• 1. Murrell JC, Hellebrekers LJ. Medetomidine and dexmedtomidine: a review of cardiovascular effects and analgesic properties in the dog. Vet Anaesth Analg 2005; 32: 117127.

    • Search Google Scholar
    • Export Citation
  • 2. Vainio O, Palmu L. Cardiovascular and respiratory effects of medetomidine in dogs and influence of anticholinergics. Acta Vet Scand 1989; 30: 401408.

    • Search Google Scholar
    • Export Citation
  • 3. Bloor BC, Frankland M, Alper G, et al. Hemodynamic and sedative effects of dexmedetomidine in dog. J Pharmacol Exp Ther 1992; 263: 690697.

    • Search Google Scholar
    • Export Citation
  • 4. Pypendop BH, Verstegen JP. Hemodynamic effects of medetomidine in the dog: a dose titration study. Vet Surg 1998; 27: 612622.

  • 5. Ruffolo RR Jr, Nichols AJ, Stadel JM, et al. Pharmacologic and therapeutic applications of alpha 2-adrenoceptor subtypes. Annu Rev Pharmacol Toxicol 1993; 33: 243279.

    • Search Google Scholar
    • Export Citation
  • 6. MacMillan LB, Hein L, Smith MS, et al. Central hypotensive effects of the αA–adrenergic receptor subtype. Science 1996; 273: 801803.

    • Search Google Scholar
    • Export Citation
  • 7. Brahim JS, Thut PD. Hemodynamic changes during isoflurane anesthesia. Anesth Prog 1984; 31: 207212.

  • 8. Mutoh T, Nishimura R, Kim HY, et al. Cardiopulmonary effects of sevoflurane, compared with halothane, enflurane, and isoflurane, in dogs. Am J Vet Res 1997; 58: 885890.

    • Search Google Scholar
    • Export Citation
  • 9. Keegan RD, Greene SA, Bagley RS, et al. Effects of medetomidine administration on intracranial pressure and cardiovascular variables of isoflurane-anesthetized dogs. Am J Vet Res 1995; 56: 193198.

    • Search Google Scholar
    • Export Citation
  • 10. Sinclair MD, McDonell WN, O'Grady M, et al. The cardiopulmonary effects of romifidine in dogs with and without prior or concurrent administration of glycopyrrolate. Vet Anaesth Analg 2002; 29: 113.

    • Search Google Scholar
    • Export Citation
  • 11. Sinclair MD, O'Grady MR, Kerr CL, et al. The echocardiographic effects of romifidine in dogs with and without prior or concurrent administration of glycopyrrolate. Vet Anaesth Analg 2003; 30: 211219.

    • Search Google Scholar
    • Export Citation
  • 12. Short CE. Effects of anticholinergic treatment on the cardiac and respiratory systems in dogs sedated with medetomidine. Vet Rec 1991; 129: 310313.

    • Search Google Scholar
    • Export Citation
  • 13. Alibhai HI, Clarke KW, Lee YH, et al. Cardiopulmonary effects of combinations of medetomidine hydrochloride and atropine sulphate in dogs. Vet Rec 1996; 138: 1113.

    • Search Google Scholar
    • Export Citation
  • 14. Ko JC, Fox SM, Mandsager RE. Effects of preemptive atropine administration on incidence of medetomidine-induced bradycardia in dogs. J Am Vet Med Assoc 2001; 218: 5258.

    • Search Google Scholar
    • Export Citation
  • 15. Congdon JM, Marquez M, Niyom S, et al. Evaluation of the sedative and cardiovascular effects of intramuscular administration of dexmedetomidine with and without concurrent atropine administration in dogs. J Am Vet Med Assoc 2011; 239: 8189.

    • Search Google Scholar
    • Export Citation
  • 16. Clineschmidt BV, Pettibone DJ, Lotti VJ, et al. A peripherally acting alpha-2 adrenoceptor antagonist: L-659,066. J Pharmacol Exp Ther 1988; 245: 3240.

    • Search Google Scholar
    • Export Citation
  • 17. Enouri SS, Kerr CL, McDonell WN, et al. Effects of a peripheral α2 adrenergic-receptor antagonist on the hemodynamic changes induced by medetomidine administration in conscious dogs. Am J Vet Res 2008; 69: 728736.

    • Search Google Scholar
    • Export Citation
  • 18. Honkavaara JM, Raekallio MR, Kuusela EK, et al. The effects of L-659,066, a peripheral alpha2-adrenoceptor antagonist, on dexmedetomidine-induced sedation and bradycardia in dogs. Vet Anaesth Analg 2008; 35: 409413.

    • Search Google Scholar
    • Export Citation
  • 19. Honkavaara JM, Restitutti F, Raekallio MR, et al. The effects of increasing doses of MK-467, a peripheral alpha(2)-adrenergic receptor antagonist, on the cardiopulmonary effects of intravenous dexmedetomidine in conscious dogs. J Vet Pharmacol Ther 2011; 34: 332337.

    • Search Google Scholar
    • Export Citation
  • 20. Rolfe NG, Kerr CL, McDonell WN. Cardiopulmonary and sedative effects of the peripheral α2-adrenoceptor antagonist MK 0467 administered intravenously or intramuscularly concurrently with medetomidine in dogs. Am J Vet Res 2012; 73: 587594.

    • Search Google Scholar
    • Export Citation
  • 21. Salla K, Bennett RC, Restitutti F, et al. A comparison in dogs of medetomidine, with or without MK-467, and the combination acepromazine-butorphanol as premedication prior to anaesthesia induced by propofol and maintained with isoflurane. Vet Anaesth Analg 2014; 41: 163173.

    • Search Google Scholar
    • Export Citation
  • 22. Salla K, Restitutti F, Vainionpää M, et al. The cardiopulmonary effects of a peripheral alpha-2-adrenoceptor antagonist, MK-467, in dogs sedated with a combination of medetomidine and butorphanol. Vet Anaesth Analg 2014; 41: 567574.

    • Search Google Scholar
    • Export Citation
  • 23. Bennett RC, Salla KM, Raekallio MR, et al. Effects of MK-467 on the antinociceptive and sedative actions and pharmacokinetics of medetomidine in dogs. J Vet Pharmacol Ther 2016; 39: 336343.

    • Search Google Scholar
    • Export Citation
  • 24. Mason DJ, O'Grady M, Woods JP, et al. Assessment of lithium dilution cardiac output as a technique for measurement of cardiac output in dogs. Am J Vet Res 2001; 62: 12551261.

    • Search Google Scholar
    • Export Citation
  • 25. Reeves RB, Park JS, Lapennas GN, et al. Oxygen affinity and Bohr coefficients of dog blood. J Appl Physiol 1982; 53: 8795.

  • 26. Haskins S, Pascoe PJ, Ilkiw JE, et al. Reference cardiopulmonary values in normal dog. Comp Med 2005; 55: 156161.

  • 27. European Medicines Agency. Guideline on bioanalytical method validation. Available at: www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500109686.pdf. Accessed Oct 10, 2013.

  • 28. Proakis AG, Harris GB. Comparative penetration of glycopyrrolate and atropine across the blood-brain and placental barriers in anesthetized dogs. Anesthesiology 1978; 48: 339344.

    • Search Google Scholar
    • Export Citation
  • 29. Gelman S. Venous function and central venous pressure: a physiologic story. Anesthesiology 2008; 108: 735748.

  • 30. Kaartinen J, del Castillo JR, Salla K, et al. Haemodynamic interactions of medetomidine and the peripheral alpha-2 antagonist MK-467 during step infusions in isoflurane-anaesthetised dogs. Vet J 2014; 202: 353360.

    • Search Google Scholar
    • Export Citation
  • 31. Lin GY, Robben JH, Murrell JC, et al. Dexmedetomidine constant rate infusion for 24 hours during and after propofol or isoflurane anaesthesia in dogs. Vet Anaesth Analg 2008; 35: 141153.

    • Search Google Scholar
    • Export Citation
  • 32. Pascoe PJ. The cardiopulmonary effects of dexmedetomidine infusions in dogs during isoflurane anesthesia. Vet Anaesth Analg 2015; 42: 360368.

    • Search Google Scholar
    • Export Citation
  • 33. Hughes D, Rozanski ER, Shofer FS, et al. Effect on sampling site, repeated sampling, pH, and Pco2 on plasma lactate concentration in healthy dogs. Am J Vet Res 1999; 60: 521524.

    • Search Google Scholar
    • Export Citation
  • 34. Ko JC, Fox SM, Mandsager RE. Anesthetic effects of ketamine or isoflurane induction prior to isoflurane anesthesia in medetomidine-premedicated dogs. J Am Anim Hosp Assoc 2001; 37: 411419.

    • Search Google Scholar
    • Export Citation
  • 35. Pascoe PJ, Raekollio M, Kuusela E, et al. Changes in the minimum alveolar concentration of isoflurane and some cardiopulmonary measurements during three continuous infusion rates of dexmedetomidine in dogs. Vet Anaesth Analg 2006; 33: 97103.

    • Search Google Scholar
    • Export Citation
  • 36. Enouri SS, Kerr CL, McDonell WN, et al. Cardiopulmonary effects of anesthetic induction with thiopental, propofol, or a combination of ketamine hydrochloride and diazepam in dogs sedated with a combination of medetomidine and hydromorphone. Am J Vet Res 2008; 69: 586595.

    • Search Google Scholar
    • Export Citation
  • 37. Ambrisko TD, Kabes R, Moens Y. Influence of drugs on the response characteristics of the LiDCO sensor: an in vitro study. Br J Anaesth 2013; 110: 305310.

    • Search Google Scholar
    • Export Citation
  • 38. Dutta S, Lal R, Karol MD, et al. Influence of cardiac output on dexmedetomidine pharmacokinetics. J Pharm Sci 2000; 89: 519527.

  • 39. Honkavaara J, Restitutti F, Raekallio M, et al. Influence of MK-467, a peripherally acting α2-adrenoceptor antagonist on the disposition of intravenous dexmedetomidine in dogs. Drug Metab Dispos 2012; 40: 445449.

    • Search Google Scholar
    • Export Citation
  • 40. Reid J, Nolan AM. Pharmacokinetics of propofol as an induction agent in geriatric dogs. Res Vet Sci 1996; 61: 169171.

Advertisement

Cardiovascular effects of premedication with medetomidine alone and in combination with MK-467 or glycopyrrolate in dogs subsequently anesthetized with isoflurane

Kati M. Salla DVM1, Cosmin I. Tuns DVM2, Rachel C. Bennett DVM3, Marja R. Raekallio DVM, Phd4, Mika Scheinin MD, Phd5,6, Erja Kuusela DVM, Phd7, and Outi M. Vainio DVM, Phd8
View More View Less
  • 1 Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Yliopistonkatu 4, 00100 Helsinki, Finland.
  • | 2 Faculty of Veterinary Medicine, Agriculture Science University, 300645 Timişoara, Romania.
  • | 3 Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Yliopistonkatu 4, 00100 Helsinki, Finland.
  • | 4 Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Yliopistonkatu 4, 00100 Helsinki, Finland.
  • | 5 Department of Pharmacology, Drug Development and Therapeutics, University of Turku, 20500 Turku, Finland.
  • | 6 Unit of Clinical Pharmacology, Turku University Hospital, 20521 Turku, Finland.
  • | 7 Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Yliopistonkatu 4, 00100 Helsinki, Finland.
  • | 8 Department of Equine and Small Animal Medicine, Faculty of Veterinary Medicine, University of Helsinki, Yliopistonkatu 4, 00100 Helsinki, Finland.

Abstract

OBJECTIVE To compare cardiovascular effects of premedication with medetomidine alone and with each of 3 doses of MK-467 or after glycopyrrolate in dogs subsequently anesthetized with isoflurane.

ANIMALS 8 healthy purpose-bred 5-year-old Beagles.

PROCEDURES In a randomized crossover study, each dog received 5 premedication protocols (medetomidine [10 μg/kg, IV] alone [MED] and in combination with MK-467 at doses of 50 [MMK50], 100 [MMK100], and 150 [MMK150] μg/kg and 15 minutes after glycopyrrolate [10 μg/kg, SC; MGP]), with at least 14 days between treatments. Twenty minutes after medetomidine administration, anesthesia was induced with ketamine (0.5 mg/kg, IV) and midazolam (0.1 mg/kg, IV) increments given to effect and maintained with isoflurane (1.2%) for 50 minutes. Cardiovascular variables were recorded, and blood samples for determination of plasma dexmedetomidine, levomedetomidine, and MK-467 concentrations were collected at predetermined times. Variables were compared among the 5 treatments.

RESULTS The mean arterial pressure and systemic vascular resistance index increased following the MED treatment, and those increases were augmented and obtunded following the MGP and MMK150 treatments, respectively. Mean cardiac index for the MMK100 and MMK150 treatments was significantly greater than that for the MGP treatment. The area under the time-concentration curve to the last sampling point for dexmedetomidine for the MMK150 treatment was significantly lower than that for the MED treatment.

CONCLUSIONS AND CLINICAL RELEVANCE Results indicated concurrent administration of MK-467 with medetomidine alleviated medetomidine-induced hemodynamic changes in a dose-dependent manner prior to isoflurane anesthesia. Following MK-467 administration to healthy dogs, mean arterial pressure was sustained at acceptable levels during isoflurane anesthesia.

Contributor Notes

Address correspondence to Dr. Salla (kati.salla@helsinki.fi).