• View in gallery

    Least squares mean ± SEM SAP (A), MAP (B), and DAP (C) in 5 New Zealand White rabbits (Oryctolagus cuniculus) after anesthesia with isoflurane (2%) for 30 minutes (baseline; circles) and during isoflurane-induced anesthesia 30 minutes after administration of a bolus of lidocaine (2 mg/kg, IV) followed by a lidocaine CRI at 50 μg/kg/min (squares) and 100 μg/kg/min (triangles).

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    Least squares mean ± SEM heart rate in 5 New Zealand White rabbits after anesthesia with isoflurane for 30 minutes (baseline) and during isoflurane-induced anesthesia 30 minutes after IV administration of a bolus of lidocaine (2 mg/kg) followed by a lidocaine CRI at 50 and 100 μg/kg/min. See Figure 1 for remainder of key.

  • 1. Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg 1993; 77: 10481056.

    • Search Google Scholar
    • Export Citation
  • 2. Bailey PL, Egan TD, Stanley TH. Intravenous opioid anesthetics. In: Miller RD, ed. Anesthesia. 5th ed. Philadelphia: Churchill Livingstone, 2000;273376.

    • Search Google Scholar
    • Export Citation
  • 3. Steffey EP. Inhalation anesthetics. In: Thurmon JC, Tranquilli WJ, Benson GJ, eds. Lumb and Jones' veterinary anesthesia. 3rd ed. Philadelphia: Lea & Febiger, 1996;297329.

    • Search Google Scholar
    • Export Citation
  • 4. Doherty TJ, Frazier DL. Effect of intravenous lidocaine on halothane minimum alveolar concentration in ponies. Equine Vet J 1998; 30: 300303.

    • Search Google Scholar
    • Export Citation
  • 5. DiFazio CA, Neiderlehner JR, Burney RG. The anesthetic potency of lidocaine in the rat. Anesth Analg 1976; 55: 818821.

  • 6. Phillips OC, Lyons WB, Harris LC, et al. Intravenous lidocaine as an adjunct to general anesthesia: a clinical evaluation. Anesth Analg 1960; 39: 317322.

    • Search Google Scholar
    • Export Citation
  • 7. Groudine SB, Fisher HAG, Kaufman RP, et al. Intravenous lidocaine speeds the return of bowel function, decreases postoperative pain, and shortens hospital stay in patients undergoing radical retropubic prostatectomy. Anesth Analg 1998; 86: 235239.

    • Search Google Scholar
    • Export Citation
  • 8. Valverde A, Doherty TJ, Hernandez J, et al. Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 2004; 31: 264271.

    • Search Google Scholar
    • Export Citation
  • 9. Pypendop BH, Ilkiw JE. The effects of intravenous lidocaine administration on the minimum alveolar concentration of isoflurane in cats. Anesth Analg 2005; 100: 97101.

    • Search Google Scholar
    • Export Citation
  • 10. Doherty T, Redua MA, Queiroz-Castro P, et al. Effect of intravenous lidocaine and ketamine on the minimum alveolar concentration of isoflurane in goats. Vet Anaesth Analg 2007; 34: 125131.

    • Search Google Scholar
    • Export Citation
  • 11. Eger EI, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 1965; 26: 756763.

    • Search Google Scholar
    • Export Citation
  • 12. Rorarius MG, Baer GA, Metsä-Ketelä T. The effect of diclofenac and ketoprofen on halothane MAC in rabbits. Agents Actions 1993; 38: 286289.

    • Search Google Scholar
    • Export Citation
  • 13. Turner PV, Kerr CL, Healy AJ, et al. Effect of meloxicam and butorphanol on minimum alveolar concentration of isoflurane in rabbits. Am J Vet Res 2006; 67: 770774.

    • Search Google Scholar
    • Export Citation
  • 14. Egger CM, Souza MJ, Greenacre CB, et al. Effect of intravenous administration of tramadol hydrochloride on the minimum alveolar concentration of isoflurane in rabbits. Am J Vet Res 2009; 70: 945949.

    • Search Google Scholar
    • Export Citation
  • 15. Koppert W, Weigand M, Neumann F, et al. Perioperative intravenous lidocaine has preventive effects on postoperative pain and morphine consumption after major abdominal surgery. Anesth Analg 2004; 98: 10501055.

    • Search Google Scholar
    • Export Citation
  • 16. Heavner JE, de Jong RH. Lidocaine blocking concentrations for B- and C-nerve fibers. Anesthesiology 1974; 40: 228233.

  • 17. Woolf CJ, Wiesenfeld-Hallin Z. The systemic administration of local anesthetics produces a selective depression of C-afferent fiber evoked activity in the spinal cord. Pain 1985; 23: 361374.

    • Search Google Scholar
    • Export Citation
  • 18. Dohi S, Kitahata LM, Toyooka H, et al. An analgesic action of intravenously administered lidocaine on dorsal-horn neurons responding to noxious thermal stimulation. Anesthesiology 1979; 51: 123126.

    • Search Google Scholar
    • Export Citation
  • 19. Butterworth J, Cole L, Marlow G. Inhibition of brain cell excitability by lidocaine, QX314, and tetrodotoxin: a mechanism for analgesia from infused local anesthetics? Acta Anaesthesiol Scand 1993; 37: 516523.

    • Search Google Scholar
    • Export Citation
  • 20. Peiró JR, Barnabe PA, Cadioli FA, et al. Effects of lidocaine infusion during experimental endotoxemia in horses. J Vet Intern Med 2010; 24: 940948.

    • Search Google Scholar
    • Export Citation
  • 21. Malone E, Ensink J, Turner T, et al. Intravenous continuous infusion of lidocaine for treatment of equine ileus. Vet Surg 2006; 35: 6066.

    • Search Google Scholar
    • Export Citation
  • 22. Wallin G, Cassuto J, Hogstrom S, et al. Effects of lidocaine infusion on the sympathetic response to abdominal surgery. Anesth Analg 1987; 66: 10081013.

    • Search Google Scholar
    • Export Citation
  • 23. Himes RS, DiFazio CA, Burney RG. Effects of lidocaine on the anesthetic requirements for nitrous oxide and halothane. Anesthesiology 1977; 47: 437440.

    • Search Google Scholar
    • Export Citation
  • 24. Dzikiti TB, Hellebrekers LJ, van Dijk P. Effects of intravenous lidocaine on isoflurane concentration, physiological parameters, metabolic parameters and stress-related hormones in horses undergoing surgery. J Vet Med A Physiol Pathol Clin Med 2003; 50: 190195.

    • Search Google Scholar
    • Export Citation
  • 25. Feary DJ, Mama KR, Wagner AE, et al. Influence of general anesthesia on pharmacokinetics of intravenous lidocaine infusion in horses. Am J Vet Res 2005; 66: 574580.

    • Search Google Scholar
    • Export Citation
  • 26. Kalso E, Tramèr MR, Moore RA, et al. Systemic local anesthetic type drugs in chronic pain: a qualitative systematic review. Eur J Pain 1998; 2: 314.

    • Search Google Scholar
    • Export Citation
  • 27. Bach FW, Jensen TS, Kastrup J, et al. The effect of intravenous lidocaine on nociceptive processing in diabetic neuropathy. Pain 1990; 40: 2934.

    • Search Google Scholar
    • Export Citation
  • 28. Wallace MS, Dyck JB, Rossi SS, et al. Computer-controlled lidocaine infusion for the evaluation of neuropathic pain after peripheral nerve injury. Pain 1996; 66: 6977.

    • Search Google Scholar
    • Export Citation
  • 29. de Clive-Lowe SG, Desmond J, North J. Intravenous lidocaine anesthesia. Anesthesiology 1958; 13: 138146.

  • 30. Murrell JC, White KL, Johnson CB, et al. Investigation of the EEG effects of intravenous lidocaine during halothane anesthesia in ponies. Vet Anaesth Analg 2005; 32: 212221.

    • Search Google Scholar
    • Export Citation
  • 31. Ikeda Y, Oda Y, Nakamura T, et al. Pharmacokinetics of lidocaine, bupivacaine, and levobupivacaine in plasma and brain in awake rats. Anesthesiology 2010; 112: 13961403.

    • Search Google Scholar
    • Export Citation
  • 32. Meyer GA, Lin HC, Hanson RR, et al. Effects of intravenous lidocaine overdose on cardiac electrical activity and blood pressure in the horse. Equine Vet J 2001; 33: 434437.

    • Search Google Scholar
    • Export Citation
  • 33. DiFazio C, Brown RE. Lidocaine metabolism in normal and phenobarbital-pretreated dogs. Anesthesiology 1972; 36: 238243.

  • 34. Mather LE, Runciman WB, Carapetis RJ, et al. Hepatic and renal clearances of lidocaine in conscious and anesthetized sheep. Anesth Analg 1986; 65: 943949.

    • Search Google Scholar
    • Export Citation
  • 35. Taniguchi T, Shibata K, Yamamoto K, et al. Lidocaine attenuates the hypotensive and inflammatory responses to endotoxemia in rabbits. Crit Care Med 1996; 24: 642646.

    • Search Google Scholar
    • Export Citation
  • 36. Drummond JC. MAC for halothane, enflurane, and isoflurane in the New Zealand White rabbit: a test for the validity of MAC determinations. Anesthesiology 1985; 62: 336338.

    • Search Google Scholar
    • Export Citation
  • 37. Valverde A, Morey TE, Hernández J, et al. Validation of several types of noxious stimuli for use in determining the minimum alveolar concentration for inhalation anesthetics in dogs and rabbits. Am J Vet Res 2003; 64: 957962.

    • Search Google Scholar
    • Export Citation
  • 38. Ortega M, Cruz I. Evaluation of a constant rate infusion of lidocaine for balanced anesthesia in dogs undergoing surgery. Can Vet J 2011; 52: 856860.

    • Search Google Scholar
    • Export Citation
  • 39. Rowland M, Thomson PD, Guichard A, et al. Disposition kinetics of lidocaine in normal subjects. Ann N Y Acad Sci 1971; 179: 383398.

  • 40. Ngo LY, Tam YK, Tawfik S, et al. Effects of intravenous infusion of lidocaine on its pharmacokinetics in conscious instrumented dogs. J Pharm Sci 1997; 86: 944952.

    • Search Google Scholar
    • Export Citation
  • 41. Thomasy SM, Pypendop BH, Ilkiw JE, et al. Pharmacokinetics of lidocaine and its active metabolite, monoethylglycinexylidide, after intravenous administration of lidocaine to awake and isoflurane-anesthetized cats. Am J Vet Res 2005; 66: 11621166.

    • Search Google Scholar
    • Export Citation
  • 42. Milligan M, KuKanich B, Beard W, et al. The disposition of lidocaine during a 12-hour intravenous infusion to postoperative horses. J Vet Pharmacol Ther 2006; 29: 495499.

    • Search Google Scholar
    • Export Citation
  • 43. KT, Maurice H, Du Souich P. First-pass metabolism of lidocaine in the anesthetized rabbit. Contribution of the small intestine. Drug Metab Dispos 1996; 24: 711716.

    • Search Google Scholar
    • Export Citation
  • 44. Plumb D. Lidocaine HCl. Plumb's veterinary drug handbook. 5th ed. Ames, Iowa: Blackwell Publishing Professional, 2005;460462.

  • 45. Santa Cruz Biotechnology. Lidocaine hydrochloride material safety data sheet. sc-215245. Santa Cruz, Calif: Santa Cruz Biotechnology, 2009.

    • Search Google Scholar
    • Export Citation
  • 46. Nunes de Moraes A, Dyson DH, O'Grady MR, et al. Plasma concentrations and cardiovascular influence of lidocaine infusions during isoflurane anesthesia in healthy dogs and dogs with subaortic stenosis. Vet Surg 1998; 27: 486497.

    • Search Google Scholar
    • Export Citation
  • 47. Imai A, Steffey EP, Ilkiw JE, et al. Comparison of clinical signs and hemodynamic variables used to monitor rabbits during halothane- and isoflurane-induced anesthesia. Am J Vet Res 1999; 60: 11891195.

    • Search Google Scholar
    • Export Citation
  • 48. Kurashina T, Sakamaki T, Yagi A, et al. A new device for indirect blood pressure measurement in rabbits. Jpn Circ J 1994; 58: 264268.

  • 49. Ypsilantis P, Didilis VN, Politou M, et al. A comparative study of invasive and oscillometric methods of arterial blood pressure measurement in the anesthetized rabbit. Res Vet Sci 2005; 78: 269275.

    • Search Google Scholar
    • Export Citation
  • 50. Valverde A, Gunkelt C, Doherty TJ, et al. Effect of a constant rate infusion of lidocaine on the quality of recovery from sevoflurane or isoflurane general anesthesia in horses. Equine Vet J 2005; 37: 559564.

    • Search Google Scholar
    • Export Citation
  • 51. Jacobson NS, Truax P. Clinical significance: a statistical approach to Denning meaningful change in psychotherapy research. J Consult Clin Psychol 1991; 59: 1219.

    • Search Google Scholar
    • Export Citation
  • 52. Haskins SC. Monitoring the anesthetized patients. In: Thurmon JC, Tranquilli WJ, Benson GJ, eds. Lumb and Jones' veterinary anesthesia. 3rd ed. Philadelphia: Lea & Febiger, 1996;409499.

    • Search Google Scholar
    • Export Citation

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Effects of lidocaine administration via continuous rate infusion on the minimum alveolar concentration of isoflurane in New Zealand White rabbits (Oryctolagus cuniculus)

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  • 1 Department of Clinical Science, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.
  • | 2 Department of Clinical Science, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.
  • | 3 Department of Clinical Science, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.
  • | 4 Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.
  • | 5 Health Sciences Center, Ontario Veterinary College, University of Guelph, Guelph, ON N1G 2W1, Canada.
  • | 6 Department of Clinical Science, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506.

Abstract

Objective—To evaluate the effect of a continuous rate infusion (CRI) of lidocaine on the minimum alveolar concentration (MAC) of isoflurane in rabbits.

Animals—Five 12-month-old female New Zealand White rabbits (Oryctolagus cuniculus).

Procedures—Rabbits were anesthetized with isoflurane. Baseline isoflurane MAC was determined by use of the tail clamp technique. A loading dose of lidocaine (2.0 mg/kg, IV) was administered followed by a CRI of lidocaine at 50 μg/kg/min. After 30 minutes, isoflurane MAC was determined. Another loading dose was administered, and the lidocaine CRI then was increased to 100 μg/kg/min. After 30 minutes, isoflurane MAC was determined again. Plasma samples were obtained for lidocaine analysis after each MAC determination.

Results—Baseline isoflurane MAC was 2.09%, which was similar to previously reported values in this species. Lidocaine CRI at 50 and 100 μg/kg/min induced significant reductions in MAC. The 50 μg/kg/min CRI resulted in a mean plasma lidocaine concentration of 0.654 μg/mL and reduction of MAC by 10.5%. The 100 μg/kg/min CRI of lidocaine resulted in a mean plasma concentration of 1.578 μg/mL and reduction of MAC by 21.7%. Lidocaine also induced significant decreases in arterial blood pressure and heart rate. All cardiopulmonary variables were within reference ranges for rabbits anesthetized with inhalation anesthetics. No adverse effects were detected; all rabbits had an uncomplicated recovery from anesthesia.

Conclusions and Clinical Relevance—Lidocaine administered as a CRI at 50 and 100 μg/kg/min decreased isoflurane MAC in rabbits. The IV administration of lidocaine may be a useful adjunct in anesthesia of rabbits.

Abstract

Objective—To evaluate the effect of a continuous rate infusion (CRI) of lidocaine on the minimum alveolar concentration (MAC) of isoflurane in rabbits.

Animals—Five 12-month-old female New Zealand White rabbits (Oryctolagus cuniculus).

Procedures—Rabbits were anesthetized with isoflurane. Baseline isoflurane MAC was determined by use of the tail clamp technique. A loading dose of lidocaine (2.0 mg/kg, IV) was administered followed by a CRI of lidocaine at 50 μg/kg/min. After 30 minutes, isoflurane MAC was determined. Another loading dose was administered, and the lidocaine CRI then was increased to 100 μg/kg/min. After 30 minutes, isoflurane MAC was determined again. Plasma samples were obtained for lidocaine analysis after each MAC determination.

Results—Baseline isoflurane MAC was 2.09%, which was similar to previously reported values in this species. Lidocaine CRI at 50 and 100 μg/kg/min induced significant reductions in MAC. The 50 μg/kg/min CRI resulted in a mean plasma lidocaine concentration of 0.654 μg/mL and reduction of MAC by 10.5%. The 100 μg/kg/min CRI of lidocaine resulted in a mean plasma concentration of 1.578 μg/mL and reduction of MAC by 21.7%. Lidocaine also induced significant decreases in arterial blood pressure and heart rate. All cardiopulmonary variables were within reference ranges for rabbits anesthetized with inhalation anesthetics. No adverse effects were detected; all rabbits had an uncomplicated recovery from anesthesia.

Conclusions and Clinical Relevance—Lidocaine administered as a CRI at 50 and 100 μg/kg/min decreased isoflurane MAC in rabbits. The IV administration of lidocaine may be a useful adjunct in anesthesia of rabbits.

Anesthesia with a single agent, such as a volatile inhalation anesthetic, can require doses that cause excessive hemodynamic depression. Balanced anesthesia is a concept whereby several anesthetic and analgesic drugs are administered concurrently, thus lowering the drug doses so that no single drug is administered at a dose that causes adverse effects.1 Balanced anesthesia decreases the requirements for inhalation anesthetics and thereby may limit their cardiovascular effects.2 Isoflurane is known to cause a dose-dependent decrease in systemic vascular resistance and blood pressure.3

Lidocaine, an amino amide local anesthetic, is commonly administered IV in both human and veterinary anesthesia in multimodal protocols to reduce the MAC of inhalation anesthetics and to provide intraoperative and postoperative analgesia.4–10 The MAC of an inhalation anesthetic can be determined objectively by measuring the concentration of anesthetic agent required to prevent gross purposeful movement in 50% of subjects in response to a noxious stimulus. This technique can also be used to measure the potency of a volatile inhalation anesthetic and to compare the analgesic or sedative effects of various drugs on anesthetic requirements.3,11

Few studies have been conducted to investigate the MAC-sparing effects of analgesics in rabbits. Investigators in 1 study12 found that discontinuation of diclofenac and ketoprofen leads to an increase in the MAC of halothane. In another study,13 investigators found that the administration of butorphanol (alone or in combination with meloxicam) significantly reduced the MAC of isoflurane by 7.6% and 12.4%, respectively. A study14 conducted to investigate the effects of IV administration of tramadol in rabbits revealed a reduction in the MAC of isoflurane by 9%.

Lidocaine contributes to multimodal analgesia, in part, by blocking sodium channels in sensory nerve fibers, thereby inhibiting the activity, amplitude, and conduction of electrical impulses.15 These effects are dose dependent and occur rapidly in the fibers responsible for transmitting pain sensations (ie, unmyelinated C nerve fibers and the small, thinly myelinated A-δ fibers).16,17 Lidocaine also causes suppression of spinal cord sensitization and inhibition of spinal visceromotor neurons.18,19 It also has substantial anti-inflammatory and free-radical scavenging properties that may reduce postoperative pain and have a direct excitatory effect on intestinal smooth muscles, which are thought to be the result of inhibition of the myenteric plexus.15 Systemic administration of lidocaine has been used in both human and veterinary medicine to reduce the requirements of volatile inhalation agents, reduce intraoperative and postoperative pain, promote gastrointestinal tract motility, and reduce the release of endotoxin and inflammatory mediators.20–22

Studies in equids,4 rodents,5 humans,6,7 dogs,8 cats,9 and small ruminants10 have revealed that IV administration of lidocaine significantly reduces the MAC of inhalation anesthetics. To the authors’ knowledge, the analgesic or MAC-sparing effects of lidocaine in rabbits have not been reported. The purpose of the study reported here was to evaluate the effects of a CRI of lidocaine on isoflurane MAC in rabbits. Specifically, we hypothesized that administration of lidocaine would decrease isoflurane MAC in rabbits.

Materials and Methods

Animals—Five female New Zealand White rabbits (Oryctolagus cuniculus) were included in the study. Rabbits were 12 months old and weighed between 4.0 and 4.7 kg. Rabbits were considered healthy on the basis of medical histories, results of physical examinations, evaluation of behavior, and assessment of serum total protein concentrations and Hct values. Rabbits were housed separately in pens in a temperature-controlled environment (20°C) with regulated lighting (12 hours of light and 12 hours of darkness). All were fed a diet consisting of timothy haya and pelletsb daily and were given water ad libitum. The protocol for the study was approved by the Kansas State University Institutional Animal Care and Use Committee.

Experimental procedures—Anesthesia was induced with 5% isoflurane in oxygen (2 L/min) administered via face mask from a coaxial circuit system (Bain breathing circuit). Rabbits were endotracheally intubated with a cuffed 3.5-mm endotracheal tube.c Anesthesia was maintained with isoflurane in oxygen (2 L/min) administered by use of a small animal anesthesia machine. Rabbits were positioned in dorsal recumbency.

The ETiso and Petco2 were monitored continually. A 5F polypropylene catheterd was passed through the lumen of the endotracheal tube and positioned such that the tip was 5 mm distal to the end of the tube. This catheter was used to sample end-tidal gases, which were analyzed with an infrared sidestream gas analyzer.e The infrared gas analyzer was calibrated before each experiment by use of a standardized calibration gas mixture designed for the analyzer. A mechanical ventilatorf was used to maintain Petco2 between 30 and 45 mm Hg.

A 24-standard gauge catheterg was placed in a cephalic vein for infusion of lactated Ringer's solutionh (5 mL/kg/h). Body temperature was monitored with an esophageal thermometer probe, and an electric heating blanketi was used to maintain esophageal temperature between 37° and 40°C. Oscillometric blood pressurej was measured by placing a cuff (width, 40% to 50% of limb circumference) at a location halfway between the elbow and carpal joints of an extended forelimb. Heart rate and ECG readings were monitored continuously. Arterial hemoglobin saturation was also monitored continuously with a pulse oximeterk placed on each rabbit's tongue. Temperature, heart rate, ECG, Spo2, SAP, DAP, MAP, Petco2, and ETiso were recorded every 5 minutes.

Approximately 30 minutes after induction of anesthesia, with ETiso held constant at 2.0% for at least 15 minutes, the baseline MAC was determined by use of a bracketing technique. A 24-cm Babcock tissue forcepsl with protective plastic tubing was clamped (to the first notch) at a location 5 cm distal to the base of the tail of each rabbit. The clamp was maintained for a maximum of 30 seconds or until purposeful movement was detected. Gross proposal movement was defined as a jerking or twisting motion of the head or running motion of the extremities. Coughing, straining, stiffening, and chewing were not considered gross purposeful movements. When purposeful movement was detected, ETiso was increased by 0.1%; after a 15-minute equilibration period, the tissue forcep was reapplied to the tail. When no purposeful movement was detected, ETiso was decreased by 0.1%; after a 15-minute equilibration period, the tissue forceps was reapplied to the tail. This procedure was repeated until the MAC of isoflurane (ie, ETiso values at which movement was and was not detected) was determined. This MAC determination was performed in duplicate, and the mean value was recorded as the MAC for that rabbit. A blood sample (4 mL) was collected from the lateral saphenous vein of each rabbit at the point of MAC determination. Blood samples were placed in lithium heparin tubes. Plasma was harvested and stored at −70°C until used for analysis.

Each rabbit then received a bolus of lidocaine hydrochloridem (2 mg/kg, IV), which was administered over a 5-minute period, followed by a CRI of lidocainen (50 μg/kg/min), which was administered with a syringe pump.o For the CRI, lidocaine was diluted by the addition of sterile saline (0.9% NaCl) solution to a final concentration of 2 mg/mL and administered through one of the ports of the catheter. The lidocaine CRI was administered for a period of 30 minutes to achieve a steady-state plasma concentration. Once the steady state was reached, the previously described bracketing technique for MAC determination was performed. The CRI was continued throughout the MAC determination. The isoflurane MAC for a CRI of 50 μg of lidocaine/kg/min was determined for each rabbit in duplicate. Once the MAC was determined, a blood sample (4 mL) was collected from the lateral saphenous vein. Plasma was harvested and stored at −70°C until used for analysis.

Each rabbit then received another lidocaine bolus (2 mg/kg, IV), which was administered over a 5-minute period, followed by a CRI of lidocaine (100 μg/kg/min). Thirty minutes after onset of the lidocaine CRI, the same bracketing procedure was performed in duplicate to determine the isoflurane MAC for a CRI of 100 μg of lidocaine/kg/min. The CRI was continued throughout the MAC determination. After the isoflurane MAC for a CRI of 100 μg of lidocaine/kg/min was established, a blood sample (4 mL) was collected from the lateral saphenous vein. Plasma was harvested and stored at −70°C until used for analysis.

Rabbits were allowed to recover from anesthesia. Interval from termination of isoflurane administration until extubation was recorded for each rabbit.

Measurement of plasma concentrations of lidocaine—Plasma lidocaine concentrations were determined by use of liquid chromatographyp with triple quadrupole mass spectrometry.q Plasma samples and standards (0.1 mL) were treated with 0.4 mL of methanol that contained mepivacaine (250 ng/mL) as the internal standard. The qualifying ion for lidocaine had an m/z of 235, whereas the quantifying ion had an m/z of 86. The qualifying ion for the internal standard had an m/z of 247, whereas the quantifying ion had an m/z of 98. The mobile phase consisted of acetonitrile and 0.1% formic acid with a phenyl column (150 × 3 mm; 5 μM) used to achieve separation. The mobile phase gradient started at 90% formic acid with a linear gradient to 40% formic acid at 4 minutes, followed by a linear gradient to 90% formic acid at 5 minutes (total run time, 6.5 minutes). Mean ± SD accuracy of the assay was 95 ± 9%, which was determined on triplicate replicates for each of 3 concentrations (0.25, 1, and 2.5 μg/mL).

Statistical analysis—Longitudinal data analysis was performed with linear mixed modeling on the various outcome variables with time, treatment (baseline, lidocaine at 50 μg/kg/min, and lidocaine at 100 μg/kg/min), the time-by-treatment interaction, and ETiso (except when ETiso was the response) as fixed effects and subjects as a random effect. Residual plots were used to assess linearity, homogeneity of variances, normality, and outliers. Shapiro-Wilk tests and quantile plots were performed on the residuals of the treatment groups. Autocorrelation of the residuals over time was assessed with the autocorrelation function method. Regression models assumed that residuals were not correlated but that a significant and important autocorrelation of the residuals over time was evident (first-order autocorrelation, 0.86). This resulted from the procedure used, whereby modification of isoflurane concentration was based on isoflurane concentrations 5 minutes preceding a time point. Manipulation of the covariance matrix by use of a serial correlation structure was unsuccessful in addressing this autocorrelation. Adding the first-order lag for isoflurane concentration (isoflurane concentration 5 minutes preceding a time point) as a predictor in the model successfully removed autocorrelation, significantly improved fit, and allowed other model assumptions to be validated. Competing models were compared with standardized residuals plots and the Akaike information criterion. Differences between the 2 concentrations of lidocaine CRI were assessed with preplanned comparisons by contrast statements. When interaction terms were not significant, main effects were reported. Analyses were performed with a statistical packager for linear mixed modeling and contrasts. A value of α = 0.05 was used to determine significance.

Results

Time did not significantly affect isoflurane concentrations, which depended mainly on the preceding concentrations in accordance with the experimental design. However, there was a significant treatment effect, with both treatments reducing the MAC. Doubling the concentration of the lidocaine CRI resulted in a doubling of the effect on MAC reduction (Table 1). There was a significant (P = 0.005) difference in the magnitude of MAC reduction between the 2 CRIs. Because isoflurane concentration was a function of preceding concentrations (it was changed on the basis of the response to the concentration 5 minutes preceding a time point), the MAC was obtained by the following equation: Isoflurane MAC = β0 + (β1 × Iso5) + (β2 × lidocaine50)+ (β3 × lidocaine100), where β0 is the intercept, β1–3 are the parameter estimates (constant) for the model variables, Iso5 is the isoflurane concentration 5 minutes prior to the current time point, and lidocaine50 and lidocaine100 are dummy variables (0,1) indicating the CRI treatment evaluated. This corresponded to a stabilization of the isoflurane concentration and meant that there was no increase or decrease in the isoflurane concentration because the MAC was reached. Parameter estimates were determined for the final model (Table 2).

Table 1—

Reduction in isoflurane MAC after administration of a bolus of lidocaine (2 mg/kg, IV) followed by a lidocaine CRI in 5 New Zealand White rabbits (Oryctolagus cuniculus).

VariableMAC95% CIMAC reduction (%)P value
Baseline isoflurane MAC2.01.9–2.1NANA
Isoflurane MAC with lidocaine CRI at 50 μg/kg/min1.81.7–1.910.40.003
Isoflurane MAC with lidocaine CRI at 100 μg/kg/min1.61.5–1.621.7< 0.001

CI = Confidence interval. NA = Not applicable.

Table 2—

Estimates for a mixed linear model of isoflurane concentration used in 5 New Zealand White rabbits to determine the isoflurane MAC after bolus administration of lidocaine (2.0 mg/kg, IV) followed by CRI of lidocaine at 50 and 100 μg/kg/min.

VariableEstimate95% CIP value*
Intercept0.270.17 to 0.37< 0.001
First order lag of isoflurane0.860.82 to 0.91< 0.001
Lidocaine CRI at 50 μg/kg/min–0.03–0.05 to 0.010.003
Lidocaine CRI at 100 μg/kg/min–0.06–0.09 to 0.03< 0.001
SD attributed to rabbits0.0160.006 to 0.0420.015
Residual SD0.0600.056 to 0.064NA

See Table 1 for key.

Isoflurane significantly decreased arterial blood pressure (Table 3). There was a mild positive effect of time on the arterial blood pressure, except for the DAP. When controlling for the isoflurane concentration and time, lidocaine CRI induced a significant decrease in indirect arterial blood pressure (Figure 1). This decrease was not significantly different between the 50 and 100 μg/kg/min CRIs for the MAP (P = 0.30) and SAP (P = 0.89) but was for the DAP (P = 0.007). Lidocaine CRI significantly (P = 0.005) decreased the heart rate, with the 50 μg/kg/min CRI inducing the greatest effects (Figure 2). The heart rate also significantly decreased with time but significantly increased at higher isoflurane concentrations.

Figure 1—
Figure 1—

Least squares mean ± SEM SAP (A), MAP (B), and DAP (C) in 5 New Zealand White rabbits (Oryctolagus cuniculus) after anesthesia with isoflurane (2%) for 30 minutes (baseline; circles) and during isoflurane-induced anesthesia 30 minutes after administration of a bolus of lidocaine (2 mg/kg, IV) followed by a lidocaine CRI at 50 μg/kg/min (squares) and 100 μg/kg/min (triangles).

Citation: American Journal of Veterinary Research 74, 11; 10.2460/ajvr.74.11.1377

Figure 2—
Figure 2—

Least squares mean ± SEM heart rate in 5 New Zealand White rabbits after anesthesia with isoflurane for 30 minutes (baseline) and during isoflurane-induced anesthesia 30 minutes after IV administration of a bolus of lidocaine (2 mg/kg) followed by a lidocaine CRI at 50 and 100 μg/kg/min. See Figure 1 for remainder of key.

Citation: American Journal of Veterinary Research 74, 11; 10.2460/ajvr.74.11.1377

Table 3—

Percentage decrease of each variable attributable to various factors in 5 New Zealand White rabbits used to determine the isoflurane MAC after bolus administration of lidocaine (2.0 mg/kg, IV) followed by CRI of lidocaine at 50 and 100 μg/kg/min.

VariableTime (h)Isoflurane (%)Lidocaine CRI at 50 μg/kg/minLidocaine CRI at 100 μg/kg/min
MAP (mm Hg)–1.4*17.46.88.9
SAP (mm Hg)–2.1*11.85.86.5
DAP (mm Hg)NA25.58.212.6
Heart rate (beats/min)2.6–12.59.06.2
Petco2 (mm Hg)–1.9*NA–3.6–8.3
Spo2 (%)–0.5NA–1.5–2.2

A negative value represents an increase in the value for a variable and a positive value represents a decrease in the value for a variable.

Effect is significant (P < 0.05).

Effect is significant (P = 0.01).

Lidocaine CRI significantly (P < 0.001) increased Petco2; this effect was greatest for the 100 μg/kg/min CRI. Finally, there was a significant (P < 0.001) increase in Spo2 during lidocaine CRIs; this effect also was greatest for the 100 μg/kg/min CRI. Both Petco2 and Spo2 increased significantly with time but not with increases in isoflurane concentration.

The random effect of rabbit was also significant for all models. This reflected interindividual variability.

The mean ± SD total anesthetic time was 7 hours and 14 minutes ± 2 hours and 13 minutes. Mean interval from end of isoflurane administration until extubation was 14 ± 3 minutes. All rabbits recovered from the procedures without complications. Most rabbits were observed eating 1 hour after extubation.

Discussion

The gas-sparing effects of IV administration of lidocaine have been established. Decreases in MAC differ depending on the study design, dose of lidocaine, and species of animal. Studies on the use of lidocaine in rabbits are lacking. In rodents, lidocaine reduces the MAC requirement of cyclopropane by approximately 40%.5 In cats, lidocaine at plasma concentrations of 3 μg/mL decreased isoflurane requirements by 7% to 28% and at 11 μg/mL reduced the MAC by as much as 59%.9 In a study8 in dogs, a loading dose of 2 mg/kg followed by CRI of 50 μg/kg/min resulted in a lidocaine plasma concentration of approximately 1.5 mg/mL and reduced the MAC of isoflurane by 18.7%. In that same study,8 administration of a loading dose of 2 mg/kg followed by CRI of 200 μg/kg/min resulted in a plasma concentration of approximately 4.5 μg/mL and decreased the MAC by 43.3%. In goats, a loading dose of 2.5 mg/kg and CRI of 100 μg/kg/min caused a reduction of 19% in the MAC of isoflurane.10 In human patients anesthetized with nitrous oxide and halothane, IV administration of lidocaine reduced MAC requirements by 10% to 28%.23

The administration of lidocaine in the present study and the subsequent plasma concentrations correlated well with the reduction of isoflurane MAC. A loading dose of 2 mg/kg followed by CRI at 50 μg/kg/min resulted in a mean plasma lidocaine concentration of 0.654 μg/mL and reduction of MAC by 10.5%. A loading dose of 2 mg/kg followed by CRI at 100 μg/kg/min resulted in a mean plasma concentration of 1.578 μg/mL and reduction of isoflurane MAC by 21.7%. A comparison of the percentage reduction initially yielded the impression that rabbits were less responsive than other species to the effects of lidocaine; however, examination of plasma concentrations of lidocaine in relationship to the MAC reduction revealed that rabbits responded in a similar manner. Analysis of lidocaine doses versus plasma concentrations suggested that rabbits might need to be administered a higher dose to achieve desired effects. The steady-state plasma concentrations achieved with a given dose are inversely proportional to the plasma clearance because as the clearance increases, the plasma concentration will decrease for a given dose. A lidocaine CRI at 50 μg/kg/min to isoflurane-anesthetized horses resulted in a median concentration of approximately 3.0 to 4.0 μg/mL24,25 In another study4 in halothane-anesthetized horses, a lidocaine CRI at 100 μg/kg/min resulted in plasma concentrations between 3.0 and 7.0 mg/dL, which is a 2- to 4-fold increase in plasma concentrations. Therefore, analysis of these results suggested that rabbits in the present study had a faster plasma clearance than values reported for other species.

The analgesic properties of lidocaine must be considered when comparing results for the present study with results of other lidocaine studies. It has been suggested26 that lidocaine provides a multimodal analgesic response to acute pain. Lidocaine can suppress spinal cord sensitization and inhibit spinal visceromotor neurons through blockage of sodium ion channels.15,18,27 Lidocaine also depresses activity, amplitude, and conduction in myelinated A-δ and unmyelinated C nerve fibers that are responsible for transmitting pain sensations.16,17

It currently is unclear whether the dose-dependent reduction of the isoflurane MAC was associated with an analgesic or sedative effect of lidocaine. Regardless of the mechanism, there is considerable evidence of the efficacy of lidocaine infusion to provide analgesia in a number of species and situations. In rodents, IV administration of lidocaine selectively blocks polysynaptic activity of central C fibers associated with stimulation of the sural nerve.17 In humans, lidocaine decreases the sympathetic pain response to surgery.22 Analgesic effects of lidocaine in humans with neuropathic pain have been established, with patients reporting a significant decrease in pain scores at plasma lidocaine concentrations ≥ 1.5 μg/mL28 Preoperative or intraoperative administration of lidocaine also reduces postoperative analgesic requirements. Investigators in 1 study29 reported a decrease of 90% in postoperative pain in patients who received IV administration of lidocaine during surgery. A study30 involving horses undergoing castration revealed that IV administration of a lidocaine CRI at 100 μg/kg/min decreased arousal and pain response measured with electroencephalogram analysis.

The analgesic and sedative effects of lidocaine have also been described for conscious humans,7 rats,31 horses,32 dogs,33 and sheep.34 In a controlled study7 of men undergoing prostatectomy, lidocaine administered IV during and after surgery decreased the incidence of pain, hastened the return of intestinal motility, and shortened the duration of a hospital stay. In equids, lidocaine is commonly administered IV after colic surgery. Studies21,25 in horses suggest that lidocaine shortens the duration and severity of postoperative ileus and gastrointestinal pain and improves survival times. Lidocaine plasma concentrations of 1.0 μg/mL in conscious horses provide somatic analgesia32; however, plasma concentrations between 1.85 and 4.50 μg/mL can cause adverse effects such as sedation, collapse, and seizures.32 These effects are postulated to be attributable to a combination of direct excitatory effects on intestinal smooth muscle, blockade of inhibitory spinal and peritoneal sympathetic reflexes, inhibition of central hyperalgesia, and anti-inflammatory and antiendotoxic actions.20,35 It is possible that systemic administration of lidocaine provides species-specific effects that may differ in accordance with the nature of the pain. We are not aware of any studies performed to determine these effects in conscious rabbits.

The baseline isoflurane MAC of 2.09% in the present study is similar to other values of isoflurane MAC reported for New Zealand White rabbits in which the tail clamp technique was used as the noxious stimulus for MAC determination.3 Another study36 involving New Zealand White rabbits in which a digit-clamp technique was used revealed MAC values of 2.08% and 2.49%. The MAC of an inhalation anesthetic can differ substantially among animals of the same species and even among strains of the same species.3 Interindividual and intra-individual variations in MAC are typically reported to be < 20% and 10%, respectively.3

A study37 conducted to compare the relationship of various noxious stimuli on isoflurane MAC in rabbits and dogs found that there were no significant differences between an electrical stimulus and a clamping technique but that there was a significant underestimation of MAC when comparing these noxious stimuli to surgical stimuli to the skin. In another study,11 investigators found that mechanical and electrical stimuli result in similar effects on the reduction of halothane MAC. In the present study, use of the tail clamp technique as the noxious stimulus resulted in isoflurane MAC values at baseline and after lidocaine administration that are comparable to the values determined in other studies.

In the present study, there was no ceiling effect in the reduction of MAC over the range of plasma lidocaine concentrations. Isoflurane MAC decreased linearly as a function of the plasma lidocaine concentration. The plasma lidocaine concentration approximately doubled from 0.654 to 1.578 μg/mL; concurrently, there was a reduction of isoflurane MAC from 10.4% to 21.7%. It is unclear if further increases in lidocaine doses and subsequent plasma concentrations would have continued to induce a decrease in the MAC. In dogs, a ceiling effect on halothane MAC was observed at lidocaine concentrations > 1.16 μg/mL.23 Additional studies must be performed to determine whether there is a similar plateau effect for lidocaine.

The pharmacodynamic characteristics of lidocaine administered IV have not been evaluated in rabbits, and the dose used in the present study was chosen on the basis of doses of lidocaine that appear to be safe for use in anesthetized dogs.37,38 We elected to start with the low-dose lidocaine CRI followed by the high-dose CRI, rather than to randomize the treatments. Lidocaine administered as a single bolus dose is rapidly redistributed, and achieving steady-state therapeutic concentrations requires IV administration of a loading dose prior to a CRI.33,34,39–42 In 1 pharmacokinetic study43 performed in rabbits, investigators found that IV administration of lidocaine results in a mean ± SD half-life of 8.9 ±1.2 minutes. In the present study, lidocaine was administered for 30 minutes to achieve steady-state concentrations before we proceeded to determine any MAC values. Furthermore, isoflurane was administered for 15 minutes after any changes to provide steady-state concentrations of isoflurane for the study.

Differences among species in the metabolism of lidocaine have been reported.33,34,39–42 Approximately 95% of lidocaine is metabolized in the liver by several hepatic cytochrome P450s to form the pharmacologically active metabolite, MEGX, and then subsequently to form the inactive metabolite, glycinexylidide. In small animal medicine, MEGX has a longer half-life than lidocaine does, but MEGX is a less potent sodium channel blocker than lidocaine. In contrast, a pharmacokinetic study43 performed in rabbits revealed that MEGX and glycinexylidide were not detected when lidocaine was administered IV, which may indicate different routes of metabolism in rabbits.

The potential adverse effects of IV administration of lidocaine include disorientation, signs of anxiety, vocalization, seizures, vomiting, muscle twitching, respiratory depression, bradycardia, decreases in cardiac output, and hypotension.44 These adverse effects are most commonly reported after IV administration of large bolus doses of lidocaine. The LD50 of lidocaine in rabbits is reported to be quite high (25 mg/kg), which gives rabbits a wide safety margin in comparison to the safety margin in many other companion animals.45 Throughout the present study, no adverse effects were detected during anesthesia or the recovery phase. No detrimental effects on the cardiovascular system were detected, although cardiac output was not measured. Both lidocaine CRIs caused a significant decrease in the MAP, SAP, DAP, and heart rate. However, the magnitude of the differences was small and not clinically meaningful. Persistent hypotension or bradycardia was not observed in any of the rabbits. Although the highest dose of lidocaine decreased the MAC by 21.7%, it also reduced the MAP and DAP by approximately 8.9% and 6.5%, respectively. Comprehensively, the net influence on arterial blood pressure was negligible, providing that anesthetists decrease the isoflurane concentration accordingly after starting a lidocaine CRI. Thus, we believe that lidocaine has minimal cardiovascular adverse effects providing the isoflurane concentration is decreased to account for the MAC reduction. These findings are in agreement with those of other studies25,46 involving the use of lidocaine and indicate that lidocaine administered at low doses over time has minimal effects on cardiac index, heart rate, systemic vascular resistance, and blood pressure.

However, when comparing the effect of isoflurane alone on blood pressure, it appeared that rabbits were more sensitive to vasodilatory effects of inhalation anesthetics than are other animals. Even at a low isoflurane concentration of 0.8 MAC, hypotension has been reported in rabbits.13,47 Experiments revealed that isoflurane at 2.5% and 1.5% reduced the MAP to 27.5 ± 0.9 mm Hg and 47 ± 5 mm Hg, respectively.47 These results provide evidence that a multimodal approach, such as one that involves the IV administration of lidocaine, should be implemented during anesthesia to reduce the concentration of inhalation anesthetics to improve blood pressure.

Direct measurement of blood pressure is the criterion-referenced standard. Thus, one of the limitations of the study reported here is that blood pressure was measured via indirect techniques. Studies48,49 performed in rabbits to compare different methods of measuring blood pressure indicated positive agreement between both indirect and direct measurement of blood pressure, which supports the validity of the use of indirect blood pressure in the present study.

To obtain the most accurate and comparable Petco2 and ETiso, gas samples were collected from a catheter located 5 mm distal to the end of the endotracheal tube. This allowed collection of gas samples that were most consistent with alveolar gases. Comparison of results for the present study with comparable values for baseline MAC, MAC after a lidocaine CRI at 50 μg/kg/min, and MAC after a lidocaine CRI at 100 μg/kg/min in other studies4–10,50 performed in other species revealed that the end-tidal gas values in the study reported here were as expected.

During the IV administration of lidocaine, there was a significant and dose-dependent increase in Spo2 and Petco2. Both Spo2 and Petco2 increased significantly with time but not with increases in isoflurane concentrations. Readers should be cautious not to overinterpret these effects of systemic administration of lidocaine on ventilatory variables. It is important not to confuse significant differences detected via statistical analysis with clinical relevance.51 A 2.2% change in Spo2, a variable measured on a 100-point scale, is likely of little clinical importance because the values for Spo2 remained within clinically acceptable limits throughout the anesthetic period. Changes in Petco2 during lidocaine administration represented an 8.3% increase during administration of the 100 μg/kg/min CRI. However, hypercapnia was not detected in any of the rabbits in the present study, and Petco2 values did not deviate from mammalian reference ranges.52 Small changes in pulmonary vascular resistance or cardiac output as a result of lidocaine administration or alterations in isoflurane concentrations over time may have induced increased delivery of CO2 to the lungs or improved the dead space-to-tidal volume ratio during ventilation to cause subtle but significant changes in Spo2 and Petco2 as a result of the infusions. Because cardiac output and vascular resistances were not measured or calculated, the effects that systemic administration of lidocaine may have had in this study are unknown.

Another limitation of the present study was the design. Because of logistics, time, and expense, this study consisted of a crossover experiment whereby both drugs were administered during the same anesthetic event. The order in which the drugs were administered was not randomized; instead, the 50 μg/kg/min CRI was administered first, which was then followed by the 100 μg/kg/min CRI. Despite the lack of a prolonged washout period between CRIs, we believe the results are reliable because lidocaine has a fairly short half-life. Furthermore, each CRI was preceded by administration of a bolus of lidocaine (2 mg/kg) and followed by a 30-minute period to ensure plasma drug concentrations reached a steady state. Additionally, plasma drug concentrations correlated well between infusion rate and MAC.

To our knowledge, the study reported here is the first in which investigators have determined the gas-sparing effects of IV administration of lidocaine on isoflurane MAC in rabbits. Whether this reduction was attributable to the analgesic or sedative effects of lidocaine is unclear. However, the analgesic effects must be considered when comparing the properties of lidocaine in other species. Systemic administration of lidocaine has been used in human and veterinary medicine to reduce the requirements of inhalation anesthetics, reduce preoperative and postoperative pain, promote gastrointestinal motility, and reduce the release of endotoxin and inflammatory mediators. Administration of a lidocaine CRI at the doses and rates described for the present study may be a useful adjunct to provide a balanced anesthetic technique (ie, multimodal analgesia) in rabbits. Further studies to assess the effects of lidocaine on anesthesia with isoflurane in clinical patients are needed.

ABBREVIATIONS

CRI

Continuous rate infusion

DAP

Diastolic arterial blood pressure

ETiso

End-tidal concentration of isoflurane

MAC

Minimum alveolar concentration

MAP

Mean arterial blood pressure

MEGX

Monoethylglycinexylidide

Petco2

End-tidal partial pressure of carbon dioxide

SAP

Systolic arterial blood pressure

Spo2

Oxygen saturation as measured by pulse oximetry

a.

Oxbow Animal Health, Murdock, Neb.

b.

Timothy hay Oxbow pellets, Oxbow Animal Health, Murdock, Neb.

c.

Rusch, Teleflex Medical, Kernen, Germany.

d.

Kendall, Tyco Healthcare, Mansfield, Mass.

e.

Cardiocap5, GE Healthcare, Technologies Datex-Ohmeda Inc, Madison, Wis.

f.

Anesthesia work station, model 2002, Hallowell EMC, Pittsfield, Mass.

g.

Baxter Healthcare Corp, Irvine, Calif.

h.

Baxter Healthcare Corp, Deerfield, Ill.

i.

Hotdog electric heating blanket, Augustine Biomedical and Design, Eden Prairie, Minn.

j.

Cardell Oscillometric blood pressure, Sharn Veterinary Inc, Tampa, Fla.

k.

Tyco Healthcare, Gosport, Hampshire, England.

l.

Bolton Surgical Ltd, Chapeltown, Sheffield, South Yorkshire, England.

m.

Lidocaine hydrochloride (20 mg/mL), Hospira Inc, Lake Forest, Ill.

n.

Lidocaine hydrochloride (2 mg/mL), Hospira Inc, Lake Forest, Ill.

o.

Medfusion 2010i syringe pump, Medex Co, Duluth, Ga.

p.

Shimadzu Prominence, Shimadzu Scientific Instruments, Columbia, Md.

q.

API 2000 triple quadrupole mass spectrometer, Applied Biosystems, Foster City, Calif.

r.

R development core team (2012). R foundation for statistical computing, Vienna, Austria.

References

  • 1. Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg 1993; 77: 10481056.

    • Search Google Scholar
    • Export Citation
  • 2. Bailey PL, Egan TD, Stanley TH. Intravenous opioid anesthetics. In: Miller RD, ed. Anesthesia. 5th ed. Philadelphia: Churchill Livingstone, 2000;273376.

    • Search Google Scholar
    • Export Citation
  • 3. Steffey EP. Inhalation anesthetics. In: Thurmon JC, Tranquilli WJ, Benson GJ, eds. Lumb and Jones' veterinary anesthesia. 3rd ed. Philadelphia: Lea & Febiger, 1996;297329.

    • Search Google Scholar
    • Export Citation
  • 4. Doherty TJ, Frazier DL. Effect of intravenous lidocaine on halothane minimum alveolar concentration in ponies. Equine Vet J 1998; 30: 300303.

    • Search Google Scholar
    • Export Citation
  • 5. DiFazio CA, Neiderlehner JR, Burney RG. The anesthetic potency of lidocaine in the rat. Anesth Analg 1976; 55: 818821.

  • 6. Phillips OC, Lyons WB, Harris LC, et al. Intravenous lidocaine as an adjunct to general anesthesia: a clinical evaluation. Anesth Analg 1960; 39: 317322.

    • Search Google Scholar
    • Export Citation
  • 7. Groudine SB, Fisher HAG, Kaufman RP, et al. Intravenous lidocaine speeds the return of bowel function, decreases postoperative pain, and shortens hospital stay in patients undergoing radical retropubic prostatectomy. Anesth Analg 1998; 86: 235239.

    • Search Google Scholar
    • Export Citation
  • 8. Valverde A, Doherty TJ, Hernandez J, et al. Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 2004; 31: 264271.

    • Search Google Scholar
    • Export Citation
  • 9. Pypendop BH, Ilkiw JE. The effects of intravenous lidocaine administration on the minimum alveolar concentration of isoflurane in cats. Anesth Analg 2005; 100: 97101.

    • Search Google Scholar
    • Export Citation
  • 10. Doherty T, Redua MA, Queiroz-Castro P, et al. Effect of intravenous lidocaine and ketamine on the minimum alveolar concentration of isoflurane in goats. Vet Anaesth Analg 2007; 34: 125131.

    • Search Google Scholar
    • Export Citation
  • 11. Eger EI, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration: a standard of anesthetic potency. Anesthesiology 1965; 26: 756763.

    • Search Google Scholar
    • Export Citation
  • 12. Rorarius MG, Baer GA, Metsä-Ketelä T. The effect of diclofenac and ketoprofen on halothane MAC in rabbits. Agents Actions 1993; 38: 286289.

    • Search Google Scholar
    • Export Citation
  • 13. Turner PV, Kerr CL, Healy AJ, et al. Effect of meloxicam and butorphanol on minimum alveolar concentration of isoflurane in rabbits. Am J Vet Res 2006; 67: 770774.

    • Search Google Scholar
    • Export Citation
  • 14. Egger CM, Souza MJ, Greenacre CB, et al. Effect of intravenous administration of tramadol hydrochloride on the minimum alveolar concentration of isoflurane in rabbits. Am J Vet Res 2009; 70: 945949.

    • Search Google Scholar
    • Export Citation
  • 15. Koppert W, Weigand M, Neumann F, et al. Perioperative intravenous lidocaine has preventive effects on postoperative pain and morphine consumption after major abdominal surgery. Anesth Analg 2004; 98: 10501055.

    • Search Google Scholar
    • Export Citation
  • 16. Heavner JE, de Jong RH. Lidocaine blocking concentrations for B- and C-nerve fibers. Anesthesiology 1974; 40: 228233.

  • 17. Woolf CJ, Wiesenfeld-Hallin Z. The systemic administration of local anesthetics produces a selective depression of C-afferent fiber evoked activity in the spinal cord. Pain 1985; 23: 361374.

    • Search Google Scholar
    • Export Citation
  • 18. Dohi S, Kitahata LM, Toyooka H, et al. An analgesic action of intravenously administered lidocaine on dorsal-horn neurons responding to noxious thermal stimulation. Anesthesiology 1979; 51: 123126.

    • Search Google Scholar
    • Export Citation
  • 19. Butterworth J, Cole L, Marlow G. Inhibition of brain cell excitability by lidocaine, QX314, and tetrodotoxin: a mechanism for analgesia from infused local anesthetics? Acta Anaesthesiol Scand 1993; 37: 516523.

    • Search Google Scholar
    • Export Citation
  • 20. Peiró JR, Barnabe PA, Cadioli FA, et al. Effects of lidocaine infusion during experimental endotoxemia in horses. J Vet Intern Med 2010; 24: 940948.

    • Search Google Scholar
    • Export Citation
  • 21. Malone E, Ensink J, Turner T, et al. Intravenous continuous infusion of lidocaine for treatment of equine ileus. Vet Surg 2006; 35: 6066.

    • Search Google Scholar
    • Export Citation
  • 22. Wallin G, Cassuto J, Hogstrom S, et al. Effects of lidocaine infusion on the sympathetic response to abdominal surgery. Anesth Analg 1987; 66: 10081013.

    • Search Google Scholar
    • Export Citation
  • 23. Himes RS, DiFazio CA, Burney RG. Effects of lidocaine on the anesthetic requirements for nitrous oxide and halothane. Anesthesiology 1977; 47: 437440.

    • Search Google Scholar
    • Export Citation
  • 24. Dzikiti TB, Hellebrekers LJ, van Dijk P. Effects of intravenous lidocaine on isoflurane concentration, physiological parameters, metabolic parameters and stress-related hormones in horses undergoing surgery. J Vet Med A Physiol Pathol Clin Med 2003; 50: 190195.

    • Search Google Scholar
    • Export Citation
  • 25. Feary DJ, Mama KR, Wagner AE, et al. Influence of general anesthesia on pharmacokinetics of intravenous lidocaine infusion in horses. Am J Vet Res 2005; 66: 574580.

    • Search Google Scholar
    • Export Citation
  • 26. Kalso E, Tramèr MR, Moore RA, et al. Systemic local anesthetic type drugs in chronic pain: a qualitative systematic review. Eur J Pain 1998; 2: 314.

    • Search Google Scholar
    • Export Citation
  • 27. Bach FW, Jensen TS, Kastrup J, et al. The effect of intravenous lidocaine on nociceptive processing in diabetic neuropathy. Pain 1990; 40: 2934.

    • Search Google Scholar
    • Export Citation
  • 28. Wallace MS, Dyck JB, Rossi SS, et al. Computer-controlled lidocaine infusion for the evaluation of neuropathic pain after peripheral nerve injury. Pain 1996; 66: 6977.

    • Search Google Scholar
    • Export Citation
  • 29. de Clive-Lowe SG, Desmond J, North J. Intravenous lidocaine anesthesia. Anesthesiology 1958; 13: 138146.

  • 30. Murrell JC, White KL, Johnson CB, et al. Investigation of the EEG effects of intravenous lidocaine during halothane anesthesia in ponies. Vet Anaesth Analg 2005; 32: 212221.

    • Search Google Scholar
    • Export Citation
  • 31. Ikeda Y, Oda Y, Nakamura T, et al. Pharmacokinetics of lidocaine, bupivacaine, and levobupivacaine in plasma and brain in awake rats. Anesthesiology 2010; 112: 13961403.

    • Search Google Scholar
    • Export Citation
  • 32. Meyer GA, Lin HC, Hanson RR, et al. Effects of intravenous lidocaine overdose on cardiac electrical activity and blood pressure in the horse. Equine Vet J 2001; 33: 434437.

    • Search Google Scholar
    • Export Citation
  • 33. DiFazio C, Brown RE. Lidocaine metabolism in normal and phenobarbital-pretreated dogs. Anesthesiology 1972; 36: 238243.

  • 34. Mather LE, Runciman WB, Carapetis RJ, et al. Hepatic and renal clearances of lidocaine in conscious and anesthetized sheep. Anesth Analg 1986; 65: 943949.

    • Search Google Scholar
    • Export Citation
  • 35. Taniguchi T, Shibata K, Yamamoto K, et al. Lidocaine attenuates the hypotensive and inflammatory responses to endotoxemia in rabbits. Crit Care Med 1996; 24: 642646.

    • Search Google Scholar
    • Export Citation
  • 36. Drummond JC. MAC for halothane, enflurane, and isoflurane in the New Zealand White rabbit: a test for the validity of MAC determinations. Anesthesiology 1985; 62: 336338.

    • Search Google Scholar
    • Export Citation
  • 37. Valverde A, Morey TE, Hernández J, et al. Validation of several types of noxious stimuli for use in determining the minimum alveolar concentration for inhalation anesthetics in dogs and rabbits. Am J Vet Res 2003; 64: 957962.

    • Search Google Scholar
    • Export Citation
  • 38. Ortega M, Cruz I. Evaluation of a constant rate infusion of lidocaine for balanced anesthesia in dogs undergoing surgery. Can Vet J 2011; 52: 856860.

    • Search Google Scholar
    • Export Citation
  • 39. Rowland M, Thomson PD, Guichard A, et al. Disposition kinetics of lidocaine in normal subjects. Ann N Y Acad Sci 1971; 179: 383398.

  • 40. Ngo LY, Tam YK, Tawfik S, et al. Effects of intravenous infusion of lidocaine on its pharmacokinetics in conscious instrumented dogs. J Pharm Sci 1997; 86: 944952.

    • Search Google Scholar
    • Export Citation
  • 41. Thomasy SM, Pypendop BH, Ilkiw JE, et al. Pharmacokinetics of lidocaine and its active metabolite, monoethylglycinexylidide, after intravenous administration of lidocaine to awake and isoflurane-anesthetized cats. Am J Vet Res 2005; 66: 11621166.

    • Search Google Scholar
    • Export Citation
  • 42. Milligan M, KuKanich B, Beard W, et al. The disposition of lidocaine during a 12-hour intravenous infusion to postoperative horses. J Vet Pharmacol Ther 2006; 29: 495499.

    • Search Google Scholar
    • Export Citation
  • 43. KT, Maurice H, Du Souich P. First-pass metabolism of lidocaine in the anesthetized rabbit. Contribution of the small intestine. Drug Metab Dispos 1996; 24: 711716.

    • Search Google Scholar
    • Export Citation
  • 44. Plumb D. Lidocaine HCl. Plumb's veterinary drug handbook. 5th ed. Ames, Iowa: Blackwell Publishing Professional, 2005;460462.

  • 45. Santa Cruz Biotechnology. Lidocaine hydrochloride material safety data sheet. sc-215245. Santa Cruz, Calif: Santa Cruz Biotechnology, 2009.

    • Search Google Scholar
    • Export Citation
  • 46. Nunes de Moraes A, Dyson DH, O'Grady MR, et al. Plasma concentrations and cardiovascular influence of lidocaine infusions during isoflurane anesthesia in healthy dogs and dogs with subaortic stenosis. Vet Surg 1998; 27: 486497.

    • Search Google Scholar
    • Export Citation
  • 47. Imai A, Steffey EP, Ilkiw JE, et al. Comparison of clinical signs and hemodynamic variables used to monitor rabbits during halothane- and isoflurane-induced anesthesia. Am J Vet Res 1999; 60: 11891195.

    • Search Google Scholar
    • Export Citation
  • 48. Kurashina T, Sakamaki T, Yagi A, et al. A new device for indirect blood pressure measurement in rabbits. Jpn Circ J 1994; 58: 264268.

  • 49. Ypsilantis P, Didilis VN, Politou M, et al. A comparative study of invasive and oscillometric methods of arterial blood pressure measurement in the anesthetized rabbit. Res Vet Sci 2005; 78: 269275.

    • Search Google Scholar
    • Export Citation
  • 50. Valverde A, Gunkelt C, Doherty TJ, et al. Effect of a constant rate infusion of lidocaine on the quality of recovery from sevoflurane or isoflurane general anesthesia in horses. Equine Vet J 2005; 37: 559564.

    • Search Google Scholar
    • Export Citation
  • 51. Jacobson NS, Truax P. Clinical significance: a statistical approach to Denning meaningful change in psychotherapy research. J Consult Clin Psychol 1991; 59: 1219.

    • Search Google Scholar
    • Export Citation
  • 52. Haskins SC. Monitoring the anesthetized patients. In: Thurmon JC, Tranquilli WJ, Benson GJ, eds. Lumb and Jones' veterinary anesthesia. 3rd ed. Philadelphia: Lea & Febiger, 1996;409499.

    • Search Google Scholar
    • Export Citation

Contributor Notes

Supported by the Department of Clinical Science, College of Veterinary Medicine, Kansas State University.

Presented in part as an abstract at the Association of Exotic Mammal Veterinarians Conference, Seattle, August 2011.

Address correspondence to Dr. Schnellbacher (schnell@uga.edu).