1Westfälische Wilhelms-Universität, Münster, Germany. 2Universitaire Ziekenhuis Gent, Ghent University Hospital, Belgium. 3Royal Melbourne Hospital, Melbourne, Australia. 4Foothills Hospital, Calgary, Canada. 5University Hospital Gasthuisberg, Leuven, Belgium. 6Sahlgrenska University Hospital, Göteborg, Sweden. 7Volvat Medical Centre, Oslo, Norway. 8Glaxo Wellcome Research and Development, London, UK*Corresponding author: Abteilung Anästhesie, Intensivmedizin und Schmerztherapie, Marienhospital Aachen, Zeise 4, D-52066 Aachen, Germany
Accepted for publication: June 12, 2001
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Br J Anaesth 2001; 87: 71826
Keywords: surgery, coronary artery bypass; analgesia opioid, remifentanil; analgesia opioid, fentanyl; anaesthetics i.v., propofol
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Remifentanil hydrochloride is a potent µ-opioid receptor agonist characterized by a predictable rapid offset of action as a result of its metabolism by non-specific esterases in blood and other tissues. The aim of this study was to compare the efficacy and safety of remifentanil using a total i.v. anaesthesia technique in combination with propofol (high-dose opioid regimen) with a commonly used low/medium-dose fentanyl plus propofol regimen in patients undergoing elective coronary artery bypass graft (CABG) surgery who were potentially eligible for early extubation/ICU discharge.
![]() |
Patients and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
All patients included in the study were potentially eligible for early extubation/ICU discharge. Patients with severely impaired left ventricular function (ejection fraction <0.3), significant arrhythmias, evidence of severe congestive heart failure, intra-aortic balloon assist device preoperatively, or severely impaired major organ function were excluded. Patients were also excluded from the study if they required preoperative inotropic support, or were undergoing CABG with simultaneous valve repair/replacement, or any other combined surgical procedure. Other exclusion criteria were body weight over 50% above ideal body weight, hypersensitivity to opioids or propofol and administration of opioids or long acting benzodiazepines within 12 h before the start of the study.
All patients were pre-medicated with diazepam 10 mg orally 1 h before surgery. Upon arrival to the anaesthetic area, midazolam 0.05 mg kg 1 i.v. was administered for sedation before placement of cannulae. Baseline systolic blood pressure (SBP) was recorded before instrumentation and a baseline blood sample was collected for cardiac enzyme analysis. Before induction of anaesthesia, each patient was given 100% oxygen for at least 3 min. Anaesthesia was induced with propofol 0.5 mg kg1 followed by additional boluses of 10 mg every 10 s until loss of consciousness (LOC), which was defined as loss of response to verbal commands. At LOC, pancuronium 0.100.15 mg kg1 was administered to facilitate tracheal intubation and propofol maintenance infusion 3 mg kg 1 h1 was started. Simultaneously, as indicated by randomization, the loading dose and infusion of remifentanil placebo loading dose, 1 µg kg1 min1 infusion or fentanyl (15 µg kg1 loading dose, placebo infusion) were started. Tracheal intubation was performed at least 6 min after the start of opioid administration.
Management of inadequate and excessive anaesthesia
During maintenance of anaesthesia, responses to surgical stimuli indicating inadequate anaesthesia were defined as one or more of the following:
SBP >15 mm Hg above preoperative baseline or >140 mm Hg for 1 min; arterial pressure (AP) >80 mm Hg for
1 min during bypass.
Heart rate (HR) >90 beats min1 for 1 min (pre-bypass); non-paced HR >100 beats min1 for
1 min (post-bypass).
Somatic responses: gross movement, swallowing, grimacing, eye opening.
Autonomic responses: lachrymation, sweating.
Inadequate anaesthesia was treated in a sequential manner beginning with simultaneous bolus dose administration (remifentanil 1 µg kg1, fentanyl 2 µg kg1) and infusion increments equivalent to 0.5 or 1.0 µg kg1 min1 remifentanil (unless there were intervening decreases). A maximum of three to six maintenance rate increases were allowed up to a maximum infusion rate of remifentanil 4 µg kg1 min1 or placebo equivalent. All infusion rate increases were preceded by a bolus dose. If a response was not controlled within 5 min of adjusting the opioid infusion rate or if the maximum infusion rate was reached, the propofol infusion rate was increased as required. If the response was still not controlled, other agents (e.g. sodium nitroprusside, beta-blockers) could be given. Once the patient had achieved a stable, non-responding status, the propofol infusion rate was then titrated back down but the opioid maintenance infusion was left at the higher rate unless hypotension occurred.
Excessive anaesthesia was defined as one or more of the following:
SBP <80 mm Hg for 1 min; AP <40 mm Hg for
1 min during bypass.
HR <40 beats min1 for 1 min.
Hypotension was treated by administration of fluids if the patient was hypovolaemic. Otherwise these responses were treated by decreasing the opioid and/or propofol infusion rate. The opioid maintenance infusion rate was reduced by 50% of the current rate or in decrements equivalent to remifentanil 0.250.5 µg kg1 min1. If blood pressure fell rapidly, the opioid maintenance infusion rate decrease could be accompanied by simultaneous administration of vasopressors. Further vasopressor treatment was to be used if these interventions were not successful. Bradycardia was treated by decreasing the opioid and/or hypnotic infusion rate and/or the use of anticholinergic drugs as required.
In addition to the treatment of inadequate anaesthesia, the study procedure allowed preventative measures at the discretion of individual investigators. Study opioid bolus and infusion rate increases were allowed in advance of surgical stimuli to prevent anticipated responses up to a maximum infusion rate equivalent to remifentanil 4 µg kg1 min 1.
After surgery, once the patient was settled in the ICU, the opioid and propofol infusions were reset (remifentanil 1 µg kg1 min1, placebo in the fentanyl group, propofol 0.5 mg kg 1 h1 in both groups). The infusions were continued until the patient met the criteria for the start of weaning for extubation, that is, normothermia, haemodynamic stability (no uncontrolled arrhythmias, stable vital signs), no excessive bleeding (institutionally defined) and adequate urine output (0.5 ml1 kg 1 h1). The propofol infusion rate could be adjusted accordingly if additional sedation was required. If additional analgesia was required a bolus dose of open label morphine could be administered at the minimum dose necessary to provide patient comfort according to standard local practice and this was recorded as rescue treatment.
Once the patient had met the criteria for the start of weaning from study opioid infusion, a double-blind analgesic bolus was administered (morphine 0.15 mg kg1 in the remifentanil group, placebo in the fentanyl group). The down titration period started 30 min later (as long as the patient still met the criteria for weaning from study opioid). The propofol infusion was stopped and the study opioid infusion was down-titrated at 10 min intervals in 50% decrements three to four times in order to maximize smooth transition to alternative regimens, and then discontinued. Weaning of the patient from the ventilator was started during commencement of this down-titration. If additional analgesia was required during this period, an open label bolus dose of morphine (minimum dose 0.05 mg kg1) was administered and recorded as rescue treatment.
Patients were extubated if the following criteria were met: responsive to commands; SpO2 95% at FIO2
0.5, pH >7.25, PaCO2
7.33 kPa and ventilatory frequency adequate to maintain oxygenation. If the patient had not met the criteria for beginning the extubation sequence by 4.5 h after entry into the ICU, the analgesic opioid bolus was administered at this time and the down-titration of the study opioid was then started 30 min later. Patients were eligible for transfer from ICU if stable conditions continued.
Monitoring
Vital signs were recorded immediately before induction of anaesthesia (baseline values) and at regular intervals throughout surgery and in the ICU. These consisted of SBP, DBP, MAP, HR, CVP, and SpO2. During the pre-bypass period, patients vital signs were recorded 1 min before and every minute for 5 min after each major surgical stress event (MSE), then every 15 min from the MSE until the next MSE. MSEs were defined as intubation, sternal skin incision, sternotomy, maximal sternal spread (MSS), and sternal wire placement. Arterial pressure was recorded at the start of cardiopulmonary bypass and every 15 min until the patient went off bypass.
After entry into the ICU, patients vital signs were recorded immediately and at 15 min intervals thereafter until extubation. In addition, vital signs, pain, and sedation scores were recorded every 10 min during the down-titration of study opioid. Pain was assessed using a four-point patient self-rated scale (0=no pain, 1=mild, 2=moderate, 3=severe), while sedation was assessed using a five-point scale (1=fully awake and orientated, 5=eyes closed and cannot be roused by mild physical stimulation). Vital signs and pain and sedation scores were also recorded at 15, 30, 45, 60, 90, and 120 min after discontinuation of study opioid infusion.
12-lead ECG recordings were obtained within 14 days before surgery and on postoperative day 1, and at the end of day 5 or on the morning of day 6 (or day of hospital discharge if prior to this). Blood samples were obtained at 8, 16, 24, and 48 h after aortic cross clamp release for analysis of plasma cardiac enzyme concentrations (CK-CKMB).
Outcome measures
The primary efficacy endpoint was response to MSS. Secondary efficacy endpoints included responses to intubation, sternal skin incision, sternotomy, and sternal wire placement. Efficacy was evaluated by the number of patients who showed signs of inadequate anaesthesia and by the number of treatments for responses indicative of inadequate or excessive anaesthesia. Overall use of study drug, propofol and other medications were noted. Patients were continually assessed for occurrence of adverse events (including negative cardiac outcomes) throughout the perioperative period and up to the end of postoperative day 5 (or up to hospital discharge if this occurred earlier). Negative cardiac outcomes were defined as ventricular failure (requirement for postoperative intra-aortic balloon pump or ventricular assist device), myocardial infarction (CK-MB >50 unit litre1 and presence of new Q-waves on 12-lead ECG) or death from cardiac causes (e.g. ventricular failure or congestive heart failure) before hospital discharge.
Statistical analysis
The primary endpoint assumed a response rate of 7% and 18% for patients receiving remifentanil and fentanyl, respectively. One hundred and thirty five patients per treatment would have a power of 80% to detect this difference at a two-sided 5% level of significance. To compensate for withdrawals and to obtain additional safety data, up to 300 randomized patients were to be included in the study. The study was stopped when 297 patients had been recruited because of time restriction. Patients were randomized to receive either remifentanil or fentanyl by assignment of treatment randomization details contained in a hidden entry envelope, which had been computer-generated before the study set-up. The hidden entry envelopes were allocated sequentially to each subject eligible for study entry and the corresponding treatment allocation and drug preparation was performed by a named person, independent to the conduct of the study. In most instances this was the hospital pharmacist.
All tests of statistical significance were two-sided and carried out at the 5% level. Logistic regression analyses were used to analyse the proportions of patients with responses to MSS. Estimates of the odds ratios and 95% confidence intervals were calculated. The weighted mean pain and sedation scores during the ICU down titration were analysed using the Wilcoxon rank sum test. The treatment differences in overall use of alternate analgesics until extubation, were analysed using logistic regression analysis.
The incidences of the most commonly reported adverse events (defined as occurring in at least 5% of patients in any treatment group) were analysed using Fishers exact test.
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
The two groups were well matched with regard to gender, ethnic origin, age, height, weight, and ASA status distribution (Table 1). The mean ejection fraction was similar in the remifentanil (0.62) and fentanyl (0.63) groups. Most patients required three arteries to be grafted (41% in the remifentanil group and 45% in the fentanyl group). Two patients in each group had previous CABG surgery. The median durations of surgery, of bypass, and of aortic cross clamping were comparable between the two groups. The median (SD) time from the start of study drug to skin closure was 3.67 h (1.85, 6.3) in the remifentanil group and 3.58 h (1.97, 8.7) in the fentanyl group. The median (SD) durations of bypass and of aortic cross clamping were 1.31 (0.45, 2.4) and 0.75 h (0.22, 3.6), respectively, in the remifentanil group and 1.23 (0.17, 2.85) and 0.73 h (0.08, 2.33), respectively, in the fentanyl group.
|
Hypertension was the most common type of response in those patients who had an inadequate anaesthesia response, occurring in seven patients (5%) in the remifentanil group and 75 patients (50%) in the fentanyl group. There was a mean increase in SBP (from the pre-MSS value to the maximum within 5 min of MSS) of 6 mm Hg in the remifentanil group compared with a mean increase of 15 mm Hg in the fentanyl group (P<0.001). A tachycardic response was recorded in 10 patients (7%) in the remifentanil group and eight patients (5%) in the fentanyl group.
Overall, the weighted mean infusion rate for remifentanil (R) during maintenance of anaesthesia (from pre-bypass to end of surgery) varied between 1.29 (0.69) µg kg1 min1 pre-bypass; 1.23 (0.73) µg kg1 min1 during bypass; 1.21 (0.77) µg kg1 min1 post-bypass. Fentanyl (F) cumulative bolus doses were 7.38 (3.63) µg kg1 pre-bypass; 3.16 (1.56) µg kg 1 during bypass; and 2.92 (1.63) µg kg1 post-bypass. Propofol varied between (R) 2.98 (0.69) vs (F) 3.58 (0.99) mg kg1 h1 pre-bypass; (R) 2.86 (0.45) vs (F) 3.46 (1.44) mg kg1 h1 bypass; (R) 2.8 (0.78) vs (F) 3.45 (1.4) mg kg 1 h1 post-bypass; (R) 2.72 (0.85) vs (F) 3.32 (1.17) mg kg1 h1 end of surgery.
During tracheal intubation, more patients in the remifentanil group showed signs of inadequate anaesthesia compared with those in the fentanyl group (R 24%, F 9%, P<0.001). Response to sternal skin incision (R 11%, F 36%, P<0.001), sternotomy (R 14%, F 60%, P<0.001) and MSS (R 11%, F 52%, P<0.001) were significantly and clinically less in the remifentanil group. During sternal wire placement no statistical or clinically significant difference was noted (R 10%, F 13%).
Figures 1 and 2 present the SBP and HR profiles during key stages during surgery for both treatment groups. SBP fell after pre-induction (baseline) but remained stable within each treatment group compared with baseline values. SBP values were higher in the fentanyl group pre- and post-skin incision compared with remifentanil values at similar time intervals. HR remained stable and similar between treatment groups compared with pre-induction values.
|
|
Table 2 summarizes the postoperative recovery times in the remifentanil and fentanyl anaesthesia groups. The median times to eligibility for weaning for extubation, and for the actual start of the extubation sequence, were longer in the remifentanil group than in the fentanyl group (P<0.05). The median times to eligibility for, and the actual start of extubation were also significantly longer in the remifentanil group than in the fentanyl group (P<0.05). The median times to eligibility for, and for actual transfer from the ICU to less intense monitoring were similar in the remifentanil and fentanyl groups. The median times to hospital discharge were also similar in the remifentanil and fentanyl groups and a similar proportion of patients in each group (17% R, 20% F) were discharged by the end of postoperative day 5 or morning of day 6.
|
During the ICU transition period, the weighted mean sedation score was slightly but significantly higher in the remifentanil group (score 3.61) compared with the fentanyl group (score 2.92; P<0.001).
Safety and tolerability
Both anaesthetic regimens were well tolerated. In total, 138 patients (80%) in the remifentanil group and 113 patients (76%) in the fentanyl group experienced at least one adverse event (P=0.347). The most common adverse events recorded during the study (defined as events occurring in 5% of patients in either treatment group) are listed in Table 3. Overall, the incidences of these events were similar in the remifentanil and fentanyl anaesthesia groups, except for hypertension and shivering which had a significantly higher incidence in the remifentanil group compared with the fentanyl group (P<0.001 and P=0.049, respectively). Both of these events were most commonly reported during the ICU period. Significantly more drug-related adverse events were reported in the remifentanil group compared with the fentanyl group (R 44% vs F 31%, P=0.016). The most common drug-related adverse events were nausea (20% of patients in each group), vomiting (R 6%, F 8%) and shivering (R 11%, F 5%). The only significant differences in drug-related events between groups were hypertension during the immediate postoperative period (R 5%, F 0%, P=0.008) and postoperative ache(s) (R 2%, F 0%; P=0.016).
|
Serious adverse events were reported in 25 patients (15%) in the remifentanil group and in 12 patients (8%) who received fentanyl. The majority of events in both the remifentanil group (12/25, 48%) and the fentanyl group (8/12, 67%) involved the cardiovascular system. There were no reports of drug-related serious adverse events in the fentanyl group. In six patients in the remifentanil group the serious adverse events were considered to be related possibly to the study drug. These included three cases of hypertension, two of which were also associated with shivering. All three cases were considered related to the withdrawal of remifentanil during the transition to alternate analgesic regimens. There were three serious cases of respiratory depression in the ICU in the remifentanil group, all of which resolved. In one of these cases the patient had a history of sleep apnoea.
A similar proportion of patients in each group showed signs of ischaemia during the perioperative period (13% of patients in the remifentanil group and 10% of those in the fentanyl group; P =0.44). Only one of these episodes in the fentanyl group was reported as a drug-related adverse event. There was also no significant difference between the two treatment groups in the incidence of negative cardiac outcomes (ventricular failure, myocardial infarction or death as a result of cardiac causes). Ventricular failure was reported in two of 146 patients (1%) in the remifentanil group; myocardial infarction was reported in four of 146 patients (3%) and three of 148 patients (2%) in the remifentanil and fentanyl groups, respectively (P=0.689). There were no deaths as a result of cardiac causes before hospital discharge. None of the three deaths reported during the study were considered to be related to the study drug.
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Intraoperative infusion rates indicate that 1 µg kg1 min1 was an appropriate starting dose for remifentanil, which could be subsequently titrated up or down to the effect required in the individual patient. The minimum and maximum dose of remifentanil administered, reflect the wide inter-patient variability in the dose required to achieve adequate analgesia with an opioid in combination with the hypnotic component. Similar variations in initial remifentanil dose requirements for cardiac surgery are reported in the recent literature. 1115
Hypertension was the most commonly treated inadequate anaesthesia response in both groups, although the incidence was much higher in the fentanyl group. The majority of patients in both treatment groups (78% remifentanil vs 77% fentanyl) were receiving beta-blockers before the start of study treatment, which may help explain the very low incidence of tachycardia observed as a response to the major stress events.
It is recognized that opioids interact with such agents and blunt the sympathetic response to stress events and may exacerbate bradycardic and hypotensive episodes. Indeed recent reports of clinically significant bradycardia with use of remifentanil in cardiac patients 16 17 have cautioned its use in such patient groups although our experience did not indicate clinically significant treatment differences in bradycardia. Where hypotension did occur, the episodes were transient and managed by appropriate measures which included fluid loading, infusion rate adjustments of remifentanil and propofol and pharmacological intervention as required.
After transport to the ICU, both groups received the same starting infusion of propofol in combination with an opioid infusion (placebo in the fentanyl group). The mean pain score during the ICU transition period (i.e. down titration to alternate postoperative pain management regimens) was comparable between treatment groups. The pharmacokinetic profile of remifentanil may be expected to result in a rapid offset of action. Indeed there were some reports of hypertension and shivering observed during the transition from a remifentanil regimen to an alternative postoperative regimen, which may have been as a result of suboptimal management of the rapid offset of effects of remifentanil with respect to transition to alternative analgesics. The transition to an effective alternative analgesic regimen is a key consideration in the postoperative management of the patient when using a remifentanil regimen. Morphine administration as adopted in this study, may not be the best solution for fast track anaesthesia, although its cautious use during remifentanil based cardiac anaesthesia may have its place. Alternative and effective transition regimens have been suggested in the literature. 14 18
Patients who received the low/medium-dose fentanyl regimen were eligible for extubation and were extubated earlier than the patients who received remifentanil. This may relate to the higher level of sedation in the remifentanil-treated patients during the postoperative period, which may have influenced the investigators decision as to whether to actively intervene in extubating an otherwise calm and sedated patient. Similar consideration in actively managing early extubation regimens has been reported in the literature.19 It would, therefore, appear that proactive intervention may be necessary with regard to extubation when using this dose of remifentanil in combination with propofol for weaning. In contrast, alternate transition regimens to that administered in this study have demonstrated comparable or superior recovery compared with a fast track fentanyl regimen.13 15
Despite the longer time to extubation in the remifentanil group compared with fentanyl-treated patients, there were no statistically significant differences between the two groups in the median times to eligibility for, or actual transfer from the ICU to less intense monitoring or to hospital discharge. The data probably reflect the fact that although the protocol-specified anaesthetic and postoperative treatment regimens ensured that patients could be extubated within a reasonable timeframe, subsequent management of patients would largely have depended upon whether or not hospital procedures were in place to fast track patients to hospital discharge. It was not possible to standardize these in this large multi-centre international study. This is supported by the fact that in the majority of cases where patients were not discharged from hospital by the end of postoperative day 5, the reasons listed included institutional practice rather than any influence of the anaesthetic regimen used. Similar observations have been reported in other studies in which early extubation and recovery has not always resulted in faster ICU and/or hospital discharge times.4 7 20 In this regard, it is also notable that many of the studies that have demonstrated significant reductions in ICU and/or hospital stay were conducted at single centres, 4 7 21 22 reducing the impact of variations in procedures for extubation, ICU, and hospital discharge. However, in this study, the use of the high dose remifentanil opioid regimen resulted in a similar duration of ICU stay and postoperative hospitalization as the fentanyl regimen.
Both anaesthetic regimens were well tolerated and the recorded adverse event profiles are typical of potent µ-opioid receptor agonists and predictable in these patients following CABG surgery. There was little difference in the overall incidence of adverse events between the remifentanil and fentanyl treatment groups, although the incidences of drug-related adverse events and of serious adverse events were higher in the remifentanil group than in the fentanyl group. Postoperative shivering and hypertension can increase oxygen consumption and precipitate episodes of myocardial ischaemia, which may adversely influence outcome, including risk of myocardial infarction.2 23 However, the increased frequency of hypertensive events in the remifentanil group compared with the fentanyl group was not associated with any significant difference in the incidence of perioperative negative cardiac outcomes.
The serious cases of postoperative respiratory depression observed in the remifentanil group is an unexpected finding given the rapid offset of action of remifentanil. However, of the three reported cases, one included a patient with an underlying sleep apnoea disorder. Administration of the active blinded morphine bolus doses in the remifentanil group may have contributed to the higher incidence of respiratory depression observed compared with the placebo-treated fentanyl group.
In summary, our data show that high-dose remifentanil in combination with propofol is effective and well-tolerated when used to provide anaesthesia in CABG patients. Importantly, the data show that the remifentanil regimen provided superior control of some of the major stress events, but not to intubation. Intraoperative haemodynamic stability was associated with both treatment groups but use of a high-dose remifentanil regimen did not compromise patients overall recovery times compared with the low/medium-dose fast track fentanyl regimen. However, transition from a remifentanil-based regimen to alternate postoperative pain management regimens must be carefully and proactively managed to ensure rapid and smooth transition to alternate analgesic regimens.
![]() |
Acknowledgements |
---|
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Mangano DT, Siliciano D, Hollenberg M, et al. Postoperative myocardial ischemia. Therapeutic trials using intensive analgesia following surgery. The Study of Perioperative Ischemia (SPI) Research Group. Anesthesiology 1992; 76: 34253[ISI][Medline]
3 Cheng DC, Karski J, Peniston C, et al. Early tracheal extubation after coronary artery bypass graft surgery reduces costs and improves resource use. A prospective, randomized, controlled trial. Anesthesiology 1996; 85: 130010[ISI][Medline]
4 Chong JL, Grebenik C, Sinclair M, Fisher A, Pillai R, Westaby S. The effect of a cardiac surgical recovery area on the timing of extubation. J Cardiothorac Vasc Anesth 1993; 7: 13741[Medline]
5 Chong JL, Pillai R, Fisher A, Grebenik C, Sinclair M, Westaby S. Cardiac surgery: moving away from intensive care. Br Heart J 1992; 68: 4303[Abstract]
6 Cheng DC, Karski J, Peniston C, et al. Morbidity outcome in early versus conventional tracheal extubation after coronary artery bypass grafting: a prospective randomized controlled trial. J Thorac Cardiovasc Surg 1996; 112: 75564
7 Berry PD, Thomas SD, Mahon SP, et al. Myocardial ischaemia after coronary artery bypass grafting: early vs late extubation. Br J Anaesth 1998; 80: 205[ISI][Medline]
8 Mangano DT. Perioperative cardiac morbidity. Anesthesiology 1990; 72: 15384[ISI][Medline]
9 Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology 1985; 62: 23441[ISI][Medline]
10 Camu F, Royston D. Inpatient experience with remifentanil. Anesth Analg 1999; 89: S1521[ISI][Medline]
11 Duthie DJ, Stevens JJ, Doyle AR, Baddoo HH. Remifentanil and coronary artery surgery. Lancet 1995; 345: 64950
12 Gerhardt MA, Grichnik KP. Early extubation and neurologic examination following combined carotid endarterectomy and coronary artery bypass grafting using remifentanil. J Clin Anesth 1998; 10: 24952[ISI][Medline]
13 Djaiani G, Cheng D. Minimally invasive direct coronary artery bypass grafting techniques. J Cardiothorac Vasc Anesth 1999; 13: 3756[Medline]
14 Zarate E, Latham P, White PF, et al. Fast-track cardiac anesthesia: use of remifentanil combined with intrathecal morphine as an alternative to sufentanil during desflurane anesthesia. Anesth Analg 2000; 91: 2837
15 Bacon R, Chandrasekan V, Haigh A, Royston BD, Royston D, Sundt T. Early extubation after open-heart surgery with total intravenous anaesthetic technique. Lancet 1995; 345: 1334
16 Wang JY, Winship SM, Thomas SD, Gin T, Russell GN. Induction of anaesthesia in patients with coronary artery disease: a comparison between sevoflurane-remifentanil and fentanyl-etomidate. Anaesth Intensive Care 1999; 27: 3638[ISI][Medline]
17 Elliott P, OHare R, Bill KM, Phillips AS, Gibson FM, Mirakhur RK. Severe cardiovascular depression with remifentanil. Anesth Analg 2000; 91: 5861
18 Kochs E, Cote D, Deruyck L, et al. Postoperative pain management and recovery after remifentanil-based anaesthesia with isoflurane or propofol for major abdominal surgery. Remifentanil Study Group. Br J Anaesth 2000; 84: 16973
19 Coe V. Early extubation: perspective from a community hospital. J Cardiothorac Vasc Anesth 1995; 9: 3743[ISI][Medline]
20 Higgins TL. Safety issues regarding early extubation after coronary artery bypass surgery. J Cardiothorac Vasc Anesth 1995; 9: 249[ISI][Medline]
21 Bell J, Sartain J, Wilkinson GA, Sherry KM. Propofol and fentanyl anaesthesia for patients with low cardiac output state undergoing cardiac surgery: comparison with high-dose fentanyl anaesthesia. Br J Anaesth 1994; 73: 1626[Abstract]
22 Sherry KM, McNamara J, Brown JS, Drummond M. An economic evaluation of propofol/fentanyl compared with midazolam/fentanyl on recovery in the ICU following cardiac surgery. Anaesthesia 1996; 51: 3127[ISI][Medline]
23 Hall RI. Anaesthesia for coronary artery surgery a plea for a goal-directed approach. Can J Anaesth 1993; 40: 117894[Abstract]