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Effects of vatinoxan in dogs premedicated with medetomidine and butorphanol followed by sevoflurane anaesthesia: a randomized clinical study

Open AccessPublished:September 14, 2022DOI:https://doi.org/10.1016/j.vaa.2022.08.002

      Abstract

      Objective

      To investigate effects of vatinoxan in dogs, when administered as intravenous (IV) premedication with medetomidine and butorphanol before anaesthesia for surgical castration.

      Study design

      A randomized, controlled, blinded, clinical trial.

      Animals

      A total of 28 client-owned dogs.

      Methods

      Dogs were premedicated with medetomidine (0.125 mg m−2) and butorphanol (0.2 mg kg−1) (group MB; n = 14), or medetomidine (0.25 mg m−2), butorphanol (0.2 mg kg−1) and vatinoxan (5 mg m−2) (group MB-VATI; n = 14). Anaesthesia was induced 15 minutes later with propofol and maintained with sevoflurane in oxygen (targeting 1.3%). Before surgical incision, lidocaine (2 mg kg−1) was injected intratesticularly. At the end of the procedure, meloxicam (0.2 mg kg−1) was administered IV. The level of sedation, the qualities of induction, intubation and recovery, and Glasgow Composite Pain Scale short form (GCPS-SF) were assessed. Heart rate (HR), respiratory rate (fR), mean arterial pressure (MAP), end-tidal concentration of sevoflurane (Fe′Sevo) and carbon dioxide (Pe′CO2) were recorded. Blood samples were collected at 10 and 30 minutes after premedication for plasma medetomidine and butorphanol concentrations.

      Results

      At the beginning of surgery, HR was 61 ± 16 and 93 ± 23 beats minute−1 (p = 0.001), and MAP was 78 ± 7 and 56 ± 7 mmHg (p = 0.001) in MB and MB-VATI groups, respectively. No differences were detected in fR, Pe′CO2, Fe′Sevo, the level of sedation, the qualities of induction, intubation and recovery, or in GCPS-SF. Plasma medetomidine concentrations were higher in group MB-VATI than in MB at 10 minutes (p = 0.002) and 30 minutes (p = 0.0001). Plasma butorphanol concentrations were not different between groups.

      Conclusions and clinical relevance

      In group MB, HR was significantly lower than in group MB-VATI. Hypotension detected in group MB-VATI during sevoflurane anaesthesia was clinically the most significant difference between groups.

      Keywords

      Introduction

      α2-Adrenoceptor agonists, such as medetomidine, are widely used for sedation and premedication in dogs (
      • Murrell J.C.
      • Hellebrekers L.J.
      Medetomidine and dexmedetomidine: a review of cardiovascular effects and antinociceptive properties in the dog.
      ). However, all drugs in this class have relevant cardiovascular adverse effects including vasoconstriction and marked bradycardia followed by decreases in cardiac output and oxygen delivery (
      • Bloor B.C.
      • Franklund M.
      • Alper G.
      • et al.
      Hemodynamic and sedative effects of dexmedetomidine in dogs.
      ;
      • Pypendop B.H.
      • Verstegen J.P.
      Hemodynamic effects of medetomidine in the dog: a dose titration study.
      ). Although the desired effects of sedation and antinociception of α2-adrenoceptor agonists originate in the central nervous system (CNS), the initial impact on the cardiovascular system is mainly mediated peripherally via activation of α2-adrenoceptors within vascular smooth muscle leading to vasoconstriction (
      • Clough D.P.
      • Hatton R.
      Hypotensive and sedative effects of alpha-adrenoceptor agonists: relationship to alpha1- and alpha2-adrenoceptor potency.
      ;
      • Horn P.T.
      • Kohle J.D.
      • Listinsky J.J.
      • Goldberg L.I.
      Regional variation in the alpha-adrenergic receptors in the canine resistance vessels.
      ). In addition, the centrally mediated general sympatholysis after the administration of α2-adrenoceptor agonists could contribute to the bradycardia (
      • Honkavaara J.M.
      • Raekallio M.R.
      • Kuusela E.K.
      • et al.
      The effects of L-659,066, a peripheral alpha2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia in dogs.
      ).
      Vatinoxan is a selective α2-adrenoceptor antagonist, which penetrates poorly into the mammalian CNS (
      • Clineschmidt B.
      • Pettibone D.
      • Lotti V.
      • et al.
      A peripherally acting alpha-2 adrenoceptor antagonist: L-659,066.
      ;
      • Honkavaara J.M.
      • Raekallio M.R.
      • Syrja P.M.
      • et al.
      Concentrations of medetomidine enantiomers and vatinoxan, an α2-adrenoceptor antagonist, in plasma and central nervous tissue after intravenous coadministration in dogs.
      ) limiting the pharmacological effects to tissues outside the blood–brain barrier. Numerous studies have shown that vatinoxan prevents the vasoconstriction and the following cardiovascular depression without marked effects on sedation attributed to dexmedetomidine or medetomidine in dogs (
      • Pagel P.S.
      • Proctor L.T.
      • Devcic A.
      • et al.
      A novel alpha2-adrenoceptor antagonist attenuates the early, but preserves the late cardiovascular effects of intravenous dexmedetomidine in conscious dogs.
      ;
      • Enouri S.S.
      • Kerr C.L.
      • McDonell W.N.
      • et al.
      Effects of a peripheral alpha2 adrenergic-receptor antagonist on the hemodynamic changes induced by medetomidine administration in conscious dogs.
      ;
      • Honkavaara J.M.
      • Raekallio M.R.
      • Kuusela E.K.
      • et al.
      The effects of L-659,066, a peripheral alpha2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia in dogs.
      ,
      • Honkavaara J.M.
      • Restitutti F.
      • Raekallio M.R.
      • et al.
      The effects of increasing doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs.
      ;
      • Restitutti F.
      • Honkavaara J.M.
      • Raekallio M.R.
      • et al.
      Effects of different doses of L-659,066 on the bispectral index and clinical sedation in dogs treated with dexmedetomidine.
      ). Furthermore, vatinoxan substantially reduces the plasma concentrations of α2-adrenoceptor agonists when administered simultaneously intravenously (IV). This effect is likely mediated via improvement of global haemodynamic function resulting in higher clearance and increased volume of distribution (
      • Honkavaara J.
      • Restitutti F.
      • Raekallio M.
      • et al.
      Influence of MK-467, a peripherally acting α2-adrenoceptor antagonist on the disposition of intravenous dexmedetomidine in dogs.
      ;
      • Bennett R.C.
      • Salla K.M.
      • Raekallio M.R.
      • et al.
      Effects of MK-467 on the antinociceptive and sedative actions and pharmacokinetics of medetomidine in dogs.
      ). Interestingly, equal plasma dexmedetomidine concentrations were detected with medetomidine (20 μg kg−1) alone and with a twofold dosage (40 μg kg−1) of medetomidine administered IV concomitantly with vatinoxan (
      • Huuskonen V.
      • Restitutti F.
      • Honkavaara J.M.
      • et al.
      Investigation of the effects of vatinoxan on somatic and visceral antinociceptive efficacy of medetomidine in dogs.
      ).
      The benefit of various dosages of vatinoxan on cardiovascular function was demonstrated in Beagle dogs premedicated with medetomidine before general anaesthesia with isoflurane (
      • Salla K.
      • Bennett R.C.
      • Restitutti F.
      • et al.
      A comparison in dogs of medetomidine, with or without MK-467, and the combination acepromazine-butorphanol as premedication prior to anaesthesia induced by propofol and maintained with isoflurane.
      ,
      • Salla K.M.
      • Tuns C.I.
      • Bennett R.C.
      • et al.
      Cardiovascular effects of premedication with medetomidine alone and in combination with MK-467 or glycopyrrolate in dogs subsequently anesthetized with isoflurane.
      ). Isoflurane reduces mean arterial pressure (MAP) in dogs, mainly attributed to decrease in systemic vascular resistance (
      • Brahim J.S.
      • Thut P.D.
      Hemodynamic changes during isoflurane anesthesia.
      ;
      • Mutoh T.
      • Nishimura R.
      • Kim H.-Y.
      • et al.
      Cardiopulmonary effects of sevoflurane, compared with halothane, enflurane, and isoflurane, in dogs.
      ). The vasoconstriction and isoflurane-sparing effects of medetomidine may counteract the vasodilation effects of isoflurane (
      • Bloor B.C.
      • Franklund M.
      • Alper G.
      • et al.
      Hemodynamic and sedative effects of dexmedetomidine in dogs.
      ).
      At present, only one clinical study has been published regarding the effects of vatinoxan in dogs sedated with intramuscular (IM) medetomidine and butorphanol (
      • Kallio-Kujala I.J.
      • Turunen H.A.
      • Raekallio M.R.
      • et al.
      Peripherally acting α-adrenoceptor antagonist MK-467 with intramuscular medetomidine and butorphanol in dogs: A prospective, randomized, clinical trial.
      ). Further investigation of the effects of vatinoxan in dogs premedicated with α2-adrenoceptor agonists before general anaesthesia is important. Our aim was to document effects of vatinoxan in healthy, client-owned dogs, when administered with a routine IV premedication of medetomidine and butorphanol prior to general anaesthesia. We hypothesized 1) that vatinoxan would decrease the incidence of bradycardia after premedication with IV medetomidine and butorphanol; and 2) that concomitant administration of vatinoxan with medetomidine and butorphanol will not change the intensity of sedation, the maintenance of a surgical plane of anaesthesia or the quality of recovery.

      Materials and methods

      This study was performed at the Veterinary Teaching Hospital, Faculty of Veterinary Medicine, University of Helsinki and was approved by Animal Experiment Board (ESAVI/6851/2017). Informed owner consent was obtained. Based on power analysis (two-sided equality) according to the previous results from experimental dogs (
      • Salla K.
      • Bennett R.C.
      • Restitutti F.
      • et al.
      A comparison in dogs of medetomidine, with or without MK-467, and the combination acepromazine-butorphanol as premedication prior to anaesthesia induced by propofol and maintained with isoflurane.
      ), 10 dogs per group were required to detect a 20 ± 15 beats minute−1 difference in heart rate (HR) and a 20 ± 15 mmHg difference in MAP with a power of 80% and an alpha-level set at 0.05 (http://powerandsamplesize.com). The study design was a randomized, controlled, blinded, clinical trial. Randomization was performed in blocks for body weights (5–10, 10.1–30 and 30.1–50 kg) by blindly picking a paper note from an envelope. Randomization in blocks aimed to ensure relatively homogenous populations between groups.
      Male dogs assigned to class I or II according to the criteria described by the American Society of Anesthesiologists (
      • Dugdale A.
      Veterinary Anaesthesia, Principles to Practice.
      ) scheduled for prescrotal castration were included. Dogs with body weight <5 or >50 kg, body condition score ≥4/5, breed-related risks for general anaesthesia (e.g. brachycephalic syndrome), age <6 months or >10 years, and intolerance to IV catheter placement without sedation were excluded.
      After physical examination, a catheter was placed in a cephalic or saphenous vein to obtain blood samples for haematology and basic serum chemistry tests. After IV catheterisation, dogs rested in their cages for at least 30 minutes. The dogs were assigned to group MB, medetomidine [0.125 mg m−2; Medetomidine Hydrochloride, 0.5 mg mL−1 (Recipharm, Sweden) or Cepetor, 1 mg mL−1 (CP-Pharma, Germany)] and butorphanol (0.2 mg kg−1; Butordol, 10 mg mL−1; Intervet International BV, The Netherlands) IV or group MB-VATI, medetomidine (0.25 mg m−2) and butorphanol (0.2 mg kg−1) and vatinoxan (5 mg m−2; MK-467 HCl, 10 mg mL−1; Vetcare Ltd, Finland) IV. The body surface area (BSA) was calculated using:
      BSA = 10.1 × (body weight in kg)0.67 × 10−2 (m2)


      (
      • White C.R.
      • Kearney M.R.
      Metabolic scaling in animals: methods, empirical results, and theoretical explanations.
      ;
      • Pypendop B.H.
      • Jones J.H.
      Indexing cardiovascular and respiratory variables: allometric scaling principles.
      ). The dose of medetomidine (0.125 mg m−2) in group MB corresponds to a dose of 7 μg kg−1 for a 5 kg dog and 4.5 μg kg−1 for a 50 kg dog.
      Drugs were prepared by another investigator not involved in data collection. All premedication drugs were drawn up separately and mixed in a single syringe before administration. In group MB, saline was added to reach equal administration volumes. The syringes were covered with opaque tape for blinding.
      Before drug administration (baseline; T0), HR, from the electrocardiogram, and noninvasive oscillometric blood pressure (NIBP) were recorded in the recumbent dog (Life Scope TR; Nihon Kohden, Japan). The blood pressure cuff, width approximately 40% of the limb circumference, was placed over the metatarsus.
      Premedication was administered IV as bolus over 10 seconds and flushed with 10 mL saline. After premedication, IV fluid therapy (5 mL kg−1 hour−1) with balanced crystalloid solution (Ringer-Acetat Baxter Viaflo; Baxter Ltd, Finland) was provided until the end of the surgical procedure. Blood samples (3 mL for ethylenediamine tetra-acetic acid tube) for analysis of plasma drug concentrations were collected at 10 and 30 minutes after premedication from the jugular vein by using 5 mL syringe and 25 gauge needle. Actual times of blood sampling were recorded.
      Sedation was assessed at 10 minutes (T10) using a composite simple descriptive sedation score ranging from 0 (no sedation) to 15 points (deep sedation) (
      • Raszplewicz J.
      • MacFarlane P.
      • West E.
      Comparison of sedation scores and propofol induction doses in dogs after intramuscular premedication with butorphanol and either dexmedetomidine or medetomidine.
      ). After the sufficient level of sedation was achieved, a 22 gauge, 25 mm catheter (Terumo Europe NV, Belgium) for monitoring invasive blood pressures (IBP) was placed in the dorsal pedal artery. Only two attempts were allowed. For each dog, a new pressure transducer kit (Gabarith PMSET; Becton Dickinson, UT, USA) was used, flushed with saline, zeroed to atmospheric pressure and positioned level with the manubrium.
      General anaesthesia was induced with propofol (PropoVet, 10 mg mL−1; Abbott Laboratories Ltd, UK) administered with a loading dose (0.5 mg kg−1) followed by constant rate infusion (CRI; 1 mg kg−1 minute−1). Start of induction was 15 minutes after premedication, with the actual time recorded. Achieved loss of consciousness was evaluated by assessing palpebral reflexes and the rotation of eyes every 5–10 seconds. The trachea was intubated when palpebral reflexes disappeared and the mandible could be pulled down without resistance. Propofol CRI was stopped after successful endotracheal intubation and the total dose of propofol was recorded. The quality of induction and intubation were scored ranging from 1 (ideal induction, or smooth intubation) to 4 (induction not reached) or 5 (intubation failed) (
      • Casoni D.
      • Spadavecchia C.
      • Adami C.
      S-ketamine versus racemic ketamine in dogs: their relative potency as induction agents.
      ). General anaesthesia was maintained with sevoflurane in 60% oxygen in air–oxygen mixture set on flowmeters with rebreathing circle system (Dräger Perseus A500; OneMed Ltd, Finland). End-tidal sevoflurane concentration (Fe′Sevo) was targeted to 1.3% but was adjusted if needed to maintain surgical plane of anaesthesia (absent palpebral reflex, rotated eye globe, relaxed jaw tone and no movement in response to surgery). Fe′Sevo was recorded.
      During anaesthesia, HR, fR, SpO2, NIBP and IBP (when applicable) and oesophageal temperature (TOES) were monitored (Life Scope TR; Nihon Kohden), and inspired fraction of oxygen, end-tidal partial pressure of carbon dioxide (Pe′CO2) and Fe′Sevo with anaesthesia station (Dräger Perseus A500, OneMed Ltd; gas analyser calibrated during yearly maintenance) and recorded at 5-minute intervals until the end of surgery. The duration of surgical procedure was recorded. Dogs were breathing spontaneously, but if apnoea >30 seconds occurred or Pe′CO2 increased >55 mmHg (7.3 kPa), mechanical intermittent positive pressure ventilation (IPPV) was instituted. The need for IPPV was recorded as yes or no. Surgical site infiltration and intratesticular injection of lidocaine (total dosage 2 mg kg−1, divided into three volumes; Lidocain, 20 mg mL−1; Orion Pharma, Finland) was performed. Dogs were covered with hot-air devices, electrical heating mattress and blankets to maintain TOES >36 °C.
      Rescue analgesia was implemented if two of three variables (HR, fR, MAP) were increased during the surgery >20% from the values recorded at a stable plane of anaesthesia before incision. In that case, another dose of lidocaine was injected into the surgical site and spermatic cords. If lidocaine (4 mg kg−1) did not produce sufficient analgesia, fentanyl (3 μg kg−1; Fentanyl-Hameln, 50 μg mL−1; Hameln Pharma Plus Gmbh, Germany) was administered IV. Intraoperative rescue analgesia was recorded as yes or no.
      In case of concomitantly recorded invasive (when applicable) or noninvasive MAP <60 mmHg and SAP <90 mmHg during anaesthesia, a step-based approach was initiated according to the study anaesthesia guidelines (
      • Bednarski R.
      • Grimm K.
      • Harvey R.
      • et al.
      AAHA anesthesia guidelines for dogs and cats.
      ) with 10 mL kg−1 crystalloid bolus administered within 5 minutes, followed by a 2 mL kg−1 colloid bolus (Gelofusin, 40 mg mL−1; B Braun Melsungen AG, Germany) and dopamine (Dopmin 40 mg mL−1; Orion Corporation, Finland) CRI at 2.5–10 μg kg−1 minute−1. The correction of hypotension using crystalloid, colloid bolus or dopamine CRI were recorded as yes or no.
      At the end of general anaesthesia, the dog recovered in a dedicated room. Supplemental oxygen was administered via loose face mask and SpO2, HR and fR were monitored by the same anaesthetist (KS) until the dog was able to lift the head and was responsive to verbal stimuli. The time of extubation and head lift were recorded. The quality of the early recovery phase was scored approximately 30 minutes after extubation with a simple numerical score ranging from 1 (smooth transition to alertness) to 5 points (extreme excitement, re-sedation necessary) (
      • Jiménez C.P.
      • Mathis A.
      • Mora S.S.
      • et al.
      Evaluation of the quality of the recovery after administration of propofol or alfaxalone for induction of anaesthesia in dogs anaesthetized for magnetic resonance imaging.
      ; Appendix A). Atipamezole (0.5 mg m−2; Antisedan, 5 mg mL−1; Orion Pharma Ltd) was administered IM if the dog was deeply sedated and bradycardia (HR <60 minute−1) persisted after tracheal extubation for more than 10 minutes. In case of severe excitation during early recovery, dexmedetomidine (0.5 μg kg−1; Dexdomitor, 0.1 mg mL−1; Orion Pharma Ltd) was administered IV.
      Meloxicam (0.2 mg kg−1; Metacam, 5 mg mL−1; Vetcare Ltd) IV was administered for postoperative analgesia at the end of surgery, followed by 0.1 mg kg−1 orally once per day at home for 3–5 days. Pain assessment was performed by the same anaesthetist (KS) 1 hour after extubation with Glasgow Composite Pain Scale short form (GCPS-SF) (
      • Reid J.
      • Nolan A.M.
      • Hughes J.M.L.
      • et al.
      Development of short-form Glasgow Composite Measure Pain Scale (CMPS-SF) and derivation of an analgesic intervention score.
      ). A dog with a GCPS-SF pain score ≥6/24 was treated with IV buprenorphine (0.015 mg kg−1; Bupaq Multidose, 0.3 mg mL−1; Richter Pharma, Austria). The dogs were closely observed and discharged from hospital when their locomotor ability was normal.
      On the following day, a researcher (HT, VP) contacted the owner by phone and requested responses to a questionnaire regarding lethargy, appetite, nausea or vomiting, consistency of the faeces and the signs of pain or distress of their dog. Neither the researcher nor the owners were aware of the assigned group during the telephone call.

      Plasma drug concentration analysis

      Plasma was separated by centrifugation (3000 g for 15 minutes) and stored at –20 °C until analysed. The concentrations of medetomidine, butorphanol and vatinoxan were determined using liquid chromatography–tandem mass spectrometry as reported earlier (
      • Kallio-Kujala I.J.
      • Turunen H.A.
      • Raekallio M.R.
      • et al.
      Peripherally acting α-adrenoceptor antagonist MK-467 with intramuscular medetomidine and butorphanol in dogs: A prospective, randomized, clinical trial.
      ). The precursor ions (m z−1) for medetomidine, butorphanol, vatinoxan and internal standard (phenacetin) were 201, 328, 419 and 180, respectively. Fragmented ions (m z−1) used for quantification were 95, 310, 82 and 110 for medetomidine, butorphanol, vatinoxan and internal standard, respectively. The interassay accuracy of the quality control samples ranged from 92.1% to 105.7% for medetomidine, from 87.8% to 105.5% for vatinoxan and from 94.9% to 102.8% for butorphanol.

      Statistical analysis

      All statistical tests were performed by using SPSS Version 27 (IBM SPSS Statistics; IBM Corp., NY, USA). The normality of data distribution was evaluated with Shapiro–Wilk test. Repeatedly measured variables were analysed with mixed model of analysis of variance with post hoc Bonferroni correction at selected time points. Parametric variables measured only once were compared with unpaired two-tailed t tests. Categorical variables and non-normally distributed variables were compared between treatments with Mann–Whitney U test. For categorical variables recorded yes/no, Fisher exact test was used. Data are presented mean ± standard deviation or median (range) as appropriate. An alpha-level <0.05 was considered statistically significant.

      Results

      A total of 28 dogs scheduled for prescrotal castration were included in the study and equal numbers assigned to groups MB and MB-VATI. Dogs in groups MB and MB-VATI were aged 3.1 ± 2.5 and 3.8 ± 2.7 years (p = 0.50) and weighed 21.1 ± 10.5 and 22.8 ± 11.7 kg (p = 0.429), respectively. Most of the dogs (n = 17) weighed 10.1–30 kg, five dogs weighed >30 kg and six dogs <10 kg. The dog breeds were mixed breed (n = 8), Border Collie (n = 4), Labrador Retriever (n = 3), German Shepherd (n = 2) and one each Australian Kelpie, Belgian Shepherd, Collie, Dachshund, Giant Schnauzer, Keeshond, Lagotto Romagnolo, Mittelspitz, Schapendoes, Welsh Corgi and Whippet.
      There were no significant differences between groups regarding the qualities of sedation, induction, intubation and recovery, or in the induction, incision, end of surgery, extubation and head lift times or in the duration of surgery (Table 1). Total doses of propofol for intubation were 2.8 ± 0.6 mg kg−1 in group MB and 2.8 ± 0.9 mg kg−1 in group MB-VATI (p = 0.158).
      Table 1The sedation scores 10 minutes after sedation (T10), qualities of induction, intubation and recovery, and induction, incision, end of surgery, length of surgery, extubation and head lift times in minutes in dogs premedicated intravenously with either medetomidine 0.125 mg m−2 and butorphanol 0.2 mg kg−1 (group MB, n = 14) or medetomidine 0.25 mg m−2, butorphanol 0.2 mg kg−1 and vatinoxan 5 mg m−2 (group MB-VATI, n = 14) followed by propofol induced sevoflurane anaesthesia for surgical castration.
      VariablesGroupP
      MBMB-VATI
      Sedation score at T1014 (11–14)14 (4–14)0.210
      Induction time (minutes)16.4 ± 0.716.2 ± 1.00.250
      Quality of induction1 (1–2)1 (1–2)1.000
      Quality of intubation1 (1–2)1 (1–3)0.610
      Incision time (minutes)

      End of surgery (minutes)

      Length of surgery (minutes)

      Extubation time (minutes)
      52.5 ± 7.0

      98.6 ± 16.7

      46.1 ± 12.8

      115.8 ± 20.7
      53.2 ± 8.7

      100.7 ± 14.9

      47.3 ± 8.3

      116.8 ± 16.3
      0.813

      0.723

      0.772

      0.783
      Head lift time (minutes)121.4 ± 22.9121.5 ± 16.00.472
      Quality of recovery2 (1–3)2 (1–5)0.147
      In both groups, HR decreased from baseline after the administration of IV premedication. HR was significantly higher in group MB-VATI than in group MB between T5 and T90 (p < 0.001; Fig. 1). After 5 minutes from the administration of premedication, HR were 43 ± 15 and 67 ± 17 beats minute−1 in groups MB and MB-VATI, respectively (p = 0.002). In group MB-VATI, an abrupt decrease in HR from 80 to 30–35 beats minute−1 occurred in one dog during ligation of a spermatic cord, 98 minutes after premedication, and atropine (0.02 mg kg−1; Atropin, 1 mg mL−1; Takeda Ltd, Finland) was administered IV. The HR increased and subsequent values of cardiovascular variables were excluded from further analysis.
      Figure 1
      Figure 1Mean ± standard deviation of heart rates (HR) in dogs before (T0) and after premedication (T5–T15) with intravenous medetomidine (0.125 mg m−2) and butorphanol (0.2 mg kg−1; group MB, n = 14), or medetomidine (0.25 mg m−2), butorphanol (0.2 mg kg−1) and vatinoxan (5 mg m−2; group MB-VATI, n = 14), followed by propofol induction and sevoflurane anaesthesia before (T25–T30) and during surgical castration (T60–T90). ∗Significantly different between groups (p < 0.05).
      During the procedure, both IBP MAP (p < 0.001) (Fig. 2) and NIBP MAP (p = 0.001) (Table 2) were significantly lower in group MB-VATI than in group MB. More than half of the dogs in group MB-VATI (eight out of 14) needed an intervention for hypotension in comparison with one dog in group MB (p = 0.013). In group MB-VATI, four out of eight hypotensive dogs required dopamine CRI in addition to the fluid boluses.
      Figure 2
      Figure 2Mean ± standard deviation invasive mean arterial pressures in dogs after premedication (T15) with intravenous medetomidine (0.125 mg m−2) and butorphanol (0.2 mg kg−1; group MB, n = 13) or medetomidine (0.25 mg m−2), butorphanol (0.2 mg kg−1) and vatinoxan (5 mg m−2; group MB-VATI, n = 13) followed by propofol induction and sevoflurane anaesthesia before (T25–T30) and during surgical castration (T60–T90). ∗Significantly different between groups (p < 0.05).
      Table 2Noninvasive mean arterial blood pressure (NIBP, MAP), respiratory rate (fR), end-tidal partial pressure of carbon dioxide (Pe′CO2), and end-tidal sevoflurane concentration (Fe′Sevo) in dogs at baseline (T0) and at 15 minutes (T15) after intravenous premedication with either medetomidine (0.125 mg m−2) and butorphanol (0.2 mg kg−1; group MB) or medetomidine (0.25 mg m−2), butorphanol (0.2 mg kg−1) and vatinoxan (5 mg m−2; group MB-VATI), and after induction of anaesthesia with propofol and sevoflurane for surgical castration (T30, skin incision, Surgery start; skin sutures, Surgery end). Data are from 14 dogs in each group except where indicated. Data are presented as mean ± standard deviation. n, number of dogs; na, not assessed.
      VariableGroupTime point
      T0T15T30Surgery startSurgery end
      NIBP, MAPMB (n = 13)111 ± 2196 ± 20
      Significant difference between groups (p < 0.05).
      80 ± 17
      Significant difference between groups (p < 0.05).
      70 ± 14
      Significant difference between groups (p < 0.05).
      69 ± 10
      (mmHg)MB-VATI (n = 13)110 ± 2280 ± 1262 ± 1458 ± 1262 ± 13
      fR (breaths minute−1)MBna15 ± 39 ± 510 ± 615 ± 11
      MB-VATIna14 ± 67 ± 37 ± 214 ± 15
      Pe′CO2MBnana48.6 ± 6.547.9 ± 5.146.1 ± 4.8
      (mmHg)MB-VATInana48.5 ± 6.846.1 ± 7.046.3 ± 7.8
      Pe′CO2MBnana6.5 ± 0.96.4 ± 0.76.4 ± 0.6
      (kPa)MB-VATInana6.5 ± 0.96.1 ± 0.96.2 ± 1.0
      Fe′Sevo (%)MBnana1.5 ± 0.41.5 ± 0.21.5 ± 0.2
      MB-VATInana1.3 ± 0.21.4 ± 0.21.5 ± 0.2
      Significant difference between groups (p < 0.05).
      No dog required intraoperative rescue analgesia or IPPV. There were no differences in fR (p = 0.452), Pe′CO2 (p = 0.811) or Fe′Sevo (p = 0.158) between groups (Table 2). TOES were >36 °C in both groups.
      Atipamezole was administered during recovery in four dogs in group MB and five dogs in group MB-VATI (p = 1.000). At the time of extubation, additional dexmedetomidine was needed in two dogs in group MB-VATI (p = 0.481). The median GCPS-SF was 4 (1–8) and 2.5 (1–8) in groups MB and MB-VATI, respectively (p = 0.168). Rescue analgesia with buprenorphine was administered to four dogs in group MB and two dogs in group MB-VATI (p = 0.648). As several dogs in both groups needed additional drugs shortly after extubation (atipamezole or dexmedetomidine), no comparisons were made for HR, SpO2 or fR during the postoperative period.
      Plasma medetomidine concentrations were significantly higher in group MB-VATI than in group MB at 10 (p = 0.001) and 30 minutes (p < 0.001) after drug administration, whereas no differences were detected in plasma butorphanol concentrations or blood sampling times between groups at those time points (Table 3).
      Table 3Blood sampling times and plasma concentrations for medetomidine, butorphanol and vatinoxan in dogs at 10 (T10) and 30 (T30) minutes after intravenous premedication with either medetomidine 0.125 mg m−2 and butorphanol 0.2 mg kg−1 (group MB, n = 12) or medetomidine 0.25 mg m−2, butorphanol 0.2 mg kg−1 and vatinoxan 5 mg m−2 (group MB-VATI, n = 12). Anesthesia was induced with propofol 15 minutes after premedication and maintained with sevoflurane. Data are presented as mean ± standard deviation.
      VariableTime pointGroup
      MBMB-VATI
      Blood sampling time (minutes)T10

      T30
      10.6 ± 0.7

      30.6 ± 0.8
      10.7 ± 1.5

      30.6 ± 1.0
      Medetomidine (ng mL−1)T103.1 ± 0.5
      Significant difference between groups (p < 0.05).
      5.1 ± 1.8
      Significant difference between groups (p < 0.05).
      T301.4 ± 0.3
      Significant difference between groups (p < 0.05).
      2.2 ± 0.5
      Significant difference between groups (p < 0.05).
      Butorphanol (ng mL−1)T1078.8 ± 20.664.0 ± 20.8
      T3036.5 ± 8.530.0 ± 7.5
      Vatinoxan (ng mL−1)T10741 ± 235
      T30482 ± 144
      Significant difference between groups (p < 0.05).
      In the telephone call the day after surgery, decreased appetite (p = 0.015) and soft faeces (p = 0.030) were reported more often in group MB than in MB-VATI (Table 4). Owners (one from each group) could not be reached for the interview.
      Table 4Responses from dog owners on the day following sevoflurane anaesthesia and castration obtained during a telephone call. Investigator and owners were unaware which premedication was assigned to the dog; medetomidine (0.125 mg m−2) and butorphanol (0.2 mg kg−1; group MB, n = 13) or medetomidine (0.25 mg m−2), butorphanol (0.2 mg kg−1) and vatinoxan (5 mg m−2; group MB-VATI, n = 13). Data are presented as the number of dogs with the observed behaviour.
      At-home behaviourGroup
      MBMB-VATI
      Lethargy118
      Decrease in appetite6
      Significantly different between groups (p < 0.05).
      0
      Nausea10
      Soft faeces7
      Significantly different between groups (p < 0.05).
      1
      Pain or distress911
      Significantly different between groups (p < 0.05).

      Discussion

      This randomized, clinical trial describes the perianaesthetic effects of vatinoxan with a combination of medetomidine and butorphanol in client-owned dogs scheduled for prescrotal castration under sevoflurane anaesthesia. The most significant findings in this study were the differences in HR and blood pressures between groups.
      In the present study, HR was significantly higher in MB-VATI than MB group throughout the procedure. This is in line with results obtained from previous study in laboratory dogs sedated IV with the combination of medetomidine, butorphanol and vatinoxan (
      • Salla K.
      • Restitutti F.
      • Vainionpää M.
      • et al.
      The cardiopulmonary effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in dogs sedated with a combination of medetomidine and butorphanol.
      ). Moreover, HR was significantly higher during isoflurane anaesthesia in laboratory Beagle dogs when vatinoxan was combined only with medetomidine (
      • Salla K.
      • Bennett R.C.
      • Restitutti F.
      • et al.
      A comparison in dogs of medetomidine, with or without MK-467, and the combination acepromazine-butorphanol as premedication prior to anaesthesia induced by propofol and maintained with isoflurane.
      ,
      • Salla K.M.
      • Tuns C.I.
      • Bennett R.C.
      • et al.
      Cardiovascular effects of premedication with medetomidine alone and in combination with MK-467 or glycopyrrolate in dogs subsequently anesthetized with isoflurane.
      ). Adverse cardiovascular effects, such as tachyarrhythmias and hypertension, have been reported after administration of an anticholinergic agent to treat or prevent bradycardia after medetomidine in dogs (
      • Enouri S.S.
      • Kerr C.L.
      • McDonell W.N.
      • et al.
      Effects of a peripheral alpha2 adrenergic-receptor antagonist on the hemodynamic changes induced by medetomidine administration in conscious dogs.
      ;
      • Salla K.M.
      • Tuns C.I.
      • Bennett R.C.
      • et al.
      Cardiovascular effects of premedication with medetomidine alone and in combination with MK-467 or glycopyrrolate in dogs subsequently anesthetized with isoflurane.
      ). Therefore, these drugs are not suitable for routine correction of bradycardia induced by medetomidine. However, despite the initial decrease in HR and cardiac output after a bolus of α2-agonist, these variables return close to baseline values during subsequent isoflurane anaesthesia in dogs (
      • Grasso S.C.
      • Ko J.C.
      • Weil A.B.
      • et al.
      Hemodynamic influence of acepromazine or dexmedetomidine premedication in isoflurane-anesthetized dogs.
      ;
      • Salla K.
      • Bennett R.C.
      • Restitutti F.
      • et al.
      A comparison in dogs of medetomidine, with or without MK-467, and the combination acepromazine-butorphanol as premedication prior to anaesthesia induced by propofol and maintained with isoflurane.
      ,
      • Salla K.M.
      • Tuns C.I.
      • Bennett R.C.
      • et al.
      Cardiovascular effects of premedication with medetomidine alone and in combination with MK-467 or glycopyrrolate in dogs subsequently anesthetized with isoflurane.
      ). These findings present the anaesthetist with the dilemma of whether to treat the initial bradycardia after medetomidine in dogs during inhalation anaesthesia. In practice, the decision is driven by the concurrent measurements of blood pressure and the severity of bradyarrhythmia.
      The most significant finding in the present study was the moderate to marked hypotension in group MB-VATI.
      • Hector R.C.
      • Rezende M.L.
      • Mama K.R.
      • et al.
      Combined effects of dexmedetomidine and vatinoxan infusions on minimum alveolar concentration and cardiopulmonary function in sevoflurane-anesthetized dogs.
      demonstrated that the presence of vatinoxan attenuates dexmedetomidine-induced decrease in sevoflurane minimum alveolar concentration (MAC) in dogs. In the present study, Fe′Sevo was approximately 35% lower (at 1.5%) in both groups than the reported MAC (2.3%) of sevoflurane in dogs (
      • Kazama T.
      • Ikeda K.
      Comparison of MAC and the rate of rise of alveolar concentration of sevoflurane with halothane and isoflurane in the dog.
      ). Moreover, the required Fe′Sevo was higher than the targeted Fe′Sevo of 1.3%, indicating that the sevoflurane administration could not be decreased further. In addition, despite the fact that increased medetomidine dose in group MB-VATI was associated with higher plasma concentration during sevoflurane anaesthesia, hypotension and higher HR were more common in group MB-VATI than in group MB. Therefore, we consider that these differences in cardiovascular effects between groups are the result of including vatinoxan. Similarly, several studies with experimental dogs, horses and cats have recorded lower blood pressures during inhalation anaesthesia with the presence of vatinoxan in comparison with α2-adrenoceptor agonists alone (
      • Salla K.
      • Bennett R.C.
      • Restitutti F.
      • et al.
      A comparison in dogs of medetomidine, with or without MK-467, and the combination acepromazine-butorphanol as premedication prior to anaesthesia induced by propofol and maintained with isoflurane.
      ,
      • Salla K.M.
      • Tuns C.I.
      • Bennett R.C.
      • et al.
      Cardiovascular effects of premedication with medetomidine alone and in combination with MK-467 or glycopyrrolate in dogs subsequently anesthetized with isoflurane.
      ;
      • Pakkanen S.A.
      • Raekallio M.R.
      • Mykkänen A.K.
      • et al.
      Detomidine and the combination of detomidine and MK-467, a peripheral alpha-2 adrenoceptor antagonist, as premedication in horses anaesthetized with isoflurane.
      ;
      • Martin-Flores M.
      • Sakai D.M.
      • Honkavaara J.
      • et al.
      Hemodynamic effects of MK-467 following intravenous administration to isoflurane-anesthetized cats concurrently receiving dexmedetomidine.
      ;
      • Jaeger A.T.
      • Pypendop B.H.
      • Ahokoivu H.
      • Honkavaara J.
      Cardiopulmonary effects of dexmedetomidine, with and without vatinoxan, in isoflurane-anesthetized cats.
      ;
      • Tapio H.
      • Raekallio M.
      • Mykkänen A.
      • et al.
      Effects of vatinoxan on cardiorespiratory function and gastrointestinal motility during constant-rate medetomidine infusion in standing horses.
      ).
      In previous studies, the increased HR and decreased blood pressures following the administration of various doses of vatinoxan with an α2-agonist in dogs resulted in improved cardiac outputs and oxygen delivery in comparison with α2-agonist treatment alone (
      • Honkavaara J.
      • Restitutti F.
      • Raekallio M.
      • et al.
      Influence of MK-467, a peripherally acting α2-adrenoceptor antagonist on the disposition of intravenous dexmedetomidine in dogs.
      ;
      • Salla K.
      • Bennett R.C.
      • Restitutti F.
      • et al.
      A comparison in dogs of medetomidine, with or without MK-467, and the combination acepromazine-butorphanol as premedication prior to anaesthesia induced by propofol and maintained with isoflurane.
      ,
      • Salla K.
      • Restitutti F.
      • Vainionpää M.
      • et al.
      The cardiopulmonary effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in dogs sedated with a combination of medetomidine and butorphanol.
      ;
      • Bennett R.C.
      • Salla K.M.
      • Raekallio M.R.
      • et al.
      Effects of the α2 adrenoceptor agonist medetomidine on the distribution and clearance of alfaxalone during coadministration by constant rate infusion in dogs.
      ). However, cardiac output or oxygen delivery were not measured in the present clinical study, and interventions were required to treat clinically unacceptable MAP in more than half of the dogs in MB-VATI group.
      The dose ratio of medetomidine to vatinoxan (1:20) was chosen based on the previous studies in laboratory Beagle dogs premedicated with various dose ratios followed by isoflurane anaesthesia (
      • Salla K.
      • Bennett R.C.
      • Restitutti F.
      • et al.
      A comparison in dogs of medetomidine, with or without MK-467, and the combination acepromazine-butorphanol as premedication prior to anaesthesia induced by propofol and maintained with isoflurane.
      ,
      • Salla K.M.
      • Tuns C.I.
      • Bennett R.C.
      • et al.
      Cardiovascular effects of premedication with medetomidine alone and in combination with MK-467 or glycopyrrolate in dogs subsequently anesthetized with isoflurane.
      ). However, it should be noted that in these experimental studies the dose of medetomidine was higher and butorphanol was not administered (
      • Salla K.
      • Bennett R.C.
      • Restitutti F.
      • et al.
      A comparison in dogs of medetomidine, with or without MK-467, and the combination acepromazine-butorphanol as premedication prior to anaesthesia induced by propofol and maintained with isoflurane.
      ,
      • Salla K.M.
      • Tuns C.I.
      • Bennett R.C.
      • et al.
      Cardiovascular effects of premedication with medetomidine alone and in combination with MK-467 or glycopyrrolate in dogs subsequently anesthetized with isoflurane.
      ) in comparison with the present study. Therefore, further investigations are needed to explore whether different doses or dose ratios of medetomidine and vatinoxan, another administration route such as IM, or the use of other anaesthetic agents for maintenance could provide clinically satisfactory blood pressures during general anaesthesia in various dog populations.
      In the present study, the dose of medetomidine in group MB-VATI was twice that in group MB intended to achieve similar plasma concentrations of medetomidine in both treatments, based on earlier results in laboratory Beagle dogs (
      • Honkavaara J.
      • Restitutti F.
      • Raekallio M.
      • et al.
      Influence of MK-467, a peripherally acting α2-adrenoceptor antagonist on the disposition of intravenous dexmedetomidine in dogs.
      ;
      • Huuskonen V.
      • Restitutti F.
      • Honkavaara J.M.
      • et al.
      Investigation of the effects of vatinoxan on somatic and visceral antinociceptive efficacy of medetomidine in dogs.
      ). However, this goal was not reached and plasma concentrations of medetomidine were higher in group MB-VATI, although less than twofold higher than in group MB. In addition, plasma concentrations of butorphanol were not different between groups. The probable cause of the variability in drug plasma concentrations for administered doses, alongside the minor inaccuracy in blood sampling times among individual dogs, could be physiological and metabolic differences across dog breeds that are responsible for breed-related diversity in the dose–exposure relationship of drugs (
      • Martinez M.N.
      • Antonovic L.
      • Court M.
      • et al.
      Challenges in exploring the cytochrome P450 system as a source of variation in canine drug pharmacokinetics.
      ). In horses premedicated with detomidine and butorphanol with or without vatinoxan, plasma concentrations of butorphanol during isoflurane anaesthesia were not statistically different between treatments at selected time points (
      • Pakkanen S.A.
      • Raekallio M.R.
      • Mykkänen A.K.
      • et al.
      Detomidine and the combination of detomidine and MK-467, a peripheral alpha-2 adrenoceptor antagonist, as premedication in horses anaesthetized with isoflurane.
      ). However, the area under the plasma concentration time curve for butorphanol was less with vatinoxan treatment. Moreover, the present study was not designed to compare pharmacokinetic variables, and owing to the clinical nature of the study only two blood samples were collected for plasma drug concentrations analysis, preventing a thorough interpretation of the pharmacokinetic behaviour of the drug combinations. Nevertheless, the dose of propofol, the level of sedation, the qualities of induction, intubation or recovery or GCPS-SF did not differ between groups. It is possible that the sedation scoring system used in the study may not have discriminated between slight differences in the deep levels of sedation. Also noted is that this study was not powered to detect a difference in GCPS-SF and procedural times varied among individual dogs as expected in clinical practice, which could have influenced the results regarding recovery quality and GCPS-SF. However, some dogs required postoperative rescue analgesia, similarly reported by
      • Huuskonen V.
      • Hughes L.J.
      • Bañon E.E.
      • West E.
      Intratesticular lidocaine reduces the response to surgical castration in dogs.
      . In addition, administration of either atipamezole or dexmedetomidine in the early recovery phase was indicated for several dogs, consequently, routine monitoring during the recovery phase is recommended. Further studies are warranted to investigate the influence of vatinoxan on the plasma drug concentrations at the postoperative phase and on the need for postoperative analgesic agents. Gastrointestinal side effects such as decreased appetite or soft faeces were reported less frequently by the owners of dogs in group MB-VATI. By contrast, in a previous study the administration of α2-adrenoceptor antagonist was accompanied with soft faeces in sedated dogs (
      • Kallio-Kujala I.J.
      • Turunen H.A.
      • Raekallio M.R.
      • et al.
      Peripherally acting α-adrenoceptor antagonist MK-467 with intramuscular medetomidine and butorphanol in dogs: A prospective, randomized, clinical trial.
      ). Therefore, further studies regarding the incidence of gastrointestinal side effects after general anaesthesia in small animal medicine are also warranted.

      Conclusions

      HR decreased less in dogs premedicated with medetomidine–butorphanol–vatinoxan than in dogs premedicated without vatinoxan. Increased incidence of hypotension was the most clinically relevant effect of vatinoxan during sevoflurane anaesthesia. Therefore, monitoring blood pressure with a plan for treatment of hypotension is recommended when vatinoxan is combined with medetomidine and butorphanol and anaesthesia is maintained with sevoflurane in dogs.

      Authors’ contributions

      KMS: study design, data collection, analysis and interpretation of data, writing the original draft of the manuscript. HAT and IJK: study design, data collection, writing the original draft of the manuscript. VP, JL and PB: study design, data collection. DCC, MRR and OV: study design. All authors contributed to review and editing of the manuscript.

      Conflict of interest statement

      At the time of the study design and data collection, HT was a PhD student in University of Helsinki, Finland, but is currently employed by Vetcare Ltd, Finland. Vetcare Ltd provided the drugs used in this study but did not contribute to the study design, data collection, analysis of data or interpretation of the results. The authors declare no conflict of interest.

      Acknowledgements

      The authors thank Vetcare Ltd (Mäntsälä, Finland) for donating the drugs used in the study. Veterinary Medicine Research Foundation ( ETTS , Finland) funded the analysis of plasma drug concentrations. The authors thank the personnel from the Veterinary Teaching Hospital, University of Helsinki for their kind and supportive atmosphere. Presented in part as a poster at the AVA Autumn Meeting at Vetsuisse University Bern, Switzerland, September 2022.

      Appendix A

      Scoring of early recovery 30 minutes after sevoflurane anaesthesia. Modified from
      • Jiménez C.P.
      • Mathis A.
      • Mora S.S.
      • et al.
      Evaluation of the quality of the recovery after administration of propofol or alfaxalone for induction of anaesthesia in dogs anaesthetized for magnetic resonance imaging.
      .
      Tabled 1
      ScoreDescription
      1After extubation smooth transition to alertness. No paddling, vocalization, trembling or vomiting. Coordinated movements within 10 minutes.
      2Fairly smooth or slow transition to alertness. No paddling, vocalization, trembling or vomiting. No body movements attempted in 10 minutes, may need atipamezole.
      3Moderately smooth with mild excitement. Mild paddling, vocalization, trembling or vomiting. Some incoordination in body movements.
      4Excitement. Uncoordinated whole body movements. Paddling, vocalization or vomiting observed.
      5Extreme excitement, emergence delirium. Uncoordinated whole body movements that cannot not be easily restrain. Dogs needs re-sedation.

      References

        • Bednarski R.
        • Grimm K.
        • Harvey R.
        • et al.
        AAHA anesthesia guidelines for dogs and cats.
        J Am Anim Hosp Assoc. 2011; 47: 377-385
        • Bennett R.C.
        • Salla K.M.
        • Raekallio M.R.
        • et al.
        Effects of MK-467 on the antinociceptive and sedative actions and pharmacokinetics of medetomidine in dogs.
        J Vet Pharmacol Ther. 2016; 39: 336-343
        • Bennett R.C.
        • Salla K.M.
        • Raekallio M.R.
        • et al.
        Effects of the α2 adrenoceptor agonist medetomidine on the distribution and clearance of alfaxalone during coadministration by constant rate infusion in dogs.
        Am J Vet Res. 2017; 78: 956-964
        • Bloor B.C.
        • Franklund M.
        • Alper G.
        • et al.
        Hemodynamic and sedative effects of dexmedetomidine in dogs.
        J Pharmacol Exp Ther. 1992; 263: 690-697
        • Brahim J.S.
        • Thut P.D.
        Hemodynamic changes during isoflurane anesthesia.
        Anesth Prog. 1984; 31: 207-212
        • Casoni D.
        • Spadavecchia C.
        • Adami C.
        S-ketamine versus racemic ketamine in dogs: their relative potency as induction agents.
        Vet Anaesth Analg. 2015; 42: 250-259
        • Clineschmidt B.
        • Pettibone D.
        • Lotti V.
        • et al.
        A peripherally acting alpha-2 adrenoceptor antagonist: L-659,066.
        J Pharmacol Exp Ther. 1988; 245: 32-40
        • Clough D.P.
        • Hatton R.
        Hypotensive and sedative effects of alpha-adrenoceptor agonists: relationship to alpha1- and alpha2-adrenoceptor potency.
        Br J Pharmacol. 1981; 73: 595-604
        • Dugdale A.
        Veterinary Anaesthesia, Principles to Practice.
        Blackwell Publishing Ltd, UK2010: 4
        • Enouri S.S.
        • Kerr C.L.
        • McDonell W.N.
        • et al.
        Effects of a peripheral alpha2 adrenergic-receptor antagonist on the hemodynamic changes induced by medetomidine administration in conscious dogs.
        Am J Vet Res. 2008; 69: 728-736
        • Grasso S.C.
        • Ko J.C.
        • Weil A.B.
        • et al.
        Hemodynamic influence of acepromazine or dexmedetomidine premedication in isoflurane-anesthetized dogs.
        J Am Vet Med Assoc. 2015; 246: 754-764
        • Hector R.C.
        • Rezende M.L.
        • Mama K.R.
        • et al.
        Combined effects of dexmedetomidine and vatinoxan infusions on minimum alveolar concentration and cardiopulmonary function in sevoflurane-anesthetized dogs.
        Vet Anaesth Analg. 2021; 48: 314-323
        • Honkavaara J.M.
        • Raekallio M.R.
        • Kuusela E.K.
        • et al.
        The effects of L-659,066, a peripheral alpha2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia in dogs.
        Vet Anaesth Analg. 2008; 35: 409-413
        • Honkavaara J.M.
        • Restitutti F.
        • Raekallio M.R.
        • et al.
        The effects of increasing doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs.
        J Vet Pharmacol Ther. 2011; 34: 332-337
        • Honkavaara J.
        • Restitutti F.
        • Raekallio M.
        • et al.
        Influence of MK-467, a peripherally acting α2-adrenoceptor antagonist on the disposition of intravenous dexmedetomidine in dogs.
        Drug Metab Dispos. 2012; 40: 445-449
        • Honkavaara J.M.
        • Raekallio M.R.
        • Syrja P.M.
        • et al.
        Concentrations of medetomidine enantiomers and vatinoxan, an α2-adrenoceptor antagonist, in plasma and central nervous tissue after intravenous coadministration in dogs.
        Vet Anaesth Analg. 2020; 47: 47-52
        • Horn P.T.
        • Kohle J.D.
        • Listinsky J.J.
        • Goldberg L.I.
        Regional variation in the alpha-adrenergic receptors in the canine resistance vessels.
        Naunyn Schmiedebergs Arch Pharmacol. 1982; 318: 166-172
        • Huuskonen V.
        • Hughes L.J.
        • Bañon E.E.
        • West E.
        Intratesticular lidocaine reduces the response to surgical castration in dogs.
        Vet Anaesth Analg. 2013; 40: 74-82
        • Huuskonen V.
        • Restitutti F.
        • Honkavaara J.M.
        • et al.
        Investigation of the effects of vatinoxan on somatic and visceral antinociceptive efficacy of medetomidine in dogs.
        Am J Vet Res. 2020; 81: 299-308
        • Jaeger A.T.
        • Pypendop B.H.
        • Ahokoivu H.
        • Honkavaara J.
        Cardiopulmonary effects of dexmedetomidine, with and without vatinoxan, in isoflurane-anesthetized cats.
        Vet Anaesth Analg. 2019; 46: 753-764
        • Jiménez C.P.
        • Mathis A.
        • Mora S.S.
        • et al.
        Evaluation of the quality of the recovery after administration of propofol or alfaxalone for induction of anaesthesia in dogs anaesthetized for magnetic resonance imaging.
        Vet Anaesth Analg. 2012; 39: 151-159
        • Kallio-Kujala I.J.
        • Turunen H.A.
        • Raekallio M.R.
        • et al.
        Peripherally acting α-adrenoceptor antagonist MK-467 with intramuscular medetomidine and butorphanol in dogs: A prospective, randomized, clinical trial.
        Vet J. 2018; 240: 22-26
        • Kazama T.
        • Ikeda K.
        Comparison of MAC and the rate of rise of alveolar concentration of sevoflurane with halothane and isoflurane in the dog.
        Anesthesiology. 1988; 68: 435-437
        • Martin-Flores M.
        • Sakai D.M.
        • Honkavaara J.
        • et al.
        Hemodynamic effects of MK-467 following intravenous administration to isoflurane-anesthetized cats concurrently receiving dexmedetomidine.
        Am J Vet Res. 2018; 79: 711-717
        • Martinez M.N.
        • Antonovic L.
        • Court M.
        • et al.
        Challenges in exploring the cytochrome P450 system as a source of variation in canine drug pharmacokinetics.
        Drug Metab Rev. 2013; 45: 218-230
        • Murrell J.C.
        • Hellebrekers L.J.
        Medetomidine and dexmedetomidine: a review of cardiovascular effects and antinociceptive properties in the dog.
        Vet Anaesth Analg. 2005; 32: 117-127
        • Mutoh T.
        • Nishimura R.
        • Kim H.-Y.
        • et al.
        Cardiopulmonary effects of sevoflurane, compared with halothane, enflurane, and isoflurane, in dogs.
        Am J Vet Res. 1997; 58: 885-890
        • Pagel P.S.
        • Proctor L.T.
        • Devcic A.
        • et al.
        A novel alpha2-adrenoceptor antagonist attenuates the early, but preserves the late cardiovascular effects of intravenous dexmedetomidine in conscious dogs.
        J Cardiothorac Vasc Anesth. 1998; 12: 429-434
        • Pakkanen S.A.
        • Raekallio M.R.
        • Mykkänen A.K.
        • et al.
        Detomidine and the combination of detomidine and MK-467, a peripheral alpha-2 adrenoceptor antagonist, as premedication in horses anaesthetized with isoflurane.
        Vet Anaesth Analg. 2015; 42: 527-536
        • Pypendop B.H.
        • Verstegen J.P.
        Hemodynamic effects of medetomidine in the dog: a dose titration study.
        Vet Surg. 1998; 27: 612-622
        • Pypendop B.H.
        • Jones J.H.
        Indexing cardiovascular and respiratory variables: allometric scaling principles.
        Vet Anaesth Analg. 2015; 42: 343-349
        • Raszplewicz J.
        • MacFarlane P.
        • West E.
        Comparison of sedation scores and propofol induction doses in dogs after intramuscular premedication with butorphanol and either dexmedetomidine or medetomidine.
        Vet Anaesth Analg. 2013; 40: 584-589
        • Reid J.
        • Nolan A.M.
        • Hughes J.M.L.
        • et al.
        Development of short-form Glasgow Composite Measure Pain Scale (CMPS-SF) and derivation of an analgesic intervention score.
        Anim Welfare. 2007; 16: 97-104
        • Restitutti F.
        • Honkavaara J.M.
        • Raekallio M.R.
        • et al.
        Effects of different doses of L-659,066 on the bispectral index and clinical sedation in dogs treated with dexmedetomidine.
        Vet Anaesth Analg. 2011; 38: 415-422
        • Salla K.
        • Bennett R.C.
        • Restitutti F.
        • et al.
        A comparison in dogs of medetomidine, with or without MK-467, and the combination acepromazine-butorphanol as premedication prior to anaesthesia induced by propofol and maintained with isoflurane.
        Vet Anaesth Analg. 2014; 41: 163-173
        • Salla K.
        • Restitutti F.
        • Vainionpää M.
        • et al.
        The cardiopulmonary effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in dogs sedated with a combination of medetomidine and butorphanol.
        Vet Anaesth Analg. 2014; 41: 567-574
        • Salla K.M.
        • Tuns C.I.
        • Bennett R.C.
        • et al.
        Cardiovascular effects of premedication with medetomidine alone and in combination with MK-467 or glycopyrrolate in dogs subsequently anesthetized with isoflurane.
        Am J Vet Res. 2017; 78: 1245-1254
        • Tapio H.
        • Raekallio M.
        • Mykkänen A.
        • et al.
        Effects of vatinoxan on cardiorespiratory function and gastrointestinal motility during constant-rate medetomidine infusion in standing horses.
        Equine Vet J. 2019; 51: 646-652
        • White C.R.
        • Kearney M.R.
        Metabolic scaling in animals: methods, empirical results, and theoretical explanations.
        Compr Physiol. 2014; 4: 231-256