Isobolographic analysis of sedative and hypnotic interactions of propofol with ketamine and xylazine in chicks.

Introduction Propofol is a non-narcotic ultra short acting anesthetic agent used in humans (Smith et al 1994; Lundstrom et al 2010; McGrane et al 2012) and various animal species (Short & Bufalari 1999; Glowaski & Wetmore 1999; Papich 2011). The drug modulates the inhibitory effect of gamma-aminobutyric acid via GABAA receptors and potentiates glycinergic neurotransmission in the central nervous system (CNS) and the spinal cord to produce sedation, analgesia and anesthesia (Dong & Xu 2002; Vasileiou et al. 2009). Xylazine is a centrally acting alpha-2 adrenoceptor agonist which induces sedation, analgesia, sleep and muscle relaxation in animals (Greene & Thurmon 1988; Lizarraga & Chambers 2012; Coetzee 2013). Ketamine is a dissociative anesthetic agent widely used in humans and animals for anesthesia and pain management (Carter & Story 2013; Persson 2013; Tawfic 2013). More recently, it has been used against treatment-resistant depression in humans (Browne & Lucki 2013). Ketamine antagonizes N-methyl-D-aspartate receptors in the CNS (Persson 2013; Tawfic 2013). Ketamine combinations with sedatives, tranquilizers and analgesics are also widely used as balanced anesthetics and restraining agents in animals (Short 1992; Carter & Story 2013; Coetzee 2013). Ketamine has the limitations of producing emesis, agitation during recovery from anesthesia with long recovery time (White et al 1982). Xylazine is not an anesthetic agent (Greene & Thurmon 1988), but it rather improves the quality of anesthesia or its recovery, including those of propofol, in animals (Short & Bufalari 1999; Frias et al 2003; Wagner et al 2012). Propofol on the other hand causes hypotension and depresses respiration (Smith et al 1994; Mortero et al 2001). Many studies have reported the beneficial procedural sedation, analgesia and hypnosis of ketamine and propofol combination, named ketofol, in humans (Willman & Andolfatto 2007; Andolfatto et al 2012; Coulter et al 2014) and animals (Lerche et al 2000; Ravasio et al 2012) including the avian species (Fitzgerald & Cooper 1990; Lierz & Korbel 2012). The rationale for using ketofol is to reduce the dose of either drug required to produce procedural sedation, analgesia and hypnosis or anesthesia; hence the reduction of the adverse effects of both drugs (Slavik 2007; Coulter et al 2014). However, concerns appeared regarding the best anesthetic combination ratio of propofol and ketamine or xylazine and the type of drug interactions between them, whether it is a simple additive or synergistic or even none at all (Lerche et al 2000; Frias et al 2003; Mair et al 2009; Andolfattoet al 2012; Abstract. Objective: Propofol is an ultra-short acting anesthetic agent used in humans and animals. Ketamine, a dissociative anesthetic and xylazine, a sedative-analgesic agent can be used with propofol to improve the quality of sedation and anesthesia. The purpose of the present study was to apply an isobolographic analysis to examine the sedative and hypnotic interactions of propofol (given intraperitoneally) with ketamine and xylazine (given intramuscularly) in young chick model. Methods: The up-and-down method was used to determine the median effective sedative and hypnotic doses (ED50s) of propofol, ketamine and xylazine administered alone, or propofol-ketamine and propofol-xylazine combinations (50:50 ED50 values) in 7-10 day-old chicks. Isobolographic analysis was applied to determine the type of interaction between them. Results: The ED50 values for propofol, ketamine and xylazine were 1.83, 5.39 and 0.18 mg/kg for the induction of sedation, and they were 5.71, 12.24 and 3.83 mg/kg for the induction of sleep, respectively. Combined administration of propofol and ketamine or xylazine resulted in ED50 values of 0.63 + 2.63 and 0.86 + 0.09 mg/kg for sedation and 4.12 + 8.12 and 2.92 + 1.92 mg/kg for sleep, respectively. The ED50 values of propofol, ketamine and xylazine in the drug combinations decreased by 28 to 66% for the induction of sedation and sleep. Isobolographic analysis of the ED50 values of the three drugs revealed synergistic interactions between propofol and ketamine or xylazine for the induction of sedation in chicks. For the induction of sleep in chicks, no interaction (additive effect) occurred between propofol and xylazine and it was antagonistic between propofol and ketamine. Conclusion: The interaction reduced dose ratio of propofol with ketamine or xylazine (50:50 ED50 values) which produced the required end points of sedation and sleep in chicks. This could be of value clinically in the avian species or could be extended after further studies to mammals.