Evaluating clinical assessment parameters of xylazine efficacy using objective pharmacokinetic measures

Abstract

Clinical evaluations of sedative efficacy typically utilize scoring systems based on subjective observations in stimulated and nonstimulated horses. Studies in other species have identified links between subjectively evaluated sedation and pharmacokinetic measures of α-2 agonist drugs, yet little investigation has been conducted in horses to explore the clinical presentation of metabolic variation. This study aims to evaluate the degree to which subjective clinical sedative evaluations reflect pharmacokinetic measurements of drug metabolism. Xylazine hydrochloride, an α-2 agonist, was administered to 36 horses of varying breed and age at a dosage rate of 0.5 mg/kg body weight. Subjective clinical parameters were scored at 5, 15, 30, 45, and 60 min post xylazine administration by a single expert and included responsiveness to sound, touch, and visual stimuli, as well as observed degree of ataxia. Blood was collected at each time interval to determine serum plasma concentrations of xylazine (XC) and 4-OH-xylazine (OHXC). Correlation coefficients were calculated between each combination of subjective and objective measures using Spearman's and Kendall's rank correlations, with P-values calculated to assess the significance of associations. Observed degree of ataxia recorded the strongest correlation coefficient, showing a moderate positive correlation with both OHXC and XC (r = 0.63 and r = 0.58, respectively). While individual responses to stimuli measures were all significantly (P < 0.05) associated with both OHXC and XC, the strength of correlation for each was classified as negligible, ranging from r = −0.158 to −0.247. When accounting for all subjective clinical parameters assessed including ataxia, significant correlations (P < 0.05) with both XC and OHXC (r = −0.448 and r = −0.423, respectively) were greater than that seen when combining stimuli-based parameters. While degree of ataxia more strongly correlated with pharmacokinetic parameters, it is typically assessed in the undisturbed horse and may not best reflect the clinical efficacy. However, diminishing responsiveness to sound stimuli at later time intervals and the negligible correlation of stimuli parameters indicate they may inadvertently be assessing temperamental attributes of the horse and, in the case of repeated measures, the rate of desensitization. This study shows limited correlation between commonly used clinical stimuli-based assessment parameters in isolation in reflecting xylazine serum plasma concentrations, and presents multiple factors to be considered when evaluating equine xylazine sedation.