20Objectives The aim of this study was to optimize dexmedetomidine and alfaxalone 21 dosing, for intramuscular administration with butorphanol, to perform minor surgeries 22 in cats. 23Methods Initially, cats were assigned to one of 5 groups, each composed of 6 animals 24 and receiving, in addition to 0.3 mg/kg butorphanol IM, one of the following: A: 0.005 25 mg/kg dexmedetomidine, 2 mg/kg alfaxalone; B: 0.008 mg/kg dexmedetomidine, 1.5 26 mg/kg alfaxalone; C: 0.012 mg/kg dexmedetomidine, 1 mg/kg alfaxalone; D: 0.005 27 mg/kg dexmedetomidine, 1 mg/kg alfaxalone; and E: 0.012 mg/kg dexmedetomidine, 2 28 mg/kg alfaxalone. Thereafter, a modified "direct search" method, conducted in a 29 stepwise manner, was used to optimize drugs dosing. The quality of anaesthesia was 30 evaluated on the basis of composite scores (one for anaesthesia and one for recovery), 31 of Visual Analogue Scales, and of propofol requirement to suppress spontaneous 32 movements. The medians or means of these variables were used to rank the treatments: 33 "unsatisfactory" and "promising" combinations were identified to calculate, through the 34 equation first described by Berenbaum in 1990, new dexmedetomidine and alfaxalone 35 doses to be tested in the next step. At each step, 5 combinations (one new plus the best 36 previous four) were tested. 373 Results None of the tested combinations resulted in adverse effects. Four steps and 120 38 animals were necessary to identify the optimal drug combination (0.014 mg/kg 39 dexmedetomidine, 2.5 mg/kg alfaxalone and 0.3 mg/kg butorphanol). 40Conclusions and relevance The investigated drug mixture, at the doses found with the 41 optimization method, is suitable for cats undergoing minor clinical procedures. 42 43

Background: In veterinary practice, most minor procedures such as radiographs, skin biopsies and wound treatments require sedation. The combination of butorphanol, ketamine and dexmedetomidine is commonly used, but the ideal dosages for this combination have not been reported. This randomized prospective clinical trial initially tested 8 clinically relevant combinations in a blinded procedure in 50 dogs. The quality of each combination was rated using a purposefully developed negative score (NS; 0-21.5, the lower the NS the better the quality of sedation), to judge the quality of sedation, the occurrence of side effects, and need for additional anaesthetics. Then the combinations were divided into "promising" and "unsatisfactory" subgroups and their centroids Pc and Uc were determined before a new combination (N) was calculated using the formula N=Pc+α*(Pc-Uc). The combination N was tested in 6 dogs and then it replaced the worst of the previous 8 combinations. The same procedure was repeated after each new combination until the NS did not improve any further. As a last step, the best combination was tested in 100 adult dogs undergoing diagnostic or therapeutic procedures. Results: The optimal combination found was dexmedetomidine 0.005 mg/kg, ketamine 1 mg kg-1, and butorphanol 0.3 mg kg-1 with a median NS of 1.5 (interquartile range 1.5-2.4). In all 112 dogs receiving this combination, the quality of sedation was satisfactory and no severe side effects were detected. Conclusions: The application of this optimization method allowed the calculation of an optimal drug combination for sedation in healthy dogs. This combination revealed safe after being tested in 100 animals. This combination can now be used in daily clinical practice for healthy adult dogs undergoing minor procedures.