or doxapram on laryngeal motion and quality of examination in dogs

Veterinary Anaesthesia and Analgesia 2018, xxx, 1e9

https://doi.org/10.1016/j.vaa.2017.08.014

RESEARCH PAPER

Comparison of the effects of alfaxalone and propofol with acepromazine, butorphanol and/ or doxapram on laryngeal motion and quality of examination in dogs Denise I Radkeya, Robert J Hardieb & Lesley J Smithb a

University of Wisconsin Veterinary Care, Section of Anesthesia and Pain Management, School of Veterinary Medicine, University of Wisconsin, Madison, WI, USA b

Department of Surgical Sciences, School of Veterinary Medicine, University of Wisconsin,

Madison, WI, USA Correspondence: Lesley J Smith, Department of Surgical Sciences, 2015 Linden Drive, University of Wisconsin School of Veterinary Medicine, Madison, WI 53706, USA. E-mail: [email protected]

Abstract Objective To compare the effects of alfaxalone and propofol, with and without acepromazine and butorphanol followed by doxapram, on laryngeal motion and quality of laryngeal examination in dogs. Study design Randomized, study.

crossover,

blinded

Animals Ten female Beagle dogs, aged 11e13 months and weighing 7.2e8.6 kg. Methods The dogs were administered four intravenous (IV) treatments: alfaxalone (ALF), alfaxalone þ acepromazine and butorphanol (ALFeAB), propofol (PRO) and propofol þ AB (PROeAB). AB doses were standardized. Dogs were anesthetized 5 minutes later by administration of alfaxalone or propofol IV to effect. Arytenoid motion during maximal inspiration and expiration was captured on video before and after IV doxapram (0.25 mg kg1). The change in rima glottidis surface area (RGSA) was calculated to measure arytenoid motion. An investigator blinded to the treatment scored laryngeal examination quality. Results A 20% increase in RGSA was the minimal arytenoid motion that was detectable. RGSA was significantly less in ALF before doxapram compared with all other treatments. A <20% increase in RGSA was measured in eight of 10 dogs in PRO and in all dogs in ALF before doxapram. After doxapram, RGSA was significantly increased

for PRO and ALF; however, 20% of dogs in PRO and 50% of dogs in ALF still had <20% increase in RGSA. A <20% increase in RGSA was measured in five of 10 dogs in PROeAB and ALFeAB before doxapram. All dogs in PROeAB and ALFeAB with <20% increase in RGSA before doxapram had 20% increase in RGSA after doxapram. Examination quality was significantly better in PROeAB and ALFeAB. Conclusions and clinical relevance The use of acepromazine and butorphanol improved the quality of laryngeal examination. Any negative impact on arytenoid motion caused by these premedications was overcome with doxapram. Using either propofol or alfaxalone alone is not recommended for the evaluation of arytenoid motion. Keywords acepromazine, alfaxalone, butorphanol, canine, laryngeal function, propofol. Introduction Laryngeal paralysis is a common respiratory abnormality in older large breed dogs (Gaber et al. 1985; White 1989; Broome et al. 2000; Rudorf et al. 2001). One method for the diagnosis of laryngeal paralysis is direct observation of the lack of arytenoid motion during deep inspiration and expiration. The ideal anesthetic protocol for laryngeal examination would result in an adequate anesthetic depth to allow jaw relaxation sufficient enough to position a laryngoscope for the examination of the larynx while 1

Please cite this article in press as: Radkey DI, Hardie RJ, Smith LJ Comparison of the effects of alfaxalone and propofol with acepromazine, butorphanol and/or doxapram on laryngeal motion and quality of examination in dogs, Veterinary Anaesthesia and Analgesia (2018), https://doi.org/10.1016/j.vaa.2017.08.014

Protocol for laryngeal examination in dogs DI Radkey et al.

maintaining intact laryngeal reflexes. It is crucial that the anesthetic agent does not inhibit arytenoid motion to avoid a false positive diagnosis of laryngeal paralysis. A challenge in administering anesthesia for a laryngeal examination is that even light anesthesia may result in apnea or shallow inspirations, confounding an accurate diagnosis. When the plane of anesthesia lightens and deep inspirations have returned, the dog is often too awake to allow laryngoscopy. Several anesthetic protocols have been examined for their effect on arytenoid motion in dogs without (Gross et al. 2002; Jackson et al. 2004) and with doxapram (McKeirnan et al. 2014). While the methodologies differ, thiopental was suggested as the drug of choice for laryngeal examination (Jackson et al. 2004). Thiopental is not available in the USA; therefore, propofol is the most commonly administered drug for laryngeal examination. Alfaxalone, recently available in the USA, is an injectable anesthetic with effects similar to those of propofol (Ambros et al. 2008). Alfaxalone results in similar induction quality but a less desirable recovery than propofol when administered to unpremedicated dogs (Maney et al. 2013). Alfaxalone administered to premedicated cats provided a good quality laryngeal examination with normal arytenoid motion (Nelissen et al. 2012). In that study, the normalized glottal gap area was not different between alfaxalone, propofol or ketamineediazepam. However, no arytenoid motion was observed in some cats anesthetized with ketamineediazepam or propofol despite chest excursions and obvious breathing, whereas all cats administered alfaxalone displayed arytenoid motion throughout the examination (Nelissen et al. 2012). A direct comparison of alfaxalone and propofol for laryngeal examination in dogs was recently published (Smalle et al. 2017); however, arytenoid motion was not evaluated via laryngoscopy, but rather by direct observation. The objectives of this study were to evaluate arytenoid motion, the quality of laryngeal examination and the effect of doxapram on arytenoid motion in normal dogs anesthetized with either alfaxalone or propofol, with or without premedication with acepromazine and butorphanol. We hypothesized that alfaxalone would provide a similar quality of laryngeal examination and have an equivalent effect on arytenoid motion compared with propofol, that these specific premedications would improve the quality of the laryngeal examination, and that doxapram administration would increase arytenoid motion in all anesthetic treatments. 2

Methods Animals A group of 10 young adult purpose-bred female Beagle dogs were studied. A power calculation revealed that nine dogs per treatment would allow a ¼ 0.05 and b ¼ 0.2, with 80% power, to show a 50% difference in rima glottidis surface area (RGSA) between treatments. Dogs weighed 7.2e8.6 kg and were aged 11e13 months. Normal health status was assessed by physical examination and measured packed cell volume (PCV) and total protein (TP) within normal reference ranges. The dogs were obtained from a commercial facility, and the study was approved by the Institutional Animal Care and Use Committee of Ridglan Laboratories, Inc. (Ridglan Laboratories, Inc., WI, USA) where the study was performed. Study design and experimental protocol The 10 dogs were assigned to four anesthetic treatments in a randomly assigned crossover design (Research Randomizer; www.researchrandomizer. com). The four treatments included: alfaxalone þ saline (treatment ALF), alfaxalone þ acepromazine and butorphanol (treatment ALFeAB), propofol þ saline (treatment PRO) and propofol þ acepromazine and butorphanol (treatment PROeAB). A minimum of 7 days elapsed between treatments. The dogs were housed in the facility where the study was performed; therefore, no acclimation time was required. Food, but not water, was withheld for 12 hours before each study day. Prior to the start of each treatment, a 20 gauge catheter was placed in a cephalic vein. Oxygen saturation of hemoglobin (SpO2) was estimated with a pulse oximetry probe placed on the pinna (Vetcorder; Sentier Health Connect LLC, WI, USA). Heart rate (HR) was measured by palpation of the femoral artery, and respiratory rate (fR) was measured by observing thoracic excursions. Each variable was recorded before administration of any treatment and after laryngoscopy was completed. In ALFeAB and PROeAB, acepromazine (0.03 mg kg1; acepromazine maleate; VetOne, ID, USA) and butorphanol (0.2 mg kg1; Torbugesic; Fort Dodge Animal Health, NY, USA) were administered intravenously (IV), and in ALF and PRO, 0.3 mL saline (0.9% NaCl; Hospira Inc., IL, USA) was administered IV. After 5 minutes, either propofol (0.5 mg kg1; Diprivan; Fresenius Kabi, IL, USA) or

© 2018 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., ▪, 1e9

Please cite this article in press as: Radkey DI, Hardie RJ, Smith LJ Comparison of the effects of alfaxalone and propofol with acepromazine, butorphanol and/or doxapram on laryngeal motion and quality of examination in dogs, Veterinary Anaesthesia and Analgesia (2018), https://doi.org/10.1016/j.vaa.2017.08.014

Protocol for laryngeal examination in dogs DI Radkey et al.

alfaxalone (0.5 mg kg1; Alfaxan with preservative; Jurox, NSW, Australia) was administered IV over 15 seconds. Subsequently, additional supplements of propofol or alfaxalone, respectively, were manually administered IV over 15 seconds until there was sufficient jaw relaxation to safely insert a Miller laryngoscope blade within 30 seconds from the end of the last supplement administration. In response to any purposeful movement of the limbs or head, coughing, gagging or any other events that did not allow video laryngoscopy, additional propofol (0.25 mg kg1) or alfaxalone (0.2 mg kg1) was administered IV over 1e2 seconds. Laryngoscopy was performed as described below before and after administration of doxapram (0.25 mg kg1; Doxapram HCl Injection; West-Ward Pharmaceutical Corp., NJ, USA) IV. Laryngoscopy After the induction of anesthesia, the dog was positioned in sternal recumbency, the jaw opened and the maxillary canines positioned on a metal rack to suspend the head and allowing a view of the larynx. A tongue depressor was placed between the maxillary incisors and the metal rack to lift the soft palate. A rigid 7 mm digital video-endoscope (Digital Endoscope Model Y002; Supereyes Tech Co. Ltd, Guangdong, China) was positioned on the blade of a Miller laryngoscope. The laryngoscope blade was placed gently on the dorsal surface of the base of the epiglottis to allow a view of the larynx. The laryngoscope blade and its positioning was the same for all dogs. The tip of the laryngoscope blade was marked with a 7 mm line that was used for calibrating the surface area of the rima glottidis. Video recordings of at least five complete maximal inspirations and expirations were obtained after administration of the treatment and approximately 15e30 seconds after administration of doxapram. Maximal inspiratory and expiratory efforts were announced by an assistant who was manually restraining and observing the dog and who was not involved in video recording. It was during these maximal efforts that footage was recorded and marked with the dog identification number. The recordings were saved for future analysis on a computer (Dell Latitude E5550; Dell Corporation, TX, USA) connected to the digital endoscope. The number of events of coughing, gagging or struggling were recorded during the examination and were translated into an overall examination quality rating, where zero to one event indicated excellent

rating and six or more events indicated a poor rating (Appendix A). Immediately upon completion of the laryngeal examination, HR and fR were recorded. Apnea was defined as no breaths for  30 seconds. The dog recovered in a quiet room until normothermic ( 36.7  C) and was able to walk unassisted to the housing area. Objective image analysis Digital videos were imported and edited using an online program (Windows Live Movie Maker; Windows Vista Version 2.6, Microsoft Corporation, WA, USA). Still images of three maximal inspirations and three maximal expirations from separate breaths were captured by the same investigator (DR) for each treatment before and after doxapram administration for a total of 12 images per treatment. All images were selected during breath cycles where motion appeared to be at its maximum. The images were imported into a Java-based processing program (ImageJ; National Institute of Health, MD, USA) for surface area analysis. Each set of recordings was coded with a number unrelated to the treatment to mask the evaluator (DR) during image analysis. The 7 mm calibration line placed at the tip of the laryngoscope was visible in all images. This line was used to set the scale for measuring RGSA such that measurements were in mm2. RGSA of each set of three inspiratory and expiratory images before and after doxapram was calculated by digitally outlining the area of the rima glottidis (three times for each individual image), and the values were averaged as described above. Finally, the averaged surface areas for each of the three sets of inspiratory and three sets of expiratory images were averaged to create a total average surface area for inspiration and expiration for each treatment before and after doxapram. RGSA for each treatment was calculated using the formula: [(inspiratory measurement e expiratory measurement)/ expiratory measurement]  100.

Percent increase in RGSA was then compared before and after administration of doxapram within each treatment and among treatments. Once all measurements were obtained for each treatment, the videos were re-examined to determine the minimum increase in RGSA detectable with the naked eye. This value was 20%; thus, any increase in RGSA  20% was defined as clinically detectable arytenoid motion.

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Please cite this article in press as: Radkey DI, Hardie RJ, Smith LJ Comparison of the effects of alfaxalone and propofol with acepromazine, butorphanol and/or doxapram on laryngeal motion and quality of examination in dogs, Veterinary Anaesthesia and Analgesia (2018), https://doi.org/10.1016/j.vaa.2017.08.014

Protocol for laryngeal examination in dogs DI Radkey et al.

Statistical analysis Data were tested for normality (ShapiroeWilk test). Non-normally distributed data are reported as median (range). Comparisons of RGSA before and after doxapram administration were made within and between treatments. Data for RGSA were not normally distributed; therefore, the Friedman repeated measures analysis of variance (ANOVA) on ranks was used to compare RGSA among treatments before and after doxapram administration. A KruskaleWallis oneway ANOVA on ranks test was used to compare the differences in RGSA among treatments before and after doxapram for dogs with clinically detectable RGSA because numbers in each treatment were not equal. Statistical significance was set at p  0.05. All calculations were performed using SigmaStat (SyStat Software Inc., CA, USA). Results Physical examinations, PCV and TP were normal in all dogs. No dog showed any signs of laryngeal paralysis or other respiratory disease upon physical examination. The duration of laryngeal examination for all treatments was 5e14 minutes. None of the dogs developed apnea, and all 10 dogs completed all four treatments of the study. For each treatment before doxapram, median (range) increase in RGSA was 10% (0e24%) for PRO, 0% (0e9%) for ALF, 18.8% (0e151%) for PROeAB and 28% (0e182%) for ALFeAB. Treatment ALF had significantly less arytenoid motion than all other treatments (p ¼ 0.002).

Evaluation of the above digital data revealed that the percent increase in RGSA was minimal and unlikely to be identifiable by the naked eye for some dogs. Using the established criteria that a  20% increase in RGSA was necessary to accurately assess arytenoid motion by the naked eye, two of 10 dogs in PRO, no dogs in ALF, five of 10 dogs in PROeAB and five of 10 dogs in ALFeAB had clinically detectable arytenoid motion (Fig. 1). After doxapram administration, the median percent increase in RGSA was 60% (14e191%) for PRO, 26% (7131%) for ALF, 48% (9e233%) for PROeAB and 49% (7e232%) for ALFeAB. There was no significant difference in the percent increase in RGSA among treatments (p ¼ 0.75). Within treatments, there was a significant increase for PRO (p ¼ 0.006) and ALF (p ¼ 0.002) and no significant increase for PROeAB and ALFeAB (Fig. 2). Two of 10 dogs in PROeAB and one of 10 dogs in ALFeAB had <20% increase in RGSA after doxapram even though all three dogs had clinically detectable arytenoid motion before doxapram administration (Fig. 1). In these specific three dogs, no additional induction drug was administered before or after doxapram, and the arytenoid motion was paradoxical (i.e. adduction on inspiration and abduction on expiration). Of the five dogs in PROeAB and ALFeAB that had no clinically detectable arytenoid motion before doxapram, all had a  20% increase in RGSA after doxapram; median (range) 53% (26e233%) in PROeAB (p ¼ 0.04) and 83% (35e232%) in ALFeAB (p ¼ 0.03). Of the eight dogs in PRO without

Figure 1 Percent change in rima glottidis surface area (RGSA) between expiration and inspiration in 10 dogs administered propofol (PRO), alfaxalone (ALF), acepromazine-butorphanol-propofol (PROeAB), or acepromazine-butorphanol-alfaxalone (ALFeAB). The dotted line at 20% increase in RGSA is the limit below which arytenoid motion was clinically undetectable. *Significantly different from the other anesthetic protocols (p ¼ 0.002). 4

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Please cite this article in press as: Radkey DI, Hardie RJ, Smith LJ Comparison of the effects of alfaxalone and propofol with acepromazine, butorphanol and/or doxapram on laryngeal motion and quality of examination in dogs, Veterinary Anaesthesia and Analgesia (2018), https://doi.org/10.1016/j.vaa.2017.08.014

Protocol for laryngeal examination in dogs DI Radkey et al.

Figure 2 Percent change in rima glottidis surface area (RGSA) between expiration and inspiration after intravenous administration of doxapram (0.25 mg kg1) to 10 dogs anesthetized with propofol (PRO), alfaxalone (ALF), acepromazinebutorphanol-propofol (PROeAB), or acepromazine-butorphanol-alfaxalone (ALFeAB). The dotted line at 20% increase in RGSA is the limit below which arytenoid motion was clinically undetectable.

clinically detectable arytenoid motion before doxapram, six had a >20% increase in RGSA, median 37% (14e79%), and two had no increase in RGSA after doxapram (p ¼ 0.16). Of the 10 dogs in ALF with no clinically detectable arytenoid motion before doxapram, five dogs were unchanged after doxapram and five had a significant increase in RGSA of 79% (34e131%) (p ¼ 0.007) (Fig. 2). The total dose of drug used for the induction and maintenance of anesthesia, inclusive of supplements administered before and after doxapram, was significantly different between PRO and PROeAB (p ¼ 0.001) and between ALF and ALFeAB (p < 0.001). The doses, mean ± standard deviation, for propofol were 6.2 ± 2.6 mg kg1 in PRO and 2.1 ± 0.3 mg kg1 in PROeAB and for alfaxalone were 2.3 ± 0.5 mg kg1 in ALF and 0.8 ± 0.7 mg kg1 in ALFeAB. When doses of induction drug were compared within treatments for dogs that had clinically detectable arytenoid motion and those that did not, there was no difference in doses of propofol or alfaxalone. The dose in PROeAB was 1.8 ± 0.3 mg kg1 in dogs with clinically detectable arytenoid motion and 2.1 ± 0.2 mg kg1 in those without clinically detectable arytenoid motion. The dose in PRO was 7.2 ± 3.5 mg kg1 in dogs with clinically detectable arytenoid motion and 5.9 ± 2.5 mg kg1 in those without clinically detectable arytenoid motion. The two dogs in PRO that did not exhibit an increase in RGSA after doxapram did not receive significantly more propofol (8.7 and 6.2 mg kg1) than other dogs in PRO (6.2 ± 2.6 mg kg1). The dose in ALFeAB

was 0.8 ± 0.8 mg kg1 in dogs with clinically detectable arytenoid motion and 0.8 ± 0.7 mg kg1 in those without clinically detectable arytenoid motion. The dose in ALF was 2.3 ± 0.2 mg kg1 in dogs without arytenoid motion (all dogs). The five dogs in ALF that did not exhibit an increase in RGSA after doxapram did not receive more alfaxalone (2.2 mg kg1) than other dogs in ALF (p ¼ 0.14). The examination quality scores are shown in Table 1. Dogs in PRO coughed and gagged significantly more than dogs in PROeAB (p ¼ 0.009, p ¼ 0.02) and ALFeAB (p ¼ 0.05, p ¼ 0.01), respectively. Dogs in ALF coughed and gagged significantly more than dogs in PROeAB (p ¼ 0.009, p ¼ 0.001) and ALFeAB (p ¼ 0.001, p ¼ 0.001), respectively. No difference in examination quality scores was found between PRO and ALF or between PROeAB and ALFeAB (Table 1). Recovery quality was not recorded by treatment, as this was not germane to the study hypothesis or objectives. Subjectively, PROeAB, PRO and ALFeAB dogs recovered more smoothly than ALF dogs. No difference was found between treatments regarding pre- and post-treatment SpO2. Pretreatment HR was significantly higher in ALF than in ALFeAB and PROeAB (134 ± 17 versus 106 ± 24 and 107 ± 23 beats minute1), respectively (p ¼ 0.03). Post-treatment HR was significantly higher in ALF than in ALFeAB and PROeAB (144 ± 22 versus 98 ± 17 and 96 ± 25 beats minute1), respectively (p ¼ 0.0001). fR was significantly higher post-treatment in PRO than in PROeAB (28 ± 8 versus 16 ± 4 breaths minute1), respectively (p ¼ 0.007).

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Protocol for laryngeal examination in dogs DI Radkey et al. Table 1 Rating quality of laryngoscopy and concurrent events in 10 dogs anesthetized with propofol (PRO), alfaxalone (ALF), acepromazine-butorphanol-propofol (PROeAB) and acepromazine-butorphanol-alfaxalone (ALFeAB). Events were recorded in total, before and after doxapram administration Laryngoscopy examination Rating Poor Fair Good Excellent Events Coughing Gagging Struggling

Anesthetic treatments PRO

ALF

PROeAB*

ALFeAB*

4 3 2 1

6 4 0 0

0 2 3 5

0 2 3 5

27y 15z 4

31y 22z 5

10 2 3

12 2 3

*Significantly higher number of better quality examinations than in PRO or ALF (p < 0.05). ySignificantly higher number of coughing events than in PROeAB or ALFeAB (p < 0.05). zSignificantly higher number of gagging events than in PROeAB or ALFeAB (p < 0.05).

Discussion The results of this study supported our hypothesis that premedication with acepromazine and butorphanol improved the quality of laryngeal examination. The results also suggest that when either alfaxalone or propofol are used for anesthetic induction in dogs that are premedicated with acepromazine and butorphanol, arytenoid motion can be reliably detected before doxapram in approximately 50% of dogs, and that the other 50% will show definitive arytenoid motion after doxapram administration. Furthermore, neither propofol nor alfaxalone, when used alone for anesthesia, result in reliable arytenoid motion either before or after doxapram. Additionally, neither drug when used alone provides an ideal quality of laryngeal examination. Alfaxalone in 2-hydroxyypropyl-b-cyclodextrin is a steroid anesthetic used for the induction and maintenance of general anesthesia. Anesthetic effects produced by alfaxalone are attributed to the modulation of the inhibitory gamma (g) aminobutyric acid (GABA) neurotransmitter at the GABA receptor (Lambert et al. 2003). Several studies have shown that propofol and alfaxalone have very similar pharmacodynamics (Musk et al. 2005; Muir et al. 2008; Psatha et al. 2011; Amengual et al. 2013). The formulation of alfaxalone used in this study contained ethanol (150 mg mL1), chlorocresol (1.0 mg mL1) and benzethonium chloride (0.2 6

mg mL1). It is unlikely that these preservatives were the reason for differences in examination quality and in percent increases in RGSA between alfaxalone and propofol. While this possibility cannot be discounted, these preservatives are not biologically active and have no known anesthetic effects (Rowe et al. 2009). Various methods exist for the evaluation of laryngeal function, including subjective evaluation (Gross et al. 2002; Nelissen et al. 2012; McKeirnan et al. 2014, Smalle et al. 2017), measurement of normalized glottal gap area (Omori et al. 1998; Tobias et al. 2004; Nelissen et al. 2012) and change in RGSA (Miller et al. 2002; Hardie 2016). In this study, a ‘clinical threshold’ was created to provide an understanding of the statistical versus clinical significance of the data and to allow application to the clinical setting where calculating change in RGSA via video analysis is not practical. This threshold was determined to be a 20% increase in RGSA and was then applied to provide more clinically relevant conclusions with respect to each of the anesthetic treatments. This 20% threshold is not necessarily equivalent to impaired laryngeal function in affected dogs, but it is the minimal amount of laryngeal motion needed to be visible to the naked eye, as during a clinical laryngeal examination. The large percentage of dogs in all treatments that had arytenoid motion below the clinical threshold of 20% is of concern and highlights the impact that anesthetic protocols can have on laryngeal function in normal dogs. The results defined 80% of dogs in PRO, 100% in ALF and 50% in both ALFeAB and PROeAB, with <20% increase in RGSA prior to doxapram. Interestingly, of the 50% of dogs in both ALFeAB and PROeAB with no motion prior to doxapram, all had motion after doxapram. However, of the 50% of dogs in ALFeAB and PROeAB with obvious laryngeal motion before doxapram (i.e. over the 20% threshold), not all had improved motion after doxapram. Doxapram hydrochloride is a central nervous system stimulant that increases fR and tidal volume (Franz 1985; Arrioja 2001). Its use as a diagnostic tool for evaluating normal dogs and dogs with laryngeal paralysis has been shown useful for differentiating normal versus affected dogs (Tobias et al. 2004), and its effectiveness is further supported by the results of this study. The dose of doxapram used (0.25 mg kg1) was at the low end of the range (0.25e2.2 mg kg1) but was chosen based on efficacy at stimulating 15e30 seconds of rapid and deep breaths without the side effects of hypertension, cardiac arrhythmias and seizures that may occur

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Please cite this article in press as: Radkey DI, Hardie RJ, Smith LJ Comparison of the effects of alfaxalone and propofol with acepromazine, butorphanol and/or doxapram on laryngeal motion and quality of examination in dogs, Veterinary Anaesthesia and Analgesia (2018), https://doi.org/10.1016/j.vaa.2017.08.014

Protocol for laryngeal examination in dogs DI Radkey et al.

with higher doses (Plumb 2011). All dogs in this study exhibited signs consistent with increased respiratory drive (i.e. deep chest excursions and increased fR) within approximately 15e30 seconds of doxapram administration. In this study, doxapram was effective at increasing arytenoid motion for most dogs that initially had <20% increase in RGSA. However, its overall effect was different for premedicated versus unpremedicated dogs. The results suggest that dogs premedicated with acepromazine and butorphanol, anesthetized with either propofol or alfaxalone, and show no detectable laryngeal motion, the administration of doxapram will result in a reliable laryngeal examination with little chance of a false positive diagnosis of laryngeal paralysis. By contrast, in similarly premedicated dogs anesthetized with propofol or alfaxalone that exhibit good laryngeal motion prior to doxapram, diagnosis of laryngeal motion is unlikely to be improved after doxapram. In fact, if these dogs have good laryngeal motion, doxapram administration appears to result in paradoxical motion. It is possible that the increased respiratory drive caused by doxapram in dogs with good laryngeal motion evident induced a degree of increased inspiratory effort that resulted in adduction of the arytenoids. In unpremedicated dogs with <20% increase RGSA during anesthesia, administration of doxapram resulted in six of eight dogs in PRO and five of 10 dogs in ALF with clinically detectable arytenoid motion. Thus, when evaluating RGSA before and after doxapram, a 20e50% false positive diagnostic rate of laryngeal paralysis may occur when either propofol or alfaxalone, respectively, are used alone for anesthesia. The lack of detectable arytenoid motion in ALF before (100%) and after (50%) doxapram was a surprising result that was inconsistent with the hypothesis that alfaxalone would have a similar effect on arytenoid motion as propofol. One explanation for the lack of arytenoid motion in ALF is the dose of alfaxalone. Initially, a lower dose of alfaxalone was administered according to study protocol; however, the unpremedicated dogs were not sufficiently anesthetized to allow laryngoscopy, and supplemental doses of alfaxalone were administered. The anesthetizing doses are consistent with several sources (Ferre et al. 2006; Ambros et al. 2008; Nelissen et al. 2012; Maney et al. 2013), and the higher dose administered in ALF when compared with ALFeAB was most certainly due to the lack of premedication. Titration of alfaxalone slowly to

effect was unsatisfactory, causing excitement rather than induction of anesthesia; therefore, the speed of alfaxalone administration may have played a role in our results. A similarly unexpected result was identified when evaluating PRO, where 80% of dogs had no detectable arytenoid motion before doxapram. Not surprisingly, dogs in PRO received significantly more propofol than dogs in PROeAB, which again is most likely due to the lack of premedication. Even in the unpremedicated dogs, however, slow titration of propofol was successful in allowing laryngoscopy. Despite this fact, these results are of concern because the use of propofol as a sole agent for laryngeal examination is common. Furthermore, based on results of this study, the negative effects of propofol on arytenoid motion cannot be reliably overcome with the use of a low dose of doxapram. Administration of alfaxalone or propofol alone did not provide a good quality of examination, whereas premedication with acepromazine and butorphanol improved examination quality. Most injectable anesthetic agents are known respiratory depressants; consequently, the lower doses of alfaxalone or propofol administered to the premedicated dogs likely resulted in less overall central nervous system depression. Some statistically significant differences in cardiopulmonary variables were found within and among groups; however HR remained within normal limits. Similarly, although fR was different between PRO and PROeAB, all values remained within normal limits. Because the pulse oximeter was placed on the pinna, SpO2 values were approximate. The results of the present study differ somewhat from a recently published similar study (Smalle et al. 2017). In that study, arytenoid motion was graded subjectively by visual observation by a blinded observer. There were a smaller number of Beagle dogs used in that randomized trial (n ¼ 6), and the induction drugs evaluated (thiopental, propofol and alfaxalone) were administered by syringe pump to effect. Dogs were not premedicated, and the total administered doses of propofol and alfaxalone were similar to those in the present study. No doxapram was administered. The authors concluded that there was no significant difference between the three induction agents with respect to total arytenoid movements; however, the timing of when those movements were evaluated (i.e. induction, early recovery and late recovery) is important and differs between the three agents with respect to the

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Please cite this article in press as: Radkey DI, Hardie RJ, Smith LJ Comparison of the effects of alfaxalone and propofol with acepromazine, butorphanol and/or doxapram on laryngeal motion and quality of examination in dogs, Veterinary Anaesthesia and Analgesia (2018), https://doi.org/10.1016/j.vaa.2017.08.014

Protocol for laryngeal examination in dogs DI Radkey et al.

laryngeal examination. The fact that these authors reported no obvious differences between alfaxalone and propofol is likely attributable to the different methodology and, possibly, the smaller number of subjects. The current study had several limitations. When considering breed predisposition for acquired laryngeal paralysis, the use of large breed dogs would have provided a better clinical representation of patients likely to require anesthesia for the evaluation of laryngeal function. Additionally, the relatively small sample size may have been insufficient to detect subtle differences in the effects of the various treatments on arytenoid motion or examination quality scores. In conclusion, results of this study indicate that the use of acepromazine and butorphanol as premedications prior to induction with alfaxalone or propofol for laryngeal examination in normal dogs improves examination quality and allows accurate evaluation of laryngeal function. The use of alfaxalone or propofol without premedication cannot be recommended owing to the dose-dependent depressant effects on laryngeal function that cannot be reliably overcome with doxapram, leading to a risk of false positive diagnoses of laryngeal paralysis. Acknowledgements The authors thank Jurox, Inc. for their generous donation of alfaxalone, the University of Wisconsin Companion Animal Foundation (grant no. 875100 233 AAA8626), and Sara Darr and Katie Kierski of University of Wisconsin Veterinary Care for technical assistance. Authors’ contributions DIR: data collection and analysis, drafted the manuscript. RJH: study design, data analysis, manuscript preparation. LJS: study design, supervision of data collection and analysis, manuscript preparation and critical review. Conflict of interest statement Authors confirm no conflict of interest. References Ambros B, Duke-Novakovski T, Pasloske KS (2008) Comparison of the anesthetic efficacy and cardiopulmonary effects of alfaxalone-2-hydroxypropyl-betacyclodextrin and propofol in dogs. Am J Vet Res 69, 1391e1398. 8

Amengual M, Flaherty D, Auckburally A et al. (2013) An evaluation of anesthetic induction in healthy dogs using rapid intravenous injection of propofol or alfaxalone. Vet Anaesth Analg 40, 115e123. Arrioja A (2001) Compendium of Veterinary Products (6th edn). Arrioja A (ed.). Bayley AJ/North American Compendiums Inc., USA. pp. 1349e1350. Broome C, Burbidge HM, Pfeiffer DU (2000) Prevalence of laryngeal paresis in dogs undergoing general anaesthesia. Aust Vet J 78, 769e772. Ferre PJ, Pasloske K, Whittem T et al. (2006) Plasma pharmacokinetics of alfaxalone in dogs after intravenous bolus of Alfaxan-CD RTU. Vet Anaesth Analg 33, 229e236. Franz D (1985) Central nervous system stimulants. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics (7th ed.). Gilman AG, Goodman LS, Rall TW, Murad F (eds) Macmillan Publishing Co, USA. pp. 582e588. Gaber CE, Amis TC, LeCouteur RA (1985) Laryngeal paralysis in dogs: a review of 23 cases. J Am Vet Med Assoc 186, 377e380. Gross ME, Dodam JR, Pope ER, Jones BD (2002) A comparison of thiopental, propofol, and diazepamketamine anesthesia for evaluation of laryngeal function in dogs premedicated with butorphanol-glycopyrrolate. J Am Anim Hosp Assoc 38, 503e506. Hardie RJ (2016) Translaryngeal percutaneous arytenoid lateralization technique in a canine cadaveric study. J Vet Emerg Crit Care 26, 659e663. Jackson AM, Tobias K, Long C et al. (2004) Effects of various anesthetic agents on laryngeal motion during laryngoscopy in normal dogs. Vet Surg 33, 102e106. Lambert JJ, Belelli D, Peden DR et al. (2003) Neurosteroid modulation of GABAA receptors. Prog Neurobiol 71, 67e80. Maney JK, Shepard MK, Braun C et al. (2013) A comparison of cardiopulmonary and anesthetic effects of an induction dose of alfaxalone or propofol in dogs. Vet Anaesth Analg 40, 237e244. McKeirnan KL, Gross ME, Rochat M, Payton M (2014) Comparison of propofol and propofol/ketamine anesthesia for evaluation of laryngeal function in healthy dogs. J Am Anim Hosp Assoc 50, 19e26. Miller CJ, McKiernan BC, Pace J, Fettman MJ (2002) The effects of doxapram hydrochloride (dopram-V) on laryngeal function in healthy dogs. J Vet Intern Med 16, 524e528. Muir W, Lerche P, Wiese A et al. (2008) Cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in dogs. Vet Anaesth Analg 35, 451e462. Musk GC, Pang DS, Beths T, Flaherty DA (2005) Targetcontrolled infusion of propofol in dogs e evaluation of four targets for induction of anesthesia. Vet Rec 157, 766e770.

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Please cite this article in press as: Radkey DI, Hardie RJ, Smith LJ Comparison of the effects of alfaxalone and propofol with acepromazine, butorphanol and/or doxapram on laryngeal motion and quality of examination in dogs, Veterinary Anaesthesia and Analgesia (2018), https://doi.org/10.1016/j.vaa.2017.08.014

Protocol for laryngeal examination in dogs DI Radkey et al. Nelissen P, Corletto F, Aprea F, White RA (2012) Effect of three anesthetic induction protocols on laryngeal motion during laryngoscopy in normal cats. Vet Surg 41, 876e883. Omori K, Slavit DH, Kacker A, Blaugrund SM (1998) Influence of size and etiology of glottal gap area in glottic incompetence dysphonia. Laryngoscope 108, 514e518. Plumb DC (2011) Plumb’s Veterinary Drug Handbook (7th ed.). Plumb DC (ed.) Wiley-Blackwell, USA. pp. 325e326. Psatha E, Alibhai H, Jimenez-Lozano A et al. (2011) Clinical efficacy and cardiorespiratory effects of alfaxalone, or diazepam/fentanyl for induction of anesthesia in dogs that are a poor anesthetic risk. Vet Anaesth Analg 38, 24e36. Rowe RS, Sheskey PJ, Quinn ME (2009) Handbook of Pharmaceutical Excipients (6th ed.). Rowe RC, Sheskey PJ, Quinn ME (eds) Pharmaceutical Press, UK. pp. 17e19. 168e171. Rudorf H, Barr FJ, Lane JG (2001) The role of ultrasound in the assessment of laryngeal paralysis in the dog. Vet Radiol Ultrasound 42, 338e343. Smalle TM, Hartman MJ, Bester L et al. (2017) Effects of thiopentone, propofol and alfaxalone on laryngeal motion during oral laryngoscopy in healthy dogs. Vet Anaesth Analgesia 44, 427e434.

Tobias KM, Jackson AM, Harvey RC (2004) Effects of doxapram HCl on laryngeal function of normal dogs and dogs with naturally occurring laryngeal paralysis. Vet Anaesth Analgesia 31, 258e263. White RAS (1989) Unilateral arytenoid lateralization: an assessment of technique and long term results in 62 dogs with laryngeal paralysis. J Small Anim Pract 30, 543e549. Received 17 April 2017; accepted 27 August 2017. Available online xxx

Appendix A. Examination quality rating.

Rating

Number of events*

Excellent Good Fair Poor

0e1 2e3 4e5 6

*Events recorded: cough, gag, struggle.

© 2018 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., ▪, 1e9

9

Please cite this article in press as: Radkey DI, Hardie RJ, Smith LJ Comparison of the effects of alfaxalone and propofol with acepromazine, butorphanol and/or doxapram on laryngeal motion and quality of examination in dogs, Veterinary Anaesthesia and Analgesia (2018), https://doi.org/10.1016/j.vaa.2017.08.014