Cerebral Nimodipine Concentrations Following Oral, Intra-venous and Intra-arterial Administration

Determination of Cerebral Nimodipine Concentrations Following Oral, Intra-venous and Intra-arterial Administration - a Descriptive Pharmacokinetic/Pharmacodynamics Study

Nimodipine reduces the risk of poor outcome and delayed cerebral ischemia in patients suffering aneurysmal subarachnoid haemorrhage (SAH), but its mode of action is unknown. Its beneficial effect is assumed to be due its neuroprotective effects by reducing intracellular calcium and thereby cellular apoptosis, but higher concentrations might induce marked systemic hypotension, thereby inducing cerebral ischemia. Since several dosing regimes and routes of administration with inconclusive superiority exist and since the target site concentration of nimodipine - the unbound drug concentrations beyond the blood-brain barrier - is still not known, it is reasonable to measure nimodipine concentrations within the blood, cerebrospinal fluid (CSF) and interstitial brain tissue following oral, intra-venous and intra-arterial administration and correlate intra-arterial nimodipine administration to measures of cerebral metabolism and oxygenation.

Therefore, the investigators propose to investigate in 30 patients suffering severe aneurysmal SAH and requiring cerebral microdialysis for cerebral neurochemical monitoring:

• the ability of nimodipine to penetrate into the brain of neurointensive care patients by comparing exposure in brain, CSF and plasma, dependent on the route of administration (i.e. oral, intra-venous, and intra-arterial) and dosing intra-venously (0.5 - 2mg/h)
• the impact of orally, intra-venously, and intra-arterially delivered nimodipine on cerebral metabolism, i.e. lactate/pyruvate ratio, pbtO2 and transcranial doppler flow velocities
• the effect of oral and intra-venous nimodipine on systemic hemodynamic and cardiac parameters, using continuous Pulse Contour Cardiac Output (PiCCO) monitoring
• the penetration properties of ethanol - as an excipient of nimodipine infusion - into the brain by comparing exposure in brain, CSF and plasma and quantifying the neuronal exposure to alcohol dependent on blood levels

Study Overview

• Status: Recruiting
• Conditions: Subarachnoid Hemorrhage, Aneurysmal; Delayed Cerebral Ischemia; Vasospasm, Cerebral
• Intervention / Treatment: Drug: Nimodipine

• Study Type: Observational
• Enrollment (Estimated): 30

Contacts and Locations

• Study Contact: Name: Arthur Hosmann, MD PhD; Phone Number: 25650 +43/1/40400; Email: arthur.hosmann@meduniwien.ac.at

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Recruiting
    • Medical University of Vienna
    • Contact: Arthur Hosmann, MD PhD; Phone Number: 25650 +43/1/40400; Email: arthur.hosmann@meduniwien.ac.at

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 93 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients requiring intensive care and bedside cerebral microdialysis for cerebral neurochemical monitoring as standard care with a clinical indication for concomitant treatment with either oral, intra-venous or intra-arterial nimodipin

Description

Inclusion Criteria:

• patient age > 18 years
• aneurysmal subarachnoid hemorrhage
• sedated and mechanically ventilated
• application of brain microdialysis as standard care (due to the severity of subarachnoid haemorrhage or secondary deterioration)
• oral, intra-venous or intra-arterial administration of nimodipine due to clinical indication

Exclusion Criteria:

• contraindication for nimodipine
• no need of intensive care and bedside cerebral microdialysis as standard care
• any disease considered relevant for proper performance of the study or risks to the patient, at the discretion of the investigator

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
oral nimodipine; 60mg of nimodipine is orally administered every 4 h,	Drug: Nimodipine; If application of nimodipine is clinically indicated patients will be enrolled in the study protocol according to the inclusion and exclusion criteria. The clinically appropriate route of administration will be administered according to the recommended regimen of the study drug; i.e. within the first 10-14 days intra-venous infusion and thereafter oral administration. Intra-arterial infusion will be performed due to severe cerebral vasospasm with impending stroke.
intra-venous nimodipine; nimodipine is continuously administered intra-venously, starting with 0.5 mg/h on day 1 and increased every day for 0.5 mg/h to a maximum dose of 2.0mg/h on day 4	Drug: Nimodipine; If application of nimodipine is clinically indicated patients will be enrolled in the study protocol according to the inclusion and exclusion criteria. The clinically appropriate route of administration will be administered according to the recommended regimen of the study drug; i.e. within the first 10-14 days intra-venous infusion and thereafter oral administration. Intra-arterial infusion will be performed due to severe cerebral vasospasm with impending stroke.
intra-arterial nimodipine; during endovascular procedure 2mg of nimodipine is infused via a microcatheter into the internal carotid artery for 20 minutes	Drug: Nimodipine; If application of nimodipine is clinically indicated patients will be enrolled in the study protocol according to the inclusion and exclusion criteria. The clinically appropriate route of administration will be administered according to the recommended regimen of the study drug; i.e. within the first 10-14 days intra-venous infusion and thereafter oral administration. Intra-arterial infusion will be performed due to severe cerebral vasospasm with impending stroke.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cerebral nimodipine concentrations	Area under the concentration-time curve in brain, cerebrospinal fluid and serum, dependent on the route of administration (i.e. oral, intra-venous, and intra-arterial)	during the intervention
cerebral ethanol concentrations	Area under the concentration-time curve and maximum concentrations in brain tissue, CSF and blood after intravenous administration	during the intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cerebral lactate/pyruvate ratio (LPR)	determined by cerebral microdialysis	during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration
brain tissue oxygen tension (pbtO2)	determined by cerebral parenchymal probes	during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration
cardiac output	measured by Pulse Contour Cardiac Output (PiCCO) monitoring	during the intervention
fluid responsiveness	measured by Pulse Contour Cardiac Output (PiCCO) monitoring	during the intervention
extravascular lung water index	measured by Pulse Contour Cardiac Output (PiCCO) monitoring	during the intervention
systemic vascular resistance index	measured by Pulse Contour Cardiac Output (PiCCO) monitoring	during the intervention
transcranial doppler flow velocities	measured in the middle cerebral artery ipsilateral to the microdialysis probe	during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration
angiographic vasospasm	mild: vessel diameter from 60-99%, moderate: vessel diameter from 30-59%, severe: vessel diameter <30% of the physiological lumen	immediately after the intervention
cerebral perfusion pressure	measured continuously via intra-arterial and intracranial probes	during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration
incidence of delayed ischemic strokes	ischemic strokes on CT scans	3-21 days following subarachnoid haemorrhage

Collaborators and Investigators

• Sponsor: Medical University of Vienna
• Collaborators: University of Vienna; Austrian Science Fund (FWF)

Study record dates

Study Major Dates

• Study Start (Actual): November 25, 2020
• Primary Completion (Estimated): July 31, 2024
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: November 16, 2020
• First Submitted That Met QC Criteria: November 24, 2020
• First Posted (Actual): December 2, 2020

Study Record Updates

• Last Update Posted (Actual): October 19, 2023
• Last Update Submitted That Met QC Criteria: October 18, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• 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; Vasospasm, Intracranial; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Nimodipine
• Other Study ID Numbers: Brain_MD_Nimodipine

Drug and device information, study documents

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