Chloral hydrate as a sedating agent for neurodiagnostic procedures in children

Abstract

Background

This is an updated version of a Cochrane Review published in 2017.

Paediatric neurodiagnostic investigations, including brain neuroimaging and electroencephalography (EEG), play an important role in the assessment of neurodevelopmental disorders. The use of an appropriate sedative agent is important to ensure the successful completion of the neurodiagnostic procedures, particularly in children, who are usually unable to remain still throughout the procedure.

Objectives

To assess the effectiveness and adverse effects of chloral hydrate as a sedative agent for non‐invasive neurodiagnostic procedures in children.

Search methods

We searched the following databases on 14 May 2020, with no language restrictions: the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 12 May 2020). CRS Web includes randomised or quasi‐randomised controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform, the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialised registers of Cochrane Review Groups including Cochrane Epilepsy.

Selection criteria

Randomised controlled trials that assessed chloral hydrate agent against other sedative agent(s), non‐drug agent(s), or placebo.

Data collection and analysis

Two review authors independently evaluated studies identified by the search for their eligibility, extracted data, and assessed risk of bias. Results were expressed in terms of risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, with 95% confidence intervals (CIs).

Main results

We included 16 studies with a total of 2922 children. The methodological quality of the included studies was mixed. Blinding of the participants and personnel was not achieved in most of the included studies, and three of the 16 studies were at high risk of bias for selective reporting. Evaluation of the efficacy of the sedative agents was also underpowered, with all the comparisons performed in small studies.

Fewer children who received oral chloral hydrate had sedation failure compared with oral promethazine (RR 0.11, 95% CI 0.01 to 0.82; 1 study; moderate‐certainty evidence). More children who received oral chloral hydrate had sedation failure after one dose compared to intravenous pentobarbital (RR 4.33, 95% CI 1.35 to 13.89; 1 study; low‐certainty evidence), but there was no clear difference after two doses (RR 3.00, 95% CI 0.33 to 27.46; 1 study; very low‐certainty evidence). Children with oral chloral hydrate had more sedation failure compared with rectal sodium thiopental (RR 1.33, 95% CI 0.60 to 2.96; 1 study; moderate‐certainty evidence) and music therapy (RR 17.00, 95% CI 2.37 to 122.14; 1 study; very low‐certainty evidence). Sedation failure rates were similar between groups for comparisons with oral dexmedetomidine, oral hydroxyzine hydrochloride, oral midazolam and oral clonidine.

Children who received oral chloral hydrate had a shorter time to adequate sedation compared with those who received oral dexmedetomidine (MD −3.86, 95% CI −5.12 to −2.6; 1 study), oral hydroxyzine hydrochloride (MD −7.5, 95% CI −7.85 to −7.15; 1 study), oral promethazine (MD −12.11, 95% CI −18.48 to −5.74; 1 study) (moderate‐certainty evidence for three aforementioned outcomes), rectal midazolam (MD −95.70, 95% CI −114.51 to −76.89; 1 study), and oral clonidine (MD −37.48, 95% CI −55.97 to −18.99; 1 study) (low‐certainty evidence for two aforementioned outcomes). However, children with oral chloral hydrate took longer to achieve adequate sedation when compared with intravenous pentobarbital (MD 19, 95% CI 16.61 to 21.39; 1 study; low‐certainty evidence), intranasal midazolam (MD 12.83, 95% CI 7.22 to 18.44; 1 study; moderate‐certainty evidence), and intranasal dexmedetomidine (MD 2.80, 95% CI 0.77 to 4.83; 1 study, moderate‐certainty evidence).

Children who received oral chloral hydrate appeared significantly less likely to complete neurodiagnostic procedure with child awakening when compared with rectal sodium thiopental (RR 0.95, 95% CI 0.83 to 1.09; 1 study; moderate‐certainty evidence).

Chloral hydrate was associated with a higher risk of the following adverse events: desaturation versus rectal sodium thiopental (RR 5.00, 95% 0.24 to 102.30; 1 study), unsteadiness versus intranasal dexmedetomidine (MD 10.21, 95% CI 0.58 to 178.52; 1 study), vomiting versus intranasal dexmedetomidine (MD 10.59, 95% CI 0.61 to 185.45; 1 study) (low‐certainty evidence for aforementioned three outcomes), and crying during administration of sedation versus intranasal dexmedetomidine (MD 1.39, 95% CI 1.08 to 1.80; 1 study, moderate‐certainty evidence). Chloral hydrate was associated with a lower risk of the following: diarrhoea compared with rectal sodium thiopental (RR 0.04, 95% CI 0.00 to 0.72; 1 study), lower mean diastolic blood pressure compared with sodium thiopental (MD 7.40, 95% CI 5.11 to 9.69; 1 study), drowsiness compared with oral clonidine (RR 0.44, 95% CI 0.30 to 0.64; 1 study), vertigo compared with oral clonidine (RR 0.15, 95% CI 0.01 to 2.79; 1 study) (moderate‐certainty evidence for aforementioned four outcomes), and bradycardia compared with intranasal dexmedetomidine (MD 0.17, 95% CI 0.05 to 0.59; 1 study; high‐certainty evidence). No other adverse events were significantly associated with chloral hydrate, although there was an increased risk of combined adverse events overall (RR 7.66, 95% CI 1.78 to 32.91; 1 study; low‐certainty evidence).

Authors' conclusions

The certainty of evidence for the comparisons of oral chloral hydrate against several other methods of sedation was variable. Oral chloral hydrate appears to have a lower sedation failure rate when compared with oral promethazine. Sedation failure was similar between groups for other comparisons such as oral dexmedetomidine, oral hydroxyzine hydrochloride, and oral midazolam. Oral chloral hydrate had a higher sedation failure rate when compared with intravenous pentobarbital, rectal sodium thiopental, and music therapy. Chloral hydrate appeared to be associated with higher rates of adverse events than intranasal dexmedetomidine. However, the evidence for the outcomes for oral chloral hydrate versus intravenous pentobarbital, rectal sodium thiopental, intranasal dexmedetomidine, and music therapy was mostly of low certainty, therefore the findings should be interpreted with caution.

Further research should determine the effects of oral chloral hydrate on major clinical outcomes such as successful completion of procedures, requirements for an additional sedative agent, and degree of sedation measured using validated scales, which were rarely assessed in the studies included in this review. The safety profile of chloral hydrate should be studied further, especially for major adverse effects such as oxygen desaturation.

Plain language summary

The effectiveness of chloral hydrate as a sedative agent for children undergoing neurodiagnostic procedures

Review question

In children undergoing non‐invasive neurodiagnostic procedures, is chloral hydrate more effective at producing adequate sedation (slowing of brain activity) and safer than other ways of achieving sedation?

Background

Neurodiagnostic procedures are non‐invasive neurological investigations important for children with suspected neurological disorders. These investigations include brain imaging and brain electrical activity testing. For these tests to be successfully performed, the child needs to remain still for at least 30 to 45 minutes during the investigation period. Sedative agents are required for children, who are usually unable to remain still for this period of time.

Search date

The evidence is current to May 2020.

Study characteristics

We included 16 studies involving a total of 2922 children (age up to 18 years old) in the review. All of the included studies were performed in hospitals that provided neurodiagnostic services. Most studies assessed the following three main outcomes: proportion of children who were unsuccessfully sedated for the neurodiagnostic procedure; length of time taken for adequate sedation; and side effects associated with the sedative agent. The quality of the evidence was mixed, ranging from very low to high. The main reason for lowering the quality of the evidence was that those closely involved in the trials, such as the doctors giving the sedation or the parents of the child, were not masked to the sedative agent used in the child, which could have affected their recording or interpretation of the results.

Key results

We summarised the evidence of effectiveness and harms of oral chloral hydrate sedation when compared with other sedative agents. Our review suggests that oral chloral hydrate is just as effective a sedative agent with similar sedation failure rate when compared with oral dexmedetomidine, oral hydroxyzine hydrochloride, oral midazolam, and oral clonidine; and probably a more effective sedative agent with a lower sedation failure rate when compared with oral promethazine. Whilst most of the included studies showed that chloral hydrate was safe with no increase in side effects when compared to other sedative agents, one study reported an increased risk of side effects with oral chloral hydrate when compared with intranasal dexmedetomidine.

Quality of the evidence

The quality of most of the evidence was poor due to flaws in study methods and the small sample size of each study, therefore our confidence in the results of the studies is reduced.

Conclusions

Apart from intravenous pentobarbital, rectal sodium thiopental, and music therapy, oral chloral hydrate is either just as effective or more effective as a sedating agent when compared to other sedating agents for children undergoing non‐invasive neurodiagnostic procedures. Given the poor quality of the evidence, we could draw no clear conclusions on the effectiveness or safety of any of the paediatric sedative agents studied in the review. Further study is needed to look at the side effects of oral chloral hydrate when compared to other sedatives.

Summary of findings

Summary of findings 1. Chloral hydrate oral (50 mg/kg or 100 mg/kg) compared to dexmedetomidine oral (2 µg/kg or 3 µg/kg) as sedating agents for neurodiagnostic procedures in children.

Chloral hydrate oral (50 mg/kg or 100 mg/kg) compared to dexmedetomidine oral (2 µg/kg or 3 µg/kg) as sedating agents for neurodiagnostic procedures in children
Patient or population: children undergoing neurodiagnostic procedures Setting: paediatric hospital or outpatient Intervention: chloral hydrate oral (50 mg/kg or 100 mg/kg) Comparison: dexmedetomidine oral (2 µg/kg or 3 µg/kg)
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with dexmedetomidine	Risk with chloral hydrate
Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)	The mean EEG time onset for adequate sedation (minutes) was 35.2.	The mean EEG time onset for adequate sedation (minutes) in the intervention group was 3.86 minutes shorter (5.12 shorter to 2.6 shorter).	‐	160 (1 RCT)	⊕⊕⊕⊝ MODERATE 1
Proportion of children who had sedation failure or inadequate level of sedation	Study population		RR 1.14 (0.51 to 2.53)	160 (1 RCT)	⊕⊕⊕⊝ MODERATE 2
	119 per 1000	136 per 1000 (61 to 301)
Sedation duration (minutes)	The mean duration of sedation/sleep was 112.1 minutes.3	The mean EEG sedation/sleep duration in the intervention group was 16.47 minutes longer (9.21 to 23.72 minutes longer).	‐	160 (1 RCT)	⊕⊕⊕⊝ MODERATE 4
Number of children with clinical adverse events (any)	Study population		RR 7.66 (1.78 to 32.91)	160 (1 RCT)	⊕⊕⊝⊝ LOW 5
	24 per 1000	182 per 1000 (42 to 784)
*The risk in the intervention group (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). CI: confidence interval; EEG: electroencephalogram; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹The 95% CI for this estimate ranges from 2.6 to 5.1 minutes of difference, which in terms of length of sedation is wide. Certainty of evidence downgraded one level due to risk of bias.
²The 95% CI for this estimate ranges from substantial benefits favouring chloral hydrate to substantial benefits favouring dexmedetomidine. Certainty of evidence downgraded one level due to imprecision.
³The mean was derived by averaging the mean values of the two subgroups of children receiving two different doses of oral dexmedetomidine (2 mg/kg and 3 mg/kg), each of which consisted of 40 children.
⁴The 95% CI for this estimate ranges from about 9 more minutes to 23 more minutes of sleep duration, which is too wide in the context of sedation for neurodiagnostic procedures. Certainty of evidence downgraded one level due to imprecision.
⁵The 95% CI for this estimate is very wide. Certainty of evidence downgraded two levels due to imprecision.

Summary of findings 2. Chloral hydrate oral (75 mg/kg) compared to pentobarbital intravenous (5 mg/kg) as sedating agents for neurodiagnostic procedures in children.

Chloral hydrate oral (75 mg/kg) compared to pentobarbital intravenous (5 mg/kg) as sedating agents for neurodiagnostic procedures in children
Patient or population: children undergoing neurodiagnostic procedures Setting: paediatric hospital or outpatient Intervention: chloral hydrate oral (75 mg/kg) Comparison: pentobarbital intravenous (5 mg/kg)
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with pentobarbital	Risk with chloral hydrate
Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)	The mean time to adequate sedation was 9 minutes.	The mean time to adequate sedation in the intervention group was 19 minutes longer (16.61 to 21.39 minutes longer).	‐	70 (1 RCT)	⊕⊕⊝⊝ LOW 1 2
Proportion of children who had sedation failure after 1 dose of sedative agent	Study population		RR 4.33 (1.35 to 13.89)	70 (1 RCT)	⊕⊕⊝⊝ LOW 1 3
	86 per 1000	371 per 1000 (116 to 1000)
Proportion of children who had sedation failure after 2 doses of sedative agent (same or different)	Study population		RR 3.00 (0.33 to 27.46)	70 (1 RCT)	⊕⊝⊝⊝ VERY LOW 1 3
	29 per 1000	86 per 1000 (9 to 785)
Non‐interpretable neuroimaging finding	Study population		RR 0.23 (0.03 to 1.94)	54 (1 RCT)	⊕⊝⊝⊝ VERY LOW 1 4
	154 per 1000	35 per 1000 (5 to 298)
Number of children with clinical adverse event: oxygen desaturation	Study population		RR 0.67 (0.21 to 2.16)	70 (1 RCT)	⊕⊝⊝⊝ VERY LOW 1 5
	171 per 1000	115 per 1000 (36 to 370)
*The risk in the intervention group (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). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹The single included study had unclear risk of bias for allocation concealment and blinding of outcome assessor and high risk of bias for blinding of participants and personnel. Certainty of evidence downgraded one level due to risk of bias.
²Although both ends of the 95% CI clearly indicate a longer onset of adequate sedation for the chloral hydrate group, the range of 95% CI for this estimate was too wide to permit a confident estimate on the time difference. Certainty of evidence downgraded one level due to imprecision.
³The 95% CI for this estimate ranges from slightly higher risk of sedation failure for chloral hydrate group to substantially higher risk of sedation failure for chloral hydrate group. Certainty of evidence downgraded two levels due to imprecision.
⁴The 95% CI for this estimate ranges from substantially favouring chloral hydrate group to substantially favouring pentobarbital group. Certainty of evidence downgraded two levels due to imprecision.
⁵The 95% CI for this estimate ranges from substantially lower risk of sedation failure for chloral hydrate group to substantially higher risk of sedation failure for chloral hydrate group. Certainty of evidence downgraded two levels due to imprecision.

Summary of findings 3. Chloral hydrate oral (100 mg/kg or 75 mg/kg) compared to midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg) as sedating agents for neurodiagnostic procedures in children.

Chloral hydrate oral (100 mg/kg or 75 mg/kg) compared to midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg) as sedating agents for neurodiagnostic procedures in children
Patient or population: children undergoing neurodiagnostic procedures Setting: paediatric hospital or outpatient Intervention: chloral hydrate oral (100 mg/kg or 75 mg/kg) Comparison: midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg)
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with midazolam	Risk with chloral hydrate
Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)	The mean time to adequate sedation was 10.92 minutes (intranasal midazolam).	The mean time to adequate sedation in the intervention group was 12.83 minutes longer (7.22 to 18.44 minutes longer).	‐	60 (1 RCT)	⊕⊕⊕⊝ MODERATE 1
Proportion of children with inadequate level of sedation (Ramsay score below 4)	Study population		RR 0.11 (0.03 to 0.44)	60 (1 RCT)	⊕⊕⊕⊝ MODERATE 1
	600 per 1000	66 per 1000 (18 to 264)
Proportion of children who had sedation failure after 1 dose of sedative agent	Study population		RR 0.17 (0.02 to 1.12)	33 (1 RCT)	⊕⊕⊝⊝ LOW 2
	545 per 1000	93 per 1000 (11 to 611)
Sedation duration (minutes)	The mean duration of sedation or sleep was 76 minutes (oral midazolam).	The mean duration of sedation or sleep in the intervention group was 19 minutes longer (3.4 minutes shorter to 41.4 minutes longer).	‐	33 (1 RCT)	⊕⊕⊝⊝ LOW 3
EEG sedative‐induced artefact	Study population		RR 0.58 (0.44 to 0.76)	198 (1 RCT)	⊕⊕⊕⊕ HIGH
	700 per 1000	406 per 1000 (308 to 532)
Number of children with clinical adverse events (any)	Study population		RR 0.20 (0.01 to 4.20)	198 (1 RCT)	⊕⊕⊝⊝ LOW 2
	20 per 1000	4 per 1000 (0 to 84)
*The risk in the intervention group (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). CI: confidence interval; EEG: electroencephalogram; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹The 95% CI for this estimate is wide, although both ends are on the same direction of effect. Certainty of evidence downgraded one level due to imprecision.
²The 95% CI for this estimate ranges from substantially lower risk to higher risk for chloral hydrate group. Certainty of evidence downgraded two levels due to imprecision.
³The 95% CI for this estimate ranges from slightly shorter to substantially higher for chloral hydrate group. Certainty of evidence downgraded two levels due to imprecision.

Summary of findings 4. Chloral hydrate oral (50 mg/kg) compared to melatonin oral as sedating agents for neurodiagnostic procedures in children.

Chloral hydrate oral (50 mg/kg) compared to melatonin oral as sedating agents for neurodiagnostic procedures in children
Patient or population: children undergoing neurodiagnostic procedures Setting: paediatric hospital or outpatient Intervention: chloral hydrate oral (50 mg/kg) Comparison: melatonin oral
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with melatonin	Risk with chloral hydrate
Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Proportion of children who had sedation failure or inadequate level of sedation	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
EEG sedative‐induced artefact	Study population		RR 0.33 (0.14 to 0.82)	348 (1 RCT)	⊕⊕⊝⊝ LOW 1 2
	103 per 1000	34 per 1000 (14 to 85)
Number of children with clinical adverse events (any)	Study population		RR 1.00 (0.25 to 3.93)	348 (1 RCT)	⊕⊕⊝⊝ LOW 1 2
	23 per 1000	23 per 1000 (6 to 90)
*The risk in the intervention group (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). CI: confidence interval; EEG: electroencephalogram; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹The single included study was at unclear risk of bias for random sequence generation, allocation concealment, and blinding of outcome assessors, and high risk of bias for blinding of participants and personnel. Certainty of evidence downgraded one level due to risk of bias.
²The 95% CIs were too wide to permit a confident estimate of the effect sizes. Certainty of evidence downgraded one level due to imprecision.

Summary of findings 5. Chloral hydrate oral (50 mg/kg + 50 mg/kg) compared to hydroxyzine hydrochloride oral (1 mg/kg + 1 mg/kg) as sedating agents for neurodiagnostic procedures in children.

Chloral hydrate oral (50 mg/kg + 50 mg/kg) compared to hydroxyzine hydrochloride oral (1 mg/kg + 1 mg/kg) as sedating agents for neurodiagnostic procedures in children
Patient or population: children undergoing neurodiagnostic procedures Setting: paediatric hospital or outpatient Intervention: chloral hydrate oral (50 mg/kg + 50 mg/kg) Comparison: hydroxyzine hydrochloride oral (1 mg/kg + 1 mg/kg)
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with hydroxyzine hydrochloride	Risk with chloral hydrate
Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
TIme to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)	The time onset to adequate sedation was 23.7 minutes.	The mean time to adequate sedation in the intervention group was 7.5 minutes shorter (7.85 to 7.15 minutes shorter).	‐	282 (1 RCT)	⊕⊕⊕⊝ MODERATE 1
Proportion of children who had sedation failure or inadequate level of sedation	Study population		RR 0.33 (0.11 to 1.01)	282 (1 RCT)	⊕⊕⊝⊝ LOW 1 2
	85 per 1000	28 per 1000 (9 to 86)
Sedation duration (minutes)	The mean duration of sedation or sleep was 85.1 minutes.	The mean duration of sedation or sleep in the intervention group was 3.1 minutes longer (2.23 to 3.97 minutes longer).	‐	282 (1 RCT)	⊕⊕⊕⊝ MODERATE 1
Number of children with clinical adverse event: behavioural change	Study population		RR 1.17 (0.40 to 3.38)	282 (1 RCT)	⊕⊕⊝⊝ LOW 1 2
	43 per 1000	50 per 1000 (17 to 144)
Number of children with clinical adverse event: nausea or vomiting	Study population		RR 1.25 (0.34 to 4.56)	282 (1 RCT)	⊕⊕⊝⊝ LOW 1 2
	28 per 1000	35 per 1000 (10 to 129)
*The risk in the intervention group (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). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹The single included study was at unclear risk of bias for random sequence generation, allocation concealment, blinding of participants and personnel, and blinding of outcome assessors. Certainty of evidence downgraded one level due to risk of bias.
²The 95% CI for this estimate ranges from substantially lower risk to marginally to moderately higher risk of sedation failure for the chloral hydrate group. Certainty of evidence downgraded one level due to imprecision.

Summary of findings 6. Chloral hydrate oral (70 mg/kg) compared to promethazine oral (1 mg/kg) as sedating agents for neurodiagnostic procedures in children.

Chloral hydrate oral (70 mg/kg) compared to promethazine oral (1 mg/kg) as sedating agents for neurodiagnostic procedures in children
Patient or population: children undergoing neurodiagnostic procedures Setting: paediatric hospital or outpatient Intervention: chloral hydrate oral (70 mg/kg) Comparison: promethazine oral (1 mg/kg)
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with promethazine	Risk with chloral hydrate
Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)	The mean time to adequate sedation was 33.84 minutes.	The mean time to adequate sedation in the intervention group was 12.11 minutes shorter (18.48 to 5.74 minutes shorter).	‐	60 (1 RCT)	⊕⊕⊕⊝ MODERATE 1
Proportion of children with inadequate level of sedation (Ramsay score below 4)	Study population		RR 0.03 (0.00 to 0.45)	60 (1 RCT)	⊕⊕⊝⊝ LOW 2
	567 per 1000	17 per 1000 (0 to 255)
Proportion of children who had sedation failure or inadequate level of sedation	Study population		RR 0.11 (0.01 to 0.82)	60 (1 RCT)	⊕⊕⊕⊝ MODERATE 1
	300 per 1000	33 per 1000 (3 to 246)
Number of children with clinical adverse event: behavioural change	Study population		RR 0.20 (0.01 to 4.00)	60 (1 RCT)	⊕⊕⊕⊝ MODERATE 1
	67 per 1000	13 per 1000 (1 to 267)
Number of children with clinical adverse event: vomiting or nausea	Study population		RR 13.00 (0.76 to 220.96)	60 (1 RCT)	⊕⊕⊝⊝ LOW 3
	0 per 1000	0 per 1000 (0 to 0)
*The risk in the intervention group (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). CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹The 95% CI for this estimate is wide but falls on the same direction of effect. Certainty of evidence downgraded one level due to imprecision.
²The 95% CI for this estimate is very wide, especially if the data are inverted. Certainty of evidence downgraded two levels due to serious imprecision.
³The 95% CI for this estimate is very wide. Certainty of evidence downgraded two levels due to imprecision.

Summary of findings 7. Chloral hydrate oral (60 mg/kg) compared to music therapy as sedating agents for neurodiagnostic procedures in children.

Chloral hydrate oral (60 mg/kg) compared to music therapy as sedating agents for neurodiagnostic procedures in children
Patient or population: children undergoing neurodiagnostic procedures Setting: paediatric inpatient or outpatient Intervention: chloral hydrate oral (60 mg/kg) Comparison: music therapy
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with music therapy	Risk with chloral hydrate
Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)	The mean EEG time onset for adequate sedation was 23 minutes.	The mean EEG time onset for adequate sedation in the intervention group was 9 minutes more (2.15 fewer to 20.15 more).	‐	58 (1 RCT)	⊕⊝⊝⊝ VERY LOW 1 2
Proportion of children who had sedation failure or inadequate level of sedation	Study population		RR 17.00 (2.37 to 122.14)	58 (1 RCT)	⊕⊝⊝⊝ VERY LOW 1 3
	29 per 1000	500 per 1000 (70 to 1000)
Sedation duration (minutes)	The mean EEG sedation/sleep duration was 66 minutes.	The mean EEG sedation/sleep duration in the intervention group was 160 minutes more (121.07 more to 198.93 more).	‐	58 (1 RCT)	⊕⊝⊝⊝ VERY LOW 1 2
Number of children with clinical adverse events (any)	‐	‐	‐	‐	‐	No study in this comparison assessed this outcome.
*The risk in the intervention group (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). CI: confidence interval; EEG: electroencephalogram; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹Very serious concerns regarding the trial methodology led to a judgement of high risk of selection bias (using alternation rather than true randomisation), performance and detection biases (non‐blinding of participants and care personnel as well as outcome assessors), and reporting bias. Certainty of evidence downgraded two levels due to risk of bias.
²The 95% CI was wide. Certainty of evidence downgraded one level due to imprecision.
³The 95% CI was very wide. Certainty of evidence downgraded two levels due to imprecision.

Summary of findings 8. Chloral hydrate oral (50 mg/kg) compared to sodium thiopental rectal (25 mg/kg) for neurodiagnostic procedures in children.

Chloral hydrate oral (50 mg/kg) compared to sodium thiopental rectal (25 mg/kg) for neurodiagnostic procedures in children
Patient or population: neurodiagnostic procedures in children Setting: paediatric hospital or outpatient Intervention: chloral hydrate (50 mg/kg) oral Comparison: sodium thiopental rectal (25 mg/kg)
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with sodium thiopental	Risk with chloral hydrate
Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening	Study population		RR 0.95 (0.83 to 1.09)	140 (1 RCT)	⊕⊕⊕⊝ MODERATE 1
	871 per 1000	828 per 1000 (723 to 950)
Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)	The mean onset sedation (minutes) was 28.7 minutes.	MD 4.2 minutes lower (6.08 lower to 2.32 lower)	‐	140 (1 RCT)	⊕⊕⊕⊝ MODERATE 2
Proportion of children who had sedation failure or inadequate level of sedation	Study population		RR 1.33 (0.60 to 2.96)	140 (1 RCT)	⊕⊕⊕⊝ MODERATE 3
	129 per 1000	171 per 1000 (77 to 381)
Sedation duration (minutes	The mean sedation duration (minutes) was 13.7 minutes.	MD 0.8 minutes lower (1.7 lower to 0.1 higher)	‐	140 (1 RCT)	⊕⊕⊕⊝ MODERATE 4
Number of children with clinical adverse event: desaturation	Study population		RR 5.00 (0.24 to 102.30)	140 (1 RCT)	⊕⊕⊝⊝ LOW 5
	0 per 1000	0 per 1000 (0 to 0)
Number of children with clinical adverse event: diarrhoea	Study population		RR 0.04 (0.00 to 0.72)	140 (1 RCT)	⊕⊕⊕⊝ MODERATE 6
	157 per 1000	6 per 1000 (0 to 113)
Mean diastolic blood pressure during procedure (mmHg)	The mean diastolic blood pressure during procedure (mmHg) was 53 mmHg.	MD 7.4 mmHg higher (5.11 higher to 9.69 higher)	‐	140 (1 RCT)	⊕⊕⊕⊝ MODERATE 7
*The risk in the intervention group (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). CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹The 95% confidence interval ranges from a moderate reduction to a slight increase in risk in a single‐study analysis with a small sample.
²The 95% confidence interval ranges from a marked decrease to a modest decrease in a single‐study analysis with a small sample.
³The 95% confidence interval ranges from a marked decrease to a marked increase in risk in a single‐study analysis with a small sample.
⁴The 95% confidence interval ranges from a marked reduction to a slight increase in a single‐study analysis with a small sample.
⁵The small number of events in the single‐study analysis resulted in very wide 95% confidence interval; certainty of evidence downgraded two levels.
⁶The 95% confidence interval ranges from a marked reduction to a moderate reduction in the risk of diarrhoea in a single study with a small sample.
⁷Whilst the mean diastolic blood pressure was reported as representing the possible adverse effect of hypotension, the reported measure here does not provide a direct indication of the risk of hypotension, which is usually reported as the number of participants with hypotension.

Summary of findings 9. Chloral hydrate oral (50 mg/kg) compared to clonidine oral (4 μg/kg) for neurodiagnostic procedures in children.

Chloral hydrate oral (50 mg/kg) compared to clonidine oral (4 μg/kg) for neurodiagnostic procedures in children
Patient or population: neurodiagnostic procedures in children Setting: hospital or outpatient Intervention: chloral hydrate oral (50 mg/kg) Comparison: clonidine oral (4 μg/kg)
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with clonidine	Risk with chloral hydrate
Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score) (minutes)	The mean onset sedation (minutes) was 86.28 minutes.	MD 37.48 minutes lower (55.97 lower to 18.99 lower)	‐	198 (1 RCT)	⊕⊕⊝⊝ LOW 1 2
Sedation duration (minutes)	The mean sedation duration (minutes) was 74.2 minutes.	MD 6.07 minutes lower (15.32 lower to 3.18 higher)	‐	198 (1 RCT)	⊕⊕⊝⊝ LOW 1 3
Number of children with clinical adverse event: drowsiness	Study population		RR 0.44 (0.30 to 0.64)	198 (1 RCT)	⊕⊕⊕⊝ MODERATE 1
	580 per 1000	255 per 1000 (174 to 371)
Number of children with clinical adverse event: vertigo	Study population		RR 0.15 (0.01 to 2.79)	198 (1 RCT)	⊕⊕⊕⊝ MODERATE 1
	30 per 1000	5 per 1000 (0 to 84)
*The risk in the intervention group (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). CI: confidence interval; EEG: electroencephalogram; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹The single included study had a high risk of selection bias.
²Wide 95% confidence interval that ranges from a major reduction to a modest reduction in the time taken for onset of sedation.
³Wide 95% confidence interval that ranges from a moderate reduction to a slight increase in sleep duration.

Summary of findings 10. Chloral hydrate oral (50 mg/kg) compared to dexmedetomidine intranasal (3 μg/kg) for neurodiagnostic procedures in children.

Chloral hydrate oral (50 mg/kg) compared to dexmedetomidine intranasal (3 μg/kg) for neurodiagnostic procedures in children
Patient or population: neurodiagnostic procedures in children Setting: hospital or outpatient Intervention: chloral hydrate oral (50 mg/kg) Comparison: dexmedetomidine intranasal (3 μg/kg)
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)
	Risk with dexmedetomidine	Risk with chloral hydrate
Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score) (minutes)	The mean sedation onset (minutes) was 19.6 minutes.	MD 2.8 minutes higher (0.77 higher to 4.83 higher)	‐	194 (1 RCT)	⊕⊕⊕⊝ MODERATE 1
Number of children with clinical adverse event: bradycardia	Study population		RR 0.17 (0.05 to 0.59)	194 (1 RCT)	⊕⊕⊕⊕ HIGH
	161 per 1000	27 per 1000 (8 to 95)
Number of children with clinical adverse event: unsteadiness within 24 h after discharge	Study population		RR 10.21 (0.58 to 178.52)	173 (1 RCT)	⊕⊕⊝⊝ LOW 2
	0 per 1000	0 per 1000 (0 to 0)
Number of children with clinical adverse event: crying during administration of sedation	Study population		RR 1.39 (1.08 to 1.80)	194 (1 RCT)	⊕⊕⊕⊝ MODERATE 3
	483 per 1000	671 per 1000 (521 to 869)
Number of children with clinical adverse event: vomiting	Study population		RR 10.59 (0.61 to 185.45)	194 (1 RCT)	⊕⊕⊝⊝ LOW 2
	0 per 1000	0 per 1000 (0 to 0)
*The risk in the intervention group (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). CI: confidence interval; MD: mean difference; RCT: randomised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence High certainty: We are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

¹The 95% confidence interval ranges from a slight increase to a moderate increase in duration of sedation in a single included study.
²Low event rate in a single included study resulted in a very wide 95% confidence interval.
³95% confidence interval ranges from 8% to 80% increase in the risk of crying during administration of medication.

Background

This is an updated version of a Cochrane Review published in 2017 (Fong 2017).

Description of the condition

Paediatric neurodevelopmental disorders are collectively a common problem that affect between 5% and 10% of all children (Horridge 2011; Shevell 2003; Shevell 2008). A structured clinical evaluation together with targeted neurodiagnostic investigations of children with possible neurodevelopmental disorders is important to establish the aetiology of the disorder, predict the prognosis, and develop management strategies (Horridge 2011; Shevell 2003; Shevell 2008; Silove 2013).

Paediatric neurodiagnostic (non‐interventional) investigations used in the assessment of children with possible neurodevelopmental disorders include brain neuroimaging and electroencephalography (EEG). Successful completion of neurodiagnostic procedures is challenging in the paediatric age group, as the child is required to be immobile during the procedure. In addition, routine paediatric EEG recording requires recording of a period of sleep. Sleep state EEG recording is important as it increases the yield in detecting interictal epileptiform abnormalities. Achieving spontaneous sleep is not possible in some children despite behavioural intervention (prior sleep deprivation). The use of an appropriate sedative agent in children who are unable to be immobile or do not naturally sleep (for EEG recording), or both, thus plays a pivotal role in ensuring successful completion of the procedure.

Selection of the most appropriate pharmacological and non‐pharmacological agents is an important factor for the success and safety of the neurodiagnostic procedure. Moreover, there are other pharmacological considerations when choosing a sedative agent for paediatric EEG because some sedative agents can suppress abnormal EEG activity or background activity (e.g. anaesthesia), and others can induce background activity changes that may obscure abnormalities (e.g. benzodiazepines and barbiturates).

Children with neurodevelopmental disorders can present with a variety of symptoms including epilepsy, developmental impairment, developmental regression, social communication deficits, and behavioural difficulties. These children will require a structured clinical evaluation with targeted investigations to enable an accurate diagnosis, provide appropriate intervention, and assist in predicting long‐term prognosis.

Neurodiagnostic investigations include EEG and brain neuroimaging. The duration of a standard awake and sleep paediatric EEG recording is approximately 30 to 60 minutes; a routine paediatric brain magnetic resonance imaging (MRI) scan takes approximately 45 to 60 minutes. Routine EEG is an important investigation tool in evaluating children with a clinical history suggestive of epilepsy (NICE 2012). The EEG will assist in defining the specific epilepsy syndrome (Pillai 2006). Neuroimaging investigations (particularly brain MRI) are useful in detecting major or minor structural brain abnormalities that may assist in establishing the cause of the child's neurodevelopmental disorder (Battaglia 2003; Rodriguez 2007). Current guidelines advocate that neuroimaging investigations should be considered in those children with an abnormal antenatal or perinatal history, an abnormal neurological examination, a history of focal epilepsy, and in all epilepsies in children under two years of age (Battaglia 2003; NICE 2012; Rodriguez 2007).

Description of the intervention

Sedation is defined as a drug‐induced depression of consciousness, which is a continuum from wakefulness to anaesthesia (Starkey 2011). It assists in reducing anxiety, providing pain control, and minimising movement of the patient when undergoing a procedure. There are different levels of sedation, as defined by the American Society of Anesthesiologists. These include minimal sedation, moderation sedation, and deep sedation (ASA 2007). Moderate sedation involves the technique of administering sedatives to induce a state of depressed level of consciousness whilst allowing the patient to maintain independent control of their airway and oxygenation by preserving their protective airway reflexes (NICE 2010). Current guidelines recommend moderate sedation over deep sedation and general anaesthesia for painless paediatric procedures (NICE 2010).

The ideal sedative agent to achieve moderate sedation should have rapid onset, a moderate duration of action, minimal or no adverse effects, and low cost. There is no ideal or first‐line sedative agent at present. The agents currently available for painless procedures include the following.

• Chloral hydrate, a non‐opiate and non‐benzodiazepine sedative hypnotic drug.

• Benzodiazepines, which act via the γ‐aminobutyric acid A receptors.

• Hydroxyzine, a long‐acting first‐generation H₁ antagonist with central nervous system depressant activity and minimal circulatory and depressant activity.

• Melatonin, a pineal hormone and natural sleep agent that can modulate the circadian rhythm of sleep through action on the suprachiasmatic nucleus in the hypothalamus.

• Promethazine, an antiemetic and antisialagogue with sedative properties.

• Dexmedetomidine, a selective alpha₂‐adrenoceptor agonist with sedative properties.

• Clonidine, an alpha₂‐ adrenoceptor agonist with sedative properties.

• Sodium thiopental, a short‐acting barbiturate with sedative properties.

In addition, non‐pharmacological approaches such as music therapy have been shown to be beneficial in providing sedation during procedures in adult patients (Bechtold 2009), whilst there is some evidence that breastfeeding or breast milk helps infants tolerate painful or uncomfortable procedures better by reducing crying and improving infants' physiological responses during the procedures (Shah 2012).

How the intervention might work

Chloral hydrate is a central nervous system depressant and is one of the oldest sedatives (discovered in 1832). It is well absorbed orally as well as rectally and is rapidly metabolised into the active metabolite trichloroethanol, which is responsible for its hypnotic and sedative effects. It is one of the most frequently used conscious sedative agents for children undergoing neurodiagnostic procedures including neuroimaging and EEG recording, as it has a good safety profile when used at sedative doses, with little effect on EEG background activity (Malviya 1997). Doses vary from 55 to 100 mg/kg in neonates and children younger than 12 years old, with a maximum dose of 2 g (Starkey 2011). Chloral hydrate is absorbed from the gastrointestinal tract and starts to exert its effect within 60 minutes. Adverse reactions occur in 1.7% to 20% of children, with gastrointestinal side effects, particularly vomiting, being the most common (Starkey 2011). There have also been some concerns with regard to respiratory depression, long duration of action, and potential carcinogenicity (Haselkorn 2006; Kao 1999).

Why it is important to do this review

Neurodiagnostic procedures (particularly neuroimaging) in children are important investigative tools and have been increasingly used over the last decade to assess and manage children with neurodevelopmental disorders. However, a significant proportion of children may be unable to complete the procedure due to sedation failure. Sedation failure is a great inconvenience to the child and their family and requires rescheduling of another hospital admission to complete the procedure, often under general anaesthesia (which carries additional associated risks).

Both the National Institute for Health and Care Excellence (NICE) 2010 guideline and the American College of Emergency Physicians 2008 guideline recommend chloral hydrate for moderate sedation during painless procedures in the paediatric population (Mace 2008; NICE 2010). However, neither guideline has suggested the superiority of chloral hydrate over other agents. Some studies have shown that chloral hydrate is unsuccessful in a significant proportion of children, resulting in failure to complete the procedure (Beebe 2000; Malviya 1997). Few randomised controlled trials (RCTs) have been conducted comparing the efficacy of chloral hydrate with other sedative agents and complementary therapy (e.g. music therapy). However, to date no meta‐analysis of the previously published RCTs has been performed in order to determine superiority amongst these agents.

The aim of this review was to allow clinicians to take an evidence‐based approach in deciding which sedating agent is best for children undergoing neurodiagnostic procedures. The care of children would improve if both sedation failure rates and adverse effects due to sedation were kept to a minimum.

Objectives

To assess the effectiveness and adverse effects of chloral hydrate as a sedative agent for non‐invasive neurodiagnostic procedures in children.

Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi‐randomised trials.

Types of participants

Children (from birth to 18 years old) who underwent non‐invasive neurodiagnostic procedures (including brain neuroimaging and sleep EEG) who required sedation before the procedure.

Types of interventions

Oral or rectal chloral hydrate.

Comparison: other sedative/sleep‐inducing agents (e.g. promethazine, hydroxyzine, melatonin, midazolam, pentobarbital, etomidate, sevoflurane, clonidine, sodium thiopental, dexmedetomidine) or complementary therapies (e.g. music therapy), or achieved sleep without a sedative agent, for instance after a milk feed.

Types of outcome measures

Primary outcomes

• Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening.

• Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent.

• Time to adequate sedation (in minutes or as measured by specific validated scales such as the Ramsay Sedation Score).

Secondary outcomes

• Proportion of children who had sedation failure or inadequate level of sedation.

• Sedation duration.

• Yield of EEG findings (expressed either as the rate of abnormal EEG findings or additional EEG artefact findings attributable to the sedative agent, which may prevent interpretation of the EEG) or yield of neuroimaging findings (expressed as the rate of non‐interpretable MRI attributable to motion artefact due to inadequate sedation).

• Number of children with clinical adverse effects and severe drug side effects (e.g. hypotension, hypoxia, apnoea, laryngospasm, significant vomiting, refractory agitation, bradycardia, persistent drowsiness, diarrhoea.

Search methods for identification of studies

Electronic searches

We ran searches for the original review in July 2017 and subsequent searches in April 2019. For the latest update, we searched the following databases on 14 May 2020.

• Cochrane Register of Studies (CRS Web), using the search strategy shown in Appendix 1. This includes randomised or quasi‐randomised controlled trials from PubMed, Embase, US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), Chinese Clinical Trials Registry, Iranian Registry of Clinical Trials and the specialised registers of Cochrane Review Groups including Cochrane Epilepsy.

• MEDLINE (Ovid, 1946 to 12 May 2020), using the search strategy shown in Appendix 2.

We previously searched Embase (1980 to 19 July 2017) separately using the search strategy shown in Appendix 3.

We did not apply any language restrictions in our searches.

Searching other resources

We searched references cited in relevant studies, Cochrane Reviews, guidelines, review articles, and conference proceedings, including abstracts from the Society for Pediatric Anesthesia and the European Society for Paediatric Anaesthesiology. We also contacted experts in the field to identify further relevant studies.

Data collection and analysis

Selection of studies

Two review authors (WKL, LL) independently performed the first round of searching for potentially relevant studies. They then screened the identified studies for inclusion in the analysis with the help of an arbiter (CYF), using the predefined inclusion and exclusion criteria.

We collected information on study design and setting, participant characteristics (including age and the presence of additional comorbidities such as cerebral palsy), study eligibility criteria, details of the intervention(s) given, and outcomes assessed. We also collected information on study funding source and any conflicts of interest stated by the investigators.

We accepted published and unpublished studies, both in full article and abstract form, given that adequate extraction of outcome data was possible. We contacted the authors of unpublished studies and studies available only as abstracts to request further information, including specific details of the methodologies employed as well as the full outcome data, to permit inclusion in meta‐analysis. We only included final data from each study and not data from interim analyses.

Data extraction and management

Two review authors (WKL, LL) independently extracted relevant data from each included study using a data collection form adapted for this review. We gathered the following information from each study.

• Study design (RCT, quasi‐RCT, or cluster‐RCT, and the number of arms evaluated)

• Risk of bias items, including the methods used and our risk of bias judgement (low risk, high risk, or unclear risk)

  • Random sequence generation

  • Allocation concealment

  • Blinding of participants, care personnel, and evaluators

  • Missing data (loss to follow‐up)

  • Risk of selective outcome reporting

  • Other possible sources of bias

• Stratification factors

• Participant factors

  • Number (total per group)

  • Setting

  • Diagnostic criteria

  • Country

  • Age

  • Sex

  • Underlying diagnoses

  • Indications for neurodiagnostic procedure: whether for diagnostic or monitoring purposes

• Intervention data: route of administration, dosage, and duration of chloral hydrate and comparator medication, and whether chloral hydrate was administered alone or in combination with another medication

• Follow‐up data

  • Duration of follow‐up period

  • Numbers lost to follow‐up

  • Reasons for loss to follow‐up

• Outcome data, grouped into dichotomous and continuous outcomes, including adverse events

For studies with incomplete reporting of outcome data, we derived the necessary data for meta‐analysis when possible. For example, Ashrafi 2020 reported the mean value of each group along with P value of the difference, without providing the corresponding standard deviation (SD). We worked out the average SD values to be used in both allocated groups by following the recommendations in Section 7.7.3.3 of the Cochane Handbook for Systematic Reviews of Interventions (Higgins 2021).

For details of each outcome included in our review (names, definitions, and possible unit of measurement), please refer to Types of outcome measures.

We screened for multiple enrolment by matching the initial number of participants recruited against the total numbers at each step in the study. We contacted the authors of the study for clarity regarding important aspects of the trial where necessary. Any disagreements were resolved by discussion leading to consensus, or by involving an arbiter (CYF) if necessary.

Assessment of risk of bias in included studies

Two review authors (WKL, LL) independently assessed the risk of bias for each trial using the Cochrane risk of bias tool as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any inconsistencies were resolved by discussion with a third review author (CYF). We assessed the included studies as at low, high, or unclear risk of bias on six domains applicable to RCTs: randomisation method, allocation concealment, blinding methods, incomplete outcome data, selective outcome reporting, and other sources of bias.

Measures of treatment effect

We reported the outcome estimates for categorical data using risk ratios (RRs), risk differences (RDs), and the number needed to treat for an additional beneficial outcome (NNTB) or the number needed to treat for an additional harmful outcome (NNTH), with their respective 95% confidence intervals (CIs). For continuous data, which included time to adequate sedation and duration of sedation, we used mean differences (MDs) with their respective 95% CIs. If pooled analyses were not possible for reasons such as major discrepancies in study characteristics or outcome reporting as detailed in Assessment of heterogeneity, we reported the results of the studies narratively.

Unit of analysis issues

We included no cluster‐RCTs in this review. Had we included cluster‐RCTs, we would have adopted the following strategy when dealing with such studies.

For cluster‐RCTs (e.g. trials in which the assignment to the intervention or control group was made at the level of the unit or hospital ward), we would have assessed whether an adjustment had been made for the effects of clustering in order to account for non‐independence amongst the participants in a cluster via the use of an appropriate analysis model, such as the generalised estimating equation (GEE) model. If the unit of analysis was not stated in the study, we would have inspected the width of the standard error (SE) or 95% CI of the estimated treatment effects. Had we found an inappropriately small SE or a narrow 95% CI, we would have asked the authors of the study to provide information on the unit of analysis.

If no adjustment was made for the effects of clustering, we would have performed adjustment by multiplying the SEs of the final effect estimates by the square root of the 'design effect', represented by the formula '1 + (M − 1) x ICC', where M is the average cluster size (number of children per cluster) and ICC is the intracluster correlation. We would have determined the average cluster size (M) from each trial by dividing the total number of children by the total number of clusters. We would have used a relatively large assumed ICC of 0.10, as we consider this to be a realistic estimate based on previous studies about implementation research (Campbell 2001). We would have combined the adjusted final effect estimates from each trial with their SEs in meta‐analysis using generic inverse‐variance methods, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021).

If determination of the unit of analysis was not possible, we would have included the studies concerned in a meta‐analysis using whatever effect estimates were provided by the authors. We would have then performed a sensitivity analysis to assess how the overall results were affected by inclusion of these studies.

For multiple‐arm studies, we would have adjusted the data according to the methods described in Chapter 16 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2021). Specifically, if only two arms were relevant, we would have only included the relevant arms. If there were more than two relevant arms (e.g. chloral hydrate of two different dosages versus placebo), we would have set up separate pair‐wise comparisons, for example higher‐dose chloral hydrate versus placebo (Comparison 1) and lower‐dose chloral hydrate versus placebo (Comparison 2). In such cases, we would not total the number of children in the placebo group to avoid double‐counting.

Dealing with missing data

We determined the dropout rates for each study. We also assessed whether the authors analysed their data according to the intention‐to‐treat principle by comparing the number of children initially randomised and the total number analysed. We considered an absolute dropout rate of 20% or higher as important. We also adopted a 'worst‐case scenario' approach in judging the dropout rate: if we found that the direction of the effect estimate changed with the worst‐case scenario approach, we considered the dropout rate as significant.

If we found a significant dropout rate with no reasonable explanation, we classified the study as having a high risk of attrition bias. If we considered the missing data to be critical to the final estimates in our meta‐analysis, we contacted the authors of the individual studies to request further data.

We planned to perform sensitivity analyses to assess how the overall results were affected by the inclusion of studies with a high risk of attrition bias.

Assessment of heterogeneity

We assessed clinical heterogeneity by comparing the distribution of important participant factors between trials (age, gender, seizure type, duration of epilepsy) and trial factors (clinical setting of the studies, the use of co‐interventions, risk of bias items including random sequence generation, allocation concealment, blinding, and losses to follow‐up).

To evaluate statistical heterogeneity, we first visually inspected the forest plots to see if there was any gross inconsistency in the trial results. We used the I² statistic to quantify the extent and importance of inconsistency in the results (Higgins 2021). We used the following cutoffs for the reporting of heterogeneity.

• 0% to 40%: heterogeneity might not be important

• 30% to 60%: may represent moderate heterogeneity

• 50% to 90%: may represent substantial heterogeneity

• 75% to 100%: considerable heterogeneity

If we found moderate, substantial, or considerable heterogeneity, we re‐examined the clinical and methodological characteristics of the studies using the criteria listed above to determine whether the degree of heterogeneity could be explained by differences in those characteristics, and whether a pooled analysis would be appropriate. If we considered a pooled analysis to be appropriate, we performed the analysis using a random‐effects model.

Assessment of reporting biases

Had there been more than 10 studies available for a given outcome to enable a meaningful assessment, we would have used a funnel plot to screen for publication bias. If we detected significant asymmetry in the funnel plot, which is suggestive of the possibility of publication bias, we would have assessed it further using Begg's rank correlation and Egger's test and would have included a statement in the Results with a corresponding note of caution in the Discussion.

Data synthesis

We performed meta‐analyses using Review Manager 5 software with a fixed‐effect model (Review Manager 2020), unless there was moderate or high heterogeneity, in which case we used the random‐effects model alongside an exploration of possible causes of heterogeneity, as described in the Assessment of heterogeneity section. Our primary data analyses followed the intention‐to‐treat principle; namely, we used the original number of participants allocated to each study arm as the denominator in subsequent analyses. We expressed our results as RRs, RDs, NNTB, NNTH, and MDs with their respective 95% CIs, as detailed in the Measures of treatment effect section.

Subgroup analysis and investigation of heterogeneity

We planned to conduct the following subgroup analyses if sufficient data were available; however we were unable undertake these analyses due to insufficient data.

• Different neurodiagnostic procedures (e.g. brain MRI versus brain computed tomography (CT) versus EEG).

• Age group of children (e.g. neonates versus older children).

In addition, we found a study (Gumus 2015) which included separate data for high and low doses of chloral hydrate for the major outcomes assessed. We therefore incorporated on a post‐hoc basis the subgroups of high dose (100 mg/kg) and low dose (50 mg/kg) in the meta‐analysis of comparison between chloral hydrate and dexmedetomidine (Analysis 1.1, Analysis 1.2; Analysis 1.3; Analysis 1.4; Analysis 1.5; Analysis 1.6; Analysis 1.7; Analysis 1.7; Analysis 1.8; Analysis 1.9).

1.1. Analysis.

Comparison 1: Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2 µg/kg or 3 µg/kg), Outcome 1: EEG time onset for adequate sedation (minutes)

1.2. Analysis.

Comparison 1: Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2 µg/kg or 3 µg/kg), Outcome 2: EEG sedation failure

1.3. Analysis.

Comparison 1: Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2 µg/kg or 3 µg/kg), Outcome 3: EEG sedation / sleep duration (minutes)

1.4. Analysis.

Comparison 1: Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2 µg/kg or 3 µg/kg), Outcome 4: EEG sedation adverse event: total

1.5. Analysis.

Comparison 1: Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2 µg/kg or 3 µg/kg), Outcome 5: EEG sedation adverse event: hypotension

1.6. Analysis.

Comparison 1: Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2 µg/kg or 3 µg/kg), Outcome 6: EEG sedation adverse event: bradycardia

1.7. Analysis.

Comparison 1: Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2 µg/kg or 3 µg/kg), Outcome 7: EEG sedation adverse event: behavioural change

1.8. Analysis.

Comparison 1: Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2 µg/kg or 3 µg/kg), Outcome 8: EEG sedation adverse event: nausea or vomiting

1.9. Analysis.

Comparison 1: Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2 µg/kg or 3 µg/kg), Outcome 9: EEG sedation adverse event: oxygen desaturation

Sensitivity analysis

We planned to perform sensitivity analyses for the primary outcomes and any secondary outcomes for which sufficient numbers of studies were available, by evaluating the change in the effect estimates following exclusion of studies at high risk of:

• selection bias (high risk for random sequence generation or allocation concealment, or both);

• attrition bias.

However, we were unable to perform the sensitivity analyses as specified above due to insufficient number of studies included in each comparison‐outcome combination.

Summary of findings and assessment of the certainty of the evidence

We used the GRADE approach, as outlined in the GRADE Handbook, to assess the certainty of evidence for the most important outcomes across all comparisons as listed below, whether or not data were available (Schünemann 2013).

Prespecified primary outcomes

• Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening.

• Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent.

• Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score).

Prespecified secondary outcomes

• Proportion of children who had sedation failure or inadequate level of sedation.

• Sedation duration (minutes).

• Yield of EEG findings, including non‐interpretable EEG or sedative‐induced artefact.

• Number of children with clinical adverse events (any).

Two review authors independently assessed the certainty of the evidence for each of the outcomes listed above. We considered evidence from RCTs initially as high quality, downgrading the evidence one level for serious (or two levels for very serious) limitations based on the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates, and presence of publication bias (Guyatt 2008; Schünemann 2013). We used GRADEpro GDT software to create summary of findings tables to report the certainty of the evidence (GRADEpro GDT).

The GRADE approach results in an assessment of the certainty of a body of evidence in one of four grades, as follows.

• High: we are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.

• Low: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

• Very low: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of the effect.

Results

Description of studies

Results of the search

We identified 310 records from our search of CENTRAL, MEDLINE, and Embase. We identified a further 50 potentially relevant records from our search of ClinicalTrials.gov, Chinese Clinical Trials Registry, Iranian Registry of Clinical Trials, and the WHO ICTRP. After removal of duplicates, 233 records remained, of which 75 articles appeared to be relevant after title inspection. We excluded 54 of these 75 articles after evaluation of the abstract or full text, or both. Of the remaining 21 articles, we excluded one article that was a duplicate publication of an included study; assessed another article for which we have requested additional information from the authors as awaiting classification; and identified three ongoing studies awaiting further information from the authors regarding the research data. We included a total of 16 studies in the review. The study flow diagram from the initial search to the meta‐analysis is shown in Figure 1.

1.

Study flow diagram.

Included studies

For details, see Characteristics of included studies.

We included 16 RCTs that were conducted in six countries: Iran (6 studies), Turkey (3 studies), the USA (3 studies), and Israel, Chile, China, and Spain (1 study each). Fifteen trials were single‐centre RCTs, and 1 trial was dual‐centre RCT. The number of children recruited ranged from 40, in D'Agostino 2000, to 582, in Thompson 1982. All studies were conducted on paediatric patients (age up to 18 years old). All studies included children of both sexes.

Five trials were sedation trials conducted on neuroimaging studies (4 studies on brain CT, 2 studies on brain MRI, 1 study on brain MRI or CT) (Azizkhani 2014; D'Agostino 2000; Fallah 2013; Malviya 2004; Marti‐Bonmati 1995; Thompson 1982; Yuen 2017a), whilst the remaining nine trials were sedation trials conducted on EEG studies (Ashrafi 2010; Ashrafi 2013; Ashrafi 2020; Bektas 2014; Gumus 2015; Loewy 2005; Lopez 1995; Razieh 2013; Sezer 2013).

There were 13 comparisons.

• Oral chloral hydrate (50 mg/kg or 100 mg/kg) versus oral dexmedetomidine (Gumus 2015).

• Oral chloral hydrate (75 mg/kg) versus intravenous pentobarbital (Malviya 2004).

• Oral chloral hydrate (75 mg/kg or 100 mg/kg) versus midazolam (given either orally or intranasally) (Ashrafi 2013; D'Agostino 2000; Fallah 2013).

• Oral chloral hydrate (50 mg/kg) versus oral melatonin (Ashrafi 2010).

• Oral chloral hydrate (60 mg/kg) versus music therapy (Loewy 2005).

• Oral chloral hydrate (50 mg/kg) versus oral hydroxyzine hydrochloride (Sezer 2013).

• Oral chloral hydrate (70 mg/kg) versus oral promethazine (Razieh 2013).

• Rectal chloral hydrate (50 mg/kg) versus rectal midazolam (Lopez 1995).

• High‐dose oral chloral hydrate (100 mg/kg) versus low‐dose oral chloral hydrate (70 mg/kg) (Marti‐Bonmati 1995).

• High‐dose oral chloral hydrate (100 mg/kg) versus low‐dose oral chloral hydrate (50 mg/kg) (Gumus 2015).

• Oral chloral hydrate (50 mg/kg) versus rectal sodium thiopental (25 mg/kg) (Azizkhani 2014).

• Oral chloral hydrate (50 mg/kg) versus oral clonidine (4 μg/kg) (Ashrafi 2020).

• Oral chloral hydrate (50 mg/kg) versus intranasal dexmedetomidine (3 μg/kg) (Yuen 2017a).

The initial sedation dose of chloral hydrate used in the studies ranged from 25 mg/kg to 100 mg/kg oral and 50 mg/kg rectal. The type and doses of the sedation agents used varied amongst the included studies: dexmedetomidine either orally 2 or 3 μg/kg, Gumus 2015, or intranasally 3 μg/kg (Yuen 2017a); intravenous pentobarbital 5 mg/kg (Malviya 2004); midazolam either 0.5 mg/kg orally, Ashrafi 2013; D'Agostino 2000, 0.2 mg/kg intranasally, Fallah 2013, or rectal midazolam 1 mg/kg (Lopez 1995); oral hydroxyzine hydrochloride 1 mg/kg (Bektas 2014; Sezer 2013); oral promethazine 1 mg/kg (Razieh 2013); intramuscular atropine/meperidine/promethazine/secobarbital (AMPS) cocktail 0.08 mL/kg (Thompson 1982); rectal sodium thiopental 25 mg/kg (Azizkhani 2014); and oral clonidine 4 μg/kg (Ashrafi 2020). Two studies compared sedation of high‐dose (100 mg/kg) chloral hydrate versus low‐dose (50 or 70 mg/kg) chloral hydrate orally (Gumus 2015; Marti‐Bonmati 1995). Dose of melatonin was not stated (Ashrafi 2010), and dosing/intensity was not stated for music therapy (Loewy 2005).

In general, the included studies assessed outcomes of success of sedation based on the following.

• Time to onset to adequate sedation in minutes in 11 studies (Ashrafi 2020; Azizkhani 2014; Fallah 2013; Gumus 2015; Loewy 2005; Lopez 1995; Malviya 2004; Marti‐Bonmati 1995; Razieh 2013; Sezer 2013; Yuen 2017a).

• Failure of sedation preventing successful completion of neurodiagnostic investigation in nine studies (Azizkhani 2014; D'Agostino 2000; Fallah 2013; Gumus 2015; Loewy 2005; Malviya 2004; Marti‐Bonmati 1995; Razieh 2013; Sezer 2013).

• Total sedation/sleep duration in eight studies (Ashrafi 2020; Azizkhani 2014; D'Agostino 2000; Gumus 2015; Loewy 2005; Lopez 1995; Marti‐Bonmati 1995; Sezer 2013).

• Sedative adverse events in 12 studies (Ashrafi 2010; Ashrafi 2013; Ashrafi 2020; Azizkhani 2014; D'Agostino 2000; Fallah 2013; Gumus 2015; Malviya 2004; Marti‐Bonmati 1995; Razieh 2013; Sezer 2013; Yuen 2017a).

• Uninterpretable neurodiagnostic investigation due to either excessive motion artefact for neuroimaging studies or excessive fast background activity on EEG studies in five studies (Ashrafi 2010; Ashrafi 2013; Lopez 1995; Malviya 2004; Sezer 2013).

Other outcomes assessed included caregiver's satisfaction scale (Razieh 2013), hospital stay post sedation (Razieh 2013), and return to normal baseline activity (Malviya 2004; Yuen 2017a).

Excluded studies

For details of the excluded studies and the reasons for their exclusion, see Characteristics of excluded studies.

We excluded a total of 54 studies based on one or more of the following.

• Study design or article type (37 studies): retrospective or prospective cohort studies, cross‐over study, prospective non‐randomised intervention studies, literature review articles, a questionnaire study, studies with research questions or outcomes that did not match our review, or commentaries.

• Population (6 studies): children undergoing dental procedures, auditory brainstem response tests, or ophthalmic examination.

• Intervention (22 studies): the studies either assessed efficacy of chloral hydrate alone or in combination with other sedative agents, or efficacy of other sedative agents that were not the intervention of interest.

• Outcome (2 studies): the studies reported effects of sedation on EEG results and did not assess the success of sedation.

Risk of bias in included studies

Risk of bias in the included studies varied widely. There was at least one high‐risk domain in 10 of the 16 included studies (Ashrafi 2010; Ashrafi 2013; Ashrafi 2020; Bektas 2014; Gumus 2015; Loewy 2005; Lopez 1995; Malviya 2004; Thompson 1982; Yuen 2017a). We judged all of these 10 studies to be at high risk for blinding of participants, except Bektas 2014 and Ashrafi 2020, which we judged to be at unclear risk. Three studies were at low risk of bias for all domains (Fallah 2013; Lopez 1995; Marti‐Bonmati 1995). The proportions of included studies at low, high, and unclear risk of bias in each domain, and the risk of bias judgement of each included study in each domain, are illustrated in Figure 2 and Figure 3. A detailed description of the risk of bias of each study is provided in the risk of bias table in Characteristics of included studies.

2.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

We judged eight studies to be at low risk of bias for random sequence generation (Azizkhani 2014; D'Agostino 2000; Fallah 2013; Gumus 2015; Lopez 1995; Malviya 2004; Marti‐Bonmati 1995; Razieh 2013), and five studies to be at low risk of bias for allocation concealment (D'Agostino 2000; Lopez 1995; Marti‐Bonmati 1995; Razieh 2013; Yuen 2017a). The authors of these studies clearly stated the method of sequence generation, which involved some form of random number scheme using either computers, random number table, or the toss of a coin. There were also clear statements in the methods confirming the independence between sequence generation and allocation. We judged three studies to be at high risk of bias for sequence generation as well as allocation concealment (Ashrafi 2020; Loewy 2005; Thompson 1982), as children were allocated following a predictable sequence based on the day of the week they were admitted or via alternating and rotational assignments. We assessed six studies as at unclear risk of bias in one or both domains as the information provided in the articles was insufficient to permit a judgement of low or high risk of bias (Ashrafi 2010; Ashrafi 2013; Azizkhani 2014; Bektas 2014; Sezer 2013; Yuen 2017a).

Blinding

We judged eight studies to be at high risk of bias for blinding of participants (Ashrafi 2010; Ashrafi 2013; Bektas 2014; Gumus 2015; Loewy 2005; Malviya 2004; Thompson 1982; Yuen 2017a). In four studies (Azizkhani 2014; D'Agostino 2000; Fallah 2013; Marti‐Bonmati 1995), it was stated clearly that blinding of participants was achieved, whilst in the other four studies (Ashrafi 2020; Lopez 1995; Razieh 2013; Sezer 2013), no statements were made regarding the blinding status of the participants. We considered blinding for these four studies to be unlikely because they compared chloral hydrate with another solution of a different appearance/preparation and taste.

Nine studies did not report blinding of outcome assessors (Ashrafi 2010; Ashrafi 2013; Ashrafi 2020; Azizkhani 2014; Bektas 2014; Gumus 2015; Malviya 2004; Sezer 2013; Thompson 1982). We judged one study to be at high risk of detection bias, as the modality of sedation intervention given in this study (oral chloral hydrate versus music therapy via music therapist) was clearly different, precluding blinding of the outcome assessors (Loewy 2005). In the remaining six studies (D'Agostino 2000; Fallah 2013; Lopez 1995; Marti‐Bonmati 1995; Razieh 2013; Yuen 2017a), it was clearly stated that the outcome assessors were blinded.

Incomplete outcome data

In all studies except two (Lopez 1995; Thompson 1982), all children enrolled appeared to be included in the analysis. Both studies with missing data had a dropout rate of over 20% (22% in Lopez 1995 and 42.3% in Thompson 1982), resulting in a judgement of high risk of bias for this domain. We judged a third study as having a high risk of attrition bias, as the authors did not conduct an intention‐to‐treat analysis (Bektas 2014).

Selective reporting

We judged 13 studies as at low risk of bias for this domain (Ashrafi 2010; Ashrafi 2013; Ashrafi 2020; Azizkhani 2014; D'Agostino 2000; Fallah 2013; Gumus 2015; Lopez 1995; Malviya 2004; Marti‐Bonmati 1995; Razieh 2013; Sezer 2013; Yuen 2017a). We judged three studies, Bektas 2014; Loewy 2005; Thompson 1982, as at high risk of reporting bias; Loewy 2005 used a different categorical outcome sedation score between both comparison groups (reported sleep score 4 for chloral hydrate group and sleep score 3 for music therapy), making it unsuitable for direct comparison, or the studies reported outcomes without sufficient detail for a meta‐analysis, for example reporting means without standard deviations (Thompson 1982).

Other potential sources of bias

We identified an additional potential source of bias in one study (Ashrafi 2020). There was an imbalance in participant characteristics in which there was skewness in data, with the mean age of children assigned to the clonidine group (mean 57.4 months) being older than the mean age of children assigned to the chloral hydrate group (mean 21.8 months), and the difference showing a tendency towards statistical significance (P < 0.05).

Effects of interventions

See: Table 1; Table 2; Table 3; Table 4; Table 5; Table 6; Table 7; Table 8; Table 9; Table 10

Overall, we carried out 13 comparisons, with variations related to the specific interventions compared in Comparison 3 (difference in mode of administration of midazolam, i.e. either intranasal or oral), Comparison 7 (difference with non‐drug music therapy), and Comparisons 9 and 10 (difference between different doses of chloral hydrate). We did not include four studies in the analysis as the data were skewed (Ashrafi 2010; Ashrafi 2013; Bektas 2014; Thompson 1982). Thompson 1982 had a high dropout rate (42.3%), with no details provided regarding the missing data; Bektas 2014 also had incomplete outcome data, and the study did not follow an intention‐to‐treat analysis. Details of these studies are provided in Table 11.

1. Outcomes with skewed data as reported by individual studies.

Comparison	Outcome	Study ID	Effect estimate	P value
Chloral hydrate versus melatonin	Sleep onset latency	Ashrafi 2010	Median (range) in minutes Chloral hydrate group (35 (10 to 150)), melatonin group (45 (5 to 210))	0.113
	Sleep duration	Ashrafi 2010	Median (range) in minutes Chloral hydrate group (60 (15 to 240)), melatonin group (30 (15 to 240))	< 0.001
	Drowsiness time	Ashrafi 2010	Median (range) in minutes Chloral hydrate group (60 (0 to 300)), melatonin group (20 (0 to 300))	< 0.001
Chloral hydrate versus midazolam	Sleep onset latency	Ashrafi 2013	Median (range) in minutes Chloral hydrate group (32 (20 to 95)), midazolam group (20 (0 to 300))	< 0.001
	Sleep duration	Ashrafi 2013	Median (range) in minutes Chloral hydrate group (66.5 (56 to 98)), midazolam group (25.5 (12 to 38))	< 0.001
	Drowsiness time	Ashrafi 2013	Median (range) in minutes Chloral hydrate group (32 (21 to 36)), midazolam group (6 (2 to 9))	< 0.001
Chloral hydrate versus hydroxyzine	Time of sleep	Bektas 2014	Median (range) in minutes Chloral hydrate group (20 (5 to 120)), hydroxyzine group (30 (5 to 240))	0.309
	Excessive fast activity	Bektas 2014	Percentage Chloral hydrate (24.5%) vs hydroxyzine (11.6%)	0.02
	Success in falling asleep	Bektas 2014	Percentage Chloral hydrate (90.7%) vs hydroxyzine (89.6%)	0.841
Chloral hydrate versus intramuscular AMPS	Time to sedation	Thompson 1982	Mean (minutes) Chloral hydrate (55) vs AMPS (53)	N/A
	Imaging failure	Thompson 1982	Percentage Chloral hydrate (15%) vs AMPS (12%)	N/A

AMPS: atropine/meperidine/promethazine/secobarbital
N/A: not applicable

We performed analysis on the remaining 10 studies with a total of 1794 children in the 13 comparisons.

• Comparison 1: Chloral hydrate oral (50 mg/kg or 100 mg/kg) compared to dexmedetomidine oral (2 µg/kg or 3 µg/kg) (160 children) (Gumus 2015).

• Comparison 2: Chloral hydrate oral (75 mg/kg) compared to pentobarbital intravenous (5 mg/kg) (70 children) (Malviya 2004).

• Comparison 3: Chloral hydrate oral (100 mg/kg or 75 mg/kg) compared to midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg) (291 children) (Ashrafi 2013; D'Agostino 2000; Fallah 2013).

• Comparison 4: Chloral hydrate oral (50 mg/kg) compared to melatonin oral (348 children) (Ashrafi 2010).

• Comparison 5: Chloral hydrate oral (50 mg/kg + 50 mg/kg) compared to hydroxyzine hydrochloride oral (1 mg/kg + 1 mg/kg) (282 children) (Sezer 2013).

• Comparison 6: Chloral hydrate oral (70 mg/kg) compared to promethazine oral (1 mg/kg) (60 children) (Razieh 2013).

• Comparison 7: Chloral hydrate oral (60 mg/kg) compared to music therapy (58 children) (Loewy 2005).

• Comparison 8: Chloral hydrate oral (50 mg/kg) compared to midazolam rectal (1 mg/kg) (59 children) (Lopez 1995).

• Comparison 9: Chloral hydrate oral high dose (100 mg/kg) compared to chloral hydrate oral low dose (70 mg/kg) (97 children) (Marti‐Bonmati 1995).

• Comparison 10: Chloral hydrate oral high dose (100 mg/kg) compared to chloral hydrate oral low dose (50 mg/kg) (76 children) (Gumus 2015).

• Comparison 11: Chloral hydrate oral (50 mg/kg) compared to sodium thiopental rectal (25 mg/kg) (140 children) (Azizkhani 2014).

• Comparison 12: Chloral hydrate oral (50 mg/kg) compared to clonidine oral (4 μg/kg) (198 children) (Ashrafi 2020).

• Comparison 13: Chloral hydrate oral (50 mg/kg) compared to dexmedetomidine intranasal (3 μg/kg) (194 children) (Yuen 2017a).

Our outcomes of interest for each comparison are reported below.

Comparison 1: Chloral hydrate versus dexmedetomidine

Gumus 2015 was the only study comparing oral chloral hydrate to oral dexmedetomidine, in two different dosing regimens. There were four arms in this study, namely low‐dose chloral hydrate (50 mg/kg), high‐dose chloral hydrate (100 mg/kg), low‐dose dexmedetomidine (2 µg/kg), and high‐dose dexmedetomidine (3 µg/kg). This made two pair‐wise comparisons of comparable dosages possible, thus we formed two separate subgroups in our analysis: one comparing low‐dose chloral hydrate against low‐dose dexmedetomidine, and another comparing high‐dose chloral hydrate against high‐dose dexmedetomidine. The major outcomes for this comparison with the corresponding certainty of evidence are displayed in Table 1.

Primary outcomes

Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening

No studies assessed this outcome.

Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent

No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)

Children who received oral chloral hydrate had a significantly shorter mean EEG time onset for adequate sedation compared with children who received oral dexmedetomidine (mean difference (MD) −3.86, 95% confidence interval (CI) −5.12 to −2.60; 160 children, moderate‐certainty evidence, downgraded one level due to imprecision) (Analysis 1.1). Our subgroup analysis showed that high‐dose oral chloral hydrate (100 mg/kg) achieved a significantly shorter mean onset of sedation of 5.6 minutes compared with high‐dose oral dexmedetomidine, whilst low‐dose oral chloral hydrate (50 mg/kg) achieved a significantly shorter mean onset of sedation of 1.9 minutes compared with low‐dose oral dexmedetomidine. The test of subgroup differences was significant (P = 0.004). No studies assessed the outcome of adequate sedation with validated scales.

Secondary outcomes

Proportion of children who had sedation failure or inadequate level of sedation

There was no significant difference in sedation failure between oral chloral hydrate and oral dexmedetomidine (risk ratio (RR) 1.14, 95% CI 0.51 to 2.53; 160 children, moderate‐certainty evidence, downgraded one level due to imprecision) (Analysis 1.2). There were no significant differences between the high‐ and low‐dose subgroup comparisons.

Sedation duration

The duration of sedation was significantly longer in the oral chloral hydrate group by 16.5 minutes compared with oral dexmedetomidine (MD 16.47, 95% CI 9.21 to 23.72; 160 children, moderate‐certainty evidence, downgraded one level due to imprecision) (Analysis 1.3). There were no significant differences between the high‐ and low‐dose subgroup comparisons.

Yield of EEG or neuroimaging findings

No studies assessed this outcome.

Adverse effects (any)

Oral chloral hydrate had significantly more adverse events in total when compared with oral dexmedetomidine (RR 7.66, 95% CI 1.78 to 32.91; 160 children, low‐certainty evidence, downgraded two levels due to serious imprecision) (Analysis 1.4). There were no significant differences between the high‐ and low‐dose subgroup comparisons. Regarding individual adverse events, there were no significant differences between the two groups for all adverse events (Analysis 1.5; Analysis 1.6; Analysis 1.7; Analysis 1.9), except for nausea or vomiting, for which children who received oral chloral hydrate were reported to have significantly higher risk compared to children who received oral dexmedetomidine (RR 12.04, 95% CI 1.58 to 91.96; 160 children) (Analysis 1.8). There were no significant differences between the high‐ and low‐dose subgroup comparisons.

Comparison 2: Chloral hydrate versus pentobarbital

Malviya 2004 was the only study comparing oral chloral hydrate to intravenous pentobarbital. The major outcomes for this comparison with the corresponding certainty of evidence are displayed in Table 2.

Primary outcomes

Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening

No studies assessed this outcome.

Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent

No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)

Children who received oral chloral hydrate had a significantly longer mean time to adequate sedation compared with children who received intravenous pentobarbital (MD 19, 95% CI 16.61 to 21.39; 70 children, low‐certainty evidence, downgraded due to risk of bias (one level) and imprecision (one level)) (Analysis 2.1). No studies assessed the outcome of adequate sedation with validated scales. However, there was no significant difference in sedation failure between groups after two doses (RR 3.00, 95% CI 0.33 to 27.46; 1 study, very low‐certainty evidence, downgraded three levels due to risk of bias (one level) and very serious imprecision (two levels)) (Analysis 2.2).

2.1. Analysis.

Comparison 2: Chloral hydrate oral (75 mg/kg) versus pentobarbital intravenous (5 mg/kg), Outcome 1: Neuroimaging time onset for adequate sedation (minutes)

2.2. Analysis.

Comparison 2: Chloral hydrate oral (75 mg/kg) versus pentobarbital intravenous (5 mg/kg), Outcome 2: Neuroimaging sedation failure after 2 administrations of sedative agent (same or different)

Secondary outcomes

Proportion of children who had sedation failure or inadequate level of sedation

Oral chloral hydrate had significantly more sedation failure after one dose than intravenous pentobarbital (RR 4.33, 95% CI 1.35 to 13.89; 70 children, low‐certainty evidence, downgraded two levels due to very serious imprecision) (Analysis 2.3).

2.3. Analysis.

Comparison 2: Chloral hydrate oral (75 mg/kg) versus pentobarbital intravenous (5 mg/kg), Outcome 3: Neuroimaging sedation failure after 1 administration of sedative agent

Sedation duration

No studies assessed this outcome.

Yield of EEG or neuroimaging findings

There was no significant difference in non‐interpretable neuroimaging findings between the two groups (RR 0.23, 95% CI 0.03 to 1.94; 54 children, very low‐certainty evidence, downgraded three levels due to risk of bias (one level) and very serious imprecision (two levels)) (Analysis 2.4).

2.4. Analysis.

Comparison 2: Chloral hydrate oral (75 mg/kg) versus pentobarbital intravenous (5 mg/kg), Outcome 4: Neuroimaging uninterpretable

Adverse effects (any)

The study did not evaluate overall adverse effects between the two groups. Regarding individual adverse events, there was no significant difference in oxygen desaturation (RR 0.67, 95% CI 0.21 to 2.16; 70 children, very low‐certainty evidence, downgraded three levels due to risk of bias (one level) and serious imprecision (two levels)) (Analysis 2.5); nausea or vomiting; and paradoxical reaction between the two groups (Analysis 2.6; Analysis 2.7). Children who received oral chloral hydrate had a significantly shorter mean time (hours) to return to normal behaviour postdischarge when compared with intravenous pentobarbital (MD −6.0, 95% CI −11.43 to −0.57; 70 children) (Analysis 2.8).

2.5. Analysis.

Comparison 2: Chloral hydrate oral (75 mg/kg) versus pentobarbital intravenous (5 mg/kg), Outcome 5: Neuroimaging sedation adverse event: oxygen desaturation

2.6. Analysis.

Comparison 2: Chloral hydrate oral (75 mg/kg) versus pentobarbital intravenous (5 mg/kg), Outcome 6: Neuroimaging sedation adverse event: nausea or vomiting

2.7. Analysis.

Comparison 2: Chloral hydrate oral (75 mg/kg) versus pentobarbital intravenous (5 mg/kg), Outcome 7: Neuroimaging sedation adverse event: paradoxical reaction

2.8. Analysis.

Comparison 2: Chloral hydrate oral (75 mg/kg) versus pentobarbital intravenous (5 mg/kg), Outcome 8: Neuroimaging sedation adverse event: return to baseline activity postdischarge

Comparison 3: Chloral hydrate versus midazolam

Three studies compared oral chloral hydrate to midazolam: Fallah 2013, which used intranasal midazolam, and D'Agostino 2000 and Ashrafi 2013, which used oral midazolam. Data in Ashrafi 2013 were skewed and were therefore not included in the meta‐analysis. The major outcomes for this comparison with the corresponding certainty of evidence are displayed in Table 3.

Primary outcomes

Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening

No studies assessed this outcome.

Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent

No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)

Ashrafi 2013 reported that children who received oral chloral hydrate had significantly shorter sleep onset latency, but significantly longer sleep duration and drowsiness time (Table 11). Fallah 2013 reported that children who received oral chloral hydrate took a significantly longer time in minutes to achieve adequate sedation compared with intranasal midazolam (MD 12.83, 95% CI 7.22 to 18.44; 60 children, 1 study, moderate‐certainty evidence, downgraded one level due to imprecision) (Analysis 3.1). Children who received oral chloral hydrate appeared to be significantly less likely to suffer from an inadequate level of sedation (Ramsay score below 4) compared with intranasal midazolam (RR 0.11, 95% CI 0.03 to 0.44; 60 children, 1 study, moderate‐certainty evidence, downgraded one level due to imprecision) (Analysis 3.2).

3.1. Analysis.

Comparison 3: Chloral hydrate oral (100 mg/kg or 75 mg/kg) versus midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg), Outcome 1: Neuroimaging time onset for adequate sedation (minutes)

3.2. Analysis.

Comparison 3: Chloral hydrate oral (100 mg/kg or 75 mg/kg) versus midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg), Outcome 2: Neuroimaging inadequate level of sedation achieved (Ramsay score 4)

Secondary outcomes

Proportion of children who had sedation failure or inadequate level of sedation

There was no significant difference for sedation failure after one dose of sedative agent between oral chloral hydrate and oral midazolam (RR 0.17, 95% CI 0.02 to 1.12; 33 children, 1 study, low‐certainty evidence, downgraded two levels due to very serious imprecision) (Analysis 3.3).

3.3. Analysis.

Comparison 3: Chloral hydrate oral (100 mg/kg or 75 mg/kg) versus midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg), Outcome 3: Neuroimaging sedation failure after 1 administration of sedative agent

Sedation duration

D'Agostino 2000 reported that there was no significant difference in the mean duration of sedation between oral chloral hydrate and oral midazolam, with mean time for chloral sedation 19 minutes longer (MD 19, 95% CI −3.4 to 41.4; 33 children, 1 study, low‐certainty evidence, downgraded two levels due to very serious imprecision) (Analysis 3.4).

3.4. Analysis.

Comparison 3: Chloral hydrate oral (100 mg/kg or 75 mg/kg) versus midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg), Outcome 4: Neuroimaging sedation / sleep duration (minutes)

Yield of EEG or neuroimaging findings

Ashrafi 2013 reported that children who received oral chloral hydrate were significantly less likely to have sedative‐induced artefact on their EEG recording compared to children who received intranasal midazolam (RR 0.58, 95% CI 0.44 to 0.76; 198 children, 1 study, high‐certainty evidence) (Analysis 3.5).

3.5. Analysis.

Comparison 3: Chloral hydrate oral (100 mg/kg or 75 mg/kg) versus midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg), Outcome 5: EEG sedative‐induced artefact

Adverse effects (any)

There was no statistical significant difference in any adverse effects between oral chloral hydrate and oral midazolam groups (RR 0.20, 95% CI 0.01 to 4.2; 198 children, 1 study, low‐certainty evidence, downgraded two levels due to very serious imprecision) (Analysis 3.6).

3.6. Analysis.

Comparison 3: Chloral hydrate oral (100 mg/kg or 75 mg/kg) versus midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg), Outcome 6: EEG sedation adverse event: total

Comparison 4: Chloral hydrate versus melatonin

Ashrafi 2010 was the only study comparing oral chloral hydrate to oral melatonin; however, the data were skewed and were therefore not included in the meta‐analysis. The major outcomes for this comparison with the corresponding certainty of evidence are displayed in Table 4.

Primary outcomes

Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening

No studies assessed this outcome.

Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent

No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)

Data in Ashrafi 2010 were skewed and were therefore not included in the meta‐analysis. Ashrafi 2010 reported no significant difference between children who received oral chloral hydrate and those who received oral melatonin in sleep onset latency, but children who received oral chloral hydrate had significantly longer sleep duration and drowsiness time (Table 11). No studies assessed the outcome of adequate sedation with validated scales.

Secondary outcomes

Proportion of children who had sedation failure or inadequate level of sedation

No studies assessed this outcome.

Sedation duration

No studies assessed this outcome.

Yield of EEG or neuroimaging findings

The occurrence of EEG sedative drug artefact (increased fast activity and slow dysrhythmia) was significantly less likely in the oral chloral hydrate group compared to the oral melatonin group (RR 0.33, 95% CI 0.14 to 0.82; 348 children, low‐certainty evidence, downgraded due to risk of bias (one level) and imprecision (one level)) (Analysis 4.1).

4.1. Analysis.

Comparison 4: Chloral hydrate oral (50 mg/kg) versus melatonin oral, Outcome 1: EEG sedative‐induced artefact

Adverse effects (any)

There was no significant difference in any adverse effects between the two groups (RR 1.00, 95% CI 0.25 to 3.93; 348 children, low‐certainty evidence, downgraded due to risk of bias (one level) and imprecision (one level)) (Analysis 4.2).

4.2. Analysis.

Comparison 4: Chloral hydrate oral (50 mg/kg) versus melatonin oral, Outcome 2: EEG sedation adverse event: total

Comparison 5: Chloral hydrate versus hydroxyzine hydrochloride

Sezer 2013 was the only study comparing oral chloral hydrate to oral hydroxyzine hydrochloride. The major outcomes for this comparison with the corresponding certainty of evidence are displayed in Table 5.

Primary outcomes

Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening

No studies assessed this outcome.

Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent

No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)

Children receiving oral chloral hydrate had a significantly shorter mean time to adequate sedation compared with oral hydroxyzine hydrochloride (MD −7.5, 95% CI −7.85 to −7.15; 282 children, moderate‐certainty evidence, downgraded one level due to imprecision) (Analysis 5.1). No studies assessed the outcome of adequate sedation using validated scales.

5.1. Analysis.

Comparison 5: Chloral hydrate oral (50 mg/kg + 50 mg/kg) versus hydroxyzine hydrochloride oral (1 mg/kg + 1 mg/kg), Outcome 1: EEG time onset for adequate sedation (minutes)

Secondary outcomes

Proportion of children who had sedation failure or inadequate level of sedation

There was no statistically significant difference in risk of sedation failure between the two groups (RR 0.33, 95% CI 0.11 to 1.01; 282 children, low‐certainty evidence, downgraded due to risk of bias (one level) and imprecision (one level)) (Analysis 5.2).

5.2. Analysis.

Comparison 5: Chloral hydrate oral (50 mg/kg + 50 mg/kg) versus hydroxyzine hydrochloride oral (1 mg/kg + 1 mg/kg), Outcome 2: EEG sedation failure

Sedation duration

Children receiving oral chloral hydrate had a significantly longer mean sleep duration compared to those receiving oral hydroxyzine hydrochloride (MD 3.1, 95% CI 2.23 to 3.97; 282 children, moderate‐certainty evidence, downgraded one level due to imprecision) (Analysis 5.3).

5.3. Analysis.

Comparison 5: Chloral hydrate oral (50 mg/kg + 50 mg/kg) versus hydroxyzine hydrochloride oral (1 mg/kg + 1 mg/kg), Outcome 3: EEG sedation / sleep duration (minutes)

Yield of EEG or neuroimaging findings

There was no significant difference in EEG sedative drug artefact between the two groups (RR 1.33, 95% CI 0.47 to 3.74; 282 children, moderate‐certainty evidence, downgraded one level due to imprecision) (Analysis 5.4).

5.4. Analysis.

Comparison 5: Chloral hydrate oral (50 mg/kg + 50 mg/kg) versus hydroxyzine hydrochloride oral (1 mg/kg + 1 mg/kg), Outcome 4: EEG sedative‐induced artefact

Adverse effects (behavioural change and nausea or vomiting)

There was no significant difference between the two groups for behavioural change (RR 1.17, 95% CI 0.40 to 3.38; 282 children, low‐certainty evidence, downgraded due to risk of bias (one level) and imprecision (one level)) (Analysis 5.5), or for nausea or vomiting (RR 1.25, 95% CI 0.34 to 4.56; 282 children, low‐certainty evidence, downgraded due to risk of bias (one level) and imprecision (one level)) (Analysis 5.6).

5.5. Analysis.

Comparison 5: Chloral hydrate oral (50 mg/kg + 50 mg/kg) versus hydroxyzine hydrochloride oral (1 mg/kg + 1 mg/kg), Outcome 5: EEG sedation adverse event: behavioural change

5.6. Analysis.

Comparison 5: Chloral hydrate oral (50 mg/kg + 50 mg/kg) versus hydroxyzine hydrochloride oral (1 mg/kg + 1 mg/kg), Outcome 6: EEG sedation adverse event: nausea or vomiting

Comparison 6: Chloral hydrate versus promethazine

Razieh 2013 was the only study comparing oral chloral hydrate to oral promethazine. The major outcomes for this comparison with the corresponding certainty of evidence are displayed in Table 6.

Primary outcomes

Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening

No studies assessed this outcome.

Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent

No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)

Children in the chloral hydrate group had a significantly shorter mean time to adequate sedation compared with promethazine (MD −12.11, 95% CI −18.48 to −5.74; 60 children, moderate‐certainty evidence, downgraded one level due to imprecision) (Analysis 6.1). A significantly lower number of children who received oral chloral hydrate had an inadequate level of sedation (Ramsay score below 4) compared with oral promethazine (RR 0.03, 95% CI 0.00 to 0.45; 60 children, low‐certainty evidence, downgraded two levels due to very serious imprecision) (Analysis 6.2).

6.1. Analysis.

Comparison 6: Chloral hydrate oral (70 mg/kg) versus promethazine oral (1 mg/kg), Outcome 1: EEG time for adequate sedation (minutes)

6.2. Analysis.

Comparison 6: Chloral hydrate oral (70 mg/kg) versus promethazine oral (1 mg/kg), Outcome 2: EEG inadequate level of EEG sedation achieved (Ramsay score 4)

Sedation duration

No studies assessed this outcome.

Secondary outcomes

Proportion of children who had sedation failure or inadequate level of sedation

Children in the oral chloral hydrate group had significantly less sedation failure compared with oral promethazine (RR 0.11, 95% CI 0.01 to 0.82; 60 children, moderate‐certainty evidence, downgraded one level due to imprecision) (Analysis 6.3).

6.3. Analysis.

Comparison 6: Chloral hydrate oral (70 mg/kg) versus promethazine oral (1 mg/kg), Outcome 3: EEG sedation failure

Sedation duration

No studies assessed this outcome.

Yield of EEG or neuroimaging findings

No studies assessed this outcome.

Adverse effects (behavioural change and nausea or vomiting)

There was no significant difference between the two groups for behavioural change (RR 0.20, 95% CI 0.01 to 4.00; 60 children, moderate‐certainty evidence, downgraded one level due to imprecision) (Analysis 6.4), or for nausea or vomiting (RR 13.00, 95% CI 0.76 to 220.96; 60 children, low‐certainty evidence, downgraded two levels due to very serious imprecision) (Analysis 6.5).

6.4. Analysis.

Comparison 6: Chloral hydrate oral (70 mg/kg) versus promethazine oral (1 mg/kg), Outcome 4: EEG sedation adverse event: behavioural change

6.5. Analysis.

Comparison 6: Chloral hydrate oral (70 mg/kg) versus promethazine oral (1 mg/kg), Outcome 5: EEG sedation adverse event: vomiting or nausea

Comparison 7: Chloral hydrate versus music therapy

Loewy 2005 was the only study comparing oral chloral hydrate to music therapy. The major outcomes for this comparison with the corresponding certainty of evidence are displayed in Table 7.

Primary outcomes

Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening

No studies assessed this outcome.

Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent

No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)

There was no difference between the two groups in time to adequate sedation (MD 9.00 minutes, 95% CI −2.15 to 20.15; 58 children, very low‐certainty evidence, downgraded due to very serious risk of bias (two levels) and imprecision (one level)) (Analysis 7.1). No studies assessed the outcome of adequate sedation with validated scales.

7.1. Analysis.

Comparison 7: Chloral hydrate oral (60 mg/kg) versus music therapy, Outcome 1: EEG time onset for adequate sedation (minutes)

Secondary outcomes

Proportion of children who had sedation failure or inadequate level of sedation

Children who received oral chloral hydrate had significantly higher sedation failure compared with children who received music therapy (RR 17.00, 95% CI 2.37 to 122.14; 58 children, very low‐certainty evidence, downgraded due to very serious risk of bias (two levels) and very serious imprecision (two levels)) (Analysis 7.2).

7.2. Analysis.

Comparison 7: Chloral hydrate oral (60 mg/kg) versus music therapy, Outcome 2: EEG sedation failure

Sedation duration

The duration of sedation was significantly longer in the oral chloral hydrate group by 160 minutes compared with the music therapy group (MD 160.00, 95% CI 121.07 to 198.93; 58 children, very low‐certainty evidence, downgraded due to very serious risk of bias (two levels) and imprecision (one level)) (Analysis 7.3).

7.3. Analysis.

Comparison 7: Chloral hydrate oral (60 mg/kg) versus music therapy, Outcome 3: EEG sedation / sleep duration (minutes)

Yield of EEG or neuroimaging findings

No studies assessed this outcome.

Adverse effects (any)

No studies assessed this outcome.

Comparison 8: Chloral hydrate versus midazolam

Lopez 1995 was the only study comparing oral chloral hydrate to rectal midazolam.

Primary outcomes

Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening

No studies assessed this outcome.

Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent

No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)

Children receiving oral chloral hydrate had a significantly shorter mean time to adequate sedation (in minutes) compared with rectal midazolam (MD −95.70, 95% CI −114.51 to −76.89; 59 children) (Analysis 8.1). No studies assessed the outcome of adequate sedation with validated scales.

8.1. Analysis.

Comparison 8: Chloral hydrate oral (50 mg/kg) versus midazolam rectal (1 mg/kg), Outcome 1: EEG time onset for adequate sedation (minutes)

Secondary outcomes

Proportion of children who had sedation failure or inadequate level of sedation

No studies assessed this outcome.

Sedation duration

The duration of sedation (in minutes) was significantly longer in the oral chloral hydrate group compared with the rectal midazolam group (MD 15.10, 95% CI 3.35 to 26.85; 59 children) (Analysis 8.2).

8.2. Analysis.

Comparison 8: Chloral hydrate oral (50 mg/kg) versus midazolam rectal (1 mg/kg), Outcome 2: EEG sedation/ sleep duration (minutes)

Yield of EEG or neuroimaging findings

There was no significant difference in EEG sedative drug artefact between the two groups (RR 1.25, 95% CI 0.73 to 2.12; 53 children) (Analysis 8.3).

8.3. Analysis.

Comparison 8: Chloral hydrate oral (50 mg/kg) versus midazolam rectal (1 mg/kg), Outcome 3: EEG sedative‐induced artefact

Adverse effects (any)

No studies assessed this outcome.

Comparison 9: Chloral hydrate high dose versus chloral hydrate low dose

Marti‐Bonmati 1995 was the only study comparing high‐dose oral chloral hydrate (100 mg/kg) to low‐dose oral chloral hydrate (70 mg/kg).

Primary outcomes

Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening

No studies assessed this outcome.

Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent

No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)

Children receiving high‐dose oral chloral hydrate had a significantly shorter mean time to adequate sedation (in minutes) compared with those receiving low‐dose oral chloral hydrate (MD −7.00, 95% CI −7.62 to −6.38; 97 children) (Analysis 9.1). No studies assessed the outcome of adequate sedation with validated scales.

9.1. Analysis.

Comparison 9: Chloral hydrate oral high dose (100 mg/kg) versus chloral hydrate oral low dose (70 mg/kg), Outcome 1: Neuroimaging time onset for adequate sedation (minutes)

Secondary outcomes

Proportion of children who had sedation failure or inadequate level of sedation

There was no significant difference in the proportion of children who had sedation failure between groups (RR 0.46, 95% CI 0.19 to 1.09; 97 children) (Analysis 9.2).

9.2. Analysis.

Comparison 9: Chloral hydrate oral high dose (100 mg/kg) versus chloral hydrate oral low dose (70 mg/kg), Outcome 2: Neuroimaging sedation failure after 1 administration of sedative agent

Sedation duration

The duration of sedation was longer in the high‐dose oral chloral hydrate group by 8 minutes compared with the low‐dose oral chloral hydrate group (MD 8.00, 95% CI 5.81 to 10.19; 97 children) (Analysis 9.3).

9.3. Analysis.

Comparison 9: Chloral hydrate oral high dose (100 mg/kg) versus chloral hydrate oral low dose (70 mg/kg), Outcome 3: Neuroimaging sedation / sleep duration (minutes)

Yield of EEG or neuroimaging findings

No studies assessed this outcome.

Adverse effects (any)

There was no significant difference in adverse effects between groups (RR 1.06, 95% CI 0.49 to 2.32; 97 children) (Analysis 9.4).

9.4. Analysis.

Comparison 9: Chloral hydrate oral high dose (100 mg/kg) versus chloral hydrate oral low dose (70 mg/kg), Outcome 4: Neuroimaging sedation adverse event: total

Comparison 10: Chloral hydrate high dose versus chloral hydrate low dose

Gumus 2015 was the only study comparing high‐dose oral chloral hydrate (100 mg/kg) to low‐dose oral chloral hydrate (50 mg/kg).

Primary outcomes

Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening

No studies assessed this outcome.

Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent

No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)

Children receiving high‐dose oral chloral hydrate had a significantly shorter time to adequate sedation (in minutes) compared with those receiving low‐dose oral chloral hydrate (MD −5.10, 95% CI −7.05 to −3.15; 76 children) (Analysis 10.1). No studies assessed the outcome of adequate sedation with validated scales.

10.1. Analysis.

Comparison 10: Chloral hydrate oral high dose (100 mg/kg) versus chloral hydrate oral low dose (50 mg/kg), Outcome 1: EEG time onset for adequate sedation (minutes)

Secondary outcomes

Proportion of children who had sedation failure or inadequate level of sedation

Children receiving high‐dose oral chloral hydrate were significantly less likely to have sedation failure compared with those receiving low‐dose oral chloral hydrate (RR 0.23, 95% CI 0.05 to 0.99; 76 children) (Analysis 10.2).

10.2. Analysis.

Comparison 10: Chloral hydrate oral high dose (100 mg/kg) versus chloral hydrate oral low dose (50 mg/kg), Outcome 2: EEG sedation failure

Sedation duration

The duration of sedation (in minutes) was significantly longer in the high‐dose oral chloral hydrate group compared with the low‐dose oral chloral hydrate group (MD 17.80, 95% CI 8.50 to 27.10; 76 children) (Analysis 10.3).

10.3. Analysis.

Comparison 10: Chloral hydrate oral high dose (100 mg/kg) versus chloral hydrate oral low dose (50 mg/kg), Outcome 3: EEG sedation/sleep duration (minutes)

Yield of EEG or neuroimaging findings

No studies assessed this outcome.

Adverse effects (any)

There was no significant difference in adverse effects between groups (RR 2.25, 95% CI 0.77 to 6.55; 76 children) (Analysis 10.4).

10.4. Analysis.

Comparison 10: Chloral hydrate oral high dose (100 mg/kg) versus chloral hydrate oral low dose (50 mg/kg), Outcome 4: EEG sedation adverse event: total

Comparison 11: Chloral hydrate versus sodium thiopental

Azizkhani 2014 was the only study comparing oral chloral hydrate (50 mg/kg) to rectal sodium thiopental (25 mg/kg).

Primary outcomes

Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening

Children receiving sodium thiopental were significantly more likely to complete the neurodiagnostic procedure than those receiving chloral hydrate (RR 0.95, 95% CI 0.83 to 1.09; 140 children) (Analysis 11.1).

11.1. Analysis.

Comparison 11: Chloral hydrate oral (50 mg/kg) versus sodium thiopental rectal (25 mg/kg), Outcome 1: Neuroimaging adequate sedation (Ramsay score 4)

Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent

No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)

Children receiving chloral hydrate had a significantly shorter time to adequate sedation (in minutes) as assessed by Ramsay Sedation Score > 3 compared with those receiving sodium thiopental (MD −4.20, 95% CI −6.08 to −2.32; 140 children) (Analysis 11.2).

11.2. Analysis.

Comparison 11: Chloral hydrate oral (50 mg/kg) versus sodium thiopental rectal (25 mg/kg), Outcome 2: Neuroimaging onset sedation (minutes)

Secondary outcomes

Proportion of children who had sedation failure or inadequate level of sedation

Children receiving sodium thiopental were significantly less likely to have sedation failure compared with those receiving chloral hydrate (RR 1.33, 95% CI 0.60 to 2.96; 140 children) (Analysis 11.3).

11.3. Analysis.

Comparison 11: Chloral hydrate oral (50 mg/kg) versus sodium thiopental rectal (25 mg/kg), Outcome 3: Neuroimaging sedation failure after 1 administration of sedation agent

Sedation duration

There was no significant difference between the two groups for the duration of sedation (in minutes) (MD −0.80, 95% CI −1.70 to 0.10; 140 children) (Analysis 11.4).

11.4. Analysis.

Comparison 11: Chloral hydrate oral (50 mg/kg) versus sodium thiopental rectal (25 mg/kg), Outcome 4: Neuroimaging sedation duration (minutes)

Yield of EEG or neuroimaging findings

No studies assessed this outcome.

Adverse effects (desaturation, diarrhoea, mean diastolic blood pressure during procedure)

Children receiving sodium thiopental were significantly less likely to have desaturation compared with those receiving chloral hydrate (RR 5.00, 95% 0.24 to 102.30; 140 children) (Analysis 11.5). On the other hand, children receiving chloral hydrate were significantly less likely to have diarrhoea (RR 0.04, 95% CI 0.00 to 0.72; 140 children) or mean diastolic blood pressure during procedure (mmHg) (MD 7.40, 95% CI 5.11 to 9.69; 140 children) compared with those receiving sodium thiopental (Analysis 11.6; Analysis 11.7).

11.5. Analysis.

Comparison 11: Chloral hydrate oral (50 mg/kg) versus sodium thiopental rectal (25 mg/kg), Outcome 5: Neuroimaging adverse effect: desaturation

11.6. Analysis.

Comparison 11: Chloral hydrate oral (50 mg/kg) versus sodium thiopental rectal (25 mg/kg), Outcome 6: Neuroimaging adverse effect: diarrhoea

11.7. Analysis.

Comparison 11: Chloral hydrate oral (50 mg/kg) versus sodium thiopental rectal (25 mg/kg), Outcome 7: Mean diastolic blood pressure during procedure (mmHg)

Comparison 12: Chloral hydrate versus clonidine

Ashrafi 2020 was the only study comparing oral chloral hydrate (50 mg/kg) to oral clonidine (4 μg/kg).

Primary outcomes

Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening

No studies assessed this outcome.

Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent

No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)

Children receiving chloral hydrate had a significantly shorter time to adequate sedation (in minutes) compared with those receiving clonidine (MD −37.48, 95% CI −55.97 to −18.99; 198 children) (Analysis 12.1). No studies assessed the outcome of adequate sedation with validated scales.

12.1. Analysis.

Comparison 12: Chloral hydrate oral (50 mg/kg) versus clonidine oral (4 μg/kg), Outcome 1: EEG onset sedation (minutes)

Secondary outcomes

Proportion of children who had sedation failure or inadequate level of sedation

No studies assessed this outcome.

Sedation duration

There was no significant difference in the duration of sedation (in minutes) between chloral hydrate and clonidine (MD −6.07, 95% CI −15.32 to 3.18; 198 children) (Analysis 12.2).

12.2. Analysis.

Comparison 12: Chloral hydrate oral (50 mg/kg) versus clonidine oral (4 μg/kg), Outcome 2: EEG sedation / sleep duration (minutes)

Yield of EEG or neuroimaging findings

No studies assessed this outcome.

Adverse effects (drowsiness, vertigo)

Children receiving chloral hydrate were statistically significantly less likely to have drowsiness (RR 0.44, 95% CI 0.30 to 0.64; 198 children) (Analysis 12.3) or vertigo (RR 0.15, 95% CI 0.01 to 2.79; 198 children) (Analysis 12.4) compared with those receiving clonidine.

12.3. Analysis.

Comparison 12: Chloral hydrate oral (50 mg/kg) versus clonidine oral (4 μg/kg), Outcome 3: EEG sedation adverse event: drowsiness

12.4. Analysis.

Comparison 12: Chloral hydrate oral (50 mg/kg) versus clonidine oral (4 μg/kg), Outcome 4: EEG sedation adverse event: vertigo

Comparison 13: Chloral hydrate versus dexmedetomidine

Yuen 2017a was the only study comparing oral chloral hydrate (50 mg/kg) to intranasal dexmedetomidine (3 μg/kg).

Primary outcomes

Proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening

No studies assessed this outcome.

Proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent

No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by specific validated scales such as the Ramsay Sedation Score)

Children receiving dexmedetomidine had a significantly shorter time to adequate sedation (in minutes) based on the 'somnolent' component of the University of Michigan Sedation Scale compared with those receiving chloral hydrate (MD 2.80, 95% CI 0.77 to 4.83; 194 children) (Analysis 13.1).

13.1. Analysis.

Comparison 13: Chloral hydrate oral (50 mg/kg) versus dexmedetomidine intranasal (3 μg/kg), Outcome 1: Neuroimaging sedation onset (minutes)

Secondary outcomes

Proportion of children who had sedation failure or inadequate level of sedation

No studies assessed this outcome.

Sedation duration

No studies assessed this outcome.

Yield of EEG or neuroimaging findings

No studies assessed this outcome.

Adverse effects (bradycardia, unsteadiness, crying during administration of sedation, vomiting)

Children receiving chloral hydrate were less likely to have bradycardia compared with those receiving dexmedetomidine (MD 0.17, 95% CI 0.05 to 0.59; 194 children) (Analysis 13.2). Compared with those receiving chloral hydrate, children receiving dexmedetomidine were less likely to experience the following adverse effects: unsteadiness within 24 hours after discharge (MD 10.21, 95% CI 0.58 to 178.52; 194 children) (Analysis 13.3); crying during administration of sedation (MD 1.39, 95% CI 1.08 to 1.80; 194 children) (Analysis 13.4); or vomiting (MD 10.59, 95% CI 0.61 to 185.45; 194 children) (Analysis 13.5).

13.2. Analysis.

Comparison 13: Chloral hydrate oral (50 mg/kg) versus dexmedetomidine intranasal (3 μg/kg), Outcome 2: Neuroimaging adverse event: bradycardia

13.3. Analysis.

Comparison 13: Chloral hydrate oral (50 mg/kg) versus dexmedetomidine intranasal (3 μg/kg), Outcome 3: Neuroimaging adverse event: unsteadiness within 24 h after discharge

13.4. Analysis.

Comparison 13: Chloral hydrate oral (50 mg/kg) versus dexmedetomidine intranasal (3 μg/kg), Outcome 4: Neuroimaging adverse event: crying during administration of sedation

13.5. Analysis.

Comparison 13: Chloral hydrate oral (50 mg/kg) versus dexmedetomidine intranasal (3 μg/kg), Outcome 5: Neuroimaging adverse event: vomiting

Discussion

Summary of main results

Apart from oral chloral hydrate, this review identified a variety of sedation agents used for neurodiagnostic procedures, of which the majority were given in an oral preparation (dexmedetomidine, midazolam, melatonin, hydroxyzine hydrochloride, promethazine, and clonidine). Five studies used non‐oral preparation (intranasal midazolam, intranasal dexmedetomidine, rectal midazolam, rectal sodium thiopental, or intravenous pentobarbital), and one study used a non‐drug therapy (music therapy). Despite a wide variety of agents used, each sedation agent was represented by a very small number of studies, and all were only evaluated by a single study. Our review also identified paediatric participants undergoing neurodiagnostic procedures from all age groups, ranging from birth to 18 years old.

For the primary outcome measure of time to adequate sedation, the efficacy of oral chloral hydrate when compared with other sedative agents was mixed. Six studies showed that oral chloral hydrate had a shorter time to achieve adequate sedation when compared with oral dexmedetomidine, oral hydroxyzine hydrochloride, oral promethazine, oral clonidine, rectal midazolam, or rectal sodium thiopental. On the other hand, another three studies showed that chloral hydrate took a longer time to achieve adequate sedation when compared with intravenous pentobarbital, intranasal midazolam, or intranasal dexmedetomidine. Children had a shorter time to achieve adequate sedation with a higher dose of oral chloral hydrate compared to a lower dose.

For the primary outcome measure of successfully completing neurodiagnostic procedure without the child awaking, one study showed that rectal sodium thiopental appeared be more successful than oral chloral hydrate in completing the procedure. No other studies assessed this outcome measure.

For the secondary outcome of proportion of children who had sedation failure or inadequate level of sedation, oral chloral hydrate appeared to have lower sedation failure when compared with oral promethazine. Chloral hydrate had more sedation failure after one dose compared with intravenous pentobarbital, but there was no difference between groups after two doses. Another two studies showed that chloral hydrate appeared to have more sedation failure compared with music therapy and rectal sodium thiopental. Sedation failure rates appeared to be similar between oral chloral hydrate and oral dexmedetomidine, oral midazolam, and oral hydroxyzine hydrochloride. Two comparative oral chloral hydrate dosing studies showed oral chloral hydrate 100 mg/kg to have lower sedation failure than oral chloral hydrate 50 mg/kg, and no difference between groups when compared with oral chloral hydrate 70 mg/kg. Most analyses were underpowered with insufficient evidence to enable any clear conclusions.

For the secondary outcome of sedation duration, oral chloral hydrate achieved a longer duration of sedation when compared with oral hydroxyzine hydrochloride and music therapy. Three studies found no difference in duration of sedation between oral chloral hydrate and oral midazolam, oral clonidine, and rectal sodium thiopental. Another study showed oral chloral hydrate to have a shorter duration of sedation when compared with oral dexmedetomidine. A higher dose of oral chloral hydrate appeared to achieve longer sedation duration than a lower dose.

Five studies assessed the secondary outcome measure of sedative effect on yield of neurodiagnostic procedure (four studies evaluated yield of EEG procedure, and one study evaluated yield of neuroimaging procedure). Two of the four EEG studies showed oral chloral hydrate to have less sedative EEG artefact when compared with intranasal midazolam or oral melatonin. The other two studies showed no difference in sedative artefact on EEG when compared with oral hydroxyzine hydrochloride or rectal midazolam. In the single study evaluating yield of neuroimaging procedure, no difference was seen between oral chloral hydrate and intravenous pentobarbital.

Eleven studies assessed the secondary outcome measure of adverse effects of sedation. Seven of these studies showed no difference between groups in adverse effects. One study found that children receiving oral chloral hydrate had a higher total number of adverse effects compared to those receiving oral dexmedetomidine. One study showed mixed adverse effects between children receiving oral chloral hydrate compared to those receiving rectal sodium thiopental, with a higher total number of desaturation seen amongst children receiving oral chloral hydrate, and a higher total number of diarrhoea and hypotension amongst children receiving rectal sodium thiopental. Another study also showed mixed adverse effects between children receiving oral chloral hydrate compared to those receiving intranasal dexmedetomidine, with a higher total number of bradycardia seen amongst children receiving intranasal dexmedetomidine, and a higher total number of unsteadiness within 24 hours postdischarge, vomiting, or crying during sedation procedure seen amongst children receiving oral chloral hydrate. The remaining study showed children receiving oral clonidine to have a higher total number of drowsiness and vertigo compared to those receiving oral chloral hydrate.

Overall completeness and applicability of evidence

We identified 16 studies that matched our inclusion criteria in terms of population, sedation intervention, comparison, and outcomes. A total of 2922 children (age range from birth to 18 years old) were assessed. The studies were conducted in Asia, Europe, and the USA, from 1982 to 2020. The included studies were performed in hospitals that provided neurodiagnostic services. Most of the agents evaluated in comparison with oral chloral hydrate were those commonly used in practice, and the doses of oral chloral hydrate evaluated were commonly used doses. However, there are certain limitations in the completeness of this review. For example, some of our key prespecified outcomes were not assessed in most of the included studies, such as proportion of children who successfully completed neurodiagnostic procedure without interruption by the child awakening and proportion of children who required a further dose of either the same sedative agent or the addition of a different sedative agent.

Quality of the evidence

The evidence for the majority of the outcomes assessed was overall of very low to moderate certainty, due to the small number of studies included in each comparison and variable risk of bias of the included studies. The strongest evidence came from studies that compared oral chloral hydrate with either intranasal midazolam, oral midazolam (D'Agostino 2000; Fallah 2013), or oral promethazine (Razieh 2013), for which there were three studies. However, all the comparisons in this review involved small numbers of trials and participants, which in most cases translated to imprecision that required downgrading of the certainty of the evidence. Also, in the case of statistically significant difference, an analysis with a small number of trials lessens the reliability of the results due to concerns about the effects of small studies exacerbating the impact of biases (Sterne 2011). A second major limitation in the quality of evidence gathered was related to performance bias, for which eight studies had high risk and four had unclear risk. In studies at high risk of performance bias or detection bias, lack of blinding of participants or assessors, or both, makes it highly likely that the outcome results were influenced, thus affecting the quality of evidence. Overall, the body of evidence gathered in this review did not allow us to draw a robust conclusion regarding the effectiveness of chloral hydrate as a sedating agent for neurodiagnostic procedures in children.

Potential biases in the review process

We performed a comprehensive search of multiple databases with independent screening, selection, and assessment of identified studies. However, we were unable to obtain all relevant data, as one study is still awaiting assessment despite our contacting the author via email. We excluded some RCTs on the basis of wrong type of outcome measure whereby these studies did not have a direct comparison with another sedative agent. These studies assessed the efficacy of chloral hydrate with other second‐line sedative agents after failure of first‐line chloral hydrate sedation. In addition, the primary outcome measure of efficacy of chloral hydrate was made by assessing adequacy of sedation, proportion of sedation failure, and sedation duration as a whole. We did not differentiate efficacy of chloral hydrate according to EEG or neuroimaging procedure. Our failure to adjust for type of neurodiagnostic procedure may also have affected the summary of the results.

Agreements and disagreements with other studies or reviews

There are three reviews on this topic. Meyer and colleagues 2007 is a narrative review discussing the current status of sedation for brief diagnostic procedures in children (Meyer 2007). Mace and colleagues 2008 is a systematic review of the literature between 1976 to 2006 to develop a clinical policy of effective and safe medications for providing procedural sedation in the emergency department (Mace 2008). NICE 2010 is a systematic review of the literature between 1950 to 2010 to develop a clinical guideline offering evidence‐based advice on the care and treatment of children and young people having sedation for therapeutic or diagnostic procedures (NICE 2010).

The findings of our review are broadly in line with the conclusions of these other reviews, which state that oral chloral hydrate is one of the preferred sedative drugs for non‐invasive procedural studies in children with a wide margin of safety (Mace 2008; Meyer 2007; NICE 2010), with a dosing of 50 to 100 mg/kg (Mace 2008). Based on the two comparative oral chloral hydrate studies (Gumus 2015; Marti‐Bonmati 1995), chloral hydrate of 100 mg/kg or 70 mg/kg appeared to be more effective than chloral hydrate 50 mg/kg. Our review differed from the conclusion of previous reviews that oral chloral hydrate should only be considered in young children either under 3 years old (Meyer 2007), under 15 kg (NICE 2010), or under 2 years old (Mace 2008), with one review stating that this was due to reduced efficacy in older children (Mace 2008). However, the number of paediatric chloral hydrate RCTs prior to 2010 when these three reviews were written was limited; since 2010 there have been 10 paediatric chloral hydrate RCTs. The majority of chloral hydrate RCTs included the whole range of paediatric age group, up to 14 years old, and not just confined to children under 3 years of age (Ashrafi 2013; Ashrafi 2020; Azizkhani 2014; Bektas 2014; D'Agostino 2000; Fallah 2013; Gumus 2015; Malviya 2004; Razieh 2013; Sezer 2013). Apart from Malviya 2004 and Azizkhani 2014, all of the studies that included older children showed oral chloral hydrate to be just as effective as or more effective than the comparator sedative agent (Ashrafi 2013; Ashrafi 2020; Bektas 2014; D'Agostino 2000; Fallah 2013; Gumus 2015; Razieh 2013; Sezer 2013). Apart from Azizkhani 2014 and Yuen 2017b, no other studies showed oral chloral hydrate to have a higher rate of adverse effects.

Authors' conclusions

Implications for practice.

For children undergoing neurodiagnostic procedures, very low‐ to moderate‐certainty evidence suggests that oral chloral hydrate is either just as effective a sedative agent with similar sedation failure rate when compared with oral dexmedetomidine, oral hydroxyzine hydrochloride, or oral midazolam; and probably a more effective sedative agent with lower sedation failure rate when compared with oral promethazine or intranasal midazolam. Based on the limited evidence gathered in our review, the most effective oral chloral hydrate doses appear to be 100 mg/kg and 70 mg/kg. However, there was a report of increased risk of total adverse effects with oral chloral hydrate when compared to dexmedetomidine; given the low certainty of evidence associated with this outcome, caution should be exercised in the use of oral chloral hydrate until further evidence on its safety profile is available.

Implications for research.

With the increasing need for neurodiagnostic procedures amongst children, further trials evaluating the efficacy of sedative agents in children undergoing such procedures is warranted. This review highlights the paucity of research performed in this area. Future trials should include major clinical outcomes as stipulated as the primary outcomes of our review, such as successful completion of procedure, requirements for additional sedative agent, degree of sedation measured using validated scales, and major adverse effects, especially bradycardia, hypotension, and oxygen desaturation. Further trials should ensure that blinding of participants and personnel is achieved with measures in place to reduce selection bias, and include clear documentation of trial methodologies.

What's new

Date	Event	Description
14 May 2020	New search has been performed	Searches updated 14 May 2020; three new studies have been included.
14 May 2020	New citation required but conclusions have not changed	Conclusions remain unchanged.

History

Protocol first published: Issue 7, 2015
Review first published: Issue 11, 2017

Appendices

Appendix 1. CRS Web/CENTRAL search strategy

For the latest update, the Cochrane Register of Studies (CRS Web) was searched using the following search strategy.

1. child* or infant* or neonat* or newborn* or paediatric* or pediatric* or toddler* or adolescen* or teenage* AND CENTRAL:TARGET

2. MESH DESCRIPTOR Child EXPLODE ALL AND CENTRAL:TARGET

3. MESH DESCRIPTOR Child Health EXPLODE ALL AND CENTRAL:TARGET

4. MESH DESCRIPTOR Infant EXPLODE ALL AND CENTRAL:TARGET

5. MESH DESCRIPTOR Infant Health EXPLODE ALL AND CENTRAL:TARGET

6. MESH DESCRIPTOR Pediatrics EXPLODE ALL AND CENTRAL:TARGET

7. MESH DESCRIPTOR Minors EXPLODE ALL AND CENTRAL:TARGET

8. MESH DESCRIPTOR Adolescent EXPLODE ALL AND CENTRAL:TARGET

9. MESH DESCRIPTOR Adolescent Health EXPLODE ALL AND CENTRAL:TARGET

10. MESH DESCRIPTOR Adolescent Medicine EXPLODE ALL AND CENTRAL:TARGET

11. #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10

12. noninvasive or "non‐invasive" or noninterventional or "non‐interventional" or investigation* or assessment* or evaluation* AND CENTRAL:TARGET

13. MESH DESCRIPTOR Brain EXPLODE ALL AND CENTRAL:TARGET

14. MESH DESCRIPTOR Tomography EXPLODE ALL AND CENTRAL:TARGET

15. MESH DESCRIPTOR Diagnostic Techniques, Neurological EXPLODE ALL AND CENTRAL:TARGET

16. MESH DESCRIPTOR Image Interpretation, Computer‐Assisted EXPLODE ALL AND CENTRAL:TARGET

17. MESH DESCRIPTOR Neural Conduction EXPLODE ALL AND CENTRAL:TARGET

18. MESH DESCRIPTOR Nuclear Medicine EXPLODE ALL AND CENTRAL:TARGET

19. neurodiagnos* or brain or cerebral or neuroimag* or nuclear medicine or electroencephalograph* or EEG AND CENTRAL:TARGET

20. magnetic resonance imag* or MRI or tomograph* or SPECT or nerve conduction AND CENTRAL:TARGET

21. #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20

22. MESH DESCRIPTOR Chloral Hydrate EXPLODE ALL AND CENTRAL:TARGET

23. chloral hydrate or trichloroacetaldehyde monohydrate or noctec or somnos AND CENTRAL:TARGET

24. #22 OR #23

25. #11 AND #21 AND #24

26. MESH DESCRIPTOR Anesthesia, Dental EXPLODE ALL AND CENTRAL:TARGET

27. MESH DESCRIPTOR Dental Care EXPLODE ALL AND CENTRAL:TARGET

28. #26 OR #27

29. #25 NOT #28

For the original review, CENTRAL was searched using the following search strategy.

#1	child*:ti,ab,kw
#2	MeSH descriptor: [Child] explode all trees
#3	infant*:ti,ab,kw
#4	neonat*:ti,ab,kw
#5	MeSH descriptor: [Infant, Newborn] explode all trees
#6	"newborn":ti,ab,kw
#7	paediatric*:ti,ab,kw
#8	"toddler":ti,ab,kw
#9	adolescent:ti,ab,kw
#10	MeSH descriptor: [Adolescent] explode all trees
#11	"teenager":ti,ab,kw
#12	(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11)
#13	"non‐invasive":ti,ab,kw
#14	"non‐interventional":ti,ab,kw
#15	investigation*:ti,ab,kw
#16	assessment*:ti,ab,kw
#17	evaluation*:ti,ab,kw
#18	#13 Or #14 OR #15 OR #16 OR #17
#19	neurodiagnos*:ti,ab,kw
#20	"brain":ti,ab,kw
#21	MeSH descriptor: [Brain] explode all trees
#22	cerebral:ti,ab,kw
#23	neuroimaging:ti,ab,kw
#24	MeSH descriptor: [Neuroimaging] explode all trees
#25	"nuclear medicine":ti,ab,kw
#26	MeSH descriptor: [Nuclear Medicine] explode all trees
#27	electroencephalography:ti,ab,kw
#28	MeSH descriptor: [Electroencephalography] explode all trees
#29	EEG:ti,ab,kw
#30	"magnetic resonance imaging":ti,ab,kw
#31	MeSH descriptor: [Magnetic Resonance Imaging] explode all trees
#32	MRI:ti,ab,kw
#33	"computed tomography":ti,ab,kw
#34	MeSH descriptor: [Tomography, X‐Ray Computed] explode all trees
#35	Single‐photon emission computed tomography:ti,ab,kw
#36	MeSH descriptor: [Tomography, Emission‐Computed, Single‐Photon] explode all trees
#37	SPECT:ti,ab,kw
#38	Positron emission tomography:ti,ab,kw
#39	MeSH descriptor: [Positron‐Emission Tomography] explode all trees
#40	nerve conduction study:ti,ab,kw
#41	MeSH descriptor: [Neural Conduction] explode all trees
#42	#19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 or #38 OR #39 OR #40 OR #41
#43	Chloral hydrate:ti,ab,kw
#44	MeSH descriptor: [Chloral Hydrate] explode all trees
#45	Trichloroacetaldehyde monohydrate:ti,ab,kw
#46	Noctec:ti,ab,kw
#47	Somnos:ti,ab,kw
#48	#43 OR #44 OR #45 OR #46 OR #47
#49	#12 and (#18 or #42) and #48 in trials

Appendix 2. MEDLINE/PubMed search strategy

For the latest update, MEDLINE (Ovid) was searched using the following search strategy. This includes a modification of the Cochrane Highly Sensitive Search Strategy for identifying randomized trials (Lefebvre 2021).

1. (child$ or infant$ or neonat$ or newborn$ or paediatric$ or pediatric$ or toddler$ or adolescen$ or teenage$).tw.

2. exp Child/ or exp Child Health/

3. exp Infant/ or exp Infant Health/

4. exp Pediatrics/ or exp minors/

5. exp Adolescent/ or exp Adolescent Health/ or exp Adolescent Medicine/

6. 1 or 2 or 3 or 4 or 5

7. (noninvasive or "non‐invasive" or noninterventional or "non‐interventional" or investigation$ or assessment$ or evaluation$).tw.

8. exp Brain/

9. exp tomography/ or exp diagnostic techniques, neurological/

10. exp Image Interpretation, Computer‐Assisted/ or exp Neural Conduction/ or exp Nuclear Medicine/

11. (neurodiagnos$ or brain or cerebral or neuroimag$ or nuclear medicine or electroencephalograph$ or EEG).tw.

12. (magnetic resonance imag$ or MRI or tomograph$ or SPECT or nerve conduction).tw.

13. 7 or 8 or 9 or 10 or 11 or 12

14. Chloral Hydrate/

15. (chloral hydrate or trichloroacetaldehyde monohydrate or noctec or somnos).tw.

16. 14 or 15

17. 6 and 13 and 16

18. (randomized controlled trial or controlled clinical trial or pragmatic clinical trial).pt. or (randomi?ed or placebo or randomly).ab.

19. clinical trials as topic.sh.

20. trial.ti.

21. 18 or 19 or 20

22. exp animals/ not humans.sh.

23. 21 not 22

24. 17 and 23

25. exp *anesthesia, dental/ or exp *dental care/

26. 24 not 25

27. remove duplicates from 26

For the original review, PubMed was searched using the following search strategy.

#1	Search child*[Text Word]
#2	Search children[MeSH Terms]
#3	Search infant*[Text Word]
#4	Search neonat*[Text Word]
#5	Search neonates[MeSH Terms]
#6	Search newborn[Text Word]
#7	Search infant, newborn[MeSH Terms]
#8	Search paediatric*[Text Word]
#9	Search toddler[Text Word]
#10	Search adolescent[Text Word]
#11	Search adolescent[MeSH Terms]
#12	Search teenager[Text Word]
#13	Search teenager[MeSH Terms]
#14	Search (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13)
#15	Search "non‐invasive"[Text Word]
#16	Search "non‐interventional"[Text Word]
#17	Search investigation*[Text Word]
#18	Search assessment*[Text Word]
#19	Search evaluation*[Text Word]
#20	Search (#15 OR #16 OR #17 OR #18 OR #19)
#21	Search neurodiagnos*[Text Word]
#22	Search brain[Text Word]
#23	Search brain[MeSH Terms]
#24	Search cerebral[Text Word]
#25	Search cerebral[MeSH Terms]
#26	Search neuroimaging[Text Word]
#27	Search neuroimaging[MeSH Terms]
#28	Search nuclear medicine[Text Word]
#29	Search nuclear medicine[MeSH Terms]
#30	Search electroencephalography[Text Word]
#31	Search electroencephalography[MeSH Terms]
#32	Search "EEG"[Text Word]
#33	Search EEG[MeSH Terms]
#34	Search magnetic resonance imaging[Text Word]
#35	Search magnetic resonance imaging[MeSH Terms]
#36	Search "MRI"[Text Word]
#37	Search MRI[MeSH Terms]
#38	Search Computed tomography[Text Word]
#39	Search Computed tomography[MeSH Terms]
#40	Search Single‐photon emission computed tomography[Text Word]
#41	Search Single‐photon emission computed tomography[MeSH Terms]
#42	Search "SPECT"[Text Word]
#43	Search SPECT[MeSH Terms]
#44	Search Positron emission tomography[Text Word]
#45	Search Positron emission tomography[MeSH Terms]
#46	Search nerve conduction study[Text Word]
#47	Search nerve conduction[MeSH Terms]
#48	Search (#21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 or #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47)
#49	Search Chloral hydrate[Text Word]
#50	Search Chloral hydrate[MeSH Terms]
#51	Search Trichloroacetaldehyde monohydrate[Text Word]
#52	Search Trichloroacetaldehyde monohydrate[MeSH Terms]
#53	Search Noctec[Text Word]
#54	Search Somnos[Text Word]
#55	Search (#49 OR #50 OR #51 OR #52 OR #53 OR #54)
#56	Search (#14 AND (#20 OR #48) AND #55)
#57	Search "randomized controlled trial"[Publication Type]
#58	Search "controlled clinical trial"[Publication Type]
#59	Search (randomised[Title/Abstract]) OR randomized[Title/Abstract]
#60	Search placebo[Title/Abstract]
#61	Search clinical trials[MeSH Major Topic]
#62	Search randomly[Title/Abstract]
#63	Search trial[Title]
#64	Search (#57 OR #58 OR #59 OR #60 OR #61 OR #62 OR #63)
#65	Search (animals [mh] NOT humans [mh])
#66	Search (#64 NOT #65)
#67	Search (#56 AND #66)

Appendix 3. Embase search strategy

#1	child*:ab,ti
#2	"children"/exp
#3	infant*:ab,ti
#4	neonat*:ab,ti
#5	newborn:ab,ti
#6	"infant, newborn"/exp
#7	paediatric*:ab,ti
#8	toddler: ab,ti
#9	adolescent:ab,ti
#10	"adolescent"/exp
#11	teenager:ab,ti
#12	#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11
#13	'non‐invasive':ab,ti
#14	'non‐interventional':ab,ti
#15	investigation*:ab,ti
#16	assessment*:ab,ti
#17	evaluation*:ab,ti
#18	#13 OR #14 OR #15 OR #16 OR #17
#19	neurodiagnos*:ab,ti
#20	brain:ab,ti
#21	"brain"/exp
#22	cerebral:ab,ti
#23	"cerebral"/exp
#24	neuroimaging:ab,ti
#25	"neuroimaging"/exp
#26	nuclear medicine:ab,ti
#27	"nuclear medicine"/exp
#28	electroencephalography:ab,ti
#29	"electroencephalography"/exp
#30	"EEG":ab,ti
#31	magnetic resonance imaging:ab,ti
#32	"magnetic resonance imaging"/exp
#33	"MRI":ab,ti
#34	computed tomography:ab,ti
#35	"computed tomography"/exp
#36	Single‐photon emission computed tomography:ab,ti
#37	"Single‐photon emission computed tomography"/exp
#38	"SPECT":ab,ti
#39	Positron emission tomography:ab,ti
#40	"Positron emission tomography"/exp
#41	nerve conduction study:ab,ti
#42	"nerve conduction"/exp
#43	#19 OR #20 Or #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 or #38 OR #39 OR #40 OR #41 OR #42
#44	'Chloral hydrate':ab,ti
#45	"Chloral hydrate"/exp
#46	'Trichloroacetaldehyde monohydrate':ab,ti
#47	'Noctec':ab,ti
#48	'Somnos':ab,ti
#49	#44 OR #45 OR #46 OR #47 OR #48
#50	'randomized controlled trial'/exp
#51	'randomization'/exp
#52	'controlled study'/exp
#53	'multicenter study'/exp
#54	'double blind procedure'/exp
#55	'single blind procedure'/exp
#56	random* OR cross?over* OR factorial* OR placebo* OR volunteer*:ab,ti
#57	(singl* OR doubl* OR trebl* OR tripl*) NEAR (blind*:ab,ti OR mask*:ab,ti)
#58	#50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57
#59	#12 AND (#18 OR #43) AND #49 AND #58

Data and analyses

Comparison 1. Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2 µg/kg or 3 µg/kg).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 EEG time onset for adequate sedation (minutes)	1	160	Mean Difference (IV, Fixed, 95% CI)	‐3.86 [‐5.12, ‐2.60]
1.1.1 high dose (100 mg/kg chloral hydrate vs 3 µg/kg dexmedetomidine)	1	82	Mean Difference (IV, Fixed, 95% CI)	‐5.60 [‐7.33, ‐3.87]
1.1.2 low dose (50 mg/kg chloral hydrate vs 2 µg/kg dexmedetomidine)	1	78	Mean Difference (IV, Fixed, 95% CI)	‐1.90 [‐3.74, ‐0.06]
1.2 EEG sedation failure	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	1.14 [0.51, 2.53]
1.2.1 high dose	1	82	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.12, 3.97]
1.2.2 low dose	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.54, 3.32]
1.3 EEG sedation / sleep duration (minutes)	1	160	Mean Difference (IV, Fixed, 95% CI)	16.47 [9.21, 23.72]
1.3.1 high dose	1	82	Mean Difference (IV, Fixed, 95% CI)	21.70 [11.76, 31.64]
1.3.2 low dose	1	78	Mean Difference (IV, Fixed, 95% CI)	10.50 [‐0.11, 21.11]
1.4 EEG sedation adverse event: total	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	7.66 [1.78, 32.91]
1.4.1 high dose	1	82	Risk Ratio (M‐H, Fixed, 95% CI)	10.50 [1.41, 78.33]
1.4.2 low dose	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	4.67 [0.55, 39.89]
1.5 EEG sedation adverse event: hypotension	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.34]
1.5.1 high dose	1	82	Risk Ratio (M‐H, Fixed, 95% CI)	0.35 [0.01, 8.34]
1.5.2 low dose	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.6 EEG sedation adverse event: bradycardia	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	0.39 [0.02, 9.23]
1.6.1 high dose	1	82	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.6.2 low dose	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	0.39 [0.02, 9.23]
1.7 EEG sedation adverse event: behavioural change	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	5.24 [0.26, 105.97]
1.7.1 high dose	1	82	Risk Ratio (M‐H, Fixed, 95% CI)	5.24 [0.26, 105.97]
1.7.2 low dose	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	Not estimable
1.8 EEG sedation adverse event: nausea or vomiting	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	12.04 [1.58, 91.96]
1.8.1 high dose	1	82	Risk Ratio (M‐H, Fixed, 95% CI)	15.73 [0.93, 266.73]
1.8.2 low dose	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	8.14 [0.43, 152.41]
1.9 EEG sedation adverse event: oxygen desaturation	1	160	Risk Ratio (M‐H, Fixed, 95% CI)	3.31 [0.35, 31.16]
1.9.1 high dose	1	82	Risk Ratio (M‐H, Fixed, 95% CI)	3.15 [0.13, 75.05]
1.9.2 low dose	1	78	Risk Ratio (M‐H, Fixed, 95% CI)	3.49 [0.15, 83.03]

Comparison 2. Chloral hydrate oral (75 mg/kg) versus pentobarbital intravenous (5 mg/kg).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
2.1 Neuroimaging time onset for adequate sedation (minutes)	1	70	Mean Difference (IV, Fixed, 95% CI)	19.00 [16.61, 21.39]
2.2 Neuroimaging sedation failure after 2 administrations of sedative agent (same or different)	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	3.00 [0.33, 27.46]
2.3 Neuroimaging sedation failure after 1 administration of sedative agent	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	4.33 [1.35, 13.89]
2.4 Neuroimaging uninterpretable	1	54	Risk Ratio (M‐H, Fixed, 95% CI)	0.23 [0.03, 1.94]
2.5 Neuroimaging sedation adverse event: oxygen desaturation	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.21, 2.16]
2.6 Neuroimaging sedation adverse event: nausea or vomiting	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	6.00 [0.76, 47.29]
2.7 Neuroimaging sedation adverse event: paradoxical reaction	1	70	Risk Ratio (M‐H, Fixed, 95% CI)	0.09 [0.01, 1.58]
2.8 Neuroimaging sedation adverse event: return to baseline activity postdischarge	1	70	Mean Difference (IV, Fixed, 95% CI)	‐6.00 [‐11.43, ‐0.57]

Comparison 3. Chloral hydrate oral (100 mg/kg or 75 mg/kg) versus midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
3.1 Neuroimaging time onset for adequate sedation (minutes)	1	60	Mean Difference (IV, Fixed, 95% CI)	12.83 [7.22, 18.44]
3.2 Neuroimaging inadequate level of sedation achieved (Ramsay score 4)	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.03, 0.44]
3.3 Neuroimaging sedation failure after 1 administration of sedative agent	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.17 [0.02, 1.12]
3.4 Neuroimaging sedation / sleep duration (minutes)	1	33	Mean Difference (IV, Fixed, 95% CI)	19.00 [‐3.40, 41.40]
3.5 EEG sedative‐induced artefact	1	198	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.44, 0.76]
3.6 EEG sedation adverse event: total	1	198	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.01, 4.20]
3.7 Neuroimaging adverse event: behavioural change	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.87]
3.8 Neuroimaging adverse event: vomiting	2	93	Risk Ratio (M‐H, Fixed, 95% CI)	5.29 [0.84, 33.14]
3.9 Neuroimaging sedation failure with intranasal midazolam	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.39 [0.19, 0.79]
3.10 Neuroimaging sedation failure with oral midazolam	1	33	Risk Ratio (M‐H, Fixed, 95% CI)	0.08 [0.01, 1.30]

3.7. Analysis.

Comparison 3: Chloral hydrate oral (100 mg/kg or 75 mg/kg) versus midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg), Outcome 7: Neuroimaging adverse event: behavioural change

3.8. Analysis.

Comparison 3: Chloral hydrate oral (100 mg/kg or 75 mg/kg) versus midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg), Outcome 8: Neuroimaging adverse event: vomiting

3.9. Analysis.

Comparison 3: Chloral hydrate oral (100 mg/kg or 75 mg/kg) versus midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg), Outcome 9: Neuroimaging sedation failure with intranasal midazolam

3.10. Analysis.

Comparison 3: Chloral hydrate oral (100 mg/kg or 75 mg/kg) versus midazolam (intranasal 0.2 mg/kg or oral 0.5 mg/kg), Outcome 10: Neuroimaging sedation failure with oral midazolam

Comparison 4. Chloral hydrate oral (50 mg/kg) versus melatonin oral.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
4.1 EEG sedative‐induced artefact	1	348	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.14, 0.82]
4.2 EEG sedation adverse event: total	1	348	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.25, 3.93]

Comparison 5. Chloral hydrate oral (50 mg/kg + 50 mg/kg) versus hydroxyzine hydrochloride oral (1 mg/kg + 1 mg/kg).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
5.1 EEG time onset for adequate sedation (minutes)	1	282	Mean Difference (IV, Fixed, 95% CI)	‐7.50 [‐7.85, ‐7.15]
5.2 EEG sedation failure	1	282	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.11, 1.01]
5.3 EEG sedation / sleep duration (minutes)	1	282	Mean Difference (IV, Fixed, 95% CI)	3.10 [2.23, 3.97]
5.4 EEG sedative‐induced artefact	1	282	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.47, 3.74]
5.5 EEG sedation adverse event: behavioural change	1	282	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.40, 3.38]
5.6 EEG sedation adverse event: nausea or vomiting	1	282	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.34, 4.56]
5.7 EEG failure after 1 administration of sedative agent	1	282	Risk Ratio (M‐H, Fixed, 95% CI)	0.50 [0.18, 1.43]

5.7. Analysis.

Comparison 5: Chloral hydrate oral (50 mg/kg + 50 mg/kg) versus hydroxyzine hydrochloride oral (1 mg/kg + 1 mg/kg), Outcome 7: EEG failure after 1 administration of sedative agent

Comparison 6. Chloral hydrate oral (70 mg/kg) versus promethazine oral (1 mg/kg).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 EEG time for adequate sedation (minutes)	1	60	Mean Difference (IV, Fixed, 95% CI)	‐12.11 [‐18.48, ‐5.74]
6.2 EEG inadequate level of EEG sedation achieved (Ramsay score 4)	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.03 [0.00, 0.45]
6.3 EEG sedation failure	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.11 [0.01, 0.82]
6.4 EEG sedation adverse event: behavioural change	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	0.20 [0.01, 4.00]
6.5 EEG sedation adverse event: vomiting or nausea	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	13.00 [0.76, 220.96]
6.6 EEG Ramsay Sedation Score after 1 administration of sedative agent	1	60	Mean Difference (IV, Fixed, 95% CI)	1.53 [1.00, 2.06]

6.6. Analysis.

Comparison 6: Chloral hydrate oral (70 mg/kg) versus promethazine oral (1 mg/kg), Outcome 6: EEG Ramsay Sedation Score after 1 administration of sedative agent

Comparison 7. Chloral hydrate oral (60 mg/kg) versus music therapy.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 EEG time onset for adequate sedation (minutes)	1	58	Mean Difference (IV, Fixed, 95% CI)	9.00 [‐2.15, 20.15]
7.2 EEG sedation failure	1	58	Risk Ratio (M‐H, Fixed, 95% CI)	17.00 [2.37, 122.14]
7.3 EEG sedation / sleep duration (minutes)	1	58	Mean Difference (IV, Fixed, 95% CI)	160.00 [121.07, 198.93]

Comparison 8. Chloral hydrate oral (50 mg/kg) versus midazolam rectal (1 mg/kg).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
8.1 EEG time onset for adequate sedation (minutes)	1	59	Mean Difference (IV, Fixed, 95% CI)	‐95.70 [‐114.51, ‐76.89]
8.2 EEG sedation/ sleep duration (minutes)	1	59	Mean Difference (IV, Fixed, 95% CI)	15.10 [3.35, 26.85]
8.3 EEG sedative‐induced artefact	1	53	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.73, 2.12]

Comparison 9. Chloral hydrate oral high dose (100 mg/kg) versus chloral hydrate oral low dose (70 mg/kg).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Neuroimaging time onset for adequate sedation (minutes)	1	97	Mean Difference (IV, Fixed, 95% CI)	‐7.00 [‐7.62, ‐6.38]
9.2 Neuroimaging sedation failure after 1 administration of sedative agent	1	97	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.19, 1.09]
9.3 Neuroimaging sedation / sleep duration (minutes)	1	97	Mean Difference (IV, Fixed, 95% CI)	8.00 [5.81, 10.19]
9.4 Neuroimaging sedation adverse event: total	1	97	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.49, 2.32]

Comparison 10. Chloral hydrate oral high dose (100 mg/kg) versus chloral hydrate oral low dose (50 mg/kg).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 EEG time onset for adequate sedation (minutes)	1	76	Mean Difference (IV, Fixed, 95% CI)	‐5.10 [‐7.05, ‐3.15]
10.2 EEG sedation failure	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	0.22 [0.05, 0.99]
10.3 EEG sedation/sleep duration (minutes)	1	76	Mean Difference (IV, Fixed, 95% CI)	17.80 [8.50, 27.10]
10.4 EEG sedation adverse event: total	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	2.25 [0.77, 6.55]
10.5 EEG sedation adverse event: behavioural change	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	4.51 [0.22, 90.96]
10.6 EEG sedation adverse event: nausea or vomiting	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	2.10 [0.59, 7.52]
10.7 EEG sedation adverse event: oxygen desaturation	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.06, 13.87]

10.5. Analysis.

Comparison 10: Chloral hydrate oral high dose (100 mg/kg) versus chloral hydrate oral low dose (50 mg/kg), Outcome 5: EEG sedation adverse event: behavioural change

10.6. Analysis.

Comparison 10: Chloral hydrate oral high dose (100 mg/kg) versus chloral hydrate oral low dose (50 mg/kg), Outcome 6: EEG sedation adverse event: nausea or vomiting

10.7. Analysis.

Comparison 10: Chloral hydrate oral high dose (100 mg/kg) versus chloral hydrate oral low dose (50 mg/kg), Outcome 7: EEG sedation adverse event: oxygen desaturation

Comparison 11. Chloral hydrate oral (50 mg/kg) versus sodium thiopental rectal (25 mg/kg).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
11.1 Neuroimaging adequate sedation (Ramsay score 4)	1	140	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.83, 1.09]
11.2 Neuroimaging onset sedation (minutes)	1	140	Mean Difference (IV, Random, 95% CI)	‐4.20 [‐6.08, ‐2.32]
11.3 Neuroimaging sedation failure after 1 administration of sedation agent	1	140	Risk Ratio (M‐H, Random, 95% CI)	1.33 [0.60, 2.96]
11.4 Neuroimaging sedation duration (minutes)	1	140	Mean Difference (IV, Random, 95% CI)	‐0.80 [‐1.70, 0.10]
11.5 Neuroimaging adverse effect: desaturation	1	140	Risk Ratio (M‐H, Random, 95% CI)	5.00 [0.24, 102.30]
11.6 Neuroimaging adverse effect: diarrhoea	1	140	Risk Ratio (M‐H, Random, 95% CI)	0.04 [0.00, 0.72]
11.7 Mean diastolic blood pressure during procedure (mmHg)	1	140	Mean Difference (IV, Random, 95% CI)	7.40 [5.11, 9.69]

Comparison 12. Chloral hydrate oral (50 mg/kg) versus clonidine oral (4 μg/kg).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
12.1 EEG onset sedation (minutes)	1	198	Mean Difference (IV, Random, 95% CI)	‐37.48 [‐55.97, ‐18.99]
12.2 EEG sedation / sleep duration (minutes)	1	198	Mean Difference (IV, Random, 95% CI)	‐6.07 [‐15.32, 3.18]
12.3 EEG sedation adverse event: drowsiness	1	198	Risk Ratio (M‐H, Random, 95% CI)	0.44 [0.30, 0.64]
12.4 EEG sedation adverse event: vertigo	1	198	Risk Ratio (M‐H, Random, 95% CI)	0.15 [0.01, 2.79]

Comparison 13. Chloral hydrate oral (50 mg/kg) versus dexmedetomidine intranasal (3 μg/kg).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
13.1 Neuroimaging sedation onset (minutes)	1	194	Mean Difference (IV, Random, 95% CI)	2.80 [0.77, 4.83]
13.2 Neuroimaging adverse event: bradycardia	1	194	Risk Ratio (M‐H, Random, 95% CI)	0.17 [0.05, 0.59]
13.3 Neuroimaging adverse event: unsteadiness within 24 h after discharge	1	173	Risk Ratio (M‐H, Random, 95% CI)	10.21 [0.58, 178.52]
13.4 Neuroimaging adverse event: crying during administration of sedation	1	194	Risk Ratio (M‐H, Random, 95% CI)	1.39 [1.08, 1.80]
13.5 Neuroimaging adverse event: vomiting	1	194	Risk Ratio (M‐H, Random, 95% CI)	10.59 [0.61, 185.45]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Ashrafi 2010.

Study characteristics
Methods	Single‐centre RCT (Iran)
Participants	All patients aged 1 to 72 months that were uncooperative with the EEG setup or referred to our electrodiagnostic department for sleep EEG recording were enrolled. A total of 348 children (male‐to‐female ratio of 1.3:1) were enrolled, 174 children in each group of oral chloral hydrate (1 to 72 months of age) and oral melatonin (2 to 64 months of age).
Interventions	2‐arm comparison: Oral chloral hydrate 5% (1 mL/kg; 174 children) Oral melatonin (2 to 6 mg orally; 174 children) 0.5 to 1 h before EEG performance
Outcomes	Sleep onset latency Sleep duration Drowsiness time Adverse events
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Materials and methods: “Patients were randomly divided in two groups of melatonin and chloral hydrate for sedation.” The authors stated that participants were randomised, but no further detail on the methods of randomisation was provided.
Allocation concealment (selection bias)	Unclear risk	As above
Blinding of participants and personnel (performance bias) All outcomes	High risk	It was not stated whether participants and personnel were blinded to the allocation. However, blinding appeared to be very unlikely, as melatonin and chloral hydrate differed in appearance and taste. As the data collected included neurological diagnosis, sleep onset latency, sleep duration, drowsiness time, and adverse drug events, which included outcomes that required subjective assessment, non‐blinding of the personnel could have influenced the care of participants and the outcomes.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It was unclear whether the 2 neurologists who interpreted the EEG and the EEG technicians who recorded the rest of the outcome data were blinded to the allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Although the numbers of withdrawals or participants with missing data were not directly stated, it appeared that all 348 children (174 in each group) who were initially randomised were analysed, as calculated from the results section based on the number of EEGs obtained.
Selective reporting (reporting bias)	Low risk	The prespecified outcomes of sleep onset latency, sleep duration, drowsiness time, and adverse drug events were reported in the results. An additional outcome of EEG yield, or the number of abnormal EEGs, which was specified in our review, was also reported. However, the data for the continuous outcomes of sleep onset latency, sleep duration, and drowsiness time were skewed, and reported in median and range, and were therefore unsuitable for inclusion in meta‐analysis.
Other bias	Low risk	None identified.

Ashrafi 2013.

Study characteristics
Methods	Single‐centre RCT (Iran)
Participants	Children aged between 1 month and 10 years who were referred for EEG recording and were uncooperative with the device setup or were referred for sleep EEG recording 198 consecutive patients were enrolled and randomly assigned to receive either oral midazolam or oral chloral hydrate.
Interventions	2‐arm comparison: Oral midazolam (0.5 mg/kg; 100 children) Oral chloral hydrate 5% (1 mL/kg; 98 children) Of body weight orally, 1 hour before EEG recording
Outcomes	Sleep onset latency Sleep duration Drowsiness time Adverse events
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Materials and methods, study location, sample, and design: "198 consecutive patients were enrolled and randomly assigned to receive either oral midazolam (midazolam group, n = 100) or chloral hydrate (chloral group, n = 98).” The authors state that children were randomised but provide no further details on the methods of randomisation.
Allocation concealment (selection bias)	Unclear risk	Materials and methods, study location, sample and design: ”198 consecutive patients were enrolled and randomly assigned to receive either oral midazolam (midazolam group, n = 100) or chloral hydrate (chloral group, n = 98).” As above, no further description on the randomisation process or the person performing the randomisation, which precluded an assessment of whether random sequence was generated independently from allocation.
Blinding of participants and personnel (performance bias) All outcomes	High risk	It was not stated whether the participants and personnel were blinded to the allocation. However, blinding appeared to be unlikely, as midazolam and chloral hydrate probably had a different appearance and taste. As the data collected included neurological diagnosis, sleep onset latency, sleep duration, drowsiness time, and adverse drug events, which included outcomes that required subjective assessment, non‐blinding of the personnel could have influenced the care of participants and the outcomes.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It was unclear whether the trained child neurologist who interpreted the EEG and the trained staff who recorded the rest of the outcome data were blinded to the allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Although the numbers of withdrawals or participants with missing data were not directly stated, it appeared that all 198 children who were initially randomised were analysed, as calculated from the results section based on the number of EEGs obtained.
Selective reporting (reporting bias)	Low risk	The prespecified outcomes of sleep onset latency, sleep duration, drowsiness time, and adverse drug events were reported in the results. An additional outcome of EEG yield, or the number of abnormal EEGs, which was specified in our review, was also reported. However, the data for the continuous outcomes of sleep onset latency, sleep duration, and drowsiness time were skewed, and were reported in median and range, and were therefore unsuitable for inclusion in meta‐analysis.
Other bias	Low risk	None identified.

Ashrafi 2020.

Study characteristics
Methods	Prospective, randomised, single‐blinded design (Iran)
Participants	Paediatric patients scheduled for EEG recording at a paediatric university hospital in Tehran, Iran A total of 198 paediatric patients (age range 9 to 156 months; 81 females, 117 males) were enrolled and randomly assigned to receive either oral clonidine (100 children) or oral chloral hydrate (98 children).
Interventions	2‐arm comparison: Oral clonidine (4 μg/kg) Oral chloral hydrate (50 mg/kg)
Outcomes	Sleep onset latency Sleep duration Drowsiness time Adverse effects that occurred within 4 hours after EEG recording, including drowsiness and vertigo
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Materials and methods: “Patients were randomly allocated to one of the two premedication options of oral clonidine or chloral hydrate” and in the abstract section of materials and methods "Patients .... were randomly divided into two groups .... on an alternative day basis." Although the authors state that children were randomly allocated on alternate‐day basis, this is quasi‐randomisation, as allocation was predictable.
Allocation concealment (selection bias)	High risk	Participants were allocated to treatment on an alternate‐day basis (stated in abstract methods section). It is likely that personnel and possibly even participants would have been able to predict to which treatment arm children had been allocated, as the randomisation followed a predictable sequence.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	No details provided on whether participants or medical personnel were blinded in the study.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No statement was made as to whether participants were blinded to the allocation or whether medical personnel conducting the study were blinded. Study had a single‐blind design, so we assumed that participants were blinded. The outcomes collected included participant’s sleep onset latency, sleep duration, and drowsiness time, which required a subjective assessment. Non‐blinding of the trained staff who collected the required data could have influenced the care of participants and the outcomes.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No participants were reported to have dropped out from the study after recruitment.
Selective reporting (reporting bias)	Low risk	The prespecified outcomes, which included sleep onset latency, sleep duration, drowsiness time, and adverse events, were reported in the results.
Other bias	Unclear risk	There was an imbalance in participant characteristics in which there was skewness in data, with the mean age of children assigned to the clonidine group (mean 57.4 months) being older than the mean age of children assigned to the chloral hydrate group (mean 21.8 months), and the difference showing a tendency towards statistical significance (P < 0.001).

Azizkhani 2014.

Study characteristics
Methods	RCT (Iran)
Participants	Paediatric patients (2 to 6 years old) who were referred for brain CT scan at the Alzahra and Kashani Esfehani Hospitals, Esfehan, Iran. A total of 70 children (45 males and 25 females) were enrolled and randomly assigned to receive either oral chloral hydrate or rectal sodium thiopental.
Interventions	2‐arm comparison: Oral chloral hydrate (50 mg/kg) Rectal sodium thiopental (25 mg/kg)
Outcomes	Sedation onset Sedation duration Sedation failure requiring further administration of sedative agent Adverse events including desaturation, reduced mean diastolic blood pressure, and diarrhoea
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Materials and methods: “They were randomly divided in to two groups of oral chloral hydrate and rectal sodium thiopental, based on block randomization method.”
Allocation concealment (selection bias)	Unclear risk	There was insufficient information in the paper to enable a meaningful assessment of the relationship between sequence generation and allocation.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Blinding was not possible, as participants received different route of administration of the intervention (either oral chloral hydrate or rectal sodium thiopental). No statement was made as to whether the radiology nurse who recorded the outcome was blinded to the intervention.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	No statement was made as to whether outcome assessors were blinded. It is possible that the radiology nursing staff who collected the relevant data, such as total time of sedation, onset of action, duration of action, and complications, was aware of the medication received, as the route of administration for each medication was different.
Incomplete outcome data (attrition bias) All outcomes	Low risk	As stated in the results section, no participants dropped out from the study.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported in the results section.
Other bias	Low risk	None identified.

Bektas 2014.

Study characteristics
Methods	Single‐centre RCT (Turkey)
Participants	341 children (mean age: 60.92 ± 53.81 months; 194 male and 147 female) who were uncooperative with the EEG setup or referred for sleep EEG were enrolled. Children were randomly divided into 2 groups of oral hydroxyzine and oral chloral hydrate.
Interventions	2‐arm comparison: Oral chloral hydrate administered orally as a suspension (mean dosage 26.38 ± 14.73 mg/kg; 147 children) Oral hydroxyzine administered orally as a solution (mean dosage 1.43 ± 0.74 mg/kg; 112 children) If the first drug failed, the other drug (oral hydroxyzine or oral chloral hydrate) was given (28 children received a combination of chloral hydrate and hydroxyzine).
Outcomes	Frequency of EEG background rhythm, sleep onset latency The amplitude of the background rhythm, epileptic abnormalities (focal epileptic discharges, generalised epileptic discharges, multifocal epileptic discharges), the presence of fast activity, amplitude and frequency of sleep spindles Duration of sleep Number of children with successful sedation (spontaneous sleep) Side effects
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Methods: "The patients who could not sleep spontaneously were randomly divided in two groups of hydroxyzine and chloral hydrate taking into account age, diagnosis, and mental retardation." The authors stated that participants were randomised but provided no further detail on the methods of randomisation.
Allocation concealment (selection bias)	Unclear risk	As above
Blinding of participants and personnel (performance bias) All outcomes	High risk	It was not stated whether the participants and personnel were blinded to the allocation. However, blinding appeared to be very unlikely, as hydroxyzine and chloral hydrate differed in appearance and taste. Furthermore, those children who failed the first drug were given the second drug. As the data collected included neurological diagnosis, sleep onset latency, sleep duration, drowsiness time, and adverse drug events, which included outcomes that required subjective assessment, non‐blinding of the personnel could have influenced the care of participants and the outcomes.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It was unclear whether the EEG technicians who recorded the side effects were blinded to the allocation. It was also unclear who recorded the number of successful sedation and time interval to go to sleep.
Incomplete outcome data (attrition bias) All outcomes	High risk	Although the numbers of withdrawals or participants with missing data were not directly stated, it appears that all children who were initially randomised were analysed, as calculated from the results section based on the number of EEGs obtained. However, the authors did not follow intention‐to‐treat analysis, as they put the 28 children who failed chloral hydrate or hydroxyzine and who received a second sedative agent in a separate group (chloral hydrate and hydroxyzine group).
Selective reporting (reporting bias)	High risk	The prespecified outcomes of frequency, sleep onset latency, EEG changes (the amplitude of the background rhythm, epileptic abnormalities), sleep duration, and adverse drug events were reported in the results. An additional outcome of EEG yield, or the number of abnormal EEGs, which was specified in our review, was also reported. However, the data for the continuous outcomes of time of sleep were skewed, and were reported in median and range, and were therefore unsuitable for inclusion in meta‐analysis.
Other bias	Low risk	None identified.

D'Agostino 2000.

Study characteristics
Methods	Double‐blinded, single‐centre RCT (USA)
Participants	Children were enrolled in an outpatient neuroimaging study. Eligible were children between 2 months and 8 years of age. 40 children enrolled in the study, 33 completed the protocol.
Interventions	2‐arm comparison: Oral chloral hydrate (75 mg/kg, maximum 2 g; 11 children) Oral midazolam (0.5 mg/kg, maximum 10 mg; 22 children) Identically appearing, cherry‐flavoured liquids If inadequately sedated after 30 min, child received a supplementary dose of the same medication at 50% of the original dosage.
Outcomes	The principal outcome measurement was the ability to induce sufficient sedation to perform the intended neuroimaging study. A secondary efficacy outcome was the proportion of children who required supplementary medication. Side effects
Notes	Due to an unexpectedly high sedation failure rate, an interim analysis was performed after the first 40 children were enrolled, and the study was terminated as a result of the findings.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Methods: "A randomized sequence of 100 total subjects with 50 in each group was generated using a random number table." Randomisation method was explained and valid.
Allocation concealment (selection bias)	Unclear risk	As above, no further description on the person performing the randomisation to enable an assessment as to whether random sequence was generated independently from allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Methods: "Children were administered freshly prepared, identically appearing, cherry flavored liquids in body weight equivalent volumes.... Neither the patient nor any of the investigators were aware of the active component given to individual patients." Blinding of participants was well described.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Neither the participant nor any of the investigators were aware of the active component given to individual participants.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Results: “Randomized children who did not complete the protocol included one with respiratory distress, one who ate a full meal prior to intended drug administration, one who fell asleep after intravenous line placement and four patients who cancelled their appointments after randomization.” Due to an unexpectedly high sedation failure rate, an interim analysis was performed after the first 40 patients were enrolled. The study was terminated early as a result of the findings showing high failure rate in 1 arm.
Selective reporting (reporting bias)	Low risk	The prespecified outcomes of the ability to induce sufficient sedation, duration of sedation, maximum change in anxiety scores, proportion of patients who required supplementary medication, and side effects were reported in the results.
Other bias	Low risk	None identified.

Fallah 2013.

Study characteristics
Methods	Single‐blinded, single‐centre RCT (Iran)
Participants	Children aged 1 to 10 years, referred to CT centre for elective brain CT scan. Children were in ASA class 1 or 2. 60 children were recruited.
Interventions	2‐arm comparison: 100 mg/kg oral chloral hydrate with 1 mL of intranasal normal saline as placebo (30 children) 0.2 mg/kg intranasal midazolam with oral normal saline as placebo (30 children)
Outcomes	The primary outcomes were efficacy in adequate sedation and completing of CT scan. Secondary outcomes included clinical side effects.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The trial used computer generated equal randomization and allocation ratio was 1:1 for the two groups. Randomisation and blinding was done by an investigator with no clinical involvement in the trial. Data collectors, outcome assessors and data analysts were all kept blinded to the allocation.” The stated method of randomisation was use of a computer‐generated equal randomisation for the 2 groups.
Allocation concealment (selection bias)	Low risk	“The trial used computer generated equal randomization and allocation ratio was 1:1 for the two groups. Randomisation and blinding was done by an investigator with no clinical involvement in the trial. Data collectors, outcome assessors and data analysts were all kept blinded to the allocation.”
Blinding of participants and personnel (performance bias) All outcomes	Low risk	“Randomisation and blinding was done by an investigator with no clinical involvement in the trial. Data collectors, outcome assessors and data analysts were all kept blinded to the allocation.” “The children were randomized to receive either single dose of 100 mg/kg oral chloral hydrate with one millilitre of intranasal normal saline as placebo (Group I) or 0.2 mg/kg intranasal midazolam with oral normal saline as placebo (Group II).” The participants and personnel were blinded to the appearance of the medications, as both were served (either 1 is placebo). Even though intranasal normal saline and oral normal saline (as placebo) taste differently from the medications, children would not be able to identify which medication they received. The investigators were not involved in the trial.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	“The trial used computer generated equal randomization and allocation ratio was 1:1 for the two groups. Randomisation and blinding was done by an investigator with no clinical involvement in the trial. Data collectors, outcome assessors and data analysts were all kept blinded to the allocation.” All personnel involved in the assessment were blinded.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The author did not report any withdrawals or missing data; however, it appears that all of the 60 children who were initially randomised were analysed, as calculated from the results section based on the number of CT brain obtained.
Selective reporting (reporting bias)	Low risk	"The primary outcomes were efficacy in adequate sedation and completing of CT scan. Secondary outcomes included clinical side effects, serious adverse events.” The author reported data on rate of successful CT brain and Ramsay Sedation Score for the primary outcomes. In addition, time from drug administration to adequately sedated, time after taking the drug to completing CT scan, caregiver's satisfaction scale, and total stay time in CT centre were also reported.
Other bias	Low risk	None identified.

Gumus 2015.

Study characteristics
Methods	Single‐centre RCT (Turkey)
Participants	160 children who were uncooperative during EEG recording or who were referred to electrodiagnostic unit for sleep EEG recording. All children were classified as ASA class I or II.
Interventions	4‐arm comparison: Oral dexmedetomidine (2 µg/kg; 42 children) Oral dexmedetomidine (3 µg/kg; 42 children) Oral chloral hydrate (50 mg/kg; 36 children) Oral chloral hydrate (100 mg/kg; 40 children)
Outcomes	The primary aim of the study was to evaluate the efficacy of sedation induction for successful recording of sleep EEG. Secondary outcome measures included times of sedation and adverse effects of different dexmedetomidine and chloral hydrate doses.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“The patients were randomly allocated to 1 of the 4 groups by a computer‐generated drawing lot.” Children were randomised according to computer‐generated drawing method.
Allocation concealment (selection bias)	Unclear risk	“The patients were randomly allocated to 1 of the 4 groups by a computer‐generated drawing lot.” “Sedative agents were prepared and administered by a trained nurse under the supervision of the attending pediatric neurologist in all patients.” It was unclear whether random sequence was generated independently from allocation.
Blinding of participants and personnel (performance bias) All outcomes	High risk	“Sedative agents were prepared and administered by a trained nurse under the supervision of the attending pediatric neurologist in all patients.” “In groups D1 and D2, corresponding amounts of dexmedetomidine (Precedex 100 mg/mL; Abbott Laboratories, IL) in 3mL normal saline were given to patients via the oral route. In the D1 and D2 groups, patients received oral dexmedetomidine doses of 2 and 3 mg/kg, respectively. In groups C1 and C2, corresponding amounts of chloral hydrate (100 mg/mL) in freshly prepared, cherry‐flavored liquids were given to patients in a single dose orally. In these groups (C1 and C2), patients received oral chloral hydrate doses of 50 and 100 mg/kg, respectively.” Blinding of participants is unlikely, as both medications were different in taste and quantity (amount served).
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Status of data collectors, outcome assessors, and data analysts was not mentioned.
Incomplete outcome data (attrition bias) All outcomes	Low risk	“Overall, 160 patients (85 male and 75 female) were included in this study.” The author did not report any withdrawals or missing data; however, it appears that all of the 160 children who were initially randomised were analysed, as calculated from the results section based on the number of EEGs obtained.
Selective reporting (reporting bias)	Low risk	“... aimed to compare the efficacy and safety of oral chloral hydrate and dexmedetomidine in achieving adequate sedation for sleep EEG recordings in children.” “The primary aim of the study was to evaluate the efficacy of sedation induction for successful recording of sleep EEG. Secondary outcome measures included times of sedation and adverse effects of different dexmedetomidine and chloral hydrate doses.” The prespecified outcomes of sedation failure rate in each group, as well as induction time, recovery time, and adverse reactions, were evaluated.
Other bias	Low risk	None identified.

Loewy 2005.

Study characteristics
Methods	Single‐centre RCT (Israel)
Participants	58 children from a paediatric inpatient unit who underwent EEG procedure over a 4‐year period
Interventions	2‐arm comparison of success of sedation: Oral chloral hydrate administered orally at 60 mg/kg (up to a maximum of 1.5 g; 34 children) Music therapy whereby child was played and sung soothing music according to caregiver's request (24 children)
Outcomes	Child's level of sleep/sedation during procedure using Beth Israel Medical Center sedation scale Time to achieve sleep/sedation from the onset of the intervention Length of sleep/sedation from beginning of the EEG until awakening
Notes	Quasi‐RCT whereby the children were identified and assigned to 1 of 2 treatment groups, chloral hydrate or music therapy, based on the day of the week they were admitted. Children recruited on Mondays received chloral hydrate, children recruited on Tuesdays received music therapy.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Method: “The subjects were identified and assigned to one of 2 treatment groups, chloral hydrate or music therapy, based on the day of the week they were admitted. Subjects recruited on Mondays received chloral hydrate, and subjects recruited on Tuesdays received music therapy.” Quasi‐randomisation was performed according to the day children were recruited, which is predictable. In addition, allocation of the 58 children to the 2 groups was not balanced, with 34 in the music therapy group and 24 in the chloral hydrate group. Furthermore, data were skewed, with the mean age of children assigned to the music therapy group (mean 2.44) lower than the mean age of children assigned to the chloral hydrate group (mean 3.21), and the difference showing a tendency towards statistical significance (P = 0.53).
Allocation concealment (selection bias)	High risk	Method: “The subjects were identified and assigned to one of 2 treatment groups, chloral hydrate or music therapy, based on the day of the week they were admitted. Subjects recruited on Mondays received chloral hydrate, and subjects recruited on Tuesdays received music therapy.” As stated above, allocation follows a predictable sequence (according to day child was recruited).
Blinding of participants and personnel (performance bias) All outcomes	High risk	Blinding was not possible, as participants received completely different modality of intervention (either chloral hydrate or music therapy).
Blinding of outcome assessment (detection bias) All outcomes	High risk	The authors do not state whether the outcome assessors were blinded to the allocation; however blinding seems to be unlikely, as the modality of intervention was completely different (chloral hydrate given orally or music therapy with music therapist). As the outcomes collected included child’s level of sleep/sedation during procedure, time to achieve sleep/sedation, and length of sleep/sedation, some of which required a subjective assessment, non‐blinding of personnel could have influenced the care of participants and the outcomes. Medical residents or music therapy interns who recorded the outcome data were not blinded to the allocation, as they collected the data before, during, and after the EEG procedure, which would have included witnessing the music therapy taking place.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Results: “Of the total, 2 children (1 from each group: music therapy and chloral hydrate) were not able to go through the EEG on the day of the test and were not included in the analyses. One patient was using a medication that interacted with chloral hydrate and the other patient cancelled and rescheduled due to the parent’s request to be present during the test.” The missing outcome data were equal across both groups and a small number (1 = 1.7% for each group). However, although not stated, it is possible that the 1 participant who cancelled and rescheduled could be related to the type of sedation assigned for the EEG procedure. It is unlikely that the missing data meaningfully changed the outcome of the study.
Selective reporting (reporting bias)	High risk	The prespecified outcomes of length of sleep/sedation, time to achieve sleep/sedation, and level of sleep/sedation were reported in the results. The level of sleep/sedation was reported as a categorical outcome (scale of 0 to 5) in medication; however, the outcome was reported inappropriately whereby the author reported sleep score 4 for chloral hydrate and sleep score 3 for music therapy, making it unsuitable for direct comparison.
Other bias	Low risk	None identified.

Lopez 1995.

Study characteristics
Methods	Randomised study (Chile)
Participants	Children aged 1 to 5 years, sent to “Servicio de Neuropsiquiatrfa Infantil, Hospital Clinico San Borja‐Arriara'n” for EEG from June to December 1993, excluding those who were treated with barbiturates or benzodiazepines. 92 children were recruited.
Interventions	Sedation group assignment was based on a tossed coin to receive either rectal chloral hydrate (50 mg/kg; 32 children) or rectal midazolam (1 mg/kg; 27 children), with another control group of 33 children.
Outcomes	Time to achieve sleep/sedation from the onset of the intervention Sleep duration EEG artefact due to sedative agent
Notes	Article was in Spanish, and assessment was performed with English translation.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The assignment was based on coin tossing for sedation group (rectal chloral hydrate vs rectal midazolam).
Allocation concealment (selection bias)	Unclear risk	“To the children who were not sleepy or sleeping at the time of launch the examination nor had contraindications to the sedation, were administered 50 mg /kg of chloral hydrate in solution 5% or midazolam at 5 mg/ml dose parenteral solution 1 mg/kg, both rectally. Due to the small volume of midazolam it was diluted with 3 ml of solution of NaCl 0.9%, to avoid that it stays in the probe.” It is unclear whether allocation was concealed.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	“the EEG tracings were analyzed by two medical electro‐encephalographers (EM, LT) who did not know what sedatives were administered and who were asked to review possible base alterations attributable to a sedative (impregnation), and to what medication it was attributed to” It is unclear whether or not participants and personnel were blinded.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	“the EEG tracings were analyzed by two medical electro‐encephalographers (EM, LT) who did not know what sedatives were administered and who were asked to review possible base alterations attributable to a sedative (impregnation), and to what medication it was attributed to” 2 independent electroencephalographers interpreted the EEG result.
Incomplete outcome data (attrition bias) All outcomes	High risk	Participants dropped out of the midazolam group, as EEG outcome data were only reported for 21 children (originally 27 children were recruited in this arm). The dropout rate of 22% was significant.
Selective reporting (reporting bias)	Low risk	Data were skewed in the chloral hydrate group (sleep latency 21.8 ± 17.5 min; and duration of sleep 61 ± 31.2 min).
Other bias	Low risk	None identified.

Malviya 2004.

Study characteristics
Methods	Single‐centre RCT (USA)
Participants	70 children who were undergoing sedation for MRI over a 1‐year period
Interventions	2‐arm comparison of the efficacy and adverse events of sedation: Oral chloral hydrate (75 mg/kg orally up to maximum dose of 2 g; 35 children) Oral pentobarbital (incremental 2 mg/kg intravenous doses titrated to a maximum of 5 mg/kg or 150 mg; 35 children)
Outcomes	The primary outcome was success of sedation using validated University Michigan Sedation Scale (scale of 0 to 4 with score 4 being unrousable, i.e. sedation successful). Secondary outcome measures: Quality of MRI scans (score 1 to 3, with score 3 major motion artefact with scan incomplete) Parents' overall satisfaction with sedation experience (score 1 to 4; score 4 = very satisfied) Procedural adverse events
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Method: "Using random number tables, children were randomized to one of two study groups. Group 1 received incremental 2 mg/kg) intravenous (i.v.) doses of PB, titrated to a maximum of 5 mg/kg or 150 mg, administered approximately 10 min prior to MRI. Group 2 received 75 mg/kg of CH orally (maximum dose 2 g) in a single dose approximately 20 min prior to the procedure."
Allocation concealment (selection bias)	Unclear risk	There was no description to enable an assessment of whether random sequence was generated independently from allocation.
Blinding of participants and personnel (performance bias) All outcomes	High risk	It was not stated whether participants and personnel were blinded to the allocation. However, blinding seems to be unlikely given the different routes of administration of the interventions.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It was not stated whether the outcome assessors were blinded to the allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No withdrawals were reported. Although children with missing data were not specifically reported, it appears that all of the 70 children who were initially randomised were analysed as calculated from the results section.
Selective reporting (reporting bias)	Low risk	The prespecified outcomes of success of sedation using the University Michigan Sedation Scale, time interval to readiness of procedure, quality of MRI scans (score 1 to 3, with score 3 major motion artefact with scan incomplete), parents' overall satisfaction with sedation experience (score 1 to 4; score 4 = very satisfied), and procedural adverse events were reported.
Other bias	Low risk	None identified.

Marti‐Bonmati 1995.

Study characteristics
Methods	Double‐blinded, single‐centre RCT (Spain)
Participants	97 consecutive children receiving sedation for MRI
Interventions	2‐arm comparison: Oral chloral hydrate (70 mg/kg; 50 children) Oral chloral hydrate (100 mg/kg; 47 children)
Outcomes	Primary outcome: successful sedation and completion of scan Secondary outcome: adverse reactions
Notes	Comparison is chloral hydrate itself.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Materials and methods: “We entered 97 consecutive children receiving sedation for MRI in a prospective, controlled, double‐blind, randomized trial” and “The children were randomly allocated, by means of a computer generated chart, to oral chloral hydrate 70 mg/kg (group A, n = 50) or 100 mg/kg (group B, n = 47).”
Allocation concealment (selection bias)	Low risk	Materials and methods: “Two strawberry‐flavoured chloral hydrate syrups containing 70 or 100mg/ml were prepared by the pharmacy department.” As described above, allocation concealment occurred, as chloral hydrate medication of 2 different concentrations of the same flavour were made by pharmacy.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	As described above, blinding occurred for participants and personnel, as chloral hydrate medication of 2 different concentrations of the same flavour and volume were made by pharmacy.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	A nurse performed the outcome assessment. Although not stated, it is likely that blinding of outcome assessment occurred for the reasons stated above.
Incomplete outcome data (attrition bias) All outcomes	Low risk	No withdrawals were reported, and no missing data were specifically stated. It appeared that all 97 children who were initially randomised were analysed as calculated from the results section.
Selective reporting (reporting bias)	Low risk	The prespecified outcomes of mean time to onset of sedation, mean time to spontaneous awakening, effectiveness of sedation, and adverse reactions were reported in the results.
Other bias	Low risk	None identified.

Razieh 2013.

Study characteristics
Methods	Single‐centre RCT (Iran)
Participants	60 children seen in clinic or inpatient referred to EEG unit by a paediatric neurologist
Interventions	2‐arm comparison of efficacy of sedation: Chloral hydrate (70 mg/kg orally single dose; 30 children) Promethazine (1 mg/kg orally; 30 children)
Outcomes	Primary outcome measure: success of sedation using a validated Ramsay Sedation Scale to assess sedation level. A Ramsay score of 4 was considered as adequately sedated. Secondary outcome measure: failure to achieve adequate sedation (child awakened or moved, interfered with completion of EEG, inadequate sedation and need for administration of other sedative drug) and procedure abortion due to serious adverse events were considered as failure of sedation regimen.
Notes	If child was not sedated after 30 minutes of drug ingestion, the second dose of the drug (half of the first dose) was administered.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Subjects and methods: “The trial used computer generated equal randomization and allocation ratio was 1:1 for the two groups. Randomisation was done by a computer generated random number list and blinding was done by employing an investigator with no clinical involvement in the trial.”
Allocation concealment (selection bias)	Low risk	Subjects and methods: “The trial used computer generated equal randomization and allocation ratio was 1:1 for the two groups. Randomisation was done by a computer generated random number list and blinding was done by employing an investigator with no clinical involvement in the trial. Data collectors, outcome assessors and data analysts were all kept blinded to the allocation but the interventionists (EEG staff). The trial adhered to established procedures to maintain separation between person who took outcome assessment and staff that delivered the intervention. The drug was delivered by EEG staff and primary and secondary outcomes were assessed by the resident of research who was not informed of the drug group assignment. Investigators, staff and participants were all kept masked to outcome measurements and trial results."
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	As above, it was stated that outcome assessors were blinded to allocation of sedation; it was not stated if children were blinded to allocation. Although both forms of sedation were given orally diluted in water, it is possible that they had a different appearance and taste, which could have affected participant blinding.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	As stated above
Incomplete outcome data (attrition bias) All outcomes	Low risk	No withdrawals were reported, and no missing data were specifically stated. It appears that all 60 children who were initially randomised were analysed as calculated from the findings section of the proportion of children who achieved adequate sedation in both subgroups.
Selective reporting (reporting bias)	Low risk	The prespecified outcomes of acquired Ramsay scale with first drug, time from drug administration to adequate sedation, time after taking drug to record EEG, caregiver’s satisfaction scale, and stay time in EEG unit were reported in the results.
Other bias	Low risk	None identified.

Sezer 2013.

Study characteristics
Methods	Single‐centre RCT (Turkey)
Participants	282 children from 1 hospital referred for a sleep EEG recording
Interventions	2‐arm comparison study of efficacy of sedation: Oral chloral hydrate (50 mg/kg orally with an additional dose of 50 mg/kg after 30 minutes if no sedation achieved, maximum dose of 1 g; 141 children) Oral hydroxyzine hydrochloride (1 mg/kg orally with additional dose of 1 mg/kg after 30 minutes if no sedation achieved; 141 children)
Outcomes	Primary outcome of success of sedation measured by sleep onset latency and sleep duration. Secondary outcome measures included the presence or absence of epileptiform discharges on the EEG and all adverse events.
Notes	No clear description of how randomisation was performed
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Subjects and methods: “The trial used computer generated equal randomization and allocation ratio was 1:1 for the two groups. Randomisation was done by a computer generated random number list and blinding was done by employing an investigator with no clinical involvement in the trial.”
Allocation concealment (selection bias)	Unclear risk	Materials and methods: “These patients were randomly divided into two groups of 141: a CH group and a HH group.” As above, no further description on the randomisation process and the person performing the randomisation was provided to enable an assessment on whether random sequence was generated independently from allocation.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Materials and methods: “These patients were randomly divided into two groups of 141: a CH group and a HH group. Chloral hydrate was mixed with milk for infants and in juice, milk, or yogurt for older children in order to mask its bitter taste.” It was not stated whether the participants and personnel were blinded to the allocation. Despite stating that chloral hydrate was mixed with milk, juice, or yoghurt, it was not reported if this same method of mixing was followed for the HH group; it was unclear whether the methods of preparation were systematically different between the intervention and the control arms.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	It was unclear if the personnel who collected the outcome data were blinded to the allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Although the number of withdrawals or participants with missing data was not directly stated, it appeared that all the 282 children who were initially randomised were analysed, as calculated from the results section.
Selective reporting (reporting bias)	Low risk	The prespecified outcomes of sleep onset latency, sleep duration, failure of sedation, and adverse drug events were reported in the results. An additional outcome of EEG yield, or the number of abnormal EEGs, which was specified in the review, was also reported.
Other bias	Low risk	None identified.

Thompson 1982.

Study characteristics
Methods	Single‐centre RCT (USA)
Participants	All children from birth through 9th birthday who were scheduled for CT examination of the head. 582 children were randomised into 2 groups: inpatient and outpatient.
Interventions	Outpatient arm: Oral chloral hydrate (80 mg/kg, maximum 2 g; 140 children) Intramuscular AMPS cocktail (0.08 mL/kg; 139 children) Inpatient arm: General anaesthesia (101 children) Oral chloral hydrate (80 mg/kg, maximum 2 g; 101 children) Intramuscular AMPS cocktail (0.08 mL/kg; 101 children) Supplementation with intravenous secobarbital if necessary, 2 mg/kg (maximum)
Outcomes	The primary outcomes were efficacy in adequate sedation and completing of CT scan. Secondary outcomes included clinical side effects.
Notes	Part of the study also includes retrospective analysis of another non‐randomised group.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	High risk	“Both groups included all children from birth through their ninth birthday who were scheduled for CT examination of the head. Certain children could not be included in the randomization for sedation and these 253 (28%) were excluded from the study protocol for the following reasons ...” "An alternating assignment for outpatients and a rotational assignment for inpatients helped to reduce the chance of selecting a particular method for a particular patient. For outpatients, the sedation regimen was assigned when the patient arrived for CT, using an alternating list kept at the scheduling desk. In the case of a sedation failure, this was recorded, and upon the child’s return for a second trial, the number for the next‐in‐line alternate type of sedation was assigned. When both sedation regimens failed for outpatients, general anesthesia was usually given, but not as part of the inpatient randomization. For inpatients, the rotational assignment included general anesthesia but generally only one sedation was tried before resorting to general anesthesia.” Randomisation via alternating and rotational assignments, thus risk of bias was high.
Allocation concealment (selection bias)	High risk	Randomisation via alternating and rotational assignments, which is predictable, thus risk of bias was high.
Blinding of participants and personnel (performance bias) All outcomes	High risk	“... two sedation methods, one oral and one intramuscular, were chosen ...” “... but a preference for CH developed in the nurses and technologists because of the patient discomfort from the dual intramuscular injections of AMPS.” No blinding, as intramuscular injection of AMPS cocktail and oral chloral hydrate differed in the nature and route of administration. The nurses and technologists were biased.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Blinding of outcome assessment was not stated.
Incomplete outcome data (attrition bias) All outcomes	High risk	Randomised sedation (582) = outpatient (279) + inpatient (303); only 129 outpatients and 207 inpatients were reviewed. Significant dropout/portions of missing data (42.3%). Details of missing data were not provided.
Selective reporting (reporting bias)	High risk	The authors reported some outcomes without providing sufficient detail for a meta‐analysis. For example, the outcome of time of onset of sedation was reported only as means without standard deviation. There was a significant amount of missing data, as only 129 outpatients were reviewed from the randomised group of 279, and 207 inpatients were reviewed from the randomised group of 303. Details of the proportion of children requiring supplementation with an additional sedative agent were insufficient/unclear.
Other bias	Low risk	None identified.

Yuen 2017a.

Study characteristics
Methods	2‐centre RCT (China)
Participants	Children scheduled for brain computerised tomographic scan under sedation between March 2013 and February 2015 at either Queen Mary Hospital, Hong Kong or Guanzhou Women & Children's Medical Centre, China were recruited. A total of 194 children (aged 14 months to 36 months) were enrolled to randomly receive either oral chloral hydrate (107 children) or intranasal dexmedetomidine (87 children).
Interventions	2‐arm comparison of efficacy: Oral chloral hydrate (50 mg/kg) Intranasal dexmedetomidine (3 µg/kg)
Outcomes	Sedation onset (minutes) Sedation adverse effect: crying during drug administration Sedation time to recover to normal activities (hours) Sedation adverse effect: vomiting Sedation adverse effect: bradycardia Sedation adverse effect: unsteadiness in the first 24 hours
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	In the Methods section: "The subjects were randomized using a computerized random sequence." However, it was not stated how this randomisation was performed, and we note that the numbers of participants in the 2 arms were not balanced: 108 children in the chloral hydrate group vs 88 children in the dexmedetomidine group. In addition, participant characteristics of the 2 groups were not reported in the study.
Allocation concealment (selection bias)	Low risk	Allocation of participants was randomised with computerised randomisation method. The pharmacist who generated the sequence was not involved in the trial.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Despite blinding being performed on both participants and investigators using placebo in the 2 intervention arm groups, it was not reported whether the radiologist (Hong Kong centre) or paediatric anaesthetist (Guangzhao centre) who gave an additional sedative was blinded, as they have to give either a further dose of either intravenous midazolam (Hong Kong) or intranasal dexmedetomidine (China). We note that a different "rescue agent of sedation" which involved a different route was used by the Hong Kong team, making blinding of participants and personnel unlikely.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding was done on both participants and investigators using a placebo in the 2 study groups.
Incomplete outcome data (attrition bias) All outcomes	Low risk	1 participant from each group was excluded due to sedation failure.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported in the study.
Other bias	Low risk	None identified.

AMPS: atropine/meperidine/promethazine/secobarbital
ASA: American Society of Anesthesiologists
CH: chloral hydrate
CT: computed tomography
EEG: electroencephalogram
HH: hydroxyzine hydrochloride
MRI: magnetic resonance imaging
RCT: randomised controlled trial

Characteristics of excluded studies [ordered by study ID]

Study	Reason for exclusion
Badalaty 1990	Study compared a high and low dose of diazepam with chloral hydrate in the sedation of young children for dental treatment; the outcome measure is dental procedure. Basis of exclusion: type of population and outcome measure.
Bluemke 2000	Study performed based on a sedation database to evaluate the successful sedation procedures, adverse reactions, and cost‐effectiveness of various sedative agents (chloral hydrate, pentobarbital sodium, diazepam, alprazolam). This is not an RCT. Basis of exclusion: study design.
Casillas 1995	Non‐randomised single‐group study, only oral chloral hydrate was being assessed, with additional second dose if first dose failed for MRI sedation; outcomes were successful sedation and adverse reaction. Basis of exclusion: study design and intervention.
ChiCTR1800014574	RCT that compared different doses of intranasal dexmedetomidine plus chloral hydrate given orally for MRI sedation in infants. Does not meet the eligibility criterion for type of comparison (only assessed the efficacy of different doses of dexmedetomidine whilst keeping chloral hydrate at a constant dose). Basis of exclusion: type of intervention.
ChiCTR1900020694	An RCT comparing the efficacy of intranasal dexmedetomidine, or in combination with either chloral hydrate of sevoflurane inhalation, in children with MRI sedation. Does not meet eligibility criterion for type of intervention (no comparison of chloral hydrate with dexmedetomidine or sevoflurane). Basis of exclusion: type of intervention.
ChiCTR1900021847	An RCT evaluating the efficacy and safety of sedation of oral midazolam in combination with intranasal dexmedetomidine for magnetic resonance imaging in paediatric patients. Does not compare chloral hydrate alone with oral midazolam or dexmedetomidine. Basis of exclusion: type of intervention.
Conway 2016	A systematic review to determine the evidence on the effectiveness of midazolam versus various sedative agents (intravenous diazepam, intravenous etomidate, intravenous fentanyl, intravenous flunitrazepam, intravenous propofol, oral chloral hydrate, oral diazepam, oral clonidine, and oral ketamine) for sedation when administered before a procedure (neurodiagnostic and non‐neurodiagnostic tests). Not an RCT. Basis of exclusion: study design.
Cortellazzi 2007	Retrospective study on the efficacy of chloral hydrate sedation and supplementation with sevoflurane, intramuscular or intravenous ketamine, and intravenous pentobarbital and midazolam if failed chloral hydrate. Not an RCT. Basis of exclusion: study design.
Cutler 2007	A retrospective review of all sedations administered by a paediatric sedation service to children (aged 0 to 18 years) undergoing imaging procedures in the radiology department. This was not an RCT. Basis of exclusion: study design.
Dacher 1996	This article was in the French language and was not an RCT. The participants received both rectal chloral hydrate and oral hydroxyzine. Basis of exclusion: study design and intervention.
Dallman 2001	Whilst this was an RCT, it compared the safety, efficacy, and recovery time of intranasal midazolam spray administered using an atomiser to orally administered chloral hydrate and promethazine for the sedation of paediatric dental patients. Does not meet eligibility criteria for types of outcome (dental procedure) and intervention (chloral hydrate + promethazine vs intranasal midazolam). Basis of exclusion: population type and intervention.
Dearlove 2007	Letter to editor (commentary on adverse reaction). Not an RCT. Basis of exclusion: type of article.
Dirani 2017	A non‐randomised study that compared sequential administration of melatonin, hydroxyzine (if needed), and chloral hydrate (if needed) and chloral hydrate alone in children undergoing EEG. Children in the 2 comparison groups were recruited at different periods. Basis of exclusion: study design.
Donnelly 2001	A prospective, non‐randomised, observational study evaluating the success and safety of a structured sedation programme using either oral chloral hydrate or intravenous pentobarbital for dynamic sleep fluoroscopy. Not an RCT. Basis of exclusion: study design.
Edwards 2011	Review evaluating the advantages and disadvantage of sedation and anaesthesia for MRI and alternatives including neonatal comforting techniques, sleep manipulation, and appropriate adaptation of the physical environment. Several factors that would influence the choice of imaging preparation were also discussed. Not an RCT (review article). Basis of exclusion: type of article.
Eich 2011	Comparative observational study aiming to evaluate 2 institutional anaesthetic protocols for children undergoing elective MRI: propofol only vs propofol plus S‐ketamine. Not an RCT (a comparative observational study) and does not meet eligibility criteria for types of intervention (propofol and ketamine). Basis of exclusion: study design and intervention.
Fallah 2014a	This was an RCT. Children aged 1 to 7 years who did not naturally sleep and who were unco‐operative for EEG were recruited. Children were in ASA class 1 (healthy individuals) or class 2. 90 children (39 girls and 51 boys) aged 3.34 ± 1.47 years were investigated. 3‐arm comparison: Chloral hydrate 40 mg/kg Chloral hydrate 40 mg/kg and promethazine 1 mg/kg Chloral hydrate 40 mg/kg and hydroxyzine 2 mg/kg All intervention and comparison groups received chloral hydrate, therefore not the intervention of interest. Basic of exclusion: type of intervention.
Fallah 2014b	This was an RCT. Children aged 1 to 7 years in ASA class 1 or 2 were recruited to assess the efficacy of sedative agents inducing deep sedation and completion of MRI examination. Secondary outcomes included clinical side effects. 2 arm comparison: Chloral hydrate 40 mg/kg and hydroxyzine 2 mg/kg Chloral hydrate 40 mg/kg and midazolam 0.5 mg/kg Both intervention and comparison groups received chloral hydrate, therefore not the intervention of interest. Basic of exclusion: type of intervention.
Finnemore 2014	This was a retrospective cohort study of all infants sedated for clinical or research MRI scanning. The aim of this study was to look for clinically significant adverse effects of chloral hydrate used in a large cohort of infants sedated for MRI. Not an RCT (retrospective study), did not meet eligibility criteria for outcome measures (only assessed adverse reaction of chloral hydrate), and did not compare chloral hydrate with another sedation agent. Basis of exclusion: study design.
Funk 2000	Review article discussing various factors that influenced MRI/CT: general anaesthesia or sedation, anaesthesia and image quality, and technical developments. Not an RCT (review article). Basis of exclusion: type of article.
Gan 2016	RCT comparing different dosages of intranasal dexmedetomidine as rescue medication in paediatric ophthalmic examination after chloral hydrate failed. Basis of exclusion: population and intervention.
Greenberg 1991	Prospective non‐randomised study in which high‐dose oral chloral hydrate (80 to 100 mg/kg) and low‐dose oral chloral hydrate (40 to 75 mg/kg), with a maximum total dose of 2 g, was administered to children for CT examinations (did not state the specified body parts and including abdomen). Success rate and adverse reactions were evaluated. Not an RCT (single‐group study: high‐dose and low‐dose chloral hydrate without comparison). Basis of exclusion: study design.
Greenberg 1994	Prospective non‐randomised study evaluating the safety and efficacy of thioridazine as an adjunct to chloral hydrate sedation in children undergoing MRI who were difficult to sedate. All children in the study had a history of unsuccessful sedation with chloral hydrate alone or were mentally retarded. Not an RCT and did not meet eligibility criterion for type of intervention (no comparison). Basis of exclusion: study design and intervention.
Gupta 2010	This was an oral presentation abstract to determine if the currently available evidence supports the use of melatonin for EEG sedation. Not an RCT (abstract). Basis of exclusion: type of article.
Hare 2012	Review article evaluating 4 randomised trials and comparing the efficacy and safety of chloral hydrate versus midazolam for use in paediatric sedation for painless imaging including echocardiography. Not an RCT (review article). Basis of exclusion: type of article.
Hoffman 2002	This article evaluated the risk reduction in paediatric procedural sedation. Not an RCT. Basis of exclusion: type of article and study design.
Hollman 1996	Letter to editor and commentary on chloral hydrate vs midazolam sedation for neuroimaging studies. Not an RCT (letter to editor and commentary). Basis of exclusion: type of article.
Hubbard 1992	Non‐comparative retrospective study evaluating the safety and efficacy of oral chloral hydrate in infants and intravenous pentobarbital in older children. Not an RCT (non‐comparative retrospective study). Basis of exclusion: study design.
Kannikeswaran 2009	Retrospective study of children 1 to 18 years old who required sedation for an elective brain MRI. Children < 2 years of age were sedated with oral chloral hydrate, whilst children 1 to 7 years of age were sedated with intravenous pentobarbital. Additional doses of pentobarbital or fentanyl were administered if failed sedation. Children older than 8 years of age were given midazolam intravenously or orally for sedation. Not an RCT (retrospective study) and does not meet eligibility criteria for types of comparison (pentobarbital vs fentanyl). Basis of exclusion: study design and intervention.
Keeter 1990	Questionnaire study that aimed to document current sedation practices in CT examination of children in the USA. A questionnaire was sent to a random sample of 2000 hospitals with CT scanners. Not an RCT (questionnaire survey). Basis of exclusion: study design.
Keidan 2004	Retrospective study conducted in 2 large urban hospitals in Israel. The study population consisted of 200 infants who underwent auditory brainstem response examination and who were sedated with chloral hydrate (no comparison). This study was not an RCT (non‐comparative retrospective study) and does not meet eligibility criteria for types of study design, population, and intervention. Basis of exclusion: study design, population, and intervention.
Lee 2012	This retrospective study aimed to evaluate sedation success in children given chloral hydrate at 2 dosing regimens for brain MRI scan. This was not an RCT and does not met eligibility criteria for types of comparison used (no direct comparison with another sedative agent). Basis of exclusion: study design and intervention.
Li 2014	This prospective, randomised study aimed to evaluate sedation success in children for brain CT, auditory brainstem responses, and visual evoked potentials who failed chloral hydrate sedation. Child was then randomly assigned to receive intranasal dexmedetomidine at various doses. The study does not meet eligibility criteria for types of intervention (intranasal dexmedetomidine used only for children who failed chloral hydrate sedation) and types of comparison used. Basis of exclusion: type of intervention.
Li 2018	This RCT compared sedation success rate after oral chloral hydrate and intranasal dexmedetomidine plus buccal midazolam for an auditory brainstem response test. Does not meet eligibility criterion for type of participant (sedation used for auditory test, not neurodiagnostic procedure). Basis of exclusion: type of participant.
Low 2008	This retrospective study aimed to evaluate the success and safety of chloral hydrate sedation protocol for children undergoing brain MRI. Not an RCT (retrospective study evaluating efficacy of chloral hydrate) and does not meet eligibility criteria for types of comparison used. Basis of exclusion: study design and type of intervention.
Marchi 2004	Prospective observational study of children undergoing deep sedation (using either chloral hydrate or propofol) for brain MRI. Not an RCT, as the children were not randomised. Basis of exclusion: study design.
Mason 2004	This retrospective study aimed to evaluate the success of sedation using chloral hydrate (patients sedated between 1997 and 1999) and pentobarbital (patients sedated between 2000 and 2002) for brain imaging. Not an RCT (retrospective review comparing chloral hydrate with pentobarbital). Basis of exclusion: study design.
Mathew 2014	Prospective RCT of children undergoing auditory brainstem response testing randomised for sedation with either midazolam nasal spray with oral placebo or syrup chloral hydrate with placebo nasal spray. Does not meet eligibility criterion for type of participant (sedation used for auditory test, not neurodiagnostic procedure). Basis of exclusion: population type.
McCarver‐May 1996	Cross‐over study. Term newborn infants who had both CT and single‐photon emission CT scanning after extracorporeal membrane oxygenation bypass were re‐emitted for the study. The order of neuroimaging studies was randomised. Chloral hydrate was given orally for the first study. After 48 hours, midazolam was given intravenously for the second study. Not an RCT (cross‐over study). Basis of exclusion: study design.
Mehta 2004	Prospective observational study of efficacy of clonidine as sedating agent in children with autism undergoing EEG. Not an RCT, and does not meet eligibility criterion of type of intervention (did not use chloral hydrate for sedation). Basis of exclusion: study design and type of intervention.
Nichols 2005	Retrospective review of children who failed sedation using chloral hydrate or midazolam for diagnostic brain imaging. Not an RCT. Basis of exclusion: study design.
Poonai 2020	A systematic review comparing intranasal dexmedetomidine with various sedative agents (oral chloral hydrate, oral midazolam, intranasal midazolam, and oral dexmedetomidine) for procedural (neurodiagnostic and non‐neurodiagnostic tests) distress in children. Not an RCT. Basis of exclusion: study design.
Reynolds 2016	Double‐blinded RCTs comparing the efficacy of intranasal dexmedetomidine and oral chloral hydrate for auditory brainstem response in children. Does not meet eligibility criterion for type of participant (sedation was used for auditory test, not neurodiagnostic procedure). Basis of exclusion: population type.
Ronchera‐Oms 1994	Retrospective review of the efficacy of chloral hydrate sedation for children undergoing brain MRI scan. Not an RCT, and does not meet eligibility criterion for type of comparison (no comparison with other sedative agent). Basic of exclusion: study design and type of intervention.
Rooks 2003	A prospective, non‐randomised, observational study assessing the sedation effects of oral pentobarbital sodium against oral chloral hydrate in 2 separate groups of children who were undergoing radiologic imaging. Although the method of allocation was not stated, it is unlikely that participants were randomised. Basis of exclusion: study design.
Rues 2002	Retrospective review and prospective observational study assessing the efficacy of sedation using a pre‐existing sedation protocol (for under 2 years old: oral chloral hydrate +/‐ oral diphenhydramine/hydroxyzine followed by IV midazolam; for over 2 years old: IV pentobarbital +/‐ IV midazolam) for brain MRI or CT. Not an RCT, and does not meet eligibility criterion for type of intervention (children over 2 years old were given IV medication, not chloral hydrate). Also, does not meet eligibility criterion for type of comparison (looked at effectiveness of sedation protocol with no comparison to other sedative agents). Basis of exclusion: study design and type of intervention.
Sury 2006	RCT of children who received additional second‐line sedation (either melatonin or placebo) after failure of first‐line chloral hydrate sedation for brain MRI. Basis of exclusion: type of intervention.
Takasaka 1999	Retrospective review of effect of sedation on EEG recording. Not an RCT, and does not meet eligibility criterion for type of outcome measure (assessed whether sedatives alter EEG recording, not success of sedation). Basis of exclusion: study design and type of outcome measure.
Treluyer 2004	Retrospective study assessing the efficacy of chloral hydrate sedation for brain CT or MRI. Not an RCT, and does not meet eligibility criterion for type of comparison (only assessed efficacy of chloral hydrate). Basis of exclusion: study design and type of intervention.
Wang 2005	RCT assessing the effect of sedation (chloral hydrate) versus sleep deprivation on brain EEG results. Does not meet eligibility criteria for type of comparison (as no other sedative agent was used) and type of outcome measure (assessed the effect of sedation on EEG results, not the success of sedation). Basis of exclusion: type of intervention and type of outcome measure.
Yuen 2017b	Retrospective study comparing melatonin versus chloral hydrate as a sedating agent in children undergoing EEG. Basis of exclusion: study design.
Zhang 2016	RCT assessing the effectiveness of intranasal dexmedetomidine as a rescue sedative agent compared to a second dose of chloral hydrate in children who had 1 dose of chloral hydrate whilst undergoing non‐invasive diagnostic procedures. Basis of exclusion: intervention.
Zhang 2020	A systematic review evaluating the efficacy and safety of intranasal dexmedetomidine as compared to other sedative agents (chloral hydrate, ketamine, or midazolam) as premedication for children undergoing CT or MRI. Not an RCT. Basis of exclusion: study design.

ASA: American Society of Anesthesiologists
CT: computed tomography
EEG: electroencephalogram
IV: intravenous
MRI: magnetic resonance imaging
RCT: randomised controlled trial

Characteristics of studies awaiting classification [ordered by study ID]

Hijazi 2014.

Methods	Prospective, double‐blind, randomised study Randomisation of the study drugs was performed by an independent pharmacist using a computer‐generated random number program and was concealed from the study investigators. Child, investigators, and healthcare providers did not know the active component of the study medication.
Participants	All paediatric patients ≤ 12 years of age who were judged to need sedation for diagnostic or therapeutic procedures in Day Care Unit, King Abdulaziz Medical City, Riyadh, Saudi Arabia
Interventions	2‐arm comparison: Chloral hydrate (75 mg/kg, maximum dose of 2 g) Prepared midazolam (0.5 mg/kg, maximum dose of 10 mg) The second dose was 30 mg/kg for the chloral hydrate group and 0.25 mg/kg for the midazolam group if failed sedation with the first dose. This study also involves non‐neurodiagnostic procedures, eye exam and others besides MRI and CT scan. However, no specific parts of body were mentioned for MRI and CT scan sessions. No separate analysis for these groups (neurodiagnostic procedure) were available.
Outcomes	Primary outcome: successful sedation Secondary outcome: adverse reaction
Notes	Wrote and emailed author on 4 November 2015 requesting the separate number of MRI and CT brain performed and the analyses.

CT: computed tomography
MRI: magnetic resonance imaging

Characteristics of ongoing studies [ordered by study ID]

ChiCTR1800014579.

Study name	Comparison of chloral hydrate, midazolam and dexmedetomidine for MRI sedation in infants: a prospective randomised controlled trial
Methods	Randomised controlled trial
Participants	Infants with ASA physical status 1 to 3, aged 0 ~ 1 years who were scheduled for MRI test under sedation
Interventions	3 groups: 50 mg/kg oral chloral hydrate 25 mg/kg oral chloral hydrate plus 2 μg/kg intranasal dexmedetomidine 0.3 mg/kg oral chloral hydrate plus 2 μg/kg intranasal dexmedetomidine
Outcomes	Sedation success rate Adverse reaction
Starting date	18 February 2018
Contact information	yjsheh@yeah.net
Notes	Wrote and emailed author on 11 June 2020 requesting the status of the trial and available trial results.

IRCT20180129038549N4.

Study name	Comparison of sedative effect of intranasal midazolam spray and chloral hydrate in children with head trauma for imaging in emergency department
Methods	Randomised, parallel‐group, double‐blind, placebo‐controlled clinical trial
Participants	Children aged 1 to 8 years with head trauma who are alert and require a CT scan
Interventions	The intervention group receives a single dose of intranasal midazolam 0.3 mg/kg and oral syrup. The control group receives oral chloral hydrate 75 mg/kg and intranasal placebo.
Outcomes	Primary outcomes: Sedation level of the patient Successful in undergoing CT scan Secondary outcomes: Side effects Vital signs (blood oxygen saturation level, pulse rate, and respiratory rate per minute) The time interval from taking the drugs to adequate sedation The interval time between drug taking and CT scan The time interval from taking the drug to child's full consciousness The parents' satisfaction
Starting date	11 April 2018
Contact information	drfarhadheydari@gmail.com
Notes	Wrote and emailed author on 11 June 2020 requesting the status of the trial and available trial results.

IRCT20180520039739N3.

Study name	Comparison between the effect of oral chloral hydrate and intranasal dexmedetomidine on pediatric sedation for EEG in Isfahan Imam Hossein Hospital
Methods	Double‐blinded RCT: simple randomisation (random number table): even numbers for chloral hydrate and odds for dexmedetomidine
Participants	60 patients between 3 months and 3 years old undergoing EEG test
Interventions	Intervention group 1: treatment with 50 mg/kg chloral hydrate 10% (Kimia teb pajohan gharb) 30 minutes before EEG Intervention group 2: treatment with 2 μg/kg dexmedetomidine (behestan daro) 30 minutes before EEG
Outcomes	Sedation status in 1 hour using Ramsay score
Starting date	21 April 2018
Contact information	Gsmhabibzadeh@yahoo.com
Notes	Wrote and emailed author on 11 June 2020 requesting the status of the trial and available trial results.

ASA: American Society of Anesthesiologists
CT: computed tomography
EEG: electroencephalogram
MRI: magnetic resonance imaging
RCT: randomised controlled trial

Differences between protocol and review

1.We amended the secondary outcome 'proportion of children who had sedation failure' to 'proportion of children who had sedation failure or inadequate level of sedation' because an included study evaluated this outcome in both ways, namely complete sedation failure as well as inadequate level of sedation, as indicated by a Ramsay score of below 4 (see Table 6).

2. As we found a study (Gumus 2015) with separate data for high and low doses of chloral hydrate in the major outcomes assessed, we incorporated on a post‐hoc basis the subgroups of high dose (100 mg/kg) and low dose (50 mg/kg) in the meta‐analysis of comparison between chloral hydrate and dexmedetomidine (Analysis 1).

Contributions of authors

All authors participated in writing the review update.

Sources of support

Internal sources

• Department of Paediatrics, Faculty of Medicine, The University of Malaya, Malaysia

• Department of Paediatrics, School of Medicine, Taylor's University, Malaysia

External sources

• National Institute for Health Research (NIHR), UK

Declarations of interest

CYF: none known.
WKL: none known.
LL: none known.
NML: none known.

New search for studies and content updated (no change to conclusions)