Physiological and pharmacokinetic effects of multilevel caging on Sprague Dawley rats under ketamine-xylazine anesthesia

Abstract

While the cage refinement is a necessary step towards improving the welfare of research rats, increasing the complexity and surface area of the living space of an animal may have physiological impacts that need to be taken into consideration. In this study, ketamine (80 mg/kg) and xylazine (10 mg/kg) caused a short duration anesthesia that was significantly decreased in Sprague-Dawley rats housed in multilevel cages (MLC), compared to rats housed in standard cages (SDC). The withdrawal reflex, the palpebral reflexes and the time-to-sternal all occurred earlier in MLC housed rats, suggesting an effect of housing on the physiology of the rats. In addition, during anesthesia, cardiac frequencies were increased in animals housed in the smaller SDC. Respiratory frequencies, the blood oxygen saturation and rectal temperatures during anesthesia did not vary between conditions during the anesthesia. While xylazine pharmacokinetics were unchanged with caging conditions, the clearance and half-lives of ketamine and its metabolite, norketamine, were altered in the rats housed in MLC. Finally, while no difference was ultimately seen in rat body weights, isolated liver and adrenal gland weights were significantly lighter in rats housed in the MLC. Increasing cage sizes, while having a positive impact on wellbeing in rats, can alter anesthetic drug metabolism and thus modify anesthesia parameters and associated physiological processes.

Oxygen inhalation improves postoperative survival in ketamine-xylazine anaesthetised rats: An observational study

“…Anaesthesia with KX is known to trigger respiratory depression and a decrease in SpO 2 in rats [7, 32, 33], as it did in this experiment. The initial drop of SpO 2 in the AA group is not shown here, as the period in which the sedation starts working is not recorded, in order to minimise stress for the animals.…”

Applying the 3Rs: A Case Study on Evidence and Perceptions Relating to Rat Cage Height in the UK

“…As described in the introduction, the current standard for rat cage height in the UK is based on four or five publications and 'good current practice' [4,12]. Looking again at two of the papers cited by the Council of Europe's Group of Experts [8,9], taken with the four papers listed in Table 2 [13][14][15][16] and the good practice examples identified in the survey, we propose that there is sufficient evidence to justify increasing rat cage height to a minimum of 30 cm. This is already happening in some establishments, but not others, and it is important to understand the reasons for this.…”

“…Dodelet-Devillers et al (2016) [15] Physiology and pharmacology of ketamine-xylazine anaesthesia on rats housed in cages 20.5 cm or 40.4 cm high.…”

“…• Making rats rise to an erect, bipedal stance for feeding, in cages 28-35.5 cm high, increased body and hind limb muscle mass, tibial bone mineral concentration and periosteal cortical bone formation in male SD rats [38] • Increased activity benefiting cardiovascular system, evidenced by faster recovery from anaesthesia and lower heart rates [15] There also seemed to be a perception that evaluation studies would have to be done in-house, consuming resources, rather than implementing the results of research done by others. This was due to a number of factors, such as a desire to observe how the change functioned in the specific context and constraints of their particular facility, a desire to personally witness the evidence, and a scientific concern for the models used in external studies to be translatable to their own animal model.…”

“…Since the EU and UK standards were published, the literature on evaluating the impact of rat cage height has increased (Table 1). There is evidence that housing in cages that permit upright standing leads to reduced anxiety and stress, positive welfare and increased natural behaviours including exploratory behaviour [13][14][15][16]. It is important to recognise that wild-type behaviour is often conserved in domestic animals if they have the opportunity to express this [7,17,18].…”