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

Subarachnoid Hemorrhage, Aneurysmal Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04649398
• Other study ID #: Brain_MD_Nimodipine
• Status: Recruiting
• Start date: November 25, 2020
• Est. completion date: December 31, 2025

Study information

• Verified date: October 2023
• Source: Medical University of Vienna
• Contact: Arthur Hosmann, MD PhD
• Phone: +43/1/40400
• Email: arthur.hosmann[@]meduniwien.ac.at
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 31, 2025
• Est. primary completion date: July 31, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 95 Years

Eligibility

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

Related Conditions & MeSH terms

• Brain Ischemia
• Cerebral Infarction
• Delayed Cerebral Ischemia
• Hemorrhage
• Ischemia
• Subarachnoid Hemorrhage
• Subarachnoid Hemorrhage, Aneurysmal
• Vasospasm, Cerebral
• Vasospasm, Intracranial

Intervention

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.

Locations

Country	Name	City	State
Austria	Medical University of Vienna	Vienna

Sponsors (3)

Lead Sponsor	Collaborator
Medical University of Vienna	Austrian Science Fund (FWF), University of Vienna

Country where clinical trial is conducted

Austria, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	cardiac output	measured by Pulse Contour Cardiac Output (PiCCO) monitoring	during the intervention
Secondary	fluid responsiveness	measured by Pulse Contour Cardiac Output (PiCCO) monitoring	during the intervention
Secondary	extravascular lung water index	measured by Pulse Contour Cardiac Output (PiCCO) monitoring	during the intervention
Secondary	systemic vascular resistance index	measured by Pulse Contour Cardiac Output (PiCCO) monitoring	during the intervention
Secondary	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
Secondary	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
Secondary	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
Secondary	incidence of delayed ischemic strokes	ischemic strokes on CT scans	3-21 days following subarachnoid haemorrhage