Cerebral Hemodynamic Optimization by Milrinone to Prevent Delayed Cerebral Ischemia

Phase 2RecruitingNCT04282629

University Hospital, Toulouse234 enrolled

Overview

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.

Study Type

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * 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. Exclusion Criteria: * 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

Locations (5)

University Hospital Bordeaux

Bordeaux, France

ACTIVE_NOT_RECRUITING

CHUGA

Grenoble, France

ACTIVE_NOT_RECRUITING

University Hospital of La Réunion

La Réunion, France

RECRUITING

HCL

Lyon, France

RECRUITING

University Hospital of Toulouse

Toulouse, France

RECRUITING

Outcomes

Primary Outcomes

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

Secondary Outcomes

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

Time frame: 1 month

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

Time frame: 1 month

Mortality at 3 month

Time frame: 3 month

Mortality at 6 month

Time frame: 6 month

Mortality at 1 year

Time frame: 1 year

number of days of hospitalization

Time frame: 1 year

Cerebral Hemodynamic Optimization by Milrinone to Prevent Delayed Cerebral Ischemia

Overview

Conditions

Interventions

Eligibility

Locations (5)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts