Effects of 2 different infusion rates of medetomidine on sedation score, cardiopulmonary parameters, and serum levels of medetomidine in healthy dogs

Abstract

The effects of 2 different continuous rate infusions (CRIs) of medetomidine over an 8-hour period on sedation score, selected cardiopulmonary parameters, and serum levels of medetomidine were evaluated in 6 healthy, conscious dogs using a crossover study design. The treatment groups were: CONTROL = saline bolus followed by saline CRI; MED1 = 2 μg/kg body weight (BW) medetomidine loading dose followed by 1 μg/kg BW per hour CRI; and MED2 = 4 μg/kg BW medetomidine loading dose followed by 2 μg/kg BW per hour CRI. Sedation score (SS), heart rate (HR), respiratory rate (RR), temperature (TEMP), systolic arterial pressure (SAP), mean arterial pressure (MAP), and diastolic arterial pressure (DAP), arterial and mixed venous blood gas analyses, lactate, and plasma levels of medetomidine were evaluated at baseline, at various intervals during the infusion, and 2 h after terminating the infusion. Statistical analysis involved a repeated measures linear model. Both infusion rates of medetomidine-induced dose-dependent increases in SS and dose-dependent decreases in HR, SAP, MAP, and DAP were measured. Respiratory rate (RR), TEMP, central venous pH, central venous oxygen tension, and oxygen extraction ratio also decreased significantly in the MED2 group at certain time points. Arterial oxygen and carbon dioxide tensions were not significantly affected by either infusion rate. In healthy dogs, both infusion rates of medetomidine-induced clinically relevant sedative effects, accompanied by typical alpha₂ agonist-induced hemodynamic effects, which plateaued during the infusion and subsequently returned to baseline. While additional studies in unhealthy animals are required, the results presented here suggest that medetomidine infusions at the doses studied may be useful in canine patients requiring sedation for extended periods.

Introduction

Medetomidine is classified as an alpha₂-adrenergic receptor agonist (alpha₂ agonist) and is used clinically in veterinary medicine to produce sedation and analgesia (1–3). It is a racemic mixture of 2 optical enantiomers, levomedetomidine and dexmedetomidine. Levomedetomidine is considered to be pharmacologically inert, while dexmedetomidine induces all of the relevant alpha₂ receptor-mediated effects (4,5). The drug is highly selective for the alpha₂ receptor with an alpha₂:alpha₁ binding ratio of 1620:1 (4). Due to its lipophilic structure, medetomidine is rapidly absorbed after intramuscular (IM) administration and reaches peak plasma concentrations in approximately 0.5 h (6). Intravenous (IV) administration results in a more rapid onset of action and potentially more profound cardiovascular effects than the intramuscular route (7). The drug is eliminated relatively swiftly, with reported half-lives ranging from 1 to 1.3 h (5,6).

Medetomidine and, more recently, dexmedetomidine are commonly used in dogs requiring sedation and analgesia for short, noninvasive procedures or as part of a preanesthetic protocol prior to induction of general anesthesia. Despite the desirable clinical properties of these drugs, 2 major factors limit the scope of their use in a clinical setting: i) the adverse cardiovascular side effect profile, and ii) the limited duration of action of a single bolus injection.

Medetomidine bolus administration is associated with time-dependent changes in arterial blood pressure (hypertension followed by normotension or hypotension), increased systemic vascular resistance, decreased heart rate, and decreased cardiac index (7–9). It is still unclear whether or not these cardiovascular effects are dose-dependent in dogs. Pypendop and Verstegen (7) performed a dose titration study and reported hemodynamic changes after intravenous bolus administration of doses as low as 1 to 2 μg/kg bodyweight (BW), although these changes were less pronounced than those observed with higher doses. Despite the persistence of hemodynamic effects at these low doses, sedation was minimal or absent (7). Due to concerns about the cardiovascular side effect profile of medetomidine, the drug is usually reserved for use in patients with normal hemodynamic function and often at doses lower than those recommended on the label.

Intravenous bolus administration of medetomidine is associated with a relatively short duration of action that appears to be dose-dependent (7). In a study by Kuo and Keegan (9), a single injection of 20 μg/kg BW, IV produced a mean duration of lateral recumbency of 103.4 min and a mean interval until normal walking of 153.7 min. Lower doses are associated with considerably shorter durations of effect (7). While this time frame facilitates completion of short procedures requiring sedation and analgesia, there is considerable interest in extending the duration of effect of medetomidine or dexmedetomidine by administering them as continuous rate infusions (CRIs).

Several studies have evaluated the effects of dexmedetomidine during anesthesia with isoflurane (10–12) or propofol (12). The investigators concluded that dexmedetomidine CRIs may be useful adjuncts as part of a balanced anesthetic protocol. One of these studies also evaluated the continued administration of dexmedetomidine (approximately 1 μg/kg BW per hour) for an additional 22 h after a 2-h anesthetic episode, but only reported heart rate (HR), respiratory rate (RR), temperature (TEMP), and electrocardiographic findings during this period (12). In a recent study, Carter et al (13) administered medetomidine at 1, 2, and 3 μg/kg BW per hour for 60 min to conscious dogs and reported significant decreases in cardiac index and heart rate. Similarly, Grimm et al (14) administered medetomidine at 1.5 μg/kg BW per h for 11 h in combination with a 15 μg/kg BW bolus of fentanyl and documented significant reductions in cardiac index and heart rate, as well as significant increases in left atrial pressure. Ethier et al (15) also administered medetomidine at 1 μg/kg BW per hour in combination with a benzodiazepine and morphine to mechanically ventilated dogs for 24 h and reported significant reductions in heart rate and cardiac index and increases in oxygen consumption and oxygen extraction ratio.

The objective of this study was to evaluate the effects of 2 different CRIs of medetomidine in conscious dogs over an 8-hour period compared to a saline control group. We hypothesized that both doses of medetomidine would induce significant sedative and hemodynamic effects compared to a saline control and that the magnitude of these effects would be dose-dependent, correlating with plasma medetomidine levels.

Materials and methods

Animals

All procedures were approved by the Animal Care Committee of the University of Prince Edward Island. Six purpose-bred, intact beagles (3 male and 3 female), 22 to 23 mo old and weighing 6.5 to 8.1 kg, were studied. Based on physical examination, complete blood (cell) counts (CBC), and serum biochemical profiles, all dogs were found to be in good health before the study. The dogs were fed a standard commercially prepared diet and provided access to outdoor exercise twice daily throughout the trial. Experiments were conducted in a separate room away from the dogs’ regular housing facility. The dogs were purposely not acclimated to the room or the investigator before the study began in an effort to mimic a veterinary hospital setting. Food was withheld on the morning of the trials and all trials started at 8 am. All dogs had a rest period of at least 10 d between treatments.

Treatments

There were 3 treatment groups, each consisting of an intravenous loading dose followed by an 8-hour CRI: CONTROL = saline bolus followed by a saline CRI; MED1 = medetomidine [as hydrochloride (Domitor; Pfizer Animal Health, Kirkland, Quebec)] at 2 μg/kg BW loading dose followed by a 1 μg/kg BW per hour CRI; and MED2 = medetomidine at 4 μg/kg BW loading dose followed by a 2 μg/kg BW per hour CRI. Each dog received all 3 treatments administered in random order with intervals of at least 10 d between treatments. All treatments were prepared and labeled by an individual not directly involved with the investigation and the volumes were adjusted with sterile water when necessary to ensure that all injected volumes were equal. Investigators were blinded as to which treatment was administered. Additional data on plasma catecholamine, cortisol, glucose, and insulin levels were collected concurrently and are presented elsewhere.

Study procedure

Before treatment was administered, each dog underwent a brief (approximately 10 min) episode of anesthesia to facilitate the placement of venous and arterial catheters. Sevoflurane (Sevoflo; Abbott Laboratories, North Chicago, Illinois, USA) was delivered at 5% in oxygen via a face mask using a rebreathing system (Universal F-Circuit; Dispomed, Joliette, Quebec) and a small animal anesthetic machine (Moduflex Elite; Dispomed). The oxygen flow rate was 4 L/min. The trachea was intubated, the dog placed in lateral recumbency, and the vaporizer and oxygen flow rate adjusted to maintain a light plane of anesthesia (approximately 2.5% to 3.5% and 1 L/min, respectively). A 20-ga, 2.5-cm peripheral catheter (Angiocath; BD Canada, Toronto, Ontario) was placed in the cephalic vein for drug delivery, an 18-ga, 20-cm single lumen central venous catheter (Arrow Medical Products, Toronto, Ontario) was placed via the jugular vein and advanced to the level of the right atrium for central venous sampling, and a 22-ga, 2.5-cm peripheral catheter (Angiocath; BD Canada) was placed in the dorsal pedal artery to measure arterial blood pressures and for arterial sampling. Hair was shaved in 3 areas over the thorax and adhesive patches (Life Patches EKG Electrodes; Medtronic of Canada, Toronto, Ontario) were placed to facilitate continuous electrocardiographic (ECG) monitoring. After these procedures were completed, sevoflurane was discontinued and the dogs were allowed to recover on the anesthetic table for at least 20 min after extubation before being placed in the holding cage for collection of baseline data.

Data were collected using a standard protocol for all trials. Sedation was scored first, then cardiopulmonary parameters and rectal body temperature were recorded, and finally arterial and venous blood samples were collected. After baseline data were collected, the loading dose was administered over 10 min, followed by initiation of the CRI using an automated syringe pump (Medfusion 3500; Smith Medical Canada, Markham, Ontario). The pump was placed outside the cage and connected to the cephalic catheter using an extension set. Throughout the study, the dogs remained in this cage on a circulating warm-water blanket in a quiet room with the door closed and away from other animals. They were not subjected to any particular auditory or tactile stimulation before sedation scoring. At the 10-h mark, 2 h after the infusion had ended, and when data collection was complete, the catheters and ECG electrodes were removed and the dogs were returned to their normal housing facility.

Evaluation of sedative effects

Sedation was scored by the primary investigator using a 1- to 6-point ordinal scale (Table I) (16) at baseline, 0.25, 1, 2, 4, 6, 8, and 10 h.

Table I.

Sedation scale used to score level of sedation at baseline, during the 8-hour infusion, and 2 hours after terminating the infusion in dogs receiving saline (CONTROL), medetomidine at 1 μg/kg BW per hour (MED1), or medetomidine at 2 μg/kg BW per hour (MED2)

Alert	No motor deficits, equivalent to pre-baseline	1
Faint sedation	Stands, walks, some ataxia and disorientation	2
Slight sedation	Stands but ataxic, can remain sternal	3
Mild sedation	Cannot stand, can remain sternal, may struggle	4
Moderate sedation	Can raise head, usually laterally recumbent	5
Heavy sedation	Nonresponsive, cannot raise head	6

Evaluation of cardiopulmonary effects

Electrocardiographic leads remained attached throughout the experiment and were connected to a multiparameter patient monitor (DASH 2000 Patient Monitor; GE Healthcare Bio-Sciences, Piscataway, New Jersey, USA) and set to display lead II. This facilitated evaluation of HR and rhythm. Arterial blood pressures were measured by connecting the dorsal pedal catheter to a 30.5 cm length of heparinized saline-filled pressure tubing, which was in turn connected to a resistance-type pressure transducer (TruWave Disposable Pressure Transducer Kit; Edwards Lifesciences Canada, Mississauga, Ontario). The transducer interfaced with the same patient monitor that displayed the graphical representation of the arterial waveform and the numeric values for pulse rate, systolic arterial pressure (SAP), mean arterial pressure (MAP), and diastolic arterial pressure (DAP). The transducer was placed at the level of the right atrium with the dog in lateral recumbency and a 1-point static calibration was performed by exposing the transducer to atmospheric pressure. Values for HR, RR, SAP, MAP, DAP, and TEMP were recorded at baseline, 0.25, 1, 2, 4, 6, 8, and 10 h.

Samples for analysis of arterial and central venous blood gas were obtained from the dorsal pedal and central venous catheters, respectively. The first 1 mL of blood drawn was discarded and the sample was collected into a heparinized syringe (Quik ABG; Vital Signs, Totowa, New Jersey, USA) and the catheter was flushed with heparinized saline solution. Samples were analyzed immediately (IRMA TruPoint Blood Analysis System; ITC, Piscataway, New Jersey, USA) and all values were corrected to body temperature. Values for arterial and central venous pH, oxygen tension [arterial partial pressure (PaO₂) and central venous partial pressure (PcvO₂), respectively], oxygen saturation [saturation of hemoglobin in arterial blood (SaO₂) and in central-venous blood (ScvO₂), respectively], arterial carbon dioxide tension (PaCO₂), bicarbonate concentration (HCO₃⁻), and hemoglobin concentration (Hb) were recorded at baseline, 1, 8, and 10 h. The oxygen extraction ratio (ERO₂) was calculated as

$$\begin{array}{l}\{[(\text{Hb}\times {\text{SaO}}_2\times 1.34)+(0.0031\times {\text{PaO}}_2)]-\\ [(\text{Hb}\times {\text{ScvO}}_2\times 1.34)+(0.0031\times {\text{PcvO}}_2)]\}/\\ [(\text{Hb}\times {\text{SaO}}_2\times 1.34)+(0.0031\times {\text{PaO}}_2)].\end{array}$$

Samples for whole blood arterial lactate concentrations were obtained and analyzed immediately using a portable lactate test meter (Lactate Pro; Arkray, Kyoto, Japan). Lactate levels were also recorded at baseline, 1, 8, and 10 h.

Evaluation of serum medetomidine concentrations

Venous samples for medetomidine analyses (5 mL) were obtained from the central venous catheter and transferred to 10-mL dry vacuum tubes and allowed to clot at room temperature for at least 30 min. Tubes were centrifuged for 10 min at 1500 × g at room temperature and the serum was harvested and stored at −80°C pending analysis with liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI/MS/MS) (LC-MS/MS System PESciex API 3+; Applied Biosystem/MDS Sciex, Concord, Ontario) according to a technique published previously (17). The lower limit of detection for this method was 50 pg/mL, the coefficient of variation for the analysis was ≤ 6.9%, and the percentage bias was ≤ 6%. Medetomidine concentrations were obtained at baseline, 0.25, 1, 8, and 10 h.

Statistical analysis

All numerical variables were analyzed using a repeated measures analysis of variance for a crossover design based on the following factors: treatment, time, treatment sequence, and treatment by time interaction, with the animal nested into treatment as a random effect variable. Selected a priori contrasts were also performed to evaluate differences between pairs of means as follows: i) differences between mean values at various time points compared to baseline within a particular treatment group, and ii) differences between mean values at various time points between treatment groups. For sedation score (SS), the Wilcoxon rank-sum test was applied. For all tests, the level of significance was set at P < 0.05. Data are expressed as mean [standard deviation (SD)] unless otherwise indicated.

Results

It took approximately 10 min to catheterize the 3 sites under sevoflurane anesthesia, although 1 dog required 20 min of general anesthesia to complete instrumentation for 2 of the trials. Subsequent recovery from anesthesia was uneventful in all dogs for all trials, although 1 dog consistently vocalized for approximately 5 min during recovery in each of the trials. Interestingly, none of the dogs in any of the trials urinated during the 8-hour study period, but 1 dog in the control group and 2 dogs in each of the medetomidine groups urinated between the 8- and 10-hour mark.

Sedative effects

Both infusion rates of medetomidine induced obvious sedative effects within minutes of beginning the loading dose. In both MED groups at all time points during the infusion (except at 1 h in the MED1 group where P = 0.0550), SS was significantly higher than in the CONTROL group. Signs of sedation began to wane in the dogs receiving medetomidine within 20 to 40 min of stopping the infusions, although this was variable and recovery times were not specifically analyzed. No differences were noted between the 2 infusion rates of medetomidine. At 2 h after termination of the infusion, SS had returned toward baseline and was not significantly different from the CONTROL group. The level of sedation also appeared to be dose-dependent as SS was significantly higher in the MED2 group than in the MED1 group at 0.25, 2, 4, and 6 h during the infusions, although these differences did not reach statistical significance at 1 and 8 h. A slight trend toward increasing SS was also evident in the CONTROL group during the infusion, with SS at 6 h significantly higher than at baseline and 10 h (P = 0.0040) (Figure 1).

Figure 1.

Mean (± SD) sedation scores versus time in dogs receiving saline (CONTROL), medetomidine at 1 μg/kg body weight (BW) per hour (MED1), or medetomidine at 2 μg/kg per hour (MED2). See Table I for description of sedation scale.

Cardiopulmonary effects

Heart rates (HRs) were not different among the 3 groups at baseline. In both MED groups at all time points during the infusion, HR was significantly lower than in the CONTROL group. Two hours after termination of the infusion, HR in both groups had returned toward baseline and was not significantly different from the CONTROL group. There was some evidence that the effect on HR was dose-dependent, with HR significantly lower in the MED2 group than in the MED1 group, although this was evident only at 0.25 and 1 h. There was a downward trend in HR in the CONTROL group during the infusion with HR at 2, 4, 6, and 8 h significantly lower than at baseline and 10 h (Table II, Figure 2).

Table II.

Cardiopulmonary, arterial and central venous blood gas, oxygen extraction ratio, and whole blood arterial lactate data (mean ± SD) measured at baseline, during the 8 hour infusion, and 2 hours after terminating the infusion in dogs receiving saline (CONTROL), medetomidine at 1 μg/kg body weight (BW) per hour (MED1), or medetomidine at 2 μg/kg BW per hour (MED2)

		Baseline	During infusion						Post-infusion
Variable	Group	0 hours	0.25 hours	1 hour	2 hours	4 hours	6 hours	8 hours	10 hours
HR (bpm)	CONTROL	115 ± 23	103 ± 12	95 ± 15	83 ± 11c	68 ± 8c	64 ± 8c	76 ± 13c	101 ± 12
	MED1	118 ± 19	68 ± 11a,c	69 ± 9a,c	61 ± 13a,c	53 ± 11a,c	48 ± 11a,c	51 ± 11a,c	102 ± 12
	MED2	114 ± 16	50 ± 5a,b,c	51 ± 6a,b,c	48 ± 10a,c	44 ± 8a,c	42 ± 7a,c	43 ± 8a,c	107 ± 11
SAP (mmHg)	CONTROL	152 ± 10	154 ± 15	153 ± 10	147 ± 6	154 ± 10	157 ± 9	155 ± 9	154 ± 17
	MED1	155 ± 12	144 ± 10	142 ± 6a	141 ± 12	141 ± 12	145 ± 12	142 ± 15	153 ± 17
	MED2	155 ± 9	137 ± 5a,c	130 ± 4a,b,c	128 ± 7a,c	131 ± 9a,c	129 ± 8a,b,c	129 ± 4a,c	152 ± 13
MAP (mmHg)	CONTROL	129 ± 6	122 ± 16	124 ± 7	112 ± 11	115 ± 9	118 ± 13	120 ± 6	121 ± 9
	MED1	130 ± 7	112 ± 6c	109 ± 9a,c	110 ± 12c	111 ± 5c	110 ± 8c	109 ± 13c	118 ± 12
	MED2	129 ± 5	109 ± 6c	103 ± 5a,c	102 ± 4c	101 ± 3a,b,c	103 ± 2a,c	101 ± 7a,c	119 ± 8
DAP (mmHg)	CONTROL	109 ± 6	102 ± 15	100 ± 7	95 ± 8	95 ± 9	100 ± 14	98 ± 12	100 ± 12
	MED1	112 ± 9	94 ± 11	93 ± 10c	87 ± 12c	98 ± 9	93 ± 9c	91 ± 12c	99 ± 9
	MED2	111 ± 6	94 ± 8c	90 ± 8c	84 ± 4a,c	83 ± 6a,b,c	85 ± 4a,c	83 ± 8c	102 ± 11
TEMP (°C)	CONTROL	37.3 ± 0.4	38.0 ± 0.3c	38.0 ± 0.3c	38.0 ± 0.2c	37.6 ± 0.3	37.6 ± 0.3	37.7 ± 0.3	38.0 ± 0.3c
	MED1	37.4 ± 0.4	37.8 ± 0.2	37.8 ± 0.3	37.6 ± 0.3	37.5 ± 0.4	37.4 ± 0.4	37.5 ± 0.6	38.4 ± 0.5c
	MED2	37.0 ± 0.2	37.4 ± 0.2a,b	37.2 ± 0.2a,b	37.3 ± 0.5a	37.2 ± 0.6	37.2 ± 0.6	37.5 ± 0.4	38.4 ± 0.3c
RR (brpm)	CONTROL	28 ± 3	23 ± 2c	23 ± 2c	21 ± 2c	20 ± 0c	19 ± 2c	20 ± 3c	24 ± 4
	MED1	26 ± 3	21 ± 4c	21 ± 2c	19 ± 2c	18 ± 2c	17 ± 2c	17 ± 2c	22 ± 2
	MED2	27 ± 3	19 ± 2c	19 ± 2a,c	17 ± 2a,c	17 ± 2c	16 ± 0a,c	17 ± 2a,c	23 ± 2c
ERO2 (%)	CONTROL	13.9 ± 3.0		12.5 ± 3.6				14.7 ± 9.2	19.3 ± 5.9
	MED1	13.7 ± 3.4		13.8 ± 4.1				23.5 ± 6.2c,d	19.1 ± 2.7
	MED2	15.9 ± 3.8		18.6 ± 3.6a				21.6 ± 5.5	16.2 ± 5.7
Arterial pH	CONTROL	7.38 ± 0.03		7.40 ± 0.03				7.40 ± 0.03	7.40 ± 0.01
	MED1	7.38 ± 0.01		7.40 ± 0.02				7.42 ± 0.01	7.38 ± 0.03
	MED2	7.36 ± 0.03		7.39 ± 0.03				7.40 ± 0.03	7.42 ± 0.06
PaO2 (mmHg)	CONTROL	119.1 ± 8.4		122.1 ± 7.9				107.5 ± 10.1d	107.2 ± 6.3d
	MED1	122.2 ± 4.1		118.5 ± 9.4				114.0 ± 9.0	111.9 ± 5.4
	MED2	119.8 ± 5.8		115.6 ± 7.6				109.7 ± 12.1	109.3 ± 9.3
PaCO2 (mmHg)	CONTROL	37.7 ± 1.7		35.7 ± 2.2				37.4 ± 3.6	35.5 ± 2.5
	MED1	37.8 ± 0.8		36.8 ± 0.8				35.9 ± 2.0	37.0 ± 3.2
	MED2	39.5 ± 1.6		38.4 ± 2.3				36.2 ± 2.0	38.3 ± 1.6
HCO3− (mmol/L)	CONTROL	21.9 ± 1.4		21.7 ± 0.5				22.5 ± 0.8	21.6 ± 0.7
	MED1	21.9 ± 0.6		22.1 ± 0.9				22.7 ± 1.0	21.9 ± 0.3
	MED2	22.6 ± 0.6		22.8 ± 1.3				22.3 ± 1.6	22.5 ± 1.4
Venous pH	CONTROL	7.35 ± 0.04		7.39 ± 0.03				7.40 ± 0.03	7.38 ± 0.04
	MED1	7.34 ± 0.03		7.35 ± 0.02a				7.37 ± 0.04	7.36 ± 0.01
	MED2	7.32 ± 0.03		7.34 ± 0.03a				7.36 ± 0.02	7.38 ± 0.02
PcvO2 (mmHg)	CONTROL	50.6 ± 4.6		53.7 ± 4.1				53.9 ± 3.8	47.7 ± 4.1
	MED1	51.2 ± 3.3		52.3 ± 5.0				46.0 ± 2.7a	49.9 ± 2.7
	MED2	50.8 ± 6.7		47.2 ± 4.0				46.8 ± 4.0a	51.6 ± 6.1
Lactate (mmol/L)	CONTROL	1.5 ± 0.4		1.4 ± 0.3				0.7 ± 0.3c	0.9 ± 0.5c
	MED1	1.5 ± 0.4		1.1 ± 0.2				0.9 ± 0.3c	0.9 ± 0.3c
	MED2	1.8 ± 0.5		1.4 ± 0.2				1.1 ± 0.6c	0.8 ± 0.3c

^aMean differs from CONTROL group at same time point (P < 0.05).

^bMean differs from MED1 group at same time point (P < 0.05).

^cMean differs from baseline within group (P < 0.05).

^dMean differs from time = 1 hour within group (P < 0.05).

SD — standard deviation; HR — heart rate; SAP — systolic arterial pressure; MAP — mean arterial pressure; DAP — diastolic arterial pressure; TEMP — temperature; RR — respiratory rate; ERO₂ — oxygen extraction ratio; PaO₂ — arterial partial pressure of oxygen; PaCO₂ — arterial carbon dioxide tension; HCO₃⁻ — bicarbonate concentration of oxygen; PcvO₂ — central venous partial pressure of oxygen.

Figure 2.

Mean (± SD) heart rate versus time in dogs receiving saline (CONTROL), medetomidine at 1 μg/kg body weight (BW) per hour (MED1), or medetomidine at 2 μg/kg BW per hour (MED2).

Systolic arterial pressures (SAPs) were not different among the 3 groups at baseline or at 10 h. In the MED2 group, SAP was significantly lower than in the CONTROL group at all time points during the infusion, while in the MED1 group the difference was only statistically significant at 1 h. There was some evidence that the effect on SAP was dose-dependent, with SAP in the MED2 group significantly lower than in the MED1 group, although this difference was significant only at 1 and 6 h (Table II).

Results for MAP were similar to SAP, with MAP significantly lower in the MED2 group than in CONTROL at 1, 4, 6, and 8 h, but only at 1 h in the MED1 group. In MED2, MAP was significantly lower than in MED1 at 4 h only (Table II, Figure 3). For DAP, there were fewer differences among groups, with DAP in the MED2 group significantly lower than in the CONTROL group at 2, 4, and 6 h only. At no time point was DAP in MED1 different from the CONTROL group. In MED2, however, DAP was significantly lower than in MED1 at 4 h (Table II).

Figure 3.

Mean (± SD) mean arterial pressure versus time in dogs receiving saline (CONTROL), medetomidine at 1 μg/kg body weight (BW) per hour (MED1), or medetomidine at 2 μg/kg BW per hour (MED2).

The ERO₂ values tended to be higher in the MED2 group than in the CONTROL group, but this difference was significant only at 1 h (P = 0.031). The ERO₂ values tended to increase from baseline during the infusion in both the MED1 and MED2 groups, but this was significant in the MED1 group only at 8 h (Table II).

Body temperatures were not different among the 3 groups at baseline. In the MED2 group, TEMP was significantly lower than in the CONTROL group at 0.25, 1, and 2 h and significantly lower than in the MED1 group at 0.25 and 1 h. From 4 to 10 h, there were no significant differences among the 3 groups. In the CONTROL group, TEMP was significantly higher at 0.25, 1, 2, and 10 h than at baseline (Table II).

Respiratory rates (RRs) were not different among the 3 groups at baseline. In the MED2 group, RR was significantly lower than in the CONTROL group at 1, 2, 6, and 8 h. At 2 h after termination of the infusion, RR had returned toward baseline in MED2 and was not significantly different from the CONTROL group. While RR in the MED1 group tended to be lower than in the CONTROL group at all time points during the infusion, these differences were not statistically significant. While RR tended to be lower in the MED2 group than in the MED1 group during the infusion, these differences were not statistically significant either. There was a downward trend in RR in the CONTROL group during the infusion, with RR significantly lower than at baseline at all of the time points (Table II).

There were no significant differences among the 3 groups for arterial pH at any time points. Central venous pH values tended to be lower in the MED2 and MED1 groups than in the CONTROL group but this difference was significant only at 1 h (Table II). There were no significant differences among the 3 groups for PaO₂ at any time point. Arterial oxygen tensions tended to decrease over the 10-hour duration of the experiment in all 3 groups, but this decrease was significant in the CONTROL group only at 8 and 10 h compared to 1 h in MED1 and MED2. Central venous oxygen tensions tended to be lower than CONTROL in both the MED2 and MED1 groups and this difference was significant for both the MED1 and MED2 groups at 8 h (P = 0.0041 and 0.0097, respectively) (Table II). There were no significant effects of treatment or time for PaCO₂ or HCO₃⁻. Although there were no significant differences among the 3 groups for lactate at any time point, lactate levels in all 3 groups decreased significantly over time from baseline at 8 and 10 h (Table II).

Serum medetomidine concentrations

At 0.25 h, serum concentrations of medetomidine had increased significantly to 3.43 ± 0.7 μg/L in the MED1 group and to 6.17 ± 1.5 μg/L in the MED2 group. Serum concentrations in both groups remained significantly higher than in the CONTROL group throughout the duration of the infusion and concentrations in the MED2 group remained significantly higher than in the MED1 group. Two hours after the infusions were terminated (10 h), serum concentrations had fallen to 0.58 ± 0.2 μg/L in the MED1 group and 0.75 ± 0.3 μg/L in the MED2 group. These values were not significantly different from each other or from the CONTROL group (Figure 4).

Figure 4.

Mean (± SD) serum medetomidine concentrations versus time in dogs receiving saline (CONTROL), medetomidine at 2 μg/kg body weight (BW) loading dose then 1 μg/kg BW per hour (MED1), or medetomidine at 4 μg/kg BW loading dose then 2 μg/kg BW per hour (MED2).

Discussion

When administered as a loading dose followed by an 8-hour CRI, medetomidine induced statistically and clinically significant sedative and cardiopulmonary effects that appear to be dose-dependent, at least in part. We elected to compare 2 different dosing regimens to a saline control group. These doses were selected based on recent studies involving medetomidine or equipotent doses of dexmedetomidine administered by CRI to conscious dogs (12–15,17,18).

Based on the sedation score (SS), slight to mild sedation was produced in the MED1 group, while mild to moderate sedation was produced in the MED2 group. These results are comparable to those reported by Pypendop and Verstegen (7) after administration of bolus doses of medetomidine similar to those used here as loading doses. These effects were evident by 0.25 h and reached a plateau throughout the remainder of the infusion period with no apparent cumulative effect in either group. These results correlate well with the corresponding serum levels of medetomidine, which similarly increased rapidly after the loading dose, reached a plateau from 0.25 to 8 h, and then returned toward baseline 2 h later at 10 h. While serum levels of medetomidine in MED1 and MED2 are comparable to those reported by Kaartinen et al (17) with doses of 1 and 1.7 μg/kg BW per hour, respectively, it is not possible to compare sedative effects as the latter study involved isoflurane-anesthetized dogs. Even in the CONTROL group, the sedation score increased at 6 h (faint sedation) compared to at baseline and 10 h (alert). This time effect presumably reflects the normal daily sleep patterns of the dogs over the 8-hour duration of the infusion. For all treatment groups, dogs were confined to cages throughout the infusion in a relatively quiet room away from other animals. The dogs were not subjected to any particular auditory or tactile stimulation before sedation scoring. While it is the authors’ opinion that both doses used are clinically relevant, it must be noted that in a hospital setting where patients may be subjected to pain or other types of stimulation and manipulation, the level of sedation achieved with the MED1 and MED2 dosing regimens may be less than that achieved in this quiet experimental setting.

It is well-established that administering medetomidine by single bolus or CRI consistently produces bradycardia (7–9,13) and the results of the current study support this finding. Based on the 2 dosing regimens studied here, the bradycardia may, at least in part, be dose-dependent as there was a mean reduction in HR of 40 ± 14.9% in the MED1 group and 55 ± 10.3% in the MED 2 group at 0.25 h compared to baseline. Mean maximal reductions in HR over the entire 8-h duration of the infusion, however, were similar in both groups (61 ± 9.8% for the MED1 group and 64 ± 6.3% for the MED2 group) and the lowest recorded HR values were also similar (33 bpm in the MED1 group and 34 bpm in the MED2 group).

The HR data of the saline control group is particularly noteworthy in this study. Even in the CONTROL group, HR decreased with a mean maximal reduction in HR over the entire 8-hour duration of the infusion of 46 ± 13.4% and a lowest recorded HR value of 54 bpm in this group. The lower HR observed in the CONTROL group presumably reflected the normal daily routine and sleep patterns of these dogs. Most of them were accustomed to being active in the morning when they are fed and exercised, then resting throughout the late morning and into the afternoon, and finally becoming more active in the late afternoon when they are fed again. These findings are significant because they highlight the importance of a control group when interpreting results in a study such as this in which experiments may last several hours or more.

Other studies have shown that arterial blood pressure has a biphasic response when medetomidine or dexmedetomidine are administered (5,7,8). In this study, we did not observe an initial increase in SAP, MAP, or DAP in either of the groups receiving medetomidine. There are 2 possible explanations for this discrepancy. Firstly, because we did not begin recording parameters until 0.25 h after initiating the loading dose, we may simply have missed the hypertensive window. Secondly, due to the conservative loading doses used in this study (2 μg/kg BW and 4 μg/kg BW) compared with other studies in which medetomidine was administered at 20 μg/kg BW or more, it is possible that vasoconstriction was minimal and there really was no hypertensive episode. This conclusion is supported by Pypendop and Verstegen (7) who showed the absence of a significant increase in blood pressure in conscious dogs with doses of 1 and 2 μg/kg BW, and only a small and transient increase with a dose of 5 μg/kg BW. Similarly, no initial increase in blood pressure was documented when Carter et al (13) infused medetomidine at 1, 2, and 3 μg/kg BW per hour without a loading dose. In our study, arterial pressures decreased over the course of the infusion in both groups receiving medetomidine, which was presumably a result of reduced cardiac output secondary to bradycardia. Despite this decrease, mean MAP values were never less than 100 mmHg and true hypotension (MAP < 80 mmHg) was never documented in any dog. While not statistically significant, we also noted a downward trend in arterial pressure in the CONTROL group over time, which presumably reflected the impact of normal sleep on blood pressure.

The question of whether or not an 8-hour infusion of medetomidine is associated with cumulative effects on cardiovascular function is of considerable interest. From our data, HR and MAP decreased rapidly after the loading dose was administered and the infusion began, plateaued over the 8-hour infusion period, and then increased again 2 h after the infusion was terminated. These findings roughly parallel the corresponding concentrations of serum medetomidine, which suggests that there is no significant cumulative effect on these 2 hemodynamic parameters. Similar findings have been reported with a 24-hour CRI of dexmedetomidine administered at approximately 1 μg/kg BW per hour (12). The absence of cardiac output data is a limitation of the current study. We elected not to place cardiac catheters for thermodilution because of our crossover study design and because we viewed this as a pilot study to determine which dosing regimen (MED1 or MED2) would strike the best balance between sedation and cardiopulmonary side effects. In the study by Carter et al (13) in which medetomidine was infused at 1, 2, and 3 μg/kg BW per hour for 60 min, significant reductions in cardiac index were reported that were attributed primarily to bradycardia, since reductions in stroke volume were less profound. As the magnitude of the bradycardia reported by Carter et al (13) was comparable to our findings, it is reasonable to assume that cardiac index may have been similarly reduced in our dogs.

We elected to calculate the oxygen extraction ratio (ERO₂) as a surrogate estimate of cardiac output using measured Hb concentrations and arterial and central venous blood gas analyses. The ERO₂ describes the relationship between oxygen consumption (VO₂) and oxygen delivery (DO₂) as follows:

$$\begin{array}{l}{\text{ERO}}_2={\text{VO}}_2/{\text{DO}}_2=[\text{cardiac\hspace{0.17em}output}\times \text{arteriovenous\hspace{0.17em}oxygen}\\ \text{difference\hspace{0.17em}}({\text{CaO}}_2-{\text{CvO}}_2)]/[\text{cardiac\hspace{0.17em}output}\times \text{arterial\hspace{0.17em}oxygen}\\ \text{content\hspace{0.17em}}({\text{CaO}}_2)].\end{array}$$

Because cardiac output appears in both the numerator and the denominator, this equation can be further simplified to:

$${\text{ERO}}_2=({\text{CaO}}_2-{\text{CvO}}_2)/{\text{CaO}}_2.$$

The equations for calculating arterial and venous oxygen contents are provided in the Materials and methods section.

While using central venous samples instead of true mixed venous samples to calculate ERO₂ may introduce a source of error, the usefulness of this technique has been validated (19) and the same error would presumably have been introduced in all 3 groups. In general, an increase in the ERO₂ reflects an imbalance in oxygen delivery relative to oxygen consumption and is usually the result of decreased cardiac output. Not surprisingly, a trend toward increasing ERO₂ was noted in both MED1 and MED2 groups and we presume this is a function of decreased cardiac index secondary to bradycardia. This increase has also been documented by other investigators with infusion of comparable doses of medetomidine (14,15). It is of interest that, despite the trend toward increasing ERO₂ in the medetomidine-treated groups, the magnitude of the changes was small and values in all 3 groups remained within a clinically acceptable range (20).

Core body temperatures were significantly lower in the MED2 group than in the CONTROL group during the first 4 h of the infusion and were significantly lower in the MED2 group than in the MED1 group during the first hour of the infusion. Temperatures were somewhat low in all 3 groups at baseline (37.3°C ± 0.4°C in the CONTROL group, 37.4°C ± 0.4°C in the MED1 group, and 37.0°C ± 0.2°C in the MED2 group). This may have been due to the previous brief episode of sevoflurane anesthesia to facilitate catheterization. Despite the lower temperatures noted in the MED2 group than in the CONTROL group, body temperatures remained within clinically acceptable limits in all groups.

While RR was significantly lower in the MED2 group than in the CONTROL group during the infusion, this decrease did not impact minute ventilation, as arterial PaCO₂ values were not significantly different among groups and remained between 35 and 40 mmHg at all time points in all groups. As was the case with HR, RR also decreased over time in the CONTROL group and then returned to baseline at 2 h after the infusion was terminated. Presumably this is a result of normal physiologic variation, with lower RR observed while the dogs were sleeping during the day. Despite the effect of time on RR, PaCO₂ values were not affected.

There was a trend in the blood gas data toward lower central venous pH and oxygen tensions in both the MED1 and MED2 groups compared to the CONTROL group, although this difference was significant only at certain time points during the infusion. The lower PcvO₂ values are reflected in the higher ERO₂ values discussed previously. Interestingly, lactate values were not different among the 3 groups and actually tended to decrease over the course of the infusion, with values significantly lower at 8 and 10 h than at baseline in each group. The reasons for this are not clear as the dogs received minimal intravenous fluid support (the total volume of 0.9% saline ± drug administered was approximately 0.5 mL/kg BW per hour). As well, the first 1 mL of blood drawn from the sampling catheter was always discarded before the actual sample was obtained, which slightly lowered circulating blood volume over time.

While no significant differences were noted in arterial oxygen tensions among the 3 groups, PaO₂ values tended to be high, ranging from 107.2 ± 6.3 to 122.2 ± 4.1 mmHg. These values reflect the relatively high barometric pressure on Prince Edward Island (often 770 to 780 mmHg) and are within the normal reference range for the analyzer used in this study.

In conclusion, investigators in both veterinary and human medicine (21–24) continue to explore novel ways to use medetomidine and dexmedetomidine in various critical care settings. In the current study, both infusion rates of medetomidine evaluated induced clinically relevant sedative effects and were associated with typical hemodynamic effects induced by alpha₂ agonists, which plateaued and persisted for the 8-hour duration of the infusion. While additional studies are necessary to further characterize the effects on cardiac output and oxygen delivery in both healthy and unhealthy animals, the results presented here suggest that medetomidine infusions at the doses studied may be useful in canine patients requiring sedation for extended periods.