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The efficacy and safety of topical rocuronium bromide to induce bilateral mydriasis in Hispaniolan Amazon parrots (Amazona ventralis).

Abstract: The efficacy and safety of topically applied rocuronium in Hispaniolan Amazon parrots (Amazona ventralis) was assessed in a group of 10 adult birds. A complete ophthalmic examination (including Schirmer tear test, ocular reflexes, applanation tonometry, fluorescein staining, and slit-lamp biomicroscopy) was performed, and rocuronium bromide (0.15 mg in both eyes) was administered. Pupillary light reflex (PLR) and pupillary diameter were recorded in a darkened room at the following time points: 0, 10, 20, 30, 40, 50, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 300, and 360 minutes, and 24 hours. Fluorescein staining in both eyes was performed at 24 hours. By 10 minutes, PLR was absent in all birds (at 5 minutes, 8 birds; at 10 minutes, remaining 2 birds). Pupil diameter differed significantly from baseline at all time points. Additionally, PLR was decreased in 7/10 birds at 360 minutes and normal in all birds at 24 hours. Superficial corneal ulceration was observed at 24 hours in the left eye of 2/10 of the birds after fluorescein stain application. This study demonstrated that rocuronium bromide was an effective mydriatic agent in Hispaniolan Amazon parrots with rapid onset and prolonged duration of action.

Key words: mydriasis, eye, ophthalmic examination, pupil, dilation, rocuronium, avian, Hispaniolan Amazon parrot, Amazona ventralis

Introduction

To perform a complete ophthalmic examination of the avian eye, the fundus must be examined; however, the unique anatomy of the avian iris makes pupil dilation challenging. The avian iris musculature is composed mainly of striated muscle fibers with variable amounts of nonstriated muscle fibers (myoepithelium and/or smooth muscle). (1,2) This is in contrast to the mammalian iris, which contains mostly smooth muscle fibers. Consequently, topical or intraocular parasympatholytic (atropine) and sympathomimetic (phenylephrine) mydriatic agents used to dilate mammalian pupils are not effective in a variety of avian species because of the high proportion of striated sphincter muscle fibers. (3-5)

In addition, variation appears to exist in the development and arrangement of muscle fiber types among different avian families. (1,2) Therefore, although studies have been performed to evaluate the effects of intracameral and topical nondepolarizing neuromuscular blocking agents on avian pupils, mydriasis is inconsistent, and the side effects associated with administration can be severe. Specifically, studies that evaluated topical d-tubocurarine showed variable mydriasis. (3,5,6) Excellent mydriasis was achieved in pigeons (Columba livid) by using topical d-tubocurarine in 0.025% benzalkonium chloride solution or oil suspension without side effects; however, topical d-tubocurarine in 0.025% benzalkonium chloride solution or in saponin showed minimal to absent mydriasis in cockatoos (Cacatua species) and pigeons. (3,5,6) Intracameral injections of d-tubocurarine were effective at producing mydriasis in pigeons; however, significant side effects such as iridial hemorrhage, anterior uveitis, cataract formation, posterior synechia, and globe collapse are potentially associated with the administration technique. (6) In European kestrels (Falco tinnunculus), mydriasis was inconsistent with topical pancuronium bromide, and although effectively achieved with topical alcuronium chloride, birds developed temporary inferior eyelid paralysis (5/8 birds) and neck and limb paralysis (1/8 birds) with topical alcuronium chloride. (7) Evaluation of topical vecuronium bromide showed good mydriasis without side effects in double-crested cormorants (Phalacrocorax auritus); signs of ocular irritation and mild systemic effects (rapid shallow breathing and ataxia) developed in African gray (Psittacus erithacus) and blue-fronted Amazon {Amazona aestiva) parrots in another study. (4,5)

Rocuronium bromide, a nondepolarizing neuromuscular blocking agent, is a derivative of vecuronium bromide. Rocuronium bromide provides safe and reliable pupil dilation when used topically in tawny owls (Strix aluco), common buzzards (Buteo buteo), little owls (Athene rtoctua), and European kestrels. (8-10) No side effects were observed when the drug was administered to both eyes simultaneously, and a second dose applied 15 minutes after the first did not improve pupil dilation. (8-10) Given the efficacy and lack of side effects in previous studies, rocuronium bromide appears to be a better alternative than other topical and intracameral neuromuscular blocking agents in the species examined. To our knowledge, no data have been published in the peer-reviewed literature on topical rocuronium use in parrot species. However, a recently presented abstract described an evaluation of topical rocuronium in Hispaniolan Amazon parrots (Amazona ventralis) (11) In that study, mydriasis was achieved; however, transient lower eyelid paresis was documented in 3/8 study birds. The purpose of the current study was to evaluate the efficacy and safety of bilateral topical rocuronium bromide for pupil dilation in Hispaniolan Amazon parrots.

Materials and Methods

Adult Hispaniolan Amazon parrots (N = 10) housed at the Knoxville Zoological Gardens (Knoxville, TN, USA) were used. They had been in residence at the zoo for approximately 2 years before the start of the study and had previously been part of a closed research collection at the University of Tennessee College of Veterinary Medicine. The birds had no previous pertinent medical concerns and had not been used in a research project for 20 months before initiation of this project. The birds were housed indoors in various-sized wire cages with 1 to 2 birds per cage and received a pelleted diet and various fresh fruits and vegetables (Parrot Maintenance, Mazuri, PMI Nutrition International, Arden Hills, MN, USA). At the beginning of the study, the birds were transported to the University of Tennessee and were housed individually in medium-sized carriers covered with a towel for the duration of the study. The birds were weighed, and a complete physical examination was done before the study began. The University of Tennessee Institutional Animal Care and Use Committee approved the experimental protocol.

A complete ophthalmic examination was performed in both eyes. Specifically, the globe was evaluated for gross abnormalities, a Schirmer tear test I was performed (Schirmer tear test strips, Intervet Schering, Boxmeer, Netherlands), and ocular reflexes, including palpebral, menace, and direct pupillary light reflex (PLR) were recorded. Direct PLR was measured by using a bright, focal, circular light beam from a slit lamp (Kowa SL-15, Kowa, Tokyo, Japan) on a 3-point scale (normal, decreased, absent). A drop of 0.5% proparacaine hydrochloride was administered in each eye, and intraocular pressure was measured by applanation tonometry (Icare Finland Oy, Vantaa, Finland). Fluorescein staining (HUB Pharmaceuticals, Rancho Cucamonga, CA, USA) was performed. The anterior segment was evaluated via slit-lamp biomicroscopy (Kowa SL-15). Rocuronium bromide (10 mg/mL, Merck, Kenilworth, NJ, USA) was administered without dilution at 0.15 mg in both eyes using a micropipette; the left eye (OS) was treated first, followed by the right eye (OD). The third eyelid was not retracted as described in previous studies. (8-10) Pupillary light reflex and pupillary diameter were recorded in a darkened room, with the birds individually restrained, at the following time points: 0, 10, 20, 30, 40, 50, 60, 80, 100, 120, 140, 160, 180, 200, 220, 240, 300, and 360 minutes, and 24 hours. A 5-minute time point was added after the second bird was started due to the rapid pupillary dilation noted clinically. Eyes were examined OS followed by OD at all time points. Once the pupil was fully dilated, a fundic examination was performed in both eyes using indirect ophthalmoscopy (28 D handheld lens. Volk Optical, Mentor, OH, USA; Vantage Plus Wireless Headset, Keeler Instruments, Broomall, PA, USA). Fluorescein staining was performed in both eyes at 24 hours. The birds were monitored for the duration of the study for any side effects, including ocular irritation (lacrimation, blepharospasm, conjunctival hyperemia, chemosis), local or systemic muscle paralysis (eyelid, wings, legs, neck), and respiratory distress.

Pupillary diameter was measured by evaluating photographic images of the pupil. Photographs were taken at a fixed focal distance at specific time points in a darkened room by using a flash. The photographs were obtained by using a 105-mm macro lens (Nikon AF Micro, Nikkor 105 mm, Nikon Corporation, Tokyo, Japan) and camera (Nikon D100, Nikon) at a maximum macro focus; photographs were taken when the pupil was in focus. A ruler was then photographed using the same technique. The images were then uploaded on a commercial software system (Photoshop CC, Adobe Systems, San Jose, CA, USA) and pupil diameter measured for each image by using the ruler available on the program. Any blurry images or images where the pupil was obscured by the eyelids were not used. Magnification was calculated by measuring 10 mm on the ruler with the commercial software system and comparing the actual ruler measurement (10 mm) to the calculated measurement (110 mm). The calculated magnification was 9.1%.

Because of the small sample size, the distribution of pupil diameters was assumed to be nonparametric. The mean pupil diameter of the right and left eye of each bird at each time point was used for statistical analysis. A Wilcoxon matched-pairs signed-rank test was performed to determine if a difference existed between pupil diameter at baseline (time 0) and each subsequent time point (SPSS 19 Statistics Software, Armonk, NY, USA). Multiple testing was adjusted for by the Simes method. Results were considered significant at P < .05.

Results

The physical examination findings were unremarkable and included changes in feather quality, patchy feather loss, and increased body condition score. The median body weight was 283g (range 265-355 g). Of the 10 birds examined, 8 had ocular changes that included nuclear sclerosis, eyelid scaring, corneal scar, and incipient cataracts. One bird had nuclear sclerosis in both eyes, and another had eyelid scarring OS and an incipient cataract OD. Incipient cataracts were observed in 1 eye in 3 birds and both eyes in 3 birds. The median Schirmer tear test value was 8 mm/min OD (range 5-12 mm/min) and 8.5 mm/min OS (range 7-11 mm/min). Median intraocular pressure was 9.5 OD (range 6-18) and 8 OS (range 6-14).

Actual pupil diameter was calculated for all time points except in 3 birds. Data from bird 5 OD at 100 minutes were not included because of poor image quality. Data at 5 minutes were not available for the first 2 birds since that time point was added after initiation of the study.

The median, first, and third quartiles, and P values are shown in Table 1. Pupil diameter differed significantly from baseline at all time points. Only 8 pairs were compared for the 5-minute time point and only 9 pairs were compared for the 100-minute time point because of missing data. At 10 minutes, PLR was absent in all birds: at 5 minutes, it was absent in 8 birds, and at 10 minutes it was absent in the remaining 2 birds. The PLR was decreased in 7/10 birds at 360 minutes and normal in all birds at 24 hours.

Ocular irritation, local and systemic muscle paralysis, and respiratory distress were not identified in any study bird; however, superficial corneal ulceration was noted OS in 2/10 study birds after fluorescein stain application at 24 hours. Both birds were placed on topical triple antibiotic ophthalmic ointment (neomycin, polymyxin B, and bacitracin) twice daily and were negative for fluorescein stain uptake after 2 days. One of the birds with corneal ulceration also had palpebral and periorbital bruising associated with the same eye, which was likely caused by trauma secondary to repeated capture.

Discussion

Topical rocuronium bromide caused rapid and effective mydriasis in Hispaniolan Amazon parrots in this study. Pupil diameter was significantly different than baseline at all time points. The time needed for pupil diameter to return to baseline appears variable between species: 270, 180, 300 (direct light), and 420 minutes in kestrels, tawny owls, little owls, and Hispaniolan Amazon parrots, respectively. (8-11) Pupil diameter had not returned to baseline in common buzzards and ambient light in little owls after 240 and 320 minutes, respectively. (9) One limiting factor in comparing previous studies was lack of consistency in time points; previous studies did not evaluate pupil diameter and PLR at 24 hours. In the current study, PLR returned for 7/ 10 birds at 360 minutes although the pupil remained dilated. This was similar to other studies where PLR returned before pupil diameter returned to baseline. (8-10)

Although the ophthalmic examination on the study birds revealed abnormalities associated with the eyelid, cornea, and/or lens, they were still included in the study because the changes were not likely to affect pupil dilation. Interestingly, incipient cataracts were not noted until the pupil was dilated in 2/6 birds with cataracts. This highlights the importance of pupil dilation for complete ophthalmic examination, especially for subtle lesions. In a nondilated Amazon parrot it is difficult to obtain an image of the fundus with a 28 D lens (typically a 60 D is needed); however, in the dilated study birds, a good image was obtained using a 28 D lens. Similar to other studies evaluating topical rocuronium in avian species, we used the Schirmer tear test rather than the phenol red thread test despite the smaller size of the phenol red thread. (8-10) Both the Schirmer tear test and phenol red thread test have been shown to be appropriate measures of tear production in Hispaniolan Amazon parrots. (12)

In previous studies, the third eyelid was retracted after rocuronium administration. (8-10) However, practitioners who clinically used the drug in parrot species noted that topical anesthesia was sufficient in many birds to avoid third eyelid movement during rocuronium application (G. Barsotti, unpublished data, November 2013). Retraction was not performed in this study because proparacaine was applied to provide topical anesthesia before rocuronium administration; retraction in a nonsedated, medium-sized bird has the potential for traumatic complications as well. Subjectively, the birds seemed to blink the upper and lower eyelids more than the third eyelid after rocuronium administration in this study. Lack of retraction may have affected the volume of drug exposure and, ultimately, absorption in this study; however, given the degree of pupil dilation, it was not likely clinically significant.

Another variable that may have affected rocuronium absorption was application of proparacaine before rocuronium administration. Proparacaine contains benzalkonium chloride and EDTA as preservative agents, and both compounds also function as drug penetration enhancers. (13) Benzalkonium chloride enhances corneal absorption of medications by enlarging intercellular spaces in the superficial corneal layers as well as forming polar defects in the lipid layer of the cell membranes. (13) The agent EDTA enhances the effect of the benzalkonium chloride. (13) As a result, topical rocuronium bromide absorption was potentially increased. An increased absorption might explain the difference in onset of action and duration of action between this study and another study in Hispaniolan Amazon parrots. (11) Proparacaine was not used topically in the previous study in Hispaniolan Amazon parrots; however, onset of action was slower (20 minutes) and duration of action was shorter (420 minutes) despite holding the birds in lateral recumbency for 2 minutes after rocuronium application.

The dose of topical rocuronium used in this study was 0.3 mg (15 [micro]L) per eye. When based on weight, the dose used was a median of 0.5 mg/kg per eye (range 0.42-0.55 mg/kg) and was similar to or on the low end of the range of other studies evaluating topical rocuronium bromide in both eyes. The dose ranges were 0.48-0.6 mg/kg, 0.6-0.8 mg/kg, and 1.17-1.5 mg/kg per eye for European kestrels, common buzzards, and little owls, respectively. (8-10) A study evaluating topical application into 1 eye in tawny owls used a range of 0.7-2.0 mg/kg. (10) Given the lack of systemic side effects and efficacy, the dose used in this study is likely appropriate for mydriasis in Hispaniolan Amazon parrots.

Ocular irritation, local and systemic muscle paralysis, and respiratory distress were not identified in this study; however, superficial corneal ulceration developed in 2 study birds. Because one of the birds also had associated bruising, this is likely a side effect associated with capture and restraint. Superficial corneal ulceration was not documented in previous studies; however, corneal irritation secondary to drug administration cannot be ruled out, especially given the acidity of the medication. (8-10) According to the manufacturer, the rocuronium solution is adjusted to isotonicity with sodium chloride and to a pH of 4 with acetic acid and/or sodium hydroxide. (14) For ophthalmic medications, ideal pH is 7.2-7.4, and a pH outside the range of 6-8 is likely to cause discomfort. (15) A pH of 4 would be expected to cause discomfort; however, no signs of irritation were observed after administration (lacrimation, blepharospasm, conjunctival hyperemia, or chemosis). Lack of clinical signs may be caused by topical proparacaine and the local anesthetic effects before rocuronium application. Rocuronium bromide, when administered intravenously in humans, has been documented to cause discomfort associated with injection. (16) Additional studies need to be performed to evaluate adverse effects associated with topical rocuronium bromide use in avian patients.

Another adverse effect to consider with induction of mydriasis is retinal light toxicity, especially in this study, since the duration of mydriasis was prolonged after topical administration of rocuronium in Hispaniolan Amazon parrots. This phenomenon has been well documented in laboratory species and people under a variety of natural and iatrogenic circumstances. (17,18) Factors that influence retinal toxicity include the quality, exposure duration, and intensity of light, and age and body temperature of the animal. (17) Studies evaluating the protective effect of pupillary constriction showed retinal damage after mydriasis with cycled ambient illumination. (19) The birds in this study were covered with towels between time points, and the room was darkened during restraint for evaluation. Care should be taken to prevent unnecessary light exposure with prolonged mydriasis.

This study demonstrated that rocuronium bromide was an effective mydriatic agent in Hispaniolan Amazon parrots and had rapid onset and prolonged duration of action. Systemic adverse effects were not documented; however, superficial corneal ulceration was noted in 2 birds. Additional studies need to be performed to evaluate the safety of this drug before clinical use in other species.

Katherine Baine, DVM, Dipl ABVP (Avian), Diane V. H. Hendrix, DVM, Dipl ACVO, Sonia E. Kuhn, DVM, Dipl ACVO, Marcy J. Souza, MPH, DVM, Dipl ABVP (Avian), Dipl ACVPM, and Michael P. Jones, DVM, Dipl ABVP (Avian)

From the Departments of Small Animal Clinical Sciences (Baine, Hendrix. Kuhn, Jones) and Biomedical and Diagnostic Sciences (Souza), College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA. Present address: Animal Emergency and Specialty Center, 10213 Kingston Pike, Knoxville, TN 37922, USA (Baine); Upstate Veterinary Specialists, 393 Woods Lake Road, Greenville, SC 29607, USA (Kuhn).

Acknowledgments: We thank Misty Bailey for editorial support and Dr Agricola Odoi for statistical consultation.

References

(1.) Oliphant LW, Johnson MR, Murphy C, Howland H. The musculature and pupillary response of the great horned owl iris. Exp Eve Res. 1983;37(6):583-595.

(2.) Peirone SM, Sisto-Daneo L, Filogamo G. Embryogenesis of the avian iris sphincter muscle: in vivo and in vitro studies. Int J Dev Neurosci. 1990;8(1): 17-31.

(3.) Campell HS, Smith JL. The pharmacology of the pigeon pupil. Arch Ophthalmol. 1962;67:501-504.

(4.) Loerzel SM, Smith PJ, Howe A, Samuelson DA. Vecuronium bromide, phenylephrine and atropine combinations as mydriatics in juvenile double-crested cormorants (Phalacrocorax auritus). Vet Ophthalmol. 2002;5(3): 149-154.

(5.) Ramer JC, Paul-Murphy J, Brunson D, Murphy CJ. Effects of mydriatic agents in cockatoos, African gray parrots, and blue-fronted Amazon parrots. J Am Vet Med Assoc. 1996;208(2):227-230.

(6.) Verschueren CP, Lumeij JT. Mydriasis in pigeons (Columbia livia domestica) with d-tubocurarine: topical instillation versus intracameral injection. J Vet Pharmacol Ther. 1991 ;14(2):206-208.

(7.) Mikaelian I, Paillet I, Williams D. Comparative use of various mydriatic drugs in kestrels (Falco tinnunculus). Am J Vet Res. 1994;55(2):270-272.

(8.) Barsotti G, Briganti A, Spratte JR, et al. Safety and efficacy of bilateral topical application of rocuronium bromide for mydriasis in European kestrels (Falco tinnunculus). J Avian Med Surg. 2012;26(1): 1-5.

(9.) Barsotti G, Briganti A, Spratte JR, et al. Bilateral mydriasis in common buzzards (Buteo buteo) and little owls (Athene noctua) induced by concurrent topical administration of rocuronium bromide. Vet Ophthalmol. 2010; 13(Suppl):35-40.

(10.) Barsotti G, Briganti A, Spratte JR. et al. Mydriatic effect of topically applied rocuronium bromide in tawny owls (Strix aluco): comparison between two protocols. Vet Ophthalmol. 2010; 13{Suppl):9-13.

(11.) Petritz OA, Guzman DSM, Gustavsen KA, et al. Evaluation of the mydriatic effects of topical administration of rocuronium bromide in Hispaniolan Amazon parrots (Amazona ventralis). Proc Annu Conf Assoc Avian Vet. 2014:13-14.

(12.) Storey ES, Carboni DA, Kearney MT, Tully TN. Use of phenol red thread tests to evaluate tear production in clinically normal Amazon parrots and comparison with Schirmer tear test findings. J Am Vet Med Assoc. 2009;235(10): 1181-1187.

(13.) Regnier A. Clinical pharmacology and therapeutics. Part 1: drug delivery and pharmacokinetics. In: Gelatt KN, Gilger BC, Kern TJ, eds. Veterinary Ophthalmology. 5th ed. Vol 1. Ames, 1A: Wiley-Blackwell; 2013:351-380.

(14.) Highlights of prescribing information. ZEMURON (rocuronium bromide) injection solution for intravenous use. Merck Web site. http://www.merck. com/product/usa/pi_circulars/z/zemuron/ zemuron_pi.pdf. Accessed July 21, 2014.

(15.) Abelson MB, Gifford S, Chapin M. Pharmacokinetics: what you need to know. Rev Ophthalmol. 2002;9:60-63.

(16.) Singh M, Chauhan H, Rath GP, et al. Effect of narcotic pretreatment on pain after rocuronium injection: a randomized, double-blind controlled comparison with lidocaine. J Anesth. 2007;21(4):510-512.

(17.) Mudry MCDV, Kronenberg S, Komatsu SI, Aguirre GD. Blinded by the light: retinal phototoxicity in the context of safety studies. Toxicol Pathol. 2013;41 (6):813-825.

(18.) Youssef PN, Sheibani N, Albert DM. Retinal light toxicity. Eye. 2010;25(1): 1-14.

(19.) Williams RA, Howard AG, Williams TP. Retinal damage in pigmented and albino rats exposed to low levels of cyclic light following a single mydriatic treatment. Curr Eye Res. 1985;4(2):97-102.
Table 1. Mean pupil diameter of Hispaniolan Amazon
parrots (N =10) after application of rocuronium at time
0 minutes.

                     Median pupil
                     diameter, mm
Time, min    (1st quartile, 3rd quartile)   P value (a)

0                   3.3 (3.1, 3.6)
5                   4.3 (4.2, 4.4)             .011
10                  4.4 (4.3, 4.6)             .005
20                  4.5 (4.5, 4.6)             .005
30                  4.6 (4.6, 4.7)             .005
40                  4.6 (4.5, 4.7)             .005
50                  4.8 (4.6, 4.8)             .005
60                  4.8 (4.7, 4.8)             .005
80                  4.8 (4.6, 4.9)             .005
100                 4.8 (4.6, 4.9)             .008
120                 4.8 (4.6, 4.9)             .005
140                 4.7 (4.6, 4.9)             .005
160                 4.7 (4.6, 4.9)             .005
180                 4.8 (4.7, 5.0)             .005
200                 4.7 (4.6, 5.0)             .005
220                 4.8 (4.8, 4.9)             .005
240                 4.8 (4.7, 4.9)             .005
300                 4.8 (4.5, 4.9)             .005
360                 4.8 (4.4, 5.0)             .005
1440                3.5 (3.3, 3.8)             .017

(a) P <.05. statistically significant versus baseline (time 0).
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Title Annotation:Original Study
Author:Baine, Katherine; Hendrix, Diane V.H.; Kuhn, Sonia E.; Souza, Marcy J.; Jones, Michael P.
Publication:Journal of Avian Medicine and Surgery
Article Type:Report
Date:Mar 1, 2016
Words:3836
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