Our results demonstrate that MAC using dexmedetomidine-midazolam-fentanyl for chemoport insertion has no difference in the onset time, time to spontaneous eye opening, recovery room stay, the incidences of inadequate analgesia, hypotension and bradycardia compared with dexmedetomidine-ketamine group. The DMF group displayed better sedation quality and satisfaction scores from the patients, surgeon, and anesthesiologist despite the lower infusion rate of dexmedetomidine and higher incidence of BIS < 60 than in the DK group.
Chemoport insertion is a painful and discomforting procedure which usually requires MAC for analgesia and sedation. There have been a growing number of reports of the use of dexmedetomidine for procedural sedation. However, dexmedetomidine lacks an analgesic effect for heat and electrical pain even at doses causing severe sedation [9]. Moreover, the sole use of dexmedetomidine for colonoscopy is limited by the frequent requirement of supplemental fentanyl, profound hemodynamic instability, and prolonged recovery [2]. In particular, the co-administration of ketamine is rising to compensate for the slow onset, hypotension, bradycardia, and inadequate analgesia from the sole use of dexmedetomidine [5–8, 13]. However, meticulous care is required for using ketamine due to its adverse effects including emergence delirium, visual and auditory hallucinations, and vivid unpleasant dreams. We therefore compared the analgesic and sedative effects of the dexmedetomidine-ketamine combination with the dexmedetomidine-midazolam-fentanyl combination during MAC for chemoport insertion.
There was no difference in the mean onset time of sedation between the two groups in this study. In both groups, it was around 6–7 min, which is shorter than the minimum 10 min which is usually required when adopting loading dose of dexmedetomidine, but longer than the onset of sedation with propofol [14]. Therefore, the addition of ketamine or midazolam-fentanyl to dexmedetomidine can speed the onset of sedation from dexmedetomidine alone.
There was no difference in the number of patients requiring rescue analgesics between the two groups in this study. However, there was a significant difference in the number of patients requiring rescue sedatives. No patient required rescue sedatives in the DMF group, while six patients (24 %) in the DK group required rescue sedatives due to an OAA/S score of 5 despite a maximal infusion rate of dexmedetomidine (1.0 μg.kg−1h−1). On the other hand, more patients {21 (77.8 %)} in the DMF group showed an OAA/S score of 2 reflecting deep sedation than in the DK group {10 (40.0 %)}. To reproduce a clinical setting, we did not fix the continuous infusion rate of dexmedetomidine in this study. To achieve adequate sedation (a modified OAA/S score of 3–4), we adjusted the infusion rate up or down by 0.2 μg.kg−1h−1. We usually had to increase and decrease the continuous infusion rate of dexmedetomidine in DK and DMF groups, respectively. Therefore the infusion rate of dexmedetomidine in the DMF group was significantly lower than in the DK group from 15 to 21 min after the start of the drug administration.
The BIS in the DMF group was significantly lower than in the DK group throughout the study. The hypnotic effect of ketamine is characterized by a dissociative mechanism, ketamine-induced unconsciousness is characterized by suppression of high-frequency gamma activity and a breakdown of cortical coherence [15]. The BIS increase in response to ketamine is paradoxical in so far as the anesthesia level is deepened by the administration of an additional anesthetic agent [16]. The BIS usage has limitation to determine the anesthetic depth in MAC with ketamine, so we used the modified OAA/S for the adjustment of anesthetic depth.
However, the finding that six patients (24 %) in the DK group but none in the DMF group needed rescue sedatives implied inadequate sedation or inconvenience during the procedural sedation. This is also consistent with the finding that the satisfaction scores of the patients, surgeon, and anesthesiologist in the DMF group were significantly higher than in the DK group (Fig. 7).
The common adverse effects of dexmedetomidine are hypotension, hypertension, and bradycardia [17]. Dexmedetomidine has a biphasic effect on blood pressure, causing a decrease in the mean arterial pressure at low plasma concentrations (<1.9 ng.ml−1) due to vasodilation from the activation of the α2A receptor, and an increase at higher plasma concentrations due to vasoconstriction from the activation of the peripheral α2B receptor [18]. In a human study, a 2-min infusion of 1 or 2 μg.kg−1 dexmedetomidine produced an early transient increase in MBP (16 or 24 %, respectively, peak at 3 min lasting < 11 min) with a concomitantly reduced HR [19]. In our study, dexmedetomidine was administered as a 1 μg.kg−1 loading infusion over 10 min, followed by a continuous infusion of 0.2–1.0 μg.kg−1h−1. The co-administration of midazolam and fentanyl in the DMF group did not decrease the MBP as compared with the baseline value, except for a significant decrease in MBP by 10.4 % only 3 min after the start of the drug administration. By contrast, the ketamine co-administered in the DK group significantly increased the MBP by 15 % as compared with the baseline value 3 and 6 min after the start of the drug administration, and did not show significant changes thereafter. In terms of HR change, both groups showed significant decreases by 12–20 % as compared with the baseline value throughout the study, except for a lack of change only 3 min after the start of the drug administration in the DK group. Those levels of hemodynamic changes were within the clinically acceptable range. In addition, the number of patients requiring ephedrine for hypotension and atropine for bradycardia was 10 of 52 (7 of 25 in the DK group and 3 of 27 in the DMF group) and 3 of 52 (in the DK group only), respectively, and the patients recovered easily after treatment. These differences were not statistically significant between the two groups. Taking the results in the hemodynamic changes mentioned above, we suggest that the administration of ketamine or midazolam-fentanyl as dexmedetomidine adjuvants is safe in terms of hemodynamic stability.
The great advantage of dexmedetomidine for procedural sedation or sedation in the intensive care unit is the lack of respiratory depression [2, 20, 21]. There was no evidence of respiratory depression in the present study despite the co-administration of midazolam-fentanyl in the DMF group. This could be attributed to the fact that the use of a small dose of midazolam and fentanyl was possible as dexmedetomidine was the mainstream drug used for the sedation, and a local infiltration of lidocaine was also performed in this study.
In a study of conscious sedation for colonoscopy, the dexmedetomidine group showed a prolonged recovery time (mean = 39 min) as compared with the midazolam-meperidine (20 min) or fentanyl (17 min) groups [2]. Koruk et al. reported that pediatric patients undergoing extracorporeal shock wave lithotripsy showed prolonged recovery time after dexmedetomidine-ketamine sedation compared midazolam-ketamine sedation [7]. In our study, both the DK and DMF groups showed a similar mean time to spontaneous eye opening (around 7 min) and mean recovery room stay length (around 11–12 min), which were shorter than in the above-mentioned study. The difference between the previous results [2, 7] may be attributed to the types of procedures, the subjects, and the drug combinations.
The anterograde amnesia and anxiolytic action of midazolam may contribute to better sedation quality and patient satisfaction scores in DMF group. However, using midazolam is not always ensure the improvement of patient satisfaction. Dere et al. reported that midazolam-fentanyl group showed lower satisfaction scores compared dexmedatomidine-fentanyl group for conscious sedation [22]. Thus, it is essential that the appropriate combination of drugs for individual procedure and careful adjustment of the dose is required to improve patient satisfaction.
This study had several limitations. First, we did not enrolled elderly or critically ill patients. Forty three out of fifty two patients were breast cancer patients, and forty one out of fifty two patients were ASA status I, and the average age of the patients was around 50 years. Second, the anesthesiologist were not blinded to the group assignment for titration of the drugs and management of the adverse effects. Third, the present study shows large standard deviations in recovery time, so it may have been underpowered to detect the differences in recovery time. Thus, further studies are needed to determine the best combination of analgo-sedative drugs and the appropriate dosage of drugs to avoid adverse effects in elderly or critically ill patients.