Determination of Cerebral Nimodipine Concentrations Following Oral, Intra-venous and Intra-arterial Administration - a Descriptive Pharmacokinetic/Pharmacodynamics Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 1
- 主要终点
- cerebral nimodipine concentrations
研究概览
简要总结
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
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 95 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
oral nimodipine
60mg of nimodipine is orally administered every 4 h,
干预措施: Nimodipine (Drug)
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
干预措施: Nimodipine (Drug)
intra-arterial nimodipine
during endovascular procedure 2mg of nimodipine is infused via a microcatheter into the internal carotid artery for 20 minutes
干预措施: Nimodipine (Drug)
结局指标
主要结局
cerebral nimodipine concentrations
时间窗: 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
时间窗: during the intervention
Area under the concentration-time curve and maximum concentrations in brain tissue, CSF and blood after intravenous administration
次要结局
- brain tissue oxygen tension (pbtO2)(during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration)
- extravascular lung water index(during the intervention)
- transcranial doppler flow velocities(during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration)
- cerebral perfusion pressure(during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration)
- fluid responsiveness(during the intervention)
- cerebral lactate/pyruvate ratio (LPR)(during the intervention for oral and intravenous administered nimodipine, 12 hours after the intervention for intra-arterial nimodipine administration)
- angiographic vasospasm(immediately after the intervention)
- cardiac output(during the intervention)
- systemic vascular resistance index(during the intervention)
- incidence of delayed ischemic strokes(3-21 days following subarachnoid haemorrhage)
研究者
Arthur Hosmann
Principal Investigator
Medical University of Vienna