Effect of Two Constant Rate Infusions of Lidocaine on the Anesthetic Requirement of Isoflurane in Pigs (Sus scrofa domestica)
Lidocaine infusions are used in several species to reduce anesthetic requirements and decrease the negative impact of high inhalant concentrations on the cardiorespiratory system. The objective of this study was to determine the effect of 2 dosages of lidocaine administered as constant rate infusions on isoflurane requirement (IR) in swine and to measure plasma concentrations of lidocaine and, its metabolite, monoethylglycinexylidide (MEGX) corresponding to IR. Six healthy commercial-bred pigs aged 74 ± 5.3 d and weighing 31.7 ± 5.4 kg were anesthetized and maintained with isoflurane during mechanical ventilation. Baseline IR was determined using a supramaximal mechanical stimulus on the dewclaw of the hind limb. After randomization for treatment allocation, lidocaine (loading dose; 2 mg/kg IV) was administered, followed by either 50 (CRI50) or 200 (CRI200) µg/kg/min and maintained for 30 min to reach a steady state and redetermination of IR. The study was repeated with the alternate infusion rate after a minimum washout period of 6 d. Lidocaine and MEGX plasma concentrations were quantified with HPLC and compared between groups. Heart rate, arterial blood pressure, end-tidal partial pressure of carbon dioxide, body temperature, and time to extubation were measured and compared between treatment groups. Baseline IR was 1.77% ± 0.34%. In pigs receiving CRI50 (1.53%) and CRI200 (1.61%), IR was lower than baseline IR, with a sparing effect of 7.8% (P = 0.046) and 13.4% (P = 0.041), respectively. Plasma concentrations of MEGX were inversely correlated to IR in pigs receiving CRI50 but not CRI200. Cardiovascular variables did not differ between treatments. Time to extubation was similar between groups (P = 0.92), 10.2 ± 4.5 min in subjects receiving CRI50 and 11 ± 3.6 min in pigs receiving CRI200. Infusion of lidocaine produced a nonlinear sparing effect on isoflurane requirement without appreciable, clinically relevant changes in cardiovascular variables or extubation time.
Introduction
Pigs are considered one of the major animal species used in translational research. They are increasingly being used as an alternative to dogs or primates as the nonrodent species of choice for preclinical toxicological testing of drugs and have replaced dogs as the general surgical model for research and training.34 Inhalant anesthesia is reportedly the preferred method for prolonged anesthesia in pigs and for specific experimental studies due to the rapid, smooth transitions between anesthetic planes and more rapid recovery of modern inhalant agents compared with many injectable medications.19 The main goal of adding an intravenous injectable agent to an inhalatory anesthetic regimen is to reduce anesthetic requirements and thereby decrease the negative impact of high inhalant concentrations on the cardiorespiratory system,32 which can be detrimental to a patient’s homeostasis.
Lidocaine is an amide-type local anesthetic that undergoes almost exclusive hepatic metabolism by microsomal enzymes (CYP450), although pulmonary first-pass metabolism has been reported in vitro in pulmonary microsomes of the rat.1 Lidocaine is metabolized through hydroxylation and N-deethylation to 2 main metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). Previous studies described the use of lidocaine as a component of balanced anesthesia in conjunction with inhalant anesthetic agents, where decreases in the minimum alveolar concentration (MAC) of isoflurane in goats,4 horses,39 calves,38 dogs,22,37 and cats26 were observed. The pharmacokinetic profile of lidocaine in pigs has been determined in a previous study,20 showing that a steady state can be rapidly achieved in this species after a single bolus.
Despite the common use of lidocaine in combination with isoflurane in swine, the sparing effect of lidocaine in isoflurane-anesthetized swine and on correspondent plasma concentrations is unknown. Based on previous data regarding the isoflurane sparing effects of lidocaine in other species, the tested null hypothesis was that isoflurane requirement (IR) in commercial pigs would be unaffected by 2 constant rate infusions (CRIs), 50 μg/kg/min (CRI50) and 200 μg/kg/min (CRI200) administered intravenously. This route and these dosages of administration were chosen to mimic clinical and research scenarios including partial intravenous general anesthesia with lidocaine and isoflurane in pigs.
Materials and Methods
Animals.
This study was approved by the Oregon State University IACUC (ACUP No. 4657) before commencement of the study. Six healthy, commercial-bred, juvenile pigs (Sus scrofa domestica; 2 barrows and 4 gilts), weighing 31.7 ± 5.4 kg and aged 74 ± 5.3 d, were enrolled in this prospective, randomized, crossover study. Represented breeds were Yorkshire (n = 3), Duroc (n = 2), and Berkshire (n = 1). Pigs were determined to be healthy based on history and physical examination. All pigs were housed in the same concrete-floored pen (3.6 × 4 m) with tap water ad libitum offered via a water nipple system, fed twice a day at set times with an age-appropriate commercial feed (Rogue Quality Feed Hog Gro-Fin Ration; Grange-Op, Medford, OR), and were on a 12-h artificial light cycle. The day before each trial, a complete physical examination was performed on the subject to confirm the American Society of Anesthesiologists5 status of I. Pigs were excluded if there were any changes in routine behavior or if any abnormalities were found on physical exam. Food was withheld 12 h before the start of the experiment. Subjects were randomized to establish animal order and subsequently the treatment sequence for the first anesthetic trial. The opposite treatment was administered in the second anesthetic trial. A washout period of 6 d was respected to exceed the general recommendation of waiting 10× elimination half-lives between treatments. The elimination half-life published by Mets was used for this estimation.20
Anesthetic technique.
Anesthesia was induced with 5% isoflurane (Isoflo; Abbott Animal Health, Abbott Park, IL) in 7 L/min of oxygen (O2) administered via face mask as injectable compounds would have affected the study methods and findings. Pigs were placed in sternal recumbency, and the trachea was intubated after desensitization of the larynx with lidocaine (4 mg; Lidocaine 2% Injectable; Vet One, Boise, ID). The endotracheal tube was connected to a circle system (Excel 210; Ohmeda, Madison, WI) through a universal F-circuit (One Nexus Unilimb Circuit; MMS Sales Corporation, McAllen, TX), and the O2 flow rate was reduced to 2 L/min. The calibrated vaporizer (Isotec 5; Datex Ohmeda Division, Helsinki, Finland) was set to deliver between 2.0 and 2.5 volume percent isoflurane. Mechanical ventilation was used to maintain normocapnia (EtCO2 = 35 to 45 mm Hg) and minute ventilation constant. Heart rate and rhythm, peripheral oxygen saturation (SpO2), arterial systolic (SAP), mean (MAP), and diastolic blood pressure (DAP) were monitored with a multiparameter monitor (Spectrum, Datascope Mahawah, NJ). A blood pressure transducer (DTXPlus; BD Medical Systems, Sandy, UT) positioned at the level of the heart and connected to a catheter inserted in the left caudal auricular artery was used to measure SAP, MAP, and DAP. A side-stream respiratory gas analyzer (Gas Module GE, Datascope Mahawah, NJ) was used to monitor inspired and expired fractions of oxygen, inspired (FiISO) and expired (EtISO) anesthetic agent concentrations, end-tidal partial pressure of carbon dioxide (EtCO2), respiratory pattern, and respiratory frequency. The gas analyzer was calibrated daily 30 min before each anesthetic episode with a standardized calibration gas mixture (Airgas Specialty Gases, Lenexa, KS) as per the manufacturer’s recommendations. All parameters were monitored at 5-min intervals. Dedicated venous catheters were placed in the left and right caudal auricular veins for fluid and drug administration. Lactated Ringer’s solution was administered through one of the venous catheters at a rate of 3 mL/kg/h. If MAP was lower than 60 mm Hg at any time point throughout the anesthetic episode, the lactated Ringer solution rate was increased to 10 mL/kg/h and maintained until normotension was reestablished. The second venous catheter was used to administer the loading dose and CRI of lidocaine.
Temperature management.
Body temperature (BT) was monitored every 15 min by inserting an esophageal temperature probe connected to the multiparameter monitor into the esophagus and the tip of the probe was positioned in proximity to the eighth intercostal space. At the beginning of the anesthetic episode, if BT was elevated (103 °F [39.4 °C]), ice packs were positioned between the ventral region of the pig and the vacuum positioner bag (Animal Positioner; Hug-U-Vac, Salem, OR), and alcohol was applied to the pig’s lumbar region. Ice packs were maintained in place until BT was ≥101.5 °F (38.6 °C), and the pig was left uncovered if normal BT was maintained. If BT was ≥101 °F (38.3 °C), a blanket was applied to cover the animal, leaving the head and limbs uncovered.
Determination of Isoflurane Requirement.
The alveolar concentration of isoflurane was allowed to equilibrate for a period of 15 to 30 min. Baseline isoflurane requirement (IRB) was defined as the volume percentage of EtISO to prevent gross purposeful movement assessed using a supramaximal mechanical stimulus on the dewclaw of the hind limbs8 in the absence of other drugs administered to the subject. The jaws of a 16 cm Crile curved forceps were closed to the first ratchet, 5 mm above the coronary band of declaw, and left in place for 30 seconds. Clamping of the dewclaw was preferred to tail clamp due to previous results in the literature showing a lower and more variable MAC obtained with the latter in pigs.8 Sole movement of the clamped hind limb was not sufficient to consider the response as positive; instead, purposeful movement of another limb or head was necessary. The noxious stimulus was applied alternatively to the 4 declaws of the hind limbs to minimize injury. If no response was obtained from the application of the noxious stimulus, the vaporizer setting was decreased by 10%. EtISO was maintained unchanged for 15 min to allow alveolar to arterial equilibration of EtISO. Vaporizer settings were decreased by 10%, followed by 15 min of equilibration until a positive response was obtained. If movement in response to supramaximal stimulus occurred, vaporizer settings were increased by 10%, and a 15-min equilibration period was allowed. The lowest value of EtISO at which the animal did not respond to the noxious stimulus applied to the dewclaw (RNEG), and the value at which the subject purposely moved in response to the same noxious stimulus (RPOS), were arithmetically averaged to calculate baseline IR. Determination of baseline IR was performed in duplicate. Following the determination of baseline IR, the vaporizer setting was returned to those producing the RNEG value. A loading dose of lidocaine (2 mg/kg of Lidocaine 2% Injectable; Vet One, Boise, ID) was then administered IV over 2 min, followed by a CRI of 50 or 200 μg/kg/min administered via a calibrated syringe pump (Graseby 3400; Graseby Ltd., Watford, UK). The CRI was maintained for 30 min and IR during lidocaine CRI was reassessed as previously described for the baseline value. Arterial blood samples were collected once IRL50 and IRL200 were established. Lidocaine CRI and isoflurane administration were then discontinued, catheters were removed, and the pigs were allowed to recover in a quiet, dark location to minimize stress. Once two consecutive swallowing movements and jaw movements following slight rotation of the endotracheal tube were present, animals were extubated. Time to extubation was defined as the time between discontinuation of isoflurane and extubation of the animal (when 2 consecutive swallows occurred within a continuous 15-second period). Triple antibiotic (neomycin, polymyxin B, bacitracin) ointment (Fougera Triple Antibiotic Ointment; Nycomes US; Melville, NY) and a diclofenac-based cream (Surpass; Boehringer Ingelheim Vetmedica, St. Joseph, MO) were applied on each declaw, above the coronary band, to minimize inflammation and prevent bacterial infection at the end of each anesthetic trial. After a washout period of 6 d, the study was repeated assessing IR with the alternate dose. During the second testing period, the contralateral dewclaw was used to apply the noxious stimulus.
Processing of Plasma Samples.
Arterial blood samples (5 mL) were collected from the arterial catheter each time point the noxious stimulus was applied and stored in lithium heparin tubes (BD vacuum phlebotomy tube blood tubes; Becton, Dickinson and Company, Franklin Lakes, NJ). Samples were centrifuged at 1,500 rpm and plasma was separated and stored at −80 °C until analysis. Only samples taken at RNEG and RPOS during the establishment of IRB, ISOL50, and ISOL200 were analyzed for plasma concentrations of lidocaine and MEGX. After thawing, samples were vortexed for 30 s, and 50 μL of plasma was added to 250 μL of acetonitrile containing 60 μg/L of mepivacaine as an internal standard. Increasing the ratio of acetonitrile to plasma from 2:1 to 5:1 provided more consistent results. Samples were then centrifuged at 1,200 rpm for 19 min at 0 °C. The supernatant (20 μL) was added to 1,040 μL of a 70:30 solution ratio of aqueous formic acid (0.01%) and acetonitrile.
Analysis of lidocaine and MEGX.
Assays of plasma concentrations of lidocaine and MEGX were performed by liquid chromatography (LC) and mass spectrometry (MS). The analytic method used in the present study is a modification from a previously published study.19 A MS system (4000 Q Trap Applied Biosystem LC/MS/MS system; Applied Biosystem SCIEX, Foster City, CA) was used for the analysis of the samples, and the software Analyst (1.6 version; AB Sciex, Concord, Ontario, Canada) used for quantification and data elaboration. A standard curve of mepivacaine (Carbocaine-V, Zoetis, NY) used as internal standard, MEGX (MEGX 98% SML0087; Sigma-Aldrich, St. Louis, MO), and lidocaine (Lidocaine Hydrochloride 98%; Alfa Aesar, Ward Hill, MA), respectively at 1, 2.5, 5, 10, 50, 125, 250, 500, 1,000, 5,000, and 10,000 mg/L for each compound diluted in plasma were used to calibrate the instrument. For quality control, a mixture of lidocaine (50 mg/L), MEGX (50 mg/L), and mepivacaine (60 mg/L) was used intermittently during the analysis to ensure accuracy of results.
Statistical Analysis.
Statistical analysis was performed using open-access statistical software (R, 2014 version; Bell Laboratories). Normality was tested through evaluation of Q-Q plots. Parametric data and isoflurane concentrations are presented as mean ± SD. IRB, ISOL50, and ISOL200 were analyzed using repeated measures ANOVA and reported as mean ± SE. The sparing effect was calculated separately for each group (CRI50 and CRI200) since IR was different between groups. In the linear model, subject, dose, sequence, and BT at RPOS were included as fixed factors. Differences in plasma concentrations of lidocaine and its metabolites between the 2 infusion rates were analyzed with a one-way ANOVA and reported as mean ± SE. Heart rate, SAP, DAP, MAP, and EtCO2 were analyzed with a one-way ANOVA and reported as mean ± SE. Only cardiovascular parameters collected during the 30-min equilibration period were included in the statistical analysis to avoid confounding factors such as a sympathetic response secondary to the application of the noxious stimulus. Correlation between plasma concentrations of lidocaine and its metabolites, and isoflurane-sparing effects were tested using a linear regression model. Differences in recovery time between treatments were tested with a paired t test. For all tests, significance was set at P < 0.05. A post hoc power calculation was performed to estimate the achieved power.
Results
Six pigs entered the study but 5 concluded it due to a nonanesthetic-related death. Therefore, statistical analysis was conducted on 5 subjects receiving CRI50 and 6 receiving CRI200. Average anesthesia time was 178.9 ± 41.2 min, with a mean IR assessment procedure time of 174.2 ± 46.5 min for the CRI50 group, and 146.5 ± 44.6 min for the CRI200 group. The total administered dose of lidocaine in pigs receiving CRI50 and CRI200 was 155.1 ± 63.2 mg and 493.7 ± 311.7 mg, respectively. The combined isoflurane IRB for the 2 treatment groups was 1.77 ± 0.34% (1.66% for CRI50 and 1.86% for CRI200). IRL50 and IRL200 were 1.53 ± 0.28% and 1.61 ± 0.42%, respectively, indicating a significant reduction from IRB of 7.8% (P = 0.046) and 13.4% (P = 0.041). No difference was found between IRL50 and IRL200. Cardiovascular parameters (Table 1) were clinically stable and statistically non-significant. Time to extubation was 10.2 ± 4.5 min in subjects receiving CRI50 and 11 ± 3.6 min in pigs receiving CRI200, with no difference between treatments (P = 0.92).
| Time point (min) | HR | DAP | SAP | MAP | ||||
|---|---|---|---|---|---|---|---|---|
| CRI50 | CRI200 | CRI50 | CRI200 | CRI50 | CRI200 | CRI50 | CRI200 | |
| 0 | 115.8 ± 5.3 | 117.8 ± 15.2 | 45.2 ± 3.5 | 45.5 ± 5.9 | 83.8 ± 8.5 | 84 ± 12.6 | 59.6 ± 5 | 59.5 ± 9.0 |
| +5 | 119.4 ± 6.2 | 112.5 ± 14.4 | 46.8 ± 5.1 | 42 ± 3.9 | 84 ± 5.9 | 81.8 ± 9.4 | 59.6 ± 5.4 | 54.8 ± 5.3 |
| +10 | 117.2 ± 18.5 | 112.5 ± 10.3 | 49.6 ± 9.8 | 45.8 ± 5.8 | 87 ± 7.6 | 82.8 ± 9.4 | 62.2 ± 9.7 | 58.5 ± 7.2 |
| +15 | 118.4 ± 13.8 | 111.5 ± 11.3 | 49.6 ± 10.1 | 47.1 ± 4.6 | 86.4 ± 7.3 | 85.1 ± 10.5 | 61.8 ± 10.8 | 59.5 ± 7.1 |
| +20 | 111.2 ± 6.4 | 111.2 ± 9.9 | 45 ± 1.8 | 47.3 ± 3.7 | 80.2 ± 3.3 | 85.6 ± 9.0 | 56 ± 2.3 | 59.5 ± 5.2 |
| +25 | 112.2 ± 6.4 | 111.3 ± 10.1 | 45.6 ± 4.5 | 50.3 ± 7.5 | 82.2 ± 3.5 | 88.3 ± 11.8 | 57.2 ± 3.9 | 62.8 ± 9.1 |
| +30 | 115 ± 13.8 | 112 ± 10.2 | 49.8 ± 12.5 | 49.1 ± 4.4 | 86.6 ± 8.4 | 88.5 ± 10.8 | 61.8 ± 13.0 | 62.1 ± 6.8 |
For more information on acquisition of data, see Materials and Methods. DAP, diastolic arterial pressure; HR, heart rate; MAP, mean arterial pressure; SAP, systolic arterial pressure.
Plasma concentrations of lidocaine and MEGX at RNEG and RPOS for both CRI rates are reported in Table 2. As shown in Figures 1 and 2, a strong correlation between IR reduction and MEGX plasma concentration was found at both RNEG and RPOS time points when CRI50 was administered (R2 = 0.8094 at RNEG; R2 = 0.8417 at RPOS). However, this correlation was not significant with lidocaine plasma concentrations (R2 ≤ 0.4) or when CRI200 was administered. The calculated post hoc power to detect a true difference between the 2 lidocaine dosages was 65%.
| IRB (%) | IR reduction (%) | Lidocaine concentration (ng/mL) | MEGX concentration (ng/mL) | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 50 | 200 | 50 | 200 | 50 | 200 | ||||||
| RNEG | RPOS | RNEG | RPOS | RNEG | RPOS | RNEG | RPOS | ||||
| Mean ± SD | 1.77 ± 0.34 | 7.98 | 11.95 | 173 ± 21.4 | 184.8 ± 23.7 | 386.3 ± 45.3 | 387.3 ± 51.3 | 36.6 ± 10 | 37.3 ± 11.2 | 52.3 ± 19.2 | 56.5 ± 24.6 |
IR, isoflurane requirement; MEGX, monoethylglycinexylidide.
Citation: Journal of the American Association for Laboratory Animal Science 64, 2; 10.30802/AALAS-JAALAS-24-106
Citation: Journal of the American Association for Laboratory Animal Science 64, 2; 10.30802/AALAS-JAALAS-24-106
Discussion
The reduction in anesthetic requirement in pigs administered lidocaine at two different dosages found in this study was statistically significant but marginally relevant from a clinical standpoint. Baseline IR obtained in the present study is consistent with MACs reported in the literature for swine (1.45% to 2.04%).8,9,16,17,31,36 The MAC is defined as the end-tidal concentration of an anesthetic agent at a pressure of 1 atmosphere that produces immobility in 50% of subjects exposed to a supramaximal noxious stimulus. Local anesthetic agents like lidocaine, inhibit glutaminergic transmission in the spinal dorsal horn neurons, reducing NMDA and neurokinin-mediated depolarization.10,23 Although the mechanism responsible for the MAC-sparing effect of lidocaine has not been determined, various possible mechanisms have been postulated. Lidocaine may have an additive effect on voltage-gated sodium channels of the central nervous system28 to the one exerted by inhalant anesthetics. In addition, because of its analgesic effect at the level of the spinal cord after intravenous administration, lidocaine may cause a reduction in anesthetic requirements.2 Intravenous administration of lidocaine has also been shown to exert an analgesic effect during different types of pain in humans33,41 and laboratory animals.24,30 These hypotheses would explain the coexistence of the analgesic effect and the reduction in anesthetic requirements produced by systemic administration of lidocaine, which may contribute to lowering IRs.
Despite the reduction in IR reported in this study, a previous study in dogs resulted in a greater reduction in IRs. The reported isoflurane reduction in dogs was 18.7% under a regimen of 50 μg/kg/min, and 43.3% under 200 μg/kg/min.37 In horses and calves, lidocaine infusion at 50 μg/kg/min decreased IR by 25% and 16.7%, respectively.7 These results demonstrate the failure of lidocaine to reduce IR in pigs as much as in other species. A similar finding was reported in a study that demonstrated that the addition of morphine or fentanyl and ketamine to a lidocaine CRI failed to reduce MAC of sevoflurane in pigs.27 Other researchers in the past have documented the lack of MAC-sparing effects of opioids in pigs compared with other species.21,31
In our study, it would be plausible to attribute the relative lack in reduction of IR in pigs to the low plasma concentrations of lidocaine achieved. Lidocaine infusion in dogs during isoflurane anesthesia reported in one study (rate infusions of 50 and 200 μg/kg/min IV) resulted in higher MAC reduction compared with the ones obtained in the present study.37 In fact, MAC reduction in dogs was 18.7% under a regimen of 50 μg/kg/min and 43.3% under 200 μg/kg/min,37 corresponding to a mean plasma concentration of lidocaine ranging, respectively, between 1,465 and 1,537 ng/mL, and 4,350 and 4,691 ng/mL. In the present study, we obtained a much smaller reduction in anesthetic requirements, with 7.8% and 13.4% less than MACB, corresponding to mean plasma concentrations of lidocaine of respectively 173 to 184 ng/mL for CRI50 and 386.3 and 387.3 ng/mL for CRI200. We suspect that the failure of lidocaine in decreasing IRs in pigs as much as reported in other species may be caused by insufficient plasma concentrations of lidocaine and MEGX. Furthermore, the lack of a linear increase in IR with CRI200 may suggest the presence of a ceiling effect of lidocaine in swine, where IR reduction is not a function of the plasma concentration of lidocaine and its metabolites in this species. The existence of species-specific sensitivity to lidocaine has been reported in the literature, and it appears to be correlated to the metabolism and/or the elimination of the drug and its metabolites.13 The authors hypothesize that different metabolism and redistribution of lidocaine may occur in swine. Also, variability in plasma concentrations may be caused by the first-pass pulmonary uptake of amide-type local anesthetics in venous blood, which temporarily decreases plasma concentration.14,25 However, in the present study, this phenomenon has been prevented by the administration of a CRI, which was maintained for 30 min before sampling was initiated. The main active metabolite of lidocaine, MEGX, has been shown to be the most potent among the active metabolites of lidocaine,3 with approximately 80% of lidocaine’s potency.35 The other metabolite, GX, was not measured due to its low pharmacologic activity.6 In the present study, in subjects administered a CRI50, there is a strong linear correlation between the plasma concentration of this metabolite and MAC sparing on isoflurane at both infusion rates, that suggest that MEGX may be responsible for the clinical effect seen in this study. However, at CRI200, this robust linear relationship was lost, providing a solid explanation for the lack of significant difference in IR sparing between the 2 infusion rates. This lack of effectiveness of lidocaine in reducing anesthetic requirements has also been recently reported in foals.15
MAC is influenced by many factors, including hypoxemia, hypercarbia (PaCO2 > 90 mm Hg), arterial blood pressure, and BT. Values of SpO2, EtCO2, and invasive blood pressure measurements suggested that these factors played no role in the assessment of IRs in the present study. Although BT may affect MAC, responses at RNEG and RPOS were obtained at BT of 101.17 ± 1.28 °F in our cohort of animals, which falls in the physiologic range of BT for swine, as demonstrated in a study conducted on unrestrained, nonanesthetized pigs, which reported physiologic resting temperatures to be ranging between 37.7 and 40 °F when measured by radio-telemetry implants in undisturbed swine.12 Finally, the anatomic location at which the noxious stimulus is applied in pigs appears to consistently affect MAC values, with greater MAC values when the stimulus was applied to the declaw of the pelvic limb compared with the tail as demonstrated by another study.8
Cardiovascular changes while lidocaine was administered to achieve a steady state did not occur over time and were not affected by dosage. Lidocaine has been reported to exert negative inotropic effects, leading to a reduction in cardiac output,26 as well as a decrease in heart rate,15 while potentially increasing systemic vascular resistance.26 These effects vary based on dose and animal species. However, although HR was maintained fairly constant, an overall borderline hypotensive state (when hypotension was defined as a MAP < 60 mm Hg)18 was present at all time points in both groups, as reported in Table 1.
A consistent pattern of rise in BT was found immediately postinduction in 54.5% of the subjects in this study (n = 6, BT > 104 °C), with peaks of 105.6 °F (40.9 °C). The authors attributed this phenomenon to stress and exertion during transport to the induction room and mask induction. Malignant hyperthermia was initially considered as a possible cause of the event, although the increase in BT was manageable with treatment with ice packs and alcohol baths, and animals never reached temperatures higher than 105.4 °F (40.8 °C). Furthermore, all pigs recovered well from general anesthesia, as compared with the low-rate survival of subjects with malignant hyperthermia. However, characteristics of the typical hypermetabolic state occurring during malignant hyperthermia such as hypercarbia and increased lactic acid levels in arterial blood [(blood gas analysis was performed in 72.7% (n = 8) pigs after induction of anesthesia)] were similar.
Despite the longer duration of the anesthetic episode in the CRI200 treatment, extubation times did not significantly differ in the 2 groups, and no neurologic signs were present during recovery. Only one subject that received a higher average dose of lidocaine compared with other animals, showed prolonged ataxia (up to 1 h postextubation). Potential reported side effects of lidocaine in swine include sedation, stupor, ataxia, recumbency, myoclonus, and seizure.29,40 In the present study, none of these reported side effects occurred and pigs were ready to be reintroduced to the herd in less than one hour from the end of the anesthetic episode.
Study limitations include the lack of a negative control treatment in the crossover design, and the moderate power detected on post hoc analysis, which was affected by the relatively low number of subjects included in this study. Although a greater number of animals would have been ideal, the use of 6 to 8 subjects is a common recurrence in veterinary medicine and warrants caution in the interpretation of results. Finally, inhibition of purposeful movement by isoflurane may be less effective in pigs than in other species,11 which makes interspecies comparison between sparing agents difficult.
Conclusions.
Infusion of lidocaine did not produce significant changes in cardiovascular variables and extubation time in this cohort of animals. Lidocaine decreased IR in a nondose-dependent fashion, indicating a ceiling effect in MAC sparing on isoflurane. Therefore, based on these results, these authors recommend a dosage of 50 µg/kg/min in swine for the purpose of reducing anesthetic requirements, as the higher dosage did not produce further reduction. Plasma concentrations of MEGX were found to have a stronger correlation with reduction in IR than lidocaine plasma concentrations. Further investigation is needed to assess the role of a higher plasma concentration of lidocaine in decreasing anesthetic requirements of inhalational agents, as well as the incorporation of high doses of lidocaine in a multidrug maintenance regimen for isoflurane-anesthetized pigs.
Plasma concentrations of MEGX at RNEG and their relationship with isoflurane requirement reduction at the 2 infusion rates (linear regression).
Plasma concentrations of MEGX at RPOS and their relationship with isoflurane requirement reduction at the 2 infusion rates (linear regression).
Contributor Notes