Intravenous ketamine for long term anesthesia in rats

Abstract

Ketamine/xylazine anesthesia has been used primarily for short term procedures in animals, but two prior reports used intravenous ketamine/xylazine for experiments taking many hours. However, there is a discrepancy about the appropriate dose, which is resolved here. Adult Long-Evans rats were used for recording from the retina. Doses of Ketamine/xylazine were adjusted to minimize anesthetic in terminal experiments lasting 10 h. An allometric relation was fitted to the resulting data on doses as a function of body weight, and compared to prior work. The allometric relationship between the continuously infused specific dose and weight was: dose = 9.13 (weight)^-1.213 (r² = 0.73), where dose is in mg-kg^-1-hr^-1 and rat weight is in kg. The dose of xylazine was 3.3% of the ketamine dose. No attempt was made to explore different relative doses of xylazine and ketamine. Prior work is consistent with this relationship, showing that the earlier discrepancy resulted from using rats of different sizes. Ketamine at the doses used here still depressed the electroretinogram relative to historical controls using urethane. We conclude that intravenous ketamine dosing in rats should not use the same mg-kg^-1-hr^-1 dose for all rats, but take into account the strong allometric relationship between dose and rat weight. There is an advantage in using smaller doses in order to prevent unnecessary depression of neural responses.

Keywords: Anesthesia; Biological sciences; ERG; Electroretinogram; Ketamine; Laboratory medicine; Neuroscience; Ophthalmology; Physiology; Rat; Retina; Xylazine.

Figure 1

Dose of ketamine (mg-kg⁻¹-hr⁻¹) administered intravenously to three rats as a function of time. Xylazine was mixed with ketamine and administered at 3.3% of the dose rate of ketamine in all cases. Filled circles show when the animal was paralyzed with pancuronium bromide and artificially respirated.

Figure 2

Ketamine doses as a function of body weight. a. Time-averaged specific ketamine dose rate (mg-kg⁻¹-hr⁻¹) for each animal (filled circles). The average dose from (Simpson, 1997) shown as an open circle, and average doses from (Barriga-Rivera et al., 2018) are shown as open squares. The square at the lower body weight is for females and the one at the higher body weight is for males. The error bars for the open circle and squares are ranges rather than standard deviations, which were not available in those references, except for the horizontal error bars for the open squares, which show the standard deviation. The regression line is a power law fit: dose = 14.27 (weight)^−0.884 (r² = 0.56; p < 0.001) where dose is in mg-kg⁻¹-hr⁻¹ and weight is in kg. b. Final running specific dose rate for each animal (filled circles). As in a, filled circles each represent one animal in this study, and open symbols are from previous studies. The regression line is a power law fit: dose = 9.13 (weight)^−1.213 (r² = 0.73; p<<0.001).

Figure 3

The electroretinogram at different illuminations recorded in one animal. The stimulus illumination is given in terms of log units relative to the maximum available, which was about 2 log units above rod saturation. The gray bar and black line below the traces indicate the stimulus duration of 2.5 s, and the vertical line is 0.5 mV.

Figure 4

Average intensity response curves for the b-wave and c-wave from stimulus-response functions like that shown in Figure 3 from urethane-anesthetized animals (blue) (n = 40 from 27 animals) and ketamine-anesthetized animals (red) (n = 17 from 12 animals). Points are mean and standard error of the mean.

Figure 5

Depression of the electroretinogram (ERG) by increased ketamine. Each response is an average of 5 individual vitreal ERG responses to -1.0 relative log illumination obtained with 2.5 s flashes. The rate of ketamine administration was 10.7 mg/h for several hours preceding and during the control response. At time = 0, the rate was increased to 22.4 mg/h, and responses at times after this are indicated.