1 Department of Anaesthesia and Critical Care and 2 Department of Neurosurgery, University of Saarland, Homburg/Saar, Germany. 3 Institute for Clinical Chemistry University Hospital of Zurich, Switzerland
*Corresponding author: Département dAnesthésie et de Réanimation, Centre Hospitalier Universitaire Nancy/Brabois, 4 Rue du Morvan, F-54500 Vandoeuvres-Les-Nancy, France. E-mail: t.fuchs-buder@chu-nancy.fr Declaration of interest: This study was supported in part by a grant from Organon, The Netherlands.
Accepted for publication: October 20, 2003
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Abstract |
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Methods. Twenty patients with subarachnoid haemorrhage were randomly allocated to receive a bolus dose (bolus group), or a bolus followed by a continuous infusion of rocuronium (infusion group) (n=10 for each group). Arterial blood and ventricular CSF were sampled 2 h after the rocuronium bolus. Samples were analysed by liquid chromatography electrospray ionization-tandem mass spectrometry.
Results. Rocuronium could be detected in all the CSF samples. The mean (range) CSF concentration was 2.2 (0.94.6) ng ml1 in the bolus group and 12.4 (2.434.6) ng ml1 in the infusion group; P<0.01.
Conclusions. This study demonstrated that rocuronium, normally not considered to cross the bloodbrain barrier, is regularly found in the CSF of patients undergoing cerebral clipping; continuous infusion of the drug led to higher plasma and CSF concentrations than after a single bolus dose.
Br J Anaesth 2004; 92: 41921
Keywords: bloodbrain barrier, mass spectrometry high pressure liquid chromatography; neuromuscular blocking agents, rocuronium; surgery, cerebrovascular
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Introduction |
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Methods and results |
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Baseline arterial blood samples (5 ml), needed to control to linearity of the analytical method, were taken before induction of anaesthesia. Baseline CSF samples were obtained from patients undergoing elective surgery under spinal anaesthesia. In the first five of 10 patients in each group, blood and CSF were sampled at 1, 2, and 4 h after the initial dose of rocuronium. In the second five patients, blood and CSF were sampled at 2 h. After collection, the samples were centrifuged at 4°C, and 1 ml of plasma or CSF was added to tubes containing 0.2 ml of 1 M sodium hydrogen phosphate solution also as a stabilizer. These samples were kept frozen at 70°C until analysis. The concentration of rocuronium was determined by liquid chromatography electrospray ionization-tandem mass spectrometry.5 The detection limit of the method was 0.5 ng ml1 for rocuronium in CSF and 5 ng ml1 for rocuronium in plasma, and the inter-assay coefficient of variation was less than 8%.
Data are expressed as individual values or as median or mean and range. Patient characteristics and rocuronium concentrations at 2 h in the two groups were compared using the MannWhitney test. The time course of the plasma and CSF concentration of rocuronium was compared with a one-way ANOVA for repeated measures followed by a Bonferroni correction. Differences were considered significant when P<0.05.
One patient in the infusion group had to be excluded because of violation of the study protocol. The physical characteristics and surgical data were comparable between the two groups (Table 1). Preliminary analysis after 10 patients (five in each group) revealed that in the infusion group the concentration of rocuronium was highest after 2 h; the corresponding values at 1, 2, and 4 h were 3.8 (2.45.3), 5.7 (2.413.2) (P<0.05 compared with 1 h), and 3.8 (1.17.5) ng ml1, respectively, n=5. The respective values in the bolus group were 2.2 (0.67.5), 2.0 (0.94.5), and 1.8 (0.74.7) ng ml1; n.s, n=5. The final analysis demonstrated that the CSF concentration of rocuronium at 2 h was 2.2 (0.94.6) ng ml1 in the bolus group (n=10) and 12.4 (2.434.6) ng ml1 in the infusion group (n=9); P<0.01 (Table 1).
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Discussion |
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Our results are surprising, as in previous studies NMBAs were not regularly detected in the CSF. Tassonyi and co-workers found atracurium in the CSF of only five out of 10 patients undergoing cerebral aneurysm clipping.4 However, their lower limit of detection was 10 ng ml1. In the present study the lower detection limit for rocuronium in the CSF was 0.5 ng ml1, allowing quantification of very small amounts of the drug. Moreover, most studies investigating the CSF concentration of NMBA have sampled the CSF in the lumbar subarachnoid space.3 4 Circulation of CSF from the brain to the lumbar subarachnoid space takes about 90 min, and approximately 0.25% of total CSF volume is replaced by freshly formed CSF each minute. Thus, sampling of CSF from the lumbar subarachnoid space reflects neither the time course of the passage of NMBA into the CSF or its maximum concentration in the CNS. In the present study, the low detection limit of the analytical method and sampling directly from the ventricular system may have contributed to the consistent section of rocuronium in the CSF.
There is controversy in the literature about the origin of NMBA detected in the CSF. Eddlestone and co-workers3 thought that the presence of atracurium in the CSF in two out of 10 patients (80 and 1460 ng ml1) could be accounted for by blood contamination. This factor cannot be excluded in our study. However, CSF containing haemolysed blood was only observed in one patient. Moreover, the CSF concentrations of rocuronium were dose-dependent, a continuous infusion leading to higher concentrations than a single bolus, and in both groups the CSF concentration was within a narrow range (Table 1).
There is a dose-dependent relationship between an NMBA causing inhibition or activation of nAChR. Thus, the possible clinical consequences of the CSF concentration of rocuronium measured in this study have to be considered. Cholinergic neurotransmission plays a role in regulation of respiratory pattern, and inhibition of nAChR may lead to central respiratory depression.6 As recently shown, NMBAs may inhibit the major brain 4ß2 human nAChR,2 and thus lead to central respiratory inhibition. However, the concentrations required to produce inhibition of nACh receptors were in the µM range, being about 1000-fold higher than the concentrations detected in this study.2 NMBAs may also produce excitatory CNS effects. Pancuronium and vecuronium may cause a sustained increase in cytosolic calcium by initiating prolonged activation of brain nAChR, thus leading to uncontrolled neuronal excitability and seizure activity.7 Case reports of accidental intrathecal injection of NMBAs confirmed this property.8 9 However, about 10 000-fold higher concentrations than those measured in this study were necessary to elicit seizures.6 Thus, according to the current literature, no convincing evidence exists of major CNS effects from the concentrations of rocuronium found in the CSF in this study.
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References |
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