Anesth Analg 2000;91:1269-1273
© 2000 International Anesthesia Research Society
GENERAL ARTICLES
A Comparison of Remifentanil and Sufentanil as Adjuvants During Sevoflurane Anesthesia with Epidural Analgesia for Upper Abdominal Surgery: Effects on Postoperative Recovery and Respiratory Function
Andrea Casati, MD,
Andrea Albertin, MD,
Guido Fanelli, MD,
Francesco Deni, MD,
Marco Berti, MD,
Giorgio Danelli, MD,
Federica Grifoni, MD, and
Giorgio Torri, MD
Department of Anesthesiology, University of Milan, IRCCS H. San Raffaele, Milan, Italy
Address correspondence and reprint requests to Andrea Casati, MD, Department of Anesthesiology, IRCCS H San Raffaele, Via Olgettina 60, 20132 Milan, Italy. Address e-mail to casati.andrea @hsr.it.
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Abstract
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We compared the recovery profile and postoperative SpO2 after the administration of general anesthesia with either sevoflurane-remifentanil or sevoflurane-sufentanil in 30 healthy patients undergoing upper abdominal surgery. They were randomly allocated to receive general anesthesia with sevoflurane and small doses of either remifentanil (n = 15) or sufentanil (n = 15), followed by postoperative epidural analgesia. The median sevoflurane minimum alveolar anesthetic concentration-hour was 2.3 (1.2–6.3) in group Remifentanil and 2.6 (1.4–5.2) in group Sufentanil (P = 0.39), while the median consumption of remifentanil was 1.3 mg (0.7–3.4 mg) and sufentanil 0.09 mg (0.05–0.6 mg). Tracheal extubation required 10 min (6–18 min) with remifentanil and 14 min (8–24 min) with sufentanil (P = 0.05); however, no differences in time to discharge from the recovery area were reported (24 min [12–75 min] with remifentanil and 30 min [12–135 min] with sufentanil; P = 0.35). From the first to seventh hour after surgery, SpO2 was decreased more in the sufentanil than in the remifentanil group (P = 0.001), and seven patients in the sufentanil group showed at least one episode with SpO2 
90% for more than 1 min (P = 0.006) (median: 1 episode; range: 0–17 episodes; P = 0.003). When added to sevoflurane, remifentanil is as effective as sufentanil during the intraoperative period, but provides shorter time to tracheal extubation and fewer effects on postoperative SpO2 in the first 7 h after surgery.
Implications: In this double-blinded study, we evaluated the effects of adding small infusions of either remifentanil or sufentanil to sevoflurane in combination with postoperative epidural analgesia for upper abdominal surgery. We demonstrated that remifentanil is as effective as sufentanil during the intraoperative period, but that it provides shorter time to extubation and fewer effects on postoperative SpO2 in the first 7 h after surgery.
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Introduction
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Remifentanil is a potent µ opioid receptor agonist providing intense analgesia of rapid onset and very short duration (1). The pharmacokinetic and pharmacodynamic properties of remifentanil, as well as its propensity not to accumulate in human tissues, could make it advantageous for surgical anesthesia in procedures of intermediate-long duration. Few data are available comparing intraoperative and postoperative effects of remifentanil during general anesthesia with those of other opioids after upper abdominal surgery. The aim of this prospective, randomized, double-blinded study was to compare the effects on intraoperative cardiovascular homeostasis, recovery profile, and postoperative SpO2 after sevoflurane anesthesia with small doses of either remifentanil or sufentanil in combination with postoperative epidural analgesia.
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Methods
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With ethics committee approval and patients’ written, informed consent, 30 ASA physical status I and II patients scheduled for elective upper abdominal surgery (including gastrectomy, pancreaticoduodenectomy, and hepatic resections) under general anesthesia, were prospectively enrolled. Patients older than 70 yr, with relevant cardiovascular or respiratory diseases, as well as those with contraindications to epidural catheter placement were excluded. After arrival in the operating theater, an 18-gauge IV catheter was inserted, and 0.05 mg/kg midazolam IV was given, followed by 10 mL/kg lactated Ringer’s solution. Then, an epidural catheter was placed at the T8-9 or T9-10 interspaces, while 40 mg of 2% plain lidocaine was injected to exclude intrathecal placement of the epidural catheter.
Standard monitoring was used throughout the study. After baseline measurements, by using a sealed envelope technique, patients were randomly allocated to receive sevoflurane general anesthesia with the combination of small doses of remifentanil (Remifentanil group, n = 15) or sufentanil (Sufentanil group, n = 15). Syringes containing aqueous solution of remifentanil (50 µg/mL) or sufentanil (5 µg/mL) were prepared in a double-blinded fashion by one of the authors not involved in data recording. In both groups, the initial dose was infused for a 60-s period and followed by a continuous IV infusion. Remifentanil group patients received a 1-µg/kg bolus followed by a 0.15-µg · kg-1 · min-1 infusion; while Sufentanil group patients received a 0.1-µg/kg initial dose followed by a 0.01-µg · kg-1 · min-1 infusion. The pump infusing the study drug was activated by the investigator preparing the syringes who was not involved in data recording, while the blinded observer remained unaware of when the initial dose infusion started. The start time for infusing the initial dose was 5 min before the induction in the Sufentanil group, and 1 min before the induction in the Remifentanil group, according to the time to peak effect of the two drugs.
General anesthesia was induced with propofol (2 mg/kg) and atracurium (0.5-mg/kg bolus followed by a 0.5-mg · kg-1 · h-1 continuous infusion) to facilitate tracheal intubation. Then, the lungs were mechanically ventilated by using a 60% nitrous oxide in oxygen mixture. An 8-mL · kg-1 · h-1 IV infusion of lactated Ringer’s solution was given throughout surgery, while 3 mL of the same solution was infused for every 1 mL of blood loss; allogenic red blood cells were given to compensate for blood losses exceeding 20% of circulating blood volume. During the procedure, systolic arterial blood pressure was maintained within ±20% of baseline values by adjusting the end-tidal concentrations of sevoflurane within the range of 0.6%–1.2%. If this proved to be ineffective, the infusion rate of the study drug was increased or decreased by steps of 25% of the initial infusion rate. When the infusion rate had to be increased, an initial dose was also infused for 30 s (0.25 µg/kg in the Remifentanil group and 0.025 µg/kg in the Sufentanil group).
The hemodynamic variables, as well as the actual infusion rate of the study drug, end-tidal concentration of sevoflurane and carbon dioxide, and SpO2 were recorded every 15 min until the end of surgery. Thirty minutes before the end of surgery, the atracurium infusion was stopped while the syringe containing the study drug was changed in a double-blinded fashion: in the Remifentanil group, the second syringe was still filled with remifentanil at the same concentration, whereas in the Sufentanil group, the second syringe was filled with normal saline. At the same time, a 10-mL epidural bolus of 1% lidocaine was given to prevent postoperative pain (divided in 3- to 4-mL doses every 10 min). After the last skin suture (end of surgery), both inhaled drugs and the study drug infusion were discontinued, and residual neuromuscular block antagonized with prostigmine (2 mg IV) and atropine (1 mg IV), while the lungs were manually ventilated with 100% oxygen until spontaneous ventilation resumed. Extubation was performed when the patient was judged to be awake (making purposeful movements), breathing regularly, with adequate oxygenation (SpO2 > 92% when breathing room air). Patients were considered eligible to be discharged from the postanesthesia care unit when showing a modified Aldrete score (2) 
9, having stable vital signs and adequate airway, and being alert and responsive with pain and nausea controlled (3). Times from discontinuation of the inhaled drug to extubation (extubation time), opening eyes on verbal commands (emergence time), squeezing the observer’s hand on command (response time), and being judged suitable for discharge from the recovery area (discharge time) were also recorded.
The anesthetic exposure (minimum alveolar anesthetic concentration [MAC]-hour) was calculated based on the area under the end-tidal anesthetic concentration versus time curve, taking into account the use of a 60% N2O in oxygen mixture (4).
Postoperative analgesia consisted of 100 mg IV ketoprofen every 8 h and patient-controlled epidural analgesia by using a standard PCA pump (CADD-PCA; Deltec, St. Paul, MN). The patient-controlled epidural analgesia infusion was initially set to deliver 4 mL/h of 0.2% ropivacaine, with 1.5-mL incremental doses and a 20-min lockout time. The degree of pain was assessed during coughing by using a four-point Verbal Rating Scale (0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain) when patients were discharged from the recovery area, and then 1, 3, 6, and 12 h after the end of surgery. If analgesia was inadequate (Verbal Rating Score > 2), the background infusion rate was increased to 6 mL/h while the epidural catheter was tested with 5 mL of 1% lidocaine, to ensure correct placement.
After patients had been discharged to the surgical ward, SpO2 was continuously recorded during the first 12 h after surgery (Oxypac Station; Dräger, Lubeck, Germany) while patients were spontaneously breathing room air. Heart rate, SpO2, and time of the day were stored every 30 s in the memory of the pulse oximeter and transferred at the end of the day to a personal computer (5,6). Data for the first and last 3 min of monitoring were excluded to eliminate artifacts resulting from positioning and removal of the probe. Episodes of SpO2 90% were classified as hypoxemia or artifact. A single datum point differing by more than 4% from the surrounding data, as well as loss of signal (as indicated by the pulse oximeter), occurring immediately before or after the episode of low SpO2, were considered artifacts. To further increase the detection of artifacts, all other episodes of SpO2 < 90% were inspected visually by one author blinded for the group from which the data originated: if there were jitters of SpO2 and heart rate, a movement artifact was suspected. After artifacts had been excluded, SpO2 changes over time were analyzed in each patient by using an Excel 5.0 worksheet (Microsoft, Redmond, WA). Because it has been demonstrated that episodes of SpO2 < 90% for more than 1 min are likely to be associated with a clinically relevant decrease in the PaO2 (7), we considered a minor respiratory complication a SpO2 decrease < 90% for more than three consecutive measurements. A decrease in respiratory rate < 10 bpm, together with deep sedation and hypoxia, was considered a major respiratory complication and was treated with naloxone IV. Minor respiratory complications not resolved by simple verbal stimulation of the patient were treated with a 30-min supplemental oxygen therapy by face mask, and the need for oxygen therapy was recorded. In each patient, the mean SpO2 values per hour were also calculated from the patient worksheet. When nausea occurred, metoclopramide 10 mg IV was given, and the need for antiemetic drug was recorded.
Statistical analysis was performed by using the program Systat 7.0 (SPSS Inc, Chicago, IL). The Mann-Whitney U-test was used to compare continuous variables. A two-way analysis of variance for repeated measures was used to analyze changes over time. Ordinal data were analyzed by using the contingency table analysis with Fisher’s exact test. Continuous variables were presented as median (range) unless otherwise indicated, whereas ordinal data were presented as number (%). A value of P 0.05 was considered significant.
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Results
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The two studied groups were similar with respect to age, height, weight, sex, smoking, type and duration of surgery, and sevoflurane’s MAC-hour (Table 1). No severe adverse events, including bradycardia, hypotension, chest wall rigidity, or other opioid-related untoward events were reported in studied patients. No differences in hemodynamic variables were reported intraoperatively between the two groups. The median consumption of remifentanil throughout the study was 1.3 mg (0.7–3.4 mg) whereas the Sufentanil group patients received a median dose of 0.09 mg (0.05–0.6 mg) of the study drug. No differences in blood loss, total diuresis, and volume of crystalloid infusion during surgery were observed between the two groups.
Tracheal extubation required 10 min (6–18 min) with remifentanil and 14 min (8–24 min) with sufentanil (P = 0.05), whereas no differences were observed between the two groups in emergence time (9 min [3–16 min] with remifentanil versus 10 min [5–21 min] with sufentanil; P = 0.27), response time (15 min [8–30 min] with remifentanil versus 18 min [7–40 min] with sufentanil; P = 0.67), and discharge time (24 min [12–75 min] with remifentanil versus 30 min [12–135 min] with sufentanil; P = 0.35).
Similar pain relief was reported during coughing in the two studied groups at discharge from the recovery area and during the following study period (Figure 1). Four patients in the Remifentanil group (26%) and one patient in the Sufentanil group (7%) required an epidural bolus of 1% lidocaine to test the correct placement of the epidural catheter (P = 0.33). Three patients in the Sufentanil group (20%) and one patient in the Remifentanil group (7%) required metoclopramide administration because of nausea (P = 0.59).
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Figure 1. Dynamic pain measured during coughing by using a four-point verbal rating score at discharge from the recovery room, and then at 1, 3, 6, and 12 h after the end of surgery in patients receiving either remifentanil (n = 15) or sufentanil (n = 15) as adjuvants during sevoflurane anesthesia combined with postoperative epidural analgesia.
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No patients showed a decrease in respiratory rate < 10 bpm together with deep sedation and hypoxia requiring naloxone administration during the study. Face mask oxygen therapy was required in four Sufentanil group patients (P = 0.10) only; whereas seven patients in the same group showed at least one minor respiratory complication (SpO2 < 90% for more than 1 min) (P = 0.006), with a median of 1 (range 0–17) episode per patient compared with no episodes in the Remifentanil group (P = 0.003). From the first to seventh hour after admission to the surgical ward, Sufentanil group patients showed SpO2 values less than patients receiving sevoflurane-remifentanil anesthesia (P = 0.001) (Figure 2).
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Figure 2. Peripheral SpO2 measured during the first 12 h after surgery in patients receiving either remifentanil (n = 15) or sufentanil (n = 15) as adjuvants during sevoflurane anesthesia combined with postoperative epidural analgesia. Results are presented as mean (± SD). *P < 0.01 and **P < 0.001 compared with the sufentanil group.
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Discussion
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Opioid drugs are widely used as a part of a general anesthetic technique, and various studies have demonstrated that remifentanil may be administered during general anesthesia in doses that would be impractical or hazardous with other fentanyl derivatives (8–10) because of the high risk for postoperative respiratory depression. In this randomized, double-blinded study, very small infusions of either remifentanil or sufentanil were used as adjuvants during sevoflurane anesthesia; nonetheless, patients receiving the remifentanil infusion during surgery showed fewer respiratory complications during the first 12 hours after surgery, with higher SpO2 values than patients receiving continuous sufentanil infusion.
No differences in sevoflurane’s MAC-hour were observed between the two groups, whereas the ratio between remifentanil and sufentanil consumption approximated the equipotency ratio, according to their ability in reducing the MAC of a volatile anesthetic (1,11). The different pharmacokinetic profile of the two studied opioids is probably responsible for the observed differences, because remifentanil has a very rapid onset and offset of action (12), whereas a longer disappearance half-time can be expected with sufentanil (12,13).
A minor shortcoming of this study is that the opioid infusion rate was changed only after the end-tidal concentration of sevoflurane had been adjusted within a designed range. Maintaining a fixed sevoflurane concentration and adjusting only the opioid infusion rate could have provided more information about the equianalgesic ratio of the two opioids. However, no difference in sevoflurane’s MAC-hour was observed between the two groups, although using fixed concentrations of sevoflurane might result in opioid overdosing with increased respiratory effects in those patients receiving sufentanil. This was judged not ethical because patients were directly discharged from the recovery area to the surgical ward.
Hypoxemia is a potentially serious postoperative complication that can be caused by hypoventilation, pulmonary shunt, and central nervous system depression after the administration of general anesthesia. Up to 55% of patients develop one or more episodes of hypoxemia postoperatively, while the main risk factors were the duration of anesthesia, age, and smoking (14). In this study, the incidence of minor respiratory complication was less frequent than that reported in other studies, perhaps because of the strict selection of studied patients, who were substantially healthy, adult patients. However, no differences in surgical procedure, smoking habits, age distribution, or duration of surgery were observed between the two groups.
Sufentanil provides a more rapid emergence (15) and less postoperative respiratory depression than fentanyl (16), with greater intraoperative hemodynamic stability (17). Results of the present investigation demonstrated that remifentanil and sufentanil provide similar hemodynamic stability during surgery.
The rapid offset of action of remifentanil is also associated with a rapid disappearance of analgesia (11,12), but this is not desirable when postoperative pain is anticipated. At our institution, epidural analgesia is routinely provided after upper abdominal surgery (18), and it must be considered an essential part of the anesthetic technique in the present study (especially in those patients receiving remifentanil). Theoretically, however, complete inhibition of painful stimulation with epidural analgesia might have contributed in emphasizing the delay in tracheal extubation as well as the decrease in postoperative oxygenation in those patients receiving sufentanil. Nonetheless, physicians must plan and implement pain management before the end of the procedure when remifentanil is used during surgery (19). Using epidural analgesia with nonsteroidal antiinflammatory drugs administration starting from before the end of surgery provided adequate pain relief, without pain-related adverse events or delay in patient discharge from the recovery area as compared with patients receiving a longer-acting opioid during surgery.
In conclusion, few data were available comparing intra- and postoperative effects of small infusions of either remifentanil or sufentanil as adjuvants during sevoflurane anesthesia combined with postoperative epidural analgesia for upper abdominal surgery. This prospective, randomized, double-blinded study demonstrated that remifentanil is as effective as sufentanil during the intraoperative period, but that it provides a shorter time to extubation and fewer effects on postoperative SpO2 in the first seven hours after surgery.
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Acknowledgments
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The authors thank the staff of anesthesia nurses (University Dept. of Anesthesiology, IRCCS San Raffaele Hospital) without whose help and cooperation this study would not have been possible.
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Accepted for publication July 3, 2000.
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Abstract
Introduction
