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

Sponsor

Medical University of Vienna (Other)

Overall Status

Recruiting

CT.gov ID

NCT04649398

Collaborator

University of Vienna (Other), Austrian Science Fund (FWF) (Other)

Enrollment

Location

61.2

Anticipated Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Condition or Disease	Intervention/Treatment	Phase
Subarachnoid Hemorrhage, Aneurysmal Delayed Cerebral Ischemia Vasospasm, Cerebral	Drug: Nimodipine

Study Design

Study Type:

Observational

Anticipated Enrollment :

30 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

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

Actual Study Start Date :

Nov 25, 2020

Anticipated Primary Completion Date :

Jul 31, 2023

Anticipated Study Completion Date :

Dec 31, 2025

Arms and Interventions

Arm	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.

Arm

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

intra-arterial nimodipine

during endovascular procedure 2mg of nimodipine is infused via a microcatheter into the internal carotid artery for 20 minutes

Drug: Nimodipine

Outcome Measures

Primary Outcome Measures

cerebral nimodipine concentrations [during the intervention]
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)
cerebral ethanol concentrations [during the intervention]
Area under the concentration-time curve and maximum concentrations in brain tissue, CSF and blood after intravenous administration

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 95 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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