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*Henry Ford Hospital, Detroit Michigan;
St. Joseph’s Hospital and Medical Center, Barrow Neurological Institute, Phoenix, Arizona;
University of Michigan, Ann Arbor, Michigan;
§University of Texas Southwestern, Dallas, Texas;
||Abbott-Northwestern Hospital, Minneapolis, Minnesota;
¶University of South Florida, Moffitt Cancer Center, Tampa, Florida;
#Glaxo Welcome, Research Triangle Park, North Carolina; and
**Duke University Medical Center, Durham, North Carolina
Address correspondence and reprint requests to David S. Warner, MD, Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710. Address e-mail to warne002{at}mc.duke.edu
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Abstract |
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Implications: Patients given remifentanil-based anesthesia for craniotomy had faster recovery times from anesthesia than did those given fentanyl-based anesthesia.
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Introduction |
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Remifentanil was compared with fentanyl in a randomized, multiinstitutional, double-blinded, prospective trial (2). That study found remifentanil to be a reasonable alternative to fentanyl during elective supratentorial craniotomy for space-occupying lesions. The frequency of adverse events, hemodynamic profiles, and median recovery times were generally similar between groups. However, 7 of 32 patients in the fentanyl group required naloxone to recover from anesthesia compared with no patients in the remifentanil group. Some artifacts of the experimental design may have contributed to these findings. Because of the double-blinded design, remifentanil and fentanyl were given in equianalgesic doses by using the manufacturer’s recommended infusion rate for establishing the dose of remifentanil. Accordingly, substantially larger doses of fentanyl were administered than may be typical of the practice of many clinicians (i.e., the total fentanyl dose was 34 µg/kg administered for craniotomies, lasting an average of 5 h).
We designed this study, as a subset of a Phase IV prospective trial, to compare remifentanil and fentanyl when used in patients undergoing surgical procedures to remove intracranial space-occupying lesions. Remifentanil was given according to manufacturer recommendations. Fentanyl was given according to the usual practice of the anesthesiologist.
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Methods |
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Anesthesiologists were recruited from both academic and community hospitals that had an active neurosurgical practice. These anesthesiologists underwent a full day of orientation for use of remifentanil at an investigator meeting. Anesthesiologists were required to complete the remifentanil protocol (including data entry) in 10 patients undergoing surgery for removal of an intracranial space-occupying lesion before entering patients into the randomized trial. No attempt was made to blind the anesthesiologist to the anesthetic regimen received by the patient. Neurosurgeons were blinded to the group assignment for each patient.
Patients were randomly assigned to either the fentanyl or remifentanil group. For the fentanyl group, the anesthesiologists were asked to provide anesthesia in their usual manner, although use of opioids was restricted to IV fentanyl in doses customarily used by the provider for these procedures. Concomitant with fentanyl, either propofol (IV) or isoflurane (with or without nitrous oxide) was allowed for anesthetic maintenance. There were no restrictions on the dose of isoflurane or propofol administered in this group. The anesthesiologists were instructed to administer isoflurane or propofol in a dose consistent with their normal practice for these surgical procedures.
For the remifentanil group, remifentanil was administered according to recommendations in the drug package insert. Remifentanil was initially given as a continuous IV infusion at 0.5 µg · kg-1 · min-1. This infusion was begun concurrent with IV administration of other induction anesthetics (thiopental or propofol). After endotracheal intubation, the remifentanil infusion rate was reduced to 0.25 µg · kg-1 · min-1. Thereafter, the remifentanil infusion rate was adjusted as required to treat light anesthesia responses classified as somatic (purposeful movement, swallowing, grimacing, or eye opening), autonomic (tearing, sweating, or mydriasis), hyperdynamic (a clinically relevant increase in blood pressure or heart rate), or anticipated changes in magnitude of surgical stimulation. The recommended minimum dose of isoflurane was 0.4% without nitrous oxide or 0.2% with nitrous oxide although investigators were allowed to increase this dose as desired. Alternative to isoflurane, investigators could choose to maintain anesthesia with propofol (75–100 µg · kg-1 · min-1 without nitrous oxide or 50–75 µg · kg-1 · min-1 with nitrous oxide). Remifentanil was discontinued at the completion of head dressing. Propofol, isoflurane, and nitrous oxide were discontinued at the discretion of the anesthesiologist. Use of neuromuscular block (drug, dose, and antagonist) was left to the discretion of the anesthesiologist. A dose of transitional analgesia (e.g., fentanyl, ketorolac, or morphine) was recommended before emergence from anesthesia.
Light anesthesia responses were recorded at 1 min and 5 min after intubation, skin incision, pinhead holder placement, and skin closure. Incidences of adverse events were monitored throughout the perioperative period including 1) hypotension (systolic blood pressure < 80 mm Hg that is medically untoward or a systolic blood pressure that is treated with pharmacologic drugs and is medically untoward); 2) hypertension (systolic blood pressure > 180 mm Hg or a diastolic blood pressure > 110 mm Hg that is medically untoward); 3) bradycardia (heart rate < 40 bpm that is treated with pharmacologic drugs); 4) respiratory depression (respiratory rate 
8 breaths/min); 5) muscle rigidity; 6) apnea (i.e., respiratory rate of zero for 15 s or more); and 7) nausea and vomiting (as reported by the patient at the 24-h interview).
Anesthetic recovery was assessed by the investigator by using an established two-part scoring system (2,6). The first part assessed level of consciousness, orientation, ability to follow commands, motor function, and the presence of agitation. The second used a modified Aldrete Score (7). Patients were considered to have normal recovery scores when alert or arousable to quiet voice, were oriented, were able to follow commands, had motor function unchanged from their preoperative evaluation, were not agitated, and had modified Aldrete Scores of 9–10. The previously mentioned measurements were recorded before the induction of anesthesia and postoperatively, until a normal score was obtained, or 60 min had elapsed after completion of the head dressing. The anesthesiologist also assessed other acute emergence characteristics, including time to follow simple verbal commands and time to extubation of the trachea. Naloxone administration was allowed, at the discretion of the anesthesiologist, at any time during the recovery interval.
At the completion of the procedure, anesthesiologists completed an evaluation regarding the quality of the anesthetic. Anesthesiologists rated predictability of response to opioid titration, hemodynamic profile, and overall quality of anesthesia on a five-point scale (1 = poor; 2 = fair; 3 = good; 4 = very good; and 5 = excellent). By using the same scale, both anesthesiologists and neurosurgeons rated the quality of emergence according to patient comfort, hemodynamic profile, level of consciousness, and overall quality of the anesthetic.
Continuous values were described as mean ± SD. Times to tracheal extubation and recovery of ability to follow verbal commands (reported as median ± interquartile ranges) were compared by using a log rank test. Risk ratios for these same variables were calculated with 95% confidence intervals (CIs) and compared by using the Wald 
2 test adjusted for covariates in the Cox proportional hazard model. The proportion of patients achieving a normal recovery score by 10 and 20 min after the end of surgery were compared by using Fisher’s exact test. Differences between groups for anesthesiologist and neurosurgeon assessment of recovery were compared by using 2 analysis. A P value < 0.05 was considered significant.
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Results |
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Hemodynamic values were not different between groups (Table 2). At intubation, pinhead holder placement, and skin closure, light anesthesia responses were twofold more frequent in the fentanyl group, although a significant difference between groups was absent at each interval (Figure 1).
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Discussion |
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Of the previously available semisynthetic opioids (alfentanil, fentanyl, and sufentanil), few differences in efficacy profiles have been observed for use during craniotomy. From et al. (8), in a double-blinded, prospective trial, compared these three opioids. Ephedrine was used more during the induction of anesthesia with alfentanil, and postanesthetic respiratory depression was more frequently used in the sufentanil group. Otherwise, no differences were present between groups for remaining hemodynamic variables, brain condition on dural opening, time to extubation, level of consciousness in the postanesthesia care unit, duration of intensive monitoring after surgery, or final discharge neurologic condition. Investigators were unable to guess the identity of the opioid they had administered. Mutch et al. (9) compared alfentanil (small-, mid-, or large-dose) to fentanyl (8.3-µg/kg loading dose followed by 1.6 µg · kg-1 · min-1) in patients undergoing craniotomy for removal of supratentorial tumors. Perioperative hemodynamic values were not different among groups. Patients in the small-dose alfentanil group required larger doses of isoflurane during maintenance and were slower to follow commands after the completion of surgery. However, there was no difference between groups for perioperative arterial blood pressure values, emergence times to eye opening or extubation, or postanesthetic respiratory depression. Finally, Gignac et al. (10) compared alfentanil, fentanyl, and sufentanil as adjuvants during awake craniotomy for seizure surgery. Alfentanil or sufentanil offered no benefit over fentanyl. Cumulatively, these studies suggest that from a practical perspective, alfentanil, fentanyl, and sufentanil are similar when used as the opioid base for neuroanesthesia.
Remifentanil has the theoretical potential to improve at least one hallmark of a neuroanesthetic, reliability of emergence on completion of surgery. This is simply attributable to the rapid ester hydrolysis of this drug that prohibits accumulation even when administered for prolonged neurosurgical procedures (2). A recent Phase III study compared remifentanil (1.0 µg · kg-1 · min-1 for approximately 10 min followed by 0.2 µg · kg-1 · min-1) to fentanyl (2.0 µg · kg-1 · min-1 for approximately 10 min followed by 0.03 µg · kg-1 · min-1) in patients undergoing supratentorial craniotomy for space-occupying lesions (2). That study found remifentanil and fentanyl to be similar for hemodynamics during anesthesia induction, although more frequent light anesthesia responses to intubation were observed in the fentanyl group. Brain relaxation score, ICP, and median times to spontaneous ventilation, tracheal extubation, eye opening, and ability to follow verbal commands were similar between groups. However, remifentanil patients had larger systolic blood pressure values in the recovery room. Although postoperative analgesics were required with the same frequency in the two groups, analgesics were required earlier by the remifentanil group. The conclusion from that work was that remifentanil is an effective alternative to fentanyl during neurosurgery; however, some form of transitional analgesia is required at the time of emergence, if remifentanil is used.
Although the study by Guy et al. (2) demonstrated that remifentanil was appropriate for use during craniotomy, several weaknesses in study design prohibited any conclusions to be drawn regarding the superiority of remifentanil over fentanyl, and especially whether sufficient benefit is present to justify the higher cost of this proprietary drug. Guy et al. (2) designed a study to allow a double-blinded comparison between the two anesthetics. Remifentanil was used at a dosage likely to be recommended in the package insert. As a result, an attempt to administer equipotent doses of remifentanil and fentanyl was made to secure the double-blinded validity. This, however, caused substantially more fentanyl to be administered than is the customary practice by many clinicians. Therefore, the study was biased against fentanyl with respect to defining relative emergence rates from anesthesia. At the same time, fentanyl-treated patients required frequent use of naloxone. Emergence times were not corrected for use of naloxone, and in this respect, times to emergence were biased against remifentanil. Finally, at the time the study protocol was designed, there was no appreciation of postoperative analgesic requirements for patients undergoing craniotomy (11–13). Therefore, a transitional analgesia regimen was not used. This may have explained the relative hyperdynamic state observed in the remifentanil-treated patients early after emergence from anesthesia.
We therefore took the opportunity to prospectively study the neurosurgical subpopulation of the Phase IV trial to address these issues. The key advance in this study was to allow the investigators to compare remifentanil-based anesthesia to their usual fentanyl-based practice for managing patients undergoing surgical treatment of intracranial space-occupying lesions. Although an effort was made to restrict "usual care" to use of fentanyl as the opioid and isoflurane (with or without nitrous oxide) as the volatile anesthetic, no effort was made to control doses or timing of the administration of these anesthetics. This design resulted in the administration of fentanyl in doses substantially less (approximately 9 µg/kg over 342 minutes, mean values) than those used by Guy et al. (2) (34 µg/kg over 294 minutes, mean values).
Under the circumstances previously outlined, risk ratio analysis showed that remifentanil-treated patients had significantly higher probabilities of achieving the emergence criteria of following verbal commands and tracheal extubation than did fentanyl-treated patients. This finding is consistent with the known rates of redistribution and metabolism of these two opioids. However, median times to meet emergence criteria were not appreciably different for the two groups. This is consistent with other information. Todd et al. (6) compared fentanyl/nitrous oxide to isoflurane/nitrous oxide and propofol/fentanyl anesthesia when used for supratentorial craniotomy. In the fentanyl/nitrous oxide group, median time to follow commands and extubation was 2.1 minutes and 5.0 minutes, respectively. Similarly, Sneyd et al. (14) compared alfentanil with remifentanil as the opioid base for general anesthesia during craniotomy. There was no difference in median times to extubation (alfentanil = 14 minutes; remifentanil = 11 minutes) or to follow verbal commands (alfentanil = 16 minutes; remifentanil = 12 minutes). However, the range of values about the mean was different between the opioids. For example, the time to extubation ranged from 7 to 48 minutes in the alfentanil group versus 9 to 21 minutes in the remifentanil group. The findings from Guy et al. (2) are also similar. The time to extubation ranged from 1 to 15 min for remifentanil and from 1 to 40 min for fentanyl (this includes data for the 7 of 31 patients who received naloxone in the fentanyl group). These findings were repeated in the current study. Ninety-five percent of the patients were tracheally extubated within 20 minutes in the remifentanil group versus 53 minutes in the fentanyl group. Similarly, fewer outliers were seen when examining the time required for 95% of the patients to follow verbal commands (18 minutes for remifentanil versus 42 minutes for fentanyl). Therefore, although median times to recovery are minimally affected by choice of opioid, a substantial frequency of outliers was observed in the fentanyl group. We suggest that these outliers are the patients most likely to gain an advantage from remifentanil with respect to time to emergence from anesthesia.
A weakness of this study design was the use of an open-label protocol from the anesthesiologists’ perspective. Use of a double-blinded design was prohibitive, given limitations inherent in a Phase IV trial (principally cost) and the markedly different pharmacokinetics of the two opioids. To some extent, the study may have been biased in favor of fentanyl, a drug with which most anesthesiologist have vast experience. In contrast, investigators had experience with use of remifentanil in only 10 cases before beginning the randomized sequence of patients. There also is a suggestion that bias in favor of remifentanil was present in the anesthesiologists’ assessments of the anesthetics. Although anesthesiologists exhibited a highly significant favoritism for remifentanil in all four emergence categories, neurosurgeons, who were blinded to anesthetic group, found the superiority of remifentanil for only two categories. However, the fact that neurosurgeons and anesthesiologists rated the overall superiority of the remifentanil-based anesthetic warrants consideration.
There was no difference between groups for postoperative hypertension or tachycardia. This is in contrast to the study by Guy et al. (2), who found significantly higher blood pressure values in patients recovering from a remifentanil- versus fentanyl-based anesthetic. We attribute the absence of difference in the current study to instruction to the anesthesiologists to use transitional anesthesia around the time of emergence from anesthesia. The purpose of this trial was not to compare different strategies for transitional anesthesia in this population. However, when investigators chose to use fentanyl for transitional anesthesia, a dose of 152 ± 55 µg was used. It appears likely that, given the absence of relative emergence hypertension or tachycardia under these conditions, similar doses of fentanyl (or equianalgesic equivalents of other compounds) may be important in optimizing the hemodynamic profile during recovery.
The previously mentioned information leads to the following conclusions. First, a remifentanil-based anesthetic was found to provide stable and similar hemodynamics during the induction, maintenance, and emergence phases of anesthesia when compared with a fentanyl-based anesthetic. Second, the frequencies of adverse event rates for the two opioids were similar. Third, remifentanil, although not altering the rate of emergence for at least 50% of the patients, did reduce the probability of a slow emergence. Fourth, remifentanil use significantly decreased the amount of concomitant anesthetic (i.e., isoflurane) used. The chief benefit from remifentanil appears to be reduction of the frequency of outliers allowing emergence from anesthesia for craniotomy to be more predictable than is provided by a fentanyl-based anesthetic.
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Acknowledgments |
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The authors are grateful for the assistance of Ms. Deborah Thompson and Drs. Lee Fleisher, Peter Glass, Michael Roizen, Rebecca Twersky, and Kenneth Tuman who participated in the design of this study.
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