Restraint of avian patients is routinely required for physical examination, diagnostic sample collection, diagnostic imaging, and other procedures. Stress induced by handling and manual restraint of birds remains a concern because a stress-induced response can result in serious adverse effects. A stressful event (eg, manual restraint) for birds can lead to an immediate activation of the sympathetic nervous system, which results in changes to heart rate, respiratory rate, and body temperature.1–4 Physiologic changes resulting from stress may also lead to changes in the leukogram of birds, which can confound interpretation of the values.5,6
Procedural sedation allows for ease of patient handling and can result in lower morbidity and mortality rates during restraint, especially in critically ill patients.7,8 Procedural sedation is becoming increasingly commonplace in avian medicine and can offer safety benefits over immobilization attained by use of inhalation anesthetics (eg, isoflurane) alone, which can cause severe dose-dependent hypotension in birds, among other complications.9
The IN administration of sedatives offers additional benefits for birds, including improved client perception and less influence on biochemical variables, in contrast to results with IM injection.8 In birds with limited muscle mass, the IN route may lead to less adverse reactions than with IM injection of relatively large volumes. In patients with suspected or confirmed coagulopathies, the IN route avoids the risk of iatrogenic hemorrhage secondary to IM administration of drugs. Midazolam alone and midazolam combined with butorphanol administered via the IM or IN routes are commonly used for sedation or premedication in pet bird species.8,10,11 One advantage of the use of midazolam and butorphanol for sedation is that the sedative effects of the drugs are reversible with flumazenil and naloxone, respectively. Midazolam is a water-soluble benzodiazepine that modulates GABAA receptors within the nervous system, which results in sedation and anxiolysis.12 Sedation with midazolam results in an amnestic response in chicks,13 which is a desirable effect in birds when performing potentially adverse procedures (eg, beak adjustments or feather trimming). Butorphanol is a synthetic opioid drug with mixed agonist-antagonist effects, with strong effects at κ- and σ-opioid receptors and weak activity at μ-opioid receptors. It is commonly used for analgesia, especially in psittacine species, and for its sedative effects.8 Butorphanol is not typically administered as a single agent for sedation in birds; it is usually combined with other drugs such as benzodiazepines.8 A benefit of butorphanol usage in combination with midazolam for sedation is the analgesic effects of butorphanol in psittacine birds and the synergistic effect on sedation depth, which results in the ability of clinicians to perform more invasive procedures without the need for general anesthesia.8
Despite the popularity of the use of butorphanol in clinical avian medicine, there is little information regarding the efficacy of butorphanol when administered IN to birds.14 For humans, IN administration of butorphanol is used to provide analgesia, with the butorphanol rapidly absorbed from the nasal mucosa.15 Butorphanol is also rapidly absorbed when administered IN to rabbits.16
The goal of the study reported here was to investigate the sedative effects of midazolam and midazolam-butorphanol after IN administration to a popular pet bird species (cockatiels [Nymphicus hollandicus]). We hypothesized that the midazolam-butorphanol combination would result in a deeper level of sedation and that both protocols would attenuate the stress response secondary to restraint.
Materials and Methods
Animals
Nine adult cockatiels (5 females and 4 males) were obtained from a breeder. All cockatiels were < 4 years old, and mean ± SD body weight was 98 ± 9.1 g. Birds were housed in cages (76 × 46 × 46 cm) in same-sex groups (≤ 3 birds/cage) in a climate-controlled room; room temperature was 22° to 24°C, relative humidity was 40% to 55%, and the lighting cycle was 12 hours of light to 12 hours of darkness. A diet of mixed seeds fed by the breeder was used as the primary diet, and a cuttlefish bone supplement-type product was available in each cage. Millet sprigs and seed-based treats were also offered 2 to 4 times/wk. Various toys were provided for enrichment. Birds were allowed to acclimate to the housing for 2 weeks before the beginning of the experiments. The study was approved by the University of Wisconsin School of Veterinary Medicine Institutional Animal Care and Use Committee (protocol No. V005666).
Physical examination, assessment of PCV, estimation of WBC counts, and fecal parasitological examination were performed before the start of the experiments. Assessment of the results revealed no substantial abnormalities, and all birds were considered to be in good health for the duration of the study. As part of the physical examinations, the nares of each cockatiel were examined before each experimental period to ensure they were patent and did not have gross abnormalities.
Study design
A randomized, blinded, complete crossover design was used to determine the sedative effects of IN administration of midazolam and midazolam-butorphanol in cockatiels. Birds were assigned to receive each of 3 treatments: midazolama (5 mg/mL solution) administered at a dose of 3 mg/kg, IN; a combination of midazolam and butorphanolb (10 mg/mL solution) administered at a dose of 3 mg/kg, IN, for each drug (administered as a single dose); and sterile saline (0.9% NaCl) solution (1 mL/kg, IN; control treatment). To ensure that the treatment remained unknown to investigators and that the drug volume administered was not a variable, the volume of all treatments was standardized to the volume of the midazolam-butorphanol treatment (ie, 1 mL/kg). This was accomplished by adding saline solution to the midazolam treatment in a single syringe.
Cockatiels were housed in ventilated, translucent plastic rodent laboratory enclosures during the experiments to enable direct observation of the birds. Baseline measurements for head position, eye position, body position, and response to visual, auditory, and tactile stimulation were recorded. One minute later, birds were manually restrained and administered 1 of the 3 treatments; treatments were administered IN into both nares over a 10-second period by use of a 0.3-mL insulin syringec with the needle removed. Birds then were captured 10 minutes after IN administration and manually restrained for 15 minutes. At the end of the restraint period, birds receiving the midazolam and midazolam-butorphanol treatments also received flumazenila (0.1 mg/mL solution) at a dose of 0.05 mg/kg, IN, split evenly between both nares to reverse the effects of midazolam. An equivalent volume of sterile saline solution was administered IN to birds receiving the control treatment. Butorphanol was not reversed. At 15 minutes after administration of the flumazenil, a postreversal evaluation of sedation was conducted.
Sedation variables were assessed at baseline (time 0), 10 minutes after administration of the treatments at the time of capture, each minute during the 15-minute restraint period, and 15 minutes after reversal of sedation. Head, eye, and body position as well as response to visual, auditory, and tactile stimulation were scored on a scale of 0 to 2 as described elsewhere7 (Appendix). Sedation score was defined as the cumulative total for all 6 variables (range, 0 to 12), with higher numeric values equating to a deeper plane of sedation. Sedation score during the restraint period was determined on the basis of eye position and intensity of struggling; both variables were scored on a scale of 0 to 2.
First sedation effect was defined as the time when any change in eyelid, head, or body position or onset of ataxia was detected after drug administration. Cumulative sedation scores were calculated by scoring head position, eye position, body position, and response to visual, auditory, and tactile stimulation at 3 time points (baseline, 10 minutes after treatment administration at the time of capture, and 15 minutes after reversal of sedation). Response to visual stimulation was assessed by briefly moving a small white towel in front of the enclosure. Response to auditory stimulation was assessed by removing the lid of the enclosure, which produced an auditory stimulus. When a cockatiel was sedated to a depth at which it no longer had a response to visual or auditory stimulation, then the response to tactile stimulation was evaluated by lightly stroking a cotton-tipped applicator over the dorsum of the interscapular area.
Additionally, physiologic variables (heart rate, respiratory rate, and cloacal temperature) were measured every 3 minutes during the restraint period. Heart rate was determined via stethoscope auscultation over the pectoral muscles, and respiratory rate was determined on the basis of observed keel excursions. Cloacal temperature was recorded with a digital thermometerd attached to a stainless steel, 3.2-mm-diameter, rounded probe.e The probe was coated with lubricating gel and placed in the cloaca; temperature was recorded 10 seconds after insertion of the probe. The same investigator (GAD) measured all physiologic variables.
Birds were returned to group housing once fully recovered (all behavioral variables had returned to baseline values, and birds were alert and had a normal posture and level of activity). There was a minimum washout period of 7 days between experiments.
Statistical analysis
A commercial statistical software packagef was used to analyze the data. Randomization was performed with online software.g Data were tested for normality by use of a Shapiro-Wilk test and for constant variance with the Brown-Forsythe test. Data that were not normally distributed or equally distributed were ranked prior to further analysis. Repeated-measures ANOVAs were used to evaluate the data for effects of treatment and time. The Holm-Sidak method was used for post hoc pairwise multicomparison procedures. Data were reported as mean ± SD or median and range unless otherwise specified. Values were considered significant at P < 0.05.
Results
No adverse reactions, including sneezing or signs of respiratory distress, were observed in any birds for any treatment. All birds remained healthy for the duration of the study. The median volume of midazolam and butorphanol administered IN was 0.06 mL (range, 0.05 to 0.07 mL) and 0.030 mL (range, 0.030 to 0.035 mL), respectively. The maximum volume administered IN (midazolam combined with sterile saline or midazolam-butorphanol combination) was 0.09 mL (range, 0.08 mL to 0.10 mL). The median volume of flumazenil administered IN for reversal was 0.05 mL (range, 0.04 to 0.06 mL).
First sedation effects were detected at 85 seconds (range, 60 to 120 seconds) for the midazolam treatment and at 90 seconds (range, 45 to 180 seconds) for the midazolam-butorphanol treatment. Median sedation scores were determined for the 3 evaluation time points (baseline, at capture, and after reversal; Table 1). Ten minutes after drug administration (at capture), there were significant differences in sedation scores among all treatments. Median sedation scores for midazolam and midazolam-butorphanol at capture were significantly higher, compared with the baseline scores. At capture, midazolam-butorphanol induced a score of 2 for all sedation variables in a greater number of birds than those receiving midazolam alone or saline solution (Figure 1). This resulted in significantly (P = 0.046) higher sedation scores at capture for birds when they received the midazolam-butorphanol treatment.
Number of cockatiels (Nymphicus hollandicus; n = 9) at 10 minutes after IN administration of saline (0.9% NaCl) solution (control treatment), midazolam (3 mg/kg; white bars), or midazolam-butorphanol (3 mg/kg for each drug; gray bars) that had a score of 2 (scale, 0 to 2) for various sedation variables. There was a minimum washout period of 7 days between treatments. The control treatment did not result in sedation.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1246
Median (range) sedation score of 9 cockatiels (Nymphicus hollandicus) at 3 defined time points after IN administration of saline (0.9% NaCl) solution (control treatment), midazolam (3 mg/kg), or midazolam-butorphanol (3 mg/kg for each drug).
| Time point | Control | Midazolam | Midazolam-butorphanol |
|---|---|---|---|
| Baseline | 0 (0–3) | 0 (0) | 0 (0) |
| At capture | 0 (0–4)a | 6 (3–10)b | 8 (3–11)c |
| After reversal | 0 (0) | 1 (0–7) | 0 (0–6) |
Sedation variables were assessed 1 minute before treatment administration (baseline), 10 minutes after treatment administration at the time of capture, and 15 minutes after reversal of sedation by use of a scoring scale (scale of 0 to 2 for each of 6 distinct variables; total range of sedation scores, 0 to 12).
Values with different superscript letters within a time point differ significantly (P < 0.05).
During the 15-minute restraint period, midazolam-butorphanol resulted in significantly (P = 0.037) less struggling than did midazolam. Midazolam and midazolam-butorphanol resulted in significantly (P < 0.001) less struggling, compared with results for the control treatment. For both midazolam and midazolam-butorphanol, birds had their eyes closed significantly (P < 0.001) more frequently than for the control treatment, but there was no difference in eyelid position between the midazolam and midazolam-butorphanol treatments during restraint.
Heart rate did not differ significantly among treatments at any time point (Figure 2). Mean respiratory rate for the control treatment was significantly (P = 0.01) higher from 6 to 15 minutes of the restraint period, compared with the respiratory rate for the midazolam and midazolam-butorphanol treatments (Figure 3). Within the control treatment, respiratory rate was significantly (P = 0.04) higher from 9 to 15 minutes of the restraint period, compared with the baseline value. There were no significant differences in respiratory rate between or within the midazolam and midazolam-butorphanol treatments at any time point.
Mean ± SEM heart rate of 9 cockatiels during a 15-minute period of manual restraint after IN administration of saline solution (control treatment; black circles), midazolam (white circles), or midazolam-butorphanol (gray circles). Cockatiels were administered the IN treatment 10 minutes prior to restraint.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1246
Mean ± SEM respiratory rate of 9 cockatiels during a 15-minute period of manual restraint after IN administration of saline solution (control treatment), midazolam, or midazolam-butorphanol. *Within a time point, value differs significantly (P < 0.05) from the value for the other treatments. †Within a treatment group, value differs significantly (P < 0.05) from the measurement at 0 minutes. See Figure 2 for remainder of key.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1246
Cloacal temperature increased significantly (P < 0.001) for all treatments during the restraint period (Figure 4). Values from 3 to 15 minutes of the restraint period were significantly higher than baseline values for all treatments. For the control treatment, cloacal temperature increased by a median of 2.4°C (range, 1.2° to 4.0°C) during the restraint period. Cloacal temperature increased by a median of 2.2°C (range, 0° to 3.6°C) for both the midazolam and midazolam-butorphanol treatments during the restraint period.
Median ± interquartile (25th to 75th percentiles) range for cloacal temperature of 9 cockatiels during a 15-minute period of manual restraint after IN administration of saline solution (control treatment), midazolam, or midazolam-butorphanol. *Within a time point, values differ significantly (P < 0.05) from the measurement at 0 minutes for all treatment groups. See Figure 2 for remainder of key.
Citation: American Journal of Veterinary Research 79, 12; 10.2460/ajvr.79.12.1246
For both the midazolam and midazolam-butorphanol treatments, there was a significant (P = 0.01) difference in sedation scores between the baseline and postreversal time points, with higher median scores for the postreversal time point. All cockatiels were considered sufficiently awake to safely resume normal activities by the postreversal time point.
Discussion
The study reported here was conducted to examine sedative effects after IN administration of midazolam and midazolam-butorphanol in cockatiels. Subjectively, the sedation observed in the present study should have been sufficient to facilitate physical examination, venipuncture, beak and nail trimming, and diagnostic imaging in this species.
Onset of first sedation effects after IN administration of midazolam and midazolam-butorphanol in cockatiels was rapid. It is possible that onset of sedation was associated with the appearance of first effects, but handling and other stimulation were deliberately not performed during the first 10 minutes after drug administration so that they would not interfere with induction of sedation, which made it impractical to assess sedation on the basis of response to stimulation.
For the present study, midazolam-butorphanol treatment resulted in a deeper plane of sedation in cockatiels before and during restraint, compared with sedation after administration of midazolam alone. It has been recommended that midazolam-butorphanol, rather than midazolam alone, be administered to birds when a deeper plane of sedation is needed or more invasive procedures are being performed.8 This was supported by the findings of the present study because when cockatiels received only midazolam, they appeared more awake at rest and struggled more intensely during the restraint period.
Similar to results for the control treatment, administration of midazolam or midazolam-butorphanol did not cause a significant change in heart rate over time during restraint. This is similar to findings for Hispaniolan Amazon parrots (Amazona ventralis) after IN administration of midazolam (2 mg/kg).7 Heart rate of those birds over a 15-minute manual restraint period did not change significantly, compared with results for birds after IN administration of saline solution.7
Respiratory rate was significantly lower for most of the restraint period when cockatiels were sedated with midazolam or midazolam-butorphanol, compared with results after cockatiels received the control treatment. This is similar to findings in Hispaniolan Amazon parrots in which IN administration of midazolam resulted in an overall lower mean respiratory rate during restraint.7 In contrast, the respiratory rate in Hispaniolan Amazon parrots in that study7 increased significantly during a 15-minute restraint period, which is dissimilar to the findings for the cockatiels of the study reported here, which may indicate a species-specific difference in the stress response. In hooded red-tailed hawks, respiratory rate was significantly lower at numerous time points during restraint, compared with the respiratory rate for the control group, which indicates that stress alleviation may lead to differences in respiratory rate in that avian species.17
When compared with results for the control treatment, neither midazolam nor midazolam-butorphanol had a significant effect on cloacal temperature. Intranasal administration of midazolam to Hispaniolan Amazon parrots resulted in lower mean cloacal temperatures when compared with results for nonsedated birds, but cloacal temperatures continued to increase over time.7 That elevation in cloacal temperature over time mirrors the findings of the study reported here. The increasing cloacal temperature in the sedated cockatiels indicated an ability to physiologically respond to restraint stress despite evident sedation and a decrease in respiratory rate. One potential explanation for these findings is that the dosages of midazolam and midazolam-butorphanol used were insufficient to result in complete abolition of the stress response. The authors routinely use higher doses of midazolam and butorphanol than the ones used in the present study when sedating small psittacine species. It is also possible that the stress response to manual restraint in birds cannot be completely abolished without heavy sedation or general anesthesia. To the authors’ knowledge, no studies have been conducted to examine whether the physiologic alterations of the avian stress response can be fully attenuated with chemical immobilization.
Distinctions in results between the cockatiels of the present study and Hispaniolan Amazon parrots underscore the existence of species-specific responses to stress in birds and reiterate the need for further research in this area. Additional studies on the effects of dose of midazolam and midazolam-butorphanol and species on the avian stress response are needed to determine the best possible anesthetic options for avian patients.
Significant cardiorespiratory depression was not detected with midazolam or midazolam-butorphanol in the study reported here. This is similar to results for larger psittacine species in which a combination of midazolam-butorphanol administered IM did not induce significant changes in heart rate or respiratory rate.11 In another study,18 there were no changes in heart rate or respiratory rate of pigeons administered midazolam IN. Although cockatiels sedated with midazolam and midazolam-butorphanol had lower sedation scores after administration of flumazenil, compared with the sedation score at capture, scores at capture were significantly higher than baseline values, which indicated that some sedation persisted despite administration of the reversal agent. However, on the basis of the low median sedation scores and the awake clinical appearance of the cockatiels 15 minutes after administration of the reversal agent, the amount of sedation remaining was considered minimal and not clinically relevant. In Hispaniolan Amazon parrots sedated with midazolam administered IN, sedation scores returned to baseline 10 minutes after reversal with flumazenil.7 However, response to capture was used to assess sedation 10 minutes after reversal in those parrots, which may have resulted in differences in results, compared with those of the present study.
Because flumazenil was administered to all birds 25 minutes after induction, the duration of sedative effects for midazolam and midazolam-butorphanol was unknown. Further studies conducted to examine the pharmacokinetics and pharmacodynamics after IN administration of midazolam and midazolam-butorphanol in avian species are warranted.
Total volumes administered IN to the cockatiels of the present study were comparable to18 or less than19,20 the volumes used in other studies conducted to examine sedation of small pet birds after IN administration. Although volume and surface area of the nasal cavity were not evaluated in the study reported here, the volumes of the solutions administered were tolerated well by the cockatiels. It is possible that some portion of the dose administered IN was swallowed or entered the glottis during administration, which could have potentially affected absorption. Thus, the sedative dose was administered over several seconds to maximize contact time with the respiratory mucosa.
Midazolam and midazolam-butorphanol both induced sedation when administered IN to cockatiels. The midazolam-butorphanol combination induced a deeper plane of sedation in undisturbed cockatiels and in cockatiels during manual restraint. Cockatiels sedated with midazolam and midazolam-butorphanol had a lower respiratory rate during restraint, compared with that for awake cockatiels, but sedation had no effect on cloacal temperature or heart rate. Intranasal administration of midazolam and midazolam-butorphanol at the doses examined in the present study was an effective and safe option for sedating cockatiels. Results of this study indicated 2 efficacious sedative options for a common pet psittacine species.
ABBREVIATIONS
| GABA | γ-Aminobutyric acid |
| IN | Intranasal |
Footnotes
West-Ward Pharmaceuticals, Eatontown, NJ.
Fort Dodge Animal Health, New York, NY.
VetRx, UltiCare, Excelsior, Minn.
Type T thermocouple, Barnant Corp, Barrington, Ill.
RET-2 probe, Physitemp Instruments Inc, Clifton, NJ.
SigmaPlot, version 13, Access Softek Inc, Berkeley, Calif.
Research Randomizer, version 4.0, Geoffrey C. Urbaniak and Scott Plous, Middletown, Conn. Available at: www.randomizer.org. Accessed Dec 6, 2016.
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Appendix
System used to score sedation after IN administration of saline (0.9% NaCl) solution, midazolam (3 mg/kg), or midazolam-butorphanol (3 mg/kg for each drug) to 9 cockatiels (Nymphicus hollandicus).
| Sedation score | |||
|---|---|---|---|
| Variable | 0 | 1 | 2 |
| Eye position | Open | Partially closed | Fully closed |
| Head position | Upright | Hanging | Beak or head resting on floor |
| Body position | Standing | Crouched or resting on tibiotarsal-tarsometatarsal joints | Sternally recumbent |
| Visual stimulation | Head and eye movement | Reduced head or eye movement | No response |
| Auditory stimulation | Head and eye movement | Reduced head or eye movement | No response |
| Tactile stimulation | Head and eye movement | Reduced head or eye movement | No response |
| Struggling intensity | Strong and repetitive movement of head, body, wings, and hind limbs | Reduced strength and frequency of movement of head, body, wings, and hind limbs | No movement of head, body, wings, and hind limbs |
Adapted from Mans C, Sanchez-Migallon Guzman D, Lahner LL, et al. Sedation and physiologic response to manual restraint after intranasal administration of midazolam in Hispaniolan Amazon parrots (Amazona ventralis). J Avian Med Surg 2012;26:130–139. Reprinted with permission.
