Preliminary studies on the use of propofol in the domestic pigeon (Columba livia)

Research in Veterinary Science 1990, 49, 334-338

Preliminary studies on the use of propofol in the domestic pigeon

( Columba livia) G. FITZGERALD*, J. E. COOPER, Department of Pathology, Royal College of Surgeons

of England, 35-43 Lincoln's Inn Fields, London WC2A 3PN

The anaesthetic propofol was investigated in domestic pigeons (Columba livia). The agent was administered intravenously, in one group of birds as an adjunct to ketamine hydrochloride, and careful monitoring was performed. The dose of 14 mg kg- t of propofol was based on aliometric scaling for its use as a sole agent. Propofol anaesthesia was characterised by smooth rapid induction and good muscle relaxation but was only of short duration, ranging from two to seven minutes, and seemed to cause a marked respiratory depression. Indeed, a very narrow safety margin for propofol was observed in pigeons when ventilation was not assisted. The agent may have applications in avian anaesthesia but these are likely to be limited.

PROPOFOL (Rapinovet; Coopers Animal Health) is a new intravenous anaesthetic. Its active agent, 2,6-diisopropylphenol, is diluted at a concentration of 10 mg m l - 1in a milky white oil-in-water emulsion. The anaesthetic properties of propofol have been investigated in different mammals, including man, and one of the authors (J.E.C.) has used it in a range of avian species but no reports have yet been published of its use in birds. Rapid onset, short duration, smooth and rapid recovery characterise anaesthesia with propofol in most species (Glen 1980, Conseiller 1987, Watkins et al 1987, Brearley et al 1988, Waterman 1988, Morgan and Legge 1989). Propofol is mainly metabolised by the liver (Conseiller 1987); it appears to be quickly eliminated (Glen 1980, Hall and Chambers 1987, Brearley et al 1988). No cumulative effects were observed following repeated usage (Glen 1980, Conseiller 1987, Brearley et al 1988) and there appeared to be no interaction with drugs or inhalation agents (Glen 1980, Morgan and Legge 1989). The Rapinovet technical notes (Coopers Animal Health 1988) recommend three methods for the use of propofol iia dogs and cats: (i) a single dose for very *Present address: Department of Medicine, Facult6 de Mddecine Vdt6rinaire, Universit6 de Montrdal, CP 5000, St Hyacinthe, Qu6bec J2S 7C6, Canada

short procedures (lasting less than five minutes), (ii) incremental doses to effect, for induction and maintenance of general anaesthesia, and (iii) a single induction dose followed by inhalation anaesthesia. This last option was considered the most satisfactory by Hall and Chambers (1987) who investigated the continuous infusion of propofol in dogs. The increasing concern (and legal controls) in certain countries over the possible hazards to humans of exposure to anaesthetic and volatile liquids and the requirement by many research workers for shortacting, safe and dependable injectable agents justify the evaluation of propofol anaesthesia in birds. In this paper the authors report preliminary studies on the use of propofol in the domestic pigeon (Columba livia). The aim of the research was to assess safety and efficacy of propofol in this species, both on its own and in combination with an intramuscular dissociative agent. Materials and methods

Birds Nineteen adult domestic pigeons (C livia), seven males (mean weight ± SD: 457 ± 28 g) and 12 females (mean weight :t= SD: 441 ± 55 g), were used in this study. Once released from the laboratory animal supplier, they were housed indoors in groups of two or three in stainless steel cages, each measuring 61 cm deep, 48 cm wide and 36 cm high with a mesh floor. Water and commercial food were provided ad libitum. Routine physical examination and haematology (packed cell volume, total solids, blood smears) were performed on all birds. A low parasite (Ascaridia species) burden detected in a few individuals was not treated so as to avoid any drug interaction. Four birds showing slight signs of respiratory disease were withdrawn and culled with a lethal dose of propofol as part of the study.

Experimental design

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The remaining 15 clinically healthy pigeons were

Propofol anaesthesia in pigeons

335

TABLE 1 : Metabolic doses of propofol for different species Species Cat Cat Dog Dog Sheep Man

Weight (kg)

Dose (mgkg -1)

SMR* ( k c a l k g - l d -1)

Scaling dose (mgkcal-ld)

1.3-8.5t 1 . 3 - 8 - 5t 2-0-71t 2.0-71t 30-50** 70

8t 6.85 6.5t 611 3.5** 2-2.5**

41-65.6 41-65.6 24.1-58.9 24.1-58.9 26.3-29.9 24.2

O. 12~0.20 0.10-0-17 0.11-O.27 0.10-0.25 0-12-0-13 0.08-0.10

Mean ± SD 0 " 1 5 ± 0 ' 0 6 * ¢ ++ II **

Specific metabolic rate Coopers Animal Health Technical Notes, Morgan and Legge (1989) Brearley et al (1988) Watkins et al (1987) Waterman (1988)

divided into three groups of five birds: A, B and C. The birds were not fasted before anaesthesia and a minimum rest period of five days was allowed between anaesthetic trials. All the birds breathed spontaneously during anaesthesia unless otherwise stated. In order to evaluate in birds those methods for the use of propofol recommended for dogs and cats, the study was divided as follows.

Single dose trial. Before culling the four unhealthy pigeons, a dose of propofol calculated by allometric scaling (see later) was administered via the brachial (basilic) vein to two of them and intramuscularly (pectoral muscle) to the others. Group A (five birds) then received the same calculated single dose intravenously to determine the effectiveness and duration of anaesthesia with propofol alone. Incremental dose trial. Since the proposal was to use propofol as an adjunct to ketamine anaesthesia, the five birds in group B were monitored after intramuscular injection of 20 mg kg- ~of ketamine hydrochloride (Vetalar; Parke Davis) alone. This provided baseline data. Group C was then induced with ketamine in the same way and the anaesthesia deepened with propofol, administered to effect through a 25 gauge butterfly needle in the brachial vein. Induction dose followed by inhalation anaesthesia. A single calculated dose of propofol was administered via the brachial vein to the group B birds in order to induce anaesthesia. Endotracheal intubation permitted maintenance with halothane 1.5 per cent delivered through a non-rebreathing system at a flow rate of 1 litre min-~ nitrous o x i d e - oxygen 1:1. Group B was chosen because it had not received propofol previously. This last anaesthetic protocol was also used in order tO carry out surgical sexing (laparoscopy) of five pigeons. During the study 14 birds were killed with propofol in order to determine the lethal dose.

Monitoring Each bird was restrained on its back on an electrical heating pad. The following parameters were taken before induction, during induction and then every five minutes during maintenance of anaesthesia: heart rate, respiration rate and quality, muscle tone, wing fluttering, pedal and palpebral reflexes, cloacal temperature. The monitoring ceased when the bird was alert and on its feet. The heart rate was determined either by conventional auscultation with a stethoscope (heart beat count over 15 seconds) or by using a heart rate veterinary monitor (Silogic Design) set to average the heart rate on every I0 beats, at a lower limit of I00 m i n - 1 and a higher limit of 450 m i n - 1.

Dose rate calculations For the study described in this paper the allometric scaling dose of propofol was calculated as follows: Specific metabolic rate (SMR) for a man weighing 70 kg: SMR = K / W 'A = 70/(70) 'A = 24-2 kcal kg -1 d -1 where K is a constant determined for different taxonomic groups and W the weight (mass) in kg. Allometric scaling dose: dose rate/SMR = 2"5/24"2 = 0" 10 mg d kcal -~ Table 1 shows the allometric scaling dose calculated for different species in which propofol has been tested. The average dose of 0.15 mg d kcal- 1, which represents 14 mg kg-1 for a pigeon, was the calculated dose used in this study. The calculations were as follows: SMR for pigeons weighing an average of 447 g: (considered non-passerine bird, K = 78) SMR = K / W 'A = 78/(0.447) 'A = 95.4kcal k g - ~ d l Dose rate: SMR × scaling dose = 95" 4 x 0- 15 = 14 mg k g - 1.

G. Fitzgerald, J. E. Cooper

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TABLE 2: Comparison of propofol with other anaesthetic agents in birds

Ketamine

AIphaxalone-alphadolone

Propofol

Speed of induction

Rapid (iv) Slower (im)

Rapid (iv)

Rapid (iv)

Muscle relaxation

Poor unless combined with other agents

Good

Good

Reflexes

Many remain intact (dissociative agent)

Gradually abolished as anaesthesia deepens

Gradually abolished as anaesthesia deepens

Eyes

Remain open

Close

Close

Analgesia

Limited

Good

Good

Tissue reaction

None (iv) Irritance (im)

None, even if inadvertently injected subcutaneously

None, even if inadvertently injected subcutaneously

Respiratory depression

Slight

Moderate

Moderate

Recovery

May be prolonged with incoordination and opisthotonos. Prolonged but smoother (iv)

Rapid

Rapid

Safety margin (therapeutic index)

High

Moderate (?)

Low

im Intramuscular iv Intravenous

Results

Single dose trial The preliminary trial of the allometrically calculated dose of propofol (14 mg kg -1) in four pigeons (subsequently withdrawn from the study) proved uneventful. When given intravenously to two birds, the drug produced anaesthesia of about four minutes' duration and there was a very short period of apnoea in one pigeon. Both birds recovered before being culled with an additional overdose of propofol. However, the intramuscular route did not prove satisfactory. The calculated dose by intramuscular injection produced only light sedation after 10 minutes (eyes half closed but bird standing on its feet). The second bird was given a dose of 25 mg kg- 1 but still remained standing and only showed slight ataxia. All grouP A recovered from anaesthesia. A transient period of apnoea was noted at induction. Respiration was deep and regular and the rate averaged 43 ± 6 m i n - l . The heart rate, pedal and palpebral reflexes, temperature and muscle tone were not monitored during this study so as to avoid any stimulation that might have interfered with the duration of anaesthesia. No hypersalivation was observed. Voluntary movements returned after an average of 5 ± 1-9 minutes (interval two to seven minutes). Wing flapping occurred 3 to 18 minutes (mean q- SD: 8" 4 q- 5" 9 minutes) after intravenous administration of propofol. Complete recovery took I0 to 52 minutes

(mean ± SD: 23 ± 17 minutes) from injection to the time at which the bird could stand on its feet. The recovery was smooth and without excitement. No vomiting was observed.

Incremental dose trial Anaesthesia of group B with ketamine was uneventful. The effects were as published by Cooper (1984). The induction time ranged from 1 "5 to 2"0 minutes. The body temperature did not drop and the cardiorespiratory functions were maintained: mean heart rate 166 q- 36 bpm, mean respiration rate 54 + 10 rain -l. However, birds given ketamine alone never lost pedal and palpebral reflexes or neck muscle tone. Wing fluttering was often observed. Hypersalivation was not noted. There was no excitement during recovery which was completed 30 to 70 minutes after induction (mean + SD: 47 + 17 minutes). Repeated doses of propofol after ketamine induction produced a loss of muscle tone and pedal reflex for a duration of 3- 5 ± 1.3 minutes in group C. The body temperature did not fall and less wing fluttering was observed. An increase in heart rate (from 236 ± 42 to 328 -4- 54 bpm) tended to occur within the first minute after the administration of propofol as well as a decrease - - if not a transient arrest (see later) - - in the respiration rate. The four repeated doses per bird given to effect ranged from 4"1 to 8-6 mg kg-1

Propofol anaesthesia in pigeons (mean -4- SD: 6"3 ± 1"3 mg kg-t). Recovery was uneventful and the bird was standing on its feet 55 to 65 minutes (mean ± SD: 58"3 ± 5 "8 min-1)after the initial injection of ketamine. Apnoea (complete or transient) occurred following 62 per cent of the incremental doses of propofol. One bird died after a dose of 8.6 mg kg -1 when no attempt was made to assist ventilation following a prolonged period of apnoea. Another bird showed complete apnoea following the administration of 7" 8 mg kg -1 propofol but survived with artificial ventilation by manual pressure on the sternum. In one case the experiment was discontinued because the butterfly needle had come out of the vein and the propofol had been administered subcutaneously. The bird was observed carefully and there was no evidence of perivascular inflammation or necrosis up to a week afterwards.

Induction of endotracheal intubation Again tachycardia (heart rate changing from mean ± SD: 183 -4- 31 to 246 ± 32 bpm) and transient apnoea was observed in the first minute following induction with propofol. In one case artificial ventilation had to be provided, using the reservoir bag. The body temperature fell by between 0.5 to 1-7°C from initial value (42.5 ± 0.4°C). Wing flapping and coughing were observed if endotracheal intubation was delayed as a result of carrying out monitoring. The birds were maintained anaesthetised with a halothane/nitrous oxide/oxygen mixture for 15 minutes. Complete recovery followed 20 minutes afterwards. The tube had to be removed from two pigeons because it had become obstructed by white viscid secretions. For laparoscopic sexing endotracheal intubation was performed immediately after induction with propofol without the delay of monitoring the anaesthesia. This allowed inhalation anaesthesia to be provided without the bird coughing or awakening. The procedure necessitated 20 minutes of anaesthesia with 2 per cent h a l o t h a n e - n i t r o u s oxide. The recovery was uneventful and, as above, complete within 20 minutes.

Lethal dose determination At the beginning of the study four pigeons were culled by intravenous injection of 2 ml propofol which represented 46.4 ± 5"8 mg kg-1 depending upon the bird's bodyweight. Subsequently the lethal dose was determined on 10 birds by giving repeated doses of propofol starting at a dose rate of 20 mg kg 1. An intravenous injection of 23"2 ± 2.8 mg kg -~ resulted in death when ventilation was not assisted.

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Discussion

Propofol is a short-acting intravenous anaesthetic agent which in its effects is very similar to thiopentone, methohexitone or alphaxalone-alphadolone. It has an unusual white appearance but this does not hamper work and, indeed, can make it easier to ascertain whether anaesthetic is present in a syringe or butterfly. Propofol did not (in contrast to thiopentone) provoke any soft tissue damage if accidentally given by perivascular injection. The intramuscular route is not recommended since propofol is rapidly metabolised; a large volume would probably be needed. Induction was smooth and rapid. Loss of reflexes and good muscle relaxation characterised propofol anaesthesia but these were only of short duration. Excess salivation was not a problem. Recovery was rapid and smooth without excitement or vomiting. No significant difference was found in recovery time when using halothane or propofol in the cat and sheep (Brearley et al 1988, Waterman 1988) and this was clinically true in pigeons. The tachycardia observed immediately after the administration of propofol remains unexplained although a period of hypotension is a possible contributing factor. The transient or complete apnoea seen on administration is an important consideration: the anaesthetist should always be ready to assist ventilation and routine endotracheal intubation is good practice. In this study the speed of intravenous injection may have contributed to the results obtained since the calculated dose was completely administered within five seconds in a bolus injection. Some authors recommend giving half of the calculated dose rapidly and the remainder slowly to effect in order to avoid apnoea (Watkins et al 1987, Brearley et al 1988). The practical uses of propofol in birds would be limited because of the very short duration of anaesthesia it produced. The agent may have applications for induction before inhalation anaesthesia especially if there is a need (for health and safety reasons) to avoid pollution of the air by anaesthetic from a mask or chamber. Propofol may also be of value on its own for brief procedures, eg, radiography, or certain research techniques. It is, however, important to appreciate how narrow the safety margin of propofol proved to be in the pigeons used in this study. The calculated and efficacious dose of 0.7 ml for some of the birds was very near the i .0 ml dose which proved lethal when ventilation was not assisted. The study reported in this paper constitutes a clinical trial and cautious interpretation is necessary. No statistical calculations were possible because of the small numbers of animals being used. However, some useful information was obtained and further, more extensive, studies of the agent in birds may be justified.

G. Fitzgerald, J. E. Cooper

338

In evaluating propofol in birds it is important to compare and contrast it with other, established, anaesthetic agents. The two that are most frequently used are ketamine hydrochloride and alphaxalonealphadolone. Table 2 summarises the differences and similarities between these three; the assumption is that 'standard anaesthetic' doses are given. Since no dose rate recommendations were available for pigeons an initial dosage had to be established. It was predicted that in view of their higher metabolic rate, birds of the size of a pigeon would need a higher dose per unit of body mass than that for dogs and cats. The difficulty was to determine how much higher this dose should be. Some authors have suggested using the metabolic rate rather than the bodyweight for dose rate estimation. Indeed, the half-life of a drug that is metabolised and eliminated by the body will decrease as the metabolic rate increases (Kleiber 1961, Kirkwood 1983, Sedgwick 1987, Pokras et al 1988). In 1932, Kleiber surveyed the metabolic rate of mammals ranging in size from 0" 15 to 679 kg and stated that the metabolic rate was a function of the 3/4 power of the bodyweight (Kleiber 1961, Robbins 1983, Schmidt-Nielsen 1984). This led to a descriptive equation (not a biological law) of the resting metabolic rate (kcal d l) for mammals as: 70 W ~ where 70 is a constant (intercept at the unit) and W the bodyweight (mass) in kg (Kleiber 1961, Robbins 1983, Schmidt-Nielsen 1984, Sedgwick 1987, Pokras et al 1988). This new approach is termed allometric scaling (Schmidt-Nielsen 1984, Sedgwick 1987, Pokras et al 1988). Another way Of expressing the metabolic rate is to divide the resting metabolic rate by the weight to obtain the SMR in units of kcal kg-~ d - I (SchmidtNielsen 1984). The allometric scaling equation is then: SMR = K/W ~

where K is a constant determined for different taxonomic groups (70 for placental mammals, 78 for nonpasserine birds and 129 for passerine birds) and W the weight (mass) in kg (Schmidt-Nielsen 1984, Sedgwick 1987, Pokras et al 1988). Allometric scaling of the metabolic rate allows us to translate a dose rate from mg kg-~ to mg kcal-I units. For instance, the dose rate of 2.5 mg kg-l propofol in man represents in terms of metabolic scaling 0.10 mg d kcal-1. Allometric scaling is a novel and potentially important approach to the medical care of different

species but one should be aware of its limitations. The calculations provide us with an expected mean value for a 'typical' animal of a give/a size (Schmidt-Nielsen 1984): the principle is a broad generalisation and not an immutable constant. Pharmacological and physiological aspects also have to be considered. For instance, opiate drug dosages should not be extrapolated from a horse to a dog because of the different responses to such drugs in the two species. Many desert mammals have a lower metabolic rate than the allometric scaling expectation while seals and whales have a higher one.

Acknowledgements We are indebted to Coopers Animal Health for supplies of propofol for use in this study, to Silogic Design for both the loan of a heart monitor and some financial assistance and to the Canadian Veterinary Research Trust for financial support. Members of staff of the Royal College of Surgeons of England assisted with the investigations. We are grateful to them and to Mrs Jackie Brearley and Mr Anthony Sainsbury who read and commented on an earlier draft of this paper.

References BREARLEY, J. C., KELLAGHER, R. E. B. & HALL, L. W. (1988) Journal o f Small Animal Practice 29, 315-322 CONSEILLER, C. (1987) Annales Francaises d'anesthdsie et de rdanimation 6, 223-225 COOPER, J. E. (1984) Journal o f Small Animal Practice 25, 505-510 GLEN, J. B. (1980)British Journal o f Anaesthesia 52, 731-741 HALL, L. W. & CHAMBERS, J. P. (1987)Journal o f SmallAnimal Practice 28,623-637 KIRKWOOD, J. K. (1983) Veterinary Record 112, 182 KLEIBER, M. (1961) The Fire of Life. New York, John Wiley & Sons. pp 177-217 MORGAN, D. W. T. & LEGGE, K. (1989) Veterinary Record 124, 31-33 POKRAS, M, A., ZEMAN, A., KIRKWOOD, J. K. & SEDGWICK, C. J. (1988) International Symposium on the Status of Biomedical Research on Raptors, October. St Paul, Minnesota. p 4 ROBBINS, C. T. (1983) Wildlife Feeding and Nutrition. London, Academic Press. pp 105-111 SCHMIDT-NIELSEN, K. (1984) Scaling: Why is Animal Size so Important? Cambridge, Cambridge University Press. pp 56-75 SEDGWICK, C. J. (1987) Third Annual Avian Medicine Conference, Vermont Raptor Center, October. Woodstock, Vermont WATERMAN, A. E. (1988) Veterinary Record 122, 260 WATKINS, S. B., HALL, L. W. & CLARKE, K. W. (1987) Veterinary Record 120, 326-329 Received December 4, 1989 Accepted May 9, 1990