A Phase 2 interventional study of Milrinone Injection and Placebo in Aneurysmal Subarachnoid Hemorrhage, sponsored by University Hospital, Toulouse. Recruiting at 5 sites in France. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2024-09-25.
Sponsored by University Hospital, Toulouse · Phase 2, Interventional, and Treatment
The present study is a randomized, multi-center, double-blind, prospective study that tests the efficacy of intravenous milrinone to optimize cerebral hemodynamic and prevent delayed cerebral ischemia (DCI) during the high-risk period (day 4- day 14) in patients with severe subarachnoid hemorrhage due to intracranial aneurysm rupture (SAHa) (WFNS IV-V). The main objective is to evaluate, in comatose patients and / or sedated on D3 following a severe SAHa (WFNS IV -V), the effect of 10 days of milrinone versus placebo, in addition to the usual management, on the volume of DCI lesions measured on CT scan at 1 month.
After SAHa, approximately 28% of patients will present DCI. DCI is a major cause of death and disability and will condition the neurological prognosis. Its treatment is not really codified, because of the absence of scientific proof of good level. Milrinone, an inhibitor of type III phosphodiesterase, seems particularly interesting in the management of DCI. This molecule has indeed a powerful vasodilator action. In addition, its anti-inflammatory effects could inhibit the abnormal proliferation of vascular smooth muscle cells and the remodelling observed in patients with DCI via an action on interleukin-6. Finally, because of its positive inotropic effect, it is an interesting choice in these patients with neurogenic cardiomyopathy where the administration of catecholamines is to be avoided. Strong evidence for efficacy of milrinone in the treatment and / or prevention of DCI is still lacking. All patients will benefit from a computed tomography (CT) brain imaging at 48 hrs following aneurysm treatment to define baseline imaging. The standard care (SC) group will follow the recommended management of SAHa and will receive a placebo (intravenous glucose 5%) from day 4 to day 14. The milrinone (M) group will receive, in addition to standard care, administration of milrinone (0.75 μg / kg / min, intravenous) from day 4 to day 14. In case of suspicion of vasospasm and after ineffective effect of medical measures (euvolemia and increase in mean arterial pressure), an endovascular treatment will be possible. The occurrence of vasospasm will be monitored closely with clinical examination and cerebral tissue oxygen pressure (PtiO2). From day 4 to day 14, general and biological data, clinical examination will be collected daily. Intensive care unit complications (neurologic, pulmonary, cardiac and septic complications) will be collected. At 1 month, the volume of DCI lesions will be measured on CT scan. Neurologic prognosis, quality of life and mortality will be studied at 1 month, 3 month, 6 month and 1 year. Adverse events will be monitored closely.
Exclusion Criteria:
"milrinone" group benefiting from an identical treatment to the standard care group and in addition, administration of milrinone (0.75 μg / kg / min, intravenous) from Day 4 to Day 14. In case of suspicion of vasospasm and after ineffective effect of medical measures (euvolemia and increase in mean arterial pressure), an endovascular treatment will be possible. The occurrence of vasospasm will be monitored closely with clinical examination and cerebral tissue oxygen pressure (PtiO2). From D4 to D14, general and biological data, clinical examination will be collected daily. Intensive care unit complications (neurologic, pulmonary, cardiac and septic complications) will be collected. At 1 month, the volume of DCI lesions will be measured on CT scan. Neurologic prognosis, quality of life and mortality will be studied at 1 month, 3 month, 6 month and 1 year. Adverse events will be monitored closely.
Drug: Milrinone Injection
The standard care group will follow the recommended management of SAHa and will receive a placebo (intravenous glucose 5%) from Day 4 to Day 14. In case of suspicion of vasospasm and after ineffective effect of medical measures (euvolemia and increase in mean arterial pressure), an endovascular treatment will be possible. The occurrence of vasospasm will be monitored closely with clinical examination and cerebral tissue oxygen pressure (PtiO2). From D4 to D14, general and biological data, clinical examination will be collected daily. Intensive care unit complications (neurologic, pulmonary, cardiac and septic complications) will be collected. At 1 month, the volume of DCI lesions will be measured on CT scan. Neurologic prognosis, quality of life and mortality will be studied at 1 month, 3 month, 6 month and 1 year. Adverse events will be monitored closely.
Other: Placebo
administration of milrinone (0.75 μg / kg / min, intravenous) from Day 4 to Day 14
administration of placebo (intravenous glucose 5%) from Day 4 to Day 14
volume of delayed cerebral ischemia lesions
volume of DCI lesions measured on CT scan and validated by Magnetic Resonance Imaging (MRI) imaging at 1 month
Time frame: 1 month
Radiological parameters on CT at 1 month
percentage of patients with DCI lesions
Time frame: 1 month
Evolution in intensive care: Neurological complications 1
number of episodes of PtiO2 below the ischemic threshold in intensive care: PtiO2 \<20 mmHg (moderate hypoxia) and \<15 mm Hg (severe hypoxia) for at least 15 minutes
Time frame: 1 month
Evolution in intensive care: Neurological complications 2
total duration of episodes of PtiO2 \<20 mm Hg (moderate hypoxia) and \<15 mm Hg (severe hypoxia)
Time frame: 1 month
Evolution in intensive care: Neurological complications 3
number of recourse to an endovascular treatment
Time frame: 1 month
Evolution in intensive care: Neurological complications 4
intracranial hypertension in intensive care: ICP\> 20 mmHg for at least 15 minutes.
Time frame: 1 month
Number and type of non-neurological complications
non-neurological complications
Time frame: 1 month
Number of days in intensive care
Number of days in intensive care
Time frame: 1 month
Number of days with mechanical ventilation
Number of days with mechanical ventilation
Time frame: 1 month
neurological prognosis at 1 month: Rankin score
evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
Time frame: 1 month
neurological prognosis at 1 month: Glasgow Outcome scale
evaluated by the Glasgow Outcome Scale (GOS) (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3).
Time frame: 1 month
neurological prognosis at 3 month: Rankin score
evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
Time frame: 3 month
neurological prognosis at 3 month: Glasgow Outcome scale
evaluated by the the Glasgow Outcome Scale (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3)
Time frame: 3 month
neurological prognosis at 6 month: Rankin score
evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
Time frame: 6 month
neurological prognosis at 6 month: Glasgow Outcome scale
evaluated by the the Glasgow Outcome Scale (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3)
Time frame: 6 month
neurological prognosis at 1 year: Rankin score
evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
Time frame: 1 year
neurological prognosis at 1 year: Glasgow Outcome scale
evaluated by the Glasgow Outcome Scale (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3)
Time frame: 1 year
Mortality at 1 month
Mortality at 1 month
Time frame: 1 month
Mortality at 3 month
Mortality at 3 month
Time frame: 3 month
Mortality at 6 month
Mortality at 6 month
Time frame: 6 month
Mortality at 1 year
Mortality at 1 year
Time frame: 1 year
number of days of hospitalization
number of days of hospitalization
Time frame: 1 year
Plan to share: No
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University Hospital, Toulouse