Advances in the standard of veterinary care for avian species have been increasingly pursued as the popularity of birds as companion animals surges.1 Manual restraint of birds associated with the performance of various diagnostic procedures such as a physical exam, radiograph acquisition, and venipuncture can result in patient stress and detrimental impacts on the health of the patient.2 The stress response of pet birds during handling for even minimally invasive procedures may induce hyperthermia, tachypnea, and acute decompensation of critically ill individuals potentially resulting in mortality.3,4 Additionally, the struggling of psittacines during manual restraint can result in injury to both the patient and veterinary personnel.5 The utilization of safe and effective sedative and anesthetic protocols can facilitate various veterinary procedures while minimizing patient stress and morbidities.
Alfaxalone, a neuroactive steroid anesthetic acting as a γ-aminobutyric acid subtype A (GABAA) receptor agonist, has been administered in birds as a sole agent or as part of a multimodal anesthetic protocol.6–17 One formulation of alfaxalone, Alfaxan Multidose IDX (Jurox Inc), is approved for anesthetic use in dogs and cats in the United States. Recently, the U.S. Food and Drug Administration added this formulation to the Index of Legally Marketed Unapproved New Animal Drugs for Minor Species with one of the indexed indications being the sedation and anesthesia of Psittaciformes.18 Investigation into the effects of intramuscular (IM) administration of alfaxalone in Quaker parrots (Myiopsitta monachus) revealed the potential development of hyperexcitation and muscle tremors, which were reduced but not abolished in individuals who were premedicated with IM midazolam as compared to those in which alfaxalone was used as the sole sedative agent.7
Midazolam, a GABAA receptor agonist, is commonly administered to psittacines due to its sedative and muscle relaxant properties, minimal cardiovascular effects, and ease of reversibility.15,19 Butorphanol, a κ-agonist and either μ-antagonist or weak μ-agonist drug, is also administered in combination with midazolam as a part of a multimodal anesthetic protocol for psittacines.15,19–21 The use of multimodal anesthetic and sedative protocols allows for the use of lower doses of all administered drugs, with the goal of attaining the desired sedation or analgesia while producing minimal adverse effects.22
The aim of the present study was to evaluate the effects of 2 doses of alfaxalone on basic cardiopulmonary parameters, endotracheal intubation, radiographic positioning, and response to a noxious stimulus in healthy Quaker parrots previously administered intranasal (IN) midazolam and butorphanol. We hypothesized that the lower dose of alfaxalone when administered following midazolam-butorphanol would result in acceptable sedation with fewer adverse effects when compared to the higher dose of alfaxalone.
Materials and methods
This study was approved by the Institutional Animal Care and Use Committee at Texas A&M College of Veterinary Medicine and Biomedical Sciences (Institutional Animal Care and Use Committee 2021-0094). Research was conducted in January and February 2022 at the Schubot Avian Health Center (SAVC) at Texas A&M University. The manuscript is reported according to Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines.
Animals
Ten 8-year-old captive adult healthy Quaker parrots were used in this study (male = 5; female = 5). The sample size of the treatment groups (n = 10 per group) was based on a similar study that compared sedation in cockatiels (Nymphicus hollandicus) after IN administration of midazolam and midazolam-butorphanol.23 Health status was determined based on a physical examination performed on the day of treatment administration. No specific exclusion criteria were set, and no subjects were excluded from analysis.
Body weights (median [range]) of enrolled birds were 125.5 [101 to 139] grams (g) week 1 and 121.5 [99 to 135] g week 2 of the study. The parrots were born and raised as part of the research and teaching Quaker parrot colony at the SAVC. During the study, parrots were housed in groups of two or three in standard one-inch mesh wire cages (0.6 to 1.2 X 0.6 X 0.6 meters) suspended from the ceiling of the aviary. The parrots were maintained in a temperature-controlled environment (23°C) and exposed to a 12-hour light-dark cycle using a light-emitting diode system with gradual illumination and deillumination over 20 minutes. Parrot housing contained wood perches and toys for enrichment. Parrots were offered water ad libitum and a commercially available pelleted diet formulated for psittacine birds (ZuPreem FruitBlend Flavor; Premium Nutritional Products Inc; medium sized, 40 g per bird daily).
Study design
In a crossover masked design, 10 parrots were randomly assigned an order to receive 2 treatments (www.randomizer.org): treatment LDA, 1-IM injection of a low-dose of alfaxalone (2 mg/kg; 10 mg/mL; Jurox); and treatment HDA, 1-IM injection of a high-dose alfaxalone (5 mg/kg) with a 1-week washout between treatments. One investigator (SH), aware of treatment allocation, organized and administered all treatments.
On treatment day and immediately prior to handling, respiratory rate and sedation score using a simple descriptive scale (SDS; sedation score 1 to 4; Appendix 1; altered and adapted from Doss et al23) via visualization from a short distance were determined. Parrots were then manually restrained for < 10 minutes to perform a physical examination, which included the acquisition of heart rate and cloacal temperature, and then they were transferred to a container for weighing. These values were recorded and deemed baseline values. Parrots remained in the container with no stimulation for 5 minutes and then were manually restrained for the administration of midazolam (2 mg/kg; 5 mg/mL; Almaject Inc) and butorphanol (2 mg/kg; 10 mg/mL; Vet One) IN via 0.3-mL insulin syringes (Covidien) with the needle removed. Butorphanol and midazolam doses were selected based on previously published works in psittacine species.24,25 Subjects were then placed into a climate-controlled incubator with a clear plexiglass door for a 15-minute waiting period during which they were monitored without stimulation. Immediately following this 15-minute period, parrots were manually restrained by a technician experienced with handling psittacines for the injection of either treatment LDA or HDA into either the left or right pectoral muscle using a 0.3 mL insulin syringe (Covidien). Parrots were placed back into the incubator for an additional 15-minute waiting period.
At 15 minutes following alfaxalone treatment administration (T = 15), birds were removed from the incubator. For every 5 minutes thereafter, the degree of sedation was determined using the SDS as previously discussed and position without manipulation, heart rate, respiratory rate, presence or absence of muscle tremors, and presence or absence of vocalizations in the form of chattering or screaming were recorded by an investigator masked to treatments (CC). To avoid unwanted subject stress and interference with sedation scoring, cardiac auscultation was ended at T = 35. The cloacal temperature was measured at T = 15, 30, 45, 60, 75, 105, and 135, until a sedation score of ≤ 2, or until blood was detected on the thermometer following insertion.
The ability to position parrots for both lateral and ventrodorsal full-body radiograph acquisition was assessed at T = 15, 30, 45, 60, 75, 105, and 135 or until the sedation score was ≤ 2. Endotracheal intubation was attempted at T = 15, and extubation was performed when the parrots made chewing movements. Following extubation, intubation was not again attempted.
The response to noxious stimuli, in the form of a feather pluck from the lateral femoral area and in the form of pinching the superficial skin of a toe with a hemostat, was assessed at T = 15, 30, 45, 60, 75, 105, and 135, until a sedation score of ≤ 2, or otherwise at the discretion of the masked investigator (CC) based on strength of response to previous noxious stimulation. A positive response was recorded when the subject made gross purposeful movements such as flapping of wings or attempts to right itself during or immediately after the application of the noxious stimulus.
Once a sedation score of ≤ 2 was assigned, birds were placed back in an incubator and monitored for sedation from a distance until a sedation score of 1 was assigned. Administration of 3 to 5 mL Normosol-R subcutaneously (SQ) in the inguinal space was performed for all parrots within 10 minutes of return to an incubator. Monitoring and data collection ceased once a sedation score of 1 was achieved.
The temperature in the room of data collection was maintained at 23.9°C (22.2 to 25.6). All birds were maintained on an external heating unit (Thermo-Peep heated pad; K&H Pet Products) covered with an absorbent pad from T = 15 until parrots had a sedation score of ≤ 2. Parrots were returned to their regular housing enclosure once fully recovered from sedation.
Statistical analysis
R 4.1.2 (R Core Team) and JMP Pro 16.0.0 (SAS Institute Inc) were used to analyze data. Continuous data were tested for normality using a Shapiro-Wilk test. Data that were not normally distributed were compared with a paired Wilcoxon signed rank test or a Wilcoxon/Kruskal-Wallis test where appropriate and reported as median (range). Normally distributed variables were reported as mean (± standard deviation). Temperature data were analyzed using polynomial regression; the polynomial degree was optimized using Akaike’s information criteria. Categorical data were compared using Pearson’s chi-squared test. Comparisons of sedation score after drug administration to baseline sedation score were performed using Tukey’s honestly significant difference test (α = 0.05).
Results
There was a statistically significant difference between the weights of birds from week 1 (123.1 ± 13.46 g) to week 2 (119.7 ± 10.9 g) (P = .047).
All birds completed the study with full recovery from sedation (ie, sedation score of 1). One bird experienced apparent respiratory distress with open-mouth breathing 45 minutes after LDA administration that improved over time with oxygen supplementation administered into the incubator. Another bird died 1 day after completion of the study; necropsy results indicated cloacal rupture as the likely cause of death. All other birds remained apparently healthy throughout the study period.
Median [range] sedation scores were determined for baseline and T = 15 through T = 135. All birds had a sedation score of 1 at baseline (n = 20), and sedation scores were statistically lower at baseline when compared to T = 15, 30, 45, and 60 for LDA (P = .002, .002, .002, and .004, respectively) and T = 15, 30, 45, 60, and 75 for HDA (P = .002, .002, .004, .008, and .016, respectively). There were no significant differences in sedation scores between treatments at any time point. The duration of time from administration of midazolam-butorphanol to complete recovery following treatment (sedation score 1) was significantly shorter for LDA (90 [60 to 195] minutes) when compared to HDA (127.5 [90 to 210] minutes) (P = .016; Figure 1). There was not a statistically significant difference in time to recover from sedation between weeks 1 and 2 (P = .240).
Median ± interquartile (25th to 75th percentiles) range for sedation score of 10 Quaker parrots (Myiopsitta monachus) for baseline (BL) and time = 15 to 135 minutes following intramuscular administration of alfaxalone (2 mg/kg; LDA; squares) or alfaxalone (5 mg/kg; HDA; circles). All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration. *Within a treatment group, value differs significantly (P < .05) from the baseline measurement for both HDA and LDA. †Within treatment HDA but not LDA, value differs significantly (P < .05) from the baseline measurement.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
Median ± interquartile (25th to 75th percentiles) range for sedation score of 10 Quaker parrots (Myiopsitta monachus) for baseline (BL) and time = 15 to 135 minutes following intramuscular administration of alfaxalone (2 mg/kg; LDA; squares) or alfaxalone (5 mg/kg; HDA; circles). All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration. *Within a treatment group, value differs significantly (P < .05) from the baseline measurement for both HDA and LDA. †Within treatment HDA but not LDA, value differs significantly (P < .05) from the baseline measurement.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
Median ± interquartile (25th to 75th percentiles) range for sedation score of 10 Quaker parrots (Myiopsitta monachus) for baseline (BL) and time = 15 to 135 minutes following intramuscular administration of alfaxalone (2 mg/kg; LDA; squares) or alfaxalone (5 mg/kg; HDA; circles). All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration. *Within a treatment group, value differs significantly (P < .05) from the baseline measurement for both HDA and LDA. †Within treatment HDA but not LDA, value differs significantly (P < .05) from the baseline measurement.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
Heart rate was not significantly different from baseline for LDA and HDA from T = 15 to T = 35 (Figure 2). There was no significant difference in heart rate between treatments at baseline and T = 15 to T = 35. Respiratory rate was significantly higher compared to baseline for LDA from T = 15 to T = 40; for HDA at T = 15 and from T = 25 to T = 40; but not for HDA at T = 20 (Figure 3). There was no significant difference in respiratory rate between treatments at baseline and from T = 15 to T = 40. Cloacal temperature decreased significantly from baseline for LDA and HDA at T = 15 (P = .004 and P = .002, respectively), T = 30 (P = .004 and P = .002, respectively), and T = 45 (P = .016 and P = .002, respectively) and for HDA at T = 60 (P = .004) (Figure 4). There was no significant difference in cloacal temperature from baseline for LDA at T = 60 or between treatments at any time point.
Heart rate distributions in beats per minute (bpm) of 10 Quaker parrots (Myiopsitta monachus) at baseline and at time = 15 to 35 minutes following administration of intramuscular alfaxalone 2 mg/kg (LDA) or 5 mg/kg (HDA). All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
Heart rate distributions in beats per minute (bpm) of 10 Quaker parrots (Myiopsitta monachus) at baseline and at time = 15 to 35 minutes following administration of intramuscular alfaxalone 2 mg/kg (LDA) or 5 mg/kg (HDA). All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
Heart rate distributions in beats per minute (bpm) of 10 Quaker parrots (Myiopsitta monachus) at baseline and at time = 15 to 35 minutes following administration of intramuscular alfaxalone 2 mg/kg (LDA) or 5 mg/kg (HDA). All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
Median ± interquartile (25th to 75th percentiles) range for respiratory rate in breaths per minute (brpm) of 10 Quaker parrots (Myiopsitta monachus) at baseline (BL) and time = 15 to 40 minutes following administration of intramuscular alfaxalone (2 mg/kg; LDA; squares) or alfaxalone (5 mg/kg; HDA; circles). All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration. *Within a treatment group, value differs significantly (P < .05) from the baseline measurement. †Within treatment LDA but not HDA, value differs significantly (P < .05) from the baseline measurement.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
Median ± interquartile (25th to 75th percentiles) range for respiratory rate in breaths per minute (brpm) of 10 Quaker parrots (Myiopsitta monachus) at baseline (BL) and time = 15 to 40 minutes following administration of intramuscular alfaxalone (2 mg/kg; LDA; squares) or alfaxalone (5 mg/kg; HDA; circles). All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration. *Within a treatment group, value differs significantly (P < .05) from the baseline measurement. †Within treatment LDA but not HDA, value differs significantly (P < .05) from the baseline measurement.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
Median ± interquartile (25th to 75th percentiles) range for respiratory rate in breaths per minute (brpm) of 10 Quaker parrots (Myiopsitta monachus) at baseline (BL) and time = 15 to 40 minutes following administration of intramuscular alfaxalone (2 mg/kg; LDA; squares) or alfaxalone (5 mg/kg; HDA; circles). All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration. *Within a treatment group, value differs significantly (P < .05) from the baseline measurement. †Within treatment LDA but not HDA, value differs significantly (P < .05) from the baseline measurement.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
Median ± interquartile (25th to 75th percentiles) range for cloacal temperatures in degrees Celsius (°C) of 10 Quaker parrots (Myiopsitta monachus) at baseline (BL) and time = 15 to 60 minutes following administration of intramuscular alfaxalone (2 mg/kg; LDA; squares) or alfaxalone (5 mg/kg; HDA; circles). All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration. *Within a treatment group, value differs significantly (P < .05) from the baseline measurement. †Within treatment HDA but not LDA, value differs significantly (P < .05) from the baseline measurement.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
Median ± interquartile (25th to 75th percentiles) range for cloacal temperatures in degrees Celsius (°C) of 10 Quaker parrots (Myiopsitta monachus) at baseline (BL) and time = 15 to 60 minutes following administration of intramuscular alfaxalone (2 mg/kg; LDA; squares) or alfaxalone (5 mg/kg; HDA; circles). All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration. *Within a treatment group, value differs significantly (P < .05) from the baseline measurement. †Within treatment HDA but not LDA, value differs significantly (P < .05) from the baseline measurement.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
Median ± interquartile (25th to 75th percentiles) range for cloacal temperatures in degrees Celsius (°C) of 10 Quaker parrots (Myiopsitta monachus) at baseline (BL) and time = 15 to 60 minutes following administration of intramuscular alfaxalone (2 mg/kg; LDA; squares) or alfaxalone (5 mg/kg; HDA; circles). All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration. *Within a treatment group, value differs significantly (P < .05) from the baseline measurement. †Within treatment HDA but not LDA, value differs significantly (P < .05) from the baseline measurement.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
No birds exhibited muscle tremors or fasciculations at baseline physical examination. There was a significant difference in the incidence of muscle tremors or fasciculations compared to baseline for HDA at T = 15 (4/10, P = .025), 25 (4/10, P = .025), and 40 (4/10, P = .025). There were no significant differences in muscle tremors for HDA when compared to baseline at T = 20, 30, and 35 or for LDA when compared to baseline at T = 15, 20, 25, 30, 35, and 40. There was a significant difference in the occurrence of muscle tremors at T = 15 between LDA (0/10) and HDA (4/10) (P = .025). During the study period, the number of birds experiencing muscle tremors or fasciculations at any time point was greater in HDA (9/10) than in LDA (7/10) (P < .001; Figure 5).
Presence or absence of muscle tremors in Quaker parrots (Myiopsitta monachus) from time = 15 to 135 minutes after intramuscular administration of alfaxalone (2 mg/kg; LDA; no shading) or alfaxalone (5 mg/kg; HDA; gray shading), arranged by time and treatment. All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
Presence or absence of muscle tremors in Quaker parrots (Myiopsitta monachus) from time = 15 to 135 minutes after intramuscular administration of alfaxalone (2 mg/kg; LDA; no shading) or alfaxalone (5 mg/kg; HDA; gray shading), arranged by time and treatment. All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
Presence or absence of muscle tremors in Quaker parrots (Myiopsitta monachus) from time = 15 to 135 minutes after intramuscular administration of alfaxalone (2 mg/kg; LDA; no shading) or alfaxalone (5 mg/kg; HDA; gray shading), arranged by time and treatment. All subjects were administered butorphanol (2 mg/kg) and midazolam (2 mg/kg) intranasally prior to alfaxalone administration.
Citation: American Journal of Veterinary Research 83, 12; 10.2460/ajvr.22.08.0140
There was not a significant difference in the incidence of birds positioned adequately for full body radiographs at T = 15 between LDA and HDA (10/10 and 9/10, respectively; P = .305). There was a statistically significant difference over the observation period in the percent of time birds were able to be positioned adequately for radiographs or in masked investigator comfort in attempting radiograph acquisition between treatments, with HDA being positioned for radiographs for a greater percentage of the sedation time than LDA (HDA, 71.7%; LDA, 50.0%) (P = .015).
All birds in both groups responded aversely to toe pinching. There was not a significant difference between LDA and HDA in response to feather plucking at any time point (P = .315).
There was no difference in the incidence of vocalizations at any time point between LDA (3/10) and HDA (5/10) (P = .523). All birds were intubated for both treatments at T = 15.
Discussion
The purpose of this study was to examine the sedative and clinical effects of 2 different doses of IM alfaxalone in healthy Quaker parrots administered IN midazolam and butorphanol. For both treatments, sedation was adequate to facilitate intubation and radiograph acquisition with full recovery of all birds within 195 minutes following alfaxalone administration. While all birds completed the study, 1 bird died the day after 2 weeks of treatment administration. Necropsy results indicated cloacal rupture as a possible cause of death, which the authors consider to be unrelated to the sedation protocol and potentially associated with repeated cloacal temperature monitoring. Future studies requiring repeated monitoring of body temperature may consider alternative, noninvasive methods such as infrared thermometry.26
Alfaxalone has been reported to provide safe, effective sedation for noninvasive or minimally invasive procedures when administered parenterally in avian species.6,8,15–17 Intramuscular alfaxalone administered as a sole agent produces safe, dose-dependent sedation in budgerigars (Melopsittacus undulatus), with 5 mg/kg producing sedation without recumbency; 10 mg/kg producing a short duration of sedation effective for brief, minimally invasive procedures; 15 mg/kg producing reliable sedation adequate for the performance of radiographs and venipuncture; and 20 mg/kg producing induction of anesthesia with loss of glottal tone.6,15,17 Subcutaneous alfaxalone administered as a sole agent allows for radiograph acquisition in black-cheeked lovebirds (Agapornis nigrigenis) at 12.6 mg/kg and produces anesthesia with a dose-dependent decrease in induction time and increase in duration of anesthesia in Bengalese finches (Lonchura domestica) at 10, 30, and 50 mg/kg.8,16 Intravenous alfaxalone administered at 2 mg/kg produced shorter, smoother inductions than did isoflurane via facemask and significantly reduced isoflurane requirements during orthopedic surgery in rose flamingoes (Phoenicopterus roseus).9
In the present study, all birds showed signs of sedation (ie, minimal to no response to auditory or visual stimuli, no righting response when placed in dorsal recumbency, and closed eyes when not manipulated) by 15 minutes following alfaxalone administration. The duration from treatment administration to recovery from sedation was significantly different between the treatments, with LDA recovering a median of 37.5 minutes faster than HDA. Whitehead et al7 reported shorter recovery times in Quaker parrots administered higher doses of alfaxalone than used in the present study (44.0 ± 10.8 minutes for alfaxalone 10 mg/kg, IM alone and 86.2 ± 13.4 minutes for alfaxalone 25 mg/kg, IM alone), with the longest recovery time occurring in those birds administered a combination of midazolam and alfaxalone (103.5 ± 15.1 minutes for midazolam 1 mg/kg, IM + alfaxalone 10 mg/kg, IM). To the authors’ knowledge, the pharmacokinetics and duration of action of midazolam or butorphanol in Quaker parrots have not been determined for any route of administration. The plasma half-life of intravenously (IV) administered midazolam in turkeys (Meleagridis gallopavo), chickens (Gallus gallus domesticus), bobwhite quail (Colinus virginianus), and ring-necked pheasants (Phasianus colchicus) was 0.42, 1.45, 1.90, and 9.71 hours, respectively.27 In blue-fronted and orange-winged Amazon parrots (Amazona aestiva and Amazona amazonica, respectively), IN midazolam administered at 2 mg/kg provided sedation for 25.40 ± 5.72 minutes and 27.10 ± 3.73 minutes, respectively.28 The plasma half-life of 5 mg/kg butorphanol following IV and IM administration in Hispaniolan Amazon parrots (Amazona ventralis) was 0.49 and 0.51 hours, respectively.29 The longer recovery times in the present study as compared to Whitehead et al7 may be due to the inclusion of both midazolam and butorphanol in the present protocol. Administration of reversal agents for butorphanol and midazolam might have shortened the birds’ sedation times; however, this was not performed due to concerns that reversal of the sedative and muscle relaxant effects of butorphanol and midazolam might unmask the tremorgenic effects of residual alfaxalone.
For both treatments, heart rate was significantly increased compared to baseline, without a significant difference between treatments. These results differ from previous work as heart rate was reported to decrease in Quaker parrots administered higher doses of alfaxalone than used in the present study (10 mg/kg).7 Budgerigars experienced transient bradycardia with sinus arrhythmia that returned to baseline within 15 minutes following IM alfaxalone administration.17 These findings may indicate that the use of lower doses of alfaxalone in combination with midazolam-butorphanol results in a decreased risk for bradycardia in Quaker parrots. Alternatively, tachycardia may be a baroreceptor-mediated response to hypotension, as an increased heart rate can increase cardiac output, blood pressure, and tissue blood flow.30 These physiological alterations may explain the increases in heart rate observed in the present study. Future studies evaluating the effects of alfaxalone-midazolam-butorphanol combinations on cardiac output, oxygenation, and ventilation are necessary to further investigate the cause of the observed tachycardia.
Respiratory rate was significantly increased compared to baseline, which is consistent with previous work in Quaker parrots sedated with midazolam and alfaxalone with an approximate doubling of respiratory rate from baseline during the first 50 minutes following administration.7 One bird in the present study experienced apparent respiratory distress with open-mouth breathing and a sudden increase in respiratory rate from 210 to 350 breaths/min, approximately 45 minutes after LDA administration. Supplemental oxygen was provided to the subject’s incubator for 65 minutes, during which time the subject’s respiratory rate decreased and open-mouth breathing resolved. Hypoxemia may lead to increased respiratory drive via activation of peripheral chemoreceptors in the carotid and aortic bodies.30,31 Future research should involve pulse oximetry and blood gas analyses to further investigate this theory. In the meantime, oxygen supplementation via a tight-fitting mask should be considered for all birds administered the present protocol.
Compared to baseline, cloacal temperature decreased significantly for both treatments despite the provision of active thermal support. Previous work revealed sedation with IM butorphanol (1 mg/kg) and midazolam (0.5 mg/kg) in a variety of psittacid species that were maintained on a heating pad for thermal support resulted in a temperature decline of 0.04 to 0.28°C per minute.19 Tachypnea may have contributed to the decline in subjects’ cloacal temperature via increased evaporative heat loss, and the administration of opioids has been identified to interfere with thermoregulation in birds, especially when administered in combination with other drugs.30
Administration of the lower dose of alfaxalone at 2.5 mg/kg was associated with a lower incidence of muscle fasciculations and tremors. Previous studies7,10,17 in birds have reported various magnitudes and incidences of muscle activity such as muscle tremors, spastic movements, and wing fluttering following alfaxalone administration. Alfaxalone administration without prior or concurrent premedication in dogs and cats has a higher incidence of fair to poor recoveries characterized by paddling, thrashing, vocalization, opisthotonos, or seizure when compared to individuals that were administered a sedative or tranquilizer prior to alfaxalone.32 A previous study7 reported that the administration of 1 mg/kg, IM midazolam 10 minutes prior to the administration of 10 mg/kg, IM alfaxalone improved but did not abolish the incidence of muscle tremors and hyperexcitability when compared to 10 mg/kg, IM alfaxalone as a sole agent in Quaker parrots. In Bengalese finches, the combination of either butorphanol or midazolam with alfaxalone produced greater muscle relaxation than did alfaxalone alone.8 The results of the present study support the recommendation for the administration of butorphanol and midazolam prior to alfaxalone administration in Quaker parrots.
Both treatments allowed for endotracheal intubation and positioning for full-body radiographs with two orthogonal views. Over time there was a significant difference in the ability to position for radiograph acquisition or in investigator comfort in attempting radiograph acquisition between treatments, indicating that radiograph acquisition would need to be performed sooner after LDA administration than after HDA.
An aversive response to feather plucking and hemostatic toe pinch was reported with both treatments, which is consistent with findings in previous work with Quaker parrots sedated with alfaxalone and alfaxalone-midazolam.7 An aversive response to noxious stimuli was observed in all budgerigars administered alfaxalone at 10 mg/kg, IM and in all black-cheeked lovebirds administered 12.6 mg/kg alfaxalone, SQ.16,17 These findings suggest minimal to no analgesia is provided by the IM administration of midazolam, butorphanol, and alfaxalone at the doses evaluated. For invasive procedures, analgesia via alternative methods should be provided.
The body weight of birds was statistically higher in week 1 compared to week 2. Potential causes of decreased food intake and resultant weight loss may include the stress of handling and being separated from the flock during treatment administration on week 1 or fasting the night prior to treatment administration on week 1 and again on week 2. While 1 mg/kg, IM midazolam has been identified as an appetite stimulant in healthy budgerigars, more research is needed to assess the effect of the combination of alfaxalone, midazolam, and butorphanol on food intake in Quaker parrots.33
This study has several limitations. A treatment of midazolam-butorphanol without alfaxalone was not assessed, making the distinction between effects caused by midazolam-butorphanol or by alfaxalone challenging within the confines of the present study. Despite the lack of a midazolam-butorphanol control group, significant differences in the results were identified between the 2 groups. Measurement of capnography, pulse oximetry, or blood pressure was not performed, which might have provided insight into the cause for the observed changes in HR and RR as well as provided additional information regarding the safety of the treatments tested. The simple descriptive scale used to determine sedation score is nonvalidated and unique to the present study. Currently, there exist no avian-specific, validated sedation scales. The findings of the present study are directly applicable only to Quaker parrots, as significant variation in response to various sedative and anesthetic drug doses between avian species has been reported.
Administration of IN midazolam-butorphanol and IM alfaxalone at the doses examined in the present study was a safe and effective method for sedating Quaker parrots. The authors recommend the low-dose alfaxalone protocol used in the present study, as it produced adequate sedation with fewer muscle fasciculations than the high-dose alfaxalone protocol. Further research is needed to investigate the species-specific responses to this sedative protocol to determine its applicability in other pet psittacine species.
Acknowledgments
The authors declare that there were no conflicts of interest or third-party funding.
The authors thank the Schubot Avian Health Center and Debra Turner for contributions during the experimentation phase.
References
- 1.↑
Balko JA, Chinnadurai SK. Advancements in evidence-based anesthesia of exotic animals. Vet Clin North Am Exot Anim Pract. 2017;20(3):917–928. doi:10.1016/j.cvex.2017.04.014
- 2.↑
Turpen KK, Welle KR, Trail JL, Patel SD, Allender MC. Establishing stress behaviors in response to manual restraint in cockatiels (Nymphicus hollandicus). J Avian Med Surg. 2019;33(1):38–45. doi:10.1647/2017-315
- 3.↑
Martel A, Mans C, Doss GA, Williams JM. Effects of midazolam and midazolam-butorphanol on gastrointestinal transit time and motility in cockatiels (Nymphicus hollandicus). J Avian Med Surg. 2018;32(4):286–293. doi:10.1647/2017-266
- 4.↑
Mans C, Guzman DS, Lahner LL, Paul-Murphy J, Sladky KK. Sedation and physiologic response to manual restraint after intranasal administration of midazolam in Hispaniolan Amazon parrots (Amazona ventralis). J Avian Med Surg. 2012;26(3):130–139. doi:10.1647/2011-037R.1
- 5.↑
Paula VV, Otsuki DA, Auler Junior JO, Nunes TL, Ambrosio AM, Fantoni DT. The effect of premedication with ketamine, alone or with diazepam, on anaesthesia with sevoflurane in parrots (Amazona aestiva). BMC Vet Res. 2013;9:142. doi:10.1186/1746-6148-9-142
- 6.↑
Romano J, Hasse K, Johnston M. Sedative, cardiorespiratory, and thermoregulatory effects of alfaxalone on budgerigars (Melopsittacus undulatus). J Zoo Wildl Med. 2020;51(1):96–101. doi:10.1638/2019-0059
- 7.↑
Whitehead MC, Hoppes SM, Musser JMB, Perkins JL, Lepiz ML. The use of alfaxalone in Quaker parrots (Myiopsitta monachus). J Avian Med Surg. 2019;33(4):340–348. doi:10.1647/2018-393
- 8.↑
Perrin KL, Nielsen JB, Thomsen AF, Bertelsen MF. Alfaxalone anesthesia in the Bengalese finch (Lonchura domestica). J Zoo Wildl Med. 2017;48(4):1146–1153. doi:10.1638/2016-0300R.1
- 9.↑
Villaverde-Morcillo S, Benito J, Garcia-Sanchez R, Martin-Jurado O, Gomez de Segura IA. Comparison of isoflurane and alfaxalone (Alfaxan) for the induction of anesthesia in flamingos (Phoenicopterus roseus) undergoing orthopedic surgery. J Zoo Wildl Med. 2014;45(2):361–366. doi:10.1638/2012-0283R2.1
- 10.↑
Kruse TN, Messenger KM, Bowman AS, Aarnes TK, Wittum TE, Flint M. Pharmacokinetics and pharmacodynamics of alfaxalone after a single intramuscular or intravascular injection in mallard ducks (Anas platyrhynchos). J Vet Pharmacol Ther. 2019;42(6):713–721. doi:10.1111/jvp.12804
- 11.
White DM, Martinez-Taboada F. Induction of anesthesia with intravenous alfaxalone in two Isa Brown chickens (gallus Gallus Domesticus). J Exot Pet Med. 2019;29(C):119–122. doi:10.1053/j.jepm.2018.06.003
- 12.
Susanti L, Kang S, Park S, et al. Effect of three different sedatives on electroretinography recordings in domestic pigeons (Columba livia). J Avian Med Surg. 2019;33(2):115–122. doi:10.1647/2018-351
- 13.
Mastakov A, Henning J, de Gier R, Doneley R. Induction of general anesthesia with alfaxalone in the domestic chicken. J Avian Med Surg. 2021;35(3):269–279. doi:10.1647/19-00022
- 14.
Chang S, Legg-St Pierre CB, Ambros B. Comparison of sedative effects of alfaxalone-ketamine and Alfaxalone-midazolam administered intramuscularly in chickens. J Avian Med Surg. 2022;36(1):21–27. doi:10.1647/20-00111
- 15.↑
Escalante GC, Balko JA, Chinnadurai SK. Comparison of the sedative effects of alfaxalone and butorphanol-midazolam administered intramuscularly in budgerigars (Melopsittacus undulatus). J Avian Med Surg. 2018;32(4):279–285. doi:10.1647/2017-328
- 16.↑
Greunz EM, Limon D, Bertelsen MF. Alfaxalone sedation in black-cheeked lovebirds (Agapornis nigrigenis) for non-invasive procedures. J Avian Med Surg. 2021;35(2):161–166. doi:10.1647/19-00015
- 17.↑
Balko JA, Lindemann DM, Allender MC, Chinnadurai SK. Evaluation of the anesthetic and cardiorespiratory effects of intramuscular alfaxalone administration and isoflurane in budgerigars (Melopsittacus undulatus) and comparison with manual restraint. J Am Vet Med Assoc. 2019;254(12):1427–1435. doi:10.2460/javma.254.12.1427
- 18.↑
Food and Drug Administration. FDA adds Alfaxan Multidose IDX to the index of legally marketed unapproved new animal drugs for minor species. Updated 2/27/2020. Accessed May 12, 2021. www.fda.gov/animal-veterinary/cvm-updates/fda-adds-alfaxan-multidose-idx-index-legally-marketed-unapproved-new-animal-drugs-minor-species
- 19.↑
Kubiak M, Roach L, Eatwell K. The influence of a combined butorphanol and midazolam premedication on anesthesia in psittacid species. J Avian Med Surg. 2016;30(4):317–323. doi:10.1647/2013-072
- 20.
KuKanich B, Papich MG. Opioid analgesic drugs. In: Papich MG, Riviere JE, eds. Veterinary Pharmacology and Therapeutics. John Wiley & Sons; 2018:chap 13.
- 21.↑
Garner HR, Burke TF, Lawhorn CD, Stoner JM, Wessinger WD. Butorphanol-mediated antinociception in mice: partial agonist effects and mu receptor involvement. J Pharmacol Exp Ther. 1997;282(3):1253–1261.
- 22.↑
Brown EN, Pavone KJ, Naranjo M. Multimodal general anesthesia: theory and practice. Anesth Analg. 2018;127(5):1246–1258. doi:10.1213/Ane.0000000000003668
- 23.↑
Doss GA, Fink DM, Mans C. Assessment of sedation after intranasal administration of midazolam and midazolam-butorphanol in cockatiels (Nymphicus hollandicus). Am J Vet Res. 2018;79(12):1246-1252. doi:10.2460/ajvr.79.12.1246
- 24.↑
Zaheer OA, Sanchez A, Beaufrere H. Minimum anesthetic concentration of isoflurane and sparing effect of midazolam in Quaker parrots (Myiopsitta monachus). Vet Anaesth Analg. 2020;47(3):341–346. doi:10.1016/j.vaa.2020.01.005
- 25.↑
Klaphake E, Schumacher J, Greenacre C, Jones MP, Zagaya N. Comparative anesthetic and cardiopulmonary effects of pre- versus postoperative butorphanol administration in Hispaniolan Amazon parrots (Amazona ventralis) anesthetized with sevoflurane. J Avian Med Surg. 2006;20(1):2–7. doi:10.1647/1082-6742(2006)20[2:CAACEO]2.0.CO;2
- 26.↑
McCafferty DJ, Gallon, S., Nord, A. Challenges of measuring body temperatures of free-ranging birds and mammals. Animal Biotelemetry. 2015;3:1–10. doi:10.1186/s40317-015-0075-2
- 27.↑
Cortright KA, Wetzlich SE, Craigmill AL. Plasma pharmacokinetics of midazolam in chickens, turkeys, pheasants and bobwhite quail. J Vet Pharmacol Ther. 2007;30(5):429–436. doi:10.1111/j.1365-2885.2007.00880.x
- 28.↑
Schaffer DPH, de Araujo N, Raposo ACS, Filho EFM, Vieira JVR, Oria AP. Sedative effects of intranasal midazolam administration in wild caught blue-fronted Amazon (Amazona aestiva) and Orange-winged Amazon (Amazona amazonica) parrots. J Avian Med Surg. 2017;31(3):213–218. doi:10.1647/2016-201
- 29.↑
Guzman DS, Flammer K, Paul-Murphy JR, Barker SA, Tully TN Jr. Pharmacokinetics of butorphanol after intravenous, intramuscular, and oral administration in Hispaniolan Amazon parrots (Amazona ventralis). J Avian Med Surg. 2011;25(3):185–191. doi:10.1647/2009-054.1
- 30.↑
KuKanich B, Wiese AJ. Opioids. In Grimm KA, Lamont LA, Tranquilli WJ, Greene SA, Robertson SA, eds. Veterinary Anesthesia and Analgesia. Wiley; 2015:207–226.
- 31.↑
Hempleman SC, Powell FL, Prisk GK. Avian arterial chemoreceptor responses to steps of CO2 and O2. Respir Physiol. 1992;90(3):325–340. doi:10.1016/0034-5687(92)90112-a
- 32.↑
Food and Drug Administration. Freedom of information summary: NADA141-342. Updated 9/6/2012. Accessed May 12, 2021. https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/898
- 33.↑
Martel A, Berg C, Doss G, Mans C. Effects of midazolam on food intake in budgerigars (Melopsittacus undulatus). J Avian Med Surg. 2022;36(1):53–57. doi:10.1647/20-00096
Appendix 1
System used to score sedation after intramuscular administration of alfaxalone (2 mg/kg or 5 mg/kg) following intranasal administration of butorphanol (2 mg/kg) and midazolam (2 mg/kg) to Quaker parrots (Myiopsitta monachus).
| Description | Sedation score |
|---|---|
| Immediately rights when placed in dorsal recumbency; minimal ataxia | 1 |
| Eyes mostly open; head held upright | |
| Readily responds to auditory or visual stimulation | |
| Cannot be positioned for radiographs; cannot be intubated | |
| Attempts to right when placed in dorsal recumbency; minimal to moderate ataxia | 2 |
| Eyes partially or mostly closed; head hanging low or beak resting on floor | |
| Minimal response to auditory or visual stimulation | |
| Cannot be positioned for radiographs; cannot be intubated | |
| Remains in dorsal recumbency with no attempt to right | 3 |
| Eyes closed when not manipulated; head rests on floor | |
| Minimal to no response to auditory or visual stimulation | |
| Can be positioned for radiographs; cannot be intubated | |
| Remains in dorsal recumbency with no attempt to right | 4 |
| Eyes closed when not manipulated; head rests on floor | |
| Minimal to no response to auditory or visual stimulation | |
| Can be positioned for radiographs; can be intubated |
