Professional Documents
Culture Documents
Walid Albanna, MD, Miriam Weiss, Catharina Conzen, MD, Hans Clusmann, MD,
Toni Schneider, Martin Reinsch, Marguerite Müller, MD, Martin Wiesmann, MD, Anke
Höllig, MD, Gerrit Alexander Schubert, MD
PII: S1878-8750(17)30385-6
DOI: 10.1016/j.wneu.2017.03.062
Reference: WNEU 5431
Please cite this article as: Albanna W, Weiss M, Conzen C, Clusmann H, Schneider T, Reinsch M,
Müller M, Wiesmann M, Höllig A, Schubert GA, Systemic and Cerebral Concentration of Nimodipine
During Established and Experimental Vasospasm Treatment, World Neurosurgery (2017), doi: 10.1016/
j.wneu.2017.03.062.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
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Systemic and cerebral concentration of nimodipine during established and experimental vasospasm
treatment
Walid Albanna, MD1*; Miriam Weiss1*; Catharina Conzen, MD1; Hans Clusmann, MD1; Toni Schneider2;
Martin Reinsch3; Marguerite Müller, MD4; Martin Wiesmann, MD4; Anke Höllig, MD1*; Gerrit Alexander
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Schubert, MD1*
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Department of Neurosurgery, RWTH Aachen University, Germany
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Department of Neurophysiology, University of Cologne, Germany
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Analytisches Zentrum Biopharm GmbH, Berlin, Germany
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Department of Diagnostic and Interventional Neuroradiology, RWTH Aachen University, Germany
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Corresponding author
Gerrit Alexander Schubert, MD
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Department of Neurosurgery
RWTH Aachen University
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Pauwelsstr. 30
52074 Aachen, Germany
gerrit.schubert@me.com
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ABSTRACT
Background: Oral nimodipine is an established prophylactic agent for cerebral vasospasm after
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subarachnoid hemorrhage (SAH). In highly selected cases, intraarterial or intravenous application of
nimodipine may be considered; optimum dosage and modality of application, however, remain a matter of
debate. Analysis of nimodipine concentration in serum, CSF and cerebral microdialysate in context of
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currently effective dose and route of application (oral, IA, IV) is the purpose of this investigation.
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Methods: We prospectively collected 156 samples from 37 patients treated for aneurysmal
subarachnoid hemorrhage from 05/2014 to 07/2015. Treatment groups were stratified according to
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modality of application and low 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
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analysed for nimodipine concentration via HPLC and tandem mass spectrometry.
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Results: In the majority of cases (94.3%), nimodipine remained below the limit of quantification
(0.5ng/ml) within the brain (microdialysis, CSF), even during targeted, local application (intraarterial
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nimodipine). Median serum concentration for all treatment groups was 17.3ng/ml. Modality of application
(oral, IA, IV) was not associated with significant differences in serum concentrations (p=0.712), even after
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stratification for dosage (p=0.371), implying a comparable systemic distribution, if not efficacy.
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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, where lowest dose and
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Introduction:
Despite ongoing research efforts in the field of aneurysmal subarachnoid hemorrhage (aSAH) a
major proportion of patients still faces unfavorable outcome with abiding neurological deficits and high
dependency.1 While elements of early brain injury themselves may cause irreversible damage, they also
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predestine tissue to an increased vulnerability to subsequent complications.2 Patients surviving the initial
bleeding may develop delayed cerebral ischemia (DCI) manifesting in new clinical or functional
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deterioration.3 Neurological impairment owing to DCI may result in individual permanent morbidity,
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Trials investigating the pharmacological prevention of vasospasm and DCI including numerous
agents identified oral nimodipine, a selective calcium-channel blocker, as the only agent capable of
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increasing vessel diameter, reducing ischemic deficits, infarction and the odds of poor outcome.5 Standard
preventive treatment consists of 6 x 60 mg enteral nimodipine per day.6,7 While the predominant effect is
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supposed to be cerebral vasodilation, neuroprotective properties exerted within the brain parenchyma itself
There are, however, cases refractory to conservative treatment (oral nimodipine, induced
The efficacy of intravenous nimodipine is unproven and possibly limited due to its systemic effect,
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investigating the efficacy of the different delivery methods have yielded no beneficial advantage of
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intravenous nimodipine over oral administration, but due to the lack of established therapy protocols it is
being used as a common adjunct treatment option in multiple centers.10 Higher local dosage is supposedly
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reached by intraarterial application via microcatheter allowing for direct administration into the targeted
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vascular territory. Application via an indwelling microcatheter can be associated with thromboembolism or
dissection.11 Results regarding efficacy show an improvement of clinical and radiological status, yet the
overall benefit considering ultimate systemic distribution and side effects remains debatable.12
Looking beyond delivery methods, timing of parenteral application and optimum dosage are
currently merely based on empiric knowledge, leading to high inter-hospital differences with only marginal
certainty about the most favorable treatment pattern.13 It seems reasonable that any observed effect might
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be dependent on the supply of nimodipine to the affected area.14 However, analyses investigating local
concentrations are scarce and not easily comparable due to different application methods and dosing prior
to analysis.
This study aims to determine systemic (serum) and local (CSF, microdialysate) quantities of
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nimodipine dependent on application modality and dosage that, at the given time, were deemed sufficient
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Materials and methods:
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We prospectively recruited patients treated at our institution between April 2014 and July 2015
with verified aneurysmal subarachnoid hemorrhage (aSAH). Approval was given by the local ethics
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committee (EK 062/14), and written consent was obtained from all participants or authorized
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representatives. Demographic and clinical data were recorded during hospitalization, and clinical outcome
Awake patients were routinely monitored for DCI as documented by a new neurological deficit. In
sedated or comatose patients, invasive neuromonitoring for cerebral oxygenation and metabolism including
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Stockholm, Sweden) was performed within the aneurysm-carrying territory according to recent consensus
recommendations.15 Microdialysis probes were perfused at 0.3µl/min with standard perfusion fluid (NaCl
147 mmol/l, KCl 2,7 mmol/l, CaCl2 1,2 mmol/l, MgCl2 0,85 mmol/; µdialysis, Stockholm, Sweden),
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samples were collected at a minimum of 3-hour intervals and analyzed on site for glucose, lactate, pyruvate,
glutamate and glycerol (Iscusflex, µdialysis, Stockholm, Sweden) or stored for later off-line analysis.16
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Daily screening included transcranial Doppler examinations and, if indicated, perfusion-CT and cerebral
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angiography. In accordance with a standardized local treatment protocol all patients received enteral
nimodipine prophylactically,7 and, as the case may be, systemic hypertension if DCI was suspected. If signs
of persistent clinical or functional deterioration were detected despite maximized conservative therapy,
switchover from oral to intraarterial or intravenous nimodipine was considered as a measure of last resort
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As part of our prospective biomarker data bank collection, all patients with SAH are routinely sampled as
follows: a total of 10 serum samples are collected from every patient between day 1-21 (day 1-4: daily; day
5-14: every second day; day 15-21: every third day). If available, 1ml CSF from the proximal access point
of a ventricular drain (same sampling scheme) and cerebral microdialysis vials (every 6 hours daily) were
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synchronously collected. Microdialysis samples were included only after a stabilization period of 24 hours
after catheter insertion and when collected from the same day as respective serum and CSF samples. Vials
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were retained in designated storage racks to avoid evaporation. Blood samples were centrifuged
immediately after removal and serum and CSF were pipetted into suitable polypropylene cryotubes (VWR
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International GmbH, Darmstadt, Germany). All receptacles were permanently deep-frozen at -80 °C (Ultra-
low Temperature Freezer, Panasonic Biomedical, Etten-Leur, Netherlands). Protection from light exposure
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during transports and storage was ensured and only interrupted during analysis. For quantitative analysis,
samples were analyzed at a GLP certified laboratory with established chromatography procedures (AZ
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Biopharm, Berlin, Germany). Absolute nimodipine concentrations were determined via high performance
liquid chromatography (HPLC) and tandem mass spectrometry,17 LC-MS/MS, (C18 PursuitTM 150 x 2.0
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mm, Varian GmbH, Germany; API 4000TM System, AB Sciex, Germany). The method was
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characterized with regard to linearity, matrix effects, precision and validity in multiple previous
studies using calibrators and QC “quality control” samples for several matrices.18
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The technically predetermined lower limit of quantification (LLOQ) for serum was 0.1 ng/ml and
0.5 ng/ml for CSF and microdialysate, respectively. Deuterated and thus structurally different nimodipine
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was added to all samples prior to analysis for internal standardization and optimization of validity.
Nimodipine in serum samples was evaluated based on protein precipitation; CSF and microdialysates were
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assayed directly.
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For comparative analysis of application methods, patients were assigned to one of four groups (control, oral
nimodipine, intraarterial nimodipine and intravenous nimodipine). For inclusion into the control group,
termination of nimodipine treatment ≥ 48hrs was required. The remaining three treatment groups were
stratified as low dose or high dose treatment: PO1 (low dose oral nimodipine: 180mg/d, mean
109.9±18.6µg/kg/h), PO2 (high dose oral nimodipine: 360mg/d, mean 214.0±42.4 µg/kg/h), IA1 and IV1
(low dose continuous intraarterial or intravenous nimodipine: <15µg/kg/h, mean IA1 10.4±3.7µg/kg/h,
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mean IV1 12.2±3.1 µg/kg/h) and IA2 and IV2 (high dose continuous intraarterial or intravenous
nimodipine: ≥15µg/kg/h, mean IA2 28.5±11.5 µg/kg/h, mean IV2 23.5±9.1 µg/kg/h).
Samples were considered eligible for group PO1 and PO2 if oral administration had been started at
least 48 hours prior to sample retrieval. All parenteral groups had received nimodipine for a minimum of 6
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hours at a constant rate and dose before sampling, but enteral application had to have been terminated for at
least 48 hours prior. Patients in the control group were not given any nimodipine or previous application
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had been terminated for at least 48 hours. Patients with hepatic or kidney disease (total bilirubin
>51.3µmol/L, plasma creatinine ≥ 22.1µmol/L) were excluded from the study. Catecholamine requirements
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during nimodipine application were also recorded to determine potential hemodynamic influence of the
application modality.
Statistical analysis:
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Quantitative normally distributed data are presented as mean ± standard deviation (SD) and as
percentage. Student t-test was used for comparison of quantitative parameters in case of normal distribution
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or, if not applicable, Mann-Whitney U-test. Comparison of test groups was performed by analysis of
variance (ANOVA) or Kruskal-Wallis test, respectively. Analysis of covariance (ANCOVA) was used to
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evaluate the effect of administered nimodipine on the measured nimodipine level. For prognostication of
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concentration out of administered dose, a tailored model of regression without intercept was fitted for each
group. All analyses were performed with IBM® SPSS® Statistics V22.0 (IBM, Chicago, Illinois, USA).
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Statistical significance was set at p<0.05, statistical results with p<0.1 were accepted as a trend.
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Results:
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Thirty-seven consecutively recruited patients were included into this prospective observational
study. Demographic and clinical data are shown in Table 1. We collected a total of 156 samples
appertaining to the test groups as follows: PO, n=65; IA, n=41; IV, n=15; control, n=35 (Table 2).
Nimodipine levels in all groups were independent from gender (p=0.573), age (p=0.396) and treatment
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In 94.3 % of the microdialysis and CSF samples, the concentration of nimodipine within the brain
(CSF, brain parenchyma) remained below the limit of quantification (0.5 ng/ml). Hence, further analysis
focused on the analysis of nimodipine in serum samples. Regression analysis determined, that nimodipine
concentration was highly predictable for intraarterial and intravenous administration (Figure 1A & 1B)
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while oral application was associated with a higher variability, resulting only in a very weak correlation of
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Application modality (PO, IA and IV) did not result in different serum concentrations of
nimodipine (p = 0.712), even after stratification for low- and high-dose treatment (p = 0.371) (Table 3). For
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enteral application, comparable nimodipine levels were observed, irrespective of dosage (PO1: 17.3±28.2
ng/ml; PO2: 20.7±28.2 ng/ml; p = 0.851). For intraarterial and intravenous nimodipine application, a more
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pronounced increase in serum concentration for higher doses was observed, but this failed to reach
statistical significance in both modalities (IA1 19.8±3.1ng/ml, IA2 25.8±7.6ng/ml; p = 0.794; IV1 15.1±5.1
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ng/ml, IV2 22.9±2.5 ng/ml; p = 0.841). Fit plot regression analysis showed strong correlation of parenteral
dose and concentration (IA: R2=86.2%; IV: R2=94.3%), but only weak correlation for oral nimodipine
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When comparing catecholamine support to maintain a mean arterial pressure (MAP) greater than
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100mmHg within the critical phase (day 7-14; IA: 117.3±9.9mmHg, IV: 113.3±8.9mmHg, p=0.599), need
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for circulatory support as estimated by noradrenaline requirement was comparable (IA 0.93±0.74µg/kg
BW/h, IV: 0.52±0.15µg/kg BW/h, p=0.337). When including control patients (MAP 116.8±8.1) and PO
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patients (MAP 122.3±2.7) within the same time frame, a trend towards lower catecholamine requirements
was observed (control 0.25±0.24 µg/kg BW/h; PO 0.18±0.32µg/kg BW/h; p=0.054), while direct
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intergroup comparison corrected for multiple comparisons did not show any significant differences.
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Discussion:
refractory cerebral hypoperfusion, endovascular rescue therapies such as parenteral spasmolytic therapies
may be considered as measures of last resort,16 assuming that altering treatment modality as well as dosage
will lead to a different impact on the patient's clinical course. As an estimate of any true impact on clinical
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outcome is exceedingly difficult to obtain due to the large heterogeneity of clinical course, it was the aim of
this study to quantify nimodipine distribution in relation to available treatment options as a first step of
objectification.
The literature contains little information regarding the presence of nimodipine in neural tissue; in
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fact, about 98% nimodipine is bound to plasma proteins.20 Thus, it may be assumed that nimodipine in
cerebrospinal fluid and vestibular nerve samples may have been absorbed by membrane structures or
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neuroglia, in which it is known to be enriched.21 In addition, nimodipine therapy is limited by its high first-
pass effect in the liver, resulting in comparatively low oral bioavailability and poor brain entry.22 These
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characteristics may be part of the reason why nimodipine levels in our CSF and microdialysate samples
remained below the detection limit. If nimodipine was present below quantification limit in our samples, it
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remains equivocal if such small amounts could reach any relevant effect.
Most importantly for its systemic distribution, we only observed small differences in nimodipine
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serum concentration despite the variation in application modalities and dosage. The dosage of oral
nimodipine is tailored to either 180mg or 360mg/day based on individual compatibility, generally assuming
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that the higher dose results in a doubled or at least increased serum concentration. For higher dosage, we
observed an increase in serum level of nimodipine, but this failed to reach statistical significance; this
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finding was supported by a weak correlation during regression analysis, possibly explained by variable
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capacity for nimodipine absorption. Our findings imply that a lower dose may at least be sufficient to reach
comparable systemic concentration, while the optimum systemic concentration (as low as possible, but still
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Intraarterial application delivers higher concentrations to the target vessel while reducing total
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dose and systemic complications. Despite higher concentrations in local, downstream compartments of
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interest (CSF, parenchyma), nimodipine could not be detected in CSF or parenchyma. However,
nimodipine is highly lipophilic and accumulates in lipid rich neuroglia. A higher local supply of
nimodipine may predominantly be taken up by vessel walls or immediately adjacent tissue; if accumulation
is locally restricted, it may evade detection by CSF analysis or microdialysis, the latter potentially being
positioned few centimeters distant to any larger vessel. Assessment of local serum concentration
downstream to the microcatheter was not part of this analysis, but a previously published model of
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systemic blood nimodipine as determined by our analysis by 400%.23 It is plausible to assume an additional
neuroprotective effect of intraarterial nimodipine as suggested recently,8 directly on the vessel wall or
immediately adjacent neuroglia, and this effect would be triggered independently from a systemic
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accumulation. This hypothesis is supported by recent studies documenting significant functional
improvements with intraarterial application after oral treatment has failed.24 The question remains whether
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the dosage of continuous IA nimodipine treatment could be decreased significantly and still exert the
desired neuroprotective and locally vasodilatory effect with significantly less systemic accumulation.
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Beyond the hypothetical neuroprotective value and in view of the inherent risks associated with local
delivery methods, the superiority of intraarterial treatment as a rescue therapy has to be evaluated critically
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and may not always be given to the expected extent.
Intravenous nimodipine is neither compatible with vasopressor therapy beyond a certain degree
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nor specifically reaches the target vessel; it is mostly used outside standard treatment protocols.25
precluded for other reasons. A higher correlation of administered dose and serum concentration was
considered likely and was confirmed by the fit plots, allowing a more precise estimate of nimodipine
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concentration for a specific dose, while concentration after oral application of nimodipine showed a high
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variability without clear correlation. In view of the observed correlation coefficients, the lack of significant
difference in concentration increase – at least for the parenteral treatment groups - may be attributable to
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the small size of our sample group. However, it is unclear whether intravenous application of nimodipine
can present an advantage over oral nimodipine besides a better correlation of dosage and concentration.
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Though frequently used when oral nimodipine has failed and intraarterial nimodipine is not feasible,26
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serum concentrations are comparable to both oral and IA application, with similar catecholamine
requirements. Greater variability of serum concentration during oral treatment implies a subgroup of
patients with compromised absorption, where parenteral steering and control of nimodipine may be
superior. However, in view of our results with identical systemic concentrations, it must be the objective of
further studies to evaluate whether this hypothetical benefit will compensate for the associated risk profile.
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In summary, all application modalities and all doses deliver comparable systemic concentrations
of nimodipine. IA and IV treatment in the critical phase with induced hypertension require comparable
circulatory support. Superior efficacy of IV over oral nimodipine has to be questioned, while a
supplementary neuroprotective effect with local (IA) treatment is conceivable, though requiring additional
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histopathological and clinical work-up as well as titration to the minimal, yet still effective dose.
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Limitations:
Comparison of required catecholamine support to maintain perfusion in the critical phase was
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therefore limited to rescue treatments (IA and IV) in the context of comparably elevated blood pressure
goals, as oral nimodipine is used as a preventative measure only, and not as a rescue treatment for
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refractory vasospasm.
While catecholamine requirements for patients on IA and IV nimodipine were comparable, a trend
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towards lower pressor demand was observed for both control and orally treated patients. However, rather
than assuming a better tolerance to oral treatment alone, we believe that the observed difference at least in
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part is attributable to a significantly better clinical condition of patients where autoregulatory capacity is
In our small cohort of highly selected cases, differences in serum levels of nimodipine in each
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group did not allow for a meaningful correlation analysis with admission status and clinical outcome.
Equally, comparative interpretation of outcome parameters was prohibited by the clinical heterogeneity of
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patients, necessitating testing in a larger patient cohort in the future. Regarding efficacy, the current dosage
and mode of application of nimodipine was deemed sufficient at the time of sampling as determined by
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comparability of efficacy. Oral nimodipine was considered a prophylactic treatment approach; for this
reason, comparable efficacy can only be assumed for parenteral treatment groups. The authors are aware of
the limited robustness of their assumption, precluding a more detailed interpretation of efficacy at this point.
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Conclusion:
Nimodipine does not accumulate sufficiently within the brain for treatment monitoring in CSF and
and dosing, each of which carries a specific side effect and complication profile. Further studies will have
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to determine the role of efficacy-driven (rather than empiric) treatment algorithms, where the lowest dose
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Funding Statement:
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This work was supported by the START-Program of the Faculty of Medicine, RWTH Aachen,
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Competing Interests Statement:
Recording units for ptiO2-measurements (MPR Datalogger) were provided by the respective
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Contributorship Statement:
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Conceived, designed and performed the experiments: WA MW CC GAS. Analyzed the data: WA
Data Sharing:
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N/A
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References
1. Alleyne CH, Jr. Aneurysmal subarachnoid hemorrhage: have outcomes really improved?
Neurology. 2010;74(19):1486-1487.
2. Fujii M, Yan J, Rolland WB, Soejima Y, Caner B, Zhang JH. Early brain injury, an evolving
frontier in subarachnoid hemorrhage research. Transl Stroke Res. 2013;4(4):432-446.
3. Vergouwen MD, Vermeulen M, van Gijn J, et al. Definition of delayed cerebral ischemia after
PT
aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational
studies: proposal of a multidisciplinary research group. Stroke. 2010;41(10):2391-2395.
4. Rowland MJ, Hadjipavlou G, Kelly M, Westbrook J, Pattinson KT. Delayed cerebral ischaemia
after subarachnoid haemorrhage: looking beyond vasospasm. Br J Anaesth. 2012;109(3):315-329.
RI
5. Liu GJ, Luo J, Zhang LP, et al. Meta-analysis of the effectiveness and safety of prophylactic use
of nimodipine in patients with an aneurysmal subarachnoid haemorrhage. CNS Neurol Disord
Drug Targets. 2011;10(7):834-844.
SC
6. Connolly ES, Jr., Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of
aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American
Heart Association/american Stroke Association. Stroke. 2012;43(6):1711-1737.
7. Steiner T, Juvela S, Unterberg A, et al. European Stroke Organization guidelines for the
management of intracranial aneurysms and subarachnoid haemorrhage. Cerebrovasc Dis.
U
2013;35(2):93-112.
8. Bork K, Wurm F, Haller H, et al. Neuroprotective and neuroregenerative effects of nimodipine in
AN
a model system of neuronal differentiation and neurite outgrowth. Molecules. 2015;20(1):1003-
1013.
9. Sandow N, Diesing D, Sarrafzadeh A, Vajkoczy P, Wolf S. Nimodipine Dose Reductions in the
Treatment of Patients with Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care.
M
2016;25(1):29-39.
10. Soppi V, Karamanakos PN, Koivisto T, et al. A randomized outcome study of enteral versus
intravenous nimodipine in 171 patients after acute aneurysmal subarachnoid hemorrhage. World
Neurosurg. 2012;78(1-2):101-109.
D
11. Bele S, Proescholdt MA, Hochreiter A, et al. Continuous intra-arterial nimodipine infusion in
patients with severe refractory cerebral vasospasm after aneurysmal subarachnoid hemorrhage: a
feasibility study and outcome results. Acta Neurochir (Wien). 2015;157(12):2041-2050.
TE
12. Hanggi D, Turowski B, Beseoglu K, Yong M, Steiger HJ. Intra-arterial nimodipine for severe
cerebral vasospasm after aneurysmal subarachnoid hemorrhage: influence on clinical course and
cerebral perfusion. AJNR Am J Neuroradiol. 2008;29(6):1053-1060.
13. Weant KA, Ramsey CN, 3rd, Cook AM. Role of intraarterial therapy for cerebral vasospasm
EP
16. Albanna W, Weiss M, Muller M, et al. Endovascular Rescue Therapies for Refractory Vasospasm
After Subarachnoid Hemorrhage: A Prospective Evaluation Study Using Multimodal, Continuous
Event Neuromonitoring. Neurosurgery. 2017.
17. Qin F, Ma Y, Wang Y, Chen L, Wang D, Li F. Determination of nimodipine in human plasma by
ultra performance liquid chromatography-tandem mass spectrometry and pharmacokinetic
application. J Pharm Biomed Anal. 2008;46(3):557-562.
18. Scheller C, Vogel AS, Simmermacher S, et al. Prophylactic intravenous nimodipine treatment in
skull base surgery: pharmacokinetic aspects. J Neurol Surg A Cent Eur Neurosurg.
2012;73(3):153-159.
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ACCEPTED MANUSCRIPT
19. Pickard JD, Murray GD, Illingworth R, et al. Effect of oral nimodipine on cerebral infarction and
outcome after subarachnoid haemorrhage: British aneurysm nimodipine trial. BMJ.
1989;298(6674):636-642.
20. Langley MS, Sorkin EM. Nimodipine. A review of its pharmacodynamic and pharmacokinetic
properties, and therapeutic potential in cerebrovascular disease. Drugs. 1989;37(5):669-699.
21. Herbette LG, Trumbore M, Chester DW, Katz AM. Possible molecular basis for the
pharmacokinetics and pharmacodynamics of three membrane-active drugs: propranolol,
nimodipine and amiodarone. J Mol Cell Cardiol. 1988;20(5):373-378.
PT
22. Zhang QZ, Jiang XG, Wu CH. Distribution of nimodipine in brain following intranasal
administration in rats. Acta Pharmacol Sin. 2004;25(4):522-527.
23. Seker F, Hesser J, Brockmann MA, et al. Pharmacokinetic Modeling of Intra-arterial Nimodipine
Therapy for Subarachnoid Hemorrhage-Related Cerebral Vasospasm. Clin Neuroradiol. 2015.
RI
24. Musahl C, Henkes H, Vajda Z, Coburger J, Hopf N. Continuous local intra-arterial nimodipine
administration in severe symptomatic vasospasm after subarachnoid hemorrhage. Neurosurgery.
2011;68(6):1541-1547; discussion 1547.
25. Dumont AS, Tjoumakaris SI, Jabbour PM, Gonzalez LF, Rosenwasser RH. Intravenous versus
SC
enteral nimodipine in aneurysmal subarachnoid hemorrhage: is there an advantage? World
Neurosurg. 2012;78(1-2):48-49.
26. Abboud T, Andresen H, Koeppen J, et al. Serum levels of nimodipine in enteral and parenteral
administration in patients with aneurysmal subarachnoid hemorrhage. Acta Neurochir (Wien).
U
2015;157(5):763-767. AN
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Figure Legends
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to an increase in concentration by 0.89 units (ng/ml). The model quality can be described as R2 = 86.2%
with a 100% maximum and can be interpreted as adequate. B: IV Group; The analysis was based on data
of n=6 patients. The estimated regression coefficient for a given dose was calculated as 1.04. The model
quality can be described as R2 = 94.3%. C: PO Group; The analysis was based on data of 28 patients. The
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estimated regression coefficient for the given dose was calculated as 0.10, R2 = 28.3 % therefore not
allowing for a valid statement due to high variability.
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nimodipine; PO, enteral treatment of nimodipine
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Tables
Table 1: Demographic data for included patients.
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Sex
male, n 5 (13.5%)
female, n 32 (86.5%)
Age (yrs) 58.8±13.3
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Clinical grade
HH 1-3 23 (62.2%)
HH 4-5 14 (37.8%)
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Modified Fisher scale
0-2 20 (54.1%)
3-4 17 (45.9%)
Aneurysm location
anterior circulation 30 (81.1%)
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posterior circulation 7 (18.9%)
Treatment modality, n
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clipping 16 (43.2%)
coiling 21 (56.8%)
Cerebral Infarction due to DCI 9 (24.3%)
Glasgow Outcome Score
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Representative data are given in our predominantly female patient population. Aneurysms were primarily
located in the anterior circulation. More patients presented with a lower Hunt and Hess grade. The extent of
hemorrhage and treatment modalities were balanced. Outcome was favorable in 20 patients, while seven
patients died during hospitalization.
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A total of 156 samples was collected in 3 treatment groups (PO, IV, IA) and a control group. Treatment
groups were defined by route of nimodipine application and dose level for oral administration, respectively.
Patients with at least 2 out of 3 available samples were included into analysis.
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PO1, low-dose enteral treatment of nimodipine dosage (180mg/d, mean 109.9±18.6µg/kg/h); PO2 high-dose
enteral treatment of nimodipine (360mg/d, mean 214.0±42.4µg/kg/h); IA1, low dose continuous
intraarterial nimodipine administration (<15µg/kg/h); IA2, high dose continuous intraarterial nimodipine
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administration (≥15µg/kg/h); IV1, low dose continuous intravenous nimodipine administration
(<15µg/kg/h); IV2, high dose continuous intravenous nimodipine administration (≥15µg/kg/h); control, no
nimodipine or previous application had been terminated for at least 48 hours.
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PO1 109.91 ± 18.56 17.28 ± 28.21
0.851
PO2 213.95 ± 42.39 20.66 ± 28.23
IA
IA1 10.40 ± 3.66 19.84 ± 3.14
0.794
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IA2 28.51 ± 11.45 25.84 ± 7.58
IV
IV1 12.20 ± 3.08 15.08 ± 5.11
0.841
IV2 23.50 ± 9.05 22.88 ± 2.46
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Patients were stratified according to high and low dose administration. Low and high dose treatment were
classified by a 15µg/kg/h threshold as a median of parenterally administrated nimodipine. Nimodipine
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concentration did not differ significantly between groups, even with incorporation of nimodipine dose.
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ANCOVA, analysis of covariance, administered nimodipine dose as cofactor; IA, continuous intraarterial
administration of nimodipine; IV, continuous intravenous administration of nimodipine; PO, enteral
treatment of nimodipine
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Figures
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ACCEPTED MANUSCRIPT
Systemic and cerebral concentration of nimodipine during established and experimental vasospasm
treatment
Highlights:
Oral nimodipine is an established prophylactic agent for cerebral vasospasm after subarachnoid
hemorrhage (SAH). In highly selected cases, intraarterial or intravenous application of nimodipine may be
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considered; optimum dosage and modality of application, however, remain a matter of debate. Analysis of
nimodipine concentration in serum, CSF and cerebral microdialysate in context of currently effective dose and
route of application (oral, IA, IV) is the purpose of this investigation.
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156 samples from 37 SAH patients were prospectively collected and analyzed for nimodipine concentration via
HPLC and tandem mass spectrometry. Treatment groups were stratified according to modality of application and
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low or high dose treatment. In the majority of cases, nimodipine remained below the limit of quantification
within the brain (microdialysis, CSF), even during targeted, local application (intraarterial nimodipine). Modality
of application (oral, IA, IV) was not associated with significant differences in serum concentrations, even after
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stratification for dosage, implying a comparable systemic distribution.
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Nimodipine does not accumulate sufficiently within brain 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, where lowest dose and least invasive mode of
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Abbreviations:
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aSAH, aneurysmal subarachnoid hemorrhage; CSF, cerebrospinal fluid; DCI, delayed cerebral
ischemia; GOS, Glasgow Outcome Scale; HH, Hunt and Hess grade; IA, intraarterial nimodipine; IV,
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intravenous nimodipine.
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