Delayed Cerebral Ischemia, Subarachnoid Hemorrhage, Aneurysmal, Vasospasm, Cerebral
Conditions
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
Interventions
DRUGNimodipine
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.
Sponsors
University of Vienna
Austrian Science Fund (FWF)
Medical University of Vienna
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 95 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 |
| 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 |
| 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 |
Countries
Austria
Contacts
Primary ContactArthur Hosmann, MD PhD
Outcome results
None listed