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CARDIOVASCULAR ANESTHESIA

A Randomized Double-Blinded Multicenter Comparison of Remifentanil Versus Fentanyl When Combined with Isoflurane/Propofol for Early Extubation in Coronary Artery Bypass Graft Surgery

Michael B. Howie, MD^*, Davy Cheng, MD, Mark F. Newman, MD, Eric T. Pierce, PhD, MD, Charles Hogue, MD^||, Zak Hillel, MD, PhD^¶, T. Andrew Bowdle, MD, PhD^#, and Deo Bukenya, PhD^**

*Department of Anesthesia, The Ohio State University Medical Center, Columbus, Ohio; Department of Anesthesia, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; Department of Anesthesia, Duke University Medical Center, Durham, North Carolina; Department of Anesthesia, Boston University Medical Center, Boston, Massachusetts; ||Department of Anesthesia, Washington University School of Medicine, St. Louis, Missouri; ¶Department of Anesthesia, St. Luke’s-Roosevelt Hospital Center, New York, New York; #University of Washington School of Medicine, Seattle Washington; and **Glaxo Wellcome, Research Triangle Park, North Carolina

Address correspondence and reprint requests to Dr. Michael B. Howie, The Ohio State University Medical Center, Department of Anesthesiology, Division of Cardiothoracic Anesthesia, Clinical Anesthesia Research Laboratory, Doan Hall N408, 410 West 10th Ave., Columbus OH 43210-1228.

	Abstract

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We compared a fentanyl/isoflurane/propofol regimen with a remifentanil/isoflurane/propofol regimen for fast-track cardiac anesthesia in a prospective, randomized, double-blinded study on patients undergoing elective coronary artery bypass graft surgery. Anesthesia was induced with a 1-min infusion of 0.5 mg/kg propofol followed by 10-mg boluses of propofol every 30 s until loss of consciousness. After 0.2 mg/kg cisatracurium, a blinded continuous infusion of remifentanil at 1 µg · kg^-1 · min^-1 or the equivalent volume rate of normal saline was then started. In addition, a blinded bolus syringe of 1 µg/kg remifentanil or 10 µg/kg fentanyl, respectively, was given over 3 min. Blinded remifentanil, 1 µg · kg^-1 · min^-1 (or the equivalent volume rate of normal saline), together with 0.5% isoflurane, were used to maintain anesthesia. Significantly more patients (P < 0.01) in the fentanyl regimen experienced hypertension during skin incision and maximum sternal spread compared with patients in the remifentanil regimen. There were no differences between the groups in time until extubation, discharge from the surgical intensive care unit, ST segment and other electrocardiogram changes, catecholamine levels, or cardiac enzymes. The remifentanil-based anesthetic (consisting of a bolus followed by a continuous infusion) resulted in significantly less response to surgical stimulation and less need for anesthetic interventions compared with the fentanyl regimen (consisting of an initial bolus, and followed by subsequent boluses only to treat hemodynamic responses) with both drug regimens allowing early extubation.

Implications: Both fentanyl and the newer opioid remifentanil, when each is combined with isoflurane and propofol, allowed for fast-track cardiac anesthesia. The remifentanil regimen used in this study resulted in significantly less hemodynamic response to surgical stimulation.

	Introduction

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Worldwide, more than 800,000 coronary artery bypass grafting (CABG) procedures are performed annually. Although patients having these procedures are older and have more concomitant diseases, there are increasing pressures to reduce the cost of care. In the past, the most common anesthetic technique for cardiac surgery was balanced anesthesia with large doses of opioids, such as fentanyl in the range of 50 to 100 µg/kg. Early tracheal extubation and the fast-track clinical care pathways are an acceptable approach to reduce the cost of CABG surgery and possibly improve the physiologic status of the patient. Anesthetic techniques using smaller doses of opioids are a safe and effective method of decreasing costs (1,2). Anesthesia management has reduced fentanyl to less than 15 to 20 µg/kg to achieve so-called "early" tracheal extubation. A concern of this approach is increased responsiveness to surgical stimulation and hemodynamic instability. Remifentanil is an ultrashort-acting fentanyl analog with a context sensitive half-time of 3 min (3–7). Initial studies have shown that remifentanil effectively attenuates the pressor responses to intubation, skin incision, and throughout surgery when given as a bolus followed by a continuous infusion (8–10). Remifentanil given in combination with propofol reliably provides excellent conditions for tracheal intubation without the use of muscle relaxants and permits rapid return to spontaneous ventilation within 3–7 min (11). However, Wang et al. (12) have shown that remifentanil in combination with sevoflurane can cause severe bradycardia before intubation. Other studies have demonstrated the utility of remifentanil in total IV anesthesia (13–19) and for postoperative analgesia (20–22). The use of remifentanil during cardiac surgery would allow for a traditional large dose of opioid to be administered to suppress hemodynamic and stress response to surgery without compromising early tracheal extubation postoperatively (23).

Our purpose for this study was to compare in a randomized, double-blinded manner the intraoperative anesthetic and hemodynamic stability, perioperative stress hormone levels, and time to extubation and transfer to less intensive postoperative monitoring after anesthesia with either a typical fentanyl/isoflurane/propofol regimen or a remifentanil/isoflurane/propofol regimen. We hypothesized that under this protocol there would be no difference between the fentanyl/isoflurane/propofol regimen and the remifentanil/isoflurane/propofol regimen.

	Methods

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Institutional Human Subjects Review Committee approval and written informed consent were obtained at all 16 sites. Only patients scheduled for elective CABG surgery with an ASA physical status of III-IV were included in this study. Patients were excluded for severe obesity (defined as ideal body weight + 50%), substance abuses, mental impairment, or if they were prisoners or children. All premenopausal women, not surgically sterile, had a serum pregnancy test performed, and negative results were documented, within 24 h preceding surgery.

On the morning of surgery, patients received their regular medications except antiplatelet drugs 60–90 min before catheterization and monitor placement. Each patient was preoperatively sedated with 1–3 mg of midazolam IV and 0.05 mg/kg morphine IV immediately before catheterization and monitor placement. An additional 1–2 mg of midazolam IV, to a maximum of 5 mg, could be given during placement of radial and pulmonary artery catheters. After breathing FIO₂ 1.0 for 3 min, anesthesia was induced with 0.5 mg/kg propofol IV given over 1 min. Additional boluses of 10 mg of propofol IV were given every 30 s if needed until loss of consciousness, at which time a bolus of 0.2 mg/kg cisatracurium (0.15 mg/kg vecuronium at Canadian sites) was given. Patients were prospectively randomized by the hospital pharmacy by using a computer-generated randomization block-of-four design to receive either a bolus of fentanyl without subsequent opioid infusion or a bolus of remifentanil followed by a remifentanil infusion at a specific infusion rate for each patient in a double-blinded manner. After a bolus of 1 µg/kg remifentanil or 10 µg/kg fentanyl given over 3 min, patients received either 1 µg · kg^-1 · min^-1 of remifentanil or normal saline given as a blinded placebo, respectively. Endotracheal intubation was performed 6 min after administration of the opioid induction bolus. The patient’s lungs were ventilated with 100% oxygen to achieve a PCO₂ of 35 ± 5 mm Hg. Isoflurane was then started at a concentration of 0.5% end-tidal to maintain anesthesia.

During the 24 h before surgery, a baseline 12-lead electrocardiogram (ECG) recording was obtained. ST segment changes were monitored perioperatively by a dedicated observer. Postoperatively at 24 h after surgery and just before hospital discharge, additional 12-lead ECG recordings were performed. Patients were monitored continuously for signs of light anesthesia. Indications of light anesthesia were considered a heart rate >90 bpm for 1 min before cardiopulmonary bypass or a nonpaced heart rate of >100 bpm for 1 min after cardiopulmonary bypass; or a systolic blood pressure 15 mm Hg above baseline values before cardiopulmonary bypass, a mean arterial blood pressure >80 mm Hg during cardiopulmonary bypass, or a systolic blood pressure >140 mm Hg after cardiopulmonary bypass. At signs of light anesthesia, a blinded bolus syringe of 1 µg/kg remifentanil or 2 µg/kg fentanyl was given with a simultaneous increase in maintenance infusion of 0.5 to 1.0 µg · kg^-1 · min^-1 remifentanil or normal saline up to a maximal infusion rate of 4 µg · kg^-1 · min^-1. If a response was not controlled within 5 min of making a maintenance adjustment, or if the maintenance infusion rate was already at the maximum rate, the concomitant end-tidal concentration of isoflurane could be increased in increments of 0.5% for a maximum of 5 min. However, if signs of light anesthesia persisted, nitroglycerine or a ß-blocker was given. When patients achieved a stable, nonresponding status, isoflurane was reduced but the maintenance infusion of opioid was kept at the increased rate unless hypotension occurred. During maintenance of anesthesia, boluses of 0.2 mg/kg cisatracurium (0.15 mg/kg vecuronium at Canadian sites) were given as needed.

We defined a hypertensive response before and after cardiopulmonary bypass as systolic blood pressure >15 mm Hg over baseline or >140 mm Hg for more than 1 min. During bypass, an arterial pressure >80 mm Hg was considered a hypertensive response. Hypotension and bradycardia before and after cardiopulmonary bypass were treated if systolic blood pressure was <80 mm Hg for 1 min or if heart rate was <40 bpm for 1 min. First, the end-tidal isoflurane concentration was decreased by 0.5%, then the maintenance opioid infusion rate was decreased 0.5 to 1.0 µg · kg^-1 · min^-1 down to a minimum of 0.125 µg · kg^-1 · min^-1. If the hypotension or bradycardia did not respond to these changes, phenylephrine, ephedrine, glycopyrrolate, or atropine was given as clinically indicated. When patients achieved hemodynamic stability, the maintenance infusion rate could be increased, with accompanying bolus injections, up to the maximal infusion rate either prophylacti-cally or to treat responses. During cardiopulmonary bypass just after rewarming, a propofol infusion of 2 mg · kg^-1 · h^-1 was started and isoflurane was discontinued. Just before the end of surgery, the maintenance infusion rate was set to 1.0 µg · kg^-1 · min^-1 for the remifentanil regimen or an equal volume of normal saline for the fentanyl regimen.

During preoperative sedation, blood samples (15 mL) were collected for baseline arterial blood gas analyses, catecholamine (epinephrine and norepinephrine), and CPK-MB (creatine phosphokinase cardiac isoenzyme) levels. Ten minutes after the time of maximum sternal spread, a blood sample was taken for the analysis of epinephrine and norepinephrine concentrations. Additional catecholamine concentrations were measured 1 h and 8 h after the release of the aortic cross-clamp. CPK-MB concentration was measured 1, 8, 16, 24, and 48 h after release of the aortic cross-clamp.

After admission into the intensive care unit (ICU), the propofol infusion rate was reduced to 0.5 mg · kg^-1 · h^-1 and then titrated as needed for adequate sedation. A standardized method of weaning from ventilation and tracheal extubation was used. The extubation sequence began when the following criteria were met: normothermic (rewarmed and shivering controlled), hemodynamically stable and no uncontrolled arrhythmias, no excessive bleeding (as defined by institutional standards), and with adequate urine output (0.5 mL · kg^-1 · h^-1). Residual neuromuscular blockade was reversed if necessary. Ketorolac, 30 mg IV, was given unless urine output was <0.5 mL · kg^-1 · h^-1. Thirty minutes later, a double-blinded fentanyl bolus (2 µg/kg fentanyl to remifentanil subjects or 1 µg/kg fentanyl to fentanyl subjects) was given. Ten to 15 min later, the propofol infusion was stopped and the maintenance infusion rate of the study drug was decreased by 50% followed by a maintenance infusion decrease of 50% every 10 min for 2 or 3 intervals and then discontinued. Concurrently with decreases in maintenance infusion, patients were weaned from the ventilator and assessed for vital signs, pain scores, and sedation. If additional sedation was needed, the propofol infusion was restarted and titrated to the minimal effective dose. No midazolam was given during the patient’s stay in the ICU; however, if additional analgesia was needed after patients began the extubation sequence then unblinded morphine or fentanyl could be given. Propofol was again discontinued when a stable, nonresponding status was achieved. Patients who did not meet extubation sequence criteria within 4.5 h after entry into the ICU were started on the sequence as described above unless otherwise contraindicated. Subjects who failed to meet the criteria within 4.5 h because of inadequate urine output were not given ketorolac.

Extubation could take place at any time during or after the downward titration of the maintenance solution as soon as the following criteria were met: adequate mental status (follows commands), adequate SpO₂ (95% at FIO₂ 0.5%), respiratory effort adequate to maintain oxygenation, adequate pH (7.25 to 7.3), and adequate PaCO₂ (55 mm Hg). For patients who were unable to meet these criteria by 6 h after entry into the ICU, the maintenance infusion was titrated down and off and alternative analgesia and sedation were started. Patients were eligible to transfer out of the ICU when the following criteria were met: adequate SpO₂ (90% at FIO₂ 0.5% by face mask), adequate cardiac stability (no uncontrolled arrhythmias), no IV inotropes or vasopressors (however, dopamine 2–3 µg · kg^-1 · min^-1 was allowed), nominal chest-tube drainage (<50 mL/hr for 2 h), no seizure activity, and adequate urine output (>0.5 mL · kg^-1 · h^-1). The criteria for eligibility for hospital discharge were hemodynamic and cardiac rhythm stability, incisions clean and dry, afebrile, able to void and move bowels, and independently ambulating and feeding.

Data were collected from the multiple centers, and two-sided statistical tests were performed by using the Statistical Analysis System (SAS version 6.08; SAS, Cary, NC) software. Bonferroni correction was applied to the significance level for multiple comparisons. Cox proportional hazard modeling controlling for sites was used to analyze recovery times. Responses to surgical stimuli were analyzed by logistic repression analysis. Fisher’s exact test was used to analyze dichotomous data when logistic regression did not converge. The analysis of variance technique, adjusting for sites and baseline, was used to compare normally distributed continuous response variables. The sample size of 150 subjects per treatment group gave 80% power to detect a treatment difference of 17% at the 0.05 significance level for the hemodynamic variable heart rate. Other hemodynamic variables could detect smaller treatment differences; however, for the variable catecholamines and CPK-MB, treatment differences of 50% could be detected at the 0.05 significance level with 80% power.

	Results

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The recruitment of study subjects resulted in similar distributions of remifentanil or fentanyl protocols at each research site [principal investigator of Remifentanil subjects/Fentanyl subjects: Bowdle, 8:4; Fitch, 6:5; Haddow, 13:14; Hillel, 10:10; Hogue, 12:11; Howie, 27:24; McCoy, 16:15; Newman, 17:15; Nielsen, 7:5; Pierce, 17:12; Siegel, 4:3; Thielmeier, 1:0; Cheng, 21:17; Duke, 10:9; Finegan, 15:13; anonymous, 17:11]. The Remifentanil (n = 150) and Fentanyl (n = 154) groups were similar in all demographic variables, medical history, and chronic cardiac medication data, as listed in Table 1. The two groups had similar durations of surgery, cardiopulmonary bypass, cross-clamp, and duration of anesthesia. There was no significant difference between study groups for the number of patients with perioperative ST segment changes indicating ischemia (Remifentanil 12:150; Fentanyl 12:154). When compared with preoperative ECG recordings, there were no significant differences between study groups for the number of patients with new postoperative ST-T abnormalities (Remifentanil 117:142; Fentanyl 124:145), or for new postoperative Q-waves (Remifentanil 10:142; Fentanyl 9:145), or for new postoperative bundle branch blocks (Remifentanil 8:142; Fentanyl 4:145). Perioperative systolic arterial pressure, mean arterial pressure, and heart rate are displayed in Figure 1. There were no clinically significant hemodynamic differences between study groups.

View larger version (43K): [in this window] [in a new window]   Figure 1. Hemodynamic profiles. Display of the mean arterial pressure (MAP), systolic arterial pressure (SAP), and heart rate during various events. Values are shown as means with standard deviations. Events shown with a plus or minus symbol and a number represent that number of minutes after (+) or before (-) that event occurred. The asterisk indicates a statistically significant difference in systolic arterial pressure between fentanyl- and remifentanil-regimen patients that was not clinically significant. Intub = intubation, stern spread = maximum sternal spread, aortic cann = aortic cannulation, aortic decan =aortic decannulation, stern wire = placement of wires in the sternum, closure = when the chest is closed, ICU = intensive care unit, transition = change to less intensive patient monitoring, decrease = reduction in maintenance infusion rate, infuse = infusion, extub = extubation.

	Discussion

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Before extubation, there was an increase in blood pressure between the first decrease in remifentanil infusion and the discontinuation of the remifentanil infusion (Fig. 1). Even with remifentanil’s rapid offset of effects, the remifentanil-based anesthetic as used in this investigation (which includes a fentanyl bolus of 2 µg/kg) did not allow this increase in blood pressure to become significantly more than the blood pressure of the fentanyl-regimen patients. The use of a propofol infusion starting at the end of cardiopulmonary bypass may have masked the potential advantages of remifentanil’s rapid offset. The remifentanil-based anesthetic, as used in this investigation, did not result in any adverse responses, chest-wall rigidity, or problems related to rapid offset of its effects when infusion was discontinued. Furthermore, there are many factors other than drugs that affect timing of extubation and ICU discharge. Traditional clinical practices at the various institutions may have tended to standardize timing of the extubation sequence independent of patient condition.

A major limitation of this study is the comparison of a continuous infusion of remifentanil with boluses of fentanyl. A computer simulation of the remifentanil regimen used in this investigation based on the pharmacokinetic variables of Minto et al. (25), predicted a remifentanil blood concentration of approximately 29 ng/mL. A computer simulation of the fentanyl regimen used in this investigation based on the pharmacokinetic parameters of Shafer et al. (26) predicted plasma concentrations ranging from approximately 4 ng/mL at the troughs of the bolus doses, to 2 ng/mL at the end of the intraoperative period. The concentration of remifentanil in blood that produces a half-maximal effect on the electroencephalogram (EC₅₀) is approximately 20 ng/mL, according to Egan et al. (27). Thus, the concentration of remifentanil expected in this study was about 50% larger than the EC₅₀. The EC₅₀ for fentanyl is 6.9 ng/mL, according Scott et al. (28) and the concentration of fentanyl expected in this study (2–4 ng/mL) was therefore considerably smaller than the EC₅₀. This analysis based on simulation suggests that the dosing regimens for remifentanil and fentanyl in this study were not equipotent. Fentanyl has a large peripheral compartment and a slow clearance. As the plasma concentration of fentanyl decreases below that in the peripheral compartment, the latter will then act as a "reservoir," releasing drug slowly back into the plasma concentration, prolonging the elimination half-life and continuing to provide analgesia in the ICU setting. Although our study was designed to reflect actual clinical practice, another limitation of the study was the comparison of a bolus followed by a continuous infusion (remifentanil regimen) to an initial bolus with a continuous infusion of a placebo (fentanyl regimen). A more equivalent comparison would have been achieved by adding a fentanyl infusion of 2.5 µg · kg^-1 · h^-1 or giving intermittent boluses in similar amounts just before skin incision, sternotomy, and aortic cannulation. In our study, the fentanyl-regimen patients were treated with a 2 µg/kg bolus of fentanyl at any signs of light anesthesia. It could be predicted that the placebo-infusion patients (fentanyl regimen) would require an anesthetic intervention with a 2 µg/kg bolus of fentanyl at the time of skin incision and in response to maximum sternal spread. Therefore, our results that fentanyl-regimen patients required significantly more anesthetic interventions than the remifentanil-regimen patients is probably a result of our study design.

In conclusion, we were able to demonstrate a remifentanil regimen with hemodynamic stability and recovery comparable to that of small-dose fentanyl. A remifentanil-based anesthetic, as used in this investigation, provided safe and effective conditions in patients undergoing CABG and early extubation.

	Acknowledgments

 
Supported in part by Glaxo Wellcome.

The authors gratefully acknowledge the assistance of numerous physicians and nurses whose assistance made this study possible. The authors specifically acknowledge the coinvestigators Drs. Patrick McCoy, Barry Finegan, Gordon R. Haddow, Peter Duke, Vance Nielsen, Jane C. K. Fitch, Lawrence Siegal, and Kenneth Thielmeier. Additionally, the authors thank researchers Christine Doe (Boston University Medical Center) and Thomas D. McSweeney (Ohio State University Medical Center).

	References

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