Balanced anesthesia is defined as the concurrent administration of several anesthetic drugs so that no single drug is given in a dosage sufficient to produce toxicity during or after surgery. Balanced anesthesia decreases the requirements for inhaled anesthetics, and thereby may limit their cardiovascular effects (1). IV lidocaine decreases the minimum alveolar concentration (MAC) of inhaled anesthetics in various species and the requirements for other anesthetics (2–9). Only one study (4) examined the dose-effect relationship between IV lidocaine and inhaled anesthetics over a wide range of lidocaine plasma concentrations. The aim of our study was to determine the effect of six pseudo steady-state plasma lidocaine concentrations on the MAC of isoflurane in cats. We hypothesized that lidocaine would dose-dependently decrease the MAC of isoflurane.
The study was approved by the Institutional Animal Care and Use Committee of the University of California, Davis. Six healthy domestic shorthair cats, 1- to 2-yr-old, weighing 5.1 ± 0.43 kg (mean ± sd) were used. Food was withheld from the cats for 12 h before the experiments were performed.
Anesthesia was induced with isoflurane in oxygen by use of an induction box and a face mask. The trachea was then intubated with a cuffed endotracheal tube, and anesthesia was maintained with isoflurane in oxygen via a Bain circuit using a fresh gas flow rate of 500 mL · kg−1 · min−1. The cats were allowed to breathe spontaneously. A catheter was passed through the lumen of the endotracheal tube so that its tip was positioned at the end of the tube. This catheter was connected to a Raman spectrometer (Rascal II, Ohmeda, Salt Lake City, UT) for continuous measurement of inspired and end-tidal oxygen, carbon dioxide, and isoflurane concentrations. The spectrometer was calibrated with three calibration gases of known concentrations (isoflurane 0.5%, 1.5%, and 2.5%) every 80 min, corresponding to its internal calibration interval. A 22-gauge, 2.5-cm catheter was inserted in a medial saphenous vein, and lactated Ringer’s solution was administered at 3 mL · kg−1 · h−1. A 20-gauge, 4.7-cm catheter was inserted in a jugular vein for blood sampling. Electrocardiogram (lead II) was continuously monitored. A Doppler crystal and occluding cuff were placed over a median artery for systolic blood pressure determination. A pulse oximeter probe was placed on the tongue for arterial hemoglobin oxygen saturation (Spo2) measurement. A thermistor, calibrated against a certified thermometer, was placed in the esophagus at the level of the mid-thorax and connected to the physiograph for continuous temperature monitoring. External heat (warm water and/or forced air blankets) was supplied as needed to maintain body temperature between 38.5°C and 39.5°C.
For each MAC determination, end-tidal isoflurane concentration was kept constant for at least 15 min. End-tidal gas samples (20 mL) were obtained by manual collection in a glass syringe over 7 to 12 breaths. End-tidal isoflurane and carbon dioxide concentrations were determined using an infrared analyzer calibrated every 80 min with three calibration gases of known concentrations (isoflurane 0.5%, 1.5%, and 2.5%) and the Raman spectrometer, respectively. These samples were collected in triplicate, and the results were averaged. Heart rate, respiratory rate, esophageal temperature, systolic blood pressure, and Spo2 were recorded. A 20-cm Martin forceps was positioned on the tail and closed to the first ratchet until gross purposeful movement was observed or 1 min had elapsed. Isoflurane concentration was increased or decreased by 10% after a positive (gross purposeful movement) or negative response to tail clamping, respectively. The new concentration was kept constant for at least 15 min, and the measurements were repeated. Isoflurane MAC was defined as the average of two successive isoflurane concentrations, one allowing and one preventing gross purposeful movement in response to tail clamping. MAC was determined in triplicate (i.e., minimum four tail clampings), and the average is reported.
The MAC of isoflurane was determined in each cat. End-tidal isoflurane concentration was then set at 0.75 times the individual’s MAC, and 15 min were allowed for stabilization. A bolus of 2 mg/kg of lidocaine (Xylocaine, AstraZeneca LP, Wilmington, DE) was administered IV over 5 s, via the medial saphenous catheter. Blood samples (1.5 mL) were collected from the jugular catheter immediately before and 1, 2, 4, 8, 16, 30, 60, 90, 120, 150, 180, 210, and 240 min after lidocaine administration. The blood was transferred to a tube containing EDTA, immediately centrifuged for 10 min, and the plasma was collected and frozen for later lidocaine concentration determination.
In addition to the instrumentation described above, 14 surface electrodes (F-E5GH-120 gold surface electrodes, Grass-Telefactor, West Warwick, RI) were placed on the cats’ scalps for continuous electroencephalogram recording. Lidocaine was administered IV via the medial saphenous catheter using a target-controlled infusion system consisting of a syringe pump and computer program (Rugloop I, Demed, Temse, Belgium). Individual pharmacokinetic data (obtained from Experiment 1) were used. With this system, the central compartment was rapidly loaded to the desired concentration. The infusion rate was then updated every 10 s as needed to maintain pseudo steady-state plasma concentration, according to the following equation: r = CT × V1(k10 + k12e−k21t + k13e−k31t), where r is the infusion rate, CT is the target plasma concentration, V1 is the volume of the central compartment, and k10, k12, k21, k13 and k31 are the microrate constants. Target plasma concentrations were 1, 3, 5, 7, 9, and 11 μg/kg. During this experiment, each cat was anesthetized twice with at least 2 wk separating successive studies. For each cat, three concentrations were randomly selected and arranged in an ascending order to decrease experimental time. The three remaining concentrations were arranged in an increasing order and were administered during the second study. Isoflurane MAC was determined in triplicate at each lidocaine concentration using the up-and-down method within each animal. Immediately before each MAC determination, a blood sample (1.5 mL) was collected from the jugular catheter and processed as in Experiment 1 for later lidocaine plasma concentration determination.
Lidocaine and mepivacaine were obtained from Sigma Chemical Company. MEGX was obtained from Alltech Associates (State College, PA).
The reference, calibration, and test samples were prepared by pipetting 0.5 mL of the samples into autosampler vials and vortexing the contents of each tube for 5–10 s. A mixture containing 0.60 mL of acidic acetonitrile (9:1 ACN: 1 M HOAc) including 200 ng/mL mepivacaine (internal standard) was added to each sample vial. After the addition of the internal standard, the contents of each vial was again mixed for 1 min on GlasCol multipulse rack vortexer (speed, 60–70; pulse, 60) and all samples were refrigerated at 4°C for 30 min. The samples were vortexed for approximately 20 s and centrifuged at 4300 rpm for 10 min at 4°C. The vials were transferred to an autosampler rack, and 50 μL of supernatant were injected for analysis.
Quantitative analyses were conducted using a Thermo TSQ Quantum triple quadruple mass spectrometer (Thermo Electron Corporations, San Jose, CA) equipped with an Agilent model 1100 liquid chromatography system (Agilent, Palo Alto, CA). Separation of the lidocaine, MEGX, and internal standard was performed on a Discovery C18 column (inner diameter = 50 × 2 mm; particle size, 3 μm) (Supelco, Bellefonte, PA). The mobile phase composed of a solvent mixture of acetonitrile with 0.05% trifluoroacetic acid (solvent A) and water with 0.05% trifluoroacetic acid (solvent B). The liquid chromatography pump provides a gradient of the acetonitrile from 30% to 90% over 10.5 min at a flow rate of 0.9 mL/min.
The concentration of lidocaine or MEGX in each sample was determined by the internal standard method using the peak area ratio and linear regression analysis. Both lidocaine or MEGX responses were linear and gave correlation coefficients (R2) of 0.99 or better. The technique was optimized to provide a minimum limit of quantitation of 10 ng/mL for each analyte.
Nonlinear least squares regression was performed on plasma lidocaine concentrations after IV bolus administration using WinNonlin Professional software (Pharsight, Mountain View, CA). Data were fitted to two- and three-compartment models, and the appropriate model was selected using Akaike’s information criterion (10,11). Standard compartmental equations were used to estimate pharmacokinetic variables for each cat.
MAC values at the different lidocaine plasma concentrations were analyzed by a repeated-measures analysis of variance using the Huynh-Feldt correction for violation of the sphericity assumption. The form of the response to lidocaine was examined using an orthogonal polynomial decomposition of the dose effect. Pearson product-moment correlation was used to characterize the relationship between lidocaine and MEGX plasma concentrations. Moreover, the contribution of MEGX to the effect of lidocaine on MAC was examined using a mixed model analysis of covariance. Significance was set at P < 0.05. Data are reported as mean ± sd.
The MAC of isoflurane (data pooled from all cats) in this study was 2.21% ± 0.17%. A three-compartment model best described the decline in plasma lidocaine concentrations over time for all cats. V1, k10, k12, k21, k13, and k31 were 0.308 ± 0.066 l/kg, 0.077 ± 0.019 1/min, 0.540 ± 0.251 1/min, 0.381 ± 0.149 1/min, 0.103 ± 0.065 1/min, and 0.040 ± 0.011/min, respectively. Actual lidocaine plasma concentrations were 1.06 ± 0.12 μg/mL, 2.83 ± 0.39 μg/mL, 4.93 ± 0.64 μg/mL, 6.86 ± 0.97 μg/mL, 8.86 ± 2.10 μg/mL, and 9.84 ± 1.34 μg/mL in the 1, 3, 5, 7, 9, and 11 μg/mL groups, respectively (means from samples collected before all MAC determinations in all cats). Mean MEGX concentrations were 0.27 ± 0.05 μg/mL, 0.90 ± 0.32 μg/mL, 1.28 ± 0.49 μg/mL, 1.53 ± 0.44 μg/mL, 2.29 ± 0.65 μg/mL, and 2.29 ± 0.55 μg/mL at lidocaine target plasma concentrations of 1, 3, 5, 7, 9, and 11 μg/mL, respectively. MEGX concentration strongly correlated with lidocaine plasma concentration (R2 = 0.81). The MAC of isoflurane was 2.21% ± 0.17%, 2.14% ± 0.14%, 1.88% ± 0.18%, 1.66% ± 0.16%, 1.47% ± 0.13%, 1.33% ± 0.23%, and 1.06% ± 0.19% at lidocaine target plasma concentrations of 0, 1, 3, 5, 7, 9, and 11 μg/mL, respectively. Lidocaine, at target plasma concentrations of 1, 3, 5, 7, 9, and 11 μg/mL significantly (P = 0.0016) decreased isoflurane MAC by −6% to 6%, 7% to 28%, 19% to 35%, 28% to 45%, 29% to 53%, and 44% to 59%, respectively (Fig. 1). The response was linear (P = 0.0007), with no significant nonlinear component observed. Once the effect of lidocaine was accounted for, MEGX did not have a significant influence on isoflurane MAC (P = 0.6155). Systolic blood pressure, Spo2, and body temperature were 78 ± 14 mm Hg, 98% ± 2%, and 39.2°C ± 0.3°C, respectively, for all cats at all times. Electroencephalographic recordings suggestive of convulsive activity were not observed at any time with any of the lidocaine plasma concentrations studied.
This study in cats showed that lidocaine at plasma concentrations ranging from 3 to 10 μg/mL decreases isoflurane MAC in a dose-dependent manner. These results are in agreement with a previous study in dogs (4) in which halothane MAC decreased from 10 to approximately 45% at lidocaine plasma concentrations between 3 and 11.6 μg/mL.
In the present study, no ceiling effect on MAC reduction was observed within the range of lidocaine concentrations studied. Isoflurane MAC decreased linearly as a function of lidocaine plasma concentration by as much as 52% at 9.8 μg/mL. In dogs, a ceiling effect on halothane MAC was observed at concentrations larger than 11.6 μg/mL; however, very few MAC determinations were performed at lidocaine concentrations larger than 10 μg/mL (4). In a study in rats, DiFazio et al. (2) reported a maximum reduction in cyclopropane MAC with a lidocaine plasma concentration of 1 μg/mL and no further reduction at larger doses. In both studies, a maximal MAC reduction of approximately 40% was observed. The causes of the discrepancies between the plasma concentrations needed for maximal MAC reduction in these two studies are not clear. Species differences in the sensitivity to lidocaine may be involved, although comparable lidocaine concentrations affected MAC similarly in species as different as cats, dogs, and horses (3–5). A difference in the interaction between lidocaine and cyclopropane and lidocaine and halothane is possible. A difference in the metabolism and/or elimination of lidocaine between rats and dogs may be involved because the production of active metabolites and the persistence of the parent drug and metabolites appear to vary among species (12).
Lidocaine metabolism results in the production of active metabolites such as MEGX, glycylxylidide, and 3-hydroxy-lidocaine (13,14). Wide species variations in the type and amount of metabolites produced have been described, and no data are available in the feline species (12). Among these metabolites, MEGX has been reported to have potent pharmacologic activity (15). MEGX concentrations were, on average, 26% of the lidocaine plasma concentrations. However, no significant contribution of MEGX to the effect of lidocaine on isoflurane MAC was detected.
The mechanism of lidocaine-induced reduction in inhalant MAC has not been elucidated. Several possibilities exist; both inhalant anesthetics and lidocaine act on voltage-gated sodium channels in the central nervous system (16) and thus their effects could be additive. Second, systemically administered lidocaine exerts analgesia at the spinal level (17), which is expected to decrease inhalant MAC. Finally, tonic inhibition of action potential spikes and of resting brain cell excitability by lidocaine has been reported; this could explain both the analgesic and MAC reducing properties of this drug (18).
No electroencephalographic activity suggestive of seizure was recorded at any lidocaine plasma concentration in this study. This is not surprising because in cats lightly anesthetized with halothane, convulsions were observed at a mean lidocaine plasma concentration of 19.6 μg/mL (19). Moreover, 0.6 MAC of isoflurane with 70% nitrous oxide increased the lidocaine plasma concentration at onset of seizure to 88 μg/mL (20). It is therefore likely that inhalant anesthetics protect against the central nervous system toxicity of lidocaine.
The use of a target-controlled infusion system with individual pharmacokinetic variables rapidly produced and maintained pseudo steady-state lidocaine plasma concentrations close to the targeted concentrations. The difference between target and actual plasma concentration may be partially attributable to the determination of pharmacokinetic variables based on venous rather than arterial lidocaine concentrations and to the fact that the arterial compartment was targeted and the venous compartment was sampled. It is not clear why the difference between target and actual plasma concentrations was significantly larger in the 11 μg/mL group than in the other groups. Saturation of lidocaine metabolic pathways is unlikely because the actual concentration was smaller than predicted.
In conclusion, lidocaine dose-dependently decreased isoflurane requirements in cats, supporting its use as part of balanced anesthesia techniques. However, further studies are warranted to determine the cardiorespiratory depressant effects of this combination.
The authors are grateful to Scott D Stanley, California Animal Health and Food Safety Laboratory System, for the lidocaine plasma concentration determinations, and to Sara Thomasy, for the pharmacokinetic modeling. They also would like to thank Karen Park and Cristina Moreno for technical assistance.
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