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\begin{document}

\title{Safety of sugammadex for reversal of neuromuscular block: a
post-marketing study based on the World Health Organization
pharmacovigilance database}



\author[1]{Qiang Lyu}%
\author[2]{Pei Ye}%
\author[3]{Hewei Zhang}%
\author[4]{Xiaofei Ye}%
\author[4]{Yi Zheng}%
\author[5]{Jinfang Xu}%
\author[5]{Xiao Chen}%
\author[4]{Chenxin Chen}%
\author[4]{Xiaojing Guo}%
\affil[1]{Naval Medical University}%
\affil[2]{Huadong Hospital Affiliated to Fudan University}%
\affil[3]{Naval Medical University Faculty of Health Service}%
\affil[4]{Second Military Medical University Department of Health Statistics}%
\affil[5]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 31, 2024}


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





\selectlanguage{english}
\begin{abstract}
Aim: Residual neuromuscular blockade is a common complication after
general anaesthesia. Sugammadex can reverse the action of aminosteroid
neuromuscular blockers. Our study aimed to explore sugammadex safety
issues in the real world and determine the spectrum of adverse
reactions. Methods: All sugammadex-related adverse events reported in
VigiBase between 2010 and 2019 were classified by group queries
according to the Medical Dictionary for Regulatory Activities. A
disproportionality analysis of data was performed using the information
component (IC); positive IC values were deemed significant. Results:
Overall, 16,219,410 adverse events were reported, and 2032 were
associated with sugammadex. The most frequent reactions were recurrence
of neuromuscular blockade (n = 54, IC: 6.74, 95\% credibility interval
{[}CI{]}: 6.33--7.10), laryngospasm (n = 53, IC: 6.05, IC025:5.64),
bronchospasm (n = 119, IC: 5.63 , IC025:5.36), and bradycardia (n = 169,
IC: 5.13, IC025:4.90). Fatal cases were more likely with cardiac
disorders, especially in patients over 65 years. In addition, the common
adverse drug reactions (ADRs) differed between different age groups (P
\textless{} 0.01). The ADRs were higher between 0--17 years than in
other age groups. The onset time of common ADRs was typically within one
day, and 68.9\% occurred within half an hour after sugammadex
administration. Conclusions: Anaesthesiologists should carefully monitor
the anaesthesia recovery period to correct the adverse drug reactions
caused by sugammadex and recommend monitoring neuromuscular function
throughout the anaesthesia process. Sugammadex should be used carefully
in patients with cardiovascular diseases, and ECG and hemodynamic
changes monitored after medication.%
\end{abstract}%



\sloppy


\textbf{Safety of sugammadex for reversal of neuromuscular block: a
post-marketing study based on the World Health Organization
pharmacovigilance database}

\textbf{Running title:} Sugammadex safety for block reversal

Qiang Lyu\textsuperscript{1,2+}, Pei Ye\textsuperscript{3+}, Hewei
Zhang\textsuperscript{4+}, Xiaofei Ye\textsuperscript{4}, Yi
Zheng\textsuperscript{4}, Jinfang Xu\textsuperscript{4}, Xiao
Chen\textsuperscript{4}, Chenxin Chen\textsuperscript{4}, Xiaojing
Guo\textsuperscript{4*}

\textsuperscript{1}Basic Medical College, Naval Medical University,
Shanghai, China.

\textsuperscript{2}92608 Militang Hospital of PLA, Shanghai, China

\textsuperscript{3}Department of Anaesthesiology, Huadong Hospital
Affiliated to Fudan University, Shanghai, China

\textsuperscript{4}Department of Health Statistics, Faculty of Health
Service, Naval Medical University, Shanghai, China

\textsuperscript{+}Qiang Lyu, Pei Ye, and Hewei Zhang contributed
equally to this work.

\textsuperscript{*}Correspondence: guoxiaojing1003@163.com

\textbf{Keywords}

adverse drug reaction, disproportionality analysis, onset time, reversal
of neuromuscular block, sugammadex, VigiBase

Word count: 2,407

Table count: 1

Figure count: 3

\textbf{What is already known about this subject:}

\begin{itemize}
\tightlist
\item
  Previous studies on the safety of sugammadex have mostly been
  single-centre studies or meta-analyses.
\item
  The WHO global database of individual case safety reports, namely
  VigiBase, is the largest source of safety issues related to sugammadex
  in the real world.
\item
  These data were not previously analysed.
\end{itemize}

\textbf{What this study adds:}

\begin{itemize}
\tightlist
\item
  We analysed the adverse reactions associated with sugammadex in
  VigiBase.
\item
  Recurrence of neuromuscular blockade and cardiorespiratory issues were
  the most frequent adverse reactions reported in some lethal cases.
\item
  Patients should be carefully monitored after sugammadex
  administration, especially at age 0-17 years, \textgreater{} 65 years,
  or with cardiac diseases.
\end{itemize}

\textbf{Abstract}

Aim: Residual neuromuscular blockade is a common complication after
general anaesthesia. Sugammadex can reverse the action of aminosteroid
neuromuscular blockers. Our study aimed to explore sugammadex safety
issues in the real world and determine the spectrum of adverse
reactions.

\emph{Methods:} All sugammadex-related adverse events reported in
VigiBase between 2010 and 2019 were classified by group queries
according to the Medical Dictionary for Regulatory Activities. A
disproportionality analysis of data was performed using the information
component (IC); positive IC values were deemed significant.

Results: Overall, 16,219,410 adverse events were reported, and 2032 were
associated with sugammadex. The most frequent reactions were recurrence
of neuromuscular blockade (n = 54, IC: 6.74, IC\textsubscript{025}:
6.33), laryngospasm (n = 53, IC: 6.05, IC\textsubscript{025}: 5.64),
bronchospasm (n = 119, IC: 5.63 , IC\textsubscript{025}: 5.36), and
bradycardia (n = 169, IC: 5.13, IC\textsubscript{025}: 4.90). Fatal
cases were more likely with cardiac disorders, especially in patients
over 65 years of age. In addition, the common adverse drug reactions
(ADRs) differed between different age groups (P \textless{} 0.01). The
ADRs were higher between age 0--17 years than in other age groups. The
onset time of common ADRs was typically within 1 day, and 68.9\%
occurred within half an hour after sugammadex administration.

\emph{Conclusions:}Anaesthesiologists should carefully monitor the
anaesthesia recovery period to correct the ADRs caused by sugammadex and
recommend monitoring neuromuscular function throughout the anaesthesia
process. Sugammadex should be used carefully in patients with
cardiovascular diseases, and electrocardiography and hemodynamic changes
should be monitored after medication.

\textbf{Introduction}

Muscle relaxation is a fundamental element of general anaesthesia. The
neuromuscular blockers commonly used to assist general anaesthesia and
promote tracheal/mechanical ventilation can provide quality surgical
conditions by reducing muscle tension. However, residual neuromuscular
blockade is a common complication after general anaesthesia. A Chinese
study\textsuperscript{1} reported that the incidence of residual
neuromuscular blockade during extubation for anaesthesia resuscitation
was approximately 57.8\%. Residual neuromuscular blockade may lead to a
series of respiratory complications, such as hypoxemia and atelectasis,
and cause subjective discomfort to the patient; death may occur in
severe cases\textsuperscript{2, 3}.

Sugammadex is a new type of specific neuromuscular block antagonist. It
was first introduced in Europe in 2008\textsuperscript{4}; it was
approved in the United States in 2015 and China in 2017. Sugammadex is a
cyclodextrin derivative that specifically antagonizes non-depolarizing
aminosteroid muscle relaxants that contain a hydrophilic outer layer and
a lipophilic core. Rocuronium and vecuronium are specifically
encapsulated in the lipophilic core, and sugammadex exerts antagonistic
effects against them\textsuperscript{5}. Compared with the traditional
muscle relaxant antagonist, neostigmine, it achieved faster recovery of
neuromuscular function\textsuperscript{6} (mean time to effect: 3 min)
and improved patient safety\textsuperscript{7}. Therefore, the muscle
relaxants and anaesthesia reversal guidelines\textsuperscript{8} issued
by the French Society of Anaesthesiology and Critical Care Medicine in
2020 recommend that appropriate doses of sugammadex should be
administered according to body weight to antagonize the neuromuscular
block during the recovery period from general anaesthesia in patients
who have received rocuronium.

However, with the more frequent clinical use of sugammadex, reports of
its adverse reactions have recently increased, and safety issues have
become more prominent. Previous studies on the safety of sugammadex have
mostly been single-centre studies or meta-analyses; this study is based
on the World Health Organization (WHO) global database of individual
case safety reports, namely VigiBase\textsuperscript{9}, to explore the
safety issues related to sugammadex in the real world. This database can
provide data on rare adverse drug reactions (ADRs) and enable adverse
reaction mapping of a wide spectrum of events.

\textbf{Methods}

2.1 Data source

We obtained the data from VigiBase, the largest pharmacovigilance
worldwide database, maintained by the Uppsala Monitoring Centre (UMC),
the WHO Collaborating Centre for International Drug Monitoring. The UMC
receives reports of suspected ADRs from national centres in countries
participating in the WHO Program for International Drug Monitoring
(https://www.who-umc.org/vigibase/vigibase/). VigiBase contains more
than 28 million individual case safety reports (ICSRs) from
approximately 150 member states since 1968, covering approximately 99\%
of the world's population. Drugs are coded according to WHODrug, and
ADRs according to MedDRA references (version 20.1)\textsuperscript{10}.

2.2 Study design

This observational and retrospective pharmacovigilance study explored
the association between sugammadex and suspicious ADRs through a
disproportionality analysis (also known as case/non-case analysis). The
reference group included all ADRs in the VigiBase database. If the
proportion of ADRs in patients exposed to sugammadex was greater than in
patients not exposed to the drug, an association between the drug and
ADRs was suspected, a potential safety signal. We analysed the detailed
clinical characteristics of ADRs associated with sugammadex in Vigibase
to draw a spectrum of possible adverse reactions of this drug, stratify
the patients by age, and analyse the similarities and differences
between patients in different age groups. The main time window for ADRs
after using sugammadex was analysed according to the reaction onset
time.

2.3 Statistical analysis

We extracted ICSRs between January 1, 2010 and December 31, 2019, with
sugammadex as the ''suspect'' drug, excluding repetitive reports. The
information component (IC) was used to detect and quantify the
association between the target drug and suspected ADRs. Originating from
Bayesian confidence propagation neural networks, IC can provide a
conservative correlation measure and reduce the risk of highlighting
spurious associations, especially for events with very low expected
frequencies in large databases (such as VigiBase)\textsuperscript{11}.
IC and the corresponding lower end of the 95\% credibility interval
(IC\textsubscript{025}) were used to calculate the disproportionality.
These parameters compare the proportions of ICSRs of a selected ADR
between patients exposed and not exposed to the target drug. If the
proportion in the exposed patients is significantly higher than in the
control group, a signal is detected. An
IC\textsubscript{025}\textgreater{} 0 is the criterion for generating a
signal. A positive IC\textsubscript{025} value is the traditionally used
statistical significance threshold for UMC signal detection, indicating
that a particular drug-ADR combination has a higher frequency than
expected; thus, the ADR has a potential association with the
drug\textsuperscript{12}. A signal with a higher IC value indicates a
strong association between ADR and the drug. An IC value \textgreater{}
3 is defined as a strong signal\textsuperscript{13}. The statistical
formula to calculate IC\textsuperscript{14} is as follows:

IC = log\textsubscript{2}{[}(A + 0.5)/(N\textsubscript{expected} +
0.5){]}

N\textsubscript{expected} = (A + B) \selectlanguage{ngerman}× (A + C)/(A + B + C + D)

IC\textsubscript{025} = IC \selectlanguage{english}- 3.3 x (A + 0.5)\textsuperscript{-1/2} \selectlanguage{english}- 2 x
(A + 0.5)\textsuperscript{-3/2}

IC\textsubscript{975} = IC + 2.4 x (A + 0.5)\textsuperscript{-1/2} \selectlanguage{english}- 0.5
x (A + 0.5)\textsuperscript{-3/2},

where A is the number of target ADRs in patients using the target drug,
B is the number of other ADRs in patients using the target drug, C is
the number of target ADR in patients using other drugs, D is the number
of other ADRs in patients using other drugs, and
N\textsubscript{expected} is the number of case reports expected for the
drug-adverse effect combination. A, B, C, and D were obtained as the
frequencies of ICSRs calculated from VigiBase.

\textbf{Results}

Descriptive analysis

A total of 16,219,410 adverse events were reported by patients receiving
any drug treatment and included in VigiBase between January 1, 2010 and
December 31, 2019. After data deduplication and pre-processing, a total
of 2,032 patients with ADRs and sugammadex as the suspected drug were
identified. A summary of the demographic data is presented in Table 1.

Comprehensive spectrum of sugammadex-related ADRs

The disproportionality analysis of ADR reports in the full database
revealed a total of 94 sugammadex-related positive signals (Fig. 1).
They mainly involved the system organ classes (SOCs) of respiratory,
thoracic, and mediastinal disorders; cardiac disorders; injury;
poisoning and procedural complications; and investigations. A high
signal intensity was noted for the recurrence of neuromuscular blockade
(n = 54, IC: 6.74, IC\textsubscript{025}: 6.33), laryngospasm (n = 53,
IC: 6.05, IC\textsubscript{025}: 5.64), bronchospasm (n = 119, IC: 5.63,
IC\textsubscript{025}: 5.36), and bradycardia (n = 169, IC: 5.13,
IC\textsubscript{025}: 4.90).

Relationship between the sugammadex-related ADRs and patient age

The ICSR patients were divided into age-based groups (0--17 years,
18--44 years, 45--64 years, and \selectlanguage{english}[?] 65 years), and an IC analysis was
performed for each age group. The IC\textsubscript{025} value was
obtained for each group (Figs. 2 and 3); the ANOVA test showed
statistically significant differences between groups (P \textless{}
0.01) with the highest overall signal intensity in the 0--17 years
group. The ADRs most commonly reported by different age groups were
dissimilar. In the 0--17 years group: prolonged therapeutic effect (n =
1, IC: 18.00, IC\textsubscript{025}: 14.22), fixed pupils (n = 1, IC:
16.42, IC\textsubscript{025}: 12.63), and negative-pressure pulmonary
oedema (n = 1, IC: 16.29, IC\textsubscript{025}: 12.50); 18--44 years
group: recurrence of neuromuscular blockade (n = 3, IC: 12.16,
IC\textsubscript{025}: 10.09), alveolar-arterial oxygen gradient
increased (n = 1, IC: 13.53, IC\textsubscript{025}: 9.74), and
negative-pressure pulmonary oedema (n = 1, IC: 11.94,
IC\textsubscript{025}: 8.16); 45--64 years group: recurrence of
neuromuscular blockade (n = 11, IC: 12.44, IC\textsubscript{025}:
11.41), post-resuscitation encephalopathy (n = 1, IC: 13.41,
IC\textsubscript{025}: 9.62), and increased airway peak pressure (n = 4,
IC: 10.47, IC\textsubscript{025}: 8.70); \selectlanguage{english}[?] 65 years group: recurrence of
neuromuscular blockade (n = 9, IC: 12.29, IC\textsubscript{025}: 11.13),
increased airway peak pressure (n = 2, IC: 10.45, IC\textsubscript{025}:
7.87), and prolonged neuromuscular block (n = 3, IC: 9.24,
IC\textsubscript{025}: 7.17).

Onset time of sugammadex-related ADRs

The time to onset is the time from the start of medication
administration to an ADR. A total of 1,118 sugammadex-related ADRs were
reported with onset time in the database and 1,996 total ADRs. Among
these, 68.9\% (n = 1376) occurred within half an hour, 88.3\% (n = 1763)
within 1 day, and \textless{} 3\% after 7 days. ADRs with significant
positive signals, such as the recurrence of neuromuscular blockade,
laryngospasm, and bronchospasm, mainly occurred within 1 day after the
administration.

Seriousness of sugammadex-related ADRs

One patient may correspond to more than one ADR, resulting in more than
one outcome, and there are a total of 3717 outcomes of 2032 patients.
Among the 3717 ADR outcomes reported, 53 were fatal; the most frequent
fatal ADR was death (9/53, 17.0\%), and the SOC with the most frequent
fatal cases was cardiac disorders (21/53, 39.6\%). All the fatal ADRs
occurred in 27 patients, 1.33\% of sugammadex-related ICSRs; the
majority of these patients were over 65 years of age (12/27, 44.4\%),
and the number of men and women was similar.

\textbf{Discussion}

To our knowledge, this study is the most extensive safety analysis of
sugammadex in recent years, reporting the characteristics of adverse
reactions associated with sugammadex through a detailed analysis of the
WHO Global Case-safety Reporting Database (VigiBase).

We found 94 positive signals of adverse reactions related to sugammadex
through the disproportionality analysis, mainly involving the
respiratory, cardiovascular, and immune systems. The four ADRs with the
highest signal intensity for sugammadex association were the recurrence
of neuromuscular blockade, laryngospasm, bronchospasm, and bradycardia.
An online app-based study\textsuperscript{15} in 2018 showed that the
most common ADRs of sugammadex were bradycardia and incomplete
neuromuscular blockade reversal, similar to our findings.

The majority (68.9\%) of ADRs occurred within half an hour from
sugammadex administration, suggesting that the patients should be
monitored carefully to detect any adverse reactions during the
anaesthesia recovery period. Nemes et al.\textsuperscript{16} found that
the incidence of residual postoperative neuromuscular block after
reversal with sugammadex was significantly lower than with neostigmine
or placebo; however, it could still not be avoided entirely. Errando et
al.\textsuperscript{17} reported that women have a higher incidence of
residual postoperative neuromuscular block than men; furthermore, a
residual block cannot be completely avoided without neuromuscular
monitoring, regardless of the antagonism strategy. Therefore, we
recommend neuromuscular function monitoring throughout anaesthesia and
that the reversal of muscle relaxation should always be driven by the
monitored data. Appropriate reversals in terms of medication, dose, and
timing should never blindly follow established rules.

We found that sugammadex-related ADRs have the highest fatality rate
involving cardiac disorders. At the same time, cardiac disorders are
also the SOC with the highest frequency of ADRs in association with
sugammadex. Several cases\textsuperscript{18-21} of severe bradycardia
and cardiac arrest have been reported clinically, and Hunter et
al.\textsuperscript{22} found that since 2016, the number of serious
adverse cardiac events reported after sugammadex in the Food and Drug
Administration (FDA) Adverse Event Reporting System has greatly exceeded
that after neostigmine. At present, the exact mechanism of
sugammadex-induced bradycardia and asystole is still unclear; however,
Kalkan et al. found that both low and high doses of sugammadex can cause
significant histopathological changes in cardiomyocytes and other
harmful effects. Nonetheless, this finding suggests that
anaesthesiologists should use sugammadex cautiously in patients with
underlying cardiovascular diseases during clinical medication. They
should also conduct comprehensive electrocardiography (ECG) and
hemodynamic change monitoring after the medication.

We stratified the reports of adverse events by age and found that
patients aged 0--17 years were the group with the highest risk of ADRs
due to saccharides. However, in contrast to our findings, Gaver et
al.\textsuperscript{23} reported that sugammadex was as effective and
safe in the paediatric population (age \textless{} 19 years) as in
adults, whereas Honing et al.\textsuperscript{24} showed that elderly
patients were more susceptible to the adverse effects of residual
neuromuscular blockade and had a slower natural recovery. In addition,
it is worth noting that pupil fixation, a common drug toxicity reaction,
had a strong positive signal in the paediatric group, though not in the
entire database, and we suspect that this finding may be related to
renal immaturity and delayed drug metabolism in children. However, there
were some cases where the number of ADR was less than three in the
age-stratified disproportionate analysis, suggesting that the analysis
of the adverse reactions of sugammadex in different age groups requires
a larger amount of data. Currently, sugammadex has not been approved by
the FDA for use in children. There are limited data on the use of
sugammadex in children, especially infants. Further paediatric studies
are required to fully determine the safety of sugammadex in children. We
acknowledge that the VigiBase database has some limitations. Incomplete
reports of ADRs and lack of complete clinical information are common
limitations of pharmacovigilance studies. First, adverse event reporting
is voluntary and performed by various sources (e.g., doctors,
pharmacists, and other clinicians), thus increasing the risk of
incomplete information. However, 130 countries have contributed to the
database, thus ensuring a comprehensive assessment from different
clinical settings. Second, no detailed clinical information and
diagnostic criteria were available; thus, our assessment was limited to
reports from treating clinicians, which may be subject to various
biases, including underreporting (reporting only the most severe or
obvious cases) or overreporting (reporting cases without a clear
diagnosis). Inevitably, reporting of adverse events is more likely soon
after the launch of a new drug than during regular, long-standing use.
In addition, it is important to note that when conducting ADR studies,
the IC value does not indicate a causal relationship between the target
drug and the suspected ADRs; it only shows a quantitative
association\textsuperscript{13}. Therefore, prospective studies and
long-term validation of these findings are required. Despite the
limitations of VigiBase, the analysis of adverse reactions in the
pharmacovigilance database remains an important tool for drug safety
studies and post-marketing drug monitoring. It allows for signal
detection in large populations and can provide significant opportunities
for monitoring drug safety and identifying new, rare signals.

In conclusion, research based on spontaneous ADR reporting is an
important modality for drug safety research and post-marketing drug
monitoring. In the safety profile of sugammadex, our result was similar
to that of the post-marketing clinical trials. We found that adverse
effects of sugammadex were at higher risk in adolescents and more severe
in older patients, for which further research should be performed. In
addition, our findings highlight important concerns about the time onset
of adverse events and cardiac safety, and we suggest that
anesthesiologists should carefully monitor the anesthesia recovery
period, especially for ECG and hemodynamic changes in patients with
underlying cardiovascular diseases.



\textbf{Acknowledgements}

We would like to thank the research department of Uppsala Monitoring
Centre (Uppsala, Sweden) for their help in data extraction. However, the
opinions and conclusions in this study do not necessarily represent the
opinion of the World Health Organization.

\textbf{Declaration of interests}

The authors declare that they have no conflict of interest.

\textbf{Funding information}

This study was supported by the National Nature Science Foundation of
China (No. 82073671), the Leading Talents of Public Health in Shanghai
(No. GWV-10.2-XD22), the Excellent Young Scholars of Public Health in
Shanghai (No. GWV-10.2-YQ33), three-year Action Program of Shanghai
Municipality for Strengthening the Construction of Public Health System
(GWV-10.1-XK05), Big Data and Artificial Intelligence Application, and
Military Key Discipline Construction Project (Health Service--Naval
Health Service Organization and Command, No. 03).



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883-91



\textbf{Tables}

Table 1. Clinical characteristics of patients with sugammadex-related
adverse reactions in the database\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
& & n (\%)\tabularnewline
\midrule
\endhead
Sex & Sex &\tabularnewline
& Male & 892 (43.90)\tabularnewline
& Female & 894 (44.00)\tabularnewline
& Unknown & 246 (12.11)\tabularnewline
Age (years) & Age (years) &\tabularnewline
& 0-17 & 132 (6.50)\tabularnewline
& 18-44 & 363 (17.86)\tabularnewline
& 45-64 & 534 (26.28)\tabularnewline
& [?] 65 & 469 (23.08)\tabularnewline
& Unknown & 534 (26.28)\tabularnewline
Year & Year &\tabularnewline
& 2010 & 21 (1.03)\tabularnewline
& 2011 & 21 (1.03)\tabularnewline
& 2012 & 44 (2.17)\tabularnewline
& 2013 & 153 (7.53)\tabularnewline
& 2014 & 110 (5.41)\tabularnewline
& 2015 & 145 (7.14)\tabularnewline
& 2016 & 310 (15.26)\tabularnewline
& 2017 & 372 (18.31)\tabularnewline
& 2018 & 361 (17.77)\tabularnewline
& 2019 & 495 (24.36)\tabularnewline
Region & Region &\tabularnewline
& Africa & 18 (0.89)\tabularnewline
& Americas & 439 (21.60)\tabularnewline
& Asia & 968 (47.64)\tabularnewline
& Europe & 471 (23.18)\tabularnewline
& Oceania & 136 (6.69)\tabularnewline
Outcome\textsuperscript{a} & Outcome\textsuperscript{a} &\tabularnewline
& Fatal & 53 (1.43)\tabularnewline
& Not recovered/not resolved & 50 (1.35)\tabularnewline
& Recovered/resolved & 2283 (61.41)\tabularnewline
& Recovered/resolved with sequelae & 17 (0.46)\tabularnewline
& Recovering/resolving & 239 (6.43)\tabularnewline
& Unknown & 1075 (28.93)\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{a}In total, 3717 outcomes were reported in 2032
patients.



\textbf{Figure legends}

Fig. 1. Comprehensive spectrum of adverse reactions related to
sugammadex reported by VigiBase with positive results from the
disproportionate analysis. IC\textsubscript{025} \textgreater{} 3 was
considered a significant association signal, indicating that the adverse
reactions have a strong correlation with sugammadex use.

Fig. 2. Results of the analysis of variance of
IC\textsubscript{025}values of adverse drug reactions in each age group.
The ANOVA test showed statistically significant differences (P
\textless{} 0.01) between age groups, indicating that the overall
intensity of adverse reaction signals in the 0--17 years group was the
highest.

Fig. 3. Spectrum of adverse drug reactions (ADRs) in different age
groups. No signal means no related ADR in this age group or ADR with
IC\textsubscript{025} \textless{} 0.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-1/Fig-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-2/Fig-2}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Fig-3/Fig-3}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`tables.docx`  available at \url{https://authorea.com/users/466170/articles/560544-safety-of-sugammadex-for-reversal-of-neuromuscular-block-a-post-marketing-study-based-on-the-world-health-organization-pharmacovigilance-database}

\selectlanguage{english}
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\end{document}

