Discussion
The primary endpoint of this study was to determine the median effective
concentration of propofol with different doses of esketamine during
gastrointestinal endoscopy in elderly patients. We found a significant
decrease in propofol EC50 when co-administration with
0.5 mg/kg esketamine or 0.25 mg/kg esketamine. The secondary endpoint
was to compare the change of haemodynamics among three groups. Our
results show that the co-administration of esketamine and propofol
caused more stable haemodynamic responses compared with single
administration of propofol in elderly patients.
In this study, we used the modified Dixon’s up-and-down methodology to
determine the median effective concentration of propofol with different
doses of esketamine, because the Dixon’s up-and-down method has a long
history [18,19] and is often used in anesthesia research [16].
The advantage of the sequential method is that it can make full use of
the data provided by fewer cases, and get results quickly and
accurately. To adopt the sequential method, two conditions must be met:
the dosage of the drug should be easy to change, and the negative or
positive result can be quickly revealed. Both of propofol and esketamine
meet the above two conditions, so we can think that our sequential
research method is feasible.
Various types of analgesic and sedative techniques have been used during
gastrointestinal endoscopy. The propofol, a good hypnotic with rapid
onset, short duration of action, and minimal side effects, is one of the
most commonly used intravenous anesthetics during endoscopic procedure
[5,7,20,21]. However, it was reported in a guideline of anesthesia
and sedation in GI endoscopy that transient hypoxia occurs in 3% to 7%
of cases using propofol sedation and that transient hypotension occurs
in 4% to 7% of cases [22]. It is well known that propofol may
cause shows dose-dependent hemodynamic instability, such as bradycardia
and hypotension, during induction or bolus administration [23]. The
hemodynamic instability is due to dose-dependent reduced systemic
vascular resistance and myocardial contractility [24-26] especially
in elderly patients. Many studies also demonstrated that the
requirements of propofol are reduced in elderly individuals [27,28]
because of the age-related changes in pharmacodynamics, pharmacokinetics
or both [29].
Some studies are exploring the medication strategy of propofol for
endoscopic procedure, such as combination medication to reduce the
dosage of propofol requirement [9,30-32]. A randomized,
double-blinded and controlled trial for elderly patients subjected to
colonoscopy showed that EC50 of propofol was reduced
when combined with 1 μg/kg fentanyl and there was no significant
difference in adverse events but prolonged awake and discharge time
[9]. Mortero et al.[30] demonstrate that the combination of
propofol with small-dose ketamine reduced hypoventilation caused by
propofol, induced positive mood effects, and produced earlier recovery
of perception compared with propofol alone during monitored anesthesia
for surgical interventions. Recently, Susanne Eberl et
al. [32] found that the combination of esketamine with propofol for
sedation in patients undergoing ERCP is superior to a combination of
propofol with an opioid.
Esketamine, a N-methyl-D-aspartate receptor antagonist, has analgesic,
anaesthetic and sympathomimetic properties. It is reported that
esketamine cause less respiratory or cardiovascular depression than
other sedatives due to an increase in sympathetic tone[12,32].
Jonkman K et al. found that esketamine could counter opioid-induced
respiratory depression [11]. It is also reported that esketamine
nasal spray could cause transient and asymptomatic blood pressure
elevations [33]. Therefore, there has been growing interest in the
use of esketamine as an ideal adjunct to propofol for procedural
sedation and analgesia [12,34]. It was reported that the use of a
combination of propofol and esketamine for procedural analgesia and
sedation during MR-guided HIFU treatments of uterine fibroids is
feasible and safe, with a short recovery time and a low risk of major
adverse events [34]. Recently, Eberl, S. et al. demonstrated
low-dose esketamine reduces the requirement of propofol for sedation
during ERCP in ASA I-II patients without affecting recovery time, side
effects, cardiovascular or respiratory adverse events and satisfaction
of endoscopists and patients, when compared with alfentanil [12].
In this study, we demonstrated that combination medication of propofol
with esketamine reduced the propofol EC50 during
gastrointestinal endoscopy in elderly patients and caused more stable
haemodynamic responses. Due to the decrease in the dose of propofol, the
dose-dependent depression of propofol on the circulation was alleviated.
Furthermore, the sympathomimetic properties of esketamine may, at least
partially, counter propofol-induced haemodynamic depression.
There was a limitation in our study. When hypotension caused by
excessive sedation occurs, we use vasoactive drugs to increase blood
pressure without reducing the propofol infusion rate, which may lead to
excessive sedation in some patients. A Bispectral Index or entropy
monitoring should be considered during endoscopic procedure in our next
step.