Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane

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Veterinary Anaesthesia and Analgesia 2017, xxx, 1e14

http://dx.doi.org/10.1016/j.vaa.2017.02.010

RESEARCH PAPER

Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats Q6

anesthetized with isoflurane

Q5

Kristine T Siaoa, Bruno H Pypendopb, Juhana Honkavaaraa & Jan E Ilkiwb a

William R. Pritchard Veterinary Medical Teaching Hospital, School of Veterinary Medicine, University of California, Davis, CA, USA b

Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of

California, Davis, CA, USA Correspondence: Bruno Pypendop, Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of Q1

California, One Shields Avenue, Davis, CA 95616, USA. E-mail: [email protected]

Abstract Objective To characterize the hemodynamic effects of dexmedetomidine, with or without MK467, following intramuscular (IM) administration in cats. Study design Randomized, mental study. Animals Six healthy purpose-bred cats.

adult

crossover, male

expericastrated

Methods Cats were anesthetized with isoflurane in oxygen and instrumented. Cats were administered dexmedetomidine (25 mg kg
1), with (DM) or without (D) MK-467 (600 mg kg
1), IM in the epaxial muscles. Cardiovascular variables, respiratory variables, temperature, and arterial and mixed-venous pH, blood gases and electrolytes were measured prior to drug administration and at various time points for 6 hours thereafter, during anesthesia with isoflurane. Additional variables were calculated from the measurements, using standard equations. Results were analyzed with a two-way repeated-measures analysis of variance, followed by Dunnett’s and paired t tests where appropriate. Results Dexmedetomidine resulted in a significant decrease in cardiac index and significant increases in mean arterial pressure and systemic vascular resistance index. The addition of MK-467 failed to prevent most of the early cardiovascular effects of

dexmedetomidine, but the duration of systemic vasoconstriction was shorter and cardiac index (CI) did not decrease. The lowest and highest posttreatment values in each treatment were 0.1 ± 0.03 and 0.13 ± 0.03 L minute
1 kg
0.67 (D) versus 0.14 ± 0.01 and 0.19 ± 0.03 L minute
1 kg
0.67 (DM) for CI, 87 ± 13 and 181 ± 21 mmHg (D) versus 70 ± 11 and 153 ± 18 mmHg (DM) for mean arterial pressure and 58,948 ± 17,754 and 119,432 ± 40,423 dynes second cm
5 kg
0.67 (D) versus 25,870 ± 3782 and 76,498 ± 17,258 dynes second cm
5 kg
0.67 (DM) for systemic vascular resistance index, respectively. Conclusion and clinical relevance IM coadministration of MK-467 and dexmedetomidine in isoflurane-anesthetized cats shortened dexmedetomidine-induced cardiovascular effects. This drug combination may be useful in cats in which longer-lasting hypertension and hemodynamic depression is of concern. Keywords a2-agonist, antagonist, cardiopulmonary, cat, dexmedetomidine. Introduction Dexmedetomidine, an a2-adrenergic receptor agonist, is commonly used in cats to produce sedation and analgesia (Granholm et al. 2006; Nagore et al. 2013). It has also been widely used as a premedication for general anesthesia (McSweeney et al.

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Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

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Intramuscular dexmedetomidine MK-467 in cats KT Siao et al.

2012). However, despite being a potent sedative and decreasing anesthetic requirement (Maze & Tranquilli 1991), the use of dexmedetomidine can result in significant cardiovascular changes. Dexmedetomidine binds to a2-adrenergic receptors on the vascular smooth muscle, which leads to vasoconstriction and an increase in systemic and pulmonary vascular resistance. This results in increased systemic and pulmonary arterial blood pressure (Hyman & Kadowitz 1985; Ruffolo 1985; Bloor et al. 1992; Duka et al. 2000). With increases in systemic arterial blood pressure, peripheral baroreceptor stimulation leads to an increase in parasympathetic tone, resulting in reflex bradycardia (Badoer et al. 1983; Harron et al. 1985; Devcic et al. 1994). In addition, dexmedetomidine has been reported to decrease sympathetic nervous system activity and/or increase parasympathetic nervous system activity within the central nervous system, which may contribute to the bradycardia (Sharp et al. 2014). The bradycardia produced causes a significant decrease in cardiac index (CI) in cats (Pypendop et al. 2011, 2016a). These hemodynamic changes may be undesirable in debilitated animals and preclude or limit the use of a2-agonists. MK-467 is an a2-adrenergic antagonist that apparently does not cross the blood brain barrier (Clineschmidt et al. 1988). When administered with an a2-adrenergic receptor agonist such as dexmedetomidine, MK-467 may minimize the undesirable cardiovascular changes without changing the sedative effects of the a2-adrenergic receptor agonist. These effects have been recorded in dogs, horses and sheep (Pagel et al. 1998; Enouri et al. 2008; Honkavaara et al. 2008, 2011; Raekallio et al. 2010; Restitutti et al. 2011; Rolfe et al. 2012; Vainionpaa et al. 2013), and in cats after intravenous (IV) administration (Pypendop et al. 2016a; Honkavaara et al. 2017a). The dose of MK-467 required to blunt the bradycardia induced by dexmedetomidine (25 mg kg
1) following intramuscular (IM) administration has recently been determined in cats (Honkavaara et al. 2017b). Whereas the cardiovascular effects of coadministered dexmedetomidine and MK-467 IV have been reported (Pypendop et al. 2016a), IM administration is yet to be investigated. The aim of this study was to characterize the hemodynamic effects of dexmedetomidine, with or without MK-467, following IM coadministration in cats.

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Materials and methods Animals Six healthy adult male neutered Domestic Short Haired cats weighing 5.26 ± 0.47 kg (mean ± standard deviation) were used in the study. The cats were aged 1e2 years and were deemed healthy based on history and physical examination prior to the study. Husbandry was identical to that previously described for other studies conducted at the same institution, with the exception of the commercial diet (Feline 5003; LabDiet, MO, USA; Honkavaara et al. 2017b). All cats were acclimatized to laboratory conditions and handling prior to commencing the study. Cats were fasted for 12 hours prior to each study, but had free access to water. The Institutional Animal Care and Use Committee at the University of California Davis approved this study. Study instrumentation and variables measured Instrumentation and measurements, and their description are similar to those previously published for studies conducted in the same laboratory (Pypendop et al. 2011, 2016a). For induction of anesthesia, the cat was placed in a chamber and 5% isoflurane was delivered in 5 L minute
1 of oxygen. After an appropriate depth of anesthesia had been reached, the trachea was intubated and anesthesia was maintained using isoflurane (Piramal Critical Care Inc., PA, USA) in 200 mL kg
1 minute
1 oxygen, delivered via a coaxial Mapleson F circuit. The cat was placed in right lateral recumbency. The cat was allowed to breathe spontaneously during the entire study. End-tidal isoflurane concentration (FE0 Iso) was set between 1 and 2%, as needed to provide a moderate depth of anesthesia, as assessed based on lack of a palpebral reflex, eccentric eye position and mild jaw tone. A 22 gauge, 25 mm catheter was placed in a cephalic vein for administration of lactated Ringer’s solution at 5 mL kg
1 hour
1. Cefazolin (25 mg kg
1; NovaPlus, FL, USA) was administered IV before instrumentation. The left external jugular vein and left external carotid artery were exposed by surgical dissection, performed aseptically. A 22 gauge, 8 cm arterial catheter (Arteriofix V; B Braun Melsungen AG, Germany) was placed in the carotid artery. This catheter was used for arterial blood pressure and pulse rate (PR) monitoring, and for arterial blood sampling. A 5 Fr, 7.5 cm

© 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., ▪, 1e14

Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

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Intramuscular dexmedetomidine MK-467 in cats KT Siao et al.

introducer (Percutaneous Sheath Introducer; Arrow International, OH, USA) was positioned in the jugular vein. A 4 Fr, 75 cm, triple lumen thermodilution catheter (Thermodilution balloon catheter; Arrow International) was placed via the introducer so that the distal port and thermistor were located in the pulmonary artery, with the proximal port located in the right atrium or cranial vena cava. Fluoroscopy was used to assist in the placement of the thermodilution catheter. The following variables were measured using this catheter: cardiac output (CO); mean pulmonary arterial pressure (MPAP), pulmonary artery occlusion pressure (PAOP); central venous pressure (CVP); and core body temperature (T). Mixed-venous blood was sampled from the pulmonary artery via the distal catheter port. The carotid catheter and jugular introducer were sutured onto the skin using 3-0 nylon, and the skin was closed with 3-0 nylon in a simple interrupted pattern. The PR, systolic (SAP), diastolic (DAP) and mean arterial pressure (MAP), MPAP, and CVP were continuously measured and recorded using a physiograph and acquisition software (Ponemah, Version 4.7; Data Sciences International, MN, USA). PAOP was measured by inflating the balloon of the thermodilution catheter until the pulmonary arterial waveform visibly flattened. Electrocardiogram (ECG) electrodes were placed on both thoracic paws and the left pelvic paw, and connected in a lead II configuration. The ECG was continuously displayed by a multiparameter monitor (Carescape B650; GE Healthcare, WI, USA). The carotid catheter and the proximal and distal ports of the thermodilution catheter were connected to pressure transducers (DTXPlus; Argon Medical Devices, TX, USA) using saline-filled noncompliant tubing (Pressure monitoring line; Argon Medical Devices). A mercury manometer was used to calibrate all pressure transducers (DTXPlus; Argon Medical Devices) before each experiment; the level of the sternum was used to zero the transducers to atmospheric pressure. A catheter was passed through the lumen of the endotracheal tube so that its tip was positioned at the distal end of the tube. This catheter was connected to an infrared spectrometer (Carescape B650; GE Healthcare) for continuous measurement of end-tidal carbon dioxide partial pressure and FE0 Iso. Prior to each collection of data, expired gas was collected manually (10 mL collected over 4e10 breaths) for the measurement of FE0 Iso, using an infrared spectrometer (Medical Gas Analyzer LB1; Beckman Instruments, IL, USA) calibrated with three isoflurane secondary standards

FE0 Iso

(0.5, 1.5, and 2.0%) prior to each experiment. was measured in triplicate and the mean of the three measurements was recorded as the FE0 Iso. A blood gas and electrolyte analyzer (ABL 800; Radiometer America, CA, USA) was used to measure arterial and mixed venous pH, PCO2, PO2 and hemoglobin oxygen saturation (SO2) using co-oximetry, and to calculate bicarbonate concentration (HCO
3 ) and standard base excess (SBE). The results were corrected for T. In addition, blood hemoglobin concentration (Hb), and plasma sodium (Naþ), potassium (Kþ), chloride (Cl
), ionized calcium (Caþþ), and lactate concentrations, and Hb oxygen saturation were measured in arterial and mixed-venous blood using the same analyzer. Microcentrifugation and refractometry were used to determine packed cell volume (PCV) and total protein (TP) concentration, respectively, in the arterial blood. CO was measured with the thermodilution technique (Carescape B650; GE Healthcare). Three mL of 5% dextrose in water stored in melting ice were administered as a bolus via the proximal port of the thermodilution catheter for CO determination. This was repeated to obtain three measurements that differed by 10% or less; the mean of these three measurements was calculated and recorded as the CO. T was maintained between 37.5  C and 38.5  C by providing external heat as needed. Additional variables were calculated from the measurements, according to previously published equations (Appendix A; Pypendop et al. 2016a). Experimental protocol

After instrumentation, the FE0 Iso was set at 1.5e1.9% to produce a light depth of anesthesia with absence of spontaneous movement. The cat was administered dexmedetomidine (25 mg kg
1; Dexdomitor; Zoetis, NY, USA; treatment D) or dexmedetomidine (25 mg kg
1) and MK-467 (600 mg kg
1; Vetcare Ltd, Finland; treatment DM) IM in the epaxial muscles. For DM, MK-467 and dexmedetomidine were mixed in the same syringe. All cats were administered both treatments on separate days, with at least 2 weeks between treatments. The order was randomized according to a computer-generated list (www.random.org). MK-467 was reconstituted in 0.9% saline, to a concentration of 10 mg mL
1, and filtered through a 0.2 mm filter (Fisherbrand; Thermo Fisher Scientific, CA, USA). The appropriate doses of MK-467 and dexmedetomidine were then mixed in the same syringe. The final volume of all treatments was adjusted to 1 mL by adding 0.9% saline as

© 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., ▪, 1e14

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Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

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Intramuscular dexmedetomidine MK-467 in cats KT Siao et al.

necessary. Treatments were prepared within 30 minutes of administration. FE0 Iso, PR, SAP, DAP, MAP, MPAP, CVP, PAOP, CO and T were recorded 15 minutes prior to drug administration, and 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, 300 and 360 minutes after drug administration. Arterial and mixed venous blood samples were collected 15 minutes prior to drug administration, and 5, 10, 30, 60, 120, 180, 240, 300 and 360 minutes after drug administration. A total of 1 mL (0.5 mL arterial blood and 0.5 mL of mixed-venous blood) was taken at each time point, and a total of 10 mL was collected for the whole study. Blood was collected in blood gas syringes (PICO50; Radiometer America), kept at room temperature and analyzed within 30 minutes of collection. After completion of all measurements, the thermodilution catheter, introducer and arterial catheter were removed. The incisions in the carotid artery and jugular vein were closed with 5-0 polydioxanone suture. The area was flushed with sterile saline, and the intradermal layer was closed with 3-0 poliglecaprone 25 suture in a simple continuous pattern. The cat was allowed to recover from anesthesia. Meloxicam (0.2 mg kg
1; OstiLox; VetOne, ID, USA) was administered subcutaneously prior to extubation. The cat was continuously observed until alert and walking without assistance. Daily observations were performed to assess subjects for signs of pain and to verify the integrity of the surgical closure for 10 days following the studies. The pH of the dexmedetomidine and dexmedetomidine with MK-467 solutions, as prepared for a 5-kg cat in this study, was measured using pH paper.

Statistical analysis Normal distribution of the data was confirmed using the ShapiroeWilk test. A two-way repeated-measures analysis of variance was used to analyze the data for the treatment and time effects, and the treatmentetime interaction. Differences with baseline values within each treatment and differences between treatments at each time point were analyzed with Dunnett’s test and paired t-test, respectively, where appropriate. Significance was defined as p < 0.05. Data are presented as mean ± standard deviation. Results Data from one cat in DM were excluded from analysis due to outlier baseline values, specifically the difference in baseline CO between treatments was approximately double that seen in the other cats. Therefore, the results presented are from six cats in D and five cats in DM, and paired treatment comparisons were conducted on five cats only. All cats recovered from anesthesia without complications, and no abnormality or pain was detected during the 10-day postoperative observation period. All incisions were healed at the conclusion of the observation period. Mixed-venous pH, blood gas and electrolyte data ARE presented for information in Table S1 only. PR decreased following drug administration; PR was significantly lower than baseline at most time points in DM (Fig. 1); the time effect was statistically significant (p ¼ 0.0011). SAP, MAP and DAP initially increased following drug administration in both D

Figure 1 Mean ± standard deviation pulse rate (PR) before and after intramuscular administration of dexmedetomidine (25 mg kg
1; circles; n ¼ 6) or dexmedetomidine (25 mg kg
1) with MK-467 (600 mg kg
1; triangles; n ¼ 5) at time 0 in cats. *Significantly different from baseline in the dexmedetomidine with MK-467 treatment (p < 0.05). 4

© 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., ▪, 1e14

Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

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Intramuscular dexmedetomidine MK-467 in cats KT Siao et al.

Figure 2 Mean ± standard deviation mean arterial blood pressure (MAP) before and after intramuscular administration of dexmedetomidine (25 mg kg
1; circles; n ¼ 6) or dexmedetomidine (25 mg kg
1) with MK-467 (600 mg kg
1; triangles; n ¼ 5) at time 0 in cats. *Significantly different from the respective baseline value (p < 0.05). ySignificant difference between treatments at this time point (p < 0.05).

and DM and slowly returned towards baseline in D, more rapidly in DM (Fig. 2, Table 1). The time effect (p < 0.0001 for SAP, MAP, and DAP), treatment effect (p ¼ 0.0016 for SAP, p < 0.0001 for MAP and DAP) and treatmentetime interaction (p < 0.0001 for SAP, MAP and DAP) were all statistically significant. Similarly, CVP, PAP and PAOP increased after drug administration in both D and DM, but returned towards baseline faster in DM than in D; the initial increase in PAP did not reach statistical significance in DM (Table 1). The time effect (p < 0.0001 for CVP, PAP and PAOP) and treatment effect (p ¼ 0.0290 for CVP, p ¼ 0.0472 for PAP and p ¼ 0.0391 for PAOP) were statistically significant for the three variables. The treatmentetime interaction was significant for PAP (p ¼ 0.0010) and PAOP (p ¼ 0.0003). A statistically significant difference in T was found at baseline between D and DM (Table 1). T increased over time in D but decreased over time in DM. A significant time effect (p ¼ 0.0022) and treatmentetime interaction (p < 0.0001) were found for T. CI and stroke index (SI) significantly decreased following drug administration in D, but not in DM (Fig. 3, Table 2). The time effect (p < 0.0001 for CI, p ¼ 0.0008 for SI) and treatmentetime interaction (p ¼ 0.0056 for CI, p ¼ 0.0007 for SI) were statistically significant for both variables, whereas the treatment effect was statistically significant for SI only (p ¼ 0.0232). Rateepressure product (RPP) significantly increased initially in D but not DM, and later decreased in DM but not in D (Table 2). The time effect (p < 0.0001), treatment effect (p ¼ 0.0361), and treatmentetime interaction (p ¼ 0.0014) were all statistically significant. Systemic vascular

resistance index (SVRI) initially increased after drug administration in both D and DM, but remained elevated in D for longer than in DM (Fig. 4). The time effect (p < 0.0001), treatment effect (p ¼ 0.0063) and treatmentetime interaction (p < 0.0001) were statistically significant. Pulmonary vascular resistance index was significantly higher in D than in DM at most time points (Table 2). The time effect (p ¼ 0.0051) and treatment effect (p ¼ 0.0126) were statistically significant. Left ventricular stroke work index initially increased in DM but not in D (Table 2); the time effect (p < 0.0001) and treatmentetime interaction (p ¼ 0.0144) were statistically significant. Arterial oxygen concentration significantly increased following drug administration in D but not in DM (Table 2); statistically significant time (p ¼ 0.0006) and treatment (p ¼ 0.0002) effects, and treatmentetime interaction (p ¼ 0.0016) were found. Mixed venous oxygen concentration ðCvO2 Þ was significantly higher in D than in DM at several time points following drug administration (Table 2); the treatment effect (p ¼ 0.0135) and treatmentetime interaction (p ¼ 0.0069) were statistically significant. Oxygen delivery index (DO2I) decreased following drug administration (Fig. 5); a significant time effect (p ¼ 0.0048) was found, although DO2I was not significantly lower than baseline at any time point in _ IÞ either D or DM. Oxygen consumption index ðVO 2 initially increased (significantly in DM only) then decreased after drug administration (Table 2); a significant time effect (p < 0.0001) was found, although no other statistically significant difference from baseline than the initial increase in DM was found in either treatment. A significant time effect was found

© 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., ▪, 1e14

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Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

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Intramuscular dexmedetomidine MK-467 in cats KT Siao et al. Table 1 End-tidal isoflurane concentration, cardiovascular variables and body temperature in cats before and after intramuscular administration of dexmedetomidine (25 mg kg
1; treatment D; n ¼ 6) or dexmedetomidine (25 mg kg
1) with MK-467 (600 mg kg
1; treatment DM; n ¼ 5) at time 0 (data are mean ± standard deviation) Variable

Treatment

Time (minutes) 5

10

20

30

1.65 ± 0.12 1.82 ± 0.10 212 ± 24* 178 ± 26* 164 ± 19* 133 ± 15*y 16 ± 2* 13 ± 2*y 27 ± 6* 23 ± 4 22 ± 4* 17 ± 2*y 37.8 ± 0.1 38.3 ± 0.1y

1.61 ± 0.12 1.76 ± 0.17 197 ± 17* 118 ± 8 153 ± 13* 77 ± 7y 15 ± 6* 11 ± 2 28 ± 5* 20 ± 3 20 ± 4* 13 ± 3y 37.7 ± 0.2 38.1 ± 0.1y

1.66 ± 0.13 1.77 ± 0.10 180 ± 19* 105 ± 8 142 ± 13* 55 ± 4y 15 ± 2* 9 ± 3y 25 ± 4* 17 ± 3y 20 ± 4* 11 ± 3y 37.9 ± 0.2 37.9 ± 0.1

1.65 ± 0.13 1.75 ± 0.08 175 ± 19* 105 ± 6 139 ± 11* 55 ± 4y 15 ± 3* 8 ± 2y 24 ± 4 17 ± 3y 18 ± 4* 10 ± 2y 38.0 ± 0.2 37.8 ± 0.2*

45

60

90

120

180

1.57 ± 0.11 1.74 ± 0.07 144 ± 66 103 ± 7 133 ± 13* 55 ± 7y 13 ± 2 8 ± 1y 23 ± 4 16 ± 3y 16 ± 3 11 ± 3y 38.1 ± 0.2* 37.7 ± 0.2*y

1.62 ± 0.11 1.67 ± 0.17 153 ± 21* 104 ± 5 124 ± 17* 57 ± 6y 12 ± 2 8 ± 2y 21 ± 3 16 ± 3y 15 ± 3 11 ± 3y 38.3 ± 0.2* 37.8 ± 0.3y

1.65 ± 0.11 1.77 ± 0.13 136 ± 19 103 ± 4 111 ± 18* 61 ± 5y 11 ± 2 9±2 20 ± 4 18 ± 2 14 ± 4 12 ± 4 38.5 ± 0.2* 38.0 ± 0.4y

1.64 ± 0.13 1.74 ± 0.08 122 ± 17 103 ± 5 98 ± 18* 63 ± 8y 11 ± 3 8±3 20 ± 3 17 ± 2 12 ± 2 12 ± 3 38.4 ± 0.2* 38.1 ± 0.3

1.66 ± 0.07 1.76 ± 0.13 114 ± 12 111 ± 25 90 ± 16 73 ± 22 9±4 7 ± 3y 18 ± 4 17 ± 2 10 ± 3 10 ± 4 38.0 ± 0.3 38.1 ± 0.2

e15 Isoflurane (%) SAP (mmHg) DAP (mmHg) CVP (mmHg) PAP (mmHg) PAOP (mmHg) T ( C)

Variable

Isoflurane (%) SAP (mmHg) DAP (mmHg) CVP (mmHg) PAP (mmHg) PAOP (mmHg) T ( C)

Variable

1.64 ± 0.12 1.80 ± 0.09 110 ± 13 121 ± 29 72 ± 20 77 ± 31 9±4 7±1 18 ± 3 18 ± 2 12 ± 2 10 ± 2 37.7 ± 0.2 38.2 ± 0.2y

Treatment

Time (minutes)

D DM D DM D DM D DM D DM D DM D DM

Treatment

Isoflurane (%) SAP (mmHg) DAP (mmHg) CVP (mmHg) PAP (mmHg) PAOP (mmHg) T ( C)

D DM D DM D DM D DM D DM D DM D DM

D DM D DM D DM D DM D DM D DM D DM

Time (minutes) 240

300

360

1.64 ± 0.09 1.73 ± 0.12 116 ± 11 103 ± 5 91 ± 13 64 ± 8y 7±3 6±2 19 ± 3 16 ± 2y 11 ± 2 9 ± 3y 37.9 ± 0.4 38.1 ± 0.3

1.63 ± 0.10 1.72 ± 0.11 109 ± 11 102 ± 4 84 ± 11 63 ± 6y 6±3 5±2 18 ± 4 15 ± 2y 10 ± 3 8 ± 2y 37.9 ± 0.4 38.1 ± 0.1

1.69 ± 0.11 1.71 ± 0.14 103 ± 10 99 ± 5 74 ± 13 58 ± 9 7±3 5±2 17 ± 4 15 ± 2 8±2 9±4 38.1 ± 0.4 37.8 ± 0.4

SAP, systolic arterial pressure; DAP, diastolic arterial pressure; CVP, central venous pressure; PAP, pulmonary artery pressure; PAOP, pulmonary artery occlusion pressure; T, core body temperature. *Significantly different from baseline (e15 minutes; p < 0.05). ySignificantly different from D at this time point (p < 0.05).

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© 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., ▪, 1e14

Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

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Intramuscular dexmedetomidine MK-467 in cats KT Siao et al.

Figure 3 Mean ± standard deviation cardiac index (CI) before and after intramuscular administration of dexmedetomidine (25 mg kg
1; circles; n ¼ 6) or dexmedetomidine (25 mg kg
1) with MK-467 (600 mg kg
1; triangles; n ¼ 5) at time 0 in cats. BW, body weight. *Significantly different from baseline in the dexmedetomidine alone group (p < 0.05).

for oxygen extraction ratio (O2ER; p < 0.0001), shunt fraction ðQ_ s =Q_ t Þ; p ¼ 0.0124) and alveolar-toarterial PO2 difference [P(A-a)O2; p < 0.0001; Table 2]; in addition, the treatmentetime interaction was significant for P(A-a)O2 (p ¼ 0.0340). PCV and arterial Hb (Hba), increased after drug administration in D only (Table 3); the time (p < 0.0001 for PCV, p ¼ 0.0009 for Hba) and treatment (p ¼ 0.0011 for PCV, p ¼ 0.0002 for Hba) effects, and treatmentetime interaction (p ¼ 0.0001 for PCV, p ¼ 0.0023 for Hba) were statistically significant. A statistically significant time effect was found for TP (p ¼ 0.0275), arterial pH (pHa; p < 0.0001), PaCO2 (p < 0.0001), PaO2 (p < 0.0001), arterial HCO
3 (p < 0.0001), arterial SBE (p < 0.0001), arterial lactate concentration (p ¼ 0.0003), arterial Naþ (p < 0.0001), arterial Kþ (p ¼ 0.0012), arterial Cl
(p < 0.0001) and arterial Caþþ (p ¼ 0.004; Table 3). No abnormalities in the ECG were observed with either treatment. The pH of the dexmedetomidine alone solution was approximately 4, and the pH of the dexmedetomidine and MK-467 solution was approximately 3. Discussion The hemodynamic effects following IM administration of dexmedetomidine in isoflurane-anesthetized cats were qualitatively similar to those previously reported following IV administration in conscious cats (Pypendop et al. 2016a). CI significantly decreased from baseline, while MAP and SVRI significantly increased. CI decreased by 56% after IM

administration, which was similar to the 59% decrease following IV administration recorded in the previous study. However, MAP increased by 107% after IM administration in these isofluraneanesthetized cats, but by 46% with IV administration. Furthermore, SVRI increased 328% with IM administration, while in the previous study, IV administration resulted in a smaller increase at 247%. Although the magnitude of the relative increase in MAP and SVRI in this study was greater than in the IV study, baseline values of MAP and SVRI in the IV study were higher compared with the current study. Baseline MAP was 88 ± 20 mmHg in this study, compared with 122 ± 15 mmHg in the IV study, and baseline SVRI was 27,926 ± 5854 dynes second cm
5 BW
0.67 in this study, compared with 33,816 ± 5439 dynes second cm
5 BW
0.67 in the IV study. The maximum values observed were quite similar for both MAP (181 ± 21 mmHg in this study versus 177 ± 23 mmHg when administered IV) and SVRI (119,432 ± 64,132 dynes second cm
5 BW
0.67 in this study versus 116,228 ± 31,087 dynes second cm
5 BW
0.67 in the IV study). The combination of the lower baseline values with similar maximum values following IM drug administration, compared with IV drug administration, resulted in the larger relative increase observed. The most likely reason for the lower baseline MAP and SVRI may be that the cats were anesthetized with isoflurane in this study, but were awake in the IV study. Isoflurane probably produced vasodilation which would have

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7

Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Intramuscular dexmedetomidine MK-467 in cats KT Siao et al. Table 2 Calculated cardiopulmonary data in cats before and after intramuscular administration of dexmedetomidine (25 mg kg
1; treatment D; n ¼ 6) or dexmedetomidine (25 mg kg
1) with MK-467 (600 mg kg
1; treatment DM; n ¼ 5) at time 0 (data are mean ± standard deviation) Variable

Treatment Time (minutes)

SI (mL beat
1 kg
1) RPP (beats minute
1 mmHg)

D DM D DM

PVRI (dynes second cm
5 BW
0 D 67 ) DM D LVSWI (cJ kg
1) DM D RVSWI (cJ kg
1) DM D CaO2 (mL dL
1) DM D CvO2 (mL dL
1) DM D V_ O2 I(mL minute
1 BW
0 67) DM O2ER D DM D Q_ s =Q_ t DM P(A-a)O2 (mmHg) D DM Variable

5

10

20

0.85 ± 0.24 0.69 ± 0.17 17,140 ± 2619 20,391 ± 6738 2208 ± 644 3402 ± 843 0.89 ± 0.46 0.80 ± 0.38 0.10 ± 0.04 0.10 ± 0.04 12.6 ± 1.5 12.8 ± 4.5 9.9 ± 2.0 10.3 ± 5.5 6.1 ± 3.8 4.6 ± 2.5 0.21 ± 0.12 0.24 ± 0.17 0.33 ± 0.21 0.35 ± 0.27 342 ± 36 295 ± 47

0.45 ± 0.11* 0.70 ± 0.23 28,354 ± 6508* 22,675 ± 4172

0.50 ± 0.09* 0.69 ± 0.17 25,665 ± 5576* 17,236 ± 1654

0.50 ± 0.11* 0.51 ± 0.11* 0.72 ± 0.19 0.76 ± 0.16 24,121 ± 3369 23,407 ± 3533

3799 ± 1707 3201 ± 1023 0.95 ± 0.31 1.31 ± 0.55* 0.07 ± 0.05 0.10 ± 0.05 17.6 ± 2.4* 15.7 ± 1.5 9.8 ± 2.9 9.8 ± 2.3 7.9 ± 1.7 8.5 ± 2.1* 0.45 ± 0.10* 0.37 ± 0.12 0.11 ± 0.03* 0.13 ± 0.04* 315 ± 71 271 ± 31

15,242 ± 1899*y 5521 ± 1096* 3367 ± 1836 3479 ± 1304 2730 ± 602 1.01 ± 0.17 0.92 ± 0.18 0.80 ± 0.26 0.61 ± 0.22y 0.09 ± 0.05 0.07 ± 0.04 0.09 ± 0.04 0.07 ± 0.04 18.4 ± 1.4* 13.8 ± 1.1y 12.2 ± 2.9 10.3 ± 1.6 6.6 ± 2.5 6.0 ± 0.8 0.34 ± 0.13 0.26 ± 0.07 0.14 ± 0.10* 0.20 ± 0.04 267 ± 57 291 ± 35

30

15,109 ± 1690*y 3682 ± 1951 2804 ± 1122y 0.92 ± 0.20 0.64 ± 0.17 0.07 ± 0.05 0.08 ± 0.02 17.1 ± 1.7* 11.3 ± 0.4y 12.9 ± 1.5 9.2 ± 0.9y 5.0 ± 2.1 4.0 ± 1.9 0.25 ± 0.07 0.19 ± 0.06 0.20 ± 0.06 0.35 ± 0.07 335 ± 34 367 ± 30*

Treatment Time (minutes)

SI (mL beat
1 kg
1) RPP (beats minute
1 mmHg)

D DM D DM

PVRI (dynes second cm
5 BW
0 D 67 ) DM D LVSWI (cJ kg
1) DM RVSWI (cJ kg
1) D DM D CaO2 (mL dL
1) DM D CvO2 (mL dL
1) DM D V_ O2 I (mL minute
1 BW
0 67) DM D O2ER DM D Q_ s =Q_ t DM D P(A-a)O2 (mmHg) DM

8

-15

45

60

0.51 ± 0.07* 0.80 ± 0.20 20,640 ± 10,127 14,639 ± 1834*

0.51 ± 0.07* 0.46 ± 0.07* 0.46 ± 0.11* 0.49 ± 0.15* 0.75 ± 0.18 0.74 ± 0.19y 0.66 ± 0.12 0.63 ± 0.10 21,466 ± 4894 20,051 ± 5297 16,514 ± 2779 14,815 ± 1634

4496 ± 1422 2486 ± 779y 0.90 ± 0.15 0.66 ± 0.25 0.07 ± 0.03 0.08 ± 0.01

14,771 ± 1681* 4308 ± 1556 2361 ± 835y 0.82 ± 0.14 0.65 ± 0.22 0.07 ± 0.03 0.08 ± 0.01 17.3 ± 0.6* 11.2 ± 0.4y 12.6 ± 1.9 8.9 ± 1.0y 5.5 ± 1.8 4.3 ± 1.5 0.27 ± 0.09 0.21 ± 0.06 0.18 ± 0.10* 0.31 ± 0.06 302 ± 55 343 ± 27

90

14,583 ± 2361* 4163 ± 1775 2520 ± 837y 0.67 ± 0.18 0.64 ± 0.17 0.06 ± 0.02 0.09 ± 0.02

120

14,674 ± 2166* 5388 ± 1835* 2607 ± 953y 0.60 ± 0.17 0.60 ± 0.15 0.06 ± 0.03 0.08 ± 0.01 17.7 ± 1.8* 11.6 ± 1.0y 13.6 ± 2.0 8.5 ± 0.7y 4.3 ± 1.4 5.1 ± 1.5 0.23 ± 0.06 0.27 ± 0.03 0.19 ± 0.07 0.23 ± 0.04 296 ± 57 308 ± 17

180

14,888 ± 2578* 5312 ± 2913 3558 ± 956 0.59 ± 0.19 0.64 ± 0.12 0.06 ± 0.03 0.08 ± 0.02 17.8 ± 1.9* 12.7 ± 0.4y 13.7 ± 2.0 8.9 ± 0.8y 4.5 ± 1.0 5.4 ± 0.9 0.24 ± 0.05 0.30 ± 0.05 0.17 ± 0.06* 0.19 ± 0.02 283 ± 49 294 ± 27

© 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., ▪, 1e14

Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Intramuscular dexmedetomidine MK-467 in cats KT Siao et al.

Table 2 (continued)

Variable

Treatment

SI (mL beat
1 kg
1) RPP (beats minute
1 mmHg) PVRI (dynes second cm
5 BW
0 LVSWI (cJ kg
1) RVSWI (cJ kg
1) CaO2 (mL dL
1) CvO2 (mL dL
1) V_ O2 I(mL minute
1 BW
0 O2ER Q_ s =Q_ t P(A-a)O2 (mmHg)

67

)

67

)

D DM D DM D DM D DM D DM D DM D DM D DM D DM D DM D DM

Time (minutes) 240

300

360

0.51 ± 0.10* 0.67 ± 0.12 16,467 ± 3448 13,815 ± 1866* 5426 ± 1462* 3620 ± 1237 0.64 ± 0.14 0.63 ± 0.12 0.08 ± 0.02 0.09 ± 0.01 17.3 ± 2.1* 12.1 ± 0.9y 13.6 ± 2.1 8.6 ± 1.7y 4.6 ± 1.1 5.2 ± 1.2 0.22 ± 0.06 0.29 ± 0.11 0.19 ± 0.06 0.21 ± 0.05 285 ± 43 292 ± 28

0.47 ± 0.15* 0.64 ± 0.09y 16,256 ± 4204 13,250 ± 1375* 5918 ± 2157* 3895 ± 624 0.54 ± 0.18 0.60 ± 0.11 0.07 ± 0.03 0.08 ± 0.01 17.3 ± 2.0* 12.5 ± 1.2y 12.6 ± 2.0 9.0 ± 1.1y 5.3 ± 1.2 5.0 ± 1.4 0.28 ± 0.07 0.28 ± 0.05 0.16 ± 0.06* 0.21 ± 0.03 271 ± 43 293 ± 18

0.51 ± 0.12* 0.67 ± 0.12 13,469 ± 1752 12,488 ± 1444* 6844 ± 2945* 3569 ± 994 0.53 ± 0.12* 0.58 ± 0.14 0.07 ± 0.03 0.09 ± 0.01 16.9 ± 2.4* 13.0 ± 1.3y 12.4 ± 2.3 9.1 ± 1.8 5.1 ± 0.6 5.7 ± 0.5 0.27 ± 0.04 0.31 ± 0.08 0.15 ± 0.03* 0.17 ± 0.02* 270 ± 38 269 ± 27

SI, stroke index; RPP, rate pressure product; PVRI, pulmonary vascular resistance index; LVSWI, left ventricular stroke work index; RVSWI, right ventricular stroke work index; CaO2, arterial oxygen concentration; CvO2 , mixed-venous oxygen concentration; VO2I, oxygen consumption index; O2ER, oxygen extraction ratio; Q_ s =Q_ t , shunt fraction; P(A-a)O2, alveolar to arterial oxygen partial pressure difference. *Significantly different from baseline (e15 minutes; p < 0.05). ySignificantly different from D at this time point (p < 0.05). Note that variables calculated from blood gas data are only available at the time points at which blood gas data were obtained.

decreased the baseline MAP and SVRI. In addition, in the absence of anesthesia in the IV study, the cats were restrained during baseline data collection and may have had increased sympathetic tone. The similar maximum MAP and SVRI in the two studies, despite the presence of isoflurane in the present study, may suggest that dexmedetomidine, at the dose used, overcame the vasodilatory effect of isoflurane. Contrary to the observation after IV drug administration, PR did not significantly decrease following IM dexmedetomidine administration in this study. By contrast, the hemodynamic effects of dexmedetomidine with MK-467 delivered IM differed from the IV route in cats in the first 5 minutes after drug administration. During this period, PR, SVRI, CI and MAP were similar to values in D, with PR and CI decreasing, and SVRI and MAP increasing. After 5 minutes, the effects of MK-467 were apparent and the recorded cardiovascular variables were similar to those obtained after IV administration of the combination, with the exception that PR remained significantly lower than baseline. The delay in onset of MK467 effects is likely to be related to slower absorption of MK-467 compared with dexmedetomidine. Results

of a pharmacokinetic study of IM dexmedetomidine and MK-467 in cats suggested that MK-467 accelerates the absorption of dexmedetomidine, possibly due to local blocking of the vasoconstrictive effect of dexmedetomidine. When administered alone, MK467 has a faster absorption compared with dexmedetomidine; however, when administered together in a single injection, the absorption of dexmedetomidine becomes faster than that of MK-467 (Pypendop et al. 2016b). The absorption rate of MK-467 does not appear to be affected by the presence of dexmedetomidine. Based on this information, injection of the two drugs at separate locations may prevent the initial cardiovascular effects produced by dexmedetomidine. However, the need for two injections would diminish the convenience and possibly the clinical applicability of the combination. Alternatively, it is possible that mixing the drugs together alters the physicochemical characteristics of the solution, and in turn the absorption. In particular, the degree of drug ionization would be expected to affect absorption. The pKa of dexmedetomidine is 7.1, and calculated ionization of the drug at pH 3 or 4 (the pH of the solutions of dexmedetomidine with and

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9

Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Intramuscular dexmedetomidine MK-467 in cats KT Siao et al.

Figure 4 Mean ± standard deviation systemic vascular resistance index (SVRI) before and after intramuscular administration of dexmedetomidine (25 mg kg
1; circles; n ¼ 6) or dexmedetomidine (25 mg kg
1) with MK-467 (600 mg kg
1; triangles; n ¼ 5) at time 0 in cats. BW, body weight. *Significantly different from the respective baseline value (p < 0.05). ySignificant difference between treatments at this time point (p < 0.05).

Figure 5 Mean ± standard deviation oxygen delivery index (DO2I) before and after intramuscular administration of dexmedetomidine (25 mg kg
1; circles; n ¼ 6) or dexmedetomidine (25 mg kg
1) with MK-467 (600 mg kg
1; triangles; n ¼ 5) at time 0 in cats. BW, body weight.

without MK-467, respectively) is 99.9%. No information on the pKa of MK-467 could be found. In any case, it is possible that the lower pH of the combination solution would alter the change in pH, and ionization of dexmedetomidine and/or MK-467 following injection, and an effect on drug absorption cannot be excluded. DO2I was similar between the two treatments and not significantly different from baseline. This contrasts with the results of the studies performed in dogs under isoflurane anesthesia that showed a decrease in DO2 with a dexmedetomidine constant rate infusion (Lin et al. 2008; Pascoe 2015). Dexmedetomidine administration is expected to decrease DO2I resulting from decreased CI. However, Hba was 10

increased in D compared with baseline and with DM, increasing DO2I. Hba may have increased from splenic contraction induced by dexmedetomidine, or from the diuretic effect of dexmedetomidine decreasing plasma water (Saleh et al. 2005). However, TP was unchanged by both treatments in this study, suggesting that the former hypothesis may be more likely. When MK-467 was administered with dexmedetomidine, CI was preserved, and therefore DO2I was preserved as well. Therefore, while DO2I was similar with D and DM, this was due to different factors: with D, it was due to an increase in Hba in the face of decreased CI; with DM, it was due to preservation of CI. Arterial gas tensions were similar between treatments and thus did not contribute to

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Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Intramuscular dexmedetomidine MK-467 in cats KT Siao et al. Table 3 Packed cell volume, total protein concentration, and arterial pH, blood gas, lactate and electrolyte data in cats before and after intramuscular administration of dexmedetomidine (25 mg kg
1; treatment D; n ¼ 6) or dexmedetomidine (25 mg kg
1) with MK-467 (600 mg kg
1; treatment DM; n ¼ 5) at time 0 (data are mean ± standard deviation) Variable

Arterial PCV (%) Arterial TP (g dL
1) pHa PaCO2 (mmHg) PaCO2 (kPa) PaO2 (mmHg) PaO2 (kPa)
1 Arterial HCO
3 (mEq L )

Arterial SBE (mEq L
1) Hba (g dL
1) SaO2 (%) Arterial lactate (mmol L
1) Arterial Naþ (mmol L
1) Arterial Kþ (mmol L
1) Arterial Cl
(mmol L
1) Arterial Caþþ (mmol L
1)

Variable

Arterial PCV (%) Arterial TP (g dL
1) pHa PaCO2 (mmHg) PaCO2 (kPa) PaO2 (mmHg) PaO2 (kPa)
1 Arterial HCO
3 (mEq L )

Arterial SBE (mEq L
1)

Treatment

Time (minutes) 120

180

240

300

360

D DM D DM D DM D DM D DM D DM D DM D DM D DM D DM D DM D DM D DM D DM D DM D DM

26 ± 3 29 ± 8 5.0 ± 0.7 5.4 ± 0.6 7.34 ± 0.03 7.36 ± 0.05 35.5 ± 3.7 34.8 ± 6.7 4.5 ± 0.5 4.4 ± 0.80 336 ± 37 380 ± 50 44.3 ± 4.9 49.7 ± 6.8 18.7 ± 2.2 18.8 ± 1.7 -5.5 ± 2.4 -5.2 ± 1.2 8.6 ± 1.1 8.7 ± 3.3 100.0 ± 0.0 100.0 ± 0.0 1.4 ± 0.5 1.6 ± 0.3 149 ± 1 148 ± 2 3.2 ± 0.3 3.4 ± 0.4 122 ± 2 121 ± 2 1.26 ± 0.03 1.25 ± 0.04

37 ± 6* 33 ± 4 5.1 ± 0.8 5.4 ± 0.4 7.26 ± 0.03* 7.27 ± 0.04* 44.4 ± 6.0* 43.3 ± 7.1 5.7 ± 0.8* 5.5 ± 0.93 354 ± 69 394 ± 35 46.5 ± 9.2 51.6 ± 4.5 19.2 ± 1.7 19.3 ± 1.6 -6.1 ± 1.6 -5.7 ± 1.2 12.3 ± 1.8* 10.8 ± 1.0 100.0 ± 0.0 100.0 ± 0.0 1.7 ± 0.5 1.6 ± 0.3 147 ± 1 146 ± 1 3.2 ± 0.2 3.2 ± 0.4 120 ± 2 120 ± 2 1.28 ± 0.05 1.27 ± 0.03

38 ± 3* 29 ± 3y 5.1 ± 0.8 5.1 ± 0.4 7.23 ± 0.03* 7.29 ± 0.04* 44.9 ± 5.7* 41.0 ± 5.5 5.9 ± 0.8* 5.2 ± 0.67 402 ± 52 378 ± 40 53.1 ± 6.9 49.6 ± 5.3 18.2 ± 1.8 19.0 ± 1.3 -7.3 ± 1.9 -5.9 ± 1.1 12.9 ± 1.0* 9.5 ± 0.8y 100.0 ± 0.0 100.0 ± 0.0 1.8 ± 0.5 1.4 ± 0.3 145 ± 1 144 ± 2* 3.2 ± 0.4 3.3 ± 0.3 119 ± 2 119 ± 3 1.26 ± 0.06 1.24 ± 0.05

34 ± 5* 23 ± 3y 4.6 ± 0.5 4.8 ± 0.3 7.25 ± 0.03* 7.31 ± 0.03 41.6 ± 4.0 38.6 ± 5.2 5.3 ± 0.5 4.9 ± 0.67 336 ± 32 305 ± 31* 44.1 ± 4.3 40.1 ± 4.3* 17.7 ± 1.4 18.6 ± 1.5 -7.6 ± 1.6 -6.0 ± 1.3 12.0 ± 1.3* 7.7 ± 0.3y 100.0 ± 0.0 100.0 ± 0.0 1.4 ± 0.5 1.3 ± 0.4 143 ± 3* 143 ± 1* 3.5 ± 0.4 3.4 ± 0.4 119 ± 3 118 ± 2 1.19 ± 0.04 1.20 ± 0.04

34 ± 3* 23 ± 2y 5.0 ± 0.6 4.9 ± 0.4 7.28 ± 0.03 7.33 ± 0.03 41.4 ± 3.2 38.9 ± 4.8 5.2 ± 0.4 5.1 ± 0.53 369 ± 52 329 ± 32 48.3 ± 6.9 43.3 ± 4.5 18.9 ± 1.9 19.6 ± 1.2 -6.1 ± 2.1 -4.9 ± 1.0 12.1 ± 0.5* 7.6 ± 0.3y 100.0 ± 0.0 100.0 ± 0.0 1.0 ± 0.4 1.2 ± 0.2 141 ± 2* 141 ± 1* 3.9 ± 0.5 3.6 ± 0.5 117 ± 2* 116 ± 2* 1.20 ± 0.06 1.21 ± 0.04

Treatment

Time (minutes) 120

180

240

300

360

35 ± 3* 25 ± 3y 5.3 ± 0.4 5.0 ± 0.3 7.28 ± 0.06 7.31 ± 0.04 42.0 ± 2.8 41.2 ± 5.5 5.3 ± 0.3 5.2 ± 0.7 374 ± 56 361 ± 21 48.8 ± 7.5 47.3 ± 2.9 19.2 ± 1.8 20.2 ± 1.4 e5.7 ± 2.4

35 ± 4* 25 ± 1y 5.4 ± 0.4 5.1 ± 0.5 7.30 ± 0.04 7.33 ± 0.03 43.3 ± 2.3* 40.0 ± 6.5 5.6 ± 0.3* 5.1 ± 0.8 387 ± 46 376 ± 31 50.8 ± 6.0 49.2 ± 4.1 20.5 ± 2.3 20.4 ± 2.1 e4.3 ± 2.7

35 ± 4* 25 ± 3y 5.5 ± 0.5 5.0 ± 0.6 7.29 ± 0.05 7.33 ± 0.03 45.7 ± 3.3* 40.8 ± 6.4 5.9 ± 0.4* 5.2 ± 0.8 382 ± 40 377 ± 22 50.3 ± 5.3 49.5 ± 2.8 21.6 ± 2.2 20.9 ± 2.3 e3.2 ± 2.7

34 ± 4* 25 ± 3y 5.4 ± 0.5 5.1 ± 0.5 7.32 ± 0.08 7.33 ± 0.02 43.0 ± 5.7 42.5 ± 5.8 5.5 ± 0.7 5.5 ± 0.7 398 ± 43 374 ± 18 52.5 ± 5.7 49.1 ± 2.4 21.6 ± 2.7 21.8 ± 2.2 e2.9 ± 3.3

33 ± 5* 26 ± 4y 5.3 ± 0.4 5.2 ± 0.4 7.33 ± 0.08 7.33 ± 0.02 42.9 ± 8.2 44.4 ± 5.8 5.5 ± 1.1 5.7 ± 0.8 399 ± 38 397 ± 28 52.4 ± 5.1 52.3 ± 3.7 21.5 ± 2.7 22.7 ± 1.9* e3.0 ± 2.9

D DM D DM D DM D DM D DM D DM D DM D DM D

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11

Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Intramuscular dexmedetomidine MK-467 in cats KT Siao et al. Table 3 (continued ) Variable

Treatment

Hba (g dL
1) SaO2 (%) Arterial lactate (mmol L
1) Arterial Naþ (mmol L
1) Arterial Kþ (mmol L
1) Arterial Cl
(mmol L
1) Arterial Caþþ (mmol L
1)

DM D DM D DM D DM D DM D DM D DM D DM

Time (minutes) 120

180

240

300

360

e4.3 ± 1.2 12.4 ± 1.3* 7.8 ± 0.8y 100.0 ± 0.0 100.0 ± 0.0 1.0 ± 0.4 1.4 ± 0.4 141 ± 4* 141 ± 2* 4.6 ± 1.0* 3.8 ± 0.3 116 ± 3* 114 ± 1* 1.21 ± 0.05 1.23 ± 0.04

e3.9 ± 1.9 12.5 ± 1.4* 8.6 ± 0.3y 100.0 ± 0.0 100.0 ± 0.0 1.0 ± 0.3 1.3 ± 0.5 144 ± 6 143 ± 2* 4.4 ± 1.1 3.7 ± 0.4 117 ± 2* 116 ± 2* 1.24 ± 0.07 1.24 ± 0.06

e3.4 ± 2.1 12.1 ± 1.6* 8.2 ± 0.7y 100.0 ± 0.0 100.0 ± 0.0 1.0 ± 0.3 1.2 ± 0.3 146 ± 6 146 ± 2 4.0 ± 1.0 3.6 ± 0.4 118 ± 3* 116 ± 2* 1.26 ± 0.07 1.25 ± 0.04

e2.6 ± 2.1 12.0 ± 1.6* 8.5 ± 0.9y 100.0 ± 0.0 100.0 ± 0.0 0.9 ± 0.4 1.2 ± 0.3 148 ± 5 147 ± 1 3.7 ± 0.8 3.5 ± 0.5 119 ± 2 117 ± 1* 1.26 ± 0.06 1.27 ± 0.04

e1.7 ± 1.7* 11.7 ± 1.9* 8.8 ± 1.0y 100.0 ± 0.0 100.0 ± 0.0 1.1 ± 0.4 1.4 ± 0.4 149 ± 5 147 ± 1 3.7 ± 0.9 3.5 ± 0.3 119 ± 2 116 ± 2* 1.26 ± 0.05 1.29 ± 0.03

PCV, packed cell volume; TP, total protein; pHa, arterial pH; PaCO2, partial pressure of carbon dioxide in arterial blood; PaO2, partial pressure of oxygen in arterial blood; HCO
3 , bicarbonate concentration; SBE, arterial standard base excess; Hba, arterial hemoglobin concentration; SaO2, arterial hemoglobin oxygen saturation; lactate, lactate concentration; Naþ, sodium concentration; Kþ, potassium concentration, Cl
, chloride concentration; Caþþ, ionized calcium concentration. *Significantly different from baseline (e15 minutes; p < 0.05). ySignificantly different from D at this time point (p < 0.05).

differences in arterial oxygen concentration. Small but significant changes in plasma electrolyte concentrations were observed in both treatments. These changes may be related to the repeated injection of water (dextrose 5% in water) for CO determination. Interestingly, despite the effects of MK-467 on CI, MAP and SVRI, no increase in PR was seen after the initial decrease in this study. Visual inspection of data revealed that PR was similar between the two treatments throughout the study period. This is in contrast with other studies investigating MK-467 and dexmedetomidine in cats, regardless of the route of administration, in which PR was maintained, or returned, close to baseline values when MK-467 and dexmedetomidine were coadministered. While beyond the scope of the present investigation, isoflurane may have decreased the sensitivity and/or capacity of baroreflex-dependent changes in PR (Seagard et al. 1983; Sellgren et al. 1992). Further investigation is warranted, because if the improvement in PR induced by MK-467 is less in cats anesthetized with isoflurane compared with conscious cats, this may reduce the usefulness of MK-467 in many clinically relevant situations in this species. Nevertheless, the relevance of the persisting decrease in PR may be clinically limited as CI was better maintained with dexmedetomidine-MK-467 than with dexmedetomidine alone. It should be noted that PR was significantly lower than baseline at several time points in DM, whereas no significant change 12

from baseline was observed in D. This may be a statistical type II error, as the changes appear very similar in both treatments. The fact that neither a significant treatment nor a significant treatmentetime interaction was detected also suggests that the pattern in PR changes was similar with both treatments. The changes in T should be interpreted with caution given that active efforts were made to attempt to keep T within a predetermined range. T increased in D but decreased in DM, which may reflect the difference in SVRI, as vasoconstriction in D may have limited heat loss to the environment. There are several limitations to this study. First, this study is limited by its small sample size. Based on our power analysis, six cats were selected to detect a moderate difference in PR. However, one cat had significantly abnormal baseline values of CO compared with the other cats, and was excluded from the DM analysis. This reduced statistical power and may have resulted in an increase in type II errors. Second, the cats were anesthetized with isoflurane. Isoflurane has been shown to have significant cardiovascular effects in a variety of species. Isoflurane may have had an impact on the results by potentiating the decrease in CO and by minimizing the increase in SVRI. The cats in this study were maintained at a light plane of anesthesia to minimize the concentration-dependent effects of isoflurane (Pagel et al. 1991). Nevertheless, the

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Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

Intramuscular dexmedetomidine MK-467 in cats KT Siao et al.

FE0 Iso

that was used may be considered high, although adjusted to maintain mild jaw tone throughout the study. Isoflurane anesthesia was necessary, as the instrumentation was not maintained in the two first experiments, when attempting to use awake cats. The authors consider that, even with the inclusion of isoflurane, the changes during these treatments would be qualitatively similar to the temporal pattern of changes occurring in conscious cats. The similarities between the present study and the previously published IV administration study in conscious cats support this hypothesis (Pypendop et al. 2016a). In conclusion, IM coadministration of MK-467 and dexmedetomidine in isoflurane-anesthetized cats resulted in initial cardiovascular changes attributed to the effect of dexmedetomidine. These changes lasted < 10 minutes and were followed by attenuation of these cardiovascular effects and improved hemodynamics compared with dexmedetomidine administered IM alone. Intramuscular coadministration of MK-467 with dexmedetomidine may be useful in situations in which longer-lasting hypertension and hemodynamic depression is of concern. Uncited reference Q4

Siggaard-Andersen et al., 1988. Acknowledgements

Q2

This study was supported by the Miller Trust fund, San Francisco Foundation, the Winn Feline Foundation, and the Center for Companion Animal Health, School of Veterinary Medicine, University of California, Davis. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the views of the funding agencies. MK-467 was provided free of charge by Vetcare Ltd. Authors’ contributions KTS: conducted experiments, data analysis, data interpretation, drafted the manuscript. BHP: study design, conducted experiments, statistical analysis, data interpretation, edited the manuscript. JH, JEI: study design, edited the manuscript. Conflict of interest Dr. Honkavaara received funding from Vetcare Ltd. during the studies.

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Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

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Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.vaa.2017.02. 010.

© 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., ▪, 1e14

Please cite this article in press as: Siao KT, Pypendop BH, Honkavaara J et al. Hemodynamic effects of dexmedetomidine, with and without MK-467, following intramuscular administration in cats anesthetized with isoflurane, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2017.02.010

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