CD011786

Cochrane Database of Systematic Reviews
Chloral hydrate as a sedating agent for neurodiagnostic

procedures in children (Review)
Fong CY, Tay CG, Ong LC, Lai NM
Fong CY, Tay CG, Ong LC, Lai NM.

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children.
Cochrane Database of Systematic Reviews 2017, Issue 11. Art. No.: CD011786.
DOI: 10.1002/14651858.CD011786.pub2.
www.cochranelibrary.com
Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review)

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 24
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Analysis 1.1. Comparison 1 Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2 mg/kg or 3
mg/kg), Outcome 1 EEG time onset for adequate sedation (minutes). . . . . . . . . . . . . . . 78
mg/kg), Outcome 2 EEG sedation failure. . . . . . . . . . . . . . . . . . . . . . . . . 79
mg/kg), Outcome 3 EEG sedation / sleep duration (minutes). . . . . . . . . . . . . . . . . . 80
mg/kg), Outcome 4 EEG sedation adverse event: total. . . . . . . . . . . . . . . . . . . . 81
mg/kg), Outcome 5 EEG sedation adverse event: hypotension. . . . . . . . . . . . . . . . . . 82
mg/kg), Outcome 6 EEG sedation adverse event: bradycardia. . . . . . . . . . . . . . . . . . 83
mg/kg), Outcome 7 EEG sedation adverse event: behavioural change. . . . . . . . . . . . . . . 84
mg/kg), Outcome 8 EEG sedation adverse event: nausea or vomiting. . . . . . . . . . . . . . . 85
mg/kg), Outcome 9 EEG sedation adverse event: oxygen desaturation. . . . . . . . . . . . . . . 86
Analysis 2.1. Comparison 2 Chloral hydrate oral (75 mg/kg) versus pentobarbital intravenous (5 mg/kg), Outcome 1
Neuroimaging time onset for adequate sedation (minutes). . . . . . . . . . . . . . . . . . . 87
Neuroimaging sedation failure after 2 administrations of sedative agent (same or different). . . . . . . . 87
Neuroimaging sedation failure after 1 administration of sedative agent. . . . . . . . . . . . . . . 88
Neuroimaging uninterpretable. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
Neuroimaging sedation adverse event: oxygen desaturation. . . . . . . . . . . . . . . . . . . 89
Neuroimaging sedation adverse event: nausea or vomiting. . . . . . . . . . . . . . . . . . . 89
Neuroimaging sedation adverse event: paradoxical reaction. . . . . . . . . . . . . . . . . . . 90
Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) i
Neuroimaging sedation adverse event: return to baseline activity postdischarge. . . . . . . . . . . . 90
Analysis 3.1. 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). . . . . . . . . . . 91
0.5 mg/kg), Outcome 2 Neuroimaging inadequate level of sedation achieved (Ramsay score 4). . . . . . . 91
0.5 mg/kg), Outcome 3 Neuroimaging sedation failure after 1 administration of sedative agent. . . . . . 92
0.5 mg/kg), Outcome 4 Neuroimaging sedation / sleep duration (minutes). . . . . . . . . . . . . 93
0.5 mg/kg), Outcome 5 EEG sedative-induced artefact. . . . . . . . . . . . . . . . . . . . 93
0.5 mg/kg), Outcome 6 EEG sedation adverse event: total. . . . . . . . . . . . . . . . . . . 94
0.5 mg/kg), Outcome 7 Neuroimaging adverse event: behavioural change. . . . . . . . . . . . . . 94
0.5 mg/kg), Outcome 8 Neuroimaging adverse event: vomiting. . . . . . . . . . . . . . . . . 95
0.5 mg/kg), Outcome 9 Neuroimaging sedation failure with intranasal midazolam. . . . . . . . . . . 95
Analysis 3.10. 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. . . . . . . . . . . 96
Analysis 4.1. Comparison 4 Chloral hydrate oral (50 mg/kg) versus melatonin oral, Outcome 1 EEG sedative-induced
artefact. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Analysis 4.2. Comparison 4 Chloral hydrate oral (50 mg/kg) versus melatonin oral, Outcome 2 EEG sedation adverse
event: total. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
Analysis 5.1. 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). . . . . . . . . . . . . . . 98
1 mg/kg), Outcome 2 EEG sedation failure. . . . . . . . . . . . . . . . . . . . . . . . 98
1 mg/kg), Outcome 3 EEG sedation / sleep duration (minutes). . . . . . . . . . . . . . . . . 99
1 mg/kg), Outcome 4 EEG sedative-induced artefact. . . . . . . . . . . . . . . . . . . . . 99
1 mg/kg), Outcome 5 EEG sedation adverse event: behavioural change. . . . . . . . . . . . . . . 100
1 mg/kg), Outcome 6 EEG sedation adverse event: nausea or vomiting. . . . . . . . . . . . . . . 100
1 mg/kg), Outcome 7 EEG failure after 1 administration of sedative agent. . . . . . . . . . . . . . 101
Analysis 6.1. Comparison 6 Chloral hydrate oral (70 mg/kg) versus promethazine oral (1 mg/kg), Outcome 1 EEG time
for adequate sedation (minutes). . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
Analysis 6.2. 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). . . . . . . . . . . . . . . . . . 102
Analysis 6.3. Comparison 6 Chloral hydrate oral (70 mg/kg) versus promethazine oral (1 mg/kg), Outcome 3 EEG sedation
failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
adverse event: behavioural change. . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
adverse event: vomiting or nausea. . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
Analysis 6.6. 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. . . . . . . . . . . . . . . . . . . . 104
Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) ii

Analysis 7.1. Comparison 7 Chloral hydrate oral (60 mg/kg) versus music therapy, Outcome 1 EEG time onset for adequate
sedation (minutes). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104
Analysis 7.2. Comparison 7 Chloral hydrate oral (60 mg/kg) versus music therapy, Outcome 2 EEG sedation failure. 105
Analysis 7.3. Comparison 7 Chloral hydrate oral (60 mg/kg) versus music therapy, Outcome 3 EEG sedation / sleep
duration (minutes). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105
Analysis 8.1. Comparison 8 Chloral hydrate oral (50 mg/kg) versus midazolam rectal (1 mg/kg), Outcome 1 EEG time
onset for adequate sedation (minutes). . . . . . . . . . . . . . . . . . . . . . . . . . 106
Analysis 8.2. Comparison 8 Chloral hydrate oral (50 mg/kg) versus midazolam rectal (1 mg/kg), Outcome 2 EEG sedation/
sleep duration (minutes). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
Analysis 8.3. Comparison 8 Chloral hydrate oral (50 mg/kg) versus midazolam rectal (1 mg/kg), Outcome 3 EEG sedative-
induced artefact. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
Analysis 9.1. Comparison 9 High-dose chloral hydrate (100 mg/kg) versus low-dose chloral hydrate (70 mg/kg), Outcome
1 Neuroimaging time onset for adequate sedation (minutes). . . . . . . . . . . . . . . . . . 107
2 Neuroimaging sedation failure after 1 administration of sedative agent. . . . . . . . . . . . . . 108
3 Neuroimaging sedation / sleep duration (minutes). . . . . . . . . . . . . . . . . . . . . 108
4 Neuroimaging sedation adverse event: total. . . . . . . . . . . . . . . . . . . . . . . . 109
Analysis 10.1. Comparison 10 High-dose chloral hydrate (100 mg/kg) versus low-dose chloral hydrate (50 mg/kg),
Outcome 1 EEG time onset for adequate sedation (minutes). . . . . . . . . . . . . . . . . . 110
Outcome 2 EEG sedation failure. . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
Outcome 3 EEG sedation/sleep duration (minutes). . . . . . . . . . . . . . . . . . . . . 111
Outcome 4 EEG sedation adverse event: total. . . . . . . . . . . . . . . . . . . . . . . 112
Outcome 5 EEG sedation adverse event: behavioural change. . . . . . . . . . . . . . . . . . 112
Outcome 6 EEG sedation adverse event: nausea or vomiting. . . . . . . . . . . . . . . . . . 113
Outcome 7 EEG sedation adverse event: oxygen desaturation. . . . . . . . . . . . . . . . . . 114
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . . 124
Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) iii
[Intervention Review]
Chloral hydrate as a sedating agent for neurodiagnostic

procedures in children
Choong Yi Fong1 , Chee Geap Tay1 , Lai Choo Ong1 , Nai Ming Lai2
1 Division of Paediatric Neurology, Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
2 School of Medicine, Taylor’s University, Subang Jaya, Malaysia
Contact address: Choong Yi Fong, Division of Paediatric Neurology, Department of Paediatrics, Faculty of Medicine, University of
Malaya, Kuala Lumpur, 50603, Malaysia. cyfong@ummc.edu.my, choongyi@hotmail.com.
Editorial group: Cochrane Epilepsy Group.

Publication status and date: New, published in Issue 11, 2017.
Citation: Fong CY, Tay CG, Ong LC, Lai NM. Chloral hydrate as a sedating agent for neurodiagnostic procedures in children.
Cochrane Database of Systematic Reviews 2017, Issue 11. Art. No.: CD011786. DOI: 10.1002/14651858.CD011786.pub2.
ABSTRACT
Background
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 used the standard search strategy of the Cochrane Epilepsy Group. We searched MEDLINE (OVID SP) (1950 to July 2017), the
Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, Issue 7, 2017), Embase (1980 to July 2017), and
the Cochrane Epilepsy Group Specialized Register (via CENTRAL) using a combination of keywords and MeSH headings.
Selection criteria
We included randomised controlled trials that assessed chloral hydrate agent against other sedative agent(s), non-drug agent(s), or
placebo for children undergoing non-invasive neurodiagnostic procedures.
Data collection and analysis
Two review authors independently assessed the studies for their eligibility, extracted data, and assessed risk of bias. Results were expressed
in terms of risk ratio (RR) for dichotomous data, mean difference (MD) for continuous data, with 95% confidence intervals (CIs).
Main results
We included 13 studies with a total of 2390 children. The studies were all conducted in hospitals that provided neurodiagnostic services.
Most studies assessed the proportion of sedation failure during the neurodiagnostic procedure, time for adequate sedation, and potential
adverse effects associated with the sedative agent.
The methodological quality of the included studies was mixed, as reflected by a wide variation in their ’Risk of bias’ profiles. Blinding
of the participants and personnel was not achieved in most of the included studies, and three of the 13 studies had high risk of bias
Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 1
for selective reporting. Evaluation of the efficacy of the sedative agents was also underpowered, with all the comparisons performed in
single small studies.
Children who received oral chloral hydrate had lower sedation failure when compared with oral promethazine (RR 0.11, 95% CI 0.01
to 0.82; 1 study, moderate-quality evidence). Children who received oral chloral hydrate had a higher risk of sedation failure after one
dose compared to those who received intravenous pentobarbital (RR 4.33, 95% CI 1.35 to 13.89; 1 study, low-quality evidence), but
after two doses there was no evidence of a significant difference between the two groups (RR 3.00, 95% CI 0.33 to 27.46; 1 study, very
low-quality evidence). Children who received oral chloral hydrate appeared to have more sedation failure when compared with music
therapy, but the quality of evidence was very low for this outcome (RR 17.00, 95% CI 2.37 to 122.14; 1 study). Sedation failure rates
were similar between oral chloral hydrate, oral dexmedetomidine, oral hydroxyzine hydrochloride, and oral midazolam.
Children who received oral chloral hydrate had a shorter time to achieve adequate sedation when compared with those who received
oral dexmedetomidine (MD -3.86, 95% CI -5.12 to -2.6; 1 study, moderate-quality evidence), oral hydroxyzine hydrochloride (MD
-7.5, 95% CI -7.85 to -7.15; 1 study, moderate-quality evidence), oral promethazine (MD -12.11, 95% CI -18.48 to -5.74; 1 study,
moderate-quality evidence), and rectal midazolam (MD -95.70, 95% CI -114.51 to -76.89; 1 study). 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-quality evidence) and intranasal midazolam (MD 12.83, 95% CI 7.22 to 18.44; 1 study, moderate-quality
evidence).
No data were available to assess the proportion of children with successful completion of neurodiagnostic procedure without interruption
by the child awakening. Most trials did not assess adequate sedation as measured by specific validated scales, except in the comparison
of chloral hydrate versus intranasal midazolam and oral promethazine.
Compared to dexmedetomidine, chloral hydrate was associated with a higher risk of nausea and vomiting (RR 12.04 95% CI 1.58 to
91.96). No other adverse events were significantly associated with chloral hydrate (including behavioural change, oxygen desaturation)
although there was an increased risk of adverse events overall (RR 7.66, 95% CI 1.78 to 32.91; 1 study, low-quality evidence).
Authors’ conclusions
The quality of evidence for the comparisons of oral chloral hydrate against several other methods of sedation was very variable. Oral
chloral hydrate appears to have a lower sedation failure rate when compared with oral promethazine for children undergoing paediatric
neurodiagnostic procedures. The sedation failure was similar for other comparisons such as oral dexmedetomidine, oral hydroxyzine
hydrochloride, and oral midazolam. When compared with intravenous pentobarbital and music therapy, oral chloral hydrate had a
higher sedation failure rate. However, it must be noted that the evidence for the outcomes for the comparisons of oral chloral hydrate
against intravenous pentobarbital and music therapy was of very low to low quality, therefore the corresponding 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 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 the risk of major
adverse effects such as bradycardia, hypotension, and 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 oral chloral hydrate more effective at producing adequate sedation
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
We performed a search in multiple medical databases in July 2017.
Study characteristics
Thirteen studies involving a total of 2390 children fit our inclusion criteria. These studies were all performed in hospitals that provided
neurodiagnostic services. Most of the studies assessed three main outcome measures: i) proportion of children who were unsuccessfully
sedated for the neurodiagnostic procedure, ii) length of time taken for adequate sedation, and iii) side effects associated with the sedative
agent. The quality of the included studies was mixed, ranging from very low to high. The quality of the studies was affected mainly
because those closely involved in the trials, such as the doctors giving the sedation or the parents of the child, were not masked from
knowing which sedative agent was given to 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 medications.
We included 13 studies with a total of 2390 children (age up to 18 years old). The studies were all conducted in hospitals that performed
neurodiagnostic procedures. 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, and oral midazolam; and probably a more effective
sedative agent with lower sedation failure rate when compared with oral promethazine. While most of the included studies showed that
chloral hydrate was safe with no increased side effects when compared to other sedative agents, one study reported an increased risk of
adverse effects when compared with oral dexmedetomidine.
Quality of the evidence
The quality of most of the evidence was poor due to methodological flaws in the included studies and the small sample size of each
study. Consequently our confidence in the results of the studies is reduced.The major factor affecting the quality of the evidence was
lack of precision in the result estimates, as the calculated plausible range of the effects were wide.
Conclusions
Apart from intravenous pentobarbital and music therapy, oral chloral hydrate is either just as effective or more effective a sedative agent
when compared to other sedative agents for children undergoing non-invasive neurodiagnostic procedures. In view of the poor quality
of the evidence, we could draw no clear conclusions on the effectiveness or safety of any paediatric sedative agent. The side effects
profile of oral chloral hydrate when compared to other sedatives requires further study.

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Chloral hydrate orally (50 mg/ kg or 100 mg/ kg) compared to dexmedetomidine orally (2 mg/ kg or 3 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 m g/ kg or 100 m g/ kg)
Comparison: dexm edetom idine oral (2 m g/ kg or 3 m g/ kg)
Outcomes Anticipated absolute effects* (95% CI) Relative effect of participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Risk with dexmedeto- Risk with chloral hy-

midine drate
Proportion of children - - - - - No study f or this com -

who successf ully com - parison assessed this
pleted neurodiagnostic outcom e.
procedure without in-
terruption by the child
awakening

who required a f urther parison assessed this
dose of either the sam e outcom e.
sedative agent or the
addition of a dif f erent
sedative agent
Tim e to adequate se- The m ean EEG tim e on- The m ean EEG tim e on- - 160 ⊕⊕⊕
dation (m inutes or as set f or adequate seda- set f or adequate seda- (1 RCT) M ODERATE 1
m easured by specif ic tion (m inutes) was 35. tion (m inutes) in the
validated scales such 2 intervention group was
as the Ram say Sedation 3.86 m inutes shorter
Score) (5.12 shorter to 2.6
shorter)
4
Proportion of children Study population RR 1.14 160 ⊕⊕⊕

who had sedation f ail- (0.51 to 2.53) (1 RCT) M ODERATE 2
ure or inadequate level 119 per 1000 136 per 1000
of sedation (61 to 301)
Sedation duration (m in- The m ean duration The m ean EEG seda- - 160 ⊕⊕⊕
utes) of sedation/ sleep was tion/ sleep duration in (1 RCT) M ODERATE 4
112.1 m inutes 3 the intervention group
was 16.31 m inutes
longer (9.15 to 23.46
m inutes longer)
Num ber of children with Study population RR 7.66 160 ⊕⊕

clinical adverse events (1.78 to 32.91) (1 RCT) LOW 5
(any) 24 per 1000 182 per 1000
(42 to 784)
* The risk in the intervention group (and its 95% conf idence interval) is based on the assum ed risk in the com parison group and the relative effect of the intervention (and its
95% CI).
CI: conf idence interval; EEG: electroencephalogram ; RCT: random ised controlled trial; RR: risk ratio
GRADE Working Group grades of evidence

High quality: We are very conf ident that the true ef f ect lies close to that of the estim ate of the ef f ect.
M oderate quality: We are m oderately conf ident in the ef f ect estim ate: the true ef f ect is likely to be close to the estim ate of the ef f ect, but there is a possibility that it is
substantially dif f erent.
Low quality: Our conf idence in the ef f ect estim ate is lim ited: the true ef f ect m ay be substantially dif f erent f rom the estim ate of the ef f ect.
Very low quality: We have very little conf idence in the ef f ect estim ate: the true ef f ect is likely to be substantially dif f erent f rom the estim ate of ef f ect
1
The 95% CI f or this estim ate ranges f rom 2.6 to 5.1 m inutes of dif f erence, which in term s of length of sedation is wide.
Quality of evidence downgraded one level due to risk of bias.
2 The 95% CI f or this estim ate ranges f rom substantial benef its f avouring chloral hydrate to substantial benef its f avouring
dexm edetom idine. Quality of evidence downgraded one level due to im precision.
3 The m ean was derived by averaging the m ean values of the two subgroups of children receiving two dif f erent doses of oral
dexm edetom idine (2 m g/ kg and 3 m g/ kg), each of which consisted of 40 children.

4
The 95% CI f or this estim ate ranges f rom about 9 m ore m inutes to 23 m ore m inutes of sleep duration, which is too wide in
the context of sedation f or neurodiagnostic procedures. Quality of evidence downgraded one level due to im precision.
5
5 The 95% CI f or this estim ate is very wide. Quality of evidence downgraded two levels due to im precision.
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6
BACKGROUND (Battaglia 2003; Rodriguez 2007). Current guidelines advocate
that neuroimaging investigations should be considered in those
children with an abnormal antenatal or perinatal history, an ab-
Description of the condition normal neurological examination, a history of focal epilepsy, and
in all epilepsies in children under two years of age (Battaglia 2003;
Paediatric neurodevelopmental disorders are collectively a com-
NICE 2012; Rodriguez 2007).
mon 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 impor-
tant to establish the aetiology of the disorder, predict the progno- Description of the intervention
sis, and develop management strategies (Horridge 2011; Shevell
Sedation is defined as a drug-induced depression of consciousness,
2003; Shevell 2008; Silove 2013).
which is a continuum from wakefulness to anaesthesia (Starkey
Paediatric neurodiagnostic (non-interventional) investigations
2011). It assists in reducing anxiety, providing pain control, and
used in the assessment of children with possible neurodevelopmen-
minimising movement of the patient when undergoing a proce-
tal disorders include brain neuroimaging and electroencephalogra-
dure. There are different levels of sedation, as defined by the Amer-
phy (EEG). Successful completion of neurodiagnostic procedures
ican Society of Anesthesiologists. These include minimal sedation,
is challenging in the paediatric age group, as the child is required to
moderation sedation, and deep sedation (ASA 2007). Moderate
be immobile during the procedure. In addition, routine paediatric
sedation involves the technique of administering sedatives to in-
EEG recording requires recording of a period of sleep. Sleep state
duce a state of depressed level of consciousness while allowing
EEG recording is important as it increases the yield in detecting
the patient to maintain independent control of their airway and
interictal epileptiform abnormalities. Achieving spontaneous sleep
oxygenation by preserving their protective airway reflexes (NICE
is not possible in some children despite behavioural intervention
2010). Current guidelines recommend that moderate sedation is
(prior sleep deprivation). The use of an appropriate sedative agent
preferred over deep sedation and general anaesthesia for painless
in children who are unable to be immobile or do not naturally
paediatric procedures (NICE 2010).
sleep (for EEG recording), or both, thus plays a pivotal role in
The ideal sedative agent to achieve moderate sedation should have
ensuring successful completion of the procedure.
rapid onset, a moderate duration of action, minimal or no adverse
Selection of the most appropriate pharmacological and non-phar-
effects, and low cost. At present there is no ideal or first-line seda-
macological agents is an important factor for the success and sa-
tive agent. The agents currently available for painless procedures
fety of the neurodiagnostic procedure. Moreover, there are other
include the following.
pharmacological considerations when choosing a sedative agent
• Chloral hydrate, a non-opiate and non-benzodiazepine
for paediatric EEG because some sedative agents can suppress ab-
sedative hypnotic drug.
normal EEG activity or background activity (e.g. anaesthesia), and
• Benzodiazepines, which act via the γ -aminobutyric acid A
others can induce background activity changes that may obscure
receptors.
abnormalities (e.g. benzodiazepines and barbiturates).
• Hydroxyzine, a long-acting first-generation H1 antagonist
Children with neurodevelopmental disorders can present with a
with central nervous system depressant activity and minimal
variety of symptoms including epilepsy, developmental impair-
circulatory and depressant activity.
ment, developmental regression, social communication deficits,
• Melatonin, a pineal hormone and natural sleep agent that
and behavioural difficulties. These children will require a struc-
can modulate the circadian rhythm of sleep through action on
tured clinical evaluation with targeted investigations to enable an
the suprachiasmatic nucleus in the hypothalamus.
accurate diagnosis, provide appropriate intervention, and assist in
• Promethazine, an antiemetic and antisialagogue with
predicting long-term prognosis.
sedative properties.
Neurodiagnostic investigations include EEG and brain neu-
• Dexmedetomidine, a selective alpha2 -adrenoceptor agonist
roimaging. The duration of a standard awake and sleep paediatric
with sedative properties.
EEG recording is approximately 30 to 60 minutes; a routine pae-
diatric brain magnetic resonance imaging (MRI) scan takes ap-
proximately 45 to 60 minutes. Routine EEG is an important in- In addition, non-pharmacological approaches such as music ther-
vestigation tool in evaluating children with a clinical history that apy have been shown to be beneficial in providing sedation during
suggests epilepsy (NICE 2012). The EEG will assist in defining procedures in adult patients (Bechtold 2009), while there is some
the specific epilepsy syndrome (Pillai 2006). Neuroimaging in- evidence that breastfeeding or breast milk helps infants tolerate
vestigations (particularly brain MRI) are useful in detecting ma- painful or uncomfortable procedures better by reducing crying
jor or minor structural brain abnormalities that may assist in es- and improving infants’ physiological responses during the proce-
tablishing the cause of the child’s neurodevelopmental disorder dures (Shah 2012).

How the intervention might work OBJECTIVES
Chloral hydrate is a central nervous system depressant and is one To assess the effectiveness and adverse effects of chloral hydrate
of the oldest sedatives (discovered in 1832). It is well absorbed as a sedative agent for non-invasive neurodiagnostic procedures in
orally as well as rectally and rapidly metabolised into the active children.
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 proce- METHODS
dures 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
Criteria for considering studies for this review
mg/kg in neonates and children younger than 12 years old, with a
maximum dose of 2g (Starkey 2011). Chloral hydrate is absorbed
from the gastrointestinal tract and starts to exert its effect within
Types of studies
60 minutes. Adverse reactions occur in 1.7% to 20% of children,
with gastrointestinal side effects, particularly vomiting, being the We included randomised or quasi-randomised trials.
most common (Starkey 2011). There have also been some con-
cerns with regard to respiratory depression, long duration of ac- Types of participants
tion, and potential carcinogenicity (Haselkorn 2006; Kao 1999). 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
Why it is important to do this review Oral or rectal chloral hydrate.
Neurodiagnostic procedures (particularly neuroimaging) in chil- Comparison: other sedative/sleep-inducing agents (e.g. promet-
dren are important investigative tools and have been increasingly hazine, hydroxyzine, melatonin, midazolam, pentobarbital, eto-
used over the last decade to assess and manage children with neu- midate, sevoflurane) or complementary therapies (e.g. music ther-
rodevelopmental disorders. However, a significant proportion of apy), or achieved sleep without a sedative agent, for instance after
children may be unable to complete the procedure due to sedation a milk feed.
failure. Sedation failure is a great inconvenience to the child and
their family and requires rescheduling of another hospital admis- Types of outcome measures
sion to complete the procedure, often under general anaesthesia
(which carries additional associated risks).
Both the National Institute for Health and Care Excellence Primary outcomes
(NICE) 2010 guideline and the American College of Emergency 1. Proportion of children who successfully completed
Physicians 2008 guideline recommend chloral hydrate for mod- neurodiagnostic procedure without interruption by the child
erate sedation during painless procedures in the paediatric pop- awakening.
ulation (Mace 2008; NICE 2010). However, neither guideline 2. Proportion of children who required a further dose of either
has suggested the superiority of chloral hydrate over other agents. the same sedative agent or the addition of a different sedative
Some studies have shown that chloral hydrate is unsuccessful in a agent.
significant proportion of children, resulting in failure to complete 3. Time to adequate sedation (minutes or as measured by
the procedure (Beebe 2000; Malviya 1997). There have been a specific validated scales such as the Ramsay Sedation Score).
few randomised controlled trials (RCTs) comparing the efficacy
of chloral hydrate with other sedative agents and complementary
therapy (e.g. music therapy). However, to date no meta-analysis Secondary outcomes
of the previously published RCTs has been performed in order to 1. Proportion of children who had sedation failure or
determine superiority among these agents. inadequate level of sedation.
The aim of this review was to allow clinicians to take an evidence- 2. Sedation duration
based approach in deciding which sedating agent is best for chil- 3. Sleep onset latency (time interval for child to fall asleep)
dren undergoing neurodiagnostic procedures. The care of children pre-procedure.
would improve if both sedation failure rates and adverse effects 4. Yield of EEG findings (expressed either as the rate of
due to sedation were kept to a minimum. abnormal EEG findings or additional EEG artefact findings

attributable to the sedative agent, which may prevent We collected information on study design and setting, participant
interpretation of the EEG) or yield of neuroimaging findings characteristics (including age and the presence of additional co-
(expressed as the rate of non-interpretable MRI attributable to morbidities such as cerebral palsy), study eligibility criteria, details
motion artefact due to inadequate sedation). of the intervention(s) given, and the outcomes assessed. We also
5. Number of children with clinical adverse effects and severe collected study funding source and any conflicts of interest stated
drug side effects (e.g. hypotension, hypoxia, apnoea, by the investigators.
laryngospasm, significant vomiting, refractory agitation, We accepted published and unpublished studies, both in full article
bradycardia). and abstract form, as long as adequate extraction of outcome data
was possible. We contacted the authors of unpublished studies and
studies available only as abstracts to request further information
Search methods for identification of studies about the studies, including specific details of the methodologies
employed as well as the full outcome data, so as to include them
in our meta-analysis. We only included final data from each study
Electronic searches and not data from interim analyses.
We searched the following databases:
• Cochrane Epilepsy Group Specialized Register (via
Cochrane Central Register of Controlled Trials, searched on 19 Data extraction and management
July 2017) Two review authors (CYF, CGT) independently extracted relevant
• Cochrane Central Register of Controlled Trials data from each included study using a data collection form adapted
(CENTRAL) (Issue 7, 2017); for this review. We gathered the following information from each
• MEDLINE (PubMed (National Library of Medicine)) study.
(1950 to 19 July 2017); • Study design (RCT, quasi-RCT, or cluster-RCT, and the
• Embase (1980 to 19 July 2017). number of arms evaluated)
We outlined detailed search strategies for the above databases in • ’Risk of bias’ items, including the methods used and our
Appendix 1, Appendix 2, and Appendix 3. ’Risk of bias’ judgement (low risk, unclear risk, or high risk)
We also searched for ongoing clinical trials and unpublished stud- ◦ Random sequence generation
ies via the following sites: ◦ Allocation concealment
• ClinicalTrials.gov (www.clinicaltrials.gov); ◦ Blinding of participants, care personnel, and evaluators
• World Health Organization (WHO) International Clinical ◦ Missing data (loss to follow-up)
Trials Registry Platform (ICTRP) (www.who.int/ictrp/en/). ◦ Risk of selective outcome reporting
◦ Other possible sources of bias
We did not apply any language restrictions in our searches. • Stratification factors
• Participant factors
Searching other resources ◦ Number (total per group)
◦ Setting
We searched references cited in relevant studies, Cochrane Re- ◦ Diagnostic criteria
views, guidelines, review articles, and conference proceedings, in- ◦ Country
cluding abstracts from the Society for Pediatric Anesthesia and ◦ Age
the European Society for Paediatric Anaesthesiology. We also con- ◦ Sex
tacted experts in the field if necessary to identify further relevant ◦ Underlying diagnoses
studies. ◦ Indications for neurodiagnostic procedure: whether
for diagnostic or monitoring purposes
• Intervention data: route of administration, dosage, and
Data collection and analysis duration of chloral hydrate and comparator medication, and
whether chloral hydrate was administered alone or in
combination with another medication
Selection of studies • Follow-up data
Two review authors (CYF, CGT) independently performed the ◦ Duration of follow-up period
first round of searching for relevant studies. They then screened ◦ Numbers lost to follow-up
the identified studies for inclusion in the analysis with the help ◦ Reasons for loss to follow-up
of an arbiter (LCO), using the predefined inclusion and exclusion • Outcome data, grouped into dichotomous and continuous
criteria. outcomes, including adverse events

For details of each outcome included in our review (names, defi- an inappropriately small SE or a narrow 95% CI, we would have
nitions, and possible unit of measurement), please refer to Types asked the authors of the study to provide information on the unit
of outcome measures. of analysis.
We screened for multiple enrolment by matching the initial num- If no adjustment was made for the effects of clustering, we would
ber of participants recruited against the total numbers at each step have performed adjustment by multiplying the SEs of the final
in the study. We contacted the authors of the study for additional effect estimates by the square root of the ’design effect’, represented
information if we were unclear as to important aspects of the trial. by the formula ’1 + (M - 1) x ICC’, where M is the average cluster
Any disagreements were resolved by discussion, leading to a con- size (number of children per cluster) and ICC is the intracluster
sensus, or by involving an arbiter (LCO) if necessary. correlation. We would determine the average cluster size (M) from
each trial by dividing the total number of children by the total
number of clusters. We would use a relatively large assumed ICC
Assessment of risk of bias in included studies
of 0.10, as we considered this to be a realistic estimate based on
Two authors (CGT, NML) independently assessed risk of bias for previous studies about implementation research (Campbell 2001).
each of the included studies and cross-checked the results of these We would combine the adjusted final effect estimates from each
assessments. A third review author (CYF) discussed and resolved trial with their SEs in meta-analysis using generic inverse-variance
any inconsistencies. methods, as stated in the Cochrane Handbook for Systematic Reviews
In accordance with Cochrane’s tool for assessing risk of bias in of Interventions (Higgins 2011).
RCTs (Higgins 2011), we assessed the following ’Risk of bias’ If determination of the unit of analysis was not possible, we would
domains: have included the studies concerned in a meta-analysis using what-
• sequence generation; ever effect estimates were provided by the authors. We would then
• allocation concealment; perform a sensitivity analysis to assess how the overall results were
• blinding; affected by the inclusion of these studies.
• incomplete data/attrition bias; For multiple-arm studies, we would adjust the data by following
• selective outcome reporting; the methods stated in Chapter 16 of the Cochrane Handbook for
• other. Systematic Reviews of Interventions (Higgins 2011). Specifically, if
only two arms were relevant, we would only include the relevant
arms. If there were more than two relevant arms (e.g. chloral hy-
Measures of treatment effect
drate of two different dosages versus placebo), we would set up
We reported the outcome estimates for categorical data using risk separate pair-wise comparisons, for example higher-dose chloral
ratios (RRs), risk differences (RDs), and the number needed to hydrate versus placebo (Comparison 1) and lower-dose chloral hy-
treat for an additional beneficial outcome (NNTB) or the num- drate versus placebo (Comparison 2). In such cases, we would not
ber needed to treat for an additional harmful outcome (NNTH). total the number of children in the placebo group to avoid double-
For continuous data, which included time to adequate sedation counting.
and duration of sedation, we used mean differences (MDs) with
their respective 95% confidence intervals (CIs). If pooled analyses
were not possible for reasons such as major discrepancies in study Dealing with missing data
characteristics or outcome reporting as detailed under Assessment We determined the dropout rates from each study. We also assessed
of heterogeneity, we reported the results of the studies narratively. 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
Unit of analysis issues absolute dropout rate of 20% or higher as important. We also
No cluster-RCTs were included in this review. Had we included adopted a ’worst-case scenario’ approach in judging the dropout
cluster-RCTs, we would have adopted the following strategy when rate: if we found that the direction of the effect estimate changed
dealing with such studies. with the worst-case scenario approach, we considered the dropout
For cluster-RCTs (e.g. trials in which the assignment to the in- rate as significant.
tervention or control group was made at the level of the unit or If we found a significant dropout rate with no reasonable expla-
hospital ward), we would have assessed whether adjustment had nation, we classified the study as having a high risk of attrition
been made for the effects of clustering in order to account for non- bias for the domain incomplete outcome data. If we considered
independence among the participants in a cluster via the use of the missing data to be critical to the final estimates in our meta-
an appropriate analysis model, such as the generalised estimating analysis, we contacted the authors of the individual studies to re-
equation (GEE) model. If the unit of analysis was not stated in quest further data.
the study, we would have inspected the width of the standard error We planned to perform sensitivity analyses to assess how the overall
(SE) or 95% CI of the estimated treatment effects. Had we found results were affected by the inclusion of studies with a high risk of

attrition bias from incomplete outcome data. Quality of evidence
We used the GRADE approach, as outlined in the GRADE Hand-
book (Schünemann 2013), to assess the quality of evidence for the
Assessment of heterogeneity most important outcomes across all comparisons, as listed below,
We assessed clinical heterogeneity by comparing the distribution whether or not there were data for the outcome.
of important participant factors between trials (age, gender, seizure
type, duration of epilepsy) and trial factors (clinical setting of the
Prespecified primary outcomes
studies, the use of co-interventions, ’Risk of bias’ items including
random sequence generation, allocation concealment, blinding, 1. Proportion of children who successfully completed
and losses to follow-up). neurodiagnostic procedure without interruption by the child
For statistical heterogeneity, we first visually inspected the forest awakening.
plots to see if there was any gross inconsistency in the trial results. 2. Proportion of children who required a further dose of either
We used the I2 statistic to quantify the extent and importance of the same sedative agent or the addition of a different sedative
inconsistency in the results (Higgins 2011). We used the following agent.
cutoffs for the reporting of heterogeneity. 3. Time to adequate sedation (minutes or as measured by
• 0% to 40%: heterogeneity might not be important specific validated scales such as the Ramsay Sedation Score).
• 30% to 60%: may represent moderate heterogeneity
• 50% to 90%: may represent substantial heterogeneity Prespecified secondary outcomes
• 75% to 100%: considerable heterogeneity
1. Proportion of children who had sedation failure or
If we found moderate, substantial, or considerable heterogeneity, inadequate level of sedation.
we re-examined the clinical and methodological characteristics of 2. Sedation duration (minutes).
the studies, using the criteria listed above, to determine whether 3. Yield of EEG findings, including non-interpretable EEG or
the degree of heterogeneity could be explained by differences in sedative-induced artefact.
those characteristics, and whether a pooled analysis would be ap- 4. Number of children with clinical adverse events (any).
propriate. If we considered a pooled analysis appropriate, we then Two review authors independently assessed the quality of the ev-
performed this analysis using a random-effects model. idence for each of the outcomes listed above. We considered ev-
idence from RCTs as high quality, but downgraded the evidence
one level for serious (or two levels for very serious) limitations
Assessment of reporting biases based upon the following: design (risk of bias), consistency across
studies, directness of the evidence, precision of estimates, and pres-
Had there been more than 10 studies available for an outcome
ence of publication bias (Guyatt 2008; Schünemann 2013). We
to enable a meaningful assessment, we would have used a funnel
used the GRADEpro GDT platform (Gradepro GDT 2015) to
plot to screen for publication bias. If we detected significant asym-
create ‘Summary of findings’ tables to report the quality of the
metry in the funnel plot, which is suggestive of the possibility of
evidence.
publication bias, we would have further assessed it using Begg’s
The GRADE approach results in an assessment of the quality of
rank correlation and Egger’s test and would have included a state-
a body of evidence in one of four grades:
ment in the Results with a corresponding note of caution in the
• High: we are very confident that the true effect lies close to
Discussion.
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
Data synthesis
effect, but there is a possibility that it is substantially different.
We performed meta-analyses using Review Manager 5 software • Low: our confidence in the effect estimate is limited: the
with a fixed-effect model (RevMan 5.3), unless there was moderate true effect may be substantially different from the estimate of the
or high heterogeneity, in which case we used the random-effects effect.
model alongside an exploration of possible causes of heterogene- • Very low: we have very little confidence in the effect
ity, as described in the Assessment of heterogeneity section. Our estimate: the true effect is likely to be substantially different from
primary data analyses followed the intention-to-treat principle; the estimate of the effect.
namely, we used the original number of participants allocated to
each study arm as the denominator in subsequent analyses. We ex-
pressed our results as RRs, RDs, NNTB, NNTH, and MDs with Subgroup analysis and investigation of heterogeneity
their respective 95% CIs, as detailed in the Measures of treatment We planned to conduct the following subgroup analyses if relevant
effect section. data were available.

1. Different neurodiagnostic procedures (e.g. brain MRI Results of the search
versus brain computed tomography (CT) versus EEG).
2. Age group of children (e.g. neonates versus older children).
Sensitivity analysis We identified 279 records from our search of CENTRAL, MED-
We planned to perform sensitivity analyses for the primary out- LINE and Embase. We identified a further 17 records that ap-
comes and any secondary outcomes for which sufficient numbers peared to be relevant from our search of ClinicalTrials.gov and the
of studies were available by evaluating the change in the effect es- WHO ICTRP. After removing duplicates, 218 records remained,
timates following the exclusion of studies with a high risk of: of which 60 articles appeared to be relevant after we inspected the
1. selection bias (high risk for random sequence generation or titles. We evaluated the abstracts or full text of the articles, or both,
allocation concealment, or both); and excluded 45 of the 60 articles. Of the remaining 15 articles,
2. attrition bias (high risk for incomplete outcome data). we excluded one, as it was a duplicate publication of an included
study, and another article for which we have requested additional
information from the authors is awaiting further assessment of its
eligibility. We included a total of 13 articles in the review. The flow
RESULTS diagram of the studies from the initial search to the meta-analysis
is shown in Figure 1. Descriptions of all the included studies are
provided in the Characteristics of included studies table, and the
Description of studies excluded studies with the reasons for exclusion are given in the
Characteristics of excluded studies table.

Figure 1. Study flow diagram.

ies compared sedation of high-dose (100 mg/kg) chloral hydrate
Included studies
versus low-dose (50 mg/kg or 70 mg/kg) chloral hydrate orally
We included 13 RCTs that were conducted in six countries, in- (Gumus 2015; Marti-Bonmati 1995). No dose of melatonin was
cluding Iran (4 studies), Turkey (3 studies), USA (3 studies), and stated (Ashrafi 2010), and dosing/intensity was not stated for mu-
Israel, Chile, and Spain (1 study each). All 13 trials were single- sic therapy (Loewy 2005).
centre RCTs. The number of children recruited ranged from 40, In general, the included studies assessed outcomes of success of
in D’Agostino 2000, to 582, in Thompson 1982. All studies were sedation based on the following.
conducted on paediatric patients (age up to 18 years old). All stud- • Time to onset to adequate sedation in minutes in eight
ies included children of both sexes. studies (Fallah 2013; Gumus 2015; Loewy 2005; Lopez 1995;
Five of these trials were sedation trials conducted on neuroimaging Malviya 2004; Marti-Bonmati 1995; Razieh 2013; Sezer 2013).
studies (2 studies on brain CT, 2 studies on brain MRI, 1 study on • Failure of sedation preventing successful completion of
brain MRI or CT) (D’Agostino 2000; Fallah 2013; Malviya 2004; neurodiagnostic investigation in eight studies (D’Agostino 2000;
Marti-Bonmati 1995; Thompson 1982); the remaining eight were Fallah 2013; Gumus 2015; Loewy 2005; Malviya 2004;
sedation trials conducted on EEG studies (Ashrafi 2010; Ashrafi Marti-Bonmati 1995; Razieh 2013; Sezer 2013).
2013; Bektas 2014; Gumus 2015; Loewy 2005; Lopez 1995; • Total sedation/sleep duration in six studies (D’Agostino
Razieh 2013; Sezer 2013). 2000; Gumus 2015; Loewy 2005; Lopez 1995; Marti-Bonmati
There were 10 comparisons: 1995; Sezer 2013).
• oral chloral hydrate (50 mg/kg or 100 mg/kg) versus oral • Sedative adverse events in nine studies (Ashrafi 2010;
dexmedetomidine (Gumus 2015); Ashrafi 2013; D’Agostino 2000; Fallah 2013; Gumus 2015;
• oral chloral hydrate (75 mg/kg) versus intravenous Malviya 2004; Marti-Bonmati 1995; Razieh 2013; Sezer 2013).
pentobarbital (Malviya 2004); • Uninterpretable neurodiagnostic investigation due to either
• oral chloral hydrate (75 mg/kg or 100 mg/kg) versus excessive motion artefact for neuroimaging studies or excessive
midazolam (given either orally or intranasally) (Ashrafi 2013; fast background activity on EEG studies in five studies (Ashrafi
D’Agostino 2000; Fallah 2013); 2010; Ashrafi 2013; Lopez 1995; Malviya 2004; Sezer 2013).
• oral chloral hydrate (50 mg/kg) versus oral melatonin
Other outcomes assessed included caregiver’s satisfaction scale
(Ashrafi 2010);
(Razieh 2013), hospital stay post-sedation (Razieh 2013), and re-
• oral chloral hydrate (60 mg/kg) versus music therapy
turn to normal baseline activity (Malviya 2004).
(Loewy 2005);
• oral chloral hydrate (50 mg/kg) versus oral hydroxyzine
hydrochloride (Sezer 2013); Excluded studies
• oral chloral hydrate (70 mg/kg) versus oral promethazine We excluded a total of 45 studies based on one or more of the
(Razieh 2013); following.
• rectal chloral hydrate (50 mg/kg) versus rectal midazolam • Study design or article type (33 studies): the studies were
(Lopez 1995); either retrospective or prospective cohort studies, cross-over
• high-dose oral chloral hydrate (100 mg/kg) versus low-dose study, prospective non-randomised intervention studies,
oral chloral hydrate (70 mg/kg) (Marti-Bonmati 1995); literature review articles, a questionnaire study, studies with
• high-dose oral chloral hydrate (100 mg/kg) versus low-dose research questions or outcomes that did not match our review, or
oral chloral hydrate (50 mg/kg) (Gumus 2015). commentaries.
The initial sedation dose of chloral hydrate used in the studies • Population (5 studies): the participants in the studies were
ranged from 25 mg/kg to 100 mg/kg oral and 50 mg/kg rectal. either children undergoing dental procedures, auditory
The type and doses of the sedation agents used varied among the brainstem response tests, or ophthalmic examination.
included studies: oral dexmedetomidine 2 or 3 mg/kg (Gumus • Intervention (18 studies): the studies either assessed efficacy
2015); intravenous pentobarbital 5 mg/kg (Malviya 2004); mida- of chloral hydrate alone or in combination with other sedative
zolam either 0.5 mg/kg orally (Ashrafi 2013; D’Agostino 2000), agents or efficacy of other sedative agents that were not the
0.2 mg/kg intranasally (Fallah 2013), or rectal midazolam 1 mg/ intervention of our interest.
kg (Lopez 1995); oral hydroxyzine hydrochloride 1 mg/kg (Bektas • Outcome (2 studies): the studies reported effects of sedation
2014; Sezer 2013); oral promethazine 1 mg/kg (Razieh 2013); on EEG results and did not assess the success of sedation.
and intramuscular atropine/meperidine/promethazine/secobarbi- A description of each study is provided in the Characteristics of
tal (AMPS) cocktail 0.08 mL/kg (Thompson 1982). Two stud- excluded studies table.

Risk of bias in included studies
Risk of bias in the included studies varied widely. There was at
least one high-risk domain in eight out of the 13 included studies
(Ashrafi 2010; Ashrafi 2013; Bektas 2014; Gumus 2015; Loewy
2005; Lopez 1995; Malviya 2004; Thompson 1982). We judged
all of these eight studies to be at high risk for blinding of par-
ticipants, except Bektas 2014, which we judged to be at unclear
risk. Three studies were at low risk in 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 is
illustrated in Figure 2; the ’Risk of bias’ judgement of each in-
cluded study in each domain is depicted in Figure 3. We have also
provided a detailed description of the risk of bias of each study
in the Characteristics of included studies table. Our ’Risk of bias’
assessments under each domain are summarised below.
Figure 2. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.

Figure 3. Risk of bias summary: review authors’ judgements about each risk of bias item for each included
study.

Allocation
of high risk of bias for this domain. We judged a third study as
For random sequence generation, we judged seven of the 13 in- having high risk in this domain, as the authors did not follow an
cluded studies to have low risk of bias (D’Agostino 2000; Fallah intention-to-treat analysis (Bektas 2014).
2013; Gumus 2015; Lopez 1995; Malviya 2004; Marti-Bonmati
1995; Razieh 2013). For allocation concealment, four studies had
low risk of bias (D’Agostino 2000; Lopez 1995; Marti-Bonmati Selective reporting
1995; Razieh 2013). In these studies, the authors clearly stated We judged 10 studies as at low risk of bias for this domain (Ashrafi
the method of sequence generation, which involved some form of 2010; Ashrafi 2013; D’Agostino 2000; Fallah 2013; Gumus 2015;
random number scheme using either computers, random number Lopez 1995; Malviya 2004; Marti-Bonmati 1995; Razieh 2013;
table, or the toss of a coin. There were also clear statements in the Sezer 2013), and three studies at high risk (Bektas 2014; Loewy
methods that reassured the readers of the independence between 2005; Thompson 1982). The studies at high risk of reporting
sequence generation and allocation. We judged two studies to be bias used a different categorical outcome sedation score between
at high risk of bias for sequence generation as well as allocation both comparison groups (reported sleep score 4 for chloral hydrate
concealment (Loewy 2005; Thompson 1982), as children were group and sleep score 3 for music therapy), making it unsuitable for
allocated following a predictable sequence based on the day of the direct comparison (Loewy 2005), and reported outcomes without
week they were admitted or via alternating and rotational assign- sufficient details for a meta-analysis, for example reporting means
ments. Four of the 13 included studies had unclear risk of bias in without standard deviations (Thompson 1982).
one or both domains due to insufficient information provided in
the articles (Ashrafi 2010; Ashrafi 2013; Bektas 2014; Sezer 2013).
Other potential sources of bias
We did not identify other potential major sources of bias in the
Blinding included studies.
For blinding of participants, we judged seven studies to have high
risk of bias (Ashrafi 2010; Ashrafi 2013; Bektas 2014; Gumus Effects of interventions
2015; Loewy 2005; Malviya 2004; Thompson 1982). In three See: Summary of findings for the main comparison
studies (D’Agostino 2000; Fallah 2013; Marti-Bonmati 1995), Chloral hydrate oral (50 mg/kg or 100 mg/kg) compared to
it was stated clearly that blinding of participants was achieved, dexmedetomidine oral (2 mg/kg or 3 mg/kg) as sedating agents
while in the other three studies (Lopez 1995; Razieh 2013; Sezer for neurodiagnostic procedures in children; Summary of findings
2013), no statements were made regarding the blinding status of 2 Chloral hydrate oral (75 mg/kg) compared to pentobarbital
the participants. We considered blinding for these three studies to intravenous (5 mg/kg) as sedating agents for neurodiagnostic
be unlikely because they compared chloral hydrate with another procedures in children; Summary of findings 3 Chloral
solution of a different appearance/preparation and taste. hydrate oral (100 mg/kg or 75 mg/kg) compared to midazolam
Seven studies did not report blinding of outcome assessors (Ashrafi (intranasal 0.2 mg/kg or oral 0.5 mg/kg) as sedating agents for
2010; Ashrafi 2013; Bektas 2014; Gumus 2015; Malviya 2004; neurodiagnostic procedures in children; Summary of findings
Sezer 2013; Thompson 1982), and we judged one study to be at 4 Chloral hydrate oral (50 mg/kg) compared to melatonin oral
high risk of bias, as the modality of sedation intervention given as sedating agents for neurodiagnostic procedures in children;
in this study (oral chloral hydrate versus music therapy via music Summary of findings 5 Chloral hydrate oral (50 mg/kg + 50
therapist) was clearly different, making blinding of the outcome mg/kg) compared to hydroxyzine hydrochloride oral (1 mg/kg
assessors not possible (Loewy 2005). In the remaining five studies ( + 1 mg/kg) as sedating agents for neurodiagnostic procedures in
D’Agostino 2000; Fallah 2013; Lopez 1995; Marti-Bonmati 1995; children; Summary of findings 6 Chloral hydrate oral (70 mg/kg)
Razieh 2013), it was clearly stated that the outcome assessors were compared to promethazine oral (1 mg/kg) as sedating agents for
blinded. neurodiagnostic procedures in children; Summary of findings 7
Chloral hydrate oral (60 mg/kg) compared to music therapy as
sedating agents for neurodiagnostic procedures in children
Incomplete outcome data Overall, we carried out 10 comparisons, with variations related to
In all studies except two (Lopez 1995; Thompson 1982), all chil- the specific interventions compared in comparison 3 (difference
dren enrolled appeared to be included in the analysis. Both studies in mode of administration of midazolam, i.e. either intranasal or
with missing data had a dropout rate of over 20% (22% in Lopez oral), comparison 7 (difference with non-drug music therapy),
1995 and 42.3% in Thompson 1982), resulting in a judgement and comparison 9 and 10 (difference between different dosing

of chloral hydrate). Four studies were not included in the analy- under this comparison with the corresponding quality of evidence
sis as the data were skewed (Ashrafi 2010; Ashrafi 2013; Bektas are displayed in Summary of findings for the main comparison.
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
Primary outcomes
not follow an intention-to-treat analysis. Details of these studies
are given in Table 1.
We performed analysis on the remaining 10 studies with a total of
1262 children in the 10 comparisons.
Proportion of children who successfully completed
• Comparison 1: Chloral hydrate oral (50 mg/kg or 100 mg/
neurodiagnostic procedure without interruption by the child
kg) compared to dexmedetomidine oral (2 mg/kg or 3 mg/kg)
awakening
(160 children) (Gumus 2015).
• Comparison 2: Chloral hydrate oral (75 mg/kg) compared No studies assessed this outcome.
to pentobarbital intravenous (5 mg/kg) (70 children) (Malviya
2004).
• Comparison 3: Chloral hydrate oral (100 mg/kg or 75 mg/ Proportion of children who required a further dose of either
kg) compared to midazolam (intranasal 0.2 mg/kg or oral 0.5 the same sedative agent or the addition of a different sedative
mg/kg) (291 children) (Ashrafi 2013; D’Agostino 2000; Fallah agent
2013).
• Comparison 4: Chloral hydrate oral (50 mg/kg) compared No studies assessed this outcome.
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 Time to adequate sedation (minutes or as measured by
mg/kg) (282 children) (Sezer 2013). specific validated scales such as the Ramsay Sedation Score)
• Comparison 6: Chloral hydrate oral (70 mg/kg) compared
to promethazine oral (1 mg/kg) (60 children) (Razieh 2013). Children who received oral chloral hydrate had a significantly
• Comparison 7: Chloral hydrate oral (60 mg/kg) compared shorter mean EEG time onset for adequate sedation compared
to music therapy (58 children) (Loewy 2005). with children who received oral dexmedetomidine (MD -3.86,
• Comparison 8: Chloral hydrate oral (50 mg/kg) compared 95% CI -5.12 to -2.60; 160 children, moderate-quality evidence,
to midazolam rectal (1 mg/kg) (59 children) (Lopez 1995). downgraded one level due to imprecision) (Analysis 1.1). Our sub-
• Comparison 9: Chloral hydrate high dose oral (100 mg/kg) group analysis showed that high-dose oral chloral hydrate (100
compared to chloral hydrate low dose (70 mg/kg) (97 children) mg/kg) achieved a significantly shorter mean onset of sedation
(Marti-Bonmati 1995). of 5.6 minutes compared with high-dose oral dexmedetomidine,
• Comparison 10: Chloral hydrate high dose oral (100 mg/ whilst low-dose oral chloral hydrate (50 mg/kg) achieved a signif-
kg) compared to chloral hydrate low dose (50 mg/kg) (76 icantly shorter mean onset of sedation of 1.9 minutes compared
children) (Gumus 2015). with low-dose oral dexmedetomidine. The test of subgroup differ-
ences was significant (P = 0.004). No studies assessed the outcome
Below, we have reported on our outcomes of interest for each of adequate sedation with validated scales.
comparison.
Comparison 1: Chloral hydrate versus Secondary outcomes

dexmedetomidine
Gumus 2015 was the only study that compared oral chloral hy-
drate to oral dexmedetomidine, in two different dosing regimens.
Proportion of children who had sedation failure or
There were four arms in this study, namely low-dose chloral hy-
inadequate level of sedation
drate (50 mg/kg), high-dose chloral hydrate (100 mg/kg), low-
dose dexmedetomidine (2 mg/kg), and high-dose dexmedetomi- There was no significant difference in sedation failure between oral
dine (3 mg/kg). This made two pair-wise comparisons of compa- chloral hydrate and oral dexmedetomidine (risk ratio (RR) 1.14,
rable dosages possible, thus we formed two separate subgroups in 95% confidence interval (CI) 0.51 to 2.53; 160 children, mod-
our analysis: one comparing low-dose chloral hydrate against low- erate-quality evidence, downgraded one level due to imprecision)
dose dexmedetomidine, and another comparing high-dose chloral (Analysis 1.2). There were no significant differences between the
hydrate against high-dose dexmedetomidine. The major outcomes high- and low-dose subgroup comparisons.

Sedation duration Time to adequate sedation (minutes or as measured by
The duration of sedation was significantly longer in the oral specific validated scales such as the Ramsay Sedation Score)
dexmedetomidine group by 16.3 minutes compared with oral Children who received oral chloral hydrate had a significantly
chloral hydrate (mean difference (MD) 16.31, 95% CI 9.15 to longer mean time to adequate sedation compared with children
23.46; 160 children, moderate-quality evidence, downgraded one who received intravenous pentobarbital (MD 19, 95% CI 16.61 to
level due to imprecision) (Analysis 1.3). There were no signifi- 21.39; 70 children, low-quality evidence, downgraded two levels
cant differences between the high- and low-dose subgroup com- due to risk of bias (one level) and imprecision (one level)) (Analysis
parisons. 2.1). No studies assessed the outcome of adequate sedation with
validated scales. However, there was no significant difference in
sedation failure after two doses between the two groups (RR 3.00,
Yield of EEG or neuroimaging findings 95% CI 0.33 to 27.46; 1 study, very low-quality evidence, down-
No studies assessed this outcome. graded three levels due to risk of bias (one level) and very serious
imprecision (two levels)) (Analysis 2.2).
Adverse effects (any)

Oral chloral hydrate had significantly more adverse events in total Secondary outcomes
when compared with oral dexmedetomidine (RR 7.66, 95% CI
1.78 to 32.91; 160 children, low-quality evidence, downgraded
two levels due to serious imprecision) (Analysis 1.4). There were no Proportion of children who had sedation failure or
significant differences between the high- and low-dose subgroup inadequate level of sedation
comparisons. Regarding individual adverse events, there were no
Oral chloral hydrate had significantly more sedation failure af-
significant differences between the two groups in all adverse events
ter one dose when compared with intravenous pentobarbital (RR
(Analysis 1.5; Analysis 1.6; Analysis 1.7; Analysis 1.9), except for
4.33, 95% CI 1.35 to 13.89; low-quality evidence, downgraded
nausea or vomiting, for which children who received oral chloral
two levels due to very serious imprecision) (Analysis 2.3).
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
Sedation duration
significant differences between the high- and low-dose subgroup
comparisons. No studies assessed this outcome.
Comparison 2: Chloral hydrate versus pentobarbital Yield of EEG or neuroimaging findings

Malviya 2004 was the only study that compared oral chloral hy- There was no significant difference in non-interpretable neu-
drate to intravenous pentobarbital.The major outcomes under this roimaging findings between the two groups (RR 0.23, 95% CI
comparison with the corresponding quality of evidence are dis- 0.03 to 1.94; 54 children, very low-quality evidence, downgraded
played in Summary of findings 2. three levels due to risk of bias (one level) and very serious impre-
cision (two levels)) (Analysis 2.4).
Primary outcomes
The study did not evaluate overall adverse effects between the two
Proportion of children who successfully completed groups. Regarding individual adverse events, there was no signifi-
neurodiagnostic procedure without interruption by the child cant difference in oxygen desaturation (RR 0.67, 95% CI 0.21 to
awakening 2.16; 70 children, very low-quality evidence, downgraded three
No studies assessed this outcome. levels due to risk of bias (one level) and serious imprecision (two
levels)) (Analysis 2.5), nausea or vomiting, and paradoxical reac-
tion between the two groups (Analysis 2.6; Analysis 2.7). Children
Proportion of children who required a further dose of either who received oral chloral hydrate had a significantly shorter mean
the same sedative agent or the addition of a different sedative time (hours) to return to normal behaviour post-discharge when
agent compared with intravenous pentobarbital (MD -6.0, 95% CI -
No studies assessed this outcome. 11.43 to -0.57; 70 children) (Analysis 2.8).

Comparison 3: Chloral hydrate versus midazolam Sedation duration
Three studies compared oral chloral hydrate to midazolam: Fallah D’Agostino 2000 reported that there was no significant difference
2013, which used intranasal midazolam, and D’Agostino 2000 in the mean duration of sedation between oral chloral hydrate and
and Ashrafi 2013, which used oral midazolam. Data in Ashrafi oral midazolam, with mean time for chloral sedation 19 minutes
2013 were skewed, therefore they were not included in the meta- longer (MD 19, 95% CI -3.4 to 41.4; 33 children, 1 study, low-
analysis. The major outcomes under this comparison with the quality evidence, downgraded two levels due to very serious im-
corresponding quality of evidence are displayed in Summary of precision) (Analysis 3.4).
findings 3.
Yield of EEG or neuroimaging findings

Primary outcomes Ashrafi 2013 reported that children who received oral chloral hy-
drate were significantly less likely to have sedative-induced artefact
on their EEG recording compared to children who received in-
Proportion of children who successfully completed tranasal midazolam (RR 0.58, 95% CI 0.44 to 0.76; 198 children,
neurodiagnostic procedure without interruption by the child high-quality evidence) (Analysis 3.5).
awakening
No studies assessed this outcome.
There was no statistical significant difference in any adverse effects
Proportion of children who required a further dose of either between oral chloral hydrate and oral midazolam groups (RR 0.20,
the same sedative agent or the addition of a different sedative 95% CI 0.01 to 4.2; 198 children, 1 study, low-quality evidence,
agent downgraded two levels due to very serious imprecision) (Analysis
No studies assessed this outcome. 3.6).
Comparison 4: Chloral hydrate versus melatonin

Time to adequate sedation (minutes or as measured by
specific validated scales such as the Ramsay Sedation Score) Ashrafi 2010 was the only study that compared oral chloral hydrate
to oral melatonin, however as the data were skewed, they were
Ashrafi 2013 reported that children who received oral chloral hy-
not included in the meta-analysis. The major outcomes under
drate had significantly shorter sleep onset latency, but significantly
this comparison with the corresponding quality of evidence are
longer sleep duration and drowsiness time (Table 1). Fallah 2013
displayed in Summary of findings 4.
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 Primary outcomes
to 18.44; 60 children, 1 study, moderate-quality evidence, down-
graded one level due to imprecision) (Analysis 3.1). Children who
received oral chloral hydrate appeared to be significantly less likely Proportion of children who successfully completed
to suffer from inadequate level of sedation (Ramsay score below neurodiagnostic procedure without interruption by the child
4) compared with intranasal midazolam (RR 0.11, 95% CI 0.03 awakening
to 0.44; 60 children, 1 study, moderate-quality evidence, down- No studies assessed this outcome.
graded one level due to imprecision) (Analysis 3.2).
Proportion of children who required a further dose of either

Secondary outcomes the same sedative agent or the addition of a different sedative
agent
There was no significant difference for sedation failure after one Time to adequate sedation (minutes or as measured by
dose of sedative agent between oral chloral hydrate and oral mi- specific validated scales such as the Ramsay Sedation Score)
dazolam (RR 0.17, 95% CI 0.02 to 1.12; 33 children, 1 study, As data in Ashrafi 2010 were skewed, they were not included in
low-quality evidence, downgraded two levels due to very serious the meta-analysis. Ashrafi 2010 reported that there was no signifi-
imprecision) (Analysis 3.3). cant difference between children who received oral chloral hydrate

and those who received oral melatonin in sleep onset latency, but Proportion of children who required a further dose of either
children who received oral chloral hydrate had significantly longer the same sedative agent or the addition of a different sedative
sleep duration and drowsiness time (Table 1).No studies assessed agent
the outcome of adequate sedation with validated scales. No studies assessed this outcome.
Secondary outcomes 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
Proportion of children who had sedation failure or mean time to adequate sedation compared with oral hydroxyzine
inadequate level of sedation hydrochloride (MD -7.5, 95% CI -7.85 to -7.15; 282 children,
No studies assessed this outcome. moderate-quality evidence, downgraded one level due to impreci-
sion) (Analysis 5.1). No studies assessed the outcome of adequate
sedation using validated scales.
Sedation duration
No studies assessed this outcome. Secondary outcomes

The occurrence of EEG sedative drug artefact (increased fast ac- inadequate level of sedation
tivity and slow dysrhythmia) was significantly less likely in the oral
There was no statistically significant difference in risk of sedation
chloral hydrate group compared to the oral melatonin group (RR
failure between the two groups (RR 0.33, 95% CI 0.11 to 1.01;
0.33, 95% CI 0.14 to 0.82; 348 children, low-quality evidence,
282 children, low-quality evidence, downgraded two levels due to
downgraded two levels due to risk of bias (one level) and impre-
risk of bias (one level) and imprecision (one level)) (Analysis 5.2).
cision (one level)) (Analysis 4.1).
Sedation duration
Children receiving oral chloral hydrate had a significantly longer
There was no significant difference in any adverse effects between
mean sleep duration compared to those receiving oral hydroxyzine
the two groups (RR 1.00, 95% CI 0.25 to 3.93; 348 children,
hydrochloride (MD 3.1, 95% CI 2.23 to 3.97; 282 children, mod-
low-quality evidence, downgraded two levels due to risk of bias
erate-quality evidence, downgraded one level due to imprecision)
(one level) and imprecision (one level)) (Analysis 4.2).
(Analysis 5.3).
Comparison 5: Chloral hydrate versus hydroxyzine Yield of EEG or neuroimaging findings

hydrochloride
There was no significant difference in EEG sedative drug artefact
Sezer 2013 was the only study that compared oral chloral hydrate between the two groups (RR 1.33, 95% CI 0.47 to 3.74; 282
to oral hydroxyzine hydrochloride. The major outcomes under children, moderate-quality evidence, downgraded one level due to
this comparison with the corresponding quality of evidence are imprecision) (Analysis 5.4).
displayed in Summary of findings 5.
Adverse effects (behavioural change and nausea or vomiting)

Primary outcomes
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-quality evidence, downgraded two levels due to risk of bias
Proportion of children who successfully completed (one level) and imprecision (one level)) (Analysis 5.5), or for nausea
neurodiagnostic procedure without interruption by the child or vomiting (RR 1.25, 95% CI 0.34 to 4.56; 282 children, low-
awakening quality evidence, downgraded two levels due to risk of bias (one
No studies assessed this outcome. level) and imprecision (one level)) (Analysis 5.6).

Comparison 6: Chloral hydrate versus promethazine Yield of EEG or neuroimaging findings
Razieh 2013 was the only study that compared oral chloral hy- No studies assessed this outcome.
drate to oral promethazine. The major outcomes under this com-
parison with the corresponding quality of evidence are displayed
in Summary of findings 6. 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,
Primary outcomes moderate-quality evidence, downgraded one level due to impreci-
sion) (Analysis 6.4), or for nausea or vomiting (RR 13.00, 95% CI
0.76 to 220.96; 60 children, low-quality evidence, downgraded
Proportion of children who successfully completed two levels due to very serious imprecision) (Analysis 6.5).
awakening
Comparison 7: Chloral hydrate versus music therapy
Loewy 2005 was the only study that compared oral chloral hydrate
to music therapy. The major outcomes under this comparison with
Proportion of children who required a further dose of either the corresponding quality of evidence are displayed in Summary
the same sedative agent or the addition of a different sedative of findings 7.
agent
No studies assessed this outcome. Primary outcomes
Time to Adequate sedation (minutes or as measured by

Children in the chloral hydrate group had a significantly shorter awakening
mean time to adequate sedation compared with promethazine
(MD -12.11, 95% CI -18.48 to -5.74; 60 children, moderate-qual-
ity evidence, downgraded one level due to imprecision) (Analysis
6.1). A significantly lower number of children who received oral Proportion of children who required a further dose of either
chloral hydrate had inadequate level of sedation (Ramsay score the same sedative agent or the addition of a different sedative
below 4) compared with oral promethazine (RR 0.03, 95% CI agent
0.00 to 0.45; 60 children, low-quality evidence, downgraded two
levels due to very serious imprecision) (Analysis 6.2).

Sedation duration specific validated scales such as the Ramsay Sedation Score)
No studies assessed this outcome. There was no difference between the two groups in time to ad-
equate sedation (MD 9.00 minutes, 95% CI -2.15 to 20.15; 58
children, very low-quality evidence, downgraded three levels due
Secondary outcomes
to very serious risk of bias (two levels) and imprecision (one level))
(Analysis 7.1). No studies assessed the outcome of adequate seda-
tion with validated scales.
Children in the oral chloral hydrate group had significantly less Secondary outcomes
sedation failure compared with oral promethazine (RR 0.11, 95%
CI 0.01 to 0.82; 60 children, moderate-quality evidence, down-
graded one level due to imprecision) (Analysis 6.3). Proportion of children who had sedation failure or
Children who received oral chloral hydrate had significantly higher
Sedation duration sedation failure when compared with children who received music
No studies assessed this outcome. therapy (RR 17.00, 95% CI 2.37 to 122.14; 58 children, very

low-quality evidence, downgraded four levels due to very serious Secondary outcomes
risk of bias (two levels) and very serious imprecision (two levels))
(Analysis 7.2).

Sedation duration inadequate level of sedation
The duration of sedation was significantly longer in the oral chloral No studies assessed this outcome.
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-quality evidence, downgraded three levels due to very serious Sedation duration
risk of bias (two levels) and imprecision (one level)) (Analysis 7.3).
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).

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 chil-
dren) (Analysis 8.3).
Comparison 8: Chloral hydrate versus midazolam

Lopez 1995 was the only study that compared oral chloral hydrate Adverse effects (any)
to rectal midazolam.
Primary outcomes
Comparison 9: Chloral hydrate high dose versus
chloral hydrate low dose
Proportion of children who successfully completed Marti-Bonmati 1995 was the only study that compared high-dose
neurodiagnostic procedure without interruption by the child oral chloral hydrate (100 mg/kg) to low-dose oral chloral hydrate
awakening (70 mg/kg).
Primary outcomes
the same sedative agent or the addition of a different sedative
agent
No studies assessed this outcome. neurodiagnostic procedure without interruption by the child
awakening
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)
agent
(Analysis 8.1). No studies assessed the outcome of adequate seda-
tion with validated scales. No studies assessed this outcome.

Time to adequate sedation (minutes or as measured by Primary outcomes
Children receiving high-dose oral chloral hydrate had a signifi-
cantly shorter mean time to adequate sedation (in minutes) com-
pared with those receiving low-dose oral chloral hydrate (MD -
awakening
7.00, 95% CI -7.62 to -6.38; 97 children) (Analysis 9.1). No
studies assessed the outcome of adequate sedation with validated No studies assessed this outcome.
scales.
Secondary outcomes
agent

Proportion of children who had sedation failure or specific validated scales such as the Ramsay Sedation Score)
Children receiving high-dose chloral hydrate had a significantly
There was no significant difference in proportion of children who shorter time to adequate sedation (in minutes) compared with
had sedation failure between the two groups (RR 0.46, 95% CI those receiving low-dose oral chloral hydrate (MD -5.10, 95% CI
0.19 to 1.09; 97 children) (Analysis 9.2). -7.05 to -3.15; 76 children) (Analysis 10.1). No studies assessed
the outcome of adequate sedation with validated scales.
Sedation duration Secondary outcomes
The duration of sedation was longer in the high-dose oral chlo-

ral 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 chil-
dren) (Analysis 9.3).
Children receiving high-dose chloral hydrate were significantly less
likely to have sedation failure compared with those receiving low-
dose chloral hydrate (RR 0.23, 95% CI 0.05 to 0.99; 76 children)
Yield of EEG or neuroimaging findings (Analysis 10.2).
Sedation duration
The duration of sedation (in minutes) was significantly longer
Adverse effects (any) 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
There was no significant difference between the two groups for 27.10; 76 children) (Analysis 10.3).
adverse effects (RR 1.06, 95% CI 0.49 to 2.32; 97 children) (
Analysis 9.4).
Comparison 10: Chloral hydrate high dose versus

chloral hydrate low dose Adverse effects (any)
Gumus 2015 was the only study that compared high-dose oral There was no significant difference between the two groups for
chloral hydrate (100 mg/kg) to low-dose oral chloral hydrate (50 adverse effects (RR 2.25, 95% CI 0.77 to 6.55; 76 children) (
mg/kg). Analysis 10.4).

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
Chloral hydrate orally (75 mg/ kg) compared to pentobarbital intravenously (5 mg/ kg) as sedating agents for neurodiagnostic procedures in children

Intervention: chloral hydrate oral (75 m g/ kg)
Comparison: pentobarbital intravenous (5 m g/ kg)
Risk with pentobarbital Risk with chloral hy-

drate

awakening

sedative agent
Tim e to adequate se- The m ean tim e to ad- The m ean tim e to ad- - 70 ⊕⊕
dation (m inutes or as equate sedation was 9 equate sedation in the (1 RCT) LOW 12
m easured by specif ic m inutes. intervention group was
validated scales such 19 m inutes longer (16.
as the Ram say Sedation 61 to 21.39 m inutes
Score) longer)
25
Proportion of children Study population RR 4.33 70 ⊕⊕

who had sedation f ail- (1.35 to 13.89) (1 RCT) LOW 13
ure af ter 1 dose of seda- 86 per 1000 371 per 1000
tive agent (116 to 1000)
Proportion of children Study population RR 3.00 70 ⊕

who had sedation f ail- (0.33 to 27.46) (1 RCT) VERY LOW 13
ure af ter 2 doses of
sedative agent (sam e 29 per 1000 86 per 1000
or dif f erent) (9 to 785)
Non-interpretable neu- Study population RR 0.23 54 ⊕

roim aging f inding (0.03 to 1.94) (1 RCT) VERY LOW 14
154 per 1000 35 per 1000
(5 to 298)
Num ber of children with Study population RR 0.67 70 ⊕

clinical adverse event: (0.21 to 2.16) (1 RCT) VERY LOW 15
oxygen desaturation 171 per 1000 115 per 1000
(36 to 370)
95% CI).
CI: conf idence interval; RCT: random ised controlled trial; RR: risk ratio

1 The single included study had unclear risk of bias f or allocation concealm ent and blinding of outcom e assessor and high
risk of bias f or blinding of participants and personnel. Quality of evidence downgraded one level due to risk of bias.
2
Although both ends of the 95% CI clearly indicate a longer onset of adequate sedation f or the chloral hydrate group, the range
of 95% CI f or this estim ate was too wide f or a conf ident estim ate on the tim e dif f erence. Quality of evidence downgraded one
level due to im precision.
26
3 The 95% CI f or this estim ate ranges f rom slightly higher risk of sedation f ailure f or chloral hydrate group to substantially
higher risk of sedation f ailure f or chloral hydrate group. Quality of evidence downgraded two levels due to im precision.
4 The 95%CI f or this estim ate ranges f rom substantially f avouring chloral hydrate group to substantially f avouring pentobarbital
group. Quality of evidence downgraded two levels due to im precision.

5
The 95% CI f or this estim ate ranges f rom substantially lower risk of sedation f ailure f or chloral hydrate group to substantially
higher risk of sedation f ailure f or chloral hydrate group. Quality of evidence downgraded two levels due to im precision.
27
Chloral hydrate orally (100 mg/ kg or 75 mg/ kg) compared to midazolam (0.2 mg/ kg intranasally or 0.5 mg/ kg orally) as sedating agents for neurodiagnostic procedures in
children

Intervention: chloral hydrate oral (100 m g/ kg or 75 m g/ kg)
Comparison: m idazolam (intranasal 0.2 m g/ kg or oral 0.5 m g/ kg)
Risk with midazolam Risk with chloral hy-

drate

awakening

sedative agent
Tim e to adequate se- The m ean tim e to ade- The m ean tim e to ad- - 60 ⊕⊕⊕
dation (m inutes or as quate sedation was 10. equate sedation in the (1 RCT) M ODERATE 1
m easured by specif ic 92 m inutes (intranasal intervention group was
validated scales such m idazolam ) 12.83 m inutes longer
as the Ram say Sedation (7.22 to 18.44 m inutes
Score) longer)
28

with inadequate level (0.03 to 0.44) (1 RCT) M ODERATE 1
of sedation (Ram say 600 per 1000 66 per 1000
score below 4) (18 to 264)

ure af ter 1 dose of seda- 545 per 1000 93 per 1000
tive agent (11 to 611)
Sedation duration (m in- The m ean duration of The m ean duration of - 33 ⊕⊕

utes) sedation or sleep was sedation or sleep in the (1 RCT) LOW 3
76 m inutes (oral m ida- intervention group was
zolam ) 19 m inutes longer (3.4
m inutes shorter to 41.4
m inutes longer)
EEG sedative-induced Study population RR 0.58 198 ⊕⊕⊕⊕

artef act (0.44 to 0.76) (1 RCT) HIGH
700 per 1000 406 per 1000
(308 to 532)

(any) 20 per 1000 4 per 1000
(0 to 84)
95% CI).

29
1 The 95% CI f or this estim ate is wide although both ends are on the sam e direction of ef f ect. Quality of evidence downgraded
one level due to im precision.
2 The 95% CI f or this estim ate ranges f rom substantially lower risk to higher risk f or chloral hydrate group. Quality of evidence
downgraded two levels due to im precision.

3
The 95% CI f or this estim ate ranges f rom slightly shorter to substantially higher f or chloral hydrate group. Quality of evidence
downgraded two levels due to im precision.
30
Chloral hydrate orally (50 mg/ kg) compared to melatonin orally as sedating agents for neurodiagnostic procedures in children

Comparison: m elatonin oral
Risk with melatonin Risk with chloral hy-

drate

awakening

sedative agent
Tim e to adequate se- - - - - - No study f or this com -

dation (m inutes or as parison assessed this
m easured by specif ic outcom e.
validated scales such
as the Ram say Sedation
Score)
31

who had sedation f ail- parison assessed this
ure or inadequate level outcom e.
of sedation
EEG sedative-induced Study population RR 0.33 348 ⊕⊕

artef act (0.14 to 0.82) (1 RCT) LOW 12
103 per 1000 34 per 1000
(14 to 85)

(any) 23 per 1000 23 per 1000
(6 to 90)
95% CI).

1
The single included study was judged to be at unclear risk of bias f or random sequence generation, allocation concealm ent,
and blinding of outcom e assessors and high risk of bias f or blinding of participants and personnel. Quality of evidence
downgraded one level due to risk of bias.
2 The 95% CIs were too wide f or a conf ident estim ate of the ef f ect sizes. Quality of evidence downgraded one level due to
im precision.
32
Chloral hydrate orally (50 mg/ kg + 50 mg/ kg) compared to hydroxyzine hydrochloride orally (1 mg/ kg + 1 mg/ kg) as sedating agents for neurodiagnostic procedures in
children

Intervention: chloral hydrate oral (50 m g/ kg + 50 m g/ kg)
Comparison: hydroxyzine hydrochloride oral (1 m g/ kg + 1 m g/ kg)
Risk with hydroxyzine Risk with chloral hy-

hydrochloride drate

awakening

sedative agent
TIm e to adequate se- The tim e onset to ade- The m ean tim e to ad- - 282 ⊕⊕⊕
m easured by specif ic 7 m inutes. intervention group was
validated scales such 7.5 m inutes shorter (7.
as the Ram say Sedation 85 to 7.15 m inutes
Score) shorter)
33

Sedation duration (m in- The m ean duration of The m ean duration of - 282 ⊕⊕⊕
utes) sedation or sleep was sedation or sleep in (1 RCT) M ODERATE 1
85.1 m inutes. the intervention group
was 3.1 m inutes longer
(2.23 to 3.97 m inutes
longer)

clinical adverse event: (0.40 to 3.38) (1 RCT) LOW 12
behavioural change 43 per 1000 50 per 1000
(17 to 144)

nausea or vom iting 28 per 1000 35 per 1000
(10 to 129)
95% CI).

1 Thesingle included study was judged to be at unclear risk of bias f or random sequence generation, allocation concealm ent,
blinding of participants and personnel, and blinding of outcom e assessors. Quality of evidence downgraded one level due
to risk of bias.
34
2 The 95% CI f or this estim ate ranges f rom substantially lower risk to m arginally to m oderately higher risk of sedation f ailure
f or the chloral hydrate group. Quality of evidence downgraded one level due to im precision.
35
Chloral hydrate orally (70 mg/ kg) compared to promethazine orally (1 mg/ kg) as sedating agents for neurodiagnostic procedures in children

Comparison: prom ethazine oral (1 m g/ kg)
Risk with promet- Risk with chloral hy-

hazine drate

awakening

sedative agent
Tim e to adequate se- The m ean tim e to ade- The m ean tim e to ad- - 60 ⊕⊕⊕
m easured by specif ic 84 m inutes. intervention group was
validated scales such 12.11 m inutes shorter
as the Ram say Sedation (18.48 to 5.74 m inutes
Score) shorter)
36

with inadequate level (0.00 to 0.45) (1 RCT) LOW 2
of sedation (Ram say 567 per 1000 17 per 1000
score below 4) (0 to 255)

who had sedation f ail- (0.01 to 0.82) (1 RCT) M ODERATE 1
Num ber of children with Study population RR 0.20 60 ⊕⊕⊕

clinical adverse event: (0.01 to 4.00) (1 RCT) M ODERATE 1
behavioural change 67 per 1000 13 per 1000
(1 to 267)

vom iting or nausea 0 per 1000 0 per 1000
(0 to 0)
95% CI).

1
The 95% CI f or this estim ate is wide but f alls on the sam e direction of ef f ect. Quality of evidence downgraded one level due
to im precision.
2 The 95% CI f or this estim ate is very wide especially if the data are inverted. Quality of evidence downgraded two levels due
to serious im precision.
3 The 95% CI f or this estim ate is very wide. Quality of evidence downgraded two levels due to im precision.
37
Chloral hydrate oral (60 mg/ kg) compared to music therapy as sedating agents for neurodiagnostic procedures in children

Setting: paediatric inpatient or outpatient
Comparison: m usic therapy
Risk with music ther- Risk with chloral hy-

apy drate

awakening

sedative agent
Tim e to adequate se- The m ean EEG tim e on- The m ean EEG tim e on- - 58 ⊕
dation (m inutes or as set f or adequate seda- set f or adequate seda- (1 RCT) VERY LOW 13
m easured by specif ic tion was 23 m inutes tion in the intervention
validated scales such group was 9 m inutes
as the Ram say Sedation m ore (2.15 f ewer to 20.
Score) 15 m ore)
38
Proportion of children Study population RR 17.00 58 ⊕

who had sedation f ail- (2.37 to 122.14) (1 RCT) VERY LOW 12
Sedation duration (m in- The m ean EEG seda- The m ean EEG seda- - 58 ⊕
utes) tion/ sleep duration was tion/ sleep duration in (1 RCT) VERY LOW 13
66 m inutes. the intervention group
was 160 m inutes m ore
(121.07 m ore to 198.93
m ore)
Num ber of children with - - - - - No study f or this com -

clinical adverse events parison assessed this
(any) outcom e.
95% CI).

1
Very serious concerns regarding the trial m ethodology led to a judgem ent of high risk of bias f or selection bias (using
alternation rather than true random isation), perf orm ance and detection biases (non-blinding of participants and care
personnel as well as outcom e assessors), and selective outcom e reporting. Quality of evidence downgraded two levels
due to risk of bias.
2 The 95% CI was very wide. Quality of evidence downgraded two levels due to im precision.
3 The 95% CI was wide. Quality of evidence downgraded one level due to im precision.
39
DISCUSSION Five studies assessed the secondary outcome measure of sedative
effect on yield of neurodiagnostic procedure (four studies evalu-
ated yield of EEG procedure, and one study evaluated yield of
neuroimaging procedure). Two of the four EEG studies showed
Summary of main results that oral chloral hydrate had less sedative artefact when compared
with intranasal midazolam or oral melatonin. The other two stud-
Apart from oral chloral hydrate, this review identified a variety
ies showed no difference in sedative artefact on EEG when com-
of sedation agents used for neurodiagnostic procedures, of which
pared with oral hydroxyzine hydrochloride and rectal midazolam.
the majority were given in an oral preparation (dexmedetomidine,
In the only study evaluating yield of neuroimaging procedure, no
midazolam, melatonin, hydroxyzine hydrochloride, and promet-
difference was seen between oral chloral hydrate and intravenous
hazine). Three studies used non-oral preparation (intranasal mida-
pentobarbital.
zolam, rectal midazolam, or intravenous pentobarbital), and one
Eight studies assessed the secondary outcome measure of adverse
study used a non-drug therapy (music therapy). Despite a wide
effects of sedation. Seven of the eight studies showed no difference
variety of agents used, each sedation agent was represented by a
in adverse effects, while the remaining study found that children
very small number of studies, and all were only evaluated by a
receiving oral chloral hydrate had a higher total number of adverse
single study. Our review also identified paediatric participants un-
effects compared to those receiving oral dexmedetomidine.
dergoing 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 Overall completeness and applicability of
agents was mixed. Four studies showed that oral chloral hydrate evidence
had a shorter time to achieve adequate sedation when compared We identified 13 studies that matched our selection criteria in
with oral dexmedetomidine, oral hydroxyzine hydrochloride, oral terms of population, sedation intervention, comparison, and out-
promethazine, or rectal midazolam. On the other hand, another comes. A total of 2390 children (age range from birth to 18 years
two studies showed that chloral hydrate took a longer time to old) were assessed. The studies were conducted in Asia, Europe,
achieve adequate sedation when compared with intravenous pen- and the USA from 1982 to 2014. These studies were performed
tobarbital or intranasal midazolam. Children had a shorter time in hospitals that provided neurodiagnostic services. Most of the
to achieve adequate sedation with a higher dose of oral chloral agents evaluated in comparison with oral chloral hydrate were
hydrate compared to a lower dose. those commonly used in practice, and the doses of oral chloral hy-
For the secondary outcome of proportion of children who had drate evaluated were commonly used doses. However, there were
sedation failure or inadequate level of sedation, oral chloral hy- certain limitations in the completeness of this review. For example,
drate appeared to have lower sedation failure when compared with some of the key prespecified outcomes were not assessed in most of
oral promethazine and intranasal midazolam. Chloral hydrate had the included studies, such as proportion of children who success-
more sedation failure after one dose when compared with intra- fully completed neurodiagnostic procedure without interruption
venous pentobarbital, but there was no difference after two doses. by the child awakening and proportion of children who required
Another study showed that chloral hydrate appeared to have more a further dose of either the same sedative agent or the addition of
sedation failure when compared with music therapy. Sedation fail- a different sedative agent.
ure rates appeared to be similar between oral chloral hydrate and
oral dexmedetomidine, oral midazolam, and oral hydroxyzine hy-
drochloride. Two comparative oral chloral hydrate dosing studies
showed oral chloral hydrate 100 mg/kg to have lower sedation
Quality of the evidence
failure than oral chloral hydrate 50 mg/kg, and no difference when The evidence for the majority of the outcomes assessed was overall
compared with oral chloral hydrate 70 mg/kg. Most analyses were of very low to moderate quality, due to the small number of stud-
underpowered with insufficient evidence to enable clear conclu- ies included in each comparison and variable risk of bias of the
sions. included studies. The strongest evidence came from studies that
For the secondary outcome of sedation duration, oral chloral hy- compared oral chloral hydrate with either intranasal midazolam,
drate achieved a longer duration of sedation when compared with oral midazolam (D’Agostino 2000; Fallah 2013), or oral promet-
oral hydroxyzine hydrochloride and music therapy. One study hazine (Razieh 2013), for which there were three studies. However,
found no difference in duration of sedation between oral chlo- all the comparisons in this review involved small numbers of trials
ral hydrate and oral midazolam. Another study showed that oral and participants, which in most cases translated to imprecision
chloral hydrate had a shorter duration of sedation when compared that required downgrading of the quality of the evidence. Also,
with oral dexmedetomidine. A higher dose of oral chloral hydrate in the case of statistically significant difference, an analysis with a
appeared to achieve longer sedation duration than a lower dose. small number of trials lessens the reliability of the results due to

concerns about the effects of small studies exacerbating the impact 100 mg/kg or 70 mg/kg appeared to be more effective than chloral
of biases (Sterne 2011). A second major limitation in the quality hydrate 50 mg/kg. Our review differed from the previous reviews
of evidence gathered was related to performance bias, for which six in their conclusion that oral chloral hydrate should only be con-
studies had high risk and three had unclear risk. In studies at high sidered in young children either under 3 years old (Meyer 2007),
risk of performance bias, lack of blinding of the participants or under 15 kg (NICE 2010), or under 2 years old (Mace 2008),
assessors, or both, makes it highly likely that the outcome results with one review stating that this was due to reduced efficacy in
were influenced, thus affecting the quality of evidence. Overall, the older children (Mace 2008). However, the number of paediatric
body of evidence gathered in this review did not allow us to draw chloral hydrate RCTs prior to 2010 when these three reviews were
a robust conclusion regarding the effectiveness of chloral hydrate written was limited; since 2010 there have been seven paediatric
as a sedating agent for neurodiagnostic procedures in children. chloral hydrate RCTs. The majority of the chloral hydrate RCTs
conducted included the whole range of paediatric age group, up
to 14 years old, and not just confined to children under 3 years of
Potential biases in the review process age (Ashrafi 2013; Bektas 2014; D’Agostino 2000; Fallah 2013;
Gumus 2015; Malviya 2004; Razieh 2013; Sezer 2013). Apart
We performed a comprehensive search of multiple databases with from Malviya 2004, all of the studies that included older children
independent screening, selection, and assessment of eligible stud- showed that oral chloral hydrate was just as effective as or more
ies. However, we were unable to obtain all relevant data; one study effective than the comparator sedative agent (Ashrafi 2013; Bektas
is still awaiting assessment despite our contacting the author via 2014; D’Agostino 2000; Fallah 2013; Gumus 2015; Razieh 2013;
email. We excluded some RCTs on the basis of wrong type of out- Sezer 2013). None of these studies showed that oral chloral hy-
come measure whereby these studies did not have a direct com- drate had a higher adverse effect rate.
parison with another sedative agent. These studies assessed the ef-
ficacy of chloral hydrate as a sedative agent using different dosing
regimens or with other second-line sedative agents after failure of
first-line chloral hydrate sedation. In addition, the primary out-
come measure of the efficacy of chloral hydrate was made by as- AUTHORS’ CONCLUSIONS
sessing adequacy of sedation, proportion of sedation failure, and
sedation duration as a whole. We did not differentiate efficacy Implications for practice
of chloral hydrate according to EEG or neuroimaging procedure. For children undergoing neurodiagnostic procedures, very low-
Our failure to adjust for type of neurodiagnostic procedure may to moderate-quality evidence suggests that oral chloral hydrate is
also have affected the summary of the results. either just as effective a sedative agent with similar sedation failure
rate when compared with oral dexmedetomidine, oral hydroxyzine
hydrochloride, or oral midazolam; or probably a more effective
Agreements and disagreements with other sedative agent with lower sedation failure rate when compared with
studies or reviews oral promethazine or intranasal midazolam. Based on the limited
evidence gathered in our review, the most effective oral chloral
There are three reviews on this topic. Meyer and colleagues 2007
hydrate doses appear to be 100 mg/kg and 70 mg/kg. However,
is a narrative review discussing the current status of sedation for
there was a report of increased risk of total adverse effects with
brief diagnostic procedures in children (Meyer 2007). Mace and
oral chloral hydrate when compared to oral dexmedetomidine,
colleagues 2008 is a systematic review of the literature between
therefore despite the low quality of evidence associated with this
1976 to 2006 to develop a clinical policy of effective and safe
outcome, caution should be exercised in the use of oral chloral
medications for providing procedural sedation in the emergency
hydrate until further evidence on its safety profile is available.
department (Mace 2008). NICE 2010 is a systematic review of
the literature between 1950 to 2010 to develop a clinical guide-
line offering evidence-based advice on the care and treatment of
Implications for research
children and young people having sedation for therapeutic or di- With the increasing need among children for neurodiagnostic pro-
agnostic procedures (NICE 2010). cedures, further trials evaluating the efficacy of sedative agents
The findings of our review are broadly in line with the conclu- in children undergoing neurodiagnostic procedures is warranted.
sions of these other reviews, which state that oral chloral hydrate This review highlights the paucity of research performed in this
is one of the preferred sedative drugs for non-invasive procedu- area. Future trials should include major clinical outcomes as stip-
ral studies in children with a wide margin of safety (Mace 2008; ulated as the primary outcomes of our review, such as success-
Meyer 2007; NICE 2010), with a dosing of 50 to 100 mg/kg ful completion of procedure, requirements for additional sedative
(Mace 2008). Based on the two comparative oral chloral hydrate agent, degree of sedation measured using validated scales, and ma-
studies (Gumus 2015; Marti-Bonmati 1995), chloral hydrate of jor adverse effects, especially bradycardia, hypotension, and oxy-

gen desaturation. Further trials should ensure that blinding of par-
ticipants and personnel is achieved with measures in place to re-
duce selection bias, and should include clear documentation of
trial methodologies.
ACKNOWLEDGEMENTS
We are grateful to the staff of the Cochrane Epilepsy Group, in-
cluding Rachael Kelly (Managing Editor), as well as the other re-
viewers of our draft.
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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Ashrafi 2010
Methods Single-centre RCT (Iran)
Participants All patients aged 1 to 72 months that were unco-operative 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 chloral hydrate (1 to 72 months of age) and melatonin (2 to 64 months
of age)
Interventions 2-arm comparison:

1. chloral hydrate 5% (1 mL/kg; 174 children)
2. melatonin (2 to 6 mg orally; 174 children)
0.5 to 1 h before EEG performance
Outcomes 1. sleep onset latency

2. sleep duration
3. drowsiness time
4. adverse events
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Unclear risk Materials and methods: “Patients were randomly divided
bias) in two groups of melatonin and chloral hydrate for seda-
tion.” The authors stated that patients were randomised but
no further detail on the methods of randomisation was de-
scribed
Allocation concealment (selection bias) Unclear risk As above.
Blinding of participants and personnel High risk It was not stated whether the participants and personnel
(performance bias) were blinded to the allocation. However blinding appeared
All outcomes very unlikely, as melatonin and chloral hydrate differed in
appearance and taste. As the data collected included neuro-
logical diagnosis, sleep onset latency, sleep duration, drowsi-
ness time and adverse drug events, which included outcomes
that required subjective assessment, non-blinding of the per-
sonnel could have influenced the care of the participants
and the outcomes

Ashrafi 2010 (Continued)
Blinding of outcome assessment (detection Unclear risk It was unclear whether the 2 neurologists who interpreted
bias) the EEG and the EEG technicians who recorded the rest of
All outcomes the outcome data were blinded to the allocation
Incomplete outcome data (attrition bias) Low risk Although the number of withdrawals or participants with
All outcomes 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 pre-specified outcomes of sleep onset latency, sleep on-
set 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, were also reported. However,
the data for the continuous outcomes of sleep onset latency,
sleep duration and drowsiness time were skewed, and they
were reported in median and range and were unsuitable to
be included in our meta-analysis
Other bias Low risk None identified.
Ashrafi 2013
Participants Children aged between 1 month and 10 years who were referred for EEG recording and
were unco-operative 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 chloral hydrate
Interventions 2-arm comparison of:

1. oral midazolam (0.5 mg/kg; 100 children)
2. oral chloral hydrate 5% (1 mL/kg; 98 children)
of body weight orally, 1 hour before EEG recording.
Outcomes 1. sleep onset latency

2. sleep duration
3. drowsiness time
4. adverse events
Notes
Risk of bias

Ashrafi 2013 (Continued)
Random sequence generation (selection Unclear risk Materials and methods, study location, sample, and design:
bias) ”198 consecutive patients were enrolled and randomly as-
signed 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 detail 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 as-
signed to receive either oral moidazolam (midazolam group,
n=100)or chloral hydrate (chloral group, n=98).” As above,
no further description on the randomisation process and the
person performing the randomisation to enable an assess-
ment on whether random sequence was generated indepen-
dently from allocation
Blinding of participants and personnel High risk It was not stated whether the participants and personnel
(performance bias) were blinded to the allocation. However blinding appeared
All outcomes unlikely, as midazolam and chloral hydrate were likely to
have 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
the participants and the outcomes
Blinding of outcome assessment (detection Unclear risk It was unclear whether the trained child neurologist who
bias) interpreted the EEG and the trained staff who recorded the
All outcomes rest of the outcome data were blinded to the allocation
All outcomes 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 pre-specified outcomes of sleep onset latency, sleep on-
set 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, were also reported. However,
the data for the continuous outcomes of sleep onset latency,
sleep duration and drowsiness time were skewed, and they
were reported in median and range and were unsuitable to
be included in our meta-analysis

Bektas 2014
Methods Single-centre RCT (Turkey)
Participants 341 children (mean age: 60.92 ± 53.81 months, 194 male and 147 female) that were
unco-operative with the EEG setup or referred for sleep EEG were enrolled. They were
randomly divided in 2 groups of hydroxyzine and chloral hydrate

1. chloral hydrate administered orally as a suspension (mean dosage 26.38 ± 14.73
mg/kg; 147 children)
2. hydroxyzine administered orally as a solution (mean dosage 1.43 ± 0.74 mg/kg;
112 children)
If first drug failed, the other drug (hydroxyzine or chloral hydrate) was given (28 children
received a combination of chloral hydrate and hydroxyzine)
Outcomes 1. frequency of EEG background rhythm, sleep onset latency

2. 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
3. duration of sleep
4. Number of children with successful sedation (spontaneous sleep)
5. side effects
Notes
Risk of bias
Random sequence generation (selection Unclear risk Methods: “The patients who could not sleep sponta-
bias) neously were randomly divided in two groups of hydrox-
yzine and chloral hydrate taking into account age, diag-
nosis, and mental retardation.” The authors stated that
patients were randomised but no further detail on the
methods of randomisation was described
Allocation concealment (selection bias) Unclear risk As above.
Blinding of participants and personnel High risk It was not stated whether the participants and person-
(performance bias) nel were blinded to the allocation. However blinding ap-
All outcomes peared very unlikely, as hydroxyzine and chloral hydrate
differed in appearance and taste. Furthermore, those that
failed the first drug were given the second. As the data
collected included neurological diagnosis, sleep onset la-
tency, sleep duration, drowsiness time and adverse drug
events, which included outcomes that required subjective
assessment, non-blinding of the personnel could have in-
fluenced the care of the participants and the outcomes

Bektas 2014 (Continued)
Blinding of outcome assessment (detection Unclear risk It was unclear whether the EEG technicians who recorded
bias) the side effects were blinded to the allocation. It was also
All outcomes unclear who recorded the number of successful sedation
and time interval to go to sleep
Incomplete outcome data (attrition bias) High risk Although the number of withdrawals or participants with
All outcomes missing data were not directly stated, it appeared 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 those 28 in a sep-
arate group (who failed Chloral hydrate or hydroxyzine
and received 2nd sedative agent were grouped into chlo-
ral hydrate and hydroxyzine group)
Selective reporting (reporting bias) High risk The pre-specified outcomes of frequency, sleep onset la-
tency, EEG changes ( the amplitude of the background
rhythm, epileptic abnormalities), sleep duration and ad-
verse drug events were reported in the results. An addi-
tional outcome of EEG yield, or the number of abnormal
EEGs, which was specified in our review, were also re-
ported. However, the data for the continuous outcomes
of time of sleep were skewed, and they were reported in
median and range and were unsuitable to be included in
our meta-analysis
Other bias Low risk None identified
D’Agostino 2000
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

1. chloral hydrate (75 mg/kg, maximum 2 g; 11 children)
2. midazolam (0.5 mg/kg, maximum 10 mg; 22 children)
Identically appearing, cherry-flavoured liquids
If inadequately sedated after 30 min, received a supplementary dose of the same medi-
cation at 50% of the original dosage
Outcomes 1. the principal outcome measurement was the ability to induce sufficient sedation
to perform the intended neuroimaging study
2. a secondary efficacy outcome was the proportion of children who required
supplementary medication
3. side effects

D’Agostino 2000 (Continued)
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
Random sequence generation (selection Low risk Methods: “A randomized sequence of 100
bias) 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 per-
son performing the randomisation to en-
able an assessment on whether random se-
quence was generated independently from
allocation
Blinding of participants and personnel Low risk Methods: “Children were administered
(performance bias) freshly prepared, identically appearing,
All outcomes cherry flavored liquids in body weight
equivalent volumes...... Neither the patient
nor any of the investigators were aware
of the active component given to individ-
ual patients.” Blinding of participants were
well described
Blinding of outcome assessment (detection Low risk Neither the patient nor any of the investi-
bias) gators were aware of the active component
All outcomes given to individual patients
Incomplete outcome data (attrition bias) Low risk Results: “Randomized children who did
All outcomes not complete the protocol included one
with respiratory distress, one who ate a full
meal prior to intended drug administra-
tion, one who fell asleep after intravenous
line placement and four patients who can-
celled their appointments after randomiza-
tion.” Due to an unexpectedly high seda-
tion 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 one arm

D’Agostino 2000 (Continued)
Selective reporting (reporting bias) Low risk The pre-specified outcomes of the ability to
induce sufficient sedation , duration of se-
dation, maximum change in anxiety scores,
proportion of patients who required sup-
plementary medication and side effect were
reported in the results
Other bias Low risk None identified
Fallah 2013
Methods Single-blinded, single-centre RCT (Iran)
Participants Children aged 1 to 10 years, referred to CT centre for elective brain CT scan. These
children were in ASA class 1 or 2. 60 children were recruited

1. 100 mg/kg oral chloral hydrate with 1 mL of intranasal normal saline as placebo
(30 children)
2. 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
Random sequence generation (selection Low risk “The trial used computer generated equal
bias) 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 col-
lectors, outcome assessors and data analysts
were all kept blinded to the allocation.”
The stated method of randomisation was use
of a computer-generated equal randomisa-
tion 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

Fallah 2013 (Continued)
Blinding of participants and personnel Low risk “Randomisation and blinding was done by
(performance bias) an investigator with no clinical involvement
All outcomes in the trial. Data collectors, outcome asses-
sors 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 nor-
mal 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 medica-
tions, as both were served (either one is
placebo). Even though intranasal normal
saline and oral normal saline (as placebo)
taste differently from the medications, chil-
dren would not be able to tell what the ac-
tual medications they received were
The investigators were not involved in the
trial.
Blinding of outcome assessment (detection Low risk “The trial used computer generated equal
bias) randomization and allocation ratio was 1:
All outcomes 1 for the two groups. Randomisation and
All the personnel involved in the assessment
were blinded.
Incomplete outcome data (attrition bias) Low risk Even though the author did not report any
All outcomes withdrawals or missing data, it appeared that
all of the 60 children who were initially ran-
domised 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 ad-
equate sedation and completing of CT scan.
Secondary outcomes included clinical side
effects, serious adverse events.”
The author reported data on rate of success-
ful CT brain and Ramsay Sedation Score
for the primary outcomes. In addition, time
from drug administration to adequately se-
dated, time after taking the drug to complet-
ing CT scan, caregiver’s satisfaction scale,

Fallah 2013 (Continued)
and total stay time in CT centre were also

reported
Gumus 2015
Participants 160 children who were unco-operative during EEG recording or who were referred to
our electrodiagnostic unit for sleep EEG recording. All children were classified as ASA
class I or class II

1. oral dexmedetomidine (dose 2 ug/kg; 42 children)
2. oral dexmedetomidine (dose 3 ug/kg; 42 children)
3. oral chloral hydrate (dose 50 mg/kg; 36 children)
4. oral chloral hydrate (dose 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
Random sequence generation (selection Low risk “The patients were randomly allocated to 1 of the 4
bias) groups by a computer-generated drawing lot.” The chil-
dren 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 pe-
diatric neurologist in all patients.” It was unclear whether
random sequence was generated independently from al-
location
Blinding of participants and personnel High risk “Sedative agents were prepared and administered by a
(performance bias) trained nurse under the supervision of the attending pe-
All outcomes diatric neurologist in all patients.” “In groups D1 and
D2, corresponding amounts of dexmedetomidine (Pre-
cedex 100 mg/mL; Abbott Laboratories, IL) in 3mL nor-

Gumus 2015 (Continued)
mal saline were given to patients via the oral route. In the
D1 and D2 groups, patients received oral dexmedetomi-
dine 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
are different in taste and quantity (amount served)
Blinding of outcome assessment (detection Unclear risk Status of data collectors, outcome assessors, and data an-
bias) alysts was not mentioned
All outcomes
Incomplete outcome data (attrition bias) Low risk “Overall, 160 patients (85 male and 75 female) were in-
All outcomes cluded in this study.”
Even though the author did not report any withdrawals
or missing data, it appeared that all of the 160 children
who were initially randomised were analysed, as calcu-
lated 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 chlo-
ral hydrate and dexmedetomidine in achieving adequate
sedation for sleep EEG recordings in children.”
“The primary aim of the study was to evaluate the ef-
ficacy of sedation induction for successful recording of
sleep EEG. Secondary outcome measures included times
of sedation and adverse effects of different dexmedeto-
midine and chloral hydrate doses.”
The prespecified outcome of sedation failure rate in each
group, as well as induction time, recovery time, and ad-
verse reactions were evaluated
Loewy 2005
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 between:

1. chloral hydrate administered orally at 60 mg/kg (up to a maximum of 1.5 g; 34
children)
2. music therapy whereby child was played and sung soothing music according to
caregiver’s request (24 children)

Loewy 2005 (Continued)
Outcomes 1. child’s level of sleep/sedation during procedure using Beth Israel Medical Center
sedation scale
2. time to achieve sleep/sedation from the onset of the intervention
3. 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
Random sequence generation (selection High risk Method: “The subjects were identified and assigned to one
bias) 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 sub-
jects recruited on Tuesdays received music therapy.”
Quasi-randomisation was performed according to the day
children were recruited, which is predictable. In addition,
the allocation of the 58 children to these 2 groups was
not balanced, with 34 in the music therapy group and 24
in the chloral hydrate group. Data were also skewed with
the mean age of children assigned to music therapy group
(mean 2.44) being lower than the mean age assigned to the
chloral hydrate group (mean 3.21), 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 sub-
jects 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 High risk Blinding was not possible, as participants received com-
(performance bias) pletely different modality of intervention (either chloral
All outcomes hydrate or music therapy)
Blinding of outcome assessment (detection High risk The authors did not state whether the outcome assessors
bias) were blinded to the allocation, however blinding seems
All outcomes 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

Loewy 2005 (Continued)
of which required a subjective assessment, non-blinding of

personnel could have influenced the care of the participants
and 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 mu-
sic therapy taking place
Incomplete outcome data (attrition bias) Low risk Results: “Of the total, 2 children (1 from each group: music
All outcomes 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 inter-
acted 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 re-
ported as a categorical outcome (scale of score 0 to 5) in
medication, however the outcome was reported inappro-
priately whereby the author reported sleep score 4 for chlo-
ral hydrate and sleep score 3 for music therapy, making it
unsuitable for direct comparison
Lopez 1995
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

Lopez 1995 (Continued)
Outcomes 1. time to achieve sleep/sedation from the onset of the intervention

2. sleep duration
3. EEG artefact due to sedative agent
Notes Article was in Spanish, and assessment was performed with English translation
Risk of bias
Random sequence generation (selection Low risk The assignment was based on coin tossing for sedation
bias) 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 Unclear risk “the EEG tracings were analyzed by two medical electro-
(performance bias) encephalographers (EM, LT) who did not know what seda-
All outcomes tives were administered and who were asked to review pos-
sible base alterations attributable to a sedative (impregna-
tion), and to what medication it was attributed to”
It is unclear whether or not participants and personnel were
blinded
Blinding of outcome assessment (detection Low risk “the EEG tracings were analyzed by two medical electro-
bias) encephalographers (EM, LT) who did not know what seda-
All outcomes tives were administered and who were asked to review pos-
sible base alterations attributable to a sedative (impregna-
tion), and to what medication it was attributed to”
2 independent electroencephalographers interpreted the
EEG result
Incomplete outcome data (attrition bias) High risk Participants dropped out of the midazolam group, as EEG
All outcomes 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 la-
tency 21.8 ± 17.5 min; and duration of sleep 61 ± 31.2
min)

Malviya 2004
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 between:
1. chloral hydrate (75 mg/kg orally up to maximum dose of 2 g; 35 children)
2. 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 Se-
dation Scale (scale of 0 to 4 with score 4 being unrousable, i.e. sedation successful)
Secondary outcome measures included:
1. quality of MRI scans (score 1 to 3; with score 3 major motion artefact with scan
incomplete);
2. parents’ overall satisfaction with sedation experience (score 1 to 4; score 4 = very
satisfied);
3. procedural adverse events.
Notes
Risk of bias
Random sequence generation (selection Low risk Method: “Using random number tables, children were ran-
bias) domized to one of two study groups. Group 1 received in-
cremental 2 mg/kg) intravenous (i.v.) doses of PB, titrated
to a maximum of 5 mg/kg or 150 mg, administered ap-
proximately 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 High risk It was not stated whether participants and personnel were
(performance bias) blinded to the allocation. However, blinding seems unlikely
All outcomes due to the different routes of administration of the inter-
ventions
Blinding of outcome assessment (detection Unclear risk It was not stated whether the outcome assessors were
bias) blinded to the allocation
All outcomes
Incomplete outcome data (attrition bias) Low risk No withdrawals were reported. Although the children with
All outcomes missing data were not specifically reported, it appears that
all the 70 children who were initially randomised were anal-
ysed as calculated from the results section

Malviya 2004 (Continued)
Selective reporting (reporting bias) Low risk The prespecified outcomes of success of sedation using Uni-
versity 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
Marti-Bonmati 1995
Methods Double-blinded, single-centre RCT (Spain)
Participants 97 consecutive children receiving sedation for MRI

1. oral chloral hydrate (70 mg/kg; 50 children)
2. 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
Random sequence generation (selection Low risk Materials and methods: “We entered 97
bias) 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 phar-
macy department.” As described above,al-
location concealment occurred as chloral
hydrate medication of 2 different concen-
trations of the same flavour were made by
pharmacy

Marti-Bonmati 1995 (Continued)
Blinding of participants and personnel Low risk As described above, blinding occurred for
(performance bias) participants and personnel as chloral hy-
All outcomes drate medication of 2 different concentra-
tions of the same flavour and volume were
made by pharmacy
Blinding of outcome assessment (detection Low risk A nurse performed the outcome assess-
bias) ment. Although not stated, it is likely that
All outcomes blinding of outcome assessment occurred
for the reasons stated above
Incomplete outcome data (attrition bias) Low risk No withdrawals were reported and no miss-
All outcomes ing data were directly stated. It appeared
all the 97 children who were initially ran-
domised were analysed as calculated from
the results section
Selective reporting (reporting bias) Low risk The pre-specified outcomes of mean time
to onset of sedation, mean time to sponta-
neous awakening, effectiveness of sedation
and adverse reactions were reported in the
results
Razieh 2013
Participants 60 children seen in clinic or inpatient referred to EEG unit by a paediatric neurologist
Interventions 2-arm comparison of efficacy of sedation between:

1. chloral hydrate (70 mg/kg orally single dose; 30 children)
2. 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 admin-
istration 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

Razieh 2013 (Continued)
Random sequence generation (selection Low risk Subjects and methods: “The trial used computer generated
bias) 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 gener-
ated random number list and blinding was done by employ-
ing 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 as-
sessment and staff that delivered the intervention. The drug
was delivered by EEG staff and primary and secondary out-
comes 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 measure-
ments and trial results.”
Blinding of participants and personnel Unclear risk As above, it was stated that outcome assessors were blinded
(performance bias) to the allocation of sedation to the child. It was not stated if
All outcomes the children were blinded to the allocation. Although both
forms of sedation were given orally diluted in water, it is pos-
sible that they had a different appearance and taste, which
could have affected participant blinding
Blinding of outcome assessment (detection Low risk As stated above

bias)
All outcomes
Incomplete outcome data (attrition bias) Low risk No withdrawals were reported, and no missing data were
All outcomes directly stated. It appears that all 60 children who were ini-
tially randomised were analysed as calculated from the find-
ings section of the proportion of children who achieved ad-
equate 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 seda-
tion, time after taking drug to record EEG, caregiver’s sat-
isfaction scale, and stay time in EEG unit were reported in
the results

Sezer 2013
Participants 282 children from 1 hospital referred for a sleep EEG recording
Interventions 2-arm comparison study of efficacy of sedation between:

1. 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)
2. 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 dura-
tion
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
Random sequence generation (selection Unclear risk Subjects and methods: “The trial used computer gener-
bias) ated 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 randomi-
sation process and the person performing the randomi-
sation to enable an assessment on whether random se-
quence was generated independently from allocation
Blinding of participants and personnel Unclear risk Materials and methods: “These patients were randomly
(performance bias) divided into two groups of 141: a CH group and a HH
All outcomes 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 alloca-
tion. Despite stating that chloral hydrate was mixed with
milk, juice or yoghurt; they did not say that followed this
same method of mixing 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 Unclear risk It was unclear if the personnel who collected the outcome
bias) data were blinded to the allocation
All outcomes
Sezer 2013 (Continued)
All outcomes missing data were 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 pre-specified 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 spec-
ified in our review, were also reported
Thompson 1982
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:

1. oral chloral hydrate (80 mg/kg, max 2 g; 140 children)
2. intramuscular AMPS cocktail (0.08 mL/kg; 139 children)
Inpatient arm:
1. general anaesthesia (101 children)
2. oral chloral hydrate (80 mg/kg, max 2 g; 101 children)
3. intramuscular AMPS cocktail (0.08 mL/kg; 101 children)
Supplementation with intravenous secobarbital if necessary, 2 mg/kg (max)
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
Random sequence generation (selection High risk “Both groups included all children from birth through their
bias) 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 ex-
cluded 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

Thompson 1982 (Continued)
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 out-
patients, general anesthesia was usually given, but not as
part of the inpatient randomization. For inpatients, the ro-
tational assignment included general anesthesia but gener-
ally 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 preditable, thus risk of bias was high
Blinding of participants and personnel High risk “... two sedation methods, one oral and one intramuscular,
(performance bias) were chosen ...”
All outcomes “... 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 Unclear risk Blinding of outcome assessment was not stated.
bias)
All outcomes
Incomplete outcome data (attrition bias) High risk Randomised sedation (582) = outpatient (279) + inpatient
All outcomes (303); only 129 outpatient and 207 inpatient were reviewed
Significant dropout/portions of missing data (42.3%). De-
tails 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 out-
come 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 re-
viewed from the randomised group of 279, and 207 inpa-
tients were reviewed from the randomised group of 303
Details of the proportion of children requiring supplemen-
tation with an additional sedative agent were insufficient/
unclear

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
Cortellazzi 2007 Retrospective study on the efficacy of chloral hydrate sedation and supplementation with sevoflurane, intra-
muscular 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 (ages 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 This was an RCT, however, 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. Did 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 who underwent EEG. Children in the
2 groups being compared were recruited at different periods. Basis of exclusion: study design

(Continued)
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 (a review article). Basis of exclusion: type of article
Eich 2011 Comparative observational study aiming to evaluate 2 institutional anaesthetic protocols for children under-
going elective MRI: propofol only vs propofol plus S-ketamine. Not an RCT (a comparative observational
study) and did not meet eligibility criteria for types of intervention (propofol and ketamine). Basis of exclu-
sion: study design and intervention
Fallah 2014 This was an RCT. Children aged 1 to 7 years who did not naturally sleep and were unco-operative for EEG
were recruited. Children were in ASA class 1 (healthy persons) or 2
90 children (39 girls and 51 boys) aged 3.34 ± 1.47 years were investigated
3-arm comparison:
1. chloral hydrate 40 mg/kg
2. chloral hydrate 40 mg/kg and promethazine 1 mg/kg
3. chloral hydrate 40 mg/kg and hydroxyzine 2 mg/kg
All intervention and comparison groups received chloral hydrate, making them not the intervention of interest
Basic of exclusion: type of intervention.
Fallah 2014a 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:
1. chloral hydrate 40 mg/kg and hydroxyzine 2 mg/kg
2. chloral hydrate 40 mg/kg and midazolam 0.5 mg/kg
Both intervention and comparison groups received chloral hydrate, making them 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 oph-
thalmic 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

(Continued)
Greenberg 1994 Prospective non-randomised study evaluating the safety and efficacy of thioridazine as an adjunct to chloral
hydrate sedation in children undergoing MR imaging who are 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 criteria for types of intervention (no comparison). Basis of exclusion: study design
and intervention
Gupta 2010 This was an oral presentation abstract to determine if currently available evidence supports 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 for infants and
intravenous pentobarbital for older children. Not an RCT (non-comparative retrospective study). Basis of
exclusion: study design
Kannikeswaran 2009 Retrospective study of children 1 to 18 years who required sedation for an elective brain MRI. Children <
2 years of age were sedated with oral chloral hydrate, while 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 did 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 were sedated with chloral hydrate (no
comparison). This study was not an RCT (non-comparative retrospective study) and did not meet eligibility
of types of study design, population, 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 did 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 ran-
domly assigned to receive intranasal dexmedetomidine at various doses. The study did not meet eligibility
criteria for types of intervention (only used intranasal dexmedetomidine for those who failed chloral hydrate

(Continued)
sedation) and types of comparison used

Basis of exclusion: type of intervention.
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 (a retrospective study evaluating efficacy of chloral hydrate)
and did 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 propo-
fol) 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. Did not
meet eligibility criteria 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 computed tomography
scanning after extracorporeal membrane oxygenation bypass were re-emitted for the study. The order of
neuroimaging studies was randomised. For the first study, chloral hydrate was given orally. 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 observation study of efficacy of clonidine as sedating agent in children with autism undergoing
EEG. Not an RCT and did not meet eligibility criteria of type of intervention (did not use chloral hydrate
for sedation). Basis of exclusion: study design and type of intervention
Nichols 2005 Retrospecitive review of children who failed sedation using chloral hydrate or midazolam for diagnostic brain
imaging. Not an RCT. Basis of exclusion: study design
Reynolds 2016 Double-blinded RCTs comparing efficacy of intranasal dexmedetomidine and oral chloral hydrate for auditory
brainstem response in children. Did not meet eligibility criteria for type of participant (sedation was used for
auditory test not neurodiagnostic procedure)
Basis of exclusion: population type.
Ronchera-Oms 1994 Retrospective review of efficacy of chloral hydrate sedation for children undergoing brain MRI scan. Not an
RCT and did not meet eligibility criteria for types 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 the participants were randomised. Basis
of exclusion: study design

(Continued)
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 did not meet eligibility criteria for type of intervention (children over 2 years old were given
IV medication not chloral hydrate). Also did not meet eligibility criteria for type of comparison (looked at
effectiveness of sedation protocol without comparing with 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 did not meet eligibility
criteria for type of outcome measure (assessed whether sedatives alter EEG recording, did not assess success
of sedation). Basis of exclusion: study design and type of outcome measure
Treluyer 2004 Retrospective study assessing efficacy of chloral hydrate sedation for brain CT or MRI. Not an RCT and
did not meet eligibility criteria for type of comparison (only assessed efficacy of chloral hydrate). Basis of
exclusion: study design and type of intervention
Wang 2005 RCT assessing effect of sedation (chloral hydrate) versus sleep deprivation on brain EEG results. Did not
meet eligibility criteria for type of comparison (as no other sedative agent was used) and type of outcome
measure (assessed effect of sedation on EEG results, did not assess success of sedation). Basis of exclusion:
type of intervention and type of outcome measure
Yuen 2017 Retrospective study comparing melatonin versus chloral hydrate as 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 as compared to a
second dose of chloral hydrate in children who had 1 dose of chloral hydrate while undergoing non-invasive
diagnostic procedures. Basis of exclusion: intervention
ASA: American Society of Anesthesiologists

EEG: electroencephalogram
IV: intravenous
RCT: randomised controlled trial

Characteristics of studies awaiting assessment [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. Neither the child, nor any of the investigators, nor
the healthcare providers knew 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

1. chloral hydrate (75 mg/kg, maximum dose of 2 g)
2. 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 in 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


DATA AND ANALYSES
Comparison 1. Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2 mg/kg or 3 mg/kg)
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 EEG time onset for adequate 1 160 Mean Difference (IV, Fixed, 95% CI) -3.86 [-5.12, -2.60]
sedation (minutes)
1.1 high dose (100 mg/kg 1 82 Mean Difference (IV, Fixed, 95% CI) -5.60 [-7.33, -3.87]
chloral hydrate vs 3ug/kg
dexmetodimidine
1.2 low dose (50mg/kg 1 78 Mean Difference (IV, Fixed, 95% CI) -1.90 [-3.74, -0.06]
chloral hydrate vs 2ug/kg
dexmetodimidine
2 EEG sedation failure 1 160 Risk Ratio (M-H, Fixed, 95% CI) 1.14 [0.51, 2.53]
2.1 high dose 1 82 Risk Ratio (M-H, Fixed, 95% CI) 0.70 [0.12, 3.97]
2.2 low dose 1 78 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.54, 3.32]
3 EEG sedation / sleep duration 1 164 Mean Difference (IV, Fixed, 95% CI) 16.31 [9.15, 23.46]
(minutes)
3.1 high dose 1 82 Mean Difference (IV, Fixed, 95% CI) 21.70 [11.76, 31.64]
3.2 low dose 1 82 Mean Difference (IV, Fixed, 95% CI) 10.5 [0.19, 20.81]
4 EEG sedation adverse event: 1 160 Risk Ratio (M-H, Fixed, 95% CI) 7.66 [1.78, 32.91]
total
hypotension
bradycardia
behavioural change
nausea or vomiting
oxygen desaturation

Comparison 2. Chloral hydrate oral (75 mg/kg) versus pentobarbital intravenous (5 mg/kg)
No. of No. of
1 Neuroimaging time onset for 1 70 Mean Difference (IV, Fixed, 95% CI) 19.0 [16.61, 21.39]
adequate sedation (minutes)
2 Neuroimaging sedation failure 1 70 Risk Ratio (M-H, Fixed, 95% CI) 3.0 [0.33, 27.46]
after 2 administrations of
sedative agent (same or
different)
after 1 administration of
sedative agent
4 Neuroimaging uninterpretable 1 54 Risk Ratio (M-H, Fixed, 95% CI) 0.23 [0.03, 1.94]
5 Neuroimaging sedation adverse 1 70 Risk Ratio (M-H, Fixed, 95% CI) 0.67 [0.21, 2.16]
event: oxygen desaturation
event: nausea or vomiting
event: paradoxical reaction
8 Neuroimaging sedation adverse 1 70 Mean Difference (IV, Fixed, 95% CI) -6.0 [-11.43, -0.57]
event: return to baseline
activity postdischarge
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)
No. of No. of
1 Neuroimaging time onset for 1 60 Mean Difference (IV, Fixed, 95% CI) 12.83 [7.22, 18.44]
2 Neuroimaging inadequate level 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.11 [0.03, 0.44]
of sedation achieved (Ramsay
score 4)
sedative agent
4 Neuroimaging sedation / sleep 1 33 Mean Difference (IV, Fixed, 95% CI) 19.0 [-3.40, 41.40]
duration (minutes)
5 EEG sedative-induced artefact 1 198 Risk Ratio (M-H, Fixed, 95% CI) 0.58 [0.44, 0.76]
total
7 Neuroimaging adverse event: 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.33 [0.01, 7.87]
behavioural change
8 Neuroimaging adverse event: 2 93 Risk Ratio (M-H, Fixed, 95% CI) 5.29 [0.84, 33.14]
vomiting
with intranasal midazolam
with oral midazolam
Comparison 4. Chloral hydrate oral (50 mg/kg) versus melatonin oral
No. of No. of
total
Comparison 5. Chloral hydrate oral (50 mg/kg + 50 mg/kg) versus hydroxyzine hydrochloride oral (1 mg/kg + 1
mg/kg)
No. of No. of
sedation (minutes)
3 EEG sedation / sleep duration 1 282 Mean Difference (IV, Fixed, 95% CI) 3.10 [2.23, 3.97]
(minutes)
behavioural change
nausea or vomiting
7 EEG failure after 1 1 282 Risk Ratio (M-H, Fixed, 95% CI) 0.5 [0.18, 1.43]
administration of sedative
agent
Comparison 6. Chloral hydrate oral (70 mg/kg) versus promethazine oral (1 mg/kg)
No. of No. of
1 EEG time for adequate sedation 1 60 Mean Difference (IV, Fixed, 95% CI) -12.11 [-18.48, -5.
(minutes) 74]
2 EEG inadequate level of EEG 1 60 Risk Ratio (M-H, Fixed, 95% CI) 0.03 [0.00, 0.45]
sedation achieved (Ramsay
score 4)
behavioural change
vomiting or nausea
6 EEG Ramsay Sedation Score 1 60 Mean Difference (IV, Fixed, 95% CI) 1.53 [1.00, 2.06]
sedative agent
Comparison 7. Chloral hydrate oral (60 mg/kg) versus music therapy
No. of No. of
1 EEG time onset for adequate 1 58 Mean Difference (IV, Fixed, 95% CI) 9.0 [-2.15, 20.15]
sedation (minutes)
3 EEG sedation / sleep duration 1 58 Mean Difference (IV, Fixed, 95% CI) 160.0 [121.07, 198.
(minutes) 93]
Comparison 8. Chloral hydrate oral (50 mg/kg) versus midazolam rectal (1 mg/kg)
No. of No. of
1 EEG time onset for adequate 1 59 Mean Difference (IV, Fixed, 95% CI) -95.7 [-114.51, -76.
sedation (minutes) 89]
2 EEG sedation/ sleep duration 1 59 Mean Difference (IV, Fixed, 95% CI) 15.1 [3.35, 26.85]
(minutes)
Comparison 9. High-dose chloral hydrate (100 mg/kg) versus low-dose chloral hydrate (70 mg/kg)
No. of No. of
1 Neuroimaging time onset for 1 97 Mean Difference (IV, Fixed, 95% CI) -7.0 [-7.62, -6.38]
sedative agent
3 Neuroimaging sedation / sleep 1 97 Mean Difference (IV, Fixed, 95% CI) 8.0 [5.81, 10.19]
duration (minutes)
event: total
Comparison 10. High-dose chloral hydrate (100 mg/kg) versus low-dose chloral hydrate (50 mg/kg)
No. of No. of
sedation (minutes)
3 EEG sedation/sleep duration 1 76 Mean Difference (IV, Fixed, 95% CI) 17.80 [8.50, 27.10]
(minutes)
total
behavioural change
nausea or vomiting
oxygen desaturation

Analysis 1.1. Comparison 1 Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2
mg/kg or 3 mg/kg), Outcome 1 EEG time onset for adequate sedation (minutes).
Review: Chloral hydrate as a sedating agent for neurodiagnostic procedures in children
Comparison: 1 Chloral hydrate oral (50 mg/kg or 100 mg/kg) versus dexmedetomidine oral (2 mg/kg or 3 mg/kg)
Outcome: 1 EEG time onset for adequate sedation (minutes)
Mean Mean
Study or subgroup Chloral hydrate dexmedetomidine Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI
1 high dose (100 mg/kg chloral hydrate vs 3ug/kg dexmetodimidine

Gumus 2015 40 28.9 (4) 42 34.5 (4) 53.0 % -5.60 [ -7.33, -3.87 ]
Subtotal (95% CI) 40 42 53.0 % -5.60 [ -7.33, -3.87 ]

Heterogeneity: not applicable
Test for overall effect: Z = 6.34 (P < 0.00001)
2 low dose (50mg/kg chloral hydrate vs 2ug/kg dexmetodimidine
Gumus 2015 36 34 (4.6) 42 35.9 (3.5) 47.0 % -1.90 [ -3.74, -0.06 ]
Subtotal (95% CI) 36 42 47.0 % -1.90 [ -3.74, -0.06 ]

Test for overall effect: Z = 2.03 (P = 0.043)
Total (95% CI) 76 84 100.0 % -3.86 [ -5.12, -2.60 ]
Heterogeneity: Chi2 = 8.25, df = 1 (P = 0.004); I2 =88%
Test for subgroup differences: Chi2 = 8.25, df = 1 (P = 0.00), I2 =88%
-10 -5 0 5 10
Favours chloral hydrate Favours dexmedetomidine

mg/kg or 3 mg/kg), Outcome 2 EEG sedation failure.
Outcome: 2 EEG sedation failure
Study or subgroup Chloral hydrate dexmedetomidine Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 high dose
Gumus 2015 2/40 3/42 31.2 % 0.70 [ 0.12, 3.97 ]
Subtotal (95% CI) 40 42 31.2 % 0.70 [ 0.12, 3.97 ]

Total events: 2 (Chloral hydrate), 3 (dexmedetomidine)
2 low dose
Gumus 2015 8/36 7/42 68.8 % 1.33 [ 0.54, 3.32 ]
Subtotal (95% CI) 36 42 68.8 % 1.33 [ 0.54, 3.32 ]

Total (95% CI) 76 84 100.0 % 1.14 [ 0.51, 2.53 ]
Heterogeneity: Chi2 = 0.42, df = 1 (P = 0.52); I2 =0.0%
Test for subgroup differences: Chi2 = 0.41, df = 1 (P = 0.52), I2 =0.0%
0.01 0.1 1 10 100


mg/kg or 3 mg/kg), Outcome 3 EEG sedation / sleep duration (minutes).
Outcome: 3 EEG sedation / sleep duration (minutes)
Mean Mean
Study or subgroup Chloral hydrate dexmedetomidine Difference Weight Difference
1 high dose
Gumus 2015 40 70 (15.8) 42 48.3 (28.6) 51.8 % 21.70 [ 11.76, 31.64 ]
Subtotal (95% CI) 40 42 51.8 % 21.70 [ 11.76, 31.64 ]

2 low dose
Gumus 2015 40 52.2 (24.2) 42 41.7 (23.4) 48.2 % 10.50 [ 0.19, 20.81 ]
Subtotal (95% CI) 40 42 48.2 % 10.50 [ 0.19, 20.81 ]

Total (95% CI) 80 84 100.0 % 16.31 [ 9.15, 23.46 ]
Heterogeneity: Chi2 = 2.35, df = 1 (P = 0.13); I2 =57%
Test for subgroup differences: Chi2 = 2.35, df = 1 (P = 0.13), I2 =57%
-100 -50 0 50 100


mg/kg or 3 mg/kg), Outcome 4 EEG sedation adverse event: total.
Outcome: 4 EEG sedation adverse event: total
1 high dose
Gumus 2015 10/40 1/42 51.4 % 10.50 [ 1.41, 78.33 ]
Subtotal (95% CI) 40 42 51.4 % 10.50 [ 1.41, 78.33 ]

2 low dose
Gumus 2015 4/36 1/42 48.6 % 4.67 [ 0.55, 39.89 ]
Subtotal (95% CI) 36 42 48.6 % 4.67 [ 0.55, 39.89 ]

Total (95% CI) 76 84 100.0 % 7.66 [ 1.78, 32.91 ]
0.001 0.01 0.1 1 10 100 1000


mg/kg or 3 mg/kg), Outcome 5 EEG sedation adverse event: hypotension.
Outcome: 5 EEG sedation adverse event: hypotension
1 high dose
Gumus 2015 0/40 1/42 100.0 % 0.35 [ 0.01, 8.34 ]
Subtotal (95% CI) 40 42 100.0 % 0.35 [ 0.01, 8.34 ]

2 low dose
Gumus 2015 0/36 0/42 Not estimable
Subtotal (95% CI) 36 42 Not estimable

Test for overall effect: not applicable
Total (95% CI) 76 84 100.0 % 0.35 [ 0.01, 8.34 ]
Test for subgroup differences: Not applicable
0.01 0.1 1 10 100

Favours chloral hydrate Favours dexmetomidine

mg/kg or 3 mg/kg), Outcome 6 EEG sedation adverse event: bradycardia.
Outcome: 6 EEG sedation adverse event: bradycardia
1 high dose

2 low dose
Gumus 2015 0/36 1/42 100.0 % 0.39 [ 0.02, 9.23 ]
Subtotal (95% CI) 36 42 100.0 % 0.39 [ 0.02, 9.23 ]

Total (95% CI) 76 84 100.0 % 0.39 [ 0.02, 9.23 ]
0.01 0.1 1 10 100


mg/kg or 3 mg/kg), Outcome 7 EEG sedation adverse event: behavioural change.
Outcome: 7 EEG sedation adverse event: behavioural change
1 high dose
Gumus 2015 2/40 0/42 100.0 % 5.24 [ 0.26, 105.97 ]
Subtotal (95% CI) 40 42 100.0 % 5.24 [ 0.26, 105.97 ]

2 low dose

Total (95% CI) 76 84 100.0 % 5.24 [ 0.26, 105.97 ]
0.01 0.1 1 10 100


mg/kg or 3 mg/kg), Outcome 8 EEG sedation adverse event: nausea or vomiting.
Outcome: 8 EEG sedation adverse event: nausea or vomiting
1 high dose
Gumus 2015 7/40 0/42 51.3 % 15.73 [ 0.93, 266.73 ]
Subtotal (95% CI) 40 42 51.3 % 15.73 [ 0.93, 266.73 ]

2 low dose
Gumus 2015 3/36 0/42 48.7 % 8.14 [ 0.43, 152.41 ]
Subtotal (95% CI) 36 42 48.7 % 8.14 [ 0.43, 152.41 ]

Total (95% CI) 76 84 100.0 % 12.04 [ 1.58, 91.96 ]
0.001 0.01 0.1 1 10 100 1000


mg/kg or 3 mg/kg), Outcome 9 EEG sedation adverse event: oxygen desaturation.
Outcome: 9 EEG sedation adverse event: oxygen desaturation
1 high dose
Gumus 2015 1/40 0/42 51.3 % 3.15 [ 0.13, 75.05 ]
Subtotal (95% CI) 40 42 51.3 % 3.15 [ 0.13, 75.05 ]

2 low dose
Gumus 2015 1/36 0/42 48.7 % 3.49 [ 0.15, 83.03 ]
Subtotal (95% CI) 36 42 48.7 % 3.49 [ 0.15, 83.03 ]

Total (95% CI) 76 84 100.0 % 3.31 [ 0.35, 31.16 ]
0.01 0.1 1 10 100


Analysis 2.1. Comparison 2 Chloral hydrate oral (75 mg/kg) versus pentobarbital intravenous (5 mg/kg),
Outcome 1 Neuroimaging time onset for adequate sedation (minutes).
Comparison: 2 Chloral hydrate oral (75 mg/kg) versus pentobarbital intravenous (5 mg/kg)
Outcome: 1 Neuroimaging time onset for adequate sedation (minutes)
Mean Mean
Study or subgroup Chloral hydrate Phenobarbitone Difference Weight Difference
Malviya 2004 35 28 (4) 35 9 (6) 100.0 % 19.00 [ 16.61, 21.39 ]
Total (95% CI) 35 35 100.0 % 19.00 [ 16.61, 21.39 ]

-100 -50 0 50 100

Chloral hydrate Phenobarbitone
Outcome 2 Neuroimaging sedation failure after 2 administrations of sedative agent (same or different).
Outcome: 2 Neuroimaging sedation failure after 2 administrations of sedative agent (same or different)
Study or subgroup Chloral hydrate Phenobarbitone Risk Ratio Weight Risk Ratio
Malviya 2004 3/35 1/35 100.0 % 3.00 [ 0.33, 27.46 ]
Total (95% CI) 35 35 100.0 % 3.00 [ 0.33, 27.46 ]

Total events: 3 (Chloral hydrate), 1 (Phenobarbitone)
0.01 0.1 1 10 100


Outcome 3 Neuroimaging sedation failure after 1 administration of sedative agent.
Outcome: 3 Neuroimaging sedation failure after 1 administration of sedative agent
Malviya 2004 13/35 3/35 100.0 % 4.33 [ 1.35, 13.89 ]
Total (95% CI) 35 35 100.0 % 4.33 [ 1.35, 13.89 ]

0.01 0.1 1 10 100

Favours chloral hydrate Favours phenobarbitone
Outcome 4 Neuroimaging uninterpretable.
Outcome: 4 Neuroimaging uninterpretable
Malviya 2004 1/28 4/26 100.0 % 0.23 [ 0.03, 1.94 ]
Total (95% CI) 28 26 100.0 % 0.23 [ 0.03, 1.94 ]

0.01 0.1 1 10 100


Outcome 5 Neuroimaging sedation adverse event: oxygen desaturation.
Outcome: 5 Neuroimaging sedation adverse event: oxygen desaturation
Malviya 2004 4/35 6/35 100.0 % 0.67 [ 0.21, 2.16 ]
Total (95% CI) 35 35 100.0 % 0.67 [ 0.21, 2.16 ]

0.01 0.1 1 10 100

Outcome 6 Neuroimaging sedation adverse event: nausea or vomiting.
Outcome: 6 Neuroimaging sedation adverse event: nausea or vomiting
Malviya 2004 6/35 1/35 100.0 % 6.00 [ 0.76, 47.29 ]
Total (95% CI) 35 35 100.0 % 6.00 [ 0.76, 47.29 ]

0.01 0.1 1 10 100


Outcome 7 Neuroimaging sedation adverse event: paradoxical reaction.
Outcome: 7 Neuroimaging sedation adverse event: paradoxical reaction
Malviya 2004 0/35 5/35 100.0 % 0.09 [ 0.01, 1.58 ]
Total (95% CI) 35 35 100.0 % 0.09 [ 0.01, 1.58 ]

0.001 0.01 0.1 1 10 100 1000

Outcome 8 Neuroimaging sedation adverse event: return to baseline activity postdischarge.
Outcome: 8 Neuroimaging sedation adverse event: return to baseline activity postdischarge
Mean Mean
Study or subgroup Chloral hydrate Phenobarbitone Difference Weight Difference
Malviya 2004 35 11 (10) 35 17 (13) 100.0 % -6.00 [ -11.43, -0.57 ]
Total (95% CI) 35 35 100.0 % -6.00 [ -11.43, -0.57 ]

-100 -50 0 50 100


Analysis 3.1. 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).
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)
Chloral Intranasal
hydrate Mida Mean Mean
Study or subgroup 100mg/kg 0.2mg/kg Difference Weight Difference
Fallah 2013 30 23.75 (15.09) 30 10.92 (4.23) 100.0 % 12.83 [ 7.22, 18.44 ]
Total (95% CI) 30 30 100.0 % 12.83 [ 7.22, 18.44 ]

-100 -50 0 50 100

Favours CH 100mg/kg Favours nasal mida 0.2mg/
mg/kg or oral 0.5 mg/kg), Outcome 2 Neuroimaging inadequate level of sedation achieved (Ramsay score 4).
Outcome: 2 Neuroimaging inadequate level of sedation achieved (Ramsay score 4)
chloral intranasal
hydrate mida
Study or subgroup 100mg/kg 0.2mg/kg Risk Ratio Weight Risk Ratio
Fallah 2013 2/30 18/30 100.0 % 0.11 [ 0.03, 0.44 ]
Total (95% CI) 30 30 100.0 % 0.11 [ 0.03, 0.44 ]

Total events: 2 (chloral hydrate 100mg/kg), 18 (intranasal mida 0.2mg/kg)
0.001 0.01 0.1 1 10 100 1000

Favours chloral hydrate Favours intranasal mida

mg/kg or oral 0.5 mg/kg), Outcome 3 Neuroimaging sedation failure after 1 administration of sedative agent.
Chloral hy-
Study or subgroup drate75mg/kg oral mida 0.5mg/kg Risk Ratio Weight Risk Ratio
D’Agostino 2000 1/11 12/22 100.0 % 0.17 [ 0.02, 1.12 ]
Total (95% CI) 11 22 100.0 % 0.17 [ 0.02, 1.12 ]

Total events: 1 (Chloral hydrate75mg/kg), 12 (oral mida 0.5mg/kg)
0.001 0.01 0.1 1 10 100 1000

Favours CH 75mg/kg Favours mida 0.5mg/kg

mg/kg or oral 0.5 mg/kg), Outcome 4 Neuroimaging sedation / sleep duration (minutes).
Outcome: 4 Neuroimaging sedation / sleep duration (minutes)
Mean Mean
Study or subgroup CH 75mg/kg oral mida 0.5mg/kg Difference Weight Difference
D’Agostino 2000 11 95 (26) 22 76 (39) 100.0 % 19.00 [ -3.40, 41.40 ]
Total (95% CI) 11 22 100.0 % 19.00 [ -3.40, 41.40 ]

-100 -50 0 50 100

mg/kg or oral 0.5 mg/kg), Outcome 5 EEG sedative-induced artefact.
Outcome: 5 EEG sedative-induced artefact
Study or subgroup Chloral hydrate Midazolam Risk Ratio Weight Risk Ratio
Ashrafi 2013 40/98 70/100 100.0 % 0.58 [ 0.44, 0.76 ]
Total (95% CI) 98 100 100.0 % 0.58 [ 0.44, 0.76 ]

Total events: 40 (Chloral hydrate), 70 (Midazolam)
0.01 0.1 1 10 100

Favours chloral hydrate Favours midazolam

mg/kg or oral 0.5 mg/kg), Outcome 6 EEG sedation adverse event: total.
Study or subgroup Chloral hydrate Midazolam Risk Ratio Weight Risk Ratio
Ashrafi 2013 0/98 2/100 100.0 % 0.20 [ 0.01, 4.20 ]
Total (95% CI) 98 100 100.0 % 0.20 [ 0.01, 4.20 ]

Total events: 0 (Chloral hydrate), 2 (Midazolam)
0.01 0.1 1 10 100

Favours chloral hydrate Favours midazolam
mg/kg or oral 0.5 mg/kg), Outcome 7 Neuroimaging adverse event: behavioural change.
Outcome: 7 Neuroimaging adverse event: behavioural change
chloral intranasal
hydrate mida
Fallah 2013 0/30 1/30 100.0 % 0.33 [ 0.01, 7.87 ]
Total (95% CI) 30 30 100.0 % 0.33 [ 0.01, 7.87 ]

0.01 0.1 1 10 100


mg/kg or oral 0.5 mg/kg), Outcome 8 Neuroimaging adverse event: vomiting.
Outcome: 8 Neuroimaging adverse event: vomiting
chloral intranasal
hydrate mida
D’Agostino 2000 2/11 1/22 57.1 % 4.00 [ 0.41, 39.45 ]
Fallah 2013 3/30 0/30 42.9 % 7.00 [ 0.38, 129.93 ]
Total (95% CI) 41 52 100.0 % 5.29 [ 0.84, 33.14 ]

0.002 0.1 1 10 500

mg/kg or oral 0.5 mg/kg), Outcome 9 Neuroimaging sedation failure with intranasal midazolam.
Outcome: 9 Neuroimaging sedation failure with intranasal midazolam
chloral intranasal
hydrate mida
Fallah 2013 7/30 18/30 100.0 % 0.39 [ 0.19, 0.79 ]
Total (95% CI) 30 30 100.0 % 0.39 [ 0.19, 0.79 ]

0.01 0.1 1 10 100


Analysis 3.10. 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.
Outcome: 10 Neuroimaging sedation failure with oral midazolam
Study or subgroup chloral hydrate Oral midazolam Risk Ratio Weight Risk Ratio
D’Agostino 2000 0/11 11/22 100.0 % 0.08 [ 0.01, 1.30 ]
Total (95% CI) 11 22 100.0 % 0.08 [ 0.01, 1.30 ]

Total events: 0 (chloral hydrate), 11 (Oral midazolam)
0.01 0.1 1 10 100


Analysis 4.1. Comparison 4 Chloral hydrate oral (50 mg/kg) versus melatonin oral, Outcome 1 EEG
sedative-induced artefact.
Comparison: 4 Chloral hydrate oral (50 mg/kg) versus melatonin oral
Study or subgroup Chloral hydrate Melatonin Risk Ratio Weight Risk Ratio
Ashrafi 2010 6/174 18/174 100.0 % 0.33 [ 0.14, 0.82 ]
Total (95% CI) 174 174 100.0 % 0.33 [ 0.14, 0.82 ]

Total events: 6 (Chloral hydrate), 18 (Melatonin)
0.01 0.1 1 10 100

Favours chloral hydrate Favours melatonin
Analysis 4.2. Comparison 4 Chloral hydrate oral (50 mg/kg) versus melatonin oral, Outcome 2 EEG
sedation adverse event: total.
Comparison: 4 Chloral hydrate oral (50 mg/kg) versus melatonin oral
Study or subgroup Chloral hydrate Melatonin Risk Ratio Weight Risk Ratio
Ashrafi 2010 4/174 4/174 100.0 % 1.00 [ 0.25, 3.93 ]
Total (95% CI) 174 174 100.0 % 1.00 [ 0.25, 3.93 ]

Total events: 4 (Chloral hydrate), 4 (Melatonin)
0.001 0.01 0.1 1 10 100 1000

Favours chloral hydrate Favours melatonin

Analysis 5.1. 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).
Comparison: 5 Chloral hydrate oral (50 mg/kg + 50 mg/kg) versus hydroxyzine hydrochloride oral (1 mg/kg + 1 mg/kg)
Mean Mean
Study or subgroup chloral hydrate hydroxyzine Difference Weight Difference
Sezer 2013 141 16.2 (1.8) 141 23.7 (1.1) 100.0 % -7.50 [ -7.85, -7.15 ]
Total (95% CI) 141 141 100.0 % -7.50 [ -7.85, -7.15 ]

-10 -5 0 5 10
Favours chloral hydrate Favours hydroxyzine HCL
oral (1 mg/kg + 1 mg/kg), Outcome 2 EEG sedation failure.
Study or subgroup chloral hydrate hydroxyzine Risk Ratio Weight Risk Ratio
Sezer 2013 4/141 12/141 100.0 % 0.33 [ 0.11, 1.01 ]
Total (95% CI) 141 141 100.0 % 0.33 [ 0.11, 1.01 ]

Total events: 4 (chloral hydrate), 12 (hydroxyzine)
0.001 0.01 0.1 1 10 100 1000

Favours Chloral hydrate Favours hydroxyzine

oral (1 mg/kg + 1 mg/kg), Outcome 3 EEG sedation / sleep duration (minutes).
Mean Mean
Study or subgroup chloral hydrate hydroxyzine Difference Weight Difference
Sezer 2013 141 88.2 (2.6) 141 85.1 (4.6) 100.0 % 3.10 [ 2.23, 3.97 ]
Total (95% CI) 141 141 100.0 % 3.10 [ 2.23, 3.97 ]

-20 -10 0 10 20
oral (1 mg/kg + 1 mg/kg), Outcome 4 EEG sedative-induced artefact.
Sezer 2013 8/141 6/141 100.0 % 1.33 [ 0.47, 3.74 ]
Total (95% CI) 141 141 100.0 % 1.33 [ 0.47, 3.74 ]

0.002 0.1 1 10 500


oral (1 mg/kg + 1 mg/kg), Outcome 5 EEG sedation adverse event: behavioural change.
Sezer 2013 7/141 6/141 100.0 % 1.17 [ 0.40, 3.38 ]
Total (95% CI) 141 141 100.0 % 1.17 [ 0.40, 3.38 ]

0.001 0.01 0.1 1 10 100 1000

oral (1 mg/kg + 1 mg/kg), Outcome 6 EEG sedation adverse event: nausea or vomiting.
Sezer 2013 5/141 4/141 100.0 % 1.25 [ 0.34, 4.56 ]
Total (95% CI) 141 141 100.0 % 1.25 [ 0.34, 4.56 ]

0.002 0.1 1 10 500

oral (1 mg/kg + 1 mg/kg), Outcome 7 EEG failure after 1 administration of sedative agent.
Outcome: 7 EEG failure after 1 administration of sedative agent
Sezer 2013 5/141 10/141 100.0 % 0.50 [ 0.18, 1.43 ]
Total (95% CI) 141 141 100.0 % 0.50 [ 0.18, 1.43 ]

0.001 0.01 0.1 1 10 100 1000

Analysis 6.1. Comparison 6 Chloral hydrate oral (70 mg/kg) versus promethazine oral (1 mg/kg), Outcome
1 EEG time for adequate sedation (minutes).
Comparison: 6 Chloral hydrate oral (70 mg/kg) versus promethazine oral (1 mg/kg)
Outcome: 1 EEG time for adequate sedation (minutes)
Mean Mean
Study or subgroup Chloral hydrate Promethazine Difference Weight Difference
Razieh 2013 30 21.73 (7.24) 30 33.84 (16.26) 100.0 % -12.11 [ -18.48, -5.74 ]
Total (95% CI) 30 30 100.0 % -12.11 [ -18.48, -5.74 ]

-100 -50 0 50 100

Favours chloral hydrate Favours promethazine
2 EEG inadequate level of EEG sedation achieved (Ramsay score 4).
Outcome: 2 EEG inadequate level of EEG sedation achieved (Ramsay score 4)
Study or subgroup Chloral hydrate Promethazine Risk Ratio Weight Risk Ratio
Razieh 2013 0/30 17/30 100.0 % 0.03 [ 0.00, 0.45 ]
Total (95% CI) 30 30 100.0 % 0.03 [ 0.00, 0.45 ]

Total events: 0 (Chloral hydrate), 17 (Promethazine)
0.001 0.01 0.1 1 10 100 1000

3 EEG sedation failure.
Razieh 2013 1/30 9/30 100.0 % 0.11 [ 0.01, 0.82 ]
Total (95% CI) 30 30 100.0 % 0.11 [ 0.01, 0.82 ]

0.001 0.01 0.1 1 10 100 1000

4 EEG sedation adverse event: behavioural change.
Razieh 2013 0/30 2/30 100.0 % 0.20 [ 0.01, 4.00 ]
Total (95% CI) 30 30 100.0 % 0.20 [ 0.01, 4.00 ]

0.001 0.01 0.1 1 10 100 1000

5 EEG sedation adverse event: vomiting or nausea.
Outcome: 5 EEG sedation adverse event: vomiting or nausea
Razieh 2013 6/30 0/30 100.0 % 13.00 [ 0.76, 220.96 ]
Total (95% CI) 30 30 100.0 % 13.00 [ 0.76, 220.96 ]

0.002 0.1 1 10 500

6 EEG Ramsay Sedation Score after 1 administration of sedative agent.
Outcome: 6 EEG Ramsay Sedation Score after 1 administration of sedative agent
Mean Mean
Study or subgroup Chloral hydrate Promethazine Difference Weight Difference
Razieh 2013 30 4.4 (0.5) 30 2.87 (1.4) 100.0 % 1.53 [ 1.00, 2.06 ]
Total (95% CI) 30 30 100.0 % 1.53 [ 1.00, 2.06 ]

-10 -5 0 5 10
Analysis 7.1. Comparison 7 Chloral hydrate oral (60 mg/kg) versus music therapy, Outcome 1 EEG time
onset for adequate sedation (minutes).
Comparison: 7 Chloral hydrate oral (60 mg/kg) versus music therapy
Mean Mean
Study or subgroup Chloral hydrate Music therapy Difference Weight Difference
Loewy 2005 24 32 (24.2579) 34 23 (16.3613) 100.0 % 9.00 [ -2.15, 20.15 ]
Total (95% CI) 24 34 100.0 % 9.00 [ -2.15, 20.15 ]

-100 -50 0 50 100

Favours chloral hydrate Favours music therapy
Analysis 7.2. Comparison 7 Chloral hydrate oral (60 mg/kg) versus music therapy, Outcome 2 EEG sedation
failure.
Study or subgroup Chloral hydrate Music therapy Risk Ratio Weight Risk Ratio
Loewy 2005 12/24 1/34 100.0 % 17.00 [ 2.37, 122.14 ]
Total (95% CI) 24 34 100.0 % 17.00 [ 2.37, 122.14 ]

Total events: 12 (Chloral hydrate), 1 (Music therapy)
0.01 0.1 1 10 100

Analysis 7.3. Comparison 7 Chloral hydrate oral (60 mg/kg) versus music therapy, Outcome 3 EEG sedation
/ sleep duration (minutes).
Mean Mean
Study or subgroup Chloral hydrate Music therapy Difference Weight Difference
Loewy 2005 24 226 (94.8713) 34 66 (25.6908) 100.0 % 160.00 [ 121.07, 198.93 ]
Total (95% CI) 24 34 100.0 % 160.00 [ 121.07, 198.93 ]

-500 -250 0 250 500

Analysis 8.1. Comparison 8 Chloral hydrate oral (50 mg/kg) versus midazolam rectal (1 mg/kg), Outcome 1
EEG time onset for adequate sedation (minutes).
Comparison: 8 Chloral hydrate oral (50 mg/kg) versus midazolam rectal (1 mg/kg)
Mean Mean
Study or subgroup rectal chloral hydrate rectal midazolam Difference Weight Difference
Lopez 1995 32 21.8 (17.5) 27 117.5 (47.2) 100.0 % -95.70 [ -114.51, -76.89 ]
Total (95% CI) 32 27 100.0 % -95.70 [ -114.51, -76.89 ]

-200 -100 0 100 200

Favours rectal CH Favours rectal mida
EEG sedation/ sleep duration (minutes).
Outcome: 2 EEG sedation/ sleep duration (minutes)
Mean Mean
Study or subgroup rectal chloral hydrate rectal midazolam Difference Weight Difference
Lopez 1995 32 61 (31.2) 27 45.9 (12.2) 100.0 % 15.10 [ 3.35, 26.85 ]
Total (95% CI) 32 27 100.0 % 15.10 [ 3.35, 26.85 ]

-100 -50 0 50 100

EEG sedative-induced artefact.
Study or subgroup rectal chloral hydrate rectal midazolam Risk Ratio Weight Risk Ratio
Lopez 1995 19/32 10/21 100.0 % 1.25 [ 0.73, 2.12 ]
Total (95% CI) 32 21 100.0 % 1.25 [ 0.73, 2.12 ]

Total events: 19 (rectal chloral hydrate), 10 (rectal midazolam)
0.01 0.1 1 10 100

Analysis 9.1. Comparison 9 High-dose chloral hydrate (100 mg/kg) versus low-dose chloral hydrate (70
mg/kg), Outcome 1 Neuroimaging time onset for adequate sedation (minutes).
Comparison: 9 High-dose chloral hydrate (100 mg/kg) versus low-dose chloral hydrate (70 mg/kg)
Chloral Chloral
hydrate high hydrate low Mean Mean
Study or subgroup dose dose Difference Weight Difference
Marti-Bonmati 1995 47 21 (1) 50 28 (2) 100.0 % -7.00 [ -7.62, -6.38 ]
Total (95% CI) 47 50 100.0 % -7.00 [ -7.62, -6.38 ]

-10 -5 0 5 10
Favours CH high dose Favours CH low dose
mg/kg), Outcome 2 Neuroimaging sedation failure after 1 administration of sedative agent.
Chloral Chloral
hydrate high hydrate low
Study or subgroup dose dose Risk Ratio Weight Risk Ratio
Marti-Bonmati 1995 6/47 14/50 100.0 % 0.46 [ 0.19, 1.09 ]
Total (95% CI) 47 50 100.0 % 0.46 [ 0.19, 1.09 ]

Total events: 6 (Chloral hydrate high dose), 14 (Chloral hydrate low dose)
0.01 0.1 1 10 100

Favours high dose CH Favours low dose CH
mg/kg), Outcome 3 Neuroimaging sedation / sleep duration (minutes).
Outcome: 3 Neuroimaging sedation / sleep duration (minutes)
Chloral Chloral
hydrate high hydrate low Mean Mean
Study or subgroup dose dose Difference Weight Difference
Marti-Bonmati 1995 47 30 (5) 50 22 (6) 100.0 % 8.00 [ 5.81, 10.19 ]
Total (95% CI) 47 50 100.0 % 8.00 [ 5.81, 10.19 ]

-20 -10 0 10 20
mg/kg), Outcome 4 Neuroimaging sedation adverse event: total.
Outcome: 4 Neuroimaging sedation adverse event: total
Chloral Chloral
hydrate high hydrate low
Study or subgroup dose dose Risk Ratio Weight Risk Ratio
Marti-Bonmati 1995 10/47 10/50 100.0 % 1.06 [ 0.49, 2.32 ]
Total (95% CI) 47 50 100.0 % 1.06 [ 0.49, 2.32 ]

Total events: 10 (Chloral hydrate high dose), 10 (Chloral hydrate low dose)
0.01 0.1 1 10 100

mg/kg), Outcome 1 EEG time onset for adequate sedation (minutes).
High dose low dose

CH CH Mean Mean
Study or subgroup 100mg/kg 50mg/kg Difference Weight Difference
Gumus 2015 40 28.9 (4) 36 34 (4.6) 100.0 % -5.10 [ -7.05, -3.15 ]
Total (95% CI) 40 36 100.0 % -5.10 [ -7.05, -3.15 ]

-100 -50 0 50 100

mg/kg), Outcome 2 EEG sedation failure.
High dose low dose

CH CH
Study or subgroup 100mg/kg 50mg/kg Risk Ratio Weight Risk Ratio
Gumus 2015 2/40 8/36 100.0 % 0.23 [ 0.05, 0.99 ]
Total (95% CI) 40 36 100.0 % 0.23 [ 0.05, 0.99 ]

Total events: 2 (High dose CH 100mg/kg), 8 (low dose CH 50mg/kg)
0.01 0.1 1 10 100

mg/kg), Outcome 3 EEG sedation/sleep duration (minutes).
Outcome: 3 EEG sedation/sleep duration (minutes)
High dose low dose

CH CH Mean Mean
Study or subgroup 100mg/kg 50mg/kg Difference Weight Difference
Gumus 2015 40 70 (15.8) 36 52.2 (24.2) 100.0 % 17.80 [ 8.50, 27.10 ]
Total (95% CI) 40 36 100.0 % 17.80 [ 8.50, 27.10 ]

-100 -50 0 50 100

mg/kg), Outcome 4 EEG sedation adverse event: total.
High dose low dose

CH CH
Gumus 2015 10/40 4/36 100.0 % 2.25 [ 0.77, 6.55 ]
Total (95% CI) 40 36 100.0 % 2.25 [ 0.77, 6.55 ]

0.01 0.1 1 10 100

mg/kg), Outcome 5 EEG sedation adverse event: behavioural change.
High dose low dose

CH CH
Gumus 2015 2/40 0/36 100.0 % 4.51 [ 0.22, 90.96 ]
Total (95% CI) 40 36 100.0 % 4.51 [ 0.22, 90.96 ]

0.01 0.1 1 10 100

mg/kg), Outcome 6 EEG sedation adverse event: nausea or vomiting.
High dose low dose

CH CH
Gumus 2015 7/40 3/36 100.0 % 2.10 [ 0.59, 7.52 ]
Total (95% CI) 40 36 100.0 % 2.10 [ 0.59, 7.52 ]

0.01 0.1 1 10 100

mg/kg), Outcome 7 EEG sedation adverse event: oxygen desaturation.
Outcome: 7 EEG sedation adverse event: oxygen desaturation
High dose low dose

CH CH
Gumus 2015 1/40 1/36 100.0 % 0.90 [ 0.06, 13.87 ]
Total (95% CI) 40 36 100.0 % 0.90 [ 0.06, 13.87 ]

0.01 0.1 1 10 100

ADDITIONAL TABLES
Table 1. Outcomes with skewed data as reported by individual studies
Comparison Outcome Study ID Effect estimate P value
Chloral hydrate versus Sleep onset latency Ashrafi 2010 Median (range) in minutes 0.113
melatonin Chloral hydrate group (35
(10 to 150)), melatonin
group (45 (5 to 210))
Sleep duration Ashrafi 2010 Median (range) in minutes 0.0001

Chloral hydrate group (60
(15 to 240)), melatonin
group (30 (15 to 240))
Drowsiness time Ashrafi 2010 Median (range) in minutes 0.0001

(0 to 300)), melatonin group
(20 (0 to 300))
Chloral hydrate versus Sleep onset latency Ashrafi 2013 Median (range) in minutes < 0.001
midazolam Chloral hydrate group (32
(20 to 95)), midazolam
Table 1. Outcomes with skewed data as reported by individual studies (Continued)
group (20 (0 to 300))
Sleep duration Ashrafi 2013 Median (range) in minutes < 0.001

Chloral hydrate group (66.
5 (56 to 98)), midazolam
group (25.5 (12 to 38))
Drowsiness time Ashrafi 2013 Median (range) in minutes < 0.001

(21 to 36)), midazolam
group (6 (2 to 9))
Chloral hydrate versus Time of sleep Bektas 2014 Median (range) in minutes 0.309
hydroxyzine Chloral hydrate group (20 (5
to 120)), hydroxyzine group
(30 (5 to 240))
Excessive fast activity Bektas 2014 Percentage 0.02

Chloral hydrate (24.5%) vs
hydroxyzine (11.6%)
Success in falling asleep Bektas 2014 Percentage 0.841

Chloral hydrate (90.7%) vs
hydroxyzine (89.6%)
Chloral hydrate versus Time to sedation Thompson 1982 Mean (minutes) N/A
intramuscular AMPS Chloral hydrate (55) vs
AMPS (53)
Imaging failure Thompson 1982 Percentage N/A

Chloral hydrate (15%) vs
AMPS (12%)
AMPS: atropine/meperidine/promethazine/secobarbital
N/A: not applicable
APPENDICES
Appendix 1. MEDLINE (PubMed) 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]
(Continued)
#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]
(Continued)
#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 2. CENTRAL 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
(Continued)
#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
(Continued)
#48 #43 OR #44 OR #45 OR #46 OR #47
#49 #12 and (#18 or #42) and #48 in trials
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
(Continued)
#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
(Continued)
#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
CONTRIBUTIONS OF AUTHORS
All authors participated in writing the draft review. NML developed the ’Summary of findings’ table.
DECLARATIONS OF INTEREST
CYF: none known.
CGT: none known.
LCO: none known.
NML: none known.
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.
This review was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Epilepsy.
The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews
Programme NIHR, National Health Service (NHS), or the Department of Health.
DIFFERENCES BETWEEN PROTOCOL AND REVIEW

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 Ramsay score of below 4 (see Summary of findings 6).

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Cochrane Database of Systematic Reviews

Chloral hydrate as a sedating agent for neurodiagnostic

Fong CY, Tay CG, Ong LC, Lai NM

Fong CY, Tay CG, Ong LC, Lai NM.

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review)

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) ii

Chloral hydrate as a sedating agent for neurodiagnostic

Editorial group: Cochrane Epilepsy Group.

PLAIN LANGUAGE SUMMARY

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 3

Patient or population: children undergoing neurodiagnostic procedures

Risk with dexmedeto- Risk with chloral hy-

Proportion of children - - - - - No study f or this com -

Proportion of children - - - - - No study f or this com -

Proportion of children Study population RR 1.14 160 ⊕⊕⊕

Num ber of children with Study population RR 7.66 160 ⊕⊕

GRADE Working Group grades of evidence

dexm edetom idine (2 m g/ kg and 3 m g/ kg), each of which consisted of 40 children.

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 7

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 8

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 9

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 10

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 11

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 12

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 13

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 14

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 15

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 16

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 17

Comparison 1: Chloral hydrate versus Secondary outcomes

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 18

Adverse effects (any)

Comparison 2: Chloral hydrate versus pentobarbital Yield of EEG or neuroimaging findings

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 19

Yield of EEG or neuroimaging findings

Comparison 4: Chloral hydrate versus melatonin

Proportion of children who required a further dose of either

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 20

Secondary outcomes Time to Adequate sedation (minutes or as measured by

Yield of EEG or neuroimaging findings

Comparison 5: Chloral hydrate versus hydroxyzine Yield of EEG or neuroimaging findings

Adverse effects (behavioural change and nausea or vomiting)

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 21

Time to Adequate sedation (minutes or as measured by

Time to adequate sedation (minutes or as measured by

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 22

Proportion of children who had sedation failure or

Yield of EEG or neuroimaging findings

Comparison 8: Chloral hydrate versus midazolam

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 23

Time to adequate sedation (minutes or as measured by

Sedation duration Secondary outcomes

The duration of sedation was longer in the high-dose oral chlo-

Comparison 10: Chloral hydrate high dose versus

Chloral hydrate as a sedating agent for neurodiagnostic procedures in children (Review) 24

Patient or population: children undergoing neurodiagnostic procedures

Risk with pentobarbital Risk with chloral hy-

Proportion of children - - - - - No study f or this com -

Proportion of children - - - - - No study f or this com -

Proportion of children Study population RR 4.33 70 ⊕⊕

Proportion of children Study population RR 3.00 70 ⊕

Non-interpretable neu- Study population RR 0.23 54 ⊕

Num ber of children with Study population RR 0.67 70 ⊕

GRADE Working Group grades of evidence