Comparison of systemic effects of midazolam, ketamine, and isoflurane anaesthesia in rabbits

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Introduction: Clinical doses of anaesthetic agents were administered to rabbits and effects on the brain, heart, and liver were investigated biochemically and histopathologically. Material and Methods: The rabbits were randomly divided into three main groups (16 rabbits each) and each group into study (n = 8) and control (n = 8) groups. All study group rabbits received 3 mg/kg of midazolam (M) intramuscularly. Group 1.1 (M) received nothing further, group 2.1 (MK) also received 25 mg/kg of ketamine, and group 3.1 (MKI) besides ketamine was also given 2% isoflurane to induce anaesthesia for 30 min. NaCl solution in the same volume as midazolam and ketamine was injected into the controls. Results: In clinical evaluation significant differences were detected in respiratory and heart rates. In blood gas analysis the PO2 and PCO2 values showed statistical differences in anaesthesia intervals. Significant biochemical value changes were recorded in creatine kinase-Mb, glucose, and total protein. Histopathological liver examinations revealed higher total apoptotic and normal cell numbers in the MK than in the M and MKI groups. Apoptotic cell numbers were statistically significant in M and MK groups. Conclusion: Anaesthetic agents may increase programmed apoptosis. The MKI anaesthetics combination was found to cause less cell destruction in general than the other study groups. It was indicated that MKI was the safer anaesthetic combination in rabbits.

1. Amiot M.J., Fleuriet A., Macheix J.J.: Importance and evolution of phenolic compounds in olive during growth and maturation. J Agric Food Chem 1986, 34, 823–826.

2. Ardiaca M., Bonvehi C., Montesinos A.: Point-of-care blood gas and electrolyte analysis in rabbits. Vet Clin North Am Exot Anim Pract 2013, 16, 175–195.

3. Auroy P., Schoeffler P., Maillot C., Haberer J.P., Woda A.: Intrathecal tolerability of midazolam. Histological study. Ann Fr Anesth Reanim 1988, 7, 81–82.

4. Bion J.F.: Infusion analgesia for acute war injuries. A comparison of pentozocaine and ketamine. Anaesthesia 1984, 39, 560–564.

5. Braun S., Gaza N., Werdehausen R., Hermanns H., Bauer I., Durieux M.E., Hollmann M.W., Stevens M.F.: Ketamine induces apoptosis via the mitochondrial pathway in human lymphocytes and neuronal cells. Br J Anaesth 2010, 105, 347–354.

6. But K.A., Durmus M., Toprak H.I., Ozturk E., Demirbilek S., Ersoy M.O.: Hemodynamic, hepatorenal, and postoperative effects of desflurane-fentanyl and midazolam-fentanyl anesthesia in coronary artery bypass surgery. J Cardiothorac Vasc Anesth 2005, 19, 597–602.

7. Cattano D., Young C., Straiko M.M., Olney J.W.: Subanesthetic doses of propofol induce neuroapoptosis in the infant mouse brain. Anesth Analg 2008, 106, 1712–1714.

8. Close B., Banister K., Baumans B., Bernoth E.M., Bromage N., Bunyan J., Erhartd W., Flecknell P., Gregory N., Hackbarth H.: Recommendation for euthanasia of experimental animals: part 1. Laboratory animals 1996, 30, 293–316.

9. Del Alamo A.M., Mandsager R.E., Riebold T.W., Payton M.E.: Evaluation of intravenous administration of alfoxalone, propofol, and ketamine-diazepam for anesthesia in alpacas. Vet Anaesth Analgesia 2015, 42, 72–82.

10. Driessen B.: Assisted recovery in horses awakening from general anesthesia. Int Vet Inform Service, Ithaca NY (

11. Dugdale A.: Veterinary anaesthesia principles to practice. Blackwell Publishing Ltd, UK, 2010.

12. Erdine S., Yücel A., Ozyalçin S., Ozyuvacı E., Talu G.K., Ahiskalı B., Apak H., Savci N.: Neurotoxicity of midazolam in the rabbit. Pain 1999, 80, 419–423.

13. Fredriksson A., Ponten E., Gordh T., Eriksson P.: Neonatal exposure to a combination of N-Methyl-D aspartate and aminobutyric acid type a receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 2007, 107, 427–436.

14. Gianotti G., Valverde A., Sinclair M., Dyson D.H., Gibson T., Johnson R.: Prior determination of baseline minimum alveolar concentration (MAC) of isoflurane does not influence the effect of ketamine on MAC in rabbits. C J Vet Res 2012, 76, 261–267.

15. Greene A.: Veterinary anesthesia and pain management secrets, Hanley & Belfus Inc., Philadelphia, 2002.

16. Grint N.J., Murison P.J.: A comparison of ketamine-midazolam and ketamine-medetomidine combinations for induction of anaesthesia in rabbits. Vet Anaesth Analgesia 2007, 35, 113–121.

17. Grint N.J., Murison P.J.: Peri-operative body temperatures in isoflurane-anaesthetized rabbits following ketamine-midazolam or ketamine-medetomidine. Vet Anaesth Analgesia 2008, 34, 181–189.

18. Hall L.W., Clarke K.W., Trim C.M.: Veterinary Anaesthesia, W.B. Saunders, Philadelphia 2000.

19. Henke J., Astner S., Brill T., Eissner B., Busch R., Erhardt W.: Comparative study of three intramuscular anaesthetic combinations (medetoidine/ketamine, medetomidine /fentanyl/ midazolam and xylazine/ketamine) in rabbits. Vet Anaesth Analgesia 2005, 32, 261–270.

20. Lee H.J., Kim J.W., Yim S.V., Kim M.J., Kim S.A., Kim Y.J., Kim C.J. Chung J.H.: Fluoxetine enhances cell proliferation and prevents apoptosis in dentate gyrus of maternally separated rats. Mol Psychiatry 2001, 610, 725–728.

21. Loftis G.K., Collins S., McDowell M.: Anesthesia-induced neuronal apoptosis during synaptogenesis: A review of the literature. Am J Nurse Anesth 2012, 80, 291–298.

22. Massoco C., Palermo-Neto J.: Effects of midazolam on equine innate immune response: a flow cytometric study. Vet Immunol Immunopathol 2003, 95, 11–19.

23. Orszulak-Michalak D., Owczarek J., Wiktorowska-Owczarek A.K.: Influence of midazolam pharmocokinetics of verapamil in rabbits. Pol J Pharmacol 2002, 54, 501–506.

24. Ozkan C., Kaya A., Akgül Y.: Normal values of hematological and some biochemical parameters in serum and urine of New Zealand white rabbits. World Rabbit Sci 2012, 20, 253–259.

25. Schroeder A.C., Smith L.J.: Respiratory rates and arterial blood-gas tensions in healthy rabbits given buprenorphine, butorphanol, midazolam, or their combinations. J Am Assoc Lab Anim Sci, 2011, 50, 205–211.

26. Stevens M.F., Werdehausen R., Gaza N., Hermanns H., Kremer D., Bauer I., Küry P., Hollmann M.W., Braun S.: Midazolam activates the intrinsic pathway of apoptosis independent of benzodiazepine and death receptor signaling. Reg Anesth Pain Med 2011, 36, 343–349.

27. Wells S.M., Sleeper M.: Cardiac troponins. J Vet Emerg Critical Care, 2008, 18, 235–245.

28. Yamashita K., Tsubakishita S., Futaoka S., Ueda I., Hamaguci H., Seno T., Katoh S., Uzimasawa Y., Muir W.W.: Cardiovascular effects of medetomidine, detomidine and xylazine in horses. J Vet Med Sci 2000, 62, 1025–1032.

Journal of Veterinary Research

formerly Bulletin of the Veterinary Institute in Pulawy

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CiteScore 2018: 0.68

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