Discussion
We determined the EC50 of TCI propofol with different
doses of dexmedetomidine during gastrointestinal endoscopy. The
EC50 of TCI propofol when co-administration with 0.5 or
1.0 μg/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 EC50 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
EC50 of TCI propofol with different doses of
dexmedetomidine. This method has a long history [18-20]. Pace NLet 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
EC50 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 EC50 was
decreased when co-administration with fentanyl 1.0 μg/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 EC50 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 EC50 of TCI propofol during gastrointestinal
endoscopy. As dexmedetomidine suppresses neuronal activity and
facilitates vagal activity by α2 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%, P = 0.029) in the study by Nonaka T [16],
in which the dexmedetomidine was administrated a loading dose of 1 μg/kg
in 10 min and a maintenance infusion at the rate of 0.5 μg/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 μg/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
T4 time point (at scope intubation); but in the
co-administration group, MAP did not increased at T4time 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 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 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 μg/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
EC50 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 μg/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.