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

Study Overview
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Brief Summary
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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

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

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

Intervention / Treatment
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* Drug: Nimodipine


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| oral nimodipine<br>60mg of nimodipine is orally administered every 4 h, | Drug: Nimodipine<br>* 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.<br>|
| intra-venous nimodipine<br>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<br>* 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.<br>|
| intra-arterial nimodipine<br>during endovascular procedure 2mg of nimodipine is infused via a microcatheter into the internal carotid artery for 20 minutes | Drug: Nimodipine<br>* 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.<br>|

What is the study measuring?
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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 |