Cerebral Hemodynamic Optimization by Milrinone to Prevent Delayed Cerebral Ischemia (OPTIMIL)

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

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.

Study Overview

• Status: Recruiting
• Conditions: Aneurysmal Subarachnoid Hemorrhage
• Intervention / Treatment: Drug: Milrinone Injection; Other: Placebo

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 Type: Interventional
• Enrollment (Estimated): 234
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Thomas Geeraerts, MD PhD; Phone Number: 33 056-177-2100; Email: geeraerts.t@chu-toulouse.fr
• Study Contact Backup: Name: Nadera AINAOUI; Phone Number: 33 056-177-2498; Email: nadera.ainaoui@inserm.fr

Study Locations

• France
  • Bordeaux, France
    • Active, not recruiting
    • University Hospital Bordeaux
  • Grenoble, France
    • Active, not recruiting
    • CHUGA
  • La Réunion, France
    • Recruiting
    • University Hospital of La Réunion
    • Contact: Romain ASMOLOV, MD
  • Lyon, France
    • Recruiting
    • HCL
    • Contact: Baptiste BALANCA, MD
    • Contact: Baptiste BALANCA
  • Toulouse, France
    • Recruiting
    • University Hospital of Toulouse
    • Contact: GEERAERTS Thomas, MD
    • Contact: Thomas GEERAERTS, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality at 1 year	Mortality at 1 year	1 year
Radiological parameters on CT at 1 month	percentage of patients with DCI lesions	1 month
Evolution in intensive care: Neurological complications 3	number of recourse to an endovascular treatment	1 month
Evolution in intensive care: Neurological complications 4	intracranial hypertension in intensive care: ICP> 20 mmHg for at least 15 minutes.	1 month
Number and type of non-neurological complications	non-neurological complications	1 month
Number of days in intensive care	Number of days in intensive care	1 month
Number of days with mechanical ventilation	Number of days with mechanical ventilation	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)	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)	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)	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)	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)	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)	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)	1 year
Mortality at 1 month	Mortality at 1 month	1 month
Mortality at 3 month	Mortality at 3 month	3 month
Mortality at 6 month	Mortality at 6 month	6 month
number of days of hospitalization	number of days of hospitalization	1 year
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
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
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

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Thomas Geeraerts, MD PhD, University Hospital, Toulouse

Study record dates

Study Major Dates

• Study Start (Actual): July 25, 2021
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: February 17, 2020
• First Submitted That Met QC Criteria: February 20, 2020
• First Posted (Actual): February 25, 2020

Study Record Updates

• Last Update Posted (Actual): September 25, 2024
• Last Update Submitted That Met QC Criteria: September 23, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Vasospasm; Milrinone; Delayed Cerebral Ischemia
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Infarction; Stroke; Brain Infarction; Intracranial Hemorrhages; Brain Ischemia; Ischemia; Hemorrhage; Cerebral Infarction; Subarachnoid Hemorrhage; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Cardiotonic Agents; Phosphodiesterase Inhibitors; Phosphodiesterase 3 Inhibitors; Milrinone
• Other Study ID Numbers: RC31/18/0472

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No