OPTIMIL: Cerebral Hemodynamic Optimization by Milrinone to Prevent Delayed Cerebral Ischemia

Sponsor

University Hospital, Toulouse (Other)

Overall Status

Recruiting

CT.gov ID

NCT04282629

Collaborator

(none)

234

Enrollment

Locations

Arms

35.2

Anticipated Duration (Months)

117

Patients Per Site

3.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Aneurysmal Subarachnoid Hemorrhage	Drug: Milrinone Injection Other: Placebo	Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

234 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

2 ARMS: milrinone versus placebo2 ARMS: milrinone versus placebo

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Efficacy of 10 Days Intravenous Milrinone Treatment to Optimize Cerebral Hemodynamic and Prevent Delayed Cerebral Ischemia (DCI) in Patients With Severe Subarachnoid Hemorrhage Due to Intracranial Aneurysm Rupture

Actual Study Start Date :

Jul 25, 2021

Anticipated Primary Completion Date :

Jul 1, 2024

Anticipated Study Completion Date :

Jul 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Milrinone "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 administration of milrinone (0.75 μg / kg / min, intravenous) from Day 4 to Day 14
Placebo Comparator: Standard Care 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 placebo (intravenous glucose 5%) from Day 4 to Day 14

Arm

Intervention/Treatment

Experimental: Milrinone

"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

administration of milrinone (0.75 μg / kg / min, intravenous) from Day 4 to Day 14

Placebo Comparator: Standard Care

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 placebo (intravenous glucose 5%) from Day 4 to Day 14

Outcome Measures

Primary Outcome Measures

volume of delayed cerebral ischemia lesions [1 month]
volume of DCI lesions measured on CT scan and validated by RMI imaging at 1 month

Secondary Outcome Measures

Radiological parameters on CT at 1 month [1 month]
percentage of patients with DCI lesions
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 <15mmHg (severe hypoxia) for at least 15 minutes
Evolution in intensive care: Neurological complications 2 [1 month]
total duration of episodes of PtiO2 <20mmHg (moderate hypoxia) and <15mmHg (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.
Number and type of non-neurological complications [1 month]
non-neurological complications
Number of days in intensive care [1 month]
Number of days in intensive care
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 1 month: Glasgow Outcome scale [1 month]
evaluated by the Glasgow Outcome Scale (good prognosis: GOS 4 and 5 / poor prognosis: GOS 1, 2 and 3).
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 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)
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)
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)
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 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)
Mortality at 1 month [1 month]
Mortality at 1 month
Mortality at 3 month [3 month]
Mortality at 3 month
Mortality at 6 month [6 month]
Mortality at 6 month
Mortality at 1 year [1 year]
Mortality at 1 year
number of days of hospitalization [1 year]
number of days of hospitalization

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

patients with severe SAHa (WFNS IV and V,) whose neurological examination is impossible because of coma 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.

Exclusion Criteria:

patients with non-severe SAHa (WFNS I, II and III)
Occurrence of a documented ischemic complication during the procedure of aneurysm treatment: transient or permanent arterial occlusion, visualization of a thrombus, and dissection of an axis requiring stenting.
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
pregnancy, breastfeeding
permanent contraindications to MRI
participation in another clinical study