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.