Chloral hydrate as a sedating agent for neurodiagnostic procedures in children

Abstract

Background: This is an updated version of a Cochrane Review published in 2017. Paediatric neurodiagnostic investigations, including brain neuroimaging and electroencephalography (EEG), play an important role in the assessment of neurodevelopmental disorders. The use of an appropriate sedative agent is important to ensure the successful completion of the neurodiagnostic procedures, particularly in children, who are usually unable to remain still throughout the procedure.

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

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

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

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

Main results: We included 16 studies with a total of 2922 children. The methodological quality of the included studies was mixed. Blinding of the participants and personnel was not achieved in most of the included studies, and three of the 16 studies were at high risk of bias for selective reporting. Evaluation of the efficacy of the sedative agents was also underpowered, with all the comparisons performed in small studies. Fewer children who received oral chloral hydrate had sedation failure compared with oral promethazine (RR 0.11, 95% CI 0.01 to 0.82; 1 study; moderate-certainty evidence). More children who received oral chloral hydrate had sedation failure after one dose compared to intravenous pentobarbital (RR 4.33, 95% CI 1.35 to 13.89; 1 study; low-certainty evidence), but there was no clear difference after two doses (RR 3.00, 95% CI 0.33 to 27.46; 1 study; very low-certainty evidence). Children with oral chloral hydrate had more sedation failure compared with rectal sodium thiopental (RR 1.33, 95% CI 0.60 to 2.96; 1 study; moderate-certainty evidence) and music therapy (RR 17.00, 95% CI 2.37 to 122.14; 1 study; very low-certainty evidence). Sedation failure rates were similar between groups for comparisons with oral dexmedetomidine, oral hydroxyzine hydrochloride, oral midazolam and oral clonidine. Children who received oral chloral hydrate had a shorter time to adequate sedation compared with those who received oral dexmedetomidine (MD -3.86, 95% CI -5.12 to -2.6; 1 study), oral hydroxyzine hydrochloride (MD -7.5, 95% CI -7.85 to -7.15; 1 study), oral promethazine (MD -12.11, 95% CI -18.48 to -5.74; 1 study) (moderate-certainty evidence for three aforementioned outcomes), rectal midazolam (MD -95.70, 95% CI -114.51 to -76.89; 1 study), and oral clonidine (MD -37.48, 95% CI -55.97 to -18.99; 1 study) (low-certainty evidence for two aforementioned outcomes). However, children with oral chloral hydrate took longer to achieve adequate sedation when compared with intravenous pentobarbital (MD 19, 95% CI 16.61 to 21.39; 1 study; low-certainty evidence), intranasal midazolam (MD 12.83, 95% CI 7.22 to 18.44; 1 study; moderate-certainty evidence), and intranasal dexmedetomidine (MD 2.80, 95% CI 0.77 to 4.83; 1 study, moderate-certainty evidence). Children who received oral chloral hydrate appeared significantly less likely to complete neurodiagnostic procedure with child awakening when compared with rectal sodium thiopental (RR 0.95, 95% CI 0.83 to 1.09; 1 study; moderate-certainty evidence). Chloral hydrate was associated with a higher risk of the following adverse events: desaturation versus rectal sodium thiopental (RR 5.00, 95% 0.24 to 102.30; 1 study), unsteadiness versus intranasal dexmedetomidine (MD 10.21, 95% CI 0.58 to 178.52; 1 study), vomiting versus intranasal dexmedetomidine (MD 10.59, 95% CI 0.61 to 185.45; 1 study) (low-certainty evidence for aforementioned three outcomes), and crying during administration of sedation versus intranasal dexmedetomidine (MD 1.39, 95% CI 1.08 to 1.80; 1 study, moderate-certainty evidence). Chloral hydrate was associated with a lower risk of the following: diarrhoea compared with rectal sodium thiopental (RR 0.04, 95% CI 0.00 to 0.72; 1 study), lower mean diastolic blood pressure compared with sodium thiopental (MD 7.40, 95% CI 5.11 to 9.69; 1 study), drowsiness compared with oral clonidine (RR 0.44, 95% CI 0.30 to 0.64; 1 study), vertigo compared with oral clonidine (RR 0.15, 95% CI 0.01 to 2.79; 1 study) (moderate-certainty evidence for aforementioned four outcomes), and bradycardia compared with intranasal dexmedetomidine (MD 0.17, 95% CI 0.05 to 0.59; 1 study; high-certainty evidence). No other adverse events were significantly associated with chloral hydrate, although there was an increased risk of combined adverse events overall (RR 7.66, 95% CI 1.78 to 32.91; 1 study; low-certainty evidence).

Authors' conclusions: The certainty of evidence for the comparisons of oral chloral hydrate against several other methods of sedation was variable. Oral chloral hydrate appears to have a lower sedation failure rate when compared with oral promethazine. Sedation failure was similar between groups for other comparisons such as oral dexmedetomidine, oral hydroxyzine hydrochloride, and oral midazolam. Oral chloral hydrate had a higher sedation failure rate when compared with intravenous pentobarbital, rectal sodium thiopental, and music therapy. Chloral hydrate appeared to be associated with higher rates of adverse events than intranasal dexmedetomidine. However, the evidence for the outcomes for oral chloral hydrate versus intravenous pentobarbital, rectal sodium thiopental, intranasal dexmedetomidine, and music therapy was mostly of low certainty, therefore the findings should be interpreted with caution. Further research should determine the effects of oral chloral hydrate on major clinical outcomes such as successful completion of procedures, requirements for an additional sedative agent, and degree of sedation measured using validated scales, which were rarely assessed in the studies included in this review. The safety profile of chloral hydrate should be studied further, especially for major adverse effects such as oxygen desaturation.

Trial registration: ClinicalTrials.gov NCT02077712 NCT01255904 NCT02239445.

Conflict of interest statement

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

Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Figures

1

Study flow diagram.

2

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

3

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

1.1. Analysis

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

1.2. Analysis

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

1.3. Analysis

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

1.4. Analysis

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

1.5. Analysis

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

1.6. Analysis

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

1.7. Analysis

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

1.8. Analysis

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

1.9. Analysis

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

2.1. Analysis

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

2.2. Analysis

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

2.3. Analysis

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

2.4. Analysis

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

2.5. Analysis

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

2.6. Analysis

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

2.7. Analysis

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

2.8. Analysis

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

3.1. Analysis

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

3.2. Analysis

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

3.3. Analysis

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

3.4. Analysis

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

3.5. Analysis

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

3.6. Analysis

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

3.7. Analysis

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

3.8. Analysis

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

3.9. Analysis

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

3.10. Analysis

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

4.1. Analysis

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

4.2. Analysis

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

5.1. Analysis

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

5.2. Analysis

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

5.3. Analysis

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

5.4. Analysis

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

5.5. Analysis

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

5.6. Analysis

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

5.7. Analysis

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

6.1. Analysis

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

6.2. Analysis

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

6.3. Analysis

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

6.4. Analysis

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

6.5. Analysis

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

6.6. Analysis

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

7.1. Analysis

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

7.2. Analysis

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

7.3. Analysis

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

8.1. Analysis

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

8.2. Analysis

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

8.3. Analysis

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

9.1. Analysis

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

9.2. Analysis

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

9.3. Analysis

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

9.4. Analysis

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

10.1. Analysis

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

10.2. Analysis

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

10.3. Analysis

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

10.4. Analysis

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

10.5. Analysis

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

10.6. Analysis

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

10.7. Analysis

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

11.1. Analysis

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

11.2. Analysis

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

11.3. Analysis

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

11.4. Analysis

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

11.5. Analysis

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

11.6. Analysis

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

11.7. Analysis

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

12.1. Analysis

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

12.2. Analysis

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

12.3. Analysis

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

12.4. Analysis

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

13.1. Analysis

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

13.2. Analysis

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

13.3. Analysis

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

13.4. Analysis

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

13.5. Analysis

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