intrathecal Nicardipine Treatment for Vasospasm (S4.005)

<h3>Objective:</h3> Determining the effect of intrathecal nicardipine on microvascular cerebral blood flow <h3>Background:</h3> A common complication of subarachnoid hemorrhage is cerebral vasospasm, which is associated with delayed cerebral ischemia (DCI), a predictor of poor functional outcome. Intrathecal administration of nicardipine (ITn) upon detection of vasospasm holds promise as a treatment that reduces the incidence of secondary stroke. Herein, we utilize a novel non-invasive optical measurement of regional microvascular perfusion to determine the effect of ITn on microvascular cerebral blood flow (CBF). <h3>Design/Methods:</h3> In this observational study, we prospectively studied 20 patients with non-traumatic subarachnoid hemorrhage who were treated with ITn as part of usual care for evolving cerebral vasospasm. Regional microvascular CBF in the frontal cortex was measured with diffuse correlation spectroscopy for up to 90 min after the first treatment dose, and for a subset of patients, on days 2 and 3 of treatment as well. Outcome was assessed as the presence of DCI on imaging. <h3>Results:</h3> CBF increased significantly over the 90 min of monitoring after the first and subsequent doses (p&lt;0.001) in the absence of systemic hemodynamic changes. In general, the CBF response was heterogeneous across subjects. Using data from the first dose, a latent class mixture model was used to classify 19/20 patients into two distinct classes of cerebral blood flow response: patients in class 1 (n=6) showed a decrease or no change in CBF, while patients in class 2 (n=13) showed a pronounced increase in CBF in response to nicardipine. The incidence of DCI was 5/6 in class 1 and 0/13 in class 2 (p&lt;0.001). Similar significant differences in CBF response in patients with and without DCI were also observed on days 2 and 3 (both p&lt;0.001). <h3>Conclusions:</h3> Microvascular CBF monitoring is feasible in critically ill subarachnoid hemorrhage patients. CBF response may provide a valuable biomarker for treatment responsiveness. <b>Disclosure:</b> Dr. Sathialingam has nothing to disclose. Mr. Cowdrick has nothing to disclose. Ms. Urner has nothing to disclose. Ms. Liew has nothing to disclose. Dr. Sigman has nothing to disclose. Dr. Akbik has nothing to disclose. Dr. Samuels has received publishing royalties from a publication relating to health care. Dr. Kandiah has nothing to disclose. Dr. Buckley has received research support from Global Blood Therapeutics. Dr. Buckley has received research support from NIH. Ofer Sadan has received intellectual property interests from a discovery or technology relating to health care.

Microvascular cerebral blood flow response to intrathecal nicardipine is associated with delayed cerebral ischemia.

One of the common complications of non-traumatic subarachnoid hemorrhage (SAH) is delayed cerebral ischemia (DCI). Intrathecal (IT) administration of nicardipine, a calcium channel blocker (CCB), upon detection of large-artery cerebral vasospasm holds promise as a treatment that reduces the incidence of DCI. In this observational study, we prospectively employed a non-invasive optical modality called diffuse correlation spectroscopy (DCS) to quantify the acute microvascular cerebral blood flow (CBF) response to IT nicardipine (up to 90 min) in 20 patients with medium-high grade non-traumatic SAH. On average, CBF increased significantly with time post-administration. However, the CBF response was heterogeneous across subjects. A latent class mixture model was able to classify 19 out of 20 patients into two distinct classes of CBF response: patients in Class 1 (n = 6) showed no significant change in CBF, while patients in Class 2 (n = 13) showed a pronounced increase in CBF in response to nicardipine. The incidence of DCI was 5 out of 6 in Class 1 and 1 out of 13 in Class 2 (p < 0.001). These results suggest that the acute (<90 min) DCS-measured CBF response to IT nicardipine is associated with intermediate-term (up to 3 weeks) development of DCI.

Abstract WP220: Platelet Inhibition Prevents Delayed Cerebral Ischemia After Subarachnoid Hemorrhage In Mice

Subarachnoid hemorrhage (SAH) induces delayed cerebral ischemia (DCI) in about 30% of patients which is characterized by functional decline. As microthrombi is a cause of DCI, platelets may be a therapeutic target for preventing microthrombi formation and development of DCI. Clinical trials of anti-platelets have been inconclusive for their effect on outcome. However, clinical trials used different anti-platelets. Since platelets have numerous receptors which can each prevent thrombosis, there is no clear choice to target for SAH. Here, we utilize 6 platelet antagonists to identify if any receptor is a therapeutic target for DCI after SAH. Our hypothesis is that P2Y receptor inhibition will prevent microthrombi and reduce DCI after SAH. Male and female mice were randomly assigned into sham, SAH+vehicle, SAH+P2Y antagonism, SAH+PAR4 antagonism, SAH+PAF antagonism, SAH+TPβ-R antagonism, and SAH+GPIIb/IIIa antagonism. Mice were euthanized 2 (n=10/group) or 7 days (n=15/group) post-SAH. All outcomes were performed and data was analyzed by a blinded investigator. Behavior was assessed daily. Brain microthrombi were counted. Both male and female SAH mice treated with inhibitors of PAF and TPβ-R had significantly better day 1 function than vehicle-treated mice. Significantly better function on day 1 was also observed in only male mice treated the P2Y antagonists or GPIIb/IIIa antagonist. Neither sex had improved behavior for the PAR-4 inhibitor. Mice exhibiting better function had fewer brain microthrombi with the exception of the GPIIb/IIIa antagonist which reduced microthrombi in female mice but did not correspond with improved behavior. This suggests there may be another deleterious mechanism which is more prevalent/detrimental in females that is not prevented by GPIIb/IIIa inhibition, such as platelet degranulation. However, this needs to be further investigated. Additionally, inhibition of TPβ-R reduced the incidence of DCI compared to vehicle-treated mice. In conclusion, an anti-platelet drug for SAH needs to be chosen carefully as not all antagonists have a beneficial effect after SAH; of vital importance is that anti-platelet drugs may not have similar beneficial effects in both sexes.

Effect of antiplatelet treatment on aneurysmal subarachnoid hemorrhage patients after endovascular treatment: a systematic review with meta-analysis.

Antiplatelet treatment (APT) has been reported to be used in some patients with aneurysmal subarachnoid hemorrhage (aSAH) after endovascular treatment, but there is controversy among different studies regarding its clinical effects. This study intends to conduct a meta-analysis to evaluate the impact of APT on aSAH patients after endovascular treatment. The PubMed, EMBASE, and Cochrane Library databases were systematically searched up to January 2022 for eligible English publications. Quality assessment was conducted for the included studies. Publication bias and heterogeneity were assessed by Egger's test and the I2 statistic, respectively. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by meta-analysis. Robustness was checked by subgroup and sensitivity analyses. In total, 597 and 522 patients with and without APT, respectively, in 5 retrospective studies were retained for the meta-analysis. Pooled analyses showed that the APT group had a lower mortality (41/499 [8%] versus 56/402 [14%]; OR = 0.533; 95% CI, 0.347-0.820; P = 0.004) and a higher proportion of favorable clinical outcomes (400/532 [75%] versus 266/421 [63%]; OR = 1.801; 95% CI, 1.359-2.414; P = 0.000) than the control group. There was no significant difference in the incidence of hemorrhagic complications (39/564 [7%] versus 26/503 [5%]; OR = 1.386; 95% CI, 0.825-2.329; P = 0.218) between groups. Although the incidence of delayed cerebral ischemia (DCI) was significantly lower in the APT group (65/512 [13%] versus 105/447 [23%]; OR = 0.325; 95% CI, 0.107-0.988; P = 0.048), it showed substantial heterogeneity (I2 = 64.7%). Subsequent sensitivity analysis suggested that the meta-analysis was robust. Subgroup analyses revealed that long-term (> 2weeks) APT (60/479 [13%] versus 103/428 [24%]; OR = 0.212; 95% CI, 0.056-0.806; P = 0.023) significantly reduced the DCI rate and that different grouping methods in the included studies may be a source of heterogeneity. In the absence of randomized controlled trials, a meta-analysis of retrospective studies suggested that APT was associated with reduced mortality and better functional outcomes in aSAH patients after endovascular treatment without an increased incidence of hemorrhagic complications. Long-term APT was also associated with a decrease in the incidence of DCI. Well-designed randomized controlled trials are warranted and updated meta-analyses are needed to verify our findings.

Higher Levels of Admission N-Terminal Pro-brain Natriuretic Peptide are Associated with Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) greatly influences the prognosis of patients with aneurysmal subarachnoid hemorrhage (aSAH). We aimed to determine whether higher levels of admission N-terminal pro-brain natriuretic peptide (NT-pro BNP) were related to neurogenic cardiac injury and predicted DCI occurrence in patients with aSAH. We retrospectively reviewed consecutive patients with aSAH between January 2018 and April 2021 in our department. Patients with admission NT-pro BNP were included for analysis. The associations between admission NT-pro BNP levels and admission cardiac troponin T levels and electrocardiogram characteristics, as well as the incidence of DCI, were investigated. A total of 415 patients with aSAH were included, among whom DCI occurred in 53 (12.8%). The admission NT-pro BNP levels were positively correlated with the cardiac troponin T levels and were significantly higher in patients with abnormal electrocardiogram characteristics. The admission log NT-pro BNP levels were higher in patients with DCI than in those without DCI. Multivariable analysis revealed that admission log NT-pro BNP levels and modified Fisher scale were independent predictors of the incidence of DCI. Compared with the modified Fisher scale alone (area under the curve = 0.739), combining the modified Fisher scale with admission NT-pro BNP (area under the curve = 0.794) significantly improved the prediction accuracy for DCI (p < 0.001). Higher admission levels of NT-pro BNP correlated with neurogenic cardiac injury and predicted the occurrence of DCI in patients with aSAH. A combination of the modified Fisher scale and admission NT-pro BNP significantly improved the prediction accuracy for DCI.

Low serum albumin as a risk factor for delayed cerebral ischemia following aneurysmal subarachnoid hemorrhage: eICU collaborative research database analysis.

Delayed cerebral ischemia (DCI) represents a devastating complication of aneurysmal subarachnoid hemorrhage (aSAH) and is a significant predictor of morbidity and mortality. Recent studies have implicated inflammatory processes in the pathogenesis of DCI. aSAH patient data were retrospectively obtained from the eICU Collaborative Research Database (eICU CRD). Multivariable logistic regression models and receiver operating characteristic (ROC) curve analyses were employed to assess the association between low serum albumin (<3.4 g/dL) and clinical endpoints: DCI and in-hospital mortality. Among 276 aSAH patients included in the analysis, 35.5% (N.=98) presented with low serum albumin levels and demonstrated a higher incidence of DCI (18.4% vs. 8.4%, OR=2.45, 95% CI=1.17, 5.10; P=0.017) and in-hospital mortality (27.6% vs. 16.3%, OR=1.95, 95% CI=1.08, 3.54; P=0.027) compared to patients with normal admission albumin values. In a multivariable model controlling for age and World Federation of Neurosurgical Societies grade, low serum albumin remained significantly associated with DCI (OR=2.52, 95% CI=1.18, 5.36; P=0.017), but not with in-hospital mortality. A combined model for prediction of DCI, encompassing known risk factors in addition to low serum albumin, achieved an area under the curve of 0.65 (sensitivity = 0.55, specificity = 0.75). Serum albumin, a routine and inexpensive laboratory measurement, may potentially aid in the identification of patients with aSAH at risk for the development of DCI.

Application of Intracranial Pressure-Directed Therapy on Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage

ObjectiveElevated ICP is a well-recognized phenomenon in aneurysmal subarachnoid hemorrhage (aSAH) that has been demonstrated to lead to poor outcomes. Delayed cerebral ischemia (DCI) is the most important reason for a poor clinical outcome after a subarachnoid hemorrhage. DCI is understood as a multifactorial process that evolves over time, largely caused by the sequelae of increased intracranial pressure (ICP). The study aimed to assess how to better define the association between ICP and DCI, and whether rational ICP management can improve the outcome of aSAH patients.MethodsWe prospectively reviewed patients diagnosed with aSAH and received microsurgery clipping at our department from December 2019 to January 2021. Subdural ICP monitoring devices were kept to monitor the ICP. The ICP values were recorded every 1-h epochs. ICP -guided dehydration treatments were routinely performed to control the ICP level of patients after surgery. To evaluate whether the subdural ICP-directed management improved the prognosis of the aSAH patients, we compared the outcome data of the patients in our cohort with those treated at another ward of our hospital at the same period.ResultsIn total, 144 consecutive aSAH patients received microsurgery clipping at our department, 68 of whom underwent ICP monitoring. A total of 11,424 1-h ICP measurements were recorded for the included patients (1.30 years of recordings). Of 68 patients with ICP monitoring, 27 (27/68, 39.7%) patients developed DCI. Univariate analysis showed that higher Hunt-Hess grade (OR 2.138, 95% CI 1.025–4.459, p = 0.043), higher preoperative modified Rankin Scale score (OR 1.534, 95% CI 1.033–2.276, p = 0.034), and the max ICP value of each day value >28.5 mmHg (OR 4.442, 95% CI 1.509–13.082, p = 0.007) were associated with DCI. Also, patients with ICP-directed treatment showed a significantly lower DCI incidence than patients without ICP monitoring.ConclusionOur study suggests that I less than 15 mmHg possibly constitute normal values and that 28.5 mmHg is the ICP threshold most strongly associated with the occurrence of DCI in aSAH patients. Patients who received the ICP-directed treatment presented a lower incidence of DCI. Our findings provide a basis for the recommendation of ICP-directed treatment after aSAH.Trial Registration NumberNCT04785976.

Neuroprotective effect of dapsone in patients with aneurysmal subarachnoid hemorrhage: a prospective, randomized, double-blind, placebo-controlled clinical trial.

In this study, the authors sought to define the differences in the incidence of delayed cerebral ischemia (DCI) between patients treated with dapsone and those treated with placebo. Secondary objectives were to define the clinical outcome at discharge and 3 months and the incidence of brain infarction. A prospective, randomized, double-blind, placebo-controlled study was performed and included patients with aneurysmal subarachnoid hemorrhage (SAH) within 5 days from ictus who were candidates for aneurysm occlusion, and who had a Fisher grade of 3 or 4. Patients with sulfa or sulfone drug allergies, hemoglobin < 11 g/dl, known G6PD deficiency, and those refusing informed consent were excluded. A minimal relevant effect decrease of 35% in the incidence of DCI was established. Patients were randomly assigned to receive a regimen of dapsone 2.5 ml (100 mg) daily or a placebo (aluminum hydroxide suspension, 2.5 ml daily). Both groups received validated treatment for aneurysmal SAH. The appearance of DCI on CT was assessed in every patient at discharge and 3 months later. We used the chi-square test to compare the DCI incidence between both groups, and the Student t-test or nonparametric tests to compare quantitative variables. Overall, 48 patients (70.8% women and 29.2% men) were included. The mean age was 50 years (SD 14.28 years, range 18-72 years). Prerandomization and postrandomization characteristics were balanced, except for the necessity of intra-arterial nimodipine administration in patients treated with placebo (15.4% vs 45.5%, p = 0.029. The incidence of DCI, the primary endpoint, for the whole cohort was 43.8% and was significantly lower in the dapsone group (26.9% vs 63.6%, p = 0.011). In addition, the irreversible DCI incidence was lower in the dapsone group (11.5% vs 54.5%, p = 0.12). A favorable modified Rankin Scale score was more frequent in the dapsone group at discharge and at 3 months (76.9% vs 36.4%, p = 0.005 and 80% vs 38.9%, p = 0.019, respectively). Also, the brain infarction incidence was lower in the dapsone group (19.2% vs 63.6%, p = 0.001). There was no difference between groups regarding adverse events. Dapsone seems to play a role as a prophylactic agent in patients at high risk of developing DCI after aneurysmal SAH. A multicenter investigation is necessary to increase the study population and confirm the consistency of the results observed in this study.

Update on intrathecal management of cerebral vasospasm: a systematic review and meta-analysis.

Aneurysmal subarachnoid hemorrhage (aSAH) accounts for a relatively small portion of strokes but has the potential to cause permanent neurological deficits. Vasospasm with delayed ischemic neurological deficit is thought to be responsible for much of the morbidity associated with aSAH. This has illuminated some treatment options that have the potential to target specific components of the vasospasm cascade. Intrathecal management via lumbar drain (LD) or external ventricular drain (EVD) offers unique advantages in this patient population. The aim of this review was to provide an update on intrathecal vasospasm treatments, emphasizing the need for larger-scale trials and updated protocols using data-driven evidence. A search of PubMed, Ovid MEDLINE, and Cochrane databases included the search terms (subarachnoid hemorrhage) AND (vasospasm OR delayed cerebral ischemia) AND (intrathecal OR intraventricular OR lumbar drain OR lumbar catheter) for 2010 to the present. Next, a meta-analysis was performed of select therapeutic regimens. The primary endpoints of analysis were vasospasm, delayed cerebral ischemia (DCI), cerebral infarction, and functional outcome. Twenty-nine studies were included in the analysis. There were 10 studies in which CSF drainage was the primary experimental group. Calcium channel antagonists were the focus of 7 studies. Fibrinolytics and other vasodilators were each examined in 6 studies. The meta-analysis included studies examining CSF drainage via LD (n = 4), tissue plasminogen activator in addition to EVD (n = 3), intraventricular nimodipine (n = 2), and cisternal magnesium (n = 2). Results showed that intraventricular nimodipine decreased vasospasm (OR 0.59, 95% CI 0.37-0.94; p = 0.03). Therapies that significantly reduced DCI were CSF drainage via LD (OR 0.47, 95% CI 0.25-0.88; p = 0.02) and cisternal magnesium (OR 0.27, 95% CI 0.07-1.02; p = 0.05). CSF drainage via LD was also found to significantly reduce the incidence of cerebral infarction (OR 0.35, 95% 0.24-0.51; p < 0.001). Lastly, functional outcome was significantly better in patients who received CSF drainage via LD (OR 2.42, 95% CI 1.39-4.21; p = 0.002). The authors' results showed that intrathecal therapy is a safe and feasible option following aSAH. It has been shown to attenuate cerebral vasospasm, reduce the incidence of DCI, and improve clinical outcome. The authors support the use of intrathecal management in the prevention and rescue management of cerebral vasospasm. More randomized controlled trials are warranted to determine the best combination of pharmaceutical agents and administration route in order to formulate a standardized treatment approach.

Rebleeding After Aneurysmal Subarachnoid Hemorrhage in Two Centers Using Different Blood Pressure Management Strategies.

BackgroundHigh systolic blood pressure (SBP) after aneurysmal subarachnoid hemorrhage (aSAH) has been associated with an increased risk of rebleeding. It remains unclear if an SBP lowering strategy before aneurysm treatment decreases this risk without increasing the risk of a delayed cerebral ischemia (DCI). Therefore, we compared the rates of in-hospital rebleeding and DCI among patients with aSAH admitted in two tertiary care centers with different SBP management strategies.MethodsRetrospective cohort study. Consecutive patients from Utrecht and Toulouse admitted within 24 h after the aSAH onset were enrolled. In Toulouse, the target SBP before aneurysm treatment was ≤140 mm Hg, while, in Utrecht, an increased SBP was only treated in extreme situations. We compared SBP levels, the incidence of rebleeding within 24 h after admission, and DCI during hospitalization.ResultsWe enrolled 373 patients in Utrecht and 149 in Toulouse. The mean SBP on admission was similar but lower in Toulouse 4 h after admission (127.3 ± 17.4 vs. 138. ± 25.7 mmHg; p < 0.0001). After a median delay of 3.7 h (IQR, 2.3–7.4) from admission, 4 patients (3%) in Toulouse vs. 29 (8%) in Utrecht experienced a rebleeding. After adjustment for Prognosis on Admission of Aneurysmal Subarachnoid Hemorrhage (PAASH) score, aneurysm size, age, and delay from ictus to admission, the HR was 0.66 (95% CI: 0.23–1.92). Incidence of DCI was 18% in Toulouse and 25% in Utrecht (adjusted OR, 0.68; 95% CI: 0.41–1.11).ConclusionOur results suggest that an intensive SBP lowering strategy between admission and aneurysm treatment does not decrease the risk of rebleeding and does not increase the risk of DCI compared to a more conservative strategy.

Targeting Hemoglobin to Reduce Delayed Cerebral Ischemia After Subarachnoid Hemorrhage.

Delayed cerebral ischemia (DCI) continues to be a sequela of aneurysmal subarachnoid hemorrhage (aSAH) that carries significant morbidity and mortality. Aside from nimodipine, no therapeutic agents are available to reduce the incidence of DCI. Pathophysiologic mechanisms contributing to DCI are poorly understood, but accumulating evidence over the years implicates several factors. Those have included microvessel vasoconstriction, microthrombosis, oxidative tissue damage, and cortical spreading depolarization as well as large vessel vasospasm. Common to these processes is red blood cell leakage into the cerebrospinal fluids (CSF) and subsequent lysis which releases hemoglobin, a central instigator in these events. This has led to the hypothesis that early blood removal may improve clinical outcome and reduce DCI. This paper will provide a narrative review of the evidence of hemoglobin as an instigator of DCI. It will also elaborate on available human data that discuss blood clearance and CSF drainage as a treatment of DCI. Finally, we will address a recent novel device that is currently being tested, the Neurapheresis CSF Management System™. This is an automated dual-lumen lumbar drainage system that has an option to filter CSF and return it to the patient.

Abstract WMP111: Microvascular Occlusion Precedes Delayed Deficits In Mice With Subarachnoid Hemorrhage

Subarachnoid hemorrhage (SAH) induces delayed cerebral ischemia (DCI) in about 30% of patients which is characterized by functional decline. Microvascular occlusion, via microvessel constriction or microthrombi, may be a cause of DCI. Our hypothesis is that microvascular occlusion and reduced cerebral blood flow (CBF) precede the onset of delayed deficits in mice with SAH. Mice were randomly assigned into sham, SAH+saline, and SAH+A3P5P+Clopidogrel (platelet antagonists). Laser speckle imaging (to assess large and microvessel perfusion) and behavior were assessed daily. All outcomes were performed and data was analyzed by a blinded investigator. Both large artery and microvessel/tissue perfusion recover to baseline in SAH mice which do not get delayed deficits. However, in SAH mice which develop delayed deficits, microvessel/tissue perfusion has a prolonged reduction (Figure 1A). Interestingly, large artery perfusion recovers in these mice. Antiplatelets prevent microthrombi, attenuating microvessel occlusion, and reduce delayed deficits (Figure 2B-C). Our findings suggest that 1) microvessel occlusion and prolonged tissue perfusion are causative factors for DCI and 2) preventing platelet activation may be a therapeutic target to reduce the incidence of DCI. Our data also suggests a sex difference in the response to platelet antagonists (data not shown).

DCI after Aneurysmal Subarachnoid Hemorrhage Is Related to the Expression of MFG-E8.

Objective To explore the predictive value of milk fat globule epidermal growth factor 8 (MFG-E8) in the occurrence of delayed cerebral ischemia (DCI) after an aneurysmal subarachnoid hemorrhage (aSAH). Methods We recruited 32 patients with aSAH as the case group and 24 patients with unruptured aneurysms as the control group. Serum MFG-E8 levels were measured by western blot and enzyme-linked immunosorbent assay. We analyzed the relationship between MFG-E8 levels and the risk of DCI. Results The levels of serum MFG-E8 in the case group (mean = 11160.9 pg/mL) were significantly higher than those in the control group (mean = 3081.0 pg/mL, p < 0.001). MFG-E8 levels highly correlated with the World Federation of Neurosurgical Societies (WFNS) and modified Fisher scores (r = −0.691 and − 0.767, respectively, p < 0.001). In addition, MFG-E8 levels in patients with DCI (5882.7 ± 3162.4 pg/mL) were notably higher than those in patients without DCI (15818.2 ± 3771.6 pg/mL, p < 0.001). A receiver operating characteristic curve showed that the occurrence of DCI could effectively be predicted by MFG-E8 (area under the curve = 0.976, 95%CI = 0.850–1.000). Kaplan–Meier survival analysis showed a remarkable decrease in the incidence of DCI in case group individuals with high levels of MFG-E8 (≥11160.9 pg/mL, p < 0.001). Conclusion MFG-E8 may be a useful predictive marker for DCI after an aSAH and could be a promising surrogate end point.

A Double-Blind, Randomized, Placebo-Controlled Trial of Soluble Epoxide Hydrolase Inhibition in Patients with Aneurysmal Subarachnoid Hemorrhage.

Epoxyeicosatrienoates (EETs) are endogenous regulators of neuroinflammation and cerebral blood flow. Their metabolism to dihydroxyeicosatrienoates (DHETs) is catalyzed by soluble epoxide hydrolase (sEH). After subarachnoid hemorrhage (SAH), EETs' pathway amplification may be a therapeutic target for the prevention of delayed cerebral ischemia (DCI). We conducted a double-blind, placebo-controlled, phase Ib randomized trial of GSK2256294, a pharmacologic inhibitor of sEH, to evaluate the safety profile and to assess biomarkers of neurovascular inflammation in patients with aneurysmal SAH. Patients were randomly assigned to receive 10 mg of GSK2256294 or a placebo treatment once daily for 10 days, beginning within 72 hours after aneurysm rupture. The primary study end point was safety. Secondary end points included serum and cerebrospinal fluid (CSF) EETs-to-DHETs ratio, cytokine levels, and serum endothelial injury biomarkers, measured at day 7 and day 10 after SAH. Tertiary end points included neurologic status, disposition, length of stay, incidence of DCI, and mortality; these were assessed at hospital discharge and at 90 days. Ten patients received GSK2256294 and nine patients received a placebo. There were no adverse events related to the study drug. GSK2256294 administration resulted in a significant increase in the EET/DHET ratio at day 7 and day 10 in serum, but not in the CSF. There was a trend for decreased CSF inflammatory cytokines following GSK2256294 administration, but this did not reach statistical significance. GSK2256294 administration was safe and well tolerated in critically ill patients with SAH, producing an increase in serum EETs and the EET-to-DHET ratio. Our findings support future studies in a larger population to evaluate the role of sEH inhibition in the prevention of DCI after SAH and other forms of brain injury and inflammatory conditions. ClinicalTrials.gov: NCT03318783.

Nicardipine Prolonged Release Implants for Prevention of Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis

ObjectivesA paucity of treatments to prevent delayed cerebral ischemia (DCI) has stymied recovery after aneurysmal subarachnoid hemorrhage (aSAH). Nicardipine has long been recognized as a potent cerebrovascular vasodilator with a history off-label use to prevent vasospasm and DCI. Multiple centers have developed nicardipine prolonged release implants (NPRI) that are directly applied during clip ligation to locally deliver nicardipine throughout the vasospasm window. Here we perform a systematic review and meta-analysis to assess whether NPRI confers protection against DCI and improves functional outcomes after aSAH. Materials and methodsA systematic search of PubMed, Ovid Embase, and Cochrane databases was performed for studies reporting the use of NPRI after aSAH published after January 1, 1980. We included all studies assessing the association of NPRI with DCI and or functional outcomes. Findings from studies with control arms were analyzed using a random effects model. A separate network meta-analysis was performed, including controlled NPRI studies, single-arm NPRI reports, and the control-arms of modern aSAH randomized clinical trials as additional comparators. ResultsThe search identified 214 unique citations. Three studies with 284 patients met criteria for the random effects model. The pooled summary odds ratio for the association of NPRI and DCI was 0.21 (95% CI 0.09–0.49, p = 0.0002) with no difference in functional outcomes (OR 1.80, 95% CI 0.63 – 5.16, p = 0.28). 10 studies of 866 patients met criteria for the network meta-analysis. The pooled summary odds ratio for the association of NPRI and DCI was 0.30 (95% CI 0.13–0.89,p = 0.017) with a trend towards improved functional outcomes (OR 1.68, 0.63 – 4.13 95% CI, p = 0.101). ConclusionsIn these meta-analyses, NPRI decreases the incidence of DCI with a non-significant trend towards improvement in functional outcomes. Randomized trials on the role of intrathecal calcium channel blockers are warranted to evaluate these observations in a prospective manner.