Cerebral Hemodynamic Optimization by Milrinone to Prevent Delayed Cerebral Ischemia
- Conditions
- Aneurysmal Subarachnoid Hemorrhage
- Interventions
- Other: Placebo
- Registration Number
- NCT04282629
- Lead Sponsor
- University Hospital, Toulouse
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 234
- patients with severe SAHa (WFNS IV and V,) whose neurological examination is impossible because of coma (Glasgow coma score of 8 or less) or need for sedation at D3
- absence of pre-existing neurological handicap (mRS 0-2)
- major patient (≥ 18 years)
- affiliation to social security or benefiting through a third person
- free patient, without tutorship or curatorship or under judicial protection
- obtaining a signed informed consent by a relative (or the person of trust) after clear and fair information about the study.
- patients with non-severe SAHa (WFNS I, II and III)
- Occurrence of a major complication (haemorrhagic or ischaemic) documented during the procedure of securing the aneurysm and endangering the short-term vital prognosis
- heart failure requiring inotropic administration at the time of randomization
- ICHT at the time of randomisation (ICP> 25 mmHg for at least 20 min)
- known severe obstructive heart diseases
- flutter patient or atrial fibrillation
- hypotension and / or severe hypovolemia with hemodynamic instability
- septic shock
- acute / chronic renal insufficiency (Cl <50ml / min)
- major hydroelectrolytic disorders (hypokalemia <3 mmol / L)
- known hypersensitivity to milrinone or any of the excipients
- early limitation of life-sustaining care
- pregnancy, breastfeeding
- permanent contraindications to MRI
- participation in another clinical interventional study
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Milrinone Milrinone Injection "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. Standard Care Placebo 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.
- Primary Outcome Measures
Name Time Method volume of delayed cerebral ischemia lesions 1 month volume of DCI lesions measured on CT scan and validated by Magnetic Resonance Imaging (MRI) imaging at 1 month
- Secondary Outcome Measures
Name Time Method Number of days in intensive care 1 month Number of days in intensive care
Radiological parameters on CT at 1 month 1 month percentage of patients with DCI lesions
Number of days with mechanical ventilation 1 month Number of days with mechanical ventilation
neurological prognosis at 1 month: Rankin score 1 month evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
neurological prognosis at 3 month: Glasgow Outcome scale 3 month evaluated by the the Glasgow Outcome Scale (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3)
Mortality at 3 month 3 month Mortality at 3 month
neurological prognosis at 1 year: Glasgow Outcome scale 1 year evaluated by the Glasgow Outcome Scale (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3)
Evolution in intensive care: Neurological complications 1 1 month 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
Number and type of non-neurological complications 1 month non-neurological complications
neurological prognosis at 1 month: Glasgow Outcome scale 1 month evaluated by the Glasgow Outcome Scale (GOS) (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3).
neurological prognosis at 6 month: Glasgow Outcome scale 6 month evaluated by the the Glasgow Outcome Scale (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3)
Mortality at 1 month 1 month Mortality at 1 month
Mortality at 1 year 1 year Mortality at 1 year
Evolution in intensive care: Neurological complications 2 1 month total duration of episodes of PtiO2 \<20 mm Hg (moderate hypoxia) and \<15 mm Hg (severe hypoxia)
Evolution in intensive care: Neurological complications 3 1 month number of recourse to an endovascular treatment
Evolution in intensive care: Neurological complications 4 1 month intracranial hypertension in intensive care: ICP\> 20 mmHg for at least 15 minutes.
neurological prognosis at 3 month: Rankin score 3 month evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
neurological prognosis at 1 year: Rankin score 1 year evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
neurological prognosis at 6 month: Rankin score 6 month evaluated by the modified Rankin score (good prognosis: mRS 0, 1 and 2 / poor prognosis: mRS 3, 4 and 5)
Mortality at 6 month 6 month Mortality at 6 month
number of days of hospitalization 1 year number of days of hospitalization
Trial Locations
- Locations (5)
University Hospital Bordeaux
🇫🇷Bordeaux, France
CHUGA
🇫🇷Grenoble, France
University Hospital of La Réunion
🇫🇷La Réunion, France
HCL
🇫🇷Lyon, France
University Hospital of Toulouse
🇫🇷Toulouse, France