Studies of alfaxalone in horses

Goodwin, Wendy (2013). Studies of alfaxalone in horses PhD Thesis, School of Veterinary Science, The University of Queensland.

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Author Goodwin, Wendy
Thesis Title Studies of alfaxalone in horses
School, Centre or Institute School of Veterinary Science
Institution The University of Queensland
Publication date 2013
Thesis type PhD Thesis
Supervisor Helen Keates
Martin Pearson
Kirby Pasloske
Total pages 243
Total colour pages 17
Total black and white pages 226
Language eng
Subjects 070701 Veterinary Anaesthesiology and Intensive Care
070710 Veterinary Pharmacology
Formatted abstract
The anaesthetic-related mortality rate in horses is relatively high compared with other species. Traditionally, anaesthesia has been maintained in horses with inhalational anaesthetic agents after induction of anaesthesia with an injectable agent. However, recent evidence suggests that total intravenous anaesthesia (TIVA) may have several advantages over inhalant techniques in the horse including superior cardiopulmonary stability and fewer metabolic and hormonal changes. Unfortunately, there is currently no intravenous anaesthetic agent suitable for use as the sole agent to maintain TIVA in horses. The pharmacokinetic profile of the majority of currently used TIVA agents precludes their use during prolonged anaesthetic and surgical procedures (> 60 minutes). The cumulative effect of these intravenous (IV) agents (e.g. ketamine) inevitably results in prolonged anaesthetic recovery times and unstable anaesthetic conditions. The recent introduction of propofol into equine anaesthesia has been met with some success.

Alfaxalone (3a-hydroxy-5a-pregnane-11, 20-dione), a progesterone analogue, is a neurosteroid which interacts with the gamma aminobutyric acid type A receptor and produces anaesthesia and muscle relaxation. Alfaxan®, alfaxalone in 2-hydroxypropyl-beta cyclodextrin, is registered in several countries for IV induction and maintenance of anaesthesia in dogs and cats. Recent studies in the dog and cat have found it to have a number of properties that support its use in TIVA; it is non-cumulative, has a high therapeutic index, has minimal cardiac and blood pressure effects, causes no perivascular irritation and results in a rapid and smooth recovery. The aims of the thesis were to:
1. Determine the pharmacokinetics and pharmacodynamics of IV alfaxalone in the adult horse and foal so that alfaxalone could be optimally used as part of a TIVA technique.
2. Investigate the detailed pharmacodynamic variables of alfaxalone administered as an infusion to maintain long duration anaesthesia in horses.
3. Compare alfaxalone, administered as an infusion, to other currently used TIVA protocols and establish any clinical advantages or applications.

The results of this study found that alfaxalone, when used for induction of anaesthesia, resulted in smooth inductions and rapid, controlled recoveries in both horses and foals. Additionally, after a single IV injection, alfaxalone was rapidly cleared from the plasma of both adult horses and foals making it potentially suitable for maintaining anaesthesia via an infusion in this species. Alfaxalone was then used as an infusion to maintain anaesthesia for 3 hours duration in adult horses. Although cardiovascular variables were well maintained, a number of shortcomings were identified. These included respiratory depression and excitement and hyperaesthesia for periods during the recovery phase.

In order to overcome these shortcomings, alfaxalone was combined with medetomidine, to lower the dose of alfaxalone required and provide a more balanced anaesthetic technique. Castration surgeries were performed in the field using this combination and anaesthesia was maintained for 45 minutes duration with no complications. However, when alfaxalone and medetomidine was used to maintain anaesthesia for a longer duration (2-3 hours) respiratory depression and unacceptable recovery periods were again evident.

Based on these results, it was decided that there was no benefit in comparing long term alfaxalone infusions to maintain anaesthesia in horses with other TIVA combinations. It was hypothesised that the neuroexcitation seen in the recovery phase may be due to dysregulation of inhibitory neurotransmitters, such as glycine, in the central nervous system. A preliminary study was conducted to examine the levels of glycine in horse cerebrospinal fluid during alfaxalone anaesthesia. The results were inconclusive but emphasised the need for further work, beyond the scope of this project, to investigate potential causes for this unexpected finding.

Finally, the effect of alfaxalone infusion on the minimum alveolar concentration (MAC) of isoflurane in horses was investigated. Intravenous infusion of alfaxalone significantly reduced the isoflurane MAC in horses indicating that alfaxalone could be useful in providing a more balanced anaesthetic technique in horses.

In conclusion, the thesis project found that alfaxalone was suitable for short term anaesthesia in adult horses and foals. The combination of alfaxalone with medetomidine, administered as an infusion, was suitable for maintaining anaesthesia (45 minutes) for minor surgical procedures in horses. Alfaxalone was also found to be useful when administered to horses during isoflurane anaesthesia to provide a more balanced anaesthetic technique. However, alfaxalone administered alone or with medetomidine, is unsuitable for maintaining anaesthesia for prolonged durations in horses due to the neuroexcitation seen in the recovery period. The exact mechanisms for the neuroexcitation remain unclear and warrant further research.
Keyword Alfaxalone
Pharmacokinetic (PK)
Pharmacodynamic (PD)
Total intravenous anaesthesia

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Created: Mon, 18 Nov 2013, 15:41:01 EST by Wendy Goodwin on behalf of Scholarly Communication and Digitisation Service