Cerebral vasospasm is a common and serious complication after aneurysmal subarachnoid hemorrhage and is an important cause of delayed cerebral ischemia and poor neurological outcomes. Although standardized medical management is widely used, effective treatment options for cerebral vasospasm remain limited. Endovascular treatment, including intra-arterial drug infusion and mechanical angioplasty, may relieve vasospasm and improve cerebral perfusion after aneurysmal subarachnoid hemorrhage. However, most available evidence comes from retrospective or observational studies, and high-quality randomized evidence remains insufficient. Milrinone is a phosphodiesterase inhibitor with multiple potentially beneficial effects, including vasodilation, positive inotropic activity, anti-inflammatory properties, and endothelial protection. These effects may make milrinone a promising therapeutic agent for relieving cerebral vasospasm, reducing delayed cerebral ischemia, and ultimately improving clinical outcomes after aneurysmal subarachnoid hemorrhage. This study is a multicenter, prospective, randomized controlled clinical trial designed to evaluate whether early continuous milrinone-based endovascular therapy improves outcomes in patients with cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Eligible participants will be randomly assigned to receive either standardized medical management alone or milrinone-based endovascular therapy plus standardized medical management. In the intervention group, patients will receive intra-arterial milrinone during endovascular treatment, with mechanical angioplasty when clinically indicated, followed by continuous intravenous milrinone infusion for 72 hours after intra-arterial administration. The study will evaluate whether this continuous treatment strategy reduces poor neurological outcomes at 3 months after randomization. It will also assess the effects of treatment on delayed cerebral ischemia, vasospasm resolution, cognitive function, quality of life and so on. The results of this trial may provide high-quality evidence for early continuous milrinone-based endovascular therapy as a treatment strategy for cerebral vasospasm after aneurysmal subarachnoid hemorrhage.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
306
Continuous milrinone-based endovascular therapy will be administered in addition to standardized medical management. Cerebral angiography will first be performed, followed by intra-arterial infusion of milrinone 8 mg into the artery supplying the vasospastic territory over approximately 30 minutes. If vasodilation is incomplete, the infusion may be repeated once in the same territory. For diffuse vasospasm, milrinone may be administered in different vascular territories, with a maximum total intra-arterial dose of 24 mg. If severe proximal stenosis persists after intra-arterial treatment, mechanical angioplasty may be performed at the operator's discretion. After intra-arterial treatment, intravenous milrinone will be continued for 72 hours, starting at 0.5 mcg/kg/min and gradually increasing to a maximum of 1.5 mcg/kg/min when clinically needed and well tolerated. If vasospasm recurs, the treatment protocol may be repeated at the investigator's discretion.
Standardized medical management will be provided after aneurysm treatment for aSAH. It will include oral or enteral nimodipine at a total daily dose of 360 mg, fluid management with 24-hour intake and output monitoring to maintain euvolemia, blood pressure augmentation when clinically indicated to support cerebral perfusion, and other guideline-recommended supportive treatments.
Department of Neurosurgery, Beijing Tiantan Hospital
Beijing, Beijing Municipality, China
Neurological function prognosis
The primary outcome is poor neurological outcome within 90 days after randomization, defined as a modified Rankin Scale (mRS) score of 3-6.
Time frame: Up to 90 days after randomization
Delayed cerebral ischemia
new focal neurological deficit or decreased level of consciousness within 3 weeks after treatment, not attributable to rebleeding, seizure, infection, metabolic disturbance, or other causes, with imaging support for ischemic change (CT/MRI as applicable)
Time frame: Up to 21 days after randomization
Vasospasm resolution rate
Proportion of participants with vasospasm resolution within 21 days after randomization, defined as a reduction in mean flow velocity of the vasospastic vessel to \<120 cm/s on transcranial Doppler, or improvement in vasospasm severity compared with baseline. CTA or DSA may be used when clinically necessary.
Time frame: Up to 14 days after randomization/at discharge
Severity of patients' clinical condition
assessed at 3 weeks by WFNS grade after treatment, with change from baseline recorded
Time frame: Up to 21 days after randomization。
Cognitive function assessed using the Montreal Cognitive Assessment (MoCA) at baseline and 90 Days
Cognitive function will be assessed using the Montreal Cognitive Assessment (MoCA). The MoCA total score ranges from 0 to 30, with higher scores indicating better cognitive function.
Time frame: at baseline and 90 days after randomization
Health-related quality of life assessed using the EuroQol 5-Dimension questionnaire (EQ-5D) at 90 Days
Health-related quality of life will be assessed using the EuroQol 5-Dimension questionnaire (EQ-5D). The EuroQol Visual Analog Scale (EQ VAS) score ranges from 0 to 100, with higher scores indicating better health-related quality of life.
Time frame: 90 days after randomization
Total Hospitalization Cost
Total hospitalization cost will be calculated as the total cost incurred during the index hospitalization
Time frame: Up to 14 days after randomization/at discharge
Length of Total Hospital Stay
Total hospital stay will be measured as the number of days from randomization to hospital discharge
Time frame: Up to 14 days after randomization/at discharge
Length of Intensive Care Unit Stay
Intensive care unit stay will be measured as the total number of days spent in the intensive care unit during the index hospitalization
Time frame: Up to 14 days after randomization/at discharge
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