Systemic and Cerebral Concentration of Nimodipine During Established and Experimental Vasospasm Treatment.
BACKGROUND
Oral nimodipine is an established prophylactic agent for cerebral vasospasm after subarachnoid hemorrhage (SAH). In highly selected cases, intra-arterial (IA) or intravenous (IV) application of nimodipine may be considered; however, the optimum dosage and modality of application remain a matter of debate. The purpose of this investigation is analysis of nimodipine concentration in serum, cerebrospinal fluid, and cerebral microdialysate in the context of currently effective dose and route of application (oral, IA, IV).


METHODS
We prospectively collected 156 samples from 37 patients treated for aneurysmal SAH from May 2014 to July 2015. Treatment groups were stratified according to modality of application and low-dose or high-dose treatment. At time of sampling, current dose and modality of application effectively sustained cerebral perfusion as documented by common diagnostics. Samples were analyzed for nimodipine concentration via high-performance liquid chromatography and tandem mass spectrometry.


RESULTS
In most cases (94.3%), nimodipine remained below the limit of quantification (0.5 ng/mL) within the brain (microdialysis, cerebrospinal fluid), even during targeted, local application (IA nimodipine). The median serum concentration for all treatment groups was 17.3 ng/mL. Modality of application (oral, IA, IV) was not associated with significant differences in serum concentrations (P = 0.712), even after stratification for dosage (P = 0.371), implying a comparable systemic distribution, if not efficacy.


CONCLUSIONS
Nimodipine does not accumulate sufficiently within the target organ for treatment monitoring. Comparable systemic concentrations can be observed irrespective of application modality and dosing. Future studies will clarify the role of efficacy-driven treatment algorithms, in which lowest dose and least invasive mode of application still effective should be identified.
Department of Neurosurgery, RWTH Aachen University, Aachen, Germany.
Walid
W
Albanna
Department of Neurosurgery, RWTH Aachen University, Aachen, Germany.
Miriam
M
Weiss
Department of Neurosurgery, RWTH Aachen University, Aachen, Germany.
Catharina
C
Conzen
Department of Neurosurgery, RWTH Aachen University, Aachen, Germany.
Hans
H
Clusmann
Department of Neurophysiology, University of Cologne, Cologne, Germany.
Toni
T
Schneider
Analytisches Zentrum Biopharm GmbH, Berlin, Germany.
Martin
M
Reinsch
Department of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, Aachen, Germany.
Marguerite
M
Müller
Department of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, Aachen, Germany.
Martin
M
Wiesmann
Department of Neurosurgery, RWTH Aachen University, Aachen, Germany.
Anke
A
Höllig
Department of Neurosurgery, RWTH Aachen University, Aachen, Germany. Electronic address: gerrit.schubert@me.com.
Gerrit Alexander
GA
Schubert
D000368:Aged; D002540:Cerebral Cortex / Q000378:metabolism*; D002853:Chromatography, Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009553:Nimodipine / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D013345:Subarachnoid Hemorrhage / Q000150:complications; D053719:Tandem Mass Spectrometry; D014665:Vasodilator Agents / Q000097:blood / Q000134:cerebrospinal fluid / Q000627:therapeutic use; D020301:Vasospasm, Intracranial / Q000188:drug therapy* / Q000209:etiology
D014665:Vasodilator Agents; D009553:Nimodipine
Cerebral microdialysis; Delayed cerebral ischemia; Nimodipine; Subarachnoid hemorrhage; Vasospasm