Background. This study assessed the concentration of rocuronium in the cerebrospinal fluid (CSF) of patients undergoing cerebral aneurysm clipping, and investigated whether the mode of administration (single bolus vs continuous infusion) influenced the CSF concentration. 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 (0.9-4.6) ng ml-1 in the bolus group and 12.4 (2.4-34.6) ng ml-1 in the infusion group; P<0.01. Conclusions. This study demonstrated that rocuronium, normally not considered to cross the blood-brain 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: 419-2

Fuchs‐Buder, T.

Kleinschmidt, S.

Philipp‐Osterman, S.

Rentsch, K.

Schreiber, J. U.

Strowitzki, M.

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British Journal of Anaesthesia 92 (3): 419±21 (2004)DOI: 10.1093/bja/aeh062 Advanced Access publication January 22, 2004Concentration of rocuronium in cerebrospinal ¯uid of patientsundergoing cerebral aneurysm clipping²T. Fuchs-Buder1*, M. Strowitzki2, K. Rentsch3, J. U. Schreiber1, S. Philipp-Osterman1 andS. Kleinschmidt11Department of Anaesthesia and Critical Care and 2Department of Neurosurgery, University of Saarland,Homburg/Saar, Germany. 3Institute for Clinical Chemistry University Hospital of Zurich, Switzerland*Corresponding author: DeÂpartement d'AnestheÂsie et de ReÂanimation, Centre Hospitalier Universitaire Nancy/Brabois, 4 Rue du Morvan, F-54500 Vandoeuvres-Les-Nancy, France. E-mail: t.fuchs-buder@chu-nancy.frBackground. This study assessed the concentration of rocuronium in the cerebrospinal ¯uid(CSF) of patients undergoing cerebral aneurysm clipping, and investigated whether the mode ofadministration (single bolus vs continuous infusion) in¯uenced the CSF concentration.Methods. Twenty patients with subarachnoid haemorrhage were randomly allocated toreceive 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 hafter the rocuronium bolus. Samples were analysed by liquid chromatography electrosprayionization-tandem mass spectrometry.Results. Rocuronium could be detected in all the CSF samples. The mean (range) CSF concen-tration was 2.2 (0.9±4.6) ng ml±1 in the bolus group and 12.4 (2.4±34.6) ng ml±1 in the infusiongroup; P<0.01.Conclusions. This study demonstrated that rocuronium, normally not considered to crossthe blood±brain 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 singlebolus dose.Br J Anaesth 2004; 92: 419±21Keywords: blood±brain barrier, mass spectrometry high pressure liquid chromatography;neuromuscular blocking agents, rocuronium; surgery, cerebrovascularAccepted for publication: July 8, 2003Neuronal nicotinic acetylcholine receptors (nAChR) areubiquitously present in CNS and involved in chemicalsignalling in the brain.1 When given in suf®cient amounts,neuromuscular blocking agents (NMBA) interact with thesenAChR, leading dose dependently to activation or inhibitionof different nAChR subtypes.2 To estimate the clinicalrelevance of this interaction, quantitative data on thecerebrospinal ¯uid (CSF) concentration of NMBAs arerequired. Whilst NMBAs are considered not to cross theintact blood±brain barrier, these molecules may pass intothe CSF when its function is impaired.3 4 Only a littleinformation about re-entry of rocuronium, a NMBA used inneurosurgical patients, into the CSF is available. This, studyaimed ®rst to investigate the CSF concentration ofrocuronium in patients undergoing cerebral aneurysmclipping, and secondly to assess whether the mode ofadministration (single bolus or continuous infusion) has anyin¯uence on its CSF concentration.Methods and resultsThe study was approved by the hospital Ethics Committee;the patients or their next of kin gave informed consent orassent, respectively. Twenty patients undergoing cerebralaneurysm clipping with CSF drainage were randomlyallocated to the bolus group or infusion group.Anaesthesia was induced with thiopentonal (3±5 mg kg±1),fentanyl (1±2 mg kg±1), and rocuronium (0.6 mg kg±1);patients in the infusion group also received a continuous²Declaration of interest: This study was supported in part by a grantfrom Organon, The Netherlands.Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2004infusion of rocuronium to maintain constant neuromuscularblock, that is 90±95% twitch depression. Anaesthesia wasmaintained with continuous infusions of midazolam (0.05±0.2 mg kg±1 h±1) and fentanyl (2±5 mg kg±1 h±1). Thepatients' lungs were ventilated to normocarbia withiso¯urane 0.5% and nitrous oxide 60% in oxygen. Beforethe beginning of the craniotomy, an external CSF drainagewas placed into the lateral ventricle by the neurosurgeon viaa single bore hole approach.Baseline arterial blood samples (5 ml), needed to controlto linearity of the analytical method, were taken beforeinduction of anaesthesia. Baseline CSF samples wereobtained from patients undergoing elective surgery underspinal anaesthesia. In the ®rst ®ve of 10 patients in eachgroup, blood and CSF were sampled at 1, 2, and 4 h after theinitial dose of rocuronium. In the second ®ve patients, bloodand CSF were sampled at 2 h. After collection, the sampleswere centrifuged at 4°C, and 1 ml of plasma or CSF wasadded to tubes containing 0.2 ml of 1 M sodium hydrogenphosphate solution also as a stabilizer. These samples werekept frozen at ±70°C until analysis. The concentration ofrocuronium was determined by liquid chromatographyelectrospray ionization-tandem mass spectrometry.5 Thedetection limit of the method was 0.5 ng ml±1 forrocuronium in CSF and 5 ng ml±1 for rocuronium in plasma,and the inter-assay coef®cient of variation was less than 8%.Data are expressed as individual values or as median ormean and range. Patient characteristics and rocuroniumconcentrations at 2 h in the two groups were compared usingthe Mann±Whitney test. The time course of the plasma andCSF concentration of rocuronium was compared with a one-way ANOVA for repeated measures followed by a Bonferronicorrection. Differences were considered signi®cant whenP<0.05.One patient in the infusion group had to be excludedbecause of violation of the study protocol. The physicalcharacteristics and surgical data were comparable betweenthe two groups (Table 1). Preliminary analysis after 10patients (®ve in each group) revealed that in the infusiongroup the concentration of rocuronium was highest after 2 h;the corresponding values at 1, 2, and 4 h were 3.8 (2.4±5.3),5.7 (2.4±13.2) (P<0.05 compared with 1 h), and 3.8 (1.1±7.5) ng ml±1, respectively, n=5. The respective values in thebolus group were 2.2 (0.6±7.5), 2.0 (0.9±4.5), and 1.8 (0.7±4.7) ng ml±1; n.s, n=5. The ®nal analysis demonstrated thatthe CSF concentration of rocuronium at 2 h was 2.2 (0.9±4.6) ng ml±1 in the bolus group (n=10) and 12.4 (2.4±34.6)ng ml±1 in the infusion group (n=9); P<0.01 (Table 1).DiscussionIn the present study rocuronium could be detected in all CSFsamples, and a continuous infusion led to higher CSFconcentrations than a single bolus dose. In the ®rst ®ve of 10patients in each group, the time course of CSF penetration ofrocuronium was assessed; we focused on a 4-h periodbecause it has recently been demonstrated that in the patientpopulation studied the CSF concentration of NMBA may behighest at this time point.4 Based on the results of the ®rstpart of the study blood and CSF were only sampled at 2 h inthe second ®ve of 10 patients in each group.Our results are surprising, as in previous studies NMBAswere not regularly detected in the CSF. Tassonyi and co-workers found atracurium in the CSF of only ®ve out of 10patients undergoing cerebral aneurysm clipping.4 However,their lower limit of detection was 10 ng ml±1. In the presentstudy the lower detection limit for rocuronium in the CSFwas 0.5 ng ml±1, allowing quanti®cation of very smallamounts of the drug. Moreover, most studies investigatingthe CSF concentration of NMBA have sampled the CSF inthe lumbar subarachnoid space.3 4 Circulation of CSF fromthe brain to the lumbar subarachnoid space takes about90 min, and approximately 0.25% of total CSF volume isreplaced by freshly formed CSF each minute. Thus,sampling of CSF from the lumbar subarachnoid spacere¯ects neither the time course of the passage of NMBA intothe CSF or its maximum concentration in the CNS. In thepresent study, the low detection limit of the analyticalmethod and sampling directly from the ventricular systemmay have contributed to the consistent section ofrocuronium in the CSF.There is controversy in the literature about the origin ofNMBA detected in the CSF. Eddlestone and co-workers3thought that the presence of atracurium in the CSF in twoout of 10 patients (80 and 1460 ng ml±1) could be accountedfor by blood contamination. This factor cannot be excludedin our study. However, CSF containing haemolysed bloodwas only observed in one patient. Moreover, the CSFconcentrations of rocuronium were dose-dependent, acontinuous infusion leading to higher concentrations thana single bolus, and in both groups the CSF concentrationwas within a narrow range (Table 1).Table 1 Physical characteristic, surgical data, and rocuronium plasma andCSF concentrations. Data are absolute values (sex ratio), mean or median(range, or SD); n.a., not applicable; *P<0.01. Plasma and CSF concentrationswere determined 2 h after the initial dose of rocuronium. Hunt and Hessclassi®cation: 0, unruptured aneurysm; 1, asymptomatic or minimal headacheand slight nuchal rigidity; 2, moderate to severe headache, nuchal rigidity,but no neurological de®cit other than cranial nerve palsy; 3, drowsiness,confusion, or mild focal de®cit; 4, stupor, mild to severe hemiparesis,possible early decerebrate rigidity, vegetative disturbance; 5, deep coma,decerebrate rigidity, moribund appearance.10 Time to surgery: time betweendiagnosis of subarachnoid haemorrhage and aneurysm clippingBolus group Infusion group(n=10) (n=9)Gender-ratio (males/females) 5/5 4/5Age (yr) 48 (38±57) 42 (24±60)Weight (kg) 75 (61±95) 72 (60±85)Hunt and Hess classi®cation 2 (0±3) 2 (0±3)Time to surgery (h) 40 (57) 31 (40)Duration of rocuronium-infusion (min) n.a. 192 (140±275)Plasma concentration (ng ml±1) 144 (57±347) 1123 (604±1530)*CSF concentration (ng ml±1) 2.2 (0.9±4.6) 12.4 (2.4±34.6)*Fuchs-Buder et al.420There is a dose-dependent relationship between anNMBA causing inhibition or activation of nAChR. Thus,the possible clinical consequences of the CSF concentrationof rocuronium measured in this study have to be considered.Cholinergic neurotransmission plays a role in regulation ofrespiratory pattern, and inhibition of nAChR may lead tocentral respiratory depression.6 As recently shown, NMBAsmay inhibit the major brain a4b2 human nAChR,2 and thuslead to central respiratory inhibition. However, the concen-trations required to produce inhibition of nACh receptorswere in the mM range, being about 1000-fold higher than theconcentrations detected in this study.2 NMBAs may alsoproduce excitatory CNS effects. Pancuronium andvecuronium may cause a sustained increase in cytosoliccalcium by initiating prolonged activation of brain nAChR,thus leading to uncontrolled neuronal excitability andseizure activity.7 Case reports of accidental intrathecalinjection of NMBAs con®rmed this property.8 9 However,about 10 000-fold higher concentrations than thosemeasured in this study were necessary to elicit seizures.6Thus, according to the current literature, no convincingevidence exists of major CNS effects from the concentra-tions of rocuronium found in the CSF in this study.References1 Tassonyi E, Charpantier E, Muller D, Dumont L, Bertand D. Therole of nicotinic acetylcholine receptors in the mechanisms ofanesthesia. Brain Res Bull 2002; 57: 133±502 Chiodini F, Charpentier E, Muller D, Tassonyi E, Fuchs-Buder T,Bertrand D. Blockade and activation of the human neuronalnicotinic acetylcholine receptors by atracurium and laudanosine.Anesthesiology 2001; 94: 643±513 Eddlestone JM, Harper NJN, Pollard BJ, Edwards D, GwinnuttCL. Concentrations of atracurium and laudanosine incerebrospinal ¯uid and plasma during intracranial surgery. Br JAnaesth 1989; 63: 525±394 Tassonyi E, Fathi M, Hughes GJ, et al. Cerebrospinal ¯uidconcentrations of atracurium in neurosurgical patients. ActaAnaesthesiol Scand 2002; 46: 1236±415 Gutteck-Amsler U, Rentsch KM. Quanti®cation of theaminosteroidal non-depolarizing neuromuscular blocking agentrocuronium and vecuroniumin plasma with liquid-chromatography-tandem mass spectrometry. Clin Chem 2000;46: 1413±56 Shao XM, Feldman JL. Pharmacology of nicotinic receptors in thepreBotzinger complex that mediate modulation of respiratorypattern. J Neurophysiol 2002; 88: 1851±87 Cardone C, Szenohradszky J, Yost S, Bickler PE. Activation ofbrain acetylcholine receptors by neuromuscular drugs.Anesthesiology 1994; 80: 1155±618 Goonewardene TW, Sentheshanmuganathan S, Kamalanathan S,Kanagasunderam R. Accidental subarachnoid injection ofgallamine: a case report. Br J Anaesth 1975; 47: 889±939 Foster PA. Potassium depletion and the central action of curare.Br J Anaesth 1956; 28: 488±9410 Hunt WE, Hess RM. Surgical risk as related to time ofintervention in the repair of intracranial aneurysms. J Neurosurg1968; 28: 14±20MAC of xenon in swineÓ The Board of Management and Trustees of the British Journal of Anaesthesia 2004

Concentration of rocuronium in cerebrospinal fluid of patients undergoing cerebral aneurysm clipping†

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