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\begin{document}

\title{Safety and effectiveness of Chloral Hydrate in Auditory Brainstem
Response tests: a single-center and cross-sectional study}



\author[1]{Xiangling Zhang}%
\author[1]{Haotian Liu}%
\author[1]{Xinyi Yao}%
\author[1]{Min Liu}%
\author[1]{Youyou Jin}%
\author[1]{Yun Zheng}%
\author[1]{Wei Zhang}%
\author[1]{Zhaoli Meng}%
\author[2]{Yu Zhao}%
\affil[1]{Sichuan University West China Hospital}%
\affil[2]{West China Hospital,Sichuan University}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Objective: Chloral Hydrate is the most commonly used sedative for
Auditory Brainstem Response (ABR) test. The aim of this study was to
retrospectively analyze the safety and effectiveness of Chloral Hydrate
in patients undergoing ABR tests through a single-center and large
sample size cross-sectional study. Methods: Data were collected from
December 2015 to March 2022, which included 7,176 ABR tests (6,106
patients). Basic information was collected, then telephone follow-up was
conducted for patients with two or more consecutive tests less than 60
days, and administration method, failure performance, and adverse events
were collected. Total sedation failure rate, sedation failure rates in
different age groups ([?]0.5 years, 0.5-3 years, 3-12 years, [?]12 years)
and incidence of adverse events were calculated. Results: A total of
4,967(69.21\%) ABR tests were younger than 3 years of age. The sedation
failure rate was 3.11\% with a Chloral Hydrate dose of 30 mg/kg of
weight, which ranged from 1.44\% to 4.31\% in different age groups. In
the sedation failure tests, insufficient sedation was found in 74.44\%
of the tests. The incidence of adverse events was 0.35\%, with most
commonly vomiting. Conclusion: The sedation failure rate and the
incidence of adverse events in this study are relatively low compared
with other previous studies, and Chloral Hydrate can be considered a
safe and effective sedative with the permissible dose. However, there
were still many patients who failed to complete the test due to
insufficient sedation (mostly infants and children), which imply that
alternative sedatives with easier preparation process are needed.%
\end{abstract}%



\sloppy


\textbf{Safety and effectiveness of Chloral Hydrate in Auditory
Brainstem Response tests: a single-center and cross-sectional study}

\textbf{Abstract}

\textbf{Objective:} Chloral Hydrate is the most commonly used sedative
for Auditory Brainstem Response (ABR) test. The aim of this study was to
retrospectively analyze the safety and effectiveness of Chloral Hydrate
in patients undergoing ABR tests through a single-center and large
sample size cross-sectional study.

\textbf{Methods:} Data were collected from December 2015 to March 2022,
which included 7,176 ABR tests (6,106 patients). Basic information was
collected, then telephone follow-up was conducted for patients with two
or more consecutive tests less than 60 days, and administration method,
failure performance, and adverse events were collected. Total sedation
failure rate, sedation failure rates in different age groups ([?]0.5
years, 0.5-3 years, 3-12 years, [?]12 years) and incidence of adverse
events were calculated.

\textbf{Results:} A total of 4,967(69.21\%) ABR tests were younger than
3 years of age. The sedation failure rate was 3.11\% with a Chloral
Hydrate dose of 30 mg/kg, which ranged from 1.44\% to 4.31\% in
different age groups. In the sedation failure tests, insufficient
sedation was found in 74.44\% of the tests. The incidence of adverse
events was 0.35\%, with most commonly vomiting.

\textbf{Conclusion:} The sedation failure rate and the incidence of
adverse events in this study are relatively low compared with other
previous studies, and Chloral Hydrate can be considered a safe and
effective sedative with the permissible dose. However, there were still
many patients who failed to complete the test due to insufficient
sedation (mostly infants and children), which imply that alternative
sedatives with easier preparation process are needed.

\textbf{Key words:} Chloral Hydrate; Auditory brainstem response;
Sedation; Failure rate

\textbf{Key points}

A single-center cross-sectional clinical study with large sample size.

The safety and effectiveness of ABR with chloral hydrate in 7176
patients were reported by telephone follow-up.

In this study, the sedation failure rate of Chloral Hydrate for ABR test
was 3.11\% and the incidence of adverse events was 0.35\%.

Chloral Hydrate can be considered a safe and effective sedative with the
permissible dose.

Many patients who failed to complete the ABR test due to insufficient
sedation (mostly infants and children).

\textbf{Introduction}

Hearing loss is common in society, which can have negative effects on
speech, language development, and social
communication.\textsuperscript{1} For patients with suspected hearing
loss, early diagnosis is significant for subsequent clinical
intervention. The auditory brain stem response (ABR) is an objective,
non-invasive method to estimate auditory threshold and neurological
diagnosis in clinics, and commonly used in infants and children who
cannot complete a subjective audiologic assessment. Guidelines for Early
Hearing Detection and Intervention Programs (EHDI) emphasized ABR is the
gold standard for hearing diagnosis in children younger than 6 months of
age.\textsuperscript{1,2} The successful completion of ABR is
challenging for patients; as patients are required to sleep soundly
during the procedure to minimize myoelectrical interference and get more
accurate test results.\textsuperscript{3} For some patients, especially
in infants and children, it is not easy to get spontaneous sleep despite
preferential intervention, , so using the appropriate sedative agent in
patients plays a significant role in the successful completion of the
procedure.\textsuperscript{4}

Chloral Hydrate is a non-opiate and non-benzodiazepine sedative-hypnotic
drug, which widely used in otolaryngology, imaging, and other clinical
departments over the past decades in China. However, concerns have been
expressed about safety and effectiveness, particularly with regard to
potential advert effects, such as vomiting, restlessness,
sedation-induced hypoxemia, bradycardia and so
on.\textsuperscript{3,5}Nevertheless, Chloral Hydrate is considered safe
and effective for patients undergoing painless diagnostic procedures
with appropriate doses and settings.\textsuperscript{6}

In the Hearing Center of our hospital, as most other hospitals, Chloral
Hydrate has been used for sedation of patients in ABR tests for nearly
30 years. Although Chloral Hydrate sedation has a low incidence of
severe adverse events and is considered safe, it is still important to
assess adverse events that may occur. Therefore, the aim of this study
was to report the sedation failure rate as well as the incidence of
adverse events and to analyze the safety and effectiveness of Chloral
Hydrate for the ABR test. Furthermore, this study aimed to identify the
potential risk through a large sample of data and was expected to
provide a reference for future practice.

\textbf{Materials and Methods}

\textbf{Clinical procedure}

ABR was routinely conducted for patients to assess their auditory
threshold and neurological diagnosis in our hospital. After a
consultation with an otolaryngology department specialist, the Chloral
Hydrate was administered by a trained nurse or audiologist under the
supervision of the Otolaryngologists, by the oral route without
exceptional circumstances.

Chloral Hydrate was administered at a concentration of 10\%, at a dose
of 30 mg/kg. In consideration of safety, the drug was not further
supplemented. Chloral Hydrate can be mixed with dairy products or other
liquids to mask its bitter taste to help children complete ingestion.
Furthermore, if not sedated after 45--60 minutes, the appointment would
be rescheduled. Patients were required to perform sleep deprivation and
fast for at least three hours before the ABR test, as these were
believed to help them fall asleep.

\textbf{Data Collection}

The clinical study was approved by the Ethics Committee, and all
clinical data use and telephone follow-ups were carried out after
obtaining the consent of patients.

Medical records for patients who underwent sedated ABR tests between
December 2015 and March 2022 were reviewed, and 7,176 ABR tests (6,106
patients) with sufficient data were included. The collected data were as
follows: clinic registration number, gender, age, and telephone number.
Telephone follow-up was conducted for patients with two or more
consecutive tests within 60 days (according to hospital regulations and
clinical experience, patients who failed sedation should complete the
examination within 60 days), and 729 ABR tests were included (Figure 1).
Telephone follow-up data were as follows: history of sedation failure,
administration method (mixed or direct), sleep deprivation (yes or no),
failure performance (failure to sleep, insufficient sedation, and
superficial sleep), and adverse events (vomiting, agitation, etc.). The
success of sedation was considered as patients who kept quiet and
completed the test without incident. The failure to sleep was considered
patients who were restless and unable to sleep. Insufficient sedation
meant patients woke up in the middle of the tests and did not complete
the tests on the same day. Superficial sleep meant patients did not
reach the required sleep depth.

\textbf{Data Analysis}

Continuous variables are described as median and interquartile ranges
(IQR). Categorical variables are presented as numbers with percentages.
The chi-square test or Fisher's exact test was used to compare
categorical variables among groups. Total sedation failure rate,
sedation failure rates in different age groups ([?]0.5 years, 0.5-3 years,
3-12 years, [?]12 years) and incidence of adverse events were calculated.
Grouped by administration method and failure performance in sedation
failure patient, then calculated the proportion of patients in different
age groups. All statistical analyses were performed using R (version
4.2.0. R Core Team,2022). All P values were 2-sided, and \emph{P} = 0.05
was used to indicate statistical significance.

\textbf{Results}

The study included 7,176 ABR tests (6,106 patients) between December
2015 and March 2022. A total of 3101(43.21\%) ABR tests were females and
4075(56.79\%) ABR tests were males. The median (interquartile range
{[}IQR{]}) age was 1(8 -- 0.42) year, with a range of 1 month to 84
years. There were 223(3.11\%) ABR tests which were sedation failed. A
total of 102(45.74\%) ABR tests were females and 121(54.26\%) ABR tests
were males. The median (interquartile range {[}IQR{]}) age was 1(3 --
0.42) year, with a range of 1 month to 68 years. When we grouped
patients by age ([?]0.5 years, 0.5-3 years, 3-12 years, [?]12 years), the
failure rates ranged from 1.44\% to 4.31\%, with significant differences
(\emph{P} \textless{}0 .001) (Table 1)(Table 2).

Some infants and children need to mix the medicine with dairy products
or other liquids, to facilitate better medication. There were
99(44.40\%) ABR tests in the mixed group and 124(55.60\%) ABR tests in
the direct group. According to telephone follow-up results, the sedation
performance was divided into three categories, of which 166(74.44\%) ABR
tests were insufficient sedation after taking Chloral Hydrate. Fifty
(22.42\%) ABR tests were unable to fall asleep and 7(3.14\%) ABR tests
were in superficial sleep. The vast majority of patients reported
performing sleep deprivation, but the specific implementation has not
been followed up. Most patients (43.05\%) in the mixed group were
younger than 3 years old, and patients over 3 years old were mainly
taken Chloral Hydrate directly, there were significant differences
between the administration method among different age groups
(\emph{P}\textless{} 0.001). Insufficient sedation was the main
performance of sedation failure in the [?]0.5 years group and the 0.5-3
years group. Failure to sleep was the main performance of sedation
failure in the [?]12 years group. In addition, there were 6(2.69\%) ABR
tests in the[?]12 years group and only 1(0.45\%) ABR tests in the group of
[?]0.5 years who were in superficial sleep. There were significant
differences in the failure performance among different age groups
(\emph{P} \textless{} 0.001) (Table 2).

No severe adverse event (apnea, bradycardia) was observed in our study.
The adverse events included 25(0.35\%) ABR tests that experienced minor
adverse events such as vomiting, agitation, and tension. There were
18(0.25\%) ABR tests experienced vomiting, and 5(0.07\%) ABR tests
experienced agitation, and 2(0.03\%) ABR tests experienced tension
throughout the test (Table 1).

\textbf{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.\textsuperscript{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\%.\textsuperscript{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\%.\textsuperscript{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.\textsuperscript{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 (\emph{P} \textless{} 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.\textsuperscript{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. \textsuperscript{14} \textsuperscript{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.\textsuperscript{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.\textsuperscript{17,18} In addition, sleep needs and
the effects of sleep deprivation are different at different
ages.\textsuperscript{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\%.\textsuperscript{6}The 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) .\textsuperscript{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.\textsuperscript{6}The 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 \textless{}0.01\%) in
outpatient procedural sedation among people younger than 21 years from
2007 to 2018.\textsuperscript{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,\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.

\textbf{Conclusion}

As a traditional sedative with long-term use, the sedation failure rate
and the incidence of adverse events of Chloral Hydrate in this study
were relatively low compared with other previous studies, and Chloral
Hydrate can be considered a safe and effective product within the
permissible dose. However, there were still many people who failed to
complete the test due to insufficient sedation (mostly infants and
children), which suggests alternative sedatives with easier preparation
process are needed.

\textbf{References}

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14. Saper CB, Fuller PM, Pedersen NP, Lu J, Scammell TE. Sleep state
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15. Peirano P, Algar\selectlanguage{ngerman}ín C, Uauy R. Sleep-wake states and their regulatory
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16. Keidan llan, Gozal D, Minuskin T, Weinberg M, Barkaly H, Augarten A.
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19. Ong HT, Lim KJL, Low PC, Low PS. Simple instructions for partial
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20. Kamat PP, McCracken CE, Simon HK, Stormorken A, Mallory M,
Chumpitazi CE, et al. Trends in Outpatient Procedural Sedation:
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21. Cozzi G, Norbedo S, Barbi E. Intranasal Dexmedetomidine for
Procedural Sedation in Children, a Suitable Alternative to Chloral
Hydrate. Paediatr Drugs. 2017 Apr;19(2):107--11.

22. Haselkorn T, Whittemore AS, Udaltsova N, Friedman GD. Short-term
chloral hydrate administration and cancer in humans. Drug Saf.
2006;29(1):67--77.

23. Abulebda K, Patel VJ, Ahmed SS, Tori AJ, Lutfi R, Abu-Sultaneh S.
Comparison between chloral hydrate and propofol-ketamine as sedation
regimens for pediatric auditory brainstem response testing. Braz J
Otorhinolaryngol. 2019 Feb;85(1):32--6.

24. Coté CJ, Wilson S. Guidelines for Monitoring and Management of
Pediatric Patients Before, During, and After Sedation for Diagnostic and
Therapeutic Procedures. Pediatrics. 2019 Jun;143(6):e20191000.

\textbf{Figure Legends}

Figure 1. Flow diagram of study participants\selectlanguage{english}
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