Pharmacologic Reduction of Angiographic Vasospasm in Experimental Subarachnoid Hemorrhage: Systematic Review and Meta-Analysis

Abstract

Animal models have been developed to simulate angiographic vasospasm secondary to subarachnoid hemorrhage (SAH) and to test pharmacologic treatments. Our aim was to evaluate the effect of pharmacologic treatments that have been tested in humans and in preclinical studies to determine if animal models inform results reported in humans. A systematic review and meta-analysis of SAH studies was performed. We investigated predictors of translation from animals to humans with multivariate logistic regression. Pharmacologic reduction of vasospasm was effective in mice, rats, rabbits, dogs, nonhuman primates (standard mean difference of À1.74; 95% confidence interval À2.04 to À1.44) and humans. Animal studies were generally of poor methodologic quality and there was evidence of publication bias. Subgroup analysis by drug and species showed that statins, tissue plasminogen activator, erythropoietin, endothelin receptor antagonists, calcium channel antagonists, fasudil, and tirilazad were effective whereas magnesium was not. Only evaluation of vasospasm > 3 days after SAH was independently associated with successful translation. We conclude that reduction of vasospasm is effective in animals and humans and that evaluation of vasospasm > 3 days after SAH may be preferable for preclinical models.

The Cross-Talk between Canonical and Non-Canonical Wnt-Dependent Pathways Regulates P-Glycoprotein Expression in Human Blood–Brain Barrier Cells

“…13 Fasudil, the clinically prescribed analog of Y27632, is used to prevent vasospasms after subarachnoid hemorrhage, 28 to improve tissue perfusion during cerebral ischemia, 29 to prevent the progression of cerebral aneurisms. 30 Our work suggests that Fasudil might be used to improve the delivery of Pgp substrates through the BBB.…”

Hydrogen-Rich Saline Attenuated Subarachnoid Hemorrhage-Induced Early Brain Injury in Rats by Suppressing Inflammatory Response: Possible Involvement of NF-κB Pathway and NLRP3 Inflammasome

“…By mainly affecting middle-aged patients and a highest fatality in all stroke subtypes, SAH brings about a huge burden on economy and society [1][2][3]. Plenty of researches have focused on the cerebral vasospasm, which was traditionally deemed as the principal cause of poor prognosis in SAH patients [4][5][6][7][8][9]. Although animal experiments targeting post-SAH vasospasm and subsequent delayed ischemic neurological deficit (DIND) have reached promising results, it was not the same story recent clinical trials told [10][11][12].…”

“…Most of SAH occurs due to aneurysm rupture, afterwards, abundant of oxyhemoglobin generated from erythrocytes hemolysis was released into the subarachnoid space. Oxyhemoglobin subsequently induces a wide range of stress reaction, including activation of inflammatory responses and production of inflammatory cytokines [4]. Among all the explored underlying mechanism, our previous study has proved that P2X7R/cryopyrin inflammasome signaling may be involved in neuroinflammation following SAH, partially through caspase-1 activation and IL-1β/IL-18 production maturity [23].…”

Endovascular Perforation Subarachnoid Hemorrhage Fails to Cause Morris Water Maze Deficits in the Mouse

“…Despite successfully reducing angiographic vasospasm, long-term patient outcome was not affected by administration of the non-glucocorticoid 21-aminosteroid tirilazad 11 or the endothelin receptor antagonist clazosentan. 12 It may be that, beyond examining short-term preclinical outcomes (such as early brain injury and cerebral vasospasm), the successful translation of putative therapies would be predicted by evaluation of long-term neurobehavioral outcomes in preclinical models, 13 as recommended by the Stroke Therapy Academic Industry Roundtable criteria. 14 Experimental SAH research has thus sought to model long-term neurobehavioral outcomes and elucidate the mechanisms responsible.…”