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Sedative effects of intranasal midazolam administration in wild caught blue-fronted amazon (Amazona aestiva) and or ange-winged Amazon (Amazona amazonica) parrots.

Abstract: Safe and effective sedation protocols are important for chemical restraint of birds in clinical and diagnostic procedures, such as clinical evaluations, radiographic positioning, and blood collection. These protocols may reduce stress and ease the management of wild-caught birds, which are susceptible to injury or death when exposed to stressful situations. We compare the sedative effect of intranasal midazolam in wild-caught blue-fronted (Amazona aestiva) and orange-winged (Amazona amazonica) Amazon parrots. Ten adult parrots of each species (n = 20), of unknown sex, weighing 0.337 [+ or -] 0.04 (blue-fronted) and 0.390 [+ or -] 0.03 kg (orange-winged), kg were used. Midazolam (2 mg/kg) was administered intranasally and the total volume of the drug was divided equally between the 2 nostrils. Onset time and total sedation time were assessed. Satisfactory sedation for clinical evaluation was induced in all birds. Onset time and total sedation times were similar in both species: 5.36 [+ or -]1.16 and 25.40 [+ or -] 5.72 minutes, respectively, for blue-fronted Amazons and 5.09 [+ or -] 0.89 and 27.10 [+ or -] 3.73 minutes, respectively, for orange-winged Amazons. A total of 15 animals showed absence of vocalization, with moderate muscle relaxation and wing movement upon handling, and 2 animals presented with lateral recumbence, with intense muscle relaxation and no wing movement, requiring no restraint. Three blue-fronted Amazons had no effective sedation. Intranasally administered midazolam at a dose of 2 mg/kg effectively promoted sedative effects with a short latency time and fast recovery in wild-caught parrots.

Key words: benzodiazepine, premedication, bird, muscle relaxant, restraint, sedation, avian, wildcaught parrot, blue-fronted Amazon parrot. Amazona aestiva, orange-winged Amazon parrot. Amazona amazonica

Introduction

Parrots must be restrained manually for a variety of diagnostic and therapeutic procedures. (1) However, this induces a stress response in avian patients. (1-3) Chemical restraint usually is necessary to avoid stress and to facilitate safe handling, especially for birds that are not accustomed to handling and restraint. (3-5)

In avian medicine, anesthetics and sedatives can be injected into the vein, muscle, or intraosseous tissue. However, these routes are invasive, can elicit pain, and can be difficult to perform in small birds, particularly in those with decreased muscle mass, and they can present the risk of accidental intracoelomic or intravascular drug administration when related to intramuscular injection. (1,6) Pain associated with intramuscular injection may be considerable, particularly with agents that are irritants or with increased volumes administered. (1,7-10)

Intranasal (INS) administration of sedative drugs has been reported rarely in avian anesthesia. (3,6) Considered as an acceptable method of drug delivery, some investigators have described it as a noninvasive, painless, and suitable mode of drug administration. (2,7) Different drugs have been used for intranasal sedation in birds, (2,3,7) including the [alpha]-2 agonists, such as xylazine (3,4,7,8,11) and dexmedetomidine; (6) opioids, such as butorphanol; (12) and benzodiazepines, such as midazolam (1,3,6,7,11,13) and diazepam, (2-4,7,8) with or without ketamine. (5,9-11) In addition, for sedative protocols comparing intramuscular and intranasal routes, the latter had a shorter onset of sedation and recovery time. (9,10)

Midazolam is a hydrosoluble benzodiazepine with anxiolytic and muscle-relaxant effects in several animal species. (6) In avian species, this drug, with high doses (7 mg/kg and 13 mg/kg), is sufficient to enable good tolerance of the dorsal recumbent position. (2,11) In addition, intranasal application of midazolam has been shown to be effective for rapid induction of sedation in several bird species, (1,3,6,8-11-13) with onset times ranging from 1.02 [+ or -] 0.29 minutes in zebra finches (Taereopygici guttata)1 to 3.2 [+ or -] 1.3 minutes in pigeons (Columba livia)8 and 1.9 [+ or -] 1.0 minutes in canaries (Serinus canaria). (2)

In pigeons, Hornak et al (6) described some signs of excitation during recovery. Nevertheless, the advantage of midazolam's short sedation time, as cited for other bird species, (2,3,8) overcomes this side effect. The total sedation time reported in birds ranges from 74.2 [+ or -] 8.7 minutes in zebra finches (7) to 71.6 [+ or -] 8.9 minutes in budgerigars (Melopsitticus undulatus), (3) and 39.7 [+ or -] 13.4 minutes in canaries, at the same doses of 13 mg/kg.

The rapid onset and duration of action of sedatives administered intranasally in birds are topics of interest for clinicians who routinely work with avian species. (3,13) We compared the sedative effects after intranasal administration of midazolam in two species of wild-caught parrots, the bluefronted Amazon (Amazona aestiva) and orangewinged Amazon (Amazona amazonica).

Materials and Methods

Study protocol

Adult parrots (10 blue-fronted and 10 orange-winged Amazons) of unknown sex, weighing 0.347 [+ or -] 0.04 and 0.390 [+ or -] 0.03 kg, respectively, from the Triage Center of Wild Animals (CETAS/IBAMA, Salvador, Bahia, Brazil) were assessed. These animals were housed in outdoor enclosures for approximately 12 months until wildlife reintroduction. For this study, the birds were fasted (water and food) for 2 hours and placed individually in wire cages (50 X 49 X 35 cm) in an air-conditioned environment, with temperature ranging from 77.2[degrees]F to 80.2[degrees]F (25.1[degrees]C-26.8[degrees]C) and humidity ranging from 61% to 65%. Birds always were physically restrained by the same operator, who evaluated the response to handling and the vocalization intensity at two time points: at first capture, when the parrot was physically restrained with the aid of a blanket and leather gloves for individual weighing on a scale, and at second capture, after the sedation-score assessment. The sequence of performed procedures is described in Figure 1.

For sedation, the birds were gripped firmly around the back of the neck with the thumb and forefinger of one hand to restrict head movement, and the wings were held folded against the body with the other hand. Midazolam 0.5% was administered at a dose of 2 mg [kg.sup.-1] INS with a 24-gauge intravenous catheter (Solidor; Lamedid Comercial e Servicos LTDA, Barueri/SP, Brazil) inserted approximately 2 to 4 mm into each nostril (Fig 2). The total administered volume was divided equally between the 2 nostrils to avoid discomfort or drug overflow. Noise, movement, and other stimuli were minimized after drug administration.

Birds then were placed in the cages for evaluation of sedation quality, assessed according to the Ramsay sedation scale, adapted for birds by Schaffer et al (13) (Table 1), and onset of sedation, defined as the time elapsed after drug administration until the animals showed major signs of sedation (beak on the ground, seated position, or recumbence). For vocalization intensity evaluation, the grading described by Mans et al (1) was used, in which vocalization of the birds, under restraint, was assessed (normal/screaming, reduced/chattering, or absent).

Immediately after the birds exhibited major sedative behavior and the evaluator recorded the sedation score, the birds underwent clinical assessment for 2 to 5 minutes. The clinical assessment consisted of a physical and external biometrie examination, performed by the same operator. At the end of the evaluation, the birds were returned to their cages for the total sedation time measurement, from midazolam administration until the bird returned to a bipedal position and perching.

Statistical analysis

Data were subjected to the Shapiro-Wilk normality test (P > .05). The unpaired Student's t-test was used to analyze onset time and total sedation time, with the purpose of comparing means and standard deviations (SD) of the 2 parrot species. The Mann-Whitney U test was used to compare medians/ranges of sedation and vocalization scores. For analysis, the GraphPad Prism program, version 4.12 (GraphPad Software, Inc., La Jolla, CA, USA), was used and the level of significance was set to P < .05.

Results

Every bird accepted the intranasal administration without resistance. However, 2 blue-fronted Amazons began sneezing immediately after the drug's administration.

There was a marked decrease in vocalization intensity during the second handling, similar in both studied species when compared to vocalization during the first restraint. Six blue-fronted Amazons (6/10) showed absence of vocalization and four (4/10) maintained reduced/chattering vocalization. Eight orange-winged Amazons (8/ 10) showed absence of vocalization and the remaining two (2/10) had reduced/chattering vocalization (Fig 3).

Time to onset of sedation and total sedation time were fast after intranasal midazolam administration in blue-fronted Amazons (5.36 [+ or -] 1.16 and 25.40 [+ or -] 5.72 minutes, respectively) and orange-winged Amazons (5.09 [+ or -] 0.89 and 27.10 [+ or -] 3.73 minutes, respectively), as given in Table 2. The animals showed initial signs of sedation (Fig. 4), such as yawning followed by drowsiness (slower eyelid incursion--nap) and ambulation inside the cage (roam) until adoption of a "seated" position (seat); that is, relaxed, slightly opened wings, and body weight on the hock.

No significant difference was found between the sedation scores reached by both studied species (P = .42). Three blue-fronted Amazons had a score of 1, 15 (5 blue-fronted and 10 orange-winged Amazons) had a score of 2, and two blue-fronted Amazons had a score of 3. A sedation score of 4 was not observed in this study.

Discussion

The administration of 2 mg/kg INS midazolam promoted light-to-moderate sedative effects in wild-caught parrots, with short latency time and fast recovery. Every bird achieved sufficient satisfactory sedation to perform a clinical evaluation and remained stable, without any signs of excitation or deep sedation

The intranasal route has been demonstrated to be an effective method of drug delivery for sedation in these parrots, with no resistance, (8) as well as reported in other birds, due to rich vascularization and high permeability of the nasal passage, resulting in rapid absorption and short latency time. (7,9) The use of a catheter coupled to the syringe for intranasal drug administration in the present investigation facilitated the sedative agent's instillation without inducing injury, (13) in contrast to the situation described for budgerigars, (5) which used a 30-International Unit (TU) insulin syringe.

The dose used in our study was chosen from reported doses ranging from 1 to 13 mg/kg in different bird species. (2,6,7,11) Doses of midazolam exceeding 6.5 mg/kg have been associated with longer recovery times. (8) Therefore, the dose of 2 mg/kg was chosen, as used previously in Hispaniolan parrots (Amazona ventralis) (1) and macaws (Ara araruana). (13)

The total sedation time observed in our study was similar to that reported in parrots (1) and macaws, (13) with the same dose (2 mg/kg), and in canaries with 13 mg kg (1,2) ranging from 15 to 40 minutes. A longer sedation time was observed in pigeons (approximately 82 minutes) and budgerigars (71.6 [+ or -] 8.9 minutes), but this might have been associated with a higher dose of administered midazolam (6.5 [+ or -] 1.0 and 13 mg/kg, respectively) or differences on the metabolism of the studied species. (8,14)

Birds are intensely vocal creatures, and communication by sound has a central role in their lives. (14,15) A decrease or absence of vocalization is considered the major indicator of sedation in some birds, (1,5,13) and this reduction was observed in all birds handled in our study after intranasal administration of midazolam.

The onset of sedation observed in our study was similar to that found for Hispaniolan parrots, with a dose of 2 mg [kg.sup.-1], which showed signs of sedation at 3 minutes, and a higher degree of sedation 6 minutes after intranasal midazolam administration. (1) The onset of sedation was shorter in canaries (1.9 [+ or -] 1.0 minutes) (2) and finches (1.02 [+ or -] 0.29 minutes), (7) possibly because of their smaller body size and associated higher metabolism. However, doses of 6.5 mg/kg in pigeons (3.2 [+ or -] 1.3 minutes) (8) and 2 mg/kg in macaws (2.0 [+ or -] 0.5 minutes) (13) also achieved a short onset of sedation in large birds, possibly because of less agitated behavior.

Signs of sedation, such as those found in our study (blinking, keeping the eyes partially or completely closed, and a standing or broad-based body position or resting on hocks) have been reported in Hispaniolan parrots.' Positioning the beak on the ground has been reported as a sign of sedation in macaws, (13) but was not observed clearly in this study, perhaps because of the parrots' agitated behavior. Dorsal recumbence was not observed in any parrot after midazolam administration, even when placed in this position during sedation assessment, but it has been described after intranasal administration of midazolam and diazepam in pigeons (8) and canaries. (2) Moreover, intranasal administered midazolam lightly decreased respiratory rate in canaries, budgerigars, and Canada geese (Branla canadensis), but had no effect on hemoglobin saturation or on the values of venous blood gas variables. (2,7,16) The use of midazolam did not promote damage to cardiovascular functions in geese. (16) In our study, physiologic data were not recorded. All parrots had a smooth recovery and did not show signs of respiratory distress during sedation. Nevertheless, further studies are necessary to evaluate the effects of midazolam on other cardiovascular and respiratory parameters, such as arterial blood pressure and end-tidal carbon dioxide level.

Aside from some sneezing in 2 parrots, no serious adverse effects were observed in this study. Some investigators have described persistent sneezing, noise in the upper airway, and trembling, myoclonic seizures, and muscle tremors in canaries and macaws. (2,7,13)

The administration of 2 mg/kg INS midazolam achieved light-to-moderate sedative effects in wild-caught parrots, with a short latency time and fast recovery. Every animal achieved sufficient satisfactory sedation to perform a clinical evaluation and remained stable, without any signs of excitation or deep sedation. In our study, intranasal drug delivery was well tolerated and no complications were observed.

Acknowledgments: We thank Josiano Cordeiro Torezani and Fernanda de Azevedo Liborio (Screening Center for Wild Animals--Salvador) for their contributions to the study.

Supported by FAPESB (Bahia Research Foundation).

References

(1.) Mans C, Guzman DSM, 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(3): 130-139.

(2.) Vesal N, Zare P. Clinical evaluation of intranasal benzodiazepines, alpha2-agonists and their antagonists in canaries. Vet Anaesth Analg. 2006;33(3): 143-148.

(3.) Sadegh AB. Comparison of intranasal administration of xylazine, diazepam, and midazolam in budgerigars (Melopsittacus undulatus): clinical evaluation./Zoo Wildl Med. 2013;44(2):241-244.

(4.) Al-Shebani WHS. The sedative effect of intranasal administration of some sedative agents in budgerigar (Melopsittacus undulatus). Al-Anbar J Vet Sei. 2011;4(2):171-177.

(5.) Trevisan GA, Silva ELD, Carvalho ALD. Luiz RM. Anesthetics effects of intranasal or intramuscular association of midazolam and racemic or S+ ketamine in budgerigars (Melopsittacus undulatus). Cienc Anim Bras. 2016;17(1): 126-132.

(6.) Hornak S, Liptak T, Ledecky V, et al. A preliminary trial of the sedation induced by intranasal administration of midazolam alone or in combination with dexmedetomidine and reversal by atipamezole for a short-term immobilization in pigeons. Vet Anaesth Analg. 2015;42(2): 192-196.

(7.) Bigham AS, Zamani Moghaddam AK. Finch (Taeneopygia guttata) sedation with intranasal administration of diazepam, midazolam or xylazine. J Vet Pharmacol Ther. 2013;36(1): 102-104.

(8.) Moghadam AZ. Sadegh AB, Sharifi S. Habibian S. Comparison of intranasal administration of diazepam, midazolam and xylazine in pigeons: clinical evaluation. Iranian J Vet Sei Technol. 2009; 1(1): 12-26.

(9.) Beier SL, Rosa AC, Oleskovicz N, et al. Efeitos anestesicos da administracao intranasal ou intramuscular de cetamina S+ e midazolam em pombarola (Streptotelia sp.). Pesq Vet Bras. 2013;33(4): 5)7-522.

(10.) Bitencourt EH, Padilha VS. Lima MP, et al. Efeitos sedativos da associacao de Cetamina e Midazolam administrados pela via intranasal ou intramuscular em papagaio (Amazona aestiva e Amazona vinacea). Pesq Vet Bras. 2013;33(9):1125-1129.

(11.) Vesal N, Eskandari MH. Sedative effects of midazolam and xylazine with or without ketamine and detomidine alone following intranasal administration in ring-necked parakeets. J Am Vet Med Assoc. 2006;228(3):383-388.

(12.) Mans C. Sedation of pet birds. J Exot Pet Med. 2014;23(2): 152-157.

(13.) Schaffer D, Raposo A, Liborio F, et al. Intranasal administration of midazolam in blue-and yellow macaws (Ara araruana): evaluation of sedative effects. Vet Anaesth Analg. 2016;43(4):459-460.

(14.) Catchpole CK, Slater PJB. Bird Song: Biological Themes and Variations. 2nd ed. New York: Cambridge University Press; 2008.

(15.) Hu Y, Cardoso GC. Which birds adjust the frequency of vocalizations in urban noise? Anim Behav. 2010;79(4):863-867.

(16.) Valverde A. Honeyman VL, Dyson D, Valliant AE. Determination of a sedative dose and influence of midazolam on cardiopulmonary function in Canada geese. J Am J Vet Res. 1990:51 (7): 1071-1074.

Debora P. H. Schaffer, MS, Nayone L. L. C. de Araujo, MS, Ana Claudia S. Raposo, MS, Emanoel F. Martins Filho, DVM, Joao Victor R. Vieira, and Arianne P. Oria, DVM

From the School of Veterinary Medicine and Zootechny, Federal University of Bahia (UFBA), Avenida Adhemar de Barros, n. 500--Ondina. Salvador--Bahia. Brazil. 40170-110.

Caption: Figure 1. Timeline of procedures performed during the study designed to investigate the effects of intranasal administered midazolam in blue-fronted and orange-winged Amazon parrots.

Caption: Figure 2. Intranasal midazolam administration in blue-fronted and orange-winged Amazon parrots.

Caption: Figure 3. Vocalization intensity after intranasal midazolam administration in blue-fronted and orange-winged Amazon parrots. Scale bars: Interquartile range.

Caption: Figure 4. Signs of sedation after intranasal midazolam administration in blue-fronted and orange-winged Amazon parrots. (A) Nap. (B) Yawn. (C) Seat.
Table 1. Sedation-assessment scale suggested for use in
birds (Schaffer et al (13)).

Score   Behavior

1       Uncooperative patient, absence of muscular
        relaxation, wing movements, physical
        restraint required

2       Cooperative patient, moderate muscular
        relaxation, wing movements upon handling,
        light restraint required

3       Sedated patient, intense muscle relaxation, no
        wing movements, lateral position, restraint
        not required

4       Patient unresponsive to external stimulation

Table 2. Time to onset, signs, and duration of sedation (mean [+ or -]
SD) in minutes after intranasal midazolam administration in
blue-fronted and orange-winged Amazon parrots.

                        Blue-fronted Amazon   Orange-winged Amazon

Time to onset, min       5.4 [+ or -] 1.2       5.1 [+ or -] 0.9
Signs of sedation
Nap, min                 2.7 [+ or -] 1.3       2.6 [+ or -] 1.1
Roam, min                3.5 [+ or -] 0.7       2.8 [+ or -] 0.9
Seat, min                4.3 [+ or -] 1.3       3.7 [+ or -] 0.8
Duration of sedation,    25.6 [+ or -] 5.7     27.1 [+ or -] 3.7
  min

                        P value

Time to onset, min        .57
Signs of sedation
Nap, min                  .91
Roam, min                 .13
Seat, min                 .35
Duration of sedation,     .50
  min
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Title Annotation:Original Study
Author:Schaffer, Debora P.H.; Raposo, Ana Claudia S.; Filho, Emanoel F. Martins; Vieira, Joao Victor R.; Or
Publication:Journal of Avian Medicine and Surgery
Date:Sep 1, 2017
Words:3115
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