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Effect of intravenous butorphanol infusion on the minimum alveolar concentration of isoflurane in cats

  • Bruno H. Pypendop
    Correspondence
    Correspondence: Bruno Pypendop, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, One Shields Avenue, Davis, CA, 95616, USA.
    Affiliations
    Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, CA, USA
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  • Mariela Goich
    Affiliations
    School of Veterinary Medicine, Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile
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  • Yael Shilo-Benjamini
    Affiliations
    Koret School of Veterinary Medicine, The Robert H Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel
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Open AccessPublished:December 21, 2021DOI:https://doi.org/10.1016/j.vaa.2021.12.004

      Abstract

      Objective

      To determine the effect of butorphanol, administered by intravenous (IV) infusion, on the minimum alveolar concentration of isoflurane (MACISO) in cats and to examine the dosage dependence of this effect.

      Study design

      Randomized, placebo-controlled, crossover experimental study.

      Animals

      A group of six healthy adult male neutered cats.

      Methods

      Cats were anesthetized with isoflurane in oxygen. A venous catheter was placed for fluid and drug administration, and an arterial catheter was placed for measurement of arterial pressure and blood sampling. Four treatments were administered at random with at least 2 week interval between treatments: saline (control), butorphanol low dosage (treatment LD; 0.25 mg kg–1 IV bolus followed by 85 μg kg–1 minute–1 for 20 minutes, then 43 μg kg–1 minute–1 for 40 minutes, then 19 μg kg–1 minute–1), medium dosage (treatment MD, double the dosages in LD) and high dosage (treatment HD, quadruple the dosages in LD). MACISO was determined in duplicate using the bracketing technique and tail clamping. Pulse rate, arterial pressure, hemoglobin oxygen saturation, end-tidal partial pressure of carbon dioxide and arterial blood gas and pH were measured.

      Results

      Butorphanol reduced MACISO in a dosage-dependent manner, by 23 ± 8%, 37 ± 12% and 68 ± 10% (mean ± standard deviation) in treatments LD, MD and HD, respectively. The main cardiopulmonary effect observed was a decrease in pulse rate, significant in treatment HD compared with control.

      Conclusions and clinical relevance

      Butorphanol caused a dosage-dependent MACISO reduction in cats. IV infusion of butorphanol may be of interest for partial IV anesthesia in cats.

      Keywords

      Introduction

      Opioids are commonly used in small animal anesthesia to produce analgesia and decrease inhalant anesthetic requirements. In cats, the effects of the full μ-opioid agonists on the minimum alveolar concentration (MAC) of inhaled anesthetics appear modest and variable, with some studies reporting no effect, and others reporting up to 35% MAC reduction (
      • Ilkiw J.E.
      • Pascoe P.J.
      • Fisher L.D.
      Effect of alfentanil on the minimum alveolar concentration of isoflurane in cats.
      ,
      • Ilkiw J.E.
      • Pascoe P.J.
      • Tripp L.D.
      Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats.
      ;
      • Brosnan R.J.
      • Pypendop B.H.
      • Siao K.T.
      • Stanley S.D.
      Effects of remifentanil on measures of anesthetic immobility and analgesia in cats.
      ,
      • Brosnan R.J.
      • Pypendop B.H.
      • Stanley S.D.
      Phenylpiperidine opioid effects on isoflurane minimum alveolar concentration in cats.
      ;
      • Ferreira T.H.
      • Aguiar A.J.
      • Valverde A.
      • et al.
      Effect of remifentanil hydrochloride administered via constant rate infusion on the minimum alveolar concentration of isoflurane in cats.
      ,
      • Ferreira T.H.
      • Steffey E.P.
      • Mama K.R.
      • et al.
      Determination of the sevoflurane sparing effect of methadone in cats.
      ).
      Butorphanol is a synthetic agonist/antagonist opioid analgesic with market authorization for use in cats in several European countries and in North America, where it is widely used (
      • Bortolami E.
      • Love E.J.
      Practical use of opioids in cats: a state-of-the-art, evidence-based review.
      ). Butorphanol produces sedation and analgesia in cats; the analgesic effect appears variable (
      • Ilkiw J.E.
      • Pascoe P.J.
      • Tripp L.D.
      Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats.
      ;
      • Robertson S.A.
      • Taylor P.M.
      • Lascelles B.D.
      • Dixon M.J.
      Changes in thermal threshold response in eight cats after administration of buprenorphine, butorphanol and morphine.
      ;
      • Lascelles B.D.
      • Robertson S.A.
      Antinociceptive effects of hydromorphone, butorphanol, or the combination in cats.
      ,
      • Lascelles B.D.
      • Robertson S.A.
      Use of thermal threshold response to evaluate the antinociceptive effects of butorphanol in cats.
      ;
      • Johnson J.A.
      • Robertson S.A.
      • Pypendop B.H.
      Antinociceptive effects of butorphanol, buprenorphine, or both, administered intramuscularly in cats.
      ). Butorphanol was also reported to decrease the MAC of isoflurane (
      • Ilkiw J.E.
      • Pascoe P.J.
      • Tripp L.D.
      Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats.
      ;
      • Zwijnenberg R.J.
      • del Rio C.L.
      • Pollet R.A.
      • Muir W.W.
      Effects of perzinfotel, butorphanol tartrate, and a butorphanol-perzinfotel combination on the minimum alveolar concentration of isoflurane in cats.
      ) and sevoflurane (
      • Ko J.C.
      • Abbo L.A.
      • Weil A.B.
      • et al.
      Effect of orally administered tramadol alone or with an intravenously administered opioid on minimum alveolar concentration of sevoflurane in cats.
      ) in cats following single intramuscular (IM) or intravenous (IV) administration. In these studies, at dosages ranging from 0.08 to 0.8 mg kg–1, butorphanol reduced MAC by 15–51%.
      In published studies of the effect of butorphanol on MAC, a single IV bolus or IM dose was administered. MAC determination using the bracketing method, as performed in these studies, takes time, resulting in IV bolus or IM administration being arguably not optimal. This is because the plasma and effect site drug concentrations, and therefore the effect, are expected to change over time. Time dependence of the effect was actually demonstrated in one of the studies (
      • Ilkiw J.E.
      • Pascoe P.J.
      • Tripp L.D.
      Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats.
      ). In addition, it is common in small animal clinical practice to administer opioids as IV infusions as part of balanced anesthesia, in an attempt to improve the consistency of the effect (
      • Ilkiw J.E.
      Balanced anesthetic techniques in dogs and cats.
      ;
      • Duke T.
      Partial intravenous anesthesia in cats and dogs.
      ). No peer-reviewed published studies were found on the effects of IV infusion of butorphanol on the MAC of inhalant anesthetics in cats. Accordingly, the aim of this study was to determine the effect of butorphanol administered by IV infusion on the MAC of isoflurane (MACISO) in cats, as well as the dosage dependence of this effect. We hypothesized that butorphanol would reduce MACISO in a dosage-dependent manner.

      Materials and methods

       Animals

      A total of six healthy male neutered cats, aged 1–2 years and weighing 5.2 ± 0.3 kg [mean ± standard deviation (SD)] were used in this study. Cats were deemed healthy based on the lack of historical disease and the results of a physical examination prior to the study. Cats were housed together in a single room. Husbandry conditions for this facility have been previously described (
      • Honkavaara J.
      • Pypendop B.
      • Turunen H.
      • Ilkiw J.
      The effect of MK-467, a peripheral a2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia after intravenous administration in conscious cats.
      ). The study was approved by the Institutional Animal Care and Use Committee at the University of California, CA, USA (21003).

       Instrumentation and measurements

      Anesthesia was induced with 5% isoflurane in 5 L minute–1 oxygen delivered in an acrylic chamber via a Bain system. Once the righting reflex was lost, the cat was removed from the chamber and the trachea was intubated with a 4.5 mm endotracheal tube, or anesthesia was deepened by application of a facemask and administration of 4–5% isoflurane in 2 L minute–1 oxygen. Following endotracheal intubation, anesthesia was maintained with isoflurane in 2 L minute–1 oxygen. Isoflurane concentration was adjusted to maintain light surgical depth of anesthesia (mild to moderate jaw tone, eyes in an eccentric position, no palpebral reflex). Cats were placed in lateral recumbency. A 2.5 cm, 22 gauge catheter (Insyte; Becton Dickinson, CA, USA) was placed in a cephalic vein for butorphanol and lactated Ringer’s solution (Baxter Healthcare Corp., IL, USA) administration at 3 mL kg–1 hour–1. Cefazolin (25 mg kg–1; Cefazolin Sodium; Sagent Pharmaceuticals Inc., IL, USA) was administered IV. A 22 gauge, 4.4 cm catheter was placed in a femoral or carotid artery, via surgical cutdown, for continuous measurement of arterial pressure and blood sampling. The catheter was connected to a transducer (Meritrans DTXPlus; Merit Medical Systems Inc., UT, USA) using saline-filled noncompliant tubing. Reference (atmospheric, 0) pressure was established at the level of the sternum. The transducer was calibrated daily against a mercury manometer and connected to a data acquisition system and software (Ponemah; DSI, MN, USA). A pulse oximeter probe was placed on the tongue and connected to a monitor (Carescape B650; GE Healthcare, WI, USA) for continuous measurement of pulsatile hemoglobin oxygen saturation (SpO2) and pulse rate (PR). Airway gas was continuously sampled from a catheter positioned within the endotracheal tube so that the tip of the catheter was close to the distal (animal) end of the tube and analyzed for inspired and end-tidal partial pressure of carbon dioxide (Pe′CO2) and isoflurane concentration using infrared spectrophotometry (Carescape B650; GE Healthcare). Respiratory frequency (fR) was also determined by the spectrophotometer. Data measured by the spectrophotometer were corrected according to an equation obtained daily by linear regression of measured versus known isoflurane concentration in room air (i.e. isoflurane concentration of 0%) and with four isoflurane standards spanning the range of measurements (isoflurane concentrations of 0.51–3.33%). A thermistor, calibrated each day against a certified thermometer and connected to the data acquisition system, was inserted in the distal esophagus to continuously measure body temperature. Body temperature was maintained within 38.5–39.5 °C by supplying heat using a heating blanket as necessary (Hotdog; Augustine Surgical Inc., MN, USA). Cats were allowed to breathe spontaneously throughout the experiments.

       MACISO measurement

      MACISO was measured in duplicate using tail clamping and the bracketing method, as previously described (
      • Pypendop B.H.
      • Ahokoivu H.
      • Honkavaara J.
      Effects of dexmedetomidine, with or without vatinoxan (MK-467) on the minimum alveolar concentration of isoflurane in cats.
      ). Initial isoflurane concentration was set between 1% and 2%, depending on the treatment. The isoflurane concentration was maintained constant for a minimum of 15 minutes after each change. End-tidal gas samples (approximately 30 mL each) were collected in triplicate by hand in a glass syringe and analyzed for isoflurane concentration using the calibrated spectrophotometer; the mean of three concentrations was considered the end-tidal isoflurane concentration (Fe′Iso). A 20 cm Martin forceps was applied to the tail until movement was observed or for 1 minute, and Fe′Iso was increased or decreased by up to 15% following movement of the limbs or head or lack of movement, respectively. This was repeated until two successive Fe′Iso were found, one preventing and one allowing movement. The mean of these two concentrations was considered a MACISO, and the two MACISO from the duplicate determinations were averaged and considered the MACISO for that treatment.

       Treatments

      Butorphanol tartrate (Torbugesic; Zoetis Inc., NJ, USA) was administered IV at three dosages, each consisting of a loading dose and three successive constant rate infusions. Each dosage was administered on a different day. In addition, an equivalent volume of isotonic saline (control treatment) was administered on a separate day. All cats were administered all treatments, with at least 2 weeks between treatments. The order of treatments was randomized using an online application (www.random.org). The dosages of butorphanol were as follows: low dosage (treatment LD): loading dose of 0.25 mg kg–1, then 85 μg kg–1 minute–1 for 20 minutes, then 43 μg kg–1 minute–1 for 40 minutes, then 19 μg kg–1 minute–1 for the remainder of the study; medium dosage (treatment MD): twice the dosages in treatment LD; high dosage (treatment HD): four times the dosages in treatment LD.
      The butorphanol solution (10 mg mL–1) was diluted with isotonic saline (Baxter Healthcare Corp.) to 2.5 mg mL–1 for treatment LD and to 5 mg mL–1 for treatment MD and used undiluted for treatment HD so that the volumes administered in all treatments were identical.

       Measurements

      Following instrumentation, butorphanol or saline administration was started. After a minimum of 30 minutes, MAC determination was performed as described above. Prior to each stimulation, Fe′Iso was measured, and PR, fR, SpO2, systolic (SAP), mean (MAP) and diastolic (DAP) arterial pressure, body temperature and Pe′CO2 were recorded. In addition, 0.5 mL of arterial blood was collected in syringes containing dry heparin (PICO50; Radiometer America, CA, USA) 30 and 60 minutes after commencing the IV infusion and immediately after the last MACISO determination for blood gas and pH analysis (ABL800 FLEX; Radiometer America), performed within 10 minutes of collection. Lastly, arterial blood samples (2 mL) were also collected into plain syringes prior to drug administration and immediately after the last MACISO determination. These samples were transferred to tubes containing ethylenediaminetetraacetic acid and centrifuged at 3901 g and 4 °C for 10 minutes immediately after collection. The plasma was separated and frozen at –80 °C until analysis for butorphanol concentration.
      At the completion of the experiment, cats were administered meloxicam (0.1 mg kg–1; OstiLox; VetOne, ID, USA) subcutaneously. Catheters and monitoring equipment were removed, and the cats were allowed to recover from anesthesia and return to their housing facility. Cats were offered for adoption after the last experiment had been conducted.

       Butorphanol concentration analysis

      Plasma butorphanol concentration was measured using liquid chromatography/tandem mass spectrometry as previously described (
      • Knych H.K.
      • Casbeer H.C.
      • McKemie D.S.
      • Arthur R.M.
      Pharmacokinetics and pharmacodynamics of butorphanol following intravenous administration to the horse.
      ;
      • Pypendop B.H.
      • Shilo-Benjamini Y.
      Pharmacokinetics of butorphanol in male neutered cats anesthetized with isoflurane.
      ). The lower limit of quantitation was 0.1 ng mL–1. Accuracy and imprecision were verified at 0.3, 80, 1000 and 5000 ng mL–1 and ranged from 102% to 112% and 3% to 11%, respectively.

       Statistical analysis

      Power analysis conducted using recent data from our laboratory suggested that six cats would be sufficient to detect a 25% difference in MACISO with a power > 0.8 and the alpha level set at 0.05 (
      • Pypendop B.H.
      • Shilo-Benjamini Y.
      Pharmacokinetics of butorphanol in male neutered cats anesthetized with isoflurane.
      ). Data were analyzed using a mixed model analysis of variance, with the treatment set as a repetition and the cat as a random factor. Cardiopulmonary data obtained at each measurement used for MACISO determination were averaged so that a single value was analyzed for each cat at each treatment. Time and the treatment–time interaction were analyzed as additional fixed effects for blood gas data. Tukey test was used for pairwise comparisons of treatments for MACISO data, and Dunnett test was used for pairwise comparisons of treatments to control (saline) for all other data. In addition, linear regression analysis of the mean plasma butorphanol concentration versus MACISO data was performed. Normality of the residuals was assessed by observation of the QQ plots. All analyses were conducted in Prism 9.2.0 (GraphPad Software, CA, USA). Significance was set at p < 0.05. Data are presented as mean ± SD.

      Results

      The femoral artery catheter became dislodged early during treatment HD in one cat. The study was aborted because of the need to ensure hemostasis. Therefore, data are available for six cats in treatments control, LD and MD and for five cats in treatment HD.
      Plasma butorphanol concentration was 0 ± 0, 1165 ± 207, 2206 ± 525 and 4941 ± 1145 ng mL–1 in treatments control, LD, MD and HD, respectively. The blood sample for plasma butorphanol concentration measurement was collected at 138 ± 44 minutes after administration of the initial butorphanol bolus. Control MACISO was 1.98 ± 0.17%. Butorphanol caused a significant and dosage-dependent reduction in MACISO by 23 ± 8%, 37 ± 12% and 68 ± 10% in treatments LD, MD and HD, respectively (p < 0.0001; Fig. 1). The relationship between mean plasma butorphanol concentration and MACISO was linear with R2 of 0.82.
      Figure 1
      Figure 1Mean ± standard deviation minimum alveolar concentration (MAC) of isoflurane in cats administered intravenously saline (treatment control, n = 6); low dosage of butorphanol (treatment LD, 0.25 mg kg–1 bolus followed by continuous infusion 85 μg kg–1 minute–1 for 20 minutes, then 43 μg kg–1 minute–1 for 40 minutes, then 19 μg kg–1 minute–1, n = 6); medium dosage (treatment MD, double the dosages in treatment LD, n = 6); or high dosage (treatment HD, quadruple the dosages in treatment LD, n = 5). The values within the bars represent the mean MAC. The p values for the pairwise comparisons are shown. LD was not significantly different from MD (p > 0.05).
      No significant effect of treatment was found for fR, SAP, MAP and DAP, SpO2, temperature, arterial pH, partial pressures of carbon dioxide (PaCO2) and oxygen and SpO2 (Table 1, Table 2). Compared with treatment control, PR was significantly lower in treatment HD (p = 0.0113), Pe′CO2 was significantly lower in treatment MD (p = 0.0202), arterial bicarbonate concentration was significantly lower in treatment MD (p = 0.0202) and HD (p = 0.0031) at 30 minutes and in HD (p = 0.031) after the last MAC determination, and standard base excess (SBE) was significantly lower (p = 0.0132) in treatment HD at 30 minutes (Table 1, Table 2). A significant time effect was found for arterial pH (p = 0.0405).
      Table 1Mean ± standard deviation cardiopulmonary data in isoflurane-anesthetized cats administered intravenously saline (treatment Control, n = 6); low dosage of butorphanol (treatment LD, 0.25 mg kg–1 bolus followed by continuous infusion 85 μg kg–1 minute–1 for 20 minutes, then 43 μg kg–1 minute–1 for 40 minutes, then 19 μg kg–1 minute–1, n = 6); medium dosage (treatment MD, double the dosages in treatment LD, n = 6); or high dosage (treatment HD, quadruple the dosages in treatment LD, n = 5). DAP, diastolic arterial pressure; fR, respiratory frequency; MAP, mean arterial pressure; PR, pulse rate; SAP, systolic arterial pressure
      VariableTreatment
      ControlLDMDHD
      PR (beats minute–1)165 ± 19143 ± 23137 ± 17116 ± 20
      Significantly different from control (p < 0.05).
      fR (breaths minute–1)20 ± 829 ± 1323 ± 1519 ± 7
      SAP (mmHg)99 ± 17118 ± 20113 ± 22109 ± 21
      MAP (mmHg)75 ± 1590 ± 1991 ± 1885 ± 20
      DAP (mmHg)59 ± 1469 ± 1571 ± 1463 ± 19
      Temperature (°C)38.8 ± 0.339.0 ± 0.338.9 ± 0.239.1 ± 0.3
      Significantly different from control (p < 0.05).
      Table 2Mean ± standard deviation arterial pH, partial pressure of carbon dioxide (PaCO2), partial pressure of oxygen (PaO2), bicarbonate concentration (HCO3) and standard base excess (SBE) in isoflurane-anesthetized cats administered intravenously saline (treatment control, n = 6); low dosage of butorphanol (treatment LD, 0.25 mg kg–1 bolus followed by continuous infusion 85 μg kg–1 minute–1 for 20 minutes, then 43 μg kg–1 minute–1 for 40 minutes, then 19 μg kg–1 minute–1, n = 6); medium dosage (treatment MD, double the dosages in treatment LD, n = 6); or high dosage (treatment HD, quadruple the dosages in treatment LD, n = 5). Values were recorded 30 and 60 minutes following the start of butorphanol administration, and after the last determination of the minimum alveolar concentration of isoflurane (MAC)
      VariableTreatmentTime points
      30 minutes60 minutesMAC
      pHControl7.346 ± 0.0667.339 ± 0.0397.353 ± 0.059
      LD7.315 ± 0.0287.346 ± 0.0467.364 ± 0.061
      MD7.328 ± 0.0697.345 ± 0.17.398 ± 0.046
      HD7.292 ± 0.0817.326 ± 0.0267.374 ± 0.067
      PaCO2 (mmHg)Control38.7 ± 8.039.2 ± 6.938.6 ± 6.6
      LD39.6 ± 3.537.6 ± 4.736.3 ± 7.1
      MD36.2 ± 4.735.0 ± 5.632.4 ± 4.4
      HD36.1 ± 4.932.0 ± 3.729.3 ± 1.7
      PaCO2 (kPa)Control5.2 ± 1.15.2 ± 0.95.1 ± 0.9
      LD5.3 ± 0.55.0 ± 0.64.8 ± 0.9
      MD4.8 ± 0.64.7 ± 0.74.3 ± 0.6
      HD4.8 ± 0.74.3 ± 0.53.9 ± 0.2
      PaO2 (mmHg)Control507 ± 49477 ± 35495 ± 46
      LD504 ± 53499 ± 44514 ± 29
      MD500 ± 24517 ± 33544 ± 32
      HD521 ± 31483 ± 44538 ± 25
      PaO2 (kPa)Control67.6 ± 6.563.6 ± 4.766.0 ± 6.2
      LD67.2 ± 7.166.6 ± 5.868.5 ± 3.9
      MD66.7 ± 3.268.9 ± 4.572.6 ± 4.3
      HD69.5 ± 4.264.4 ± 5.871.7 ± 3.3
      HCO3 (mEq L–1)Control20.2 ± 1.520.3 ± 2.120.5 ± 1.5
      LD19.5 ± 0.919.9 ± 0.919.7 ± 1.3
      MD18.3 ± 1.5
      Within the same time point, significantly different from control (p < 0.05).
      18.4 ± 2.019.3 ± 1.9
      HD16.9 ± 2.2
      Within the same time point, significantly different from control (p < 0.05).
      16.3 ± 2.516.7 ± 2.7
      Within the same time point, significantly different from control (p < 0.05).
      SBE (mEq L–1)Control–4.0 ± 1.2–4.0 ± 1.8–3.6 ± 1.3
      LD–5.1 ± 0.9–4.3 ± 1.0–4.3 ± 0.8
      MD–6.1 ± 2.1–5.8 ± 2.9–4.3 ± 2.1
      HD–7.9 ± 2.9
      Within the same time point, significantly different from control (p < 0.05).
      –8.2 ± 2.7–7.2 ± 3.4
      Within the same time point, significantly different from control (p < 0.05).

      Discussion

      In this study, butorphanol decreased MACISO in cats in a dosage-dependent manner. The maximum mean MACISO reduction observed was 68%, and a ceiling on MACISO reduction was not observed within the range of dosages studied. The magnitude of MAC reduction was larger than in previously published studies in which butorphanol was administered as a single IV bolus or IM (
      • Ilkiw J.E.
      • Pascoe P.J.
      • Tripp L.D.
      Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats.
      ;
      • Ko J.C.
      • Abbo L.A.
      • Weil A.B.
      • et al.
      Effect of orally administered tramadol alone or with an intravenously administered opioid on minimum alveolar concentration of sevoflurane in cats.
      ;
      • Zwijnenberg R.J.
      • del Rio C.L.
      • Pollet R.A.
      • Muir W.W.
      Effects of perzinfotel, butorphanol tartrate, and a butorphanol-perzinfotel combination on the minimum alveolar concentration of isoflurane in cats.
      ). This may be related to the dosages administered. The magnitude of the MAC reduction observed is also larger than that reported for full μ-opioid agonists in cats, even when administered at high dosages and/or when a ceiling effect on MAC reduction was observed (
      • Ilkiw J.E.
      • Pascoe P.J.
      • Fisher L.D.
      Effect of alfentanil on the minimum alveolar concentration of isoflurane in cats.
      ,
      • Ilkiw J.E.
      • Pascoe P.J.
      • Tripp L.D.
      Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats.
      ;
      • Brosnan R.J.
      • Pypendop B.H.
      • Siao K.T.
      • Stanley S.D.
      Effects of remifentanil on measures of anesthetic immobility and analgesia in cats.
      ,
      • Brosnan R.J.
      • Pypendop B.H.
      • Stanley S.D.
      Phenylpiperidine opioid effects on isoflurane minimum alveolar concentration in cats.
      ;
      • Ferreira T.H.
      • Aguiar A.J.
      • Valverde A.
      • et al.
      Effect of remifentanil hydrochloride administered via constant rate infusion on the minimum alveolar concentration of isoflurane in cats.
      ,
      • Ferreira T.H.
      • Steffey E.P.
      • Mama K.R.
      • et al.
      Determination of the sevoflurane sparing effect of methadone in cats.
      ). Full μ-opioid agonists reduce MAC more than butorphanol in some other species, including dogs. For example, a recent study in dogs reported a 77% MACISO reduction with a high dosage of fentanyl, whereas butorphanol was reported to not decrease MAC or decrease MAC by a maximum of 20% following IV or IM administration at dosages up to 4 mg kg–1 (
      • Murphy M.R.
      • Hug Jr, C.C.
      The enflurane sparing effect of morphine, butorphanol, and nalbuphine.
      ;
      • Quandt J.E.
      • Raffe M.R.
      • Robinson E.P.
      Butorphanol does not reduce the minimum alveolar concentration of halothane in dogs.
      ;
      • Ko J.C.
      • Lange D.N.
      • Mandsager R.E.
      • et al.
      Effects of butorphanol and carprofen on the minimal alveolar concentration of isoflurane in dogs.
      ;
      • Zwijnenberg R.J.
      • del Rio C.L.
      • Pollet R.A.
      • Muir W.W.
      Effects of perzinfotel on the minimum alveolar concentration of isoflurane in dogs when administered as a preanesthetic via various routes or in combination with butorphanol.
      ;
      • Williamson A.J.
      • Soares J.H.N.
      • Pavlisko N.D.
      • et al.
      Isoflurane minimum alveolar concentration sparing effects of fentanyl in the dog.
      ). The cause for the difference between dogs and cats is unclear, but may be related to increases in brain catecholamines induced by full μ-opioid agonists in cats, as suggested in a recent publication (
      • Brosnan R.J.
      • Pypendop B.H.
      Evaluation of whether acepromazine maleate causes fentanyl to decrease the minimum alveolar concentration of isoflurane in cats.
      ). It is not known whether butorphanol causes such increase in central catecholamines. If butorphanol lacks this effect, it may explain the difference in the efficacy of full μ-opioid agonists for their MAC-reducing effects in dogs and cats. However, it would not explain the much larger MAC reduction caused by butorphanol in cats compared with dogs. Additional factors that may have contributed to the smaller magnitude of changes in MAC in previously published studies in cats and dogs include the use of IV bolus or IM administration. Because MAC determination using the bracketing method takes time, IV infusions are advantageous over bolus administration because they are expected to produce a sustained, stable effect. It is therefore possible that the previous studies did not measure the maximum MAC reduction for the dose administered. In one study in cats, no dose dependence in MACISO reduction was observed, although MACISO appeared moderately lower at the higher dose administered at the later time points (
      • Ilkiw J.E.
      • Pascoe P.J.
      • Tripp L.D.
      Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats.
      ). Similarly, a study in dogs examining the effect of a wide range of butorphanol doses on MAC did not find dose dependence (
      • Murphy M.R.
      • Hug Jr, C.C.
      The enflurane sparing effect of morphine, butorphanol, and nalbuphine.
      ). The reasons for this lack of dose dependence are unclear and in disagreement with the findings in this study.
      The butorphanol dosing regimens used in this study were designed to maintain plasma butorphanol concentrations corresponding to the peak concentrations following an IV bolus of 0.2, 0.4 and 0.8 mg kg–1 for treatments LD, MD and HD, respectively, based on published pharmacokinetic data (
      • Pypendop B.H.
      • Shilo-Benjamini Y.
      Pharmacokinetics of butorphanol in male neutered cats anesthetized with isoflurane.
      ). This arbitrary selection was made to maximize the likelihood to observe an effect on MAC as no data were available to suggest a plasma butorphanol concentration effective to reduce MAC, with the result that dosages were likely higher than those currently used in clinical practice. Pharmacokinetic simulation demonstrated that a loading dose followed by a single constant rate infusion would not produce stable plasma butorphanol concentrations for over 8 hours, but that the three-step infusion regimen as used in the present study was expected to result in plasma drug concentrations within 10% of target after approximately 20 minutes of infusion (
      • Pypendop B.H.
      • Shilo-Benjamini Y.
      Pharmacokinetics of butorphanol in male neutered cats anesthetized with isoflurane.
      ). Accordingly, MACISO determinations were started after a minimum of 30 minutes of butorphanol administration. Mean plasma butorphanol concentrations at the time of the last MACISO measurement were moderately (28–43%) higher than their respective targets, suggesting that the pharmacokinetic model was not completely predictive of the disposition of butorphanol in these cats.
      The main cardiovascular effect observed in this study was a decrease in PR, significant in treatment HD compared with control. Limited effects on cardiovascular function were also reported previously, although neither the present nor the previous studies were designed to explore cardiopulmonary effects of butorphanol in detail (
      • Ko J.C.
      • Abbo L.A.
      • Weil A.B.
      • et al.
      Effect of orally administered tramadol alone or with an intravenously administered opioid on minimum alveolar concentration of sevoflurane in cats.
      ;
      • Zwijnenberg R.J.
      • del Rio C.L.
      • Pollet R.A.
      • Muir W.W.
      Effects of perzinfotel, butorphanol tartrate, and a butorphanol-perzinfotel combination on the minimum alveolar concentration of isoflurane in cats.
      ). The lower PR in treatment HD compared with control was not accompanied by hypotension. The cardiovascular effects of butorphanol in anesthetized cats warrant additional investigation.
      Pe′CO2 was lower in treatment MD than during control in the present study. Butorphanol has been reported to cause respiratory depression, which is in disagreement with this finding (
      • Pircio A.W.
      • Gylys J.A.
      • Cavanagh R.L.
      • et al.
      The pharmacology of butorphanol, a 3,14-dihydroxymorphinan narcotic antagonist analgesic.
      ). Controlled ventilation was used in previous studies on butorphanol in anesthetized cats, precluding the assessment of the effects on Pe′CO2 (
      • Ilkiw J.E.
      • Pascoe P.J.
      • Tripp L.D.
      Effects of morphine, butorphanol, buprenorphine, and U50488H on the minimum alveolar concentration of isoflurane in cats.
      ;
      • Ko J.C.
      • Abbo L.A.
      • Weil A.B.
      • et al.
      Effect of orally administered tramadol alone or with an intravenously administered opioid on minimum alveolar concentration of sevoflurane in cats.
      ;
      • Zwijnenberg R.J.
      • del Rio C.L.
      • Pollet R.A.
      • Muir W.W.
      Effects of perzinfotel, butorphanol tartrate, and a butorphanol-perzinfotel combination on the minimum alveolar concentration of isoflurane in cats.
      ). No significant effect on PaCO2 was found, which may be related to low statistical power. Significant effects of treatment were observed for arterial bicarbonate concentration and SBE, suggesting that a metabolic acid-base imbalance may have developed. However, the effect on SBE was only observed at the first time point in treatment HD, 30 minutes after starting butorphanol administration. Although pH at that time was lower than control, the difference did not reach statistical significance. The changes observed in bicarbonate concentrations for the other treatments and at other time points may have been related to small changes in PaCO2, since neither SBE nor pH was significantly affected. Conversely, it is also possible that the observed difference in Pe′CO2 between treatments control and MD was in response to the change in bicarbonate concentration.
      The results of this study should be interpreted in view of several limitations. The investigator assessing the response to noxious stimulation for MAC determination was aware of the treatments, possibly causing conscious or unconscious bias. However, the changes in MACISO were large and considered unlikely to be attributable to such bias. The sample size was small and based on power analysis to detect changes in MACISO. In addition, data from one less cat were available in treatment HD than in other treatments. The statistical power for detecting effects on variables other than MACISO is unknown but likely low. The study was not designed to explore the cardiopulmonary effects of butorphanol in anesthetized cats in detail. In addition, the measurements were obtained at isoflurane concentrations close to MAC, that is at concentrations that do not result in surgical depth of anesthesia. This limits their clinical relevance, and further studies are warranted to characterize these effects in a more clinically relevant context. Nevertheless, the available data suggests that if present, butorphanol-induced cardiopulmonary depression may be modest at the dosages used and, at least in part, balanced by the impact on cardiopulmonary depression by the decrease in MACISO. The cardiopulmonary data recorded in the present study confirm that the reduction in MACISO was not related to severe hypotension, hypoxemia or hypoventilation (
      • Quasha A.L.
      • Eger II, E.I.
      • Tinker J.H.
      Determination and applications of MAC.
      ). PR was measured rather than heart rate. Although no arrhythmia was detected based on the arterial and pulse oximetry waveforms, use of electrocardiography would be superior to characterize the effects of butorphanol on heart rhythm. Because cardiovascular data were collected in conjunction with MACISO measurements, the actual timing of the measurements was variable among cats. Although this is deemed unlikely to have affected the interpretation of these data, if present, temporal effects may have added variability, further limiting statistical power for the detection of treatment effects. This study was not designed to examine whether butorphanol provides antinociception or analgesia. Lack of such effects would limit the usefulness of butorphanol as an anesthetic adjunct by complicating the provision of postoperative analgesia through antagonistic effects at μ-opioid receptors. All subjects in this study were healthy, young adult male neutered cats. The effects of butorphanol on MACISO reported here may not apply to older cats or cats with systemic disease. Although sex differences for the effect of butorphanol on MAC have not been reported to the authors’ knowledge, they cannot be ruled out. A high variability in plasma butorphanol concentration was observed among individuals. This is probably resulting at least in part from interindividual variability in the disposition of butorphanol. Indeed, the pharmacokinetic study used to design the infusion regimens reported a large interindividual variability for some parameters (
      • Pypendop B.H.
      • Shilo-Benjamini Y.
      Pharmacokinetics of butorphanol in male neutered cats anesthetized with isoflurane.
      ). In addition, the sample was obtained after the last MACISO determination rather than at a fixed time, possibly increasing the variability in plasma butorphanol concentration further, particularly if concentration was changing over time. Because only one concentration per butorphanol dosage is reported for each cat, assessment of temporal changes is not possible. Lastly, the quality of recovery was not rated. Although clinically important recovery complications were not noted, further information on the possible impact of butorphanol infusion on recovery from anesthesia should be obtained before recommending its clinical use.

      Conclusions

      Butorphanol decreased MACISO in a dosage-dependent manner by up to 68%. A ceiling effect on MAC reduction was not observed. Butorphanol IV infusions may be of interest for partial IV anesthesia in cats. The effects of butorphanol infusion on cardiopulmonary function and autonomic responses to noxious stimulation need to be studied further.

      Authors’ contributions

      BHP: study design, experiments, statistical analysis, data interpretation, manuscript preparation. MG: experiments, manuscript preparation. YSB: study design, manuscript preparation. All authors read and approved the final version of the manuscript.

      Conflict of interest statement

      The authors declare no conflict of interest.

      Acknowledgements

      This study was funded by the Center for Companion Animal Health , School of Veterinary Medicine, University of California, Davis and the Koret School of Veterinary Medicine , Hebrew University of Jerusalem ( 2018-71-KG ).

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