This Article Abstract Résumé de cet Article Full Text (PDF) Submit a scholarly reply Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cox, R. G. Articles by Crowe, M.-J. Search for Related Content PubMed PubMed Citation Articles by Cox, R. G. Articles by Crowe, M.-J.

Evidence-based clinical update: Does premedication with oral midazolam lead to improved behavioural outcomes in children?

[Mise à jour basée sur des données probantes : Améliore-t-on le comportement des enfants par une prémédication au midazolam par la bouche ?]

Robin G. Cox, MB BS MRCP(UK) FRCA FRCPC^*, Ulyana Nemish, BSc MSc^*, Alastair Ewen, MB ChB FRCA FRCPC^* and Marie-Josée Crowe, MD FRCPC

^* From the Division of Pediatric Anesthesia, Alberta Children’s Hospital, University of Calgary, Calgary, Alberta; and the
Department of Anesthesiology, University of Montréal, Montréal, Québec, Canada.

Address correspondence to: Dr. Robin G. Cox, Division of Pediatric Anesthesia, Alberta Children’s Hospital, 2888 Shaganappi Trail NW, Calgary, Alberta T3B 6A8, Canada. Phone: 403-955-7260; Fax: 403-955-7606; E-mail: robin.cox{at}calgaryhealthregion.ca

	Abstract

TOP Abstract Introduction Clinical question Methods Review of current best... Limitations of this EBCU Conclusions Recommendations References

 
Purpose: The purpose of this evidence-based clinical update was to identify the best evidence to determine if behavioural outcomes are improved in children after oral midazolam premedication.

Methods: A literature search was conducted using both PubMed and OVID programs, utilizing the terms "midazolam", and either "premedication" or "preoperative treatment". Search limits that were employed included randomized controlled trials (RCTs), English language, human studies, children aged 0–18 yr, and publication dates 1990 – present (January 2006). A review of the 171 abstracts obtained was undertaken and, of these, 30 papers were identified that concerned oral midazolam in children prior to general anesthesia, and that involved a RCT with a placebo or control arm. These studies were assigned levels of evidence, and grades of recommendation were made according to Centre for Evidence-Based Medicine criteria.

Results: Oral midazolam premedication in children was found to reduce the anxiety associated with separation from parents/guardians, and with induction of anesthesia. Recovery times are not significantly delayed. There is no consistent evidence to suggest a reduction in the phenomenon of emergence agitation. Evidence suggesting an improvement in behavioural outcomes at home is also inconsistent.

Conclusion: Premedication with midazolam 0.5 mg·kg^–1 po administered 20–30 min preoperatively, is effective in reducing both separation and induction anxiety in children (grade A recommendation), with minimal effect on recovery times. However improved postoperative behavioural outcomes in the postanesthesia care unit, or at home cannot be predicted on a consistent basis.

	Introduction

TOP Abstract Introduction Clinical question Methods Review of current best... Limitations of this EBCU Conclusions Recommendations References

 
OVER the years, various types of premedication have been administered to children prior to the induction of anesthesia. With the advent of volatile agents that lack pungency and airway irritability, the need for a routine antisialogogue premedicant has waned. The main goal of premedication currently is to allay anxiety during the various phases of the perioperative period. Midazolam, a relatively short-acting benzodiazepine, has found favour in this regard, and is most commonly given by the oral route in children. A considerable body of evidence about this form of premedication has now accumulated, and this evidence-based clinical update (EBCU) will evaluate the benefit of this intervention, particularly with respect to behavioural outcomes.

	Clinical question

TOP Abstract Introduction Clinical question Methods Review of current best... Limitations of this EBCU Conclusions Recommendations References

 
The clinical question for analysis was as follows: Does premedication with oral midazolam lead to improved behavioural outcomes in children? Specifically, this update seeks to determine whether clinical outcomes are improved at separation from parents/guardians, at induction, in the postanesthesia care unit (PACU), and once the child has returned home.

	Methods

TOP Abstract Introduction Clinical question Methods Review of current best... Limitations of this EBCU Conclusions Recommendations References

 
A structured literature search was conducted in accordance with the EBCU format of the Journal (posted at: www.cja-jca.org). Search methodology entailed the use of both PubMed and OVID programs, utilizing the terms "midazolam", and either "premedication" or "preoperative treatment". Search limits that were employed included randomized controlled trials (RCTs), English language, human studies, children aged 0–18 yr, and publication dates 1990 – present (January 2006). We had previously determined that there were no systematic reviews of RCTs on this topic in the literature using these search terms. This methodology produced almost identical results using the two search platforms. One hundred and seventy-one abstracts were obtained, which were then reviewed by two of the authors (R.G.C. and U.N.). If it was clear that the study did not address premedication prior to general anesthesia, did not contain a placebo or control group, did not entail midazolam being given by the oral route, or was not a RCT, then that study was withdrawn from the data base. If there was any doubt as to the nature of the study, the full version of the paper was obtained.

Following this initial screening, 30 papers remained for further analysis.^1–3 A hand search of the bibliographies of these 30 papers did not identify any further key studies. Complete versions of papers were then reviewed in detail by all four authors. An Excel spread-sheet was constructed, to collect key data and facilitate the grading of the studies. Three of the authors (R.G.C., A.E., M.J.C.), all experienced pediatric anesthesiologists, graded the papers as being either good quality (level 1b) or poor quality (level 2b) RCTs, and assigned each study a level of evidence according to the criteria of the Oxford Centre for Evidence-Based Medicine.³¹ With three independent anesthesiologists evaluating, a simple majority of opinion determined the grading. The criteria used to determine the quality of individual RCTs included, but were not limited to, the confidence intervals, power analysis/sample size calculation, standardization of anesthesia and surgery, validation of the anxiety scoring system and standardization of other factors, such as parental presence at induction. Detailed review of the 30 papers allowed the authors to answer in whole or in part the clinical questions posed. Grades of recommendation were assigned to the evidence, as defined by the Centre for Evidence-Based Medicine (Appendix), together with levels of evidence criteria for individual studies.

	Review of current best evidence

TOP Abstract Introduction Clinical question Methods Review of current best... Limitations of this EBCU Conclusions Recommendations References

Table I provides a summary of the key methodological components of the studies reviewed. Of the 30 papers, 14 included a detailed sample size calculation, and only 11 included details of the randomization methodology. Twenty studies were double-blinded, nine were single-blinded, and one was not blinded. Anesthesia induction drugs were standardized in 24 studies; the remaining six were either unspecified or allowed for variation. Techniques for anesthesia maintenance were standardized in 17 studies; the remaining 13 had an unspecified anesthetic technique, or allowed for variation. Surgical procedures were multiple in nature in 20 studies; in ten studies the procedures were specified (e.g., only adenoidectomy, or only inguinal hernia repair). All studies provided details of the statistical analysis, the most frequent instruments being ANOVA, ², and t test, depending on the variables being analyzed. In 20 studies the design specified whether parents were present or not for induction; in the remaining ten, this was unspecified or variable. The majority of papers used a simple three- or four-point scale to grade anxiety, without evidence as to scale validation, rather than employing a more robust, validated scoring system such as the Modified Yale Preoperative Anxiety Score (mYPAS). The mYPAS is the current gold standard for evaluating anxiety at induction of anesthesia in children.

Following detailed evaluation of the scientific methodology, the authors determined that 14 of the studies were high quality RCTs. Table II summarizes the main outcomes of all 30 papers.

Induction anxiety
Induction anxiety was evaluated in 24 studies. Of these, 17 showed a reduction in induction anxiety with midazolam, while seven others did not show a statistically significant benefit or were uncertain. When considering the 11 high quality RCTs that examined this question, all showed a benefit.^{5,9,10,17,18,23,26–30} Accordingly, very consistent level 1 evidence indicates that induction anxiety is ameliorated by oral midazolam. Again, the less well designed studies were more variable in their results.

Emergence agitation (EA)
Eight studies addressed EA, or some equivalent phenomenon, such as "postoperative confusion". Of these eight studies, only two showed a reduction in EA with midazolam premedication,^21,25 one of which demonstrated a benefit only with sevoflurane anesthesia. ²¹ One study provided evidence that midazolam increases the incidence of EA.²² Five of these studies^{17,18,20,22,29} were of good quality, and none showed a benefit. Accordingly, there is no consistent evidence to suggest that midazolam premedication decreases the incidence of EA.

Recovery times
Eighteen studies evaluated emergence or awakening times. Of these, seven showed a delay in emergence, however the delay was usually quite brief. Of the eight high quality studies, only two demonstrated a delay in emergence.^20,22

Discharge from either PACU or the institution was measured in 21 studies. Of these, just two showed a delay from PACU^3,21 and four showed a delay from the institution.^8,11,15,20 Of the nine high quality studies which evaluated this outcome, only one²⁰ showed a delay in discharge. The studies therefore provide little evidence to suggest a significant delay in recovery in midazolam-premedicated children.

Longer term outcomes
Six studies evaluated behavioural outcomes for a period of a week or more following anesthesia. Parents or guardians completed questionnaires that evaluated such behavioural dysfunction as nightmares, temper tantrums, and bed wetting. Of these six studies, three showed a reduction in negative behaviours during the first two postoperative weeks.^6,8,19 One study demonstrated worse behavioural outcomes at one week in the midazolam-treated group.¹⁶ Three of these six studies were rated to be of high quality, with only one showing a benefit.¹⁹ This well-conducted study showed a benefit for the first postoperative week only.¹⁹ Accordingly, the data addressing the issue of behavioural outcomes in the first few weeks postoperatively is inconsistent.

Dose and timing
Five studies^1,3,5,18,29 evaluated different doses of midazolam, ranging from 0.1 mg·kg^–1 – 1 mg·kg^–1. The consensus of opinion from these studies is that a midazolam dose of 0.5 mg·kg^–1 po is required to produce consistent preoperative anxiolysis in children < 12 yr. Increasing the dose to 0.75 mg·kg^–1 or even 1 mg·kg^–1 does not increase the anxiolytic benefit, and may cause ataxia preoperatively,⁵ or prolonged sedation postoperatively. Other published studies examine different doses of oral midazolam, but unless a placebo or control group was included, these studies were not included in this review.

The studies varied considerably with respect to the timing of midazolam administration, ranging from ten minutes to two hours preoperatively. Some studies allowed for a considerable range in the timing. The most frequently used interval prior to separation or induction was 20–30 min. As there were often other variables at play (e.g., dosing, induction technique), it was not possible to determine from these papers what the optimal time for administration should be, although studies that have specifically examined this question suggest that the interval can be quite short (10–30 min preoperatively).

Patient selection
One study³⁰ addressed the issue of patient selection prior to the use of oral midazolam. This study demonstrated that children with high baseline levels of anxiety benefit the most from midazolam premedication, however high levels of trait impulsivity may contraindicate the use of midazolam as a preoperative medication. Easy, reliable ways of determining these psychological types need to be developed.

	Limitations of this EBCU

TOP Abstract Introduction Clinical question Methods Review of current best... Limitations of this EBCU Conclusions Recommendations References

 
The clinical question under consideration was addressed using the EBCU format of the Journal. There are other strategies that may be applied in order to answer a clinical question, such as meta-analysis. Meta-analyses have the advantage of being able to increase the statistical power of multiple studies, however they are limited by the quality of the science of the individual studies. In this particular situation, there was much variability in study design, and poor control of numerous confounding factors in many of the studies. We felt therefore that the EBCU format would be particularly suitable to provide a structured evidence-based expert opinion on the topic.

In determining whether a RCT was of good or poor quality, the three reviewers assessed numerous aspects of study design including, but not limited to, the confidence intervals, power analysis/sample size calculation, standardization of anesthesia and surgery, validation of the anxiety scoring system and standardization of other factors, such as parental presence at induction. There are published assessment tools, such as the Jadad score,³² that address the quality of RCTs, however these are generally limited to certain aspects of study design. For example, the Jadad score only assesses studies on the basis of randomization, blinding and withdrawals/dropouts. Furthermore, the Centre for Evidence-Based Medicine does not have absolute criteria for grading the quality of RCTs. We elected therefore to use a broader, albeit less structured, evaluation of quality.

	Conclusions

TOP Abstract Introduction Clinical question Methods Review of current best... Limitations of this EBCU Conclusions Recommendations References

 
When considering the cumulative data, it must be remembered that several studies did not include a sample size estimation, standardized methodology, or a validated anxiety scoring system. With some of the sample sizes being as small as 12, the possibility of type 2 statistical errors cannot be excluded. Despite these limitations, several conclusions can be drawn.

Overall, there is evidence that premedication with oral midazolam reduces anxiety in children, both at separation from parents or guardians, and particularly at induction of anesthesia. There is no consistent evidence, however, to indicate that the incidence of emergence agitation is significantly moderated. Awakening times appear to be delayed minimally, and there is inconsistent evidence that discharge times are prolonged by the use of midazolam premedication. There is conflicting evidence suggesting a benefit in terms of behavioural changes for the first few weeks postoperatively.

Given the modest size of all the studies evaluated, the safety of oral midazolam premedication cannot be predicted with certainty. Hhowever, in healthy children at least, there are no reports of serious side-effects in the literature reviewed. More research needs to be done to further determine which children would benefit most from this intervention.

	Recommendations

TOP Abstract Introduction Clinical question Methods Review of current best... Limitations of this EBCU Conclusions Recommendations References

 
Premedication with midazolam 0.5 mg·kg^–1 po administered 20–30 min preoperatively, is effective in reducing both separation and induction anxiety in children (grade A recommendation), with minimal effect on recovery times. Oral midazolam premedication may be considered either routinely, or in children who display high levels of baseline anxiety preoperatively.

There is insufficient evidence at this time to recommend preoperative midazolam as a means of improving behavioural outcomes either in the PACU or for the first few weeks postoperatively. Furthermore, the efficacy and safety of oral midazolam premedication in medically compromised children has not been addressed.

	Footnotes

 
Accepted for publication August 31, 2006. Revision accepted September 18, 2006.

	References

TOP Abstract Introduction Clinical question Methods Review of current best... Limitations of this EBCU Conclusions Recommendations References

 
1 Feld LH, Negus JB, White PF. Oral midazolam preanesthetic medication in pediatric outpatients. Anesthesiology 1990; 73: 831–4.[Medline]

2 Payne KA, Coetzee AR, Mattheyse FJ, Dawes T. Oral midazolam in paediatric premedication. S Afr Med J 1991; 79: 372–5.[Medline]

3 Parnis SJ, Foate JA, van der Walt JH, Short T, Crowe CE. Oral midazolam is an effective premedication for children having day-stay anaesthesia. Anaesth Intensive Care 1992; 20: 9–14.[Medline]

4 Weldon BC, Watcha MF, White PF. Oral midazolam in children: effect of time and adjunctive therapy. Anesth Analg 1992; 75: 51–5.[Abstract/Free Full Text]

5 McMillan CO, Spar-Schopfer IA, Sikich N, Hartley E, Lerman J. Premedication of children with oral midazolam. Can J Anaesth 1992; 39: 545–50.[Abstract/Free Full Text]

6 Payne KA, Coetzee AR, Mattheyse FJ, Heydenrych JJ. Behavioural changes in children following minor surgery - is premedication beneficial? Acta Anaesthesiol Belg 1992: 43: 173–9.[Medline]

7 Vetter TR. A comparison of midazolam, diazepam, and placebo as oral anesthetic premedicants in younger children. J Clin Anesth 1993; 5: 58–61.[Medline]

8 McCluskey A, Meakin GH. Oral administration of midazolam as a premedicant for paediatric day-case anaesthesia. Anaesthesia 1994; 49: 782–5.[Medline]

9 Lyons B, Cregg N, Conway F, Casey W, Doherty P, Moore KP. Premedication for ambulatory surgery in preschool children: a comparison of oral midazolam and rectal thiopentone. Can J Anaesth 1995; 42: 473–8.[Abstract/Free Full Text]

10 Gillerman RG, Hinkle AJ, Green HM, Cornell L, Dodge CP. Parental presence plus oral midazolam decreases frequency of 5% halothane inductions in children. J Clin Anesth 1996; 8: 480–5.[Medline]

11 Cray SH, Dixon JL, Heard CM, Selsby DS. Oral midazolam premedication for paediatric day case patients. Paediatr Anaesth 1996; 6: 265–70.[Medline]

12 Ong BC, Ng AS, Chew SL. Oral premedications in paediatric day surgery. Singapore Med J 1996; 37: 139–42.[Medline]

13 Mitchell V, Grange C, Black A, Train J. A comparison of midazolam with trimeprazine as an oral premedicant for children. Anaesthesia 1997; 52: 416–21.[Medline]

14 Riva J, Lejbusiewicz G, Papa M, et al. Oral premedication with midazolam in paediatric anaesthesia. Effects on sedation and gastric contents. Paediatr Anaesth 1997; 7: 191–6.[Medline]

15 Bevan JC, Veall GR, Macnab AJ, Ries CR, Marsland C. Midazolam premedication delays recovery after propofol without modifying involuntary movements. Anesth Analg 1997; 85: 50–4.[Abstract]

16 McGraw T, Kendrick A. Oral midazolam premedication and postoperative behaviour in children. Paediatr Anaesth 1998; 8: 117–21.[Medline]

17 Kain ZN, Mayes LC, Wang SM, Caramico LA, Hofstadter MB. Parental presence during induction of anesthesia versus sedative premedication: which intervention is more effective? Anesthesiology 1998; 89: 1147–56.[Medline]

18 Khalil S, Philbrook L, Rabb M, et al. Sublingual midazolam premedication in children: a dose response study. Paediatr Anaesth 1998; 8: 461–5.[Medline]

19 Kain ZN, Mayes LC, Wang SM, Hofstadter MB. Postoperative behavioral outcomes in children: effects of sedative premedication. Anesthesiology 1999; 90: 758–65.[Medline]

20 Viitanen H, Annila P, Viitanen M, Tarkkila P. Premedication with midazolam delays recovery after ambulatory sevoflurane anesthesia in children. Anesth Analg 1999; 89: 75–9.[Abstract/Free Full Text]

21 Lapin SL, Auden SM, Goldsmith LJ, Reynolds AM. Effects of sevoflurane anaesthesia on recovery in children: a comparison with halothane. Paediatr Anaesth 1999; 9: 299–304.[Medline]

22 Viitanen H, Annila P, Viitanen M, Yli-Hankala A. Midazolam premedication delays recovery from propofol-induced sevoflurane anesthesia in children 1–3 yr. Can J Anesth 1999; 46: 766–71.[Abstract/Free Full Text]

23 Kain ZN, Hofstadter MB, Mayes LC, et al. Midazolam: effects on amnesia and anxiety in children. Anesthesiology 2000; 93: 676–84.[Medline]

24 Pandit UA, Collier PJ, Malviya S, Voepel-Lewis T, Wagner D, Siewert MJ. Oral transmucosal midazolam premedication for preschool children. Can J Anesth 2001; 48: 191–5.[Abstract/Free Full Text]

25 Ko YP, Huang CJ, Hung YC, et al. Premedication with low-dose oral midazolam reduces the incidence and severity of emergence agitation in pediatric patients following sevoflurane anesthesia. Acta Anaesthesiol Sin 2001; 39: 169–177.[Medline]

26 Brosius KK, Bannister CF. Oral midazolam premedication in preadolescents and adolescents. Anesth Analg 2002; 94: 31–6.[Abstract/Free Full Text]

27 Kain ZN, Caldwell-Andrews AA, Mayes LC, Wang SM, Krivutza DM, LoDolce ME. Parental presence during induction of anesthesia: physiological effects on parents. Anesthesiology 2003; 98: 58–64.[Medline]

28 Kain ZN, Caldwell-Andrews AA, Krivutza DM, et al. Interactive music therapy as a treatment for preoperative anxiety in children: a randomized controlled trial. Anesth Analg 2004; 98: 1260–6.[Abstract/Free Full Text]

29 Samarkandi A, Naguib M, Riad W, et al. Melatonin vs. midazolam premedication in children; a double-blind, placebo-controlled study. Eur J Anaesthesiol 2005; 22: 189–96.[Medline]

30 Finley GA, Stewart SH, Buffett-Jerrott S, Wright KD, Millington D. High levels of impulsivity may contraindicate midazolam premedication in children. Can J Anesth 2006; 53: 73–8.[Abstract/Free Full Text]

31 Centre for Evidenced-Based Medicine. Oxford-Centre for Evidence Based Medicine. Available from URL; www.cebm.net

32 Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996; 17: 1–12.[Medline]

This article has been cited by other articles:

				V. M. Yuen, T. W. Hui, M. G. Irwin, and M. K. Yuen A Comparison of Intranasal Dexmedetomidine and Oral Midazolam for Premedication in Pediatric Anesthesia: A Double-Blinded Randomized Controlled Trial Anesth. Analg., June 1, 2008; 106(6): 1715 - 1721. [Abstract] [Full Text] [PDF]

				R. G. Cox Anesthetic management of pediatric adenotonsillectomy Can J Anesth, December 1, 2007; 54(12): 1021 - 1025. [Full Text] [PDF]

This Article Abstract Résumé de cet Article Full Text (PDF) Submit a scholarly reply Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cox, R. G. Articles by Crowe, M.-J. Search for Related Content PubMed PubMed Citation Articles by Cox, R. G. Articles by Crowe, M.-J.