Ketamine and alpha-2 agonist combinations

The text on this page is taken from an informal compilation of opinions of contributors to the online VOLE List. As such, they are not peer reviewed and may contain differences of opinion. Those wishing to contact the list may contact Adrian Smith.

We are wondering if any groups have experienced a change in adverse events using their established ketamine/a2 combinations, and if so what do you think were factors?

One of the groups I work with has recently started to experience increased dyspnoea/mortality using ketamine-xylazine combination intraperitoneally in BL6 based mice for a 45-90 minute long imaging protocol, with a ~30 minute top-up and atipamisol reversal, having used this for years with a reported ~1-5% mortality rate. The animals seemed to develop progressive respiratory failure, or if the alpha-2 agonist is reversed, start to recover regaining righting reflex but then decline and die.

We have made changes (reducing ketamine dosage, no longer giving a top-up, and swapping the alpha-2 agonist to medetomidine - now animals have a single induction dose of 70mg/kg ketamine and 0.5mg/kg medetomidine injected ip, plus reversal) which has improved things considerably, but we are now looking at investing in engineering solutions to permit isoflurane use instead as a long-term solution with multiple benefits.

We have engaged in brainstorming, but remain unsure what may have changed to explain the need for lower doses, except for housing in IVCs and the observation that 'it's been quieter' during Covid shutdown (possibly less baseline stress in the mice?) - although problems were noted back in December 2019 by this and a different group (using rats). We have reviewed many obvious possibilities e.g. strain, drugs in date, training of new staff, drug dilutions, dose calculations, health status has been consistent, subcutaneous fluids, pre-GA food availability, gender, incidence in control v. experimental animals, etc.

Just a thought if the mortality risk appeared linked to the bolus top up of anesthetic agents. For prolonged anesthesia where inhalation agents are contraindicated, we get a nice, uninterrupted plane of surgical anesthesia using an intraperitoneal continuous-rate infusion with ketamine/alpha-2 agonist in mice (to avoid a second bolus injection). You just need a syringe driver and an extension line/catheter, so it is technically simple and we do not see many adverse incidences (reverse as needed).

Here is the original research article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029825

Maybe you could also try reducing the alpha-2 dose if you are seeing significant respiratory depression (although the doses you quote look standard)?