Midazolam for sedation before procedures
Abstract
Background
Midazolam is used for sedation before diagnostic and therapeutic medical procedures. It is an imidazole benzodiazepine that has depressant effects on the central nervous system (CNS) with rapid onset of action and few adverse effects. The drug can be administered by several routes including oral, intravenous, intranasal and intramuscular.
Objectives
To determine the evidence on the effectiveness of midazolam for sedation when administered before a procedure (diagnostic or therapeutic).
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL to January 2016), MEDLINE in Ovid (1966 to January 2016) and Ovid EMBASE (1980 to January 2016). We imposed no language restrictions.
Selection criteria
Randomized controlled trials in which midazolam, administered to participants of any age, by any route, at any dose or any time before any procedure (apart from dental procedures), was compared with placebo or other medications including sedatives and analgesics.
Data collection and analysis
Two authors extracted data and assessed risk of bias for each included study. We performed a separate analysis for each different drug comparison.
Main results
We included 30 trials (2319 participants) of midazolam for gastrointestinal endoscopy (16 trials), bronchoscopy (3), diagnostic imaging (5), cardioversion (1), minor plastic surgery (1), lumbar puncture (1), suturing (2) and Kirschner wire removal (1). Comparisons were: intravenous diazepam (14), placebo (5) etomidate (1) fentanyl (1), flunitrazepam (1) and propofol (1); oral chloral hydrate (4), diazepam (2), diazepam and clonidine (1); ketamine (1) and placebo (3); and intranasal placebo (2). There was a high risk of bias due to inadequate reporting about randomization (75% of trials). Effect estimates were imprecise due to small sample sizes. None of the trials reported on allergic or anaphylactoid reactions.
Intravenous midazolam versus diazepam (14 trials; 1069 participants)
There was no difference in anxiety (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.39 to 1.62; 175 participants; 2 trials) or discomfort/pain (RR 0.60, 95% CI 0.24 to 1.49; 415 participants; 5 trials; I² = 67%). Midazolam produced greater anterograde amnesia (RR 0.45; 95% CI 0.30 to 0.66; 587 participants; 9 trials; low‐quality evidence).
Intravenous midazolam versus placebo (5 trials; 493 participants)
One trial reported that fewer participants who received midazolam were anxious (3/47 versus 15/35; low‐quality evidence). There was no difference in discomfort/pain identified in a further trial (3/85 in midazolam group; 4/82 in placebo group; P = 0.876; very low‐quality evidence).
Oral midazolam versus chloral hydrate (4 trials; 268 participants)
Midazolam increased the risk of incomplete procedures (RR 4.01; 95% CI 1.92 to 8.40; moderate‐quality evidence).
Oral midazolam versus placebo (3 trials; 176 participants)
Midazolam reduced pain (midazolam mean 2.56 (standard deviation (SD) 0.49); placebo mean 4.62 (SD 1.49); P < 0.005) and anxiety (midazolam mean 1.52 (SD 0.3); placebo mean 3.97 (SD 0.44); P < 0.0001) in one trial with 99 participants. Two other trials did not find a difference in numerical rating of anxiety (mean 1.7 (SD 2.4) for 20 participants randomized to midazolam; mean 2.6 (SD 2.9) for 22 participants randomized to placebo; P = 0.216; mean Spielberger's Trait Anxiety Inventory score 47.56 (SD 11.68) in the midazolam group; mean 52.78 (SD 9.61) in placebo group; P > 0.05).
Intranasal midazolam versus placebo (2 trials; 149 participants)
Midazolam induced sedation (midazolam mean 3.15 (SD 0.36); placebo mean 2.56 (SD 0.64); P < 0.001) and reduced the numerical rating of anxiety in one trial with 54 participants (midazolam mean 17.3 (SD 18.58); placebo mean 49.3 (SD 29.46); P < 0.001). There was no difference in meta‐analysis of results from both trials for risk of incomplete procedures (RR 0.14, 95% CI 0.02 to 1.12; downgraded to low‐quality evidence).
Authors' conclusions
We found no high‐quality evidence to determine if midazolam, when administered as the sole sedative agent prior to a procedure, produces more or less effective sedation than placebo or other medications. There is low‐quality evidence that intravenous midazolam reduced anxiety when compared with placebo. There is inconsistent evidence that oral midazolam decreased anxiety during procedures compared with placebo. Intranasal midazolam did not reduce the risk of incomplete procedures, although anxiolysis and sedation were observed. 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.
PICOs
Plain language summary
Midazolam for sedation before procedures
Review question
We wanted to find out whether midazolam makes medical procedures more comfortable for children and adults, as well as whether it makes the procedure easier to perform.
Background
Children and adults can become anxious during medical procedures and the procedures can be painful. Pain and anxiety can sometimes make the procedure more difficult to perform for the medical staff, due to movement or a lack of co‐operation from the patient. Sedative medications, including midazolam, are used to reduce pain and anxiety. They can be injected directly into the bloodstream (with an almost immediate effect), injected into muscle tissue, given as a nasal spray, or swallowed as a tablet or solution.
Study characteristics
The evidence is up‐to‐date to January 2016. We included 30 trials involving 2319 participants. We looked at trials that compared midazolam with no active treatment ('dummy' treatment/placebo) or a different medication for sedation before a procedure. The trials involved children and adults having procedures to diagnose medical problems rather than procedures for treatment of a disease. We disregarded trials where people received a general anaesthetic or other medications for sedation or pain relief in addition to midazolam during their procedure.
Key results
Midazolam administered into the bloodstream compared with other medications did not seem to make the participants more drowsy, reduce anxiety or pain, or make the procedure easier to perform. This is based on the low‐quality evidence currently available. A potential benefit is that children and adults who received midazolam compared with no active treatment did not remember as much about the procedures. Midazolam made them drowsy, reduced anxiety and made it easier to perform a procedure. There is moderate‐quality evidence that a solution of midazolam given to children to drink before a procedure was not as effective as a different medication called chloral hydrate. A nasal spray of midazolam before a procedure made the participants drowsy and reduced their anxiety, but this did not make it easier to perform procedures on them. This review cannot be used to assess the harms of midazolam for sedation before a procedure.
Quality of the evidence
We rated the evidence, in the main, as being of low quality. Particularly concerning was that many trials did not explain how participants were randomized to either midazolam or to a different treatment, and that the results did not give us a very clearly defined answer.
Authors' conclusions
Summary of findings
| Intravenous midazolam compared to diazepam for sedation before procedures | ||||||
| Patient or population: adults and children requiring sedation before gastrointestinal endoscopy and bronchoscopy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Diazepam | Midazolam | |||||
| Level of sedation on a sedation assessment scale | 75 (1 study) | very low1 | The mean level of sedation in the midazolam group was 3.2 and the mean level of sedation in the diazepam group was 2.7 on a scale that ranged from 0 to 4 (higher scores indicating more sedation). Measured with a scale that ranged from 0 ‐ 4 (higher scores indicating the participant was more sedated). | |||
| Numeric rating of anxiety or rated as anxious | 167 per 1000 | 133 per 1000 | RR 0.80 | 175 | low2 | Effect estimate calculated for number of participants rated as anxious |
| Incomplete procedure | 170 (1 study) | All procedures were completed in both groups | ||||
| Anterograde amnesia (defined by number of participants who recalled the procedure) | 481 per 1000 | 216 per 1000 | RR 0.45 | 587 | low3 | |
| Disinhibition or excitation | No studies reported on this outcome | |||||
| Discomfort/pain | 202 per 1000 | 121 per 1000 | RR 0.60 | 415 | low2 | |
| Allergic or anaphylactoid reaction | No studies reported on this outcome | |||||
| *The basis for the assumed risk is the control group risk across studies or the average risk for pooled data and the control group risk for single studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded by three levels due to very serious concerns about study limitations (risk of bias) and very serious concerns about imprecision. | ||||||
| Intravenous midazolam compared to placebo for sedation before procedures | ||||||
| Patient or population: adults requiring sedation before gastrointestinal endoscopy and bronchoscopy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Intravenous midazolam | |||||
| Level of sedation on a sedation assessment scale | 100 (1 study) | low1 | Participants who were randomized to midazolam were more sedated (the mean score on the Ramsay scale (1 to 6 with higher scores indicating the participant was more sedated) was 2.77 ± 1.19 in the midazolam group and 1.72 ± 0.50 in the placebo group. | |||
| Numeric rating of anxiety or rated as anxious | 100 (1 study) | low1 | Authors of this trial reported that fewer participants who received midazolam were anxious (3/50 in midazolam group; 15/50 in placebo group) but results of statistical tests were not reported. | |||
| Incomplete procedures | No studies reported on this outcome | |||||
| Anterograde amnesia (defined by number of participants who recalled the procedure) | No studies reported on this outcome | |||||
| Disinhibition or excitation | No studies reported on this outcome | |||||
| Discomfort/pain | 167 (1 study) | very low2 | There was no difference in the number of participants who had discomfort/pain during upper gastrointestinal endoscopy (3/85 in midazolam group; 4/82 in placebo group; P = 0.876). Measured in the trial as 'uncomfortable' | |||
| Allergic or anaphylactoid reaction | No studies reported on this outcome | |||||
| *The basis for the assumed risk is the control group risk across studies or the average risk for pooled data and the control group risk for single studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded two levels due to concerns about study limitations and imprecision. | ||||||
| Oral midazolam compared to chloral hydrate for sedation before procedures | ||||||
| Patient or population: children requiring sedation before procedures that require motion control, including echocardiography, lumbar puncture, micturating cystourethrograms and neuroimaging | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Chloral hydrate | Oral midazolam | |||||
| Level of sedation on sedation assessment scale | 160 (1) | moderate1 | 61 participants (76.25%) in the chloral hydrate group were rated at the highest level of sedation compared with 12 (15%) in the midazolam group (scores ranged from 1 = agitated to 4 = eyes closing spontaneously but response to minor stimuli) | |||
| Numeric rating of anxiety or rated as anxious | The mean rating of anxiety in D'Agostino 2000 was 2.5 The mean rating of anxiety in Akil 2005 was 49.4 | The mean rating of anxiety in the D'Agostino 2000 trial (33 participants) was The mean rating of anxiety in the Akil 2005 trial (35 participants) was 1.83 lower (on the Spielberger's Trait Anxiety Inventory) | 88 | very low2 | We did not conduct meta‐analysis because this outcome was measured differently in the trials (could have been answered by parents or children in Akil 2005). | |
| Incomplete procedures | 56 per 1000 | 226 per 1000 | RR 4.01 | 268 | moderate1 | |
| Anterograde amnesia (defined by number of participants who recalled the procedure) | No studies reported on this outcome | |||||
| Disinhibition or excitation | No studies reported on this outcome | |||||
| Discomfort | No studies reported on this outcome | |||||
| Allergic or anaphylactoid reaction | No studies reported on this outcome | |||||
| *The basis for the assumed risk is the control group risk across studies or the average risk for pooled data and the control group risk for single studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level due to concerns about study limitations. | ||||||
| Oral midazolam compared to placebo for sedation before procedures | ||||||
| Patient or population: children requiring sedation before micturating cystourethrograms and Kirschner wire removal and adults undergoing flexible sigmoidoscopy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Midazolam | |||||
| Level of sedation on a sedation assessment scale | 99 (1) | moderate1 | Reported that level of sedation became statistically significantly different at 10 minutes after administration of medication but mean and standard deviations for midazolam and placebo group level of sedation were not reported in the article. Scores ranged from 0 = awake to 3 = asleep, responsive only to direct verbal or physical stimulus. | |||
| Numeric rating of anxiety or rated as anxious | The mean rating of anxiety in the Kuganeswaran 1999 trial was 4.2 The mean rating of anxiety in Templeton 2010 was 2.6 The mean rating of anxiety in Akil 2005 was 52.8 | The mean anxiety score in Kuganeswaran 1999 (99 participants) was 2.52 lower (minimum score 0, maximum score 10; higher score indicates greater anxiety) The mean anxiety score in Templeton 2010 (42 participants) was 0.90 lower (minimum score 0, maximum score 8; higher score indicate greater anxiety) The mean anxiety score in Akil 2005 (35 participants) was 5.20 lower (on the Spielberger's Trait Anxiety Inventory) | 176 | very low2 | We did not conduct meta‐analysis because of clinical heterogeneity (children and adults undergoing different procedures). | |
| Incomplete procedure | 179 (3 studies) | very low3 | We did not conduct meta‐analysis because of clinical heterogeneity (children and adults undergoing different procedures). There was one incomplete procedure in the midazolam group in one of the three trials that reported on this outcome. | |||
| Anterograde amnesia (defined by number of participants who recalled the procedure) | No studies reported on this outcome | |||||
| Disinhibition or excitation | No studies reported on this outcome | |||||
| Discomfort/Pain | 99 (1 study) | moderate1 | Statistically significant reduction in discomfort/pain (mean 2.56 (SD 0.49) in midazolam group; mean 4.62 (SD 1.49) in placebo group; P < 0.005; scores ranged from 0 to 10; higher score indicated more pain). | |||
| Allergic or anaphylactoid reaction | No studies reported on this outcome | |||||
| *The basis for the assumed risk is the control group risk across studies or the average risk for pooled data and the control group risk for single studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level due to concerns about study limitations. | ||||||
| Intranasal midazolam compared to placebo for sedation before procedures | ||||||
| Patient or population: Children requiring sedation before voiding cystourethrograms and adults undergoing MRI | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Intranasal midazolam | |||||
| Level of sedation on a sedation assessment scale | 54 (1 study) | moderate1 | Deeper level of sedation was observed in the midazolam group (mean 3.15 (SD 0.36) in midazolam group; mean 2.56 (SD 0.64) in placebo group; P < 0.001). Level of sedation measured 15 minutes after medication by one of the authors using a five‐point sedation scale (1 = agitated, non‐co‐operative; 2 = alert, restless; 3 = calm, eyes spontaneously open; 4 = drowsy, responds to minor stimulation; 5 = asleep, rousable but does not respond to minor stimulation). | |||
| Numeric rating of anxiety or rated as anxious | 54 (1 study) | moderate1 | Reduction in a numerical rating of anxiety among participants who received midazolam prior to magnetic resonance imaging procedure (mean 17.3 (SD 18.58) in midazolam group; mean 49.3 (SD 29.46) in placebo group; P < 0.001). Numerical rating of anxiety measured 15 minutes after medication on a Visual Analogue Scale of Anxiety comprised an undivided 100‐mm line, with 0 meaning “I am not anxious at all,” and 100 meaning “I am extremely anxious.” | |||
| Incomplete procedure | 81 per 1000 | 11 per 1000 | RR 0.14 | 149 | low2 | |
| Anterograde amnesia (defined by number of participants who recalled the procedure) | No studies reported on this outcome | |||||
| Disinhibition or excitation | No studies reported on this outcome | |||||
| Discomfort/pain | No studies reported on this outcome | |||||
| Allergic or anaphylactoid reaction | No studies reported on this outcome | |||||
| *The basis for the assumed risk is the control group risk across studies or the average risk for pooled data and the control group risk for single studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded two levels due to concerns about study limitations. | ||||||
Background
Midazolam is used for sedation before diagnostic and therapeutic medical procedures. It is an imidazole benzodiazepine that has depressant effects on the central nervous system (CNS) with rapid onset of action, good effectiveness and few adverse effects. The drug can be administered by several routes including oral, intravenous, intranasal and intramuscular. We compare the effectiveness of midazolam versus placebo and other sedatives.
Description of the condition
The major goal of premedication is to provide sedation and anxiolysis in order to facilitate therapeutic and diagnostic interventions. The characteristics of midazolam are that it has a rapid onset of action, short duration of sedation and low toxicity.
Description of the intervention
Midazolam is one of the most commonly used sedative medications for surgical and non‐surgical procedures. It is currently indicated for sedation, anxiolysis and amnesia preoperatively and during procedures, including ventilation of critically‐ill patients; as a co‐induction agent; and as a supplement to nitrous oxide and oxygen.
Flumazenil is a benzodiazepine antagonist that can be used to rapidly reverse the sedative and other CNS effects of midazolam.
How the intervention might work
Midazolam has a fast recovery time and is used as premedication for many procedures including colonoscopy (Lazaraki 2007); gastrointestinal endoscopy (Fakheri 2010); magnetic resonance imaging (Hollenhorst 2001); and flexible bronchoscopy (Rolo 2012). The anterograde amnesic property of midazolam may be useful for premedication before a procedure, to reduce any associated unpleasant memories (Riss 2008). The disadvantages of midazolam include drug interactions, tolerance, and withdrawal syndrome, as well as adverse events including cognitive impairment (Riss 2008). There is also the possibility that midazolam‐induced anterograde amnesia may be viewed by some patients as undesirable.
Why it is important to do this review
Midazolam is used for sedation before procedures in a wide range of medical specialties. These include gastroenterology, respiratory medicine, gynaecology, cardiology and radiology. As midazolam is often not the only drug used for procedural sedation, it is important to determine if there are any relevant clinical differences between the effects of midazolam and other drugs. It may also be important to determine whether clinicians choose different medications according to patient characteristics (age, weight, gender), or if medication choice is influenced by the type of procedure or context. To our knowledge, no systematic review has been done on the use of midazolam for sedation prior to procedures. Our review aims to fill this gap.
Objectives
To determine the evidence on the effectiveness of midazolam for sedation when administered before a procedure (diagnostic or therapeutic).
Methods
Criteria for considering studies for this review
Types of studies
We included randomized controlled trials (RCTs) in which midazolam was used for sedation before a procedure (diagnostic or therapeutic). We included studies irrespective of language and publication status. We excluded prospective cohort studies and quasi‐randomized studies.
Types of participants
We included participants of any age (adults and children) who were undergoing a procedure preceded by sedation. We excluded any participants undergoing dental procedures, because a Cochrane review has been published about sedation with midazolam specifically in that setting (Lourenço‐Matharu 2012).
Types of interventions
We included midazolam by any route, at any dose or time, administered before a procedure. Participants who received a placebo before a procedure constituted the control group. We also included studies that compared midazolam with another drug for sedation before a procedure. We performed a separate analysis for each different drug comparison (for example, midazolam versus sedative A; midazolam versus sedative B).
We excluded studies that simultaneously compared different drugs and different routes (for example, intranasal midazolam plus intravenous sedative A versus intranasal sedative A plus intravenous midazolam; intravenous midazolam versus intranasal sedative A). We excluded studies where dexmedetomidine was the comparator, as there is another Cochrane review about sedation for this medication (Shailaja 2013).
Types of outcome measures
Primary outcomes
Effective sedation corresponding to adequate sedation level, anxiolysis, ability to complete proposed procedure. This was evaluated by:
1.1. Level of sedation on a sedation assessment scale;
1.2. Numeric rating scale of anxiety or number of participants rated as anxious;
1.3. Vital signs (heart rate, blood pressure, respiratory rate, and oxygen saturation);
1.4. Tolerance of procedure or participant co‐operation (as defined/measured by the authors of the trial);
1.5. Participant or proceduralist satisfaction (as defined/measured by the authors of the trial);
1.6. Proportion of incomplete procedures or where there was difficulty performing the procedures.
Secondary outcomes
2.1. Duration of sedation;
2.2. Onset time of sedation;
2.3. Offset time of sedation;
2.4. Anterograde amnesia (defined by number of participants who recalled the procedure);
2.5. Oversedation (as defined/measured by the authors of the trial);
2.6. Disinhibition or excitation;
2.7. Quality of recovery (as defined/measured by the authors of the trial);
2.8. Discomfort/pain (as defined/measured by the authors of the trial);
2.9. Allergic or anaphylactoid reactions;
2.10. Sedation reversal.
Search methods for identification of studies
Electronic searches
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) to January 2016, MEDLINE in Ovid (1966 to January 2016) and Ovid EMBASE (1980 to January 2016).
We combined the sensitive strategies described in Section 6.4 of theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) to search for RCTs in MEDLINE and EMBASE.
We searched CENTRAL using the terms given in Appendix 1. We adapted our MEDLINE search strategy (Appendix 2) to reflect the subject headings found in the thesauri used by EMBASE (Appendix 3). We used the free‐text terms in all databases and in combination with subject headings when thesauri are a component of a database.
We imposed no language restrictions.
Searching other resources
For ongoing trials, we searched the following databases on 13th July 2015: metaRegister of Controlled Trials (www.controlled‐trials.com/mrct) and Clinical Trials (clinicaltrials.gov). We also screened the reference lists of all eligible trials and reviews.
Data collection and analysis
Selection of studies
We screened all titles and abstracts for eligibility. Two authors (AC and JR) independently performed this screening (see Appendix 4 for a copy of the study selection form). We resolved disagreements by discussion to decide on trial inclusion. In the case of insufficient published information to make a decision about inclusion, we attempted to contact the first author of the relevant trial. We compiled a list of eligible trials, each with a unique identifier on a 'Form for eligible trials' (see Appendix 5).
Data extraction and management
Two authors (AC and JR) independently extracted data onto a paper form. A copy of this paper form is in Appendix 6. We resolved discrepancies by discussion. AC attempted to contact an author of the relevant trial if we required additional information.
Assessment of risk of bias in included studies
Two authors (AC and JR) independently assessed the methodological quality of the eligible trials. We resolved disagreements by discussion.
We performed 'Risk of bias' assessment using the 'Risk of bias' tool as described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) and by Jüni 2001. A copy of the form we used for this is in Appendix 7.
We assessed each trial according to the quality domains of random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and any other potential threats to validity.
We considered a trial as having a low risk of bias if we assessed all domains as adequate. We considered a trial as having a high risk of bias if we assessed one or more domains as inadequate or unclear. We planned to conduct sensitivity analyses to determine whether excluding studies at high risk of bias affected the results of the meta‐analysis.
We reported the 'Risk of bias' table as part of the Characteristics of included studies table, and present 'Risk of bias' summary figures that detail all of the judgements made for all included studies in the review.
Measures of treatment effect
For dichotomous variables, we calculated the risk ratio (RR). For continuous variables, we calculated the mean difference (MD) when studies reported their results through the same variables measured with the same instruments (same units of measurement). When continuous data were related to the same aspect in the participants but were measured with different instruments (and did not have an interchangeable unit of measurement) we pooled them using the standardized mean difference (SMD). We calculated the 95% confidence interval (CI) as the measure of variance for all statistical methods.
Unit of analysis issues
To avoid unit of analysis issues, we planned to consider repeated observations as separate outcomes and group them accordingly for analysis (Morão 2011). However, the trials included in the review reported the change in time‐separated observations (such as the change in oxygen saturation from before to after the administration of sedation), so we were unable to do this (Differences between protocol and review). We sought pre‐cross‐over data for trials that used a cross‐over design.
Dealing with missing data
If trials did not report withdrawals, we assumed there were none. We used an available‐case analysis as the default for meta‐analysis and we also considered sensitivity analysis using best‐case (all participants who withdrew did not experience the event) and worst‐case (all participants who withdrew did experience the event) scenarios for any missing data. No outcomes measured with continuous variables had missing data that needed to be included in the meta‐analyses.
Assessment of heterogeneity
We assessed the clinical heterogeneity of included trials as:
-
clinical diversity (e.g. different types of procedures, different forms of midazolam administration, participants' ages, etc.);
-
methodological diversity ('Risk of bias' assessment);
-
statistical heterogeneity (a manifestation of clinical or methodological diversity, or both, among the trials).
We assessed statistical heterogeneity with the I² statistic, thereby estimating the percentage of total variance across studies due to heterogeneity rather than chance (Higgins 2002). We considered an I² statistic value greater than 50% as considerable heterogeneity or if the Chi² test was significant (see Data synthesis).
Assessment of reporting biases
As per the original protocol, we planned to assess publication bias and small‐study effects using a funnel plot if there were 10 or more studies included in the meta‐analysis (Morão 2011). However, we did not perform this analysis because fewer than 10 studies were included in each meta‐analysis.
Data synthesis
We generated meta‐analytic estimates for outcomes reported by two or more studies. We performed the analysis using Review Manager 5 software (Review Manager 2014). Because the population is varied, we included all types of procedures. Due to this variation, the intervention effect could have varied across the different studies. We therefore expected that a random‐effects model would be suitable for the meta‐analyses. However, a smaller value of the I² statistic (less than 50%) prompted consideration of the use of a fixed‐effect model. We performed all analyses according to the intention‐to‐treat (ITT) principle.
Subgroup analysis and investigation of heterogeneity
We planned to perform subgroup analyses for age (children, adults (16 years of age or older)), type of procedure (diagnostic, therapeutic) and medical specialty (surgical, non‐surgical) (Morão 2011). However, there was not enough evidence to conduct any subgroup analysis.
Sensitivity analysis
We planned to perform sensitivity analyses by trials with a low risk of bias versus moderate or high risk of bias (Morão 2011). However, we rated most studies to be of either low or very low quality, and this was not appropriate.
'Summary of findings' table
We used the principles of the GRADE system (Guyatt 2008) to assess the quality of the body of evidence associated with the following specific outcomes: level of sedation on a sedation assessment scale; numerical rating of scale of anxiety or number of participants rated as anxious; incomplete procedures; anterograde amnesia (recalled procedures); disinhibition or excitation; discomfort/pain; allergic or anaphylactoid reactions; and we constructed 'Summary of findings' tables using the GRADE software.
The GRADE approach appraises the quality of a body of evidence based on the extent to which one can be confident that an estimate of effect or association reflects the item being assessed. The quality of a body of evidence is based on within‐study risk of bias (methodologic quality), the directness of the evidence, heterogeneity of the data, precision of effect estimates and risk of publication bias. The GRADE approach specifies four levels of quality (high, moderate, low, very low). The highest quality rating is for randomized trial evidence and the lowest is for triple‐downgraded randomized trials, downgraded observational studies or case series and case reports.
Results
Description of studies
Results of the search
Figure 1 summarizes the search results to January 2016. The searches identified 4033 hits. We retrieved 163 papers for consideration and included 30 trials in this review.
Study flow diagram.
Included studies
We include 30 trials with 2319 participants (Characteristics of included studies) that compared midazolam via the intravenous, oral and intranasal routes of administration, either to placebo or to another medication for sedation before a procedure. The included trials were conducted in both adult and paediatric populations. 16 trials enrolled participants having gastrointestinal endoscopy procedures (Bell 1988; Bhalla 2006; Bianchi Porro 1988; Cole 1983; Córdova 1992; Fakheri 2010; Gilvarry 1990; Kuganeswaran 1999; Lavies 1988; Lazaraki 2007; Lee 1989; Sainpy 1984; Takrouri 1988; Tolia 1990; Whitwam 1983; Yuno 1996) and there were three trials involving bronchoscopy (Aktogu 1994; Korttila 1985; Rolo 2012). Diagnostic imaging was performed in five trials (Akil 2005; D'Agostino 2000; Hollenhorst 2001; Stokland 2003; Wheeler 2001), one trial (Coll‐Vinent 2003) was conducted with participants undergoing cardioversion, and another (De Alencar 2010) for participants undergoing minor office‐based plastic surgery. Four trials were conducted with children undergoing minor procedures that required motion control, including lumbar puncture (Derakhshanfar 2013), suturing (Everitt 2002; Younge 2001) and Kirschner wire removal (Templeton 2010).
There was geographic variability across the included trials. Trials were performed in the United Kingdom (Gilvarry 1990; Templeton 2010; Whitwam 1983; Younge 2001), USA (Cole 1983; D'Agostino 2000; Kuganeswaran 1999; Lavies 1988; Tolia 1990; Wheeler 2001), Turkey (Akil 2005; Aktogu 1994), India (Bhalla 2006), Italy (Bianchi Porro 1988), Spain (Coll‐Vinent 2003), Mexico (Córdova 1992), Brazil (De Alencar 2010), Iran (Derakhshanfar 2013; Fakheri 2010), Australia (Everitt 2002), Germany (Hollenhorst 2001), Finland (Korttila 1985), Greece (Lazaraki 2007), Jamaica (Lee 1989), Portugal (Rolo 2012), France (Sainpy 1984), Sweden (Stokland 2003), Jordan (Takrouri 1988) and Japan (Yuno 1996).
Regarding the characteristics of the interventions, for intravenous midazolam, four trials used weight‐based calculation with a dose of 0.1 mg/kg (Córdova 1992; Korttila 1985; Sainpy 1984; Tolia 1990). Other trials used smaller doses, including 0.07 mg/kg (Bianchi Porro 1988; Lee 1989; Whitwam 1983), 0.06 mg/kg (Aktogu 1994) and 0.05 mg/kg (Rolo 2012). One trial used a higher dose of 0.2 mg/kg (Coll‐Vinent 2003). Other trials did not use participants' weight to calculate doses. These trials used either 2.5 mg (Bell 1988), 5 mg (Bhalla 2006; Cole 1983;), 10 mg (Gilvarry 1990) or 15 mg (De Alencar 2010). Some trials used smaller doses for elderly participants (Bell 1988; Bhalla 2006; Cole 1983). Other trials reported only the mean or range of dose that was administered instead of the planned method of titration (Lavies 1988; Lazaraki 2007; Takrouri 1988). For oral midazolam, only one trial did not use a weight‐based dose calculation (Kuganeswaran 1999). Weight‐based doses of oral midazolam used were 0.5 mg/kg (D'Agostino 2000; Derakhshanfar 2013; Wheeler 2001), 0.6 mg/kg (Akil 2005), 0.7 mg/kg (Younge 2001) and 1 mg/kg (Everitt 2002; Templeton 2010). For intranasal midazolam, Hollenhorst 2001 used a standard dose of 4 mg whereas Stokland 2003 used a dose of 0.2 mg/kg up to 5 mg.
The comparator arms were: intravenous diazepam in 14 trials with 1069 participants (Aktogu 1994; Bhalla 2006; Bell 1988; Bianchi Porro 1988; Cole 1983; Córdova 1992; Gilvarry 1990; Korttila 1985; Lavies 1988; Lee 1989; Sainpy 1984; Takrouri 1988; Tolia 1990; Whitwam 1983); intravenous placebo in five trials with 493 participants (Bhalla 2006; Fakheri 2010; Lavies 1988; Rolo 2012; Yuno 1996); intravenous etomidate in one trial with 17 participants (Coll‐Vinent 2003); intravenous fentanyl in one trial with 126 participants(Lazaraki 2007); intravenous flunitrazepam in one trial with 86 participants (Takrouri 1988); intravenous propofol in one trial with 17 participants (Coll‐Vinent 2003); oral chloral hydrate in four trials with 268 participants (Akil 2005; D'Agostino 2000; Derakhshanfar 2013; Wheeler 2001); oral diazepam in two trials with 122 participants (De Alencar 2010; Everitt 2002); oral diazepam and clonidine in one trial with 34 participants (De Alencar 2010); oral ketamine in one trial with 59 participants (Younge 2001); oral placebo in three trials with 176 participants (Akil 2005; Kuganeswaran 1999; Templeton 2010); and intranasal placebo two trials with 149 participants (Hollenhorst 2001; Stokland 2003).
For three trials, we pooled two different groups, as the trials compared midazolam with: both a placebo and with chloral hydrate (Akil 2005); or both placebo and diazepam (Bhalla 2006; Lavies 1988). Three trials (Coll‐Vinent 2003; De Alencar 2010; Takrouri 1988) compared midazolam with two different medications. One trial compared two different doses of midazolam with another medication (Korttila 1985). For this review, we considered only the outcomes reported from the higher dose of midazolam used, as this dose was comparable with the doses used in the other included trials. Two included articles presented results from the same trial (Bhalla 2006).
Financial support was provided by industry for two trials (Cole 1983; Kuganeswaran 1999). Yuno 1996 and Templeton 2010 reported receiving funding for their trials from non‐industry sources. No other trials reported the source of funding in their publications.
Excluded studies
We needed to review a large number of papers in full text, as it was unclear from the title and abstract whether or not analgesia was administered concurrently with midazolam and whether or not the sedation was administered intraprocedurally or just before the procedure. We excluded 122 articles that we reviewed in full text. A selection of 18 of these excluded articles are included in the Characteristics of excluded studies table, to display the common reasons for exclusion. These include intraprocedural sedation used in addition to preprocedural sedation (Mui 2005; Muttu 2005), the concomitant use of analgesia or other sedative medication with midazolam (Brouillette 1989; Dere 2010; Nascimento 2007; Salmon 1992; Sajedi 2006; Sherry 1989; Tamayo 1993), routine use of flumazenil (Ristikankare 1999; Ristikankare 2000a; Ristikankare 2000b; Uygur‐Bayramiçli 2002), wrong research design (Sandler 1992; Tesoro 2007; Weinstein 2010), midazolam used in control group if initial sedation was ineffective (Bonta 2003), and placebo being administered by a different route to midazolam (Yildirim 2006).
Studies awaiting classification
We await more information in order to classify a further 10 studies (Characteristics of studies awaiting classification). We attempted to contact the authors of four of them (Bardhan 1984; Green 1984; Ogden 1993; Theroux 1993) to clarify details but we either could not locate their current contact details or we did not receive a response from the authors. The remaining six studies awaiting classification still require data extraction because they were not published in English (Frisancho 1996; Mendes 1986; Mignonsin 1994; Münte 2002; Thakur 2003; Wild 1988).
Ongoing studies
We identified three ongoing studies from our search of the clinical trials databases that might be eligible for inclusion in future updates of the review (NCT00563069; Puttapitakpong 2015; NCT01925898) (see Characteristics of ongoing studies).
Risk of bias in included studies
We present summaries of the judgements of the risk of bias of included trials in Figure 2 and Figure 3. Details of the included trials are in the Characteristics of included studies tables. The overall risk of performance bias and detection bias was low for 50% of included trials. For randomization sequence generation and allocation concealment the quality assessment yielded low risk of bias for approximately 25% or less of the included trials. The risk of attrition bias for the primary outcomes was low for more than 75% of trials.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Allocation
Reporting of methods used for randomization sequence generation and allocation concealment was unclear in the majority of trials. As such, it is unclear as to the impact that potential selection bias might have on the estimates of the effects.
Blinding
Overall, there was a low risk of bias from blinding, due to the double‐blinded design used for most trials.
Incomplete outcome data
The trials were generally of short duration in an environment that was conducive to a low attrition rate for intra‐ and post‐procedural data that were collected before the participant was discharged. As such, there is low risk of attrition bias for the primary outcomes set for this review. However, one trial (Everitt 2002) reported high attrition rates for the 'quality of recovery' outcome, which was measured with a post‐discharge survey, meaning there is a high risk of attrition bias, but only for this secondary outcome.
Selective reporting
We found no definite evidence of selective reporting. However, we did not seek trial protocols because most included trials were published prior to the establishment of clinical trial registries. It is therefore unclear whether the outcomes infrequently reported or absent from the included trials, such as allergic or anaphylactoid reactions and sedation reversal, were collected but not reported.
Other potential sources of bias
We did not identify any other definite source of potential bias.
Effects of interventions
See: Summary of findings for the main comparison Intravenous midazolam compared to diazepam for sedation before procedures; Summary of findings 2 Intravenous midazolam compared to placebo for sedation before procedures; Summary of findings 3 Oral midazolam compared to chloral hydrate for sedation before procedures; Summary of findings 4 Oral midazolam compared to placebo for sedation before procedures; Summary of findings 5 Intranasal midazolam compared to placebo for sedation before procedures
Intravenous midazolam versus diazepam (comparison 1, outcomes 1.1 to 1.6 and 2.1 to 2.10)
Intravenous midazolam was compared with diazepam in 14 trials in 1069 participants (Aktogu 1994; Bhalla 2006; Bell 1988; Bianchi Porro 1988; Cole 1983; Córdova 1992; Gilvarry 1990; Korttila 1985; Lavies 1988; Lee 1989; Sainpy 1984; Takrouri 1988; Tolia 1990; Whitwam 1983). We present the doses of midazolam and diazepam that were used in each of these trials in Table 1.
| Study | Dose of midazolam | Dose of diazepam |
| 0.06 mg/kg | 0.15 mg/kg | |
| 5 mg (3 mg if older than 65) | 5 mg (3 mg if older than 65) | |
| 2.5 mg or 1 mg for elderly (mean 6.0 ± 2.8) | 5 mg or 2 mg for elderly (mean 11.5 ± 6.7) | |
| 0.07 mg/kg | 0.15 mg/kg | |
| 5 mg bolus with 2.5 ‐ 3.75 mg increments at 30‐ ‐ 60‐second intervals as required. Half doses for elderly | 5 mg bolus with 2.5 ‐ 3.75 mg increments at 30‐ ‐ 60‐second intervals as required. Half doses for elderly | |
| 0.10 mg/kg | 0.15 mg/kg | |
| 10 mg | 20 mg | |
| 0.1 mg/kg | 0.2 mg/kg | |
| 2.5 ‐ 7.5 mg | 2.5 ‐ 10 mg | |
| 0.07 mg/kg | 0.15 mg/kg | |
| 0.1 mg under 65 yrs and 0.085 mg over 65 yrs infused in 30 seconds | 0.2 mg under 65 yrs and 0.15 mg over 65 yrs infused in 30 seconds | |
| mean 5.8 mg | mean 5 mg | |
| 0.1 ‐ 0.15 mg/kg | 0.2 ‐ 0.4 mg/kg | |
| 0.07 mg/kg | 0.15 mg/kg |
Primary outcomes
Outcome 1.1. Level of sedation on a sedation assessment scale
One trial with 75 participants (Takrouri 1988) reported on the difference in level of sedation on a sedation assessment scale. The midazolam group were given a mean dose of 5.8 mg and the diazepam group a mean dose of 5 mg. The mean level of sedation in the midazolam group was 3.2 and the mean level of sedation in the diazepam group was 2.7 on a scale that ranged from 0 to 4 (higher scores indicating more sedation). No effect estimate was reported in the trial.
Outcome 1.2. Numeric rating scale of anxiety or number of participants rated as anxious
Two trials (175 participants) reported on this outcome, with 91 (52%) receiving midazolam and 84 (48%) diazepam (Takrouri 1988; Whitwam 1983). Twelve participants (13.2%) receiving midazolam were rated as anxious compared to 14 (16.7%) receiving diazepam (RR 0.80, 95% CI 0.39 to 1.62, I² = 0%; Analysis 1.1). In Takrouri 1988, both groups were given a similar mean dose of sedative medication (midazolam 5.8 mg; diazepam 5 mg). In Whitwam 1983, the midazolam group was given a dose of 0.07 mg/kg and the diazepam group was given 0.15 mg/kg.
Outcome 1.3. Vital signs
The difference in vitals signs between the midazolam and diazepam groups could not be combined in a meta‐analysis due to disparities in how they were reported. In a trial of 170 participants, a 5 mg (or 3 mg if older than 65) dose of sedative medication was given to both the midazolam and diazepam groups (Bhalla 2006). They found no difference between groups in oxygen desaturation (35/85 in midazolam group; 29/85 in diazepam group), minimum oxygen saturation (mean 90.7 (SD 3.9) in midazolam group; mean 90.8 (SD 3.15) in diazepam group), tachycardia (15/85 in midazolam group; 10/85 in diazepam group), bradycardia (no events in either group) or hypertension (2/85 in midazolam group; 2/85 in diazepam group). Bell 1988 reported a difference between groups in the change in oxygen saturation post‐sedation (mean 3.5 (SD 2.07) in midazolam group; mean 2.8 (SD 3.7) in diazepam group; P < 0.001) in their trial of 102 participants (doses used were: midazolam 2.5 mg or 1 mg for elderly, diazepam 5 mg or 2.5 mg for elderly). In a smaller trial with 40 participants, Cole 1983 identified that the change in respiration rate was greater after administration of midazolam compared with diazepam (mean 1.7 (SD 0.7) in the 19 participants randomized to midazolam compared with mean 3.9 (SD 0.8) in the 21 participants randomized to midazolam) but there was no difference between groups for the change in heart rate (mean 3.3 (SD 1.6) in midazolam group; mean 4.6 (SD 2) in diazepam group) or diastolic blood pressure (mean ‐3.7 (SD 1.9) in midazolam group; mean 1.5 (SD 1.9) in diazepam group). The doses used in both groups were a 5 mg bolus with 2.5 to 3.75 mg increments at 30‐ to 60‐second intervals as required with half doses for elderly (Cole 1983). In a similar‐sized trial (46 participants), Bianchi Porro 1988 reported that systolic blood pressure (mean 116.1 (SD 26.5) in midazolam group; mean 129.1 (SD 14.8) in diazepam group) and diastolic blood pressure (mean 83.7 (SD 10.7) in midazolam group; mean 85.4 (SD 9.3) in diazepam group) was similar between groups. The midazolam group was given a dose of 0.07 mg/kg and the diazepam group was given 0.15 mg/kg in this trial.
Outcome 1.4. Tolerance of procedure or participant co‐operation
Five trials (Lee 1989; Bhalla 2006; Takrouri 1988; Tolia 1990; Whitwam 1983) including 486 participants reported on this outcome, with 247 (51%) receiving midazolam and 239 (49%) diazepam. Forty‐eight participants (19%) who received midazolam were deemed 'not co‐operative' in comparison with 55 (23%) in the diazepam group (RR 0.96, 95% CI 0.53 to 1.72; I² = 63%; Analysis 1.2). The dosing strategy differed between these trials, which may account for the considerable degree of inconsistency observed for this result (Table 1).
Outcome 1.5. Participant or proceduralist satisfaction
Two trials (Cole 1983; Korttila 1985) with 91 participants reported proceduralist satisfaction and participant satisfaction using a scale from 0 to 100, with higher scores equating to better satisfaction. Higher doses of midazolam than diazepam were used in both of these trials (Table 1). Meta‐analysis of participant satisfaction (MD 2.17, 95% CI ‐0.51 to 4.85; I² = 12%; Analysis 1.3) and proceduralist satisfaction (MD 1.09, 95% CI ‐10.43 to 12.60; Analysis 1.4) was not statistically significantly different between the midazolam group (43 participants; 47%) and the diazepam group (48 participants; 53%).
Outcome 1.6. Incomplete procedures/difficulty performing procedures
Meta‐analysisof results from three trials (Lee 1989; Takrouri 1988; Whitwam 1983) for the number of procedures rated as 'difficult to perform' revealed no important difference between the midazolam group (procedures for 23 of 144 participants were difficult to perform) and the diazepam group (procedures for 32 of 133 participants were difficult to perform) (RR 0.66, 95% CI 0.41 to 1.07; I² = 0%; Analysis 1.5). The dosing strategies differed between these trials (Table 1).One trial with 170 participants, where both groups received the same dose of midazolam or diazepam (5 mg, or 3 mg for elderly participants), reported that there were no incomplete procedures in either group (Bhalla 2006).
Secondary outcomes
Outcome 2.1. Duration of sedation
Three trials with 224 participants reported on the duration of sedation using different definitions (Córdova 1992; Sainpy 1984; Whitwam 1983). For this reason, we did not conduct meta‐analysis. The dose of midazolam was lower than the diazepam dose in all three trials (Table 1). Córdova 1992, with 60 participants, reported that there was a reduction in minutes until recovery (mean 16 minutes (SD 8) in midazolam group; mean 35 minutes (SD 19) in diazepam group; P < 0.01). The other two trials did not identify a difference in duration of sedation between groups. The mean duration of sedation recovery (measured in minutes until sense of direction and temporospatial recovery) in the 32 participants randomized to midazolam in Sainpy 1984 trial was 24.9 minutes (SD 14.4) compared with 25.2 minutes (SD 14.9) for the 32 participants randomized to diazepam. In Whitwam 1983, the mean duration of sedation recovery (time in minutes until ready for discharge) was 75.3 minutes (SD 23.2) for the 50 participants randomized to midazolam compared with 76.4 minutes (SD 30.9) for the 50 participants randomized to diazepam.
Outcome 2.2. Onset time of sedation
Meta‐analysis of two trials (Cole 1983; Whitwam 1983) with 140 participants (69 participants received midazolam; 50%) demonstrated that the onset of sedation was similar for participants who received midazolam0 (MD ‐1.80 minutes, 95% CI ‐3.76 to 0.16; I2 = 99%; Analysis 1.6). The high heterogeneity could be explained by the doses of sedation used, with Cole 1983 using the same dosing regimen for both midazolam and diazepam (5 mg) whereas Whitwam 1983 administered 0.07 mg/kg midazolam or 0.15 mg/kg diazepam.
Outcome 2.3. Offset time of sedation
Whitwam 1983, with 100 participants, reported this outcome. There was no clear difference between the midazolam and diazepam groups (14.6 minutes (SD 5.7) in the midazolam group; 12.9 minutes (SD 5.2) in the diazepam group).
Outcome 2.4. Anterograde amnesia (defined by number of participants who recalled the procedure)
A meta‐analysis of results from nine trials (Aktogu 1994; Córdova 1992; Gilvarry 1990; Korttila 1985; Lee 1989; Sainpy 1984; Takrouri 1988; Tolia 1990; Whitwam 1983) with 587 participants revealed that those who received midazolam (58 of 296 participants recalled the procedure) had greater anterograde amnesia than those who received diazepam (140 of 291 participants recalled the procedure) (RR 0.45, 95% CI 0.30 to 0.66; downgraded to low‐quality evidence due to concerns about study limitations and inconsistency; I² = 65%; Analysis 1.7). It should be noted that two participants randomized to the midazolam group in Tolia 1990 withdrew, which meant that there were missing data for this outcome. Sensitivity analysis using best‐case and worst‐case scenarios did not significantly change the result.
Outcome 2.5. Oversedation
One participant in the midazolam group of Whitwam 1983, with 100 participants, was rated as being oversedated compared with no participants in the diazepam group.
Outcome 2.6. Disinhibition or excitation
No trials reported this outcome for the intravenous midazolam versus diazepam comparison.
Outcome 2.7. Quality of recovery
Three trials (Cole 1983; Korttila 1985; Takrouri 1988) with 166 participants reported on quality of recovery (measured in the trials as delayed recovery). There was no difference between those who received midazolam (8 of 84 participants; 10%) or diazepam (13 of 82 participants; 16%) (RR 0.72, 95% CI 0.08 to 6.63; I² = 67%; Analysis 1.8). This result was inconsistent and imprecise, so we downgraded the evidence that informed this outcome to low quality.
Outcome 2.8. Discomfort/pain
There was no difference in the occurrence of discomfort/pain during the procedure between midazolam (24 of 207 participants; 12%) and diazepam (42 of 208 participants; 20%) in a meta‐analysis of five trials (Cole 1983; Lee 1989; Bhalla 2006; Sainpy 1984; Tolia 1990) with 415 participants (RR 0.60, 95% CI 0.24 to 1.49; Analysis 1.9). However, there was substantial statistical heterogeneity (I² = 76%) and the result was imprecise.
Outcome 2.9. Allergic or anaphylactoid reactions
No trials reported this outcome for the intravenous midazolam versus diazepam comparison.
Outcome 2.10. Sedation reversal
No trials reported this outcome for the intravenous midazolam versus diazepam comparison.
Intravenous midazolam versus etomidate (comparison 2, outcomes 1.1 to 1.6 and 2.1 to 2.10)
We identified one trial with 17 participants that investigated the use of midazolam versus etomidate before electrical cardioversion (Coll‐Vinent 2003). Eight participants were randomized to midazolam and nine to receive etomidate. The doses of both midazolam and etomidate were 0.2 mg/kg.
Primary outcomes
Outcome 1.1. Level of sedation on a sedation assessment scale
Level of sedation (measured using the Ramsay scale) was similar between groups: median score of 6 with interquartile range 5 and 6 in both groups.
Outcome 1.2. Numeric rating scale of anxiety or number of participants rated as anxious
No trials reported this outcome for the intravenous midazolam versus etomidate comparison.
Outcome 1.3. Vital signs
There were no statistically significant differences in systolic blood pressure, measured by the Kruskall‐Wallis test. Median systolic blood pressure in the midazolam group was 141 mmHg (range 99 ‐ 165) compared with 139 mmHg in the etomidate group (range 118 ‐ 150). One participant randomized to midazolam experienced an oxygen desaturation event (SpO₂ < 90%) in comparison to four events in the etomidate group.
Outcome 1.4. Tolerance of procedure or participant co‐operation
No trials reported this outcome for the intravenous midazolam versus etomidate comparison.
Outcome 1.5. Participant or proceduralist satisfaction
No trials reported this outcome for the intravenous midazolam versus etomidate comparison.
Outcome 1.6. Incomplete procedures/difficulty performing procedures
No trials reported this outcome for the intravenous midazolam versus etomidate comparison.
Secondary outcomes
Outcome 2.1. Duration of sedation
The median duration of sedation was lower in the etomidate group compared with midazolam by 11.5 minutes, and this difference was noted to be significantly different (P = 0.05).
Outcome 2.2 Onset time of sedation
The median onset time of sedation was 30 seconds lower in the etomidate group compared with the midazolam group. This difference was noted to be statistically non‐significant (P value for this comparison was not reported in publication Coll‐Vinent 2003).
Outcome 2.3. Offset time of sedation
The median offset time of sedation was 31 minutes lower in the etomidate group compared with the midazolam group, and this difference was noted to be statistically significantly (P = 0.015).
Outcome 2.4. Anterograde amnesia (defined by number of participants who recalled the procedure)
No trials reported this outcome for the intravenous midazolam versus etomidate comparison.
Outcome 2.5. Oversedation
No trials reported this outcome for the intravenous midazolam versus etomidate comparison.
Outcome 2.6. Disinhibition or excitation
No trials reported this outcome for the intravenous midazolam versus etomidate comparison.
Outcome 2.7. Quality of recovery
No trials reported this outcome for the intravenous midazolam versus etomidate comparison.
Outcome 2.8. Discomfort/pain
No trials reported this outcome for the intravenous midazolam versus etomidate comparison.
Outcome 2.9. Allergic or anaphylactoid reactions
No trials reported this outcome for the intravenous midazolam versus etomidate comparison.
Outcome 2.10. Sedation reversal
No trials reported this outcome for the intravenous midazolam versus etomidate comparison.
Intravenous midazolam versus fentanyl (comparison 3, outcomes 1.1 to 1.6 and 2.1 to 2.10)
Intravenous midazolam was compared with fentanyl for sedation before colonoscopy in one trial with 126 participants (Lazaraki 2007). Mean dosage for midazolam was 4.6 mg and for fentanyl was 36 mcg.
Primary outcomes
Outcome 1.1. Level of sedation on a sedation assessment scale
No trials reported this outcome for the intravenous midazolam versus fentanyl comparison.
Outcome 1.2. Numeric rating scale of anxiety or number of participants rated as anxious
No trials reported this outcome for the intravenous midazolam versus fentanyl comparison.
Outcome 1.3. Vital signs
Midazolam was associated with more oxygen desaturation, defined as SpO₂ below 90% (23/60 in midazolam group; 0/66 in fentanyl group; P = 0.001).
Outcome 1.4. Tolerance of procedure or participant co‐operation
No trials reported this outcome for the intravenous midazolam versus fentanyl comparison.
Outcome 1.5. Participant or proceduralist satisfaction
There were no differences between the groups in the effectiveness of the sedation in terms of participant satisfaction, which was measured in this trial as the acceptability of undergoing another procedure with the same sedative medication (5/60 in midazolam group; 4/66 in fentanyl group).
Outcome 1.6. Incomplete procedures/difficulty performing procedures
There were no differences between the groups in the effectiveness of the sedation in terms of incomplete procedures (3/60 in midazolam group; 1/66 in fentanyl group).
Secondary outcomes
Outcome 2.1. Duration of sedation
No trials reported this outcome for the intravenous midazolam versus fentanyl comparison.
Outcome 2.2. Onset time of sedation
No trials reported this outcome for the intravenous midazolam versus fentanyl comparison.
Outcome 2.3. Offset time of sedation
No trials reported this outcome for the intravenous midazolam versus fentanyl comparison.
Outcome 2.4. Anterograde amnesia (defined by number of participants who recalled the procedure)
Midazolam produced more anterograde amnesia (32/60 in midazolam group; 66/66 in fentanyl group; P = 0.001).
Outcome 2.5. Oversedation
No trials reported this outcome for the intravenous midazolam versus fentanyl comparison.
Outcome 2.6. Disinhibition or excitation
No trials reported this outcome for the intravenous midazolam versus fentanyl comparison.
Outcome 2.7. Quality of recovery
No trials reported this outcome for the intravenous midazolam versus fentanyl comparison.
Outcome 2.8. Discomfort/pain
No trials reported this outcome for the intravenous midazolam versus fentanyl comparison.
Outcome 2.9. Allergic or anaphylactoid reactions
No trials reported this outcome for the intravenous midazolam versus fentanyl comparison.
Outcome 2.10. Sedation reversal
There were no differences between groups in the number of participants who required sedation reversal (no events in either group).
Intravenous midazolam versus flunitrazepam (comparison 4, outcomes 1.1 to 1.6 and 2.1 to 2.10)
We identified one trial with 86 participants that compared intravenous midazolam with flunitrazepam (Takrouri 1988) before gastrointestinal endoscopy. The mean dose of midazolam was 5.8 mg and 0.65 mg for flunitrazepam. In this trial 41 participants were randomized to midazolam and 45 participants to flunitrazepam.
Primary outcomes
Outcome 1.1. Level of sedation on a sedation assessment scale
The mean level of sedation was 0.5 higher (on a scale that ranged from 0 to 4) in the midazolam group.
Outcome 1.2. Numeric rating scale of anxiety or number of participants rated as anxious
No trials reported this outcome for the intravenous midazolam versus flunitrazepam comparison.
Outcome 1.3. Vital signs
Post‐sedation heart rate (mean 88 (SD 7.2) in midazolam group; mean 92 (SD 6.3) in flunitrazepam group; P = 0.001) was lower in participants randomized to midazolam. There was no difference between groups for systolic blood pressure (mean 91 mmHg (SD 6.3) in the midazolam group; mean 98 mmHg (SD 10) in the flunitrazepam group; P = 0.5) or for diastolic blood pressure (mean 58 mmHg (SD 7) in midazolam group; mean 61 mmHg (SD 6.7) in flunitrazepam group; P = 0.5). Mean respiration rate was similar between groups, with 21 in the flunitrazepam group and 20 in the midazolam group.
Outcome 1.4. Tolerance of procedure or participant co‐operation
There were no differences between groups for participant co‐operation, which was measured in this trial as the number of participants who were rated as 'not co‐operative' (9/41 in the midazolam group; 12/45 in the flunitrazepam group).
Outcome 1.5. Participant or proceduralist satisfaction
No trials reported this outcome for the intravenous midazolam versus flunitrazepam comparison.
Outcome 1.6. Incomplete procedures/difficulty performing procedures
There were no differences between groups for difficulty performing procedures (8/41 in the midazolam group; 7/45 in the flunitrazepam group).
Secondary outcomes
Outcome 2.1. Duration of sedation
No trials reported this outcome for the intravenous midazolam versus flunitrazepam comparison.
Outcome 2.2. Onset time of sedation
No trials reported this outcome for the intravenous midazolam versus flunitrazepam comparison.
Outcome 2.3. Offset time of sedation
No trials reported this outcome for the intravenous midazolam versus flunitrazepam comparison.
Outcome 2.4. Anterograde amnesia (defined by number of participants who recalled the procedure)
The risk of recalling a procedure was reduced in the midazolam group (11/41 in the midazolam group; 36/45 in the flunitrazepam group).
Outcome 2.5. Oversedation
No trials reported this outcome for the intravenous midazolam versus flunitrazepam comparison.
Outcome 2.6. Disinhibition or excitation
No trials reported this outcome for the intravenous midazolam versus flunitrazepam comparison.
Outcome 2.7. Quality of recovery
Recovery was delayed in no participants randomized to midazolam, compared with 17/45 in the flunitrazepam group.
Outcome 2.8. Discomfort/pain
No trials reported this outcome for the intravenous midazolam versus flunitrazepam comparison.
Outcome 2.9. Allergic or anaphylactoid reactions
No trials reported this outcome for the intravenous midazolam versus flunitrazepam comparison.
Outcome 2.10. Sedation reversal
No trials reported this outcome for the intravenous midazolam versus flunitrazepam comparison.
Intravenous midazolam versus placebo (comparison 5, outcome 1.1 to 1.6 and 2.1 to 2.10)
Intravenous midazolam was compared with placebo in five trials with 493 participants (Bhalla 2006; Fakheri 2010; Lavies 1988; Rolo 2012; Yuno 1996). The doses of midazolam used are presented in Table 2. We downgraded the evidence identified to inform the intravenous midazolam versus placebo comparison to low quality, due to concerns about study limitations and imprecision (summary of findings Table 2).
| Study | Dose of midazolam |
| 5 mg (3 mg if over 65 years old) | |
| mean 3.2 mg (SD 1.6) | |
| 2.5 ‐ 7.5 mg | |
| 0.05 mg/kg | |
| 0.05 mg/kg |
Primary outcomes
Outcome 1.1. Level of sedation on a sedation assessment scale
Participants who were randomized to midazolam were more sedated: the mean score on the Ramsay scale (1 to 6, with higher scores indicating the participant was more sedated) was 2.77 ± 1.19 in the midazolam group and 1.72 ± 0.50 in the placebo group) (Rolo 2012; 100 participants).
Outcome 1.2. Numeric rating scale of anxiety or number of participants rated as anxious
One trial (Rolo 2012; 100 participants) reported that fewer participants who received midazolam were anxious (3/50 in midazolam group; 15/50 in placebo group).
Outcome 1.3. Vital signs
Meta‐analysis of two trials (Bhalla 2006; Yuno 1996), with 207 participants (105 randomized to midazolam; 51%) revealed that midazolam was associated with a statistically significant reduction in the lowest recorded oxygen saturation (MD ‐1.50 %, 95% CI ‐1.77 to ‐1.23; I2 = 0%; Analysis 2.1). The rate of oxygen desaturation was reported by three trials (Bhalla 2006; Fakheri 2010; Rolo 2012), with 535 participants. Forty‐seven of 225 participants (21%) randomized to midazolam experienced oxygen desaturation in comparison to 41 of the 222 participants (18%) randomized to placebo (RR 1.12, 95% CI 0.79 to 1.58; I² = 0%; Analysis 2.2). Three trials (307 participants) reported on the rate of hypotension (Rolo 2012; Yuno 1996). No events occurred in either group in the Bhalla 2006 trial. One of 70 participants randomized to midazolam became hypotensive in comparison to three of 70 participants randomized to placebo (RR 0.43, 95% CI 0.07 to 2.78; participants = 140; studies = 2; I2 = 0%; Analysis 2.3). Two trials (207 participants) reported on the rate of tachycardia (Bhalla 2006; Yuno 1996). Eighteen of the 105 participants (17%) randomized to midazolam became tachycardic in comparison to 12 of the 152 participants (8%) randomized to placebo (RR 1.46, 95% CI 0.74 to 2.87; I² = 0%; Analysis 2.4). Two trials (207 participants) reported on the rate of hypertension (Bhalla 2006; Yuno 1996). Seven of the 105 participants (7%) randomized to midazolam became hypertensive in comparison to six of the 152 participants (4%) randomized to placebo (RR 1.15, 95% CI 0.43 to 3.13; I² = 0%; Analysis 2.5).
Outcome 1.4. Tolerance of procedure or participant co‐operation
No trials reported this outcome for the intravenous midazolam versus placebo comparison.
Outcome 1.5. Participant or proceduralist satisfaction
Proceduralist satisfaction was greater for participants randomized to midazolam in a trial of 40 participants (Yuno 1996): mean 0.9 (SD 0.22) for 20 participants randomized to midazolam; mean 2.7 (SD 0.22) for 20 participants randomized to placebo; P < 0.001; measured on a four‐point scale with lower scores indicating greater satisfaction. Participant satisfaction (measured as the number of participants reporting that they would not be willing to undergo another procedure with the same medication) was greater in the midazolam group (50/50 in midazolam group versus 41/50 in placebo group; P = 0.003; Rolo 2012). Participant satisfaction was also greater in the midazolam group of the trial of 40 participants (Yuno 1996); mean 1.45 (SD 0.15) for 20 participants randomized to midazolam; mean 3.1 (SD 0.16) for 20 participants randomized to placebo; P < 0.001; measured on a four‐point scale with lower scores indicating greater satisfaction.
Outcome 1.6. Incomplete procedures/difficulty performing procedure
Midazolam reduced the risk of difficulty performing the procedure in Bhalla 2006, with 167 participants (3/85 in midazolam group; 8/82 in placebo group; P = 0.129).
Secondary outcomes
Outcome 2.1. Duration of sedation
No trials reported this outcome for the intravenous midazolam versus placebo comparison.
Outcome 2.2. Onset time of sedation
No trials reported this outcome for the intravenous midazolam versus placebo comparison.
Outcome 2.3. Offset time of sedation
No trials reported this outcome for the intravenous midazolam versus placebo comparison.
Outcome 2.4. Anterograde amnesia (defined by number of participants who recalled the procedure)
No trials reported this outcome for the intravenous midazolam versus placebo comparison.
Outcome 2.5. Oversedation
No trials reported this outcome for the intravenous midazolam versus placebo comparison.
Outcome 2.6. Disinhibition or excitation
No trials reported this outcome for the intravenous midazolam versus placebo comparison.
Outcome 2.7. Quality of recovery
No trials reported this outcome for the intravenous midazolam versus placebo comparison.
Outcome 2.8. Discomfort/pain
There was no difference in the number of participants who had discomfort/pain in Bhalla 2006 (167 participants) who had upper gastrointestinal endoscopy (3/85 in the midazolam group; 4/82 in the placebo group; P = 0.876).
Outcome 2.9. Allergic or anaphylactoid reactions
No trials reported this outcome for the intravenous midazolam versus placebo comparison.
Outcome 2.10. Sedation reversal
Rolo 2012 (100 participants) reported on the requirement for sedation reversal; however, no events were reported in either group.
Intravenous midazolam versus propofol (comparison 6, outcomes 1.1 to 1.6 and 2.1 to 2.10)
We identified one trial with 17 participants that investigated the use of midazolam versus propofol before electrical cardioversion (Coll‐Vinent 2003). The midazolam group (eight participants) were given a dose of 0.2 mg/kg and the propofol group (nine participants) were given a dose of 1.5 mg/kg.
Primary outcomes
Outcome 1.1. Level of sedation on a sedation assessment scale
Level of sedation (measured using the Ramsay scale) was similar between groups: median score of 6 with interquartile range 5 and 6 in both groups.
Outcome 1.2. Numeric rating scale of anxiety or number of participants rated as anxious
No trials reported this outcome for the intravenous midazolam versus propofol comparison.
Outcome 1.3. Vital signs
There were no statistically significant differences in the vital signs measured between groups. Median systolic blood pressure after sedation in the midazolam group was 141 mmHg (range 99 ‐ 165) and 120 mmHg (range 100 ‐ 172) in the propofol group. One participant in the midazolam group experienced oxygen desaturation, with SpO₂ below 90%, and no events occurring in the propofol group.
Outcome 1.4. Tolerance of procedure or participant co‐operation
No trials reported this outcome for the intravenous midazolam versus propofol comparison.
Outcome 1.5. Participant or proceduralist satisfaction
No trials reported this outcome for the intravenous midazolam versus propofol comparison.
Outcome 1.6. Incomplete procedures/difficulty performing procedures
No trials reported this outcome for the intravenous midazolam versus propofol comparison.
Secondary outcomes
Outcome 2.1. Duration of sedation
The median duration of sedation was lower in the propofol group compared with midazolam by 13 minutes (median 21 minutes with range from 1 ‐ 42 minutes in midazolam group; median 8 minutes with range from 3 ‐ 15 minutes in propofol group; P = 0.021).
Outcome 2.2. Onset time of sedation
The median onset time of sedation was 70 seconds lower in the propofol group compared with midazolam (median 120 seconds in the midazolam group; median 50 seconds in the propofol group, with range from 30 ‐ 100 seconds; P = 0.28).
Outcome 2.3. Offset time of sedation
The median offset time of sedation was 35 minutes lower in the propofol group compared with midazolam (median offset time was 45 minutes with range from 20 ‐ 60 minutes in the midazolam group; median offset time was 10 minutes with range from 5 ‐ 15 minutes in the propofol group; P = 0.002).
Outcome 2.4. Anterograde amnesia (defined by number of participants who recalled the procedure)
No trials reported this outcome for the intravenous midazolam versus propofol comparison.
Outcome 2.5. Oversedation
No trials reported this outcome for the intravenous midazolam versus propofol comparison.
Outcome 2.6. Disinhibition or excitation
No trials reported this outcome for the intravenous midazolam versus propofol comparison.
Outcome 2.7. Quality of recovery
No trials reported this outcome for the intravenous midazolam versus propofol comparison.
Outcome 2.8. Discomfort/pain
No trials reported this outcome for the intravenous midazolam versus propofol comparison.
Outcome 2.9. Allergic or anaphylactoid reactions
No trials reported this outcome for the intravenous midazolam versus propofol comparison.
Outcome 2.10. Sedation reversal
No trials reported this outcome for the intravenous midazolam versus propofol comparison.
Oral midazolam versus chloral hydrate (comparison 7, outcomes 1.1 to 1.6 to 2.1 to 2.10)
Four trials (Akil 2005; D'Agostino 2000; Derakhshanfar 2013; Wheeler 2001) with 268 participants compared oral midazolam with chloral hydrate for sedation of children (summary of findings Table 3). Doses for midazolam and chloral hydrate differed between the trials (Table 3).
| Study | Oral midazolam | Oral chloral hydrate |
| 0.6 mg/kg (max 15 mg) | 25 mg/kg (max 0.5 g) | |
| 0.5 mg/kg (max 10 mg) | 75 mg/kg (max 2 g) | |
| 0.5 mg/kg midazolam. Additional dose up to 8 mg for inadequate sedation | 80 mg/kg chloral hydrate followed by further dose 20 mg/kg if required 20 minutes later | |
| 0.5 mg/kg midazolam; second dose 30 minutes after the initial dose, either 0.25 mg/kg | 75 mg/kg oral chloral hydrate; 30 minutes after the initial dose 25 mg/kg |
Primary outcomes
Outcome 1.1. Level of sedation on a sedation assessment scale
In one trial (Derakhshanfar 2013) with 160 participants, more children (n = 61; 76.25%) in the chloral hydrate group were rated at the highest level of sedation compared with the midazolam group (n = 12; 15%), measured using Wheeler's sedation scale (Wheeler 2001) with scores ranging from 1 = agitated to 4 = eyes closing spontaneously but response to minor stimuli. We downgraded the evidence from this trial to moderate quality, due to concerns about study limitations.
Outcome 1.2. Numeric rating scale of anxiety or number of participants rated as anxious
Although a numerical rating of anxiety was reported in two trials with 88 participants, we did not conduct meta‐analysis because of differences in how this outcome was measured (by children using a numerical rating scale in D'Agostino 2000, and by parents using the Speilberger's Trait Anxiety Inventory in Akil 2005). There was no difference between groups in either D'Agostino 2000 (mean 1.4 (SD 2.26) in midazolam group; mean 2.5 (SD 0.97) in the chloral hydrate group; P = 0.07) or in Akil 2005 (mean 47.56 (SD 11.68) in midazolam group; 49.39 (SD 16) in chloral hydrate group; not significant at P < 0.05 level). We downgraded the evidence for this outcome to very low, due to concerns about study limitation, inconsistency and imprecision.
Outcome 1.3. Vital signs
No trials reported this outcome for the oral midazolam versus chloral hydrate comparison.
Outcome 1.4. Tolerance of procedure or participant co‐operation
Tolerance of the procedure was measured using the Frankl behaviour rating scale (range 1 to 4, with higher scores indicating better tolerance) in Akil 2005 with 35 participants. The difference between groups in tolerance was not statistically significant (mean 2.25 (SD 0.86) in the midazolam group; mean 2.5 (SD 1.1) in the chloral hydrate group; not significant at P < 0.05 level). Participant co‐operation was measured using the Houpt behavioural scale (range 1 to 6, with higher scores indicating better co‐operation) in Akil 2005. Participant co‐operation was rated better in the midazolam group (mean 4.94 (SD 1.12) in the midazolam group; mean 4.78 (SD 1) in the chloral hydrate group; P = 0.018).
Outcome 1.5. Participant or proceduralist satisfaction
No trials reported this outcome for the oral midazolam versus chloral hydrate comparison.
Outcome 1.6. Incomplete procedures/difficulty performing procedures
All four trials (268 participants) included in this comparison reported on this outcome (Akil 2005; D'Agostino 2000; Derakhshanfar 2013; Wheeler 2001). There were 37 incomplete procedures in the midazolam group (from 144 participants; 26%) in comparison to seven incomplete procedures in the chloral hydrate group (124 participants; 6%) (RR 4.01, 95% CI 1.92 to 8.40; I² = 0%; Analysis 3.1). We downgraded the quality of evidence to moderate, due to concerns about study limitations.
Secondary outcomes
Outcome 2.1. Duration of sedation
No trials reported this outcome for the oral midazolam versus chloral hydrate comparison.
Outcome 2.2. Onset time of sedation
Meta‐analysis of the two trials (Derakhshanfar 2013; Wheeler 2001) with 200 participants (105 in midazolam group; 53%) revealed that there was no difference in the onset of sedation between midazolam and chloral hydrate (MD 8.37 minutes, 95% CI ‐3.49 to 20.23; Analysis 3.2). The results were inconsistent (I² = 98%) even though similar dosing regimens were used (Table 3).
Outcome 2.3. Offset time of sedation
There was no difference in the offset of sedation (MD ‐12.87 minutes, 95% CI ‐63.24 to 37.50; Analysis 3.3) between midazolam (127 participants; 55%) and chloral hydrate (106 participants; 45%) in meta‐analysis of three trials (D'Agostino 2000; Derakhshanfar 2013; Wheeler 2001) with 233 participants. There was unexplained heterogeneity (I² = 99%).
Outcome 2.4. Anterograde amnesia (defined by number of participants who recalled the procedure)
No trials reported this outcome for the oral midazolam versus chloral hydrate comparison.
Outcome 2.5. Oversedation
No trials reported this outcome for the oral midazolam versus chloral hydrate comparison.
Outcome 2.6. Disinhibition or excitation
There was no difference in disinhibition or excitation between midazolam or chloral hydrate groups in Derakhshanfar 2013 (13/67 in midazolam group; 10/70 in chloral hydrate group; P = 0.208). No events were observed in either group in Wheeler 2001 (40 participants).
Outcome 2.7. Quality of recovery
No trials reported this outcome for the oral midazolam versus chloral hydrate comparison.
Outcome 2.8. Discomfort/pain
No trials reported this outcome for the oral midazolam versus chloral hydrate comparison.
Outcome 2.9. Allergic or anaphylactoid reactions
No trials reported this outcome for the oral midazolam versus chloral hydrate comparison.
Outcome 2.10. Sedation reversal
No trials reported this outcome for the oral midazolam versus chloral hydrate comparison.
Oral midazolam versus diazepam (comparison 8, outcomes 1.1 to 1.6 and 2.1 to 2.10)
Oral midazolam was compared with diazepam in two trials with 122 participants (De Alencar 2010; Everitt 2002). In De Alencar 2010 the midazolam group was given a 15 mg dose and the diazepam group was given a 10 mg dose. The midazolam dose was 1.0 mg/kg (maximum 15 mg) and the diazepam dose was 0.5 mg/kg (maximum 10 mg) in Everitt 2002.
Primary outcomes
Outcome 1.1. Level of sedation on a sedation assessment scale
More participants who received midazolam (14/17) in De Alencar 2010 were sedated to the level of 'somnolence' than the diazepam group (3/18). In a trial with 87 participants that compared oral midazolam with diazepam in children undergoing laceration repair, midazolam produced higher levels of sedation, regardless of whether sedation was rated by the investigator: mean 16 (SD 19) for 45 participants randomized to midazolam; mean 33 (SD 31) for 42 participants randomized to diazepam (Everitt 2002).
Outcome 1.2. Numeric rating scale of anxiety or number of participants rated as anxious
No trials reported this outcome for the oral midazolam versus diazepam comparison.
Outcome 1.3. Vital signs
Changes in vital signs one hour after the administration of sedation were reported in one trial with 35 participants that compared oral midazolam with diazepam administered before undergoing blepharoplasty (De Alencar 2010). The mean change in systolic blood pressure after administration of midazolam was ‐1.9 mmHg (SD 3.06) compared with an increase of 3.8 mmHg (SD 6.77) after administration of diazepam. The mean change in diastolic blood pressure after administration of midazolam was ‐9.7 mmHg (SD 3.43) compared with an increase of 4.4 mmHg (SD 3.78) after administration of diazepam. The mean change in heart rate after administration of midazolam was ‐4.5 (SD 2.87) compared with ‐6.3 (SD 2.39) after administration of diazepam. The mean change in oxygen saturation after administration of midazolam was ‐0.31% (SD 0.38) compared with ‐1.35% (SD 1.06) after administration of diazepam.
Outcome 1.4. Tolerance of procedure or participant co‐operation
No trials reported this outcome for the oral midazolam versus diazepam comparison.
Outcome 1.5. Participant or proceduralist satisfaction
No trials reported this outcome for the oral midazolam versus diazepam comparison.
Outcome 1.6. Incomplete procedures/difficulty performing procedures
No trials reported this outcome for the oral midazolam versus diazepam comparison.
Secondary outcomes
Outcome 2.1. Duration of sedation
No trials reported this outcome for the oral midazolam versus diazepam comparison.
Outcome 2.2. Onset time of sedation
No trials reported this outcome for the oral midazolam versus diazepam comparison.
Outcome 2.3. Offset time of sedation
No trials reported this outcome for the oral midazolam versus diazepam comparison.
Outcome 2.4. Anterograde amnesia (defined by number of participants who recalled the procedure)
No trials reported this outcome for the oral midazolam versus diazepam comparison.
Outcome 2.5. Oversedation
No trials reported this outcome for the oral midazolam versus diazepam comparison.
Outcome 2.6. Disinhibition or excitation
No trials reported this outcome for the oral midazolam versus diazepam comparison.
Outcome 2.7. Quality of recovery
Quality of recovery was reported in one trial (Everitt 2002). More children were reported to be drowsy after discharge in the midazolam group (18/35 compared with 10/31; P = 0.032).
Outcome 2.8. Discomfort/pain
No trials reported this outcome for the oral midazolam versus diazepam comparison.
Outcome 2.9. Allergic or anaphylactoid reactions
No trials reported this outcome for the oral midazolam versus diazepam comparison.
Outcome 2.10. Sedation reversal
No trials reported this outcome for the oral midazolam versus diazepam comparison.
Oral midazolam versus diazepam and clonidine (comparison 9, outcomes 1.1 to 1.6)
Oral midazolam was compared with a combination of diazepam and clonidine in one trial with 34 participants (De Alencar 2010). Seventeen participants were randomized to receive 15 mg midazolam and 17 participants to receive 10 mg diazepam with 0.15 mg clonidine.
Primary outcomes
Outcome 1.1. Level of sedation on a sedation assessment scale
Level of sedation was measured using the Michigan University Scale, with a range in scores from 0 = awake to 4 = unrousable to stimuli. Measures of central tendency were not reported in the article.
Outcome 1.2. Numeric rating scale of anxiety or number of participants rated as anxious
No trials reported this outcome for the oral midazolam versus diazepam and clonidine comparison.
Outcome 1.3. Vital signs
The mean change in systolic blood pressure one hour after administration of midazolam was ‐1.9 mmHg (SD 3.06) compared with an increase of 5.8 mmHg (SD 4.65) after administration of diazepam. The mean change in diastolic blood pressure after administration of midazolam was ‐9.7 mmHg (SD 3.43) compared with an increase of 6.1 mmHg (SD 2.54) after administration of diazepam. The mean change in heart rate after administration of midazolam was ‐4.5 (SD 2.87) compared with ‐9.2 (SD 1.98) after administration of diazepam. The mean change in oxygen saturation after administration of midazolam was ‐0.31% (SD 0.38) compared with ‐0.11% (SD 0.48) after administration of diazepam.
Outcome 1.4. Tolerance of procedure or participant co‐operation
No trials reported this outcome for the oral midazolam versus diazepam and clonidine comparison.
Outcome 1.5. Participant or proceduralist satisfaction
No trials reported this outcome for the oral midazolam versus diazepam and clonidine comparison.
Outcome 1.6. Incomplete procedures/difficulty performing procedures
No trials reported this outcome for the oral midazolam versus diazepam and clonidine comparison.
Secondary outcomes
None of the secondary outcomes were reported by the included trials.
Oral midazolam versus ketamine (comparison 10, outcomes 1.1 to 1.6 and 2.1. to 2.10)
Younge 2001 compared 0.7 mg/kg oral midazolam with 10 mg/kg oral ketamine in a RCT for sedation before laceration repair in 59 children.
Primary outcomes
Outcome 1.1. Level of sedation on a sedation assessment scale
Children who received ketamine were more deeply sedated (median score 2 versus 3 (lower score = deeper sedation)).
Outcome 1.2. Numeric rating scale of anxiety or number of participants rated as anxious
No trials reported this outcome for the oral midazolam versus ketamine comparison.
Outcome 1.3. Vital signs
There was no significant difference between the medications for oxygen desaturation (2/29 in midazolam group; 1/30 in ketamine group).
Outcome 1.4. Tolerance of procedure or participant co‐operation
No trials reported this outcome for the oral midazolam versus ketamine comparison.
Outcome 1.5. Participant or proceduralist satisfaction
No trials reported this outcome for the oral midazolam versus ketamine comparison.
Outcome 1.6. Incomplete procedures/difficulty performing procedures
No trials reported this outcome for the oral midazolam versus ketamine comparison.
Secondary outcomes
Outcome 2.1. Duration of sedation
No trials reported this outcome for the oral midazolam versus ketamine comparison.
Outcome 2.2. Onset time of sedation
No trials reported this outcome for the oral midazolam versus ketamine comparison.
Outcome 2.3. Offset time of sedation
No trials reported this outcome for the oral midazolam versus ketamine comparison.
Outcome 2.4. Anterograde amnesia (defined by number of participants who recalled the procedure
No trials reported this outcome for the oral midazolam versus ketamine comparison.
Outcome 2.5. Oversedation
No trials reported this outcome for the oral midazolam versus ketamine comparison.
Outcome 2.6. Disinhibition or excitation
Six of the 29 participants randomized to midazolam experienced disinhibition/excitation in comparison to none of the 30 participants randomized to ketamine (P = 0.01).
Outcome 2.7. Quality of recovery
No trials reported this outcome for the oral midazolam versus ketamine comparison.
Outcome 2.8. Discomfort/pain
No trials reported this outcome for the oral midazolam versus ketamine comparison.
Outcome 2.9. Allergic or anaphylactoid reactions
No trials reported this outcome for the oral midazolam versus ketamine comparison.
Outcome 2.10. Sedation reversal
No trials reported this outcome for the oral midazolam versus ketamine comparison.
Oral midazolam versus placebo (comparison 11, outcomes 1.1 to 1.6 and 2.1 to 2.10)
Three trials (Akil 2005; Kuganeswaran 1999; Templeton 2010) with 176 participants compared midazolam administered via the oral route with a placebo (summary of findings Table 4). Kuganeswaran 1999 was conducted in adults undergoing outpatient sigmoidoscopy (99 participants) and used a 7.5 mg dose of midazolam. Templeton 2010 was conducted in children undergoing removal of Kirschner wires (42 participants) and the 20 participants randomized to midazolam received 0.2 mL/kg of 1 mg/mL midazolam oral solution. Akil 2005 enrolled children undergoing micturating cystourethrography (35 participants). The 16 participants randomized to midazolam received a 0.6 mg/kg maximum 15 mg) dose.
Primary outcomes
Outcome 1.1. Level of sedation on a sedation assessment scale
Kuganeswaran 1999 reported that levels of sedation became statistically significantly different between the midazolam and placebo groups 10 minutes after administration. However, the actual summary statistics were not reported in the article.
Outcome 1.2. Numeric rating scale of anxiety or number of participants rated as anxious
There was no difference in anxiety between groups in Templeton 2010 (mean 1.7 (SD 2.4) for 20 participants randomized to midazolam; mean 2.6 (SD 2.9) for 22 participants randomized to placebo; P = 0.216), nor in Akil 2005 (mean Spielberger's Trait Anxiety Inventory score was 47.56 (SD 11.68) in the midazolam group compared with mean 52.78 (SD 9.61) in placebo group; P > 0.05). In contrast, there was a statistically significant reduction in numerical rating of anxiety in Kuganeswaran 1999 (mean 1.52 (SD 0.3) in midazolam group; mean 3.97 (SD 0.44) in placebo group; P < 0.0001).
Outcome 1.3. Vital signs
The rate of hypotension was reported in Kuganeswaran 1999. There was no difference between groups (2/51 midazolam; 0/48 placebo).
Outcome 1.4. Tolerance of procedure or participant co‐operation
Tolerance of the procedure was measured using the Frankl behaviour rating scale (range 1 to 4, with higher scores indicating better tolerance) in Akil 2005 with 35 participants. The difference between groups in tolerance was not statistically significant (mean 2.25 (SD 0.86) in midazolam group; mean 2.12 (SD 1.05) in placebo group). Participant co‐operation was measured using the Houpt behavioural scale (range 1 to 6, with higher scores indicating better co‐operation) in Akil 2005 with 35 participants. The mean participant co‐operation rating was 4.94 (SD 1.12) in the midazolam group compared with 4.12 (SD 1.05) in the placebo group.
Outcome 1.5. Participant or proceduralist satisfaction
Participant satisfaction (measured by participants' perception that they received inadequate sedation for their procedure) in Kuganeswaran 1999 was superior in the midazolam group (14/51 in midazolam group; 31/48 in placebo group; P < 0.05).
Outcome 1.6. Incomplete procedures/difficulty performing procedures
There were no incomplete procedures in either the midazolam or placebo groups in either Kuganeswaran 1999 or Templeton 2010, and only one procedure could not be completed in the midazolam group in Akil 2005.
Secondary outcomes
Outcome 2.1. Duration of sedation
No trials reported this outcome for the oral midazolam versus placebo comparison.
Outcome 2.2. Onset time of sedation
No trials reported this outcome for the oral midazolam versus placebo comparison.
Outcome 2.3. Offset time of sedation
No trials reported this outcome for the oral midazolam versus placebo comparison.
Outcome 2.4. Anterograde amnesia (defined by number of participants who recalled the procedure)
There was no difference in anterograde amnesia between midazolam (41/51 participants) and placebo (44/48 participants) in Kuganeswaran 1999.
Outcome 2.5. Oversedation
No trials reported this outcome for the oral midazolam versus placebo comparison.
Outcome 2.6. Disinhibition or excitation
No trials reported this outcome for the oral midazolam versus placebo comparison.
Outcome 2.7. Quality of recovery
No trials reported this outcome for the oral midazolam versus placebo comparison.
Outcome 2.8. Discomfort/pain
Kuganeswaran 1999, conducted with 99 participants undergoing sigmoidoscopy, reported that the administration of oral midazolam resulted in a statistically significant reduction in discomfort/pain compared with placebo (mean 2.56 (SD 0.49) in midazolam group; mean 4.62 (SD 1.49) in placebo group; P < 0.005).
Outcome 2.9. Allergic or anaphylactoid reactions
No trials reported this outcome for the oral midazolam versus placebo comparison.
Outcome 2.10. Sedation reversal
No trials reported this outcome for the oral midazolam versus placebo comparison.
Intranasal midazolam versus placebo (comparison 12, outcomes 1.1 to 1.6)
Two trials (149 participants) compared midazolam administered via the intranasal route for sedation before a procedure with placebo (Hollenhorst 2001; Stokland 2003). Hollenhorst 2001 compared intranasal midazolam with placebo in adults undergoing magnetic resonance imaging, while Stokland 2003 was conducted in children requiring cystourethrography.
Primary outcomes
Outcome 1.1. Level of sedation on a sedation assessment scale
A deeper level of sedation was observed in the midazolam group (mean 3.15 (SD 0.36) in midazolam group; mean 2.56 (SD 0.64) in placebo group; P < 0.001) in Hollenhorst 2001. We downgraded this evidence to moderate quality, due to concerns about study limitations arising from an unclear risk of bias from randomization sequence generation and allocation concealment.
Outcome 1.2. Numeric rating scale of anxiety or number of participants rated as anxious
Hollenhorst 2001 reported a marked reduction in a numerical rating of anxiety among participants who received midazolam prior to their magnetic resonance imaging procedure (mean 17.3 (SD 18.58) in midazolam group; mean 49.3 (SD 29.46) in placebo group; P < 0.001). We downgraded this evidence to moderate quality, due to concerns about study limitations arising from an unclear risk of bias from randomization sequence generation and allocation concealment.
Outcome 1.3. Vital signs
No trials reported this outcome for the intranasal midazolam versus placebo comparison.
Outcome 1.4. Tolerance of procedure or participant co‐operation
No trials reported this outcome for the intranasal midazolam versus placebo comparison.
Outcome 1.5. Participant or proceduralist satisfaction
No trials reported this outcome for the intranasal midazolam versus placebo comparison.
Outcome 1.6. Incomplete procedures/difficulty performing procedures
One of the primary outcomes, incomplete procedures, was reported in both of these trials (Hollenhorst 2001; Stokland 2003). Meta‐analysis of results from the 149 participants showed that the administration of midazolam compared with placebo had no impact on incomplete procedures (no incomplete procedures from 75 participants in midazolam group compared with six incomplete procedures from 74 participants in placebo group; RR 0.14, 95% CI 0.02 to 1.12; I² = 0%; Analysis 4.1). It should be noted that results from a further study that is awaiting classification, which is published in German and requires translation, is likely to have an impact on the effect estimates, so we have downgraded the quality of this evidence to 'low'.
Secondary outcomes
None of the secondary outcomes for this comparison were reported by the included trials.
Discussion
Summary of main results
The largest amount of evidence involved the comparison of intravenous midazolam with diazepam for endoscopic procedures (summary of findings Table for the main comparison). The administration of intravenous midazolam produced greater anterograde amnesia, as the risk of participants recalling the procedures was reduced by 55% (RR 0.45, 95% CI 0.30 to 0.66; 587 participants; 9 trials; Analysis 1.7). However, it is unclear how important anterograde amnesia is in regard to the effectiveness of sedation, as there was no difference in participant satisfaction between midazolam and diazepam (MD 2.17, 95% CI ‐0.51 to 4.85; scale ranged from 0 to 100 with higher scores equating to better satisfaction; 91 participants; 2 trials; Analysis 1.3). We judged the quality of this evidence to be very low or low.
Intravenous midazolam may be more effective than placebo for procedural sedation because fewer participants were rated as anxious (one trial; 100 participants; RR 0.20, 95% CI 0.06 to 0.65; Rolo 2012). However, we judged the quality of the evidence to be low (summary of findings Table 2).
Based on meta‐analysis of four trials (Akil 2005; D'Agostino 2000; Derakhshanfar 2013; Wheeler 2001) with 268 participants, midazolam was found to be inferior to chloral hydrate for sedation before procedures in children in regard to the number of incomplete procedures (RR 4.01, 95% CI 1.92 to 8.40; Analysis 3.1) However, we rated the quality of the evidence as moderate (summary of findings Table 3).
In two trials (De Alencar 2010; Everitt 2002) conducted with 122 participants (results could not be combined in meta‐analysis because of differences in measurement), midazolam produced deeper levels of sedation than diazepam when administered orally. There were no other data reported in the trials to make a definitive determination as to the superiority of midazolam over diazepam in terms of pain, anxiety or the participants' satisfaction with or tolerance of the procedures.
The evidence for the effect of oral midazolam compared with placebo on anxiety was inconsistent (summary of findings Table 4) and we judged it to be of very low quality, meaning that we are very uncertain about the effect estimates.
The administration of intranasal midazolam compared with placebo had no impact on incomplete procedures (RR 0.14, 95% CI 0.02 to 1.12; 149 participants; 2 trials; I² = 0%; Analysis 4.1). It should be noted that Hollenhorst 2001 reported a reduction in a numerical rating of anxiety (100 mm line, with 0 meaning “I am not anxious at all,” and 100 meaning “I am extremely anxious”) among participants who received midazolam prior to their magnetic resonance imaging procedure (MD ‐32.00, 95% CI ‐45.14 to ‐18.86). This result is likely due to the higher level of sedation observed in the midazolam group (MD 0.59, 95% CI 0.31 to 0.87; measured on a five‐point scale with a higher score indicating higher level of sedation). We downgraded this evidence to moderate quality, due to concerns about study limitations arising from an unclear risk of bias from randomization sequence generation and allocation concealment (summary of findings Table 5).
Overall completeness and applicability of evidence
The evidence from trials included in this review and conducted in the 1980s and 1990s that compared midazolam with diazepam have been superceded by more contemporary sedative regimens that include continuous infusions of propofol or bolus doses of benzodiazepines and opioids, which are titrated to effect throughout the procedure (Qadeer 2005; Thomson 2010; Wang 2013).
We were not able to collect data on the primary outcome from all the included trials. It is not clear that selective reporting of outcomes, if present, would favour midazolam over placebo or another medication for sedation before a procedure.
It should be noted that the participant populations were from a range of elective, mostly adult outpatients with low risk of anaesthesia‐related adverse events (American Society of Anesthesiology Class < III). The results should therefore not be considered generalizable to people undergoing urgent procedures or people at higher risk of adverse events.
This review cannot be used to draw conclusions about the harms of midazolam administered for sedation before procedures. Only allergic or anaphylactoid reactions were a prespecified outcome and no trials reported on them. Further, as only randomized controlled trials were included in this review, we were unable to detect rare adverse events that are known to be associated with the administration of sedation in large observational studies, such as death arising from undetected respiratory depression and hypoxia.
Quality of the evidence
Incomplete reporting of trial designs led to challenges in interpreting the risk of bias. Attrition was low, as is expected with short‐term trials of sedative medications. There were few data for most outcomes. As such, there was considerable uncertainty in the estimates of the effects of the interventions due to inconsistency and imprecision. For these reasons, we downgraded the evidence to moderate, low and very low quality for all outcomes included in the 'Summary of findings' tables.
Potential biases in the review process
Due to relative ambiguity in the primary outcome set in the original protocol for this review (Morão 2011), we needed to make decisions about the handling of the data after seeing it, which may have introduced bias to the review process. Another potential source of bias is that we did not seek trial protocols because most included trials were published prior to the establishment of clinical trial registries. It is also possible that if future trials use alternative (either higher or lower) doses of midazolam, results may be different from those found in the trials included in this review. For these reasons, we have been cautious about the interpretations of results of the evidence syntheses.
We were unable to classify 10 potentially eligible papers because they were not published in English and we were not able to have them translated in time (Frisancho 1996; Mendes 1986; Mignonsin 1994; Münte 2002; Thakur 2003; Wild 1988), we could not locate current contact details of authors (Bardhan 1984; Green 1984; Theroux 1993) or results were published only in abstract form and we were unable to retrieve further information from the study authors (Ogden 1993) (Characteristics of studies awaiting classification). Four of the unclassified studies could have been included in the comparison of intravenous midazolam versus diazepam (Bardhan 1984; Frisancho 1996; Green 1984; Mignonsin 1994). One of the studies could contribute further evidence about the effectiveness of intranasal midazolam versus placebo (Münte 2002). Two unclassified studies compared intramuscular midazolam with hydrocodonum for sedation before bronchoscopy (Mendes 1986; Wild 1988). One unclassified study compared oral midazolam with tricolofos sodium for sedation of children undergoing echocardiography (Thakur 2003).
Agreements and disagreements with other studies or reviews
Some results of our review are consistent with a previous meta‐analysis (McQuaid 2008), which focused only on endoscopic procedures. McQuaid 2008 also found that midazolam has a greater amnesic effect than diazepam undergoing endoscopic procedures and that participants preferred to undergo procedures with sedation rather than without. Guidelines for sedation during endoscopy recommend that a combination of a benzodiazepine and an opioid can be used to adequately sedate most patients (Cohen 2006). Results of our review do not provide any evidence to suggest otherwise.
Single‐agent sedation without additional analgesia is more often used in contemporary clinical practice for 'motion control', mainly in children for diagnostic procedures that are not painful. It is important to note that our results contrast with recommendations from the National Institute of Health and Clinical Excellence in the United Kingdom regarding the use of midazolam and chloral hydrate for paediatric sedation during diagnostic procedures (NICE 2010). Both of these medications are recommended in the guidelines if sedation is required for painless diagnostic procedures, whereas results from our meta‐analysis suggest that chloral hydrate is superior to midazolam in terms of procedural completion. A potential reason for the disagreement is that the trials included in our systematic review were not included in the guidelines report (NICE 2010) even though three of the four studies were published prior to publication of the guidelines (Akil 2005; D'Agostino 2000; Wheeler 2001). We are unsure whether they were excluded from the review or were not uncovered in the literature search strategy used by the guideline developers.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Intravenous midazolam versus diazepam, Outcome 1 Number of participants rated as 'anxious'.
Comparison 1 Intravenous midazolam versus diazepam, Outcome 2 Participant co‐operation (not co‐operative).
Comparison 1 Intravenous midazolam versus diazepam, Outcome 3 Participant satisfaction.
Comparison 1 Intravenous midazolam versus diazepam, Outcome 4 Proceduralist satisfaction.
Comparison 1 Intravenous midazolam versus diazepam, Outcome 5 Difficulty performing procedures (rated as difficult to perform procedure).
Comparison 1 Intravenous midazolam versus diazepam, Outcome 6 Onset of sedation.
Comparison 1 Intravenous midazolam versus diazepam, Outcome 7 Anterograde amnesia (defined as the number of participants who recalled procedure).
Comparison 1 Intravenous midazolam versus diazepam, Outcome 8 Quality of recovery (rated as delayed recovery).
Comparison 1 Intravenous midazolam versus diazepam, Outcome 9 Discomfort/Pain.
Comparison 2 Intravenous midazolam versus placebo, Outcome 1 Vital signs (mean lowest oxygen saturation).
Comparison 2 Intravenous midazolam versus placebo, Outcome 2 Vital signs (oxygen desaturation).
Comparison 2 Intravenous midazolam versus placebo, Outcome 3 Vital signs (hypotension).
Comparison 2 Intravenous midazolam versus placebo, Outcome 4 Vital signs (tachycardia).
Comparison 2 Intravenous midazolam versus placebo, Outcome 5 Vital signs (hypertension).
Comparison 3 Oral midazolam versus chloral hydrate, Outcome 1 Incomplete procedure.
Comparison 3 Oral midazolam versus chloral hydrate, Outcome 2 Onset time of sedation.
Comparison 3 Oral midazolam versus chloral hydrate, Outcome 3 Offset time of sedation.
Comparison 4 Intranasal midazolam versus placebo, Outcome 1 Incomplete procedure.
| Intravenous midazolam compared to diazepam for sedation before procedures | ||||||
| Patient or population: adults and children requiring sedation before gastrointestinal endoscopy and bronchoscopy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Diazepam | Midazolam | |||||
| Level of sedation on a sedation assessment scale | 75 (1 study) | very low1 | The mean level of sedation in the midazolam group was 3.2 and the mean level of sedation in the diazepam group was 2.7 on a scale that ranged from 0 to 4 (higher scores indicating more sedation). Measured with a scale that ranged from 0 ‐ 4 (higher scores indicating the participant was more sedated). | |||
| Numeric rating of anxiety or rated as anxious | 167 per 1000 | 133 per 1000 | RR 0.80 | 175 | low2 | Effect estimate calculated for number of participants rated as anxious |
| Incomplete procedure | 170 (1 study) | All procedures were completed in both groups | ||||
| Anterograde amnesia (defined by number of participants who recalled the procedure) | 481 per 1000 | 216 per 1000 | RR 0.45 | 587 | low3 | |
| Disinhibition or excitation | No studies reported on this outcome | |||||
| Discomfort/pain | 202 per 1000 | 121 per 1000 | RR 0.60 | 415 | low2 | |
| Allergic or anaphylactoid reaction | No studies reported on this outcome | |||||
| *The basis for the assumed risk is the control group risk across studies or the average risk for pooled data and the control group risk for single studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded by three levels due to very serious concerns about study limitations (risk of bias) and very serious concerns about imprecision. | ||||||
| Intravenous midazolam compared to placebo for sedation before procedures | ||||||
| Patient or population: adults requiring sedation before gastrointestinal endoscopy and bronchoscopy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Intravenous midazolam | |||||
| Level of sedation on a sedation assessment scale | 100 (1 study) | low1 | Participants who were randomized to midazolam were more sedated (the mean score on the Ramsay scale (1 to 6 with higher scores indicating the participant was more sedated) was 2.77 ± 1.19 in the midazolam group and 1.72 ± 0.50 in the placebo group. | |||
| Numeric rating of anxiety or rated as anxious | 100 (1 study) | low1 | Authors of this trial reported that fewer participants who received midazolam were anxious (3/50 in midazolam group; 15/50 in placebo group) but results of statistical tests were not reported. | |||
| Incomplete procedures | No studies reported on this outcome | |||||
| Anterograde amnesia (defined by number of participants who recalled the procedure) | No studies reported on this outcome | |||||
| Disinhibition or excitation | No studies reported on this outcome | |||||
| Discomfort/pain | 167 (1 study) | very low2 | There was no difference in the number of participants who had discomfort/pain during upper gastrointestinal endoscopy (3/85 in midazolam group; 4/82 in placebo group; P = 0.876). Measured in the trial as 'uncomfortable' | |||
| Allergic or anaphylactoid reaction | No studies reported on this outcome | |||||
| *The basis for the assumed risk is the control group risk across studies or the average risk for pooled data and the control group risk for single studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded two levels due to concerns about study limitations and imprecision. | ||||||
| Oral midazolam compared to chloral hydrate for sedation before procedures | ||||||
| Patient or population: children requiring sedation before procedures that require motion control, including echocardiography, lumbar puncture, micturating cystourethrograms and neuroimaging | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Chloral hydrate | Oral midazolam | |||||
| Level of sedation on sedation assessment scale | 160 (1) | moderate1 | 61 participants (76.25%) in the chloral hydrate group were rated at the highest level of sedation compared with 12 (15%) in the midazolam group (scores ranged from 1 = agitated to 4 = eyes closing spontaneously but response to minor stimuli) | |||
| Numeric rating of anxiety or rated as anxious | The mean rating of anxiety in D'Agostino 2000 was 2.5 The mean rating of anxiety in Akil 2005 was 49.4 | The mean rating of anxiety in the D'Agostino 2000 trial (33 participants) was The mean rating of anxiety in the Akil 2005 trial (35 participants) was 1.83 lower (on the Spielberger's Trait Anxiety Inventory) | 88 | very low2 | We did not conduct meta‐analysis because this outcome was measured differently in the trials (could have been answered by parents or children in Akil 2005). | |
| Incomplete procedures | 56 per 1000 | 226 per 1000 | RR 4.01 | 268 | moderate1 | |
| Anterograde amnesia (defined by number of participants who recalled the procedure) | No studies reported on this outcome | |||||
| Disinhibition or excitation | No studies reported on this outcome | |||||
| Discomfort | No studies reported on this outcome | |||||
| Allergic or anaphylactoid reaction | No studies reported on this outcome | |||||
| *The basis for the assumed risk is the control group risk across studies or the average risk for pooled data and the control group risk for single studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level due to concerns about study limitations. | ||||||
| Oral midazolam compared to placebo for sedation before procedures | ||||||
| Patient or population: children requiring sedation before micturating cystourethrograms and Kirschner wire removal and adults undergoing flexible sigmoidoscopy | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Midazolam | |||||
| Level of sedation on a sedation assessment scale | 99 (1) | moderate1 | Reported that level of sedation became statistically significantly different at 10 minutes after administration of medication but mean and standard deviations for midazolam and placebo group level of sedation were not reported in the article. Scores ranged from 0 = awake to 3 = asleep, responsive only to direct verbal or physical stimulus. | |||
| Numeric rating of anxiety or rated as anxious | The mean rating of anxiety in the Kuganeswaran 1999 trial was 4.2 The mean rating of anxiety in Templeton 2010 was 2.6 The mean rating of anxiety in Akil 2005 was 52.8 | The mean anxiety score in Kuganeswaran 1999 (99 participants) was 2.52 lower (minimum score 0, maximum score 10; higher score indicates greater anxiety) The mean anxiety score in Templeton 2010 (42 participants) was 0.90 lower (minimum score 0, maximum score 8; higher score indicate greater anxiety) The mean anxiety score in Akil 2005 (35 participants) was 5.20 lower (on the Spielberger's Trait Anxiety Inventory) | 176 | very low2 | We did not conduct meta‐analysis because of clinical heterogeneity (children and adults undergoing different procedures). | |
| Incomplete procedure | 179 (3 studies) | very low3 | We did not conduct meta‐analysis because of clinical heterogeneity (children and adults undergoing different procedures). There was one incomplete procedure in the midazolam group in one of the three trials that reported on this outcome. | |||
| Anterograde amnesia (defined by number of participants who recalled the procedure) | No studies reported on this outcome | |||||
| Disinhibition or excitation | No studies reported on this outcome | |||||
| Discomfort/Pain | 99 (1 study) | moderate1 | Statistically significant reduction in discomfort/pain (mean 2.56 (SD 0.49) in midazolam group; mean 4.62 (SD 1.49) in placebo group; P < 0.005; scores ranged from 0 to 10; higher score indicated more pain). | |||
| Allergic or anaphylactoid reaction | No studies reported on this outcome | |||||
| *The basis for the assumed risk is the control group risk across studies or the average risk for pooled data and the control group risk for single studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded one level due to concerns about study limitations. | ||||||
| Intranasal midazolam compared to placebo for sedation before procedures | ||||||
| Patient or population: Children requiring sedation before voiding cystourethrograms and adults undergoing MRI | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| Placebo | Intranasal midazolam | |||||
| Level of sedation on a sedation assessment scale | 54 (1 study) | moderate1 | Deeper level of sedation was observed in the midazolam group (mean 3.15 (SD 0.36) in midazolam group; mean 2.56 (SD 0.64) in placebo group; P < 0.001). Level of sedation measured 15 minutes after medication by one of the authors using a five‐point sedation scale (1 = agitated, non‐co‐operative; 2 = alert, restless; 3 = calm, eyes spontaneously open; 4 = drowsy, responds to minor stimulation; 5 = asleep, rousable but does not respond to minor stimulation). | |||
| Numeric rating of anxiety or rated as anxious | 54 (1 study) | moderate1 | Reduction in a numerical rating of anxiety among participants who received midazolam prior to magnetic resonance imaging procedure (mean 17.3 (SD 18.58) in midazolam group; mean 49.3 (SD 29.46) in placebo group; P < 0.001). Numerical rating of anxiety measured 15 minutes after medication on a Visual Analogue Scale of Anxiety comprised an undivided 100‐mm line, with 0 meaning “I am not anxious at all,” and 100 meaning “I am extremely anxious.” | |||
| Incomplete procedure | 81 per 1000 | 11 per 1000 | RR 0.14 | 149 | low2 | |
| Anterograde amnesia (defined by number of participants who recalled the procedure) | No studies reported on this outcome | |||||
| Disinhibition or excitation | No studies reported on this outcome | |||||
| Discomfort/pain | No studies reported on this outcome | |||||
| Allergic or anaphylactoid reaction | No studies reported on this outcome | |||||
| *The basis for the assumed risk is the control group risk across studies or the average risk for pooled data and the control group risk for single studies. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded two levels due to concerns about study limitations. | ||||||
| Study | Dose of midazolam | Dose of diazepam |
| 0.06 mg/kg | 0.15 mg/kg | |
| 5 mg (3 mg if older than 65) | 5 mg (3 mg if older than 65) | |
| 2.5 mg or 1 mg for elderly (mean 6.0 ± 2.8) | 5 mg or 2 mg for elderly (mean 11.5 ± 6.7) | |
| 0.07 mg/kg | 0.15 mg/kg | |
| 5 mg bolus with 2.5 ‐ 3.75 mg increments at 30‐ ‐ 60‐second intervals as required. Half doses for elderly | 5 mg bolus with 2.5 ‐ 3.75 mg increments at 30‐ ‐ 60‐second intervals as required. Half doses for elderly | |
| 0.10 mg/kg | 0.15 mg/kg | |
| 10 mg | 20 mg | |
| 0.1 mg/kg | 0.2 mg/kg | |
| 2.5 ‐ 7.5 mg | 2.5 ‐ 10 mg | |
| 0.07 mg/kg | 0.15 mg/kg | |
| 0.1 mg under 65 yrs and 0.085 mg over 65 yrs infused in 30 seconds | 0.2 mg under 65 yrs and 0.15 mg over 65 yrs infused in 30 seconds | |
| mean 5.8 mg | mean 5 mg | |
| 0.1 ‐ 0.15 mg/kg | 0.2 ‐ 0.4 mg/kg | |
| 0.07 mg/kg | 0.15 mg/kg |
| Study | Dose of midazolam |
| 5 mg (3 mg if over 65 years old) | |
| mean 3.2 mg (SD 1.6) | |
| 2.5 ‐ 7.5 mg | |
| 0.05 mg/kg | |
| 0.05 mg/kg |
| Study | Oral midazolam | Oral chloral hydrate |
| 0.6 mg/kg (max 15 mg) | 25 mg/kg (max 0.5 g) | |
| 0.5 mg/kg (max 10 mg) | 75 mg/kg (max 2 g) | |
| 0.5 mg/kg midazolam. Additional dose up to 8 mg for inadequate sedation | 80 mg/kg chloral hydrate followed by further dose 20 mg/kg if required 20 minutes later | |
| 0.5 mg/kg midazolam; second dose 30 minutes after the initial dose, either 0.25 mg/kg | 75 mg/kg oral chloral hydrate; 30 minutes after the initial dose 25 mg/kg |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Number of participants rated as 'anxious' Show forest plot | 2 | 175 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.80 [0.39, 1.62] |
| 2 Participant co‐operation (not co‐operative) Show forest plot | 4 | 316 | Risk Ratio (M‐H, Random, 95% CI) | 0.94 [0.48, 1.84] |
| 3 Participant satisfaction Show forest plot | 2 | 91 | Mean Difference (IV, Fixed, 95% CI) | 2.17 [‐0.51, 4.85] |
| 4 Proceduralist satisfaction Show forest plot | 2 | 91 | Mean Difference (IV, Fixed, 95% CI) | 1.09 [‐10.43, 12.60] |
| 5 Difficulty performing procedures (rated as difficult to perform procedure) Show forest plot | 3 | 277 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.66 [0.41, 1.07] |
| 6 Onset of sedation Show forest plot | 2 | 140 | Mean Difference (IV, Random, 95% CI) | ‐1.80 [‐3.76, 0.16] |
| 7 Anterograde amnesia (defined as the number of participants who recalled procedure) Show forest plot | 9 | 587 | Risk Ratio (M‐H, Random, 95% CI) | 0.45 [0.30, 0.66] |
| 8 Quality of recovery (rated as delayed recovery) Show forest plot | 3 | 166 | Risk Ratio (M‐H, Random, 95% CI) | 0.72 [0.08, 6.63] |
| 9 Discomfort/Pain Show forest plot | 5 | 415 | Risk Ratio (M‐H, Random, 95% CI) | 0.60 [0.24, 1.49] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Vital signs (mean lowest oxygen saturation) Show forest plot | 2 | 207 | Mean Difference (IV, Fixed, 95% CI) | ‐1.50 [‐1.77, ‐1.23] |
| 2 Vital signs (oxygen desaturation) Show forest plot | 3 | 447 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.12 [0.79, 1.58] |
| 3 Vital signs (hypotension) Show forest plot | 2 | 140 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.43 [0.07, 2.78] |
| 4 Vital signs (tachycardia) Show forest plot | 2 | 207 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.46 [0.74, 2.87] |
| 5 Vital signs (hypertension) Show forest plot | 2 | 207 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.15 [0.43, 3.13] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incomplete procedure Show forest plot | 4 | 268 | Risk Ratio (M‐H, Fixed, 95% CI) | 4.01 [1.92, 8.40] |
| 2 Onset time of sedation Show forest plot | 2 | 200 | Mean Difference (IV, Random, 95% CI) | 8.37 [‐3.49, 20.23] |
| 3 Offset time of sedation Show forest plot | 3 | 233 | Mean Difference (IV, Random, 95% CI) | ‐12.87 [‐63.24, 37.50] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Incomplete procedure Show forest plot | 2 | 149 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.14 [0.02, 1.12] |
