Colonoscopy is the preferred diagnostic tool for the investigation of lower gastrointestinal disorders and is generally performed in an outpatient setting. Sedative and analgesic agents are frequently needed because of pain and vasovagal reactions [1–7]. The ideal agent for colonoscopy should have rapid onset, be effective throughout the procedure, and have rapid recovery with minimal side effects. Generally, a combination of benzodiazepines and propofol with opioids is preferred . Although propofol is a good hypnotic, it may be needed in high doses for optimal conditions for the procedure, and this may result in hypotension, respiratory depression, and loss of protective reflexes, and because of the lack of its analgesic effect, there are some limitations for its use as a single drug [7,8]. Other regimens including midazolam and an opioid generally provide sufficient comfort. However, the effective period of these drugs is longer than the period needed for colonoscopy, and this may result in delayed recovery with a prolonged discharge time. For this reason, a combination of a short-acting hypnotic agent with an opioid seems to be more appropriate [1,7]. Etomidate seems to be an appropriate hypnotic agent because of its rapid onset (5–15 s) and recovery (5–15 min) and minimal adverse effects on cardiovascular and respiratory parameters . There are studies with etomidate–opioid (fentanyl and morphine) combination as a sedative regimen for procedural sedoanalgesia [5,8–11]. However, there is no information for the use of an etomidate–remifentanil combination during colonoscopy as a sedative regimen in the literature. The aim of the present study was to compare etomidate–remifentanil and propofol–remifentanil combinations on the basis of their effects on haemodynamic, recovery and adverse effects, and physician's satisfaction in colonoscopy cases.
After Ethics Committee approval and informed written patient consent, 60 unpremedicated ASA I-II patients (age 18–65 years) scheduled to elective colonoscopy were included in this prospective study. Exclusion criteria included patients with epilepsy, the use of drugs affecting the central nervous system, known allergy to the study drugs, chronic sedative or opioid analgesic use, general anaesthesia in the past 7 days, adrenocortical insufficiency, pregnancy, and psychiatric disorders. Patients were randomized into the etomidate group (Etomidate-Lipuro, Braun, Melsungen, Germany) and the propofol group (Propofol 1% Fresenius, Fresenius Kabi, Uppsala, Sweden) by closed envelope method. Patients were then randomly assigned into one of two groups. Assignment to the groups was determined by random drawing of consecutively numbered envelopes containing the labels propofol or etomidate. Patients, endoscopists, and postoperative observers were blind to the group allocation.
Remifentanil (Ultiva Glaxo Smith Kline, Genval, Belgium) was prepared as a 40 μg.ml−1 solution and administered as 0.1 μg kg−1 min−1continuous intravenous infusions to all patients. Etomidate or propofol was administered 2 min after the remifentanil infusion started. Patients in the etomidate group (n = 30) received etomidate (0.1 mg kg−1) intravenously; 0.05 mg kg−1 additional doses were given to keep the Ramsay sedation score (RSS) between 3 and 4 as needed. Patients in the propofol group (n = 30) received propofol (0.5 mg kg−1); 0.25 mg kg−1 additional doses were given to keep the RSS between 3 and 4 as needed. No lidocaine was added to the propofol.
Noninvasive blood pressure (BP), peripheral oxygen saturation (SpO2), respiratory rate and ECG were monitored in the endoscopy room. In all patients, venous access was performed with a 20-gauge intravenous cannula and intravenous 0.9% normal saline infusion was initiated. During colonoscopy, 6 l.min−1 oxygen was administered by a face mask. Heart rate (HR), mean arterial pressure (MAP), SpO2, respiratory rate and RSS were measured and recorded at 2-min intervals for the first 10 min after starting the remifentanil infusion followed by 5-min intervals until the end of the colonoscopy.
All colonoscopic interventions were made by the same experienced gastroenterology fellow using the Fujinon EC-450WL5 colonoscope (Fuji Photo Optical Co., Ltd., Saitama, Japan). Total etomidate, propofol, and remifentanil dosage throughout the colonoscopy, colonoscopy duration, caecal intubation time (time to reach caecum), time to reach RSS 2 after colonoscopy was completed, and recovery time were recorded.
All occurrences of hypoventilation (respiratory rate <8 min−1), apnoea (no respiration for 30 s), airway obstruction, hypotension (MAP decreases >30% when compared with baseline values) , hypertension (MAP increases >30% when compared with baseline values) , arrhythmia, bradycardia (<50 min−1), decrease of SpO2 less than 95%, and other adverse events were recorded. The satisfaction of the gastroenterologist was evaluated and recorded at the end of colonoscopy. ‘Poor’, ‘fair’, ‘good’, and ‘very good’ choices were used for evaluation.
If the SpO2 fell to less than 95%, oxygen flow was increased to 10 l.min−1. Jaw thrust manoeuvre was applied for hypoventilation. In case of apnoea and SpO2 falling to 90%, the remifentanil infusion was decreased by 50%. The remifentanil infusion was stopped if SpO2 was less than 90%.
Patients with RSS 2 were transferred from the endoscopy theatre to the recovery room and postanaesthetic discharge scores (Alderete score)  were monitored at 10-min intervals. Patients with a postanaesthetic discharge score of 9 or more were discharged. The mean discharge time was 1 h.
A priori power analysis resulted in a total of 60 patients when performed using G Power program and with systolic arterial pressure difference of 25%, α = 0.05, β = 0.05. Statistical analysis was performed using SPSS for Windows version 11.0. Data are represented as mean ± standard deviation. Student's t test was used for comparisons between groups and Mann–Whitney U test for values after 30 min. A P value of less than 0.05 was accepted as statistically significant. Data are represented as mean ± standard deviation for RSS, and chi-square test or Fisher's exact test was used when appropriate.
There was no statistical significance between characteristics of patients such as age, body weight, sex and the diagnoses of patients (P = 0.38, P = 0.18, and P = 0.50, respectively) (Table 1). There was no significant difference between groups for MAP values at 0, 2, 35, 40, and 45 min; however, in the propofol group, MAP decreased significantly between 4 and 30 min (P = 0.001) (Fig. 1). There was significantly more hypotension in the propofol group (P = 0.001). HR values of the propofol group significantly decreased at the 8th and 30th minute (P = 0.03 and P = 0.02, respectively), and there was no significant difference in other measurement periods (P > 0.05) (Fig. 2). There was a bradycardia requiring atropine in three patients in the propofol group. All these patients had baseline HR of 60 min−1 or less. There was no statistical significance in bradycardia incidence.
There was no difference between the groups with respect to respiratory rate at 0, 2, 4, 30, 35, 40, and 45 min; however, in the propofol group, respiratory rate decreased significantly at 6, 8, 10, 15 min, and between the 6th and 25th minute (P <0.05) (Fig. 3). There was no significance between groups for SpO2 (Fig. 4). There was more apnoea in the propofol group (P = 0.001). ‘Jaw thrust’ was applied to 3% of the etomidate group and 63% of the propofol group.
Although apnoea was more frequent in the propofol group, there was no difference between peripheral SpO2 values with the help of the reduction of remifentanil infusion dosage. Baseline RSS for etomidate and propofol groups were 2. RSS values were maintained at 3–4 during the intervention in both groups. Patients were transferred to the recovery room when their scores were 2. There was no significance between groups for mean RSS values (Table 2).
There was no statistical significance between groups for caecal intubation time and total colonoscopy duration. Values for time to transfer to recovery room were significantly lower in the etomidate group (P = 0.01). Recovery time was shorter in the etomidate group (P = 0.01) (Table 3). The discharge time was 1 h as per the protocol of our clinic. There was no statistical significance in physician's satisfaction between groups (Table 4).
All adverse events observed are presented in Table 5. There was significantly more nausea and vomiting in the etomidate group (P = 0.02). There was significantly more myoclonus in the etomidate group (P = 0.01). There was significantly more injection site pain in the propofol group (P = 0.005). Drug dosages are presented in Table 6. Average remifentanil dosage was less in the propofol group because the remifentanil dosage was decreased.
Colonoscopy that is used in the diagnosis and therapy of lower gastrointestinal system disorders is an intervention that necessitates sedative and analgesic drugs and results in pain and vasovagal reactions frequently [1,9]. Opioids, benzodiazepines, propofol, and their combinations are used for sedation and analgesia [1,13,14]. Concomitant use of midazolam and pethidine for conscious sedation may result in a discharge time of 48–80 min after the intervention is completed [1,13]. Patients subjected to colonoscopy with propofol–remifentanil infusion recovered psychomotor functions and fulfilled the criteria for discharge 15 min after the intervention .
In the present study, MAP values of patients in the propofol group were found to be lower in comparison with the etomidate group between 4 and 30 min. It can be suggested that the number of patients still in colonoscopy was decreased after 30 min, and this resulted in no difference after this period. It is well known that etomidate has few cardiovascular side effects. Hypotension related to propofol is caused by sympathetic inhibition and disturbances in baroreflex mechanisms; however, etomidate preserves haemodynamic stability by stabilizing sympathetic responses and preserving autonomic reflexes . Other studies have found that the etomidate group during cardioversion had a higher arterial BP than the propofol group, but this was not statistically significant [14,15]. In this study, there was no difference in HR values between the two groups.
In a similar study , there was a significant decrease in respiratory rate and apnoea when propofol bolus and remifentanil infusion were used for sedation during colonoscopy. Although we found a decrease in respiratory rate and apnoea in the propofol group, because of the interventions we applied, there was no difference between the values of SpO2. Furthermore, we used short-acting agents and respiratory problems recovered rapidly. Coll-Vinent et al. did not show a significant difference in apnoea incidence when they used etomidate or propofol for sedation. Miner et al. reported 42% subclinical respiratory depression (>10 mmHg increase in end-tidal CO2, SpO2 <92%, airway obstruction) in the propofol group, whereas it was 34% in the etomidate group in short-term sedation/analgesia.
In this study, sedation levels as determined by RSS were similar between the two groups during the study period. In a study examining sedation levels of etomidate and propofol, the effects of the two drugs were found to be similar. However, the incidence of recalling the intervention was higher in patients receiving etomidate . In the same study, sedation levels were evaluated by bispectral index (BIS) or sedation score; the drug dose administered and sedation depth as determined by the two methods were similar . For this reason, in our study, patients were evaluated and drugs were adjusted by sedation score rather than BIS which necessitated separate equipment.
A frequent adverse event observed with etomidate is myoclonus . The incidence of etomidate-related myoclonus in sedation/analgesia situations is 20–45% [5,16,19]. In our study, the incidence was 20% and was similar to other sedation/analgesia reports. Myoclonus after 0.1 mg kg−1 etomidate was short lasting (less than 30 s), mild, and was observed as fasciculation in fingers, or part of the face and did not relapse in six patients. No long-lasting or tonic–clonic seizure activity was seen. It is possible that remifentanil administration before etomidate and the low dose of etomidate used (initially 0.1 mg kg−1, then 0.05 mg kg−1) might have decreased the myoclonus incidence. Mild and short-lasting myoclonus did not impair the performance of the colonoscopic procedure.
In our study, there was injection site pain in seven patients in the propofol group (23%) but did not occur in the etomidate group. It is possible that opioid treatment before etomidate might have prevented injection site pain. In the present study, no lidocain was added to propofol; however, injection site pain incidence was low because of remifentanil pretreatment .
In the present study, there was nausea or vomiting in five patients in the etomidate group (17%), whereas no nausea or vomiting occurred in the propofol group. Nausea or vomiting is common with etomidate. This adverse effect occurs with an incidence of 50% with repeated doses . Remifentanil infusion can also result in nausea and vomiting . In a study with remifentanil infusion or meperidine bolus application for sedation in colonoscopy, remifentanil resulted in more frequent nausea or vomiting . It is possible that concomitant etomidate and remifentanil administration might have increased the incidence of nausea and vomiting. Furthermore, the mean remifentanil dose was higher in the etomidate group than in the propofol group, and this also might have increased the incidence of nausea and vomiting. Lack of nausea and vomiting might be related to the antiemetic effects of propofol. Nausea and vomiting in the etomidate group were not severe and did not delay discharge. Metoclopramide was used for treatment.
Remifentanil was used at a dose of 3.1 μg kg−1 in the etomidate group and 2.5 μg kg−1 in the propofol group. Because of more apnoea or respiratory problems in the propofol group, remifentanil infusion rate was decreased or stopped. This resulted in less mean remifentanil dose in the propofol group. Mean etomidate dose was comparable to similar sedation applications.
Miner et al. gave etomidate, initially at 0.1 mg kg−1 (total 0.26 mg kg−1), or propofol, initially at 1 mg kg−1 (total 1.8 mg kg−1), together with morphine as a sedative for short interventions. In a similar study, etomidate was used in a dose range of 0.07–0.5 mg kg−1. McDowall et al.  used a higher (mean 0.43 mg kg−1) etomidate dose without opioid in paediatric patients; however, 2% respiratory problems (hypoxemia SpO2 <94%) occurred with this dose.
In our study, there was no difference between groups in colonoscopy duration and caecal intubation time. In various studies, average colonoscopy duration was 12–34 min [1,2,13,23], and time to caecal intubation was 3.2–9.8 min [2,6]. The reasons for similar colonoscopy duration and caecal intubation time in our study may be the result of similarity of sedation scores of patients and performance of colonoscopy by the same physician in all patients.
The transfer time to the recovery room after colonoscopy was finished was determined by the awakening of patients (opening the eyes and reacting to verbal commands). Average time to transfer to recovery room was 4.4 min in the etomidate group and 7.06 min in the propofol group. Herregods et al. found that when they used etomidate or propofol for sedation in cardioversion, patients opened their eyes and reacted to verbal commands within shorter periods in the propofol group. The reported time to open eyes was 6.1 min and reacting to verbal commands was 8.5 min in the etomidate group, whereas they were 4.7 and 6.7 min, respectively, in the propofol group. According to Aldrete score and psychomotor tests, recovery time was shorter in the propofol group. In contrast to the present study, in the study by Herregods et al., they used single doses of 0.2 mg kg−1 etomidate or 1 mg kg−1 propofol with no opioids. Miner et al. reported that after short-term sedation/analgesia with etomidate or propofol in the emergency department, patients in the propofol group recovered baseline mental state 2 min earlier, but this was not statistically significant. Rudner et al. found that after sedation with 1 mg kg−1 bolus propofol, with additional 10 and 0.2 μg kg−1 remifentanil during colonoscopy, the average time to transfer to recovery room was 2.9 min. Investigators performed conscious sedation and did not allow RSS to exceed 3. In the present study, RSS was 3–4, which resulted in a difference in time to recovery room.
Recovery time was evaluated as the period for which patients stayed in the recovery room until discharge. Recovery time was significantly shorter in the etomidate group (average 24.6 min) than the propofol group (average 32.8 min). Although patients were haemodynamically stable, cooperative, and oriented in the etomidate group, average time may be increased because of the prolonged follow-up time in patients with nausea and vomiting. However, patients in the etomidate group were discharged earlier. The reason for longer recovery time in the propofol group may be related to the time needed for postanaesthetic discharge scores to be within 20% in comparison with baseline values and also to the somnolence of the patients. Green  also reported that physician's satisfaction was similar in sedation with etomidate or propofol. One of the drawbacks of this study is that patient satisfaction and recalls of the procedural events were not assessed.
One of the most important adverse effects with etomidate is adrenocortical suppression . A limitation of the present study is that we did not measure plasma cortisol and adrenocorticotropic hormone levels. However, we did not observe clinical signs of adrenocortical suppression such as hypotension and arrhythmia.
Propofol is used as a short-acting agent in sedation applications. As it is short acting, recovery and discharge criteria are reached rapidly, and also, because of its antiemetic properties, it is preferred for short-term sedation applications.
Etomidate has been used for a long time in anaesthesia practice, but its use is generally limited to patients lacking cardiac stability because of its adverse effects such as adrenocortical suppression and myoclonus. However, as it has been demonstrated that adrenocortical suppression occurs mainly with long-duration and high-dose infusions, its use is increasing.
In short-lasting sedation applications, propofol can be preferred because it does not affect the haemodynamic stability and it has a short recovery time. As adverse effects such as myoclonus, injection pain, and nausea or vomiting are rare, preventable and transient, they can be ignored. Patients undergoing colonoscopy are generally elderly and have cardiac or respiratory diseases or they may have electrolyte disturbances due to colonic preparation. Therefore, etomidate seems to be an appropriate agent for providing haemodynamic stability in these patients.
We have shown that, when a remifentanil infusion is used for colonoscopy, the combination with etomidate provides fewer haemodynamic and respiratory complications than the combination with propofol but is more frequently associated with myoclonus and postoperative nausea and vomiting. In addition, recovery time and emergence from anaesthesia are shorter with etomidate–remifentanil than with propofol–remifentanil.
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