Detrimental Effect of Early Clazosentan Administration on Neurogenic Pulmonary Edema Following Subarachnoid Hemorrhage and Safety of Its Delayed Administration: Laboratory Investigation

BACKGROUND: Clazosentan, an endothelin A receptor antagonist, has been used to prevent cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH). It is unclear whether clazosentan is safe for patients presenting neurogenic pulmonary edema (NPE) because pulmonary edema is a well-known side effect of clazosentan. This study aimed to evaluate the effects of clazosentan on SAH-induced NPE. METHODS: SAH was induced by endovascular perforation in male mice. Clazosentan (10 mg/kg) or saline was administered 3 hours after SAH onset (early administration). The mice were euthanized 24 hours after onset, and wet/dry ratios of the excised brain, lung, liver, and kidney were measured. Histopathological images of each tissue were evaluated. Furthermore, similar evaluations were performed in mice that received clazosentan one day after onset (delayed administration) and were euthanized two days after onset. RESULTS: In the experiment with early clazosentan administration, the lung water content in the SAH+clazosentan group was significantly higher than that in the SAH+vehicle group (P<0.05). The histopathological score for lung injury in the SAH+clazosentan group was significantly higher than that in the SAH+vehicle group (P<0.05). In the experiment with delayed clazosentan administration, no significant differences in lung water contents and histopathological scores were observed between the groups. CONCLUSIONS: While the early administration of clazosentan exacerbated SAH-induced NPE, delayed administration did not exhibit this detrimental effect. Clazosentan may safely be utilized in clinical settings for patients with SAH who develop NPE, provided that NPE shows improvement.