scholarly journals Intrathecal Nicardipine for Cerebral Vasospasm Post Subarachnoid Hemorrhage–a Retrospective Propensity-Based Analysis

Author(s):  
Ofer Sadan ◽  
Hannah Waddel ◽  
Reneé Moore ◽  
Chen Feng ◽  
Yajun Mei ◽  
...  

AbstractObjectivesCerebral vasospasm and delayed cerebral ischemia (DCI) contribute to poor outcome following subarachnoid hemorrhage (SAH). With the paucity of effective treatments, we describe our experience with intrathecal (IT) nicardipine for this indication.MethodsPatients admitted to Emory University Hospital Neuroscience ICU between 2012-2017 with non-traumatic SAH, either aneurysmal or idiopathic, were included in the analysis. This patient cohort was compared using a propensity-score model to patients in the SAH international trialist (SAHIT) repository who did not receive intrathecal nicardipine. The primary outcome was DCI. Secondary outcomes were long-term functional outcome and adverse events.ResultsThe analysis included 1,351 patients, 422 of whom were diagnosed with cerebral vasospasm and treated with IT nicardipine. When compared with patients with no vasospasm (n=859) the treated group was younger (51.1±12.4 vs. 56.7±14.1, p<0.01), had a higher World Federation of Neurological Surgeons score (WFNS), modified Fisher grade, and more likely to undergo clipping of the ruptured aneurysm as compared to endovascular treatment (30.3% vs. 11.3%, p<0.01). Treatment with IT nicardipine decreased daily mean transcranial Doppler velocities in 77.3% of the treated patients. When compared to patients not receiving IT nicardipine, treatment was not associated with an increase rate of bacterial ventriculitis (3.1% compared with 2.7%, p>0.1) yet higher rates of ventriculoperitoneal shunting were noted (19.9% vs. 8.8%, p<0.01). In a propensity score comparison to the SAHIT database, the odds ratio to develop DCI with IT nicardipine treatment was 0.61 with 95% CI[0.44-0.84], and to have a favorable functional outcome (mRS≤2) was 2.17[1.61-2.91].ConclusionsIT nicardipine was associated with improved outcome and reduced DCI compared with propensity matched controls. There was an increased need for permanent CSF diversion but no other safety issues. This data should be considered when selecting medications and treatments to study in future randomized controlled clinical trial for SAH.

2021 ◽  
pp. 1-10
Author(s):  
Ofer Sadan ◽  
Hannah Waddel ◽  
Reneé Moore ◽  
Chen Feng ◽  
Yajun Mei ◽  
...  

OBJECTIVE Cerebral vasospasm and delayed cerebral ischemia (DCI) contribute to poor outcome following subarachnoid hemorrhage (SAH). With the paucity of effective treatments, the authors describe their experience with intrathecal (IT) nicardipine for this indication. METHODS Patients admitted to the Emory University Hospital neuroscience ICU between 2012 and 2017 with nontraumatic SAH, either aneurysmal or idiopathic, were included in the analysis. Using a propensity-score model, this patient cohort was compared to patients in the Subarachnoid Hemorrhage International Trialists (SAHIT) repository who did not receive IT nicardipine. The primary outcome was DCI. Secondary outcomes were long-term functional outcome and adverse events. RESULTS The analysis included 1351 patients, 422 of whom were diagnosed with cerebral vasospasm and treated with IT nicardipine. When compared with patients with no vasospasm (n = 859), the treated group was significantly younger (mean age 51.1 ± 12.4 years vs 56.7 ± 14.1 years, p < 0.001), had a higher World Federation of Neurosurgical Societies score and modified Fisher grade, and were more likely to undergo clipping of the ruptured aneurysm as compared to endovascular treatment (30.3% vs 11.3%, p < 0.001). Treatment with IT nicardipine decreased the daily mean transcranial Doppler velocities in 77.3% of the treated patients. When compared to patients not receiving IT nicardipine, treatment was not associated with an increased rate of bacterial ventriculitis (3.1% vs 2.7%, p > 0.1), yet higher rates of ventriculoperitoneal shunting were noted (19.9% vs 8.8%, p < 0.01). In a propensity score comparison to the SAHIT database, the odds ratio (OR) to develop DCI with IT nicardipine treatment was 0.61 (95% confidence interval [CI] 0.44–0.84), and the OR to have a favorable functional outcome (modified Rankin Scale score ≤ 2) was 2.17 (95% CI 1.61–2.91). CONCLUSIONS IT nicardipine was associated with improved outcome and reduced DCI compared with propensity-matched controls. There was an increased need for permanent CSF diversion but no other safety issues. These data should be considered when selecting medications and treatments to study in future randomized controlled clinical trials for SAH.


2020 ◽  
Vol 81 (05) ◽  
pp. 412-417
Author(s):  
Daniel Dubinski ◽  
Sae-Yeon Won ◽  
Bedjan Behmanesh ◽  
Nina Brawanski ◽  
Volker Seifert ◽  
...  

Abstract Background The role of reactive thrombocytosis in non-aneurysmal subarachnoid hemorrhage (NA-SAH) is largely unexplored to date. Therefore, the impact of a quantitative thrombocyte dynamic in patients with NA-SAH and its clinical relevance were analyzed in the present study. Methods In this retrospective analysis, 113 patients with nontraumatic and NA-SAH treated between 2003 and 2015 at our institution were included. World Federation of Neurosurgical Societies admission status, cerebral vasospasm, delayed infarction, hydrocephalus, need for ventriculoperitoneal (VP) shunt, and Fisher grade were analyzed for their association with reactive thrombocytosis. Results Reactive thrombocytosis was not associated with hydrocephalus (p ≥ 0.05), need for VP shunt implantation (p ≥ 0.05), cerebral vasospasm (p ≥ 0.05), or delayed cerebral ischemia (p ≥ 0.05). Conclusion Our study is the first to investigate the role of thrombocyte dynamics, reactive thrombocytosis, and the clinical course of NA-SAH patients. Our analysis showed no significant impact of thrombocyte count on NA-SAH sequelae.


Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Ofer Sadan ◽  
Chen Feng ◽  
David T Pearce ◽  
Jacqueline Kraft ◽  
Cederic Pimentel ◽  
...  

Introduction: Cerebral vasospasm leading to delayed cerebral ischemia (DCI) is one of the most significant factors impacting functional outcome in patients diagnosed with non-traumatic subarachnoid hemorrhage (SAH). Effective treatment in this setting is lacking. We now report a single center retrospective cohort experience with intrathecal (IT) Nicardipine for this indication. Methods: All patients discharged between 2013-2017 diagnosed with non-traumatic SAH, either aneurysmal or idiopathic, were included in the analysis. Demographics, risk factors, clinical courses, radiological DCI, and functional outcomes were analyzed. Results: 1,085 patients were admitted with aneurysmal (n=796) or idiopathic (n=289) SAH. The mean age was 54.5±14.1 and 67.7% were women. Low grade hemorrhage (WFNS 1) was found in 42.4%, medium (WFNS 2-3) in 26.9%, and high grade (WFNS 4-5) in 30.7%. Cerebral vasospasm was diagnosed in 36.6% of the patients, and 85.4% of those received IT Nicardipine (n=339). Only 8.4% of all patients required angiography to treat vasospasm. TCD data was available for 159 patients who received IT Nicardipine. Treatment reduced mean velocities in all arteries within one day by 15.4% on average (p<0.01). This reduction was sustained for the duration of treatment. Nineteen patients (1.8%) suffered from bacterial ventriculitis, and no statistically significant correlation was noted between IT treatment and infection (OR 1.06 95%CI[0.42-2.7]). The incidence of radiological DCI, identified by blinded assement of imaging, was 9.4% and clinical DCI was 5.7%. In this cohort, 65.5% had a favorable functional outcome (mRS≤2) at 90 days. Conclusions: In a retrospective analysis, off-label IT Nicardipine is a safe and potentially effective treatment for cerebral vasospasm and prevention of the subsequent cerebral ischemia. Being the largest of its kind, this cohort could serve as a baseline for future clinical trial designs assessing IT Nicardipine safety and efficacy in a prospective, controlled fashion.


Neurology ◽  
2019 ◽  
Vol 93 (5) ◽  
pp. e458-e466 ◽  
Author(s):  
Ramazan Jabbarli ◽  
Daniela Pierscianek ◽  
Roland Rölz ◽  
Marvin Darkwah Oppong ◽  
Klaus Kaier ◽  
...  

ObjectiveDelayed cerebral ischemia (DCI) is strongly associated with poor outcome after subarachnoid hemorrhage (SAH). Cerebral vasospasm is a major contributor to DCI and requires special attention. To evaluate the effect of vasospasm management on SAH outcome, we performed a pooled analysis of 2 observational SAH cohorts.MaterialsData from 2 institutional databases with consecutive patients with SAH treated between 2005 and 2012 were pooled. The effect of 2 institutional standards of conservative and endovascular vasospasm treatment (EVT) on the rates of DCI (new cerebral infarcts not visible on the post-treatment imaging) and unfavorable outcome (modified Rankin Scale score >2) at 6 months follow-up was analyzed.ResultsThe final analysis included 1,057 patients with SAH. There was no difference regarding demographic (age and sex), clinical (Hunt & Hess grades, acute hydrocephalus, treatment modality, and infections), and radiographic (Fisher grades and aneurysm location) characteristics of the populations. However, there was a significant difference in the rate (24.4% [121/495] vs 14.4% [81/562], p < 0.0001) and timing (first treatment on day 6 vs 8.9 after SAH, p < 0.0001) of EVT. The rates of DCI (20.8% vs 29%, p = 0.0001) and unfavorable outcome (44% vs 50.6%, p = 0.04) were lower in the cohort with more frequent and early EVT. Multivariate analysis confirmed independent effect of EVT standard on DCI risk and outcome.ConclusionsA preventive strategy utilizing frequent and early EVT seems to reduce the risk of DCI in patients with SAH and improve their functional outcome. We recommend prospective evaluation of the value of preventive EVT strategy on SAH.Classification of evidenceThis study provides Class III evidence that for patients with SAH, a frequent and early EVT to treat vasospasm reduces the risk of DCI and improves functional outcome.


2020 ◽  
Vol 133 (2) ◽  
pp. 360-368
Author(s):  
Victor M. Lu ◽  
Christopher S. Graffeo ◽  
Avital Perry ◽  
Lucas P. Carlstrom ◽  
Leonardo Rangel-Castilla ◽  
...  

OBJECTIVEDelayed 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.METHODSThe 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.RESULTSFour 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.CONCLUSIONSRebleeding 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.


2020 ◽  
pp. 1-12 ◽  
Author(s):  
Yasser B. Abulhasan ◽  
Johanna Ortiz Jimenez ◽  
Jeanne Teitelbaum ◽  
Gabrielle Simoneau ◽  
Mark R. Angle

OBJECTIVEIntravenous (IV) milrinone is a promising option for the treatment of cerebral vasospasm with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, data remain limited on the efficacy of treating cases that are refractory to standard therapy with IV milrinone. The aim of this study was to determine predictors of refractory vasospasm/DCI despite treatment with IV milrinone, and to analyze the outcome of rescue therapy with intraarterial (IA) milrinone and/or mechanical angioplasty.METHODSThe authors conducted a retrospective cohort study of all patients with aSAH admitted between 2010 and 2016 to the Montreal Neurological Institute and Hospital. Patients were stratified into 3 groups: no DCI, standard therapy, and rescue therapy. The primary outcome was frequency of DCI-related cerebral infarction identified on neuroimaging before hospital discharge. Secondary outcomes included functional outcome reported as modified Rankin Scale (mRS) score, and segment reversal of refractory vasospasm.RESULTSThe cohort included 322 patients: 212 in the no DCI group, 89 in the standard therapy group, and 21 in the rescue therapy group. Approximately half (52%, 168/322) were admitted with poor-grade aSAH at treatment decision (World Federation of Neurosurgical Societies grade III–V). Among patients with DCI and imaging assessing severity of vasospasm, 62% (68/109) had moderate/severe radiological vasospasm on DCI presentation. Nineteen percent (21/110) of patients had refractory vasospasm/DCI and were treated with rescue therapy. Targeted rescue therapy with IA milrinone reversed 32% (29/91) of the refractory vasospastic vessels, and 76% (16/21) of those patients experienced significant improvement in their neurological status within 24 hours of initiating therapy. Moderate/severe radiological vasospasm independently predicted the need for rescue therapy (OR 27, 95% CI 8.01–112). Of patients with neuroimaging before discharge, 40% (112/277) had developed new cerebral infarcts, and only 21% (23/112) of these were vasospasm-related. Overall, 65% (204/314) of patients had a favorable functional outcome (mRS score 0–2) assessed at a median of 4 months (interquartile range 2–8 months) after aSAH, and there was no difference in functional outcome between the 3 groups (p = 0.512).CONCLUSIONSThe aggressive use of milrinone was safe and effective based on this retrospective study cohort and is a promising therapy for the treatment of vasospasm/DCI after aSAH.


Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Sean Neifert ◽  
Eric Oermann ◽  
J D Mocco ◽  
Michael M Todd ◽  
James Torner ◽  
...  

Introduction: Subarachnoid hemorrhage (SAH) mortality is decreasing, but data on functional outcomes over time is lacking. Methods: We created trends of good (Glasgow Outcomes Scale [GOS] of 4 or 5) and optimal (GOS of 5) functional outcomes and mortality (GOS of 1) using linear regression in 15 SAH trials and registries from 1982 to 2014. Models adjusted for age, sex, history of hypertension, World Federation of Neurological Surgeons grade, Fisher grade, aneurysm size, location, and repair modality, and whether data was from a clinical trial or registry. Analyses were repeated separately for the clinical trials and registries. Missing data were handled with multiple imputation. Results: Overall, 13,343 SAH patients were included. 9,524 (71%) patients had good functional outcome, while 1,608 (12%) died. There was a 0.6% adjusted improvement (95% confidence interval [CI]: 0.5% to 0.7%; p<0.001) per year in good functional outcome and a 0.1% adjusted reduction (95% CI: -0.2% to -0.08%; p<0.001) per year in mortality. For patients enrolled in clinical trials, there was no change good functional outcomes (0%; 95% CI: -0.2% to 0.1%; p=0.923) or mortality (0.0% change per year; 95% CI: -0.09% to 0.1%; p=0.676). Clinical registry patients experienced a 1.2% improvement (95% CI: 1.0% to 1.4%; p<0.001) in good functional outcome and a 0.3% reduction (95% CI: -0.4% to -0.1%; p<0.001) in mortality. Conclusions: SAH morbidity and mortality decreased from the 1980s to 2010s. This data can be helpful for researchers planning trials, clinicians discussing expected outcomes with patients and family members, and healthcare administrators planning resource utilization.


2020 ◽  
Vol 133 (6) ◽  
pp. 1842-1849 ◽  
Author(s):  
Christopher J. Stapleton ◽  
Animesh Acharjee ◽  
Hannah J. Irvine ◽  
Zoe C. Wolcott ◽  
Aman B. Patel ◽  
...  

OBJECTIVEMetabolite profiling (or metabolomics) can identify candidate biomarkers for disease and potentially uncover new pathways for intervention. The goal of this study was to identify potential biomarkers of functional outcome after subarachnoid hemorrhage (SAH).METHODSThe authors performed high-throughput metabolite profiling across a broad spectrum of chemical classes (163 metabolites) on plasma samples taken from 191 patients with SAH who presented to Massachusetts General Hospital between May 2011 and October 2016. Samples were drawn at 3 time points following ictus: 0–5, 6–10, and 11–14 days. Elastic net (EN) and LASSO (least absolute shrinkage and selection operator) machine learning analyses were performed to identify metabolites associated with 90-day functional outcomes as assessed by the modified Rankin Scale (mRS). Additional univariate and multivariate analyses were then conducted to further examine the relationship between metabolites and clinical variables and 90-day functional outcomes.RESULTSOne hundred thirty-seven (71.7%) patients with aneurysmal SAH met the criteria for inclusion. A good functional outcome (mRS score 0–2) at 90 days was found in 79 (57.7%) patients. Patients with good outcomes were younger (p = 0.002), had lower admission Hunt and Hess grades (p < 0.0001) and modified Fisher grades (p < 0.0001), and did not develop hydrocephalus (p < 0.0001) or delayed cerebral ischemia (DCI) (p = 0.049). EN and LASSO machine learning methods identified taurine as the leading metabolite associated with 90-day functional outcome (p < 0.0001). Plasma concentrations of the amino acid taurine from samples collected between days 0 and 5 after aneurysmal SAH were 21.9% (p = 0.002) higher in patients with good versus poor outcomes. Logistic regression demonstrated that taurine remained a significant predictor of functional outcome (p = 0.013; OR 3.41, 95% CI 1.28–11.4), after adjusting for age, Hunt and Hess grade, modified Fisher grade, hydrocephalus, and DCI.CONCLUSIONSElevated plasma taurine levels following aneurysmal SAH predict a good 90-day functional outcome. While experimental evidence in animals suggests that this effect may be mediated through downregulation of pro-inflammatory cytokines, additional studies are required to validate this hypothesis in humans.


2020 ◽  
Vol 132 (4) ◽  
pp. 1096-1104 ◽  
Author(s):  
Andrej Paľa ◽  
Julia Schick ◽  
Moritz Klein ◽  
Benjamin Mayer ◽  
Bernd Schmitz ◽  
...  

OBJECTIVEDelayed cerebral ischemia (DCI) is a major factor contributing to the inferior outcome of patients with spontaneous subarachnoid hemorrhage (SAH). Nimodipine and induced hypertension using vasopressors are an integral part of standard therapy. Consequences of the opposite effect of nimodipine and vasopressors on blood pressure on patient outcome remain unclear. The authors report the detailed general characteristics and influence of nimodipine and vasopressors on outcome in patients with SAH.METHODSThe authors performed a 2-center, retrospective, clinical database analysis of 732 SAH patients treated between 2008 and 2016. Demographic and clinical data such as age, sex, World Federation of Neurosurgical Societies (WFNS) grade, BMI, Fisher grade, history of arterial hypertension and smoking, aneurysm location, C-reactive protein (CRP) level, and detailed dosage of vasopressors and nimodipine during the treatment period were evaluated. Clinical outcome was analyzed using the modified Rankin Scale (mRS) 6 months after treatment. Univariate and multivariate regression analyses were performed. Additionally, mean arterial pressure (MAP), age, nimodipine, and vasopressor dose cutoff were evaluated with regard to outcome. The level of significance was set at ≤ 0.05.RESULTSFollow-up was assessed for 397 patients, 260 (65.5%) of whom achieved a good outcome (defined as an mRS score of 0–3). Univariate and multivariate analyses confirmed that nimodipine (p = 0.049), age (p = 0.049), and CRP level (p = 0.002) are independent predictors of good outcome. WFNS grade, Fisher score, hypertension, initial hydrocephalus, and total vasopressor dose showed significant influence on outcome in univariate analysis, and patient sex, smoking status, BMI, and MAP showed no significant association with outcome. A subgroup analysis of patients with milder initial SAH (WFNS grades I–III) revealed that initial hydrocephalus (p = 0.003) and CRP levels (p = 0.001) had significant influence on further outcome. When evaluating only patients with WFNS grade IV or V, age, CRP level (p = 0.011), vasopressor dose (p = 0.030), and nimodipine dose (p = 0.049) were independent predictors of patient outcome. Patients with an MAP < 93 mm Hg, a nimodipine cutoff dose of 241.8 mg, and cutoff total vasopressor dose of 523 mg had better outcomes.CONCLUSIONSAccording to the authors’ results, higher doses of vasopressors can safely provide a situation in which the maximum dose of nimodipine could be administered. Cutoff values of the total vasopressor dose were more than 3 times higher in patients with severe SAH (WFNS grade IV or V), while the nimodipine cutoff remained similar in patients with mild and severe SAH. Hence, it seems encouraging that a maximum nimodipine dosage can be achieved despite the need for a higher vasopressor dose in patients with SAH.


Author(s):  
GE Pickett ◽  
MH Schmidt ◽  
JS Shankar

Background: Cerebral vasospasm is a leading cause of neurological disability following aneurysmal subarachnoid hemorrhage (aSAH). Clinical features associated with vasospasm development include blood burden on CT, neurological status, age and aneurysm location. Early cerebral CT perfusion (CTP) scanning in aSAH may be an independent predictor of vasospasm and/or delayed cerebral ischemia (DCI). Methods: Forty-one patients with aSAH were prospectively enrolled. Baseline data collected included WFNS grade, loss of consciousness at ictus, and modified Fisher grade. CTP was obtained at baseline and on day 6 post SAH. Cerebral blood volume, cerebral blood flow and mean transit time were measured. DCI was confirmed by a combination of clinical assessments, non-contrast CT and CTP. Radiological vasospasm was assessed with CT angiography. Results: Despite 80% of patients having a modified Fisher grade 3 or 4 aSAH, one-third presenting with ictal LOC and half having anterior communicating artery aneurysms, only one patient developed clinical evidence of vasospasm/DCI. Two others had asymptomatic radiological vasospasm. CTP parameters did not differ between groups defined by clinical predictors. Conclusions: In an unexpected finding, clinical and radiological vasospasm were very uncommon in this cohort. Clinical predictive variables correlated poorly with development of vasospasm. CTP may help refine the model but further work is needed.


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