Midazolam is a water-soluble benzodiazepine that can be administered either by the intramuscular or intravenous route (Cao et al. 2002; Lemke 2007). It has mild cardiovascular and respiratory effects at clinical dosages and is commonly used as a mild sedative, muscle relaxant and anticonvulsant (Galatos 2011; Lemke 2007). Midazolam is reported to cause a significant reduction in the dose of propofol required for induction of anaesthesia in goats when administered intramuscularly alone and when combined with butorphanol (Dzikiti et al. 2009).

Butorphanol, a synthetic opioid, is an agonist at κ-opioid receptors and an antagonist at μ-opioid receptors (Carroll et al. 1997; Lamont & Mathews 2007; Valverde & Gunkel 2005). Opioids are traditionally included in balanced anaesthetic protocols for their analgesic effects, but they also have species-specific sedative effects (Lemke 2007). Butorphanol has useful analgesic effects in ruminants, but it can also cause central nervous system stimulation (Carroll et al. 2001; Doherty, Rohrbach & Geiser 2002). Butorphanol at a dose range of 0.02 mg/kg – 0.50 mg/kg, administered intramuscularly or intravenously, increases the degree of sedation obtainable from acepromazine or benzodiazepines (Dzikiti et al. 2009; Riebold 2007; Valverde & Gunkel 2005). At the same time, the sedatives (benzodiazepines) help to diminish the inherent excitatory effects of butorphanol (hyperactivity, increased myoclonic activity) in goats (Carroll et al. 2001; Dzikiti et al. 2009).

Alfaxalone is a synthetic, neuroactive steroid hypnotic agent (Ferré et al. 2006); several research teams have recently assessed the anaesthetic and cardiorespiratory effects of it. Its pharmacokinetic and pharmacodynamic profiles make it ideal for intravenous induction and maintenance of general anaesthesia in dogs (Ambrisko et al. 2011; Ambros et al. 2008; Ferré et al. 2006; Jiménez et al. 2012; Maddern et al. 2010; Michou et al. 2012; Muir et al. 2008; Psatha et al. 2011; Rodríguez et al. 2012; Suarez et al. 2012). Alfaxalone has been reported to be a suitable anaesthetic-induction agent at a dose of 2.00 mg/kg in unsedated sheep (Andaluz et al. 2012, Torres et al. 2012), sedated dogs (Maddern et al. 2009; Suarez et al. 2012) and ponies (Klöppel & Leece 2011; Leece et al. 2010). Dosages of 3.47 mg/kg − 4.70 mg/kg have been reported for sedated cats (Martinez Taboada & Murison 2010; Mathis et al. 2012).

To the knowledge of the authors, there are currently no scientific reports on the effects of commonly used sedatives on the induction dose of alfaxalone in goats, as well as the impact of these agents on the quality of general anaesthesia arising from their use. The present study tested the null hypothesis that midazolam, alone or combined with butorphanol, does not affect the induction dose of alfaxalone versus the alternative hypothesis that midazolam and butorphanol affect the alfaxalone induction dose in goats.

For measurement of arterial blood pressure and collection of arterial blood samples for analyses, a 24-gauge catheter (Jelco, Medex Medical Ltd, Rossendale, Great Britain) was percutaneously introduced into the auricular artery. The catheter was connected to a recently calibrated transducer (DTX Plus transducer, BD Medical, Johannesburg, South Africa) for measurement of systolic, diastolic and mean arterial blood pressures. For transducer calibration to atmospheric pressure, the scapulo-humeral joint or the point of the sternum were used as zero reference points in sternally-recumbent or laterally-recumbent goats, respectively. Blood pressure readings were read from an electronic strain gauge transducer connected to a multi-parameter monitor (Cardiocap/5, Datex-Ohmeda Corporation, Helsinki, Finland).

The goats were premedicated by the intramuscular route with saline (Intramed Sodium Chloride 0.9%^® Fresenius, Bodene, trading as Intramed, Port Elizabeth, South Africa) at 0.05 mL/kg (Treatment Control), or midazolam (Dormicum^®, Roche Products, Isando, South Africa) at 0.30 mg/kg (Treatment MID), or butorphanol (Torbugesic^®, Fort Dodge Animal Health, Fort Doge, USA) at 0.10 mg/kg (Treatment BUT), or a combination of midazolam at 0.30 mg/kg with butorphanol at 0.10 mg/kg (Treatment MIDBUT). The treatment drugs were calculated, drawn up and injected by a person other than the principal investigator, who was blinded to the treatments until the end of the data collection. This was so that the degree of sedation, the alfaxalone dose required for induction of general anaesthesia, the induction quality score and the recovery quality could be determined without bias. The degree of sedation was scored 30 min after administration of the treatments on a 0−3 scale, with 0 representing absence of apparent sedation (Table 3).

Once sedation had been assessed, an 18-gauge catheter (Jelco; Medex Medical Ltd, Rossendale, Great Britain) was introduced into the left forelimb cephalic vein for administration of alfaxalone and fluids. Thirty minutes (30 min) after administration of the treatments, alfaxalone (Alfaxalone^®-CD RTU, Jurox Pty Ltd, Rutherford, Australia) was administered intravenously to induce a level of anaesthesia adequate for placement of an endotracheal tube. The main bolus dosage of alfaxalone at 1.50 mg/kg was administered using a volumetric syringe-driving pump (Perfusor^® Space, B Braun Medical, Bethlehem, USA) over a 30 s period, followed by incremental boluses as required, at 0.50 mg/kg every 15 s. Depth of anaesthesia was checked by jaw tone and reflexes, immediately after administration of each intermittent bolus of alfaxalone, until the jaw was relaxed enough, and the swallowing and laryngeal reflexes, to see if they were diminished enough to allow endotracheal intubation. Placement of the endotracheal tube (silicone tube, internal diameter 7.5 mm) was performed using an illuminated laryngoscope, with the goats in sternal recumbency. Immediately after tracheal intubation, the goats were placed in right lateral recumbency and the exact total dose of alfaxalone required for induction of general anaesthesia was recorded. The quality of induction was assessed on a 0−2 score scale, with 0 representing failed intubation (Table 3).

Immediately after induction, the goats were allowed to recover from general anaesthesia, during which time they breathed room air spontaneously. Oxygen was supplemented if the goats became hypoxaemic (saturation of haemoglobin with oxygen in peripheral tissues [SpO₂] < 90%). Ringer Lactate solution (Intramed Ringer-Lactate^® Fresenius, Bodene, trading as Intramed, Port Elizabeth, South Africa) was administered intravenously using a volumetric fluid infusion pump (Infusomat^® Space, B Braun Medical, Bethlehem, USA) at a rate of 4.00 mL/kg/hour, beginning from just before induction of general anaesthesia to about 30 min after induction of general anaesthesia. The endotracheal tube was removed once the goats regained a swallowing reflex. Time to extubation, sternal recumbency, standing and voluntary motion were recorded. All times were determined as the interval between the time the last amount of alfaxalone was administered and the time a particular event occurred. Quality of recovery was scored on a 0−3 score scale, with 0 representing the worst possible quality of recovery (Table 3).

Cardiopulmonary parameters including systolic, diastolic and mean arterial pressures, heart rate, respiratory rate and SpO₂, as well as body temperature, were recorded prior to and 30 min after administration of the treatments and 2 min, 15 min and 30 min after administration of alfaxalone (Tables 1 and Table 2).

Arterial blood samples for gas analyses were collected in 2 mL pre-heparinised syringes (BD A-Line, Becton™, Dickinson & Company, New Jersey, USA) prior to (baseline) and 30 min after administration of the treatments, and 2 min and 30 min after administration of alfaxalone. The syringes were sealed immediately and the samples were analysed for blood gases within 5 min. Oxygen tension (P_aO₂), carbon dioxide tension (P_aCO₂), hydrogen ion concentration negative logarithm (pH), bicarbonate ion ([HCO₃^–]) concentration and oxygen saturation (S_aO₂) were measured using a pre-calibrated blood gas analyser (Rapidlab™ 348 pH/Blood Gas and Electrolyte Analyser, Siemens Medical Solutions Diagnostics, Midrand, South Africa).

To verify respiratory status, the P_aO₂/ F_IO₂ ratio was calculated by dividing the measured arterial oxygen tension by the fraction of inspired oxygen (21% or 0.21 in the present study). During normal respiratory function this ratio is greater than 250, whilst in patients with severe respiratory failure the ratio is less than 200 (Lagutchik 2001).

The control dose of alfaxalone required for induction of general anaesthesia was 3.00 mg/kg (2.50 mg/kg – 3.00 mg/kg). The alfaxalone induction dose was statistically significantly higher than doses of 2.00 mg/kg (2.00 mg/kg – 2.13 mg/kg) and 1.75 mg/kg (1.5 mg/kg – 2.00 mg/kg) required following MID (p = 0.0023) and MIDBUT (p = 0.000038) treatments, respectively. An alfaxalone induction dose of 2.25 mg/kg (2.00 mg/kg – 2.52 mg/kg), which was required following BUT treatment was not significantly different from the control dose. The percentage reductions in the dose of alfaxalone required for induction of general anaesthesia following MID and MIDBUT treatments were 33.3% and 41.8%, respectively and were statistically significant, whilst BUT treatment caused a statistically insignificant reduction of 24.9% (Table 4 and Figure 1). The alfaxalone induction doses observed following MID or MIDBUT treatment were not statistically significantly different from each other.

FIGURE 1: Box plot of the dose of alfaxalone (median [interquartile range])following pre-anaesthetic saline, midazolam, butorphanol and a combination of midazolam and butorphanol before intravenous alfaxalone for induction of anaesthesia in goats.

Of the cardiovascular variables assessed, statistically significant differences were observed only in heart rate, which was higher than the baseline reading from within the same treatment group across all treatments, including the control, from 2 min of induction of general anaesthesia onwards (Table 1).

Respiratory and arterial blood gas variables showed very few statistically significant differences (Table 2). Statistically significant increases in P_aCO₂ were observed 2 min following induction of general anaesthesia within all treatment groups except Control. The P_aO₂/F_IO₂ ratio stayed above 250 with all treatments throughout the period of blood gas assessment.

The goats recovered calmly from general anaesthesia following all treatments. Times to extubation and sternal position were statistically significantly longer than the Control equivalents (p = 0.003 and 0.002, respectively) only for MIDBUT treatment. The time taken to attain standing position did not show any statistically significant differences amongst treatments and ranged from 17.5–32.5 min following BUT treatment and both MID and MIDBUT treatments, respectively (Table 4).

Adverse effects observed following induction of anaesthesia with alfaxalone included: frequent bloat of varying degrees; some increased muscle activity in the form of brisk palpebral movements and nystagmus; and muscle twitches and spasms, involving mostly muscles of the face, neck and upper forelimb. The observed increased muscle activity in a select group of muscles did not seem to be associated with gross purposeful movement of any body parts or depth of anaesthesia.

Midazolam, administered alone or with butorphanol at dosages used in the present study, caused moderate to profound sedation, which was significantly different from that observed following administration of either saline or butorphanol alone. Midazolam has been previously reported to cause profound sedation in goats (Dzikiti et al. 2009; Stegmann & Bester 2001). Butorphanol alone, as with saline, caused no apparent sedation in goats, in agreement with observations reported in earlier studies (Dzikiti et al. 2009). The sedative effects of butorphanol can be unpredictable and erratic (Carroll et al. 2001; Dzikiti et al. 2009), confirming the observations of the present study. Butorphanol does not seem to improve the level of sedation obtainable from midazolam alone, as no differences were observed in the level of sedation when the two were co-administered in comparison with midazolam alone. Butorphanol has been suspected to stimulate the central nervous system in goats, with effects such as restlessness and abnormal vocalisation cited (Carroll et al. 2001; Galatos 2011; Doherty et al. 2002). These excitatory effects were not observed in the present study.

The observed alfaxalone induction doses (1.75 mg/kg –

3.00 mg/kg) are similar to those reported in earlier studies in other species such as: sheep (Andaluz et al. 2012; Torres et al. 2012); dogs (Maddern et al. 2010; Suarez et al. 2012); and ponies (Klöppel & Leece 2011; Leece et al. 2009), but lower than doses reported in cats (Martinez Taboada & Murison 2010; Mathis et al. 2012). The reason for the lack of agreement in alfaxalone dose could be the difference in the rate at which alfaxalone was administered. Administration of intravenous anaesthetic drugs for induction at slower rates significantly reduced the total dose required in humans (Berthoud et al. 1993; Peacock et al. 1990) and dogs (Dugdale et al. 2005). If the rate of administration is too rapid, there is a tendency to over-estimate the induction dose (Dugdale et al. 2005). Another factor that can influence the total dose required for induction is cardiac output (Dugdale et al. 2005); which was not measured in the present study.

The reductions in the dose of alfaxalone required for induction, especially following administration of midazolam alone or combined with butorphanol, demonstrate that midazolam-based premedication regimens can be used to supplement alfaxalone anaesthesia in goats, thereby reducing the dose of alfaxalone required to maintain general anaesthesia. The role of butorphanol in clinical settings would be to provide analgesia, especially for minor noxious procedures. The extent of reduction of the alfaxalone induction dose observed in the present study following MID, BUT and MIDBUT treatment of 33.3%, 24.9% and 41.8%, respectively, closely resemble those observed in an earlier study of 39.7%, 22.1% and 38.1% for propofol induction dose reduction following administration of the same premedication drugs at the same dosages in goats (Dzikiti et al. 2009). This observation demonstrates that midazolam and butorphanol reduce the amount of propofol or alfaxalone required for induction of general anaesthesia in a similar way in the goat. Pre-anaesthetic medication of goats with midazolam, alone or combined with butorphanol, clearly has an important role in balanced anaesthetic regimens in which alfaxalone or propofol is the induction agent.

During induction of general anaesthesia the goats were calm, irrespective of the sedation regimen used in the present study. This demonstrates that alfaxalone causes excitement-free induction in goats, even without prior calming of the goats by sedatives. This is similar to what has been reported for propofol, a closely related induction agent (Bettschart-Wolfensberger et al. 2000; Dzikiti et al. 2009; Pablo et al. 1997; Prassinos et al. 2005).

The statistically significant increase in heart rate observed following administration of alfaxalone – a common finding following all treatments in the present study – cannot be explained easily from the basic cardiovascular parameters measured, as the blood pressure did not change much during the same period. Had the other determinants of mean arterial blood pressure, namely cardiac output and peripheral vascular resistance, been measured, it may have been possible to explain the reason for the increase in heart rate observed in the present study. The increase in heart rate, accompanied by hardly any changes in blood pressure, mirror observations previously reported in sheep following alfaxalone administration (Andaluz et al. 2012). Change of body position to lateral recumbency was presumed to be the reason for the increase in heart rate in sheep by Andaluz’s research team. Alfaxalone appears not to cause clinically significant alterations in cardiovascular function based on observations from the present study, notwithstanding the increase in heart rate.

Respiratory and blood gas parameters were largely unaffected by the alfaxalone and midazolam or butorphanol administered for premedication. The statistically significant increase in P_aCO₂ observed in all three treatments was not clinically significant, as the values still remained below the 45 mmHg upper limit. Further confirmation of unaffected respiratory function is obtained from the P_aO₂/F_IO₂ ratio, which remained higher than 250 throughout the anaesthetic period. Patients with compromised respiratory function have P_aO₂/F_IO₂ ratios below 200 (Lagutchik 2001). In sheep, alfaxalone causes minimal respiratory changes, but induction apnoea and bradypnoea have been reported in dogs (Muir et al. 2008; Whittem et al. 2008).

Recovery from general anaesthesia was excitement-free following all treatments and the goats were able to attain standing position within 30 min of induction, as has been previously reported for propofol in goats (Dzikiti et al. 2009).

The adverse effects observed in the present study have been previously reported following administration of alfaxalone in other species. Bloat is known to occur in laterally recumbent goats despite prior starvation (Dzikiti 2013; Galatos 2011; Taylor 1991). Brisk palpebral movements and nystagmus have been reported in horses (Goodwin et al. 2011). Referred muscle movements have previously been reported in anaesthetised goats and other species, even with other induction agents such as propofol and thiopentone (Benson & Thurmon 1990; Dzikiti et al. 2009; Mathis et al. 2012).

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