Efficacy of oral midazolam for minimal and moderate sedation in pediatric patients: A systematic review

Abstract One of the most widely used options for minimal/moderate sedation in pediatric patients is oral midazolam, as it presents an alternative to less well‐accepted routes of administration (eg, intravenous or intranasal) of this well‐known efficacious and well‐tolerated short‐acting benzodiazepine. A systematic review of the literature was conducted in order to identify clinical studies evaluating the effectiveness of oral midazolam for sedation in pediatric patients in the context of premedication before anesthesia or during diagnostic/treatment procedures. The percentage of responders (response rate) after single administration of oral midazolam was evaluated and compared versus placebo in a subset of placebo‐controlled studies. The range of oral midazolam doses providing effective sedation in the different pediatric age subsets was analyzed in order to assess optimum dosing strategies. A total of 25 pediatric clinical studies, utilizing a variety of measures of sedation effectiveness, were selected. These studies included a total of 1472 patients (aged 4 months‐18 years) treated with midazolam (0.25‐1.5 mg/kg) and 138 patients treated with placebo. The response rates [95% confidence interval] with oral midazolam ranged from 36.7% [21.6%, 54.9%] to 97.8% [86.1%, 99.7%], while with placebo response rates ranged from 4.0% [0.6%, 23.5%] to 41.0% [29.4%, 53.6%]. When considering the 4 placebo‐controlled studies, the odds ratios [95% confidence interval] for the comparison of midazolam vs. placebo ranged from 13.4 [5.0, 36.0] to 25.9 [6.7, 100.6]. The analysis of subgroups by context of sedation showed response rates [95% confidence interval] with oral midazolam ranging from 36.7% [21.6%, 54.9%] to 97.0% [94.8%, 98.3%] for anesthetic premedication and from 56.1% [43.1%, 68.4] to 97.8% [86.1%, 99.7%] for medical procedures. The efficacy of midazolam for pediatric minimal/moderate sedation from a dose of 0.25 mg/kg and above was demonstrated. The probability of occurrence of adverse events and over‐sedation increases with increasing doses.


| INTRODUC TI ON
It is estimated that more than 50% of children could benefit from minimal to moderate sedation during perioperative or procedural periods to treat or prevent behavioral stress and anxiety, caused by separation from their families, the presence of an unfamiliar environment, or fear of pain. [1][2][3][4] The objective of minimal/moderate sedation is to enable the accomplishment of a scheduled intervention with a child who is calm, in order to prevent psychological distress prior to or during the intervention, to avoid poor compliance or cancelation, and any potential negative impact on postoperative recovery or other possible longterm psychological consequences. [4][5][6] Midazolam has a very long track record of use for minimal and moderate sedation and remains the most commonly used oral sedative for anxiolysis in children. A recent Cochrane review evaluated midazolam for sedation before procedures and discussed data about the effectiveness of midazolam in adults and pediatric patients (by any route) in comparison with other medications using different outcome measures. 7 Among the drugs used for moderate sedation, oral midazolam offers the advantage of being an efficacious, short-acting benzodiazepine, with anxiolytic, sedative, and hypnotic properties, with a favorable benefit/risk ratio. 8 Since the late 1980s, a number of clinical trials have been published evaluating the efficacy of oral midazolam for sedation in children; hence, a large volume of information relating to oral midazolam as a sedative in pediatric patients is available. There is, however, a broad range of oral doses used in pediatric patients for minimal/ moderate sedation, and the optimum dosing in different contexts of sedation remains unclear.
The major aims of the present review were to summarize and analyze the available literature data related to minimal/moderate sedation with oral midazolam in pediatric patients, both prior to anesthesia and during minor procedures, and to evaluate oral midazolam doses providing effective minimal or moderate sedation in different pediatric age subsets and contexts of sedation.

| Study selection and outcomes
Only randomized studies that assessed the efficacy of midazolam as a sole medication using evaluation scales related to minimal/ moderate sedation, and where the effectiveness of oral midazolam for sedation in terms of number of responders with respect to the number of treated children (generally within 30-45 minutes postadministration, and up to 1 hour) was reported, were considered.
All studies evaluating moderate sedation using discrete sedation scales were selected.

| Classification of literature data and statistical methods
As shown in Figure 1  TA B L E 2 (Continued)

| Evaluation of effectiveness
Sedation was measured using a variety of discrete sedation scales, with a sedation success criterion defined for each study. The scales used in the studies for the evaluation of sedation in the present review were mainly 3-to 5-point scales, and two studies were identified that utilized the Observer's Assessment of Alertness/Sedation (OAA/S) scale. It was, however, not possible to find a group of studies with perfectly consistent and relevant success criteria. Also, it was noted that the sedation levels "drowsy" or "awake but calm" in the 20-point scale). 10 As expected, it was observed that the response rates tended to decrease when the type of success criterion became more restrictive (see Table 2).
The most restrictive criterion used the OAA/S scale, specifically designed to evaluate drug-induced sedation with benzodiazepines.
The OAA/S scale was methodologically validated and evaluated for its reliability with midazolam in healthy adult subjects and has shown a high discriminatory power and a high sensitivity, using its composite score or sum score. 11 Correlation was shown between OAA/S and other commonly used scales. 12 Rating is more subjective with 3-to 5-point scales, and the OAA/S scale is more reliable for measuring sedation in clinical studies; 11 however, only two studies were found using the OAA/S scale for the evaluation of sedation oral midazolam and fulfilling the selection criteria. 10,13 The variability of the rating scales used clearly contributes to the heterogeneity in the response rates observed in the different studies. The observed heterogeneity could be further explained by the context of sedation, and the age of the patients and the dose, but other elements of the design or the methodologies used in the different studies (eg, time of evaluation of sedation) and population characteristics (eg, their ASA status and the presence of heart disease), could also contribute to this heterogeneity.   Figure 2).

| Effectiveness in different contexts of sedation
Although it could be argued that different sedation criteria should be used between premedication and sedation before procedures, the reality of the studies was that differences observed in sedation scales or success criteria were not associated with the context of sedation (there were studies with nonrestrictive and more restrictive success criteria both for medical procedures and for premedication before anesthesia). There was no apparent difference in terms of response rates between both contexts of sedation.
Only six of the studies fulfilled the selection criteria for sedation before procedures, and therefore, limited information could be gathered from studies performed in this indication. The effectiveness of midazolam in children undergoing procedures, such as dental treatment, has already been reported in a previous review. 14
The number of responders with midazolam and with placebo in the individual studies is shown in Figure 3.

| Comparison of midazolam doses
The dose most frequently used in the trials, irrespective of the con- observed. 18 Two out of the six studies that evaluated different doses did not observe a dose-response trend and obtained higher response rates at low doses than at high doses. 16,19 In noncooperative children, midazolam was shown to be efficacious for dental procedures, both when used as premedication before general anesthesia (0.5-1.0 mg/kg) 20,21 and for sedation (0.3-0.5 mg/kg). 19,22

| Effectiveness considering different age groups
The age of the patients included in the different studies is shown in

| Safety
Descriptive and/or quantitative safety information from the selected studies has been summarized in Table 2. The main adverse events observed were paradoxical reactions, nausea and vomiting and respiratory events. According to the available safety data from the studies, higher midazolam doses generally resulted in a higher incidence of adverse events and of cases of over-sedation (particularly 1-1.5 mg/kg doses). It has been shown that doses of midazolam higher than 0.5 mg/kg may be associated with increased levels of adverse events such as loss of balance and head control, dysphoria and blurred vision, hypotension, respiratory depression, dysphoric reactions, and ataxia 9,16,18 and lead to a higher incidence of deep sedation. 18,21,23 Cases of deep sedation with an oral dose of 0.5 mg/kg have also been reported. 24 It was noted that some of the adverse events reported are observed when oral midazolam is used in combination with other drugs (following induction of anesthesia, or after administration of treatments used for local anesthesia, or other medications required for the respective interventions) and can therefore not be attributed to midazolam treatment exclusively.

| Oral midazolam products used
Some of the studies were performed using commercial oral syrups of midazolam (five studies, N = 614), but the majority used liquid extemporaneous preparations made from existing parenteral formulations, generally mixed with syrups or flavorings to improve palatability (21 studies, N = 810). Unfortunately, these extemporaneous preparations suffer from a lack of standardization, particularly with regard to pH, concentration, and ingredients. In one of the studies, 24 the parental form was administered by the oral route without preparation (N = 48). Considering the high solubility and absorption of midazolam, provided there is adequate solubilization of midazolam in the preparation, these different liquid forms cannot be considered to be different in terms of bioavailability, 25 as the limiting factor for midazolam is firstpass metabolism.

| Other comparators
Certain studies used other drugs (ketamine, dexmedetomidine,  Table 2. Among the studies reviewed, some compared oral midazolam 0.5 mg/kg to oral ketamine 5-6 mg/kg and demonstrated that both presented similar efficacy. [26][27][28][29] However, ketamine is characterized by undesirable effects, such as excessive salivation, emesis, vertigo, and hallucinations, 28,29 and midazolam has been reported to afford shorter recovery times than ketamine. 20,26,27 One of the studies indicated that midazolam 0.5 mg/kg and intranasal administration of dexmedetomidine 2 µg/kg were comparable in terms of response rates, although intranasal dexmedetomidine could be more useful when the intervention requires sleep induction. 30 When compared to other alternative noninvasive routes, midazolam (0.5 mg/kg) administered orally produced equivalent response rates as rectal (0.5 mg/kg), intranasal (0.3 mg/kg), and sublingual (0.3 mg/kg) midazolam. Intranasal presented the most rapid onset of action but was less well-tolerated. 31,32 Most of these alternative medications are used off-label in children.

| CON CLUS ION
Oral midazolam is an efficacious medication with an adequate safety profile for use in minimal or moderate sedation in children from