M. A. Crist, N. S. Matthews, N. L. Oberle, and C. Pappas Effect of 1- and 10-Day Administration of Tepoxalin on Minimum Alveolar Concentration of Isoflurane and Sevoflurane in Dogs* M. A. Crist, DVM a N. S. Matthews, DVM, DACVA a N. L. Oberle b C. Pappas, DVM c a Department of Small Animal Clinical Sciences b Fourth-Year Student Texas A&M University College Station, TX 77843-4474 INTRODUCTION effect for carprofen, 9 whereas potentiation of Because most anesthetic agents have relatively low therapeutic indices, overdosage could lead to morbidity or mortality. Drug interactions opioids by NSAIDs has been shown for carprofen and meloxicam. 11 Other studies demonstrated no potentiation of a morphine MACments. can lead to decreased anesthetic requiresparing effect by meloxicam 12 or flunixin 13 For example, opioids and sedatives have been shown to decrease the required dose of inhalant anesthetics in dogs 1 3 and other species, 4,5 co-administration. Previously, NSAIDs were not commonly administered to dogs undergoing general anesthesia because of safety concerns. and drugs such as ketamine 6 and lidocaine, 7 In recent years, the approval and market- both alone and in combination with an opioid, 8 have also been shown to decrease inhalant anesthetic requirements. The effect of NSAIDs on inhalant anesthetic requirements does not appear to be as clear. One study detected no minimum alveolar concentration (MAC) sparing ing of NSAIDs for both perioperative pain and chronic osteoarthritis have resulted in a much greater incidence of NSAIDs being co-administered with inhalant anesthesia. The purpose of this study was to determine if either a single dose or a 10-day course of tepox- *This study was sponsored by Schering-Plough Animal Health, Summit, New Jersey. c Schering-Plough Animal Health 556 Morris Avenue Summit, NJ 07901 CLI NI CA L RE L E VA N C E Analgesics given preoperatively have the potential to decrease the amount of inhalant anesthetic required intraoperatively (i.e., to decrease the minimum alveolar concentration [MAC] for the inhalant). Tepoxalin is an NSAID approved for the treatment of arthritis in dogs in the United States and, hence, could be administered to patients undergoing anesthesia. In this study, administration of a single dose or a 10-day course of tepoxalin did not affect the minimum alveolar concentration for isoflurane or sevoflurane. 107
Veterinary Therapeutics Vol. 8, No. 2, Summer 2007 alin (Zubrin Rapidly-Disintegrating Tablets, Schering-Plough Animal Health) alters MAC for isoflurane and sevoflurane in dogs. Tepoxalin inhibits both cyclooxygenase and lipooxygenase; the products of both pathways cause inflammation that results in pain. Because these effects should not produce central nervous system depression (as do inhalant anesthetics), there should be little or no effect on MAC. Treatment 3: 10-day administration of tepoxalin followed by sevoflurane maintenance Treatment 4: 10-day administration of placebo followed by sevoflurane maintenance Treatment 5: 1-day administration of tepoxalin followed by isoflurane maintenance Treatment 6: 1-day administration of placebo followed by isoflurane maintenance Treatment 7: 1-day administration of tepoxalin followed by sevoflurane maintenance Treatment 8: 1-day administration of placebo followed by sevoflurane maintenance Tepoxalin (10 mg/kg) or placebo (the same rapidly disintegrating vehicle as for Zubrin but without the active ingredient; supplied by Schering-Plough Animal Health) was always given in a small amount (meatball sized) of canned food. This was done to blind There was no difference in MAC between tepoxalin and placebo with either 1- or 10-day administration. MATERIALS AND METHODS Dogs and Treatments Eight (four males and four females) hound Labrador cross-bred dogs, 2 to 3 years old and weighing 27.5 kg (SD: 2.7 kg), were used in this study. The dogs were healthy (as judged by physical examinations, health records, complete blood counts, biochemical panels, and urinalyses) and were accustomed to being handled. They were vaccinated, maintained on heartworm preventive, and fed a commercial ration once daily. Dogs were housed in kennels open to the outside and were exercised in outside runs almost daily. Food, but not water, was withheld for at least 8 hours before anesthesia. All procedures were approved by the Texas A&M University Animal Care and Use Committee. Each dog received eight treatments in a randomized, crossover design. The treatments were as follows: Treatment 1: 10-day administration of tepoxalin followed by isoflurane maintenance Treatment 2: 10-day administration of placebo followed by isoflurane maintenance the anesthetist as to whether tepoxalin or placebo had been administered because tepoxalin can leave a small amount of residue in the oral cavity. The meatball-sized food portion containing drug or placebo was presented to each dog, which was carefully observed until it swallowed the food. Tepoxalin or placebo was given 2 hours before anesthesia for 1-day administration treatments and 2 hours before anesthesia on the last day of the 10-day protocol. Drug administration was based on the label data indicating that the maximum concentration of the parent drug occurs at 2.3 ± 1.4 hours on day 0. 14 A minimum of 1 week washout was allowed between treatments. 108
M. A. Crist, N. S. Matthews, N. L. Oberle, and C. Pappas Inhalant Anesthesia and Monitoring Anesthesia sufficient for endotracheal intubation was induced with an IV bolus of propofol (6.6 mg/kg) given slowly over 60 to 70 seconds. Dogs were placed in lateral recumbency and connected to a small animal anesthesia circuit with an agent-specific vaporizer (sevoflurane or isoflurane). Dogs were mechanically ventilated to maintain end-expired carbon dioxide between 35 and 45 mm Hg. Electrocardiogram (ECG), oxygen saturation (via a pulse oximeter probe placed on the tongue), esophageal temperature, and heart and respiratory rates were dogs were instrumented. Once inspired and expired agent concentrations were stabilized at percentages greater than the reported MACs of 1.3% for isoflurane and 2.3% for sevoflurane, MAC determination began using an established method. 15 Briefly, a large hemostat was placed on the tail and closed to the first rachet for 30 to 60 seconds; a positive response was considered to be purposeful movement within 60 seconds of hemostat placement. After a negative response (i.e., no purposeful movement), vaporizer settings were decreased by 0.1% and the dog was restimulated when the The lack of a MAC-sparing effect would appear to indicate that there is no disadvantage to administering tepoxalin in the perianesthetic period. monitored (Cardell 9403, Sharn Veterinary, Tampa, FL). Direct arterial blood pressure was monitored by placement of a catheter in the dorsal pedal artery and connected to a transducer and monitor (Propaq 106 EL, Protocol, Beaverton, OR). The transducer was always zeroed at the level of the dog s heart. End-expired carbon dioxide and expired anesthetic agent concentration were measured using nondispersive infrared technology (Poet IQ2, Criticare System, Waukesha, WI). The dogs were given IV fluids (10 ml/kg/hr) to maintain mean arterial blood pressure above 60 mm Hg and were insulated from the table and covered to maintain body temperature between 37 C and 38 C. Measurement of MAC An arterial blood sample was drawn and immediately analyzed for ph, partial pressure of carbon dioxide (PaCO 2 ), and partial pressure of oxygen (PaO 2 ) (IRMA, ITCorp, Edison, NJ) to confirm adequate ventilation (PaCO 2 = 35 to 45 mm Hg and ph = 7.35 to 7.45) after the expired percentage was stable (10 to 20 minutes depending on inhalant). The inhalant concentration was decreased and increased until the lowest concentration eliciting a negative response and the highest concentration eliciting a positive response had been bracketed in triplicate. The MAC was calculated as midway between the highest value at which purposeful movement occurred and the lowest value at which no purposeful movement occurred. Following determination of MAC, a second blood gas sample was drawn for analysis of ph, PaCO 2, and PaO 2, and mean blood pressure and heart and respiratory rates were recorded. Dogs were then allowed to recover from anesthesia and were extubated when able to swallow. Statistical Analysis A repeated measures analysis of variance was performed on the natural logarithm transformed MAC values, including the three factors (duration, inhalant, and tepoxalin). A significance level of P <.05 was used. 109
Veterinary Therapeutics Vol. 8, No. 2, Summer 2007 TABLE 1. Minimum Alveolar Concentrations (mean ± SD) for Isoflurane and Sevoflurane in Dogs Pretreated with Tepoxalin (10 mg/kg) versus Placebo for 1 and 10 days before Anesthesia Pretreatment Protocol Isoflurane Sevoflurane 10-Day administration Tepoxalin 1.35 (0.12) 2.29 (0.47) Placebo 1.41 (0.16) 2.08 (0.35) 1-Day administration Tepoxalin 1.27 (0.19) 2.13 (0.65) Placebo 1.41 (0.17) 2.08 (0.46) RESULTS MACs are presented in Table 1. There was no difference in MAC between tepoxalin and placebo with either 1- or 10-day administration. MAC was predicted by inhalant (i.e., isoflurane versus sevoflurane). A slight but nonsignificant decrease in isoflurane MAC (4% to 9%) was seen with both 1- and 10-day tepoxalin administration; this observation was reversed with sevoflurane MAC, for which a 2% to 9% increase occurred with both 1- and 10-day tepoxalin administration compared with placebo. Mean arterial blood pressure, heart and respiratory rates, PaCO 2, ph, and PaO 2 recorded at the time MAC was determined are shown in Table 2; no differences were seen between placebo and tepoxalin administration at either dose in these variables. DISCUSSION The lack of isoflurane MAC-sparing effect seen in this study with tepoxalin is consistent with results from studies assessing other NSAIDs and inhalant requirements for anesthesia. Carprofen produced no significant MAC-sparing effect in dogs when given orally before anesthesia 10 or when given intravenously during anesthesia. 9 Meloxicam produced no significant isoflurane MAC-sparing effect in rabbits 11 or rats. 12 Flunixin given IV in goats during anesthesia 13 also produced no significant isoflurane MAC-sparing effect. Consistent with the results from this study, slight but statistically insignificant decreases in MAC were seen in all of these studies. This is probably not surprising, since inhibition of cyclooxygenase or lipooxygenase pathways should not produce central nervous system depression as do inhalant anesthetics and therefore should not produce a MAC-sparing effect. However, because NSAIDs are often used with anesthesia, it is important to know if a reduction in inhalant concentration is required to prevent excessive depth of anesthesia. We were unable to find any studies on the effect of NSAIDs on sevoflurane anesthetic requirement that might explain the slight increase in MAC seen with tepoxalin administration. It is also possible that these nonsignificant increases were the result of individual variations in anesthetic requirement. Because each dog was anesthetized on eight occasions over a period of months, treatment variability may have been higher than in studies in which subjects underwent only one or two anesthetic episodes. Changes in individual MAC values related to multiple treatments have been previously reported. 2 Machado and associates 2 reported that the lowest MAC value was consistently determined on the third assessment (i.e., the last assessment in their study). We were not able to find any correlation of high or low values to the order of determinations (treatments 1 through 8), but MAC values varied randomly from dog to dog, as expected. We were unable to find other studies in which MAC determinations were conducted in the same dogs 110
M. A. Crist, N. S. Matthews, N. L. Oberle, and C. Pappas TABLE 2. Mean (±SD) Arterial Blood Pressures, a Heart and Respiratory Rates, ph, PaCO 2, and PaO 2 in Dogs Anesthetized with Isoflurane or Sevoflurane and Pretreated with Tepoxalin (10 mg/kg) or Placebo for 1 or 10 Days Isoflurane Sevoflurane Parameter Placebo Tepoxalin Placebo Tepoxalin 1-Day administration MAP (mm Hg) 74.6 (9.6) 82 (9.2) 86.5 (14.8) 90.8 (6.7) Heart rate (bpm) 130.0 (7.5) 117.6 (14.0) 102.2 (17.8) 105.8 (36.1) Respiratory rate (breaths/min) 7.0 (1.2) 9.0 (1.9) 9.8 (2.6) 9.1 (1.4) ph 7.31 (0.04) 7.31 (0.03) 7.31 (0.02) 7.32 (0.02) PaCO 2 (mm Hg) 40.1 (3.7) 40.4 (3.0) 42.6 (2.7) 40.3 (2.0) PaO 2 (mm Hg) 578.2 (51.9) 543.7 (76.8) 590.5 (72.0) 653.5 (37.5) 10-Day administration MAP (mm Hg) 77.5 (14.8) 71.6 (11.9) 90.0 (16.6) 81.0 (15.7) Heart rate (bpm) 130.8 (10.1) 115.2 (18.0) 105.4 (25.3) 100.0 (21.3) Respiratory rate (breaths/min) 10.2 (1.8) 10.3 (1.7) 10.2 (4.3) 10.0 (1.3) ph 7.31 (0.03) 7.32 (0.03) 7.33 (0.04) 7.32 (0.04) PaCO 2 (mm Hg) 40.5 (3.3) 40.1 (2.9) 40.0 (5.4) 41.1 (4.2) PaO 2 (mm Hg) 481.4 (144.8) 508.9 (102.3) 530.4 (162.1) 530.6 (158.6) a Values were recorded at MAC. MAP = mean arterial pressure; PaCO 2 = partial pressure of carbon dioxide, arterial; PaO 2 = partial pressure of oxygen, arterial. eight consecutive times, so we did not know how much treatment variability to expect during the eight MAC determinations in each dog in our study. The MACs reported in this study for both isoflurane (1.27 to 1.41) and sevoflurane (2.08 to 2.29) are similar to those previously reported, 6,7,16 18 even though this study used propofol for induction of anesthesia rather than mask induction. Because propofol has a very short duration of effect, the propofol was likely metabolized before the dogs were instrumented and MAC determination began. Additionally, we had previous information about the duration of effect of the same dose of propofol for each dog used in this study. 19 We were looking for a MAC-sparing effect caused by administration of tepoxalin, as opposed to trying to establish the MAC for both inhalants, so if a slight variability by propofol induction did occur, it would have been the same for all treatments, thus cancelling out any effect. Other variables that can alter MAC include extremes of PacO 2 and PaO 2 and increases or decreases in body temperature. The values for ph, PaCO 2, and PaO 2 reported in Table 2 were well within the normal range that does not al- 111
Veterinary Therapeutics Vol. 8, No. 2, Summer 2007 ter anesthetic inhalant requirements. 20 Body temperature, although not reported, was closely monitored and controlled by adding external heat sources to keep the dogs near normal body temperature. Another recognized variable influencing MACs are the different stimuli (i.e., mechanical versus electrical) used in making the assessment, although a recent study concluded that they are essentially equal. 15 CONCLUSION No MAC-sparing effect for isoflurane and sevoflurane was seen with either 1- or 10-day administration of tepoxalin compared with placebo administration. The lack of a MACsparing effect would appear to indicate that there is no disadvantage to administering tepoxalin in the perianesthetic period. REFERENCES 1. Hellyer P, Mama K, Shafford H, et al: Effects of diazepam and flumazenil on minimum alveolar concentrations for dogs anesthetized with isoflurane or a combination of isoflurane and fentanyl. Am J Vet Res 62:555 560, 2001. 2. Machado C, Dyson D, Maxie MG: Effects of oxymorphone and hydromorphone on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 33:70 77, 2006. 3. Grimm K, Tranquilli W, Thurmon J, Benson GJ: Duration of nonresponse to noxious stimulation after intramuscular administration of butorphanol, medetomidine, or a butorphanol-medetomidine combination during isoflurane administration in dogs. Am J Vet Res 61:42 47, 2000. 4. Ilkiw J, Pascoe P, Tripp L: Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats. Am J Vet Res 63:1198 1202, 2002. 5. Criado A, Gomez de Segura A, Tendillo F, et al: Reduction of isoflurane MAC with buprenorphine and morphine in rats. Lab Anim 34:252 259, 2000. 6. Solano A, Pypendop B, Boscan P, et al: Effect of intravenous administration of ketamine on the minimum alveolar concentration of isoflurane in anesthetized dogs. Am J Vet Res 67:21 25, 2006. 7. Valverde A, Doherty T, Hernandez J, et al: Effect of lidocaine on the minimum alveolar concentration of isoflurane in dogs. Vet Anaesth Analg 31:264 271, 2004. 8. Muir W, Wiese A, March P: Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane. Am J Vet Res 64:1155 1159, 2003. 9. Alibhai H, Clarke K: Influence of carprofen on minimum alveolar concentration of halothane in dogs. J Vet Pharmacol Therap 19:320 321, 1996. 10. Ko J, Lange D, Mandsager R, et al: Effects of butorphanol and carprofen on the minimal alveolar concentration of isoflurane in dogs. JAVMA 217:1025 1028, 2000. 11. Turner P, Kerr C, Healy A, et al: Effect of meloxicam and butorphanol on minimum alveolar concentration of isoflurane in rabbits. Am J Vet Res 67:770 774, 2006. 12. Santos M, Kunkar V, Garcia-Iturralde P, et al: Meloxicam, a specific COX-2 inhibitor, does not enhance the isoflurane minimum alveolar concentration reduction produced by morphine in the rat. Anesth Analg 98: 359 363, 2004. 13. Doherty T, Will W, Rohrbach B, et al: Effect of morphine and flunixin meglumine on isoflurane minimum alveolar concentration in goats. Vet Anaesth Analg 31: 97 101, 2004. 14. Zubrin Tablets [package insert]: Summit, NJ, Schering-Plough Animal Health, 2006. 15. Valverde A, Morey T, Hernandez 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 64: 957 962, 2003. 16. Mutoh T, Nishimura R, Sasake N: Effects of nitrous oxide on mask induction of anesthesia with sevofluarne or isoflurane in dogs. Am J Vet Res 62:1727 1733, 2001. 17. Galloway D, Ko J, Reaugh H, et al: Anesthetic indices of sevoflurane and isoflurane in unpremedicated dogs. JAVMA 225:700 704, 2004. 18. Johnson R, Striler E, Sawyer D, et al: Comparison of isoflurane with sevoflurane for anesthesia induction and recovery in adult dogs. Am J Vet Res 59:478 481, 1998. 19. Matthews N, Belz K, Fosgate G, Pappas C: Effect of preoperative administration of tepoxalin on induction dose of injectable anesthetics in dogs. Vet Ther 8(1): 5 17, 2007. 20. Eger E: MAC, in Anesthetic Uptake and Action. Baltimore, Williams & Wilkins, 1974, pp 1 25. 112