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| Name | Class |
|---|---|
| The First Affiliated Hospital of Henan Medical University | UNKNOWN |
| Hebei General Hospital | OTHER |
| Nanfang Hospital, Southern Medical University | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control Group (Standardized Medical Management Group) | Active Comparator | Participants assigned to the control group will receive standardized medical management after aneurysm treatment for aSAH, including oral or enteral nimodipine at a total daily dose of 360 mg, maintenance of euvolemia, blood pressure augmentation when clinically indicated to support cerebral perfusion, and other guideline-recommended supportive treatments. |
|
| Experimental Group (Continuous Milrinone-Based Endovascular Therapy Plus Standardized Medical Mana ) | Experimental | Participants assigned to this arm will receive standardized medical management as described for the comparator arm plus continuous milrinone-based endovascular therapy. Endovascular angiography will be performed, followed by intra-arterial milrinone 8 mg infused into the artery supplying the vasospastic territory over approximately 30 minutes. The dose may be repeated if clinically needed, with a maximum total intra-arterial dose of 24 mg. Mechanical angioplasty may be considered for persistent severe proximal stenosis. After intra-arterial treatment, intravenous milrinone will be continued for 72 hours at 0.5 to 1.5 μg/kg/min according to clinical need and tolerability. If vasospasm recurs, the treatment protocol may be repeated at the investigator's discretion. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Intra-arterial and Intravenous Milrinone Therapy | Other | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | Up to 90 days after randomization |
| Measure | Description | Time Frame |
|---|---|---|
| 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) | Up to 21 days after randomization |
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Inclusion Criteria:
Participants must meet all of the following criteria:
Aged 18 to 80 years.
SAH confirmed by cranial CT, with an intracranial aneurysm identified by CTA, MRA, or DSA and determined to be the source of bleeding.
Prior treatment of the aneurysm by endovascular intervention or surgical clipping.
Evidence suggestive of CVS within 14 days after onset, defined by at least one of the following:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Wenqiang Li, MD | Contact | 13521199810 | lwqsurgeon@163.com |
| Name | Affiliation | Role |
|---|---|---|
| Xinjian Yang, MD | Beijing Tiantan Hospital | Study Chair |
| Liping Liu, MD | Beijing Tiantan Hospital | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Beijing Tiantan Hospital | Recruiting | Beijing | Beijing Municipality | 100070 | China |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 34478028 | Result | Lakhal K, Hivert A, Alexandre PL, Fresco M, Robert-Edan V, Rodie-Talbere PA, Ambrosi X, Bourcier R, Rozec B, Cadiet J. Intravenous Milrinone for Cerebral Vasospasm in Subarachnoid Hemorrhage: The MILRISPASM Controlled Before-After Study. Neurocrit Care. 2021 Dec;35(3):669-679. doi: 10.1007/s12028-021-01331-z. Epub 2021 Sep 3. | |
| 28004163 |
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Individual participant data will not be shared because of patient privacy, ethical restrictions, and the absence of a predefined data-sharing mechanism.
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| Henan Provincial People's Hospital |
| OTHER |
| Binzhou Medical University | OTHER |
| Hunan University of Medicine General Hospital | OTHER |
| First Affiliated Hospital of Harbin Medical University | OTHER |
| Second Affiliated Hospital, School of Medicine, Zhejiang University | OTHER |
| First Affiliated Hospital of Wannan Medical College | OTHER |
| Zhongnan Hospital | OTHER |
| The First Affiliated Hospital of Nanchang University | OTHER |
| First Affiliated Hospital of Xinjiang Medical University | OTHER |
| Chinese PLA General Hospital | OTHER |
| Shaoyang Central Hospital | UNKNOWN |
| Ji an central people's Hospital | UNKNOWN |
| The second People's Hospital of Guiyang, China | UNKNOWN |
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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.
|
| Standardized Medical Management | Other | 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. |
|
| Vasospasm resolution rate |
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. |
| 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 | 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. | 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. | 90 days after randomization |
| Total Hospitalization Cost | Total hospitalization cost will be calculated as the total cost incurred during the index hospitalization | 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 | 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 | Up to 14 days after randomization/at discharge |
| Department of Neurosurgery, Beijing Tiantan Hospital | Not yet recruiting | Beijing | Beijing Municipality | 100070 | China |
|
| Boulouis G, Labeyrie MA, Raymond J, Rodriguez-Regent C, Lukaszewicz AC, Bresson D, Ben Hassen W, Trystram D, Meder JF, Oppenheim C, Naggara O. Treatment of cerebral vasospasm following aneurysmal subarachnoid haemorrhage: a systematic review and meta-analysis. Eur Radiol. 2017 Aug;27(8):3333-3342. doi: 10.1007/s00330-016-4702-y. Epub 2016 Dec 21. |
| 18239182 | Result | Fraticelli AT, Cholley BP, Losser MR, Saint Maurice JP, Payen D. Milrinone for the treatment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke. 2008 Mar;39(3):893-8. doi: 10.1161/STROKEAHA.107.492447. Epub 2008 Jan 31. |
| 31278116 | Result | Jabbarli R, Pierscianek D, Rolz R, Darkwah Oppong M, Kaier K, Shah M, Taschner C, Monninghoff C, Urbach H, Beck J, Sure U, Forsting M. Endovascular treatment of cerebral vasospasm after subarachnoid hemorrhage: More is more. Neurology. 2019 Jul 30;93(5):e458-e466. doi: 10.1212/WNL.0000000000007862. Epub 2019 Jul 5. |
| ID | Term |
|---|---|
| D013345 | Subarachnoid Hemorrhage |
| D020301 | Vasospasm, Intracranial |
| ID | Term |
|---|---|
| D020300 | Intracranial Hemorrhages |
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D006470 | Hemorrhage |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
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| ID | Term |
|---|---|
| D007261 | Infusions, Intra-Arterial |
| ID | Term |
|---|---|
| D007263 | Infusions, Parenteral |
| D004333 | Drug Administration Routes |
| D004358 | Drug Therapy |
| D013812 | Therapeutics |
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