In children undergoing non-invasive neurodiagnostic procedures, is chloral hydrate more effective at producing adequate sedation (slowing of brain activity) and safer than other ways of achieving sedation?
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.
The evidence is current to May 2020.
We included 16 studies involving a total of 2922 children (age up to 18 years old) in the review. All of the included studies were performed in hospitals that provided neurodiagnostic services. Most studies assessed the following three main outcomes: proportion of children who were unsuccessfully sedated for the neurodiagnostic procedure; length of time taken for adequate sedation; and side effects associated with the sedative agent. The quality of the evidence was mixed, ranging from very low to high. The main reason for lowering the quality of the evidence was that those closely involved in the trials, such as the doctors giving the sedation or the parents of the child, were not masked to the sedative agent used in the child, which could have affected their recording or interpretation of the results.
We summarised the evidence of effectiveness and harms of oral chloral hydrate sedation when compared with other sedative agents. Our review suggests that oral chloral hydrate is just as effective a sedative agent with similar sedation failure rate when compared with oral dexmedetomidine, oral hydroxyzine hydrochloride, oral midazolam, and oral clonidine; and probably a more effective sedative agent with a lower sedation failure rate when compared with oral promethazine. Whilst most of the included studies showed that chloral hydrate was safe with no increase in side effects when compared to other sedative agents, one study reported an increased risk of side effects with oral chloral hydrate when compared with intranasal dexmedetomidine.
Quality of the evidence
The quality of most of the evidence was poor due to flaws in study methods and the small sample size of each study, therefore our confidence in the results of the studies is reduced.
Apart from intravenous pentobarbital, rectal sodium thiopental, and music therapy, oral chloral hydrate is either just as effective or more effective as a sedating agent when compared to other sedating agents for children undergoing non-invasive neurodiagnostic procedures. Given the poor quality of the evidence, we could draw no clear conclusions on the effectiveness or safety of any of the paediatric sedative agents studied in the review. Further study is needed to look at the side effects of oral chloral hydrate when compared to other sedatives.
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.
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.
To assess the effectiveness and adverse effects of chloral hydrate as a sedative agent for non-invasive neurodiagnostic procedures in children.
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.
Randomised controlled trials that assessed chloral hydrate agent against other sedative agent(s), non-drug agent(s), or placebo.
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).
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).