Etomidate is a popular used anesthetic induction agent in the clinical practice, which is characterized by rapid onset, very few side effects on cardiovascular and respiratory functions, as well as minimum histamine release.1-5 However, it has less inhibitory effect on pharyngolaryngeal reflex.6,7 Consequently, opioids is often combined with etomidate for anesthetic induction. Since the pharmacodynamic profiles of opioids are different from each other, it is important to determine which kind of opioids is more favorable to be used with etomidate to produce a smooth anesthetic induction and minimize the adverse effects. Fentanyl, remifentanil, and sufentanil are all commonly used opioids in the clinical practice.7-12 But most of studies concerning these three opioids used for anesthetic induction were often performed under the propofol-based induction and there were big differences in drug doses and measuring variables.8-12 The bispectral index (BIS) has been proposed as a measure of hypnotic state and so of the depth of anesthesia.2,10 Lallemand et al2 had proved a BIS value of 50 to be a reliable indicator of adequate depth of anesthesia for etomidate induction. Moreover, BIS-titrated anesthesia allowed less consumption of anesthetic agents with advantage of preventing intraoperative awareness and explicit recall.2,13 Therefore, in this study a BIS monitor was used during anesthetic induction with etomidate and small doses of remifentanil, fentanyl or sufentanil. We aimed to investigate the effects of these three opioids on etomidate consumption, peri-intubation hemodynamics and conscious level changes.
After institutional ethical approval and informed consent were obtained, 90 adult patients with American Society of Anesthesiologists (ASA) physical status I or II undergoing elective major abdominal surgery under general anesthesia were enrolled in the study. The characteristics of the patients were shown in Table 1. Exclusion criteria include: the patients with neurological, respiratory or cardiovascular diseases, hepatic and renal dysfunction, those who have taken drugs known to affect neurological or cardiovascular function and those with predicted difficult airway or aged over 60 years.
All subjects were randomly allocated in a double-blind fashion using a sealed envelope technique into three groups (n=30 in each group), groups R, F and S. In groups F, S and R, the patients were given a bolus dose of fentanyl 1 μg/kg, sufentanil 0.1 μg/kg or remifentanil 1 μg/kg over 60 seconds, followed by a continuous infusion of 0.1 μg·kg-1·min-1, 0.01 μg·kg-1·min-1 or 0.1 μg·kg-1·min-1 (Graseby 3500 Diprifusor®; Graseby Medical Ltd, Watford, UK), respectively. The solutions containing opioids were prepared and administrated by an anesthesiologist who was not involved in data recording.
All patients were unpremedicated and fasted overnight. On arrival at the operating room, the monitoring of electrocardiogram, noninvasive blood pressure, pulse oximetry, end-tidal carbon dioxide and BIS (Aspect Medical Systems Inc., Natick, MA, USA) were applied. After all patients were prehydrated with 7 ml/kg lactated Ringers solution, the baseline values of heart rate (HR), systolic and diastolic blood pressure (SBP and DBP), pulse oxygen saturation (SPO2) were recorded. The patients were preoxygenated via a face mask for 5 minutes and anesthetic induction was initiated with fentanyl, remifentanil and sufentanil in groups F, R, S, respectively, according to the opioids administration regimens described above. After 5 minutes from start of opioid infusion, etomidate was titrated at a rate of 20 mg/min to a decrease in BIS to 50. Then, rocuronium 0.6 mg/kg was given to facilitate endotracheal intubation which was performed one minute after injection of the muscle relaxant using a Murphy endotracheal tube of internal diameter (ID) 7.5 mm or 7.0 mm in male and female patients, respectively. The patients' lungs were ventilated to keep end-tidal carbon dioxide concentration within normal range and sevoflurane 2% (dialed concentration) was delivered in 100% oxygen at a fresh gas flow of 2.5 L/min.
The intubation time from insertion of a laryngoscope to placement of an endotracheal tube into the trachea was recorded. Two kinds of induction time, from administration of etomidate to loss of eyelash reflex and to a decrease in BIS to 50 were also recorded. The consumptions of etomidate at t1 and t2 time points were calculated. SBP, DBP and HR were recorded immediately before intubation (T0), at intubation (T1), and 1 minute (T2), 3 minutes (T3) and 5 minutes (T4) after intubation. The maximum percent change of SBP (|maximal or minimal measuring value-baseline|/baseline×100%) for each patient and the average value of that for each group during observation period were calculated. The numbers of patients who experienced great hemodynamic changes were noted: SBP or HR increases or decreases of more than 30% of baselines, SBP<90 mmHg or >140 mmHg; HR<50 beats per minute or >100 beats per minute. The patients who required more than one attempt or 60 seconds to achieve successful endotracheal intubation were excluded from analysis.
Statistical analyses were performed using SPSS 11.0 (SPSS, Chicago, IL, USA). The continuous and discrete variables were expressed with mean±standard deviation (SD) or the numbers of patients, respectively. The hemodynamic data were analyzed with two-way analysis of variance (ANVOA) with post hoc Bonferroni test. The other continuous data were compared with one-way ANVOA or Kruskal-Wallis test for non-normal distribution. Discrete data were analyzed with chi-square test or Kruskal-Wallis test as appropriate. P <0.05 was considered statistically significant.
All patients were successfully intubated as required by the study protocol. The patients' physical characteristics and the intubation time were comparable among the three groups (Table 1). The time and the dosage per body weight of etomidate necessary to loss consciousness were greater in group F than in groups S and R (F vs S or R for both time and dosages, P <0.01), but those two variables for achieving an adequate anesthesia (BIS=50) were not significantly different among the groups (Figures 1 and 2).
The baseline values of HR, SBP and DBP were comparable among the three groups (Table 2). After induction (T0), SBP and HR were significantly reduced in groups S (7%, 9%) and R (12%, 27%) compared with the baselines, respectively (P <0.05 for all comparisons). The endotracheal intubation caused marked increases in SBP, DBP and HR in groups F and S, but not in group R (P <0.01 for all comparisons). Those hemodynamic variables at intubation (T1) were significantly lower in group R compared with those in groups F and S (P <0.01 for all comparisons). SBP, DBP and HR were still higher at T2 time point than before induction in group F (P <0.01 for all comparisons). The blood pressure restored approximately to the normal levels in groups F and S whereas decreasing to the level below the baselines in group R (P <0.001) at T3 time point. HR was kept higher from T1 to T4 time points in group F and from T1 to T3 time points in group S when compared with that before induction (P <0.05 for all comparisons). SBP and DBP of group R at T4 time point were significantly lower, but were within normal range, than the baselines (P <0.01 for SBP comparison; P <0.05 for DBP comparison). The heart rate of group R was kept relatively stable during the study period except at T0 time point. The average maximum changes of SBP were significantly different among the three groups: F, (25±6)% vs R, (13±4)% or S, (12±5)% (P <0.001, Table 2).
The numbers of patients experienced great hemodynamic changes were shown in Table 3. The episodes of SBP or HR increases of more than 30% of the baselines, SBP >140 mmHg and HR >100 beats per minute occurred more frequently in group F (47%, 53%, 83%, 40%, respectively) than in groups R (0 for all) and S (0, 3%, 43%, 13%, respectively) (P <0.01 for all comparisons). More patients had SBP >140 mmHg in group S than in group R (P <0.001). Although the incidence of HR decreases of more than 30% of the baselines after anesthetic induction was higher in group R (20%) compared with groups F (0) and S (0) (P <0.01), HR was above 50 beats per minute in all but two patients and significantly elevated by the endotracheal intubation. The episodes of SBP<90 mmHg and HR<50 beats per minute each was found in two patients of group R (no significant difference between group comparison) after induction, which were transient and resolved spontaneously without any interventions. All the other great hemodynamic changes were diminished within 3-5 minutes with the gradual deepening of anesthesia.
Our results showed that during BIS-guided etomidate anesthetic induction, although small doses of sufentanil (0.1 μg/kg bolus followed by 0.01 μg·kg-1·min-1 continuous infusion) and remifentanil (1 μg/kg bolus followed by 0.1 μg·kg-1·min-1 continuous infusion) reduced the time and the amount of etomidate necessary to loss consciousness compared with small dose of fentanyl (1 μg/kg bolus followed by 0.1 μg·kg-1·min-1 continuous infusion), similar time interval and etomidate consumption were required to achieve adequate depth of anesthesia (BIS=50). Small dose of fentanyl failed to suppress the blood pressure and heart rate increases caused by endotracheal intubation in view of about 50% patients on fentanyl experiencing SBP or HR increase of more than 30% of the baseline. Small dose of remifentanil was more effective in blunting the cardiovascular response to endotracheal intubation than sufentanil, nevertheless, accompanying significant lower HR after induction.
The doses of the opioids used in the present study were determined on the basis of previous studies comparing the profiles of anesthetic induction with these three kinds of opioids.8-12 Since the relative potencies of sufentanil, remifentanil and fentanyl are 10:1:1,8-12 both the bolus and infusion doses for these three opioids in our study can be considered as equal potency. As a matter of fact, because the context-sensitive half-time of remifentanil is so short as to result in a rapid declination in the plasma concentration of it, especially after a single bolus, it seems to be difficult to establish an equipotent comparison of these opioids. The adminstration regimen using a single bolus injection plus continuous infusion in our study aimed to maintain a stable drug plasma concentration as possible, which was in accordance with those of the other comparative studies.8,10
The BIS has been proposed as a measure of hypnotic state and so of the depth of anesthesia, although with confounding results.2,13 Lallemand et al2 found that for etomidate induction, a BIS of 50 was associated with the absence of purposeful movement during tracheal intubation and the absence of postoperative explicit recall. Iannuzzi et al10 also used a BIS <50 as an indicator of satisfactory depth of anesthesia in a study of comparing the effects of remifentanil and sufentanil on blunting the cardiovascular responses to endotracheal intubation. However, BIS may not reflect the synergistic hypnotic effects of the opioids and intravenous anesthetics,13-16 which was demonstrated in our study by the fact that the three groups took different time to loss consciousness but similar time to achieve a BIS decrease in 50. This might because opioids actions on the “noncortical” regions for example, locus coeruleus, cannot be detected by BIS.14 Also, BIS value often shows a steep decrease during induction period, which tends to make the reading BIS value higher than the actual one. In addition, etomidate-induced myoclonia is likely to influence the BIS readings. We did not observe the myoclonia during the study period probably due to the use of opioids and the adminstration of etomidate with a infusion rather than a bolus.3-5,17
Cafiero's study suggested that blood pressure and HR increases during intubation were better controlled with 0.2 μg·kg-1·min-1 infusion of remifentanil in comparison with 2 μg/kg bolus of fentanyl.11 The results of Wilhelm's study comparing remifentanil (given as infusion at 0.5 μg·kg-1·min-1) and fentanyl (1.5 μg/kg bolus)-etomidate anesthetic induction showed that less doses of etomidate and more suppression on the cardiovascular response to intubation but also a 14% decrease in mean blood pressure were associated with remifentanil.1 Xue et al9 found that sufentanil 0.2 μg/kg was more effective in attenuating the intubation response than fentanyl 2 μg/kg. All those previous studies showed remifentanil or sufentanil had a greater suppression on the hemodynamic responses to intubation compared with fentanyl, which was consistent with ours. Furthermore, in our study remifentanil conferred more stable hemodynamics during intubation than sufentanil but was associated with a great decrease of HR after induction. However, in Iannuzzi and Casati's studies,8,10 small doses of sufentanil and remifentanil, which were given in a similar administration regimen to ours, produced the comparable effects on blunting the cardiovascular response to intubation without significant changes in HR. This can be attributed to the differences in the intravenous induction agents and premedication. Our patients were unpremedicated and received etomidate for induction whereas the patients in Iannuzzi and Casati's studies received atropine or midazolam as premedication and propofol for induction. Etomidate has less effects on inhibiting the upper airway reflex and producing vasodilatation than propofol6,7,18,19 and hence the use of propofol is likely to enhance the opioids effect, blurring the comparison between sufentanil and remifentanil, and also may account for the greater decrease in blood pressure associated with remifentanil-propofol induction compared with remifentanil-etomidate induction.1 In addition, small does of fentanyl in the present study failed to suppress intubation response in view of about 50% patients on fentanyl experiencing the SBP or HR increase of more than 30% of the baseline. This is not surprising because that 500 μg of fentanyl has been proved to be necessary to abolish such an adverse response during etomidate induction.5
The disadvantage of using remifentanil is related to the great decreases in blood pressure and HR. Remifentanil-induced vasodilatation may be a contributing factor.20,21 In the remifentanil group of our study, although the patients were prehydrated with 7 ml/kg lactated Ringers solution before induction, the percent decrease of SBP relative to the baseline still reached 12% and two patients experienced the episode of SBP<90 mmHg after induction. As well, 20% of patients receiving remifentanil had the HR decrease of more than 30% of the baseline with HR<50 beats per minute in two. These transient great hemodynamic changes will not cause adverse effects in healthy young adult patients, but seem to be a potential danger for cardiovascular compromised patients.
Notwithstanding our results, it is noteworthy that the endotracheal intubation was not performed at the time to peak effects of remifentanil, fentanyl and sufentanil in the present study. However, the adminstration regimen using a bolus followed by a continuous infusion is helpful to maintain a stable drug concentration, thereby may minimize this limitation of our study.8,10
In conclusion, in normotensive and unpremedicated young adult patients receiving etomidate induction, small doses of remifentanil or sufentanil significantly reduced the time and the amount of etomidate taken to loss consciousness compared with small dose of fentanyl, but similar time interval and doses of etomidate were required to acquire adequate depth of anesthesia (BIS=50) for these three opioids. Remifentanil was more effective in blunting the cardiovascular responses to endotracheal intubation, nevertheless, accompanying significant lower heart rate after induction.
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