Comparison of mepivacaine and lidocaine for intravenous regional anaesthesia: pharmacokinetic study and clinical correlation
British Journal of Anaesthesia, 2002, Vol. 88, No. 4 516-519
© 2002 The Board of Management and Trustees of the British Journal of Anaesthesia
Clinical Investigations
Comparison of mepivacaine and lidocaine for intravenous regional anaesthesia: pharmacokinetic study and clinical correlation
P. Prieto-Álvarez*,1, A. Calas-Guerra2, J. Fuentes-Bellido2, E. Martínez-Verdera3, A. Benet-Català4 and J. P. Lorenzo-Foz2
1Service of Anaesthesiology, Resuscitation and Pain Clinic, Hospital Universitario Sant Joan de Reus, Reus, Tarragona, Spain. 2Service of Anaesthesiology, Resuscitation and Pain Clinic, 3Laboratory of Clinical Analysis and 4Research Unit, Department of Internal Medicine, Pius Hospital de Valls, Valls, Tarragona, Spain*Corresponding author: Passatge dels Grallers 24, E-43205 Reus, Tarragona, Spain
Accepted for publication: November 22, 2001
Abstract
Background. Limitations to the use of lidocaine for intravenousregional anaesthesia (IVRA) include lack of optimal intraoperativeanalgesia and systemic toxic reactions.This randomized double-blindstudy was conducted to compare intraoperative and postoperativeanalgesia, adverse effects, and plasma concentrations of mepivacaineor lidocaine, on release of the tourniquet in patients undergoingIVRA for distal upper limb surgery.
Methods. Forty-two adult patients were randomly allocated toreceive either a 0.5% lidocaine solution 3 mg kg–1 (n=20)or mepivacaine 5 mg kg–1 (n=22). Plasma concentrationsof both anaesthetic agents were measured at 5, 10, 20, 30, 45,and 60 min after deflation of the tourniquet by gas chromatography.
Results. Although plasma concentrations of mepivacaine and lidocainewere comparable 5 min after deflation, concentrations of lidocainedecreased significantly thereafter, whereas plasma concentrationsof mepivacaine were similar over the 60-min study period. Supplementaryanalgesia during the intraoperative period was required by 45%of patients in the lidocaine group as compared with 9% in themepivacaine group (P=0.02). No adverse effects were observedin patients given mepivacaine. In the lidocaine group, adverseeffects were observed in 10% of the patients. The total ischaemiatime, volume of the local anaesthetic, and duration of the surgicalprocedure were not significantly different between the two groups.
Conclusions. Mepivacaine 5 mg kg–1 ensured better intraoperativeanalgesia than lidocaine 3 mg kg–1 when used for IVRA.Plasma concentrations of lidocaine decreased significantly between5 and 60 min following tourniquet deflation, whereas blood concentrationsof mepivacaine remained below the toxic concentration.
Br J Anaesth 2002; 88: 516–19
Keywords: anaesthetic techniques, i.v., regional; anaesthetics local, lidocaine; anaesthetic local, mepivacaine
Introduction
Intravenous regional anaesthesia (IVRA) is a simple and effectivetechnique for distal upper limb surgery of less than 1 h duration.1 Some clinical studies have recently shown that the additionof a non-steroidal anti-inflammatory agent,2 an opioid,3 neuromuscularblocking agents,4 clonidine,5 and even ketamine6 to lidocainecan improve the quality of the regional anaesthesia. Althoughlidocaine is one of the least toxic local anaesthetics, in ourexperience, limitations to its use include lack of optimal intraoperativeanalgesia and systemic toxic reactions. In our clinical experienceof more than 10 yr, we found that the use of mepivacaine 5 mgkg–1 for IVRA was a satisfactory alternative to the classicalIVRA technique and that systemic reactions after tourniquetdeflation did not occur. Therefore, a randomized double-blindstudy was designed to compare IVRA using lidocaine or mepivacainein forearm and hand surgery. Plasma concentrations of the drugson release of the tourniquet, intraoperative and postoperativeanalgesia and adverse effects were determined.
Methods
The procedure for this study was approved by the Ethics Committeeof the hospital. Informed consent was obtained. Forty-two adultASA physical status I or III patients of both sexes undergoingelective minor forearm and hand surgery gave written informedconsent to participate in this prospective double-blind study.Patients with liver disorders, history of allergic reactionto local anaesthetics, those not wishing the IVRA technique,or in whom venipuncture was difficult were excluded. Patientswere allocated to one of two groups according to a table ofrandom numbers. Patients in one group (n=22) received 0.5–1%mepivacaine 5 mg kg–1 up to a maximal dose of 400 mg andmaximal volume of 40 ml, whereas those in the other group (n=20)received 0.5% lidocaine 3 mg kg–1 up to a maximal doseof 400 mg and maximal volume of 40 ml.
Patients 50 kg and/or with respiratory disease were premedicatedwith diazepam 5 mg, whereas patients weighing greater than 50kg were given diazepam 10 mg. A 20-gauge catheter was introducedinto a vein on the dorsum of the hand to be operated upon andanother 16-gauge catheter was inserted into a vein of the armnot requiring surgery for fluid infusion and blood sampling.The operative arm was exanguinated by elevating it and wrappingit with a rubber Esmarch bandage. The proximal cuff of a doubletourniquet was then inflated to 350 mm Hg and 20 ml min–1 of either mepivacaine or lidocaine was injected in a double-blindfashion into the indwelling cannula. After approximately 15min, the distal cuff was inflated to the same pressure. A minimumtotal ischaemia time of 40 min was established for safety reasonsbecause of the use of mepivacaine in doses much larger thanthose reported in the literature. Midazolam 1 mg every 10 minup to a maximum of 5 mg was used for intraoperative sedationtrying to maintain the patient at level 2–3 on the Ramsaysedation scale.7 Supplementary intraoperative analgesia consistedof intravenous boluses of fentanyl 50 µg every 10 minup to a total dose of 150 µg. Boluses of fentanyl wereprovided whenever there was a 20% increase in baseline valuesof arterial pressure and/or heart rate or when analgesia wasgraded as poor by the patient. Patient’s vital signs (arterialpressure, ventilatory frequency, pulse oximeter), analgesicrequest, and presence of adverse events related to unexpecteddeflation of the tourniquet were assessed intraoperatively.
Venous blood samples were obtained from the opposite arm at5, 10, 20, 30, 45, and 60 min after release of the tourniquet.The samples were centrifuged and the plasma frozen at –20°Cand stored. Plasma concentrations of local anaesthetics wereanalysed by gas chromatography/mass spectrometry.
After tourniquet release and at the end of surgery, patientswere asked to report any adverse effects. Symptoms of dizziness,nystagmus, tinnitus, facial dysaesthesia, convulsions, depressionof the central nervous system, bradypnoea (ventilatory frequency10 breaths min–1), bradycardia (heart rate 50 beats min–1),and cardiovascular depression (25% decrease in baseline arterialpressure) were noted, if present. Patient’s vital signsand time to the first analgesic request after cuff release (timeof residual analgesia) were recorded in the postanaesthesiacare unit.
The sample size was calculated according to the main objectiveof the study, that is adequate intraoperative analgesia withmepivacaine for IVRA, which was determined by the need for supplementarymedication intraoperatively, for a sensitivity of 20%, betaerror of 0.10 and an alpha error of 0.05. Patient characteristicsand data related to the anaesthetic technique and the surgicalprocedure were recorded in both groups. Comparison of categoricalvariables was carried out with the Pearson’s chi-squaredtest. All quantitative variables with the exception of timeof residual analgesia were normally distributed and were analysedusing the Student’s t-test if variances were comparableor with the Mann–Whitney U test if variances were notcomparable. Paired data were analysed with the paired t-test.Kaplan–Meier survival analysis was performed for timeof residual analgesia. Statistical analysis was performed withthe SPSS/PC+ (version 8.0, SPSS Inc., Chicago, IL) softwareprogramme. Data are expressed as mean (SD) unless indicatedotherwise.
Results
Patients characteristics and data of the anaesthetic and surgicaltechniques in both study groups are shown in Table 1. Therewere no statistically significant differences in relation toweight, height, gender, volume of local anaesthetic agent used,time of ischaemia, duration of operation, and type of surgicalprocedure. However, patients in the mepivacaine group were significantlyyounger (47.4 (22–78) yr) than those in the lidocainegroup (57.9 (31–85) yr) (P=0.04).
Table 1 Patient characteristics and data of the anaesthetic technique and surgical procedure. *P<0.05
Intraoperative analgesia was significantly better amongst mepivacaine-treatedpatients because supplementary analgesia with fentanyl was requiredby 9% of patients in the mepivacaine group as compared with45% in the lidocaine group (P=0.02). Median times required forsupplementary analgesia were 35 min (95% confidence interval(CI) 18–52 min) in the mepivacaine group and 30 min (95%CI 19–41 min) in the lidocaine group. With regard to thefrequency of adverse events on release of the tourniquet, noadverse effects were observed in patients given mepivacaine,whereas in the lidocaine group, transient bradycardia, and dizzinesswere experienced by one patient each within 5 min after tourniquetdeflation.
Plasma concentrations of both local anaesthetic agents are shownin Table 2. Five minutes after cuff deflation, plasma concentrationsof mepivacaine and lidocaine were comparable. However, plasmaconcentrations of lidocaine decreased significantly between5 and 60 min following tourniquet deflation (P<0.001), whereasblood concentrations of mepivacaine did not change during theobservation period. At 60 min, plasma concentrations of mepivacainewere significantly higher than those of lidocaine (P<0.001).
Table 2 Plasma concentrations of mepivacaine and lidocaine (µg ml–1) during the observation period at the of surgery. *P<0.05
Discussion
Different anaesthetic agents including procaine, lidocaine,and prilocaine8 have been used for IVRA since the initial descriptionof this technique by Bier in 1908. Research in this field hasbeen focused on the search for the ideal agent for IVRA thatwould be the one with which adequate intraoperative analgesiais attained, but without the systemic toxicity in the eventof tourniquet release. The inadvisability of using bupivacainefor IVRA is related to the sudden occurrence of dangerous cardiotoxicity,9–11 whereas the use of chloroprocaine in IVRA ceased after reportsof hypersensitivity reactions and postanaesthetic thrombophlebitis.12 The ideal anaesthetic agent for IVRA would be the one that hadthe requisite degree of local anaesthetic activity, but withlow cardiovascular and central nervous system toxicity. Lidocaineis probably the local anaesthetic most commonly chosen for thistechnique,13 14 although prilocaine is better tolerated in termsof systemic toxicity than lidocaine.15
The dose of lidocaine recommended for classical IVRA technique(3 mg kg–1 as a 0.5% lidocaine solution) was used. Withrespect to mepivacaine, we used a dose of 5 mg kg–1 withwhich consistent satisfactory results had been obtained by ourgroup as well as by others.16 17 According to the study of Rawaland co-workers18 in which plasma concentrations of mepivacaine,lidocaine, and prilocaine when given at the 3 mg kg–1 dose peaked within 5 min after tourniquet release, we decidedto start measurements of plasma drug concentrations at 5 minfollowing tourniquet deflation, with the last measurement at60 min because in the pharmacokinetic study of Simon and associates8 less than 1 µg ml–1 of lidocaine was measured fromthat time. Although in the case of mepivacaine for IVRA, noprevious studies have evaluated plasma concentrations of thisagent at 60 min after deflation, a pharmacokinetic behavioursimilar to that of lidocaine was assumed as in the study ofRawal and co-workers,18 mepivacaine and lidocaine showed similarpharmacokinetics 5 min after tourniquet release.
As compared with lidocaine, mepivacaine 5 mg kg–1 providedbetter intraoperative analgesia with no adverse effects on releaseof the tourniquet. Moreover this finding is supported by plasmaconcentrations of the drugs that were comparable 5 min afterdeflation (1.68 (0.73) µg ml–1 for lidocaine and1.62 (0.52) µg ml–1 for mepivacaine), whilst plasmaconcentrations of lidocaine decreased significantly (0.81 (0.21)µg ml–1) at 60 min as opposed to plasma concentrationsof mepivacaine that did not vary (1.68 (0.41) µg ml–1).The observation of similar plasma concentrations of both anaestheticagents despite the use of almost double concentrations of mepivacainemay be explained by the vascular effects of mepivacaine (vasoconstriction)in IVRA19 and a much more sustained release to the systemiccirculation as compared with the predominatly vasodilatory effectsof lidocaine.20 Therefore, toxic plasma concentrations of mepivacaineare not reached rapidly as opposed to lidocaine 3 mg kg–1 when adverse events may appear within the first minute aftertourniquet release as reported by Simon and associates.8 Onthe other hand, the relatively prolonged nature of the increasein systemic mepivacaine concentrations might produce longerterm psychometric effects. However, we did not examine thisin our study.
Up to the present time, toxic plasma concentrations of localanaesthetics greater than 4 µg ml–1 for lidocaineand between 5 and 6 µg ml–1 for mepivacaine havebeen quoted.15 In our study, however, plasma drug concentrationswithin the first 5 min after tourniquet release were not measuredbut in that interval a case of dizziness and a case of bradycardiaoccurred. No patient in the lidocaine group showed plasma concentrationsgreater than 3 µg ml–1, although there was a greaterdispersion of lidocaine values at 5 min (predominately 2–3µg ml–1). In our study, there were no statisticallysignificant differences in the occurrence of adverse events,probably because of the small sample size. In the study of Simonand co-workers,8 five of the 10 patients showed plasma concentrationsof lidocaine greater than 4 µg ml–1 during the firstminute after release of the tourniquet. This is in contrastto findings of Rawal and associates18 who reported plasma concentrationsof lidocaine less than 1 µg ml–1 at this time. Itshould be noted, however, that in the first study8 high-performanceliquid chromatography was used for the assessment of plasmadrug concentrations in 10 patients, whereas in the second study18 gas chromatography in 20 patients. In the study of Simon andco-workers,8 although toxic plasma concentrations were obtainedin half of the patients, none of them experienced any adverseeffect. In contrast, in the study of Rawal and colleagues,18 four patients in the lidocaine group experienced dizziness ascompared with none in the mepivacaine group.
This preliminary study in a small number of patients indicatesthat mepivacaine 5 mg kg–1 has a closer profile of theideal local anaesthetic agent for IVRA than lidocaine 3 mg kg–1.Mepivacaine offered adequate intraoperative analgesia with noincidence of adverse effects on release of the tourniquet despitepersistence of plasma drug concentrations during the 60-minstudy period.
Acknowledgement
We thank Dr Marta Pulido for editing the manuscript and editorialassistance.
References
1 Estebe JP. Anesthésie locorégionale intraveineuse. Ann Fr Anesth Reanim 1999; 18: 663–73[ISI][Medline]
2 Steinberg RB, Reuben SS, Gardner G. The dose–response relationship of ketorolac as a component of intravenous regional anesthesia with lidocaine. Anesth Analg 1998; 86: 791–3[Abstract]
3 Reuben SS, Steinberg RB, Lurie SD, Gibson CS. A dose–response study of intravenous regional anesthesia with meperidine. Anesth Analg 1999; 88: 831–5[Abstract/Free Full Text]
4 Starzk F, Thiocoipé M, Favarel-Garrigues JF, Lassié P, Petitjean ME, Dabadie P. The use of 0.25% lidocaine with fentanyl and pancuronium for intravenous regional anesthesia. Anesth Analg 1997; 84: 777–9[Abstract]
5 Gentili M, Bonnet F, Bernard JM. Clonidine for intravenous regional anesthesia (IVRA) (Abstract). Anesthesiology 1996; 89: A826
6 Durrani Z, Winnie AP, Zsigmond EK, Burnett ML. Ketamine for intravenous regional anesthesia. Anesth Analg 1989; 68: 328–32[Abstract]
7 Ramsay MAE, Savege TM, Simpson BRJ. Goodwin R. Controlled sedation with alphaxalone-alphadolone. BMJ 1974; 2: 656–9[ISI][Medline]
8 Simon MAM, Gielen MJM, Vree TB, Booij LHDJ. Disposition of lignocaine for intravenous regional anaesthesia during day-case surgery. Eur J Anaesth 1998; 15: 32–7[ISI][Medline]
9 Davies JAH, Gill SS. Intravenous regional analgesia using bupivacaine. Anaesthesia 1981; 36: 1059–60[Medline]
10 Heath ML. Bupivacaine toxicity after Bier blocks. Anesthesiology 1983; 59: 481[ISI][Medline]
11 Heath ML. Deaths after intravenous regional anaesthesia. BMJ 1982; 285: 913–4[ISI][Medline]
12 Pitkänen MT, Suzuki N, Rosenberg PH. Intravenous regional anaesthesia with 0.5% prilocaine or 0.5% chloroprocaine. Anaesthesia 1992; 47: 618–9[ISI][Medline]
13 Simon MAM, Gielen MJM, Alberink N, Vree TB, van Egmond J. Intravenous regional anesthesia with 0.5% articaine, 0.5% lidocaine or 0.5% prilocaine. A double blind randomised study. Reg Anesth 1997; 22: 29–34[ISI][Medline]
14 Bader AM, Concepcion M, Hurley RJ, Arthur GR. Comparison of lidocaine and prolicaine for intravenous regional anesthesia. Anesthesiology 1988; 69: 409–12[ISI][Medline]
15 Mather LE, Cousins MJ. Local anesthetics and their current clinical use. Drugs 1979; 18: 185–205[ISI][Medline]
16 Kaiser H, Niesel HC, Biscoping J, Al-Rafa S, Klimpel L. Plasma prilocaine and mepivacaine concentrations after combined lumbosacral pleuxus block. Acta Anaesthesiol Scand 1992; 36: 689–91[ISI][Medline]
17 Vree TB, Beumer EMC, Lagerwerf AJ, Simon MAM, Gielen MJM. Clinical pharmacokinetics of R(+)- and S(–)-mepivacaine after high doses of racemic mepivacaine with epinephrine in the combined psoas compartment/sciatic nerve block. Anesth Analg 1992; 75: 75–80[Abstract]
18 Rawal N, Hallén J, Amilon A, Hellstrand P. Improvement in i.v. regional anaesthesia by re-exanguination before surgery. Br J Anaesth 1993; 70: 280–5[Abstract]
19 Kalman S, Björhn KC, Tholén EK, Lisander B. Mepivacaine as an intravenous regional block interferences with reactive hyperemia and decreases steady-state blood flow. Reg Anesth 1997; 22: 552–6[ISI][Medline]
20 Johns RA, DiFrazio CA, Longnecker DE. Lidocaine constricts or dilates rat arterioles in a dose-dependent manner. Anesthesiology 1985; 62: 141–4[ISI][Medline]
taufiksenjaya 