scholarly journals Stereotactic cisternal lavage in patients with aneurysmal subarachnoid hemorrhage with urokinase and nimodipine for the prevention of secondary brain injury (SPLASH): study protocol for a randomized controlled trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Roland Roelz ◽  
Fabian Schubach ◽  
Volker A. Coenen ◽  
Carolin Jenkner ◽  
Christian Scheiwe ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Neurological Outcome ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Standard Of Care ◽  
Secondary Brain Injury ◽  
Ringer’S Solution ◽  
Randomized Controlled ◽  
Therapy Protocol

Abstract Background Delayed cerebral infarction (DCI) is a major cause of death and poor neurological outcome in patients with aneurysmal subarachnoid hemorrhage (aSAH). Direct intrathecal therapies with fibrinolytic and spasmolytic drugs have appeared promising in clinical trials. However, access to the subarachnoid space for intrathecal drug administration is an unsolved problem so far, especially in patients with endovascular aneurysm securing. We investigate a therapy protocol based on stereotactic catheter ventriculocisternostomy (STX-VCS), a new approach to overcome this problem. The primary objective of this study is to assess whether cisternal lavage with urokinase, nimodipine, and Ringer’s solution administered via a stereotactically implanted catheter into the basal cisterns (= investigational treatment (IT)) is safe and improves neurological outcome in patients with aSAH. Methods This is a randomized, controlled, parallel-group, open-label phase II trial. Fifty-four patients with severe aSAH (WFNS grade ≥ 3) will be enrolled at one academic tertiary care center in Southern Germany. Patients will be randomized at a ratio of 1:1 to receive either standard of care only or standard of care plus the IT. The primary endpoint is the proportion of subjects with a favorable outcome on the Modified Rankin Scale (defined as mRS 0–3) at 6 months after aSAH. Further clinical and surrogate outcome parameters are defined as secondary endpoints. Discussion New approaches for the prevention and therapy of secondary brain injury in patients with aSAH are urgently needed. We propose this RCT to assess the clinical safety and efficacy of a novel therapy protocol for intrathecal administration of urokinase, nimodipine, and Ringer’s solution. Trial registration Deutsches Register Klinischer Studien (German Clinical Trials Register), DRKS00015645. Registered on 8 May 2019

Evidence for a conditioning effect of inhalational anesthetics on angiographic vasospasm after aneurysmal subarachnoid hemorrhage

2020 ◽  
Vol 133 (1) ◽  
pp. 152-158 ◽  
Author(s):  
Umeshkumar Athiraman ◽  
Diane Aum ◽  
Ananth K. Vellimana ◽  
Joshua W. Osbun ◽  
Rajat Dhar ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Multivariate Logistic Regression Analysis ◽  
Secondary Brain Injury ◽  
Large Artery ◽  
Inhalational Anesthetics ◽  
Angiographic Vasospasm ◽  
Inhalational Anesthetic

OBJECTIVEDelayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) is characterized by large-artery vasospasm, distal autoregulatory dysfunction, cortical spreading depression, and microvessel thrombi. Large-artery vasospasm has been identified as an independent predictor of poor outcome in numerous studies. Recently, several animal studies have identified a strong protective role for inhalational anesthetics against secondary brain injury after SAH including DCI—a phenomenon referred to as anesthetic conditioning. The aim of the present study was to assess the potential role of inhalational anesthetics against cerebral vasospasm and DCI in patients suffering from an SAH.METHODSAfter IRB approval, data were collected retrospectively for all SAH patients admitted to the authors’ hospital between January 1, 2010, and December 31, 2013, who received general anesthesia with either inhalational anesthetics only (sevoflurane or desflurane) or combined inhalational (sevoflurane or desflurane) and intravenous (propofol) anesthetics during aneurysm treatment. The primary outcomes were development of angiographic vasospasm and development of DCI during hospitalization. Univariate and logistic regression analyses were performed to identify independent predictors of these endpoints.RESULTSThe cohort included 157 SAH patients whose mean age was 56 ± 14 (± SD). An inhalational anesthetic–only technique was employed in 119 patients (76%), while a combination of inhalational and intravenous anesthetics was employed in 34 patients (22%). As expected, patients in the inhalational anesthetic–only group were exposed to significantly more inhalational agent than patients in the combination anesthetic group (p < 0.05). Multivariate logistic regression analysis identified inhalational anesthetic–only technique (OR 0.35, 95% CI 0.14–0.89), Hunt and Hess grade (OR 1.51, 95% CI 1.03–2.22), and diabetes (OR 0.19, 95% CI 0.06–0.55) as significant predictors of angiographic vasospasm. In contradistinction, the inhalational anesthetic–only technique had no significant impact on the incidence of DCI or functional outcome at discharge, though greater exposure to desflurane (as measured by end-tidal concentration) was associated with a lower incidence of DCI.CONCLUSIONSThese data represent the first evidence in humans that inhalational anesthetics may exert a conditioning protective effect against angiographic vasospasm in SAH patients. Future studies will be needed to determine whether optimized inhalational anesthetic paradigms produce definitive protection against angiographic vasospasm; whether they protect against other events leading to secondary brain injury after SAH, including microvascular thrombi, autoregulatory dysfunction, blood-brain barrier breakdown, neuroinflammation, and neuronal cell death; and, if so, whether this protection ultimately improves patient outcome.

Effect of heparin on secondary brain injury in patients with subarachnoid hemorrhage: an additional ‘H’ therapy in vasospasm treatment

2017 ◽  
Vol 9 (7) ◽  
pp. 659-663 ◽  
Author(s):  
Markus Bruder ◽  
Sae-Yeon Won ◽  
Sepide Kashefiolasl ◽  
Marlies Wagner ◽  
Nina Brawanski ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Favorable Outcome ◽  
Matched Pair ◽  
Control Group ◽  
High Morbidity ◽  
Secondary Brain Injury ◽  
Heparin Group ◽  
Vasomotor Function

ObjectiveSecondary brain injury leads to high morbidity and mortality rates in patients with aneurysmal subarachnoid hemorrhage (aSAH). However, evidence-based treatment strategies are sparse. Since heparin has various effects on neuroinflammation, microthromboembolism and vasomotor function, our objective was to determine whether heparin can be used as a multitarget prophylactic agent to ameliorate morbidity in SAH.MethodsBetween June 1999 and December 2014, 718 patients received endovascular treatment after rupture of an intracranial aneurysm at our institution; 197 of them were treated with continuous unfractionated heparin in therapeutic dosages after the endovascular procedure. We performed a matched pair analysis to evaluate the effect of heparin on cerebral vasospasm (CVS), cerebral infarction (CI), and outcome.ResultsThe rate of severe CVS was significantly reduced in the heparin group compared with the control group (14.2% vs 25.4%; p=0.005). CI and multiple ischemic lesions were less often present in patients with heparin treatment. These effects were enhanced if patients were treated with heparin for >48 hours, but the difference was not significant. Favorable outcome at 6-month follow-up was achieved in 69% in the heparin group and in 65% in the control group.ConclusionsPatients receiving unfractionated continuous heparin after endovascular aneurysm occlusion have a significant reduction in the rate of severe CVS, have CI less often, and tend to have a favorable outcome more often. Our findings support the potential beneficial effects of heparin as a multitarget therapy in patients with SAH, resulting in an additional ‘H’ therapy in vasospasm treatment.

scholarly journals Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury

2021 ◽  
pp. 0271678X2110206
Author(s):  
Kevin Akeret ◽  
Raphael M Buzzi ◽  
Christian A Schaer ◽  
Bart R Thomson ◽  
Florence Vallelian ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Ex Vivo ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Unmet Need ◽  
Aneurysm Rupture ◽  
Secondary Brain Injury ◽  
Oxidative Potential ◽  
Macrophage Response

Secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH-SBI) contributes to poor outcomes in patients after rupture of an intracranial aneurysm. The lack of diagnostic biomarkers and novel drug targets represent an unmet need. The aim of this study was to investigate the clinical and pathophysiological association between cerebrospinal fluid hemoglobin (CSF-Hb) and SAH-SBI. In a cohort of 47 patients, we collected daily CSF-samples within 14 days after aneurysm rupture. There was very strong evidence for a positive association between spectrophotometrically determined CSF-Hb and SAH-SBI. The accuracy of CSF-Hb to monitor for SAH-SBI markedly exceeded that of established methods (AUC: 0.89 [0.85-0.92]). Temporal proteome analysis revealed erythrolysis accompanied by an adaptive macrophage response as the two dominant biological processes in the CSF-space after aneurysm rupture. Ex-vivo experiments on the vasoconstrictive and oxidative potential of Hb revealed critical inflection points overlapping CSF-Hb thresholds in patients with SAH-SBI. Selective depletion and in-solution neutralization by haptoglobin or hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb. Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex-vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target.

scholarly journals Role of Anesthetics and Their Adjuvants in Neurovascular Protection in Secondary Brain Injury after Aneurysmal Subarachnoid Hemorrhage

2021 ◽  
Vol 22 (12) ◽  
pp. 6550
Author(s):  
Umeshkumar Athiraman ◽  
Gregory J Zipfel
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Clinical Success ◽  
Clinical Care ◽  
Cerebrovascular Disorders ◽  
Delayed Cerebral Ischemia ◽  
Secondary Brain Injury ◽  
Neurovascular Protection

Aneurysmal rupture accounts for the majority of subarachnoid hemorrhage and is responsible for most cerebrovascular deaths with high mortality and morbidity. Initial hemorrhage severity and secondary brain injury due to early brain injury and delayed cerebral ischemia are the major determinants of outcomes after aneurysmal subarachnoid hemorrhage. Several therapies have been explored to prevent these secondary brain injury processes after aneurysmal subarachnoid hemorrhage with limited clinical success. Experimental and clinical studies have shown a neuroprotective role of certain anesthetics in cerebrovascular disorders including aneurysmal subarachnoid hemorrhage. The vast majority of aneurysmal subarachnoid hemorrhage patients require general anesthesia for surgical or endovascular repair of their aneurysm. Given the potential impact certain anesthetics have on secondary brain injury after SAH, appropriate selection of anesthetics may prove impactful on overall outcome of these patients. This narrative review focuses on the available evidence of anesthetics and their adjuvants in neurovascular protection in aneurysmal subarachnoid hemorrhage and discusses current impact on clinical care and future investigative directions.

scholarly journals Cerebrospinal fluid hemoglobin drives subarachnoid hemorrhage-related secondary brain injury

2021 ◽  
Author(s):  
Kevin Akeret ◽  
Raphael M. Buzzi ◽  
Christian A. Schaer ◽  
Bart R. Thomson ◽  
Florence Vallelian ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cerebrospinal Fluid ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Ex Vivo ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Unmet Need ◽  
Aneurysm Rupture ◽  
Secondary Brain Injury ◽  
Macrophage Response

AbstractSecondary brain injury after aneurysmal subarachnoid hemorrhage (SAH-SBI) is a significant contributor to poor outcomes in patients after rupture of an intracranial aneurysm. The lack of diagnostic biomarkers and novel drug targets represent an unmet need. Prior experimental evidence has suggested cell-free hemoglobin in the cerebrospinal fluid (CSF-Hb) as a pathophysiological driver of SAH-SBI. The aim of this study was to investigate the clinical and pathophysiological association between CSF-Hb and SAH-SBI. We prospectively enrolled 47 consecutive patients and collected daily CSF samples within 14 days after aneurysm rupture. There was very strong evidence for a positive association between CSF-Hb and SAH-SBI. The diagnostic accuracy of CSF-Hb for SAH-SBI markedly exceeded that of established methods (area under the curve: 0.89 [0.85-0.92]). Temporal LC-MS/MS CSF proteomics demonstrated that erythrolysis accompanied by an adaptive macrophage response are the two dominant biological processes occurring in the CSF space after aneurysm rupture. To further investigate the pathophysiology between CSF-Hb and SAH-SBI, we explored the vasoconstrictive and lipid peroxidation activities of Hb ex-vivo. These experiments revealed critical inflection points overlapping CSF-Hb concentration thresholds in patients with SAH-SBI. Selective Hb depletion and in-solution neutralization by the Hb-scavenger haptoglobin or the heme-scavenger hemopexin efficiently attenuated the vasoconstrictive and lipid peroxidation activities of CSF-Hb in patient CSF. Collectively, the clinical association between high CSF-Hb levels and SAH-SBI, the underlying pathophysiological rationale, and the favorable effects of haptoglobin and hemopexin in ex-vivo experiments position CSF-Hb as a highly attractive biomarker and potential drug target.

scholarly journals CompLement C5 Antibodies for decreasing brain injury after aneurysmal Subarachnoid Hemorrhage (CLASH): study protocol for a randomized controlled phase II clinical trial

2020 ◽  
Author(s):  
Inez Koopman ◽  
Gabriel J.E. Rinkel ◽  
Mervyn D.I. Vergouwen
Keyword(s):  
Clinical Trial ◽  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Phase Ii ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Intervention Group ◽  
Case Fatality ◽  
Phase Ii Clinical Trial ◽  
Efficacy And Safety ◽  
Randomized Controlled

Abstract BackgroundThe inflammatory response after aneurysmal subarachnoid hemorrhage (aSAH) has been associated with early brain injury, delayed cerebral ischemia, poor functional outcome, and case-fatality. In experimental SAH studies, complement C5 antibodies administered shortly after SAH reduce brain injury with approximately 40%. Complement component C5 may be a new therapeutic target to reduce brain injury and hereby improve outcome after aSAH. We aim to investigate the pharmacodynamic efficacy and safety of eculizumab (complement C5 antibody) in patients with aSAH.MethodsA randomized, controlled, open-label, phase II clinical trial with blinded outcome assessment. Eculizumab (1200 mg) is administered intravenously <12 hours, on day 3 and on day 7 after ictus. Patients in the intervention group receive prophylactic antibiotics for 4 weeks, and those with a central line or an external ventricular shunt and a positive fungal or yeast culture also receive prophylactic antifungal therapy for 4 weeks. The primary outcome is C5a concentration in cerebrospinal fluid (CSF) on day 3 after ictus. Secondary outcomes include the occurrence of adverse events, inflammatory parameters in blood and CSF, cerebral infarction on magnetic resonance imaging, and clinical- and cognitive outcomes. We aim to evaluate 26 patients with CSF assessments, 13 in the intervention group and 13 in the control group. To compensate for early case fatality and inability to obtain CSF, we will include 20 patients per group.DiscussionThe CLASH trial is the first trial to investigate the pharmacodynamic efficacy and safety of eculizumab in the early phase after aSAH.Trial registrationNetherlands Trial Register: NTR6752, https://www.trialregister.nl/trial/6579. Registered on 27 October 2017. European Clinical Trials Database: EudraCT 2017-004307-51.

Abstract TMP21: Cilostazol for Prevention of Cerebral Vasospasm and Cerebral Ischemia in Patients With Aneurysmal Subarachnoid Hemorrhage: A Meta-Analysis of Randomized Controlled Clinical Trials

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Iryna Lobanova ◽  
Kathryn Qualls ◽  
Renee L Martin ◽  
Niraj Arora ◽  
Premkumar Nattanmai ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Subarachnoid Hemorrhage ◽  
Cerebral Ischemia ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Meta Analysis ◽  
Phase Iii ◽  
Controlled Clinical Trials ◽  
Randomized Controlled Clinical Trials ◽  
Randomized Controlled ◽  
Symptomatic Vasospasm

Introduction: Cilostazol, a selective inhibitor of phosphodiesterase 3, may reduce symptomatic vasospasm and associated cerebral ischemia and improve outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH) due to its anti-platelet, anti-proliferative, and vasodilatory effects. Due to recent publication of randomized controlled clinical trials, a meta-analysis was performed to identify the common treatment effect. Methods: We performed a meta-analysis of four randomized controlled clinical trials. The primary endpoint of interest was cerebral ischemia related to vasospasm. Secondary endpoints were angiographic vasospasm, new cerebral infarct, mortality, and death or disability at the 90 days following randomization. Using random-effects models with study as a random effect, relative risks (RR) and 95% confidence intervals (CI) were generated Results: A total of 405 subjects (200 randomized to oral cilostazol 100 mg twice per day) were included in the meta-analysis. The proportion of subjects with cerebral ischemia related to vasospasm was significantly lower in those who were assigned to cilostazol treatment (RR 0.46; 95% CI 0.21-1.00; p< 0.050) without any heterogeneity between the trials (Cochran’s Q statistic 1.52, df 2; P = .468, I 2 =0.0%). The proportion of subjects who had new cerebral infarction was significantly lower in subjects who were assigned to cilostazol treatment (RR 0.40, 95% CI 0.32-0.49, p=0.0009). There was a lower rate of death or disability at 90 days in subjects who were assigned to cilostazol treatment (RR 0.44, 95% 0.28-0.70, p=0.011) without any heterogeneity between the trials (Cochran’s Q statistics 1.49, df 3; P = .685, I 2 =0.0%). The proportion of subjects who had any adverse events was not significantly different in subjects who were assigned to cilostazol treatment (RR 1.24, 95% 0.68-2.25, p=0.26). Conclusion: The reduction in rates of cerebral ischemia related to vasospasm and death or disability at follow-up support further evaluation of oral cilostazol in patients with aSAH in a phase III large randomized clinical trial.

scholarly journals Isofurans and isoprostanes as markers of delayed brain injury and mitochondrial dysfunction following aneurysmal subarachnoid hemorrhage. A prospective observational study

2021 ◽  
Author(s):  
Joao A. Gomes ◽  
Ginger Milne ◽  
Asha Kallianpur ◽  
Leah Shriver
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Brain Injury ◽  
Mitochondrial Dysfunction ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Laboratory Data ◽  
Rank Test ◽  
Secondary Brain Injury ◽  
Parametric Data ◽  
Delayed Brain Injury ◽  
Non Parametric

AbstractIntroductionF2-Isoprostanes (F2-IsoPs) and Isofurans (IsoF), specific markers of lipid peroxidation in vivo, have been reported to be elevated and have prognostic implications following subarachnoid hemorrhage (SAH). Platelet activation and vasoconstriction are attributed to these compounds. Elevated IsoF: F2-IsoPs ratios have been previously suggested as indicative of mitochondrial dysfunction. In this small study we examined their performance as specific biomarkers for delayed brain injury (DBI) development following SAH. We also explored if evidence of mitochondrial dysfunction could be found in a cohort of SAH patients.MethodsEighteen patients with SAH and 7 controls with normal neuroimaging and CSF analysis results underwent CSF sampling and abstraction of clinical, demographic, and laboratory data. Samples (two) of CSF were collected on day 1 and once on days 5-8 post-bleed. F2-IsoP and IsoF assays were performed at Vanderbilt Eicosanoid Core Lab by gas chromatography/mass spectroscopy. Levels are expressed in median (IQR) for non-parametric data. Repeated sample measurement were compared using the Wilcoxon signed-rank test, whereas the Mann Whitney test was used for other non-parametric data.ResultsMean age was 61.2 + 15.7 (SAH cases) vs. 47.6 + 10 (controls) years, and 80% of SAH patients were female. Median Hunt-Hess score was 3 (2-4) and modified Fisher scale 3 (3-4). Thirty nine percent of patients developed DBI. F2-IsoP were significantly higher in SAH cases than in controls [47.5 (30.2-53.5) vs. 26.0 (21.2-34.5) pg/mL]. No significant differences were observed in patients with or without DBI [41 (33.5-52) vs. 44 (28.5-55.5) pg/mL]. IsoF were elevated in the second CSF sample in 9 patients, but undetectable in the remainder cases and all controls. Patients who developed DBI had significantly higher IsoF than cases who did not [(57 (34-72) vs. 0 (0-34) pg/mL]. Patients who met criteria for delayed injury had a significantly higher IsoF: F2IsoPs ratio on the late CSF sample [1.03 (1-1.38) vs. 0 (0-0.52)].ConclusionsPreliminary findings from this study suggest that IsoF may represent a specific biomarker predicting DBI following SAH and provide possible evidence of CNS mitochondrial dysfunction in SAH. Future studies to further explore the value of IsoF as biomarkers of secondary brain injury and the contribution of mitochondrial dysfunction and ferroptosis to clinical outcomes following SAH seem warranted.

Sign in / Sign up

Export Citation Format

Share Document