Oral preanesthetic medication in children – comparison between midazolam alone and in combination with ketamine: a systematic review and meta-analysis
Getúlio Rodrigues de Oliveira Filho; Carlos Maestri Castilhos; Jean Philippe Kriegl; Giulia Nonticuri Bianchi
Abstract
Background
Up to 60% of pediatric surgical patients develop high levels of preoperative anxiety. This study compared the effects of oral combinations of midazolam and ketamine with oral midazolam alone for pediatric preanesthetic medication.
Methods
The study protocol was registered in PROSPERO as CRD42020172920. A systematic literature search was conducted using Medline, Cochrane, EMBASE, CENTRAL, and Web of Science for randomized controlled trials comparing oral combinations of midazolam and ketamine with midazolam alone as preanesthetic medication in elective surgical pediatric patients. Meta-analyses included the following outcomes: anxiety and sedation levels, child’s behavior during separation from parents, face mask acceptance, and venipuncture. The quality of evidence was assessed using GRADE criteria.
Results
Twenty studies were included. The following effects (RR (95% CI)) were observed for combinations of ketamine and midazolam relative midazolam alone: anxiolysis (1.2 (0.94–1.52);p = 0.15; I2 = 80%; GRADE = very low); satisfactory sedation (1.2 ( 1.10–1.31); p < 0.001; I2 = 71%; GRADE = very low); behavior during parental separation (1.2 (1.06–1.36); p = 0.003; I2 = 88%; GRADE = very low); facial mask acceptance (1.13 (1.04–1.24); p = 0.007; I2 = 49%; GRADE = very low); behavior during venipuncture (1.32 (1.11–1.57); p = 0.002; I2 = 66%; GRADE = very low).
Conclusions
While similar probabilities of obtaining anxiolysis were found, adequate sedation, calm behavior during child’s separation from parents, low levels of fear during face mask adaptation, and cooperative behavior during peripheral venous cannulation were more likely with midazolam-ketamine combinations.
Keywords
References
1 Z.N. Kain, L.C. Mayes, T.Z. O’Connor, et al. Preoperative anxiety in children. Predictors and outcomes Arch Pediatr Adolesc Med, 150 (1996), pp. 1238-1245
2 Z.N. Kain, L.C. Mayes, A.A. Caldwell-Andrews, et al. Preoperative anxiety, postoperative pain, and behavioral recovery in young children undergoing surgery Pediatrics, 118 (2006), pp. 651-658
3 Z.N. Kain, A.A. Caldwell-Andrews, I. Maranets, et al. Preoperative anxiety and emergence delirium and postoperative maladaptive behaviors Anesth Analg, 99 (2004), pp. 1648-1654
4 A. Manyande, A.M. Cyna, P. Yip, et al. Non-pharmacological interventions for assisting the induction of anaesthesia in children Cochrane Database Syst Rev (2015), Article Cd006447
5 W. Funk, W. Jakob, T. Riedl, et al. Oral preanaesthetic medication for children: double-blind randomized study of a combination of midazolam and ketamine vs midazolam or ketamine alone Br J Anaesth, 84 (2000), pp. 335-340
6 C. Walia, Pankaj, M Prabhu, et al. Oral premedication in children: Comparison of combination of midazolam-ketamine and oral midazolam-A Randomised trial Indian J Clin Anaesth, 5 (2018), pp. 249-254
7 M.A. Manso, C. Guittet, F. Vandenhende, et al. Efficacy of oral midazolam for minimal and moderate sedation in pediatric patients: A systematic review Pediatric Anesthesia, 29 (2019), pp. 1094-1106
8 H.B. Gutstein, K.L. Johnson, M.B. Heard, et al. Oral ketamine preanesthetic medication in children Anesthesiology, 76 (1992), pp. 28-33
9 D. Moher, A. Liberati, J. Tetzlaff, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement PLoS Med, 6 (2009), Article e1000097
10 U.S. National Institute of Health Research. PROSPERO. International prospective register of systematic reviews. https://www.crd.york.ac.uk/prospero/. Accessed 09/23/2019.
11 Engauge Digitizer Software [computer program]. Version 62015.
12 J.A.C. Sterne, J. Savović, M.J. Page, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials Br Med J, 366 (2019), p. l4898
13 S. Duval, R. Tweedie Trim and Fill: A Simple Funnel-Plot–Based Method of Testing and Adjusting for Publication Bias in Meta-Analysis Biometrics, 56 (2000), pp. 455-463
14 T.M. Palmer, A.J. Sutton, J.L. Peters, et al. Contour-enhanced funnel plots for meta-analysis Stata J, 8 (2008), pp. 242-254
15 J.L. Peters, A.J. Sutton, D.R. Jones, et al. Contour-enhanced meta-analysis funnel plots help distinguish publication bias from other causes of asymmetry J Clin Epidemiol, 61 (2008), pp. 991-996
16 R.A. Mustafa, W. Wiercioch, N. Santesso, et al. Decision-Making about Healthcare Related Tests and Diagnostic Strategies: User Testing of GRADE Evidence Tables PLoS One, 10 (2015), Article e0134553
17 R.M. Harbord, R.J. Harris, J.A.C. Sterne Updated Tests for Small-study Effects in Meta-analyses Stata J, 9 (2009), pp. 197-210
18 GRADEpro GDT [computer program], McMaster University, Hamilton (ON) (2015)
19 V. Darlong, D. Shende, M. Singh, et al. Low- versus high-dose combination of midazolam-ketamine for oral premedication in children for ophthalmologic surgeries Singapore Med J, 52 (2011), pp. 512-516
20 V. Darlong, D. Shende, M.S. Subramanyam, et al. Oral ketamine or midazolam or low dose combination for premedication in children Anaesth Intensive Care, 32 (2004), pp. 246-249
21 A. Foroutan, F. Yazdanian, A.A. Panahipour, et al. Oral premedication for pediatric cardiac surgery: a comparison of midazolam, ketamine and midazolam plus ketamine Iran Heart J, 8 (2008), pp. 17-23
22 A.S. Kulikov, V.S. Sorokin, A. Lubnin Oral premedication with midasolam and ketamine in children with neurosurgical diseases Anesteziol Reanimatol (2010), pp. 6-10
23 J. Magar, M.B.K. Kotwani, S. Kotak A double blinded comparative study of oral premedication in children with midazolam alone or in combination with ketamine Int J Contemp Pediatr, 3 (2016), p. 8
24 B. Mithun, B. Anand A comparative study between midazolam, ketamine and combination of both as a premedication in pediatric surgeries MedPulse Int J Anesthesiol, 6 (2018), pp. 27-32
25 R. Ramakrishna, K.J. Hemanth, B.V. Sunil, et al. Oral premedication in children: A randomized study of a combination of oral midazolam, ketamine with atropine vs midazolam and atropine vs ketamine and atropine Indian J Clin Anaesth, 5 (2018), pp. 261-265
26 B. Ghai, R.P. Grandhe, A. Kumar, et al. Comparative evaluation of midazolam and ketamine with midazolam alone as oral premedication Paediatr Anaesth, 15 (2005), pp. 554-559
27 M. Hasani Comparison Of Oral Premedication With Combination Of Midazolam With Ketamine Vs Midazolam Ketamine Alone In Children Children Medical Center (year 2000) Tehran Univ Med J, 60 (2002), pp. 423-428
28 P. Sajedi, O. Aghadavoudi, F. Salimi-Jazi Oral midazolam alone or in combination with ketamine as oral premedication in pediatric ophthalmologic surgeries J Isfahan Med Sch, 31 (2014), pp. 1901-1909
29 M. Astuto, N. Disma, E. Crimi Two doses of oral ketamine, given with midazolam, for premedication in children Minerva Anestesiol, 68 (2002), pp. 593-598
30 N. Sathyan Comparative Evaluation of Two Doses of Ketamine with Midazolam, Ketamine alone and Midazolam alone as Oral Premedication in Children: A Study of 100 cases Madurai Medical College, Madurai (2006)
31 K. Jain, B. Ghai, A.K. Saxena, et al. Efficacy of two oral premedicants: Midazolam or a low-dose combination of midazolam-ketamine for reducing stress during intravenous cannulation in children undergoing CT imaging Paediatr Anaesth, 20 (2010), pp. 330-337
32 A. Kumar, Z.A. Shah, Anuradha, et al. Comparative evaluation of ketamine, midazolam and combination of both as oral premedicants in children J Anaesthesiol Clin Pharmacol, 25 (2009), pp. 449-453
33 S. Majidinejad, K. Taherian, M. Esmailian, et al. Oral midazolam-ketamine versus midazolam alone for procedural sedation of children undergoing computed tomography; a randomized clinical trial Emergency, 3 (2015), pp. 64-69
34 ME Rabie Combination of oral ketamine and midazolam versus midazolam alone as a premedication in children undergoing tonsillectomy AJAIC, 8 (2005), pp. 58-64
35 Y.C. Lin, R.J. Moynihan, A. Hackel A comparison of oral midazolam, oral ketamine, and oral midazolam combined with ketamine as preanesthetic medication for pediatric outpatients Anesthesiology, 79 (1993), p. A1177
36 D.L. Warner, J. Cabaret, D. Velling Ketamine plus midazolam, a most effective paediatric oral premedicant Paediatr Anaesth, 5 (1995), pp. 293-295
37 NM Dave Premedication and Induction of Anaesthesia in paediatric patients Indian J Anaesth, 63 (2019), pp. 713-720
38 J. Marshall, A. Rodarte, J. Blumer, et al. Pediatric pharmacodynamics of midazolam oral syrup. Pediatric Pharmacology Research Unit Network J Clin Pharmacol, 40 (2000), pp. 578-589
39 P. Ryhänen, T. Kangas, S. Rantakylä Premedication for outpatient adenoidectomy: comparison between ketamine and pethidine Laryngoscope, 90 (1980), pp. 494-500
40 R. Cioacă, I. Canavea Oral transmucosal ketamine: an effective premedication in children Paediatr Anaesth, 6 (1996), pp. 361-365
41 T. Horiuchi, M. Kawaguchi, K. Kurehara, et al. Evaluation of relatively low dose of oral transmucosal ketamine premedication in children: a comparison with oral midazolam Paediatr Anaesth, 15 (2005), pp. 643-647
42 N. Poonai, K. Canton, S. Ali, et al. Intranasal ketamine for anesthetic premedication in children: a systematic review Pain Manag, 8 (2018), pp. 495-503
43 N. Weksler, L. Ovadia, G. Muati, et al. Nasal ketamine for paediatric premedication Can J Anaesth, 40 (1993), pp. 119-121
44 P. Marhofer, H. Freitag, A. Höchtl, et al. S(+)-ketamine for rectal premedication in children Anesth Analg, 92 (2001), pp. 62-65
45 X. Wang, Z.J. Zhou, X.F. Zhang, et al. A comparison of two different doses of rectal ketamine added to 0.5 mg x kg(-1) midazolam and 0.02 mg x kg(-1) atropine in infants and young children Anaesth Intensive Care, 38 (2010), pp. 900-904
46 RJ Dinis-Oliveira Metabolism and metabolomics of ketamine: a toxicological approach Forensic Sci Res, 2 (2017), pp. 2-10
47 A. Conway, J. Rolley, J.R. Sutherland Midazolam for sedation before procedures Cochrane Database Syst Rev, 2016 (2016), Article CD009491
48 L. Shi, L. Lin The trim-and-fill method for publication bias: practical guidelines and recommendations based on a large database of meta-analyses Medicine, 98 (2019), Article e15987
49 G.H. Guyatt, A.D. Oxman, S. Sultan, et al. GRADE guidelines: 9. Rating up the quality of evidence J Clin Epidemiol, 64 (2011), pp. 1311-1316
50 J. Andrews, G. Guyatt, A.D. Oxman, et al. GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations J Clin Epidemiol, 66 (2013), pp. 719-725