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Abstract

This study looked at the use and efficacy of alfaxalone for total intravenous anaesthesia (TIVA) in cats. Following intramuscular medetomidine (20 μg/kg) and morphine (0.3 mg/kg) premedication, anaesthesia was induced and maintained with intravenous alfaxalone. Patients were breathing 100% oxygen. Heart rate (HR), respiratory rate (RR), end-tidal carbon dioxide, oxygen saturation of haemoglobin and indirect arterial blood pressure via Doppler (DAP) were recorded every 5 mins. Thirty-four cats (10 males and 24 females), between the age of 6 and 18 months, and weighing between 1.8 and 5.3 kg, and undergoing neutering procedures were included in this study. The results are presented as median (min, max) values. The time to first spontaneous movement (TS) was >30 mins in 19 cats, of which 12 received atipamezole for reversal of the effects of medetomidine. The TS was 53 (43, 130) mins in these 12 cats and 50 (40, 72) mins in the other seven cats. The body temperature in those 19 cats was significantly lower than the other cats (P = 0.05). The alfaxalone induction dose and maintenance infusion rate were1.7 (0.7, 3.0) mg/kg and 0.18 (0.06, 0.25) mg/kg/min, respectively. The HR, RR and DAP were 145 (68, 235) beats/min, 17 (5, 40) breaths/min and 110 (58, 210) mmHg, respectively. Apnoea was not observed in any cat. In conclusion, alfaxalone TIVA in combination with medetomidine and morphine premedication was effective in feral and domestic cats for the performance of neutering surgery; low body temperature might have resulted in longer recoveries in some cats.

Introduction

Total intravenous anaesthesia (TIVA) consists of inducing and maintaining anaesthesia with (an) intravenous (IV) agent(s) only. This method, compared with inhalation anaesthesia, has its advantages and disadvantages, which are described elsewhere.¹ In the 1970s, a mixture of two neurosteroids, alfaxalone and alfadolone in Cremophor-EL, was registered as a new injectable anaesthetic for humans (Althesin), and cats and primates (Saffan). This mixture, in addition to being a good IV and intramuscular (IM) anaesthetic induction agent, had desirable properties to be used for infusion in cats, as well as other species such as rats, rabbits and ferrets.^2–4 Unfortunately, side effects related to the excipient used to solubilise the neurosteroids in the final formulation resulted in the removal of the product from the market for humans and, eventually, cats and primates.^5,6 Recently, a new formulation of alfaxalone alone, using hydroxypropyl-beta-cyclodextrin (HPCD) as the neurosteroid solubilising agent, has been used in dogs, cats, horses, monkeys and amphibians.^7–15 In a recent study in cats, Whittem et al¹¹ did not observed any evidence of pharmacodynamics or pharmacokinetic (PK) cumulative effect after administering a single bolus or repeated boluses of this new formulation. In addition, they did not detect any of the side effects (ie, oedema and/or hyperaemia of ear pinnae and paws, pulmonary oedema) commonly observed in the past with the alfaxalone/alfadolone mixture.^11,16 Therefore, the new formulation and history of having desirable properties for infusion would make this agent a good candidate for TIVA in the cat. The goal of the study was to look at the use and the efficacy of alfaxalone in HPCD for TIVA in medetomidine–morphine premedicated cats undergoing neutering procedures.

Materials and methods

This prospective study was approved by Ross University School of Veterinary Medicine Research and the Institutional Animal Care and Use Committee. The animals used were part of the neutering clinics where surgical procedures were undertaken by students under the supervision of Diplomates of the American College of Veterinary Surgery. Although the surgery and the recording of the anaesthetic data were performed by students, the anaesthesia was induced, maintained and adjusted as per the clinical requirements by the same anaesthetist monitoring one cat at a time.

Feral and client-owned cats brought into the Veterinary Teaching Hospital for the purpose of neutering were included in this study. While feral cats were housed in the clinic the night preceding and the night following the surgery, owned cats were usually brought in the morning of the surgery and sent home the same day. Signed owner consent was obtained for client-owned cats. All the cats underwent a full physical examination and had blood collected for a full haematology and biochemistry profile prior to premedication unless they were too fractious (feral). If a cat was too fractious, the blood sample was collected after pre-anaesthetic medication and before induction of anaesthesia. In the case of abnormal findings in either the biochemistry or haematology results, the cat was removed from the study and appropriate treatment administered if deemed necessary. Patients weighing <1.5 kg and >8 years old were excluded from the study. Water was accessible up to 1 h before pre-anaesthetic medication, and food was removed 8–10 hours before surgery.

Twenty mins after the IM administration of medetomidine (20 μg/kg) and morphine (0.3 mg/kg), a 20 G intravenous catheter was placed in a cephalic vein. Heart rate (HR) and respiratory rate (RR) were measured if the cat’s temperament permitted (owned vs feral cats). Alfaxalone (0.5–3.0 mg/kg) was then administered intravenously to effect over an approximate period of 1 min until endotracheal intubation was possible (lack of jaw tone, lack of gagging reflex and lack of coughing reflex). After endotracheal intubation, the patient was attached to an anaesthetic machine using an appropriate non-rebreathing system and was allowed to breathe 100% medical grade O₂ (200–400 ml/kg/min with a minimum of 1 l) throughout the procedure. In the event of apnoea (no breath for 30 s), cats were manually ventilated at 10 breaths/min until spontaneous ventilation resumed. After induction, all cats were placed on a heating device (Bair Hugger; Arizant Healthcare) and anaesthesia was maintained with alfaxalone administered intravenously, initially at 0.3 mg/kg/min, using a syringe driver (Graseby Medical). The syringe driver was programmed with the syringe brand and the drug concentration, as well as the weight of the patient to allow precise calculation of the amount of drug infused over time.

The depth of anaesthesia was clinically assessed using jaw tone, eye position and ocular-palpebral reflex, and the rate of infusion of alfaxalone was altered accordingly. Supportive therapy consisted of lactated Ringer’s solution infused throughout surgery at about 10 ml/kg/h by gravity through a micro drip (60 drops/ml) infusion set with burette (100 ml Burette Set; Hospira). HR from a three-lead electrocardiogram, RR and end-tidal carbon dioxide (EtCO₂) using side-stream capnography (probe placed between the endotracheal tube and the breathing system), and oxygen saturation of haemoglobin (SpO₂%) through an infra-red probe placed on the tip of the tongue were all monitored continuously (Advisor; Smiths Medical PM). Indirect arterial blood pressure was measured every 5 mins using a Doppler system (DAP) (Parks Medical Electronic). All physiological variables were recorded every 5 mins as numerical data in a study-specific anaesthesia folder. Body temperature was measured through an oesophageal probe and recorded every 15 mins.

At the end of the surgical procedure, the alfaxalone infusion was stopped and the total amount of infused agent calculated through the syringe pump integrated software was recorded. The infusion time (IT), defined as the time from the start of infusion to the end of the infusion; the extubation time (ET), defined as the time between the end of the infusion and the time of swallowing; and the time to first spontaneous movement (TS), defined as the time from the end of the infusion to the first spontaneous movement were also recorded. Meloxicam (0.2 mg/kg) was injected subcutaneously at the start of the surgery and was followed by oral doses (0.05 mg/kg) once daily for 1–3 consecutive days. Prolonged TS (>30 mins) was observed in seven cats at the beginning of the study. It was hypothesised that medetomidine used in the premedication could be responsible for this observed increase in TS, and it was decided to administer atipamezole, an alpha 2 adrenoceptor antagonist, at a dose of 0.05 mg/kg IM in cats with a TS >30 mins.

Criteria for inadequate anaesthesia were a sudden increase in DAP of >20%, a sudden increase in HR of 10% in the absence of hypovolaemia and somatic responses such as swallowing or movement. In these cases, alfaxalone infusion was increased by 0.05 mg/kg/min increments every minute until no response to noxious stimulation was observed. Between increments, the surgeon was asked to stop the procedure. A DAP <80 mmHg (hypotension) was treated by increasing fluid therapy from 10 to 50 ml/kg/h. In addition, if possible, the alfaxalone infusion rate was decreased by a 0.02 mg/kg/min increment every 5 mins. If hypotension had not resolved after 15 mins, dopamine at 7 μg/kg/min was started. Once the blood pressure reached 80 mmHg, the fluid bolus was stopped and the pre-hypotension fluid rate was re-established. If hypotension was associated with bradycardia (defined as HR <100 beats/min [bpm]) atropine (0.01 mg/kg) was administered IV. In the event of apnoea, the patient was manually ventilated at a rate of 8–10 breaths/min and with a tidal volume of 10–20 ml/kg (Wright/Haloscale Respirometer; Grace Medical).

Statistics

This is a descriptive study, and descriptive statistics were performed for most of the measured parameters using SigmaPlot 12 (Systat Software). In addition, males and females were compared for parameters such as age, weight, body temperature at the end of the anaesthesia, IT, ET and TS, and alfaxalone induction and maintenance doses, as well as infusion rate. Normality test (P >0.05) was used for all data (Shapiro–Wilk). Depending of the results, Student’s t-test or Whitney Rank Sum Test was used for paired comparison. A P-value ≤0.05 was considered to be significant.

Results

Unless stipulated otherwise, all the results are presented as median (min., max.). Thirty-four cats (10 males and 24 females), aged 6–18 months and weighing 1.8–5.3 kg were included in this study (Table 1). Three feral cats (two males and one female) were very wild and the dose of morphine was increased from 0.3 to 0.5 mg/kg. The alfaxalone induction dose and maintenance infusion rate for both males and females were 1.7 (0.7, 3.0) mg/kg and 0.18 (0.06, 0.25) mg/kg/min, respectively.

Table 1

Age (months), weight (kg), anaesthesia and recovery times (mins), induction and total maintenance doses (mg/kg), and mean infusion rate (mg/kg/min) in a population of 10 male and 24 female cats undergoing a neutering procedure. The results are expressed as mean (± SD) for normally (Shapiro–Wilk test) distributed vales and as median (min, max) for the others

	Male	Female
Number of cats	10	24
Age (months)	8.5 (6, 15)	8 (6, 18)
Weight (kg)*	3.1 (2.0, 5.3)	2.6 (1.8, 4.1)
Infusion/anaesthesia time (mins)*	39.6 (21.3)	126.5 (24.7)
Extubation time (mins)	20 (6, 48)	16 (3, 43)
First movement (mins)*	27 (10, 48)	49 (7, 130)
Induction dose (mg/kg)	1.5 (0.5)	1.8 (0.7)
Total maintenance dose (mg)*	21.6 (15.2)	59.1 (16.8)
Mean infusion rate (mg/kg/min)	0.17 (0.06, 0.24)	0.18 (0.14, 0.25)
Temperature at recovery (°C)	37.1 (0.6)	36.4 (1.5)

Significantly different

Endotracheal intubation was achieved 1–1.5 mins after the start of the alfaxalone administration. The anaesthesia time (from endotracheal intubation to the end of the infusion) was 115.5 (14, 160) mins for all cats. ET and TS were 17 (3, 48) and 44 (7, 130) mins, respectively. TS was <30 mins in 15 cats (seven males and eight females) and >30 mins in 19 (52 [40, 130] mins). Of those 19 cats, 12 received a dose of atipamezole (TS = 53 [43, 130] mins) and seven did not (TS = 50 [40, 72] mins). A summary of cat signalment, dose rates and anaesthetic duration times are presented in Table 1 for each group (male vs female cats).

The HR, RR and DAP were 145 (68, 235) bpm, 17 (5, 40) breaths/min and 110 (58, 210) mmHg, respectively. The average HR at induction (about 112 bpm) increased progressively over time and seemed to stabilise at an average of 165 bpm at 65 mins. Hypotension, defined as a DAP of <80 mmHg, was observed in 20 cats and responded well to increasing fluid therapy and lowering the depth of anaesthesia. Five of these 20 cats were hypotensive during the first 10 mins after induction. The lowest recorded value was 58 mmHg. Eighteen cats were hypotensive for one reading (5 mins) and two cats were hypotensive for about 15 mins. No pharmacological intervention was administered to treat the hypotension except in one cat where the hypotension was associated with a low HR and atropine 0.01 mg/kg was administered IV. Four cats (one male and three females) showed, at one time or another, DAP values >160 mmHg. In all cases, the DAP seemed to respond to an increase in the alfaxalone infusion rate and/or a decrease in the noxious stimulation. Apnoea was not observed in the study and the EtCO₂ was 21 (14, 43). The spontaneous RR decreased from 23 (5, 40) breaths/min at the time to induction of anaesthesia to an average of 16 (8, 35) breaths/min 10 mins later, and stayed relatively constant throughout the study period. The SpO₂ values stayed above 96% throughout the study. The rectal temperature at the end of anaesthesia was 36.3 (34.0, 39.5) ºC. In the recovery period, three cats showed muscle twitching, which seemed to be triggered by external stimulation such as noise.

Owing to a high proportion of feral cats, pre- and post-induction values for the HR and RR were only available in 15 (non-feral) cats. While the RR values were statistically different (P <0.001), the HR values were not (P = 0.381).

Regarding the surgeries, no more bleeding than one would expect from those procedures was observed.

Discussion

This study reports and describes the use of alfaxalone for induction and maintenance of anaesthesia following premedication with medetomidine and morphine in a healthy population of cats undergoing neutering procedures.

Anaesthetic induction was smooth, and the trachea of all cats was intubated between 1 and 1.5 mins from the start of alfaxalone administration. The dose of alfaxalone needed to allow endotracheal intubation (1.7 mg/kg) was less than the clinically recommended dose (Australian label) of 2–5 mg/kg, or the one described by Taboada and Murison⁹ (4.7 mg/kg) in their comparative study between propofol and alfaxalone induction prior to isoflurane anaesthesia. In 2009, Zaki et al¹⁷ demonstrated the sparing effect of an acepromazine–butorphanol based premedication vs no premedication on the alfaxalone induction dose in cats (2.7 vs 4.2 mg/kg, respectively). In the current study, premedication consisted of the combination of medetomidine and morphine administered IM. Medetomidine is well known for its sparing effect on induction agents for anaesthesia in cats.^18–20 The addition of an opioid such as buprenorphine to medetomidine premedication has also been shown to increase the level of sedation and reduces the dose of the anaesthetic induction agent.²¹

Post-induction apnoea (PIA) was not observed in this study. When alfaxalone was originally formulated mixed with alfadolone in Cremaphor EL, a low incidence of PIA was observed when compared with other agents such as thiopental, methohexital, pentobarbital or ketamine.⁶ The current finding is consistent with the findings of Whittem et al¹¹ in unpremedicated cats with alfaxalone doses between 5 and 25 mg/kg and the findings from Taboada et al⁹ in acepromazine–meloxicam premedicated cats with alfaxalone doses of about 4.7 mg/kg. However, Zaki et al¹⁷ observed an incidence of PIA in 1/8 unpremedicated cats (alfaxalone induction dose between 2.7 and 5.8 mg/kg) and in 1/8 butorphanol–acepromazine premedicated cats (alfaxalone induction dose between 1.7 and 4.7 mg/kg). Similarly, Muir et al¹⁰ observed an incidence of PIA of 12.5, 25.0 and 100.0% in unpremedicated cats induced with alfaxalone doses of 5 (1×), 15 (3×) and 50 (10×) mg/kg, respectively. In the current study, as well as in the study by Taboada et al,⁹ alfaxalone was administered slowly to effect, a method that has been previously shown with other induction agents to decrease the incidence of PIA.^22–24

In this study, as in a study in unpremedicated cats induced (5 mg/kg) and maintained (4 consecutive boluses of 2 mg/kg as required) with alfaxalone, apnoea was not observed at induction or during the maintenance phase of anaesthesia.¹¹ Hypercapnoea (EtCO₂ >45 mmHg) was not observed during the maintenance of anaesthesia in the current study, and RR was well maintained. The incidence of hypoventilation might have been greater than observed as EtCO₂ was measured using side stream capnography with cats breathing through a non-rebreathing system – a technique previously reported as having poor sensitivity for the measurement of EtCO₂.^17,25 No information on ventilation was presented in the study by Whittem et al,¹¹ while in the study by Zaki et al¹⁷ 4/35 cats had an EtCO₂ >45 mmHg, but they used isoflurane for maintenance of anaesthesia.

Alfaxalone caused a clinically observable decrease in HR (non-significant, data available in 15 cats only), an effect that has been previously reported.^10,11,17 Nevertheless, the slow HR observed at the beginning of the anaesthesia was mostly due to the use of medetomidine and morphine for premedication. Both agents are known for inducing, at clinically relevant doses, vagally mediated decreases in HR from morphine, and even more profound bradycardia from medetomidine.^26,27 During the anaesthesia period, a slow and consistent increase in HR was observed for the first 60–80 mins before reaching a plateau. As the duration of action of medetomidine in cats is shorter than morphine (up to 2 h vs 6–8 h, respectively), this slow increase in HR might have coincided with a loss of effect of medetomidine and a change in the noxious stimulation.^28–31 During the same period of time, the alfaxalone infusion rate was decreased according to the clinical requirements of the patient, and could also have contributed to the increase in the HR observed over time.¹⁰

Although the arterial blood pressure was well maintained during the procedure, it was not uncommon to observe hypotensive (DAP <80 mmHg) phases of short duration that responded to an increased rate of fluid therapy and a decreased rate of alfaxalone infusion. Twenty of the cats (59%) were hypotensive at some point during the procedure. Five of them were hypotensive following anaesthetic induction. Muir et al¹⁰ described a dose-dependent cardiovascular depression of alfaxalone injection in unpremedicated cats, although they only observed hypotension with the supraclinical dose of 50 mg/kg (10× the high end of the anaesthetic induction dose). The incidence of hypotension in the study by Zaki et al¹⁷ varied between 69 and 85%, but anaesthesia was maintained with isoflurane and post-alfaxalone induction hypotension was not mentioned. Doppler ultrasound was used to measure blood pressure in the study. It is usually accepted that this technique gives a relatively accurate reading of the systolic arterial blood pressure in dogs and cats.^32–36 However, in a study in cats comparing Doppler and direct arterial blood pressure reading, it was established that Doppler was more representative of the mean arterial blood pressure in cats.³⁷ If we consider that the Doppler measures mean arterial blood pressure in cats, in this study only two cats were hypotensive (mean arterial blood pressure <60 mmHg) with values between 58 and 59 mmHg.^9,37

Recovery from anaesthesia was uneventful in 31 cats. Three cats presented some excitation induced by external stimulation, in particular noise, but this was short lasting (10–20 mins). This side-effect has been previously described in cats with the use of alfaxalone/alfadolone.^16,38

The administration of atipamezole to 12/19 cats with increased TS (>30 mins) did not seem to affect TS when compared with the seven cats who did not receive the alpha 2 adrenoceptor antagonist. Similar observations have been made in ketamine–midazolam–medetomidine–anaesthetised cats and in medetomidine–propofol–anaesthetised ponies where the injection of atipamezole at the end of the procedure had no effect on the recovery time.^39,40 Although the body temperature seemed clinically similar between those 19 cats with prolonged recovery and the other 15, the difference between the two groups was significant (P = 0.05). In addition, the power of this analysis was very low (0.4). The hypothermia observed in those 19 cats could have been responsible for the prolonged recovery.

The PK of alfaxalone in the cat, as in other species, has been shown to be non-linear at supra-clinical doses and therefore described as dose-dependent PK.^8,11 When Whittem et al¹¹ administered multiple boluses of alfaxalone for the maintenance of anaesthesia and compared it with their single bolus experiment, they observed a decrease in alfaxalone clearance, which could have been a sign of drug accumulation. However, that finding was not confirmed clinically, as they did not observe a relevant accumulation of drug in the plasma nor an increase in recovery time by comparison with the alfaxalone single bolus anaesthesia.¹¹ When comparing the aforementioned study with the current one, the alfaxalone infusion rate for the female cats in this study was similar to the total doses by unit of time administered in the study by Whittem et al,¹¹ but maintained for a longer period of time (60 mins in the study byWhittem et al¹¹ vs 120 mins in the current study) resulting in a higher total dose of alfaxalone being administered (ie, 13 vs 22.7 mg/kg). Although an infusion study and a multiple bolus study are different in terms of PK, it is interesting to note that prolonged anaesthesia and an increase of total alfaxalone doses administered in the current study resulted in comparable recovery times (45 vs 43 mins).

In addition, medetomidine is known to influence the metabolism of other agents through its inhibition of cytochrome P450.^41–47 As in rats and humans, alfaxalone is first metabolised in the feline liver through cytochrome P450 oxidation and reduction (B O’Hagan, 2013, personal communication).^48,49 Further work might be needed to assess whether this agent decreases the metabolism of alfaxalone, which would subsequently increase the duration of its pharmacological effect.

Conclusions

Alfaxalone TIVA in combination with medetomidine and morphine premedication was effective in feral and domestic cats for the performance of neutering surgery; low body temperature might have resulted in longer recoveries in some cats. Further studies are necessary not only to assess the effectiveness of the use of alfaxalone TIVA in other clinical situations (different premedication, American Society of Anesthesiologists 3–5 patients), but also to prove (or disprove) the lack of accumulation.

Footnotes

Funding

This work was supported by Ross University School of Veterinary Medicine Research Committee and Jurox Pty, Ltd.

Conflict of interest

The authors do not have any potential conflicts of interest to declare.

Accepted: 1 November 2013

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Clinical evaluation of alfaxalone to induce and maintain anaesthesia in cats undergoing neutering procedures

Abstract

Introduction

Materials and methods

Statistics

Results

Discussion

Conclusions

Footnotes

Funding

Conflict of interest

References