Veterinary Ophthalmology (2014) 17, Supplement 1, 149–153
DOI:10.1111/vop.12181
Effect of intravenous administration of romifidine on intraocular pressure in clinically normal horses Mohamed A. Marzok,* Sabry A. El-khodery† and Aiman H. Oheida‡ *Department of Veterinary Surgery, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt; †Department of Internal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt; and ‡Department of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Tripoli, Tripoli 13662, Libya
Address communications to: M. A. Marzok Tel.: +2 01222238237 Fax: +2 0473231311 e-mail: marzok2000@hotmail. com
Abstract Objective To evaluate the effect of intravenous administration of romifidine on the intraocular pressure (IOP) in horses. Animals studied Twenty-four horses with no ocular abnormalities. Procedure Horses were randomly assigned into two equal groups (treatment and control). All horses in the treatment group received an intravenous (IV) injection of romifidine (40 lg/kg). The horses in the control group were administrated an intravenous injection of 0.9% saline (0.4 mL/100 kg). In both groups, the IOP values were measured immediately (T0) pre-administration and at 5 (T5), 15 (T15), 30 (T30), 45 (T45), 60 (T60), 90 (T90), and 120 (T120) min after drug administration. Results The pre-treatment values (T0) of IOP for right and left eyes were 24.25 3.5 and 25.16 3.4 mmHg, respectively. A significant decrease in IOP values was observed in both right and left eyes of the horses in treatment group at T5, T15, T30, T45, T60, and T90 in comparison with the baseline values (P < 0.05). The lowest level of IOP in romifidine-treated groups was recorded at T45 for the right and left eyes (10.25 2.3 and 11.25 3.5 mmHg, respectively). Conclusion Romifidine significantly decreased IOP in clinically normal horses and may be used safely for surgery or diagnostic ocular procedures in horses when specific control of IOP is required. Key Words: applanation tonometry, horse, intraocular pressure, romifidine
INTRODUCTION
Measurement of intraocular pressure (IOP) or tonometry is part of the routine eye examination in horses.1 In recent years, measurement of IOP in the horse has been revolutionized by the development of handheld portable digital tonometers that do not require the horse to be in lateral recumbency.2 Tonometry is indicated in horses that have ocular disorders such as focal or diffuse corneal edema, red or painful eye, orbital trauma, lens luxation, glaucoma, and uveitis.3,4 Alpha-2 adrenoceptor agonists, including xylazine, detomidine, and romifidine, are used most commonly when performing ophthalmic examination and/or surgical ocular procedures in the horse.5,6 Standing sedation and analgesia is required on horses to facilitate several ophthalmic diagnostic tests especially in flighty or very painful animals.7 For short standing ocular procedures, single intravenous © 2014 American College of Veterinary Ophthalmologists
(IV) injection of standard doses of an alpha-2 agonist is often sufficient. For longer procedures, constant rate infusion (CRI) may be advantageous over repeated bolus injections to provide a consistent level of sedation.8 In equine practice, alpha-2 adrenoceptor agonists are also used for premedication in most anesthetic protocols for ophthalmic procedures. The selection of an appropriate anesthetic protocol for intraocular surgery is critical to the success of such procedure. The ability to regulate IOP is considered essential for successful ophthalmic surgery and can be greatly affected by the anesthetic protocol.9 Therefore, when performing ophthalmic examination or any surgical ocular procedures in horses, the effects of sedation on IOP should be considered. In recent years, several studies have evaluated the effects of anesthetic drugs on IOP values in horses. One study, for example, reported effects of ketamine hydrochloride, propofol, or compounded thiopental sodium administration on
150 marzok, el-khodery and oheida
IOP and qualities of induction of and recovery from anesthesia in horses. In the conclusion, the authors stated that ketamine caused a significant increase in IOP compared with baseline, propofol, and thiopental.10 Romifidine is a selective alpha-2 adrenoceptor agonist drug that is commonly administered intravenously or intrathecally to bring about sedation and analgesia in horses, and it has been shown to have systemic and analgesic effects similar to other alpha-2 agonists.11 Romifidine’s actions have demonstrated some differences from the other alpha-2 agonists in veterinary use. In horses, when compared with IV xylazine (1 mg/kg) or detomidine (20 lg/kg), romifidine at 40 and 80 lg/kg produced less ataxia and the horses’ heads were held higher. The duration of effect was longest with romifidine. The lack of ataxia with romifidine has made it very popular for use to sedate horses for standing procedures, and it is also widely used for premedication with ketamine for anesthetic induction in this species.12 Previous studies showed that sedation of horses with xylazine, acepromazine, and detomidine resulted in dramatic decreases in IOP.13–17 Nevertheless, information on effects of IV administration of romifidine on IOP is limited. A recent study in normal horses conducted using applanation tonometry reported that administration of IV romifidine at a 75 lg/kg dose causes a significant decrease in IOP.18 In that study, The IOP readings were only recorded at 5, 15, 30, 45 and, 60 min postsedation in both eyes. As the sedative effects of romifidine at a dose of 40–80 lg/kg last for approximately 80 min,11 this study did not determine whether this effect on IOP persists over the period of 80 min. Therefore, this study aimed to evaluate the effects of IV romifidine on the IOP in clinically normal horses and to document the details of IOP changes over 120 min. MATERIALS AND METHODS
Experimental animals Twenty-four horses (16 Arabian and 8 cross-breds; 8 intact males, 6 geldings, and 10 females) were used. The mean age was 6.92 4.15 years old, and the mean weight was 440.7 53.5 kg. On the basis of results of physical examination, all animals were considered healthy. The horses were allowed ad libitum access to food and water until the beginning of each experiment. Study protocol The study protocol was approved by the Animal Care Committee of the Kafer-Elsheikh University, in accordance with Egyptian ethical codes for studies on experimental animals. All animals underwent a complete ophthalmic examination, including Schirmer tear test, slitlamp biomicroscopy, and indirect ophthalmoscopy. All 24 horses had clinically normal eyes. The horses were allocated randomly to two groups with twelve horses in each
group (treatment and control). All horses in the treatment group received an intravenous injection of romifidine (10 mg/mL, Sedivetâ; Boehringer Ingelheim, Vetmedica GmbH, Ingelheim/Rhein, Germany) at a 40 lg/kg dose. The horses in the control group received only intravenous saline (0.4 mL/100 kg) (El Nasr Pharmaceutical Company, Cairo, Egypt). In the two groups, IOP of both the eyes was measured and recorded by the same investigator (M.M.). The measurements were taken immediately pre-administration (T0) and then at a 5 (T5), 15 (T15), 30 (T30), 45 (T45), 60 (T60), 90 (T90), and 120 (T120) min postadministration.
Measurement of IOP The experiment was performed indoors in a familiar, quiet environment, and all horses were restrained by the same individuals. The palpebral branch of the auriculopalpebral nerve along the dorsal zygomatic arch of each eye was blocked by subcutaneous (SC) infusion of 2.0 mL of mepivacaine hydrochloride (Mepecaine, Alexandria Co. for Pharmaceutical & Chemicals Industries, Alexandria, Egypt) to facilitate opening of the upper eyelid.15 All IOP measurements were performed with the head maintained in a normal and upright position. The horse’s head was elevated and held in the head-up position by positioning the mandible on the shoulder of one of the investigators. The head height was maintained for a minimum of 2 min prior to measurement at each time point to give enough time for normalization of pressures.1 All measurements were obtained between 8:00 and 11:00 am, to minimize individual and diurnal variations. The order of eyes examined (right vs. left) in each horse was random. The eyelids were manipulated gently to avoid pressure on the globe. Before each measurement, the cornea of both eyes was topically anesthetized using 0.2 mL of 0.5% proparacaine solution (Alcaineâ; Alcon Laboratories, INC, Fort Worth, TX, USA). An applanation tonometer (Tono-Pen AVIA; Reichert, Depew, NY, USA) was used to estimate IOP. Three measurements were obtained by lightly touching the central aspect of the cornea at 5-s intervals, after which the readings were averaged. The tonometer was factory calibrated before initiation of the study, and only IOP readings with a 5% variance (5% displays on Tono-Pen) were recorded. Statistical analysis Analysis of data was carried out using SPSS statistical software program (SPSS for Windows, version 16.0; SPSS Inc., Chicago, IL, USA). Initially, data were assessed for normal distribution using Kolmogorov–Smirnov test. Data were normally distributed; consequently, mean and standard deviation for each variable at each time point were calculated. General linear model with repeated-measures ANOVA was used to determine the main effects of time and treatment. Wilks’ lambda test was selected to evaluate within-group interactions and evidence of time 9 treatment
© 2014 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 17, 149–153
effect of romifidine on intraocular pressure in horses 151
interactions. Where Wilks’ lambda test showed a statistically significant difference between groups, t-test was used at each time point to identify which group was statistically different. Difference between means was considered significant at P < 0.05. RESULTS
All the diagnostic procedures were performed successfully, and no signs of ocular irritation or pain were detected in horses examined at any time point. Applanation tonometry was easy to perform and well tolerated by the horses. The pretreatment values (T0) of IOP for right and left eyes were 24.25 3.5 and 25.16 3.4 mmHg, respectively. Based on treatment–time interaction, IOP values were significantly decreased in treated horses (Wilks’ lambda test for treatment–time interaction, P < 0.001). In the romifidine-treated group, the IOP was significantly decreased (P < 0.05) in both right and left eyes of the horses in comparison with the control group at T5, T15, T30, T45, T60, and T90 (Tables 1 and 2). The lowest level of IOP in romifidine-treated groups was recorded at T45 for the right and left eyes (10.25 2.3 and 11.25 3.5 mmHg, respectively). In comparison with the baseline values, the percent of decrease in IOP values in both right and left eyes, respectively, of the horses in the treatment group at different time points was as follows: T5 (21.2% and 10.2%), T15 (36.7% and 32.7%), T30 (50.5% and 47.3%), T45 (58.5% and 55.2%), T60, (57.5% and 54.2%), and T90, (47.4% and 47.6%). In both eyes, the IOP returned to its normal value at T120 post-treatment. There was no significant variation in IOP between right and left eyes post-treatment with romifidine. DISCUSSION
The use of alpha-2 adrenoceptor agonist drugs has gained wide acceptance in equine veterinary practice.19 With appropriate sedation, ocular nerve blocks (especially the retrobulbar nerve block), and restraint, many ocular surgeries can be performed adequately in standing horses.20 Romifidine is known to cause substantially longer sedation and analgesia in horses, compared with xylazine and
detomidine.12 Many standing ocular procedures such as third eyelid laceration repair, suture of nonperforating corneal laceration, intraocular mass laser ablation, and third eyelid mass removal may require a longer duration of sedation and analgesia. Therefore, romifidine is often the sedative of choice when performing these procedures in standing horses. The effects of sedation on IOP should be considered while performing ophthalmic examinations and procedures in horses. When a deep ulcer, fragile cornea or laceration is present, rapid changes in IOP may result in ocular complications, such as perforation of the globe.16 The manufacturer’s labeled instructions for romifidine administration are 40 to 120 lg/kg (0.4–1.2 mL/100 kg body weight) depending on the depth and duration of sedation that is required. A low dose of romifidine (40 lg/ kg) was chosen for the present study because most equine practitioners initially start with a low dose, then increase the dose until the desired effect is obtained. During tonometry, stress and aggressive handling of the periorbital tissues or eyelids are the variables that can artificially increase IOP measurements. In the present investigation, the palpebral branch of the auriculopalpebral nerve of each eye was blocked to facilitate opening the eyelids when obtaining IOP values, thus minimizing manipulation. A previous study demonstrated that an auriculopalpebral nerve block affects the task of the orbicularis oculi muscle without considerable alteration in IOP.15 The manufacturer of the applanation tonometer recommends that IOP measurements be obtained with topical ocular application of anesthetic to facilitate tonometry. In the present study, topical administration of 0.5% proparacaine solution was used to anesthetize the corneal surface. Proparacaine is often preferred in veterinary and human medicine because of its predictability and minimal adverse effects when measuring IOP.21–23 In the present study, IOP was measured before romifidine and normal saline injection. There was no significant difference between IOP in the right and left eyes, and our baseline values were within the reference range values reported for IOPs in normal horses.15–17,24–26 The present results demonstrated that IV administration of romifidine induced a significant decrease in IOP, which exhibited the lowest level at T45 postadministration (right,
Table 1. Effect of romifidine (40 lg/kg) and saline (0.4 mL/100 kg) on intraocular pressure (IOP, mmHg, mean SD) of right eyes in 24 horses Time postadministration (min) Group Saline Romifidine
0 26.41 3.1 24.75 3.5
5
15 a
26.25 3.3 19.50 3.1b
30 a
25.75 3.3 15.66 3.1b
45 a
26.16 3.3 12.25 2.4b
60 a
26.66 2.8 10.25 2.3b
Means with different superscript letters at the same column are significantly different at P < 0.05. Wilks’ lambda test for time effect, P < 0.01. Wilks’ lambda test for time 9 treatment interaction, P < 0.01. © 2014 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 17, 149–153
90 a
26.58 2.8 10.50 2.5b
120 a
25.91 3.6 13.00 1.8b
26.16 3.4 26.00 3.9
152 marzok, el-khodery and oheida Table 2. Effect of romifidine (40 lg/kg) and saline (0.4 mL/100 kg) on intraocular pressure (IOP, mmHg, mean SD) of left eyes in 24 horses Time postadministration (min) Group Saline Romifidine
0 26.16 3.3 25.16 3.4
5
15 a
26.41 3.6 22.58 3.2b
30 a
26.66 3.6 16.91 3.4b
45 a
26.00 3.9 13.25 2.9b
60 a
26.16 3.9 11.25 3.5b
90 a
26.33 4.2 11.50 2.9b
120 a
26.16 4.0 13.16 3.0b
26.30 4.1 26.25 3.7
Means with different superscript letters at the same column are significantly different at P < 0.05. Wilks’ lambda test for time effect, P < 0.01. Wilks’ lambda test for time 9 treatment interaction, P < 0.01.
10.25 2.3; left 11.25 3.5 mmHg). This result was similar to those reported in horses after sedation with xylazine and detomidine.14–17 On the other hand, an anesthetic protocol of romifidine, tiletamine/zolazepam, and halothane with or without vecuronium has not demonstrated statistically significant alterations in horses IOP.27 In that study, however, romifidine was given IV as a preanesthetic medication, and only one IOP measurement was obtained after 5 min of romifidine administration with all other measurements influenced by other drugs and anesthesia. In a recent study in horses conducted using an anesthetic combination of xylazine and ketamine, a significant increase in IOP was noted.10 The precise mode of action of alpha-2 adrenoceptor agonist drugs in decreasing IOP in horses is unclear. Three mechanisms have been suggested to explain the alpha-2 adrenergic effects on IOP via their effects on aqueous humor production. The activation of prejunctional alpha-2 receptors causes the inhibition of norepinephrine release, subsequently reducing aqueous humor formation. Alternatively, the activation of postjunctional vascular alpha-2 receptors causes ciliary vasoconstriction and decreased ciliary blood flow. Finally, the activation of postjunctional epithelial alpha-2 receptors inhibits adenylate cyclase, thereby reducing aqueous humor production.28 An earlier study suggested that IOP values were reduced under the effects of xylazine sedation because xylazine can produce hemodynamic effects, pH changes with respiration, relaxation of extraocular muscles, and decreased rate of aqueous humor formation.13 Recently, topical application of alpha-2 agonists has been found to decrease ciliary blood flow, ciliary PO2, aqueous production, episcleral venous pressure, and thus the IOP.29 Measurement of IOP in the standing horse requires use of applanation or rebound tonometry.1,15–17 The use of applanation tonometry is considered a precise and reliable method for estimating IOP in animals.30 A portable applanation tonometer is considered the most suited and simple mean for determination the IOP in the standing horse.17 Therefore, the applanation tonometer was chosen and used for IOP measurements in our study. Many factors such as relative height of the eye above the level of the heart, head position, sedation, type of tonometer, and experience of the clinician are known to
significantly affect precision of IOP measurements in horses.1,3,13 Because of this, horses in the present study stood with their heads in a normal and upright position. Furthermore, special attention was given to minimize any pressure on the neck, especially in the throatlatch region, in order to prevent iatrogenic IOP alterations.31 CONCLUSIONS
The present study demonstrates that intravenous administration of romifidine at a dose rate of 40 lg/kg in horses may be considered as an excellent alternative sedative and analgesic drug for surgery or diagnostic ophthalmic procedures when an increase in IOP is undesirable. The findings of this study in healthy horses may not be applicable to findings in horses with ophthalmic diseases. Therefore, further investigation needs to be carried out to determine whether the effect of romifidine is reliable and suitable for use in clinical practice. REFERENCES 1. Komaromy AM, Garg CD, Ying GS et al. Effect of head position on intraocular pressure in horses. American Journal of Veterinary Research 2006; 67: 1232–1235. 2. Gilger BC, Stoppini R. Equine ocular examination route and advanced diagnostic techniques. In: Equine Ophthalmology, 2nd edn. (ed. Gilger BC) Elsevier Saunders, Maryland Heights, 2011; 1–48. 3. Knollinger AM, La Croix NC, Barrett PM et al. Evaluation of a rebound tonometer for measuring intraocular pressure in dogs and horses. Journal of American Veterinary Medicine Association 2005; 15: 244–248. 4. Brooks DE, Matthews AG. Equine ophthalmology. In: Veterinary Opthalmology, 4th edn. (ed. Gelatt KN). Blackwell Publishing, Ames, IA, 2007; 1165–1274. 5. Hendrix DVH. Eye examination techniques in horses. Clinical Techniques in Equine Practice 2005; 4: 2–10. 6. Gray H. Eyes. In: Equine Clinical Medicine, Surgery and Reproduction. (eds Munroe GA, Weese JS) Manson Publishing, London, UK, 2011; 809–872. 7. Robertson SA. Standing sedation and pain management for ophthalmic patients. Veterinary Clinics of North America; Equine Practice 2004; 20: 485–497. 8. Labelle AL, Clark-Price SC. Anesthesia for ophthalmic procedures in the standing horse. Veterinary Clinic North America: Equine Practice 2013; 29: 179–191.
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effect of romifidine on intraocular pressure in horses 153 9. Brunson DB. Anesthesia in ophthalmic surgery. Veterinary Clinics of North American Small Animal Practice 1980; 10: 481–495. 10. Ferreria TH, Brosnan RJ, Yael S et al. Effects of ketamine, propofol, or thiopental administration on intraocular pressure and qualities of induction of and recovery from anesthesia in horses. American Journal of Veterinary Research 2013; 74: 1070–1077. 11. England GC, Clarke KW, Goossens L. A comparison of the sedative effects of three alpha 2-adrenoceptor agonists (romifidine, detomidine and xylazine) in the horse. Journal of Veterinary Pharmacology and Therapeutics 1992; 15: 194–201. 12. Clarke KW, Trim CM, Hall LW. Principles of sedation, anticholinergic agents, and principles of premedication. In: Veterinary Anaesthesia, 11th edn. (eds Clarke Kw, Trim C) Elsevier Saunders, UK, 2014; 79–100. 13. McClure JR, Gelatt KN, Manning JP. The effect of parenteral acepromazine and xylazine on intraocular pressure in the horse. Veterinary Medicine Small Animal Clinic 1976; 32: 1727–1730. 14. Trim CM, Colbern GT, Martin CL. Effect of xylazine and ketamine on intraocular pressure in horses. Veterinary Record 1985; 117: 442–443. 15. Van der Woerdt A, Gilger BC, Wilkie DA. 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. 16. Holve DL. Effect of sedation with detomidine on intraocular pressure with and without topical anesthesia in clinically normal horses. Journal of American Veterinary Medical Association 2012; 240: 308–311. 17. Trbolova A, Selk Ghaffari M. Effects of intravenous detomidine on intraocular pressure readings obtained by applanation tonometry in clinically normal horses. Journal of Equine Veterinary Science 2013; 33: 182–185. 18. Stine JM, Michau TM, Williams MK et al. The effects of intravenous romifidine on intraocular pressure in clinically normal horses (abstract). 44th Annual Meeting of the American College of Veterinary Ophthalmologists 2013; 16: E26–E50. 19. England GC, Clarck KW. Alpha 2 adrenoceptor agonists in the horse-A review. British Veterinary Journal 1996; 152: 641–657.
20. Gilger BC, Davidson MG. How to prepare for ocular surgery in the standing horse. Proceedings of the Annual Convention of the American Association of Equine Practitioner 2002; 48: 66–71. 21. Stiles J, Krohne S, Rankin A et al. The efficacy of 0.5% proparacaine stored at room temperature. Veterinary Ophthalmology 2001; 4: 205–207. 22. Binder DR, Herring IP. Duration of corneal anesthesia following topical administration of 0.5% proparacaine hydrochloride solution in clinically normal cats. American Journal of Veterinary Research 2006; 67: 1780–1782. 23. Kim J, Kim N, Lee K et al. Effect of topical anesthesia on evaluation of corneal sensitivity and intraocular pressure in rats and dogs. Veterinary Ophthalmology 2013; 16: 43–46. 24. Miller PE, Pickett JP, Majors LJ. Evaluation of two applanation tonometers in horses. American Journal of Veterinary Research 1990; 51: 935–937. 25. Smith PJ, Gum GG, Whitley RD. Tonometric and tonographic studies in the normal pony eye. Equine Veterinary Journal Supplement 1990; 10: 36–38. 26. Ramsey DT, Hauptman JG, Petersen-Jones SM. Corneal thickness, intraocular pressure, and optical corneal diameter in Rocky Mountain Horses with cornea globosa or clinically normal corneas. American Journal of Veterinary Research 1999; 60: 1317–1321. 27. Bechara JN, de Moraes Barros PS, Fantoni DT et al. Intraocular pressure evaluation of equine anesthetized with romifidine, tiletamine/zolazepam, halothane and vecuronium. Ci^encia Rural, Santa Maria 1998; 28: 59–64. 28. Kaufman PL, Gabelt BT. Alpha-2-adrenergic effects on aqueous humor dynamics. Journal of Glaucoma 1995; 4: 8–14. 29. Reitsamer HA, Posey M, Kiel JW. Effects of a topical alpha 2-agonist on ciliary blood flow and aqueous production in rabbits. Experimental Eye Research 2006; 82: 405–415. 30. Rusanen E, Florin M, H€assig M et al. Evaluation of a rebound tonometer (Tonovet) in clinically normal cat eyes. Veterinary Ophthalmology 2010; 13: 31–36. 31. Pauli AM, Bentley E, Diehl KA et al. Effects of the application of neck pressure by a collar or harness on intraocular pressure in dogs. Journal of American Animal Hospital Association 2006; 42: 207–211.
© 2014 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 17, 149–153
DOI:10.1111/vop.12181
Effect of intravenous administration of romifidine on intraocular pressure in clinically normal horses Mohamed A. Marzok,* Sabry A. El-khodery† and Aiman H. Oheida‡ *Department of Veterinary Surgery, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt; †Department of Internal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt; and ‡Department of Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, University of Tripoli, Tripoli 13662, Libya
Address communications to: M. A. Marzok Tel.: +2 01222238237 Fax: +2 0473231311 e-mail: marzok2000@hotmail. com
Abstract Objective To evaluate the effect of intravenous administration of romifidine on the intraocular pressure (IOP) in horses. Animals studied Twenty-four horses with no ocular abnormalities. Procedure Horses were randomly assigned into two equal groups (treatment and control). All horses in the treatment group received an intravenous (IV) injection of romifidine (40 lg/kg). The horses in the control group were administrated an intravenous injection of 0.9% saline (0.4 mL/100 kg). In both groups, the IOP values were measured immediately (T0) pre-administration and at 5 (T5), 15 (T15), 30 (T30), 45 (T45), 60 (T60), 90 (T90), and 120 (T120) min after drug administration. Results The pre-treatment values (T0) of IOP for right and left eyes were 24.25 3.5 and 25.16 3.4 mmHg, respectively. A significant decrease in IOP values was observed in both right and left eyes of the horses in treatment group at T5, T15, T30, T45, T60, and T90 in comparison with the baseline values (P < 0.05). The lowest level of IOP in romifidine-treated groups was recorded at T45 for the right and left eyes (10.25 2.3 and 11.25 3.5 mmHg, respectively). Conclusion Romifidine significantly decreased IOP in clinically normal horses and may be used safely for surgery or diagnostic ocular procedures in horses when specific control of IOP is required. Key Words: applanation tonometry, horse, intraocular pressure, romifidine
INTRODUCTION
Measurement of intraocular pressure (IOP) or tonometry is part of the routine eye examination in horses.1 In recent years, measurement of IOP in the horse has been revolutionized by the development of handheld portable digital tonometers that do not require the horse to be in lateral recumbency.2 Tonometry is indicated in horses that have ocular disorders such as focal or diffuse corneal edema, red or painful eye, orbital trauma, lens luxation, glaucoma, and uveitis.3,4 Alpha-2 adrenoceptor agonists, including xylazine, detomidine, and romifidine, are used most commonly when performing ophthalmic examination and/or surgical ocular procedures in the horse.5,6 Standing sedation and analgesia is required on horses to facilitate several ophthalmic diagnostic tests especially in flighty or very painful animals.7 For short standing ocular procedures, single intravenous © 2014 American College of Veterinary Ophthalmologists
(IV) injection of standard doses of an alpha-2 agonist is often sufficient. For longer procedures, constant rate infusion (CRI) may be advantageous over repeated bolus injections to provide a consistent level of sedation.8 In equine practice, alpha-2 adrenoceptor agonists are also used for premedication in most anesthetic protocols for ophthalmic procedures. The selection of an appropriate anesthetic protocol for intraocular surgery is critical to the success of such procedure. The ability to regulate IOP is considered essential for successful ophthalmic surgery and can be greatly affected by the anesthetic protocol.9 Therefore, when performing ophthalmic examination or any surgical ocular procedures in horses, the effects of sedation on IOP should be considered. In recent years, several studies have evaluated the effects of anesthetic drugs on IOP values in horses. One study, for example, reported effects of ketamine hydrochloride, propofol, or compounded thiopental sodium administration on
150 marzok, el-khodery and oheida
IOP and qualities of induction of and recovery from anesthesia in horses. In the conclusion, the authors stated that ketamine caused a significant increase in IOP compared with baseline, propofol, and thiopental.10 Romifidine is a selective alpha-2 adrenoceptor agonist drug that is commonly administered intravenously or intrathecally to bring about sedation and analgesia in horses, and it has been shown to have systemic and analgesic effects similar to other alpha-2 agonists.11 Romifidine’s actions have demonstrated some differences from the other alpha-2 agonists in veterinary use. In horses, when compared with IV xylazine (1 mg/kg) or detomidine (20 lg/kg), romifidine at 40 and 80 lg/kg produced less ataxia and the horses’ heads were held higher. The duration of effect was longest with romifidine. The lack of ataxia with romifidine has made it very popular for use to sedate horses for standing procedures, and it is also widely used for premedication with ketamine for anesthetic induction in this species.12 Previous studies showed that sedation of horses with xylazine, acepromazine, and detomidine resulted in dramatic decreases in IOP.13–17 Nevertheless, information on effects of IV administration of romifidine on IOP is limited. A recent study in normal horses conducted using applanation tonometry reported that administration of IV romifidine at a 75 lg/kg dose causes a significant decrease in IOP.18 In that study, The IOP readings were only recorded at 5, 15, 30, 45 and, 60 min postsedation in both eyes. As the sedative effects of romifidine at a dose of 40–80 lg/kg last for approximately 80 min,11 this study did not determine whether this effect on IOP persists over the period of 80 min. Therefore, this study aimed to evaluate the effects of IV romifidine on the IOP in clinically normal horses and to document the details of IOP changes over 120 min. MATERIALS AND METHODS
Experimental animals Twenty-four horses (16 Arabian and 8 cross-breds; 8 intact males, 6 geldings, and 10 females) were used. The mean age was 6.92 4.15 years old, and the mean weight was 440.7 53.5 kg. On the basis of results of physical examination, all animals were considered healthy. The horses were allowed ad libitum access to food and water until the beginning of each experiment. Study protocol The study protocol was approved by the Animal Care Committee of the Kafer-Elsheikh University, in accordance with Egyptian ethical codes for studies on experimental animals. All animals underwent a complete ophthalmic examination, including Schirmer tear test, slitlamp biomicroscopy, and indirect ophthalmoscopy. All 24 horses had clinically normal eyes. The horses were allocated randomly to two groups with twelve horses in each
group (treatment and control). All horses in the treatment group received an intravenous injection of romifidine (10 mg/mL, Sedivetâ; Boehringer Ingelheim, Vetmedica GmbH, Ingelheim/Rhein, Germany) at a 40 lg/kg dose. The horses in the control group received only intravenous saline (0.4 mL/100 kg) (El Nasr Pharmaceutical Company, Cairo, Egypt). In the two groups, IOP of both the eyes was measured and recorded by the same investigator (M.M.). The measurements were taken immediately pre-administration (T0) and then at a 5 (T5), 15 (T15), 30 (T30), 45 (T45), 60 (T60), 90 (T90), and 120 (T120) min postadministration.
Measurement of IOP The experiment was performed indoors in a familiar, quiet environment, and all horses were restrained by the same individuals. The palpebral branch of the auriculopalpebral nerve along the dorsal zygomatic arch of each eye was blocked by subcutaneous (SC) infusion of 2.0 mL of mepivacaine hydrochloride (Mepecaine, Alexandria Co. for Pharmaceutical & Chemicals Industries, Alexandria, Egypt) to facilitate opening of the upper eyelid.15 All IOP measurements were performed with the head maintained in a normal and upright position. The horse’s head was elevated and held in the head-up position by positioning the mandible on the shoulder of one of the investigators. The head height was maintained for a minimum of 2 min prior to measurement at each time point to give enough time for normalization of pressures.1 All measurements were obtained between 8:00 and 11:00 am, to minimize individual and diurnal variations. The order of eyes examined (right vs. left) in each horse was random. The eyelids were manipulated gently to avoid pressure on the globe. Before each measurement, the cornea of both eyes was topically anesthetized using 0.2 mL of 0.5% proparacaine solution (Alcaineâ; Alcon Laboratories, INC, Fort Worth, TX, USA). An applanation tonometer (Tono-Pen AVIA; Reichert, Depew, NY, USA) was used to estimate IOP. Three measurements were obtained by lightly touching the central aspect of the cornea at 5-s intervals, after which the readings were averaged. The tonometer was factory calibrated before initiation of the study, and only IOP readings with a 5% variance (5% displays on Tono-Pen) were recorded. Statistical analysis Analysis of data was carried out using SPSS statistical software program (SPSS for Windows, version 16.0; SPSS Inc., Chicago, IL, USA). Initially, data were assessed for normal distribution using Kolmogorov–Smirnov test. Data were normally distributed; consequently, mean and standard deviation for each variable at each time point were calculated. General linear model with repeated-measures ANOVA was used to determine the main effects of time and treatment. Wilks’ lambda test was selected to evaluate within-group interactions and evidence of time 9 treatment
© 2014 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 17, 149–153
effect of romifidine on intraocular pressure in horses 151
interactions. Where Wilks’ lambda test showed a statistically significant difference between groups, t-test was used at each time point to identify which group was statistically different. Difference between means was considered significant at P < 0.05. RESULTS
All the diagnostic procedures were performed successfully, and no signs of ocular irritation or pain were detected in horses examined at any time point. Applanation tonometry was easy to perform and well tolerated by the horses. The pretreatment values (T0) of IOP for right and left eyes were 24.25 3.5 and 25.16 3.4 mmHg, respectively. Based on treatment–time interaction, IOP values were significantly decreased in treated horses (Wilks’ lambda test for treatment–time interaction, P < 0.001). In the romifidine-treated group, the IOP was significantly decreased (P < 0.05) in both right and left eyes of the horses in comparison with the control group at T5, T15, T30, T45, T60, and T90 (Tables 1 and 2). The lowest level of IOP in romifidine-treated groups was recorded at T45 for the right and left eyes (10.25 2.3 and 11.25 3.5 mmHg, respectively). In comparison with the baseline values, the percent of decrease in IOP values in both right and left eyes, respectively, of the horses in the treatment group at different time points was as follows: T5 (21.2% and 10.2%), T15 (36.7% and 32.7%), T30 (50.5% and 47.3%), T45 (58.5% and 55.2%), T60, (57.5% and 54.2%), and T90, (47.4% and 47.6%). In both eyes, the IOP returned to its normal value at T120 post-treatment. There was no significant variation in IOP between right and left eyes post-treatment with romifidine. DISCUSSION
The use of alpha-2 adrenoceptor agonist drugs has gained wide acceptance in equine veterinary practice.19 With appropriate sedation, ocular nerve blocks (especially the retrobulbar nerve block), and restraint, many ocular surgeries can be performed adequately in standing horses.20 Romifidine is known to cause substantially longer sedation and analgesia in horses, compared with xylazine and
detomidine.12 Many standing ocular procedures such as third eyelid laceration repair, suture of nonperforating corneal laceration, intraocular mass laser ablation, and third eyelid mass removal may require a longer duration of sedation and analgesia. Therefore, romifidine is often the sedative of choice when performing these procedures in standing horses. The effects of sedation on IOP should be considered while performing ophthalmic examinations and procedures in horses. When a deep ulcer, fragile cornea or laceration is present, rapid changes in IOP may result in ocular complications, such as perforation of the globe.16 The manufacturer’s labeled instructions for romifidine administration are 40 to 120 lg/kg (0.4–1.2 mL/100 kg body weight) depending on the depth and duration of sedation that is required. A low dose of romifidine (40 lg/ kg) was chosen for the present study because most equine practitioners initially start with a low dose, then increase the dose until the desired effect is obtained. During tonometry, stress and aggressive handling of the periorbital tissues or eyelids are the variables that can artificially increase IOP measurements. In the present investigation, the palpebral branch of the auriculopalpebral nerve of each eye was blocked to facilitate opening the eyelids when obtaining IOP values, thus minimizing manipulation. A previous study demonstrated that an auriculopalpebral nerve block affects the task of the orbicularis oculi muscle without considerable alteration in IOP.15 The manufacturer of the applanation tonometer recommends that IOP measurements be obtained with topical ocular application of anesthetic to facilitate tonometry. In the present study, topical administration of 0.5% proparacaine solution was used to anesthetize the corneal surface. Proparacaine is often preferred in veterinary and human medicine because of its predictability and minimal adverse effects when measuring IOP.21–23 In the present study, IOP was measured before romifidine and normal saline injection. There was no significant difference between IOP in the right and left eyes, and our baseline values were within the reference range values reported for IOPs in normal horses.15–17,24–26 The present results demonstrated that IV administration of romifidine induced a significant decrease in IOP, which exhibited the lowest level at T45 postadministration (right,
Table 1. Effect of romifidine (40 lg/kg) and saline (0.4 mL/100 kg) on intraocular pressure (IOP, mmHg, mean SD) of right eyes in 24 horses Time postadministration (min) Group Saline Romifidine
0 26.41 3.1 24.75 3.5
5
15 a
26.25 3.3 19.50 3.1b
30 a
25.75 3.3 15.66 3.1b
45 a
26.16 3.3 12.25 2.4b
60 a
26.66 2.8 10.25 2.3b
Means with different superscript letters at the same column are significantly different at P < 0.05. Wilks’ lambda test for time effect, P < 0.01. Wilks’ lambda test for time 9 treatment interaction, P < 0.01. © 2014 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 17, 149–153
90 a
26.58 2.8 10.50 2.5b
120 a
25.91 3.6 13.00 1.8b
26.16 3.4 26.00 3.9
152 marzok, el-khodery and oheida Table 2. Effect of romifidine (40 lg/kg) and saline (0.4 mL/100 kg) on intraocular pressure (IOP, mmHg, mean SD) of left eyes in 24 horses Time postadministration (min) Group Saline Romifidine
0 26.16 3.3 25.16 3.4
5
15 a
26.41 3.6 22.58 3.2b
30 a
26.66 3.6 16.91 3.4b
45 a
26.00 3.9 13.25 2.9b
60 a
26.16 3.9 11.25 3.5b
90 a
26.33 4.2 11.50 2.9b
120 a
26.16 4.0 13.16 3.0b
26.30 4.1 26.25 3.7
Means with different superscript letters at the same column are significantly different at P < 0.05. Wilks’ lambda test for time effect, P < 0.01. Wilks’ lambda test for time 9 treatment interaction, P < 0.01.
10.25 2.3; left 11.25 3.5 mmHg). This result was similar to those reported in horses after sedation with xylazine and detomidine.14–17 On the other hand, an anesthetic protocol of romifidine, tiletamine/zolazepam, and halothane with or without vecuronium has not demonstrated statistically significant alterations in horses IOP.27 In that study, however, romifidine was given IV as a preanesthetic medication, and only one IOP measurement was obtained after 5 min of romifidine administration with all other measurements influenced by other drugs and anesthesia. In a recent study in horses conducted using an anesthetic combination of xylazine and ketamine, a significant increase in IOP was noted.10 The precise mode of action of alpha-2 adrenoceptor agonist drugs in decreasing IOP in horses is unclear. Three mechanisms have been suggested to explain the alpha-2 adrenergic effects on IOP via their effects on aqueous humor production. The activation of prejunctional alpha-2 receptors causes the inhibition of norepinephrine release, subsequently reducing aqueous humor formation. Alternatively, the activation of postjunctional vascular alpha-2 receptors causes ciliary vasoconstriction and decreased ciliary blood flow. Finally, the activation of postjunctional epithelial alpha-2 receptors inhibits adenylate cyclase, thereby reducing aqueous humor production.28 An earlier study suggested that IOP values were reduced under the effects of xylazine sedation because xylazine can produce hemodynamic effects, pH changes with respiration, relaxation of extraocular muscles, and decreased rate of aqueous humor formation.13 Recently, topical application of alpha-2 agonists has been found to decrease ciliary blood flow, ciliary PO2, aqueous production, episcleral venous pressure, and thus the IOP.29 Measurement of IOP in the standing horse requires use of applanation or rebound tonometry.1,15–17 The use of applanation tonometry is considered a precise and reliable method for estimating IOP in animals.30 A portable applanation tonometer is considered the most suited and simple mean for determination the IOP in the standing horse.17 Therefore, the applanation tonometer was chosen and used for IOP measurements in our study. Many factors such as relative height of the eye above the level of the heart, head position, sedation, type of tonometer, and experience of the clinician are known to
significantly affect precision of IOP measurements in horses.1,3,13 Because of this, horses in the present study stood with their heads in a normal and upright position. Furthermore, special attention was given to minimize any pressure on the neck, especially in the throatlatch region, in order to prevent iatrogenic IOP alterations.31 CONCLUSIONS
The present study demonstrates that intravenous administration of romifidine at a dose rate of 40 lg/kg in horses may be considered as an excellent alternative sedative and analgesic drug for surgery or diagnostic ophthalmic procedures when an increase in IOP is undesirable. The findings of this study in healthy horses may not be applicable to findings in horses with ophthalmic diseases. Therefore, further investigation needs to be carried out to determine whether the effect of romifidine is reliable and suitable for use in clinical practice. REFERENCES 1. Komaromy AM, Garg CD, Ying GS et al. Effect of head position on intraocular pressure in horses. American Journal of Veterinary Research 2006; 67: 1232–1235. 2. Gilger BC, Stoppini R. Equine ocular examination route and advanced diagnostic techniques. In: Equine Ophthalmology, 2nd edn. (ed. Gilger BC) Elsevier Saunders, Maryland Heights, 2011; 1–48. 3. Knollinger AM, La Croix NC, Barrett PM et al. Evaluation of a rebound tonometer for measuring intraocular pressure in dogs and horses. Journal of American Veterinary Medicine Association 2005; 15: 244–248. 4. Brooks DE, Matthews AG. Equine ophthalmology. In: Veterinary Opthalmology, 4th edn. (ed. Gelatt KN). Blackwell Publishing, Ames, IA, 2007; 1165–1274. 5. Hendrix DVH. Eye examination techniques in horses. Clinical Techniques in Equine Practice 2005; 4: 2–10. 6. Gray H. Eyes. In: Equine Clinical Medicine, Surgery and Reproduction. (eds Munroe GA, Weese JS) Manson Publishing, London, UK, 2011; 809–872. 7. Robertson SA. Standing sedation and pain management for ophthalmic patients. Veterinary Clinics of North America; Equine Practice 2004; 20: 485–497. 8. Labelle AL, Clark-Price SC. Anesthesia for ophthalmic procedures in the standing horse. Veterinary Clinic North America: Equine Practice 2013; 29: 179–191.
© 2014 American College of Veterinary Ophthalmologists, Veterinary Ophthalmology, 17, 149–153
effect of romifidine on intraocular pressure in horses 153 9. Brunson DB. Anesthesia in ophthalmic surgery. Veterinary Clinics of North American Small Animal Practice 1980; 10: 481–495. 10. Ferreria TH, Brosnan RJ, Yael S et al. Effects of ketamine, propofol, or thiopental administration on intraocular pressure and qualities of induction of and recovery from anesthesia in horses. American Journal of Veterinary Research 2013; 74: 1070–1077. 11. England GC, Clarke KW, Goossens L. A comparison of the sedative effects of three alpha 2-adrenoceptor agonists (romifidine, detomidine and xylazine) in the horse. Journal of Veterinary Pharmacology and Therapeutics 1992; 15: 194–201. 12. Clarke KW, Trim CM, Hall LW. Principles of sedation, anticholinergic agents, and principles of premedication. In: Veterinary Anaesthesia, 11th edn. (eds Clarke Kw, Trim C) Elsevier Saunders, UK, 2014; 79–100. 13. McClure JR, Gelatt KN, Manning JP. The effect of parenteral acepromazine and xylazine on intraocular pressure in the horse. Veterinary Medicine Small Animal Clinic 1976; 32: 1727–1730. 14. Trim CM, Colbern GT, Martin CL. Effect of xylazine and ketamine on intraocular pressure in horses. Veterinary Record 1985; 117: 442–443. 15. Van der Woerdt A, Gilger BC, Wilkie DA. 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. 16. Holve DL. Effect of sedation with detomidine on intraocular pressure with and without topical anesthesia in clinically normal horses. Journal of American Veterinary Medical Association 2012; 240: 308–311. 17. Trbolova A, Selk Ghaffari M. Effects of intravenous detomidine on intraocular pressure readings obtained by applanation tonometry in clinically normal horses. Journal of Equine Veterinary Science 2013; 33: 182–185. 18. Stine JM, Michau TM, Williams MK et al. The effects of intravenous romifidine on intraocular pressure in clinically normal horses (abstract). 44th Annual Meeting of the American College of Veterinary Ophthalmologists 2013; 16: E26–E50. 19. England GC, Clarck KW. Alpha 2 adrenoceptor agonists in the horse-A review. British Veterinary Journal 1996; 152: 641–657.
20. Gilger BC, Davidson MG. How to prepare for ocular surgery in the standing horse. Proceedings of the Annual Convention of the American Association of Equine Practitioner 2002; 48: 66–71. 21. Stiles J, Krohne S, Rankin A et al. The efficacy of 0.5% proparacaine stored at room temperature. Veterinary Ophthalmology 2001; 4: 205–207. 22. Binder DR, Herring IP. Duration of corneal anesthesia following topical administration of 0.5% proparacaine hydrochloride solution in clinically normal cats. American Journal of Veterinary Research 2006; 67: 1780–1782. 23. Kim J, Kim N, Lee K et al. Effect of topical anesthesia on evaluation of corneal sensitivity and intraocular pressure in rats and dogs. Veterinary Ophthalmology 2013; 16: 43–46. 24. Miller PE, Pickett JP, Majors LJ. Evaluation of two applanation tonometers in horses. American Journal of Veterinary Research 1990; 51: 935–937. 25. Smith PJ, Gum GG, Whitley RD. Tonometric and tonographic studies in the normal pony eye. Equine Veterinary Journal Supplement 1990; 10: 36–38. 26. Ramsey DT, Hauptman JG, Petersen-Jones SM. Corneal thickness, intraocular pressure, and optical corneal diameter in Rocky Mountain Horses with cornea globosa or clinically normal corneas. American Journal of Veterinary Research 1999; 60: 1317–1321. 27. Bechara JN, de Moraes Barros PS, Fantoni DT et al. Intraocular pressure evaluation of equine anesthetized with romifidine, tiletamine/zolazepam, halothane and vecuronium. Ci^encia Rural, Santa Maria 1998; 28: 59–64. 28. Kaufman PL, Gabelt BT. Alpha-2-adrenergic effects on aqueous humor dynamics. Journal of Glaucoma 1995; 4: 8–14. 29. Reitsamer HA, Posey M, Kiel JW. Effects of a topical alpha 2-agonist on ciliary blood flow and aqueous production in rabbits. Experimental Eye Research 2006; 82: 405–415. 30. Rusanen E, Florin M, H€assig M et al. Evaluation of a rebound tonometer (Tonovet) in clinically normal cat eyes. Veterinary Ophthalmology 2010; 13: 31–36. 31. Pauli AM, Bentley E, Diehl KA et al. Effects of the application of neck pressure by a collar or harness on intraocular pressure in dogs. Journal of American Animal Hospital Association 2006; 42: 207–211.
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