Detomidine hydrochloride is commonly used for sedation, visceral analgesia, or premedication prior to general anesthesia in horses. The drug produces sedation and analgesia through its agonist effects at α2-adrenoceptors of the CNS.1 Detomidine also affects other tissues and systems through peripheral receptors, with cardiovascular effects being the most notable.2 Activation of peripheral a2-adrenoceptors in the walls of blood vessels causes vasoconstriction, increasing SVR, and consequently arterial blood pressure.3 Bradycardia and atrioventricular blocks typically develop,4,5 most likely owing to the centrally mediated baroreflex, and cardiac index decreases.5 After the early phase, peripheral sympathetic tone is reduced, and arterial blood pressure consequently decreases.4 The cardiovascular and sedative effects of detomidine (at doses of 20 to 30 μg/kg) are observed ≤ 10 minutes after IV administration of the drug and can last up to 90 minutes.4,6 Furthermore, duodenal motility7,8 and contractility of the cecum and large colon6,9 have been reported to decrease for approximately 1 hour after IV detomidine administration in horses.6–8 In addition, detomidine causes biochemical changes (eg, increases in blood glucose concentration).10
Atipamezole is an antagonist of central and peripheral α2-adrenoceptors. In horses, atipamezole has been shown to attenuate the cardiovascular effects of α2-adrenoceptor agonists11 and to reverse detomidine-induced gastrointestinal hypomotility,12 but it also substantially reduces the degree of sedation.11,13,14 The hydrophilic α2-adrenoceptor antagonist MK-467 (also called L-659,066; proposed international nonproprietary name, vatinoxan hydrochloride15) mainly affects peripheral receptors. In rats and marmosets, it minimally crosses the blood-brain barrier such that the concentration in the brain remains far below that of the plasma.16 Administration of MK-467 alleviated the cardiovascular effects of the α2-adrenoceptor agonists detomidine,17 medetomidine,18 and romifidine19 in awake horses when administered simultaneously with or before the α2-adrenoceptor agonist. When administered as a sole agent IV in awake horses, MK-467 was reported to increase heart rate in 1 study,19 although in another study,18 no effect on heart rate was detected. The MAP remained stable when MK-467 was administered alone.18,19 Gastrointestinal hypomotility was reduced when MK-467 was simultaneously administered with detomidine17 and romifidine.19 Whereas MK-467 coadministered with detomidine as premedication prior to general anesthesia enhanced cardiac function and oxygen delivery in horses, MAP was low during general anesthesia with MK-467.20 Although MK-467 increased the volume of distribution and clearance of detomidine17 and romifidine,19 thus decreasing the respective areas under the plasma concentration-versus-time curves, it did not have a clinically relevant effect on the degree of sedation induced by these drugs in horses.
Anticholinergics, such as atropine, glycopyrrolate, and hyoscine butylbromide, bind to muscarinic receptors and compete with acetylcholine, thus acting as parasympatholytic drugs. The antagonistic effect reduces vagal stimulation and alters, for example, heart rate and gastrointestinal motility. Atropine, glycopyrrolate, and hyoscine have been used to reduce α2-adrenoceptor agonist-induced bradycardia and cardiovascular depression in horses.21,22 Hyoscine is also used to treat spasmodic equine colic and to facilitate rectal examination because of its analgesic and spasmolytic effects,23 and as a nonspecific muscarinic antagonist, it increases heart rate and reduces gastrointestinal borborygmi in healthy horses.24 It has been shown to act as a positive chronotropic agent, reducing α2-adrenoceptor agonist-induced bradycardia without potentiating the decrease in intestinal motility induced by detomidine.22
Whereas sedative and analgesic effects of detomidine in horses are well known, the safety of the drug could be improved by diminishing its undesired peripheral effects. However, detomidine-induced bradycardia has been reversed with anticholinergics, which may potentiate some of the adverse effects of detomidine. To the best of the authors’ knowledge, the potential for MK-467 administration to reverse the effects of detomidine in horses has not previously been investigated.
The objective of the study reported here was to compare the effects of MK-467 and hyoscine on cardiorespiratory and gastrointestinal changes induced by detomidine administration in horses. The primary aim was to investigate the effects on detomidine-induced cardiovascular depression when MK-467 was administered at the approximate time of the maximum effect of detomidine, with hyoscine used as a positive control to reverse detomidine-induced bradycardia.22 We hypothesized that MK-467 would reverse the cardiovascular effects of detomidine when administered in this manner without significantly affecting the degree of detomidine-induced sedation. A secondary aim was to investigate the effects of MK-467 on gastrointestinal hypomotility induced by detomidine. Our hypothesis was that MK-467 would attenuate the gastrointestinal effects of detomidine, which hyoscine would not influence. In addition, we investigated whether MK-467 or hyoscine would affect detomidine concentrations in plasma and thus cause changes in its clinical effects.
Materials and Methods
Horses
The study was approved by the National Animal Experiment Board of Finland and conducted according to the Finnish Act on Animal Experimentation.25 This was equivalent to the US National Institutes of Health's guidelines26 regarding laboratory animals.
Six adult horses (4 Standardbreds and 2 Warm-bloods; 3 mares and 3 geldings) with a median age of 10 years (range, 5 to 19 years) and median body weight of 521 kg (range, 476 to 571 kg) were used in the study. The horses were considered healthy on the basis of results of clinical examination and routine hematologic tests (CBC and serum biochemical analysis). Before the beginning of the study, the right common carotid arteries of the horses were relocated subcutaneously with the animals under sedation and local anesthesia.27 The horses were allowed to recover from this procedure for ≥ 2 weeks prior to the start of the study. In addition, the baseline fecal output for each horse was measured prior to the start of the study. Each pile of manure was collected in a separate plastic bag, and the bag was weighed with a small animal scale, with the time of defecation recorded, over a 3-day period. From these data, a mean daily amount of feces was calculated for each horse. Horses were fed hay and had free access to water. Feed was withheld on the morning of the day of each experiment and for 3 hours after the experiment had concluded. Water was available except when the horses were brought to the room where the experiments were performed.
Instrumentation
Instrumentation was achieved with horses unmedicated and restrained in stocks. Catheter sites were aseptically prepared, and a small amount of mepivacainea (1 to 2 mL/catheter site) was injected SC for local anesthesia prior to catheter placement. A central venous catheterb was placed into the cranial vena cava via the left jugular vein accessed in the distal part of the jugular groove. An IV catheterc was placed into the left jugular vein in the proximal part of the jugular groove. An arterial catheterd was placed into the previously relocated right common carotid artery. A pulmonary arterial cathetere was introduced via the right jugular vein through a large-bore IV catheter.f The connection between the pulmonary arterial catheter and large-bore IV catheter was sealed with plastic to avoid entrainment of air. The correct locations of the central venous catheter and pulmonary arterial catheter were verified by observation of characteristic pressure waveforms on the screen of the monitor,g and then the catheters were secured. Transducer accuracy was verified against a mercury manometer in the measurement range prior to use. A lithium dilution sensorh was connected to the arterial catheter to measure Qt by the lithium dilution methodh as previously described.28 Lithium was prepared by the addition of 1.875 mL of 8M lithium chloride to 100 mL of saline (0.9% NaCl) solution to obtain a concentration of 150 mmol/L. Standard values of 10 mg of hemoglobin/dL and 140 mmol of sodium/L were used and corrected afterward to match the true values measured from the arterial blood samples drawn from the horses simultaneously with the determination of Qt at each time point.
Data collection
Baseline (pretreatment) values for heart rate and respiratory rate by auscultation, rectal temperature, Qt, SAP, MAP, diastolic arterial pressure, PAP, and CVP were obtained with each horse standing in the stocks just prior to the administration of detomidine at the start of each experiment. Arterial and venous blood was anaerobically collected into heparinized syringes.i The pH was determined and blood gas analysis1 was performed ≤ 10 minutes after sample collection, and the values were temperature corrected by the blood gas analyzer on the basis of concurrently recorded rectal temperature. Sedation was assessed before the start of the experiment by an investigator (MRR or JAM) who was unaware of the treatment assignment and followed a predefined sedation scoring system29 in which the horse's attitude, standing ability, movement, and positioning of the head, ears, and eyelid aperture were assessed and scored individually and then summed to obtain a single value with a range of possible scores from 0 (not sedated) to 10 (heavily sedated). Gastrointestinal borborygmi were auscultated in 4 quadrants (upper and lower aspects of the flank on each side of the abdomen) and scored by the same blinded investigator by use of a previously described scale.6 Briefly, the number of borborygmi in each quadrant was counted during 30 seconds of auscultation, and the numbers from 4 quadrants were summed to provide a single score of gastrointestinal borborygmi.
Each horse received 3 treatments, the order of which was assigned with a Latin square design. A minimum 7-day washout period was enforced between experiments. Horses were given a bolus of detomidine hydrochloridek (20 μg/kg, IV) over 15 seconds through a left jugular catheter at time 0. Ten minutes later, the horses received MK-467 hydrochloridel (150 μg/kg), hyoscine butylbromidem (0.2 mg/kg), or saline solution as an IV bolus over 15 seconds; each of these treatments comprised 10 mL. The drug was diluted with saline solution if necessary to obtain the predetermined injection volume. These 3 treatments were termed DET-MK, DET-HYO, and DET-S, respectively.
Heart rate, respiratory rate, SAP, MAP, diastolic arterial blood pressure, and mean, systolic, and diastolic PAP were recorded every 5 minutes for 60 minutes and at 70, 80, and 90 minutes. The Qt, mean CVP, and blood gas values from arterial and venous blood samples were measured at 5, 15, 30, 45, 60, and 90 minutes. Calculations were performed retrospectively as follows32–33:
where SV represents stroke volume, HR represents heart rate, Hb represents the hemoglobin concentration, So2 represents the oxygen saturation of hemoglobin, Do2 represents oxygen delivery, and 
o2 represents oxygen consumption.
Sedation and gastrointestinal borborygmus scoring was performed at 5, 15, 30, 45, 60, and 90 minutes by the same blinded investigator who performed baseline scoring. Areas under the score–time curve for sedation and borborygmus scores were calculated for each horse. Horses were observed at least every other hour for 24 hours after each treatment, starting when the horses were returned to their boxes from the stocks, and the feces were collected in the same manner as described for the pretreatment measurements. The amount of feces (by weight) and times of defecation were recorded during this period. The time to first defecation was defined as the time from injection of saline solution, MK-467, or hyoscine until feces were produced.
Arterial blood samples (10 mL) were collected into EDTA-containing tubes at 15, 30, 45, 60, and 90 minutes and stored at room temperature (20°C). Plasma was separated by centrifugation at 400 × g for 10 minutes ≤ 6 hours after sample collection. Harvested plasma was stored at −20°C until analyzed for drug concentrations.
Analysis of plasma drug concentrations
Pharmacokinetic parameters calculated included terminal half-life, area under the plasma concentration-versus-time curve from 15 to 90 minutes after injection of the drug of interest (detomidine, MK-467, or hyoscine), clearance, and volume of distribution. The concentrations of detomidine and MK-467 in plasma were separately analyzed with high-performance liquid chromatography–tandem mass spectrometry in separate aliquots that were processed under specific conditions for each analyte.17 Concentrations of detomidine and MK-467 were determined after solid-phase extraction with well extraction platesn with dexmedetomidineo and RS-79948p as the respective internal standards. Reverse-phase separation of detomidine was performed with a 5-μm, 11-nm, 150 × 2.0-mm columnq; for MK-467, a 3.5-μm, 9.6-nm, 150 × 2.1-mm columnr was used. Quantitative detection was performed in a multireaction monitoring mode with a triple-quadrupole mass spectrometer.s For detomidine and dexmedetomidine, the precursor ion m/z was 201.2 and 187.0, respectively. The fragment ion monitored for detomidine had an m/z of 95.05, and that for dexmedetomidine had an m/z of 81.0. For MK-467 and RS-79948, the respective precursor ions scanned had an m/z of 419.3 and 365.3, respectively. The fragment ion monitored for MK-467 had an m/z of 200.1, and that for RS-79948 had an m/z of 190.2. The chromatograms were analyzed and processed with commercially available software.t The linear calibration range of the detomidine analysis was from 0.02 to 10 ng/mL, and all quality control samples (at concentrations of 0.06, 0.9, 8.0, and 15 ng/mL) had measured values within 97.3% to 113.3% of the nominal concentration. The linear calibration range of the MK-467 assay was from 25 to 460 ng/mL, and all quality control samples (at concentrations of 70, 250, and 380 ng/mL) had measured values within 102.5% to 113.6% of the nominal concentration.
Concentrations of hyoscine were analyzed as follows. First, 150 μL of each plasma sample was precipitated on a 96-well plate with 300 μL of acetonitrile (containing internal standard propranolol). After mixing for 5 minutes at 1,350 revolutions/min, the samples were kept in a refrigerator at 8°C for 20 minutes, centrifuged for 20 minutes at 2,952 × g, and transferred to a 96-well plate to await analysis. Finally, all samples were diluted 1:20 with a 20% solution of acetonitrile in 150mM PBS solution. Both diluted and undiluted samples were analyzed. The standard samples were prepared in (blank) equine plasma by spiking with hyoscinem at concentrations of 1, 2, 5, 10, 20, 50, 100, 200, 500, 1,000, and 2,000 ng/mL. The quality control samples were prepared by spiking (blank) equine plasma with the same product at concentrations of 2, 20, and 200 ng/mL. Concentrations of hyoscine in plasma were analyzed by ultrahigh-performance liquid chromatography–mass spectrometryu with a bridged-ethylene hybrid particle C18 column.v The temperature of the column oven was 40°C, and the injection volume was 4 μL. The aqueous eluent (phase A) was 0.5% formic acid in water, and the organic eluent (phase B) was acetonitrile. The gradient elution conditions were as follows: isocratic elution of 2% phase B for 1 minute, followed by linear gradient to 50% phase B in 1 minute, linear gradient to 90% phase B in 1.5 minutes, and isocratic elution of 90% phase B for 1.5 minutes, ending with a 1-minute equilibration. The eluent flow rate was 0.5 mL/min. A positive ionization mode was used with a capillary voltage of 1,000 V. Argon was used as a collision gas, with a flow rate of 0.18 mL/min. The desolvation temperature was 650°C, and the source temperature was 150°C. Nitrogen was used as a drying gas at a flow rate of 900 L/min and as a nebulizer gas at a full flow rate. Data were collected with a single-reaction monitoring mode, and the reactions monitored were m/z 360→194 for hyoscine and m/z 260→116 for the internal standard propranolol. Quantitation was based on the peak area ratios of the analyte and the internal standard. The calibration range was 2 to 1,000 ng/mL, and all quality control samples had measured values within 85% to 115% of the nominal concentration.
Statistical analysis
Statistical analyses were performed with commercially available statistical software packages.w,x Data distributions were assessed with the Shapiro-Wilk test. For physiologic variables measured over time, data were normally distributed, and statistical differences among treatments at each time point were assessed by 2-way repeated-measures ANOVA with Tukey post hoc tests. Comparisons with baseline values within each treatment were performed with the Dunnett post hoc test. The areas under the score-versus-time curve were calculated for the sedation and borborygmus scores to investigate the overall effects and the differences in treatments over time. Inter-treatment differences for fecal output variables and for area under the score-versus-time curves (ordinal data) were investigated by nonparametric Friedman analysis. Sedation and borborygmus scores, also determined with ordinal scales, were compared with baseline values within each treatment by Friedman analysis. The calculated pharmacokinetic variables for detomidine were compared among treatments by repeated-measures ANOVA and paired Student t tests. Values of P < 0.05 were considered significant.
Results
Bradycardia (heart rate < 28 beats/min) was detected in all horses ≤ 5 minutes after IV administration of detomidine (ie, time 0) in all experiments. With DET-MK, bradycardia resolved ≤ 5 minutes after injection of MK-467, whereas tachycardia (heart rate > 58 beats/min) developed in all horses ≤ 15 minutes after hyoscine injection during the DET-HYO treatment and continued through the 30-minute time point (Figure 1).
Mean ± SD heart rate (A) and MAP (B) for 6 healthy horses immediately before (baseline) and after (time in minutes) IV administration of detomidine hydrochloride (20 μg/kg; arrow) followed by IV administration (arrowhead) of saline (0.9% NaCl) solution, MK-467 hydrochloride (150 μg/kg), or hyoscine butylbromide (0.2 mg/kg). The treatments were termed DET-S (black circles), DET-MK (white circles), and DET-HYO (triangles), respectively, and administered in a Latin square design with a minimum 7-day washout period between experiments. For these data, the time of detomidine injection was considered time 0. *Within a time point, value is significantly different between DET-S and DET-MK. †Within a time point, value is significantly different between DET-S and DET-HYO. ‡Within a time point, value is significantly different between DET-MK and DET-HYO. §Value for DET-S is significantly different from that at baseline. ‖Value for DET-MK is significantly different from that at baseline. ¶Value for DET-HYO is significantly different from that at baseline. Values of P < 0.05 were considered significant.
Citation: American Journal of Veterinary Research 79, 4; 10.2460/ajvr.79.4.376
Mean ± SD heart rate (A) and MAP (B) for 6 healthy horses immediately before (baseline) and after (time in minutes) IV administration of detomidine hydrochloride (20 μg/kg; arrow) followed by IV administration (arrowhead) of saline (0.9% NaCl) solution, MK-467 hydrochloride (150 μg/kg), or hyoscine butylbromide (0.2 mg/kg). The treatments were termed DET-S (black circles), DET-MK (white circles), and DET-HYO (triangles), respectively, and administered in a Latin square design with a minimum 7-day washout period between experiments. For these data, the time of detomidine injection was considered time 0. *Within a time point, value is significantly different between DET-S and DET-MK. †Within a time point, value is significantly different between DET-S and DET-HYO. ‡Within a time point, value is significantly different between DET-MK and DET-HYO. §Value for DET-S is significantly different from that at baseline. ‖Value for DET-MK is significantly different from that at baseline. ¶Value for DET-HYO is significantly different from that at baseline. Values of P < 0.05 were considered significant.
Citation: American Journal of Veterinary Research 79, 4; 10.2460/ajvr.79.4.376
Mean ± SD heart rate (A) and MAP (B) for 6 healthy horses immediately before (baseline) and after (time in minutes) IV administration of detomidine hydrochloride (20 μg/kg; arrow) followed by IV administration (arrowhead) of saline (0.9% NaCl) solution, MK-467 hydrochloride (150 μg/kg), or hyoscine butylbromide (0.2 mg/kg). The treatments were termed DET-S (black circles), DET-MK (white circles), and DET-HYO (triangles), respectively, and administered in a Latin square design with a minimum 7-day washout period between experiments. For these data, the time of detomidine injection was considered time 0. *Within a time point, value is significantly different between DET-S and DET-MK. †Within a time point, value is significantly different between DET-S and DET-HYO. ‡Within a time point, value is significantly different between DET-MK and DET-HYO. §Value for DET-S is significantly different from that at baseline. ‖Value for DET-MK is significantly different from that at baseline. ¶Value for DET-HYO is significantly different from that at baseline. Values of P < 0.05 were considered significant.
Citation: American Journal of Veterinary Research 79, 4; 10.2460/ajvr.79.4.376
Hypertension (MAP > 137 mm Hg) developed ≤ 5 minutes after detomidine administration (ie, prior to other drug treatments) in all horses during DET-S and DET-MK treatments and in 5 of 6 horses during DET-HYO treatment (Figure 1; Table 1). With DET-S, SAP, diastolic arterial blood pressure, and MAP gradually decreased over the observation period after the 5-minute time point; the MAP approximated its baseline (pretreatment) value from 20 through 70 minutes and was significantly (P < 0.040) lower than the baseline value at 80 and 90 minutes. With DET-MK, the MAP was significantly (P < 0.001) lower from 15 through 40 minutes, compared with that observed for other treatments, and was significantly (P < 0.018) lower than that at baseline from 15 through 70 minutes. Hypertension, with MAP > 147 mm Hg in all horses, was detected from the 15- through 25-minute time points during DET-HYO treatment.
Cardiovascular data (mean ± SD) for 6 healthy horses before (baseline) and after administration of detomidine hydrochloride (20 μg/kg; time 0) followed 10 minutes later by administration of saline (0.9% NaCl) solution (DET-S), MK-467 hydrochloride (150 μg/kg; DET-MK), or hyoscine butylbromide (0.2 mg/kg; DET-HYO) according to a Latin square design.
| Time | |||||||
|---|---|---|---|---|---|---|---|
| Variable | Treatment | Baseline | 5 minutes | 15 minutes | 30 minutes | 60 minutes | 90 minutes |
| SAP (mm Hg) | DET-S | 154 ± 18.6 | 187 ± 16.2* | 170 ± 19.2a | 168 ± 17.0a | 146 ± 19.0a | 129 ± 13.2* |
| DET-MK | 155 ± 11.0 | 180 ± 27.0* | 120 ± 7.5b* | 122 ± 13.4b* | 126 ± 11.5b* | 134 ± 9.8 | |
| DET-HYO | 149 ± 19.3 | 169 ± 14.4 | 251 ± 35.0c* | 210 ± 21.3c* | 138 ± 21.4a,b | 124 ± 8.8 | |
| DAP (mm Hg) | DET-S | 102 ± 10.1 | 144 ± 8.3* | 131 ± 8.7a* | 115 ± 9.3a | 104 ± 12.7a | 89 ± 11.6 |
| DET-MK | 104 ± 10.1 | 140 ± 17.5* | 81 ± 5.4b* | 84 ± 8.6b* | 83 ± 9.3b* | 87 ± 7.7* | |
| DET-HYO | 97 ± 20.4 | 129 ± 23.2* | 174 ± 28.4c* | 144 ± 24.2c* | 103 ± 17.0a | 83 ± 10.7 | |
| Mean CVP | DET-S | 9.5 ± 4.0 | 17.8 ± 3.8* | 14.3 ± 7.8a* | 16.5 ± 4.3a* | 8.8 ± 3.2a | 5.8 ± 5.0a,b |
| (mm Hg) | DET-MK | 8.2 ± 2.6 | 15.5 ± 2.7* | 9.2 ± 4.6b | 7.8 ± 4.7b | 6.7 ± 2.5a | 8.0 ± 4.4b |
| DET-HYO | 11.2 ± 4.4 | 15.2 ± 4.3 | 10.7 ± 5.9b | 2.0 ± 4.5c* | 1.5 ± 3.9b* | 2.5 ± 1.8a* | |
| PAP (mm Hg) Mean | DET-S | 26.7 ± 4.7 | 29.7 ± 8.2 | 29.5 ± 5.3a | 26.3 ± 5.5a | 23.3 ± 3.8a | 20.7 ± 5.4* |
| DET-MK | 22.8 ± 3.4 | 23.8 ± 4.1 | 23.5 ± 5.3b | 20.7 ± 2.0b | 18.8 ± 2.6b | 19.8 ± 2.6 | |
| DET-HYO | 23.5 ± 6.0 | 28.5 ± 4.6* | 39.5 ± 6.7c* | 22.0 ± 3.9b | 17.2 ± 4.7b* | 17.0 ± 5.0* | |
| Systolic | DET-S | 44.3 ± 7.6 | 38.7 ± 9.3 | 37.5 ± 4.1a | 35.7 ± 5.8* | 39.0 ± 6.4 | 38.2 ± 7.7 |
| DET-MK | 42.2 ± 6.0 | 35.8 ± 4.4 | 44.5 ± 5.0b | 37.7 ± 4.6 | 36.2 ± 5.0 | 38.3 ± 2.7 | |
| DET-HYO | 40.7 ± 8.8 | 39.5 ± 8.7 | 57.8 ± 7.3c* | 39.0 ± 7.7 | 33.7 ± 4.0 | 35.3 ± 4.7 | |
| Diastolic | DET-S | 11.2 ± 9.7 | 23.7 ± 12.2* | 22.0 ± 6.2a* | 17.5 ± 4.9a | 12.8 ± 4.5a | 9.0 ± 5.9a |
| DET-MK | 6.8 ± 5.0 | 15.7 ± 5.0* | 6.8 ± 5.5b | 6.0 ± 2.7b | 3.7 ± 3.7b | 5.2 ± 5.4a,b | |
| DET-HYO | 8.0 ± 5.4 | 16.8 ± 7.8* | 14.3 ± 9.4c | 5.2 ± 7.7b | 2.2 ± 6.2b | 2.3 ± 6.3b | |
| PVR (dynes/s/cm5) | DET-S | 30.5 ± 18.4 | — | 20.2 ± 6.6a | 23.3 ± 11.6 | 25.5 ± 5.5 | 25.5 ± 9.0 |
| DET-MK | 26.4 ± 12.3 | — | 29.2 ± 8.8a | 31.8 ± 10.6 | 32.6 ± 7.9 | 33.2 ± 8.4 | |
| DET-HYO | 33.5 ± 19.0 | — | 46.7 ± 9.9b | 34.2 ± 12.1 | 36.4 ± 5.0 | 37.3 ± 18.1 | |
| SV (L/beat) | DET-S | 1.1 ± 0.3 | — | 1.4 ± 0.6a | 1.3 ± 0.4a | 1.2 ± 0.2a | 1.1 ± 0.2 |
| DET-MK | 1.4 ± 0.3 | — | 1.3 ± 0.6a | 1.1 ± 0.1a | 1.2 ± 0.3a | 1.1 ± 0.1 | |
| DET-HYO | 1.1 ± 0.5 | — | 0.7 ± 0.3b* | 0.6 ± 0.2b* | 0.8 ± 0.2b | 0.9 ± 0.1 | |
| Qt (L/min) | DET-S | 42.0 ± 13.0 | — | 29.7 ± 11.5a | 31.3 ± 5.6 | 33.6 ± 4.9 | 36.9 ± 5.1 |
| DET-MK | 51.6 ± 13 | — | 50.0 ± 19.8b | 39.2 ± 9.6 | 38.2 ± 7.7 | 35.4 ± 3.3* | |
| DET-HYO | 43.8 ± 25.9 | — | 41.6 ± 7.7b | 39.4 ± 7.2 | 33.5 ± 5.5 | 33.1 ± 6.6 | |
| SVR (dynes/s/cm5) | DET-S | 230 ± 60 | — | 356 ± 125a* | 304 ± 42a* | 270 ± 47a | 215 ± 29 |
| DET-MK | 190 ± 48 | — | 157 ± 46b | 197 ± 44b | 200 ± 34b | 222 ± 16 | |
| DET-HYO | 227 ± 82 | — | 370 ± 90a* | 345 ± 48a* | 268 ± 36a | 239 ± 55 | |
| LVW (kg/m) | DET-S | 70.2 ± 23.6 | — | 51.0 ± 16.8a | 56.6 ± 12.8a | 55.1 ± 11.0 | 52.2 ± 12.8 |
| DET-MK | 87.2 ± 25 | — | 65.5 ± 23.0a* | 52.7 ± 11.3a* | 51.6 ± 11.8* | 50.8 ± 7.8* | |
| DET-HYO | 71.9 ± 49.7 | — | 112 ± 30.7b* | 90.9 ± 23.3b | 5I.2 ± 13.1 | 43.9 ± 9.8* | |
Baseline data for these variables were collected from instrumented horses just prior to detomidine administration.
Within a treatment for a given variable, value is significantly different from that at baseline.
— = Not applicable (equipment failed to register a Qt value for most horses at this time point). DAP = Diastolic arterial blood pressure. SV = Stroke volume.
Within a time point for a given variable, values with different superscript letters are significantly (P < 0.05) different from each other.
The SVR was significantly (P < 0.031) increased relative to baseline at the 15- and 30-minute time points with DET-S and DET-HYO, but with DET-MK, no significant difference from baseline was detected throughout the observation period (Table 1). The mean PAP was significantly higher with DET-S and DET-HYO (P < 0.002 and P < 0.001, respectively) than with DET-MK at the 15-minute time point but differed significantly (P < 0.001) from the baseline value only with DET-HYO; during this treatment, values were > 33 mm Hg in all horses at this time point. The mean PAP was significantly (P < 0.039) higher with DET-S than with DET-MK and DET-HYO at the 30-and 60-minute time points but did not differ significantly from the baseline value for the same treatment. The PVR was significantly (P < 0.005) higher at the 15-minute time point for DET-HYO than for other treatments but did not differ significantly from the baseline measurement at any time point. The mean CVP was significantly (P < 0.002) increased, compared with that at baseline, from 5 through 30 minutes with DET-S; this finding was observed only at the 5-minute time point (ie, prior to MK-467 injection; P = 0.001) with DET-MK. No significant increase in mean CVP was observed at any time for DET-HYO, but the value was significantly (P < 0.001) lower at 30 through 90 minutes than at baseline.
The Qt was significantly (P < 0.014) lower at the 15-minute time point for DET-S than for DET-MK or DET-HYO treatments (Table 1). Stroke volume was significantly (P < 0.041) lower, and LVW was significantly (P < 0.001) higher, with DET-HYO from 15 through 60 and 15 through 30 minutes, respectively, than with DET-S or DET-MK. At 5 minutes, the device was unable to measure the Qt in most horses, and this time point was therefore excluded from the analysis of Qt and related variables.
Respiratory rate, blood gas, and plasma glucose concentration data were summarized (Table 2). Respiratory rate remained within the reference range for all horses, regardless of treatment. The C
o2 and Po2 were significantly (P < 0.002 and P < 0.001, respectively) higher with DET-MK than with DET-S and DET-HYO at the 15-minute time point; the Po2 was also higher (P < 0.001) than that for DET-S treatment at 30 minutes and higher (P = 0.012) than that for DET-HYO at 90 minutes. Plasma glucose concentrations were significantly higher with DET-S (P < 0.001) and DET-HYO (P < 0.001) than with DET-MK from 30 through 90 minutes, although values remained within the reference range33 for all horses, regardless of treatment. During DET-MK treatment, the Pao2 values for 1 sample at the 15-minute time point and 1 sample at the 30-minute time point were considered abnormally high (121 mmHg), likely the result of sample contamination with air, and these were excluded. However, no differences were detected among groups at any time point for this variable.
Mean ± SD respiratory rate, arterial blood gas measurements, plasma glucose concentration, and calculated cardiovascular data for the same 6 horses as in Table 1.
| Time | ||||||
|---|---|---|---|---|---|---|
| Variable | Treatment | Baseline | 15 minutes | 30 minutes | 60 minutes | 90 minutes |
| RR (breaths/min) | DET-S | 15 ± 5.9 | 13.7 ± 7.8a | 12.3 ± 3.9 | 7.4 ± 2.6* | 6.7 ± 2.1* |
| DET-MK | 13.5 ± 6.1 | 12.0 ± 2.8b | 9.5 ± 3.9 | 7.0 ± 1.1* | 6.3 ± 0.8* | |
| DET-HYO | 13.8 ± 3.8 | 12.0 ± 2.2b | 13.0 ± 4.5 | 8.0 ± 0.0* | 6.3 ± 1.7* | |
| Pao2 (mm Hg) | DET-S | 106.5 ± 4.3 | 95.2 ± 12.4 | 98.1 ± 10.0 | 98.1 ± 5.6 | 104.7 ± 6.9 |
| DET-MK | 101.8 ± 9.4 | 94.4 ± 5.0 | 98.2 ± 3.6 | 101.6 ± 5.1 | 105.0 ± 7.3 | |
| DET-HYO | 106.4 ± 5.4 | 95.5 ± 9.2 | 92.4 ± 7.3* | 91.4 ± 8.4* | 99.4 ± 6.5 | |
| Po2 (mm Hg) | DET-S | 38.5 ± 4.5 | 26.1 ± 2.5a* | 29.6 ± 2.0a* | 31.0 ± 2.3* | 31.4 ± 2.7a,b* |
| DET-MK | 37.3 ± 3.3 | 39.4 ± 2.4b | 34.7 ± 1.4b | 32.9 ± 2.1* | 32.6 ± 1.6a* | |
| DET-HYO | 36.4 ± 5.3 | 27.6 ± 3.0a* | 34.5 ± 3.8b | 30.7 ± 1.7* | 29.3 ± 1.9b* | |
| Do2 (mL/min) | DET-S | 8,094 ± 2,931 | 5,152 ± 2,015* | 5,112 ± 1,460 | 4,876 ± 614* | 5,276 ± 5,276* |
| DET-MK | 9,785 ± 2,866 | 9,137 ± 4,034 | 6,070 ± 1,831* | 5,387 ± 9,612* | 5,246 ± 6,189* | |
| DET-HYO | 8,020 ± 5,105 | 7,074 ± 1,374 | 6,389 ± 1,340 | 4,647 ± 763* | 4,541 ± 944* | |
| o2 (mL/min) | DET-S | 1,574 ± 369 | 2,242 ± 1,031 | 1,741 ± 452 | 1,538 ± 256 | 1,628 ± 268 |
| DET-MK | 2,040 ± 477 | 1,607 ± 471 | 1,470 ± 375 | 1,556 ± 517 | 1,518 ± 236 | |
| DET-HYO | 1,674 ± 524 | 2,795 ± 662* | 1,579 ± 351 | 1,469 ± 208 | 1,604 ± 360 | |
| Cao2 (mL/dL) | DET-S | 19.1 ± 1.8 | 17.6 ± 1.9 | 16.2 ± 2.0a,b* | 14.6 ± 2.0* | 14.4 ± 2.3a,b* |
| DET-MK | 18.9 ± 1.8 | 17.4 ± 1.3* | 15.5 ± 1.3a* | 14.2 ± 1.2* | 14.9 ± 1.6a* | |
| DET-HYO | 18.1 ± 2.3 | 17.3 ± 1.2 | 16.2 ± 1.5b* | 14.0 ± 1.3* | 13.8 ± 1.6b* | |
| Co2 (mL/dL) | DET-S | 15.2 ± 2.1 | 10.2 ± 2.1a* | 10.7 ± 2.0* | 10.1 ± 2.1* | 9.9 ± 2.2* |
| DET-MK | 14.8 ± 1.6 | 14.1 ± 1.2b | 11.6 ± 1.0* | 10.2 ± 1.1* | 10.6 ± 1.5* | |
| DET-HYO | 14.0 ± 3.0 | 10.6 ± 1.9a* | 12.2 ± 2.1 | 9.5 ± 1.3* | 9.0 ± 1.5* | |
| Plasma glucose (mmol/L) | DET-S | 5.5 ± 0.2 | 6.4 ± 0.9 | 7.7 ± 1.4a* | 8.0 ± 2.0a* | 7.5 ± 1.8a* |
| DET-MK | 5.6 ± 0.4 | 6.4 ± 0.9 | 6.1 ± 0.8b | 5.9 ± 0.7b | 5.9 ± 0.5b | |
| DET-HYO | 5.4 ± 0.5 | 6.1 ± 1.2 | 7.5 ± 1.7a* | 7.8 ± 2.0a* | 7.5 ± 1.8a* | |
When horses received DET-MK, samples (1/time point) were excluded at 15 and 30 minutes because of suspected contamination with air.
Do2 = Oxygen delivery. RR = Respiratory rate. o2 = Oxygen consumption.
See Table 1 for remainder of key.
Intestinal borborygmus scores were significantly (P < 0.001 and P < 0.001, respectively) reduced, compared with baseline scores, from 5 through 90 minutes with DET-S and DET-HYO (Table 3). With DET-MK, these scores were reduced from 5 through 30 minutes only (P < 0.011). The area under the score-versus-time curve was significantly (P = 0.012) higher with DET-MK than with DET-HYO and appeared higher than with DET-S, but the difference was not significant (P = 0.063). Horses passed feces sooner (P < 0.013) after DET-MK than after DET-S treatment; however, the total fecal output over 24 hours after the end of the observation period did not differ significantly from the baseline value (total output over 3 days prior to the start of the study) for any treatment (Table 4).
Median (range) borborygmus and sedation scores and areas under the score-versus-time curves for the same 6 horses as in Table 1.
| Time | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Variable | Treatment | Baseline | 5 minutes | 15 minutes | 30 minutes | 45 minutes | 60 minutes | 90 minutes | AUC |
| Borborygmus | DET-S | 5.0 (4.0–7.0) | 2.0* (0.5–3.5) | 0.75* (0.0–1.5) | 0.0* (0.0–3.0) | 0.0* (0.0–1.5) | 0.0* (0.0–1.0) | 1.5* (1.0–3.0) | 58.8a,b (40.0–185.0) |
| score | DET-MK | 5.0 (3.5–7.0) | 2.25* (1.5–4.5) | 2.25* (2.0–4.0) | 3.25* (1.0–6.5) | 4.0 (2.0–6.0) | 4.25 (4.0–6.0) | 4.0 (4.0–5.5) | 331.9a (281–436) |
| DET-HYO | 5.5 (2.0–8.0) | 2.0* (0.5–3.0) | 0.25* (0.0–1.0) | 0.0* (0.0–0.5) | 0.0* (0.0–0.0) | 0.25* (0.0–1.0) | 1.0* (0.5–1.5) | 58.8b (35.0–73.8) | |
| Sedation | DET-S | 1.0 (0.0–1.0) | 7.0* (6.0–7.0) | 7.0* (7.0–8.0) | 7.0* (7.0–7.0) | 6.0* (5.0–7.0) | 3.5* (2.0–7.0) | 2.5* (1.0–3.0) | 448.8a,b (395–555) |
| score | DET-MK | 1.0 (1.0–1.0) | 7.0* (6.0–7.0) | 7.0* (6.0–8.0) | 6.0* (4.0–7.0) | 5.0* (5.0–6.0) | 3.5* (2.0–4.0) | 2.0 (1.0–3.0) | 427.5a (368–463) |
| DET-HYO | 1.0 (0.0–1.0) | 7.0* (6.0–8.0) | 7.0* (6.0–8.0) | 7.0* (7.0–8.0) | 6.0* (6.0–7.0) | 4.5* (4.0–7.0) | 2.0* (2.0–4.0) | 486.3b (443–563) | |
Scores were assessed by I investigator who was unaware of the treatment assignment of horses; predefined scoring systems6,29 were used. The borborygmus score equaled the number of auscultated borborygmi/30 s. The range of possible sedation scores was from 0 (not sedated) to 10 (heavily sedated).
AUC = Area under the curve.
See Table I for remainder of key.
Median (range) fecal output data for the same 6 horses as in Table I before and after each treatment.
| Variable | Baseline | DET-S | DET-MK | DET-HYO |
|---|---|---|---|---|
| Time to first defecation (min) | — | 220a (160–350) | 130b (60–200) | 150a,b (110–320) |
| Total fecal output (kg/24 h) | 23.2 (16.2–26.6) | 22.2 (16.1–24.6) | 22.9 (13.7–28.7) | 18.8 (14.0–30.4) |
For total fecal output, the baseline value reflects the median of mean daily fecal output per horse over a 3-day period after complete recovery from the instrumentation procedure and before any drug experiments were performed. Posttreatment fecal output measurement began at the conclusion of the 90-minute observation period for each experiment, and values represent the median of total fecal output per horse over 24 hours. The time to first defecation was measured from the time of administration of saline solution, MK-467, or hyoscine during the relevant treatment (DET-S, DET-MK, or DET-HYO, respectively).
— = Not applicable.
Within a row, values with different superscript letters are significantly (P < 0.05) different.
Total sedation scores were significantly greater than the baseline scores from 5 through 90 minutes with DET-S (P < 0.001) and DET-HYO (P < 0.001) and from 5 through 60 minutes with DET-MK (P < 0.001; Table 3). The area under the score-versus-time curve was slightly but significantly (P = 0.018) lower with DET-MK than with DET-HYO.
Pharmacokinetic parameters calculated for detomidine, MK-467, and hyoscine were summarized (Table 5). The volume of distribution for detomidine was significantly (P = 0.012) greater in DET-HYO-treated horses than in DET-S-treated horses, but no significant changes in the pharmacokinetic parameters for detomidine were detected in DET-MK-treated horses.
Mean ± SD pharmacokinetic parameters for detomidine, MK-467, and hyoscine for the same 6 horses as in Table I.
| Drug | Treatment | t1/2 (min) | AUC15–90 min (ng•min/mL) | Cl (mL•min/kg) | Vd (mL/kg) |
|---|---|---|---|---|---|
| Detomidine | DET-S | 34.5 ± 8.3 | 546.1 ± 89.5 | 33.2 ± 6.2 | 1,590 ± 108.9a |
| DET-MK | 38.6 ± 4.9 | 509.1 ± 105.8 | 35.3 ± 6.8 | 1,967 ± 435.2a,b | |
| DET-HYO | 36.1 ± 9.3 | 443.0 ± 76.I | 40.3 ± 8.7 | 2,026 ± 316.3b | |
| MK-467 | DET-MK | 53.6 ± 20.5 | 9,235 ± 2,357 | 12.5 ± 4.6 | 881.0 ± 233.9 |
| Hyoscine | DET-HYO | 21.4 ± 1.5 | 11,440 ± 2,817 | 17.9 ± 3.8 | 552.7 ± 134.8 |
For pharmacokinetic data, the time of administration of the drug of interest (detomidine, MK-467, or hyoscine) was considered time 0.
AUC15–90 min = Area under the plasma concentration-versus-time curve from 15 to 90 minutes after drug injection. Cl = Clearance. t1/2 = Terminal half-life. Vd = Volume of distribution.
For a given parameter, detomidine values with different superscript letters differ significantly (P < 0.05).
Discussion
Results of the present study indicated that MK-467 attenuated many of the peripheral effects of detomidine without notable adverse effects, whereas hyoscine reversed detomidine-induced bradycardia but also produced marked tachycardia. Hypertension was observed after detomidine injection, reflecting detomidine-induced vasoconstriction as also indicated by increased SVR, compared with that at baseline, at the 15- and 30-minute time points. This hypertensive effect was reversed by MK-467 administration. Thus, the detomidine-related cardiovascular changes, such as bradycardia and decreased Qt (although the latter change was nonsignificant), subsided. These results were attributed to the direct antagonist action of MK-467 on α2-adrenoceptors in blood vessels and the absence of a consequent baroreflex as vasoconstriction was reversed. Our results were comparable to findings in a previous study19 in which MK-467 prevented a romifidine-induced increase in arterial blood pressure in horses when it was coadministered with romifidine. In another study,20 hypotension was detected in horses under general anesthesia (induced with ketamine-midazolam and maintained with isoflurane) when MK-467 was combined with detomidine as premedication. In our study, MAP decreased relative to the baseline value for most of the observation period in horses that received DET-MK, but no significant changes in SVR were detected at any time point. The baseline measurements of MAP may have been slightly higher than resting values if the unsedated horses were excited in the stocks at the beginning of each experiment, which could explain the apparent variations in MAP for DET-MK-treated horses, although values remained within the reference range. Moreover, in the aforementioned study19 in standing horses, MK-467 did not induce changes in arterial blood pressures when administered alone. Changes in SVR can occur with or without concurrent changes in MAP, as the variable is also affected by Qt and CVP. Thus, unchanging SVR relative to baseline (where values increased for other treatments) and rapid return of CVP to approximate baseline values after MK-467 administration in our study likely reflected cardiovascular stability, as even small changes in CVP can indicate marked variations in venous blood return.34 These results supported that MK-467 reversed vasoconstriction and consequent bradycardia without causing marked hemodynamic disturbances or increasing the workload of the heart. In fact, our findings indicated hemodynamic stability was restored in detomidine-treated horses following MK-467 administration.
Marked hypertension was observed with DET-HYO, and hyoscine failed to attenuate the detomidine-induced increase in SVR in horses of the present study, although the attendant bradycardia was reversed. This was consistent with previous investigations in which anticholinergics have been combined with α2-adrenoceptor agonists in standing horses.4,22 Hyoscine may not directly cause further vasoconstriction,35 but it is a positive chronotrope and may thus exacerbate hypertension by preventing development of compensatory bradycardia.4 Our findings supported this, as horses developed tachycardia and had significantly increased heart rates relative to baseline values from the 15- through 45-minute time points with DET-HYO. With tachycardia, filling of the ventricles between systoles can be incomplete and lead to a lower stroke volume, as occurred in DET-HYO-treated horses in our study. This, in turn, probably contributed to the increased LVW relative to baseline at 15 minutes and higher LVW relative to that observed with other treatments at 15 and 30 minutes in DET-HYO-treated horses. A higher workload increases myocardial oxygen consumption and might predispose to reduced oxygenation of the myocardium, especially if oxygen delivery decreases, as has been described in horses sedated with detomidine.31 This may be of clinical importance, particularly in horses with colic, in which hyoscine has also been used. In patients with severe colic, cardiovascular function might already be compromised, and administration of hyoscine may thus lead to further adverse effects. In addition, heart rate is an important prognostic indicator of survival, and it is also used in deciding whether surgical intervention is needed in horses with colic.36,37 Thus, treatment with hyoscine might affect these interpretations shortly after its administration. However, the t1/2 of hyoscine was relatively short (approx 21 minutes) in healthy, detomidine-treated horses at the doses used in the present study, and significant increases in heart rate resolved approximately 35 minutes after injection, suggesting that its effects are short-lived. Whether this applies to clinical situations, such as in horses with colic, should be further investigated.
The Co2 and Po2 were significantly higher with DET-MK than with the other treatments at the 15-minute time point and apparently higher than those detected with other treatments, albeit not significantly, at most other postinjection time points. Similar changes in venous oxygen tension measurements were reported after romifidine administration with MK-467 in a previous study.19 The Po2 reflects oxygen delivery and tissue perfusion and is dependent on Cao2, Qt, and SVR. No consistent differences in Cao2 were detected among treatments, likely because respiratory rates remained within the reference range. Therefore, it is likely that improved SVR and improved Qt (compared with that during DET-S treatment at the 15-minute time point) after MK-467 administration contributed to the higher Co2 detected with DET-MK, which was suggestive of improved oxygen delivery and tissue perfusion, while the LVW did not increase as observed with DET-HYO. However, the clinical relevance of the differences in blood gas analysis results among the treatments during short sedation may be minor, as no differences in the calculated variables of oxygen consumption and oxygen delivery were detected. With a longer duration of sedation, or in animals with cardiovascular compromise, an improvement in Co2 may have greater clinical importance; however, further investigation is needed to determine whether such an effect is observed in clinical patients receiving DET-MK.
In the present study, DET-S treatment was associated with greater mean PAP at most time points, compared with that observed for DET-MK, although it remained comparable to values measured in healthy resting horses38 and did not increase significantly from the baseline measurements. This observation was probably related to the general vasoconstriction caused by α2-adrenoceptor agonists. The PVR did not differ significantly between DET-S and DET-MK treatments, which was likely attributable to the relatively minor increase in mean PAP after detomidine injection. In contrast, the significant increase in PAP with DET-HYO at the 15-minute time point, compared with the baseline value, could have been related to the observed changes in cardiac function, similar to findings observed in exercising horses.39 During heavy exercise, right atrial pressure and PAP increase along with increases in heart rate and Qt.39 In an exercising horse, PVR decreases, presumably because of new vascular bed employment,39 but this was not found with DET-HYO in the present study.
Many drugs, including detomidine, have been shown to affect the voltage of the lithium sensor used for continuous monitoring of Qt in vitro, but at concentrations that are not likely to be reached with clinical doses of detomidine.40 Of the α2-adrenoceptor agonists, only xylazine has been shown to alter this voltage at clinically relevant concentrations in vivo.41 Therefore, it seemed unlikely that the drugs and concentrations used in the present study could have markedly biased the results of Qt measurement. However, we could not measure Qt with this device at 5 minutes after administration of detomidine owing to abnormal curve analysis. This might have resulted from marked bradycardia at 5 minutes after detomidine administration. Measurement of Qt with the lithium dilution method is based on detection of IV injected lithium chloride in the circulation when it reaches a sensor containing a lithium-sensitive electrode attached to an arterial catheter. Cardiac output measurement is derived from the lithium dilution curve. If the amount of blood exiting the heart is decreased (eg, as in the case of an intracardial shunt42), less lithium chloride will reach the sensor, and an abnormally shaped dilution curve may result, thus biasing the derived Qt.28,42 This could also occur with a very low heart rate, resulting in a markedly decreased Qt.
Baseline measurements of physiologic variables were obtained with the horses standing in the stocks after complete recovery from the instrumentation procedure and before sedation. This may have affected some variables, such as blood pressure measurements, because the horses may have been excited. Similarly, these measurements may have been affected at the end of the observation period when the sedation lessened, and these factors should be considered when interpreting within-treatment comparisons with the baseline data.
Mean plasma glucose concentration did not differ from the baseline value with DET-MK, whereas with DET-S and DET-HYO, the values were significantly greater than baseline at all subsequent time points. This corresponded to findings in a previous study,y in which MK-467 reversed the romifidine-induced increase in blood glucose concentration in horses, although with the drug doses used in the present study, circulating glucose concentrations remained within the reference range33 regardless of treatment.
Administration of MK-467 attenuated the detomidine-induced decrease in intestinal borborygmus scores, in agreement with results of a previous study17 that found the combination of MK-467 with detomidine in horses attenuated suppression of gastrointestinal motility. Hyoscine, however, has been reported to reduce gastrointestinal motility in healthy horses24 and may further enhance this effect of α2-adrenoceptor agonists. This is of concern, particularly in horses with colic, in which hyoscine has been used as a spasmolytic drug and to facilitate rectal examination.23 Our study found no difference in borborygmus scores between DET-HYO and DET-S treatments, in which significant decreases relative to baseline were observed at all postinjection monitoring times. Horses passed feces sooner after DET-MK than after DET-S, suggesting that MK-467 could more rapidly restore gastrointestinal function in horses receiving detomidine. However, the total fecal output measured over 24 hours after the experiments did not differ among treatments. This suggested that depression of gastrointestinal motility after administration of DET-S and DET-HYO was short-lived at the doses used in this small population of healthy horses. However, with longer or multiple sedations, postsedation colic may be of clinical importance, as detomidine and romifidine can reduce intestine motility for up to 1 hour7 and 4 hours,43 respectively, after administration. By attenuating the gastrointestinal depression, MK-467 could potentially aid in the prevention of postsedation colic after α2-adrenoceptor agonist treatment, but further research is needed to confirm this.
Horses had greater sedation scores with DET-HYO than with DET-MK as evidenced by the area under the score-versus-time curve, but there were no differences in these scores between either of these treatments and DET-S. Hyoscine has been reported to cause sedation in human patients,44 and it could potentiate the sedation after detomidine administration in horses. In this study, we could not detect any effect of MK-467 on detomidine-induced sedation. Conversely, findings in earlier investigations suggested that MK-467 might reduce the sedative effects of detomidine17 and romifidine19 in horses, although not to a clinically relevant degree. The potential tendency for hyoscine to enhance sedation and for MK-467 to reduce sedation may contribute to the difference observed in sedation score between DET-MK and DET-HYO. However, in the aforementioned previous studies, MK-467 also reduced the concentrations of detomidine17 and romifidine19 in plasma, and in the present study, plasma concentrations of detomidine, expressed as area under the plasma concentration-versus-time curve, did not differ between DET-S and DET-MK, which might have been attributable to the administration of MK-467 at 10 minutes after detomidine injection, rather than concurrently. Thus, the disposition of detomidine during the first minutes was not affected in our study, whereas in dogs, simultaneously administered MK-467 affected the disposition of dexmedetomidine.45 This mainly occurred during the first 10 minutes, resulting in a lower plasma concentration of dexmedetomidine, after which the elimination curves of dexmedetomidine with and without concurrent MK-467 administration appeared to be parallel.45 A similar result was also detected in a study17 in which horses were administered detomidine and MK-467 IV separately or in the same syringe.
Overall, our findings suggested that the adverse peripheral effects of detomidine can be reversed or attenuated by administration of MK-467 10 minutes later, to better effect than that observed with hyoscine and without significantly influencing the degree of detomidine-induced sedation. In addition, hyoscine should be used with caution in horses that have cardiovascular compromise, such as patients with severe colic. Further studies are needed to determine whether the apparent advantages of MK-467 observed in these healthy horses are also found in clinical patients and to investigate whether MK-467 affects the centrally mediated analgesic effects of detomidine.
Acknowledgments
Supported in part by Vetcare Ltd (Helsinki, Finland).
Presented as a poster at the Annual Meeting of the European College of Veterinary Surgeons, Edinburgh, July 2017.
The authors thank Dr. M. Paula Larenza Menzies for contributions to the study design and Dr. Mika Scheinin and Lauri Vuorilehto for performing analysis of the plasma samples.
ABBREVIATIONS
| Cao2 | Content of oxygen in arterial blood |
| Co2 | Content of oxygen in mixed venous blood |
| CVP | Central venous blood pressure |
| DET-HYO | Detomidine followed by hyoscine |
| DET-MK | Detomidine followed by MK-467 |
| DET-S | Detomidine followed by saline solution |
| LVW | Left ventricular workload |
| MAP | Mean arterial blood pressure |
| PAP | Pulmonary arterial blood pressure |
| Po2 | Mixed venous partial pressure of oxygen |
| PVR | Pulmonary vascular resistance |
| Qt | Cardiac output |
| SAP | Systolic arterial blood pressure |
| SVR | Systemic vascular resistance |
Footnotes
Scandicain, 2% solution, AstraZeneca, Wedel, Germany.
Cavafix Certo, B. Braun, Melsungen, Germany.
Intraflon 2, Laboratoires Pharmaceutiques Vygon, Ecouen, France.
BD arterial cannula, Becton-Dickinson Critical Care Systems, Singapore.
Arrow-Berman angiographic catheter, Arrow International, Reading, Penn.
Mila 10-gauge × 15-cm IV catheter, Mila International, Florence, Ky.
S/5 compact critical care Monitor, Datex Ohmeda, Madison, Wis.
LiDCO Plus Hemodynamic Monitor, LiDCO, London, England.
PICO50, Radiometer Medical, Brønshøj, Denmark.
ABL800 Flex, Radiometer Medical, Brønshøj, Denmark.
Equisedan, Vetcare Ltd, Helsinki, Finland.
MK-467, Merck & Co, Kenilworth, NJ.
Buscopan, Boehringer-Ingelheim Intl, Ingelheim am Rhein, Germany.
Sep-Pak tC18 96-well extraction plate, Waters Co, Milford, Mass.
Toronto Research Chemicals, Toronto, ON, Canada.
Tocris Biosciences, R&D Systems, Minneapolis, Minn.
Phenomenex Gemini HPLC column, Phenomenex, Vaerlose, Denmark.
SunFire HPLC column, Waters Co, Dublin, Ireland.
4000 QTrap, AB Sciex, Framingham, Mass.
AB Sciex software, Analyst 4.1, Concord, ON, Canada.
Acquity ultrahigh-performance liquid chromatography with Waters TQ-S triple-quadrupole mass spectrometer, Waters Corp, Milford, Mass.
BEH C18, Waters Corp, Milford, Mass.
GraphPad Prism, version 6.0, GraphPad Software Inc, San Diego, Calif.
SPSS Statistics, version 22.0, IBM Finland, Espoo, Finland.
Pakkanen S, de Vries A, Raekallio M, et al. The effect of romifidine, MK-467, a peripheral α2-adrenoceptor antagonist, and their combination on plasma glucose concentrations in horses (abstr), in Proceedings. Assoc Vet Anaesth Autumn Meet 2016;70.
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