Veterinary Anaesthesia and Analgesia, 2015, 42, 623–628
doi:10.1111/vaa.12249
SHORT COMMUNICATION
Effects of medetomidine and xylazine on intraocular pressure and pupil size in healthy Beagle dogs Teppei Kanda*,†, Ayano Iguchi*, Chieko Yoshioka*, Haruka Nomura*, Kanako Higashi*, Minami Kaya*, Rie Yamamoto*, Tomoko Kuramoto* & Toshinori Furukawa† *Laboratory of Veterinary Nursing and Medication, Department of Comparative Animal Science, College of Life Science, Kurashiki University of Science and the Arts, Kurashiki, Japan †Veterinary Teaching Hospital, Kurashiki University of Science and the Arts, Kurashiki, Japan
Correspondence: Teppei Kanda, Laboratory of Veterinary Nursing and Medication, Department of Comparative Animal Science, College of Life Science, Kurashiki University of Science and the Arts, Tsurajima-cho Nishinoura 2640, Kurashiki, 712-8505 Okayama, Japan. E-mail: [email protected]
Abstract Objective To determine the effects of intramuscular (IM) administration of medetomidine and xylazine on intraocular pressure (IOP) and pupil size in normal dogs. Study design Prospective, randomized, experimental, crossover trial. Animals Five healthy, purpose-bred Beagle dogs. Methods Each dog was administered 11 IM injections of, respectively: physiological saline; medetomidine at doses of 5, 10, 20, 40 and 80 lg kg 1, and xylazine at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg kg 1. Injections were administered at least 1 week apart. IOP and pupil size were measured at baseline (before treatment) and at 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours post-injection. Results A significant decrease in IOP was observed at 6 hours after 80 lg kg 1 medetomidine compared with values at 0.25 and 0.50 hours, although there were no significant changes in IOP from baseline. In dogs treated with 8.0 mg kg 1 xylazine, significant reductions in IOP were observed at 4 and 5 hours compared with that at 0.25 hours after administration. In dogs treated with 5, 10, 20 and 40 lg kg 1 medetomidine and 0.5, 1.0 and 623
2.0 mg kg 1 xylazine, there were no significant changes in IOP. Pupil size did not change significantly after any of the medetomidine or xylazine treatments compared with the baseline value. Conclusions and clinical relevance Low or moderate doses of medetomidine or xylazine did not induce significant changes in IOP or pupil size. In contrast, high doses of medetomidine or xylazine induced significant changes up to 8 hours after treatment, but values remained within the normal canine physiological range. The results of this study suggest a lack of significant change in IOP and pupil size in healthy dogs administered low or moderate doses of xylazine or medetomidine. Keywords dog, intraocular pressure, medetomidine, pupil size, xylazine.
Introduction Ocular effects of a2-adrenoceptor agonists in dogs have been reported (Verbruggen et al. 2000; Artigas et al. 2012; Rauser et al. 2012). One study found that intravenous (IV) administration of 1500 lg m 2 medetomidine had no effect on intraocular pressure (IOP) (Verbruggen et al. 2000), whereas another found that a combination of 300 lg m 2 medetomidine and 6.0 mg m 2 butorphanol IV induced a transient increase in IOP
Effects of a2-agonists on IOP in dogs T Kanda et al. (Rauser et al. 2012). IV administration of 5 lg kg 1 dexmedetomidine, the dextrorotatory enantiomer of medetomidine, also reduced IOP significantly in dogs (Artigas et al. 2012). The validity of such comparisons is limited, however, by interstudy variability with regard to drug doses, treatment combinations and the duration of observations. Another important factor that can affect IOP is pupil size, which is affected by the administration of a2-adrenoceptor agonists. Miosis is known to reduce IOP by increasing the outflow of aqueous humor (Gelatt & Brooks 1999). Further studies are necessary to investigate the changes in IOP over time induced by sedation protocols involving different doses of medetomidine and xylazine. The aim of this prospective study was to investigate the effects of different doses of medetomidine and xylazine, respectively, on IOP and pupil size in healthy dogs. It was hypothesized that medetomidine and xylazine would each induce transient increments in IOP, followed by reductions, in healthy dogs at the higher doses tested. It was further hypothesized that the administration of each drug would be associated with reductions in pupil size. Materials and methods
anosus muscle throughout the experiment. Injections consisted of, respectively: physiological saline solution; 5, 10, 20, 40 and 80 lg kg 1 of medetomidine hydrochloride (0.1%; Domitor; Nippon Zenyaku Kogyo Co. Ltd, Japan), and 0.5, 1.0, 2.0, 4.0 and 8.0 mg kg 1 of xylazine hydrochloride (2.0%; Celactar; Bayer Yakuhin Ltd, Japan). All injections were separated by intervals of at least 1 week, and the order in which they were administered was determined using a randomized Latin square crossover design. For the sake of clarity, these treatments are subsequently referred to as control, MED-5, MED-10, MED-20, MED-40, MED-80, XYL-0.5, XYL-1, XYL-2, XYL4 and XYL-8, respectively. All dogs were acclimated to the experiment room and fasted for 12 hours before treatment. The schedule of room illumination remained consistent throughout the study. Intraocular pressure and pupil size were measured at baseline (before treatment), and at 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours after each injection. After the 8 hour measurements, dogs were kept in the experiment room regardless of whether they were still sedated and were not subjected to any treatment, including reversal treatment.
Animals All procedures were carried out with the approval of the Institutional Animal Care and Use Committee of Kurashiki University of Science and the Arts, Kurashiki, Japan. Five healthy, purpose-bred, male Beagle dogs, with a mean standard deviation (SD) age of 6.6 0.8 years and a mean SD weight of 14.3 3.5 kg were used in this study. The dogs were maintained under uniform conditions in the authors’ laboratory at the animal institution. Routine physical and ophthalmic examinations, which consisted of observations of the globe and eyelid, vision testing, direct and indirect pupillary light reflex testing, slit-lamp biomicroscopy, direct ophthalmoscopy, Schirmer’s tear test, and IOP measurements were performed prior to the start of the study and indicated no abnormalities. All dogs were evaluated as being of American Society of Anesthesiologists (ASA) class I physical status. Study protocol Each dog was administered 11 intramuscular (IM) injections of 2 mL volume into the semimembr-
Measurements Intraocular pressure was measured in the left eye using rebound tonometry (Tono Vet; Icare Finland Oy, Finland). Prior to each measurement, the tonometer was calibrated and a new probe was attached. IOP measurements were obtained while the dog was positioned in right lateral recumbency, with the head maintained in a relaxed manner at the level of the thorax. Pupil diameter was measured using Haab’s pupillometer (Muranaka Medical Instruments Co. Ltd, Japan). Statistical analysis All data were analyzed using GraphPad Prism Version 6.0 (GraphPad Software, Inc., CA, USA). Friedman’s test for repeated measures was used to evaluate the time effect in each treatment. When a significant difference was found using Friedman’s test, Dunn’s test was used to compare the baseline mean with the mean at a particular timepoint. The level of significance in all tests was set at p < 0.05.
© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 623–628
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Effects of a2-agonists on IOP in dogs T Kanda et al.
Results Intraocular pressure In the MED-80 treatment, a significant decrease in mean SD IOP was observed at 6 hours after drug administration (11.0 1.6 mmHg; p < 0.05) compared with the values at 0.25 and 0.50 hours after administration (16.6 1.5 mmHg and 15.2 2.4 mmHg, respectively), although there were no significant changes in IOP compared with the baseline value (13.0 1.2 mmHg) (Table 1). In the MED-5, MED-10, MED-20 and MED-40 treatments, there were no significant changes in IOP. In animals administered XYL-8, significant decreases in IOP were observed at 4 hours (10.2 2.3 mmHg) and 5 hours (10.6 1.9 mmHg) compared with IOP at 0.25 hours (15.8 2.2 mmHg) after administration (p < 0.05) (Table 1). A significant difference was also observed between values obtained at 4 and 0.50 hours after XYL-8 treatment (10.2 2.3 mmHg and 15.4 1.7 mmHg, respectively; p < 0.05). In the XYL-4 treatment, significant decreases in IOP were observed at 2, 4 and 7 hours after administration (11.6 2.7 mmHg, 11.4 2.7 mmHg and 11.4 1.8 mmHg, respectively; p < 0.05) compared with the value at 0.25 hours after treatment (15.8 2.9 mmHg). No significant changes in IOP were observed in the XYL-0.5, XYL-1 and XYL-2 treatments. Administration of medetomidine or xylazine did not induce significant changes in IOP compared with the baseline value, regardless of the dosage of each agent. Pupil size There were no significant changes from baseline in pupil diameter after any of the medetomidine treatments (Table 1), but a significant difference in pupil size emerged between measurements obtained at 0.25 and 6 hours after the MED-80 treatment (3.0 0.7 mm and 5.4 0.5 mm, respectively; p < 0.05). In the MED-40 treatment, a significant difference in pupil diameter was found between measurements taken at 0.25 and 7 hours after treatment (3.4 1.1 mm and 7.4 1.1 mm, respectively; p < 0.05). In the MED-20 treatment, there was a significant difference between measurements obtained at 0.75 and 6 hours after drug administration (2.8 0.8 mm and 6.2 0.8 mm, respectively; p < 0.05). 625
A significant change in pupil size was observed at 8 hours after XYL-8 treatment (5.0 0.0 mm) compared with those at 0.25 and 0.50 hours after administration (2.4 0.5 mm and 2.4 0.5 mm, respectively; p < 0.05). Measurements observed at 6, 7 and 8 hours after XYL-4 treatment (5.4 0.9 mm, 5.4 0.5 mm and 5.4 0.5 mm, respectively) differed significantly from that obtained at 0.25 hours (3.2 0.8 mm; p < 0.05). There was no significant change in pupil diameter compared with the baseline value in any of the xylazine treatments. Discussion Medetomidine and xylazine are a2-adrenoceptor agonists that reportedly reduce IOP in some species (Burke & Potter 1986; van der Woerdt et al. 1995; Artigas et al. 2012). A previous study suggested three possible mechanisms for the reduction in IOP mediated by a2-adrenoceptor agonists: 1) a reduction in aqueous humor production caused by the activation of pre-junctional a2-adrenoceptors; 2) vasoconstriction in the ciliary body triggered by activation of post-junctional a2-adrenoceptors; and 3) inhibition of adenylyl cyclase by the activation of epithelial a2-adrenoceptors to suppress the production of aqueous humor (Kaufman & Gabelt 1995). Additionally, Rauser et al. (2012) reported that medetomidine–butorphanol and dexmedetomidine– butorphanol combinations induced a transient increase and subsequent decrease in IOP in healthy dogs. In the present study, however, no significant transient increase was observed after IM administration of medetomidine or xylazine, regardless of the dosage. Furthermore, in the present experiment, IOP typically did not exceed 20 mmHg, which suggests minimal clinical significance (Rauser et al. 2012). The higher doses of medetomidine or xylazine used in this study (80 lg kg 1 medetomidine, and 4.0 and 8.0 mg kg 1 xylazine, respectively) reduced IOP after administration compared with the value obtained at 0.25 hours, but not in comparison with the baseline value. Pupillary constriction also affects IOP. In contrast with previous findings (Verbruggen et al. 2000), neither medetomidine nor xylazine induced significant pupillary constriction in the present study. The suppression of sympathetic activity induced by a2-adrenoceptor agonists such as medetomidine and xylazine inhibits constriction of the iris dilator
© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 623–628
Baseline
0.25
0.50
2.2 1.8 2.1 1.9 2.4 2.5 1.6 0.9 1.0 2.1 1.5 0.4 0.8 0.8 0.8 1.7 0.5 0.4 0.5 1.1 0.4 0.5
13.8 12.8 12.4 12.8 14.0 13.8 9.8 10.6 12.0 13.0 13.6 4.2 4.8 3.8 2.8 3.4 2.6 4.8 3.6 3.4 3.2 2.4
0.75
4.4 5.0 4.8 3.5 3.0 2.6 4.6 4.8 4.0 3.2 2.4
13.0 12.2 11.8 11.8 13.4 14.0 9.6 10.6 11.6 12.6 14.0
1
0.5 1.0 0.4 1.7 1.0 0.5 0.5 0.4 1.0 0.4 0.5
2.1 1.3 2.3 1.6 3.1 2.3 0.5 0.9 0.9 1.8 2.6 4.4 5.4 6.2 4.4 4.2 3.2 5.4 5.2 5.6 4.8 2.8
12.8 12.2 10.8 12.0 11.4 12.6 11.2 11.2 11.4 11.6 11.4
2
0.5 1.1 0.4 0.5 1.3 0.4 0.5 0.8 0.9 0.8 0.4
2.8 1.6 2.4 1.9 1.7 2.3 0.8 1.5 1.1 2.7* 1.7 4.0 5.6 6.2 5.4 4.6 3.8 5.0 5.6 5.6 4.4 3.8
13.2 12.4 11.8 12.8 11.6 12.2 11.8 11.4 11.8 11.6 11.4
3
0.7 0.9 1.1 0.5 0.9 0.4 0.7 0.5 0.9 0.5 0.8
1.3 0.9 1.6 1.6 2.1 1.5 2.5 1.5 1.3 2.2 2.8 4.6 6.4 7.2 5.6 5.6 4.0 5.0 5.2 5.4 5.0 4.4
11.6 12.8 12.0 12.2 11.8 12.2 11.6 11.2 12.4 11.4 10.2
4
0.5 1.3 1.5 0.9 1.1 0.7 0.7 0.4 0.9 0.0 0.9
1.5 1.3 1.6 1.1 2.7 2.2 2.4 1.3 2.4 2.7* 2.3*,† 4.4 6.4 7.0 5.8 6.0 4.8 5.0 5.2 5.4 5.0 4.2
12.8 12.6 12.4 11.8 11.4 11.8 11.8 12.2 11.2 12.0 10.6
5
1
0.5 1.1 1.2 0.8 1.2 0.8 1.0 0.8 0.9 0.7 0.8
2.6 0.9 1.7 1.3 2.3 2.3 2.9 1.5 1.6 3.3 1.9* 4.4 5.6 5.6 6.2 6.6 5.4 5.0 5.4 5.2 5.4 4.6
12.0 12.6 14.0 13.0 12.6 11.0 12.0 11.8 13.2 12.6 11.0
6
0.5 1.1 0.5 0.8‡ 0.5 0.5† 1.0 0.5 1.1 0.9† 0.5
1.6 1.8 1.9 0.0 2.1 1.6*,† 2.5 1.3 2.9 2.1 2.5
4.4 5.4 6.4 5.8 7.4 5.4 4.6 5.2 5.6 5.4 4.4
12.6 12.4 12.4 13.0 12.6 12.4 11.0 12.2 12.0 11.4 10.8
7
0.5 1.1 1.1 0.4 1.1† 0.5 0.9 0.4 0.9 0.5† 0.9
1.7 0.9 2.1 1.0 1.8 1.5 1.6 2.3 2.7 1.8* 1.8
) or xylazine (XYL; 0.5–8.0 mg kg
SD, standard deviation. Significantly different from value at *0.25 hour, †0.05 hour, ‡0.75 hour and §1 hour after administration (p < 0.05).
Intraocular pressure (mmHg), mean SD Control 13.2 0.8 14.2 1.6 14.0 1.2 MED-5 12.4 1.1 13.8 1.9 12.6 1.3 MED-10 11.8 1.1 12.0 2.5 12.6 1.8 MED-20 12.6 0.9 13.6 1.1 13.6 2.1 MED-40 11.8 0.8 14.2 1.5 14.2 1.9 MED-80 13.0 1.2 16.6 1.5 15.2 2.4 XYL-0.5 12.4 1.1 11.4 1.5 10.8 1.9 XYL-1 12.8 1.1 12.4 0.9 11.4 1.5 XYL-2 12.8 1.3 13.4 1.5 12.4 1.1 XYL-4 13.2 3.1 15.8 2.9 14.0 2.3 XYL-8 12.4 0.9 15.8 2.2 15.4 1.7 Pupil diameter (mm), mean SD Control 4.2 0.4 4.2 0.4 4.4 0.5 MED-5 5.2 1.3 5.2 0.4 4.8 1.1 MED-10 6.2 1.6 6.0 1.6 4.0 1.6 MED-20 4.8 1.3 4.1 1.4 3.0 1.4 MED-40 5.4 1.7 3.4 1.1 3.2 1.3 MED-80 5.4 1.1 3.0 0.7 2.4 0.5 XYL-0.5 5.0 1.0 3.8 0.4 3.6 0.5 XYL-1 4.8 0.8 3.2 1.1 3.6 0.9 XYL-2 5.2 1.1 3.0 1.0 2.6 0.5 XYL-4 4.6 0.5 3.2 0.8 2.6 0.5 XYL-8 4.2 0.8 2.4 0.5 2.4 0.5
Treatment
Time after administration (hours)
Table 1 Intraocular pressure and pupil diameter after intramuscular administration of medetomidine (MED; 5–80 lg kg
5.0 6.0 6.2 6.0 7.2 5.6 5.0 5.2 5.6 5.4 5.0
0.7 1.4 1.6 0.7 1.1 1.5 1.0 0.8 0.9 0.5† 0.0*,†,§
1.4 0.8 2.3 1.9 2.0 1.1 2.6 2.5 0.8 1.1 1.5
4.0 4.8 5.8 4.6 5.4 5.4 4.6 5.2 5.4 4.8 4.2
12.4 10.8 12.2 12.6 12.6 12.0 12.2 13.8 13.2 13.6 13.2
24
0.0 1.1 1.1 0.9 1.1 1.1 0.9 0.8 0.9 0.4 0.8
1.1 1.9 1.8 1.5 1.1 2.4 1.6 1.6 1.9 2.7 2.4
) in Beagle dogs (n = 5)
13.0 12.2 12.8 13.8 13.2 12.2 12.6 12.8 11.8 12.2 11.4
8
1
Effects of a2-agonists on IOP in dogs T Kanda et al.
© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 623–628
626
Effects of a2-agonists on IOP in dogs T Kanda et al.
muscle, which is innervated primarily by sympathetic nerves. However, inhibition of the iris dilator muscle constriction induced by a2-adrenoceptor agonists does not induce miosis; it only inhibits mydriasis. In contrast, the iris sphincter muscle is innervated not only by parasympathetic nerves, but also by sympathetic nerves (Randall 1999). Suppression of adrenergic nerve activity may also suppress inhibition of the parasympathetic cholinergic nerves that innervate the iris sphincter muscle. To date, no report has completely elucidated the mechanism of miosis induced by a2-adrenoceptor agonists in dogs. The present study has shown, at least, that a2-adrenoceptor agonists did not induce mydriasis in healthy dogs. Miosis increases aqueous humor outflow through the trabecular meshwork, which in turn reduces IOP (Gelatt & Brooks 1999). However, in this study, when a significant decrease in IOP was observed compared with the value at 0.25 hours after the administration of higher doses of medetomidine or xylazine, there were no significant differences in pupil size. Thus, this finding suggests that the changes in IOP observed in this study were not related to effects on the pupil. Body position and vomiting are also reported to affect IOP in dogs. Mean IOP measurements obtained in dorsal recumbency, sternal recumbency and sitting positions were found to differ significantly (Broadwater et al. 2008). Although no specific effects of lateral recumbency have been described, Broadwater et al. (2008) concluded that when IOP is measured in dogs, the body position used should be recorded and should be consistent in repeat evaluations. In accordance with the recommendations in that report, body position was standardized throughout this present study. In this study, MED40, MED-80, XYL-4 and XYL-8 treatments affected IOP but did not cause vomiting, which suggests that the correlation is not causative. This study has a number of limitations. Firstly, the small number of animals made it impossible to exclude statistical type I error. Nonetheless, several studies using small numbers of animals have shown significant clinical findings. Secondly, medetomidine and xylazine were not used in equipotent doses. Thirdly, a carryover effect or influence of previous drug administration may have occurred, despite the wash-out period utilized. The findings of this study suggest that low or moderate doses of medetomidine or xylazine, rather than high doses, should be utilized in situations in which a change in IOP is contraindicated. In normal 627
dogs, the changes in IOP resulting from high doses of medetomidine or xylazine did not cause IOP values to exceed the canine physiological range (Gelatt & Brooks 1999). Therefore, these a2-adrenoceptor agonists are thought to be suitable sedatives or preanesthetic agents for ocular normotensive dogs. However, the effect of medetomidine or xylazine on pupil size may make it difficult to obtain sufficient mydriasis for certain complete ophthalmoscopic examinations and other ophthalmic assessments such as electroretinography. Intraocular surgical treatments, including cataract surgery, also require complete mydriasis. To achieve mydriasis in dogs treated with an a2-adrenoceptor agonist, topical application of tropicamide, a mydriatic agent, was suggested by Wallin-H akanson & Wallin-H akanson (2001). The present study was performed in normal, healthy dogs and utilized only one eye in each dog. Further studies involving dogs with known ocular diseases or diseases affecting IOP and pupil size are required. In conclusion, low or moderate doses of medetomidine or xylazine did not induce any significant changes in IOP or pupil size, whereas high doses of medetomidine or xylazine induced significant changes up to 8 hours after treatment, although the values remained within the normal physiological canine range. The results also suggest that changes in IOP and pupil size were not significant in healthy dogs sedated with low or moderate doses of xylazine or medetomidine. This preliminary study was performed in only five dogs and therefore further studies involving larger numbers of dogs are necessary to confirm our results. Acknowledgements The authors would like to thank Professor Dr Yoshiaki Hikasa, Laboratory of Veterinary Internal Medicine, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori, Japan, for his valuable suggestions and encouragement. References Artigas C, Redondo JI, Lopez-Murcia MM (2012) Effects of intravenous administration of dexmedetomidine on intraocular pressure and pupil size in clinically normal dogs. Vet Ophthalmol 15(Suppl 1), 79–82. Broadwater JJ, Schorling JJ, Herring IP et al. (2008) Effect of body position on intraocular pressure in dogs without glaucoma. Am J Vet Res 69, 527–530.
© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 623–628
Effects of a2-agonists on IOP in dogs T Kanda et al. Burke JA, Potter DE (1986) The ocular effects of xylazine in rabbits, cats, and monkeys. J Ocul Pharmacol 2, 9–21. Gelatt KN, Brooks DE (1999) The canine glaucomas. In: Veterinary Ophthalmology (3rd edn). Gelatt KN (ed.). Lippincott Williams & Wilkins, USA. pp. 701–754. Kaufman PL, Gabelt B (1995) Alpha2-adrenergic agonist effects on aqueous humor dynamics. J Glaucoma 4(Suppl 1), 8–14. Randall HS (1999) Comparative neuro-ophthalmology. In: Veterinary Ophthalmology (3rd edn). Gelatt KN (ed.). Lippincott Williams & Wilkins, USA. pp. 1307–1400. Rauser P, Pfeifr J, Proks P et al. (2012) Effect of medetomidine–butorphanol and dexmedetomidine– butorphanol combinations on intraocular pressure in healthy dogs. Vet Anaesth Analg 39, 301–305.
Verbruggen AM, Akkerdaas LC, Hellebrekers LJ et al. (2000) The effect of intravenous medetomidine on pupil size and intraocular pressure in normotensive dogs. Vet Q 22, 179–180. Wallin-H akanson N, Wallin-H akanson B (2001) The effects of topical tropicamide and systemic medetomidine, followed by atipamezole reversal, on pupil size and intraocular pressure in normal dogs. Vet Ophthalmol 4, 3–6. van der Woerdt A, Gilger BC, Wilkie DA et al. (1995) Effect of auriculopalpebral nerve block and intravenous administration of xylazine on intraocular pressure and corneal thickness in horses. Am J Vet Res 56, 155–158. Received 2 October 2014; accepted 16 December 2014.
© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 623–628
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doi:10.1111/vaa.12249
SHORT COMMUNICATION
Effects of medetomidine and xylazine on intraocular pressure and pupil size in healthy Beagle dogs Teppei Kanda*,†, Ayano Iguchi*, Chieko Yoshioka*, Haruka Nomura*, Kanako Higashi*, Minami Kaya*, Rie Yamamoto*, Tomoko Kuramoto* & Toshinori Furukawa† *Laboratory of Veterinary Nursing and Medication, Department of Comparative Animal Science, College of Life Science, Kurashiki University of Science and the Arts, Kurashiki, Japan †Veterinary Teaching Hospital, Kurashiki University of Science and the Arts, Kurashiki, Japan
Correspondence: Teppei Kanda, Laboratory of Veterinary Nursing and Medication, Department of Comparative Animal Science, College of Life Science, Kurashiki University of Science and the Arts, Tsurajima-cho Nishinoura 2640, Kurashiki, 712-8505 Okayama, Japan. E-mail: [email protected]
Abstract Objective To determine the effects of intramuscular (IM) administration of medetomidine and xylazine on intraocular pressure (IOP) and pupil size in normal dogs. Study design Prospective, randomized, experimental, crossover trial. Animals Five healthy, purpose-bred Beagle dogs. Methods Each dog was administered 11 IM injections of, respectively: physiological saline; medetomidine at doses of 5, 10, 20, 40 and 80 lg kg 1, and xylazine at doses of 0.5, 1.0, 2.0, 4.0 and 8.0 mg kg 1. Injections were administered at least 1 week apart. IOP and pupil size were measured at baseline (before treatment) and at 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours post-injection. Results A significant decrease in IOP was observed at 6 hours after 80 lg kg 1 medetomidine compared with values at 0.25 and 0.50 hours, although there were no significant changes in IOP from baseline. In dogs treated with 8.0 mg kg 1 xylazine, significant reductions in IOP were observed at 4 and 5 hours compared with that at 0.25 hours after administration. In dogs treated with 5, 10, 20 and 40 lg kg 1 medetomidine and 0.5, 1.0 and 623
2.0 mg kg 1 xylazine, there were no significant changes in IOP. Pupil size did not change significantly after any of the medetomidine or xylazine treatments compared with the baseline value. Conclusions and clinical relevance Low or moderate doses of medetomidine or xylazine did not induce significant changes in IOP or pupil size. In contrast, high doses of medetomidine or xylazine induced significant changes up to 8 hours after treatment, but values remained within the normal canine physiological range. The results of this study suggest a lack of significant change in IOP and pupil size in healthy dogs administered low or moderate doses of xylazine or medetomidine. Keywords dog, intraocular pressure, medetomidine, pupil size, xylazine.
Introduction Ocular effects of a2-adrenoceptor agonists in dogs have been reported (Verbruggen et al. 2000; Artigas et al. 2012; Rauser et al. 2012). One study found that intravenous (IV) administration of 1500 lg m 2 medetomidine had no effect on intraocular pressure (IOP) (Verbruggen et al. 2000), whereas another found that a combination of 300 lg m 2 medetomidine and 6.0 mg m 2 butorphanol IV induced a transient increase in IOP
Effects of a2-agonists on IOP in dogs T Kanda et al. (Rauser et al. 2012). IV administration of 5 lg kg 1 dexmedetomidine, the dextrorotatory enantiomer of medetomidine, also reduced IOP significantly in dogs (Artigas et al. 2012). The validity of such comparisons is limited, however, by interstudy variability with regard to drug doses, treatment combinations and the duration of observations. Another important factor that can affect IOP is pupil size, which is affected by the administration of a2-adrenoceptor agonists. Miosis is known to reduce IOP by increasing the outflow of aqueous humor (Gelatt & Brooks 1999). Further studies are necessary to investigate the changes in IOP over time induced by sedation protocols involving different doses of medetomidine and xylazine. The aim of this prospective study was to investigate the effects of different doses of medetomidine and xylazine, respectively, on IOP and pupil size in healthy dogs. It was hypothesized that medetomidine and xylazine would each induce transient increments in IOP, followed by reductions, in healthy dogs at the higher doses tested. It was further hypothesized that the administration of each drug would be associated with reductions in pupil size. Materials and methods
anosus muscle throughout the experiment. Injections consisted of, respectively: physiological saline solution; 5, 10, 20, 40 and 80 lg kg 1 of medetomidine hydrochloride (0.1%; Domitor; Nippon Zenyaku Kogyo Co. Ltd, Japan), and 0.5, 1.0, 2.0, 4.0 and 8.0 mg kg 1 of xylazine hydrochloride (2.0%; Celactar; Bayer Yakuhin Ltd, Japan). All injections were separated by intervals of at least 1 week, and the order in which they were administered was determined using a randomized Latin square crossover design. For the sake of clarity, these treatments are subsequently referred to as control, MED-5, MED-10, MED-20, MED-40, MED-80, XYL-0.5, XYL-1, XYL-2, XYL4 and XYL-8, respectively. All dogs were acclimated to the experiment room and fasted for 12 hours before treatment. The schedule of room illumination remained consistent throughout the study. Intraocular pressure and pupil size were measured at baseline (before treatment), and at 0.25, 0.50, 0.75, 1, 2, 3, 4, 5, 6, 7, 8 and 24 hours after each injection. After the 8 hour measurements, dogs were kept in the experiment room regardless of whether they were still sedated and were not subjected to any treatment, including reversal treatment.
Animals All procedures were carried out with the approval of the Institutional Animal Care and Use Committee of Kurashiki University of Science and the Arts, Kurashiki, Japan. Five healthy, purpose-bred, male Beagle dogs, with a mean standard deviation (SD) age of 6.6 0.8 years and a mean SD weight of 14.3 3.5 kg were used in this study. The dogs were maintained under uniform conditions in the authors’ laboratory at the animal institution. Routine physical and ophthalmic examinations, which consisted of observations of the globe and eyelid, vision testing, direct and indirect pupillary light reflex testing, slit-lamp biomicroscopy, direct ophthalmoscopy, Schirmer’s tear test, and IOP measurements were performed prior to the start of the study and indicated no abnormalities. All dogs were evaluated as being of American Society of Anesthesiologists (ASA) class I physical status. Study protocol Each dog was administered 11 intramuscular (IM) injections of 2 mL volume into the semimembr-
Measurements Intraocular pressure was measured in the left eye using rebound tonometry (Tono Vet; Icare Finland Oy, Finland). Prior to each measurement, the tonometer was calibrated and a new probe was attached. IOP measurements were obtained while the dog was positioned in right lateral recumbency, with the head maintained in a relaxed manner at the level of the thorax. Pupil diameter was measured using Haab’s pupillometer (Muranaka Medical Instruments Co. Ltd, Japan). Statistical analysis All data were analyzed using GraphPad Prism Version 6.0 (GraphPad Software, Inc., CA, USA). Friedman’s test for repeated measures was used to evaluate the time effect in each treatment. When a significant difference was found using Friedman’s test, Dunn’s test was used to compare the baseline mean with the mean at a particular timepoint. The level of significance in all tests was set at p < 0.05.
© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 623–628
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Effects of a2-agonists on IOP in dogs T Kanda et al.
Results Intraocular pressure In the MED-80 treatment, a significant decrease in mean SD IOP was observed at 6 hours after drug administration (11.0 1.6 mmHg; p < 0.05) compared with the values at 0.25 and 0.50 hours after administration (16.6 1.5 mmHg and 15.2 2.4 mmHg, respectively), although there were no significant changes in IOP compared with the baseline value (13.0 1.2 mmHg) (Table 1). In the MED-5, MED-10, MED-20 and MED-40 treatments, there were no significant changes in IOP. In animals administered XYL-8, significant decreases in IOP were observed at 4 hours (10.2 2.3 mmHg) and 5 hours (10.6 1.9 mmHg) compared with IOP at 0.25 hours (15.8 2.2 mmHg) after administration (p < 0.05) (Table 1). A significant difference was also observed between values obtained at 4 and 0.50 hours after XYL-8 treatment (10.2 2.3 mmHg and 15.4 1.7 mmHg, respectively; p < 0.05). In the XYL-4 treatment, significant decreases in IOP were observed at 2, 4 and 7 hours after administration (11.6 2.7 mmHg, 11.4 2.7 mmHg and 11.4 1.8 mmHg, respectively; p < 0.05) compared with the value at 0.25 hours after treatment (15.8 2.9 mmHg). No significant changes in IOP were observed in the XYL-0.5, XYL-1 and XYL-2 treatments. Administration of medetomidine or xylazine did not induce significant changes in IOP compared with the baseline value, regardless of the dosage of each agent. Pupil size There were no significant changes from baseline in pupil diameter after any of the medetomidine treatments (Table 1), but a significant difference in pupil size emerged between measurements obtained at 0.25 and 6 hours after the MED-80 treatment (3.0 0.7 mm and 5.4 0.5 mm, respectively; p < 0.05). In the MED-40 treatment, a significant difference in pupil diameter was found between measurements taken at 0.25 and 7 hours after treatment (3.4 1.1 mm and 7.4 1.1 mm, respectively; p < 0.05). In the MED-20 treatment, there was a significant difference between measurements obtained at 0.75 and 6 hours after drug administration (2.8 0.8 mm and 6.2 0.8 mm, respectively; p < 0.05). 625
A significant change in pupil size was observed at 8 hours after XYL-8 treatment (5.0 0.0 mm) compared with those at 0.25 and 0.50 hours after administration (2.4 0.5 mm and 2.4 0.5 mm, respectively; p < 0.05). Measurements observed at 6, 7 and 8 hours after XYL-4 treatment (5.4 0.9 mm, 5.4 0.5 mm and 5.4 0.5 mm, respectively) differed significantly from that obtained at 0.25 hours (3.2 0.8 mm; p < 0.05). There was no significant change in pupil diameter compared with the baseline value in any of the xylazine treatments. Discussion Medetomidine and xylazine are a2-adrenoceptor agonists that reportedly reduce IOP in some species (Burke & Potter 1986; van der Woerdt et al. 1995; Artigas et al. 2012). A previous study suggested three possible mechanisms for the reduction in IOP mediated by a2-adrenoceptor agonists: 1) a reduction in aqueous humor production caused by the activation of pre-junctional a2-adrenoceptors; 2) vasoconstriction in the ciliary body triggered by activation of post-junctional a2-adrenoceptors; and 3) inhibition of adenylyl cyclase by the activation of epithelial a2-adrenoceptors to suppress the production of aqueous humor (Kaufman & Gabelt 1995). Additionally, Rauser et al. (2012) reported that medetomidine–butorphanol and dexmedetomidine– butorphanol combinations induced a transient increase and subsequent decrease in IOP in healthy dogs. In the present study, however, no significant transient increase was observed after IM administration of medetomidine or xylazine, regardless of the dosage. Furthermore, in the present experiment, IOP typically did not exceed 20 mmHg, which suggests minimal clinical significance (Rauser et al. 2012). The higher doses of medetomidine or xylazine used in this study (80 lg kg 1 medetomidine, and 4.0 and 8.0 mg kg 1 xylazine, respectively) reduced IOP after administration compared with the value obtained at 0.25 hours, but not in comparison with the baseline value. Pupillary constriction also affects IOP. In contrast with previous findings (Verbruggen et al. 2000), neither medetomidine nor xylazine induced significant pupillary constriction in the present study. The suppression of sympathetic activity induced by a2-adrenoceptor agonists such as medetomidine and xylazine inhibits constriction of the iris dilator
© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 623–628
Baseline
0.25
0.50
2.2 1.8 2.1 1.9 2.4 2.5 1.6 0.9 1.0 2.1 1.5 0.4 0.8 0.8 0.8 1.7 0.5 0.4 0.5 1.1 0.4 0.5
13.8 12.8 12.4 12.8 14.0 13.8 9.8 10.6 12.0 13.0 13.6 4.2 4.8 3.8 2.8 3.4 2.6 4.8 3.6 3.4 3.2 2.4
0.75
4.4 5.0 4.8 3.5 3.0 2.6 4.6 4.8 4.0 3.2 2.4
13.0 12.2 11.8 11.8 13.4 14.0 9.6 10.6 11.6 12.6 14.0
1
0.5 1.0 0.4 1.7 1.0 0.5 0.5 0.4 1.0 0.4 0.5
2.1 1.3 2.3 1.6 3.1 2.3 0.5 0.9 0.9 1.8 2.6 4.4 5.4 6.2 4.4 4.2 3.2 5.4 5.2 5.6 4.8 2.8
12.8 12.2 10.8 12.0 11.4 12.6 11.2 11.2 11.4 11.6 11.4
2
0.5 1.1 0.4 0.5 1.3 0.4 0.5 0.8 0.9 0.8 0.4
2.8 1.6 2.4 1.9 1.7 2.3 0.8 1.5 1.1 2.7* 1.7 4.0 5.6 6.2 5.4 4.6 3.8 5.0 5.6 5.6 4.4 3.8
13.2 12.4 11.8 12.8 11.6 12.2 11.8 11.4 11.8 11.6 11.4
3
0.7 0.9 1.1 0.5 0.9 0.4 0.7 0.5 0.9 0.5 0.8
1.3 0.9 1.6 1.6 2.1 1.5 2.5 1.5 1.3 2.2 2.8 4.6 6.4 7.2 5.6 5.6 4.0 5.0 5.2 5.4 5.0 4.4
11.6 12.8 12.0 12.2 11.8 12.2 11.6 11.2 12.4 11.4 10.2
4
0.5 1.3 1.5 0.9 1.1 0.7 0.7 0.4 0.9 0.0 0.9
1.5 1.3 1.6 1.1 2.7 2.2 2.4 1.3 2.4 2.7* 2.3*,† 4.4 6.4 7.0 5.8 6.0 4.8 5.0 5.2 5.4 5.0 4.2
12.8 12.6 12.4 11.8 11.4 11.8 11.8 12.2 11.2 12.0 10.6
5
1
0.5 1.1 1.2 0.8 1.2 0.8 1.0 0.8 0.9 0.7 0.8
2.6 0.9 1.7 1.3 2.3 2.3 2.9 1.5 1.6 3.3 1.9* 4.4 5.6 5.6 6.2 6.6 5.4 5.0 5.4 5.2 5.4 4.6
12.0 12.6 14.0 13.0 12.6 11.0 12.0 11.8 13.2 12.6 11.0
6
0.5 1.1 0.5 0.8‡ 0.5 0.5† 1.0 0.5 1.1 0.9† 0.5
1.6 1.8 1.9 0.0 2.1 1.6*,† 2.5 1.3 2.9 2.1 2.5
4.4 5.4 6.4 5.8 7.4 5.4 4.6 5.2 5.6 5.4 4.4
12.6 12.4 12.4 13.0 12.6 12.4 11.0 12.2 12.0 11.4 10.8
7
0.5 1.1 1.1 0.4 1.1† 0.5 0.9 0.4 0.9 0.5† 0.9
1.7 0.9 2.1 1.0 1.8 1.5 1.6 2.3 2.7 1.8* 1.8
) or xylazine (XYL; 0.5–8.0 mg kg
SD, standard deviation. Significantly different from value at *0.25 hour, †0.05 hour, ‡0.75 hour and §1 hour after administration (p < 0.05).
Intraocular pressure (mmHg), mean SD Control 13.2 0.8 14.2 1.6 14.0 1.2 MED-5 12.4 1.1 13.8 1.9 12.6 1.3 MED-10 11.8 1.1 12.0 2.5 12.6 1.8 MED-20 12.6 0.9 13.6 1.1 13.6 2.1 MED-40 11.8 0.8 14.2 1.5 14.2 1.9 MED-80 13.0 1.2 16.6 1.5 15.2 2.4 XYL-0.5 12.4 1.1 11.4 1.5 10.8 1.9 XYL-1 12.8 1.1 12.4 0.9 11.4 1.5 XYL-2 12.8 1.3 13.4 1.5 12.4 1.1 XYL-4 13.2 3.1 15.8 2.9 14.0 2.3 XYL-8 12.4 0.9 15.8 2.2 15.4 1.7 Pupil diameter (mm), mean SD Control 4.2 0.4 4.2 0.4 4.4 0.5 MED-5 5.2 1.3 5.2 0.4 4.8 1.1 MED-10 6.2 1.6 6.0 1.6 4.0 1.6 MED-20 4.8 1.3 4.1 1.4 3.0 1.4 MED-40 5.4 1.7 3.4 1.1 3.2 1.3 MED-80 5.4 1.1 3.0 0.7 2.4 0.5 XYL-0.5 5.0 1.0 3.8 0.4 3.6 0.5 XYL-1 4.8 0.8 3.2 1.1 3.6 0.9 XYL-2 5.2 1.1 3.0 1.0 2.6 0.5 XYL-4 4.6 0.5 3.2 0.8 2.6 0.5 XYL-8 4.2 0.8 2.4 0.5 2.4 0.5
Treatment
Time after administration (hours)
Table 1 Intraocular pressure and pupil diameter after intramuscular administration of medetomidine (MED; 5–80 lg kg
5.0 6.0 6.2 6.0 7.2 5.6 5.0 5.2 5.6 5.4 5.0
0.7 1.4 1.6 0.7 1.1 1.5 1.0 0.8 0.9 0.5† 0.0*,†,§
1.4 0.8 2.3 1.9 2.0 1.1 2.6 2.5 0.8 1.1 1.5
4.0 4.8 5.8 4.6 5.4 5.4 4.6 5.2 5.4 4.8 4.2
12.4 10.8 12.2 12.6 12.6 12.0 12.2 13.8 13.2 13.6 13.2
24
0.0 1.1 1.1 0.9 1.1 1.1 0.9 0.8 0.9 0.4 0.8
1.1 1.9 1.8 1.5 1.1 2.4 1.6 1.6 1.9 2.7 2.4
) in Beagle dogs (n = 5)
13.0 12.2 12.8 13.8 13.2 12.2 12.6 12.8 11.8 12.2 11.4
8
1
Effects of a2-agonists on IOP in dogs T Kanda et al.
© 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 42, 623–628
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Effects of a2-agonists on IOP in dogs T Kanda et al.
muscle, which is innervated primarily by sympathetic nerves. However, inhibition of the iris dilator muscle constriction induced by a2-adrenoceptor agonists does not induce miosis; it only inhibits mydriasis. In contrast, the iris sphincter muscle is innervated not only by parasympathetic nerves, but also by sympathetic nerves (Randall 1999). Suppression of adrenergic nerve activity may also suppress inhibition of the parasympathetic cholinergic nerves that innervate the iris sphincter muscle. To date, no report has completely elucidated the mechanism of miosis induced by a2-adrenoceptor agonists in dogs. The present study has shown, at least, that a2-adrenoceptor agonists did not induce mydriasis in healthy dogs. Miosis increases aqueous humor outflow through the trabecular meshwork, which in turn reduces IOP (Gelatt & Brooks 1999). However, in this study, when a significant decrease in IOP was observed compared with the value at 0.25 hours after the administration of higher doses of medetomidine or xylazine, there were no significant differences in pupil size. Thus, this finding suggests that the changes in IOP observed in this study were not related to effects on the pupil. Body position and vomiting are also reported to affect IOP in dogs. Mean IOP measurements obtained in dorsal recumbency, sternal recumbency and sitting positions were found to differ significantly (Broadwater et al. 2008). Although no specific effects of lateral recumbency have been described, Broadwater et al. (2008) concluded that when IOP is measured in dogs, the body position used should be recorded and should be consistent in repeat evaluations. In accordance with the recommendations in that report, body position was standardized throughout this present study. In this study, MED40, MED-80, XYL-4 and XYL-8 treatments affected IOP but did not cause vomiting, which suggests that the correlation is not causative. This study has a number of limitations. Firstly, the small number of animals made it impossible to exclude statistical type I error. Nonetheless, several studies using small numbers of animals have shown significant clinical findings. Secondly, medetomidine and xylazine were not used in equipotent doses. Thirdly, a carryover effect or influence of previous drug administration may have occurred, despite the wash-out period utilized. The findings of this study suggest that low or moderate doses of medetomidine or xylazine, rather than high doses, should be utilized in situations in which a change in IOP is contraindicated. In normal 627
dogs, the changes in IOP resulting from high doses of medetomidine or xylazine did not cause IOP values to exceed the canine physiological range (Gelatt & Brooks 1999). Therefore, these a2-adrenoceptor agonists are thought to be suitable sedatives or preanesthetic agents for ocular normotensive dogs. However, the effect of medetomidine or xylazine on pupil size may make it difficult to obtain sufficient mydriasis for certain complete ophthalmoscopic examinations and other ophthalmic assessments such as electroretinography. Intraocular surgical treatments, including cataract surgery, also require complete mydriasis. To achieve mydriasis in dogs treated with an a2-adrenoceptor agonist, topical application of tropicamide, a mydriatic agent, was suggested by Wallin-H akanson & Wallin-H akanson (2001). The present study was performed in normal, healthy dogs and utilized only one eye in each dog. Further studies involving dogs with known ocular diseases or diseases affecting IOP and pupil size are required. In conclusion, low or moderate doses of medetomidine or xylazine did not induce any significant changes in IOP or pupil size, whereas high doses of medetomidine or xylazine induced significant changes up to 8 hours after treatment, although the values remained within the normal physiological canine range. The results also suggest that changes in IOP and pupil size were not significant in healthy dogs sedated with low or moderate doses of xylazine or medetomidine. This preliminary study was performed in only five dogs and therefore further studies involving larger numbers of dogs are necessary to confirm our results. Acknowledgements The authors would like to thank Professor Dr Yoshiaki Hikasa, Laboratory of Veterinary Internal Medicine, Joint Department of Veterinary Medicine, Faculty of Agriculture, Tottori University, Tottori, Japan, for his valuable suggestions and encouragement. References Artigas C, Redondo JI, Lopez-Murcia MM (2012) Effects of intravenous administration of dexmedetomidine on intraocular pressure and pupil size in clinically normal dogs. Vet Ophthalmol 15(Suppl 1), 79–82. Broadwater JJ, Schorling JJ, Herring IP et al. (2008) Effect of body position on intraocular pressure in dogs without glaucoma. Am J Vet Res 69, 527–530.
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Effects of a2-agonists on IOP in dogs T Kanda et al. Burke JA, Potter DE (1986) The ocular effects of xylazine in rabbits, cats, and monkeys. J Ocul Pharmacol 2, 9–21. Gelatt KN, Brooks DE (1999) The canine glaucomas. In: Veterinary Ophthalmology (3rd edn). Gelatt KN (ed.). Lippincott Williams & Wilkins, USA. pp. 701–754. Kaufman PL, Gabelt B (1995) Alpha2-adrenergic agonist effects on aqueous humor dynamics. J Glaucoma 4(Suppl 1), 8–14. Randall HS (1999) Comparative neuro-ophthalmology. In: Veterinary Ophthalmology (3rd edn). Gelatt KN (ed.). Lippincott Williams & Wilkins, USA. pp. 1307–1400. Rauser P, Pfeifr J, Proks P et al. (2012) Effect of medetomidine–butorphanol and dexmedetomidine– butorphanol combinations on intraocular pressure in healthy dogs. Vet Anaesth Analg 39, 301–305.
Verbruggen AM, Akkerdaas LC, Hellebrekers LJ et al. (2000) The effect of intravenous medetomidine on pupil size and intraocular pressure in normotensive dogs. Vet Q 22, 179–180. Wallin-H akanson N, Wallin-H akanson B (2001) The effects of topical tropicamide and systemic medetomidine, followed by atipamezole reversal, on pupil size and intraocular pressure in normal dogs. Vet Ophthalmol 4, 3–6. van der Woerdt A, Gilger BC, Wilkie DA et al. (1995) Effect of auriculopalpebral nerve block and intravenous administration of xylazine on intraocular pressure and corneal thickness in horses. Am J Vet Res 56, 155–158. Received 2 October 2014; accepted 16 December 2014.
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