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Sedative effects and changes in cardiac rhythm with intravenous premedication of medetomidine, butorphanol and ketamine in dogs

  • Benedikt Schöndorfer
    Affiliations
    Clinic of Anaesthesiology and Perioperative Intensive Care, Department of Small Animals and Horses, Veterinary University Vienna, Vienna, Austria
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  • Claus Vogl
    Affiliations
    Institute of Animal Breeding and Genetics, Veterinary University Vienna, Vienna, Austria
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  • Eva Eberspächer-Schweda
    Correspondence
    Corresponding author. Eva Eberspächer-Schweda, University of Veterinary Medicine, Clinic of Anaesthesiology and perioperative Intensive Care, Veterinärplatz 1, 1210 Vienna, Austria.
    Affiliations
    Clinic of Anaesthesiology and Perioperative Intensive Care, Department of Small Animals and Horses, Veterinary University Vienna, Vienna, Austria
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Open AccessPublished:December 28, 2022DOI:https://doi.org/10.1016/j.vaa.2022.12.006

      Abstract

      Objective

      To determine the sedative effects and characteristics of cardiac rhythm with intravenous (IV) premedication of medetomidine, butorphanol and ketamine in dogs.

      Study design

      Prospective, blinded, randomized clinical trial.

      Animals

      A total of 116 client-owned healthy dogs undergoing elective surgery.

      Methods

      Dogs were randomly allocated one of four groups: group M, medetomidine 5 μg kg–1; group B, butorphanol 0.2 mg kg–1; group MB, medetomidine 5 μg kg–1 and butorphanol 0.2 mg kg–1; or group MBK, medetomidine 5 μg kg–1, butorphanol 0.2 mg kg–1 and ketamine 1 mg kg–1 IV. Sedation was assessed using a numerical descriptive scale. Heart rate (HR) and rhythm were monitored; propofol dose (mg kg–1 IV) to allow orotracheal intubation was documented. Data were analysed using anova, accounting for multiple testing with the Tukey honest significant difference test.

      Results

      Sedation scores varied significantly between all groups at all time points, except between groups MB and MBK at four time points. HR decreased in all groups: most in groups M and MB, least in group B. HR was initially higher in group MBK than in groups M and MB. Arrhythmias occurred in all groups: group B showed second-degree atrioventricular blocks occasionally, all other groups showed additionally ventricular escape complexes and bundle branch blocks.
      Dose of propofol required for orotracheal intubation was significantly higher in group B (5.0 ± 2.0 mg kg–1) than in group M (2.6 ± 0.6 mg kg–1). Although no difference could be demonstrated between groups MB (1.4 ± 0.6 mg kg–1) and MBK (0.9 ± 0.8 mg kg–1), both groups required significantly less propofol than group M.

      Conclusion and clinical relevance:

      Medetomidine-based premedication protocols led to various bradyarrhythmias. Addition of subanaesthetic doses of ketamine to medetomidine-based protocols resulted in higher HRs, fewer bradyarrhythmias and fewer animals that required propofol for intubation without causing side effects in healthy dogs.

      Keywords

      Introduction

      Medetomidine is an α2-adrenoceptor agonist commonly used alone or in combination with opioids such as butorphanol to achieve sedation in dogs (
      • Ko J.C.
      • Bailey J.E.
      • Pablo L.S.
      • Heaton-Jones T.G.
      Comparison of sedative and cardiorespiratory effects of medetomidine and medetomidine-butorphanol combination in dogs.
      ;
      • Muir III, W.W.
      • Ford J.L.
      • Karpa G.E.
      • et al.
      Effects of intramuscular administration of low doses of medetomidine and medetomidine-butorphanol in middle-aged and old dogs.
      ;
      • Yamashita K.
      • Koshi M.
      • Izumisawa Y.
      • Kotani T.
      Effect of combination of medetomidine and butorphanol for preanesthetic medication in dogs.
      ;
      • Ko J.C.
      • Fox S.M.
      • Mandsager R.E.
      Sedative and cardiorespiratory effects of medetomidine, medetomidine-butorphanol, and medetomidine-ketamine in dogs.
      ;
      • Girard N.M.
      • Leece E.A.
      • Cardwell J.
      • et al.
      The sedative effects of low-dose medetomidine and butorphanol alone and in combination intravenously in dogs.
      ;
      • Puighibet Z.
      • Costa-Farré C.
      • Santos L.
      • et al.
      The sedative effects of intramuscular low-dose medetomidine in combination with butorphanol or methadone in dogs.
      ). It provides dose-dependent moderate to profound sedation and analgesia (
      • Nilsfors L.
      • Garmer L.
      • Adolfsson A.
      Sedative and analgesic effects of medetomidine in dogs-an open clinical study.
      ) which is associated with severe bradycardia predominantly caused by vasoconstriction. Vasoconstriction results in increased arterial pressure and vomiting during the onset of sedation (
      • Nilsfors L.
      • Garmer L.
      • Adolfsson A.
      Sedative and analgesic effects of medetomidine in dogs-an open clinical study.
      ;
      • Hellebrekers L.J.
      • van Herpen H.
      • Hird J.F.
      • et al.
      Clinical efficacy and safety of propofol or ketamine anaesthesia in dogs premedicated with medetomidine.
      ;
      • Pypendop B.H.
      • Verstegen J.P.
      Hemodynamic effects of medetomidine in the dog: a dose titration study.
      ;
      • Kuo W.C.
      • Keegan R.D.
      Comparative cardiovascular, analgesic, and sedative effects of medetomidine, medetomidine-hydromorphone, and medetomidine-butorphanol in dogs.
      ;
      • Gómez-Villamandos R.J.
      • Palacios C.
      • Benítez A.
      • et al.
      Dexmedetomidine or medetomidine premedication before propofol-desflurane anaesthesia in dogs.
      ). Butorphanol is a synthetic opioid that acts mainly as κ-opioid receptor agonist and a partial antagonist at the μ-opioid receptor (
      • KuKanich B.
      • Papich M.G.
      Opioid analgesic drugs.
      ). The sedative qualities of butorphanol are mild to moderate with little effect on the cardiovascular and respiratory systems (
      • Trim C.M.
      Cardiopulmonary effects of butorphanol tartrate in dogs.
      ;
      • Tyner C.L.
      • Greene S.A.
      • Hartsfield S.M.
      Cardiovascular effects of butorphanol administration in isoflurane-O2 anesthetized healthy dogs.
      ). In addition, butorphanol at a dose of 0.4 mg kg–1 proved effective in preventing cisplatin-induced vomiting (
      • Moore A.S.
      • Rand W.M.
      • Berg J.
      • et al.
      Evaluation of butorphanol and cyproheptadine for prevention of cisplatin-induced vomiting in dogs.
      ). Combined with medetomidine, butorphanol enhances the sedative effect of medetomidine (
      • Ko J.C.
      • Bailey J.E.
      • Pablo L.S.
      • Heaton-Jones T.G.
      Comparison of sedative and cardiorespiratory effects of medetomidine and medetomidine-butorphanol combination in dogs.
      ;
      • Girard N.M.
      • Leece E.A.
      • Cardwell J.
      • et al.
      The sedative effects of low-dose medetomidine and butorphanol alone and in combination intravenously in dogs.
      ;
      • Puighibet Z.
      • Costa-Farré C.
      • Santos L.
      • et al.
      The sedative effects of intramuscular low-dose medetomidine in combination with butorphanol or methadone in dogs.
      ) while preventing vomiting induced by medetomidine (
      • Yamashita K.
      • Koshi M.
      • Izumisawa Y.
      • Kotani T.
      Effect of combination of medetomidine and butorphanol for preanesthetic medication in dogs.
      ). Ketamine is a phencyclidine derivative that acts as an agonist on the N-methyl-D-aspartate receptor. It is an induction agent that stimulates sympathetic activity resulting in an increase in heart rate (HR) (
      • Kennedy M.J.
      • Smith L.J.
      A comparison of cardiopulmonary function, recovery quality, and total dosages required for induction and total intravenous anesthesia with propofol versus a propofol-ketamine combination in healthy Beagle dogs.
      ;
      • White K.L.
      • Yates D.
      Clinical comparison of alfaxalone, ketamine and propofol following medetomidine and methadone in dogs.
      ) and arterial blood pressure (
      • Traber D.L.
      • Wilson R.D.
      • Priano L.L.
      The effect of beta-adrenergic blockade on the cardiopulmonary response to ketamine.
      ). Synergistic effects of medetomidine, opioids and ketamine in various combinations have been described in several studies and the combination seems to be safe for use in healthy small animals (
      • Tomizawa N.
      • Tomita I.
      • Nakamura K.
      • Hara S.
      A comparative study of medetomidine-butorphanol-ketamine and medetomidine-ketamine anaesthesia in dogs.
      ;
      • Sylvestre F.R.
      • Monteiro B.P.
      • Simard M.J.
      • Steagall P.V.
      Anesthetic effects of ketamine-medetomidine-hydromorphone in dogs during high-quality, high-volume surgical sterilization program under field conditions.
      ;
      • Arenillas M.
      • Canfrán S.
      • Aguado D.
      • de Segura I.A.
      Sedative and analgesic effects of two subanaesthetic doses of ketamine in combination with methadone and a low dose of dexmedetomidine in healthy dogs.
      ).
      The objective of this study was to evaluate the overall benefit of adding ketamine to commonly used premedication protocols based on butorphanol and medetomidine. Therefore, the first aim of this study was to compare numerical sedation scores in dogs administered medetomidine alone (group M), butorphanol alone (group B), medetomidine and butorphanol combined (group MB) or a combination of medetomidine, butorphanol and ketamine (group MBK) as intravenous (IV) premedication. The second aim was to determine the effect of each protocol on HR and the incidence of cardiac arrhythmias. The final aim was to compare the amount of propofol required to allow orotracheal intubation between groups. We hypothesized that the addition of ketamine to medetomidine and butorphanol would have the following effects: a shorter onset and deeper sedation level, less pronounced bradycardia, fewer cardiac arrhythmias and a lower dose of propofol required for orotracheal intubation.

      Material and methods

      This prospective, blinded, randomized clinical study was conducted in the Clinic of Anaesthesiology and perioperative Intensive Care of the Vetmeduni Vienna, Austria. The protocol was discussed and approved by the Institutional Ethics and Welfare Committee in accordance with good scientific practice guidelines and national legislation (BMWFW-68.205/0221-WF/V/3b/2016). All owners provided informed written consent prior to their dogs’ participation in the study.

      Animals

      A total of 116 client-owned adult dogs [American Society of Anesthesiologists (ASA) physical status I and II] that were eligible for elective surgery were enrolled in this study (Table 1). In designing this study, a power analysis was performed regarding the expected effects of premedication on the level of sedation. Calculations indicated that a minimum of 25 animals per group would be required. The sample size of 29 dogs per group was selected to allow for possible failures, such as equipment malfunction. Previous studies have used a similar number of animals (
      • 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.
      ). Individuals were included in the study if they were at least 12 months old and weighed between 8 and 45 kg. Doberman Pinscher, Pinscher and Boxer dogs were excluded from the study.
      Table 1Demographic information of the 116 dogs enrolled in the study and the reason for anaesthesia. The dogs were randomly allocated to four study groups: medetomidine 5 μg kg–1 (M), butorphanol 0.2 mg kg–1 (B), medetomidine 5 μg kg–1 in combination with butorphanol 0.2 mg kg–1 (MB) or medetomidine 5 μg kg–1 in combination with butorphanol 0.2 mg kg–1 and ketamine 1 mg kg–1 (MBK) intravenously. Age (months) is presented as range from youngest to oldest and mean in parentheses. Weight (kg) is presented as range from lightest to heaviest and mean in parentheses. Sex is presented in total numbers for male (m), male castrated (mc), female (f) and female spayed (fs) dogs. Type of procedures performed are listed as total numbers for each group and were assigned to five categories (castration, ophthalmologic procedure, dental procedure, biopsy and other).
      GroupDemographic informationProcedure performed
      Age (months)Weight (kg)SexCastrationOphthalmological procedureDental procedureBiopsyOther
      M12–116 (58)8.7–39.0 (22.4)13 m

      2 mc

      10 f

      4 fs
      96644
      B14–100 (41)8.2–40.2 (23.4)10 m

      2 mc

      11 f

      6 fs
      137711
      MB12–132 (49)9.7–40.3 (24.1)7 m

      4 mc

      15 f

      3 fs
      155612
      MBK12–88 (29)9.3–45.0 (26.9)17 m

      1 mc

      9 f

      2 fs
      194600

      Instrumentation and study design

      Dogs were presented at the small animal clinic on the day of the procedure and were kept in a quiet room to avoid any interference from a noisy and busy hospital environment. Food but not water was withheld for 8 to 12 hours before general anaesthesia. Each dog was weighed and clinically examined. A 20 gauge, 3.3 cm catheter (Vasofix; B. Braun Melsungen AG, Germany) was inserted either into the cephalic or the saphenous vein.
      Dogs were randomly allocated to one of four groups by drawing pre-labelled pieces of paper from an envelope: medetomidine 5 μg kg–1 (NarcoStart; Le Vet B.V., The Netherlands) (group M), butorphanol 0.2 mg kg–1 (Alvegesic; Alvetra u. Werfft GmbH, Austria) (group B), medetomidine 5 μg kg–1 in combination with butorphanol 0.2 mg kg–1 (group MB) or medetomidine 5 μg kg–1 in combination with butorphanol 0.2 mg kg–1 and ketamine 1 mg kg–1 (Ketamidor; Richter Pharma AG, Austria) (group MBK). Drugs were drawn up in a syringe and diluted to 0.1 mL kg–1 with 0.9% saline. The randomization as well as the preparation of drugs was performed in such a fashion that the evaluator of the outcome variables was blinded to the allocated group. A Holter-electrocardiogram (ECG; Televet 100; Engel Engineering Service GmbH Heusenstamm, Germany) was placed on the dog at least 15 minutes before recording 10 minutes of baseline ECG (BL ECG). HR and rhythm were recorded, and animals with consistent pre-existing arrhythmias were excluded from the study. Premedication was administered IV over a period of 20 seconds immediately after starting a second ECG recording (treatment ECG) with a minimal recording time of 21 minutes. Adverse events such as signs of nausea, vomiting and apnoea for more than 15 seconds were noted. Sedation scores were evaluated and documented by the main observer before and 5, 10, 15 and 20 minutes after drug administration using a numerical descriptive scale modified from
      • Gurney M.
      • Cripps P.
      • Mosing M.
      Subcutaneous pre-anaesthetic medication with acepromazine-buprenorphine is effective as and less painful than the intramuscular route.
      (Appendix A). Categories included were overall appearance, spontaneous posture, response to noise (handclap), eye position, palpebral reflex and toe-pinch response, resulting in a possible score between 0 (no sedation) and 16 (maximum sedation). Scores up to 5 were categorized as mild sedation, 5 to 10 as moderate sedation and greater than 10 as profound sedation. Oxygen (FiO2 = 1.0, 4 L minute–1) was provided with a mask attached via a circle system to an anaesthesia machine (Leon plus; Heinen + Löwenstein GmbH, Austria) as soon as the animal tolerated it without struggling. After recording the ECG for 20 minutes, general anaesthesia was induced with propofol 1% (Propofol ‘Fresenius’ 1%; Fresenius Kabi GmbH, Austria) according to a predetermined scheme. Dogs were administered 1 mg kg–1 propofol over 20 seconds followed by a 40 second pause after which orotracheal intubation was attempted. If this was unsuccessful owing to a light level of anaesthesia, a further bolus of 1 mg kg–1 was administered followed by a 40 second pause. Beginning with the third bolus, the dose of propofol was reduced to 0.5 mg kg–1. This was continued until successful intubation was achieved. Total administered dose of propofol (mg kg–1) was noted. ECG recordings were analysed after completion of the study. Average HR was calculated for the unpremedicated animal using BL ECG. HR in sedated dogs was calculated for the following periods: 1–6, 6–11, 11–16 and 16–21 minutes after start of the treatment ECG. In case of equipment failure, lost electrodes or unreadable ECG passages, HR was calculated using at least 1 minute of unaffected recording in the observed period. The quantity and quality of arrhythmias occurring during the observation period were documented for each animal. Recorded data were entered into a Microsoft Excel spreadsheet (Microsoft Corporation, WA, USA).

      Statistics

      Linear models were used for analysis with the target variables: numerical descriptive score, the difference in the log of HR before and after sedation, and log of propofol administered (mg kg–1). With sedation score and HR as target variables, groups were compared at different time points (5, 10, 15 and 20 minutes); with propofol as target variable, the total amount was compared among groups. In all cases, Tukey honest significant difference (HSD) tests of pairwise differences were employed to account for multiple testing. With the sedation score and HR as target variables, within each group differences among time points or time periods were analysed with a linear model (analysis of variance) where time and individual were included as factors. Arrhythmias occurred rarely, but then clustered, such that linear model assumptions would have been violated. As data on arrhythmias were not normally distributed, the results with this outcome variable are only presented descriptively. Occurrence and type of arrhythmia were counted for each group in the observed time periods (1–6, 6–11, 11–16 and 16–21 minutes). Statistical analyses were performed using the R-programming language (
      R Core Team
      A language and environment for statistical computing.
      ). For all statistical analyses, a p value below 5% (p < 0.05) was considered statistically significant.

      Results

      A total of 116 dogs were included in this study, four of which were excluded from further analysis. Reasons for exclusion were multiple premature ventricular extrasystoles [ventricular premature complexes (VPCs)] in the BL ECG in one dog in group M, ventricular escape complexes and bundle branch block (BBB) in treatment ECG in one dog in group MB, which was therefore administered atipamezole (Narcostop, Le Vet B.V., The Netherlands), technical problems in one dog in group MBK and a sudden cancellation of the surgical procedure in one dog in group MB. Another two dogs each presented with two VPCs in the 10 minute BL ECG but remained in the study. Therefore, a total number of 112 dogs were studied (group B: n = 29; group M: n = 28; group MB: n = 27; group MBK: n = 28).
      In two dogs from group B, propofol was not administered using the standardized scheme but faster due to signs of excitation. Signs of nausea were observed in one dog (3%) of group B and in two dogs (7%) of group M. While eight dogs (29%) in group M vomited. No other adverse effects such as apnoea for more than 15 seconds were observed.
      All dogs showed increased sedation compared with BL values (median 0.0; p < 0.001). With the numerical sedation score as target variable, the time point (5, 10, 15, 20 minutes) had a significant overall influence (p < 0.001) with sedation increasing with time in all dogs. For all time points, the influence of group (M, B, MB, and MBK) was significant. At all the time points, group B had the lowest sedation score (median 1.0–3.0), group M a moderate sedation score (median 6.0–9.0) and groups MB and MBK had high sedation scores (MB: median 12.0–15.0; MBK: median 13.0–15.0) (Fig. 1). For all time points, comparisons among groups (adjusted for multiple testing by Tukey’s HSD) showed significant differences (p < 0.001) for all pairs except between groups MB and MBK, which was not significant at any time point (Fig. 1). The highest sedation score (16) was observed exclusively in two dogs of group MBK.
      Figure 1
      Figure 1Sedation score of dogs 5 (a), 10 (b), 15 (c) and 20 minutes (d) after premedication with intravenous medetomidine 5 μg kg–1 [(M), n = 28], butorphanol 0.2 mg kg–1 [(B), n = 29], medetomidine 5 μg kg–1 in combination with butorphanol 0.2 mg kg–1 [(MB), n = 27] or medetomidine 5 μg kg–1 in combination with butorphanol 0.2 mg kg–1 and ketamine 1 mg kg–1 [(MBK), n = 28]. ∗Significant difference in sedation score between groups (p < 0.001). Data are presented as median (horizontal line), interquartile range (box ends), 1.5 times the interquartile range (whiskers), with values exceeding the whiskers plotted as open circles.
      An overall decrease in HR compared with BL ECG was observed in all groups (p < 0.001). Group B showed overall a mild reduction of HR with some variation: in five dogs, HR even increased more than 20% in at least one of the observed time periods. All protocols that included the use of medetomidine showed a further decrease in HR. Dogs in group B showed consistently higher HR than in all other groups. Groups M and MB showed the most distinct bradycardia (group M: 46%–52% and group MB: 46%–52% from BL values) (Fig. 2). At all time periods, the influence of group (M, B, MB, and MBK) was significant, and groups M and MB had the lowest HR (compared with BL). However, pairwise comparisons between groups M and MB did not show significant differences in HR at any time period (adjusted for multiple testing by Tukey’s HSD). HR was higher in group MBK than in groups M and MB only at time periods 5 and 10 minutes (p < 0.05). Differences between group MBK and groups M and MB became smaller and not statistically significant at time periods 15 and 20 minutes (Fig. 2). In group MBK, three dogs showed a higher HR than BL values: in one dog this increase was observed during the first 5 minutes (118% of BL), in another dog during the first 5 and 10 minutes (140% and 125% of BL, respectively) and in another dog for 15 minutes (128%, 143% and 105% of BL).
      Figure 2
      Figure 2Ratio of heart rate (HR) compared with baseline values of dogs in time periods 1–6 (a), 6–11 (b), 11–16 (c) and 16–21 minutes (d) after premedication with intravenous medetomidine 5 μg kg–1 [(M), n = 28], butorphanol 0.2 mg kg–1 [(B), n = 29], medetomidine 5 μg kg–1 in combination with butorphanol 0.2 mg kg–1 [(MB), n = 27] or medetomidine 5 μg kg–1 in combination with butorphanol 0.2 mg kg–1 and ketamine 1 mg kg–1 [(MBK), n = 28]. ∗Significant difference in HR (p < 0.001). †Significant difference in HR (p < 0.05). Data are presented as median (horizontal line), interquartile range (box ends), 1.5 times the interquartile range (whiskers), with values exceeding the whiskers plotted as open circles.
      Arrhythmias were detected in all groups after premedication. Second-degree atrioventricular (AV) blocks were detected in 19 (68%), three (10%), 14 (48%) and 12 (43%) dogs in groups M, B, MB and MBK, respectively. Ventricular escape complexes were detected in three (11%), zero (0%) and six (21%) dogs in groups M, B and MBK, respectively. BBBs were detected in two (7%), zero (0%), three (10%) and one (4%) dog in groups M, B, MB and MBK, respectively. In order to compare the total occurrence of arrhythmias between the groups, all arrhythmic beats were summed per group over the observation period of 20 minutes. The lowest number of arrhythmias was observed in group B, which consisted exclusively of second-degree AV blocks, n = 64). Dogs in group M showed a total of 947 second-degree AV blocks (n = 947), 11 ventricular escape complexes (n = 11) and eight BBB. A single dog in group M presented eight ventricular escape complexes, at least one occurring every 5 minutes and six BBB in the first 5 minutes; during BL ECG two VPCs were observed. A total of 548 second-degree AV blocks, 286 ventricular escape complexes and 117 BBB were observed in group MB. Two dogs accounted for the majority of ventricular escape complexes and BBB in group MB. Most arrhythmias occurred in the first 10 minutes after premedication (268 ventricular escape complexes and 114 BBB), in the last 10 minutes 18 ventricular escape complexes and three BBB were observed. Of all the protocols containing medetomidine, group MBK showed the fewest arrhythmias: 173 second-degree AV blocks, seven ventricular escape complexes and one BBB (Table 2).
      Table 2Type of arrhythmia, time (minutes) after intravenous administration of premedication drug(s) (group M: medetomidine 5 μg kg–1; group B: butorphanol 0.2 mg kg–1; group MB: medetomidine 5 μg kg–1 and butorphanol 0.2 mg kg–1; and group MBK: medetomidine 5 μg kg–1, butorphanol 0.2 mg kg–1 and ketamine 1.0 mg kg–1) and total occurrence (n) of arrhythmias recorded in the 113 dogs, which were randomly allocated to one of the four groups.
      Type of arrhythmiaTime (minutes) after administration of premedicationGroup M (n)Group B (n)Group MB (n)Group MBK (n)
      Second-degree atrioventricular block1–6

      6–11

      11–16

      16–21
      238

      280

      215

      214
      4

      7

      20

      33
      231

      93

      125

      99
      36

      23

      59

      55
      Ventricular escape complexes1–6

      6–11

      11–16

      16–21
      5

      2

      3

      1
      0

      0

      0

      0
      133

      135

      17

      1
      1

      6

      0

      0
      Bundle branch block1–6

      6-11

      11–16

      16–21
      6

      0

      2

      0
      0

      0

      0

      0
      45

      69

      3

      0
      1

      0

      0

      0
      The administered dose of propofol per kg required to allow orotracheal intubation varied significantly (p = 0.001) among groups (Fig. 3). Group B required significantly more propofol than all other groups (5.0 ± 2.0 mg kg–1), followed by group M (2.6 ± 0.6 mg kg–1). A single dog in group MB and 10 dogs in group MBK did not require any propofol to allow orotracheal intubation 21 minutes after premedication. The remaining dogs in groups MB and MBK required the smallest amount of propofol (1.4 ± 0.6 and 0.9 ± 0.8 mg kg–1, respectively), but no significant difference was observed between groups.
      Figure 3
      Figure 3Propofol dose (mg kg–1) required to achieve endotracheal intubation of dogs, approximately 22 minutes after premedication with intravenous medetomidine 5 μg kg–1 [(M), n = 28], butorphanol 0.2 mg kg–1 [(B), n = 29], medetomidine 5 μg kg–1 in combination with butorphanol 0.2 mg kg–1 [(MB), = 27] or medetomidine 5 μg kg–1 in combination with butorphanol 0.2 mg kg–1 and ketamine 1 mg kg–1 [(MBK), n = 28]. ∗Significant difference in propofol dose (p < 0.001). †Significant difference in heart rate (p < 0.01). Data are presented as median (horizontal line), interquartile range (box ends), 1.5 times the interquartile range (whiskers), with values exceeding the whiskers plotted as open circles.

      Discussion

      The results of this study indicate that the administration of different premedication protocols produced different levels of sedation; dogs in group B showed mild sedation, dogs in group M moderate sedation, and dogs in groups MB and MBK showed profound sedation. A decrease in HR was observed in all groups. While it was mild in group B, it resulted in severe bradycardia and bradyarrhythmias in all groups that were administered medetomidine. However, bradyarrhythmias were less frequently observed when ketamine was added (group MBK). It seemed that the required amount of propofol to achieve orotracheal intubation decreased with increasing sedation scores.
      The doses of medetomidine (5 μg kg–1), butorphanol (0.2 mg kg–1) and ketamine (1 mg kg–1) were chosen to provide a measurable level of sedation when used individually while still being within the published dose ranges for use within a combination (
      • Muir III, W.W.
      • Ford J.L.
      • Karpa G.E.
      • et al.
      Effects of intramuscular administration of low doses of medetomidine and medetomidine-butorphanol in middle-aged and old dogs.
      ;
      • Yamashita K.
      • Koshi M.
      • Izumisawa Y.
      • Kotani T.
      Effect of combination of medetomidine and butorphanol for preanesthetic medication in dogs.
      ;
      • Ko J.C.
      • Barletta M.
      • Sen I.
      • et al.
      Influence of ketamine on the cardiopulmonary effects of intramuscular administration of dexmedetomidine-buprenorphine with subsequent reversal with atipamezole in dogs.
      ;
      • Kellihan H.
      • Stepien R.
      • Hassen K.
      • Smith L.J.
      Sedative and echocardiographic effects of dexmedetomidine combined with butorphanol in healthy dogs.
      ). Premedication with only ketamine (1 mg kg–1) was discarded because of the possible adverse effects. Not all effects occurred as anticipated.
      As expected, administration of butorphanol achieved the lowest sedation score in this study, followed by moderate sedation with medetomidine (
      • Girard N.M.
      • Leece E.A.
      • Cardwell J.
      • et al.
      The sedative effects of low-dose medetomidine and butorphanol alone and in combination intravenously in dogs.
      ). The difference in onset and depth of sedation between groups MB and MBK did not reach statistical significance, as onset was similar and dogs in both groups scored mostly in the upper range of the scale and were profoundly sedated. As previously described, the addition of butorphanol to medetomidine prevented signs of nausea and vomiting (
      • Yamashita K.
      • Koshi M.
      • Izumisawa Y.
      • Kotani T.
      Effect of combination of medetomidine and butorphanol for preanesthetic medication in dogs.
      ). Numerical descriptive scores have often been used to evaluate the level of sedation in dogs (
      • Grint N.J.
      • Burford J.
      • Dugdale A.H.
      Does pethidine affect the cardiovascular and sedative effects of dexmedetomidine in dogs?.
      ;
      • Gurney M.
      • Cripps P.
      • Mosing M.
      Subcutaneous pre-anaesthetic medication with acepromazine-buprenorphine is effective as and less painful than the intramuscular route.
      ;
      • Girard N.M.
      • Leece E.A.
      • Cardwell J.
      • et al.
      The sedative effects of low-dose medetomidine and butorphanol alone and in combination intravenously in dogs.
      ;
      • 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.
      ;
      • Arenillas M.
      • Aguado D.
      • Canfrán S.
      • et al.
      Sedative effects of two doses of alfaxalone in combination with methadone and a low dose of dexmedetomidine in healthy Beagles.
      ). These scales allow high consistency and very good reliability when assessing sedation levels, even between multiple raters (
      • Wagner M.C.
      • Hecker K.G.
      • Pang D.S.J.
      Sedation levels in dogs: a validation study.
      ). However, in this study, evaluation was limited due to instrumentation; for example, part of the original sedation scale includes ‘resistance against lateral recumbency’, which could not be performed because it would have disturbed the ECG reading. To compensate for this, we decided to add the variable ‘toe-pinch response’ and used more detailed criteria for ‘spontaneous posture’. Both criteria were used in a study published by
      • Girard N.M.
      • Leece E.A.
      • Cardwell J.
      • et al.
      The sedative effects of low-dose medetomidine and butorphanol alone and in combination intravenously in dogs.
      . The inclusion of further variables in the scoring system, such as ‘jaw and tongue relaxation’ might have revealed finer differences in sedation outcomes between groups MB and MBK.
      Changes in HR (
      • Pypendop B.H.
      • Verstegen J.P.
      Hemodynamic effects of medetomidine in the dog: a dose titration study.
      ;
      • Gómez-Villamandos R.J.
      • Palacios C.
      • Benítez A.
      • et al.
      Dexmedetomidine or medetomidine premedication before propofol-desflurane anaesthesia in dogs.
      ;
      • White K.L.
      • Yates D.
      Clinical comparison of alfaxalone, ketamine and propofol following medetomidine and methadone in dogs.
      ;
      • Kato K.
      • Itami T.
      • Nomoto K.
      • et al.
      The anesthetic effects of intramuscular alfaxalone in dogs premedicated with low-dose medetomidine and/or butorphanol.
      ) and the occurrence of arrhythmias (
      • Kramer S.
      • Nolte I.
      • Jöchle W.
      Clinical comparison of medetomidine with xylazine/l-methadone in dogs.
      ) with the studied drugs have been described in previous studies. However, we are unaware of a direct comparison between a single premedication drug versus a drug mixture without the addition of other drugs (i.e., parasympatholytic drugs). A decrease in HR was observed in all groups; group B showed overall a mild reduction of HR, although some dogs had even higher HRs than those at BL. Although all precautions were taken to create a quiet and undisturbed study environment, some of these increases in HR may be attributed to environmental disturbances, such as noise from outside (barking dogs, lawnmowers) and from within the animal hospital (doors slamming, shouting, people accidentally entering the study room). In other dogs, the stress of an unfamiliar environment may have been too great to be eased with butorphanol alone. One of these dogs even started growling and showed excitation during induction. In the first 10 minutes, HRs of dogs in group MBK decreased significantly from BL values compared with groups M and MB (p < 0.05). This ‘stabilization’ of HR has been described in other studies (
      • Moens Y.
      • Fargetton X.
      A comparative study of medetomidine/ketamine and xylazine/ketamine anaesthesia in dogs.
      ;
      • Arenillas M.
      • Canfrán S.
      • Aguado D.
      • de Segura I.A.
      Sedative and analgesic effects of two subanaesthetic doses of ketamine in combination with methadone and a low dose of dexmedetomidine in healthy dogs.
      ) and probably caused by the indirect sympathomimetic effects of ketamine (
      • Traber D.L.
      • Wilson R.D.
      • Priano L.L.
      The effect of beta-adrenergic blockade on the cardiopulmonary response to ketamine.
      ;
      • White P.F.
      • Way W.L.
      • Trevor A.J.
      Ketamine its pharmacology and therapeutic uses.
      ). Owing to its limited duration of action (
      • Vlerick L.
      • Devreese M.
      • Peremans K.
      • et al.
      Pharmacokinetics, absolute bioavailability and tolerability of ketamine after intranasal administration to dexmedetomidine sedated dogs.
      ), these effects subsided over time (
      • White K.L.
      • Yates D.
      Clinical comparison of alfaxalone, ketamine and propofol following medetomidine and methadone in dogs.
      ;
      • Vlerick L.
      • Devreese M.
      • Peremans K.
      • et al.
      Pharmacokinetics, absolute bioavailability and tolerability of ketamine after intranasal administration to dexmedetomidine sedated dogs.
      ).
      As expected, arrhythmias in group B were sporadic and associated with mild bradycardia. All dogs administered medetomidine showed more arrhythmias, most of them in group MB. Two dogs with no arrhythmias in their BL ECG were responsible for most of the observed ventricular escape complexes and BBB in group MB, with most arrhythmias occurring in the first 10 minutes (275 ventricular escape complexes and 114 BBB). Atipamezole was administered to one of these two dogs at 12 minutes and 50 seconds after premedication due to safety concerns, and arrhythmias ceased immediately after that. The second dog’s cardiac rhythm spontaneously returned to normal sinus rhythm 9 minutes after premedication. Owing to the clustered occurrence of cardiac arrhythmias in group MB, no statistical analyses could be performed. It could be a coincidence that the dogs in group MBK had the lowest number of arrhythmias among the medetomidine-based premedications. However, this effect may have been caused by an increase in sympathetic tone produced by ketamine (
      • Traber D.L.
      • Wilson R.D.
      • Priano L.L.
      The effect of beta-adrenergic blockade on the cardiopulmonary response to ketamine.
      ;
      • White P.F.
      • Way W.L.
      • Trevor A.J.
      Ketamine its pharmacology and therapeutic uses.
      ), resulting in a higher HR in group MBK for the first 10 minutes. This increased sympathetic tone may be a critical advantage during sedation with minimal monitoring, such as radiographs. Even in the clinical setting, the first few minutes after premedication are rarely monitored as well as after induction of general anaesthesia. Furthermore, orotracheal intubation represents a potential vagal stimulus that could affect HR and rhythm.
      As observed in other studies (
      • Väisänen M.
      • Raekallio M.
      • Kuusela E.
      • et al.
      Evaluation of the perioperative stress response in dogs administered medetomidine or acepromazine as part of the preanesthetic medication.
      ;
      • Canfrán S.
      • Bustamante R.
      • González P.
      • et al.
      Comparison of sedation scores and propofol induction doses in dogs after intramuscular administration of dexmedetomidine alone or in combination with methadone, midazolam, or methadone plus midazolam.
      ), the amount of propofol needed to achieve orotracheal intubation was inversely correlated with the level of sedation provided by the four premedication protocols. Dogs of group B with mild sedation needed the largest amount of propofol, moderately sedated dogs of group M required less propofol and profoundly sedated dogs of group MB and MBK needed the smallest amount of propofol. Although no statistical difference in the requirement of propofol could be demonstrated between groups MB and MBK, it is noteworthy that 10 dogs in group MBK did not require any propofol at all compared with only one dog in group MB. Using a different induction scheme or a constant rate infusion of propofol may have shown significant differences in propofol dose. An attempt to achieve orotracheal intubation 10 minutes after premedication may have resulted in even fewer dogs in group MBK requiring propofol to allow orotracheal intubation. Due to the limited duration of action of ketamine, the dogs may have redistributed or metabolized most of the ketamine at the time of anaesthetic induction in our study (
      • Schmitz A.
      • Thormann W.
      • Moessner L.
      • et al.
      Enantioselective CE analysis of hepatic ketamine metabolism in different species in vitro.
      ;
      • Vlerick L.
      • Devreese M.
      • Peremans K.
      • et al.
      Pharmacokinetics, absolute bioavailability and tolerability of ketamine after intranasal administration to dexmedetomidine sedated dogs.
      ). Other studies have shown reduced requirements of induction agents after the administration of subanaesthetic doses of ketamine (
      • Bustamante R.
      • Gómez de Segura I.A.
      • Canfrán S.
      • Aguado D.
      Effects of ketamine or midazolam continuous rate infusions on alfaxalone total intravenous anaesthesia requirements and recovery quality in healthy dogs: a randomized clinical trial.
      ) or the use of two induction agents (
      • Kennedy M.J.
      • Smith L.J.
      A comparison of cardiopulmonary function, recovery quality, and total dosages required for induction and total intravenous anesthesia with propofol versus a propofol-ketamine combination in healthy Beagle dogs.
      ).
      Healthy dogs (ASA I-II), at least 12 months old with a bodyweight between 8 and 45 kg, were selected owing to safety concerns for the dogs—the administration of an α2-adrenoceptor agonist—and for practical reasons (permanent ECG monitoring had to be placed on the dog). The maximum weight of 45 kg was chosen to limit the impact of allometry but also to demonstrate the utility of these drugs in clinical practice. Purebred Doberman Pinschers, Pinschers and Boxers were excluded as a precaution since heart disease is particularly common in these dogs (
      • Wess G.
      • Schulze A.
      • Butz V.
      • et al.
      Prevalence of dilated cardiomyopathy in Doberman Pinschers in various age groups.
      ). Although all dogs appeared healthy on clinical examination, three dogs in this study had cardiac arrhythmias before premedication administration. A Labrador Retriever aged 2 years did not undergo general anaesthesia owing to frequent VPCs and died 3 weeks later without apparent cause. Therefore, and in accordance with
      • Wess G.
      • Schulze A.
      • Geraghty N.
      • Hartmann K.
      Ability of a 5-minute electrocardiography (ECG) for predicting arrhythmias in Doberman Pinschers with cardiomyopathy in comparison with a 24-hour ambulatory ECG.
      , a 5 minute ECG before anaesthetic premedication may be useful to detect potentially undiagnosed arrhythmias, and increase the safety of the procedure.

      Conclusion

      All premedication protocols evaluated in the present study in healthy dogs resulted in sedation. Sedation levels increased over the study period, giving the drugs time to reach targeted effects. Medetomidine-based combinations caused more bradyarrhythmias than butorphanol alone. Second-degree AV blocks occurred most frequently, but ventricular escape complexes and BBB were also observed in the first 10 minutes after premedication. Hence, dogs premedicated with IV medetomidine should be monitored closely. Adding ketamine to medetomidine premedications increased the HR and reduced the incidence of arrhythmias; therefore, ketamine–medetomidine combination is advisable, especially in clinical situations with limited monitoring.

      Authors’ contributions

      BS: study design, acquiring patients, data collection, analysis and interpretation, manuscript preparation. CV: study design, data analysis and interpretation, manuscript preparation. EES: study design, data collection, analysis and interpretation, preparation and critical revision of manuscript.

      Conflict of interest statement

      The authors declare no conflict of interest.

      Acknowledgements

      None.

      Appendix A. Numerical descriptive scale for assessing degree of sedation in dogs

      Tabled 1
      Overall appearance0 awake and normal
      1 tranquil
      2 stuporous
      Spontaneous posture0 standing no effect
      1 standing but tired
      2 lying but able to rise
      3 sternally recumbent
      4 laterally recumbent
      Response to noise (handclap)0 body movement
      1 head movement
      2 ear twitch
      3 no reaction
      Eye position0 normal
      2 rotated ventrally
      Palpebral reflex0 brisk
      1 slow
      2 absent
      Toe-pinch response0 normal
      1 slight damping
      2 moderate damping
      3 no response
      Reproduced and modified from
      • Gurney M.
      • Cripps P.
      • Mosing M.
      Subcutaneous pre-anaesthetic medication with acepromazine-buprenorphine is effective as and less painful than the intramuscular route.
      © Copyright 2009, John Wiley and Sons.

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