Veterinary Ophthalmology (2014) 17, Supplement 1, 134–139
DOI:10.1111/vop.12172
The effects of intravenous romifidine on intraocular pressure in clinically normal horses and horses with incidental ophthalmic findings Jessica M. Stine,* Tammy M. Michau,* Megan K. Williams,† Karen Leann Kuebelbeck† and Michele E. Stengard* *BluePearl Veterinary Partners, Tampa, FL 33614, USA; and †Surgi-Care Center for Horses, Brandon, FL, 33511, USA
Address communications to: Dr. T. M. Michau Tel.: 813-933-8944 Fax: 813-594-8456 e-mail: tammy.millermichau@ bluepearlvet.com
Supported in Part by Boehringer-Ingelheim, Ingelheim, Germany.
Abstract Design Original study. Objective To evaluate the effect of sedation with romifidine hydrochloride 1% (Sedivet: Boehringer-Ingelheim) on intraocular pressure (IOP) in the normal horse and horses with incidental ophthalmic findings as measured by applanation tonometry. Animals Nineteen clinically normal horses (13 geldings, six mares) and eight horses (three geldings, five mares) with incidental ophthalmic findings were included in this study. Procedures All horses underwent complete ophthalmic examination with pharmacologic mydriasis a minimum of 2 weeks prior to IOP evaluation. Baseline intraocular pressure values were obtained following auriculopalpebral nerve block and topical anesthetic. Immediately thereafter, romifidine was administered intravenously (75 µg/kg) and the IOP recorded at 5, 15, 30, 45 and 60 min postsedation in both eyes. Five successive readings were obtained at each time point, the low and high value discarded, and three remaining readings averaged for a mean. Results The changes with time were consistent between eyes and OD and OS results were pooled. The mean IOP at baseline was 26.35 5.57 mmHg. Mean IOP values were significantly lower than baseline at 5 (P < 0.0001), 15 (P < 0.0001), 30 (P = 0.0003), 45 (P < 0.0001) and 60 (P = 0.0005) minutes. The largest change from baseline (16.7%) was noted at t = 15 min. Conclusions and clinical relevance Administration of romifidine significantly decreased the IOP from baseline at all time points measured. The greatest decline in IOP was noted at 15 min postsedation. Results are consistent with other studies noting a decline in IOP with administration of a-2 agonists. Key Words: alpha-2 agonist, equine, intraocular pressure, romifidine, sedation, tonometry
INTRODUCTION
Romifidine hydrochloride (Sedivetâ, Boehringer-Ingelheim, Ingelheim, Germany) is a synthetic alpha-2 sympathomimetic agent that targets presynaptic receptors in the central nervous system (CNS). Its pharmacological effects are typical for the alpha-2 agonists and include sedation, muscle relaxation, reluctance to move, and reduced responsiveness to environmental stimuli. Pain tolerance is noted with increasing dose.1 Suggested uses of the drug include routine ocular, oral, or rectal examination, use
during diagnostic procedures and advanced imaging, standing surgical procedures, as a pre-anesthetic or in combination with other sedation for enhanced analgesia. There was no difference in quality or duration of recovery between romifidine and xylazine when used as part of a premedication protocol prior to general anesthesia.2 However, when used as a postanesthetic sedative, romifidine has recently been shown to improve recovery quality in healthy horses undergoing >1 h of isoflurane anesthesia. Results of this study support the use of intravenous romifidine (20 lg/kg) for postanesthetic sedation vs. xylazine © 2014 American College of Veterinary Ophthalmologists
effects romifidine iop normal horses and horses minor lesions 135
or lower doses of romifidine.3 Intravenous romifidine produces strong long-lasting sedation and apparent muscle relaxation, corresponding to a long elimination half-life of the drug. A recent comparison of the locomotor pattern of horses sedated with xylazine, detomidine, or romifidine found that romifidine had a comparably weaker effect on accelerometric variables than did detomidine or xylazine, although the difference was not significant. The duration of romifidine-associated effects on gait was significantly longer than xylazine and detomidine. Effects of romifidine (40 µg/kg IV) on stride frequency were noted for 90 min compared with only 30 min for xylazine and detomidine. Speed was reduced for up to 105 min with romifidine, compared with 30–45 min for xylazine and detomidine, respectively.4 Romifidine may be a good choice in situations where a horse’s balance and coordination are important, but a sustained sedative effect is still desired, such as traveling in a trailer. In addition, only minor alterations to stride regularity were noted; therefore, romifidine may also be useful for procedures such as farriery, loading in a trailer, or other short-duration diagnostic procedures such as radiography or other advanced imaging.4 Hemodynamic changes include a significant reduction in heart rate and cardiac index and a biphasic change in arterial blood pressure, with an initial hypertensive period followed by a prolonged hypotensive phase. Bradyarrhythmias are also reported.5 Sedation and anesthetic protocols should be adjusted accordingly for other members of the Equidae family, especially donkeys and mules. In general, an increase in the dose of xylazine and other a2-adrenoreceptor agonists has been recommended to achieve adequate sedation and analgesia. However, similar to horses, a2-adrenoreceptor agonists are capable of producing cardiac arrhythmias in donkeys. Data from pharmacologic and pharmacokinetic studies in horses should be interpreted with caution for use in donkeys and mules.6 While the reported prevalence of equine glaucoma is low, tonometry is still an important part of a complete ophthalmic examination. Patients considered at risk for glaucoma are those with active or quiescent uveitis, aged patients >15 years old, and Appaloosas.7 Glaucoma has also been reported in other pure-breds. Tonometry is also indicated in any patient with clinical signs suggestive of glaucoma.8 Sedation is often necessary for a complete ophthalmic examination and is frequently used by ophthalmologists for routine standing procedures.9 Some horses may require sedation prior to trailering to a location where an ophthalmic examination is performed. When choosing a sedative for trailering and ocular examination or procedures, it is important to consider the systemic and ocular effects of the drug. Previous studies have evaluated the effects of intravenous acepromazine and xylazine and intravenous xylazine and ketamine on IOP measurements via applanation tonometry, noting a tendency toward decreased IOP after sedation.10,11 A more recent study noted a decline in IOP after intravenous administration of
detomidine as measured via rebound tonometry.12 The use of romifidine is increasing, and to the author’s knowledge, the effect of intravenous romifidine on IOP in the horse has not yet been evaluated. The purpose of the study was to evaluate the effect of intravenous sedation with romifidine on IOP in the horse as measured by applanation tonometry. MATERIALS AND METHODS
Animals Nineteen clinically normal horses (13 geldings, six mares) and eight horses (three geldings, five mares) with incidental ophthalmic findings were included in this study. Age ranged from 1–24 years (mean, 11.9 years). Warmbloods and Thoroughbreds were over-represented (n = 7 each), followed by Quarter horses (n = 3), Oldenburg (n = 2), Warmblood 9 Thoroughbred (n = 2), and six other mixed breeds. Horses were considered normal on the basis of brief physical examination (temperature, pulse, respiration and thoracic auscultation) and complete ophthalmic examination with slit-lamp biomicroscopy (Kowaâ SL-15, Kowa Company Ltd., Tokyo, Japan), indirect (28D and 20D Indirect Lens, Volk Optical Inc, Mentor, OH, USA) and direct (Standard ophthalmoscope, Welch Allyn, Inc., Skaneateles Falls, NY, USA) ophthalmoscopy. Incidental ophthalmic findings were diagnosed when an incidental lesion was noted and was determined to be unlikely to cause IOP changes (i.e., eyelid changes) or the intraocular lesion was so small as to be irrelevant (lens and fundic changes). Pharmacologic mydriasis (Tropicacylâ Tropicamide Ophthalmic Solution USP, 1%, Akorn, Inc., Lake Forest, IL, USA) was performed for complete examination of the fundus, a minimum of 14 days prior to IOP measurement to avoid any potential effects of mydriasis on IOP.13,14 Horses were excluded if there was concurrent administration of any ocular or systemic medication, history of pre-existing cardiac disease, mean baseline IOP >40 mmHg, uveitis or history of equine recurrent uveitis, and advanced cataract or retinal disease. Body weight was recorded via weight tape (Coburnâ Horse and Pony Height-Weight Tape, Coburn, Whitewater, WI, USA). The horses’ weights ranged from 318–704 kg (mean, 509 kg). All horses were privately owned, and owner consent was obtained for each horse prior to study enrollment. The study protocol was in compliance with the FASS Guide for the Care and Use of Agricultural Animals in Research and Teaching and the Blue Pearl Institutional Animal Care and Use Committee. Measurement of IOP All measurements were performed in each horse’s typical environment (stall or pasture) with the same handlers. The palpebral branch of the auriculopalpebral nerve was blocked bilaterally by subcutaneous infusion of 0.5 mL 2% mepivacaine (Carbocaine, Pharmacia & Upjohn Company,
© 2014 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 17, 134–139
136 stine
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Division of Pfizer Inc., New York, NY, USA) just lateral to the highest point of the caudal zygomatic arch. Proparacaine hydrochloride 0.5% ophthalmic solution was applied to both eyes immediately prior to tonometry, with repeated doses applied as needed depending on response to corneal contact. The same observer performed all measurements, and the applanation tonometer (Tono-Pen Vet, Reichert Ophthalmic Instruments, Depew, NY, USA) used was within current calibration specifications of the manufacturer. Five successive readings were obtained for each eye and only those with ≤5% variance were documented. IOP readings were recorded between 10 am and 6 pm from February through April. Baseline IOP was established immediately prior to sedation, 5 min after completion of the nerve block and proparacaine application.
Sedation and tonometry Romifidine hydrochloride 1% was given intravenously (75 µg/kg) via jugular injection to each horse. The IOP was recorded at the following time points (5, 15, 30, 45 and 60 min) following sedation. Measurements were taken from both the right and left eyes of each horse. The order of eyes examined was alternated every other horse, so that an equal number of left and right eyes were examined first. Each horse’s head was maintained in the head-up position, either via manual restraint or by resting the chin on the stall door with neck partially extended. Care was taken to avoid pressure on the neck, and horses were not permitted to lean on the stall door.15,16 Triple antibiotic ophthalmic ointment (Neomycin and Polymyxin B Sulfates and Bacitracin Zinc Ophthalmic Ointment, USP, Akorn, Inc., Lake Forest, IL, USA) was applied to both eyes of each horse at completion of the IOP measurements. Data analysis The low and high values (of five successive readings) were discarded, and the three remaining readings were averaged for a mean IOP at each time point. Data analysis was performed on the mean IOP at each time point with commercially available software (SAS, version 9.2, SAS Institute Inc, Cary, NC, USA). A repeated measures model that recognized multiple observations as belonging to the same horse was used to test for changes from baseline and differences between eyes in IOP values. The full model included factors for time, eye and a time by eye interaction term. Multiple comparisons were adjusted for using Dunnett’s test. An unstructured covariance structure was used in all repeated measures models. All hypothesis tests were two-sided, and the significance level was a = 0.05. The repeated measures analysis was performed using PROC MIXED in SASj. A repeated measures model was also used to test for differences in IOP values in horses with and without incidental intraocular lesions. The full model included factors for lesion, time, eye and all two- and three-way interaction terms.
RESULTS
Of the 27 horses in the study, ophthalmic examination revealed minor abnormalities in eight individuals, six of which were intraocular changes. Two horses were noted to have cilia present in the medial caruncle, causing mild mucoserous ocular discharge. Unilateral incipient cataracts were noted in two aged horses (19 and 21 years). Four horses (ages 8.5–21 years) were noted to have mild fundic abnormalities, including pigment changes (depigmentation or hyperpigmentation with mild pigment barring) and punctate chorioretinal scars (typically 3–5 depigmented round foci with a hyperpigmented center in the peripapillary region, mostly inferior). The mean IOP in animals without lesions was 22.74 mmHg and with intraocular lesions 24.08 mmHg. There were no significant differences in IOP between horses with and without incidental lesions (lens and fundus). There were no significant interactions of lesion and eye, lesion and time, or lesion and eye and time. It was determined that inclusion of the horses with minor intraocular abnormalities did not alter the statistical outcome for any of the comparisons; therefore, they were included for further data analysis. Mean IOP values were significantly higher for the OD eye than the OS eye (P < 0.0001). There was no significant eye by time interaction effect, which means that the changes with time were consistent between eyes, that is, OD was higher than OS for the duration of the study. However, as this difference was present and consistent at each time point, it was still statistically appropriate to pool the data for increased statistical power. On this basis, OD and OS results were pooled. The mean IOP at baseline was 26.35 5.57 mmHg. Mean IOP values were significantly lower than baseline at 5 (P < 0.0001), 15 (P < 0.0001), 30 (P = 0.0003), 45 (P < 0.0001) and 60 (P = 0.0005) minutes. Mean IOP values for both eyes pooled are given in Table 1. Changes in IOP from baseline mean are summarized in Table 2. The largest change from baseline was noted at t = 15 min with a decrease of 16.7% and the smallest change from baseline was noted at t = 60 min with a decrease of 13.2%.
Table 1. Mean IOP (mmHg) reported per eye (unpooled) at each time point with standard deviation, minimum and maximum values Time (min)
N
Mean IOP (mmHg)
SD
Minimum
Maximum
0 5 15 30 45 60
54 54 54 54 54 54
26.35 22.19 21.96 22.75 22.10 22.87
5.57 6.55 5.36 5.75 5.24 6.33
14.67 10.00 12.67 12.67 11.67 11.00
40.00 35.00 35.67 42.00 32.00 37.00
© 2014 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 17, 134–139
effects romifidine iop normal horses and horses minor lesions 137 Table 2. Mean IOP (pooled for both eyes) at each time point, change in IOP from baseline reported in mmHg and % change Time (min)
Mean IOP (mmHg)
5 15 30 45 60
22.19 21.96 22.75 22.10 22.87
mmHg change from baseline mean 4.16 4.39 3.6 4.25 3.48
% Change from baseline mean 15.8 16.7 13.7 16.1 13.2
DISCUSSION
In the present study, intravenous administration of romifidine in horses significantly decreased the IOP from baseline at all time points measured – 5, 15, 30, 45, and 60 min. The greatest decline in IOP was noted at 15 min postsedation. The results are consistent with other studies noting a decline in IOP with administration of other a-2 agonists, including xylazine and detomidine.10–12,17 This is the first study to document a prolonged duration of the IOP lowering effect of an a-2 agonist, up to 60 min, as compared with previous data of 20 min or less.10–12,17 The prolonged effect noted in this study likely correlates with reported longer duration of sedation of romifidine, followed by detomidine, medetomidine, and xylazine.18–23 However, further study evaluating IOP at extended timepoints with various sedation protocols may be indicated. Horses included in this study were privately owned, mostly ridden competitively or for pleasure riding. Four of the horses had incidental fundic lesions that could be suggestive of prior ocular inflammatory disease. However, at the time of inclusion in the study, none of these horses was exhibiting any clinical signs of active ocular disease or discomfort. A recent study evaluated the significance of depigmented punctate chorioretinal foci in horses and noted that in the absence of other fundic pathology, horses with these lesions are no more likely to have intraocular disease or ERU than horses with clinically normal ocular fundi.24 Two horses had punctate cortical lens opacities that could be seen on biomicroscopy but not retroillumination. Therefore, we felt it was appropriate to include these horses as it was unlikely that the IOP was affected by either the inactive fundic changes or barely notable lens changes. This was subsequently confirmed by statistical analysis. The mean IOP values were significantly higher for the OD eye vs. the OS eye. Two recent studies also noted a significant intereye difference in the IOP of normal eyes with the OD eye consistently higher than the OS eye. However, both studies measured IOP in the OD eye first at each measurement.25,26 We attempted to minimize the effect of eye order on IOP by alternating the order of IOP measurement, so that an equal number of right and left eyes was evaluated first at each time point. Therefore, we cannot explain this difference as related to IOP mea-
surement order. In the human literature, there is discussion of eye dominance affecting IOP measurements; however, to the authors’ knowledge, this factor cannot be evaluated in horses. There is not an obvious explanation for the difference in IOP between eyes in our study. However, our study goal was to evaluate the change in IOP per individual horse, not per individual eye. While there are many statistical approaches in ophthalmology, when studying IOP it is most appropriate to pool data to avoid a decrease in power and precision of the study, as well as potential bias in choosing which data set to use (OD vs. OS). While pooling results does result in loss of information, the degree of information wasted is generally considered to be less than when only one eye is included.27 As changes in IOP were consistent with time, data for the OD eye and the OS eye were pooled for further analysis. Applanation tonometry is routinely used in clinical and field ophthalmology in equine patients with accurate results. Previous studies have demonstrated the efficacy of applanation tonometry in horses, noting repeatable consistent results with only slight underestimation of actual IOP when correlated with invasive manometry.28,29 Normal IOP in the horse as measured by applanation tonometry following auriculopalpebral nerve block is 22.5 6.46 mmHg, with a range of 11–38 mmHg.29 One horse was included in the study with mean baseline IOP OD outside of this range (40 mmHg). There were two other horses with slightly increased mean baseline IOP OD (35.67 mmHg in both patients). These horses were of varying age (8, 11, 21 years) and breed (Oldenburg, Thoroughbred, and Quarterhorse). Upon further review of the data, it was noted that the baseline IOP was measured on these horses between 4:40– 5:30 pm. While one study did not find any significant changes in IOP over a 12-h period, an evaluation of athletic horses over a 24-h period in various light cycles identified an IOP circadian rhythm with low IOP in the dark phase and high IOP during the light phase.30,31 A peak at the end of the light phase was noted at 10 h after initiation of the light phase.31 The time at which each of these horses had a marginally increased IOP correlated well with the end of the light cycle in late winter in central Florida. Normal diurnal variation could explain the marginally high baseline IOP. In addition, none of these horses had any ocular or historical changes consistent with glaucoma. The subsequent IOP readings were within the reported normal range, never greater than 33 mmHg at any time point. In addition, baseline IOP was measured without sedation. Excessive restraint or eyelid manipulation could have falsely increased the IOP. However, great care was taken to avoid this. An auriculopalpebral nerve block was performed for accurate measurement of IOP because the baseline measurement was taken without sedation. Although previous equine studies have suggested that there is no significant effect of auriculopalpebral nerve block on IOP, we know that in other species, eyelid position does have a significant effect on IOP.16,17 It has been suggested that failure
© 2014 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 17, 134–139
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to use an auriculopalpebral nerve block may result in slight overestimates of IOP; therefore, this nerve block is typically recommended.32 The recommended dose range for romifidine is 40–120 µg/kg. We chose a dose of 75 µg/kg based on the clinical experience of various practitioners with the drug in a large equine surgical referral center (personal communication, KL Kuebelbeck). We also assumed that most horses would not tolerate five sequential IOP measurements at five time points over 60 min without adequate sedation. The assessment of level of sedation was not evaluated in our study. However, clinically, we noted that the majority of horses were very easy to manage and tolerated tonometry well. All patients remained standing without assistance for the duration of the study. The mode of action of the ocular hypotensive effect of intravenous romifidine is unclear. Possible mechanisms include systemic hemodynamic effects, decreased intracranial pressure, and possibly decreased aqueous humor formation secondary to decreased plasma ultrafiltration. However, as has previously been suggested, plasma ultrafiltration is not the most important mechanism of aqueous humor formation.17 Another explanation for the ocular hypotensive effect of intravenous romifidine could be action on ocular or CNS a-2 receptors. The role of these receptors is not well described in the maintenance of normal equine IOP. We do know that other a-2 agonists such as apraclonidine are effective in treating glaucoma in dogs and cats, albeit with undesirable ocular and systemic side effects.33 Brimonidine, another a-2 agonist, is reported to have an ocular hypotensive effect similar to dorzolamide in some human patients.34 Topical medetomidine applied unilaterally has been shown to decrease IOP in cats and rabbits in both eyes. Suggested mechanism for the contralateral decrease in IOP observed following unilateral topical application is due to systemic transfer of drug to the contralateral eye.35 In our study, intravenous administration of romifidine may have stimulated ocular a-2 receptors, or, because the drug’s mechanism of action is stimulation of presynaptic CNS receptors, possibly a central role in IOP decline may be implicated. Measurement of aqueous humor concentrations of romifidine after intravenous administration could help us to determine whether a significant concentration of drug accumulates to influence aqueous humor dynamics and cause an ocular hypotensive effect. Future studies involving expression of a-2 receptors in normal and glaucomatous equine eyes may also be indicated. One horse had a severe bilateral hypersensitivity reaction at completion of the study, with marked eyelid swelling, conjunctival hyperemia and chemosis, and lagophthalmos. This could have been a reaction to the auriculopalpebral nerve block, topical proparacaine, or the prophylactic triple antibiotic ointment. The eyelid swelling resolved in 24 h, and the subsequent bilateral superficial corneal ulcers (likely secondary to lagophthalmos) were treated routinely and healed within 3 days.
In conclusion, intravenous administration of romifidine (75 µg/kg) causes a decline in IOP in clinically normal horses ranging from 13.2 to 16.7%, similar to that seen with other alpha-2 agonists.10–12 Consistent with the longer duration of sedative effects of romifidine compared with detomidine and xylazine, the duration of the ocular hypotensive effect following administration persisted for the duration of our study (60 min). REFERENCES 1. Boehringer-Ingelheim Animal Health website. Products, Horse, Pharmaceuticals - Sedivet. URL http://www.boehringer-ingelheim.com/products/animal_health.html [accessed on 30 October 2012]. 2. Bauquier S, Kona-Boun J. Comparaison des effets de la xylazine et de la romifidine administrees en periode peri-operatoire sur le reveil de chevaux anesthesies. Canadian Veterinary Journal 2011; 52: 987–993. 3. Woodhouse K, Brosnan R, Nguyen K. Effects of postanesthetic sedation with romifidine or xylazine on quality of recovery from isoflurane anesthesia in horses. Journal of the American Veterinary Medical Association 2013; 242: 533–539. 4. L opez-Sanroman J, Holmbak-Petersen R, Varela M et al. Accelerometric comparison of the locomotor pattern of horses sedated with xylazine hydrochloride, detomidine hydrochloride, or romifidine hydrochloride. American Journal of Veterinary Research 2013; 74: 828–834. 5. Wojtasiak-Wypart M, Soma LR, Rudy SA et al. Pharmacokinetic profile and pharma-codynamic effects of romifidine hydrochloride in the horse. Journal of Veterinary Pharmacology and Therapeutics 2012; 35: 478–488. 6. Lizarraga I, Sumano H, Brunbaugh GW. Pharmacological and pharmacokinetic differences between donkeys and horses. Equine Veterinary Education 2004; 16: 102–112. 7. Brooks D, Matthews A. Equine ophthalmology. In: Veterinary Ophthalmology (ed. Gelatt K) Blackwell Publishing, Ames, IA, 2007; 1233–1243. 8. Utter ME, Brooks D. Glaucoma. In: Equine Ophthalmology, 2nd edn. (ed. Gilger BC) Elsevier, Maryland Heights, MO, 2011; 350–366. 9. Robertson SA. Standing sedation and pain management for ophthalmic patients. The Veterinary Clinics of North America. Equine Practice 2004; 20: 485–497. 10. McClure J, Gelatt K, Gum G et al. The effect of parenteral acepromazine and xylazine on intraocular pressure in the horse. Veterinary Medicine, Small Animal Clinician 1976; 71: 1727–1730. 11. Trim C, Colbern G, Martin C. Effect of xylazine and ketamine on intraocular pressure in horses. The Veterinary Record 1985; 117: 442–443. 12. Holve D. Effect of sedation with detomidine on intraocular pressure with and without topical anesthesia in clinically normal horses. Journal of the American Veterinary Medical Association 2012; 240: 1–4. 13. Mughannam A, Buyukmihci N, Kass P. Effect of topical atropine on intraocular pressure and pupil diameter in the normal horse eye. Veterinary Ophthalmology 1999; 2: 213–215. 14. Herring I, Pickett J, Champagne E et al. Effect of topical 1% atropine sulfate on IOP in normal horses. Veterinary Ophthalmology 2000; 3: 139–143. 15. Komaromy AM, Garg CD, Ying G-S et al. Effect of head position on intraocular pressure in horses. American Journal of Veterinary Research 2006; 67: 1232–1235.
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effects romifidine iop normal horses and horses minor lesions 139 16. Klein HE, Krohne SG, Moore GE et al. Effect of eyelid manipulation and manual jugular compression on intraocular pressure measurement in dogs. Journal of the American Veterinary Medical Association 2011; 238: 1292–1295. 17. Van der Woerdt A, Gilger BC, Wilkie DA et al. Effect of auriculopalpebral nerve block and intravenous administration of xylazine on intraocular pressure and corneal thickness in horses. American Journal of Veterinary Research 1995; 56: 155–158. 18. England GC, Clarke KW, Goossen L. A comparison of the sedative effects of three alpha 2-adrenoreceptor agonists (romifidine, detomidine and xylazine) in the horse. Journal of Veterinary Pharmacology and Therapeutics 1992; 15: 194–201. 19. Hamm D, Turchi P, J€ochle W. Sedative and analgesic effects of detomidine and romifidine in horses. The Veterinary Record 1995; 136: 324–327. 20. Yamashita K, Tsubakishita S, Futaok S et al. Cardiovascular effects of medetomidine, detomidine and xylazine in horses. Journal of Veterinary Medical Science 2000; 62: 1025–1032. 21. Freeman SL, Bowen IM, Bettschart-Wolfensberger R et al. Cardiovascular effects of romifidine in the standing horse. Research in Veterinary Science 2002; 72: 123–129. 22. Bryant CE, England GC, Clarke KW. Comparison of the sedative effects of medetomidine and xylazine in horses. The Veterinary Record 1991; 129: 421–423. 23. Freeman SL, England GC. Investigation of romifidine and detomidine for the clinical sedation of horses. The Veterinary Record 2000; 147: 507–511. 24. Mathes RL, Burdette EL, Moore PA et al. Concurrent clinical intraocular findings in horses with depigmented punctate chorioretinal foci. Veterinary Ophthalmology 2012; 15: 81–85. 25. Liu JH, Sit AJ, Weinreb RN. Variation of 24-hour intraocular pressure in healthy individuals: right eye versus left eye. Ophthalmology 2005; 112: 1670–1675.
26. Wang X, Dong J, Wu Q. Twenty-four-hour measurement of IOP in rabbits using rebound tonometer. Veterinary Ophthalmology 2013; 16: 423–428. 27. Murdoch IE, Morris SS, Cousens SN. People and eyes: statistical approaches in ophthalmology. British Journal of Ophthalmology 1998; 82: 971–973. 28. Dziezyc J, Millichamp NJ, Smith WB. Comparison of applanation tonometers in dogs and horses. Journal of the American Veterinary Medical Association 1992; 201: 430–433. 29. Miller PE, Pickett JP, Majors LJ. Evaluation of two applanation tonometers in horses. American Journal of Veterinary Research 1990; 51: 935–937. 30. Van der Woerdt A, Gilger BC, Wilkie DA et al. Normal variation in, and effect of 2% pilocarpine on, intraocular pressure and pupil size in female horses. American Journal of Veterinary Research 1998; 59: 1459–1462. 31. Bertolucci C, Giudice E, Fazio F et al. Circadian intraocular pressure rhythms in athletic horses under different lighting regime. Chronobiology International 2009; 26: 348–358. 32. Wilkie DA. Equine glaucoma: state of the art. Equine Veterinary Journal. Supplement 2010; 37(Suppl.): 62–68. 33. Willis AM, Diehl KA, Robbin TE. Advances in topical glaucoma therapy. Veterinary Ophthalmology 2002; 5: 9–17. 34. Katz LJ, Simmons ST, Craven ER. Efficacy and safety of brimonidine and dorzolamide for intraocular pressure lowering in glaucoma and ocular hypertension. Current Medical Research and Opinion 2007; 23: 2971–2983. 35. Jin Y, Wilson S, Elko EE et al. Ocular hypotensive effects of medetomidine and its analogs. Journal of Ocular Pharmacology and Therapeutics 1991; 7: 285–296.
© 2014 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 17, 134–139
DOI:10.1111/vop.12172
The effects of intravenous romifidine on intraocular pressure in clinically normal horses and horses with incidental ophthalmic findings Jessica M. Stine,* Tammy M. Michau,* Megan K. Williams,† Karen Leann Kuebelbeck† and Michele E. Stengard* *BluePearl Veterinary Partners, Tampa, FL 33614, USA; and †Surgi-Care Center for Horses, Brandon, FL, 33511, USA
Address communications to: Dr. T. M. Michau Tel.: 813-933-8944 Fax: 813-594-8456 e-mail: tammy.millermichau@ bluepearlvet.com
Supported in Part by Boehringer-Ingelheim, Ingelheim, Germany.
Abstract Design Original study. Objective To evaluate the effect of sedation with romifidine hydrochloride 1% (Sedivet: Boehringer-Ingelheim) on intraocular pressure (IOP) in the normal horse and horses with incidental ophthalmic findings as measured by applanation tonometry. Animals Nineteen clinically normal horses (13 geldings, six mares) and eight horses (three geldings, five mares) with incidental ophthalmic findings were included in this study. Procedures All horses underwent complete ophthalmic examination with pharmacologic mydriasis a minimum of 2 weeks prior to IOP evaluation. Baseline intraocular pressure values were obtained following auriculopalpebral nerve block and topical anesthetic. Immediately thereafter, romifidine was administered intravenously (75 µg/kg) and the IOP recorded at 5, 15, 30, 45 and 60 min postsedation in both eyes. Five successive readings were obtained at each time point, the low and high value discarded, and three remaining readings averaged for a mean. Results The changes with time were consistent between eyes and OD and OS results were pooled. The mean IOP at baseline was 26.35 5.57 mmHg. Mean IOP values were significantly lower than baseline at 5 (P < 0.0001), 15 (P < 0.0001), 30 (P = 0.0003), 45 (P < 0.0001) and 60 (P = 0.0005) minutes. The largest change from baseline (16.7%) was noted at t = 15 min. Conclusions and clinical relevance Administration of romifidine significantly decreased the IOP from baseline at all time points measured. The greatest decline in IOP was noted at 15 min postsedation. Results are consistent with other studies noting a decline in IOP with administration of a-2 agonists. Key Words: alpha-2 agonist, equine, intraocular pressure, romifidine, sedation, tonometry
INTRODUCTION
Romifidine hydrochloride (Sedivetâ, Boehringer-Ingelheim, Ingelheim, Germany) is a synthetic alpha-2 sympathomimetic agent that targets presynaptic receptors in the central nervous system (CNS). Its pharmacological effects are typical for the alpha-2 agonists and include sedation, muscle relaxation, reluctance to move, and reduced responsiveness to environmental stimuli. Pain tolerance is noted with increasing dose.1 Suggested uses of the drug include routine ocular, oral, or rectal examination, use
during diagnostic procedures and advanced imaging, standing surgical procedures, as a pre-anesthetic or in combination with other sedation for enhanced analgesia. There was no difference in quality or duration of recovery between romifidine and xylazine when used as part of a premedication protocol prior to general anesthesia.2 However, when used as a postanesthetic sedative, romifidine has recently been shown to improve recovery quality in healthy horses undergoing >1 h of isoflurane anesthesia. Results of this study support the use of intravenous romifidine (20 lg/kg) for postanesthetic sedation vs. xylazine © 2014 American College of Veterinary Ophthalmologists
effects romifidine iop normal horses and horses minor lesions 135
or lower doses of romifidine.3 Intravenous romifidine produces strong long-lasting sedation and apparent muscle relaxation, corresponding to a long elimination half-life of the drug. A recent comparison of the locomotor pattern of horses sedated with xylazine, detomidine, or romifidine found that romifidine had a comparably weaker effect on accelerometric variables than did detomidine or xylazine, although the difference was not significant. The duration of romifidine-associated effects on gait was significantly longer than xylazine and detomidine. Effects of romifidine (40 µg/kg IV) on stride frequency were noted for 90 min compared with only 30 min for xylazine and detomidine. Speed was reduced for up to 105 min with romifidine, compared with 30–45 min for xylazine and detomidine, respectively.4 Romifidine may be a good choice in situations where a horse’s balance and coordination are important, but a sustained sedative effect is still desired, such as traveling in a trailer. In addition, only minor alterations to stride regularity were noted; therefore, romifidine may also be useful for procedures such as farriery, loading in a trailer, or other short-duration diagnostic procedures such as radiography or other advanced imaging.4 Hemodynamic changes include a significant reduction in heart rate and cardiac index and a biphasic change in arterial blood pressure, with an initial hypertensive period followed by a prolonged hypotensive phase. Bradyarrhythmias are also reported.5 Sedation and anesthetic protocols should be adjusted accordingly for other members of the Equidae family, especially donkeys and mules. In general, an increase in the dose of xylazine and other a2-adrenoreceptor agonists has been recommended to achieve adequate sedation and analgesia. However, similar to horses, a2-adrenoreceptor agonists are capable of producing cardiac arrhythmias in donkeys. Data from pharmacologic and pharmacokinetic studies in horses should be interpreted with caution for use in donkeys and mules.6 While the reported prevalence of equine glaucoma is low, tonometry is still an important part of a complete ophthalmic examination. Patients considered at risk for glaucoma are those with active or quiescent uveitis, aged patients >15 years old, and Appaloosas.7 Glaucoma has also been reported in other pure-breds. Tonometry is also indicated in any patient with clinical signs suggestive of glaucoma.8 Sedation is often necessary for a complete ophthalmic examination and is frequently used by ophthalmologists for routine standing procedures.9 Some horses may require sedation prior to trailering to a location where an ophthalmic examination is performed. When choosing a sedative for trailering and ocular examination or procedures, it is important to consider the systemic and ocular effects of the drug. Previous studies have evaluated the effects of intravenous acepromazine and xylazine and intravenous xylazine and ketamine on IOP measurements via applanation tonometry, noting a tendency toward decreased IOP after sedation.10,11 A more recent study noted a decline in IOP after intravenous administration of
detomidine as measured via rebound tonometry.12 The use of romifidine is increasing, and to the author’s knowledge, the effect of intravenous romifidine on IOP in the horse has not yet been evaluated. The purpose of the study was to evaluate the effect of intravenous sedation with romifidine on IOP in the horse as measured by applanation tonometry. MATERIALS AND METHODS
Animals Nineteen clinically normal horses (13 geldings, six mares) and eight horses (three geldings, five mares) with incidental ophthalmic findings were included in this study. Age ranged from 1–24 years (mean, 11.9 years). Warmbloods and Thoroughbreds were over-represented (n = 7 each), followed by Quarter horses (n = 3), Oldenburg (n = 2), Warmblood 9 Thoroughbred (n = 2), and six other mixed breeds. Horses were considered normal on the basis of brief physical examination (temperature, pulse, respiration and thoracic auscultation) and complete ophthalmic examination with slit-lamp biomicroscopy (Kowaâ SL-15, Kowa Company Ltd., Tokyo, Japan), indirect (28D and 20D Indirect Lens, Volk Optical Inc, Mentor, OH, USA) and direct (Standard ophthalmoscope, Welch Allyn, Inc., Skaneateles Falls, NY, USA) ophthalmoscopy. Incidental ophthalmic findings were diagnosed when an incidental lesion was noted and was determined to be unlikely to cause IOP changes (i.e., eyelid changes) or the intraocular lesion was so small as to be irrelevant (lens and fundic changes). Pharmacologic mydriasis (Tropicacylâ Tropicamide Ophthalmic Solution USP, 1%, Akorn, Inc., Lake Forest, IL, USA) was performed for complete examination of the fundus, a minimum of 14 days prior to IOP measurement to avoid any potential effects of mydriasis on IOP.13,14 Horses were excluded if there was concurrent administration of any ocular or systemic medication, history of pre-existing cardiac disease, mean baseline IOP >40 mmHg, uveitis or history of equine recurrent uveitis, and advanced cataract or retinal disease. Body weight was recorded via weight tape (Coburnâ Horse and Pony Height-Weight Tape, Coburn, Whitewater, WI, USA). The horses’ weights ranged from 318–704 kg (mean, 509 kg). All horses were privately owned, and owner consent was obtained for each horse prior to study enrollment. The study protocol was in compliance with the FASS Guide for the Care and Use of Agricultural Animals in Research and Teaching and the Blue Pearl Institutional Animal Care and Use Committee. Measurement of IOP All measurements were performed in each horse’s typical environment (stall or pasture) with the same handlers. The palpebral branch of the auriculopalpebral nerve was blocked bilaterally by subcutaneous infusion of 0.5 mL 2% mepivacaine (Carbocaine, Pharmacia & Upjohn Company,
© 2014 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 17, 134–139
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Division of Pfizer Inc., New York, NY, USA) just lateral to the highest point of the caudal zygomatic arch. Proparacaine hydrochloride 0.5% ophthalmic solution was applied to both eyes immediately prior to tonometry, with repeated doses applied as needed depending on response to corneal contact. The same observer performed all measurements, and the applanation tonometer (Tono-Pen Vet, Reichert Ophthalmic Instruments, Depew, NY, USA) used was within current calibration specifications of the manufacturer. Five successive readings were obtained for each eye and only those with ≤5% variance were documented. IOP readings were recorded between 10 am and 6 pm from February through April. Baseline IOP was established immediately prior to sedation, 5 min after completion of the nerve block and proparacaine application.
Sedation and tonometry Romifidine hydrochloride 1% was given intravenously (75 µg/kg) via jugular injection to each horse. The IOP was recorded at the following time points (5, 15, 30, 45 and 60 min) following sedation. Measurements were taken from both the right and left eyes of each horse. The order of eyes examined was alternated every other horse, so that an equal number of left and right eyes were examined first. Each horse’s head was maintained in the head-up position, either via manual restraint or by resting the chin on the stall door with neck partially extended. Care was taken to avoid pressure on the neck, and horses were not permitted to lean on the stall door.15,16 Triple antibiotic ophthalmic ointment (Neomycin and Polymyxin B Sulfates and Bacitracin Zinc Ophthalmic Ointment, USP, Akorn, Inc., Lake Forest, IL, USA) was applied to both eyes of each horse at completion of the IOP measurements. Data analysis The low and high values (of five successive readings) were discarded, and the three remaining readings were averaged for a mean IOP at each time point. Data analysis was performed on the mean IOP at each time point with commercially available software (SAS, version 9.2, SAS Institute Inc, Cary, NC, USA). A repeated measures model that recognized multiple observations as belonging to the same horse was used to test for changes from baseline and differences between eyes in IOP values. The full model included factors for time, eye and a time by eye interaction term. Multiple comparisons were adjusted for using Dunnett’s test. An unstructured covariance structure was used in all repeated measures models. All hypothesis tests were two-sided, and the significance level was a = 0.05. The repeated measures analysis was performed using PROC MIXED in SASj. A repeated measures model was also used to test for differences in IOP values in horses with and without incidental intraocular lesions. The full model included factors for lesion, time, eye and all two- and three-way interaction terms.
RESULTS
Of the 27 horses in the study, ophthalmic examination revealed minor abnormalities in eight individuals, six of which were intraocular changes. Two horses were noted to have cilia present in the medial caruncle, causing mild mucoserous ocular discharge. Unilateral incipient cataracts were noted in two aged horses (19 and 21 years). Four horses (ages 8.5–21 years) were noted to have mild fundic abnormalities, including pigment changes (depigmentation or hyperpigmentation with mild pigment barring) and punctate chorioretinal scars (typically 3–5 depigmented round foci with a hyperpigmented center in the peripapillary region, mostly inferior). The mean IOP in animals without lesions was 22.74 mmHg and with intraocular lesions 24.08 mmHg. There were no significant differences in IOP between horses with and without incidental lesions (lens and fundus). There were no significant interactions of lesion and eye, lesion and time, or lesion and eye and time. It was determined that inclusion of the horses with minor intraocular abnormalities did not alter the statistical outcome for any of the comparisons; therefore, they were included for further data analysis. Mean IOP values were significantly higher for the OD eye than the OS eye (P < 0.0001). There was no significant eye by time interaction effect, which means that the changes with time were consistent between eyes, that is, OD was higher than OS for the duration of the study. However, as this difference was present and consistent at each time point, it was still statistically appropriate to pool the data for increased statistical power. On this basis, OD and OS results were pooled. The mean IOP at baseline was 26.35 5.57 mmHg. Mean IOP values were significantly lower than baseline at 5 (P < 0.0001), 15 (P < 0.0001), 30 (P = 0.0003), 45 (P < 0.0001) and 60 (P = 0.0005) minutes. Mean IOP values for both eyes pooled are given in Table 1. Changes in IOP from baseline mean are summarized in Table 2. The largest change from baseline was noted at t = 15 min with a decrease of 16.7% and the smallest change from baseline was noted at t = 60 min with a decrease of 13.2%.
Table 1. Mean IOP (mmHg) reported per eye (unpooled) at each time point with standard deviation, minimum and maximum values Time (min)
N
Mean IOP (mmHg)
SD
Minimum
Maximum
0 5 15 30 45 60
54 54 54 54 54 54
26.35 22.19 21.96 22.75 22.10 22.87
5.57 6.55 5.36 5.75 5.24 6.33
14.67 10.00 12.67 12.67 11.67 11.00
40.00 35.00 35.67 42.00 32.00 37.00
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effects romifidine iop normal horses and horses minor lesions 137 Table 2. Mean IOP (pooled for both eyes) at each time point, change in IOP from baseline reported in mmHg and % change Time (min)
Mean IOP (mmHg)
5 15 30 45 60
22.19 21.96 22.75 22.10 22.87
mmHg change from baseline mean 4.16 4.39 3.6 4.25 3.48
% Change from baseline mean 15.8 16.7 13.7 16.1 13.2
DISCUSSION
In the present study, intravenous administration of romifidine in horses significantly decreased the IOP from baseline at all time points measured – 5, 15, 30, 45, and 60 min. The greatest decline in IOP was noted at 15 min postsedation. The results are consistent with other studies noting a decline in IOP with administration of other a-2 agonists, including xylazine and detomidine.10–12,17 This is the first study to document a prolonged duration of the IOP lowering effect of an a-2 agonist, up to 60 min, as compared with previous data of 20 min or less.10–12,17 The prolonged effect noted in this study likely correlates with reported longer duration of sedation of romifidine, followed by detomidine, medetomidine, and xylazine.18–23 However, further study evaluating IOP at extended timepoints with various sedation protocols may be indicated. Horses included in this study were privately owned, mostly ridden competitively or for pleasure riding. Four of the horses had incidental fundic lesions that could be suggestive of prior ocular inflammatory disease. However, at the time of inclusion in the study, none of these horses was exhibiting any clinical signs of active ocular disease or discomfort. A recent study evaluated the significance of depigmented punctate chorioretinal foci in horses and noted that in the absence of other fundic pathology, horses with these lesions are no more likely to have intraocular disease or ERU than horses with clinically normal ocular fundi.24 Two horses had punctate cortical lens opacities that could be seen on biomicroscopy but not retroillumination. Therefore, we felt it was appropriate to include these horses as it was unlikely that the IOP was affected by either the inactive fundic changes or barely notable lens changes. This was subsequently confirmed by statistical analysis. The mean IOP values were significantly higher for the OD eye vs. the OS eye. Two recent studies also noted a significant intereye difference in the IOP of normal eyes with the OD eye consistently higher than the OS eye. However, both studies measured IOP in the OD eye first at each measurement.25,26 We attempted to minimize the effect of eye order on IOP by alternating the order of IOP measurement, so that an equal number of right and left eyes was evaluated first at each time point. Therefore, we cannot explain this difference as related to IOP mea-
surement order. In the human literature, there is discussion of eye dominance affecting IOP measurements; however, to the authors’ knowledge, this factor cannot be evaluated in horses. There is not an obvious explanation for the difference in IOP between eyes in our study. However, our study goal was to evaluate the change in IOP per individual horse, not per individual eye. While there are many statistical approaches in ophthalmology, when studying IOP it is most appropriate to pool data to avoid a decrease in power and precision of the study, as well as potential bias in choosing which data set to use (OD vs. OS). While pooling results does result in loss of information, the degree of information wasted is generally considered to be less than when only one eye is included.27 As changes in IOP were consistent with time, data for the OD eye and the OS eye were pooled for further analysis. Applanation tonometry is routinely used in clinical and field ophthalmology in equine patients with accurate results. Previous studies have demonstrated the efficacy of applanation tonometry in horses, noting repeatable consistent results with only slight underestimation of actual IOP when correlated with invasive manometry.28,29 Normal IOP in the horse as measured by applanation tonometry following auriculopalpebral nerve block is 22.5 6.46 mmHg, with a range of 11–38 mmHg.29 One horse was included in the study with mean baseline IOP OD outside of this range (40 mmHg). There were two other horses with slightly increased mean baseline IOP OD (35.67 mmHg in both patients). These horses were of varying age (8, 11, 21 years) and breed (Oldenburg, Thoroughbred, and Quarterhorse). Upon further review of the data, it was noted that the baseline IOP was measured on these horses between 4:40– 5:30 pm. While one study did not find any significant changes in IOP over a 12-h period, an evaluation of athletic horses over a 24-h period in various light cycles identified an IOP circadian rhythm with low IOP in the dark phase and high IOP during the light phase.30,31 A peak at the end of the light phase was noted at 10 h after initiation of the light phase.31 The time at which each of these horses had a marginally increased IOP correlated well with the end of the light cycle in late winter in central Florida. Normal diurnal variation could explain the marginally high baseline IOP. In addition, none of these horses had any ocular or historical changes consistent with glaucoma. The subsequent IOP readings were within the reported normal range, never greater than 33 mmHg at any time point. In addition, baseline IOP was measured without sedation. Excessive restraint or eyelid manipulation could have falsely increased the IOP. However, great care was taken to avoid this. An auriculopalpebral nerve block was performed for accurate measurement of IOP because the baseline measurement was taken without sedation. Although previous equine studies have suggested that there is no significant effect of auriculopalpebral nerve block on IOP, we know that in other species, eyelid position does have a significant effect on IOP.16,17 It has been suggested that failure
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to use an auriculopalpebral nerve block may result in slight overestimates of IOP; therefore, this nerve block is typically recommended.32 The recommended dose range for romifidine is 40–120 µg/kg. We chose a dose of 75 µg/kg based on the clinical experience of various practitioners with the drug in a large equine surgical referral center (personal communication, KL Kuebelbeck). We also assumed that most horses would not tolerate five sequential IOP measurements at five time points over 60 min without adequate sedation. The assessment of level of sedation was not evaluated in our study. However, clinically, we noted that the majority of horses were very easy to manage and tolerated tonometry well. All patients remained standing without assistance for the duration of the study. The mode of action of the ocular hypotensive effect of intravenous romifidine is unclear. Possible mechanisms include systemic hemodynamic effects, decreased intracranial pressure, and possibly decreased aqueous humor formation secondary to decreased plasma ultrafiltration. However, as has previously been suggested, plasma ultrafiltration is not the most important mechanism of aqueous humor formation.17 Another explanation for the ocular hypotensive effect of intravenous romifidine could be action on ocular or CNS a-2 receptors. The role of these receptors is not well described in the maintenance of normal equine IOP. We do know that other a-2 agonists such as apraclonidine are effective in treating glaucoma in dogs and cats, albeit with undesirable ocular and systemic side effects.33 Brimonidine, another a-2 agonist, is reported to have an ocular hypotensive effect similar to dorzolamide in some human patients.34 Topical medetomidine applied unilaterally has been shown to decrease IOP in cats and rabbits in both eyes. Suggested mechanism for the contralateral decrease in IOP observed following unilateral topical application is due to systemic transfer of drug to the contralateral eye.35 In our study, intravenous administration of romifidine may have stimulated ocular a-2 receptors, or, because the drug’s mechanism of action is stimulation of presynaptic CNS receptors, possibly a central role in IOP decline may be implicated. Measurement of aqueous humor concentrations of romifidine after intravenous administration could help us to determine whether a significant concentration of drug accumulates to influence aqueous humor dynamics and cause an ocular hypotensive effect. Future studies involving expression of a-2 receptors in normal and glaucomatous equine eyes may also be indicated. One horse had a severe bilateral hypersensitivity reaction at completion of the study, with marked eyelid swelling, conjunctival hyperemia and chemosis, and lagophthalmos. This could have been a reaction to the auriculopalpebral nerve block, topical proparacaine, or the prophylactic triple antibiotic ointment. The eyelid swelling resolved in 24 h, and the subsequent bilateral superficial corneal ulcers (likely secondary to lagophthalmos) were treated routinely and healed within 3 days.
In conclusion, intravenous administration of romifidine (75 µg/kg) causes a decline in IOP in clinically normal horses ranging from 13.2 to 16.7%, similar to that seen with other alpha-2 agonists.10–12 Consistent with the longer duration of sedative effects of romifidine compared with detomidine and xylazine, the duration of the ocular hypotensive effect following administration persisted for the duration of our study (60 min). REFERENCES 1. Boehringer-Ingelheim Animal Health website. Products, Horse, Pharmaceuticals - Sedivet. URL http://www.boehringer-ingelheim.com/products/animal_health.html [accessed on 30 October 2012]. 2. Bauquier S, Kona-Boun J. Comparaison des effets de la xylazine et de la romifidine administrees en periode peri-operatoire sur le reveil de chevaux anesthesies. Canadian Veterinary Journal 2011; 52: 987–993. 3. Woodhouse K, Brosnan R, Nguyen K. Effects of postanesthetic sedation with romifidine or xylazine on quality of recovery from isoflurane anesthesia in horses. Journal of the American Veterinary Medical Association 2013; 242: 533–539. 4. L opez-Sanroman J, Holmbak-Petersen R, Varela M et al. Accelerometric comparison of the locomotor pattern of horses sedated with xylazine hydrochloride, detomidine hydrochloride, or romifidine hydrochloride. American Journal of Veterinary Research 2013; 74: 828–834. 5. Wojtasiak-Wypart M, Soma LR, Rudy SA et al. Pharmacokinetic profile and pharma-codynamic effects of romifidine hydrochloride in the horse. Journal of Veterinary Pharmacology and Therapeutics 2012; 35: 478–488. 6. Lizarraga I, Sumano H, Brunbaugh GW. Pharmacological and pharmacokinetic differences between donkeys and horses. Equine Veterinary Education 2004; 16: 102–112. 7. Brooks D, Matthews A. Equine ophthalmology. In: Veterinary Ophthalmology (ed. Gelatt K) Blackwell Publishing, Ames, IA, 2007; 1233–1243. 8. Utter ME, Brooks D. Glaucoma. In: Equine Ophthalmology, 2nd edn. (ed. Gilger BC) Elsevier, Maryland Heights, MO, 2011; 350–366. 9. Robertson SA. Standing sedation and pain management for ophthalmic patients. The Veterinary Clinics of North America. Equine Practice 2004; 20: 485–497. 10. McClure J, Gelatt K, Gum G et al. The effect of parenteral acepromazine and xylazine on intraocular pressure in the horse. Veterinary Medicine, Small Animal Clinician 1976; 71: 1727–1730. 11. Trim C, Colbern G, Martin C. Effect of xylazine and ketamine on intraocular pressure in horses. The Veterinary Record 1985; 117: 442–443. 12. Holve D. Effect of sedation with detomidine on intraocular pressure with and without topical anesthesia in clinically normal horses. Journal of the American Veterinary Medical Association 2012; 240: 1–4. 13. Mughannam A, Buyukmihci N, Kass P. Effect of topical atropine on intraocular pressure and pupil diameter in the normal horse eye. Veterinary Ophthalmology 1999; 2: 213–215. 14. Herring I, Pickett J, Champagne E et al. Effect of topical 1% atropine sulfate on IOP in normal horses. Veterinary Ophthalmology 2000; 3: 139–143. 15. Komaromy AM, Garg CD, Ying G-S et al. Effect of head position on intraocular pressure in horses. American Journal of Veterinary Research 2006; 67: 1232–1235.
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effects romifidine iop normal horses and horses minor lesions 139 16. Klein HE, Krohne SG, Moore GE et al. Effect of eyelid manipulation and manual jugular compression on intraocular pressure measurement in dogs. Journal of the American Veterinary Medical Association 2011; 238: 1292–1295. 17. Van der Woerdt A, Gilger BC, Wilkie DA et al. Effect of auriculopalpebral nerve block and intravenous administration of xylazine on intraocular pressure and corneal thickness in horses. American Journal of Veterinary Research 1995; 56: 155–158. 18. England GC, Clarke KW, Goossen L. A comparison of the sedative effects of three alpha 2-adrenoreceptor agonists (romifidine, detomidine and xylazine) in the horse. Journal of Veterinary Pharmacology and Therapeutics 1992; 15: 194–201. 19. Hamm D, Turchi P, J€ochle W. Sedative and analgesic effects of detomidine and romifidine in horses. The Veterinary Record 1995; 136: 324–327. 20. Yamashita K, Tsubakishita S, Futaok S et al. Cardiovascular effects of medetomidine, detomidine and xylazine in horses. Journal of Veterinary Medical Science 2000; 62: 1025–1032. 21. Freeman SL, Bowen IM, Bettschart-Wolfensberger R et al. Cardiovascular effects of romifidine in the standing horse. Research in Veterinary Science 2002; 72: 123–129. 22. Bryant CE, England GC, Clarke KW. Comparison of the sedative effects of medetomidine and xylazine in horses. The Veterinary Record 1991; 129: 421–423. 23. Freeman SL, England GC. Investigation of romifidine and detomidine for the clinical sedation of horses. The Veterinary Record 2000; 147: 507–511. 24. Mathes RL, Burdette EL, Moore PA et al. Concurrent clinical intraocular findings in horses with depigmented punctate chorioretinal foci. Veterinary Ophthalmology 2012; 15: 81–85. 25. Liu JH, Sit AJ, Weinreb RN. Variation of 24-hour intraocular pressure in healthy individuals: right eye versus left eye. Ophthalmology 2005; 112: 1670–1675.
26. Wang X, Dong J, Wu Q. Twenty-four-hour measurement of IOP in rabbits using rebound tonometer. Veterinary Ophthalmology 2013; 16: 423–428. 27. Murdoch IE, Morris SS, Cousens SN. People and eyes: statistical approaches in ophthalmology. British Journal of Ophthalmology 1998; 82: 971–973. 28. Dziezyc J, Millichamp NJ, Smith WB. Comparison of applanation tonometers in dogs and horses. Journal of the American Veterinary Medical Association 1992; 201: 430–433. 29. Miller PE, Pickett JP, Majors LJ. Evaluation of two applanation tonometers in horses. American Journal of Veterinary Research 1990; 51: 935–937. 30. Van der Woerdt A, Gilger BC, Wilkie DA et al. Normal variation in, and effect of 2% pilocarpine on, intraocular pressure and pupil size in female horses. American Journal of Veterinary Research 1998; 59: 1459–1462. 31. Bertolucci C, Giudice E, Fazio F et al. Circadian intraocular pressure rhythms in athletic horses under different lighting regime. Chronobiology International 2009; 26: 348–358. 32. Wilkie DA. Equine glaucoma: state of the art. Equine Veterinary Journal. Supplement 2010; 37(Suppl.): 62–68. 33. Willis AM, Diehl KA, Robbin TE. Advances in topical glaucoma therapy. Veterinary Ophthalmology 2002; 5: 9–17. 34. Katz LJ, Simmons ST, Craven ER. Efficacy and safety of brimonidine and dorzolamide for intraocular pressure lowering in glaucoma and ocular hypertension. Current Medical Research and Opinion 2007; 23: 2971–2983. 35. Jin Y, Wilson S, Elko EE et al. Ocular hypotensive effects of medetomidine and its analogs. Journal of Ocular Pharmacology and Therapeutics 1991; 7: 285–296.
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