Effect of intravenous lidocaine and ketamine on the minimum alveolar concentration of isoflurane in goats

Veterinary Anaesthesia and Analgesia, 2007, 34, 125 131 doi:10.1111/j.1467-2995.2006.00301.x RESEARCH PAPER Effect of intravenous lidocaine and ketamine on the minimum alveolar concentration of isoflurane in goats Tom Doherty* MSc, MVB, Diplomate ACVA, Marcia A Redua* MSc, DVM, Patricia Queiroz-Castro* MSc, DVM, Christine Egger MVSc, DVM, Diplomate ACVA, Sherry K Coxà PhD & Barton W Rohrbachà VMD, MPH, Diplomate ACVPM *Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA àdepartment of Comparative Medicine, College of Veterinary Medicine, University of Tennessee, Knoxville, TN, USA Correspondence: Tom Doherty, Department of Large Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA. E-mail: tdoherty@utk.edu Abstract Objective To evaluate the effects of IV lidocaine (L) and ketamine (K), alone and in combination (LK), on the minimum alveolar concentration (MAC) of isoflurane (ISO) in goats. Study design Randomized crossover design. Animals Eight, adult mixed breed castrated male goats, aged 1 2 years weighing 24 51 kg. Methods Anesthesia was induced with ISO that was delivered via a mask. The tracheas were intubated and the animals ventilated to maintain an end-tidal carbon dioxide partial pressure between 25 and 30 mmhg (3.3 4 kpa). Baseline MAC (MAC B ) that prevented purposeful movement in response to clamping a claw was determined in triplicate. After MAC B determination, each goat received one of the following treatments, which were administered as a loading (LD) dose followed by a constant rate infusion, IV: L (2.5 mg kg )1 ; 100 lg kg )1 minute )1 ), K (1.5 mg kg )1 ;50lg kg )1 minute )1 ), L and K combination or saline, and the MAC (MAC T ) was re-determined in triplicate. Plasma concentrations of L and K were measured around each MAC point and the values averaged. Results The least-squares mean MAC B for all treatments was 1.13 ± 0.03%. L, K, and LK reduced (p < 0.05) MAC B by 18.3%, 49.6% and 69.4%, respectively. Plasma concentrations for L, K, and LK were 1617 ± 385, 1535 ± 251 and 1865 ± 317/ 1467 ± 185 ng ml )1, respectively. No change (p > 0.05) occurred with saline. Conclusion Lidocaine and K caused significant decreases in the MAC of ISO. The combination (LK) had an additive effect. However, the plasma L concentrations were less than predicted, as was the MAC reduction with L. Clinical relevance The use of L, K and the combination, at the doses studied, will allow a clinically important reduction in the concentration of ISO required to maintain general anesthesia in goats. Keywords goats, isoflurane, ketamine, lidocaine, minimum alveolar concentration. Introduction Intravenous lidocaine (L) has been used as a supplement to general anesthesia (de Clive-Lowe et al. 1958; Phillips et al. 1960; Bartlett & Hutaserani 1961) and its administration perioperatively decreases post-operative pain (Groudine et al. 1998; Koppert et al. 2004). Intravenous L reduced the minimum alveolar concentration (MAC) of isoflurane (ISO) in dogs (Muir et al. 2003; Valverde et al. 2004), cats (Pypendop & Ilkiw 2005), and horses 125

(Dzikiti et al. 2003), the MAC of halothane in horses (Doherty & Frazier 1998) and dogs (Himes et al. 1977), and the MAC of cyclopropane in rats (DiFazio et al. 1976). There are no published data concerning the effects of L on the MAC of volatile anesthetics in ruminants. Ketamine (K), an N-methyl-D-aspartate (NMDA) antagonist, with analgesic and anesthetic properties, is widely used to induce anesthesia and as a supplement to general anesthesia. Ketamine reduced the MAC of ISO (Muir et al. 2003; Solano et al. 2006) and enflurane (Schwieger et al. 1991) in dogs and the MAC of halothane in horses (Muir & Sams 1992). The purpose of this study was to determine the effects of L, K, and the combination (LK) on the MAC of ISO (ISO MAC ) in goats. It was hypothesized that L, K, and LK would reduce ISO MAC. Materials and methods Animals Eight healthy, adult castrated goats of mixed breed, aged 1 2 years with a body mass between 24 and 51 kg, were used in the study. Food was withheld for 16 hours prior to anesthesia, but access to water was allowed. The University of Tennessee Animal Care and Use Committee approved the study. Experimental design The study was a randomized crossover design. Goats were studied on four occasions, receiving each treatment, with a minimum of 8 days between treatments. Anesthesia Anesthesia was induced with ISO in oxygen delivered, via a mask, from a circle system. Following endotracheal intubation, anesthesia was maintained with ISO in oxygen (3 L minute )1 ), using a small animal anesthetic machine (North American Drager, Telford, PA, USA). Ventilation was controlled to maintain the end-tidal carbon dioxide partial pressure between 25 and 30 mmhg (3.3 4 kpa). Goats were positioned in left lateral recumbency. Lactated Ringer s was infused, via a catheter, at 3 ml kg )1 hour )1 into the right jugular vein. End-tidal ISO and carbon dioxide values were monitored continually with an infrared gas analyzer (Criticare System Inc., Waukesha, WI, USA). Samples were drawn from the endotracheal tube at a rate of 50 ml minute )1. The unit was calibrated at the start of each experiment with the calibration gases supplied by the manufacturer (1% ISO in 5% CO 2 and 60% N 2 O; Criticare Systems Inc.). Body temperature was monitored using an esophageal probe (Criticare System Inc.), and a circulating warm-water blanket was used to maintain body temperature within the normal range (38.2 39.5 C). Arterial blood pressure was monitored continually from a 22 SWG catheter placed in the medial branch of the rostral auricular artery, using a disposable transducer (Baxter Healthcare Corporation, Irvine, CA, USA) and monitor (Criticare Systems Inc.). The middle of the sternum was taken as the zero point when the goats were in lateral recumbency. Transducers underwent static calibration at the start of the experiment using a mercury manometer. Approximately 45 minutes after induction of anesthesia, and with the end-tidal ISO (ET ISO ) concentration held constant at 1.3% for at least 20 minutes, the baseline MAC (MAC B ) for ISO was determined. A noxious stimulus, which consisted of clamping a claw between the jaws of a Vulsellum forceps (Miltex, Lake Success, NY, USA), was administered. The forceps were closed tightly to the first or second ratchet, depending on the claw size, just below the coronary band, and the claw was moved continually for a maximum of 1 minute, or until purposeful movement occurred. Purposeful movement was defined as gross movement of the head or extremities. If purposeful movement occurred, the ET ISO was increased by 0.1 vols%, otherwise, it was decreased by 0.1 vols% and the stimulus was re-applied following a 20-minute equilibration period. The order in which the claws were clamped was randomized. The ISO MAC was defined as the mean of the ET ISO values at which movement did and did not occur (Quasha et al. 1980). The MAC B was determined in triplicate, and the mean value was taken as the MAC B for that animal. Drug administration Following MAC B determination, each goat received one of four treatments IV through the jugular catheter. A loading dose (LD), made up to a final volume of 10 ml in normal saline or an equal volume of normal saline (control), was administered over 3 minutes and a constant rate infusion (CRI) was delivered using a syringe pump (Medifusion 126 Ó 2006 The Authors. Journal Compilation Ó 2006 Association of Veterinary Anaesthetists, 34, 125 131

2010i, Medox Inc, Duluth, GA, USA). Ketamine and L were mixed in normal saline for infusion in combination. The CRI was made up in normal saline and delivered at 1 ml minute )1 for all groups, for the duration of the study, using a disposable 60 ml syringe (Kendall, Monoject, Tyco Healthcare Group, Mansfield, MA, USA). The treatment groups were as follows. 1 Group 1: saline infusion. 2 Group 2: lidocaine (Venco Inc., St Joseph, MO, USA; LD 2.5 mg kg )1 ; CRI 100 lg kg )1 minute )1 ). 3 Group 3: ketamine (Fort Dodge Animal Heath, Fort Dodge, IA, USA; LD 1.5 mg kg )1 ; CRI 50 lg kg )1 minute )1 ). 4 Group 4: lidocaine (LD 2.5 mg kg )1 ; CRI 100 lg kg )1 minute )1 ) and ketamine (LD 1.5 mg kg )1 ; CRI 50 lg kg )1 minute )1 ) in combination. The LD and infusion rate of L were based on published values for dogs (Valverde et al. 2004) and horses (Doherty & Frazier 1998), while the K loading and infusion doses were based on published kinetic data from sheep (Waterman & Livingston 1978). Once the LD was administered, the ET ISO was decreased by 0.1 vols% following saline treatment and by 0.3 vols% following L, K or LK treatment. Post-treatment MAC (MAC T ) determination began 45 minutes after the start of the CRI with the ET ISO held constant for at least 20 minutes. MAC T was determined in triplicate as above and the mean value was used for statistical analysis. Two blood samples (5 ml) from the left jugular vein were collected into lithium heparin tubes at the time of each MAC T determination for L and K analysis. One sample corresponded to the ET ISO at which there was a purposeful response to the noxious stimulus and the other to the ET ISO at which no response occurred. As MAC T was performed in triplicate, a total of six blood samples were collected at each experiment. The plasma was harvested and stored at )80 C until analysis. The mean value of the three samples was used in determining the plasma drug concentrations at the time of MAC T determination. Drug analysis Lidocaine and its metabolites, monoethyglycinexylidide (MEGX) and glycinexylidide (GX), and K were analyzed using a modified extraction method of Flood et al. (1980). Briefly, previously frozen plasma samples were thawed and vortexed and 1 ml was transferred to a clean test tube containing 25 ll of internal standard (50 lg ml )1 trimethomprim). About 200 ll of1m sodium hydroxide was added, followed by 5 ml of methylene chloride. Tubes were placed on a tube rocker for 15 minutes, followed by centrifugation for 20 minutes at 1302 g. The organic layer was removed to a clean tube and evaporated to dryness under a steady stream of nitrogen gas. Samples were reconstituted in 1 ml of mobile phase and 100 ll was injected into the high-performance liquid chromatographic (HPLC) system. The analyses were conducted using reversedphase HPLC. The system consisted of a 2996 separations module and a 2487 UV detector (Waters, Milford, MA, USA). Separation was attained on a Waters Xterra RP 18 4.6 150 mm (5 lm) with an Xterra guard column. The mobile phase was a mixture of (A) 0.03 M potassium dihydrogen phosphate buffer (ph 6 with phosphoric acid) and (B) acetonitrile. The mixture was initially pumped at 89% A and 11% B and was linearly changed to 87% A and 13% B over 17 minutes, followed by a return to initial conditions. The flow rate was 1.1 ml minute )1 and the column temperature was ambient. Ultraviolet absorbance was measured at 205 nm. Standard curves for plasma analysis were prepared by adding K, L, and metabolites to untreated goat plasma to produce a linear concentration ranging from 50 to 7000 ng ml )1. Spiked standards were treated exactly as K and L plasma samples. Recovery ranged from 83% to 92% for all compounds. Intra-assay variability ranged from 0.5% to 6.8% and interassay variability ranged from 7.3% to 10.1% for 75, 750 and 6000 ng ml )1, respectively. The limit of quantification was 25 ng ml )1. Statistical analysis Data were analyzed using SAS version 9.1 (SAS Institute, Cary, NC, USA). A mixed model ANOVA was used to determine the effect of treatment on percentage change in MAC. Independent variables included in the model were treatment, time from baseline to treatment MAC (MAC T ), week and the interaction between week and treatment. Goat was included as a random variable in the model. A test for difference in MAC B among treatment groups was done using the same model but substituting the time to baseline for time to post-treatment MAC (MAC T ). Ó 2006 The Authors. Journal Compilation Ó 2006 Association of Veterinary Anaesthetists, 34, 125 131 127

In both models, a Tukey-Kramer multiple range test was used to determine statistical significance among levels of treatment and week. MAC B and MAC T are expressed as least-squares mean values. Percentage change in MAC for each of the treatment groups was calculated using the least-squares mean estimate for MAC B and MAC T generated from the ANOVA model and was calculated as [(MAC T ) MAC B )/ MAC B ] 100. Differences in concentrations (ng ml )1 ) of L and K in plasma, among treatments, were tested using Student s t-test. Time to extubation is expressed as the mean and standard deviation. A p-value of <0.05 was considered significant in all tests. Results The baseline and post-treatment values for ISO MAC are shown in Table 1. Data for MAC values are presented as the least-squares mean ± SE. The mean MAC B for all treatments was 1.13 ± 0.05 vols%. Saline administration did not significantly change (p > 0.05) MAC. Lidocaine, K, and LK significantly (p < 0.05) reduced MAC by 18.3%, 49.6% and 69.4%, respectively. The mean times to determine MAC B and MAC T did not differ among treatments (Table 1). There was no significant effect of time to determine MAC T on the percentage change in MAC B and the percentage change in MAC B was not affected by the order of treatment (week). Recovery from anesthesia was uneventful and extubation was completed by 6.6 ± 1.4, 6.3 ± 1.3, 6 ± 1.6 and 5.8 ± 1.3 minutes in treatment groups 1, 2, 3 and 4, respectively, following MAC T determination. Goats did not exhibit lameness following recovery, thus it was presumed that there was no residual pain from clamping the claws. Mean arterial blood pressure was >70 mmhg at all times during the study. The plasma concentrations of K and L at the times of each MAC T determination are illustrated in Fig. 1 and the plasma concentrations of MEGX and GX are presented in Table 2. Drug concentrations did not differ among treatments. Discussion The MAC B is consistent with previously reported values for goats, using the same methodology (Doherty et al. 2002). Intravenous L caused a significant reduction in ISO MAC. However, when compared with results from other species, the reduction in MAC (18.3%) was less then expected. In dogs, a lower infusion rate of L (50 lg kg )1 minute )1 ) reduced the ISO MAC by 18.7% in one study (Valverde et al. 2004) and by 29% in another (Muir et al. 2003). In horses, L (50 lg kg )1 minute )1 ) reduced the ISO MAC by 25% (Dzikiti et al. 2003) and the MAC of halothane by up to 70% at 100 lg kg )1 minute )1 (Doherty & Frazier 1998). Comparison of the percentage reduction in the ISO MAC among species initially gives the impression that goats are less sensitive than the dog and horse to the MAC-reducing effects of L. However, inspection of L plasma concentrations reveals that the concentrations were much lower than values achieved in the dog and horse studies. In the present study, the mean L concentration at the time of MAC T determination was 1617 ng ml )1. In dogs, an L infusion of 50 lg kg )1 minute )1 Table 1 Effect of IV lidocaine (100 lg kg )1 minute )1 ), ketamine (50 lg kg )1 minute )1 ) and lidocaine plus ketamine at the same doses on the MAC of isoflurane in goats (n ¼ 8) Treatment Baseline MAC B Post-treatment MAC T Change (%) Time to MAC B à Time to MAC T Saline 1.14 ± 0.05 a 1.15 ± 0.04 +0.9 a 201 ± 14 a 217 ± 17 a Lidocaine 1.20 ± 0.04 a 0.98 ± 0.06* )18.3 b 207 ± 14 a 207 ± 17 a Ketamine 1.11 ± 0.05 a 0.56 ± 0.04* )49.6 c 242 ± 14 a 255 ± 17 a Lidocaine/ketamine 1.08 ± 0.06 a 0.33 ± 0.04* )69.4 d 244 ± 14 a 226 ± 17 a MAC data are expressed as least-squares (LS) mean ± SE. *Significantly different from MAC B (p < 0.05). Percentage change from baseline MAC ¼ [(MAC T ) MAC B )/MAC B )] 100. àtime in minutes (LS mean ± SE) from induction to complete MAC B determination in triplicate. Time in minutes (LS mean ± SE) from start of CRI to complete MAC T determination in triplicate. a,b,c,d Values in the same columns with the same letter are not statistically different (p > 0.05). MAC, minimum alveolar concentration; CRI, constant rate infusion. 128 Ó 2006 The Authors. Journal Compilation Ó 2006 Association of Veterinary Anaesthetists, 34, 125 131

Figure 1 Mean (±SD) plasma concentrations (ng ml )1 ) and mean (±SD) sampling times of lidocaine ( ), ketamine ( ), lidocaine (d) following lidocaine/ketamine treatment and ketamine (r) following lidocaine/ketamine treatment at the time of each minimum alveolar concentration (MAC) T determination. MAC T was determined in triplicate hence there are three concentrations and three sampling times for each treatment. Each value represents the mean of two samples (one before and one after the MAC point) from eight goats. Table 2 Mean (±SD) plasma concentrations (ng ml )1 ) of GX and MEGX at the time of post-treatment MAC (MAC T ) determination Treatment MEGX GX Lidocaine 140 ± 57 a 175 ± 71 a 227 ± 93 a 2.88 ± 0.99 a 3 ± 0.93 a 2.63 ± 1.06 a Lidocaine/ketamine 215 ± 135 a 261 ± 134 a 299 ± 14 a 3.13 ± 0.83 a 3 ± 0.76 a 3.25 ± 1.83 a Each value represents the mean of two samples from eight goats at the time of each MAC T determination. MAC T was determined in triplicate hence there are three concentrations of each metabolite for each treatment. a Values in the same columns with the same letter are not statistically different (p > 0.05). MAC, minimum alveolar concentration; GX, glycinexylidide; MEGX, monoglycinexylidide. achieved median concentrations of approximately 1500 ng ml )1 (Valverde et al. 2004), and values of approximately 3000 4000 ng ml )1 were reported for the same infusion rate in ISO-anesthetized horses (Dzikiti et al. 2003; Feary et al. 2005). In halothane-anesthetized horses, an L infusion of 100 lg kg )1 minute )1 resulted in plasma concentrations between 3000 and 7000 ng ml )1 (Doherty & Frazier 1998). The reason for the lower than expected plasma L concentrations cannot be determined from this study and would require investigation of L kinetics in this species. In mammals, L is primarily metabolized and eliminated by the liver. There appears to be no data on L kinetics in goats, but in awake sheep (Morishima et al. 1979) the total body clearance of L was higher than in awake horses (Feary et al. 2005). This indicates that the lower than expected plasma concentrations of L in these goats may be due to a more rapid clearance. The main binding plasma proteins for L are a 1 -acid glycoprotein (AAG) and albumin. Changes in concentrations of these proteins, especially AAG, could influence the plasma concentration of L. However, total plasma protein values in the goats were within normal limits. The mechanism of L-induced MAC reduction is uncertain and may be the result of its analgesic or sedative effects or the combination. The analgesic effects of IV L have been documented in clinical trials in humans (de Clive-Lowe et al. 1958; Bartlett & Hutaserani 1961; Groudine et al. 1998; Koppert et al. 2004). In ponies, EEG analysis indicated that IV L, at plasma concentrations in the range of 1500 3000 ng ml )1, provided antinociception during surgery (Murrell et al. 2005). Lidocaine provided somatic analgesia at concentrations lower than 1000 ng ml )1 in conscious horses (Robertson Ó 2006 The Authors. Journal Compilation Ó 2006 Association of Veterinary Anaesthetists, 34, 125 131 129

et al. 2005) but not in cats (Pypendop et al. 2006). Nevertheless, systemic L also appears to have sedative effects. Intramuscular L potentiated the hypnotic effect of propofol in human subjects (Senturk et al. 2002). The sedative effect of L may be dose-related as sedation was not observed in conscious horses at plasma L concentrations <1000 ng ml )1 (Robertson et al. 2005), but was observed in horses with plasma L concentrations between 1850 and 4500 ng ml )1 (Meyer et al. 2001). Ketamine caused a decrease of approximately 50% in ISO MAC and the mean plasma K concentration was 1535 ng ml )1 at the time of MAC T determination. In horses, plasma K concentrations >1000 ng ml )1 decreased the MAC of halothane, but MAC reduction began to plateau at approximately 2000 ng ml )1 (Muir & Sams 1992). Ketamine decreased enflurane MAC in dogs in a dose-dependent manner and caused a reduction of approximately 20% at a plasma concentration of 2400 ng ml )1 (Schwieger et al. 1991). In ISOanesthetized dogs a much lower infusion rate (10 lg kg )1 minute )1 ) caused a 25% reduction in the ISO MAC (Muir et al. 2003). However, the plasma K concentrations were not reported. A more recent study in ISO-anesthetized dogs reported a MAC reduction between 27% and 44% at plasma K concentrations comparable with those reported in the present study (Solano et al. 2006). As in the case of L, the MAC-reducing effects of K may be related to its analgesic or sedative actions. The analgesic effects of K are well accepted. The intraoperative use of low-dose K in dogs (10 lg kg )1 minute )1 ) followed by a CRI (2 lg kg )1 minute )1 ) post-operatively significantly decreased pain scores in dogs (Wagner et al. 2002). Sedation was not present at these infusion rates post-operatively. In human patients, systemic K has been shown to improve postoperative analgesia and the plasma K concentration producing clinical analgesia is 100 150 ng ml )1 (Clements & Nimmo 1981). In dogs, it was not possible to determine if the MAC reduction with K was a consequence of its analgesic or sedative effects (Muir et al. 2003). The decrease in MAC following K administration was paradoxically associated with an increase in the bispectral index (Muir et al. 2003). This would indicate a decrease in the depth of anesthesia with K administration, thereby inferring that analgesia is the reason for MAC reduction. However, K has been shown to have sedating effects as demonstrated by its ability to enhance propofol-induced sedation in humans (Frey et al. 1999). The combination of L and K caused a profound decrease in the ISO MAC and the effect was additive. A synergistic effect was reported from a study in mice which showed that concurrent administration of L reduced the sedative ED 50 of K (Barak et al. 2001). The design of the present study was not suitable for determination of synergy, as this would necessitate a determination of the dose of each drug which causes a 50% reduction in MAC and subjecting the data to an isobolographic analysis. It was concluded that L and K and the combination caused a clinically significant decrease in the ISO MAC. The percentage MAC reduction with L was less than expected and this was considered to be a result of lower than predicted plasma concentrations of L. The combination had an additive effect on MAC reduction. References Barak M, Ben-Shlomo I, Katz Y (2001) Changes in effective and lethal doses of intravenous anesthetics and lidocaine when used in combination in mice. J Basic Clin Physiol Pharmacol 12, 315 322. Bartlett EE, Hutaserani O (1961) Xylocaine for relief of postoperative pain. Anesth Analg 40, 296 304. Clements JA, Nimmo WS (1981) Pharmacokinetics and analgesic effect of ketamine in man. Br J Anaesth 53, 27 30. de Clive-Lowe SG, Desmond J, North J (1958) Intravenous lignocaine anaesthesia. Anaesthesia 13, 138 146. DiFazio CA, Niederlehner JR, Burney RA (1976) The anesthetic potency of lidocaine in the rat. Anesth Analg 55, 818 821. Doherty TJ, Frazier DL (1998) Effect of intravenous lidocaine on halothane minimum alveolar concentration in ponies. Eq Vet J 30, 300 303. Doherty TJ, Rohrbach BW, Geiser DR (2002) Effect of acepromazine and butorphanol on isoflurane minimal alveolar concentration in goats. J Vet Pharmacol Ther 25, 65 67. Dzikiti TB, Hellebrekers LJ, van Dijk P (2003) Effects of intravenous lidocaine on isoflurane concentration, physiological parameters, metabolic parameters and stress-related hormones in horses undergoing surgery. J Am Vet Med Assoc 50, 190 195. Feary DJ, Mama KR, Wagner AE, et al. (2005) Influence of general anesthesia on pharmacokinetics of intravenous lidocaine infusion in horses. Am J Vet Res 66, 574 580. Flood JG, Bowers GN, McComb RB (1980) Simultaneous liquid-chromatographic determination of three anti- 130 Ó 2006 The Authors. Journal Compilation Ó 2006 Association of Veterinary Anaesthetists, 34, 125 131

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