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

NCT04649398 | Unknown FDA Drug

• 1 other identifier: Brain_MD_Nimodipine
• Study Type: observational
• Target: 30
• Locations: 1 country
• Sites: 1

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

Conditions

Subarachnoid Hemorrhage, Aneurysmal; Delayed Cerebral Ischemia; Vasospasm, Cerebral

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (10)

• cerebral lactate/pyruvate ratio (LPR)

  during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration

• brain tissue oxygen tension (pbtO2)

  during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration

• cardiac output

  during the intervention

• fluid responsiveness

  during the intervention

• extravascular lung water index

  during the intervention

Study Arms (3)

oral nimodipine

60mg of nimodipine is orally administered every 4 h,

Drug: Nimodipine

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

Interventions

Nimodipine DRUG

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; intra-venous nimodipine; oral nimodipine

Eligibility Criteria

• Age: 18 Years - 95 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Medical University of Vienna: lead
• University of Vienna: collaborator
• Austrian Science Fund (FWF): collaborator

Study Sites (1)

Medical University of Vienna

Vienna, 1090, Austria

RECRUITING

Biospecimen

Retention: SAMPLES WITHOUT DNA

plasma, cerebrospinal fluid, microdialysate

MeSH Terms

Conditions

Subarachnoid Hemorrhage; Vasospasm, Intracranial

Interventions

Nimodipine

Condition Hierarchy (Ancestors)

Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nicotinic Acids

Central Study Contacts

Arthur Hosmann, MD PhD

CONTACT

+43/1/40400; arthur.hosmann@meduniwien.ac.at

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: November 16, 2020
• First Posted: December 2, 2020
• Study Start: November 25, 2020
• Primary Completion: July 31, 2024
• Study Completion: December 31, 2025
• Last Updated: October 19, 2023

Record last verified: 2023-10

Locations

AU (1)