Cerebral Hemodynamic Optimization by Milrinone to Prevent Delayed Cerebral Ischemia

Aneurysmal Subarachnoid Hemorrhage Clinical Trial

— OPTIMIL  

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04282629
• Other study ID #: RC31/18/0472
• Status: Recruiting
• Phase: Phase 2
• Start date: July 25, 2021
• Est. completion date: July 2025

Study information

• Verified date: March 2023
• Source: University Hospital, Toulouse
• Contact: Thomas Geeraerts, MD PhD
• Phone: 05 61 77 21 00
• Email: geeraerts.t[@]chu-toulouse.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 234
• Est. completion date: July 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Aneurysmal Subarachnoid Hemorrhage
• Brain Ischemia
• Cerebral Infarction
• Hemorrhage
• Ischemia
• Subarachnoid Hemorrhage

Intervention

Drug:
• Milrinone Injection
administration of milrinone (0.75 µg / kg / min, intravenous) from Day 4 to Day 14

Other:
• Placebo
administration of placebo (intravenous glucose 5%) from Day 4 to Day 14

Locations

Country	Name	City	State
France	University Hospital Bordeaux	Bordeaux
France	CHUGA	Grenoble
France	University Hospital of La Réunion	La Réunion
France	HCL	Lyon
France	University Hospital of Toulouse	Toulouse

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Toulouse

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	1 month
Secondary	Radiological parameters on CT at 1 month	percentage of patients with DCI lesions	1 month
Secondary	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	1 month
Secondary	Evolution in intensive care: Neurological complications 2	total duration of episodes of PtiO2 <20 mm Hg (moderate hypoxia) and <15 mm Hg (severe hypoxia)	1 month
Secondary	Evolution in intensive care: Neurological complications 3	number of recourse to an endovascular treatment	1 month
Secondary	Evolution in intensive care: Neurological complications 4	intracranial hypertension in intensive care: ICP> 20 mmHg for at least 15 minutes.	1 month
Secondary	Number and type of non-neurological complications	non-neurological complications	1 month
Secondary	Number of days in intensive care	Number of days in intensive care	1 month
Secondary	Number of days with mechanical ventilation	Number of days with mechanical ventilation	1 month
Secondary	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)	1 month
Secondary	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).	1 month
Secondary	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)	3 month
Secondary	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)	3 month
Secondary	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)	6 month
Secondary	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)	6 month
Secondary	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)	1 year
Secondary	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)	1 year
Secondary	Mortality at 1 month	Mortality at 1 month	1 month
Secondary	Mortality at 3 month	Mortality at 3 month	3 month
Secondary	Mortality at 6 month	Mortality at 6 month	6 month
Secondary	Mortality at 1 year	Mortality at 1 year	1 year
Secondary	number of days of hospitalization	number of days of hospitalization	1 year