Early Positive Fluid Balance as a Clinical Marker of Systemic Capillary Leak and Clazosentan Intolerance After Aneurysmal Subarachnoid Hemorrhage

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BACKGROUND: Clazosentan, a selective endothelin A receptor antagonist, mitigates cerebral vasospasm following aneurysmal subarachnoid hemorrhage (aSAH). Although it reduces vasospasm-related events, it is also associated with adverse events (AEs) related to fluid retention, which are hypothesized to stem from systemic capillary leaks. These AEs often necessitate early discontinuation of therapy. This study aimed to identify early clinical markers of clazosentan intolerance, specifically focusing on fluid balance. METHODS: This sub-analysis utilized data from the RECOVER registry, focusing on 208 patients diagnosed with aSAH who received clazosentan. Postoperative fluid status was quantified by calculating the mean daily fluid balance during postoperative days (POD) 1-3. The primary endpoint was discontinuation of clazosentan because of AEs. To identify independent predictors, a multivariable logistic regression analysis was conducted. A favorable outcome was defined as a modified Rankin Scale score of 0-2 at discharge. RESULTS: A total of 31 (14.9%) patients discontinued clazosentan on POD 6 [interquartile range (IQR), 3-10]. Discontinuation was most frequently attributed to worsening respiratory status (13/31, 41.9%), consistent with fluid overload. During POD 1-3, fluid intake was comparable between groups, whereas urine output was lower in those who discontinued treatment, yielding an early positive balance. Spline analysis showed a sharp risk rise beyond + 750 mL/day; dichotomization at this threshold confirmed an independent association with discontinuation [≥ +750 mL/day: adjusted odds ratio (OR), 3.41; 95% confidence interval (CI), 1.29-8.92; p = 0.012). Discontinuation was associated with lower odds of a favorable outcome (46.7% vs. 68.6%; adjusted OR, 0.40; 95% CI 0.18-0.88; p = 0.023). CONCLUSIONS: Early positive fluid balance was a strong independent predictor of clazosentan discontinuation and was associated with poor functional outcomes. Early postoperative fluid balance may serve as a practical bedside marker of clazosentan intolerance and fluid-retentive physiological response, potentially involving increased vascular permeability. Goal-directed fluid management targeting euvolemia during the first 72 h may help optimize tolerability and enhance the therapeutic efficacy of clazosentan.

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