Nimodipine treatment of ischemic neurological deficits due to cerebral vasospasm after subarachnoid hemorrhage: Clinical results of a multicenter study

✓ Forty-five studies of regional cerebral blood volume (rCBV), regional cerebral blood flow (rCBF), and regional cerebral oxygen utilization (rCMRO2) were performed in 30 patients undergoing diagnostic cerebral angiography for evaluation of a subarachnoid hemorrhage due to a ruptured intracranial aneurysm. Tracer methods employing radioactive oxygen-15 were used to measure rCBV, rCBF, and rCMRO2. The patient studies were divided into groups based on their neurological status and the presence or absence of cerebral vasospasm. Subarachnoid hemorrhage, with and without vasospasm, produced significant decreases in CBF and CMRO2. In general, patients with more severe neurological deficits, and patients with more severe degrees of vasospasm, had a more marked depression of CBF and CMRO2. The most striking finding was a significant (p < 0.001) increase in CBV (to 58% above normal) in patients with severe neurological deficits associated with severe cerebral vasospasm. This large increase suggests that cerebral vasospasm consists of constriction of the large, radiographically visible extraparenchymal vessels accompanied by a massive dilation of intraparenchymal vessels.

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Long-acting statin for aneurysmal subarachnoid hemorrhage: A randomized, double-blind, placebo-controlled trial

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x17724682 ◽

2017 ◽

Vol 38 (7) ◽

pp. 1190-1198 ◽

Cited By ~ 8

Author(s):

Masato Naraoka ◽

Naoya Matsuda ◽

Norihito Shimamura ◽

Kenichiro Asano ◽

Kenichi Akasaka ◽

...

Keyword(s):

Placebo Group ◽

Subarachnoid Hemorrhage ◽

Cerebral Vasospasm ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Controlled Trial ◽

Delayed Cerebral Ischemia ◽

Pleiotropic Effects ◽

Neurological Deficits ◽

Double Blind ◽

Long Acting

Statins have pleiotropic effects that are considered beneficial in preventing cerebral vasospasm and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (aSAH). Many studies using statins have been performed but failed to show remarkable effects. We hypothesized that a long-acting statin would be more effective, due to a longer half-life and stronger pleiotropic effects. Patients with aSAH were randomly assigned to a pitavastatin group (4 mg daily; n = 54) and a placebo group ( n = 54) after repair of a ruptured aneurysm. The primary efficacy end point was vasospasm-related delayed ischemic neurological deficits (DIND), and the secondary end points were cerebral vasospasm evaluated by digital subtraction angiography (DSA), vasospasm-related new cerebral infarctions, and outcome at three months. Severe cerebral vasospasms on DSA were statistically fewer in the pitavastatin group than in the placebo group (14.8% vs. 33.3%; odds ratio, 0.32; 95% confidence interval, 0.11–0.87, p = 0.042); however, the occurrence of DIND and new infarctions and outcome showed no statistically significant differences between the groups. The present study is the first to prove the definite, statin-induced amelioration of cerebral vasospasm on DSA. However, administration of any type of statin at the acute phase of aSAH is not recommended.

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Long-Lasting Cerebral Vasospasm, Microthrombosis, Apoptosis and Paravascular Alterations Associated with Neurological Deficits in a Mouse Model of Subarachnoid Hemorrhage

Molecular Neurobiology ◽

10.1007/s12035-017-0514-6 ◽

2017 ◽

Vol 55 (4) ◽

pp. 2763-2779 ◽

Cited By ~ 13

Author(s):

Mohamad El Amki ◽

Martine Dubois ◽

Antoine Lefevre-Scelles ◽

Nicolas Magne ◽

Mélanie Roussel ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Mouse Model ◽

Cerebral Vasospasm ◽

Neurological Deficits

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Intracarotid slow bolus injection of nimodipine during angiography for treatment of cerebral vasospasm after SAH

Journal of Neurosurgery ◽

10.3171/jns.1984.61.2.0231 ◽

1984 ◽

Vol 61 (2) ◽

pp. 231-240 ◽

Cited By ~ 51

Author(s):

J. Andre Grotenhuis ◽

Winfried Bettag ◽

B. J. Othmar Fiebach ◽

Khosrow Dabir

Keyword(s):

Subarachnoid Hemorrhage ◽

Calcium Antagonist ◽

Cerebral Ischemia ◽

Cerebral Vasospasm ◽

Bolus Injection ◽

Neurological Deficits ◽

Cerebral Vessel ◽

Content Type ◽

Venous Infusion ◽

Fine Print

✓ Nimodipine was given as an intracarotid slow bolus injection in six patients with subarachnoid hemorrhage (SAH) due to rupture of a cerebral aneurysm, with angiographically demonstrated vasospasm. The patients were followed by serial angiograms for demonstration of the effect of nimodipine on vasospasm. After angiography, all patients were treated with a constant venous infusion of this new calcium antagonist. Although the therapeutic regimen was started only a few hours after onset of vasospasm, there was no change in cerebral vessel caliber detectable on angiograms following the intracarotid injection. Three patients died, two patients finally recovered with neurological deficits due to cerebral ischemia, and one patient with asymptomatic vasospasm remained symptom-free. Although nimodipine may act to prevent cerebral vasospasm after SAH, the authors believe that the intracarotid application is not effective after vasospasm has occurred.

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The role of hemoglobin in the etiology of cerebral vasospasm

Journal of Neurosurgery ◽

10.3171/jns.1983.59.2.0231 ◽

1983 ◽

Vol 59 (2) ◽

pp. 231-236 ◽

Cited By ~ 46

Author(s):

David J. Boullin ◽

Philip Tagari ◽

George du Boulay ◽

Victoria Aitken ◽

J. Trevor Hughes

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Vasospasm ◽

Cerebral Angiography ◽

Aneurysm Rupture ◽

Neurological Deficits ◽

Arterial Spasm ◽

Content Type ◽

Experimental Animals ◽

Fine Print

✓ Oxyhemoglobin was injected intracisternally into three baboons, and methemoglobin into one baboon, in an attempt to mimic the prolonged cerebral arterial spasm sometimes seen after subarachnoid hemorrhage due to aneurysm rupture. Cerebral angiography was performed for up to 7 days after injection of hemoglobin, and the degree of vasospasm was estimated from the angiograms. Oxyhemoglobin caused slight arterial narrowing, which lasted for 3 days. Methemoglobin had no significant effects. Motor neurological deficits and histopathological signs, characteristic of prolonged cerebral vasospasm, were not observed. It was concluded that hemoglobin alone is not capable of causing the cerebral vasospasm syndrome in these experimental animals.

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2-PMAP Ameliorates Cerebral Vasospasm and Brain Injury after Subarachnoid Hemorrhage by Regulating Neuro-Inflammation in Rats

Cells ◽

10.3390/cells11020242 ◽

2022 ◽

Vol 11 (2) ◽

pp. 242

Author(s):

Chieh-Hsin Wu ◽

Hung-Pei Tsai ◽

Yu-Feng Su ◽

Cheng-Yu Tsai ◽

Ying-Yi Lu ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Brain Injury ◽

Cerebral Vasospasm ◽

Neuronal Apoptosis ◽

Neurological Deficits ◽

Neuroprotective Effects ◽

Tnf Α ◽

Amino Phenol ◽

Group 5 ◽

Neuro Inflammation

A subarachnoid hemorrhage (SAH), leading to severe disability and high fatality in survivors, is a devastating disease. Neuro-inflammation, a critical mechanism of cerebral vasospasm and brain injury from SAH, is tightly related to prognoses. Interestingly, studies indicate that 2-[(pyridine-2-ylmethyl)-amino]-phenol (2-PMAP) crosses the blood–brain barrier easily. Here, we investigated whether the vasodilatory and neuroprotective roles of 2-PMAP were observed in SAH rats. Rats were assigned to three groups: sham, SAH and SAH+2-PMAP. SAHs were induced by a cisterna magna injection. In the SAH+2-PMAP group, 5 mg/kg 2-PMAP was injected into the subarachnoid space before SAH induction. The administration of 2-PMAP markedly ameliorated cerebral vasospasm and decreased endothelial apoptosis 48 h after SAH. Meanwhile, 2-PMAP decreased the severity of neurological impairments and neuronal apoptosis after SAH. Furthermore, 2-PMAP decreased the activation of microglia and astrocytes, expressions of TLR-4 and p-NF-κB, inflammatory markers (TNF-α, IL-1β and IL-6) and reactive oxygen species. This study is the first to confirm that 2-PMAP has vasodilatory and neuroprotective effects in a rat model of SAH. Taken together, the experimental results indicate that 2-PMAP treatment attenuates neuro-inflammation, oxidative stress and cerebral vasospasm, in addition to ameliorating neurological deficits, and that these attenuating and ameliorating effects are conferred through the TLR-4/NF-κB pathway.

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Sirtuin 1 Mediates Protection Against Delayed Cerebral Ischemia in Subarachnoid Hemorrhage in Response to Hypoxic Postconditioning

Journal of the American Heart Association ◽

10.1161/jaha.121.021113 ◽

2021 ◽

Author(s):

Deepti Diwan ◽

Ananth K. Vellimana ◽

Diane J. Aum ◽

Julian Clarke ◽

James W. Nelson ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Ischemia ◽

Cerebral Vasospasm ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Delayed Cerebral Ischemia ◽

Sirtuin 1 ◽

Neurological Deficits ◽

Multifactorial Disease ◽

Time Points ◽

Hypoxic Postconditioning

Background Many therapies designed to prevent delayed cerebral ischemia (DCI) and improve neurological outcome in aneurysmal subarachnoid hemorrhage (SAH) have failed, likely because of targeting only one element of what has proven to be a multifactorial disease. We previously demonstrated that initiating hypoxic conditioning before SAH (hypoxic preconditioning) provides powerful protection against DCI. Here, we expanded upon these findings to determine whether hypoxic conditioning delivered at clinically relevant time points after SAH (hypoxic postconditioning) provides similarly robust DCI protection. Methods and Results In this study, we found that hypoxic postconditioning (8% O 2 for 2 hours) initiated 3 hours after SAH provides strong protection against cerebral vasospasm, microvessel thrombi, and neurological deficits. By pharmacologic and genetic inhibition of SIRT1 (sirtuin 1) using EX527 and global Sirt1 −/− mice, respectively, we demonstrated that this multifaceted DCI protection is SIRT1 mediated. Moreover, genetic overexpression of SIRT1 using Sirt1‐Tg mice, mimicked the DCI protection afforded by hypoxic postconditioning. Finally, we found that post‐SAH administration of resveratrol attenuated cerebral vasospasm, microvessel thrombi, and neurological deficits, and did so in a SIRT1‐dependent fashion. Conclusions The present study indicates that hypoxic postconditioning provides powerful DCI protection when initiated at clinically relevant time points, and that pharmacologic augmentation of SIRT1 activity after SAH can mimic this beneficial effect. We conclude that conditioning‐based therapies administered after SAH hold translational promise for patients with SAH and warrant further investigation.

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