Clinical trial NCT04649398: Cerebral Nimodipine Concentrations Following Oral, Intra-venous and Intra-arterial Administration
Official title: Determination of Cerebral Nimodipine Concentrations Following Oral, Intra-venous and Intra-arterial Administration - a Descriptive Pharmacokinetic/Pharmacodynamics Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Subarachnoid Hemorrhage, Aneurysmal
Delayed Cerebral Ischemia
Vasospasm, Cerebral
Lead sponsor: Medical University of Vienna
Sponsor class: OTHER
Collaborators: name: University of Vienna
name: Austrian Science Fund (FWF)
First posted: 2020-12-02
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 95
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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

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


Eligibility criteria: 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

Primary outcomes:
measure: cerebral nimodipine concentrations
timeFrame: during the intervention
measure: cerebral ethanol concentrations
timeFrame: during the intervention
Secondary outcomes:
measure: cerebral lactate/pyruvate ratio (LPR)
timeFrame: during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration
measure: brain tissue oxygen tension (pbtO2)
timeFrame: during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration
measure: cardiac output
timeFrame: during the intervention
measure: fluid responsiveness
timeFrame: during the intervention
measure: extravascular lung water index
timeFrame: during the intervention
measure: systemic vascular resistance index
timeFrame: during the intervention
measure: transcranial doppler flow velocities
timeFrame: during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration
measure: angiographic vasospasm
timeFrame: immediately after the intervention
measure: cerebral perfusion pressure
timeFrame: during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration
measure: incidence of delayed ischemic strokes
timeFrame: 3-21 days following subarachnoid haemorrhage
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Medical University of Vienna
Study officials:
References: