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Department of Anesthesiology, Upstate Medical University, Syracuse, NY
Address correspondence and reprint requests to Richard A. Beers, MD, Department of Anesthesiology, Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210. Address e-mail to beersr{at}mail.hscsyr.edu
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Abstract |
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Implications: As an opioid adjuvant to general anesthesia for outpatient gynecologic laparoscopy and hysteroscopy, the benefits of remifentanil did not offset its added cost as compared with fentanyl.
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Introduction |
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As a result of its high pharmacy acquisition cost, one 2-mg vial of remifentanil is more than 60 times more costly than a 5-mL ampule of fentanyl. However, the additional cost of remifentanil may be justified by improved outcome and/or savings derived from reduced dosage of other perioperative drugs. Factors such as these must be considered when estimating the cost-effectiveness of newer anesthetic drugs (1).
Davis et al. (2) compared intraoperative characteristics and recovery profile of fentanyl versus remifentanil-based general anesthesia for pediatric outpatient tonsillectomy and adenoidectomy. Remifentanil patients were tracheally extubated sooner; however, postanesthesia care unit (PACU) and home discharge times were similar, and remifentanil patients had an increased incidence of postoperative pain.
We compared intraoperative adverse events, postoperative sequelae, recovery times, patient and provider satisfaction, and perioperative drug dosage between patients who received either fentanyl or remifentanil as an opioid adjuvant to general anesthesia for outpatient gynecologic laparoscopy or hysteroscopy. We hypothesized that remifentanil’s added direct cost compared with fentanyl would be offset by cost savings derived from improved outcome and reduced perioperative drug dosage.
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Methods |
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18 yr old and undergoing gynecologic laparoscopic (n = 26) or hysteroscopic (n = 8) procedures. Patients who had a history of substance abuse within the last year, who were taking opioid analgesics within the last 6 wk, who were unable to communicate effectively in English, whose weight exceeded 150% of their calculated ideal body weight, and who were allergic to any study protocol medication were excluded. All patients received midazolam 2 mg IV and the Bispectral (BIS) electroencephalographic sensor was applied before transport to the operating room.
Thirty-four patients were randomly assigned to either a standard practice or a study group. Baseline measurements were taken and each patient was preoxygenated. Glycopyrrolate 0.2 mg IV was given. In the standard practice group (n = 18), fentanyl 3 µg/kg was administered at least 3 min before the induction of anesthesia. D-tubocurare was given 90 s before induction. Propofol 1.5 mg/kg and succinylcholine 1.5 mg/kg were given at induction. In the study group (n = 16), a remifentanil 0.5 µg · kg · min-1 infusion was begun concomitant to the administration of propofol. 4% lidocaine (2.5 mL) was applied by using a laryngotracheal applicator, and the patient was intubated immediately after lidocaine application. Anesthesia was maintained with sevoflurane vapor and nitrous oxide 50% in oxygen at a total gas flow rate of 3 L/min. This point was defined as the start of the "maintenance period." The initial sevoflurane vaporizer settings were 2% in the standard practice group and 0.5% in the study group. The remifentanil infusion was decreased to 0.2 µg · kg · min-1 immediately after confirmation of endotracheal tube position. No subsequent muscle relaxants were administered.
The BIS index was monitored continuously and recorded every 5 min. The inspired concentration of sevoflurane was titrated to maintain the BIS index at 45–55. If the BIS score was above or below this range, then the sevoflurane concentration delivered was adjusted accordingly in increments of 25% of the inspired setting. Intraoperative adverse events were predefined, and their corresponding treatment was prescribed in written guidelines. Treatment beyond the guidelines was left to the discretion of the anesthesiologist.
Approximately 20 min before the estimated completion of the procedure, the inspired sevoflurane concentration was titrated to a BIS index of 55–65. At this time, ondansetron 4 mg and ketorolac 30 mg IV were administered for postoperative nausea and vomiting (PONV) prophylaxis and postoperative analgesia, respectively. In the standard practice group, no additional opioid analgesics were given, whereas fentanyl 25 µg IV and 75 µg IM was administered for postoperative analgesia in the study group.
Immediately after the last skin suture was placed, the remifentanil infusion was discontinued. In both groups, the inhaled anesthetics were discontinued after dressing application and 100% oxygen was administered at 6 L/min until the patient opened eyes on command. The patient was then extubated and transported to the PACU.
Immediately after the patient arrived in the PACU, a blinded nurse investigator (B.E.E.) observed the patient until discharge to home. When awake and oriented, the patient’s pain and nausea visual analog scale (VAS) scores were assessed every 5 min. VAS scores ranged from 0 = "least imaginable" to 10 = "worst imaginable." If the response was 4, then analgesia (fentanyl 25 µg IV at 5-min intervals) was administered until a subsequent VAS pain score was <4.0. Emesis, retching, or a nausea score 4.0 was treated with metoclopramide 10 mg IV. After 15 min, subsequent emesis, retching, or nausea score >4.0 was treated with ondansetron 4 mg IV.
The patient was assessed at 5-min intervals for PACU discharge eligibility by using White’s fast-tracking criteria (3). Based on the modified Aldrete score (4), White’s criteria include evaluation of the degree of pain, nausea, and vomiting. The patient was deemed eligible for PACU discharge when the fast-track score was 14/14.
After PACU discharge, pain and nausea VAS scores and home discharge eligibility were assessed every 30 min. Criteria for home discharge, based on Chung’s (5) scoring system, were: 1) vital signs within 20% of preoperative value; 2) oriented to person, place, and time; 3) steady ambulation without assistance; 4) pain and nausea VAS < 4 and no emetic symptoms; 5) minimal surgical bleeding; 6) ability to void demonstrated.
Recovery times from emergence to home discharge and to achieve predefined recovery milestones (first oral fluid intake, first ambulation, first "felt like myself again") were recorded. Patients were contacted by phone approximately 24 h after surgery and asked a series of written questions to which they were asked to give one of five responses: 1) agree strongly; 2) agree; 3) neutral; 4) disagree; or 5) disagree strongly.
Immediately after each case, the attending anesthesiologist completed a brief survey evaluating the patient’s intraoperative course and emergence. The blinded nurse observer was asked to complete a similar survey after patient home discharge.
Except for sevoflurane, drug costs were determined by the package unit dose of drug used (including wastage), because this is the way that pharmacy costs are determined. Drug costs were calculated by using pharmacy acquisition costs and do not include the added cost of the equipment and supplies used to administer the drug (such as the cost of the infusion pump, syringe, tubing, and stopcock used for the remifentanil infusion).
Sevoflurane liquid dosage was calculated by using the following formula (6):
Sevoflurane liquid dosage (mL/h) = 3 x FGF x CONC
where FGF = fresh gas flow (mL/min) and CONC = dialed vaporizer setting (%).
The recovery times, VAS scores, the BIS scores, and drug dosage and cost data were compared between groups by using Student’s t-test (P < 0.05). The incidence of intraoperative adverse events, postoperative sequelae, and rescue antiemetic treatment, and satisfaction survey results were compared by using 
2 (P < 0.05). Sample size was determined based on the times of eligibility for home discharge and discharge from the PACU. The calculated sample size for each group necessary to provide 80% power to detect a 20-min and a 40-min difference in PACU and home discharge, respectively, was 16 patients.
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Results |
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During the maintenance phase, the BIS index was significantly higher (Table 1) and the end-tidal sevoflurane concentration smaller in the study group. To maintain the BIS index in the target range, downward titrations of the sevoflurane dose were more frequent in the standard practice group and upward titrations more frequent in the study group. The incidence of intraoperative adverse events was similar. However, the standard practice group demonstrated significantly more events designated as signs of light anesthesia (4 of 18 vs 0 of 16; P = 0.045).
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Discussion |
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The incidence of PONV requiring antiemetic treatment was significantly increased in the study group versus the standard practice group. This finding may have been related to the administration of fentanyl near the end of the procedure in the remifentanil group. Previous investigations comparing alfentanil versus remifentanil as an adjuvant to isoflurane (7) or propofol (8) during ambulatory anesthesia found the incidence of PONV was similar. Investigators who compared adjuvant fentanyl versus remifentanil for inhaled anesthetics given to pediatric patients undergoing tonsillectomy and adenoidectomy also found no difference in the incidence of PONV (2). The incidence of PONV after adjunctive remifentanil infusion has been reported as infrequent as 7% after propofol-based anesthetics for less emetogenic procedures on patients who received only nonsteroidal antiinflammatory drugs for prevention and treatment of postoperative pain (9).
When remifentanil is used as an adjuvant to general anesthesia for moderately painful procedures and no intraoperative opioids are given for postoperative analgesia, the incidence and severity of postoperative pain and the analgesic dosage requirements are significantly more, compared with alfentanil (10). Philip et al. (8) found that remifentanil patients had a longer PACU recovery because they required opioid analgesia sooner and more frequently than those who received alfentanil. Because of the rapid termination of its analgesic effect, Rosow (11) recommends additional longer-lasting intraoperative opioids for postoperative analgesia when remifentanil is used for moderately painful procedures such as laparoscopy and operative hysteroscopy. Our results imply that the need for a longer-acting opioid for postoperative analgesia reduces the potential advantages of remifentanil in outpatients undergoing similar procedures.
The BIS index monitor was used to titrate the sevoflurane dose to a specific end point, and to show that each group received a "pharmacodynamically similar" dose of the hypnotic drugs. Statistically significantly fewer study patients exhibited signs of light anesthesia despite higher BIS indices in these patients. Previous investigations using similar adjuvant opioid doses found fewer intraoperative responses to noxious surgical stimuli in patients receiving remifentanil versus patients receiving fentanyl (2,10) or alfentanil (7,8). These data are consistent with the comparative minimal alveolar concentration-reducing effects of remifentanil and fentanyl.
We calculated our initial vaporizer settings for each group by using the minimal alveolar concentration-reduction effects of each opioid adjuvant. Instead of using minimal alveolar concentration, we estimated the initial sevoflurane vaporizer setting using the concentration at which 95% of patients do not respond to skin incision - the ED95 (2.96%) (12). We estimated the initial sevoflurane delivered concentration to be 0.6% in the study group and 1.9% in the standard practice group. Upward sevoflurane titrations were significantly more frequent in remifentanil patients and downward titrations significantly more frequent in fentanyl patients. This indicates that the initial settings were too low in the study group and vice versa. Despite titration, the BIS indices were higher in the patients receiving remifentanil. Our protocol for titration may have been too restrictive to allow adequate compensation for the initial settings during the short procedures.
In the study group, reduced sevoflurane dosage accounted for savings of $4.07 per patient. Despite this, perioperative drug costs were $17.74 more per patient in the study group. This significant difference was attributable to the added cost of remifentanil ($0.30 for fentanyl 5 mL vs $18.59 for a 2-mg remifentanil vial) and the significantly increased cost of antiemetic treatment in the study group ($0.93 vs $4.20). The other protocol drugs were "fixed" costs ($36.92) for both groups.
We focused only on drug costs, which are often only a small percentage of the overall costs of care (13). Because the recovery profiles were similar, we assume that staffing costs were equivalent for each group. Times from anesthetic discontinuation to extubation were similar, so operating room costs dependent on emergence time were equivalent. The increased incidence of PONV in the study group during second-stage recovery probably did not affect staffing because home discharge times were similar.
The potential clinical benefit from adjuvant remifentanil may be dependent on the patient, procedure, setting, and the anesthetic regimen. Thus, these study results may not apply to other outpatient populations (e.g., those with cardiovascular disease), surgical procedures (e.g., more noxious procedures such as direct laryngoscopy and tracheoscopy), and anesthetic techniques (e.g., total IV anesthesia). These results, however, indicate that remifentanil must be used selectively in the ambulatory setting to have potential cost-effectiveness.
In conclusion, when remifentanil is used as an adjunct to general anesthesia for gynecologic laparoscopic and hysteroscopic procedures, potential savings derived from outcome measures and perioperative drug dosage did not offset the added expense of remifentanil compared with fentanyl.
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