Alfaxalone total intravenous anaesthesia in dogs: pharmacokinetics, cardiovascular data and recovery characteristics

doi:10.1016/j.vaa.2019.04.014

Veterinary Anaesthesia and Analgesia

Volume 46, Issue 5, September 2019, Pages 605-612

https://doi.org/10.1016/j.vaa.2019.04.014 Get rights and content

Abstract

Objective

To evaluate the cardiovascular effects, pharmacokinetic (PK) data and recovery characteristics of an alfaxalone constant rate infusion (CRI) of different duration in dogs at manufacturer’s recommended dose rate.

Study design

Experimental, prospective, randomized, crossover study.

Animals

Six intact female Beagles.

Methods

Following an intravenous alfaxalone bolus (3 mg kg^–1), anaesthesia was maintained using an alfaxalone CRI at 0.15 mg kg^–1 minute^–1 for 90 (short CRI) or 180 minutes (long CRI). Venous blood samples were collected to determine the PK profile. Cardiovascular variables and recovery characteristics were evaluated. Recovery was scored on a scale ranging from 0, excellent to 4, bad. A mixed-model statistical approach was used to compare the cardiovascular parameters (global α = 0.05). An analysis of variance was performed to compare PK parameters and recovery times between treatments.

Results

No significant difference was noted between protocols for any PK parameter. Volume of distribution at steady state (935.74 ± 170.25 versus 1119.15 ± 190.65 mL kg^–1), elimination half-life (12 ± 2 versus 13 ± 3 minutes), clearance from the central compartment (26.02 ± 4.41 versus 27.74 ± 5.65 mL kg^–1 minute^–1) and intercompartmental clearance (8.47 ± 4.06 versus 12.58 ± 7.03 mL kg^–1 minute^–1) were comparable for short CRI and long CRI. Cardiovascular variables remained within physiological limits. Mechanical ventilation was necessary (short CRI: n = 1, long CRI: n = 4). The manufacturer’s recommended dose rate resulted in a light plane of anaesthesia. No significant differences in recovery times and scores were observed between treatments. The quality of recovery was scored as very poor with both protocols.

Conclusions and clinical relevance

PK data were similar between long and short infusions of alfaxalone at the manufacturer's recommended dose, with acceptable cardiovascular conditions. Nevertheless, both protocols resulted in a superficial plane of general anaesthesia with poor recovery characteristics.

Introduction

Although total intravenous anaesthesia (TIVA) is widely used in human medicine, maintenance of anaesthesia in veterinary medicine is still much more commonly performed using volatile anaesthetics. However, chronic exposure to halogenated agents may result in an increased incidence of hepatic disease, renal disease and immunological abnormalities (Irwin et al. 2009). Additionally, the halogenated chlorofluorocarbons (halothane, isoflurane and sevoflurane) are potentially harmful to the ozone layer. According to international treaties, the emission of volatile agents in the atmosphere will be prohibited from 2030 onwards (Joubert 2009). For these reasons, and because of the introduction of drugs with favourable pharmacokinetics (PK) and pharmacodynamics (PD) for use in TIVA, there is a growing interest in TIVA protocols in veterinary medicine.

Alfaxalone is a synthetic neuroactive steroid that induces muscle relaxation and anaesthesia by interacting with the gamma aminobutyric acid type A receptor in the central nervous system (Goodwin et al. 2011). Its rapid biotransformation and therefore clearance results in a low tendency to accumulate in the tissues after repeated doses (Ferré et al., 2006, Muir et al., 2008), which makes it a suitable anaesthetic agent for TIVA (Ambros et al. 2008).

Alfaxan is a water-soluble formulation of 1% w/v alfaxalone, solubilized in 2-hydroxypropyl-β-cyclodextrin. Ferré et al. (2006) and Pasloske et al. (2009) described PK of alfaxalone after a single, intravenous administration of Alfaxan in Beagle dogs and Greyhounds, respectively. Although Alfaxan is licensed for use as a constant rate infusion (CRI) in dogs, to the author’s knowledge, no studies have investigated the PK, cardiovascular effects and recovery characteristics when alfaxalone is used at the recommended rate.

The aim of this study was to evaluate the PK, cardiovascular and recovery characteristics of an alfaxalone TIVA administered at the manufacturer’s recommended dose rate for dogs and to investigate whether the duration of the CRI would alter these findings.

We hypothesized that the cardiovascular function would remain stable during alfaxalone TIVA and that PK parameters and recovery characteristics would not be affected by the duration of the infusion.

Section snippets

Animals

Six intact female laboratory Beagles were included in this experimental, prospective, randomized, crossover study. Experiments were approved by the Ethical Committee of the Faculties of Veterinary Medicine and Bioscience Engineering of Ghent University (EC 2014/180). The dogs were socially housed in small groups (2–8 dogs) on an internal surface of 15 m² with permanent access to an outside area of 15 m². The bedding material in the inner part consisted of wood shavings on top of a bottom-heated

Results

All dogs (aged 25.0 ± 0.6 months and weighing 12.2 ± 0.7 kg) completed the study. Smooth and rapid induction of anaesthesia following IV administration of alfaxalone was observed [induction score 0 (0–1) for both protocols]; all dogs lost consciousness in less than 60 seconds. No post-induction apnoea occurred. None of the dogs needed an additional dose of alfaxalone to allow intubation. Endotracheal intubation was achieved easily with both protocols [intubation score 0 (0–1)]. MV was initiated

Discussion

In the present study in healthy dogs, a CRI of alfaxalone, at the rate recommended by the manufacturer, resulted in a relatively superficial plane of anaesthesia with stable cardiovascular function but low quality recoveries. The duration of the infusion did not significantly affect the PK, cardiovascular function or recovery quality.

In the present study, no premedication was used, to avoid possible influences on the PK and PD of alfaxalone. Nevertheless, a smooth induction of anaesthesia and

Conclusion

The administration of an alfaxalone CRI resulted in acceptable cardiovascular conditions during anaesthesia in both protocols, while the duration of the infusion did not significantly affect PK variables and cardiovascular function. Nevertheless, the manufacturer’s recommended dose rate of alfaxalone CRI resulted in a superficial plane of general anaesthesia and poor recovery characteristics.

Acknowledgements

Software license for Phoenix was provided by Certara USA as part of their Centers of Excellence program. The technical assistance of An Maes, Wout Strybol and Anneleen Watteyn for the alfaxalone quantification in plasma is gratefully acknowledged.

References (26)

M. Amengual et al.
An evaluation of anaesthetic induction in healthy dogs using rapid intravenous injection of propofol or alfaxalone
Vet Anaesth Analg
(2013)
G.L. Covey-Crump et al.
Fentanyl or midazolam for co-induction of anaesthesia with propofol in dogs
Vet Anaesth Analg
(2008)
S. De Baere et al.
Quantitative determination of T-2 toxin, HT-2 toxin, deoxynivalenol and deepoxy-deoxynivalenol in animal body fluids using LC-MS/MS detection
J Chromatogr B
(2011)
P.J. Ferré et al.
Plasma pharmacokinetics of alfaxalone in dogs after an intravenous bolus of Alfaxan-CD RTU
Vet Anaesth Analg
(2006)
W.A. Goodwin et al.
The pharmacokinetics and pharmacodynamics of the injectable anaesthetic alfaxalone in the horse
Vet Anaesth Analg
(2011)
W. Goodwin et al.
Plasma pharmacokinetics and pharmacodynamics of alfaxalone in neonatal foals after an intravenous bolus of alfaxalone following premedication with butorphanol tartrate
Vet Anaesth Analg
(2012)
M.J. Kennedy et al.
A comparison of cardiopulmonary function, recovery quality, and total dosages required for induction and total intravenous anesthesia with propofol versus a propofol-ketamine combination in healthy Beagle dogs
Vet Anaesth Analg
(2015)
W. Muir et al.
Cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in dogs
Vet Anaesth Analg
(2008)
M. Suarez et al.
Comparison of alfaxalone and propofol administered as total intravenous anaesthesia for ovariohysterectomy in dogs
Vet Anaesth Analg
(2012)
B. Ambros et al.
Comparison of the anesthetic efficacy cardiopulmonary effects of continuous rate infusions of alfaxalone-2-hydroxypropyl-b-cyclodextrin and propofol in dogs
Am J Vet Res
(2008)

R.C. Bennett et al.

Effects of the α₂-adrenoceptor agonist medetomidine on the distribution and clearance of alfaxalone during coadministration by constant rate infusion in dogs

Am J Vet Res

(2017)

C. Conde Ruiz et al.

Alfaxalone for total intravenous anaesthesia in bitches undergoing elective caesarean section and its effects on puppies: a randomized clinical trial

Vet Anaesth Analg

(2015)

Commission Decision 2002/675/EC implementing Council Directive 96/23/EC concerning the performances of analytical methods and the interpretation of results

Off J European Union

(2002)

Cited by (14)

ED<inf>50</inf> and ED<inf>95</inf> of rocuronium during alfaxalone anesthesia in dogs
2023, Veterinary Anaesthesia and Analgesia
To determine the median effective dose (ED₅₀) and effective dose required to depress the twitch value by 95% (ED₉₅) of rocuronium during alfaxalone anesthesia in dogs.
A randomized, prospective, crossover experimental study.
A total of eight adult Beagle dogs (four female, four male), weighing 10.3–14.6 kg and aged 6–8 years.
The dogs were anesthetized three times with 1.25-fold the individual minimum infusion rate of alfaxalone at intervals of ≥ 14 days. Neuromuscular function was monitored with train-of-four (TOF) stimulation of the peroneal nerve by acceleromyography. After recording the control TOF ratio (TOFRC) and first twitch of TOF (T1C), a single bolus dose of rocuronium 100, 175 or 250 μg kg^–1 (treatments R100, R175 or R250) was administered intravenously. The maximum suppression of the first twitch of TOF (T1) was recorded and calibrated with T1C to construct the dose–response curve, from which ED₅₀ and ED₉₅ were calculated. Time from rocuronium administration to TOF ratio/TOFRC > 0.9 (duration TOFR0.9) was recorded.
ED₅₀ and ED₉₅ of rocuronium during alfaxalone anesthesia were 175 and 232 μg kg^–1, respectively. The median (range) duration TOFR0.9 was longer in treatment R250 [10.1 (9.2–10.9) minutes] than in treatments R100 [3.1 (2.9–4.4) minutes; p < 0.0001] and R175 [7.7 (6.9–8.1) minutes; p < 0.0001]; and longer in treatment R175 than in treatment R100 (p < 0.0001).
The duration of TOFR0.9 correlated positively with the dosage of rocuronium, indicating that recovery time of rocuronium was also dose-dependent in dogs anesthetized with alfaxalone. The duration TOFR0.9 of rocuronium 250 μg kg^–1 was 10 minutes during alfaxalone anesthesia in dogs.
Sedative and cardiorespiratory effects of intranasal atomized alfaxalone in Japanese White rabbits
2023, Veterinary Anaesthesia and Analgesia
To investigate the sedative and cardiorespiratory effects of intranasal atomization (INA) of alfaxalone using a mucosal atomization device in Japanese White rabbits.
Randomized, prospective, crossover study.
A total of eight healthy female rabbits, weighing 3.6–4.3 kg and aged 12–24 months.
Each rabbit was randomly assigned to four INA treatments administered 7 days apart: Control treatment, 0.15 mL 0.9% saline in both nostrils; treatment INA0.3, 0.15 mL 4% alfaxalone in both nostrils; treatment INA0.6, 0.3 mL 4% alfaxalone in both nostrils; treatment INA0.9, 0.3 mL 4% alfaxalone in left, then right, then left nostril. Sedation was scored 0–13 using a composite measure scoring system for rabbits. Simultaneously, pulse rate (PR), respiratory rate (f_R), noninvasive mean arterial pressure (MAP), peripheral hemoglobin oxygen saturation (SpO₂) and arterial blood gases were measured until 120 minutes. The rabbits breathed room air during the experiment and were administered flow-by oxygen when hypoxemia (SpO₂ <90% or PaO₂ <60 mmHg; 8.0 kPa) developed. Data were analyzed using the Fisher's exact test and the Friedman test (p < 0.05).
No rabbit was sedated in treatments Control and INA0.3. All rabbits in treatment INA0.9 developed loss of righting reflex for 15 (10–20) minutes [median (25th–75th percentile)]. Sedation score significantly increased from 5 to 30 minutes in treatments INA0.6 and INA0.9 with maximum scores of 2 (1–4) and 9 (9–9), respectively. f_R decreased in an alfaxalone dose-dependent manner and one rabbit developed hypoxemia in treatment INA0.9. No significant changes were observed in PR and MAP.
INA alfaxalone resulted in dose-dependent sedation and respiratory depression in Japanese White rabbits to values considered not clinically relevant. Further investigation of INA alfaxalone in combination with other drugs is warranted.
Injectable anesthetics
2023, Anesthesia and Analgesia in Laboratory Animals
Injectable anesthetics are commonly used in laboratory animal medicine. This chapter outlines the majority of injectable anesthetics and injectable combinations used in laboratory animals today. Pharmacokinetics, preparation and route of administration, and side effects seen with these anesthetics are covered in detail. While not always as commonly used, injectable anesthetic delivery systems are also covered in this chapter.
Evaluation of alfaxalone total intravenous anesthesia in rabbits (Oryctolagus cuniculus) premedicated with dexmedetomidine or dexmedetomidine and buprenorphine
2022, Veterinary Anaesthesia and Analgesia
Citation Excerpt :
Alfaxalone infusion rate adjustments were made according to interdigital skin pinch response by increasing the rate following a positive response and decreasing following a negative response. Adjustments to the infusion rate were begun 20 minutes after induction and approximately every 15 minutes after an infusion rate adjustment, based on published pharmacokinetic data (Pypendop et al. 2018; Dehuisser et al. 2019). The only time the 15 minute interval for adjustment was not observed was the following situation; if the infusion rate was decreased and an animal reacted before the 15 minutes elapsed, the infusion rate was increased back to the previous rate.
To evaluate alfaxalone for total intravenous anesthesia (TIVA) in rabbits premedicated with dexmedetomidine or dexmedetomidine and buprenorphine.
Crossover study (part 1) with observational study (part 2).
A total of eight New Zealand White rabbits (Oryctolagus cuniculus), four female and four male, aged 12–16 weeks and weighing 2.8–3.5 kg in part 1. Separately, four additional rabbits in part 2.
Crossover study design with eight rabbits per treatment. Rabbits were administered treatment D, dexmedetomidine (0.2 mg kg^–1), or treatment DB, dexmedetomidine (0.1 mg kg^–1) and buprenorphine (0.05 mg kg^–1) intramuscularly. Anesthesia was induced with alfaxalone intravenously until a supraglottic airway device was placed to deliver 100% oxygen. Anesthesia was maintained with alfaxalone (TIVA). Infusion rates were adjusted to achieve an absent pedal withdrawal reflex. Heart rate, respiratory rate, noninvasive blood pressure, end-tidal carbon dioxide partial pressure and peripheral hemoglobin oxygen saturation (SpO₂) were recorded every 5 minutes. Subsequently, four rabbits underwent ovariohysterectomy using treatment DB and alfaxalone TIVA.
The mean ± standard deviation alfaxalone infusion rate was 9.6 ± 2.6 and 4.5 ± 1.3 mg kg^–1 hour^–1 for treatments D and DB, respectively. In both treatments, blood pressure remained within acceptable range and SpO₂ was > 95%. Postinduction apnea and respiratory depression were observed in both treatments and managed with manual positive pressure ventilation. Four separate rabbits underwent successful ovariohysterectomy with treatment DB and alfaxalone TIVA. One rabbit required supplementation with inhalant anesthesia; three rabbits were successfully maintained using alfaxalone TIVA alone.
Premedication with dexmedetomidine–buprenorphine combined with alfaxalone TIVA may be a viable alternative for performing abdominal surgery in the rabbit. The use of supplemental oxygen and ability to provide respiratory support are advised.
Effects of sevoflurane, propofol or alfaxalone on neuromuscular blockade produced by a single intravenous bolus of rocuronium in dogs
2022, Veterinary Anaesthesia and Analgesia
Citation Excerpt :
Conversely, propofol, a short-acting and noncumulative injectable anesthetic that is suitable as a hypnotic for total intravenous anesthesia (TIVA), has little to no effect on the neuromuscular blockade produced by NMBAs in dogs (Kastrup et al. 2005; Nagahama et al. 2006; Chen et al. 2020). Alfaxalone is a synthetic neuroactive steroid that has an efficacy and safety similar to that of propofol and is also suitable for TIVA in dogs (Bennett et al. 2017; Bennett et al. 2019; Dehuisser et al. 2019). However, unlike propofol, alfaxalone causes less apnea (Keates & Whittem 2012), does not produce pain after IV injection (Michou et al. 2012) and is not a legally controlled drug in most countries.
To compare the effects of sevoflurane, propofol and alfaxalone on the neuromuscular blockade induced by a single intravenous bolus of rocuronium in dogs.
A randomized, prospective, crossover experimental study.
A total of eight adult Beagle dogs (four female, four male), weighing 8.9–15.3 kg and aged 5–7 years.
The dogs were anesthetized three times with 1.25× minimum alveolar concentration of sevoflurane (SEVO treatment) and 1.25× minimum infusion rate of propofol (PROP treatment) or alfaxalone (ALFX treatment) at intervals of ≥14 days. Neuromuscular function was monitored with train-of-four (TOF) stimulation of the peroneal nerve by acceleromyography. After recording the control TOF ratio (TOFRC), a single bolus dose of rocuronium (1 mg kg^–1) was administered intravenously. The times from rocuronium administration to achieving TOF count 0 (onset time), from achieving TOF count 0 to the reappearance of TOF count 4 (clinical blockade period), from 25% to 75% of TOFRC (recovery index) and from achieving TOF count 0 to TOF ratio/TOFRC >0.9 (total neuromuscular blockade duration) were recorded.
The onset time and recovery index did not differ among the treatments. The median clinical blockade period was longer in the SEVO treatment [27.3 (26.0–30.3) minutes] than in PROP [16.6 (15.4–18.0) minutes; p = 0.002] and ALFX [22.4 (18.6–23.1) minutes; p = 0.017] treatments; and longer in the ALFX treatment than in the PROP treatment (p = 0.020). The mean total neuromuscular blockade duration was longer in the SEVO treatment (43.7 ± 9.9 minutes) than in PROP (25.1 ± 2.7 minutes; p < 0.001) and ALFX (32.5 ± 8.4 minutes; p = 0.036) treatments.
Compared with alfaxalone and propofol, sevoflurane prolonged rocuronium-induced neuromuscular blockade by a significantly greater extent in dogs.
Scoping review of quality of anesthetic induction and recovery scales used for dogs
2021, Veterinary Anaesthesia and Analgesia
Citation Excerpt :
While a large number of these scales exist, there is wide disparity in size and construction, and researchers often use them interchangeably between studies. The included descriptors in the scales vary by scale, study and researcher, with frequent overlaps in descriptor usage between scales (e.g., emergence delirium used as a descriptor for a score of ‘4’ in one scale and for a score of ‘6’ in another scale) (Dehuisser et al. 2019a; Lehnus & Brearley 2019). No attempt has been made to describe and compile the expressions from these scales to examine the extent of issues such as these.
To compare, describe and assess the level of validation of all instruments measuring quality of induction and recovery from anesthesia in dogs.
A search was performed using the electronic database PubMed to find articles containing an induction quality scale, a recovery quality scale or both in dogs. Articles not directly accessible through PubMed were obtained through the Auburn University Library website and Google Scholar. The phrases ‘induction scoring systems dogs’, ‘recovery scoring systems dogs’, ‘anesthetic induction score dogs’, and ‘anesthetic recovery score dogs’ were used for searches using the ‘best match search’ function. The time frame searched was from 1980 to May 2020. The search was conducted from March 2020 to May 2020.
A thoroughly tested and validated scale for measuring the quality of induction and recovery does not exist in the current veterinary literature. A large disagreement exists between studies on the use of induction and recovery scales, and many have reported inconsistent results with current instruments. It is recommended that an induction and recovery scale intended for wide-scale use be constructed and tested extensively for psychometric validation and reliability.

View all citing articles on Scopus

View full text

RESEARCH PAPERAlfaxalone total intravenous anaesthesia in dogs: pharmacokinetics, cardiovascular data and recovery characteristics

Abstract

Objective

Study design

Animals

Methods

Results

Conclusions and clinical relevance

Introduction

Section snippets

Animals

Results

Discussion

Conclusion

Acknowledgements

Vet Anaesth Analg

Vet Anaesth Analg

J Chromatogr B

Vet Anaesth Analg

Vet Anaesth Analg

Vet Anaesth Analg

Vet Anaesth Analg

Vet Anaesth Analg

Vet Anaesth Analg

Comparison of the anesthetic efficacy cardiopulmonary effects of continuous rate infusions of alfaxalone-2-hydroxypropyl-b-cyclodextrin and propofol in dogs

Am J Vet Res

Effects of the α2-adrenoceptor agonist medetomidine on the distribution and clearance of alfaxalone during coadministration by constant rate infusion in dogs

Am J Vet Res

Alfaxalone for total intravenous anaesthesia in bitches undergoing elective caesarean section and its effects on puppies: a randomized clinical trial

Vet Anaesth Analg

Commission Decision 2002/675/EC implementing Council Directive 96/23/EC concerning the performances of analytical methods and the interpretation of results

Off J European Union

RESEARCH PAPER
Alfaxalone total intravenous anaesthesia in dogs: pharmacokinetics, cardiovascular data and recovery characteristics

Effects of the α₂-adrenoceptor agonist medetomidine on the distribution and clearance of alfaxalone during coadministration by constant rate infusion in dogs