title: Haemodynamic interactions of medetomidine and the peripheral alpha-2 antagonist MK-467 during step infusions in isoflurane-anaesthetised dogs.
abstract: The haemodynamic interactions of a step infusion with medetomidine (MED) and the peripherally acting alpha-2 antagonist MK-467 (MK) were compared with MED infused alone in isoflurane-anaesthetised dogs. Eight purposely-bred Beagles were used in a randomised crossover study. Anaesthesia was induced with propofol intravenously (IV) and maintained with isoflurane in oxygen. Dogs received 1.25 µg/kg MED as a 1 min loading dose IV, along with a step-down MED infusion at rates of 8.0 µg/kg/h (step 1: 0-20 min), 5.5 µg/kg/h (step 2: 20-40 min) and 4.0 µg/kg/h (step 3: 40-95 min). Five minutes after starting the MED infusion, the dogs received MK-467 in a step-up infusion at rates of 100 µg/kg/h (step 1: 5-35 min), 200 µg/kg/h (step 2: 35-65 min) and 500 µg/kg/h (step 3: 65-95 min). Heart rate (HR), systolic (SAP) and mean arterial (MAP) blood pressures and arteriovenous oxygen content differences (a-vO2 diff) were calculated. Plasma drug concentrations were analysed. Repeated-measures general linear mixed models with Bonferroni correction were used for statistical analyses. MED infusion alone increased SAP maximally by 24.9%, MAP by 34.7% and a-vO2 diff by 222.5%, and reduced HR by 32.3%, but these changes were significantly attenuated by MK-467. Most MED effects returned to baseline during step 2 of MK-467 infusion and step 3 of MED infusion (MED/MK-467 ratio 1:18 to 1:50). Plasma concentrations of MED tended to be lower with the addition of MK-467. The use of step infusions helped to narrow down the therapeutic range for the MED/MK-467 infusion dose ratio during isoflurane anaesthesia in dogs.
authors.affiliation: Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Finland. Electronic address: johanna.kaartinen@umontreal.ca.
authors.forename: Johanna
authors.initials: J
authors.lastname: Kaartinen
authors.affiliation: GREPAQ, Department of Veterinary Biomedical Sciences, Université de Montréal, St. Hyacinthe, Quebec, Canada.
authors.forename: Jérôme R E
authors.initials: JR
authors.lastname: del Castillo
authors.affiliation: Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Finland.
authors.forename: Kati
authors.initials: K
authors.lastname: Salla
authors.affiliation: GREPAQ, Department of Veterinary Biomedical Sciences, Université de Montréal, St. Hyacinthe, Quebec, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Troncy
authors.affiliation: Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Finland.
authors.forename: Marja R
authors.initials: MR
authors.lastname: Raekallio
authors.affiliation: Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Finland.
authors.forename: Outi M
authors.initials: OM
authors.lastname: Vainio
mesh_terms: D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D058669:Adrenergic alpha-2 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D018685:Anesthetics, Inhalation / Q000008:administration & dosage; D000818:Animals; D018592:Cross-Over Studies; D004285:Dogs / Q000378:metabolism*; D004338:Drug Combinations; D005260:Female; D006439:Hemodynamics; D007262:Infusions, Intravenous / Q000662:veterinary; D007530:Isoflurane / Q000008:administration & dosage; D008297:Male; D020926:Medetomidine / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D011807:Quinolizines / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D058647:Adrenergic alpha-2 Receptor Agonists; D058669:Adrenergic alpha-2 Receptor Antagonists; D018685:Anesthetics, Inhalation; D004338:Drug Combinations; D011807:Quinolizines; C055732:vatinoxan; D007530:Isoflurane; D020926:Medetomidine
keywords: Alpha-2 agonist; Dog; MK-467; Medetomidine; Peripheral alpha-2 antagonist