Efficacy and safety of remifentanil in coronary artery bypass graft surgery: A randomized, double-blind dose comparison study☆☆☆

Article Outline

• Abstract
• Methods
• Results
• Discussion
• Acknowledgements
• References
• Copyright

Abstract 

Objectives: To compare the efficacy and safety of 3 doses of remifentanil as part of a total intravenous anesthesia technique with low-dose propofol in patients undergoing coronary artery bypass graft (CABG) surgery. Design: Multicenter, multinational, double-blind, randomized, dose comparison study. Setting: Nine hospitals in 5 countries. Participants: One hundred forty-one patients undergoing first-time elective CABG surgery. Interventions: Patients were premedicated with a short-acting oral benzodiazepine up to 2 h before surgery and randomized to receive continuous infusions of remifentanil 1.0 μg/kg/min (n = 45), 1.5 μg/kg/min (n = 44), or 2.0 μg/kg/min (n = 43), in combination with propofol 3 mg/kg/h. Nine patients received remifentanil 1.0 μg/kg/min on an open-label basis. Three different induction sequences (IS) were used. In IS 1 (n = 31), induction was started with remifentanil infusion followed 5 minutes later by propofol 0.5 mg/kg bolus and infusion at 3 mg/kg/h. Further bolus doses of propofol (10 mg) were given if loss of consciousness (LOC) was not attained after 5 minutes; pancuronium, 0.04 to 0.1 mg/kg, was administered at LOC. In IS 2 (n = 68), a priming dose of pancuronium, 0.015 mg/kg, was administered just before starting remifentanil. In IS 3 (n = 42), bolus doses of propofol, 10 mg every 10 seconds, were given until LOC, followed by pancuronium, 0.04 to 0.1 mg/kg, and the remifentanil and propofol infusions were started. Measurements and Main Results: There were no significant differences among the remifentanil dose groups with regard to the primary outcome measure, responses to sternotomy/sternal spread/maximal sternal spread. Responses to these stimuli were recorded in 11%, 11%, and 14% of patients in the remifentanil 1.0, 1.5, and 2.0 μg/kg/min dose groups, respectively. Similarly, there were no significant differences in the responses to other surgical stimuli. There was a high incidence of muscle rigidity when remifentanil was used to induce anesthesia. Conclusions: All 3 remifentanil dose regimens provided profound suppression of responses to surgical stimuli in the majority of patients. There was no apparent advantage in starting the remifentanil infusion rate above 1.0 μg/kg/min. Remifentanil is not suitable for use as a sole induction agent. Copyright 2003, Elsevier Science (USA). All rights reserved.

Keywords:  remifentanil, propofol, coronary artery bypass graft surgery, response to sternotomy/sternal spread

Analgesia-based anesthesia using high doses of opioids is commonly used in cardiac surgery to provide effective attenuation of responses to surgical stimuli without causing severe myocardial depression. High-dose opioid anesthesia does not, however, blunt all responses to surgical stimuli¹, ², ³, ⁴, ⁵, ⁶ and adjusting the level of anesthesia in response to varying degrees of surgical stress remains a problem when using traditional opioids. In addition, postoperative respiratory depression because of opioid accumulation in the tissues limits fast-track recovery. Remifentanil hydrochloride is a potent selective μ-opioid agonist that has a rapid onset of action and is rapidly metabolized by nonspecific esterases in the blood and tissues, resulting in an elimination half-life of less than 10 minutes.⁷ A context-sensitive decrement time of only 3 minutes⁸ gives remifentanil a short, predictable duration and rapid offset of action, independent of the duration of infusion.⁹, ¹⁰, ¹¹ Thus, the use of remifentanil in conjunction with propofol may allow for profound suppression of responses to surgical stimuli because of the high-dose opioid technique without residual respiratory depression. The objective of this study was to compare the efficacy and safety of 3 doses of remifentanil combined with low-dose propofol as part of a total intravenous anesthesia technique in patients undergoing hypothermic coronary artery bypass graft (CABG) surgery.

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Methods 

This randomized, double-blind, parallel group dose comparison study was conducted at 9 centers in Europe. After obtaining local ethics committee or review board approval and informed written consent from each patient, patients aged 36 to 74 years with American Society of Anesthesiologists' status II to IV undergoing first-time elective CABG surgery were randomized to receive 1 of 3 different continuous infusions of remifentanil: 1.0, 1.5, or 2.0 μg/kg/min as part of a total intravenous anesthesia technique with propofol 3 mg/kg/h. Patients were excluded if they had a left ventricular ejection fraction <35%, significant arrhythmia, had evidence of congestive heart failure, were concurrently receiving vasoactive drugs, had severe or uncontrolled noncardiac disease, or had insulin-dependent diabetes. Also excluded were those with a body weight not within ± 50% of ideal body weight or a known hypersensitivity to opioids and patients who had received opioids within 8 weeks before the study day or long-acting benzodiazepines within the previous 12 hours. At each center, the first patient received remifentanil 1.0 μg/kg/min on an open-label basis for investigator familiarization.

On the morning of surgery, patients received their usual medications and were premedicated with diazepam, 10 mg PO up to 2 hours before transportation to the operating room. On entry to the operating area, patients' vital signs (systolic and diastolic blood pressures [SBP, DBP])and heart rate (HR) were recorded. Midazolam, 0.05 mg/kg intravenously, was given for sedation before the second intravenous catheter (dedicated for remifentanil), arterial cannulation, and introduction of a central venous catheter and pulmonary catheter. The patients' stroke volume was then calculated by using an ice-saline thermodilution technique, and those with a stroke volume of ≥50 mL were included in the study.

Before induction of anesthesia, each patient was oxygenated with pure 100% oxygen for at least 3 minutes. Three different induction sequences (ISs) were used in this study. During induction and for the remainder of the study period, muscle rigidity was assessed using the scoring system detailed in Table 1.

Table 1. Scoring system used for the assessment of muscle rigidity

IS 1 (the first 31 patients) proceeded as follows. Blinded remifentanil infusion of 1.0, 1.5, or 2.0 μg/kg/min was started, and the patient was observed for the next 5 minutes for loss of consciousness (LOC; lack of response to three consecutive verbal commands). At the end of this period, all patients received a 0.5 mg/kg intravenous bolus of propofol injected over 1 minute, and a continuous infusion of propofol 3 mg/kg/h was commenced. Patients were then observed for LOC for another 5 minutes. If at the end of this time, LOC had still not been achieved, intermittent bolus doses of propofol (10 mg every 10 seconds) were administered until LOC when a paralyzing dose of pancuronium (0.04-0.1 mg/kg) was administered. Endotracheal intubation was then performed at least 2 minutes after administration of pancuronium. Patients were not given nitrous oxide at any time during the study but were ventilated with a 50% oxygen/air mixture. End-tidal carbon dioxide concentrations were maintained at <40 mmHg (< 5.2 kPa) throughout the prebypass and postbypass periods and while the patients were ventilated in the intensive care unit (ICU). IS 2 (the next 68 patients) was adopted to reduce the risk of muscle rigidity during induction. The original IS was modified so that a priming dose of pancuronium, 0.015 mg/kg, was given before remifentanil. A second amendment to the IS was made after an incidence of severe muscle rigidity in a patient, despite administration of a priming dose of pancuronium. In IS 3 (performed on 42 patients), the sequence was changed to start induction using propofol, 10 mg (1 mL) every 10 seconds until LOC. A paralyzing dose of pancuronium, 0.04 to 0.1 mg/kg, was then administered, followed immediately by starting the continuous infusions of remifentanil and propofol. Patients were then intubated at least 5 minutes after starting the infusions and ventilated with oxygen/air. The remifentanil infusion rate remained constant throughout the study unless it had to be reduced for the treatment of hypotension.

During cardiopulmonary bypass, a hypothermic technique was used to maintain a core body temperature of 28°C. Patients' body temperature was lowered and raised in accordance with the cardiopulmonary bypass protocols in use at each center. At the start of the cooling process, the propofol infusion rate was reduced by 50% to prevent a rise in plasma propofol concentration.¹² All patients were rewarmed to a minimum core temperature of 35°C with a maximum brain temperature of 37.5°C before coming off bypass.

At the end of the operation, propofol was discontinued, and the blinded remifentanil infusion was changed to an open-label infusion of 1.0 μg/kg/min for analgesia and sedation in the ICU. After 3 hours in the ICU, patients were assessed to see when they were eligible for early extubation (normothermic, not bleeding, no significant cardiac arrhythmias, and hemodynamically stable). Eligible patients received a bolus dose of morphine (up to 0.2 mg/kg). Thirty minutes later, the patient was given a bolus dose of midazolam (1-5 mg if appropriate to control stress/agitation at the investigators discretion), and the remifentanil infusion was reduced in approximately 50% decrements every 15 to 30 minutes and stopped 15 minutes after the remifentanil infusion rate had reached 0.065 μg/kg/min. When all other conditions were considered satisfactory, the patient was extubated. Patients who were not eligible for early extubation 5 hours after entry into the ICU were treated in a similar way except the remifentanil was reduced at 15-minute intervals. For both groups, subsequent analgesia and sedation were provided at the investigators' discretion.

Patients' vital signs were recorded immediately before induction of anesthesia (baseline values), at 15, 30, and 60 minutes after intubation, and at 15, 30, and 60 minutes after going off bypass. These consisted of patients' SBP, DBP, mean arterial pressure (MAP), HR, pulmonary artery pressure, pulmonary capillary wedge pressure, central venous pressure (CVP), oxygen saturation (SpO₂), end-tidal carbon dioxide concentrations, core temperature, and cardiac output. Partial vital signs (minus pulmonary artery pressure, pulmonary capillary wedge pressure, and cardiac output) were recorded at 15-minute intervals at all other times from intubation until immediately before the start of cardiopulmonary bypass. Patients' MAP and CT were assessed at 2 and 5 minutes after the start of bypass, then every 10 minutes thereafter, and again at the end of bypass. Patients' SBP, DBP, and HR were recorded immediately before and at 2 and 5 minutes after intubation, sternal skin incision, sternotomy/sternal spread, maximal sternal spread, and aortic cannulation. All patients were continually assessed for response to surgical stimuli throughout the intraoperative period. SBP, DBP, and HR were also recorded after a surgical response.

Responses to surgical stimuli, indicating inadequate anesthesia, were defined as any one or more of the following.

Responses indicative of inadequate anesthesia were treated in a sequential manner according to the following protocol, with each treatment administered only after failure of the previous treatment to return the patient to a nonresponsive state.

During bypass, hypertension (MAP >75 mmHg for >1 minute), somatic, or autonomic responses were treated with bolus doses of a vasodilator.

Hypotension occurring before or after bypass (MAP <70 mmHg >2-3 minutes) was treated with intravenous fluids and up to 2 sequential doses of a vasopressor. If the hypotension persisted, the propofol infusion rate was decreased by 50%. If it still persisted after this, the remifentanil infusion rate could be reduced in 50% decrements every 5 minutes to return the patient to a stable hemodynamic state. Hypotension occurring during bypass (MAP <50 mmHg >2-3 minutes) was treated with a vasopressor. If boluses of the vasopressor failed to rectify the hypotension, the propofol infusion rate was reduced by 50%. If hypotension persisted, the remifentanil infusion rate could be reduced in 50% decrements every 5 minutes until the situation resolved.

The primary efficacy endpoint was the number of patients showing a response to sternotomy/sternal spread/maximal sternal spread. Secondary efficacy endpoints included achievement and time to LOC during induction of anesthesia, responses to intubation, skin incision, aortic cannulation, chest tube placement, total number of responses to surgical stimuli, number of treatments for responses indicative of inadequate, and excessive anesthesia and patients' vital signs. Patients were continually assessed for signs of awareness during the operation, and the occurrence of spontaneously reported adverse events throughout the intraoperative period and for 24 hours after surgery.

All tests of statistical significance were 2 sided and performed at the 5% level with pair-wise comparisons made between the remifentanil 1.0 μg/kg/min and 1.5 μg/kg/min dose groups and between the 1.0 μg/kg/min and 2.0 μg/kg/min dose groups. Logistic regression analyses were used to analyze the proportions of patients with responses to sternotomy/sternal spread/maximal sternal spread, skin incision, and intubation. Estimates of the odds ratios and 95% confidence intervals were calculated. The incidences of the most commonly reported spontaneously reported adverse events (defined as occurring in at least 5% of patients in any treatment group) were analyzed using the Fisher exact test.

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Results 

Of the 141 patients who entered the study, 9 were treated on an open-label basis and were not included in the intent-to-treat population for efficacy analyses although they were included in the population for safety data. The intent-to-treat population thus consisted of 132 patients, with 45, 44, and 43 patients receiving remifentanil 1.0, 1.5, and 2.0 μg/kg/min, respectively.

The patients in the 3 groups were well matched (Table 2).

Table 2. Demographic and clinical characteristics of patients in the 3 remifentanil anesthesia groups

Abbreviations: SBP, systolic blood pressure; DBP, diastolic blood pressure; ASA, American Society of Anesthesiologists.

Most had an American Society of Anesthesiologists' status of III and more than 50% required 3 or fewer arteries to be grafted. The groups were also well matched for concurrent illnesses and medications. All patients received a benzodiazepine (median dose of midazolam 3.9 mg), whereas 71% received a β-blocker, 61% a vasodilator, 55% a calcium channel blocker, 13% a diuretic, and 12% an angiotensin-converting enzyme inhibitor.

Fewer than 15% of patients showed a response to sternotomy/sternal spread/maximal sternal spread (primary outcome), and there was no significant difference among the treatment groups (Table 3). All patients showing a response had a hypertensive response, with 2 patients (one each in the 1.0 and 1.5 μg/kg/min dose groups) showing tachycardic responses and one patient (in the 1.5 μg/kg/min dose group) a somatic response. No patients showed autonomic responses to sternotomy or maximal sternal spread. The treatment of these responses is also summarized in Table 3.

Table 3. Percentages of patients (n) showing responses to sternotomy/sternal spread/maximal sternal spread and the treatment received

Abbreviations: CI, confidence interval.

The percentages of patients in the 3 groups showing responses to sternotomy/sternal spread/maximal sternal spread and to intubation, skin incision, aortic cannulation, and chest tube placement are shown in Fig 1.

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• Fig. 1. 

  Percentages of patients in the remifentanil 1.0, 1.5, and 2.0 μg/kg/min dose groups showing responses to surgical stimuli.

These other responses, the most common being hypertensive, followed a similar pattern with no significant differences among the 3 groups. No patients showed somatic or autonomic responses to any of these other surgical stimuli. Responses were most commonly treated with bolus doses of remifentanil and propofol (Table 4). Response rates to other surgical stimuli not shown in Fig 1 are also summarized in Table 4. The incidence of protocol-defined bradycardia and hypotension is summarized in Table 4. Overall, there was no significant difference in the incidence of hypotension observed across the treatment groups.

Table 4. Percentages of patients (n) showing responses and the treatment received

Figure 2 summarizes the treatment requirement for all responses to surgical stimuli and for hypotension throughout the whole intraoperative period.

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• Fig. 2. 

  Overall percentages of patients treated for responses to surgical stimuli or hypotension.

The requirements for given treatments were broadly comparable across the 3 groups. LOC assessments are summarized for IS 1 and 2 in Table 5.

Table 5. Loss of consciousness

NOTE. The 42 patients who had induction of anesthesia as described in induction sequence 3 were not analyzed for LOC data.

Abbreviation: LOC, loss of consciousness.

The median time to achieve LOC from starting the remifentanil infusion was 6 minutes in each group. Extubation times are summarized in Table 6.

Table 6. Extubation times

Overall, there were no differences observed among the 3 treatment groups.

The overall incidence of spontaneously reported adverse events in the 1.0, 1.5, and 2.0 μg/kg/min dose groups were 93%, 89%, and 100%, respectively. The majority of adverse events were of mild or moderate severity, typical for patients undergoing cardiac surgery, and there was no apparent dose relationship. No patients were withdrawn because of adverse events during the intraoperative period. The most common adverse event during the induction phase was muscle rigidity. The incidence and severity of muscle rigidity during induction of anesthesia are summarized in Table 7. The 2 modifications made to the original induction sequence were successively more effective in reducing the incidence of muscle rigidity. The incidence of muscle rigidity appeared to be dose related; in the remifentanil 2.0 μg/kg/min dose group, the incidence was significantly higher (p = 0.039) than that recorded in the 1.0 μg/kg/min dose.

Table 7. Percentages of patients (n) with muscle rigidity during induction of anesthesia

NOTE. Induction sequences (see Methods for full details): 1. remifentanil infusion followed by propofol bolus and infusion and, at LOC, a paralysing dose of pancuronium 2. priming dose of pancuronium followed by sequence described above 3. administration of propofol until LOC followed by remifentanil and propofol infusions and paralyzing dose of pancuronium.

Adverse events considered by the investigators to be remifentanil related and that occurred in more than 5% of patients are listed in Table 8.

Table 8. Percentages of patients (n) with adverse events considered remifentanil-related by investigators, which occurred with an incidence ≥5%

Other adverse events that were considered to be related to remifentanil and that occurred in 5% or less of patients included anxiety, dyspnea, and transient ST-segment depression suggestive of ischemia. This latter event, discussed in more detail later, occurred in one patient after a period of chest pain as a result of anxiety during induction of anesthesia.

There were 2 deaths during the study, neither of which was considered to be related to remifentanil. One patient (remifentanil 1.5 μg/kg/min) had a myocardial infarction in the ICU after surgery and died on the sixth postoperative day. Another patient (remifentanil 1.5 μg/kg/min) had a cardiac arrest postoperatively, with bleeding from the chest drains. Resuscitation failed, and the cause of death was aortic rupture.

Serious adverse events were recorded in 3 patients during induction of anesthesia. These were all cases of severe muscle rigidity and were all considered to be related to remifentanil. The first case, in a 66-year-old man (remifentanil 1.5 μg/kg/min) with a history of hypertension and myocardial infarction, resolved after the administration of propofol and pancuronium, and surgery was continued. In the second case, a 59-year-old woman (remifentanil, 1.0 μg/kg/min) experienced a nonfatal cardiac arrest as a result of oxygen desaturation and was treated with pancuronium, 12 mg, and cardiac massage, and within 1 minute the patient's blood pressure and heart rate returned to baseline levels and arterial oxygenation was 100%. Surgery continued without any additional problems. The third case occurred in a 56-year-old male patient (remifentanil 2.0 μg/kg/min) who received 2 mg of pancuronium at the same time as the remifentanil infusion was started and 30 seconds later developed severe muscle rigidity. The patient had not lost consciousness at this stage and became dyspneic and anxious, leading to hypertension (SBP, 220 mmHg; DBP, 120 mmHg). The patient also complained of retrosternal chest pain, and the ECG showed transient ST-segment depression suggestive of ischemia. Remifentanil was continued, and the patient was treated with glyceryl trinitrate, 1.5 mg over 1 minute. Propofol and pancuronium were then administered to facilitate emergency intubation. The episode then resolved within a few minutes, and surgery proceeded without any further events.

Four serious adverse events were reported during maintenance of anesthesia. All of these events were typical of patients undergoing major cardiac surgery or were not unexpected in patients receiving opioid agonist drugs. Two of these events were considered to be related to remifentanil. One 63-year-old male patient received remifentanil 1.0 μg/kg/min and experienced severe bradycardia during intubation, which was considered to be a result of vagal stimulation and drug-related. He was treated with atropine, 1 mg intravenously, and the event resolved 11 minutes later. The anesthetic procedure was then restarted, and surgery proceeded uneventfully. The other event was an incidence of severe hypotension in a 55-year-old man in the remifentanil 1.5 μg/kg/min dose group. Two hours into the operation, this patient experienced intermittent periods of hypotension that were considered to be caused by decreased systemic vascular resistance during and after bypass. Surgery continued; the patient was treated with phenylephrine, dobutamine, and norepinephrine, and the condition resolved within 5 hours. The investigator attributed the event to bleeding during bypass and to propofol, but also considered that it was possibly related to remifentanil.

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Discussion 

There was no clear dose-response relationship for any of the efficacy parameters measured. Notably, there were no significant differences among groups with regard to the primary efficacy outcome measure. The data do, however, indicate that all 3 remifentanil dose regimens provided effective suppression of responses to surgical stimuli. In total, 89%, 89%, and 86% of patients in the remifentanil 1.0, 1.5, and 2.0 μg/kg/min dose groups, respectively, showed no responses to sternotomy/sternal spread/maximal sternal spread. Of those patients who did respond, the predominant response was hypertension, which was effectively treated with up to 2 bolus doses of remifentanil (2 μg/kg) in most patients. A small number of patients required treatment with propofol; however, for all patients, hemodynamic control was re-established within minutes of the response occurring.

This study also investigated the potential use of remifentanil as a sole induction agent in patients premedicated with a benzodiazepine. LOC was achieved in only 6 (21%), 3 (10%), and 7 (22%) patients in the remifentanil 1.0, 1.5, and 2.0 μg/kg/min groups, respectively, without the use of a propofol induction bolus dose. In addition, muscle rigidity, which appeared to be dose related, was a problem in some patients, and the addition of a muscle relaxant to the induction sequence did not fully solve this problem. By contrast, LOC was achieved in 90%, 90%, and 100% of patients in the remifentanil 1.0, 1.5, and 2.0 μg/kg/min groups, respectively, after starting induction with propofol followed by pancuronium before starting remifentanil, and the overall incidence of muscle rigidity was reduced by 70%. Hall et al¹³ reported similar results for percentages of patients achieving LOC using sufentanil 0.2 μg/kg combined with propofol at a higher dose of 1.1 mg/kg. The results of this study clearly indicate that remifentanil should not be used as a sole induction agent and supports the work of Jhaveri et al.¹⁴ Their data show that even a 10-fold higher dose of remifentanil compared with this study does not reliably produce LOC and still adds the risk of muscle rigidity, which supports the changes to the induction sequences.

After the incorporation of propofol induction into the study protocol, only 5 minutes were allowed between the start of remifentanil infusion and intubation. In consequence, the incidences of responses to intubation across the 3 remifentanil dose groups were up to 8 times higher than those recorded before the induction protocol was changed. This was most probably the result of inadequate time to achieve steady-state remifentanil concentrations in the blood and, if so, could be overcome by allowing a longer period of time (10-15 minutes) between induction and intubation or by giving a bolus dose of remifentanil at the same time as starting the intravenous infusion.

The numbers of patients responding to skin incision, aortic cannulation, and chest tube placement were low in all 3 remifentanil groups, and these responses were successfully managed with remifentanil bolus doses of 2 μg/kg and propofol. Only one patient progressed through the treatment cascade to require treatment with a vasodilator or β-blocker, and no patients required isoflurane. The majority of those responding had no more than 3 responses, primarily hypertension, and were successfully managed using the treatment cascade according to the phase of the study. It is notable that the incidence of hypertensive (and other) responses was higher during cardiopulmonary bypass compared with the prebypass or postbypass periods. The increased incidence of hypertensive responses may have been caused by the following factors. Firstly, the criteria for defining hemodynamic responses used in this study were conservative, and secondly, the propofol infusion rate was reduced by 50% during bypass. Interestingly, Massey et al¹⁵ have shown that when propofol was administered by continuous intravenous infusion, its whole blood concentration did not change significantly during cardiopulmonary bypass, so that the reduction in this study might not have been necessary. It was expected that the combination of a propofol reduction and an increased remifentanil effect because of a 3% reduction in remifentanil elimination per degree of body temperature lowering would equalize the effect.

Hypotension was frequently observed, and there was a similar incidence across the treatment groups throughout the different phases of surgery. The treatment cascade, reflecting standard clinical practice, was effective. Administration of fluids, vasopressors, and reductions in propofol infusion was effective in controlling the majority of episodes. Reductions in remifentanil infusion rate were required in 18%, 32%, and 21% of patients in the remifentanil 1.0, 1.5, and 2.0 μg/kg/min groups, respectively.

Despite the incidence of hypotension, overall the hemodynamic status of patients in all 3 remifentanil dose groups remained stable for the majority of the time. The pharmacokinetic profiles of remifentanil and propofol with their rapid onset, short duration, and predictable offset of action allowed for rapid responses to incidences of hypotension or hypertension by dose titration. This has obvious benefits in reducing the chance of perioperative myocardial ischemia.

The majority of adverse events recorded in the patients in this study are not uncommon in patients undergoing CABG surgery, and many of the events were typical of a potent μ-opioid receptor agonist with a rapid onset of action, such as remifentanil. The most common adverse events were hypertension, hypotension, and muscle rigidity, the latter in particular appearing to be dose related. Hypertension and hypotension were usually of mild or moderate severity and resolved rapidly with treatment according to the study protocol.

In conclusion, remifentanil 1.0, 1.5 or 2.0 μg/kg/min combined with low-dose propofol 3 mg/kg/h provided profound suppression of responses to surgical stimuli in the majority of patients undergoing CABG surgery. No significant differences in efficacy were observed among the 3 dose groups, and there does not appear to be any benefit of using starting remifentanil infusion rates above 1.0 μg/kg/min. Use of remifentanil as a sole agent for the induction of anesthesia is not recommended. Further studies are required to show if a lower dose of remifentanil in combination with the same or probably higher dose of propofol can be used as safely.

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Acknowledgements 

European Remifentanil Cardiac Anesthesia Study Group: Prof S de Lange, Dr FEA Geisler, Dr J Pelzer. Academic Hospital of Maastricht, Maastricht, Netherlands; Dr D Royston, Dr A Haigh, Dr R Bacon. Harefield Hospital, Harefield, UK; Prof H Van Aken (formally of University Hospital KU Leuven), Dr R Demeyere, Dr Swinnen. University Hospital KU Leuven, Leuven, Belgium; Dr DJR Duthie (formally from Papworth Hospital), Dr A Doyle, Dr H Baddoo, Dr J Stevens. Papworth Hospital, UK; Prof S Estanove, Prof J-J Lehot, Dr MC Gruner, Dr JP Dalmas, Dr J Neidecker, Dr D Bompard, Dr M George, Dr. P Blanc, Dr. Filley. BP Lyon-Monchat, Lyon, France; Dr M Adt, Dr C Haggenmiller, Dr K J Komar, Dr S Weber-Carsten. Deutsches Herzzentrum, Berlin, Germany; Prof J-P Dupeyron, Dr F Levy, Dr Meyer, Dr Thiranos. CHU de Strasbourg, Strasbourg, France; Prof G Kenny, Dr M Mansfield (formally of Glasgow Royal Infirmary), Dr J Kinsella, Dr W Reeve, Dr J Church, Dr M Stockwell, Dr S Hickey. lasgow Royal Infirmary, Glasgow, UK; Prof J Bovill, Dr Schenk, Dr Ros, Dr Engbers. Academic Hospital Leiden, Leiden, Netherlands.

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