Determination of midazolam dose for co-induction with alfaxalone in sedated cats

Published:February 05, 2019DOI:



      To investigate the median effective dose 50 (ED50) of midazolam required for endotracheal intubation when used for co-induction of anesthesia with a low dose of alfaxalone in sedated cats.

      Study design

      Randomized up-and-down study.


      A group of 14 mixed-breed cats (eight males, six females), aged 5–12 years and weighing 4.4–6.8 kg.


      The cats were randomly assigned in a sequential allocation numbers from one to 14. Cats were sedated with dexmedetomidine (3 μg kg–1) and methadone (0.3 mg kg–1) intramuscularly. After 15 minutes, the quality of sedation was subjectively evaluated. Anesthesia induction was performed by intravenous (IV) administration of alfaxalone (0.25 mg kg–1) over a 60 second interval, followed by another 60 second interval, and then an IV dose of midazolam was administered over a 5 second interval. The initial midazolam dose was 0.3 mg kg–1; then, the midazolam dose was adjusted by ±0.1 mg kg–1 for each consecutive cat based on successful or unsuccessful endotracheal intubation of the previous animal following an up-and-down method. This sequence was followed until six nonsequential crossovers were observed. Crossover was defined as two opposite outcomes in two sequential animals. Data were analyzed using isotonic regression with bootstrapping for determination of midazolam ED50 and logistic regression for correlations (p < 0.05).


      Overall, six independent crossovers were found, and ED50 of midazolam was 0.08 ± 0.04 mg kg–1. Sedation score and successful tracheal intubation had a strong positive correlation (p = 0.02).

      Conclusions and clinical relevance

      This study determined that 0.08 ± 0.04 mg kg–1 of midazolam co-administered with 0.25 mg kg–1 of alfaxalone IV allowed smooth endotracheal intubation in half of the cats sedated with methadone and dexmedetomidine at the doses used in this study.


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        • Albertson T.E.
        • Walby W.F.
        • Joy R.M.
        Modification of GABA-mediated inhibition by various injectable anesthetics.
        Anesthesiology. 1992; 77: 488-499
        • Anderson L.
        • Robb H.
        A comparison of midazolam co-induction with propofol predosing for induction of anaesthesia.
        Anaesthesia. 1998; 53: 1117-1120
        • Bley C.R.
        • Roos M.
        • Price J.
        • et al.
        Clinical assessment of repeated propofol-associated anesthesia in cats.
        J Am Vet Med Assoc. 2007; 231: 1347-1353
        • Brandão J.M.
        Cardiovascular tolerance and safety of intravenous lidocaine in the broiler chicken (Gallus gallus domesticus). MS thesis.
        Louisiana State University, LA, USA2014: 35-39
        • Castro G.C.
        • Caldeira J.A.
        • Devito F.C.
        • et al.
        Effects of combined midazolam and propofol in anesthesia induction and recovery of cats undergoing ovariohysterectomy.
        Ciências Agrarias. 2015; 36: 4269-4276
        • Chiu K.W.
        • Robson S.
        • Devi J.L.
        • et al.
        The cardiopulmonary effects and quality of anesthesia after induction with alfaxalone in 2-hydroxypropyl-β-cyclodextrin in dogs and cats: a systematic review.
        J Vet Pharmacol Ther. 2016; 39: 525-538
        • Covey-Crump G.L.
        • Murison P.J.
        Fentanyl or midazolam for co-induction of anaesthesia with propofol in dogs.
        Vet Anaesth Analg. 2008; 35: 463-472
        • Dixon W.J.
        The up-and-down method for small samples.
        J Am Stat Assoc. 1965; 60: 967-978
        • Dixon W.J.
        • Mood A.M.
        A method for obtaining and analyzing sensitivity data.
        J Am Stat Assoc. 1948; 43: 109-126
        • Djaiani G.
        • Ribes-Pastor M.P.
        Propofol auto-co-induction as an alternative to midazolam co-induction for ambulatory surgery.
        Anaesthesia. 1999; 54: 63-67
        • Griffenhagen G.M.
        • Rezende M.L.
        • Gustafson D.L.
        • et al.
        Pharmacokinetics and pharmacodynamics of propofol with or without 2% benzyl alcohol following a single induction dose administered intravenously in cats.
        Vet Anaesth Analg. 2015; 42: 472-483
        • Hackett T.B.
        Physical examination.
        in: Silverstein D.C. Hopper K. Small Animal Critical Care Medicine. Saunders Elsevier, USA2009: 2-5
        • Hopkins A.
        • Giuffrida M.
        • Larenza M.P.
        Midazolam, as a co-induction agent, has propofol sparing effects but also decreases systolic blood pressure in healthy dogs.
        Vet Anaesth Analg. 2014; 41: 64-72
        • Ilkiw J.E.
        • Suter C.M.
        • Farver T.B.
        • et al.
        The behavior of healthy awake cats following intravenous and intramuscular administration of midazolam.
        J Vet Pharmacol Ther. 1996; 19: 205-216
        • Karlo R.
        • Singh N.R.
        • Singh K.M.
        • et al.
        Priming effects of propofol during induction of anesthesia.
        J Med Soc. 2015; 29: 92-95
        • Kataria R.
        • Singhal A.
        • Prakash S.
        • Singh I.
        A comparative study of efficacy of propofol auto-co-induction versus midazolam propofol co-induction using the priming principle.
        Indian J Anaesth. 2010; 54: 558-561
        • Lagos-Carvajal A.
        • Queiroz-Williams P.
        • Riccó C.
        • et al.
        The use of priming alfaxalone as an induction technique in cats (abstract).
        Vet Anaesth Analg. 2017; 44 (e15): 1265
        • Lambert J.J.
        • Belelli D.
        • Peden D.R.
        • et al.
        Neurosteroid modulation of GABAA receptors.
        Prog Neurobiol. 2003; 71: 67-80
        • Liao P.
        • Sinclair M.
        • Valverde A.
        • et al.
        Induction dose and recovery quality of propofol and alfaxalone with or without midazolam coinduction followed by total intravenous anesthesia in dogs.
        Vet Anaesth Analg. 2017; 44: 1016-1026
        • Mehta S.H.
        • Dabhi P.G.
        • Golwala M.P.
        • et al.
        Effect of priming principle on the induction dose requirement of propofol.
        Int J Res Med. 2015; 4: 69-73
        • Möhler H.
        • Richards J.G.
        The benzodiazepine receptor: a pharmacological control element of brain function.
        Eur J Anaesthesiol Suppl. 1988; 2: 15-24
        • Muir W.
        • Lerche P.
        • Wiese A.
        • et al.
        Cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in dogs.
        Vet Anaesth Analg. 2008; 35: 451-462
        • Muir W.
        • Lerche P.
        • Wiese A.
        • et al.
        The cardiorespiratory and anesthetic effects of clinical and supraclinical doses of alfaxalone in cats.
        Vet Anaesth Analg. 2009; 36: 42-54
        • Muñoz K.A.
        • Robertson S.A.
        • Wilson D.V.
        Alfaxalone alone or combined with midazolam or ketamine in dogs: intubation dose and select physiologic effects.
        Vet Anaesth Analg. 2017; 44: 766-774
        • Nordt S.P.
        • Clark R.F.
        Midazolam: a review of therapeutic uses and toxicity.
        J Emerg Med. 1997; 15: 357-365
        • Pace N.L.
        • Stylianou M.P.
        Advances in and limitations of up-and-down methodology: a précis of clinical use, study design, and dose estimation in anesthesia research.
        Anesthesiology. 2007; 107: 144-152
        • Pascoe P.J.
        A question of time.
        Vet Anaesth Analg. 2018; 45: 401-404
        • Robinson R.
        • Borer-Weir K.
        A dose titration study into the effects of diazepam or midazolam on the propofol dose requirements for induction of general anaesthesia in client owned dogs, premedicated with methadone and acepromazine.
        Vet Anaesth Analg. 2013; 40: 455-463
        • Robinson R.
        • Borer-Weir K.
        The effects of diazepam or midazolam on the dose of propofol required to induce anaesthesia in cats.
        Vet Anaesth Analg. 2015; 42: 493-501
        • Seddighi R.
        • Egger C.M.
        • Rohrbach B.W.
        • et al.
        The effect of midazolam on the end-tidal concentration of isoflurane necessary to prevent movement in dogs.
        Vet Anaesth Analg. 2011; 38: 195-202
        • Simmons J.P.
        • Wohl J.S.
        in: Silverstein D.C. Hopper K. Small Animal Critical Care Medicine. Saunders Elsevier, USA2009: 27-30
        • Stokes D.N.
        • Hutton P.
        Rate-dependent induction phenomena with propofol: implications for the relative potency of intravenous anesthetics.
        Anesth Analg. 1991; 72: 578-583
        • Stylianou M.
        • Flournoy N.
        Dose finding using the biased coin up-and-down design and isotonic regression.
        Biometrics. 2002; 58: 171-177
        • Taboada F.M.
        • Murison P.J.
        Induction of anaesthesia with alfaxalone or propofol before isoflurane maintenance in cats.
        Vet Rec. 2010; 167: 85-89
        • Vågerö M.
        • Sundberg R.
        The distribution of the maximum likelihood estimator in up-and-down experiments for quantal dose-response data.
        J Biopharm Stat. 1999; 9: 499-519
        • Warne L.N.
        • Beths T.
        • Whittem T.
        • et al.
        A review of the pharmacology and clinical application of alfaxalone in cats.
        Vet J. 2015; 203: 141-148
        • Whittem T.
        • Pasloske K.S.
        • Heit M.C.
        • Ranasinghe M.G.
        The pharmacokinetics and pharmacodynamics of alfaxalone in cats after single and multiple intravenous administration of Alfaxan at clinical and supraclinical doses.
        J Vet Pharmacol Ther. 2008; 31: 571-579
        • Zaki S.
        • Ticehurst K.
        • Miyaki Y.
        Clinical evaluation of Alfaxan-CD® as an intravenous anaesthetic in young cats.
        Aust Vet J. 2009; 87: 82-87