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\begin{document}

\title{Effect of different doses of dexmedetomidine on the median effective
concentration of propofol during gastrointestinal endoscopy:a
randomized controlled trial}



\author[1]{Hai-yan  Chen}%
\author[1]{Fang Deng}%
\author[1]{Shu-heng Tang}%
\author[1]{Wen  Liu}%
\author[1]{Hua Yang}%
\author[2]{Jin-Chao Song}%
\affil[1]{Affiliation not available}%
\affil[2]{Yangpu District Shidong Hospital of Shanghai}%


\vspace{-1em}



  
  \date{May 26, 2024}


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





\selectlanguage{english}
\begin{abstract}
Background: Dexmedetomidine could be an ideal adjuvant to propofol
during gastrointestinal endoscopy because it provides both analgesia and
sedation without respiratory depression. This study investigates the
effect of different doses of dexmedetomidine on the median effective
concentration of propofol during gastrointestinal endoscopy. Methods: 90
adult patients were randomly assigned to Group Control , Group DEX0.5
(0.5 \selectlanguage{greek}μ\selectlanguage{english}g/kg dexmedetomidine), or Group DEX1.0 (1.0 \selectlanguage{greek}μ\selectlanguage{english}g/kg dexmedetomidine)
. Anaesthesia during endoscopy was implemented by plasma
target-controlled infusion (TCI) of propofol with different doses of
dexmedetomidine. TCI concentration of the first patient for each group
was 2.5 \selectlanguage{greek}μ\selectlanguage{english}g/ml and the consecutive adjacent concentration gradient was
0.5 \selectlanguage{greek}μ\selectlanguage{english}g/mL. EC50 of TCI propofol for gastrointestinal endoscopy was
determined by using the modified Dixon's up-and-down method.
Cardiovascular variables were also measured. Results: EC50 of TCI
propofol and 95\% confidence interval (CI) for gastrointestinal
endoscopy were, 3.77 (3.48-4.09), 2.51 (2.27-2.78) and 2.10 (1.90-2.33)
\selectlanguage{greek}μ\selectlanguage{english}g/mL in Group Control, Group DEX0.5 and Group DEX1.0. The average
percent change from baseline in HR was 2.8 (8.9), -7.4 (7.7) and -10.5
(8.8) (P<0.001), and the average percent change from baseline in MAP
was -10.6 {[}-24.7; 3.5{]}, -9.5 {[}-29.2; 11.4{]} and -4.0 {[}-27.3;
15.5{]} (P = 0.034) in Group Control, Group DEX0.5 and Group DEX1.0,
respectively. Conclusions: Dexmedetomidine reduced the EC50 of TCI
propofol. A 0.5-1 \selectlanguage{greek}μ\selectlanguage{english}g/kg dexmedetomidine caused a decrease in HR without
bradycardia. The decrease in dosage of propofol with increasing doses of
dexmedetomidine caused more stable MAP. Dexmedetomidine is an ideal
adjuvant drug to propofol during gastrointestinal endoscopy.%
\end{abstract}%



\sloppy


\textbf{Effect of different doses of dexmedetomidine on the median
effective concentration of propofol during gastrointestinal endoscopy:a
randomized controlled trial}

Running Title: EC\textsubscript{50} of propofol with dexmedetomidine

Hai-yan Chen, M.D.*, Fang Deng, M.D.*, Shu-heng Tang, M.D.*, Wen Liu,
M.D., Hua Yang, M.D. \textsuperscript{\#}, Jin-Chao Song,
M.D.\textsuperscript{\#}

Department of Anesthesiology, Shidong Hospital Affiliated to University
of Shanghai for Science and Technology, Shanghai, China

* Hai-yan Chen, Shu-heng Tang and Fang Deng, contributed equally to this
work.

\#Corresponding Author:

Jin-chao Song, Department of Anesthesiology, Shidong Hospital of
Shanghai, University of Shanghai for Science and Technology, Shiguang
Rd., No. 999, Shanghai, China. E-mail:\emph{sjch2013@163.com}

Hua Yang, Department of Anesthesiology, Shidong Hospital of Shanghai,
University of Shanghai for Science and Technology, Shiguang Rd., No.
999, Shanghai, China. E-mail:\emph{yanghuayanghua1977@163.com}

Data Availability Statement: The data of this study are available from
the corresponding author, if the request is reasonable.

Funding: The Health Committee and the Science and Technology Commission
of Yangpu District, Shanghai: (YPM202105) and National Natural Science
Foundation of China: (NSFC, No.81371511) supported this study..

Conflicts of interest: All authors in this work declare no conflict of
interest.

Ethics approval: The trail is approved by the Committee on Ethics of
Biomedicine Research, Shidong Hospital.

Patient consent statement: Each patient signs the informed consent
before endoscopy

Permission to reproduce material from other sources: No material from
other sources.

Trial registration: Chinese Clinical Trial Registry ChiCTR2100054402.

\par\null

\textbf{WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT -}

1. Propofol is a popular drug for gastrointestinal endoscopy. However,
Propofol may result in hypotension, bradycardia, and respiratory
depression.

2. Dexmedetomidine, a \selectlanguage{greek}α\selectlanguage{english}\textsubscript{2} receptor agonist, provides
analgesia and sedation but does not cause respiratory depression.

3. Co-administration could improve anaesthetic effectiveness and reduce
the incidences of adverse events caused by a single drug.

\textbf{WHAT THIS STUDY ADDS -}

1. Combination medication of propofol with dexmedetomidine reduced the
EC\textsubscript{50} of TCI propofol during gastrointestinal endoscopy
compared with administration of propofol without dexmedetomidine.

2. A 0.5-1 \selectlanguage{greek}μ\selectlanguage{english}g/kg dexmedetomidine caused a decrease in HR without
bradycardia. The decrease in dosage of propofol with increasing doses of
dexmedetomidine caused more stable MAP.

3. Dexmedetomidine is an ideal adjuvant drug to propofol during
gastrointestinal endoscopy.



\textbf{Abstract}

\textbf{Background} : Dexmedetomidine could be an ideal adjuvant to
propofol during gastrointestinal endoscopy because it provides both
analgesia and sedation without respiratory depression. This study
investigates the effect of different doses of dexmedetomidine on the
median effective concentration of propofol during gastrointestinal
endoscopy. \textbf{Methods} : 90 adult patients were randomly assigned
to Group Control , Group DEX0.5 (0.5 \selectlanguage{greek}μ\selectlanguage{english}g/kg dexmedetomidine), or Group
DEX1.0 (1.0 \selectlanguage{greek}μ\selectlanguage{english}g/kg dexmedetomidine) . Anaesthesia during endoscopy was
implemented by plasma target-controlled infusion (TCI) of propofol with
different doses of dexmedetomidine. TCI concentration of the first
patient for each group was 2.5 \selectlanguage{greek}μ\selectlanguage{english}g/ml and the consecutive adjacent
concentration gradient was 0.5 \selectlanguage{greek}μ\selectlanguage{english}g/mL. EC\textsubscript{50} of TCI
propofol for gastrointestinal endoscopy was determined by using the
modified Dixon's up-and-down method. Cardiovascular variables were also
measured. \textbf{Results} : EC\textsubscript{50} of TCI propofol and
95\% confidence interval (CI) for gastrointestinal endoscopy were, 3.77
(3.48-4.09), 2.51 (2.27-2.78) and 2.10 (1.90-2.33) \selectlanguage{greek}μ\selectlanguage{english}g/mL in Group
Control, Group DEX0.5 and Group DEX1.0. The average percent change from
baseline in HR was 2.8 (8.9), -7.4 (7.7) and -10.5 (8.8) (\emph{P}
<0.001), and the average percent change from baseline in MAP was -10.6
{[}-24.7; 3.5{]}, -9.5 {[}-29.2; 11.4{]} and -4.0 {[}-27.3; 15.5{]}
(\emph{P} = 0.034) in Group Control, Group DEX0.5 and Group DEX1.0,
respectively. \textbf{Conclusions:} Dexmedetomidine reduced the
EC\textsubscript{50} of TCI propofol. A 0.5-1 \selectlanguage{greek}μ\selectlanguage{english}g/kg dexmedetomidine
caused a decrease in HR without bradycardia. The decrease in dosage of
propofol with increasing doses of dexmedetomidine caused more stable
MAP. Dexmedetomidine is an ideal adjuvant drug to propofol during
gastrointestinal endoscopy.

\textbf{Keywords} : The median effective concentration, Propofol,
Dexmedetomidine, Gastrointestinal endoscopy.



\textbf{Introduction}

Gastrointestinal endoscopy plays a very important role in the diagnosis
and treatment of gastrointestinal diseases. To facilitate the work of
the gastroenterologist and provide patient comfort, patients are given
sedation during the endoscopic procedures {[}1,2{]}. Propofol is a
popular drug during gastrointestinal endoscopy because of its rapid
onset, short duration of action, and minimal adverse effects {[}3-7{]}.
However, propofol may result in sedation-related adverse events such as,
respiratory depression and hypotension {[}8{]}. Adjuvants are usually
needed in endoscopic procedures in order to decrease the propofol dosage
and adverse events {[}9,10{]}. Dexmedetomidine, a
\selectlanguage{greek}α\selectlanguage{english}\textsubscript{2}receptor agonist, could be an ideal adjuvant to
propofol for endoscopy because it provides both analgesia and sedation
without respiratory depression {[}11{]}. However, the bradycardia caused
by dexmedetomidine was often reported {[}12-16{]}. Nonaka T \emph{et
al.} {[}16{]} demonstrated that that the incidence of bradycardia
(defined as a pulse rate [?] 45 bpm) in the combination of dexmedetomidine
with propofol group was higher than that in the propofol alone group
(37.9\% vs. 10.3\%). Whether dexmedetomidine is an ideal adjuvant drug
to propofol during gastrointestinal endoscopy is worthy of our further
study.

In the present study, we hypothesized that dexmedetomidine could reduce
the median effective concentration (EC\textsubscript{50}) of TCI
propofol during gastrointestinal endoscopy. The primary endpoint was to
determine the EC\textsubscript{50} of TCI propofol with different doses
of dexmedetomidine. The secondary endpoint was to compare the effects of
different doses of dexmedetomidine on heart rate (HR) and mean arterial
pressure (MAP) during gastrointestinal endoscopy.

\textbf{Materials and Methods}

Study design

The Ethics Committee of Shidong Hospital of Yangpu District in Shanghai
approved this study. The registration number of this randomized clinical
trials is ChiCTR2100054402 (The URL is http://www.chictr.org/cn/). Each
patient signs the informed consent before endoscopy. A total of 90 adult
patients undergoing gastrointestinal endoscopy between December 2021 and
February 2022, were enrolled in this study.

Inclusion and exclusion criteria

Patients undergoing gastrointestinal endoscopy, aged 18 to 65 years old;
ASA I to III; and body mass index19 to 27 kg/m\textsuperscript{2} were
enrolled in this study.

Patients with (1) allergy to either dexmedetomidine or propofol; (2)
history of long-term opioid use or alcohol abuse; (3) history of
psychological problems or psychiatric disease; (4) heart failure
(ejection fraction \textless{}40\%); significant ischemic heart disease;
(5) hypotension or bradycardia; (6) history of unregulated hypertension;
(7) severe respiratory disease; (8) hepatic or renal insufficiency were
excluded from this study.

Anesthesia protocol

A total of 90 adult patients were randomly assigned to Group Control
(saline solution) ), Group DEX0.5 (0.5 \selectlanguage{greek}μ\selectlanguage{english}g/kg dexmedetomidine), or Group
DEX1.0 (1.0 \selectlanguage{greek}μ\selectlanguage{english}g/kg dexmedetomidine). The gastroenterologists,
anesthesiologist and patients, were blinded to the grouping.

Each patient did not receive pre-medication. A 20-G intravenous catheter
was inserted into the right or left antecubital region for fluids and
medicationsHR, MAP, Electrocardiogram, noninvasive systolic arterial
pressure, respiration rate, and peripheral oxygen saturation
(SpO\textsubscript{2}) were monitored (Philips IntelliVue). All patients
were given oxygen by nasal catheter (the oxygen flow of 3-5 L/min)
during procedure.

A nurse who did not participate in this study diluted the
dexmedetomidine solution to 20 mL. After preoxygenation, patients were
given different doses of dexmedetomidine: saline solution (Group
Control), 0.5 \selectlanguage{greek}μ\selectlanguage{english}g/kg dexmedetomidine (Group DEX0.5), or 1.0 \selectlanguage{greek}μ\selectlanguage{english}g/kg
dexmedetomidine (Group DEX1.0). The same volume (20 mL) of
dexmedetomidine solutions or saline solution was administered in 5 min.
Then, propofol was given by Graseby 3500 TCI Syringe Pump with the Marsh
parameters. The plasma target-controlled concentration of the first
patient for each group was 2.5 \selectlanguage{greek}μ\selectlanguage{english}g/mL. Once the target concentration on
the TCI pump was achieved, gastroenterologists started gastroscopy. In
our endoscopy center, patients underwent gastroscopy followed by
colonoscopy in one anaesthetic treatment. Target-controlled infusion of
propofol is maintained until the end of colonoscopy. A stable sedation
without patient body movements is necessary to enhance the precision and
swiftness of the gastrointestinal endoscopy and enhance the patient
satisfaction and the gastroenterologist satisfaction. The flow chart of
the Dixon's up-and-down methodology was shown in Figure 7. Whether the
patients were ``responsive'' is determined by the anesthesiologist who
does not know the grouping and dexmedetomidine dose (saline solution). .

Emergency equipment was always on standby. Ephedrine 6-10 mg was
administered in case MAP dropped blow 60 mmHg or 30\% less than the
baseline, and atropine 0.25 mg was given in case HR were lower than 50
beats per minute. Appropriate nitroglycerin was administered in case MAP
were over 120 mmHg. If SpO\textsubscript{2} \textless{} 92\% for more
than 5 seconds, ventilation support was performed by the
anesthesiologist when necessary.

Measurements

In this study, baseline of HR and MAP are defined as the measured values
at 5 min after the patient was brought to the endoscopic room. HR, MBP
and SpO\textsubscript{2} were monitored and recorded at the designated
time points: T\textsubscript{0}: baseline values; T\textsubscript{1}:
2.5 min after administration of dexmedetomidine; T\textsubscript{2}: 5
min after administration of dexmedetomidine (Dexmedetomidine
administration is over); T\textsubscript{3}: when propofol target plasma
concentration reached the target; T\textsubscript{4}: at scope
intubation; and T\textsubscript{5-X}: by 3 min intervals.

The endoscopic time were recorded. We defined the recovery time as the
interval time from cessation of TCI propofol to the time when patients
could respond readily to name spoken in normal tone (that is Observer's
Assessment of Alertness/Sedation scale (OAA/S) = 5). Sedation-related
adverse events, such as postoperative nausea and vomiting, respiratory
depression, bradycardia, and hypotension, were also recorded.

The satisfaction of gastroenterologists (scored by 4, excellent; 3,
good; 2, fair; and 1, poor) and the satisfaction of patients (4, no
discomfort; 3, slightly uncomfortable; 2, extremely uncomfortable;
1,unacceptable) were assessed immediately after procedure and 30 minutes
after procedure, respectively. {[}7,10{]}.

The average percent change from baseline in HR and MAP, were compared
among three groups. In this study, we defined the calculation formula of
percent change from baseline at the fixed time points =
(HR\textsubscript{T1-x} --HR \textsubscript{T0})/ HR \textsubscript{T0}*
100 and (MBP\textsubscript{T1-x} -- MBP\textsubscript{T0})/
MBP\textsubscript{T0}*100. {[}7,10{]}.

Statistical analysis

. The sample size calculation, using the method described by Eberl et
al. {[}17{]}, was based on the retrospective sedation database of our
hospital, in which the propofol requirement for gastrointestinal
endoscopy was 300 (100) mg, presented as mean (standard deviation).
Given power of 0.80 and type I error of 0.05, we will need to study 28
subjects per group to decrease propofol requirement by about 25\%. And
taking into consideration a potential dropout rate of 10\%, 30 patients
for each group will be required, thus a total of 90 adult patients
should be randomly assigned.

SPSS 13.0 or the software R was performed for statistical analysis. We
used the modified Dixon's up-and-down methodology, described in 1965
{[}18{]}, to determine the EC\textsubscript{50} of TCI propofol with
different doses of dexmedetomidine. We performed a chi-squared test for
categorical variables, ANOVA test for continuous values and
Kruskal-Wallis rank sum test for discrete values as appropriate. Data
were presented as number (n), mean (standard deviation, SD), or median
{[}Min, Max{]}. A 0.05 was set as the threshold of rejecting the null
hypothesis.

\textbf{Results}

The study flow diagram was showed in Figure.1. There was no statistical
significance in preoperative laboratory values and characteristics of
patients (Table 1).

EC\textsubscript{50} of TCI propofol and its 95\% confidence interval
(CI) for gastrointestinal endoscopy were 3.77 (3.48-4.09), 2.51
(2.27-2.78) and 2.10 (1.90-2.33) \selectlanguage{greek}μ\selectlanguage{english}g/mL in Group Control, Group DEX0.5
and Group DEX1.0 (Table 2). EC\textsubscript{50} of TCI propofol in
Group DEX0.5 and Group DEX1.0 was reduced by 33.4\% and 44.3\% compared
with Group Control. Figure 2 to 4 showed that the TCI concentrations of
propofol for consecutive patients and their ``responsive'' or
``non-responsive'' during gastrointestinal endoscopy.

The average percent change from baseline in HR was 2.8 (8.9), -7.4 (7.7)
and -10.5 (8.8) (\emph{P} <0.001), and average percent change from
baseline in MAP was -10.6 {[}-24.7; 3.5{]}, -9.5 {[}-29.2; 11.4{]} and
-4.0 {[}-27.3; 15.5{]} (\emph{P} = 0.034) in Group Control, Group DEX0.5
and Group DEX1.0, respectively (Table 3). Figure 5 and Figure 6 showed
the time course of percent change from baseline in HR and MAP. The
decrease in dosage of propofol with increasing doses of dexmedetomidine
caused more stable MAP. Dexmedetomidine caused a decrease in heart rate.
However, there was no bradycardia in our study.

Recovery time were 10.9 (2.5), 9.3 (2.9), and 11.6 (3.3) min (\emph{P} =
0.015) in Group Control, Group DEX0.5 and Group DEX1.0 (Table 3). The
recovery time of Group DEX0.5 was significantly shorter than that of the
other groups.

This study was completed without any serious adverse events, such as the
need for tracheal intubation or termination of the endoscopy. Major
sedation-related adverse events were showed in Table 3.

Satisfactions of patients and gastroenterologists were showed in Table
3.

\textbf{Discussion}

We determined the EC\textsubscript{50} of TCI propofol with different
doses of dexmedetomidine during gastrointestinal endoscopy. The
EC\textsubscript{50} of TCI propofol when co-administration with 0.5 or
1.0 \selectlanguage{greek}μ\selectlanguage{english}g/mL dexmedetomidine was reduced by 33.4\% and 44.3\% compared with
Group Control. We dermonstrated that the increasing doses of
dexmedetomidine with propofol caused more stable MAP. Dexmedetomidine
caused a decrease in heart rate. However, there was no bradycardia in
our study.

In our previous study {[}10{]}, we investigated the effect of different
doses of esketamine on the EC\textsubscript{50} of TCI propofol in the
elderly population, and obtained the corresponding data for users'
reference. Due to the different mechanisms of action and different
pharmacological characteristics of dexmedetomidine and esketamine,
different combinations will have different methods of administration and
pharmacological outcome. Therefore, we decided to use the same research
method and statistical method to study the combination of propofol and
dexmedetomidine for gastrointestinal endoscopy anesthesia in adults.
This study differs from our previous studies in the following ways: (1)
There are a separate application for ethics and a separate clinical
registration in this study. (2) The subjects of the study were also
re-recruited; the elderly (over 65 years old) were recruited in the
previous study, and the adults (18-65 years old) were recruited in this
study. (3) The adjuvant drugs involved in this study (dexmedetomidine)
are also completely different from those in the previous study
(esketamine); the administration method is also different from the
previous study.

We used the modified Dixon's method to determine the
EC\textsubscript{50} of TCI propofol with different doses of
dexmedetomidine. This method has a long history {[}18-20{]}. Pace
NL\emph{et al.} demonstrated that up-and-down methodology could make
full use of the data provided by fewer cases and obtain results quickly
and accurately {[}21{]}. It was reported that 20 or more patients each
group could show statistically significant differences in the
EC\textsubscript{50} using the Dixon's methodology. So the sequential
methodology is often used in anesthesia researches {[}9,10,22{]}.

Propofol, acting at the GABAA receptors {[}23{]} and the
N-methyl-D-aspartate subtype of glutamate receptors {[}24{]}, is
popularly used during endoscopic procedure because of its properties of
fast onset of action, short duration of action, and minimal side effects
{[}3-7{]}. However, propofol may cause dose-dependent reduced myocardial
contractility and systemic vascular resistance {[}25-27{]}, which
resulted in dose-dependent hemodynamic changes, such as hypotension and
bradycardia {[}28{]}. It was reported that transient hypotension occurs
in 4\% to 7\% of cases and transient hypoxia occurs in 3\% to 7\% of
cases using propofol sedation in an anesthesia and sedation guideline in
gastrointestinal endoscopy{[}29{]}. Some medication strategies of
propofol for endoscopic procedure were explored in some studies.
Clinically, considering that drugs with different mechanisms of action
may have synergistic effects, anesthesiologists tried various
combinations of analgesic and sedative medications to reduce the total
amount of individual medications and reduce complications {[}9,17,
30-32{]}. It was showed that the propofol EC\textsubscript{50} was
decreased when co-administration with fentanyl 1.0 \selectlanguage{greek}μ\selectlanguage{english}g/kg during
colonoscopy in elderly patients {[}9{]}. Recently, it was reported that
low-dose esketamine reduced the propofol requirement during ERCP without
affecting respiratory or cardiovascular adverse events in ASA I-II
patients, when compared with alfentanil{[}17,32{]}. In our other
previous study {[}10{]}, we confirmed that combination of propofol and
esketamine could reduce the EC\textsubscript{50} of TCI propofol during
gastrointestinal endoscopy compared with propofol alone in elderly
patients.

Dexmedetomidine is a highly selective alpha2-adrenoceptor agonist. It
was reported that dexmedetomidine provided sedativeand analgesic
{[}33{]} without the risk of respiratory depression {[}11,34,35{]}. In
the past few years, some studies demonstrated that dexmedetomidine alone
in digestive endoscopic sedation has no significant advantages in
recovery time, haemodynamic stability, and patient's and
gastroenterologist's satisfaction, compared with propofol or midazolam
{[}3,36,37{]}. Recently, some researchers have studied the efficacy and
safety of using dextromethorphan as an adjuvant to propofol
{[}16,38,39{]}. A synergistic effect on sedation was observed in all
these studies, in which the total propofol requirement in the
dexmedetomidine group was significantly reduced. In our this study, we
demonstrated that combination of propofol and dexmedetomidine decreased
the EC\textsubscript{50} of TCI propofol during gastrointestinal
endoscopy. As dexmedetomidine suppresses neuronal activity and
facilitates vagal activity by \selectlanguage{greek}α\selectlanguage{english}\textsubscript{2} receptor activation in
the central nervous system; and propofol acts at the GABAA receptors and
the NMDA receptors. Therefore, we think the sedative effect of
dexmedetomidine and propofol would be synergistic.

The bradycardia caused by dexmedetomidine was often reported
{[}12-16{]}. Recently, it was reported that the incidence of bradycardia
(defined as a pulse rate [?] 45 bpm) in the combination of dexmedetomidine
with propofol group was higher than that in the propofol alone group
(37.9\% vs. 10.3\%, \emph{P} = 0.029) in the study by Nonaka T {[}16{]},
in which the dexmedetomidine was administrated a loading dose of 1 \selectlanguage{greek}μ\selectlanguage{english}g/kg
in 10 min and a maintenance infusion at the rate of 0.5 \selectlanguage{greek}μ\selectlanguage{english}g/kg/h. In our
study, the HR average percent change from baseline of
dexmedetomidine-propofol co-administration group (Group DEX0.5 and Group
DEX1.0) was significantly lower than that of Group Control (propofol
alone) (Table 3, Figure 6), which is consistent with the pharmacological
properties of dexmedetomidine itself. Dexmedetomidine caused a decrease
in heart rate. However, there were no cases of bradycardia (HR < 50
bpm) in the study. There were two possible reasons why there was no
bradycardia:(1) Compared to other studies {[}40,41{]}, our total dose
of dexmedetomidine was not high. We just administered a single dose of
dexmedetomidine of 0.5 or 1.0 \selectlanguage{greek}μ\selectlanguage{english}g/kg for 5 minutes without maintenance
infusion. (2) The dose-dependent depression of propofol on the heart
rate was weaken, owing to the decrease in dosage of propofol.

The MAP average percent change from baseline of Group DEX1.0 was
significantly higher than that of Group Control and Group DEX0.5 (Table
3, Figure 5). The possible reason why increasing doses of
dexmedetomidine caused more stable haemodynamics was that the
dose-dependent depression of propofol on the circulation was weaken
duing to the decrease in dosage of propofol. Furthermore, Figure 5
showed that the hemodynamics (MAP) of dexmedetomidine-propofol
co-administration group (Group DEX0.5 and Group DEX1.0) were more
stable. In the control group (propofol alone), MAP rebounded at
T\textsubscript{4} time point (at scope intubation); but in the
co-administration group, MAP did not increased at T\textsubscript{4}time
point, which may be due to the analgesic effect of dexmedetomidine. This
steady blood pressure and appropriately reduced heart rate (but not
bradycardia) in co-administration group may benefit the heart in
maintaining the balance of oxygen supply and demand.

In the meanwhile, it should be motioned that the loading dose of
dexmedetomidine was infused within 10 min in many previous studies
{[}11,39,42{]}, while we tried to infuse dexmedetomidine single dose
within 5 min under close monitoring {[}43-45{]}. It was showed that no
hypotension, bradycardia, tachycardia and hypertension took place after
receiving these doses of dexmedetomidine within relatively shorter time
(5 min).

Recovery time was widely concerned by endoscopists and anesthesiologists
{[}9,17,30,32,46{]}. Rapid recovery is important for patients and
hospitals. Using dexmedetomidine for sedation may cause prolonged
recovery in term of pharmacological properties, as dexmedetomidine has a
relatively long elimination half-life (approximately 2 h)
{[}33,47,48{]}. It was demonstrated that dexmedetomidine caused
prolonged recovery time in outpatient shock wave lithotripsy, compared
with midazolam/fentanyl combination {[}48{]}. Arain and Ebert et al.
demonstrated that a prolonged sedative effect occured after
intraoperative use of dexmedetomidine compared with propofol {[}49{]}.
Arzu ET \emph{et al} . {[}50{]} demonstrated that there was a slower
recovery in dexmedetomidine-propofol combination group, than in
ketamine-propofol combination group. However, in some other studies, it
was found that the use of dexamethasone did not prolong the recovery
time. In Takashi Nonaka1's study {[}16{]}, there were no significant
difference in recovery times between Combination group (dexmedetomidine
and propofol) and Propofol alone group during gastric endoscopic
submucosal dissection. The median (ranges) of recovery time was 7 (3-23)
min in Combination group and 5 (3-20) min in Propofol alone group. Even
Senem Koruk \emph{et al.} {[}39{]} demonstrated that a shorter recovery
time with the dexmedetomidine-propofol co-administration for ERCP
patients, compared with the midazolam-propofol co-administration. In our
study, we found the recovery time of Group DEX0.5 was significantly
shorter than that of the other groups. There are two possible reasons:
one is that we just gave the single dose of dexmedetomidine (0.5 \selectlanguage{greek}μ\selectlanguage{english}g/kg
dexmedetomidine in 5 min) without continuous administration, which
single dose was unlikely to cause drug accumulation and prolong
awakening time; the second is that the decrease in the
EC\textsubscript{50} of TCI propofol is also conducive to rapid
recovery. However, on the other hand, there was no difference in
recovery time between Group DEX1.0 (1.0 \selectlanguage{greek}μ\selectlanguage{english}g/kg dexmedetomidine within 5
min) and Group Control (propofol alone).

There was one limitation in our study. Although we require
gastroenterologists with the same qualifications and experience to
perform endoscopy, there are inevitably differences in operating
techniques and skills between different gastroenterologists, which may
cause patients to respond differently to the same depth of anesthesia.

\textbf{Conclusions}

Dexmedetomidine decreased the EC\textsubscript{50} of TCI propofol
during gastrointestinal endoscopy. The decrease in dosage of propofol
with increasing doses of dexmedetomidine caused more stable MAP. A
0.5-1.0 \selectlanguage{greek}μ\selectlanguage{english}g/kg dexmedetomidine caused a decrease in heart rate without
bradycardia and did not cause prolonged recovery time. We believe
dexmedetomidine is an ideal adjuvant drug to propofol during
gastrointestinal endoscopy.

\textbf{Acknowledgements}

The authors thank Professor Teng-jiao Wang and Long Qing (Naval Medical
University, China) for data analysis.

\textbf{Authors' contributions} : Study design: Hua Yang and Jin-Chao
Song. Data collection: Hai-yan Chen, Shu-heng Tang, and Fang Deng.
Statistical analysis: Hai-yan Chen. Manuscript drafting: Fang Deng and
Wen Liu. Supervision: Jin-Chao Song. Project administration: Jin-Chao
Song.

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Table 1 Characteristics and laboratory values of participants. 30
patients for each group

\textbf{Control}

\textbf{Group DEX0.5}

\textbf{Group DEX1.0}

P

\textbf{Sex (M/F)}

8/22

11/19

11/19

0.638

\textbf{Age~(yrs)}

54.5 (11.9)

54.1 (8.8)

52.2 (10.3)

0.651

\textbf{Body mass index (kg/m\textsuperscript{2})}

23.7 (3.0)

23.4 (3.0)

23.7 (2.6)

0.879

\selectlanguage{greek}\textbf{Serum total bilirubin (μmol/L)}\selectlanguage{english}

16.0 (7.8)

17.8 (10.7)

14.4 (5.1)

0.606

\textbf{Albumin} \textbf{(g/L)}

44.2 (2.3)

42.1 (3.9)

43.1 (3.1)

0.410

\textbf{Alanine aminotransferase (U/L)}

15{[}11;36{]}

18{[}8;32{]}

29{[}10;85{]}

0.562

\textbf{Aspartate aminotransferase (U/L)}

22.5{[}17;28{]}

21{[}15;28{]}

24{[}16;48{]}

0.671

\textbf{Serum creatinine (mmol/L)}

66.9 (13.0)

60.8 (13.3)

60.2 (18.4)

0.557

\textbf{Blood urea nitrogen (mmol/L)}

5.1 (1.2)

4.8 (1.4)

4.8 (1.4)

0.845

\textbf{International normalized ratio}

0.94{[}0.81;1.09{]}

0.92{[}0.83;1.10{]}

0.95{[}0.90;1.03{]}

0.581

Data are number, Median {[}Min, Max{]} or Mean (SD).

Table 2. Propofol EC\textsubscript{50} {[}95\% confidence interval{]};
30 patients for each group

\textbf{Group Control}

\textbf{Group DEX0.5}

\textbf{Group DEX1.0}

\selectlanguage{greek}\textbf{Propofol EC\textsubscript{50} (μg/mL)}\selectlanguage{english}

3.77

2.51

2.10

\selectlanguage{greek}\textbf{95\% CI (μg/mL)}\selectlanguage{english}

{[}3.48, 4.09{]}

{[}2.27, 2.78{]}

{[}1.90, 2.33{]}

Table 3. Procedure-related time, hemodynamics, and sedation-related
adverse events; 30 patients for each group

\textbf{Group Control}

\textbf{Group DEX0.5}

\textbf{Group DEX1.0}

P

\textbf{Injection site pain(yes/no)}

6/24

1/29

0/30

\textbf{0.008}

\textbf{Procedure time (min)}

18.1 (7.3)

18.3 (5.8)

19.6 (6.8)

0.650

\textbf{Recovery time (min)}

10.9 (2.5)

9.3 (2.9)\selectlanguage{ngerman}\textsuperscript{§}

11.6 (3.3)

\textbf{0.015}

\textbf{Mean arterial pressure (\%)}

-10.6 {[}-24.7; 3.5{]}

-9.5 {[}-29.2; 11.4{]}

-4.0 {[}-27.3; 15.5{]}*

\textbf{0.034}

\textbf{Heart rate (\%)}

2.8(8.9)

-7.4(7.7)\textsuperscript{\&}

-10.5(8.8)\textsuperscript{\&}

\selectlanguage{english}\textbf{<0.001}

\textbf{Satisfaction of} \textbf{patient}

4 {[}3, 4{]}

4 {[}3, 4{]}

4 {[}3, 4{]}

0.24

\textbf{Satisfaction of gastroenterologist}

4 {[}3, 4{]}

4 {[}3, 4{]}

4 {[}3, 4{]}

1

\textbf{Sedation-related adverse events}

\textbf{Hypotension}

2

2

0

-

\textbf{Respiratory depression}

1

0

0

-

\textbf{Postoperative nausea and vomiting}

1

0

0

-

Data are Median {[}Min, Max{]} or Mean (SD);

SSCompared with Control and Group DEX1.0, P \selectlanguage{english}<0.05; *Compared with
Control and Group DEX0.5, P \selectlanguage{english}<0.05;

\textsuperscript{\&}Compared with Control, P\selectlanguage{english}<0.05.

\textbf{Figure legends}

\emph{Figure 1} . Study flow diagram.

\emph{Figure 2} . TCI concentrations of propofol for consecutive
patients in control group. The horizontal line at 3.77 \selectlanguage{greek}μ\selectlanguage{english}g/mL means the
EC\textsubscript{50} of TCI propofol. The red triangle means
``responsive''. The blue dot means ``non-responsive''.

\emph{Figure 3} . TCI concentrations of propofol for consecutive
patients in DEX0.5 group. The horizontal line at 2.51 \selectlanguage{greek}μ\selectlanguage{english}g/mL means the
EC\textsubscript{50} of TCI propofol. The red triangle means
``responsive''. The blue dot means ``non-responsive''.

\emph{Figure 4} . TCI concentrations of propofol for consecutive
patients in DEX1.0 group. The horizontal line at 2.10 \selectlanguage{greek}μ\selectlanguage{english}g/mL means the
EC\textsubscript{50} of TCI propofol. The red triangle means
``responsive''. The blue dot means ``non-responsive''.

\emph{Figure 5} . The time course of percent change from baseline in
MAP. T\textsubscript{0}: baseline values; T\textsubscript{1}: 2.5 min
after administration of dexmedetomidine; T\textsubscript{2}:
Dexmedetomidine administration is over; T\textsubscript{3}: when
propofol target plasma concentration reached the target;
T\textsubscript{4}: at scope intubation and T\textsubscript{5-x}: by 3
min intervals.

\emph{Figure 6} . The time course of percent change from baseline in HR.
T\textsubscript{0}: baseline values; T\textsubscript{1}: 2.5 min after
administration of dexmedetomidine; T\textsubscript{2}: Dexmedetomidine
administration is over; T\textsubscript{3}: when propofol target plasma
concentration reached the target; T\textsubscript{4}: at scope
intubation and T\textsubscript{5-x}: by 3 min intervals.

\emph{Figure 7} . The flow chart of the Dixon's up-and-down methodology.\selectlanguage{english}
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