A Comparative evaluation of Intrnasal Dexmedetomidine, Midazolam and Ketamine for their sedative and analgesic properties: A Triple Blind Randomized Study

To evaluate and compare the efficacy and safety of Intranasal (IN) Dexmedetomidine, Midazolam and Ketamine in producing moderate sedation among uncooperative pediatric dental patients. Study Design: This randomized triple blind comparative study comprises of eighty four ASA grade I children of both sexes aged 4-14 years, who were uncooperative and could not be managed by conventional behavior management techniques. All the children were randomized to receive one of the four drug groups Dexmedetomidine 1µg/ kg (D1), 1.5µg/kg (D2), Midazolam 0.2mg/kg (M1) and Ketamine 5mg/kg (K1) through IN route. These drug groups were assessed for efficacy and safety by gauging overall success rate and by monitoring vital signs, respectively. Results: The onset of sedation was significantly rapid with M1 and K1 as compared to D1 and D2 (p=<0.001). The overall success rate was highest in D2 (85.7%) followed by D1 (81%), K1 (66.7%) and M1 (61.9%), however, the difference among them was not statistically significant (p=>0.05). Even though all the vital signs were within physiological limits, there was significant reduction in pulse rate (PR) (p=<0.001) and systolic blood pressure (SBP) (p=<0.05) among D1 and D2 as compared to M1 and K1. D1, D2 and K1 produced greater intra- and post-operative analgesia as compared to M1. There were no significant adverse effects with any group. Conclusion: Dexmedetomidine, Midazolam and Ketamine, all the three drugs evaluated in the present study can be used safely and effectively through IN route in uncooperative pediatric dental patients for producing moderate sedation.

Intranasal, Dexmedetomidine, Midazolam, Ketamine, sedation, children.

1. Greenbaum PE, Melamed BG: Pretreatment modeling: A technique forreducing children’s fear in the dental operatory. Dent Clin North Am; 32:693–704. 1988.

2. Wolfe T. R., Bernstone T. Intranasal drug delivery: an alternative to intravenous administration in selected emergency cases. J Emerg Nurs; 30: 141–7. 2004.

3. Bahetwar SK, Pandey RK, Saksena AK, Chandra G. A comparative evaluation of intranasal midazolam, ketamine and their combination for sedation of young uncooperative pediatric dental patients: a triple blind randomized crossover trial. J Clin Pediatr Dent; 35(4):415-20. 2011.

4. Pandey RK, Bahetwar SK, Saksena AK, Chandra G. A comparative evaluation of drops versus atomized administration of intranasal ketamine for the procedural sedation of young uncooperative pediatric dental patients: a prospective crossover trial. J Clin Pediatr Dent; 36(1):79-84. 2011.

5. Yuen VM, Irwin MG, Hui TW, Yuen MK, Lee LH. “A double blind crossover assessment of the sedative and analgesic effects of intranasal dexmeditomidine” Anesth Analg ; 105 (2): 374-80. 2007

6. Padmanabhan M.Y., Pande R.K., Saksena A.K., Chandra G. A comparative evaluation of agents producing Analgo-sedation in pediatric dental patients. Journal of Clinical Pediatric Dentistry; 34(2): 183-189. 2009.

7. Singh N. Pandey RK, Saksena AK, Jaiswal JN.., A comparative evaluation of oral midazolam with other sedative as premedication in pediatric dentistry. J Clin Pediatr Dent; 26(2):161-164.2002.

8. Koirala B., Pandey R.K., Saksena A.K., Kumar R., Sharma S. A comparative evaluation of newer sedatives in conscious sedation. Journal of Clinical Pediatric Dentistry; 30:273-276. 2006.

9. Xu YY, Song XR, Lin ZM, Zhang GQ, Zhang N. [Effect of dexmedetomidine on postoperative analgesia and sedation in pediatric patients undergoing cleft lip and palate repair]. Zhonghua Yi Xue Za Zhi. Apr 3;92(13):878-81. 2012.

10. American Academy of Pediatrics; American Academy of Pediatric Dentistry, Coté CJ. Wilson S. Work Group on Sedation. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: an update. Paediatr Anaesth; 18(1):9-10. 2008.

11. Citerio G, Franzosi MG, Latini R, Masson S, Barlera S, Guzzetti S, Pesenti A. Anaesthesiological strategies in elective craniotomy: randomized, equivalence, open trial--the NeuroMorfeo trial. Trials. Apr 6;10:19. doi: 10.1186/1745-6215-10-19. 2009.

12. Al-Rakaf H., Bello L.L., Turkustani A, Adenubi JO. Intranasal midazolam in conscious sedation of young paediatric dental patients. Int J Paediatr Dent; 11(1): 33-40. 2001.

13. Lee-Kim SJ., Fadavi S., Punwani I., Koerber A. Nasal Versus oral midazolam sedation for pediatric dental patients. J dent child (chic); 71(2):135- 138. 2004

14. Gilchrist F., Cairns A. M., Leitch JA. The use of intranasal midazolam in the treatment of paediatric dental patients. Anaesthesia; 62(12): 1262-5. 2007.

15. Yuen VM, Hui TW, Irwin MG, Yao TJ, Wong GL, Yuen MK. Optimal timing for the administration of intranasal dexmedetomidine for premedication in children. Anaesthesia; 65(9):922-9. 2010 .

16. Iirola T, Vilo S, Manner T, Aantaa R, Lahtinem M, Scheinin M, Olkkola KT. “Bioavailability of dexmeditomidine after intrnasal administration”. Eur J Clin Pharmcol Feb 12. 2011.

17. Kupietzy A., and Houpt M.I. Midazolam: A review of it’s uses for conscious sedation of children. Pediatric Dent; 15:237-241. 1993.

18. Parnis S.J., Foate J.A., Van der Walt J.H., Short T., Crowe C.E. Oral midazolam is an effective premedication for children having day stay anesthesia. Anaesth Intensive Care; 20:9-14. 1992.

19. Hackel A., Lin Y.C. Moynihan R.J. A comparison of oral midazolam, oral ketamine and oral midazolam combined with ketamine as preanesthetic medication for pediatric outpatients. Anesthesiology; 77:1177. 1993.

20. Jung HS, Joo JD, Jeon YS, Lee JA, Kim DW, In JH, Rhee HY, Choi JW. Comparison of an intraoperative infusion of dexmedetomidine or remifentanil on perioperative haemodynamics, hypnosis and sedation, and postoperative pain control. J Int Med Res; 39(5):1890-9. 2011.

21. Koroglu A., Demirbilek S., Teksan H., Sagar O., But AK and Ersoy MO. “Sedative, haemodunamics and respiratory effects of dexmeditomidine in children undergoing MRI examination; preliminary results.” British Journal of Anesthesia; 94 (6): 821-4. 2005.

22. Akin A, Bayram A, Esmaoglu A, Tosun Z, Aksu R, Altuntas R, Boyaci A. Dexmedetomidine vs. midazolam for premedication of pediatric patients undergoing anesthesia. Paediatr Anaesth; 22(9):871-6. 2012.

23. Cheung CW, Ng KF, Liu J, Yuen MY, Ho MH, Irwin MG. Analgesic and sedative effects of intranasal dexmedetomidine in third molar surgery under local anaesthesia. Br J Anaesth.; 107(3):430-7. 2011.

24. Gobeaux D., Sardnal F., Cohn H, Lequoy O. Intranasal midazolam in pediatric ophthalmology. Can Anesthesiol; 39(1):34-6. 1991.

25. Gharde P., Chauhan S., Kiran U. Evaluation of Efficacy of intranasal Midazolam, Ketamine and their Mixture as premedication and its relation with bispectral index in children with tetralogy of fallot undergoing intracardiac repair. Ann Card Anaesth; 9:25-30. 2006.

26. Yealy D.M., Ellis J.S., Hobbs GD, Moscati RM.. Intranasal midazolam as a sedative for children during laceration repair. Am J Emerg Med; 10(6):584-7. 1992.

27. Reid C, Hatton R, Middleton P. Case report: prehospital use of intranasal ketamine for paediatric burn injury. Emerg Med J. 2011 Apr; 28(4):328-9. Epub 2011 Feb 3.

28. Roelofse J.A., Shipton E.A., De La Harpe C.J., Blignaut R.J. Intranasal sufentanil / Midazolam Versus Ketamine/Midazolam for analgesia/sedation in the pediatric population prior to undergoing multiple dental extractions under general anesthesia: A prospective, double-blind, randomized comparison. Anesth Prog; 51:114-121. 2004.

29. Kulbe J. The use of ketmine nasal spray for short term analgesia. Home Health Nurse; 16(6):367-70. 1998.

30. Jaakola ML, Salonen M, Lehtinen R, Scheinin H. The analgesic action of dexmedetomidine-a novel alpha 2-adrenoceptor agonist—in healthy volunteers. Pain; 46:281–285. 1991.

31. Venn RM, Bradshaw CJ, Spencer R, Brealey D, Caudwell E, Naughton C, Vedio A, Singer M, Feneck R, Treacher D, Willatts SM, Grounds RM. Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit. Anaesthesia; 54:1136–1142. 1999.

32. Aho M, Erkola O, Kallio A, Scheinin H, Korttila K. Comparison of dexmedetomidine and midazolam sedation and antagonism of dexmedetomidine with atipamezole. J Clin Anesth.; 5:194-203. 1993.

33. Yoshitomi T, Kohjitani A, Maeda S, Higuchi H, Shimada M, Miyawaki T. Dexmedetomidine enhances the local anesthetic action of lidocaine via an alpha-2A adrenoceptor. Anesth Analg; 107(1):96-101. 2008.

34. Wilton N.C., Leigh J., Rosen DR., Pandit UA. Preanesthetic sedation of preschool children using intranasal midazolam. Anesthesiology; 69:972- 975. 1988.

35. Fukuta O., Braham R.L., Yanase H, Kurosu K. The sedative effect of intra - nasal midazolam administration in the dental treatment of patients with mental disabilities. Part 2: optimal concentration of intranasal midazolam. J Clin Pediatr Dent; 18(4):259-65. 1994.

36. Fuks A., Kaufman E., Ram D., Hovav S. Shapira J. Assessment of two doses of intranasal midazolam for sedation of young pediatric dental patient. Pediatr Dent; 16;301. 1994.

37. Karl H.W., Keifer A.T., Rosenberger JL, Larach MG, Ruffle JM. Comparison of the safety and efficacy of intranasal midazolam or sufen - tanil for preinduction of anaesthesia in pediatric patients. Anesthesiology; 76(2):209-15. 1992.

38. Theroux M.C., West D.W., Corddry DH, Hyde PM, Bachrach SJ, Cronan KM, Kettrick RG.. Efficacy of intranasal modazolam in facilitating suturing of lacerations in preschool children in the emergency department. Pediatrics; 91(3):624-7. 1993.

39. Hannallah R.S. and Patel R.I. Low dose intramuscular ketamine for anes - thesia preinduction in young children undergoing brief outpatient proce - dures. Anesthesiology; 70:598-600. 1989.

40. Gutstein H.B., Johnson K.l., Heard M.B., Gregory G.A. Oral ketamine preanesthetic medication in children. Anesthesiology; 76:28-33. 1992.

41. Hollister G.R. and Burn JNB. Side effects of ketamine in pediatric anes - thesia. Anesth Analg; 53:264-7. 1974.

42. Debnath S and Pande Y. A comparative study of oral premedication in chil - dren with ketamine and midazolam. Indian J Anaesth; 47(1): 45-47. 2003.

43. Damle S.G., Gandhi M., Laheri V. Comparision of oral ketamine and and oral midazolam as a sedative agents in pediatric dentistry. J Indian Soc Padod Prev Dent; 26(3):97-101. 2008.

44. Talon MD, Woodson LC, Sherwood ER, Aarsland A, McRae L, Benham T. “Intranasal dexmeditomidine premedication is comparable with midazolam in burn children undergoing reconstructive surgery.” J Burn Care Res; 30 (4):599-605. 2009.

45. Yuen VM, Irwin MG, Hui TW, Yuen MK. “A comparison of intranasal dexmeditomidine and oral midazolam for premedication in pediatric anesthesia: A double blinded randomized controlled trial.” Anesth Analg; 106:1715-21. 2008.

46. Ghali AM, Mahfouz AK, Al-Bahrani M. Preanesthetic medication in chil - dren: A comparison of intranasal dexmedetomidine versus oral midazolam. Saudi J Anaesth; 5(4):387-91. 2011.