The Efficacy of Etomidate-Fentanyl versus Dexmedetomidine-Ketamine for Procedural Sedation and Analgesia during Upper Endoscopy and Biopsy: A Prospective, Randomized Study

Objective: To assess the effectiveness of a combination of etomidate-fentanyl versus dexmedetomidineketamine for Procedural Sedation and Analgesia (PSA) in patients undergoing upper endoscopy and biopsy. Patients and methods: This is a prospective randomized observer-blinded study. This study was carried out in Tanta university hospital on 100 patients of both sexes; ASA physical status I and II, age range from 20-60 years undergone upper endoscopy and biopsy. All patients were randomly divided into two groups (each group 50 patients) Group E (etofen): patients received an initial IV bolus dose of etomidate 0.15 mg/kg + fentanyl 1 mcg/kg IV, followed by etomidate infusion at 0.01-0.03 mg/kg/min. Group D (dexmedetomidine-ketamine): patients received an initial IV bolus dose of dexmedetomidine (1 μg/kg) +ketamine (1 mg/kg) followed by dexmedetomidine infusion (0.5-1 μg/kg/hr) with supplemental bolus doses of ketamine (0.5 mg/kg) as needed. Sedation started and adjusted according to bispectral index level (BIS) range 60-80. Patients were then observed by an anesthesiologist who was blinded about sedative/analgesic received. The primary outcomes were onset, level and time of sedation and the secondary outcomes were recovery time, Length of recovery room (RR) stay (min), duration of hospital stay, VAS score, hemodynamic changes (HR, MBP, SPO2, RR), surgeon satisfaction, side effects, and patient satisfaction. Results: There was significant rapid onset of sedation in group E as compared to group D, Sedation level by BIS, showed significant increase (P<0.05) in group E in comparison with group D. Recovery time, Length of recovery room (RR) stay (min) and Length of hospital stay (hr) showed significant decrease (P<0.05) in group E in comparison with group D. Conclusion: The etomidate/fentanyl combination provides an effective and safe procedural sedation and analgesia for upper endoscope and biopsy. Etomidate/Fentanyl combination provides shorter sedation times and lighter sedation level (but enough for the procedure) when compared to the dexmedetomidine/ketamine combination. J o u r n a l o f A ne sth esia & Cical es e a r c h ISSN: 2155-6148 Journal of Anesthesia & Clinical Research Citation: EL-Shmaa NS, El-Baradey GF (2014) The Efficacy of Etomidate-Fentanyl versus Dexmedetomidine-Ketamine for Procedural Sedation and Analgesia during Upper Endoscopy and Biopsy: A Prospective, Randomized Study. J Anesth Clin Res 5: 480. doi:10.4172/21556148.1000480


Introduction
Procedural sedation and analgesia defines as the technique of administering sedatives or dissociative agents with or without analgesics to induce an altered state of consciousness that allows the patient to tolerate painful or unpleasant procedures while preserving cardiorespiratory function [1].
There is no ideal drug for analgesia and sedation during Gastrointestinal (GIT) endoscopy. Providing adequate sedation/ analgesia regimen through drug combination is an art. Targeting a moderate level of sedation that gives a better safety margin than deeper level [2,3].
Level of sedation/analgesia in endoscopy depends on the procedure; in rigid or flexible, diagnostic uncomplicated upper endoscopies moderate sedation is enough. While in prolonged or complex procedures (e.g. ERCP) deeper levels of sedation may be required [4].
Choice of sedation regimen depend on; characteristics of the procedure (length; complexity) and individual patient factors (age; existing medical conditions; prior experience with endoscopic procedures; patient anxiety; current use of opiates or other sedatives) [5].
A highly selective alpha 2-adrenoreceptor agonist dexmedetomidine has sedative, analgesic and antisialagogue effects with hemodynamic stability, minimal effects on respiration and cognitive functions [6].
Etomidate is imidazole derivative work at the g-aminobutyric acid receptor to produce hypnosis without analgesia. Etomidate offers a rapid onset, short recovery time, and minimal effect on the respiratory and cardiovascular systems. The recorded myoclonus with the initial use of etomidate, resolves without intervention [7,8].
Bispectral Index (BIS) monitoring is an advanced Electroencephalogram (EEG)-method of monitoring depth of anesthetic [9]. BIS is a number scaled from 100 to 0, with decreasing values indicating more sedation and hypnosis. BIS value of 100 indicates a normal cortical electrical activity (an awake EEG) and a value of zero indicates a cortical electrical silence (cortical suppression) [10]. BIS values of 95-100 reflecting awake state, 70-95 reflect light to moderate sedation, 60-70 reflecting deep sedation with low possibility of explicit recall. BIS values between 40 and 60 indicate a sufficient depth of anesthesia excluding intraoperative awareness and below 40 reflecting deep hypnotic state [11].
The objective of this study was to assess the effectiveness of a combination of etomidate-fentanyl versus dexmedetomidine-ketamine for procedural sedation in patients undergoing upper endoscopy and biopsy.

Patients and Methods
This is a prospective randomized observer blinded study conducted at Tanta university hospital and carried out on 100 adult patients of both sex's undergone upper endoscopy and biopsy during the period from April 2011 to February 2013 after approval by the hospital Ethical Committee.
Inclusion criteria were American Society of Anesthesiologists (ASA) physical status I-II and age between 20 and 60 years.
Exclusion criteria were known drug allergy, ASA physical status of more than II, history of a major psychiatric disorder, history of substance abuse and current opioid use.
All included participants were asked to take part in the study by the study personnel soon after admission to the ward and a written informed consent was obtained from each patient. Patients were randomly allocated into two groups of 50 patients each according to sedative/analgesic drugs used.
All patients had intravenous access secured and kept in place for duration of sedation and recovery. Lactated Ringer's solution started at rate 10 ml/kg/h IV perioperatively. Patients were connected to nasal prong at 3L/min.
The patients were given a spray of lidocaine 10% to the posterior pharynx to diminish discomfort (gag reflex) during the endoscopy. All patients were fasting for a minimum of 8 h. In the endoscope room, after wiping the skin of the forehead with an alcohol swab and allowing it to dry, a BIS-XP Quatro sensor (Aspect Medical Systems, Newton, MA, USA) was applied to the forehead of the patient according to the manufacturer's guidelines. Four electrodes are integrated in one sensor to obtain the electroencephalographic signal from the forehead. The sensor was connected to a BIS-XP monitor (BIS XP, A-2000, Aspect Medical Systems, Newton, MA, USA). This was done to evaluate the degrees of sedation for each patient. The BIS sensor was placed simultaneously with other standard monitors before induction of sedation. A baseline BIS value, blood pressure (BP), heart rate (HR) and oxygen saturation were recorded every 5 min thereafter during the procedure by the anesthesiologist blinded about sedative/analgesic received. Patients were randomly assigned to receive either etomidate/ fentanyl (E group; 50), or dexmedetomidine/ketamine (D group; 50), using the sealed envelope method.
All endoscopies were performed in the left lateral position by the same doctor. The anesthesiologist continued monitoring after completion of endoscopy until recovery of full consciousness. Side effects occurring during the study and 2 h thereafter were recorded. Side effects included a decrease in mean blood pressure of more than 30 mmHg and an oxygen saturation of less than 92% at any time during the procedure, or airway obstruction with cessation of gas exchange at any time.
At the end of the procedure, the doctor was asked to rate the ease of the procedure on a three-point scale (easy, adequate, impossible) [12].
Also, modified Aldrete score was assessed at 5 min intervals. Patients were discharged from recovery room and shifted to the postoperative ward, when they achieve a modified Aldrete score ≥ 9 [13]. Length of stay in the recovery room was recorded. Patients' assessment was performed by an anesthesiologist who was blinded to the anesthetic technique used.
Pain was assessed using the Visual Analogue Scale (VAS) where zero (0) represented no pain and 10 meant the worst possible pain [14]. Postoperative rescue analgesic in form of paracetamol 30 mg/kg IV if VAS (4-6) or pethidine 30 mg IV if VAS >6.
In addition, overall patient satisfaction with analgesia was assessed by a second anesthesiologist before hospital discharge by the use of a 4-point verbal scale ranging from very satisfied to very dissatisfied (1: very dissatisfied, 2: dissatisfied, 3: satisfied, 4: very satisfied) [15]. Also length of hospital stay was assessed ( Figure 1).

Statistical analysis
Sample size calculation was performed before patient recruitment [13]. Samples data have normal distribution. The Windows version of SPSS 11.0.1 (SPSS Inc., Chicago, IL) was used for statistical analysis. All results presented in form of mean ± standard deviation (SD). Data compared using unpaired students t-test, P value<0.05 was considered statistically significant.

Results
There were no statistically significant differences (P>0.05) between both groups with respect to demographic data and duration of endoscopy (Table 1).
There was significant rapid onset of sedation in group E as compared to group D. Sedation level by BIS, showed significant increase (P<0.05) in group E in comparison with group D. Recovery time, Length of recovery room (RR) stay (min) and Length of hospital stay (hr.) showed significant decrease (P<0.05) in group E in comparison with group D (Table 2). There were no statistically significant changes in hemodynamic (P>0.05) ( Table 3).
Adverse events in group D (28%) were significantly higher than in group E (22%) (p<0.05). Myoclonus was significantly higher in group E (16%) in comparison with group D (2%) (p<0.05). Only 4 patients in group D and 1 patient in group E required bag-mask ventilation and none of them were intubated. Higher incidence of postoperative nausea and vomiting in group D18% while 4% in group E. In addition, no significant difference was observed between two groups with respect to average postoperative VAS pain scores (P=0.2) ( Table 4).
Patient satisfaction score was significantly higher in group E as compared to group D (P=0.04), however surgeon satisfaction score was significantly higher in group D as compared to group E (P=0.03), (Table 4).

Discussion
The ideal sedation/analgesia drug combination must be with shortest duration and lightest sedation level possible to finish the procedure successfully and painlessly, Also, should maintains hemodynamic stability with no unpleasant emergence reaction, and should have antidote [16].    In this study, we evaluated the effects of a combination of etomidate-fentanyl versus dexmedetomidine-ketamine for procedural sedation in patients undergoing upper endoscopy and biopsy.
To the best of our knowledge; the present study is, to date, the first to compare etomidate-fentanyl combination and dexmedetomidineketamine combination for procedural sedation and analgesia in patients undergoing upper endoscopy and biopsy.
The major finding of the current study is that combination of etomidate-fentanyl, under BIS monitor, was associated with statistically significant rapid onset and recovery, less recovery room stay, less total hospital stay and higher patient satisfaction with analgesia and sedation compared to the combination of dexmedetomidine-ketamine with no significant difference in postoperative VAS scores of pain.
Using BIS monitor to guide anesthetic administration would allow optimization of drug delivery to the individual needs of each patient in order to avoid unnecessarily too deep or too light sedation due to overdosage or underdosage of the hypnotic medications [17].
BIS values in both groups signifies that increasing depth of sedation was associated with a decrease in BIS values and the decreasing level of sedation was associated with increasing BIS values. Similar findings have previously been found in a study done by Liu et al. [18].
The present study showed that there was no significant difference in the intraoperative hemodynamic parameters while 8 patients (16%) had myoclonus with bolus dose of etomidate and 1 patient (2%) had O 2 desaturation during procedure and 2 patients (4%) had nausea and vomiting.
Falk and Zed in their retrospective study on etomidate as a sedative in emergency department found no significant hemodynamic effects while 10% of patients had respiratory depression or apnea resulting in oxygen desaturation to <90% and the most prominent adverse effect reported with etomidate was myoclonus, occurring in 20-45% of patients [8].
Use of dexmedetomidine as the sole sedative/analgesic agent in invasive procedures was not successful due to its limited analgesic effects. In this study dexmedetomidine/ketamine combination showed long duration of sedation analgesia with cardiovascular stability these two agents have limited effects on ventilatory function [19].
In this study use of dexmedetomidine/ketamine had deeper sedation level with no significant change in hemodynamic parameters with O 2 desaturation in 4 patients (8%), higher nausea and vomiting (9 patients 18%) more surgeon and less patient satisfaction.
The hemodynamic stability explained by the addition of ketamine may prevent the bradycardia, hypotension and speeds the slow onset of sedation recorded with dexmedetomidine. Also, dexmedetomidine prevent the tachycardia, hypertension, salivation, and emergence phenomena associated with ketamine [20].
Kako et al. compared 2 doses of dexmedetomidine in combination with Ketamine (1 mg·kg -1 ) loading dose [21]. They found dexmedetomidine (0.5 μg/kg loading dose followed by an infusion at 0.5 μg/kg/h) achieved an adequate sedation level with shorter total recovery times in the perioperative unit compared with a higher dose regimen of dexmedetomidine (1.0 μg/kg loading dose followed by an infusion at 1.0 μg/kg/h). In this study the deeper sedation level and the longer recovery time may be due to use of high dose of   Koruk et al. found Sedation with dexmedetomidine-ketamine had insignificant changes in hemodynamic and respiratory parameters. Additionally, there was significant decrease in the incidence of nausea and vomiting [22].
Zor et al. in their study reported improved analgesia and a decreased incidence of adverse effects, including emergence phenomena and hallucinations related to ketamine in patients who received dexmedetomidine [23]. In this study we found more satisfaction of the doctor in dexemiditomedine-ketanine group than Etofen group and these may be due to surgeon may have subjectively felt more satisfaction to finish the procedure with longer and deeper sedation. They may also dislike the fact that etofen required more additional doses. These results are in keeping with those obtained by Sanri et al. [24].
In our study Etomidate-fentanyl combination offers lighter (yet enough depth) and shorter sedation, whereas dexmedetomidineketamine offers a deeper and longer sedation It was also associated with a very high overall patient satisfaction with analgesia without significant adverse events.
Bordo et al. demonstrated Etomidate is well tolerated with very high patient satisfaction and low adverse events for orthopedic reductions in the emergency department [25].
In conclusion, the etomidate/fentanyl combination provides an effective and safe procedural sedation and analgesia for upper endoscope and biopsy it was also associated with a very high overall patient satisfaction with analgesia without significant adverse events.