Cerebral Vasospasm After Subarachnoid Hemorrhage, Subarachnoid Hemorrhage, Aneurysmal
Conditions
Keywords
aneurysmal subarachnoid hemorrhage, Cerebral vasospasm, Milrinone, Endovascular Therapy, Outcomes
Brief summary
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.
Interventions
OTHERIntra-arterial and Intravenous Milrinone Therapy
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.
OTHERStandardized Medical Management
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.
Sponsors
Beijing Tiantan Hospital
The First Affiliated Hospital of Henan Medical University
Hebei General Hospital
Nanfang Hospital, Southern Medical University
Henan Provincial People's Hospital
Binzhou Medical University
Hunan University of Medicine General Hospital
First Affiliated Hospital of Harbin Medical University
Second Affiliated Hospital, School of Medicine, Zhejiang University
First Affiliated Hospital of Wannan Medical College
Zhongnan Hospital
The First Affiliated Hospital of Nanchang University
First Affiliated Hospital of Xinjiang Medical University
Chinese PLA General Hospital
Shaoyang Central Hospital
Ji an central people's Hospital
The second People's Hospital of Guiyang, China
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
To reduce potential assessment bias, an independent Clinical Events Committee (CEC), blinded to treatment assignment, will centrally review and adjudicate all study outcomes according to predefined criteria. These outcomes will include functional assessments, such as mRS scores, cognitive function, and quality of life; imaging-based outcomes, including vasospasm relief; and suspected clinical endpoint events, including delayed cerebral ischemia and so on. Disagreements among committee members will be resolved by consensus.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Participants must meet all of the following criteria: 1. Aged 18 to 80 years. 2. SAH confirmed by cranial CT, with an intracranial aneurysm identified by CTA, MRA, or DSA and determined to be the source of bleeding. 3. Prior treatment of the aneurysm by endovascular intervention or surgical clipping. 4. Evidence suggestive of CVS within 14 days after onset, defined by at least one of the following: 1. Clinical deterioration, including a decrease in GCS score of \>2 points and/or a new focal neurological deficit not attributable to another known neurological cause; 2. TCD confirmed vasospasm, defined as mean flow velocity (MFV) \>120 cm/s in the middle cerebral artery (MCA) and Lindegaard ratio \>3, after excluding other causes of increased flow velocity such as anemia or fever; 3. Vasospasm confirmed by DSA or CTA.
Exclusion criteria
1. Hunt-Hess grade 5 with critical illness and inability to tolerate intervention. 2. Contraindications to milrinone, including milrinone allergy, aortic or pulmonary valve stenosis, obstructive hypertrophic cardiomyopathy, acute coronary syndrome, or malignant arrhythmia. 3. Perioperative procedure-related complications that may interfere with study assessment, such as significant stenosis of the parent artery. 4. Irreversible cerebral infarction involving the entire vascular territory affected by vasospasm. 5. Poor blood pressure control, defined as systolic blood pressure \<100 mmHg. 6. Non-aneurysmal SAH, including hemorrhage due to arteriovenous malformation, vasculitis, tumor bleeding, trauma, or other non-spontaneous causes, or cases without an identified bleeding source. 7. Other severe neurological disorders with substantial pre-existing disability (mRS \>3), such as progressive cognitive impairment or status epilepticus. 8. Severe systemic disease, including significant cardiac, hepatic, renal, or psychiatric disorders. 9. Pregnant or breastfeeding women, or women planning pregnancy during the study period. 10. Any other condition considered by the investigators to make the patient unsuitable for participation or likely to limit compliance with study procedures. 11. Current participation in another interventional clinical study, inability to complete follow-up assessments, or failure to provide informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neurological function prognosis | Up to 90 days after randomization | The primary outcome is poor neurological outcome within 90 days after randomization, defined as a modified Rankin Scale (mRS) score of 3-6. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Delayed cerebral ischemia | Up to 21 days after randomization | 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) |
| Vasospasm resolution rate | Up to 14 days after randomization/at discharge | Proportion of participants with vasospasm resolution within 14 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. |
| Severity of patients' clinical condition | Up to 21 days after randomization。 | assessed at 3 weeks by WFNS grade after treatment, with change from baseline recorded |
| Cognitive function assessed using the Montreal Cognitive Assessment (MoCA) at baseline and 90 Days | at baseline and 90 days after randomization | 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. |
| Health-related quality of life assessed using the EuroQol 5-Dimension questionnaire (EQ-5D) at 90 Days | 90 days after randomization | 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. |
| Total Hospitalization Cost | Up to 14 days after randomization/at discharge | Total hospitalization cost will be calculated as the total cost incurred during the index hospitalization |
| Length of Total Hospital Stay | Up to 14 days after randomization/at discharge | Total hospital stay will be measured as the number of days from randomization to hospital discharge |
| Length of Intensive Care Unit Stay | Up to 14 days after randomization/at discharge | Intensive care unit stay will be measured as the total number of days spent in the intensive care unit during the index hospitalization |
Countries
China
Contacts
CONTACTWenqiang Li, MD
STUDY_CHAIRXinjian Yang, MD
Beijing Tiantan Hospital
STUDY_CHAIRLiping Liu, MD
Beijing Tiantan Hospital
Outcome results
None listed