Abstract
This study assessed the effects of a combination of dexmedetomidine and butorphanol on the Schirmer tear test I (STT I) values in dogs. Ninety-eight dogs were sedated with an intramuscular injection of a combination of dexmedetomidine, 5 μg/kg body weight (BW), and butorphanol, 0.2 mg/kg BW. The effects of dexmedetomidine were reversed by administering atipamezole at the end of the procedure. The combination of dexmedetomidine and butorphanol significantly decreased tear production 15 minutes after sedation. The STT I values 15 minutes after reversal of dexmedetomidine with atipamezole were significantly higher than the STT I values 15 minutes after sedation but were significantly lower than the STT I values before sedation. Gender, weight, duration of sedation, right or left eye did not affect STT I values after sedation. It is recommended that dogs sedated with a combination of dexmedetomidine and butorphanol be treated with a tear substitute to combat decreased tear production.
Résumé
Effet de l’association dexmédétomidin-butorphanol intramusculaire sur la production lacrymale chez le chien. L’étude vise à déterminer les effets de l’association dexmédétomidine-butorphanol sur les résultats du test de Schirmer I (STT I) chez le chien. Quatre-vingt-dix-huit chiens ont été sédatés avec l’association dexmédétomidine (5 μg/kg) butorphanol (0,2 mg/kg) intramusculaire. La dexmédétomidine a été antagonisée avec de l’atipamezole en fin de procédure. L’association dexmédétomidine-butorphanol diminue significativement la production lacrimale 15 minutes post-sédation. Les valeurs de STT I 15 minutes post-antagonisation de la dexmédétomidine étaient significativement plus élevées que celles de STT I 15 minutes post-sédation, mais significativement inférieures aux STT I pré-sédation. Les variables genre, poids, durée de la sédation, oeil droit/gauche, n’ont pas significativement influencé les valeurs de STT I post-sédation. L’association dexmédétomidine-butorphanol diminuant significativement leur production lacrimale il est recommandable de traiter les chiens avec des substituts lacrimaux pour éviter la sécheresse oculaire.
(Traduit par les auteurs)
Introduction
The tear film allows the cornea to act as an optical surface for the refraction of light, allows the mechanical removal of debris and bacteria, and lubricates the conjunctiva and nictitating membrane (1). It contributes to the immunity of the ocular surface by releasing secretory immunoglobulin A, albumin, lipocalin, interleukins, and antibacterial compounds (lysozyme and lactoferrin) and plays an important metabolic role in bringing nutrients to the avascular portion of the cornea (1).
The Schirmer tear test (STT) is widely used in veterinary ophthalmology as a basic assessment of tear production. The STT I measures the basal and reflex tear production and is the most commonly used. The STT II measures basal tear production after the topical application of an anesthetic and is used in animals with corneal ulceration (1). Although STT I values greater than 25 mm/min may be physiologic in dogs, STT I measurements are commonly considered normal if they range within 15 to 25 mm/min (1).
In dogs, decrease in tear production is due to genetic (2), individual, or acquired factors (3), and medication. Antibiotics (4,5), nonsteroidal anti-inflammatory drugs, and anticholinergics reduce tear production and may cause corneal dryness in dogs (6–8). It is well-known that tranquilizers, sedatives, opioids, and general anesthetic drugs affect tear production and intraocular pressure in dogs and horses (9–12). Although the decrease in tear production due to sedation or anesthesia is transient, it may lead to clinical disorders, such as corneal erosions and ulcers, which affect vision and cause discomfort (9).
Butorphanol is a κ-opioid receptor agonist and a μ-opioid receptor antagonist with analgesic and sedative properties. It induces mild or moderate sedation and causes minimal changes in cardiovascular function. A single dose of butorphanol of 0.5 mg/kg body weight (BW) significantly reduces tear production (10).
Dexmedetomidine is the dextrorotatory S-enantiomer of medetomidine and has sedative and analgesic properties (13). This drug was developed to reduce the side effects of medetomidine. In fact, even though the levorotatory isomer is not pharmacologically active, it influences the pharmacokinetics and pharmacodynamics of dexmedetomidine. The absence of the levorotatory isomer reduces the hepatic metabolic load and side effects (14). Nevertheless, the dextrorotatory isomer causes bradycardia, decreases cardiac output, and increases systemic vascular resistance (13). In dogs, dexmedetomidine causes miosis following direct inhibition of parasympathetic stimulation of the iris and reduces intraocular pressure by the activation of the α2 receptors in the iris (15).
The combination of an α2-agonist with butorphanol provides deep sedation for diagnostic and clinical procedures that is completely reversible with the use of antidotes (16). The combination of medetomidine and butorphanol significantly decreases tear production in dogs (17) but, the authors are not aware of any data on the effect of the pharmacologically active dextrorotatory isomer of medetomidine used in combination with butorphanol on aqueous tear production. The aim of this study was to evaluate the effect of a combination of dexmedetomidine and butorphanol on tear production as assessed with the Schirmer tear test I (STT I) in dogs and to evaluate the influence of gender, weight, duration of sedation and right or left eye on the STT I values after sedation.
Materials and methods
Animals
The study was performed in accordance with Legislative Decree n. 26 from March 4, 2014, under Italian Animal Welfare Legislation. The owners signed a voluntary informed consent form before enrollment of the dogs.
The inclusion criteria for this study were: patients undergoing a clinic visit, radiologic or ultrasonographic assessment, age > 1 y, no history of previous ocular disease, and no drug therapy, sedation, or anesthesia in the previous 3 mo.
Ophthalmic examination
An ocular examination was performed before sedation in an enclosed space under the same conditions of light, temperature (20°C), and relative humidity (55%). It consisted of a Schirmer tear test I (STT I) and a slit lamp examination (KOWA SL-17, Düsseldorf, Germany). The same experienced veterinarian performed all the ocular examinations, and the same Schirmer tear test I strips (Schirmer tear test; Schering Plough, Milan, Italy) were used. The strip was inserted into the lateral third of the inferior conjunctival fornix and was adhered to the cornea to avoid interference of the nictitating membrane for 1 min in each eye. Dogs with abnormalities of the ocular surface or with STT I values lower than 15 mm/min or higher than 25 mm/min (in compliance with the product labeling of the STT I strips used) were withdrawn from the study.
The STT I measurements were performed before sedation, 15 min after administration of the combination of dexmedetomidine and butorphanol, and 15 min after the injection of atipamezole. All the STT I measurements were recorded between 8:00 am and 12:00 am.
Sedation protocol
Dogs underwent physical examinations in order to classify them according to the American Society of Anesthesiologists (ASA) physical status classification system. Dogs with an ASA status ≥ 3 were withdrawn from the study.
Dogs were sedated with an intramuscular (IM) injection of dexmedetomidine (Dexdomitor; Orion Pharma, Milan, Italy), 5 μg/kg BW, combined with butorphanol (Dolorex; Intervet, Milan, Italy), 0.2 mg/kg BW, into the quadriceps muscle. The action of dexmedetomidine was completely reversed by administering atipamezole (Atipam; ATI, Ozzano dell’Emilia, Bologna, Italy), 50 μg/kg BW, into the quadriceps muscle at the end of the procedure. The duration of sedation, which was defined as the time from the administration of sedation to the injection of atipamezole, was recorded.
Data analysis
The data were analyzed with analysis of variance (ANOVA) by means of the general linear model (GLM) procedure in SAS (Version 9.4, 2012; SAS Institute, Carey, North Carolina, USA) (18); the fixed factors included sedation (before sedation, 15 min after sedation, and 15 min after the administration of atipamezole), gender (intact females, spayed females, intact males, neutered males), body weight (< 10 kg, 10 to 19.9 kg, 20 to 29.9 kg, ≥ 30 kg), duration of sedation (< 60 min, ≥ 60 min) and eye (right eye, left eye). The age (months) of the dogs was considered a covariate. The STT I values were reported as the least-squares means (LSMeans) ± standard error (SE). The age, weight, and duration of sedation were expressed as the mean ± standard deviation (SD). P-values < 0.05 were considered significant.
Results
Ninety-eight dogs met the inclusion criteria of the study. The dogs belonged to 33 breeds; their physical characteristics are reported in Table 1. The mean duration of sedation was 52.57 ± 11.41 min (Table 1). No side effects were recorded in the sedated dogs. All patients recovered and were ambulatory within 15 min after the administration of atipamezole.
Table 1.
Physical characteristics of dogs included in the study.
| Gender | |
| Number of intact females | 16 |
| Number of spayed females | 31 |
| Number of intact males | 28 |
| Number of neutered males | 23 |
| Age (y) | |
| Mean ± standard deviation | 5.2 ± 2.8 |
| Range | 1 to 11 |
| Body weight (kg) | |
| Mean ± standard deviation | 18.21 ± 9.66 |
| Range | 6 to 66 |
| Number of dogs weighing < 10 kg | 33 |
| Number of dogs weighing 10 to 19.9 kg | 23 |
| Number of dogs weighing 20 to 29.9 kg | 27 |
| Number of dogs weighing ≥ 30 kg | 15 |
| Duration of sedation (min) | |
| Mean ± standard deviation | 52.57 ± 11.41 |
| Range | 30 to 87 |
| Number of dogs with a duration of sedation < 60 min | 73 |
| Number of dogs with a duration of sedation ≥ 60 min | 25 |
Before sedation, the STT I values were significantly higher (P = 0.03) in intact females than in spayed females (Table 2). There were no significant differences with regard to the right or left eye and body weight before sedation (Table 2). Fifteen minutes after sedation, the STT I values were significantly (P = 0.0001) decreased (Table 3) and there were no significant differences in the STT I values related to gender, right or left eye or body weight (Table 2).
Table 2.
STT I values (mm/min) related to gender, eye, body weight, and duration of sedation.
| Before sedation | 15 min after sedation | 15 min after atipamezole | |
|---|---|---|---|
| Gender | |||
| Intact females | 20.84 ± 0.49c,d | 10.07 ± 0.56a | 13.84 ± 0.59b |
| Spayed females | 22.07 ± 0.39c,e | 9.92 ± 0.45a | 14.09 ± 0.48b |
| Intact males | 21.49 ± 0.39c | 9.68 ± 0.43a | 14.72 ± 0.46b |
| Neutered males | 21.88 ± 0.42c | 9.63 ± 0.48a | 13.46 ± 0.51b |
| Eye | |||
| Right eye | 21.54 ± 0.27c | 9.84 ± 0.54a | 13.89 ± 0.31b |
| Left eye | 21.96 ± 0.38c | 9.91 ± 0.54a | 13.57 ± 0.45b |
| Body weight (kg) | |||
| < 10 | 21.13 ± 0.42c | 10.40 ± 0.47a | 14.98 ± 0.49b,f |
| 10 to 19.9 | 21.39 ± 0.47c | 9.36 ± 0.52a | 12.88c ± 0.56b,d |
| 20 to 29.9 | 22.14 ± 0.42c | 10.23 ± 0.47a | 14.63 ± 0.49b,e |
| ≥ 30 | 21.60 ± 0.72c | 9.26 ± 0.81a | 13.56 ± 0.86b |
| Duration of sedation (min) | |||
| < 60 | 21.45 ± 0.25c | 9.82 ± 0.28a | 14.12 ± 0.29b |
| ≥ 60 | 21.69 ± 0.40c | 9.82 ± 0.45a | 13.91 ± 0.48b |
Data are expressed as the least-squares means (LSMeans) ± standard error (SE).
In the same row, the different superscripts indicate significantly different results (P < 0.05). The alphabetical order indicates the order of the data.
In the same column, the different superscripts indicate results that were significantly different (P < 0.05). The alphabetical order indicates the order of the data.
Table 3.
Aqueous tear production as evaluated with STT I (mm/min) before sedation, 15 min after sedation with a combination of dexmedetomidine and butorphanol, and 15 min after the injection of atipamezole.
| Before sedation | 15 min after sedation | 15 min after atipamezole | |
|---|---|---|---|
| STT I values (mm/min) | 21.53 ± 0.24c | 10.03 ± 0.24a | 14.05 ± 0.24b |
Data are expressed as the least-squares means (LSMeans) ± standard error (SE).
Different superscripts indicate results that were significantly different (P < 0.05).
Fifteen minutes after the injection of atipamezole, the STT I values were significantly higher (P = 0.0001) than the STT I values 15 min after sedation, but were significantly lower (P = 0.0001) than the values before sedation (Table 3); there were no significant differences in the STT I values related to gender, right or left eye, body weight, or duration of sedation (Table 2). Fifteen minutes after the injection of atipamezole, the STT I values were significantly lower in dogs weighing 10 to 19.9 kg compared to dogs weighing < 10 kg (P = 0.0056) and those weighing 20 to 29.9 kg (P = 0.0011) (Table 2).
Discussion
This study showed that administration of a combination of dexmedetomidine and butorphanol is associated with decreased aqueous tear production in dogs. Fifteen minutes following the administration of atipamezole, tear production increased, but the STT I values stayed below 15 mm/min even if dogs were able to walk.
Environmental and individual factors affect tear production (18–20). To reduce the influence of the ambient conditions, all the STT I measurements were performed under the same environmental conditions between 8:00 am and 12:00 am, even though the time of day does not appear to affect the STT I values in normal dogs (20,21).
Dogs with an ASA status ≥ 3 were excluded because a high ASA status often implies a greater degree of nociception. Pain pathways may alter functions of various organs and systems including the lacrimal apparatus (16), and it is not possible to predict the effects of the pain on aqueous tear production. Additionally, a poor physical status increases anesthetic risk and a dexmedetomidine-butorphanol combination is not indicated for high-risk patients because it may lead to significant cardiac, hemodynamic, and respiratory side effects (14,16).
Many reports proved that butorphanol, medetomidine, and combinations of these medications significantly reduce tear production (10,17,22). Medetomidine is a mixture of 2 optical enantiomers, dexmedetomidine and levomedetomidine. Levomedetomidine reduces the sedative and analgesic effects of dexmedetomidine and increases bradycardia (13,14). Consequently, the administration of dexmedetomidine alone may have some cardiovascular benefits over the administration of medetomidine (13). Based on the pharmacodynamics of dexmedetomidine and considering the low dose of butorphanol used in the present report compared with previous studies (10,17), we assumed that the combination of dexmedetomidine and butorphanol would not affect tear production. In contrast, our results highlight a significant reduction in aqueous tear production. A probable reason for the decreased measurable tear production is the evaporative loss caused by the sedative effects of the combination of dexmedetomidine and butorphanol, which reduces blinking (16). Therefore, the aqueous layer of the tear film can evaporate more.
Based on a previous report that demonstrated that the combination of morphine with acepromazine altered canine lacrimal gland metabolism (9), another explanation for the reduction in the STT I values is a potential alteration in the metabolism of the lacrimal glands. Nevertheless, in our opinion, the neuro-physiological mechanisms and hemodynamic changes were the most likely causes of the reduction in the tear film. We suggest that the postsynaptic activation of α-adrenoceptors in the central nervous system (CNS) due to dexmedetomidine and the changes in sympathetic activity due to butorphanol may have decreased basal tear production (10,23–25). Furthermore, the reduction in the STT I values could also be due to the decrease in reflex tear production mediated by diminished nociceptive transmission. In fact, α2-agonists modulate the transmission of nociceptive signals in the CNS, and opioids synergistically act by reducing nociceptive transmission (26).
Dexmedetomidine and butorphanol cause systemic and local hemodynamic changes (10,14,16,22). Dexmedetomidine commonly induces a decrease in heart rate and blood pressure, whereas butorphanol alone is responsible for small decreases in heart rate and blood pressure (14,16). The combination of an α2-agonist with an opioid synergistically affects hemodynamic parameters (26). Thus, it is likely that the combination of dexmedetomidine and butorphanol induces mild hypotension that is responsible for decreased perfusion of the lacrimal glands followed by a consequent decrease in aqueous tear production.
We cannot clearly ascribe the increased STT I values to the reversal of the sedative effects of dexmedetomidine with atipamezole. Nevertheless, based on the dose-dependent duration of the sedative effect of dexmedetomidine (13,14), it is likely that the effect of dexmedetomidine was still present when atipamezole was administered. Consequently, the reversal of dexmedetomidine sedation with atipamezole is a possible reason for the increased measurable tear production.
Based on the duration of action of butorphanol (16), it is likely that the effect of butorphanol was still present after the administration of atipamezole. Therefore, the STT I values after the administration of atipamezole that were lower than baseline values highlight the fact that butorphanol plays an important role in decreased tear production. The pharmacokinetics of butorphanol suggest that the STT I values can return to baseline values within 3 to 4 h after sedation (10,16).
Breed, age, gender, and weight may affect aqueous tear production (3,19,24). The influences of breed and age could not be evaluated herein because of the heterogeneous sample. To limit the influence of age, we included dogs that were older than 1 y because only these patients have complete physiological blinking and regular tear production.
The influence of gender on tear production has been widely discussed by researchers. In humans, aqueous tear production decreases after menopause in women (27), and the use of antiandrogenic substances predisposes men to dry eyes (28). Neutered dogs of both sexes show decreased tear production, whereas only spayed females show a higher incidence of keratoconjunctivitis sicca (18). In the present study, gender did not influence changes in the STT I values, but spayed females showed higher basal STT I values and a more marked reduction in tear production than did intact females. Therefore, it is likely that canine sex hormones may affect basal tear production, but further studies are needed.
Regarding body weight, the veterinary literature has reported greater tear production in heavier dogs than in lighter ones (18). In the present report, this variable did not affect either baseline STT I values or decreased STT I values after sedation. Surprisingly, after the administration of atipamezole, the STT I readings showed significant differences between the body weight classes. We suggest that tear production may have been affected by the different body composition rather than the body weight. Canine breeds show marked differences in percentages of body fat even when the body condition score and body weight are the same (29). The amount of fat influences drug metabolism, recovery from sedation, and all the effects caused by the sedation protocol, including reduced tear production (30).
In conclusion, the combination of dexmedetomidine and butorphanol was associated with decreased aqueous tear production and differences in the STT I values were not related to gender, weight, duration of sedation, and right or left eye. Reversal of dexmedetomidine with atipamezole is associated with increased values, but the STT I readings do not return to baseline values. Therefore, it is recommended that dogs be treated with a tear substitute to combat a significant reduction in tear production associated with sedation using intramuscular dexmedetomidine and butorphanol. Tear substitutes must be administered just before sedation and after recovery.
Acknowledgments
The authors thank the Veterinary Clinic of Doctor Paolo Rosi, Rezzato, Brescia, Italy, for the collaboration. We thank Mr. Giuseppe Bertaccini for proofreading our manuscript and for his technical support. The authors remember Stefano Zanichelli, full professor of veterinary surgery who passed away on 9th December 2015. We thank him for, over the past years, working tirelessly to support scientific research. CVJ
Footnotes
Use of this article is limited to a single copy for personal study. Anyone interested in obtaining reprints should contact the CVMA office (hbroughton@cvma-acmv.org) for additional copies or permission to use this material elsewhere.
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