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
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
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 |
Country | Name | City | State |
---|---|---|---|
Austria | Medical University of Vienna | Vienna |
Lead Sponsor | Collaborator |
---|---|
Medical University of Vienna | Austrian Science Fund (FWF), University of Vienna |
Austria,
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 |
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