Butorphanol tartrate, an analgesic opioid with κ-opioid receptor agonist and μ-opioid receptor antagonist properties,1 is considered by some veterinarians to be the opioid of choice for pain management in birds,2 although the extent of its analgesic efficacy remains controversial.3,4 In birds, the use of opioids with inhalation anesthetic agents as part of a balanced anesthetic technique may decrease the incidence of unwanted autonomic responses and hypotension and improve safety.5
Minimum anesthetic concentration is the median effective concentration for inhaled anesthetic agents.6 Increasing doses of κ- and μ-opioid receptor agonists are reported to decrease the MAC for isoflurane in chickens, although the effect of time on this response is unknown.5 Butorphanol (1 mg/kg, IM) decreases the MAC for isoflurane by 25% in cockatoos but again with an unknown duration of effect.7
The MACs for various inhalation anesthetic agents have been reported7,8 to decrease after the administration of drugs by either constant rate infusion or single-dose administration. However, the method typically used to determine such MAC-sparing effects can be problematic unless the pharmacokinetics of the drugs administered is known in the species being studied. If a drug has a short half-life and is rapidly cleared from the body, plasma concentrations of the drug will decrease over the course of inhalation anesthesia, and any MAC-sparing effect would decrease with time after drug administration. Conversely, if clearance rate is slow, a drug administered by constant rate infusion can cause an increase in the plasma concentration of the drug and may result in an increase in the MAC-sparing effect during the period of assessment. Thus, the administration of drugs by constant rate infusion or single-dose administration does not guarantee stable plasma concentrations of those drugs over the time required to measure the MAC for an inhalation anesthetic agent by use of traditional bracketing techniques.9
To our knowledge, the pharmacokinetics of butorphanol in guineafowl (Numida meleagris) is unknown; therefore, we believed that a novel study design was needed to meaningfully determine the temporal effects of butorphanol on the MAC for sevoflurane in this species. The purpose of the study reported here was to determine the individual MACs for sevoflurane in guineafowl by use of an established bracketing technique and subsequently measure the dose and temporal effects of butorphanol on the MAC for sevoflurane.
Materials and Methods
Birds—Ten guineafowl (3 males and 7 females) that were 3 to 6 months old were used for this study. Mean ± SD weight of the birds was 1.45 ± 0.37 kg. The birds were housed in a stall (3 × 4 × 3 m), and water and food were provided ad libitum. Results of physical examinations and hematologic evaluations were unremarkable. Food was not withheld from the birds before the anesthetic procedures, and there was at least a 1-week interval between successive experiments. Study procedures were approved by the Animal Care Committee at São Paulo State University.
Experimental procedures—For each bird, anesthesia was induced with sevofluranea in 100% oxygen via face mask and the use of a semiopen Bain circuit with a flow rate of 3 L/min and an initial sevoflurane vaporizer setting of 8%. Each bird was intubated with a noncuffed endotracheal tube (2.5 or 3.0 mm in diameter) and positioned in dorsal recumbency. Gas flow rate was reduced to 1 L/min, and birds received intermittent positive-pressure ventilationb with a peak inspiratory pressure of 10 cm H2O and an inspiration-to-expiration ratio of 1:3. Respiratory rate was adjusted to maintain Petco2 between 30 and 40 mm Hg. End-tidal gas samples were collected from a 3.5F catheterc located within the lumen of the endotracheal tube, with the catheter tip positioned close to the distal end of the endotracheal tube to minimize contamination of the samples with fresh gas from the circuit. The catheter was connected to a gas analyzerd for continuous monitoring of the sevoflurane concentration and Petco2. The gas analyzer was calibrated prior to and during the study for each bird with room air and 3 standardse of known sevoflurane concentrations (1%, 2.5%, and 5%).
In each bird, a 24-gauge catheterf was aseptically placed in an ulnar vein for administration of drugs and saline (0.9% NaCl) solution at a rate of 5 mL/kg/h, which was administered by use of a syringe pump.g A pulse oximeterh was used to monitor the heart rate and Spo2. Indirect systolic blood pressure was monitored with a Doppler ultrasonographic probei attached to a cuff with a width approximately 40% of the leg circumference, placed over the median metatarsal artery proximally on a limb. The cloacal temperature was monitored by use of a mercury thermometerj and was maintained at 40° to 41°C with a circulating warm water blanket,k warm water containers, and a heat lamp.
Measurement of the MAC for sevoflurane in individual birds—The MAC for sevoflurane was determined for each bird by use of a bracketing experimental design. In a bracketing experimental design, anesthetic agent concentrations are increased or decreased if an individual animal moves or does not move, respectively, in response to a noxious stimulus. The MAC equals the mean of the lowest anesthetic agent concentration that prevents movement and the highest anesthetic agent concentration that allows movement. For the determination of the MAC for sevoflurane in individual guineafowl, each bird was anesthetized at a constant sevoflurane concentration for 15 minutes, and the pulse rate, respiratory rate, Petco2, cloacal temperature, indirect systolic blood pressure, and Spo2 were recorded as baseline values. End-tidal gas samples were collected by hand in a glass syringe over 7 to 10 breaths; measurements were repeated in triplicate, and the mean value was recorded.
After collection of physiologic data, a noxious electrical stimulus was delivered to the medial aspect of the bird's thigh area by use of a pair of subcutaneous needle electrodes connected to an electrical stimulatorl that delivered 15 V at 50 cycles/s for 6.5 milliseconds over 1 minute.10 After every 2 electrical stimulation episodes, the 2 needles were replaced by a new pair placed in a location slightly offset from the original position to prevent possible desensitization or tissue injury.10 If gross movement (ie, movement of the contralateral leg, tail, or wings) was elicited before the stimulation period was completed, the electrical stimulus was discontinued immediately and the end-tidal sevoflurane concentration was increased by 10%. If no movement was observed, the end-tidal sevoflurane concentration was decreased by 10%. After 15 minutes at the new end-tidal concentration of sevoflurane, the electrical stimulus was repeated and the sevoflurane concentration was adjusted higher or lower accordingly. The MAC was measured in triplicate for each bird, and the mean of these values represented the MAC for sevoflurane for that individual guineafowl. Because the mean barometric pressure at our laboratory site is 716 mm Hg, MAC values were corrected to sea-level barometric pressure (760 mm Hg) by use of the following formula: MAC (%) at sea level = Measured MAC (%) × (716/760).11
Determination of the effects of butorphanol on the MAC for sevoflurane—A quantal method was used to estimate the MAC for sevoflurane after administration of butorphanol in the study birds.12 In a quantal experimental design, an individual's response to a noxious stimulus is assessed at a single concentration of anesthetic agent, and the responses (movement or no movement) to stimuli in individuals anesthetized at various anesthetic concentrations are fit to a logistic regression model to calculate the median effective anesthetic concentration. This method was chosen because it allowed us to measure the MAC for sevoflurane at 15-minute intervals after butorphanol administration. Thus, the temporal effect of a single dose of butorphanol on the MAC for sevoflurane in the study birds could be measured at exact intervals. It was expected butorphanol would reduce the MAC for sevoflurane and that this reduction would wane with time after drug administration because the plasma concentration of butorphanol would decrease.
Once the individual MAC was determined for each bird, a second experiment to measure the reduction in the MAC for sevoflurane after administration of butorphanol was immediately performed. The procedure for induction of anesthesia and monitoring was the same as that for the first experiment. The end-tidal sevoflurane concentration for the first bird was maintained constant at 0.7 times its individual MAC. After equilibration at this concentration for 15 minutes, a bolus of butorphanol tartratem (2 mg/kg, IV) was injected over 10 seconds. Fifteen minutes thereafter, a noxious electrical stimulus (as described for the bracketing experiment) was delivered, and the presence or absence of movement was recorded. If no movement was observed, the electrical stimulus was repeated every 15 minutes until movement was observed, at which time the experiment for that bird was ended, and the bird was allowed to recover from anesthesia.
The sevoflurane concentration assessed in each subsequent bird was a function of the response (movement or no movement) of the previous bird, as described in the up-and-down method for small samples.12 If the previous bird moved at a given time point after butorphanol administration, the sevoflurane concentration used in the subsequent bird was adjusted to equal a 10% increase from that used in the previous bird and was calculated on the basis of the subsequent bird's individual MAC for sevoflurane. Conversely, if the previous bird did not move at a given time point after butorphanol administration, the sevoflurane concentration in the subsequent bird was adjusted to equal a 10% decrease from that used in the previous bird and was calculated on the basis of the subsequent bird's individual MAC for sevoflurane. Consequently, temporal responses to noxious stimuli after butorphanol administration in each bird were evaluated at only 1 sevoflurane concentration.
At least 1 week after the previous anesthetic event, each guineafowl was anesthetized again by the use of the same anesthetic protocol, and a similar experiment was performed to investigate the effects of a higher dose of butorphanol (4 mg/kg, IV) on the MAC for sevoflurane. The same quantal technique was used to measure movement in response to noxious stimuli every 15 minutes. All birds were allowed to recover from anesthesia at the end of the study.
Data collected—In addition to physiologic data and MAC measurements for each bird, various intervals of interest were recorded as follows: time for induction (interval from placement of the face mask until intubation), time for instrumentation (interval between intubation and the placement of all the monitoring equipment), time to determination of the individual MAC for sevoflurane (interval between the end of the time for instrumentation and the end of MAC measurements), and time until recovery (interval between the end of sevoflurane administration and endotracheal tube removal).
Data analysis—A Shapiro-Wilk test was used to determine whether the data were normally distributed for physiologic variables, intervals of interest, and measurements of the individual MACs for sevoflurane. For physiologic data that were normally distributed, a repeated-measures ANOVA was used to compare the physiologic variables at baseline (prior to individual MAC measurement) and after each dose of butorphanol (2 or 4 mg/kg). The median and range were reported for data that were not normally distributed. For all tests, values of P ≤ 0.05 were considered significant.
For statistical analyses of the quantal experiment data, it was assumed that when there was no response to the noxious electrical stimulus after the administration of butorphanol, the drug had reduced the MAC for sevoflurane. Conversely, when there was movement in response to the noxious electrical stimulus, it was assumed that butorphanol was no longer having an effect on the MAC for sevoflurane. Also, once movement in response to the noxious electrical stimulus was observed, movement was assumed at all future time points with the same sevoflurane concentration for that bird.
To obtain a better fit of the data to a logistic model and reduce the error estimates of model variables in the quantal experiments, it was necessary to measure responses in some birds at a sevoflurane concentration equal to their individual MAC for sevoflurane. Because MAC is defined as the anesthetic agent concentration at which the probability of movement equals the probability of no movement, the electrical stimulation was performed at 15 minutes after injection and an identical response at each future time point was assumed for purposes of statistical analysis. There were also at least 3 crossover events (3 birds that moved and 3 birds that did not move) or no clinically relevant reduction in MAC (ie, < 10% reduction in MAC) at each time point. For each butorphanol dose, the percentage change in MAC for sevoflurane at each 15-minute interval was fit to a logistic regression curve from which the median effective anesthetic concentration could be calculated.9 A commercially available statistical computer programn was used for model fitting and jack-knife estimates for variables and SEs.13
Results
For the 10 guineafowl, the mean ± SE of the MAC for sevoflurane determined by use of the bracketing method was 2.9 ± 0.1%. At 15 minutes following IV administration of 2 mg of butorphanol/kg, the mean ± SE percentage reduction in the MAC for sevoflurane was 9 ± 3% (Figure 1). Eight birds were used, and all responded to the electrical stimulus at 30 minutes after administration. This suggested that the effects of the 2 mg/kg dose of butorphanol on the MAC for sevoflurane had dissipated by 30 minutes after administration. Following IV administration of 4 mg of butorphanol/kg, the mean percentage reduction in the MAC for sevoflurane was 21 ± 4% at 15 minutes after injection and 11 ± 8% at 30 minutes after injection (Figure 1). Ten birds were tested at 15 minutes after injection, and 5 of them moved. Five birds were tested at 30 minutes after injection, and 2 of them moved. All remaining birds moved in response to an electrical stimulus at 45 minutes after administration of a 4 mg/kg dose of butorphanol.
Quantal analysis curve estimations of the median percentage reduction in the MAC for sevoflurane in 10 anesthetized guineafowl (Numida meleagris) after IV administration of 2 or 4 mg of butorphanol/kg. For each bird, the 2 mg/kg dose experiment was performed after the individual MAC for sevoflurane was determined; the 4 mg/kg dose experiment was performed during a second anesthetic episode after an interval of at least 1 week. A—Quantal analysis data obtained at 15 minutes after IV administration of a 2 mg/kg dose of butorphanol. Mean ± SE percentage reduction in MAC was 9 ± 3%. B—Quantal analysis data obtained at 15 minutes after IV administration of a 4 mg/kg dose of butorphanol. Mean percentage reduction in MAC was 21 ± 4%. C—Quantal analysis data obtained at 30 minutes after IV administration of a 4 mg/kg dose of butorphanol. Mean percentage reduction in MAC was 11 ± 8%.
Citation: American Journal of Veterinary Research 73, 2; 10.2460/ajvr.73.2.183
Quantal analysis curve estimations of the median percentage reduction in the MAC for sevoflurane in 10 anesthetized guineafowl (Numida meleagris) after IV administration of 2 or 4 mg of butorphanol/kg. For each bird, the 2 mg/kg dose experiment was performed after the individual MAC for sevoflurane was determined; the 4 mg/kg dose experiment was performed during a second anesthetic episode after an interval of at least 1 week. A—Quantal analysis data obtained at 15 minutes after IV administration of a 2 mg/kg dose of butorphanol. Mean ± SE percentage reduction in MAC was 9 ± 3%. B—Quantal analysis data obtained at 15 minutes after IV administration of a 4 mg/kg dose of butorphanol. Mean percentage reduction in MAC was 21 ± 4%. C—Quantal analysis data obtained at 30 minutes after IV administration of a 4 mg/kg dose of butorphanol. Mean percentage reduction in MAC was 11 ± 8%.
Citation: American Journal of Veterinary Research 73, 2; 10.2460/ajvr.73.2.183
Quantal analysis curve estimations of the median percentage reduction in the MAC for sevoflurane in 10 anesthetized guineafowl (Numida meleagris) after IV administration of 2 or 4 mg of butorphanol/kg. For each bird, the 2 mg/kg dose experiment was performed after the individual MAC for sevoflurane was determined; the 4 mg/kg dose experiment was performed during a second anesthetic episode after an interval of at least 1 week. A—Quantal analysis data obtained at 15 minutes after IV administration of a 2 mg/kg dose of butorphanol. Mean ± SE percentage reduction in MAC was 9 ± 3%. B—Quantal analysis data obtained at 15 minutes after IV administration of a 4 mg/kg dose of butorphanol. Mean percentage reduction in MAC was 21 ± 4%. C—Quantal analysis data obtained at 30 minutes after IV administration of a 4 mg/kg dose of butorphanol. Mean percentage reduction in MAC was 11 ± 8%.
Citation: American Journal of Veterinary Research 73, 2; 10.2460/ajvr.73.2.183
Physiologic variables measured in all birds at the various MAC measurement time points were summarized (Table 1). Butorphanol administration did not significantly change any variable from its baseline value. For all anesthetics administered, the median time for induction was 3 minutes (range, 1 to 7 minutes) and time for instrumentation was 10 minutes (range, 5 to 26 minutes). The mean ± SD time to determination of the individual MAC for sevoflurane was 201 ± 92 minutes. Mean time until recovery after IV administration of the 2 or 4 mg/kg dose of butorphanol was 5 ± 1 minutes and 4 ± 2 minutes, respectively.
Mean ± SD heart rate, respiratory rate, indirect blood pressure, Petco2, Spo2, and cloacal temperature in 10 guineafowl (Numida meleagris) anesthetized with sevoflurane for measurements obtained at baseline (prior to determination of individual MACs for sevoflurane), at 15 minutes after IV administration of 2 mg of butorphanol/kg, and at 15 minutes and 30 minutes after IV administration of 4 mg of butorphanol/kg.
| Variable | Baseline | 2 mg/kg dose at 15 min* | 4 mg/kg dose at 15 min | 4 mg/kg dose at 30 min† |
|---|---|---|---|---|
| Heart rate (beats/min) | 167 ± 32 | 148 ± 23 | 150 ± 46 | 127 ± 20 |
| Respiratory rate (breaths/min) | 9 ± 2 | 9 ± 2 | 9 ± 2 | 9 ± 2 |
| Indirect blood pressure (mm Hg) | 99 ± 13 | 106 ± 27 | 106 ± 22 | 101 ± 19 |
| Petco2 (mm Hg) | 34 ± 3 | 33 ± 4 | 36 ± 6 | 34 ± 6 |
| Spo2 (%) | 99 ± 1 | 99 ± 1 | 98 ± 1 | 98 ± 1 |
| Temperature (°C) | 40.5 ± 0.1 | 40.5 ± 0.2 | 40.6 ± 0.2 | 40.5 ± 0.2 |
For each bird, the 2 mg/kg dose experiment was performed immediately after the individual MAC for sevoflurane was determined; the 4 mg/kg dose experiment was performed during a second anesthetic episode after an interval of at least 1 week. Measurements were recorded immediately before application of the electrical stimulus used for MAC determinations.
In this experiment, data for 8 birds were available at this time point.
In this experiment, data for 5 birds were available at this time point.
Discussion
In the guineafowl used in the present study, butorphanol decreased the MAC for sevoflurane in a dose-dependent manner for a short time. However, a clinically relevant reduction in the MAC for sevoflurane was observed only after administration of the higher dose of butorphanol (4 mg/kg) and only at 15 minutes after administration. No adverse effects following butorphanol administration were observed in any of the birds. The MAC for sevoflurane measured in guineafowl in the present study was 2.9%, a value that is 30% higher than that reported for chickens,14 and was similar to the reported MACs for sevoflurane in humans (1.71% and 2.05%),15,16 rabbits (3.70%),16 cats (2.58%),17 dogs (2.30%),18 and horses (2.84%).19
Intramuscular administration of 1 mg of butorphanol/kg causes a 25% reduction in the MAC for isoflurane in cockatoos,7 which is much greater than effects of higher butorphanol doses on the MAC for sevoflurane in guineafowl in the present study. Because our protocol called for increasing or decreasing the end-tidal sevoflurane concentration by 10% at each 15-minute interval in the quantal experiments, only a > 10% reduction in the MAC for sevoflurane could be considered meaningful. It is unclear why butorphanol was less effective for decreasing the MAC for an inhalation anesthetic agent in guineafowl than in cockatoos. It may be because, similar to the situation in mammals, different species of birds react differently to opioids. For example, butorphanol decreases the MAC for isoflurane in dogs and cats by approximately 20%20,21 but does not have any effect on the isoflurane requirement in rabbits.22 Even in species in which butorphanol has an MAC-sparing effect, the magnitude of the effect of butorphanol on MAC is small.
The short duration of the sparing effect of butorphanol on the MAC for sevoflurane may be explained by a high drug clearance and volume of distribution for butorphanol when it is administered IV in guineafowl. In addition to possible pharmacokinetic considerations, butorphanol may have little effect on the MAC for sevoflurane because of pharmacodynamic reasons. Butorphanol, a κ-opioid receptor agonist, could have a low binding affinity to the κ-opioid receptor in guineafowl or low efficacy once the drug is bound to the receptor. Another pharmacodynamic explanation for the results of the present study could be that the number of κ-opioid receptors in guineafowl is low at the sites within the CNS (particularly the spinal cord) that contribute to immobility during anesthesia.23
Two measurement techniques (a bracketing method and a quantal method) for determining MAC were used in the present study. Advantages of the bracketing method include the ability to determine MAC values for individual birds and obtain reasonably good population estimates of MAC when restricted by a small sample size. However, because of the long time required for bracketing measurements to be completed, and because pharmacokinetics for butorphanol are unknown in guineafowl, we could not use this method to measure the MAC-sparing effect of butorphanol without the results being confounded by time-dependent decreases in the plasma concentration of butorphanol. Instead, a quantal method was used to measure the effect of butorphanol on the MAC for sevoflurane over time. Because birds were evaluated at 15-minute intervals until movement was observed, this method allowed us to evaluate all birds at exactly the same time after butorphanol administration; therefore, the plasma concentration of butorphanol in each bird at each respective time point should be comparable. Thus, this study method provided a practical means by which the pharmacodynamics of a drug can be measured over time without knowledge of the pharmacokinetics of that drug.
The MAC for sevoflurane measured in guineafowl in the present study was similar to the range of values reported in other species. The MAC for sevoflurane decreased as the dose of butorphanol increased; however, a significant reduction in the MAC for sevoflurane was evident for only a short period. Thus, butorphanol is not a useful drug for reduction of the MAC of sevoflurane in guineafowl or higher doses are necessary to achieve a clinically relevant reduction in MAC. Further studies are needed to evaluate the efficacy and safety of high doses of butorphanol administered IV to anesthetized guineafowl.
ABBREVIATIONS
| MAC | Minimum anesthetic concentration |
| Petco2 | End-tidal partial pressure of CO2 |
| Spo2 | Oxygen saturation as measured by pulse oximetry |
Sevocris, provided by Dr. Roberto Debom, Cristália Produtos Químicos e Farmacêuticos Ltda, São Paulo, Brazil.
Conquest 3000 ventilator, HB Hospitalar Indústria e Comércio Ltda, São Paulo, Brazil.
Tom Cat 3.5F, Ortovet, São Paulo, Brazil.
Infrared gas analyzer DX-Ajaga-1 (AGA), Dixtal, Manaus, AM, Brazil.
Sevoflurane in N2 and O2, White Martins Gases Industriais SA, Rio de Janeiro, Brazil.
BD Angiocath, BD, São Paulo, Brazil.
Medfusion 2010i syringe pump, Medex Inc, Duluth, Ga.
Dixtal 2010, Dixtal, Manaus, AM, Brazil.
Ultrasonic Doppler flow detector, model 812, Parks Medical Electronic Inc, São Bernardo do Campo, SP, Brazil.
Veterinary Thermometer, Incoterm, Porto Alegre, RS, Brazil.
T/Pump, Gaymar, Orchard Park, NY.
S48 stimulator, Astro-Med Inc, West Warwick, RI.
Torbugesic, Fort Dodge Animal Health, Campinas, SP, Brazil.
SigmaStat, version 3.0.1, Systat Software, San Jose, Calif.
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