In this study, we evaluated the sedative effects of S-ketamine in combination with propofol in school-aged children undergoing gastro-duodenoscopy. The results showed that S-ketamine could improve the tolerance and the smooth placement rate during endoscope insertion, which was positively related to the dosage of S-ketamine. In addition, the effects of different doses of S-ketamine on the intraoperative hemodynamics, the dosage of propofol, the adverse reactions after recovery and the length of PACU stay were different.

Endoscope insertion is a relatively difficult procedure in gastro-duodenoscopy and can cause severe stimulation. Some studies have used different methods or different drugs to reduce the stimulation during endoscope insertion and improve the satisfaction of the first insertion of the endoscope (Kramer, et al., [15], Gotoda, et al., [11]). Although propofol is the most common sedative for gastrointestinal endoscopy in children (Alletag, et al., [3]), it has no analgesic effect and requires adjuvant analgesia to reduce the stress response of children during gastro-duodenoscopy (Yan, et al., [24]). In this study, only 16.70% of the children who received propofol alone had smooth placement of first endoscope insertion. The smooth placement of the first time of endoscope insertion in children received 0.3 mg.kg−1, 0.5 mg.kg−1 and 0.7 mg.kg−1 was 34.5%, 50.00% and 83.3%, respectively, which was significantly higher than that of children who received propofol alone. This indicates that after induction with S-ketamine, the tolerance of the children may be increased, and that the smooth placement rate of the first time of endoscope insertion is significantly improved with the increase of the S-ketamine dose. It has been shown that ketamine can increase the sensitivity of the pharynx in children (Flores-Gonzalez, et al., [9]). In this study, administration of S-ketamine did not increase the incidence of pharyngeal sensitive symptoms (such as coughing and vomiting) during endoscope insertion. Importantly, tolerance to endoscopy was increased with increasing doses of S-ketamine. Therefore, we suppose that S-ketamine may have reliable analgesic and sedative effect, which could improve the pain tolerance and anesthesia depth and serve as the main contributor to the improvement in the smooth placement rate of endoscope insertion.

Some studies have shown that propofol in combination with other adjuvants (fentanyl, dexmedetomidine, ketamine, etc.) can significantly reduce the dosage of propofol during sedation for gastroscopy in children (Akbulut, et al., [2], Mason, et al., [16]), but some other studies yield different results. For example, Akbulut et al. showed that sedation with midazolam and propofol did not reduce the dose of propofol during gastroscopy in children (Akbulut, et al., [1]). In this study, there was no obvious difference in term of total dose of propofol between 0.3 or 0.5 mg.kg−1 S-ketamine and propofol alone. The total dose of propofol was only significantly reduced in children receiving 0.7 mg.kg−1 S-ketamine compared with propofol alone. Therefore, we suppose that when propofol is used in combination with other adjuvants, the dose of adjuvant is an important factor in determining the total amount of propofol. Similar results were also obtained in previous studies (Hayes, et al., [13], Zheng, et al., [26]). Hayes et al. showed that when the combination of ketamine and propofol were used for gastro-duodenoscopy in children, the dose of ketamine greater than 0.5 mg.kg−1 could reduce the total amount of propofol, but not the dose of 0.25 mg.kg−1. Zheng et al. reported that the total amount of propofol administered during sedation in combination with S-ketamine 0.5 mg.kg−1 and 1.0 mg.kg−1 was significantly less than those in combination with S-ketamine 0.25 mg.kg−1 (Zheng, et al., [26])..

BIS monitoring can be used to avoid the risk of excessive sedation and reduce the occurrence of adverse reactions and is recommended for endoscopy under propofol-based sedation (Gotoda, et al., [11]). However, it has been shown that intravenous ketamine under general anesthesia can affect the BIS value of children in a dose-dependent manner (Peltoniemi, et al., [19]). The 0.5 mg.kg−1 of ketamine can increase the BIS value but not 0.2 mg.kg−1. In adults receiving gastroscopy, it has also been shown that the BIS value in patients receiving propofol combined with ketamine was significantly higher than that in patients receiving propofol combined with dexmedetomidine (Tekeli, et al., [21]). Similar results were also obtained in this study. BIS value at 1 min after induction in children who received S-ketamine 0.7 mg.kg−1 was higher than that of children who received propofol alone. At 5 min during the procedure, the mean BIS values of children who received 0.3 and 0.5 mg.kg−1 S-ketamine were significantly higher than those of children who received propofol alone. This may be related to the fact that the application of S-ketamine reduced the number of additional intraoperative propofol. Thus, it is limited to use BIS monitoring alone during sedation with S-ketamine. The reactions of patients, such as heart rate fluctuations and physical movement, should also be monitored.

S-ketamine administration can increase sympathetic tone and decrease the risk of cardiorespiratory depression, which is the reason for the combined used of S-ketamine and propofol (Eich, et al., [7], Eberl, et al., [6]). In this study, children received 0.5 and 0.7 mg.kg−1 S-ketamine had no significant fluctuation in heart rate, and had a significant lower incidence of hypotension than that of children received propofol alone and 0.3 mg.kg−1 S-ketamine, which is suggestive of the properties of S-ketamine to maintain stable hemodynamics. In addition, the relatively small amount of propofol during the procedure was also the reason for the lower incidence of hypotension in these two groups. Zheng et al. showed that S-ketamine (0.5 mg.kg−1 and 1.0 mg.kg−1) combined with propofol for sedation reduced the total amount of propofol, and thus decreased the risk of propofol-related hemodynamic change (Zheng, et al., [26]). It has been confirmed that, in adults receiving gastroscopy, S-ketamine 0.5 mg.kg−1 could reduce the median effective concentration of propofol by 50%, and maintain a more stable hemodynamics (Yang, et al., [25]). Moreover, the effect of propofol on blood pressure is related to dosage (Yan, et al., [24]). In this study, the incidence of hypotension in children receiving propofol alone was 23.30%, which was similar to the findings of Narula et al. (Narula, et al., [18]). However, administration of 0.3 mg.kg−1 S-ketamine did not significantly decrease the incidence of hypotension (24.10%), suggesting that this dose of S-ketamine has a poor ability to excite sympathetic activity. It is necessary to note that although S-ketamine has less effect on the central respiratory drive, it can also produce respiratory depression when administered at high doses or rapidly (Trimmel, et al., [22]). In this study, the administration rate of S-ketamine and propofol was slowed down during induction, and the breathing rhythm of the children was always monitored. This is also the reason for the lower incidence of respiratory depression in this study even when S-ketamine was used in combination with a relatively high dose of propofol (3 mg.kg−1).

Akubulut et al. (Akbulut, et al., [2]) showed that dizziness (84.9%) and visual disturbance (74.1%) were the most common adverse events in children underwent gastro-duodenoscopy with sedation of ketamine combined with midazolam. In this study, the incidence of dizziness and visual disturbance was also higher than other adverse events. The incidence of dizziness was increased with increased doses of S-ketamine, which may be indicative of a dose-related side effect (Wang, et al., [23]). Psychotomimetic effects are also the concern following ketamine administration (Erstad and Patanwala, [8], Jalili, et al., [14]). No delirium and hallucinations was reported in this study, which may be related to the lower incidence of psychotropic adverse actions following S-ketamine administration and psychotic symptom inhibition of propofol (Trimmel, et al., [22], Friedberg, [10]).

Several studies have shown that propofol in combination with ketamine/S-ketamine can reduce recovery time in children (Eich, et al., [7], Harun, et al., [12]). However, in this study, the combination of propofol and S-ketamine did not show the advantage of rapid recovery. On the contrary, the recovery time of the children was prolonged with the increase of the dose of S-ketamine, although there was no statistical difference. In addition, 0.7 mg.kg−1 S-ketamine administration had increased length of PACU stay. The high incidence of dizziness (73.3%) may prolong the length of PACU stay.

There were several limitations in this study. First, we did not evaluate the doses of propofol required to suppress the stress response to endoscopic insertion in combination of different doses of S-ketamine. Therefore, when induction is performed with the combination of propofol and S-ketamine, the median effective dose of propofol for inhibiting the stimulation of endoscopic insertion still requires further study. Second, we did not observe the sedative effect of higher doses of S-ketamine in combination with propofol, and perhaps higher doses of S-ketamine could provide more satisfactory sedative effect and less total propofol dosage. However, side effects of S-ketamine are dose-related. High incidence of dizziness associated with S-ketamine (0.7 mg.kg−1) may suggest that higher doses of S-ketamine may have higher incidence of adverse effects.