Discussion
Chloral hydrate is a traditional sedative used for auditory and other clinical examinations for a long time, but there is lack of large sample reports to summarize its clinical application status. In addition, chloral hydrate has been listed as a class 2A carcinogen by the World Health Organization (WHO), and professional academic organizations suggested replacement or accelerated elimination, therefore, it is necessary to conduct a retrospective study on its safety and effectiveness.
Sedation failure is a great inconvenience to the patients and their families and requires rescheduling of another hospital admission to complete the procedure, and some patients even require general anesthesia (additional associated risks). The results of study showed that the total sedation failure rate was 3.11% at 30 mg/kg of Chloral Hydrate. The value obtained by us was approximate to that reported by Valenzuela et al.(2016), with 3.40% at 50 mg/kg.3 At a single dose of 50mg/kg, the sedation failure rates reported by Guan(2020), Lai et al.(2019), Reynolds et al.(2016) and Dong&Qiu(2010) were all higher than that reported in this study, ranging from 6.80% to 21.50%.7–10 However, at a single dose of 75mg/kg, the sedation failure rate reported by Many et al.(2022) and Hijazi O.M. et al.(2014), was 1.3% and 23.7%.11,12 With the same dosage, the sedation failure rate was not same in different studies. Therefore, the sedative effect of Chloral Hydrate is not only affected by the total dose, but also by age, physical condition, and other factors.5 More attention should be paid to the standardized use of Chloral Hydrate in clinical sedation and the study of sedative effect factors.
Sedation failure rates in different age groups were statistically different (P < 0.001), and the sedation failure rate was the highest in 0.5-3 years old group, with 4.31%. Previous studies showed that the coordination of infants’ biological rhythms and their synchronization with the time of day developed rapidly in the first 6 months of life, and tended to be stable in the 6 months.13 In addition, the sleep/wake architecture is regulated by neuronal networks among a number of nuclei located in the hypothalamus, midbrain, and pons, and the quantity, quality, and circadian patterns of infant sleep tend to stabilize as the brain develops. 14 15 Brain function, sleep patterns, physical development, and compliance may be responsible for the different sedation failure rates at different ages.
In patients who have failed sedation, the failure performance of insufficient sedation (74.44%) accounted for the largest proportion, and it was mainly concentrated in children under 3 years old (67.72%). There are several reasons for this result. Firstly, the dose might be insufficient, because of potential safety issues, our hospital administered the minimum dose and there were no supplements. In the study of Keidan et al.(2004) and Reynolds et al.(2016), the Chloral Hydrate dosage was 50 mg/kg, the failure rate of sedation after initial administration was 15.5% and 21.5%, and the sedation failure rate decreased by 5.50% and 9.50% after tonic.9,16 Secondly, there might be insufficient sleep preparation, because usually the parents did not wake the child as instructed by the doctor and did not keep the child awake on the way to the hospital. In addition, there is also a lack of generally accepted standards for sleep preparation before sedation for ABR tests. Sleep deprivation is usually carried out one night in advance, and the time of sleep as well as awake is suddenly changed, which results in the misalignment of circadian rhythm, complex adaptive responses in the brain, increased anxiety symptoms, and emotional impact.17,18 In addition, sleep needs and the effects of sleep deprivation are different at different ages.13,19 The ABR test is of profound significance for infants and children’s auditory assessment, therefore, it is of great clinical significance to improve the examination procedures, standardize sedative application, and seek better alternative sedative to reduce the sedation failure rate.
The most common adverse event in this study was vomiting (0.25%), but higher rates were reported by Avlonitou et al.(2011) at 11.4%.6The second followed was agitation (0.07%), which was lower than the 5% reported by Valenzuela et al.(2016) and the 8% reported by Avlonitou et al.(2011) .3,6 Tension (0.03%) is more common in middle-aged and elderly people, which is an emotional reaction due to drug factors and uncertainties about test results. No severe adverse event was followed up in our study, however, Avlonitou et al.(2011) reported that in a group of 1,509 patients treated with Chloral Hydrate, the incidence of severe adverse events (Minor respiratory distress and apnea) was 0.7% at a single dose of 40 mg/kg.6The reasons for the different incidence of adverse events among previous studies may be as follows: firstly, the low dose of medication might lead to a low incidence of adverse events; secondly, some minor adverse events might occur after patients left the hospital and might not be observed; thirdly, the existing system of auditory sedation based on outpatient examination lacked electrocardiogram monitoring and mainly focuses on observation and reporting, resulting in some severe adverse events not found; fourthly, our data collection method was telephone follow-up with a long-time span which may lead to recall bias.
There was an overall significant and decreasing trend in the use of Chloral Hydrate, according to Kamat et al.(2020), early Chloral Hydrate utilization rates were 6.3% (decreased to <0.01%) in outpatient procedural sedation among people younger than 21 years from 2007 to 2018.20 A serious concern with the use of Chloral Hydrate as a standard sedative in patients is its carcinogenic potential, which has been listed by the International Agency for Research on Cancer (IARC) of the World Health Organization (WHO) as a probable human carcinogen (Group 2A),and it is banned in Italy and France,21 However, there is currently no convincing evidence to support a causal relationship between human Chloral Hydrate exposure and cancer development, and the effects of Chloral Hydrate in humans remain uncertain.22 In addition, numerous studies have demonstrated that there are many other effective sedatives with more predictable pharmacokinetic characteristics than Chloral Hydrate. As a result, the literature is full of recommendations for safer alternatives when sedating pediatric patients.23,24
This study reviewed the safety and effectiveness of Chloral Hydrate for the ABR test, which is a study with a long-time span and a large sample size. Therefore, this study may provide substantial evidence for the safety and effectiveness of Chloral Hydrate in ABR testing in clinical practice. In addition, this study highlighted some deficiencies in this field and put forward corresponding suggestions, such as standardized medication, scientific sleep preparation, etc.
The study had several limitations. Firstly, the inclusion criterion was that the interval between two or more examinations was less than 60 days, so there was selection bias. Some patients with a history of sedation failure and adverse events were not included in the follow-up cohort, which may be one of the reasons why the incidence of sedation failure and adverse events reported in this study was lower than that in other studies. Secondly, the long follow-up time and examination time interval led to recall bias, so the accuracy or completeness of the study might deviate from the real situation. Thirdly, the early data was not digitized and patients ABR test results were not available, so the effect of sedatives on patient test results was unclear, and we will continue to report this part of data in the future.