pharmaceuticals

Article
Comparative Safety Profiles of Sedatives Commonly Used in
Clinical Practice: A 10-Year Nationwide Pharmacovigilance
Study in Korea
Yeo-Jin Choi 1 , Seung-Won Yang 2 , Won-Gun Kwack 3 , Jun-Kyu Lee 4 , Tae-Hee Lee 5 , Jae-Yong Jang 6
and Eun-Kyoung Chung 7,8, *

1 Department of Clinical Pharmacy, Graduate School of Clinical Pharmacy, CHA University,

Seongnam 13488, Korea; [email protected]
2 Department of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, College of Pharmacy,
Yonsei University, Incheon 21983, Korea; [email protected]
3 Division of Pulmonary, Allergy and Critical Care Medicine, Kyung Hee University Hospital,
Seoul 02447, Korea; [email protected]
4 Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang 10326, Korea;
[email protected]
5 Institute for Digestive Research, Soonchunhyang University Seoul Hospital, Seoul 04401, Korea;
[email protected]
6 Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul 02447, Korea;
[email protected]



7

 Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Korea
8 Department of Pharmacy, Kyung Hee University Hospital at Gangdong, Seoul 05278, Korea
Citation: Choi, Y.-J.; Yang, S.-W.; * Correspondence: [email protected]; Tel.: +82-961-2122
Kwack, W.-G.; Lee, J.-K.; Lee, T.-H.;
Jang, J.-Y.; Chung, E.-K. Comparative
Abstract: This study aims to compare the prevalence and seriousness of adverse events (AEs) among
Safety Profiles of Sedatives
sedatives used in critically ill patients or patients undergoing invasive procedures and to identify
Commonly Used in Clinical Practice:
factors associated with serious AEs. Retrospective cross-sectional analysis of sedative-related AEs
A 10-Year Nationwide
voluntarily reported to the Korea Adverse Event Reporting System from 2008 to 2017 was performed.
Pharmacovigilance Study in Korea.
Pharmaceuticals 2021, 14, 783. https://
All AEs were grouped using preferred terms and System Organ Classes per the World Health
doi.org/10.3390/ph14080783 Organization—Adverse Reaction Terminology. Logistic regression was performed to identify factors
associated with serious events. Among 95,188 AEs, including 3132 (3.3%) serious events, the most
Academic Editors: common etiologic sedative was fentanyl (58.8%), followed by pethidine (25.9%). Gastrointestinal
Concetta Rafaniello and disorders (54.2%) were the most frequent AEs. The most common serious AE was heart rate/rhythm
Annalisa Capuano disorders (33.1%). Serious AEs were significantly associated with male sex; pediatrics; etiologic
sedative with etomidate at the highest risk, followed by dexmedetomidine, ketamine, and propofol;
Received: 2 July 2021 polypharmacy; combined sedative use; and concurrent use of corticosteroids, aspirin, neuromuscular
Accepted: 4 August 2021
blockers, and antihistamines (reporting odds ratio > 1, p < 0.001 for all). Sedative-induced AEs
Published: 9 August 2021
are most frequently reported with fentanyl, primarily manifesting as gastrointestinal disorders.
Etomidate is associated with the highest risk of serious AEs, with the most common serious events
Publisher’s Note: MDPI stays neutral
being heart rate/rhythm disorders.
with regard to jurisdictional claims in
published maps and institutional affil-
Keywords: sedatives; drug safety; patient safety; adverse events; pharmacovigilance; KAERS
iations.

1. Introduction
Copyright: © 2021 by the authors.
Licensee MDPI, Basel, Switzerland.
Sedation is critical in minimizing discomforts in patients, especially in those undergo-
This article is an open access article
ing invasive procedures such as gastrointestinal endoscopy or hospitalized in an intensive
distributed under the terms and care unit (ICU) [1,2]. Sedation differs from general anesthesia in a way that sedated pa-
conditions of the Creative Commons tients have limited response to repeated external stimuli, typically without impairment
Attribution (CC BY) license (https:// of cardiovascular functions, while individuals under general anesthesia completely lose
creativecommons.org/licenses/by/ response to any level of stimuli, potentially with impaired cardiovascular functions [3].
4.0/). Sedation is stratified into minimal (anxiolysis), moderate, and deep sedation [3]. Proper

Pharmaceuticals 2021, 14, 783. https://doi.org/10.3390/ph14080783 https://www.mdpi.com/journal/pharmaceuticals

Pharmaceuticals 2021, 14, 783 2 of 14

sedation not only relieves discomforts but also improves stress responses, anxiety, and
patient outcomes; however, the debate on the appropriate depth of sedation in patients
requiring critical care or invasive procedures is still ongoing [1–4]. Indeed, some previous
studies suggested inappropriate sedation, particularly oversedation, which frequently
occurs in clinical practice, may increase the duration of mechanical ventilation, hospital or
ICU stays, and in-hospital mortality [4–6].
Despite the importance of appropriate depth of sedation, optimal sedative drug ther-
apy is still a challenge in clinical practice and differs based on the purpose of sedation [1,7].
The current guideline for the management of pain, agitation/sedation, delirium, immobility,
and sleep disruption (PADIS), published by the Society of Critical Care Medicine (SCCM),
strongly recommends non-benzodiazepine sedatives such as propofol or dexmedetomi-
dine over benzodiazepines for inducing sedation in critically ill patients including those
who require mechanical ventilation because of benzodiazepine-related adverse events
(AEs) [8]. Although benzodiazepines had been the primary sedative agents previously
and still continue to be prescribed commonly in clinical practice, their use has declined
over the last decade mainly due to their AEs associated with the central nervous sys-
tem, including impaired memory, attention, learning, or visuospatial abilities [9]. These
benzodiazepine-induced AEs are associated with substantial morbidity and mortality,
such as benzodiazepine-related fall injury in elderly patients [9]. Therefore, the SCCM
recommends alternatives to benzodiazepines as the preferred sedative agent in the PADIS
guideline [8]. However, deviations from this guideline have been reported in the actually
prescribed sedative therapy, indicating potential misuse of sedatives [10–12]. Actually, the
most frequently prescribed sedatives in Korea included benzodiazepines (diazepam, mida-
zolam); non-benzodiazepines including propofol, dexmedetomidine, etomidate, ketamine,
opioids (e.g., alfentanil, fentanyl, remifentanil), and thiopental; and the combined use of
two or more different sedatives [10,13,14]. However, the safety profile of these sedative
agents, including their combined use, is yet to be comparatively evaluated despite the
increasing use of sedatives.
Sedatives are implicated in various adverse drug events (ADEs), ranging from com-
mon, mild toxicities such as gastrointestinal AEs to more serious toxicities, including
cardiac and respiratory complications [12,15,16]. These ADEs limit the use of sedatives
in clinical practice, which may be aggravated by inconsiderate sedative use and habitual
prescribing patterns, including combined sedative use [12,15]. However, each sedative
agent has a highly variable pattern of ADEs, including the type and seriousness of sedative-
related AEs, which makes the management and prevention of sedative-induced AEs even
more challenging in clinical practice [15,17]. With the variable demographic, clinical, and
sociocultural aspects associated with medication use in clinical practice, assessment of
the real-world data for sedative use in a specific country and/or ethnic group may help
promote safe and effective use of sedatives [18]. Because Korea has the National Health
Insurance (NHI) system, the NHI service sample (NHISS) cohort is usually the most
commonly used real-world data source. However, the NHISS cohort does not contain
non-reimbursement data records. Considering the majority of sedatives are prescribed
without insurance reimbursement in Korea [19], the NHISS cohort may not be the best
data source to show the real-world pattern of sedative usage and safety; rather, voluntary
AE reports may be more appropriate because (1) they include AEs associated with both
non-reimbursed and reimbursed medications and (2) healthcare practitioners are legally
required to report clinically significant AEs. Therefore, the aims of this study were to
compare the prevalence and seriousness of ADEs associated with sedatives commonly
used for invasive procedures or the management of critically ill patients in Korea and to
identify factors associated with serious sedative-related ADEs utilizing spontaneous AE
reporting data.
Pharmaceuticals 2021, 14, 783 3 of 14

Pharmaceuticals 2021, 14, x FOR PEER REVIEW 3 of 15

2. Results
2.1.2.Baseline
Results Demographics
Overall,
2.1. Baseline 95,188 sedative-related ADEs in 68,656 patients from January 2008 to Decem-
Demographics
ber 2017 were identified from the Korea
Overall, 95,188 sedative-related ADEs Adverse
in 68,656Event Reporting
patients System
from January (KAERS).
2008 to De- The
number of reported ADE cases has substantially increased every
cember 2017 were identified from the Korea Adverse Event Reporting System (KAERS). year, with a relatively
constant rate ofofsedative-induced
The number reported ADE cases ADEs at approximately
has substantially 10%
increased or less
every ofwith
year, all ADE reports
a rela-
tively constant
submitted to the rate
KAERS of sedative-induced
over the studyADEs period at approximately
(Figure 1). Among10% orthe
lesscausative
of all ADEagents
reportsin
included submitted to thefentanyl
this analysis, KAERS over the study
was the period (Figure
most common 1). Among
etiologic agent (nthe= causative
55,964; 58.8%),
agents included in this analysis, fentanyl was the most common
followed by pethidine (n = 24,668; 25.9%) (Table 1). Serious AEs occurred etiologic agent (n =in55,964;
3132 cases
58.8%),
(3.3%) followed
most by pethidine
frequently (n = with
associated 24,668; 25.9%) (Table
pethidine (n =1). Serious
1019; AEs followed
31.5%), occurred inby 3132
fentanyl
cases (3.3%) most frequently associated with pethidine (n = 1019; 31.5%), followed by fen-
(n = 819; 25.3%) and midazolam (n = 497; 15.4%). The median duration of therapy was
tanyl (n = 819; 25.3%) and midazolam (n = 497; 15.4%). The median duration of therapy
<1 day for all sedatives included in the analysis, with the maximum duration of treatment
was < 1 day for all sedatives included in the analysis, with the maximum duration of treat-
being
ment 31being
days 31until
daystheuntil
onsettheofonset
AEs.ofThe
AEs.baseline demographic
The baseline characteristics
demographic of sedative-
characteristics of
related ADE cases ADE
sedative-related are summarized in Table 2.
cases are summarized in The
Tablemajority of sedative-induced
2. The majority of sedative-inducedADE cases
occurred in females
ADE cases occurred (nin= females
62,798; (n
66.6%) and66.6%)
= 62,798; individuals with advanced
and individuals age of 50
with advanced years
age of and
older (n = 52,450;
50 years and older 55.1%).
(n = 52,450; 55.1%).

FigureFigure
1. The1. The number
number andand rateofofsedative-induced
rate sedative-induced adverse events
adverse (AEs)
events reported
(AEs) from 2008
reported fromto 2008
2017 (ADEs, adverse
to 2017 (ADEs,drug
adverse
events).
drug events).
Table 1. Sedatives implicated in certain, probable/likely, and possible adverse event (AE) cases (re-
Table 1. Sedatives implicated in certain, probable/likely, and possible adverse event (AE) cases
ported frequency (%)).
(reported frequency (%)).
Serious AEs Nonserious AEs Total AE Cases
Serious
(n = 3132)AEs Nonserious
(n = 92,056) AEs (n =Total AE Cases
95,188)
Alfentanil (n = 3132)
3 (0.1) (n = 92,056)
671 (0.7) 674 (0.7)95,188)
(n =
Dexmedetomidine
Alfentanil 365(0.1)
(2.1) 252 (0.3)
671 (0.7) 317 (0.3)
674 (0.7)
Dexmedetomidine
Diazepam 65
127(2.1)
(4.1) 252(2.4)
2214 (0.3) 317 (0.3)
2341 (2.5)
Diazepam
Etomidate 12748 (4.1)
(1.5) 2214
126 (2.4)
(0.1) 2341 (2.5)
174 (0.2)
Etomidate
Fentanyl 48 (1.5)
809 (25.8) 126(59.9)
55,155 (0.1) 174 (0.2)
55,964 (58.8)
Fentanyl 809 (25.8) 55,155 (59.9) 55,964 (58.8)
Ketamine 141 (4.5) 585 (0.6) 726 (0.8)
Ketamine 141 (4.5) 585 (0.6) 726 (0.8)
Midazolam 484 (15.5) 4398 (4.8) 4882 (5.1)
Midazolam 484 (15.5) 4398 (4.8) 4882 (5.1)
Pethidine
Pethidine 996(31.8)
996 (31.8) 23,672 (25.7)
23,672 (25.7) 24,668 (25.9)(25.9)
24,668
Propofol
Propofol 247 (7.9)
247 (7.9) 1509 (1.6)
1509 (1.6) 1756 (1.8)
1756 (1.8)
Remifentanil 186 (5.9) 2691 (2.9) 2877 (3.0)
Sufentanil 2 (0.1) 405 (0.4) 407 (0.4)
Thiopental 24 (0.8) 378 (0.4) 402 (0.4)
Pharmaceuticals 2021, 14, 783 4 of 14

Table 2. Baseline demographic characteristics of patients from whom adverse events (AEs) caused
by sedatives were reported to the KAERS (n = 95,188).

Characteristics No. of Cases (% Relative Frequency) or Median [Range]

a
Age (Years) 53 [0–115]
<10 years 1872 (2.0)
10–19 years 4648 (5.1)
20–29 years 7300 (8.0)
30–39 years 10,588 (11.5)
40–49 years 14,908 (16.2)
50–59 years 18,743 (20.4)
60 years or older 33,707 (36.7)
Sex b
Male 31,524 (33.4)
Female 62,798 (66.6)
Causality c
Certain 1822 (1.9)
Probable/likely 44,214 (46.5)
Possible 49,152 (51.6)
Treatment Duration d (Days) 0 (0–31)
<1 day 45,002 (47.3)
1 day 12,756 (13.4)
2 days 6780 (7.12)
3 days 2727 (2.86)
≥4 days 3590 (3.77)
Seriousness
Serious events e 3132 (3.3)
Nonserious events 92,056 (96.7)
Individuals Reporting the Sedative-Induced AEs f
Physicians 8367 (9.2)
Pharmacists 7066 (7.8)
Nurses 67,881 (75.0)
General Public 78 (0.1)
Others 7142 (7.90)
No. of Medications Used
1 70,392 (74.0)
2 12,930 (13.6)
3 4994 (5.3)
4 1665 (1.8)
5 814 (0.9)
6 575 (0.6)
7 460 (0.5)
8 364 (0.4)
≥9 2994 (3.1)
No. of Comorbidities g
1 61,752 (95.8)
2 1779 (2.8)
3 543 (0.8)
4 160 (0.3)
≥5 237 (0.4)
a Missing in 3422 (3.6%) cases. b Missing in 866 (0.9%) cases. c Causality was assessed according to the World
Health Organization—Uppsala Monitoring Centre (WHO-UMC) criteria. d Missing in 24,333 (25.6%) cases.
e Defined as those resulting in death, life-threatening conditions, hospitalization or prolongation of existing

hospitalization, persistent or significant disability or incapacity, congenital abnormalities or birth defects, or any
other medically significant events based on the International Conference on Harmonization (ICH) E2D Guidelines.
f Missing in 4654 (4.9%) cases. g Missing in 30,717 (32.3%) case.
Pharmaceuticals 2021, 14, 783 5 of 14

2.2. Types of ADEs Induced by Sedatives

Sedative-induced ADEs based on the System Organ Classes (SOC) classification sys-
tem are presented in Table 3. Overall, the most common ADEs associated with sedative
use were gastrointestinal disorders (n = 51,577; 54.2%), including nausea and vomiting,
followed by nervous system disorders (n = 23,833; 25.0%) such as decreased consciousness
and dizziness. The majority of sedative-related, nonserious ADEs were gastrointestinal
disorders (n = 51,317 (55.8%)) and nervous system disorders (n = 23,363 (25.4%)) (Table 3).
Among sedative-induced serious AEs (n = 3132; 3.3%), heart rate and rhythm disorders
(n = 1038; 33.1%) including, hypotension, most frequently occurred, followed by respira-
tory system disorders (n = 608; 19.4%) such as dyspnea and reduced oxygen saturation;
both heart rate/rhythm disorders and respiratory system disorders were more likely to be
serious events (ROR = 16.724 and 22.046, respectively (95% CIs 15.379–18.187 and 19.782–
24.569, respectively); p < 0.001 for both). Death occurred in 61 cases (0.06%), primarily
associated with propofol (n = 15), midazolam (n = 14), and diazepam (n = 12). No fatal
cases were reported with alfentanil, etomidate, sufentanil, and thiopental.

Table 3. System Organ Class-based adverse events (AEs) caused by sedatives.

Serious AEs Nonserious AEs Total AEs ROR

SOC Disorder Class p Value a
(n = 3132) (n = 92,056) (n = 95,188) (95% CI) b
Skin and appendages 156 (5.0) 5532 (6.0) 5688 (6.0) 0.017 0.820 (0.696–0.965)
Musculoskeletal system 9 (0.3) 91 (0.1) 100 (0.1) 0.001 2.912 (1.467–5.782)
Collagen 0 (0.0) 2 (<0.1) 2 (<0.1) N/E c N/E c
Central and peripheral nervous system
(e.g., decreased consciousness, 470 (15.0) 23,363 (25.4) 23,833 (25.0) <0.001 0.519 (0.470–0.573)
dizziness)
Vision 10 (0.3) 82 (0.1) 92 (0.1) 0.001 3.593 (1.962–6.934)
Hearing and vestibular 1 (< 0.1) 11 (<0.1) 12 (<0.1) N/E c N/E c
Special senses (other) d 0 (0.0) 4 (<0.1) 4 (<0.1) N/E c N/E c
Psychiatric 143 (4.6) 3200 (3.5) 3343 (3.5) 0.001 1.328 (1.119–1.577)
Gastrointestinal (e.g., nausea, vomiting) 260 (8.3) 51,317 (55.8) 51,577 (54.2) <0.001 0.720 (0.630–0.820)
Liver and biliary system 35 (1.1) 102 (0.1) 137 (0.1) <0.001 10.188 (6.928–14.982)
Metabolic and nutritional 9 (0.3) 127 (0.1) 136 (0.1) 0.029 2.086 (1.060–4.105)
Endocrine 0 (0.0) 2 (<0.1) 2 (<0.1) N/Ec N/E c
General cardiovascular 44 (1.4) 59 (0.1) 103 (0.1) <0.001 22.218 (15.012–32.882)
Myocardial, endocardial, pericardial,
0 (0.0) 1 (<0.1) 1 (<0.1) N/E c N/E c
and valve
Heart rate and rhythm (e.g.,
1038 (33.1) 2650 (2.9) 3688 (3.9) <0.001 16.724 (15.379–18.187)
hypotension)
Vascular (extracardiac) 11 (0.4) 72 (0.1) 83 (0.1) <0.001 4.503 (2.385–8.501)
Respiratory system (e.g., dyspnea,
608 (19.4) 995 (1.1) 1603 (1.7) <0.001 22.046 (19.782–24.569)
decreased oxygen saturation)
Red blood cell 3 (0.1) 9 (<0.1) 12 (<0.1) N/E c N/E c
White cell and reticuloendothelial
16 (0.5) 50 (0.1) 66 (0.1) <0.001 9.449 (5.375–16.609)
system
Platelet, bleeding, and clotting 8 (0.3) 19 (<0.1) 27 (<0.1) <0.001 12.405 (5.426–28.358)
Urinary system (e.g., nephrotoxicity) 51 (1.6) 1187 (1.3) 1238 (1.3) 0.1 1.267 (0.955–1.681)
Reproductive (male) 2 (0.1) 0 (0.0) 2 (<0.1) N/E c N/E c
Reproductive (female) 9 (0.3) 9 (<0.1) 18 (<0.1) <0.001 29.474 (11.692–74.301)
Fetal 1 (<0.1) 1 (<0.1) 2 (<0.1) N/E c N/E c
13.079
Neonatal and infancy 4 (0.1) 9 (<0.1) 13 (<0.1) <0.001
(4.025–42.492)
Neoplasms 0 (0.0) 1 (<0.1) 1 (<0.1) N/E c N/E c
Body as a whole—general 234 (7.5) 2748 (3.0) 2982 (3.1) <0.001 2.634 (2.293–3.025)
Application site 3 (0.1) 402 (0.4) 405 (0.4) N/E c N/E c
Resistance mechanism 5 (0.2) 3 (<0.1) 8 (<0.1) N/E c N/E c
Secondary terms—events e 2 (0.1) 6 (<0.1) 8 (<0.1) N/E c N/E c
Poison specific terms 0 (0.0) 2 (<0.1) 2 (<0.1) N/E c N/E c

Abbreviations: SOC, System Organ Class; ROR, reporting odds ratio; CI, confidence interval; N/E, not estimated. Data presented as the
number of cases (% relative frequency). a p-value from the Mantel–Haenszel test between serious and nonserious events. b ROR from the
Mantel–Haenszel test for serious events compared to nonserious events. c Statistical tests not performed due to insufficient number of
reported cases (unreliable data). d Includes metallic taste, dysgeusia, and dysosmia. e Includes off-label use, drowning, accidental drug
overdose, and medication errors.

2.3. Factors Associated with Seriousness of Sedative-Related ADEs

In the univariate analysis, the seriousness of sedative-related AEs was significantly as-
sociated with sex, age, causality, etiologic sedative agent, the number of concurrently used
medications, and the concomitantly used medication (p < 0.001, Table 4). All of the investi-
gated factors remained significantly associated with the seriousness of sedative-induced
Pharmaceuticals 2021, 14, 783 6 of 14

AEs in the multivariate regression model (p < 0.001, Table 4). Serious AEs were more likely
to be reported in the followings: male patients; patients younger than 10 years old; patients
treated with dexmedetomidine, diazepam, etomidate, ketamine, midazolam, pethidine,
propofol, remifentanil, and thiopental; and those taking multiple medications (p < 0.001 for
all). Among the tested sedatives, etomidate was associated with the highest risk for devel-
oping serious AEs (OR 52.232 (95% CI 15.943–171.118)), followed by dexmedetomidine (OR
35.784 (95% CI 11.120–115.153)), ketamine (OR 31.322 (95% CI 9.865–99.453)), and propofol
(OR 27.226 (95% CI 8.669–85.504)). Serious sedative-induced AEs were more likely to occur
in patients treated with a sedative in combination with corticosteroids (OR 2.933 (95% CI
2.187–3.935)), aspirin (OR 2.900 (95% CI 1.771–4.750)), benzodiazepines (OR 2.370 (95%
CI 1.703–3.299)), neuromuscular blockers (OR 1.640 (95% CI 1.086–1.712)), antihistamines
(OR 1.557 (95% CI 1.096–2.212)), and another sedative (OR 1.272 (95% CI 1.121–1.444)).
In contrast, patients concurrently treated with a non-steroidal anti-inflammatory drug
(NSAID), an opioid analgesic, a serotonin (5HT3 ) antagonist, or zolpidem were less likely
to develop serious sedative-related AEs.

Table 4. Univariate and multivariate analyses for the association between predictors and sedative-induced serious adverse
events (AEs).

Univariate Analysis (Number of Cases (%)) Multivariate Analysis

Predictors Serious AEs Nonserious AEs
p Value OR (95% CI) p Value
(n = 3132) (n = 92,056)
a
Sex <0.001 <0.001
Male 1460 (46.6) 30,064 (32.7) 1.421 (1.318–1.531)
Female 1622 (51.8) 61,176 (67.5) 1 (reference)
Age b <0.001 <0.001
< 10 211 (6.7) 1661 (1.8) 1 (reference)
10–19 130 (4.2) 4518 (4.9) 0.499 (0.388–0.642)
20–29 164 (5.2) 7136 (7.8) 0.413 (0.323–0.528)
30–39 249 (8.0) 10,339 (11.2) 0.427 (0.340–0.537)
40–49 374 (11.9) 14,534 (15.8) 0.470 (0.379–0.583)
50–59 515 (16.4) 18,228 (19.8) 0.486 (0.395–0.599)
≥ 60 1388 (44.3) 32,319 (35.2) 0.729 (0.599–0.886)
Causality c <0.001 <0.001
Certain 49 (1.6) 1773 (1.9) 1.015 (0.786–1.312)
Probable/likely 956 (30.5) 43,258 (47.0) 0.649 (0.598–0.704)
Possible 2127 (67.9) 47,025 (51.1) 1 (reference)
Etiologic sedative <0.001 <0.001
Alfentanil 3 (0.5) 671 (99.5) 1 (reference)
Dexmedetomidine 66 (20.8) 251 (79.2) 35.784 (11.120–115.153)
Diazepam 135 (5.8) 2206 (94.2) 8.384 (2.652–26.506)
Etomidate 49 (28.2) 125 (71.8) 52.232 (15.943–171.118)
Fentanyl 819 (1.5) 55,145 (98.5) 3.084 (0.989–9.615)
Ketamine 148 (20.4) 578 (79.6) 31.322 (9.865–99.453)
Midazolam 484 (10.0) 4398 (90.0) 18.174 (5.817–56.786)
Pethidine 1019 (4.1) 23,649 (95.9) 7.861 (2.522–24.501)
Propofol 264 (15.0) 1492 (85.0) 27.226 (8.669–85.504)
Remifentanil 199 (6.9) 2678 (93.1) 13.207 (4.200–41.528)
Sufentanil 2 (0.5) 405 (99.5) 0.786 (0.130–4.735)
Thiopental 30 (7.5) 372 (92.5) 11.049 (3.287–37.148)
Number of concurrently used medications <0.001 1.015 (1.000–1.031) <0.001
1 2062 (65.8) 68,330 (74.7)
2 498 (15.9) 12,432 (13.6)
3 216 (6.9) 4778 (5.2)
4 124 (4.0) 1541 (1.7)
≥5 232 (7.4) 4975 (0.8)
Concomitantly used medication
Antihistamine 67 (2.1) 649 (0.7) <0.001 1.557 (1.096–2.212) <0.001
NSAIDs 135 (4.3) 5605 (6.1) <0.001 0.426 (0.343–0.527) <0.001
Opioids 181 (5.8) 8137 (8.9) <0.001 0.488 (0.409–0.583) <0.001
5HT3 antagonists 38 (1.2) 2574 (2.8) <0.001 0.483 (0.346–0.676) <0.001
ASA 27 (0.9) 111 (0.1) <0.001 2.900 (1.771–4.750) <0.001
Neuromuscular blockers 152 (4.9) 1383 (1.5) <0.001 1.640 (1.086–1.712) <0.001
Corticosteroids 98 (3.1) 609 (0.7) <0.001 2.933 (2.187–3.935) <0.001
Sedatives 500 (16.0) 6568 (7.1) <0.001 1.272 (1.121–1.444) <0.001
Benzodiazepines 51 (1.6) 324 (0.4) <0.001 2.370 (1.703–3.299) <0.001
Zolpidem 10 (0.3) 207 (0.2) <0.001 0.290 (0.142–0.591) <0.001

Abbreviations: OR, odds ratio; CI, confidence interval; NSAIDs, non-steroidal anti-inflammatory drugs; 5HT, serotonin; ASA, aspirin
(i.e., acetylsalicylic acid). a Information was missing in 50 (1.5%) and 816 (0.9%) serious and nonserious cases, respectively. b Informa-
tion was missing in 101 (3.2%) and 3321 (3.6%) serious and nonserious cases, respectively. c Causality assessment was based on the
WHO-UMC criteria.
Pharmaceuticals 2021, 14, 783 7 of 14

3. Discussion
The global prevalence of sedative use is increasing every year, particularly in Ko-
rea [20]. In 2019, the Ministry of Food and Drug Safety (MFDS) in Korea reported con-
trolled substances were administered to more than 36% of the total Korean population
(18,502,227 Koreans), most frequently propofol (n = 8,505,249), followed by midazolam
(n = 6,583,018), diazepam (n = 3,248,581), meperidine (i.e., pethidine; n = 2,476,722), and
fentanyl (n = 1,905,655) [21]. Although the majority of these sedative agents were rec-
ommended to be used by physicians with anesthetic training, approximately 60% of the
sedative prescriptions were written by primary care physicians (PCPs) without adequate
anesthetic training [21,22]. Although single-dose or short-term sedative therapy might be
generally perceived to be safe among PCPs, the median time elapsed between the start of
sedative therapy and the development of sedative-induced AEs was less than 1 day in our
present study (Table 2), suggesting a substantial risk of AEs posed by short-term, acute
pharmacologic sedation [23]. Moreover, evidence-based practice of acute, short-term seda-
tion therapy for patients undergoing invasive procedures or hospitalized in an ICU is even
more challenging due to the lack of clinical practice guidelines based on comprehensive
scientific data, leading to high variability in sedative use in the real-world setting [2,12].
In fact, our current study suggested a high prevalence of sedative administration con-
comitantly with other sedatives or other medications with sedation side effects, resulting
in a significantly increased risk of developing serious AEs (Table 4). To the best of our
knowledge, the safety profile of sedatives commonly used in clinical practice has been
comparatively assessed in only a few head-to-head studies or literature reviews [24–27].
However, even the recent head-to-head studies were not statistically powered for safety
endpoints [26,27]. In addition, one of the head-to-head studies was a prospective trial
conducted in a controlled environment, suggesting limited generalizability of the trial re-
sults to the real-world practice setting [27]. Therefore, our present study may substantially
contribute to the current body of literature by characterizing the prevalence and pattern of
sedative-induced AEs as well as identifying factors associated with serious sedative-related
AEs in Korea through comprehensively analyzing the real-world spontaneous AE reports
of sedatives commonly used for invasive procedures or critical care in Korea.
In this study, the most frequently reported causative agent associated with sedative-
induced AEs was fentanyl, followed by pethidine, accounting for approximately 85% of
all sedative-related AEs (Table 1). Although the true risk of developing sedative-induced
AEs might be higher for fentanyl and pethidine compared to other sedatives, caution
should be exercised when interpreting the reported incidence of AEs in our present study.
The reported ADE incidence might be confounded by the amount of each sedative use,
potentially leaving the true relative risk of developing ADEs associated with each sedative
unclear. In fact, drug utilization data from the MFDS showed fentanyl (n = 1,905,655)
and pethidine (n = 2,476,722) were among the most commonly used sedative agents in
Korea [21]. Considering frequent non-reimbursed use of sedatives in clinical practice in
Korea, the actual use of sedatives might be much greater in the real-world setting, possibly
resulting in a high prevalence of reported AEs associated with fentanyl and pethidine [28].
However, as shown in Table 4, pethidine was associated with a significantly increased risk
of serious AEs, suggesting the true risk of pethidine-induced toxicity might be high. Future
studies are warranted to estimate the relative risk of developing AEs associated with each
sedative use while adjusting for the prevalence of their use.
Our present study suggested gastrointestinal disorders such as nausea and vomiting
and nervous system disorders including decreased consciousness and dizziness as the
most common sedative-induced AEs, accounting for approximately 80% of all sedative-
related AEs (Table 3). Our study findings were largely consistent with previous studies
reporting nervous system suppression, nausea, and vomiting as primary AEs associated
with sedatives [29]. The majority of gastrointestinal and nervous system disorders induced
by sedative use were nonserious, mild events. However, serious events did occur in 0.50%
and 1.97% of all gastrointestinal and nervous system AEs, respectively, highlighting the
Pharmaceuticals 2021, 14, 783 8 of 14

importance of adequate patient education regarding these AEs and thorough monitoring
for early detection and appropriate management.
In our current study, serious events accounted for 3.3% (n = 3132) of the total sedative-
induced AEs, suggesting a substantially lower reporting rate of serious events compared to
that in the United States (16.9%) [30]. This might be associated with the reporting pattern of
ADEs in Korea [31]. Although the spontaneous AE reporting systems have been primarily
used to report major serious AEs or rare reactions for signal detection and discovery of
potential ADEs [32], our study showed frequent reporting of common, nonserious sedative-
related AEs, potentially resulting in the apparently lower risk of serious events. Among the
sedative agents investigated in this study, pethidine was most frequently associated with
serious AEs (Table 1), implying a higher risk for pethidine to develop serious AEs. In fact,
pethidine has been notorious for its relatively high risk of serious central nervous system
AEs including tremors, muscle twitches, hyperactive reflexes, agitation, and seizures owing
to its active metabolite, normeperidine [14,33]. However, caution should be exercised when
interpreting the risk of pethidine for serious AEs because, as aforementioned, the high
reporting frequency of pethidine-induced serious AEs might result from its prevalent use in
Korea [21]. Similarly, although fentanyl was the second most commonly reported etiologic
agent of serious sedative-related AEs, it might be associated with the high prevalence of
its use, considering the relative reporting frequency of fentanyl-induced serious AE cases
compared to the total AE cases caused by fentanyl (Table 1). The major sedative-induced
serious AEs based on the SOC disorders was heart rate and rhythm disorders such as
hypotension (33.1%), followed by respiratory system disorders such as dyspnea (19.4%)
and nervous system disorders such as decreased consciousness and dizziness (15.0%),
accounting for at least two-thirds of serious sedative-related AEs (Table 4). Among them,
respiratory system disorders, as well as heart rate and rhythm disorders, were more likely
to be serious (ROR 22.046 (95% CI 19.782–24.569) for respiratory system disorders; ROR
16.724 (95% CI 15.379–18.187) for heart rate and rhythm disorders); in contrast, nervous
system disorders were less likely to be serious (ROR 0.519 (95% CI 0.470–0.573)). Our
findings were consistent with a previous study analyzing AEs associated with procedural
sedatives [34]. Similar to our current study, Mason et al. suggested that all reported
sedative-induced cardiovascular and respiratory AEs were moderate to sentinel events;
however, most of the neuropsychiatric and gastrointestinal AEs caused by procedural
sedatives were minimal to minor events [34]. Considering a number of cardiovascular
and respiratory AEs are listed as potentially serious AEs in the prescribing information
for commonly used sedatives and often occur unexpectedly [35–38], close monitoring
systems must be in place for prompt and appropriate management of sedative-induced
AEs, particularly in patients at an increased risk for developing serious AEs associated
with sedative use.
Based on the univariate and multivariate analyses, our present study suggested fac-
tors significantly increasing the risk of developing serious sedative-induced AEs (Table 4).
Similar to previous studies, serious AEs were more likely to be reported in males, patients
at the extremes of age (i.e., younger than 10 years old (Table 4), patients at the age of
60 or greater (OR = 1.987, 95% CI 1.586–2.201 when compared to those 20 to 29 years
old; data not shown)), and those taking multiple medications [39,40]. Notably, our study
comparatively evaluated the risk of etiologic sedatives for developing serious AEs as well
as the impact of concomitant medications on the risk of serious AEs (Table 4). Compared
to alfentanil with the lowest relative frequency of sedative-related serious AEs reported
in our study (Table 1), the risk of developing serious AEs was 52-, 35-, 31-, and 27-fold
higher for etomidate, dexmedetomidine, ketamine, and propofol, respectively (Table 4);
only fentanyl and sufentanil showed a comparable risk of developing sedative-induced
serious AEs to alfentanil (p > 0.05). Although the risk of etomidate, dexmedetomidine, and
ketamine for developing serious AEs, including cardiovascular and/or respiratory toxici-
ties, might be truly higher than that of other sedatives assessed in this study [30,41], their
frequent use as an adjunct therapy to other primary sedatives such as fentanyl, propofol,
Pharmaceuticals 2021, 14, 783 9 of 14

and benzodiazepines might contribute to the significantly increased risk for serious AEs
as shown in this study (Table 4). Of our great concern was the high risk of propofol for
serious AEs considering the prevalent use of propofol for sedation in patients undergoing
invasive procedures such as endoscopy and hospitalized in an ICU [29]. Previous studies
suggested propofol as a relatively safe sedative, used alone or in combination with other
adjunctive sedatives, with a lower incidence of AEs for invasive procedures and critical
care [8,30,42]. Consequently, propofol has been commonly used with or without anesthesi-
ologist involvement in various settings of clinical practice, including outpatient endoscopic
procedures in primary care clinics in Korea [21,22,43]. Because propofol is one of the
primary sedative agents possibly used in combination with other adjunct therapy [44], the
propofol-based combinational sedation therapy might contribute to the increased risk for
serious propofol-related AEs (Table 4). However, the significant increase in the risk for
serious AEs was not observed for fentanyl (p > 0.05), which is another primary sedative
in a comparable therapeutic place to propofol (Table 4), suggesting a truly high risk of
propofol for serious sedative-induced AEs such as cardiovascular events. In fact, similar
to our current study, a previous study conducted by Duprey and colleagues reported an
increased risk of serious cardiovascular AEs associated with propofol compared to other
sedatives [30].
Among the concomitantly used medications other than sedatives, our study suggested
a significantly increased risk of serious sedative-induced AEs in patients concurrently re-
ceiving corticosteroids, aspirin, neuromuscular blockers, or antihistamines; however, the
risk of serious AEs was significantly lower in those co-administered NSAIDs, opioid anal-
gesics, or serotonin (5-HT3 ) antagonists (Table 4). The higher likelihood of developing
serious AEs in patients concomitantly receiving corticosteroids and neuromuscular block-
ers might be associated with the severity of underlying diseases. Current clinical practice
guidelines suggested the scheduled use of corticosteroids for the treatment of critical illness-
related corticosteroid insufficiency commonly occurring in critically ill patients, including
those with severe bacterial infections (e.g., pneumonia, meningitis), undergoing cardiopul-
monary bypass surgery, and suffering a cardiac arrest [45,46]. Neuromuscular blocking
agents may be used for facilitating endotracheal intubation, optimizing mechanical ven-
tilation, and managing other life-threatening conditions in critically ill patients [47,48].
Considering these critically ill patients commonly have respiratory distress and hemody-
namic instability [49], the severe underlying disease rather than the concomitant use of
corticosteroids and neuromuscular blockers itself might contribute to the common serious
sedative-related AEs of heart rate/rhythm and respiratory system disorders. Similarly,
the increased risk of sedative-related serious AEs in patients concurrently taking aspirin
might be associated with their underlying cardiovascular diseases requiring aspirin ther-
apy (e.g., ischemic heart disease, myocardial infarction), potentially resulting in serious
hemodynamic complications such as hypotension (Table 4). The concomitant use of anti-
histamines (H1 antagonists) was significantly associated with an increased risk of serious
sedative-induced AEs due to additive and/or synergistic sedative effects, potentially re-
sulting in oversedation. In contrast, serious events caused by sedative agents were less
likely to occur in patients concomitantly receiving analgesic therapy, including NSAIDs
and opioids (Table 4). Optimal pain control with adequate analgesic therapy reduces the
risk of pain-related agitation [8,49]; thus, excessive use of sedatives may not be necessary
for patients concurrently treated with analgesics as well as sedatives, minimizing the risk
of oversedation through achieving adequate pain control. Therefore, the risk of serious
sedative-related AEs commonly associated with oversedation is substantially lower in
these patients. Consistently, our current study suggests a lower risk of serious AEs caused
by sedatives when used in combination with 5-HT3 antagonists due to their anti-nausea
effects contributing to a decrease in the perception of noxious stimuli. Ultimately, agitation
is less likely and can be managed without excessive sedation in these patients, leading to
fewer serious sedative-related AEs. Additional future studies are warranted to examine
the effects of concomitant medications on the risk of developing serious sedative-related
Pharmaceuticals 2021, 14, 783 10 of 14

AEs, adjusted for other confounding risk factors such as the sedative agent used in the
patient and the severity of underlying diseases.
This study has several limitations that need to be acknowledged. First, because the
KAERS database is a spontaneous reporting system, caution should be exercised when
interpreting our study results due to possible under-reporting of AEs and substantial
missing information such as indications, comorbid conditions, and concurrent medication
therapy. Second, inter-reporter variability might influence the quality of the recorded
data in the KAERS database. For example, although the seriousness of the reported ADEs
was evaluated based on the ICH guideline definition, the individual subjective judgment
might contribute to determining whether a specific ADE case was serious or not. In
addition, potential reporting bias might exist, which could result in selective over-reporting
of some ADEs and under-reporting of others [31]. Nevertheless, the majority of ADE
cases, particularly those induced by sedatives, were reported by healthcare professionals
(Table 2) [50], suggesting adequate reliability and appropriateness of the recorded ADE
data. Furthermore, the number of ADE reports for a specific medication can be influenced
by the prevalence of using the medication in clinical practice. Thus, our current study
findings should be carefully interpreted. Lastly, this study should not be translated to
determine a definite causal relationship between the reported ADE and the offending
sedative owing to the nature of the study design. Despite the verification of the causality
by a reporter and an independent record reviewer, nondrug factors or other medications
than the reported culprit sedative might result in the recorded AE. Therefore, larger-scale
clinical studies may be warranted to evaluate the effects of a specific sedative medication
on the risk of the reported ADEs, taking into account potential confounding variables such
as concomitant medications and underlying diseases.

4. Materials and Methods

4.1. Data Source and Definitions
This was a retrospective, cross-sectional study analyzing ADE records spontaneously
reported from January 2008 to December 2017 to the KAERS. The KAERS is a voluntary,
spontaneous ADE reporting system, constructed by the Korea Institute of Drug Safety and
Risk Management (KIDS), available to the public as well as healthcare professionals [18,51].
When clinically significant ADE cases occurred in clinical practice, they were reported by
the healthcare professionals or the general public using the structured ADE case reporting
form developed and validated by the KIDS, which is the national pharmacovigilance
agency in Korea [51,52]. The ADE case reports submitted to the KAERS were reviewed and
further verified by healthcare professional in the KIDS to minimize biases [18,51]. The ADE
case reporting data, collected and validated by several individuals, were then deposited
into the KAERS [18].
In the current analysis, included cases were ADEs reportedly caused by the following
sedative agents commonly used for invasive procedures or management of critically ill
patients in Korea [10,13,14]: alfentanil, dexmedetomidine, diazepam, etomidate, fentanyl,
ketamine, midazolam, pethidine (meperidine), propofol, remifentanil, sufentanil, and
thiopental. The following information was extracted from the KAERS database: (1) patient
demographics including age, sex, and comorbidities; (2) medication information including
concomitant medications, dates of treatment initiation and cessation, and the causative
agent; (3) ADE information including the year of ADE reports and causality assessment
between the reported ADE and the offending agent; and (4) seriousness of ADEs [18].
Causality of each ADE report was initially determined by the reporting individual
and later verified by healthcare professionals in the KIDS based on the World Health
Organization—Uppsala Monitoring Centre (WHO-UMC) criteria as follows: (1) certain,
(2) probable/likely, (3) possible, (4) unlikely, (5) conditional/unclassified, and (6) unassess-
able/unclassifiable [53]. Adverse drug event records with causality determined as “certain”,
“probable/likely”, and “possible” were included in the present analysis as sedative-related
ADEs [51]. All ADEs were reported in preferred terms or included terms according to the
Pharmaceuticals 2021, 14, 783 11 of 14

WHO—Adverse Reaction Terminology (WHO-ART) [54], and they were grouped into SOC
disorders. When two or more ADEs were reported in the same patient, each event was
analyzed as a separate case. The seriousness of each ADE was assessed based on the Inter-
national Conference on Harmonization (ICH) E2D Guideline, where serious ADEs were
defined as AEs leading to (1) death, (2) life-threatening conditions, (3) hospitalization or
prolongation of existing hospitalization, (4) persistent or significant disability or incapacity,
(5) congenital abnormalities or birth defects, and (6) other medically significant events [55].
The study protocol for utilizing the KAERS database was approved by the KIDS
(No. 1807A0028) and the institutional review board of Dongguk University Ilsan Hospital
(No. DUIH 2021-03-023) (Goyang, South Korea). Informed consents were exempted by
the board.

4.2. Statistical Analysis

SPSS Statistics 25.0 (Version 25.0; IBM SPSS Statistics for Windows, Armonk, NY,
USA) was utilized for all statistical analyses. Patient demographics and reported ADEs
were summarized using descriptive statistics with either mean ± standard deviation or
median and range for continuous variables based on the Kolmogorov–Smirnov normality
test results. The association of the SOC-based ADEs with their seriousness was evalu-
ated using disproportionality analysis by estimating the reporting odds ratios (RORs)
with the corresponding 95% confidence intervals (CIs) and the Mantel–Haenszel adjusted
p values [40,56,57]. Disproportionality was defined as the lower limit of the 95% CI greater
than 1 or the upper limit of the 95% CI less than one [40,56,57]. The result was considered
reliable if the number of reported cases was greater than four [40,56,57].
The univariate analysis was performed to identify factors associated with serious
AEs, and factors explored in the univariate analysis included sex, age, causality (certain,
probable/likely, or possible), etiologic sedative agent, the number of concurrently used
medications, and the use of each concomitant medication. Multiple logistic regression
using a stepwise forward method was performed by investigating the factors significantly
associated with the seriousness of sedative-related ADEs in the univariate analysis. Vari-
ables with p value < 0.1 in the univariate analysis and clinical plausibility were assessed in
multiple logistic regression. Any p value < 0.05 was considered statistically significant in
the multivariate logistic regression analysis.

5. Conclusions
The prevalence of sedative-related ADEs has been increasing every year in Korea.
The most frequent culprit drug of sedative-induced ADEs is fentanyl. The most common
AEs caused by sedatives are gastrointestinal disorders such as nausea and vomiting,
followed by nervous system disorders including impaired consciousness and dizziness,
the majority of which are nonserious events. Serious events occur relatively commonly
(approximately 3% of the total sedative-induced AEs), with pethidine reported as the
primary etiologic agent of serious AEs. The most frequently documented serious events
associated with sedative use are heart rate/rhythm disorders such as hypotension and
respiratory system disorders, including dyspnea and reduced oxygen saturation. The
risk for developing serious AEs may be different among sedatives; the risk is relatively
high with etomidate, dexmedetomidine, ketamine, and propofol, while it is relatively
low with alfentanil, fentanyl, and sufentanil. Other factors increasing the likelihood of
serious AEs include male sex; extremes of age; polypharmacy; concurrent sedative use;
and concomitant use of corticosteroids, aspirin, neuromuscular blockers, or antihistamines.
Patients concurrently receiving NSAIDs, 5-HT3 antagonists, or opioid analgesics are at
a lower risk for serious sedative-related AEs. Taking into account sedative treatment
regimens, concomitant medications, and other patient characteristics, close monitoring for
patients receiving sedation therapy is warranted to ensure patient safety in clinical practice.
 sociated with sedative use are heart rate/rhythm disorders such AEs,as and
hypotension and res-in the univariate analy
factors explored
piratory system disorders, including dyspnea and reduced oxygen saturation. The
probable/likely, risk for etiologic sedative a
or possible),
developing serious AEs may be different among sedatives; themedications,
risk is relatively
andhigh with
the use of each concomitant med
etomidate, dexmedetomidine, ketamine, and propofol, whileing it aisstepwise
relatively low with
forward method was performed b
alfentanil, fentanyl, and sufentanil. Other factors increasing the likelihoodwith
associated of serious AEs
the seriousness of sedative-relate
Pharmaceuticals 2021, 14, 783 include male sex; extremes of age; polypharmacy; concurrent sedative
ables with use; and concomi-
p value < 0.1 in the univariate
12 of 14 analysis
tant use of corticosteroids, aspirin, neuromuscular blockers, or antihistamines.
in multiple logisticPatients
regression. Any p value < 0.05
concurrently receiving NSAIDs, 5-HT3 antagonists, or opioid analgesics are at a lower
in the multivariate riskregression analysis.
logistic
for serious sedative-related AEs. Taking into account sedative treatment regimens, con-
5. Conclusions
comitant medications, and other patient characteristics, close monitoring for patients re-
Author Contributions: Conceptualization, Y.-J.C., E.-K.C. and W.-G.K.; methodology, Y.-J.C., S.-W.Y.,
ceiving sedation therapy is warranted to ensure patient safety in clinical practice.
The prevalence of sedative-related ADEs ha
T.-H.L., J.-Y.J. and E.-K.C.; software, Y.-J.C. and S.-W.Y.; validation, W.-G.K., J.-K.L. and E.-K.C.;
The most frequent culprit drug of sedative-induc
formal analysis, Y.-J.C. and Conceptualization,
Author Contributions: S.-W.Y.; investigation, J.-K.L.,
Y.-J.C., E.-K.C., andT.-H.L.,
W.-G.K.;
AEsand J.-Y.J.;
methodology,
caused byresources,
Y.-J.C., S.Y.,
sedatives J.-K.L.
are and
gastrointestinal diso
T.-H.L.,
E.-K.C.; data J.-Y.J., andY.-J.C.
curation, E.-K.C.;and
software, Y.-J.C.
E.-K.C.; and S.Y.; validation, W.-G.K.,
writing—original draft J.-K.L., and E.-K.C.;
preparation, for-J.-K.L. and
lowed by nervous Y.-J.C.,
system disorders including im
mal analysis, Y.-J.C. and S.Y.; investigation, J.-K.L., T.-H.L., and J.-Y.J.; resources, J.-K.L. and E.-K.C.;
E.-K.C.; writing—review and editing, S.-W.Y., W.-G.K., J.-K.L., T.-H.L., majority and E.-K.C.;
of which visualization,
are nonserious events. Serious
data curation, Y.-J.C. and E.-K.C.; writing—original draft preparation, Y.-J.C., J.-K.L., and E.-K.C.;
T.-H.L. and J.-Y.J.; supervision,
writing—review and editing,E.-K.C.; project
S.Y., W.-G.K., administration,
J.-K.L., proximately
J.-K.L.,
T.-H.L., and E.-K.C.; 3% T.-H.L.
T.-H.L.
visualization, of
andtheJ.-Y.J.;
total sedative-induced
and funding AE
acquisition, J.-K.L.,
J.-Y.J.; T.-H.L.,
supervision, J.-Y.J.
E.-K.C.; andadministration,
project E.-K.C. All J.-K.L.,
authors mary
haveand
T.-H.L., read etiologic
and
J.-Y.J.; agent
agreed
funding toofthe
serious
acquisition, AEs. The most fre
published
version ofJ.-K.L., T.-H.L., J.-Y.J., and E.-K.C. All authors have read and agreed to
the manuscript. sociated with sedative
the published version ofusethe are heart rate/rhythm
manuscript. piratory system disorders, including dyspnea and
This work
Funding:Funding: waswas
This work supported
supported partially
partially byby
the the Dongguk
Dongguk developing
University
University serious
Research
Research Fund AEsand
of 2020 may beofdifferent
Fund 2020 among s
and a grant from
a grant fromthe
theKorean Gastrointestinal
Korean Gastrointestinal Endoscopy
Endoscopy etomidate,
ResearchResearch
Foundation. dexmedetomidine,
Foundation.
This research This research
was sup- ketamine,
was and pr
supported by a grant (No. 21153
ported by a grant (No. 21153 규제학 601-1) from Ministry of Food andalfentanil,
Drug fentanyl,
601-1) from Ministry of Food and Drug Safety in 2021.
Safety in 2021. and sufentanil. Other factors
include male sex; extremes of age; polypharmacy
Institutional
Institutional Review Review
BoardBoard Statement:The
Statement: The study
study protocol
protocolfor utilizing
tantthe
useKAERS
for utilizing ofthe database was
corticosteroids,
KAERS aspirin,was
database neuromuscul
approved by the KIDS (No. 1807A0028) and the institutional review concurrently
board of Dongguk University
receiving NSAIDs, 5-HT3 antagonist
approvedIlsan
by Hospital
the KIDS (No. 1807A0028) and the institutional
(No. DUIH 2021-03-023) (Goyang, South Korea). review board of Dongguk University
Ilsan Hospital (No. DUIH 2021-03-023) (Goyang, South Korea). for serious sedative-related AEs. Taking into acc
Informed Consent Statement: Not applicable. comitant medications, and other patient characte
InformedData
Consent Statement:
Availability Not
Statement: datasets generated and/or analyzedceiving
Theapplicable. during sedation
the currenttherapy is warranted to ensure p
study are
not publicly available due to the inclusion of private medical information but may be available from
Data Availability Statement:
the corresponding The datasets
author upon reasonablegenerated
request. and/or analyzed during the current
Author Contributions: study areY.-J.C., E.-K
Conceptualization,
T.-H.L., J.-Y.J.,
not publicly available due to the inclusion of private medical information butandmayE.-K.C.; software, from
be available Y.-J.C. and S.Y.; v
mal analysis, Y.-J.C. and S.Y.; investigation, J.-K.L., T.-H
the corresponding author upon reasonable request.
data curation, Y.-J.C. and E.-K.C.; writing—original dr
writing—review and editing, S.Y., W.-G.K., J.-K.L., T.-
Acknowledgments: The authors acknowledge all individuals who have been contributing to estab-
J.-Y.J.; supervision, E.-K.C.; project administration, J.-K
lishing the KAERS database and the Korea Institute of Drug Safety and Risk Management,
J.-K.L., T.-H.L., as All
J.-Y.J., and E.-K.C. well as have rea
authors
the Ministry of Food and Drug Safety for providing these data. This work was supported partially
manuscript.
by the Dongguk University Research Fund of 2020 and a grantFunding:
from the ThisKorean
work was Gastrointestinal
supported partially by the Don
Endoscopy Research Foundation on behalf of Committee of Quality Management
a grant from the Korean Korean Society of
Gastrointestinal Endoscopy R
Gastrointestinal Endoscopy (KSGE). This research was supported by abygrant
ported (No.
a grant 21153 규제학601-1)
(No.21153 601-1) from Minist
from Ministry of Food and Drug Safety in 2021. Institutional Review Board Statement: The study pro
approved by the KIDS (No. 1807A0028) and the institu
Conflicts of Interest: The authors declare no conflict of interest. Ilsan Hospital (No. DUIH 2021-03-023) (Goyang, South
Informed Consent Statement: Not applicable.
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