The cardiopulmonary effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in dogs sedated with a combination of medetomidine and butorphanol

Veterinary Anaesthesia and Analgesia, 2014, 41, 567–574

doi:10.1111/vaa.12158

RESEARCH PAPER

The cardiopulmonary effects of a peripheral alpha-2adrenoceptor antagonist, MK-467, in dogs sedated with a combination of medetomidine and butorphanol €*, Jouni Junnila†, Juhana Honkavaara*, Erja Kuusela*, Kati Salla*, Flavia Restitutti*, Mari Vainionp€ aa Marja Raekallio* & Outi Vainio* *Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland †4Pharma Ltd, Espoo, Finland

Correspondence: Kati Salla, Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, P.O. Box 57, FI-00014 Helsinki, Finland. E-mail: [email protected]

Abstract Objective To compare the cardiopulmonary effects of intravenous (IV) and intramuscular (IM) medetomidine and butorphanol with or without MK-467. Study design Prospective, randomized experimental cross-over. Animals Eight purpose–bred beagles (two females, six males), 3–4 years old and weighing 14.5  1.6 kg (mean  SD). Methods All dogs received four different treatments as follows: medetomidine 20 lg kg 1 and butorphanol tartrate 0.1 mg kg 1 IV and IM (MB), and MB combined with MK-467,500 lg kg 1 (MBMK) IV and IM. Heart rate (HR), arterial blood pressures (SAP, MAP, DAP), central venous pressure (CVP), cardiac output, respiratory rate (fR), rectal temperature (RT) were measured and arterial blood samples were obtained for gas analysis at baseline and at 3, 10, 20, 30, 45 and 60 minutes after drug administration. The cardiac index (CI), systemic vascular resistance index (SVRI) and oxygen delivery index (DO2I) were calculated. After the follow-up period atipamezole 50 lg kg 1 IM was given to reverse sedation. Results HR, CI and DO2I were significantly higher with MBMK after both IV and IM administration.

Similarly, SAP, MAP, DAP, CVP, SVRI and RT were significantly lower after MBMK than with MB. There were no differences in fR between treatments, but arterial partial pressure of oxygen decreased transiently after all treatments. Recoveries were uneventful following atipamezole administration after all treatments. Conclusions and clinical relevance MK-467 attenuated the cardiovascular effects of a medetomidine-butorphanol combination after IV and IM administration. Keywords butorphanol, medetomidine, MK-467.

dog,

haemodynamics,

Introduction Intravenous administration of sedative drugs to a fractious or uncooperative animal can be a challenge. Consequently, it is often more convenient to induce sedation and restraint via the intramuscular (IM) route. Medetomidine, a potent a2-adrenoceptor agonist, is used commonly as a sedative or premedicant in small animal medicine, and it can be administered both intravenously (IV) and IM. The disadvantages in using medetomidine include the marked cardiovascular changes, such as hypertension, bradycardia with associated brady-arrhythmias, increased systemic vascular resistance, and reduced cardiac 567

Medetomidine, MK-467 and butorphanol in dogs K Salla et al.

output and oxygen delivery (Pypendop & Verstegen 1998; Murrell & Hellebrekers 2005). MK-467, also know as L-659,066, is a a2-adrenoceptor antagonist, which in rats or marmosets has been shown not to cross a blood brain barrier (Clineschmidt et al. 1988). Intravenous administration of MK-467 has been documented to prevent the peripheral cardiovascular effects of a2-agonists in many animal species (Pagel et al. 1998; Enouri et al. 2008; Honkavaara et al. 2008, 2011; Raekallio et al. € et al. 2013; 2010; Rolfe et al. 2012; Vainionp€ aa Salla et al. 2014). Butorphanol, a synthetic opioid with j-agonist activity with partial l-agonist and d-antagonist properties (Lamount & Mathews 2007), is combined frequently with medetomidine to enhance the level and quality of sedation and analgesia in dogs (Pypendop & Verstegen 1998; Ko et al. 2000; Kuo & Keegan 2004). Bartram et al. (1994) suggested that butorphanol might accentuate the cardiovascular effects of medetomidine. When administered alone, butorphanol has been shown to cause a small but significant decrease in the heart rate, mean arterial pressure, cardiac index and arterial partial pressure of oxygen (Sederberg et al. 1981; Trim 1983). Moreover, a minor increase in the systemic vascular resistance index after administration has also been detected (Sederberg et al. 1981). Butorphanol induces mild hypoventilation in dogs, although the effects are considered to be less than after pure l-agonist administration (Dodam et al. 2004). The primary aim of our study was to examine the cardiopulmonary effects of MK-467 in dogs sedated with medetomidine and butorphanol via two administration routes: IV and IM. Our secondary aim was to compare the effects between the routes of administration.

Material and methods This study was approved by the National Animal Experiment Board of Finland. Eight healthy purposebred beagles, age 3–4 years and weighing 14.5  1.6 kg (mean  SD) were used in the study. Prior to the experiments, food was withheld for 12 hours but water was provided ad libitum. The dogs were considered healthy based on thorough clinical examination, a complete blood count and routine serum chemistry.

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Instrumentation and measurement The cephalic vein was cannulated with a 20 gauge catheter (Terumo Europe N.V., Belgium). Each dog was preoxygenated using a mask (100% oxygen at 5 L minute 1) before induction of anaesthesia with propofol (Propovet 10 mg mL 1; Abbott Laboratories Ltd, UK) maximum 6 mg kg 1. Anaesthesia was maintained with isoflurane in oxygen (Isoflo; Orion Pharma Ltd, Finland). Acetated Ringer’s solution was infused at approximately 10 mL kg 1 hour 1. A 7 Fr double-lumen central venous catheter (CV-12702; Arrow International, PA, USA) was premeasured from the cranial border of the second rib at the costo-chondrial junction, and it was aseptically inserted under local anaesthesia (0.5 mL Lidocain 20 mg mL 1; Orion Pharma Ltd) through the jugular vein and secured in place. The dorsal pedal artery was aseptically cannulated with a 22 gauge catheter (Terumo; Europe N.V.). After instrumentation, dogs were allowed to recover for a minimum of 60 minutes prior to baseline measurements. A continuous lead II electrocardiogram and direct arterial and central venous pressures were monitored throughout the study (S/5 Compact Critical Care Monitor; Datex-Ohmeda, UK). The blood pressure transducers (Gabarith PMSET; Becton Dickinson, UT, USA) were zeroed to the atmosphere and calibrated with a transducer simulator tester (Delta-Cal Utah Medical Products Inc., UT, USA) prior to each experiment. Transducers were placed at the level of the manubrium sternum as the animals were positioned in lateral recumbence on a standard isolating mattress. Cardiac output was measured by the lithium indicator dilution method (LidCO Plus Hemodynamic Monitor; LidCO Ltd, UK) as previously described by Mason et al. (2001) using a standard dose 0.075 mmol of lithium chloride injected via central venous catheter. Standard values of 10 g L 1 haemoglobin and 140 mmol L 1 sodium were used initially and later corrected with measured values obtained from simultaneously taken arterial blood gas samples. Arterial samples for blood gas analysis were obtained anaerobically into pre-heparinised syringes (Pico50; Radiometer, Denmark) and analyzed (ABL 855; Radiometer). The following parameters were obtained: oxygen and carbon dioxide partial pressures (PaO2 and PaCO2, respectively) pH and bicarbonate (HCO3 ), lactate, haemoglobin and sodium concentrations. The samples were stored in iced water and analyzed within 15 minutes.

© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 567–574

Medetomidine, MK-467 and butorphanol in dogs K Salla et al. Measurements were corrected according to the rectal temperature (RT). The oxygen saturation of haemoglobin was calculated as described by Reeves et al. (1982). The cardiac index (CI), arterial oxygen content, oxygen delivery index (DO2I), systemic vascular resistance index (SVRI) and alveolar-toarterial oxygen gradient (P(A-a)O2) were later calculated by using standard equations (Haskins et al. 2005a). The respiratory rate (fR) was measured by counting chest movements during one minute. Study design Each dog received four different treatments in a randomized crossover design with a minimum washout period of 14 days between treatments. The drugs used were medetomidine (Dorbene 1 mg mL 1; laboratories Syva s.a., Spain), butorphanol (Butordol 10 mg mL 1; Intervet International B.V., the Netherlands) and MK-467 (Merck, Sharpe & Dohme, PA, USA). The treatments were as follows: • Medetomidine 20 lg kg 1 and butorphanol tartrate 0.1 mg kg 1 IV (MB IV). • Medetomidine 20 lg kg 1, butorphanol tartrate 0.1 mg kg 1 and MK-467,500 lg kg 1 IV (MBMK IV). • Medetomidine 20 lg kg 1 and butorphanol tartrate 0.1 mg kg 1 IM (MB IM). • Medetomidine 20 lg kg 1, butorphanol tartrate 0.1 mg kg 1 and MK-467,500 lg kg 1 IM (MBMK IM). MK-467 powder was dissolved in physiologic saline (Natriumklorid B.Braun 9 mg mL 1; B.Braun Melsungen AG, Germany) to a final concentration of 10 mg mL 1. All drugs were mixed in the same syringe immediately prior to administration. When necessary, saline was added to achieve an equal total volume in all treatments. After recording all baseline measurements and collecting blood samples, the treatment was administered. Intravenous treatments together with a 10 mL of saline flush were administered through the cephalic catheter over a period of 30 seconds. Intramuscular treatments were administered with a 25 gauge hypodermic needle (BD Microlance 3; Becton Dickinson) into the M. quadriceps lateralis over approximately 5–10 seconds. Correct IM administration was confirmed by aspiration prior to the injection. Recordings and blood sampling were repeated 3, 10, 20, 30, 45 and 60 minutes after drug administration. The dogs breathed room air during the observational period.

Catheters were then removed and sedation was reversed with atipamezole 50 lg kg 1 (Antisedan 5 mg mL 1; Orion Pharma Ltd) IM. Meloxicam 0.2 mg kg 1 (Metacam 5 mg mL 1; Boehringer Ingelheim Vetmedica, Ingelheim/Rhein, Germany) was given subcutaneously to relieve possible pain at the sites of catheter insertion. Statistical analysis All haemodynamic variables were analyzed separately. The change from baseline was used as the response with all of the measured variables. The differences between treatments and routes of administration in the change from baseline values were assessed with repeated measures analysis of covariance (RM ANCOVA) models. The model consisted of a baseline covariate, the main effects of treatment, period and time point of measurement and two-way interactions of period 9 time point and treatment 9 time point as fixed effects, and the main effect of dog and two-way interaction terms of period 9 dog and time point 9 dog as random effects. Haemodynamic variables were compared both over -time and at selected time points (T3, T10, T20, T30 and T60) between treatments within the administration route. Only over -time comparisons were performed between administration routes within a treatment. A p-value of <0.05 was considered as statistically significant. SAS for Windows, version 9.2 (SAS Institute Inc., NC, USA) was used for all statistical analyses. Results The main haemodynamic results are presented in Figs 1–5. HR, CI and DO2I were significantly higher during the whole observation period with MBMK IV and MBMK IM than with MB IV (p < 0.001) and MB IM (p < 0.001), respectively. Moreover, MAP and SVRI were significantly lower over-time with MBMK IV and MBMK IM than with MB IV (p < 0.001) and MB IM (p < 0.001), respectively. Also, SAP, DAP and CVP (Table 1) were significantly lower overtime with MBMK IV and MBMK IM than MB IV (p < 0.001 for all) and MB IM (p = 0.003 for SAP and p < 0.001 for DAP and CVP), respectively. RT (Table 1) was significantly lower over-time with MBMK IV and MBMK IM than with MB IV (p < 0.001) and MB IM (p < 0.001), respectively. Respiratory rates and the results from blood gas analyses are presented in Table 2. Both fR and PaO2

© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 567–574

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Medetomidine, MK-467 and butorphanol in dogs K Salla et al.

Heart rate (beats minute–1)

140 120

* *

100

*

*

20

30

*

80 60 40 20 0

0

10

40

50

60

Time (minutes)

Figure 1 Mean  SD heart rate over time in eight dogs before (baseline) and from 3 (T3) to 60 (T60) minutes after sedation with medetomidine 20 lg kg 1, butorphanol 0.1 mg kg 1 without (MB IV and MB IM) or with MK467,500 lg kg 1 (MKMB IV and MBMK IM) intravenously and intramuscularly, respectively. Statistical analyses were performed for data at baseline, T3, T10, T20, T30 and T60 minutes. *Significant difference between intravenous MBMK and MB (p < 0.05) and #between intramuscular MBMK and MB (p < 0.05).

Figure 4 Mean  SD tissue oxygen delivery index over time. For detailed legend see Fig. 1.

Figure 5 Mean  SD systemic vascular resistance index ( SD) over time. For detailed legend see Fig. 1.

Figure 2 Mean  SD cardiac indexes over time. For detailed legend see Fig. 1.

Figure 3 Mean  SD mean arterial pressures over time. For detailed legend see Fig. 1. 570

decreased after each treatment, but no differences over -time were detected between treatments. PaCO2 and P(A-a)O2 increased after each treatment, but PaCO2 increased over-time more with MBMK IV and MBMK IM than MB IV (p < 0.001) and MB IM (p = 0.012), respectively. The overall increase in P(A-a)O2 was less with MBMK IM than MB IM (p = 0.027). Blood lactate was significantly lower with MBMK than with MB for either route (p < 0.001). HCO3 increased over -time with MBMK when compared with MB within either administration route (p < 0.01 for IV and p = 0.044 for IM). When comparing administration routes within MBMK treatments, MAP (p < 0.001), SVRI (p = 0.045), PaO2 (p = 0.026), blood lactate (p = 0.035), pH (p = 0.047) were significantly higher and CI (p = 0.028), PaCO2 (p = 0.034), P(A-a)O2 (p = 0.021) and HCO3 (p = 0.047) were significantly lower after IM than IV administration. Within MB treatments, HR (p < 0.001) and pH (p = 0.048) were significantly higher and CVP

© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 567–574

Medetomidine, MK-467 and butorphanol in dogs K Salla et al. Table 1 Means  SD of systolic (SAP) and diastolic (DAP) arterial pressures, central venous pressure (CVP) and rectal temperature at selected time points in dogs (n = 8) treated with MBMK IV, MB IV, MBMK IM and MB IM (see Fig. 1 for abbreviations) Timepoints Parameters

Treatment

SAP

MB IV MBMK MB IM MBMK MB IV MBMK MB IM MBMK MB IV MBMK MB IM MBMK MB IV MBMK MB IM MBMK

DAP

CVP

Temperature (°C)

IV IM IV IM IV IM IV IM

Baseline mmHg mmHg mmHg mmHg mmHg mmHg mmHg mmHg mmHg mmHg mmHg mmHg

191 198 200 205 89 85 88 95 2 2 2 2 38.0 38.2 38.0 38.0

               

38 32 16 24 10 12 9 14 3 2 3 2 0.3 0.5 0.4 0.4

T3 218 211 209 221 127 72 99 113 8 6 4 4 38.1 38.2 38.2 38.1

T10                

16 41* 19 18 10 18* 16 12 2 1 2 3† 0.2 0.4 0.3 0.4

190 150 197 182 114 64 119 87 11 3 9 7 38.0 38.0 38.1 38.1

T20                

19 29* 9 20 6 10* 15 12† 2 1* 3 1 0.4 0.4 0.3 0.3

173 130 179 155 98 53 102 68 9 2 9 4 38.1 37.7 38.1 37.8

T30                

13 31* 18 23† 11 10* 12 12† 2 1* 1 1† 0.3 0.5* 0.2 0.3†

169 124 173 137 94 49 96 64 7 2 7 3 38.0 37.5 37.9 37.4

T60                

17 30* 17 22† 9 10* 13 13† 2 2* 1 1† 0.3 0.5* 0.4 0.5†

157 126 162 130 79 49 84 51 6 1 5 2 37.5 36.8 37.5 36.9

               

15 18* 22 18† 13 7* 12 8† 2 2* 2 1† 0.3 0.5* 0.4 0.3†

*Significant difference between intravenous treatments (i.e. MBMK IV versus MB IV) (p < 0.05), and †between intramuscular treatments (i.e. MBMK IM versus MB IM) (p < 0.05).

(p = 0.021) was significantly lower after IM than IV administration. Discussion In general, the overall cardiovascular status was maintained closer to the physiological values when MK-467 was administered simultaneously with a medetomidine-butorphanol combination via both routes. Similarly, in a recently published study by Rolfe et al. (2012), the concomitant administration of MK-467 with medetomidine both by IV and IM administration improved cardiovascular performance compared to medetomidine alone. In our study, sustained bradycardia accompanied by a marked reduction in CI was seen after MB, irrespective of the route of administration. In comparison, with MBMK, a smaller and more transient fall in HR and CI was detected for both routes. After IV administration to conscious dogs, the decreases in HR and CI observed in this study were larger (Honkavaara et al. 2011) or similar (Rolfe et al. 2012) than reported in earlier studies for a2-agonists without an opioid. Butorphanol has been shown slightly to potentiate the cardiovascular effects of

medetomidine in dogs, as the stroke index and cardiac index seem to decrease more after IV administration of medetomidine-butorphanol than after medetomidine alone (Kuo & Keegan 2004). Accordingly, it could be suggested that butorphanol might have accentuated the early cardiovascular changes seen with MBMK, which were, rather interestingly, more pronounced after IM administration. Additionally, early increases in MAP and SVRI were observed after MBMK IM, but not MBMK IV. Thus, it could be also suggested that the absorption of MK-467 after IM administration might be slower than that of medetomidine when administered concomitantly. This could be explained by molecular differences, which might facilitate a more rapid distribution of medetomidine to the site of action (central and peripheral a2-adrenoceptors) compared with MK-467 (peripheral a2-adrenoceptors), i.e. a higher lipophilicity, logP 2.80 (Savola et al. 1986) versus 1.3 (Clineschmidt et al. 1988), and smaller molecular weight, 236.74 g mol 1 versus 418.51 g mol 1, for medetomidine than MK-467, respectively. Oxygen delivery is a product of cardiac output and arterial oxygen content. In our study, the most

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Medetomidine, MK-467 and butorphanol in dogs K Salla et al. Table 2 Means  SD of respiratory rates (fR), arterial oxygen (PaO2) and carbon dioxide (PaCO2) partial pressures, alveolarto-arterial gradient (P(A-a)O2), blood lactate concentrations, pH and bicarbonate concentrations (HCO3 ) at selected time points in dogs (n = 8) treated with MBMK IV, MB IV, MBMK IM and MB IM (see Fig. 1 for abbreviations) Timepoints Parameters

Treatment

Baseline

fR (breaths minute 1)

MB IV MBMK IV MB IM MBMK IM MB IV

20 22 28 23 98 13.1 98 13.0 97 12.9 92 12.3 35 4.6 33 4.4 34 4.6 35 4.6 13 1.7 15 2.0 14 1.8 19 2.5 0.6 0.6 0.7 0.6 7.38 7.39 7.37 7.37 19.9 19.5 20.1 19.5

PaO2

MBMK IV MB IM MBMK IM MB IV

PaCO2

MBMK IV MB IM MBMK IM P(A-a)O2

MB IV MBMK IV MB IM MBMK IM

Blood lactate (mmol L 1)

pH

HCO3 (mmol L 1)

MB IV MBMK MB IM MBMK MB IV MBMK MB IM MBMK MB IV MBMK MB IM MBMK

IV IM IV IM IV IM

mmHg kPa mmHg kPa mmHg kPa mmHg kPa mmHg kPa mmHg kPa mmHg kPa mmHg kPa mmHg kPa mmHg kPa mmHg kPa mmHg kPa

                                       

3 7 14 7 7 0.9 4 0.6 5 0.7 7 0.9 2 0.2 2 0.3 2 0.3 2 0.3 7 1.0 4 0.6 4 0.5 8 1.0 0.2 0.2 0.3 0.3 0.02 0.02 0.02 0.02 0.9 1.2 1.2 0.9

T3 11 9 10 10 68 9.1 48 6.3 85 11.4 71 9.4 37 4.9 40 5.3 36 4.8 36 4.8 40 5.3 57 7.7 24 3.2 39 5.2 0.5 0.6 0.7 0.6 7.35 7.34 7.37 7.35 20.2 20.9 20.4 19.4

T10                                        

4 6 5 4 5 0.7 5* 0.6* 5 0.7 8† 1.1† 2 0.3 2* 0.3* 2 0.3 2 0.3 5 0.6 4* 0.6* 3 0.5 8† 1.1† 0.1 0.2 0.2 0.2 0.02 0.01 0.02 0.02 1.1 1.1 1.0 1.0

8 7 10 8 67 9.0 65 8.6 79 9.3 73 9.7 40 5.3 43 5.7 39 5.2 38 5.1 38 5.0 37 5.0 36 4.8 34 4.5 0.9 0.5 0.8 0.6 7.31 7.31 7.33 7.33 19.7 20.6 20.2 19.5

T20                                        

3 5 5 6 11 1.5 6 0.8 11 1.5 6 0.9 3 0.3 2* 0.3* 3 0.4 3 0.4 10 1.3 5 0.6 8 1.1 5 0.7 0.2 0.1* 0.2 0.2 0.02 0.02* 0.02 0.02 1.1 0.7* 1.3 1.3

7 7 8 6 77 10.3 73 9.7 71 9.5 74 9.9 38 5.1 44 5.8 40 5.3 43 5.7 29 3.9 28 3.7 34 4.5 28 3.7 1.0 0.4 1.0 0.6 7.31 7.30 7.32 7.30 19.0 20.9 20.0 20.2

T30                                        

2 4 3 4 9 1.1 5 0.7 8 1.1 6 0.8 3 0.4 3* 0.4* 2 0.3 2† 0.3† 8 1.0 4 0.5 7 1.0 7† 0.9† 0.2 0.1* 0.3 0.3† 0.02 0.03* 0.02 0.01† 1.3 1.1* 0.9 1.3

7 7 8 7 79 10.5 80 10.7 77 10.3 81 10.8 40 5.3 44 5.9 40 5.3 43 5.8 26 3.5 20 2.7 28 3.7 20 2.7 1.0 0.4 1.0 0.5 7.31 7.30 7.31 7.30 19.6 21.0 20.1 20.5

T60                                        

2 3 4 3 9 1.2 5 0.6 9 1.2 11† 1.4† 3 0.3 4* 0.5* 3 0.4 3† 0.4† 8 1.0 4* 0.5* 7 0.9 9† 1.2† 0.3 0.1* 0.3 0.2† 0.02 0.03 0.02 0.03 1.0 0.9* 1.1 1.3†

9 8 9 7 90 12.0 95 12.6 88 11.8 97 12.9 40 5.3 42 5.5 40 5.4 42 5.6 15 2.0 8 1.1 16 2.1 5 0.7 0.9 0.4 1.0 0.5 7.31 7.32 7.31 7.31 19.9 20.6 20.1 20.6

                                       

3 4 6 3 8 1.1 8 1.0 5 0.6 8 1.0 3 2.5 4* 0.5* 2 0.2 3† 0.4† 8 1.1 5* 0.7* 4 0.5 5† 0.7† 0.3 0.1* 0.3 0.2† 0.01 0.03 0.02 0.02 1.1 0.9* 1.0 1.1†

*Significant difference between intravenous treatments (i.e. MBMK IV versus MB IV) (p < 0.05), and †between intramuscular treatments (i.e. MBMK IM versus MB IM) (p < 0.05).

profound and sustained decrease in DO2I was detected after MB. The critical DO2I level has been discussed as to be between 160 and 280 mL minute 1 m 2 in dogs, below which there is a risk of a significant tissue oxygen debt (Van der Linden et al. 1995; Haskins et al. 2005b). With MB, DO2I gen572

erally persisted at this level throughout the one– hour follow-up period. Moreover, significantly higher lactate levels with MB than with MBMK after both administration routes also suggests that the tissue perfusion was more compromised with MB. After MBMK, DO2I decreased transiently but

© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 567–574

Medetomidine, MK-467 and butorphanol in dogs K Salla et al. returned within acceptable levels within 10– 20 minutes, depending on the administration route. This early decrease in DO2I after MBMK reflected the changes seen in CI. However, after MBMK IV the transient decrease in DO2I appeared to be more pronounced than would be expected based only on the changes in CI. This is explained by the marked early reduction in PaO2 and arterial oxygen content after IV administration of MBMK. Sedative agents might cause ventilation-perfusion mismatch by inducing both hypoventilation and alterations in the pulmonary blood flow, thus impairing arterial oxygenation. In our study, the alveolar-to-arterial oxygen partial pressure difference increased after each treatment, reflecting increased ventilation-perfusion mismatch. Three minutes after drug administration P(A-a)O2 increased the most after MBMK IV and, given the disproportionally small increase in PaCO2, is best explained by the sudden decrease in PaO2. With MBMK, the changes in P(A-a)O2 and PaO2 were greater in our study than reported in previous studies in which an opioid was not administered (Enouri et al. 2008; Honkavaara et al. 2011; Rolfe et al. 2012). This could be due to concomitant administration of butorphanol, differences in doses or both. Honkavaara et al. (2011) demonstrated that dexmedetomidine (a pure D-enantiomer of medetomidine) reduced PaO2 and fR, and increased P(A-a)O2 in conscious dogs, but MK-467 had no significant effects on these parameters. Intramuscular administration of medetomidine and butorphanol has previously been reported to increase PaCO2 and reduce fR and PaO2 more than medetomidine alone (Ko et al. 2000). In our study, fR and PaO2 decreased and PaCO2 increased slightly in each treatment. Thus, as PaCO2 remained somewhat higher with both treatments that included MK-467, it could be suggested that butorphanol promoted hypoventilation, which increased further with concomitant administration of MK-467. Additionally, MK-467 transiently potentiated the early ventilation-perfusion mismatch in butorphanol-medetomidine sedated dogs. However, these effects seemed less pronounced after IM than IV administration of MBMK. However, these early disturbances in pulmonary function were transient in nature, as PaO2 increased to acceptable levels after 10 minutes with all treatments. Nevertheless, the pathophysiology of alpha2-adrenoceptor agonistinduced hypoxemia should be further evaluated

in more detailed studies. Overall, marked improvements in CI with the administration of MK-467 ensured a higher DO2I at all times during the present study when compared with the medetomidine-butorphanol combination. Increasing the fraction of inspired oxygen would probably further increase the arterial oxygen content in clinical settings. In our study, RT declined faster with MBMK than with MB, as significant differences were seen 20– 30 minutes after drug administrations. Rolfe et al. (2012) also found that body temperature declined from baseline after concomitant administration of medetomidine and MK-467. Lower body temperatures with MBMK are considered to be due to better peripheral circulation and thus greater convection of heat to the surroundings, as demonstrated by € et al. (2013). A decrease in body temVainionp€ aa perature and subsequent rewarming might cause shivering and consequently causing a significant oxygen demand (Ralley et al. 1988). Thus, from a clinical point of view, more effort is required to maintain body temperature after the administration of MK-467. Since this work for this study was completed, evidence has been published that some agents, including medetomidine (but not butorphanol) influence the lithium sensor in a manner that will result in an over-estimation of CI (Ambrisko et al. 2013). The effect of medetomidine is not as pronounced as some other agents, and the blood levels reached in this study are unlikely to have had a major effect. Nevertheless the possibility of an influence of different blood concentrations of medetomidine at different time points, in particular when comparing the IV and IM routes on the accuracy of CI measurement and associated calculations has to be taken into consideration. In conclusion, concomitant IV or IM administration of MK-467 provides an option to ameliorate the cardiovascular performance in dogs sedated with a medetomidine-butorphanol combination. Acknowledgements MK-467 was generously donated by Merck, Sharpe & Dohme, PA, USA and medetomidine was donated by Vetcare Ltd, M€ ants€ al€ a, Finland. Vetcare Ltd and Helvi Knuuttila Foundation are acknowledged for funding this study. We also want to thank Mari Palviainen and Ann-Helena Hokkanen for their valuable help during this study.

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Medetomidine, MK-467 and butorphanol in dogs K Salla et al.

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