Milrinone Infusion for VAsospam Treatment in Subarachnoid hemoRrhage (MIVAR)

Subarachnoid hemorrhage (SAH) is a frequent and severe disease. Mortality can reach 40%. The most frequent complication of SAH is arterial vasospasm, with estimated incidence as high as 70%. Vasospasm is responsible for cerebral ischemia leading to severe morbidity, poorer quality of life and increased mortality. Intravenous Milrinone, because of vasodilatory properties could be a therapeutic option. We hypothesize that intravenous infusion of Milrinone will improve the neurological recovery of patients with vasospasm following aneurysmal SAH at 3 months. This is a Phase III, multi-center, randomized, double-blinded, placebo-controlled study. The primary outcome will be the proportion of patients with a good outcome 3 months (defined as a modified rankin score ≤2).

Subarachnoid hemorrhage (SAH) is relatively frequent, accounting for 5% of strokes, and affects a relatively young population. It is essentially caused by cerebral aneurysm rupture. Mortality can reach 40%. The most frequent complication of SAH is arterial vasospasm, with estimated incidence as high as 70%. Vasospasm is responsible for cerebral ischemia, delayed or not, which in turn is responsible for severe morbidity (neurological deficit, neuro psychiatric disorders...), poorer quality of life (institutionalization, inability to return to work ...) and increased mortality. The pathophysiology of vasospasm is complex, multifactorial and far from being fully understood. Many drugs have been studied in the treatment of symptomatic vasospasm but none has really proven its efficacy. Milrinone is proposed for the treatment of cerebral vasospasm, either as intra-arterial injection (during angiography) or intravenously using continuous infusion. Indeed, among new vasospasm's treatments, Milrinone seems to have good angiographic and clinical results. There is no randomized controlled trials evaluating Milrinone for preventive and/or curative treatment of cerebral vasospasm following aneurysmal SAH. The literature is made only of clinical cases, cases series with angiographic studies or interventional studies not controlled and with no more than 10 patients. Thus we hypothesize that the intravenous infusion of Milrinone will improve the neurological recovery of patients with vasospasm following aneurysmal SAH at 3 months. Adult patients, hospitalized for a vasospasm complicating subarachnoid hemorrhage secondary to intracranial aneurysm rupture will be included and randomized within 6 hours of the CT-scanner confirming the vasospasm diagnosis to receive either the study drug (milrinione, a 0,1 mg/kg bolus followed by a 1 μg/kg/min perfusion) or placebo (saline, with a bolus and a continuous infusion). Study drug administration will be formalized (minimum duration 48 hours, maximum duration 14 days).The primary endpoint will be the proportion of patients with a good outcome 3 months (defined as a modified rankin score ≤2).

Phase 3, multicenter, international (France, Switzerland), randomized, double blinded, placebo-controlled study

modified Rankin score ≤2 (0 = No symptoms, 1 = No significant disability. Able to carry out all usual activities, despite some symptoms, 2 = Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities, 3 = Moderate disability. Requires some help, but able to walk unassisted, 4 = Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted, 5 = Severe disability. Requires constant nursing care and attention, bedridden, incontinent, 6 = Death)

To assess mortality rates in intensive care and in hospital at 3 and 6 months after aneurysm rupture.

0 = No symptoms, 1 = No significant disability. Able to carry out all usual activities, despite some symptoms, 2 = Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities, 3 = Moderate disability. Requires some help, but able to walk unassisted, 4 = Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted, 5 = Severe disability. Requires constant nursing care and attention, bedridden, incontinent, 6 = Death

1= Death, 2=Persistent vegetative state, 3=Sever disability, 4=Moderate disability, 5=Good recovery 2. Persistent vegetative state 3. Severe disability 4. Moderate disability 5. Low disability

Evaluation of the angiographic success according to angiographic CT-scannerwith blind analysis (coted as follows: light success, moderate success or important success)

Inclusion Criteria: Adult patients hospitalized for aneurysmal SAH First episode of vasospasm, with a diagnosis confirmed on cerebral arterial CT-scanner Delay between diagnosis of vasospasm (i.e. CT-scanner) and inclusion ≤6 hours Exclusion Criteria: Initial Glasgow score at 3 with a bilateral mydriasis Moribund patient Pregnant woman Contraindication to Milrinone (obstructive cardiomyopathy…) Cerebral infarction in the vasospasm area already present on the CT-scanner at the time of diagnosis (lack of expected benefit of treatment in this case- according to medical judgement) Non-affiliation to French health care coverage, Adult patient protected under the law (guardianship) Cardiac failure necessitating inotropic agents Uncontrolled Intracranial hypertension (ICP>25 mmHg for more than 20 min) Inclusion in an interventional study using Milrinone, or evaluating a treatment of cerebral vasospasm or with the same primary endpoint (mRS at 3 months).

Lasocki S, Bruckert V, Campfort M, Leger M, Rineau E. Restrictive transfusion targets the heart now! Insight from the REALITY study. Anaesth Crit Care Pain Med. 2021 Apr;40(2):100854. doi: 10.1016/j.accpm.2021.100854. Epub 2021 Mar 27. No abstract available.