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.