1 Department of Anaesthesia, St Vincent's Hospital, Melbourne, Victoria, Australia. 2 Department of Anaesthesia and Pain Management, University of Sydney at Royal North Shore Hospital, Sydney, NSW, Australia. 3 Department of Neurosurgery, St Vincent's Hospital, Melbourne, Victoria, Australia
* Corresponding author. E-mail: cormackj{at}ozemail.com.au
Accepted for publication February 23, 2005.
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Abstract |
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Methods. Serial arterial plasma levobupivacaine concentrations following scalp blockade were measured to 2 h in 10 patients booked for awake craniotomy for epilepsy or tumour surgery. Bilateral scalp blockade providing surgical anaesthesia was achieved with a mean dose of 177 mg (2.5 mg kg1, range 1.63.2 mg kg1) of levobupivacaine (0.5%, 5 mg ml1) with epinephrine (5 µg ml1) added immediately before the block insertion.
Results. The maximum measured plasma levobupivacaine concentration was 1.58 (0.44) µg ml1 [mean (SD)] with a mean time to peak plasma concentration of 12 (4) min. There were no episodes in any of the 10 patients of symptoms or signs suggestive of either CNS or CVS toxicity.
Conclusions. This study demonstrated a relatively rapid rise of plasma levobupivacaine concentration without evidence of cardiovascular or central nervous system sequelae in a sample population of patients who may be particularly prone to perioperative seizures.
Keywords: anaesthetics local, levobupivacaine ; scalp blocks ; surgery, awake craniotomy ; toxicity
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Introduction |
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At present, clinical data relating to the use of levobupivacaine for scalp blockade in neuroanaesthesia are lacking. Accordingly, this study was performed to gain experience with this drug in this setting, to determine the time course of plasma levobupivacaine concentration with a given dosage regime and to examine the presence or absence of clinical signs of toxicity. This will allow safe dosage regimen of levobupivacaine to be determined for this setting. The authors have previously completed a similar study using ropivacaine,1 which has a similar toxicity profile, where no signs of CVS or CNS toxicity were found.
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Methods |
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Patients were pre-medicated with clonidine (3 mg kg1), 2 h before surgery. A peripheral i.v. line, an antecubital central venous line and an intra-arterial cannula were inserted whilst the patient was in the anaesthetic room before the insertion of the scalp blocks. In addition, ECG and pulse oximetry were monitored. Oxygen was administered via a naso-pharyngeal airway. Propofol (15 mg kg1 h1) and remifentanil (0.020.1 mg kg1 min1) were used for sedation during performance of the blocks as well as throughout the surgical procedure as necessary. Dexamethasone (10 mg), phenytoin (250 mg), and flucloxacillin (1 g) were given intravenously during the surgery.
Our method of scalp blockade involves targeting the six nerves supplying the scalp bilaterally at their most proximal points. The volume of injectate at each point varied according to the anatomy of the patient and the type of craniotomy, but averaged approximately 2 ml. This method has been described previously in detail.2 The local anaesthetic used was levobupivacaine (5 mg ml1) with epinephrine (5 µg ml1) being added immediately before the block insertion. The volume used was restricted to a maximum of 40 ml (200 mg); 3035 ml (150175 mg) for the initial block, which was inserted before patient positioning and the remainder divided between scalp injections before Mayfield head pin insertion and skin incision 4060 min following completion of the initial blocks.
Signs and symptoms of CNS or CVS toxicity were sought throughout the sampling period and in particular during the performance of the blocks. Apart from the monitoring equipment mentioned, a dedicated anaesthetic nurse was in constant verbal contact with the patient during the initial local anaesthetic injection and was specifically alert to the onset of facial tingling, speech alteration or any gross signs of seizure activity. Continuous ECG and arterial pressure readings were taken during the study period with specific attention given to any alterations in systemic arterial pressure, heart rate and the onset of ventricular arrhythmic activity.
Arterial blood samples were collected before the blocks and at 5, 10, 15, 30, 45, 60, 90, and 120 min following completion of the initial blocks. The samples were centrifuged and the plasma stored within 1 h of collection at 20°C until analysis. Concentrations of levobupivacaine (as base) were determined using the following modifications to a previously published method.3 Plasma (0.5 ml) was mixed in a 2 ml polypropylene tube with sodium hydroxide (1 M, 0.2 ml) n-hexane (1.0 ml) and an internal standard solution of diphenhydramine HCl (10 µg ml1, 50 µl). After vortex mixing (1 min), the tube contents were centrifuged (10 000 r.p.m., 5 min) and the organic phase transferred to a second tube then evaporated under water aspirator vacuum (Medos JAK evaporator, Dynavac Engineering, Sydney, Australia) held at 40°C. The residue was reconstituted in phosphoric acid (2 mM, 0.1 ml) of which 10 µl was chromatographed using a HPLC system (HP1100) on a cyano column (Altima, 150 x 4.6 mm) with a mobile phase consisting of acetonitrile (35%) in a pH 4.0 buffer made of ammonium formate (5 mM) and formic acid (0.02%) at 1.0 ml min1. Detection was by UV absorbance at 220 nm. Calibration performed from 0.05 to 10 mg ml1 in drug-free plasma was linear with an r2 value of 0.9997.
Levobupivacaine plasma concentration data were expressed as the maximum measured value (Cmax) and the time of its occurrence (Tmax) using the mean (SD), and range.
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Results |
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Individual patients' plasma levobupivacaine concentrations were plotted against time (Fig. 1). The mean Cmax of levobupivacaine was 1.58 (0.44) (range 0.982.51) µg ml1 and the mean Tmax was 12 (4) (range 515) min, with the earliest Tmax being found in the first samples drawn at 5 min after insertion of the block in two patients. There was evidence of a secondary rise in plasma levobupivacaine concentration in some patients following injection into the scalp of the remainder of the local anaesthetic solution at 4060 min. One patient (J) had a detectable level of levobupivacaine at baseline because of a delay in sampling until after commencement of the block.
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Discussion |
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Levobupivacaine has now been used in a wide variety of clinical areas for the provision of intra-operative anaesthesia and postoperative analgesia. A recent study of interscalene brachial plexus blockade for shoulder surgery showed levobupivacaine 0.5% (30 ml) produced a blockade of similar onset and quality as that produced by a similar volume of ropivacaine 0.5%.4
There are other studies demonstrating an acceptable safety profile of levobupivacaine when used for a wide range of different blocks510 and as with ropivacaine it has produced uniformly satisfactory blockade for all these forms of surgery. Unfortunately, there is still a paucity of human studies directly comparing the toxicity of these long-acting agents. Studies have demonstrated larger tolerated doses of i.v. ropivacaine or levobupivacaine compared with bupivacaine before the onset of CNS symptoms in humans.1113 In the study of Bardsley and colleagues, levobupivacaine was infused intravenously in volunteers until the onset of CNS symptoms. Mean peak plasma concentrations in that study were 2.62 µg ml1 and cardiovascular parameters were considered superior to bupivacaine, which was infused in the same regimen. This would imply that the concentrations reached in our study (1.58 µg ml1) are relatively safe with the understanding that the patient population being studied were having surgery for epilepsy or for tumours which may be associated with seizures, they were sedated during the blocks and were on anticonvulsant medication all of which may raise the threshold for CNS signs. More recently Stewart and colleagues14 examining CNS and CVS effects of levobupivacaine and ropivacaine, found a similar onset of effects between the two drugs at equal dose regimens. At present there are no definitive data for the effects of epinephrine on peripheral nerve blockade with levobupivacaine; however, data for epidural neuraxial blockade with levobupivacaine do not demonstrate a material advantage on either block characteristics or plasma drug concentration profiles when epinephrine was added.15
Despite the lack of human data there is now general agreement in the anaesthetic community that the wide therapeutic window between clinical efficacy and adverse side-effects seen with both levobupivacaine and ropivacaine suggests the need for these two agents to be used preferentially over bupivacaine in clinical practice. This attitude stems from an increasing volume of laboratory animal evidence pointing to the greater potential for lethal toxic effects of racemic bupivacaine compared with similar doses of levobupivacaine and ropivacaine.14 1618 Further, lethal dose (LD50) values obtained in rats, mice, and rabbits indicate that the margin of safety regarding lethality is such that 3257% more levobupivacaine is required to produce death when compared with bupivacaine.19 20 The volume of evidence for the CNS and or CVS toxicity of the longer-acting local anaesthetics has necessarily been smaller in the human model because of the obvious ethical difficulty in infusing these drugs in healthy volunteers.
This study addressed the efficacy and safety of levobupivacaine in the clinical setting of awake craniotomy. The drug was demonstrated to be a useful addition to the armamentarium of the clinical neuroanaesthetist by showing a similar plasma concentration profile to ropivacaine in the same clinical area without evidence of CNS or CVS toxic side-effects. The finding of peak plasma concentrations earlier than 15 min post-block further raises the need for heightened awareness by anaesthetic staff where there is potential for adverse CNS or CVS symptoms to occur as early as 5 min post-block insertion.
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References |
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