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What are the benefits of slow administration of alfaxalone and does co-induction with alfaxalone/midazolam have any benefits in healthy dogs?

Miller C., Hughes E. & Gurney M. (2019). Co-induction of anaesthesia with alfaxalone and midazolam in dogs: a randomized, blinded clinical trial. Vet Anaesth & Analg.  46: 613–619 https://doi.org/10.1016/j.vaa.2019.03.009

Co-induction techniques using more than one drug are regularly utilised to reduce the total dose of induction agent and to potentially reduce the side effects associated with those drugs. This randomised, blinded study was performed to assess the cardiovascular and respiratory effects of midazolam/alfaxalone co-induction compared to alfaxalone alone and to determine whether administration of midazolam following a sub-hypnotic dose of alfaxalone would reduce the total dose of alfaxalone required for induction of anaesthesia.

Method

29 client owned American Society of Anaesthesiologists physical status I or II dogs presented for elective soft-tissue or orthopaedic surgery were randomly allocated to receive midazolam (0.4mg/kg) + alfaxalone (group M, n = 14: 7 female, 7 male) or sterile saline + alfaxalone as a control (group S, n = 15: 9 female, 6 male).

All dogs were premedicated with 0.02mg/kg acepromazine plus 0.3mg/kg methadone administered intramuscularly 30 minutes prior to induction. The level of sedation was assessed at induction using a non-validated composite scoring scale.  All patients were pre-oxygenated for 3 minutes via tight fitting face mask prior to induction. Heart rate (HR), respiratory rate (RR) and oscillometric blood pressure (BP) were assessed prior to premedication, induction and at 0, 2 and 5 minutes post-induction.

Anaesthesia was induced with an initial intravenous (IV) dose of 0.5mg/kg alfaxalone administered over 30 seconds and the IV cannula was flushed with heparinised saline (both groups).  This was followed by 0.4mg/kg midazolam (group M) or saline (group S) administered over 30 seconds then flushing. Depth of anaesthesia was assessed (loss of palpebral reflex, ventromedial eye rotation, loss of jaw tone) and if the patient was not deemed suitable for intubation additional boluses of 0.25mg/kg alfaxalone were administered over 15 seconds until intubation was possible. Ease of intubation, quality of induction and total dose of alfaxalone were recorded. The primary investigator recording  all parameters was blinded to the allocated group and co-induction drugs.

Results

There were no significant differences in age, bodyweight, body condition score, HR or RR prior to premedication or at induction.

For group M the total dose of alfaxalone required for intubation was 0.65 +/- 0.2mg/kg, and 0.94 +/- 0.26mg/kg for group S demonstrating a significant difference (p = 0.002). Group M dogs were significantly more sedated and had a significantly smoother intubation (p = 0.014 and 0.016 respectively) than those in group S.  Quality of induction was similar between groups (p = 0.2). In group M at time = 0 there was a significant increase in heart rate compared to pre-induction measurements but not at other timepoints. There were no significant differences in HR between groups apart from time = 0.  Arterial BP did not vary between groups and no clinically significant hypotension was detected at any time point in either group.  There was significantly more apnoea in group M (8/14 dogs) compared to group S (0/15) (p = 0.007).

Why is this important?

1. Slow administration of alfaxalone alone results in no/minimal apnoea in healthy dogs.

In this study of healthy dogs when alfaxalone alone was administered slowly (0.5mg/kg over 30 seconds then saline over 30 seconds) followed by further alfaxalone boluses of 0.25mg/kg/15 seconds until intubation was possible, no apnoea was observed. This is similar to the observations of Bigby et al (2017) who noted 2mg/kg of alfaxalone administered over 60 seconds produced more apnoea than 0.5mg/kg over 60 seconds i.e. rapid administration caused a higher incidence of apnoea.

2. In healthy dogs, co-administration of alfaxalone with midazolam results in a higher incidence of apnoea

3. Slow administration of alfaxalone reduces the total dose required to permit intubation in healthy dogs.

The comparatively low dose of 0.94 +/- 0.26mg/kg alfaxalone administered to group S (the labelled dose for premedicated dogs is 2mgkg) could be related to the premedicants selected and the slow rate of alfaxalone administration. Additionally, a technique known as “priming” (Kumar et al, 2006) may have reduced the total dose of alfaxalone required in both groups i.e. giving a slow, sub-hypnotic, dose of an induction agent prior to administration of further boluses to allow intubation reduces the total amount of induction agent required (Stokes & Hutton, 1991).

4. The alfaxalone sparing effects of midazolam do not appear to provide any additional cardiovascular benefits in healthy dogs.

In conclusion this study demonstrated that in healthy dogs alfaxalone co-induction with midazolam did not confer any cardiovascular benefits but caused significant apnoea. Slow administration of alfaxalone alone reduced the total dose required and resulted in no apnoea. 

Article by
Dr. Karen Heskin
BVSc CertSAO MRCVS

Veterinary Technical Manager, Jurox UK

Originally published: Thursday, 7th November 2019

References

Bigby S.E., Beths T., Bauquier S., Carter J.E. et al. (2017) Effect of rate of administration of propofol or alfaxalone on induction dose requirements and occurrence of apnea in dogs. Vet Anaesth Analg. 44: 1267-1275.

Kumar A., Sanikop C.S., Kotur P.F. (2006) Effect of priming principle on the induction dose requirements of propofol - a randomized clinical trial. Indian J Anaesth. 50: 282-287.

Stokes D & Hutton P. (1991). Rate-Dependent Induction Phenomena With Propofol: Implications for the Relative Potency of Intravenous Anesthetics. Anesthesia & Analgesia. 72:578–583

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