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.