Midazolam for sedation before procedures in adults and children: a systematic review update
Authors: Conway Aaron , Chang Kristina , Mafeld Sebastian , Sutherland Joanna 
Published: March 2021

Abstract
Background
Midazolam is used for sedation before diagnostic and therapeutic medical procedures by several routes including oral, intravenous, intranasal and intramuscular. This is an update of a Cochrane review published in 2016, which aimed to determine the evidence on the effectiveness of midazolam for sedation when administered before a diagnostic or therapeutic procedure in adults and children.

Methods
We searched CENTRAL, MEDLINE, Embase and two trials registers up to May 2020 together with reference checking to identify additional studies. We imposed no language restrictions. Randomized controlled trials of midazolam in comparison with placebo or other medications used for sedation were included. Two authors independently extracted data and assessed risk of bias for each included study.

Results
Eight new trials were included in this update, which resulted in changed conclusions for the intravenous midazolam versus placebo, oral midazolam versus chloral hydrate and oral midazolam versus placebo comparisons. Effect estimates for all outcomes within the intravenous midazolam versus placebo (7 trials; 633 adults and 32 children) are uncertain due to concerns about imprecision and risk of bias. Midazolam resulted in a higher level of sedation than placebo (mean difference (MD) 1.05; 95% confidence interval (95% CI) 0.69 to 1.41; 1 study; 100 adults). There was no difference in anxiety (RR 0.43, 95% CI 0.09 to 1.99; I2 = 75%; 2 studies; 123 adults). Risk of difficulty performing procedures was lower in the midazolam group (RR 0.5; 95% CI 0.29 to 0.86; I2 = 45%; 3 studies; 191 adults and 32 children). There was no difference in discomfort (RR 0.51; 95% CI 0.25 to 1.04; I2 = 0%; 2 studies; 190 adults). Five trials with 336 children were included in the oral midazolam versus chloral hydrate comparison. Midazolam was less likely to result in moderate sedation (RR 0.30, 95% CI 0.11 to 0.82; I2 = 64%; 2 studies, 228 participants). This effect estimate is highly uncertain due to concerns about the risk of bias, imprecision and inconsistency. There was no difference in ratings of anxiety (SMD − 0.26; 95% CI − 0.75 to 0.23; I2 = 0%; 2 studies; 68 participants). Midazolam increased risk of incomplete procedures (RR 4.01; 95% CI 1.92 to 8.40; I2 = 0%; 4 studies, 268 participants). This effect estimate is uncertain due to concerns about the risk of bias. There were four trials with 359 adults and 77 children included in the oral midazolam versus placebo comparison. Midazolam reduced ratings of anxiety (SMD − 1.01; 95% CI − 1.86 to − 0.16; I2 = 92%; 4 studies; 436 participants). It is unclear if midazolam has an effect on difficulty performing procedures. Meta-analysis was not performed because there was only one incomplete procedure in the midazolam group in one of the trials. Midazolam reduced pain in one study with 99 adults (MD − 2; 95% CI − 2.5 to − 1.6; moderate quality). The effect estimate is uncertain due to concerns about the risk of bias.

Conclusion
The additional evidence arising from inclusion of new studies in this updated review has not produced sufficient high-quality evidence to determine whether midazolam produces more effective sedation than other medications or placebo in any specific population included in this review. For adults, there was low-quality evidence that intravenous midazolam did not reduce the risk of anxiety or discomfort/pain in comparison to placebo, but the sedation level was higher. By combining results from adults and children, there was low-quality evidence of a large reduction in the risk of procedures being difficult to perform with midazolam in comparison to placebo. The effect estimates for this comparison are uncertain because there was concern about risk of bias and imprecision. There is moderate-quality evidence suggesting that oral midazolam produces less-effective sedation than chloral hydrate for completion of procedures for children undergoing non-invasive diagnostic procedures. Ratings of anxiety were not different between oral midazolam and chloral hydrate. The extent to which giving oral midazolam to adults or children decreases anxiety during procedures compared with placebo is uncertain due to concerns about risk of bias and imprecision. There was moderate-quality evidence from one study that oral midazolam reduced the severity of discomfort/pain for adults during a brief diagnostic procedure in comparison with placebo.