Delayed Cerebral Ischemia Research Articles

Symptomatic Cerebral Vasospasm After Transsphenoidal Adenoma Resection of the Pituitary

Delayed cerebral ischemia (DCI) or vasospasm following transsphenoidal surgery (TSS) is a life-threatening and life-altering event that could potentially cause devastating complications, neurological morbidity, and high mortality. Herein, we report the case of a 16-year-old woman without a marked medical history and unusual complications after TSS for pituitary adenoma resection who developed cerebral vasospasm and infarction after TSS. To the best of our knowledge, this is the first case involving a patient under 18 years old and requiring thrombectomy after TSS. Additionally, we present our review of published case reports to underline the most often presentation characteristics, the interval between TSS and vasospasm, and therapeutic management. With respect to our case, we analyzed 27 cases of TSS complicated by symptomatic vasospasm. We include only pituitary adenoma resection and exclude other causes. The mean age was 47.33 ± 15.22 years at the time of surgery, and the male-to-female ratio was roughly equal among cases (female: 51.9%). Following surgery, 85.2% of patients experienced subarachnoid hemorrhage (SAH), and 22.3% experienced cerebrospinal fluid (CSF) leakage. The mean clinical presentation time of vasospasm ranged from 3 to 13 (mean: 7.5 ± 2.6) days after TSS. At discharge, 51.8% of cases at least had one neurologic complication, including six dead patients (18.5%). A high index of suspicion for vasospasm has been recommended because of the diverse symptoms of this rare condition and the high mortality rate. J Neurol Res. 2022;12(3):132-138 doi: https://doi.org/10.14740/jnr729

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.

Intravenous milrinone for delayed cerebral ischaemia in aneurysmal subarachnoid haemorrhage: a systematic review

Background Aneurysmal subarachnoid haemorrhage (aSAH) is a major contributor to mortality worldwide, with delayed cerebral ischaemia (DCI) contributing significantly to morbidity in these patients. There are limited evidence-based therapies for DCI. A 2012 case series first recommended the use of intravenous (IV) milrinone in this patient population, stating the need for formal prospective trials. However, uptake of this therapy into clinical practice has proceeded without adequate studies for efficacy and safety. Methods We sought to determine the effect of IV milrinone on DCI in patients with aSAH in terms of functional outcome through a systematic review using Embase, MEDLINE, and Cochrane Library databases. Quality assessment was performed using MINORS criteria. Results A total of 2429 studies were screened, with ten studies included in the review. Of these, no randomized trials were identified. Three observational comparative studies were included, and the remaining seven studies were non-comparative in nature, and mainly retrospective. Overall, the quality of evidence for non-comparative studies was poor. Conclusions This study reveals a paucity of evidence in the literature and highlights the need for high-quality randomized trials to investigate the safety and efficacy of IV milrinone, a commonly utilized treatment in critically ill aSAH patients with DCI. Ultimately, without evidence of efficacy and absence of harm, we caution continued use of intravenous milrinone for the treatment of DCI.

Serum concentrations of NLRP3 in relation to functional outcome and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

BackgroundNucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) participates in neuroinflammation. We endeavored to determine the role of serum NLRP3 as a biomarker of neuroinflammation, severity, delayed cerebral ischemia (DCI) and functional outcome following aneurysmal subarachnoid hemorrhage (aSAH). MethodsIn this prospective and observational study, a total of 118 aSAH patients and 118 healthy volunteers were enrolled. Serum NLRP3 concentrations, blood glucose concentrations, serum C-reactive protein concentrations, and blood leucocyte counts were quantified. A poor outcome was defined as extended Glasgow outcome scale scores of 1–4 at post-injury 90 days. ResultsAs compared to controls, significantly increased serum NLRP3 concentrations after aSAH were intimately correlated with the Glasgow coma scale scores, World Federation of Neurological Surgeons scale scores, Hunt-Hess scores, modified Fisher scores, extended Glasgow outcome scale scores, blood glucose concentrations, serum C-reactive protein concentrations and blood leucocyte counts. Serum NLRP3 emerged as an independent predictor for DCI and poor 90-day outcome. Using receiver operating characteristic curve, serum NLRP3 concentrations were significantly predictive of DCI and poor 90-day outcome. Its prognostic predictive ability was comparable to those of the Glasgow coma scale scores, World Federation of Neurological Surgeons scale scores, Hunt-Hess scores and modified Fisher scores. ConclusionsSerum NLRP3 may represent an inflammatory biomarker in relation to the severity, DCI and poor functional outcome after aSAH.

The Supratrochlear Artery Sign-A New Piece in the Puzzle of Cerebral Vasospasm.

Background: Cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH) has been extensively investigated, but the impact of collateralization remains unclear. We investigated the predictive value of collateral activation for delayed cerebral ischemia (DCI)-related infarctions and functional outcome. Methods: Data from 43 patients with CVS (January 2014 to August 2021) were evaluated for the angiographic presence of leptomeningeal and ophthalmic collaterals (anterior falcine artery (AFA), supratrochlear artery (STA), dorsal nasal artery (DNA)) on internal carotid artery angiograms. Vasospasm-related infarction and the modified Rankin Scale (mRS) score after six months were chosen as the endpoints. Results: 77% of the patients suffered from DCI-related infarctions. In 233 angiograms (at hospitalization, before spasmolysis, after six months), positive vessel signs were observed in 31 patients for STA, 35 for DNA, and 31 for AFA. The STA sign had the highest positive (84.6%) and negative (85.7%) predictive value for unfavorable outcome (mRS 4–6) in patients aged ≥50 years. DNA and AFA signs were not meaningful predictors for either endpoint. Leptomeningeal collaterals showed a positive Pearson’s correlation with the STA sign in 87.5% (p = 0.038) without providing any prediction for either endpoint. Conclusions: The STA sign is associated with clinical outcome in patients with CVS after SAH aged ≥50 years, and was correlated with the occurrence of leptomeningeal collaterals.

Admission Serum Iron as an Independent Risk Factor for Postoperative Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Propensity-Matched Analysis.

This study aimed to investigate the association between serum iron (SI) and postoperative delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH). We retrospectively analyzed 985 consecutive adult patients diagnosed with aSAH. Demographic, clinical, and laboratory data were recorded. Univariate and multivariate analyses were employed to assess the association between SI and DCI. Propensity-score matching (PSM) analysis was implemented to reduce confounding. Postoperative DCI developed in 14.38% of patients. Lower SI upon admission was detected in aSAH patients with severe clinical conditions and severe aSAH. SI was negatively correlated with WFNS grade (r = −0.3744, p < 0.001) and modified Fisher (mFisher) grade (r = −0.2520, p < 0.001). Multivariable analysis revealed lower SI was independently associated with DCI [odds ratios (OR) 0.281, 95% confidence interval (CI) 0.177–0.448, p < 0.001], while WFNS grade and mFisher grade were not. The receiver-operating characteristics (ROC) curve analysis of SI for DCI gave an area under the curve (AUC) of 0.7 and an optimal cut-off of 7.5 μmol/L (95% CI 0.665 to 0.733, p < 0.0001). PSM demonstrated the DCI group had a significantly lower SI than the non-DCI group (10.91 ± 6.86 vs. 20.34 ± 8.01 μmol/L, p < 0.001). Lower SI remained a significant independent predictor for DCI and an independent poor prognostic factor of aSAH in multivariate analysis (OR 0.363, 95% CI 0.209–0.630, p < 0.001). The predictive performance of SI for poor outcome had a corresponding AUC of 0.718 after PSM. Lower SI upon admission is significantly associated with WFNS grade, mFisher grade, and predicts postoperative DCI and poor outcome at 90 days following aSAH.

Liver Cirrhosis and Inpatient Mortality in Aneurysmal Subarachnoid Hemorrhage: A Propensity-Adjusted Analysis

Liver cirrhosis is associated with an increased risk of aneurysmal subarachnoid hemorrhage (aSAH). However, large studies analyzing the prognosis of cirrhotic patients after aSAH treatment are lacking. This study explores factors associated with inpatient mortality among aSAH patients with cirrhosis. All patients who underwent open or endovascular treatment for an aSAH at a large quaternary center between January 1, 2003, and July 31, 2019, were retrospectively reviewed. Patients were grouped into cirrhosis versus noncirrhosis groups. Univariate analysis determined variables associated with inpatient mortality. Variables with P < 0.20 were included in a propensity-adjusted multivariable logistic regression analysis to predict inpatient mortality. A total of 1419 patients were treated for aSAH; 17 (1.2%) had confirmed cirrhosis. Inpatient mortality was significantly higher among cirrhotic patients than noncirrhotic patients (35.3% vs. 6.8%; P < 0.001). In the univariate analysis for inpatient mortality, the variables cirrhosis, age >65years, Charlson Comorbidity Index >4, aneurysm size ≥10mm, Hunt and Hess grade >3, Fisher grade 4, delayed cerebral ischemia (DCI), and posterior circulation aneurysm had P < 0.20 and were included in the multivariable analysis. The propensity-adjusted stepwise multivariable logistic regression analysis showed that cirrhosis (odds ratio [OR]: 12.7, 95% confidence interval [CI]: 3.3-48.7), Hunt and Hess grade >3 (OR: 3.9, 95% CI: 2.3-6.4), Fisher grade 4 (OR: 3.7, 95% CI: 1.3-10.7), and DCI (OR: 2.4, 95% CI: 1.5-3.9) were associated with inpatient mortality (P ≤ 0.01). Cirrhosis was a predictor of inpatient mortality among aSAH patients and was a stronger predictor than DCI or a poor Hunt and Hess grade among patients in this study.

Slow recruitment in the HIMALAIA study: lessons for future clinical trials in patients with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage based on feasibility data

BackgroundOur randomized clinical trial on induced hypertension in patients with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) was halted prematurely due to unexpected slow recruitment rates. This raised new questions regarding recruitment feasibility. As our trial can therefore be seen as a feasibility trial, we assessed the reasons for the slow recruitment, aiming to facilitate the design of future randomized trials in aSAH patients with DCI or other critically ill patient categories.MethodsEfficiency of recruitment and factors influencing recruitment were evaluated, based on the patient flow in the two centers that admitted most patients during the study period. We collected numbers of patients who were screened for eligibility, provided informed consent, and developed DCI and who eventually were randomized.ResultsOf the 862 aSAH patients admitted in the two centers during the course of the trial, 479 (56%) were eligible for trial participation of whom 404 (84%) were asked for informed consent. Of these, 188 (47%) provided informed consent, of whom 50 (27%) developed DCI. Of these 50 patients, 12 (24%) could not be randomized due to a logistic problem or a contraindication for induced hypertension emerging at the time of randomization, and four (8%) were missed for randomization. Eventually, 34 patients were randomized and received intervention or control treatment.ConclusionsEnrolling patients in a randomized trial on a treatment strategy for DCI proved unfeasible: only 1 out of 25 admitted and 1 out of 14 eligible patients could eventually be randomized. These rates, caused by a large proportion of ineligible patients, a small proportion of patients providing informed consent, and a large proportion of patients with contraindications for treatment, can be used to make sample size calculations for future randomized trials in DCI or otherwise critically ill patients. Facilitating informed consent through improved provision of information on risks, possible benefits, and study procedures may result in improved enrolment.Trial registrationThe original trial was prospectively registered with ClinicalTrials.gov (NCT01613235), date of registration 07-06-2012.

Multidisciplinary and standardized management of patients with delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

BackgroundThe appropriate management of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) remains uncertain. We aimed to evaluate the effect of implementing a standardized protocol for detection and management of DCI after aSAH on cerebral infarction and functional outcome.MethodsWe studied two cohorts of aSAH patients, one before (pre-implementation cohort: January 2012 to August 2014) and one after (post-implementation cohort: January 2016 to July 2018) implementation of a multidisciplinary approach, with standardized neurological and radiological assessment and risk-based medical treatment of DCI. We assessed the presence of new hypodensities on CT within 6 weeks after aSAH and categorized cerebral infarction into overall and DCI-related infarctions (hypodensities not within 48 h after IA repair and not attributable to aneurysm occlusion or intraparenchymal hematoma). Functional outcome was assessed at 3 months using the extended Glasgow outcome scale (eGOS), dichotomized into unfavorable (eGOS: 1–5) and favorable (eGOS: 6–8). We calculated odds ratios (OR) with corresponding 95% confidence intervals (CI’s), and adjusted for age, WFNS grade, Fisher score, and treatment modality (aOR).ResultsIn the post-implementation (n = 158) versus the pre-implementation (n = 143) cohort the rates for overall cerebral infarction were 29.1% vs 46.9% (aOR: 0.41 [0.24–0.69]), for DCI-related cerebral infarction 17.7% vs. 31.5% (aOR: 0.41 [0.23–0.76]), and for unfavorable functional outcome at 3 months 37.3% vs. 53.8% (aOR: 0.30 [0.17–0.54]). For patients with DCI, the rates for unfavorable functional outcomes at 3 months in the post-implementation versus the pre-implementation cohort were 42.3% vs. 77.8% (aOR: 0.1 [0.03–0.27]).ConclusionsA multidisciplinary approach with more frequent and standardized neurological assessment, standardized CT and CT perfusion monitoring, as well as tailored application of induced hypertension and invasive rescue therapy strategies, is associated with a significant reduction of cerebral infarction and unfavorable functional outcome after aneurysmal aSAH.

The Role of VASOGRADE as a Simple Grading Scale to Predict Delayed Cerebral Ischemia and Functional Outcome After Aneurysmal Subarachnoid Hemorrhage.

The VASOGRADE is a simple aneurysmal subarachnoid hemorrhage (aSAH) grading scale that combines the modified Fisher scale (mFisher) and the World Federation of Neurological Societies (WFNS) grading system, allowing the stratification of delayed cerebral ischemia (DCI) risk. However, the VASOGRADE accuracy in predicting functional outcomes is still to be determined. We retrospectively evaluated a multiethnic cohort of consecutive patients with aSAH admitted to a high-volume center in Brazil from January 2016 to January 2019. Patients were classified according to the severity of the clinical presentation (WFNS), the amount of blood in the initial head computerized tomography (mFisher) scan, and the VASOGRADE (green, yellow, red). The primary outcome was to detect DCI-related cerebral infarction, and the secondary outcome was the functional outcome at hospital discharge according to the modified Rankin scale (mRs). Univariate and multivariate logistic regression models were employed. A total of 212 patients (71.7% female, mean age 52.7 ± 12.8) were included. Sixty-nine patients were classified as VASOGRADE-Green (32.5%), 98 patients as VASOGRADE-Yellow (46.9%), and 45 patients as VASOGRADE-Red (20.6%). DCI-related infarction was present in 39 patients (18.9%). The proportions of patients in the VASOGRADE-Green, VASOGRADE-Yellow, and VASOGRADE-Red categories with DCI-related infarction were 7.7, 61.5, and 30.8%, respectively. After a multivariable analysis including age, sex, aneurysm location, and the VASOGRADE classification as variables, both VASOGRADE-Yellow and VASOGRADE-Red were independently associated with DCI-related infarction (odds ratio [OR] 7.69, 95% confidence interval [CI] 2.13-27.8, and OR 8.07, 95% CI 2.03-32.11, respectively) and unfavorable outcome (OR 4.16, 95% CI 1.33-13.03, and OR 25.57, 95% CI 4.45-147.1, respectively). The VASOGRADE discrimination performance for DCI-related infarction (area under the receiver operating characteristic curve) was 0.67 ± 0.04 (95% CI 0.58-0.75; p = 0.001). VASOGRADE-Red had 97.5% specificity for predicting an unfavorable mRs score at discharge (95% CI 92.8-99.5%). Conversely, VASOGRADE-Green had an excellent specificity for predicting favorable outcome at discharge (mRs score 0-2, 95% CI 82.6-95.5%). In conclusion, in a multiethnic cohort of patients with aSAH, VASOGRADE-Green predicted the absence of DCI and good clinical outcome at discharge with very high specificity, and patients in this category might be selected for early intensive care unit (ICU) discharge, minimizing costs and medical complications associated with prolonged hospital stay. On the other hand, patients categorized as VASOGRADE-Yellow and VASOGRADE-Red were at the highest risk for DCI. They should, therefore, be selected as a priority for care in high-volume aSAH centers, being aggressively monitored for DCI at the ICU. Such stratification methods are crucial, especially in countries with low financial resources and high health care services demand.

ASPECT Score and Its Application to Vasospasm in Aneurysmal Subarachnoid Haemorrhage: a Case–Control Study

Delayed cerebral ischaemia (DCI) is a significant complication of aneurysmal subarachnoid haemorrhage (aSAH) and is strongly associated with poorer outcome. The Alberta Stroke Program Early Computer Tomography (ASPECT) score is an established scoring tool, used in acute ischaemic stroke, to quantify early ischaemic changes on CT head scans. We aim to identify if ASPECT scoring correlates with functional outcome in DCI following aSAH. Retrospective case–control study. Inclusion criteria: admission to the Department of Neurosurgery at Leeds Teaching Hospitals NHS Trust (a tertiary neurosurgical centre in the United Kingdom) between 2014 and 2018, with a diagnosis of anterior circulation aneurysmal subarachnoid haemorrhage; as confirmed by initial CT scan and subsequent CT angiography or catheter digital subtraction angiography. Cases were those who developed DCI (n = 43) and controls were randomly selected from those who did not develop DCI (n = 46) but otherwise met the same inclusion criteria. The primary outcome measure was Glasgow Outcome Score (GOS): assessed at discharge and 3 months. ASPECT scores were calculated from non-contrast CT head scans by three researchers blinded to each other and clinical outcome. Spearman’s rank correlation was used to calculate correlation between ASPECT scores and GOS. ASPECT score positively correlated with GOS in the cases both at discharge (Spearman rho 0.436, p = 0.003) and at 3 months (Spearman rho 0.431, p = 0.004). When corrected for Fisher grading, the adjusted odds ratio of having a high GOS with a low ASPECT score at discharge was OR 0.74 (95% CI 0.61–0.94, p = 0.003), and 3 months OR 0.73 (95% CI 0.59–0.91, p = 0.005). ASPECT score significantly correlates with clinical outcome in DCI post aSAH, even after correcting for Fisher grade. ASPECT scoring may identify patients at risk of poor outcome following DCI and represents a quick and reliable tool that aids in clinical decision-making and prognostication.

Neutrophil to lymphocyte ratio predicting poor outcome after aneurysmal subarachnoid hemorrhage: A retrospective study and updated meta-analysis.

BackgroundThe relationship between neutrophil to lymphocyte ratio (NLR) and poor outcome of aneurysmal subarachnoid hemorrhage (aSAH) is controversial. We aim to evaluate the relationship between NLR on admission and the poor outcome after aSAH.MethodPart I: Retrospective analysis of aSAH patients in our center. Baseline characteristics of patients were collected and compared. Multivariate analysis was used to evaluate parameters independently related to poor outcome. Receiver operating characteristic (ROC) curve analysis was used to determine the best cut-off value of NLR. Part II: Systematic review and meta-analysis of relevant literature. Related literature was selected through the database. The pooled odds ratio (OR) and corresponding 95% confidence interval (CI) were calculated to evaluate the correlation between NLR and outcome measures.ResultsPart I: A total of 240 patients with aSAH were enrolled, and 52 patients had a poor outcome. Patients with poor outcome at 3 months had a higher admission NLR, Hunt & Hess score, Barrow Neurological Institute (BNI) scale score, Subarachnoid Hemorrhage Early Brain Edema Score (SEBES), and proportion of hypertension history. After adjustment, NLR at admission remained an independent predictor of poor outcome in aSAH patients (OR 0.76, 95% CI 0.69-0.83; P < 0.001). The best cut-off value of NLR in ROC analysis is 12.03 (area under the curve 0.805, 95% CI 0.735 - 0.875; P < 0.001). Part II: A total of 16 literature were included. Pooled results showed that elevated NLR was significantly associated with poor outcome (OR 1.31, 95% CI 1.14-1.49; P < 0.0001) and delayed cerebral ischemia (DCI) occurrence (OR 1.32, 95% CI 1.11-1.56; P = 0.002). The results are more reliable in large sample sizes, low NLR cut-off value, multicenter, or prospective studies.ConclusionElevated NLR is an independent predictor of poor outcome and DCI occurrence in aSAH.

Biomarker Associations in Delayed Cerebral Ischemia after Aneurysmal Subarachnoid Hemorrhage.

The prognosis for patients with aneurysmal subarachnoid hemorrhage (aSAH) is heavily influenced by the development of delayed cerebral ischemia (DCI), but the adequate and effective therapy of DCI to this day has not been resolved. Multiplex serum biomarker studies may help to understand the pathophysiological processes underlying DCI. Samples were collected from patients with aSAH at two time points: (1) 24 h (Day 1) and (2) 5–7 days after ictus. Serum concentrations of eotaxin, FGF-2, FLT-3L, CX3CL1, Il-1b, IL-4, IP-10, MCP3, and MIP-1b were determined using a customized MILLIPLEX Human Cytokine/Chemokine/Growth Factor Panel A multiplex assay. The functional outcome was defined by the modified Rankin scale (favorable: 0–2, unfavorable: 3–6) measured on the 30th day after aSAH. One-hundred and twelve patients with aSAH were included in this study. The median level of CX3CL1 and MCP-3 measured on Days 5–7 were significantly higher in patients with DCI compared with those without DCI (CX3CL1: with DCI: 110.5 pg/mL, IQR: 82–201 vs. without DCI: 82.6, 58–119, p = 0.036; and MCP-3: with DCI: 22 pg/mL (0–32) vs. without DCI: 0 (0–11), p < 0.001). IP-10, MCP-3, and MIP-1b also showed significant associations with the functional outcome after aSAH. MCP-3 and CX3CL1 may play a role in the pathophysiology of DCI.

In-hospital complication-related risk factors for discharge and 90-day outcomes in patients with aneurysmal subarachnoid hemorrhage after surgical clipping and endovascular coiling: a propensity score-matched analysis.

More than 10 years have passed since the two best-known clinical trials of ruptured aneurysms (International Subarachnoid Aneurysm Trial [ISAT] and Barrow Ruptured Aneurysm Trial [BRAT]) indicated that endovascular coiling (EC) was superior to surgical clipping (SC). However, in recent years, the development of surgical techniques has greatly improved; thus, it is necessary to reanalyze the impact of the differences in treatment modalities on the prognosis of patients with aneurysmal subarachnoid hemorrhage (aSAH). The authors retrospectively reviewed all aSAH patients admitted to their institution between January 2015 and December 2020. The functional outcomes at discharge and 90 days after discharge were assessed using the modified Rankin Scale (mRS). In-hospital complications, hospital charges, and risk factors derived from multivariate logistic regression were analyzed in the SC and EC groups after 1:1 propensity score matching (PSM). The area under the receiver operating characteristic curve was used to calculate each independent predictor's prediction ability between treatment groups. A total of 844 aSAH patients were included. After PSM to control for sex, aneurysm location, Hunt and Hess grade, World Federation of Neurosurgical Societies (WFNS) grade, modified Fisher Scale grade, and current smoking and alcohol abuse status, 329 patients who underwent SC were compared with 329 patients who underwent EC. Patients who underwent SC had higher incidences of unfavorable discharge and 90-day outcomes (46.5% vs 33.1%, p < 0.001; and 19.6% vs 13.8%, p = 0.046, respectively), delayed cerebral ischemia (DCI) (31.3% vs 20.1%, p = 0.001), intracranial infection (20.1% vs 1.2%, p < 0.001), anemia (42.2% vs 17.6%, p < 0.001), hypoproteinemia (46.2% vs 21.6%, p < 0.001), and pneumonia (33.4% vs 24.9%, p = 0.016); but a lower incidence of urinary tract infection (1.2% vs 5.2%, p = 0.004) and lower median hospital charges ($12,285 [IQR $10,399-$15,569] vs $23,656 [IQR $18,816-$30,025], p < 0.001). A positive correlation between the number of in-hospital complications and total hospital charges was indicated in the SC (r = 0.498, p < 0.001) and EC (r = 0.411, p < 0.001) groups. The occurrence of pneumonia and DCI, WFNS grade IV or V, and age were common independent risk factors for unfavorable outcomes at discharge and 90 days after discharge in both treatment modalities. EC shows advantages in discharge and 90-day outcomes, in-hospital complications, and the number of risk factors but increases the economic cost on patients during their hospital stay. Severe in-hospital complications such as pneumonia and DCI may have a long-lasting impact on the prognosis of patients.

Role of Nimodipine and Milrinone in Delayed Cerebral Ischemia

The role of nimodipine and milrinone in the management of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) was studied using clinical and TCD (transcranial Doppler) parameters. In this prospective observational study, patients with DCI after aneurysmal SAH presenting between November 2020 and June 2021 who were treated by either intra-arterial nimodipine (IAN) or intravenous milrinone (IVM) were included after excluding patients in whom both IAN and IVM had been given or mechanical angioplasty was performed. Twelve-hourly TCD was performed during the course of the therapy. Clinical improvement and the development of new brain infarcts were also assessed. A P value <0.05 was considered statistically significant. Thirty-four patients fulfilled the inclusion criteria (IVM, 13/34 [38%]; IAN, 21/34 [62%]); patients in the IVM group (vs. IAN group) had poorer median Glasgow Coma Scale score (12 vs. 13), poorer motor response (<M6 response, 5/13 [38%] vs. 5/21 [24%]; P= 0.36) and higher grades (modified Fisher grade ≥3) of SAH (12/13 [92%] vs. 8/21 [86%]; P= 0.56). More patients in the IAN group (vs. IVM group) showed clinical improvement (17/21 [81%] vs. 10/13 [77%]; P= 0.77), development of new infarcts (15/21 [71%] vs. 7/13 [54%]; P= 0.29] and discharged to home (13/21 [62%] vs. 6/13 [46%]; P= 0.36) with less mortality (1/21 [9%] vs. 4/13 [23%]; P= 0.037). On TCD analysis, both IAN and IVM protocols showed similar effects in middle cerebral artery vasospasm; however, IAN proved better over time. In group-effect analysis, the IAN protocol was significantly better in anterior cerebral artery and posterior cerebral artery vasospasm compared with IVM protocol. In this single-center small study, patients in the IAN group had significantly less mortality compared with the IVM group in the management of DCI after aneurysmal SAH.

Nimodipine vs. Milrinone - Equal or Complementary Use? A Retrospective Analysis.

BackgroundCerebral vasospasm (CVS) continues to account for high morbidity and mortality in patients surviving the initial aneurysmal subarachnoid hemorrhage (SAH). Nimodipine is the only drug known to reduce delayed cerebral ischemia (DCI), but it is believed not to affect large vessel CVS. Milrinone has emerged as a promising option. Our retrospective study focused on the effectiveness of the intra-arterial application of both drugs in monotherapy and combined therapy.MethodsWe searched for patients with aneurysmal SAH, angiographically confirmed CVS, and at least one intra-arterial pharmacological angioplasty. Ten defined vessel sections on angiograms were assessed before and after vasodilator infusion. The improvement in vessel diameters was compared to the frequency of DCI-related cerebral infarction before hospital discharge and functional outcome reported as the modified Rankin Scale (mRS) score after 6 months.ResultsBetween 2014 and 2021, 132 intra-arterial interventions (144 vascular territories, 12 bilaterally) in 30 patients were analyzed for this study. The vasodilating effect of nimodipine was superior to milrinone in all intradural segments. There was no significant intergroup difference concerning outcome in mRS (p = 0.217). Only nimodipine or the combined approach could prevent DCI-related infarction (both 57.1%), not milrinone alone (87.5%). Both drugs induced a doubled vasopressor demand due to blood pressure decrease, but milrinone alone induced tachycardia.ConclusionsThe monotherapy with intra-arterial nimodipine was superior to milrinone. Nimodipine and milrinone may be used complementary in an escalation scheme with the administration of nimodipine first, complemented by milrinone in cases of severe CVS. Milrinone monotherapy is not recommended.

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.

Brain Oxygen–Directed Management of Aneurysmal Subarachnoid Hemorrhage. Temporal Patterns of Cerebral Ischemia During Acute Brain Attack, Early Brain Injury, and Territorial Sonographic Vasospasm

Neurocritical management of aneurysmal subarachnoid hemorrhage focuses on delayed cerebral ischemia (DCI) after aneurysm repair. This study conceptualizes the pathophysiology of cerebral ischemia and its management using a brain oxygen-directed protocol (intracranial pressure [ICP] control, eubaric hyperoxia, hemodynamic therapy, arterial vasodilation, and neuroprotection) in patients with subarachnoid hemorrhage, undergoing aneurysm clipping (n = 40). The brain oxygen-directed protocol reduced Lbo2 (Pbto2 [partial pressure of brain tissue oxygen] <20 mm Hg) from 67% to 15% during acute brain attack (<24 hours of ictus), by increasing Pbto2 from 11.31 ± 9.34 to 27.85 ± 6.76 (P < 0.0001) and then to 29.09 ± 17.88 within 72 hours. Day-after-bleed, Fio2 change, ICP, hemoglobin, and oxygen saturation were predictors for Pbto2 during early brain injury. Transcranial Doppler ultrasonography velocities (>20 cm/second) increased at day 2. During DCI caused by territorial sonographic vasospasm (TSV), middle cerebral artery mean velocity (Vm) increased from 45.00 ± 15.12 to 80.37 ± 38.33/second by day 4 with concomitant Pbto2 reduction from 29.09 ± 17.88 to 22.66 ± 8.19. Peak TSV (days 7-12) coincided with decline in Pbto2. Nicardipine mitigated Lbo2 during peak TSV, in contrast to nimodipine, with survival benefit (P < 0.01). Intravenous and cisternal nicardipine combination had survival benefit (Cramer Φ = 0.43 and 0.327; G2 = 28.32; P < 0.001). This study identifies 4 zones of Lbo2 during survival benefit (Cramer Φ = 0.43 and 0.3) TSV, uncompensated; global cerebral ischemia, compensated, and normal Pbto2. Admission Glasgow Coma Scale score (not increased ICP) was predictive of low Pbto2 (β = 0.812, R2 = 0.661, F1,30 = 58.41; P < 0.0001) during early brain injury. Coma was the only credible predictor for mortality (odds ratio, 7.33/>4.8∗; χ2 = 7.556; confidence interval, 1.70-31.54; P < 0.01) followed by basilar aneurysm, poor grade, high ICP and Lbo2 during TSV. Global cerebral ischemia occurs immediately after the ictus, persisting in 30% of patients despite the high therapeutic intensity level, superimposed by DCI during TSV. We propose implications for clinical practice and patient management to minimize cerebral ischemia.

Antiplatelet therapy and delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

Delayed cerebral ischemia (DCI) is a potentially preventable cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). The authors performed a meta-analysis to assess the effect of antiplatelet therapy (APT) on DCI in patients with aSAH. A systematic review of the PubMed and MEDLINE databases was performed. Study inclusion criteria were 1) ≥ 5 aSAH patients; 2) direct comparison between aSAH management with APT and without APT; and 3) reporting of DCI, angiographic, or symptomatic vasospasm rates for patients treated with versus without APT. The primary efficacy outcome was DCI. The outcomes of the APT versus no-APT cohorts were compared. Bias was assessed using the Downs and Black checklist. The overall cohort comprised 2039 patients from 15 studies. DCI occurred less commonly in the APT compared with the no-APT cohort (pooled = 15.9% vs 28.6%; OR 0.47, p < 0.01). Angiographic (pooled = 51.6% vs 68.7%; OR 0.46, p < 0.01) and symptomatic (pooled = 23.6% vs 37.7%; OR 0.51, p = 0.01) vasospasm rates were lower in the APT cohort. In-hospital mortality (pooled = 1.7% vs 4.1%; OR 0.53, p = 0.01) and functional dependence (pooled = 21.0% vs 35.7%; OR 0.53, p < 0.01) rates were also lower in the APT cohort. Bleeding event rates were comparable between the two cohorts. Subgroup analysis of cilostazol monotherapy compared with no APT demonstrated a lower DCI rate in the cilostazol cohort (pooled = 10.6% vs 28.1%; OR 0.31, p < 0.01). Subgroup analysis of surgically treated aneurysms demonstrated a lower DCI rate for the APT cohort (pooled = 18.4% vs 33.9%; OR 0.43, p = 0.02). APT is associated with improved outcomes in aSAH without an increased risk of bleeding events, particularly in patients who underwent surgical aneurysm repair and those treated with cilostazol. Although study heterogeneity is the most significant limitation of the analysis, the findings suggest that APT is worth exploring in patients with aSAH, particularly in a randomized controlled trial setting.

New Mechanisms and Targets of Subarachnoid Hemorrhage: A Focus on Mitochondria.

Spontaneous subarachnoid hemorrhage (SAH) accounts for 5-10% of all strokes and is a subtype of hemorrhagic stroke that places a heavy burden on health care. Despite great progress in surgical clipping and endovascular treatment for ruptured aneurysms, cerebral vasospasm (CVS) and delayed cerebral ischemia (DCI) threaten the long-term outcomes of patients with SAH. Moreover, there are limited drugs available to reduce the risk of DCI and adverse outcomes in SAH patients. New insight suggests that early brain injury (EBI), which occurs within 72 h after the onset of SAH, may lay the foundation for further DCI development and poor outcomes. The mechanisms of EBI mainly include excitotoxicity, oxidative stress, neuroinflammation, blood-brain barrier (BBB) destruction, and cellular death. Mitochondria are a double-membrane organelle, and they play an important role in energy production, cell growth, differentiation, apoptosis, and survival. Mitochondrial dysfunction, which can lead to mitochondrial membrane potential (Δψm) collapse, overproduction of reactive oxygen species (ROS), release of apoptogenic proteins, disorders of mitochondrial dynamics, and activation of mitochondria-related inflammation, is considered a novel mechanism of EBI related to DCI as well as post-SAH outcomes. In addition, mitophagy is activated after SAH. In this review, we discuss the latest perspectives on the role of mitochondria in EBI and DCI after SAH. We emphasize the potential of mitochondria as therapeutic targets and summarize the promising therapeutic strategies targeting mitochondria for SAH.