Veterinary Anaesthesia and Analgesia, 2016, 43,

Veterinary Anaesthesia and Analgesia, 2016, 43, 519 527 doi:10.1111/vaa.12327 RESEARCH PAPER Determination of the minimum infusion rate of propofol required to prevent purposeful movement of the extremities in response to a standardized noxious stimulus in goats Jacques P Ferreira*, Patience S Ndawana*, Loveness N Dzikiti & Brighton T Dzikiti* *Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Onderstepoort, South Africa School of Health Systems and Public Health, University of Pretoria, Onderstepoort, South Africa Correspondence: Jacques P Ferreira, Department of Companion Animal Clinical Studies, Faculty of Veterinary Science, University of Pretoria, Private Bag X04, 0110 Onderstepoort, South Africa. E-mail: jp.ferreira@up.ac.za Abstract Objective To determine the minimum infusion rate (MIR) of propofol required to prevent purposeful movement in response to a standardized stimulus in goats. Study design Prospective, experimental study. Animals Eight healthy goats (four does, four wethers). Methods Anaesthesia was induced with 4 mg kg 1 propofol intravenously (IV). A continuous IV infusion of propofol at 0.6 mg kg 1 minute 1 was initiated immediately to maintain anaesthesia. Following endotracheal intubation, goats breathed spontaneously via a circle breathing system delivering supplementary oxygen. The initial propofol infusion rate was maintained for 30 minutes before responses to noxious stimulation provided by clamping the proximal part of the claw with a Vulsellum forceps for 60 seconds were tested. In the presence or absence of purposeful movements of the extremities, the infusion rate was increased or reduced by 0.1 mg kg 1 minute 1 and held constant for 30 minutes before claw clamping was repeated. The propofol MIR for each goat was calculated as the mean of the infusion rates that allowed and abolished movement. Basic cardiopulmonary parameters were monitored, recorded and tested for statistical significance using Wilcoxon s signed rank test with Bonferroni adjustment for multiple testing. The quality of recovery from anaesthesia was assessed and scored. Results The median MIR of propofol was 0.45 mg kg 1 minute 1 (range: 0.45 0.55 mg kg 1 minute 1 ). Induction and recovery were free of adverse behaviour. No statistically significant cardiopulmonary changes in comparison with baseline were observed, but clinically relevant hypoxaemia at 2 minutes after induction of anaesthesia was consistently observed. Chewing during anaesthesia was observed in three goats. Median times to extubation and standing were 3 minutes (range: 2 6 minutes) and 10 minutes (range: 7 21 minutes), respectively. Conclusions and clinical relevance Propofol induction and maintenance of general anaesthesia minimally compromise cardiopulmonary function when oxygen is supplemented in goats. Keywords goat, minimum infusion rate, noxious stimulus, propofol, total intravenous anaesthesia. 519

Introduction Total intravenous anaesthesia (TIVA) can be used as an alternative method to maintain general anaesthesia when the use of an inhalation anaesthetic machine is impractical (e.g. for diagnostic imaging and field procedures) (Mannarino et al. 2012; Dzikiti 2013). Propofol is used commonly for this purpose and has been administered as a continuous IV infusion to achieve and maintain general anaesthesia in several veterinary species, including dogs (Mannarino et al. 2012; Suarez et al. 2012), horses (Oku et al. 2005), sheep (Runciman et al. 1990), rabbits (Li et al. 2012) and goats (Larenza et al. 2005; Doherty et al. 2007; Dzikiti et al. 2010). Plasma clearance of propofol in goats is rapid and exceeds the rates of clearance in dogs, horses and humans (Reid et al. 1993). In addition to being rapid, recovery from propofol-based anaesthesia in goats is also generally free of excitement and ataxia (Reid et al. 1993; Larenza et al. 2005). The dose of an anaesthetic agent required to prevent purposeful movement in response to a supramaximal stimulus in 50% of patients to which the drug is administered is equivalent to effective dose 50% (ED 50 ) (Oku et al. 2005). The minimum infusion rate (MIR) is defined as the ED 50 of an IV anaesthetic agent (Hall & Chambers 1987). The MIR provides a method for determining the IV dose rate required for TIVA drugs and also facilitates comparisons of the physiological effects and durations of recovery associated with equipotent doses of various injectable anaesthetic drugs (Li et al. 2012). The maintenance of anaesthesia using propofol administered by continuous rate infusion (CRI) in combination with other injectable drugs or inhalation anaesthetic agents has been previously reported in goats (Larenza et al. 2005; Doherty et al. 2007; Dzikiti et al. 2010), but its administration alone for TIVA has yet to be examined. The aim of this study was to determine the MIR of propofol required to prevent purposeful movement in response to a standardized stimulus in goats. Materials and methods The study was performed at a site situated 1252 m above sea level at which barometric (atmospheric) pressure lies in the range of 651 668 mmhg (86.8 89.1 kpa). The study was approved by the animal ethics regulatory committee of the University of Pretoria prior to commencement (V095-13). Eight adult, healthy indigenous African goats (four does and four wethers) were used. A priori calculations indicated that a sample size of six was required to estimate the MIR of propofol to be 0.5 mg kg 1 hour 1 to a confidence level of 95% assuming a standard deviation of 0.05 mg kg 1 hour 1 (Abramson 2011). Goats were included if the results of a physical examination [heart rate (HR), respiratory rate (f R ), chest auscultation, capillary refill time, rectal temperature], complete blood cell count and serum biochemical (total serum protein, blood urea nitrogen and creatinine) analysis were within normal ranges (Opara et al. 2010). Food and water were withheld from the goats for a period of 17 20 hours prior to anaesthesia for the experimental trial. Preparation Each goat was weighed on an electronic scale (Merav 2000 series; Shekel Industrial Scales, South Africa) 30 minutes prior to commencement of anaesthesia. A physical examination that included the recording of baseline measurements of HR, f R and rectal temperature was performed, before the goat was placed in a customized sling-cum-table to ease restraint. A 24 gauge IV cannula (Jelco; Smiths Medical UK, UK) was percutaneously inserted into the middle auricular artery to facilitate the measurement of arterial blood pressure and collection of arterial blood samples for gas analyses. Two 18 gauge IV cannulas were percutaneously inserted into the left and right cephalic veins, respectively. Lactated Ringer s solution [Ringer s Lactate; Fresenius Kabi South Africa (Pty) Ltd, South Africa] at a rate of 4 ml kg 1 hour 1 was administered through the cannula in the right cephalic vein. General anaesthesia and MIR determination Anaesthesia was induced with a single propofol [Propofol Fresenius 1%; Fresenius Kabi South Africa (Pty) Ltd] dose of 4 mg kg 1 administered IV over 60 seconds using a volumetric infusion pump that had been recently calibrated as recommended by the manufacturer (Perfusor Space; B Braun Melsungen AG, Germany). The goats were judged to be under a level of anaesthesia adequate to permit laryngoscope-guided intubation if a weak medial palpebral reflex was present and jaw muscles were sufficiently relaxed. The trachea was intubated using a 7.5 mm cuffed endotracheal tube with the goat positioned in 520 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 519 527

sternal recumbency. After intubation, the cuff was inflated sufficiently to prevent leakage from the breathing circuit. The goat was repositioned into right lateral recumbency and allowed to breathe spontaneously. The quality of induction was scored on a simple descriptive scale (SDS) of 0 2, on which 0 represented failed intubation and 2 represented an easy intubation that was free of excitement (Table S1, online). At 2 minutes after the induction of general anaesthesia, the goat was connected to a circle breathing system through which oxygen was delivered at 0.5 L minute 1 while spontaneous ventilation was maintained. Immediately after the completion of anaesthesia induction, an initial CRI of 0.6 mg kg 1 minute 1 of propofol was instituted for the maintenance of general anaesthesia using the volumetric infusion pump that had been used to induce general anaesthesia. Determination of MIR commenced at 30 minutes after induction. A noxious stimulus was applied by placing a Vulsellum forceps 1 cm below the coronary band of one hoof (at the proximal half of the distal phalanx, cranial to the bulb of the hoof) for 60 seconds or until purposeful movement was observed (Ndawana et al. 2014). Purposeful movement was defined as gross movement of the head or limbs. Shivering, twitching or stiffening of localized muscle groups, movement of the tail and an increase in respiratory rate were not considered to represent gross movement and were ignored. Claw clamping was performed on each one of the four claws of the non-dependent limbs at different times rotating in a clockwise manner. In the absence of purposeful movement, the propofol CRI was reduced by 0.1 mg kg 1 minute 1 and held constant for a further 30 minutes before responses to the noxious stimulus were tested once again. The stepwise reduction in propofol infusion rate was performed repeatedly until purposeful movement in response to a noxious stimulus was observed. In the event of an initial positive response (purposeful movement), the propofol CRI was adjusted in steps following a reverse order to that taken after an initial negative response to a noxious stimulus. The MIR for each goat was calculated as the median of the lowest dose of propofol CRI that abolished purposeful movement and the dose of propofol CRI that allowed purposeful movement. Once the propofol MIR had been determined, propofol administration was immediately terminated, all monitoring equipment was removed and the goat was disconnected from the breathing system. The goat was moved from the sling to a soft rubber mat and placed in sternal recumbency against a wall. Blankets were placed over the goat to help maintain normothermia. When the swallowing reflex had been regained, the trachea was extubated and the goat was allowed to continue recovering from general anaesthesia unassisted. The times from termination of propofol CRI to extubation, standing and walking were recorded. The quality of recovery from general anaesthesia was scored on a 4 point SDS of 0 3 on which a score of 0 represented the worst possible quality of recovery and a score of 3 represented an excitement-free recovery (Table S1). Once the goat had started walking consciously and recovery from anaesthesia was considered complete, a single dose of carprofen at 2 mg kg 1 was administered intramuscularly to relieve any residual inflammation and nociception that may have resulted from the claw clamping. Monitoring Heart rate, systolic blood pressure (SAP), diastolic blood pressure (DAP), mean arterial pressure (MAP), f R, haemoglobin oxygen saturation (SpO 2 ), respiratory gases [end-tidal carbon dioxide concentration (PE 0 CO 2 ), end-tidal oxygen concentration (PE 0 O 2 )] and body temperature were measured continuously during the anaesthetic period using a multi-parameter monitor (Cardiocap/5; Datex-Ohmeda Instrumentation Corp., Finland). The airway gases were sampled from a connector placed at the Y-piece of the breathing system and analysed using a recently calibrated (as recommended by the manufacturer) gas analyser which self-calibrated to atmospheric air with each start-up of the multi-parameter monitor. Inspired and expired O 2 and CO 2 concentrations as well as f R were measured continuously. If PE 0 CO 2 exceeded 50 mmhg (6.7 kpa), intermittent positive pressure ventilation was initiated and tailored to ensure a range of 35 45 mmhg (4.7 6.0 kpa) was maintained. Electrocardiogram monitoring with leads placed in a base apex configuration was also performed. Arterial blood pressure readings were obtained using a calibrated electronic strain gauge transducer [DTX Plus; BD Medical, Becton Dickinson (Pty) Ltd, South Africa]. The level of the scapulohumeral joint and point of the sternum were used as zero reference points in sternally and laterally recumbent goats, respectively. Haemoglobin oxygen saturation was measured using a hand-held SpO 2 monitor (Nonin 8500; White Medical Ltd, UK) by 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 519 527 521

placing the probe on the tongue of the goat. If low SpO 2 or MAP values (<92% and <60 mmhg, respectively) were observed, an immediate intervention involving either the initiation of inotropic support or the termination of propofol administration was performed. The goat then underwent a 2 week washout period after which, if the goat met the previously described inclusion criteria upon full re-examination, anaesthesia and MIR determination were reattempted. Any failure to determine MIR on the second attempt resulted in the goat s indefinite removal from the study and the exclusion of the respective data from the results. Rectal temperature was measured using a handheld digital thermometer (Vet-Temp DT-10; Advanced Monitors Corp., CA, USA). The target temperature range of 37.0 39.5 C was achieved by actively warming the goat with a forced air warming blanket (Bair Hugger; Augustine Medical, Inc., MN, USA) used in combination with standard blankets draped over the torso of the goat. Physiological parameters (HR, f R, SAP, DAP, MAP, SpO 2 and rectal temperature) were recorded prior to the induction of anaesthesia, at 2 and 10 minutes after the induction of anaesthesia, and every 10 minutes thereafter. Arterial blood samples were collected anaerobically prior to the induction of anaesthesia as well as at 2, 10 and 30 minutes afterwards. The samples were drawn into 2 ml pre-heparinized syringes (BD A-Line; Becton Dickinson & Co. Ltd, UK), sealed and analysed within 5 minutes on a blood gas machine (Rapid Lab TM 348 ph/blood Gas and Electrolyte Analyser; Siemens Medical Solutions Diagnostics Ltd, South Africa) that was calibrated daily. Oxygen tension (PaO 2 ), CO 2 tension (PaCO 2 ) and arterial ph (ph a ) were measured. Bicarbonate ion concentration ([HCO 3 ]), oxyhaemoglobin saturation (SaO 2) and the ratio of arterial oxygen partial pressure to fraction of inspired oxygen (PaO 2 /FiO 2 ) were calculated. Statistical analysis All data were analysed using R Version 3.1.2 (R Foundation for Statistical Computing [Platform: i386-w64-mingw32], Austria). All data were assumed to be non-parametric as a result of the sample size. Findings are expressed as the median (range). The medians and ranges of doses of propofol required for the induction of anaesthesia, propofol MIR, time required to determine MIR, induction score, as well as recovery score, extubation time, time at first voluntary motion and time to standing were calculated. Medians of all physiological measurements (HR, SAP, DAP, MAP, body temperature, f R ), airway gases (PE 0 CO 2,PE 0 O 2 ) and arterial blood parameters (SaO 2, PaO 2, PaO 2 /FiO 2 ratio, PaCO 2, [HCO 3 ], ph a) were tested for significant differences from baseline values using the Wilcoxon signed rank test with Bonferroni adjustment for multiple testing. A p-value of <0.05 was considered to indicate a difference of statistical significance. Results Eight goats with a median age of 24 months (all: 24 months) and weight of 37 kg (range: 33 49 kg) were initially enrolled in the study. All goats successfully underwent anaesthesia and subsequent determination of propofol MIR. Induction of anaesthesia was achieved in all eight goats with a single propofol bolus of 4 mg kg 1. All inductions were free of excitement and permitted easy intubation as reflected in the perfect induction scores of 2 observed in all goats. The median MIR of propofol in goats was determined to be 0.45 mg kg 1 minute 1 (range: 0.45 0.55 mg kg 1 minute 1 ). The median time required to determine MIR was 90 minutes (range: 60 90 minutes). The physiological and arterial blood gas variables observed during the experimental period are summarized in Tables 1 & 2. During the period of general anaesthesia, no statistically significant differences in these parameters were observed. Marginally clinically significant increases in HR and blood pressure (SAP, DAP, MAP) were consistently observed. A noteworthy but statistically insignificant reduction from baseline in respiratory rate was observed during the period of general anaesthesia. The decrease in f R, which was particularly evident at 10 minutes after the induction of anaesthesia, was directly associated with a marginal elevation in PaCO 2 and a transient decrease in SaO 2 as well as PaO 2, which were easily offset by oxygen supplementation that was instituted at 2 minutes after induction of general anaesthesia. At no stage during anaesthesia did any goat require intermittent positive pressure ventilation. Blood ph a, [HCO 3 ] and body temperature decreased consistently throughout anaesthesia but remained within physiological ranges. 522 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 519 527

The quality of recovery from general anaesthesia achieved a median score of 2 (range: 2 3). The median time to extubation relative to termination of propofol administration was 3 minutes (range: 2 6 minutes). The median time from termination of propofol administration to standing and walking was 10 minutes (range: 7 21 minutes). No signs of lameness, inflammation of the claws or hyperalgesia were observed during follow-up periods of up to 2 weeks. Notable spontaneous movements characterized by nibbling of the lips were observed in three goats during the period of anaesthesia. Ruminal tympany and regurgitation were not observed during the perianaesthetic period. Discussion Propofol, administered as a CRI in goats, did not result in significant cardiopulmonary depression, although oxygen supplementation was required to maintain normoxaemia. No adverse behaviour during recovery from anaesthesia was observed. The MIR of propofol in goats was successfully determined. Previously reported anaesthetic induction doses of propofol in goats lie in the range of 3 5 mgkg 1 (Reid et al. 1993; Pablo et al. 1997; Carroll et al. 1998). In studies by Reid et al. (1993) and Pablo et al. (1997), satisfactory depths of anaesthesia suitable for intubation in goats were achieved with an initial bolus of 4 mg kg 1. A propofol induction dose of 4 mg kg 1, as used in the present study, also proved to be adequate for tracheal intubation. This observation concurs with reports by Reid et al. (1993) and Pablo et al. (1997), who observed a good induction of anaesthesia at similar doses of propofol in goats. The MIR of propofol observed in goats in the present study (0.45 mg kg 1 minute 1 ) is comparatively lower than those reported in unpremedicated dogs [0.51 mg kg 1 minute 1 (Mannarino et al. 2012)] and rabbits [0.90 mg kg 1 minute 1 (Li et al. 2012)]. Propofol ED 50 studies performed in goats (Pablo et al. 1997) and dogs (Watney & Pablo 1992) demonstrated comparatively higher doses were required to induce anaesthesia in goats. The fact that the MIR of propofol in dogs (0.51 mg kg 1 ) observed by Mannarino et al. (2012) is higher than that observed in goats in the present study may indicate that the waiting period before testing for purposeful movement was Table 1 Physiological parameters observed during determination of the minimum infusion rate (MIR) of propofol required to prevent purposeful movement of the extremities in response to a standard noxious stimulus in goats Period of anaesthesia (minutes) 2 10 30 t-mir a t-mir b Parameter, median (range) Baseline Heart rate (beats minute 1 ) 74.0 (63 100) 104.5 (90 119) 105.0 (80 120) 104.0 (81 115) 102.0 (81 115) 111.0 (83 129) Systolic blood pressure (mmhg) 97.5 (93 134) 103.0 (84 157) 110.5 (89 151) 111.0 (97 129) 111.0 (97 129) 118.5 (90 133) Diastolic blood pressure (mmhg) 76.5 (58 107) 84.0 (59 123) 86.5 (56 124) 91.0 (68 103) 91.0 (68 103) 95.0 (74 110) Mean arterial blood pressure (mmhg) 84.5 (68 115) 91.5 (72 138) 97.0 (67 136) 101.5 (71 113) 101.5 (71 115) 105.0 (80 119) Respiratory rate (f R ) (breaths minute 1 ) 25 (20 30) 16 (11 30) 12 (7 17) 15 (5 33) 15 (5 33) 15 (7 26) Peripheral haemoglobin oxygen saturation (%) 96.5 (95 98) 87.0 (81 92) 98.0 (90 99) 98.5 (97 99) 98.5 (97 100) 98.5 (97 99) Temperature ( C) 39.0 (38.0 39.4) 39.0 (38.6 39.3) 38.6 (38.0 39.1) 38.1 (37.6 38.8) 38.2 (37.6 39.2) 37.9 (37.4 38.8) t-mira, time at which propofol infusion last abolished purposeful movement (lowest effective continuous infusion rate of propofol); t-mirb, time at which purposeful movement was observed and anaesthesia discontinued. 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 519 527 523

Table 2 Arterial blood gas parameters observed during determination of the minimum infusion rate (MIR) of propofol required to prevent purposeful movement of the extremities in response to a standard noxious stimulus in goats Period of anaesthesia (minutes) Parameter, median (range) Baseline 2 10 30 FiO 2 0.21 (0.21 0.21) 0.21 (0.21 0.21) 0.81 (0.54 0.95) 0.94 (0.87 0.99) PaO 2 (mmhg) 70.8 (60.2 81.0) 50.8 (43.2 60.9) 257.7 (40.2 310.5) 300.5 (195.4 376.1) PaO 2 (kpa) 9.4 (8.0 10.8) 6.8 (5.8 8.1) 34.3 (6.6 41.4) 40.1 (26.1 50.1) PaCO 2 (mmhg) 35.5 (32.1 69.4) 41.2 (32.9 69.4) 41.2 (37.5 44.3) 47.5 (42.5 54.8) PaCO 2 (kpa) 4.7 (4.3 9.3) 4.7 (4.3 9.3) 5.5 (5.0 5.9) 6.3 (5.6 7.3) PaO 2 /FiO 2 ratio (calculated) 337.1 (286.6 385.7) 241.9 (191.4 249.5) 303.5 (74.4 383.3) 327.5 (262.5 408.8) [HCO 3 ] (mmol L 1 ) 28.9 (27.2 30.9) 27.2 (23.9 29.0) 26.3 (23.4 28.7) 26.7 (25.1 30.4) Arterial ph 7.51 (7.48 7.53) 7.45 (7.41 7.48) 7.41 (7.33 7.43) 7.40 (7.36 7.44) SaO 2 (%) 95 (92 97) 87 (81 98) 99 (99 99) 99 (99 99) insufficient in the earlier study. The waiting period of 10 minutes reported by Mannarino et al. (2012) may have represented insufficient time for changes in propofol infusion dose rates to reach equilibrium, given that the elimination half-life of propofol is reportedly 75.2 minutes (Nolan & Reid 1991). Rates of propofol distribution and elimination differ among species and may result in variations in MIR values obtained. The high MIR reported in rabbits in comparison with the MIR observed in goats in the present study reflects the shorter propofol half-life of 2.1 minutes in rabbits (Cockshott et al. 1992) in comparison with the propofol half-life of 15 minutes reported in goats (Reid et al. 1993). Propofol has been reported to provide negligible antinociception (Antognini et al. 2000). In studies performed by Dzikiti et al. (2010) and Larenza et al. (2005), propofol infusion rates of 0.2 and 0.3 mg kg 1 minute 1, respectively, were reported. Both studies co-administered anaesthetic-sparing agents [fentanyl citrate, midazolam (Dzikiti et al. 2010) and ketamine (Larenza et al. 2005)], lowering the propofol dose rate required to maintain anaesthesia. The MIR, as described in the present study, provides stable anaesthesia in 50% of patients exposed to a standardized noxious stimulus (Mannarino et al. 2012). Variations in the stimulus will have profound effects on an MIR study and the standardization of a supramaximal stimulus is essential to the accurate determination of an MIR and the comparison of various anaesthetic agents (Eger et al. 1988). Previous animal studies attempting to determine the minimum alveolar concentration and MIR have provided a noxious stimulus by clamping of the claw, successfully demonstrating repeated supramaximal stimulation in a standardized manner (Eger et al. 1988; Ndawana et al. 2014). It is important to recognize that surgical stimulation may exceed the standardized supramaximal stimulus applied in the present study, resulting in comparatively high propofol dose rate requirements. This was demonstrated by Carroll et al. (1998), who reported a higher dose rate (0.52 mg kg 1 minute 1 ) than that observed in the present study in premedicated (detomidine and butorphanol) goats undergoing orchidectomy and ovariectomy. Mild but sustained tachycardia and hypertension were observed consistently shortly after induction and throughout the maintenance of anaesthesia in the present study. Sympathetic responses associated with an inadequate depth of anaesthesia, hypoxaemia or nociception have been previously reported in goats anaesthetized with propofol (Pablo et al. 1997; Bettschart-Wolfensberger et al. 2000; Prassinos et al. 2005). However, the cardiovascular changes observed in the present study are unlikely to be associated with any of the possible causes of increased sympathetic response mentioned above. The marginal cardiovascular stimulation persisted regardless of propofol infusion rate. In addition to sympathetic responses, spontaneous movements of the facial muscles and lips, as observed in three goats in the present study, have been unreliably associated with too light a level of anaesthesia and increased sympathetic stimulation (Pablo et al. 1997; Prassinos et al. 2005). The causes of these spontaneous limb and lip movements warrant further investigation. 524 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 519 527

Clinically significant hypoxaemia was observed directly after the induction of anaesthesia and prior to oxygen supplementation in the present study. Hypoxaemia was previously reported by Bettschart- Wolfensberger et al. (2000), who described resolution to normoxaemia shortly after the initiation of oxygen supplementation. Similar findings were observed in the present study, further supporting the routine administration of oxygen during propofol TIVA. Propofol administration in goats is commonly reported to induce respiratory depression and apnoea (Pablo et al. 1997; Carroll et al. 1998; Dzikiti et al. 2010). The present study demonstrated a clinically significant reduction in f R during the induction and maintenance of anaesthesia in comparison with baseline readings taken just prior to anaesthesia, but no apnoea was observed. Partial pressure of arterial CO 2 is generally indicative of ventilation performance, and the subtle but persistent increase in PaCO 2 in conjunction with the persistent decrease in ph a observed in this study supports descriptions in the previous literature of propofol-mediated respiratory depression in goats (Bisgard et al. 1986; Pablo et al. 1997). Similarly, decreases in PaO 2, SaO 2 and the PaO 2 /FiO 2 ratio were consistent clinical observations noted directly after the induction of anaesthesia and resolved by the initiation of oxygen supplementation. The findings in the present study of increased pulmonary shunting (hypoxaemia and a PaO 2 /FiO 2 ratio of <300), observed prior to the initiation of oxygen supplementation, support previous findings in dogs anaesthetized with propofol CRI and breathing room air (Ferros Lopes et al. 2013). Ruminal tympany and bloating are potential complications associated with general anaesthesia in ruminants and may cause respiratory failure if unresolved (Singh et al. 1971). An adequate starvation period should prove sufficient to facilitate rumen emptying, without compromising microbial health and inducing rumen stasis. The present study adhered to the recommended starvation period of 12 18 hours (Singh et al. 1971; Taylor 1991), which prevented the occurrence of any associated complications. Recovery from propofol TIVA in the present study was characterized by a calm return to consciousness with negligible ataxia, which supports descriptions in the previous literature of recovery from propofol anaesthesia in goats (Carroll et al. 1998; Larenza et al. 2005). Times to extubation and standing in the present study were rapid and reflected requirements for comparatively less time to recovery than in goats maintained on inhalation agents (Reid et al. 1993; Correia et al. 1996; Hikasa et al. 2002; Larenza et al. 2005). The present study was subject to some limitations. A sample size of six was required to estimate the MIR of propofol. The sample used in the present study numbered eight goats and, although adequate for MIR determination, did not completely exclude the potential occurrence of a Type II error as this sample is still too small to allow for the differentiation of changes from baseline values in physiological parameters. Taking this into consideration, a future study using a comparatively larger, more heterogeneous population of goats may further substantiate or dispute the findings reported in the present study. Propofol plasma concentrations are not reported in the present study. Ideally, plasma concentrations should attain steady state prior to testing for any response to a noxious stimulus (Hall & Chambers 1987). A 30 minute period was allowed between adjustment of the CRI and testing for purposeful movement in order to facilitate the attainment of propofol plasma concentration steady state. This period was chosen based on the reported elimination half-life of propofol in goats of 15.46 minutes (Reid et al. 1993). The MIR of propofol reported in the present study is limited to healthy goats. Propofol is a highly protein-bound drug, the potency of which is significantly increased during states of hypo-proteinaemia such as are commonly observed in active disease (Reidenburg & Affrime 1973; Russell et al. 1989). Future studies determining the MIR of propofol in goats with concurrent disease may yield results that differ from those obtained in the present study. In conclusion, TIVA using propofol alone was successfully employed to induce and maintain anaesthesia in goats breathing spontaneously. Adverse cardiopulmonary effects were minimal; however, oxygen supplementation should be routinely provided. The MIR of propofol was determined to be 0.45 mg kg 1 minute 1. Recovery from propofol anaesthesia was rapid and free of adverse behaviour and ataxia. Acknowledgements This study was funded jointly by the National Research Foundation, South Africa and the University of Pretoria. 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 519 527 525

References Abramson JH (2011) WINPEPI updated: computer programs for epidemiologists; and their teaching potential. Epidemiol Perspect Innov 8, 1. Antognini JF, Wang XW, Piercy M et al. (2000) Propofol directly depresses lumbar dorsal horn neuronal responses to noxious stimulation in goats. Can J Anaesth 47, 273 279. Bettschart-Wolfensberger R, Semder A, Alibhai H et al. (2000) Cardiopulmonary side-effects and pharmacokinetics of an emulsion of propofol (Disoprivan â ) in comparison to propofol solved in polysorbate 80 in goats. J Vet Med A Physiol Pathol Clin Med 47, 341 350. Bisgard GE, Busch MA, Daristotle L et al. (1986) Carotid body hypercapnia does not elicit ventilatory acclimatization in goats. Respir Physiol 65, 113 125. Carroll GL, Hooper R, Slater MR et al. (1998) Detomidine butorphanol propofol for carotid artery translocation and castration or ovariectomy in goats. Vet Surg 27, 75 82. Cockshott ID, Douglas EJ, Plummer GF et al. (1992) The pharmacokinetics of propofol in laboratory animals. Xenobiotica 22, 369 375. Correia D, Nolan AM, Reid J (1996) Pharmacokinetics of propofol infusions, either alone or with ketamine, in sheep premedicated with acepromazine and papaveratum. Res Vet Sci 60, 213 217. Doherty T, Redua MA, Queiroz-Castro P et al. (2007) Effect of intravenous lidocaine and ketamine on the minimum alveolar concentration of isoflurane in goats. Vet Anaesth Analg 34, 125 131. Dzikiti TB (2013) Intravenous anaesthesia in goats: a review. J S Afr Vet Assoc 84, 1 8. Dzikiti TB, Stegmann FG, Dzikiti LN et al. (2010) Total intravenous anaesthesia (TIVA) with propofol fentanyl and propofol midazolam combinations in spontaneously breathing goats. Vet Anaesth Analg 37, 519 525. Eger EI, Johnson BH, Weiskopf RB et al. (1988) Minimum alveolar concentration of I-653 and isoflurane in pigs: definition of a supramaximal stimulus. Anaesth Analg 67, 1174 1176. Ferros Lopes PC, Nunes N, Sousa MG et al. (2013) The effects of different inspired oxygen fractions on gas exchange and Tei-index of myocardial performance in propofol-anesthetized dogs. Vet Anaesth Analg 40, 573 583. Hall L, Chambers J (1987) A clinical trial of propofol infusion anaesthesia in dogs. J Small Anim Pract 28, 623 637. Hikasa Y, Hokushin S, Takase K et al. (2002) Cardiopulmonary, haematological, serum biochemical and behavioural effects of sevoflurane compared to isoflurane or halothane in spontaneously ventilating goats. Small Rumin Res 43, 167 178. Larenza MP, Bergadano A, Iff I et al. (2005) Comparison of the cardiopulmonary effects of anaesthesia maintained by continuous infusion of ketamine and propofol with anaesthesia maintained by inhalation of sevoflurane in goats undergoing magnetic resonance imaging. Am J Vet Res 66, 2135 2141. Li R, Zhang WS, Liu J et al. (2012) Minimum infusion rates and recovery times from different durations of continuous infusion of fospropofol, a prodrug of propofol, in rabbits: a comparison with propofol emulsion. Vet Anaesth Analg 39, 373 384. Mannarino R, Luna SP, Monteiro ER et al. (2012) Minimum infusion rate and hemodynamic effects of propofol, propofol lidocaine and propofol lidocaine ketamine in dogs. Vet Anaesth Analg 39, 160 173. Ndawana PS, Dzikiti TB, Zeiler GE et al. (2014) Determination of minimum infusion rate (MIR) of alfaxalone required to prevent purposeful movement of the extremities in response to a standardised noxious stimulus in goats. Vet Anaesth Analg 42, 65 71. Nolan AM, Reid J (1991) A pharmacokinetic study of propofol in the dog. Proceedings of the 4th International Congress of Veterinary Anaesthesia, Utrecht, the Netherlands. p. 40. Oku K, Ohta M, Yamanaka T et al. (2005) The minimum infusion rate (MIR) of propofol for total intravenous anaesthesia after premedication with xylazine in horses. J Vet Med Sci 67, 569 575. Opara MN, Udevi N, Okoli IC (2010) Haematological parameters and blood chemistry of the apparently healthy West African dwarf (Wad) goats in Owerri, Southeastern Nigeria. N Y Sci J 3, 68 72. Pablo L, Bailey J, Ko J (1997) Median effective dose of propofol required for induction of anaesthesia in goats. J Am Vet Med Assoc 211, 86 88. Prassinos NN, Galatos AD, Raptopoulos D (2005) A comparison of propofol, thiopental or ketamine as induction agents in goats. Vet Anaesth Analg 32, 289 296. Reid J, Nolan A, Welsh E (1993) Propofol as an induction agent in the goat: a pharmacokinetic study. J Vet Pharmacol Ther 16, 488 493. Reidenburg MM, Affrime M (1973) Influence of disease on binding of drugs to plasma proteins. Ann N Y Acad Sci 226, 115 126. Runciman WB, Mather LE, Selby DG (1990) Cardiovascular effects of propofol and of thiopentone in sheep. Br J Anaesth 65, 353 359. Russell GN, Wright EL, Fox MA et al. (1989) Propofol fentanyl anaesthesia for coronary heart surgery and cardiopulmonary bypass. Anaesthesia 44, 205 208. Singh MP, Elliot RL, Melrose DG (1971) A simple technique of anaesthesia for experimental open-heart surgery in the calf. Thorax 26, 103 107. Suarez MA, Dzikiti BT, Stegmann FG et al. (2012) Comparison of alfaxalone and propofol administered as 526 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 519 527

total intravenous anaesthesia for ovariohysterectomy in dogs. Vet Anaesth Analg 39, 236 244. Taylor P (1991) Anaesthesia in sheep and goats. In Pract 13, 31 36. Watney GC, Pablo LS (1992) Median effective dose of propofol for induction of anaesthesia in dogs. Am J Vet Res 53, 2320 2322. Table S1. Scoring system used to assess the quality of induction of and recovery from anaesthesia during determination of the minimum infusion rate (MIR) of propofol required to prevent purposeful movement of the extremities in response to a standard noxious stimulus in goats. Received 18 February 2015; accepted 1 June 2015. Supporting Information Additional Supporting Information may be found in the online version of this article: 2015 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 43, 519 527 527