Intravenous regional anaesthesia (IVRA), first described by Bier in 1908, remains a popular technique for short-duration surgery on the hand and forearm and to a lesser extent on the lower limb, especially if a tourniquet is to be applied .
Good surgical anaesthesia can be achieved rapidly following injection of the local anaesthetic agent and recovery is fast after release of the tourniquet. IVRA is a safe regional anaesthesia technique when a suitable local anaesthetic agent is administered. Bupivacaine is contraindicated because of its cardiotoxicity . Recently, we compared the clinical results of articaine and the most commonly used local anaesthetics, prilocaine and lignocaine . Lignocaine was considered a suitable agent for IVRA.
Little has been published about the pharmacokinetics of lignocaine after IVRA. The aim of this investigation was to study the pharmacokinetics of lignocaine in 10 patients undergoing intravenous(i.v.) regional anaesthesia.
The study was approved by the ethical committee of the Medisch Spectrum Twente, and written informed consent was obtained from 10 patients (ASA Grade I-II, classification according to the American Society of Anesthesiologists), scheduled for surgery of the hand or forearm (Table 1).
Three men and seven women were included in the study. The mean (±SD) body weight was 72.9±12.5 kg, and age 42.6±12.8 years.
No premedication was given. An 18-gauge cannula was introduced into a suitable vein in the dorsum of the hand of the arm to be treated. A similar cannula was introduced into a vein in the other arm, and the radial artery of that arm was cannulated for continuous invasive blood pressure monitoring and intermittent blood sampling.
Oxygen saturation via a Datex 'Satlite' pulseoximeter (Datex, Division of Instrumentarium, Helsinki, Finland), ECG, pulse rate (3 lead, I,II and III via HP 78353 B, Hewlett-Packard, Andover, USA) and continuous invasive arterial blood pressure were monitored from the time of the first venous cannulation until withdrawal of the final blood sample. A 12-lead electrocardiogram was recorded on a Hellige Multiscriptor EK 33 (Hellige, Freiburg, Germany) in all patients, before injection of lignocaine, and 5 and 15min after deflation of the tourniquet.
The arm was exsanguinated by means of an Esmarch bandage, after which a double cuffed (2 × 7.5 cm width) pneumatic tourniquet(VBM Medizintechnik GmbH, Sulz am Neckar, Germany), placed around the arm above the elbow, was inflated to 150 Torr above normal systolic pressure or 300 Torr, whichever was higher.
Lignocaine 0.5% was obtained from the Hospital Pharmacy. Forty(40) mL of the lignocaine 0.5% solution (40 × 5 mg mL−1=200 mg=0.855 mmol) were injected over a period of 30 s. Any skin reactions or subjective complaints were noted. The development of sensory blockade over the distributions of the median, radial and ulnar nerves was assessed by pinprick. Onset of the surgical analgesia was defined as the period from the end of the injection of the local anaesthetic to the loss of pinprick sensation in the distribution of all three nerves.
A total of 15 arterial blood samples were taken; one immediately before injection and then at 10-min intervals, starting 10 min after completion of injection, until the tourniquet was released (t=0); thereafter blood samples were drawn at intervals of 1, 5, 10, 15, 20, 25, 30, 45, 60, 75 and 90 min. In no case was the tourniquet released within 30 min of completing the injection. Deflation occurred within 10 s.
Blood was collected in tubes containing Li-heparin. The samples were centrifuged at 3000g, the plasma separated and stored at −20°C until analysis.
The plasma concentration of lignocaine (C14H22N2O; CAS number 137-58-6; MW 234.33; HCl H2O salt CAS number 73-78-9, MW 288.8) was determined by highperformance liquid chromatography (HPLC) as a modification of the method described by Lindberget al..
Briefly the method is as follows: Column: Spherisorb 5 ODS, 250 mm × 4.6 mm, UV detection was achieved at 210 nm, Mobile phase: (4g H3PO4, 0.6 g TMACI in 1litre of water) and acetonitrile (4:6, v/v) at 1.5 mL min−1 flow rate.
Plasma(0.3 mL) was deproteinized with acetonitrile (0.3 mL), vortexed and centrifuged at 3000g. 50 μL were injected onto the column. The limit of measurement was 0.1 μg mL−1.
The inter- and intra-day coefficients of variance for lignocaine were less than 5%.
Pharmacokinetic parameters were calculated using a two-compartment model with the MW/Pharm computer package (Mediware®, Groningen, The Netherlands) .
Cmax was the maximum plasma concentration read from the fitted plasma concentration-time curve (r2>0.98), and tmax the time at which Cmax occurred. The elimination half-life (t1/2β) values were calculated from In2/β, where the elimation rate constant β is calculated by log-linear regression analysis of the terminal log-linear phase.
AUC0-t was the area under the plasma concentration-time curve and was calculated using the linear trapezoidal rule, using Ct/β, with Ct (t=90) being the last measured concentration.
Total body clearance (CL) is described CL=Dose/AUC0-t
Vd = Dose/Co, the volume of distribution in the central compartment
Vβ = volume of distribution in the second compartment =CL/β
Vss = Dose AUMC0-t/AUC0-t2, the volume of distribution at steady-state:
Mean residence time (MRT) = AUMC0-t/AUC0-t where AUMC0-t is the area under the moment curve from zero to t=90.
The mean onset time for the local anaesthetic action of lignocaine was 11.2±5.1 min. There was no trend towards a fixed sequence, radial, median, ulnar in the development of sensory blockade.
Satisfactory surgical conditions, evidenced by good sensory blockade were reached within 20 min, and no additional analgesics were required.
None of the patients exhibited objective symptoms of toxicity, either local or systemic after releasing the tourniquet, nor were there any subjective complaints. No changes in blood pressure, heart rate or oxygen saturation were observed at any time during the procedure, nor after deflation of the tourniquet.
Figure 1 shows the mean plasma concentration-time curve of lignocaine in 10 patients after the tourniquet was released. Plasma concentrations were below the limit of measurement of the HPLC assay before the tourniquet was released and rose immediately to maximal concentrations within 1 min in 8 out of 10 patients.
The elimination of lignocaine is biexponential, with a t1/2α of 4.3±2.1 min and a t1/2β of 79.1±31.2 min.
Table 2 shows the mean values of the pharmacokinetic parameters of eight patients, who showed rapid release from the exsanguinated area. Two patients showed slow(er) absorption, and the pharmacokinetic constants of lignocaine under these circumstances are shown in Table 3. Table 4 shows the individual and mean (±SD) plasma concentrations of lignocaine in the 10 patients after release of the tourniquet.
Many different local anaesthetic agents have been used for IVRA. At the beginning of the 20th century Bier employed 40 mL 0.5% procaine . Lignocaine was first used in 1963 , and prilocaine in 1964 . The use of chloroprocaine may lead to thrombophlebitis , venous irritation and urticaria. Bupivacaine is contraindicated because of its potential for cardiotoxicity and fatal complications have been reported following i.v. injection [10-13], an event that occurs with this technique when the tourniquet is released accidentally.
The ideal agent for IVRA should achieve rapid onset of good surgical anaesthesia with low CNS and cardiotoxicity. Lignocaine has proved to be a safe local anaesthetic agent for IVRA [3, 14].
In 8 out of 10 patients investigated in the present study, the rate of increase in systemic plasma concentration of lignocaine following tourniquet release was so rapid that the maximum value was already detectable in the first blood sample drawn at 1 min. Thereafter the pattern of elimination of the drug corresponded with a biexponential decay with t1/2α of 4.3±2.1 min, and a t1/2β of 79.1±31.2 min. The pharmacokinetic data reproduced in Table 1 correspond with those in previous reports [15, 16].
In two patients (no. 9 and 10) the lignocaine from the exsanguinated arm entered the systemic circulation much more slowly, so slowly in the case of patient no. 9 that it exhibited the characteristics of a one-compartment system with extravascular disposition, such as might be expected following intramuscular (i.m.) injection. Initial re-entry of lignocaine into the systemic circulation was also delayed in patient no. 10; in this case it was associated with a short lag time. Thereafter, the plasma concentration-time curve could be described as a two-compartment elimination model following extravascular administration.
However, we are confident that extravascular injection can be excluded in these two patients; the canulae were clearly situated in the venous lumen, and there was no visible or palpable extravasation of the fluid during injection. It may be that increased capillary permeability permitted a larger than usual leakage of lignocaine into the surrounding tissues, and that this resulted in a slower systemic uptake after the tourniquet was released. Certainly a greater degree of tissue uptake and distribution, with subsequent slow release, would explain the discrepancy between the rate of increase in the plasma concentration of lignocaine observed in patients no. 9 and 10 and the remaining 8. Local anaesthetic agents will also leak from damaged vessels into the surgical field, and could, theoretically, reduce the volume available for release into the systemic circulation on deflation of the tourniquet. However, it is unlikely that there would be such a wide variation in the amount of drug lost into the wounds of patients undergoing substantially similar forms of surgery, as was the case in the present study (Table 1). There may also have been variations in the efficiency of the exsanguination, although an identical technique was employed in all 10 patients. Deflation was achieved within 10 s . The rapid increase in systemic plasma concentration of lignocaine observed in eight of the patients could be explained by poor exsanguination resulting in reduced tissue absorption and a rapid rate of increase in plasma concentration on release of the tourniquet. However, exsanguination was performed in all cases by an experienced professional employing a scrupulously standardized technique. It seems to us inconceivable that under these conditions exsanguination would be inadequate in 80% of the patients studied.
Lignocaine is metabolized by cytochrome P450 isoenzymes, N-hydroxylation, N-dealkylation (MEGX, GX), and 4-hydroxylation being the principal reactions [15, 16, 18-21]. Tissue P450 would have been capable of metabolizing lignocaine in substantial quantities to influence the amount released into the systemic circulation following a 30-min period of exsanguination of the arm. Moreover there would have to be a marked difference in the rate of metabolism in a small number of individuals in order to explain the observed discrepancy in plasma concentration between the two patients in question and their eight companions.
In conclusion, lignocaine is a suitable and safe agent for IVRA with rapid onset of good surgical anaesthesia. After releasing the tourniquet, absorption of lignocaine from the exsanguinated forearm was so fast that the maximum plasma concentration of 5.16±1.74 μg mL−1 was reached at 1 min, thereafter it is rapidly eliminated with a t1/2β of 80 min. Despite almost identical procedures in day-case surgery, two patients showed a slow(er) increase in lignocaine concentration in the systemic circulation, and one patient a slower elimination in the time frame of 90 min. It is considered important that local anaesthetic agents should be eliminated or at least metabolized to a nonactive derivative before the patient is discharged.
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