Remifentanil hydrochloride (GI87084B) is a phenylpiperidine derivative with mu-opioid agonist effects and unique pharmacokinetic properties [1-5] [1] 1 Preliminary investigations in human volunteers and anesthetized patients have shown that remifentanil has a rapid onset of effect (blood-brain equilibration time of 1.0 min), small central volume of distribution, rapid clearance and rapid offset of effect (context sensitive half-time of 3 min) and a terminal elimination half-life of about 10 min [3-5] 1 The carboxylic acid metabolite of remifentanil is primarily eliminated renally with an elimination half-life of 80-137 min [5] 1 This pharmacokinetic and pharmacodynamic profile of remifentanil suggests that this drug will be clinically useful in situations where a rapidly titratable potent opioid effect is desirable with a predictable offset of action without prolonged respiratory depression. The purpose of this multicenter study was to evaluate the efficacy of large- and small-infusion doses of remifentanil with propofol when administered as a total intravenous anesthesia (TIVA) technique to patients undergoing elective vertebral, joint replacement, intraabdominal, or thoracic surgery.
1 Data on file, Glaxo, Inc.
Methods
The protocol was approved by the institutional review boards in each of the seven participating centers. Male and female ASA physical status I-IV patients, 18 yr old or older, having elective surgery were eligible for this study. Patients were excluded for unstable medical conditions, chronic use of benzodiazepines, clonidine, opioids or opioid use within 12 h of surgery, obesity (>100% of ideal body weight), history of substance abuse, psychiatric illnesses, pregnancy or lactation, hypersensitivity to opioids or propofol/lipid emulsion, or participation in an investigational drug trial within 8 wk before treatment. All patients provided written, informed consent.
Patients received all chronic medications on the morning of surgery. After arrival in the operating room, patients were given midazolam 0.025-0.05 mg/kg intravenously (IV) for sedation and lactated Ringer's solution 5 mL/kg IV. Anesthesia induction was with remifentanil 1 micro gram/kg IV bolus followed by one of two randomly assigned, double-blind remifentanil infusions: small-dose (0.5 micro gram centered dot kg-1 centered dot min-1 ) or large-dose (1.0 micro gram centered dot kg-1 centered dot min-1 ). Three minutes after the remifentanil infusion was started, propofol 0.5-1 mg/kg was given. If loss of consciousness (LOC; lack of patient response to verbal command) did not occur, additional propofol (20 mg IV) was given every 30 s until the patients were unresponsive. At that time, a propofol infusion at 75 micro gram centered dot kg-1 centered dot min-1 was started and vecuronium 0.15 mg/kg IV was given. Endotracheal intubation was performed at least 6 min after the initial remifentanil bolus. Patients lungs were ventilated with oxygen or oxygen/air mixtures but nitrous oxide was not administered. Five minutes after endotracheal intubation, the remifentanil infusion rate was decreased by 50% (small-dose group, 0.25 micro gram centered dot kg-1 centered dot min-1 ; large-dose group, 0.5 micro gram centered dot kg-1 centered dot min-1 ).
Baseline blood pressure and heart rate were defined as the average of the two lowest measurements obtained the day before surgery, within 2 h of surgery, and before induction of anesthesia. Hemodynamics were recorded before and 1, 3, and 5 min after remifentanil administration, endotracheal intubation, and after skin incision. These measurements were also recorded 1, 3, and 5 min after signs of light anesthesia (defined below), change in remifentanil dosage, and/or every 10 min until the end of surgery. Patients were observed for light anesthesia defined as increases in systolic blood pressure > 15 mm Hg from baseline lasting >or=to 1 min, heart rate > 90 bpm lasting >or=to 1 min, patient movement, eye opening or grimacing, lacrimation, sweating, or mydriasis. When evidence of inadequate anesthesia was observed, intermittent 1 micro gram/kg IV bolus doses of remifentanil and/or infusion rate increases were given. In the small-dose group, the remifentanil infusion rate was increased in 0.5 micro gram centered dot kg-1 centered dot min-1 increments to a maximum rate of 2 micro gram centered dot kg-1 centered dot min-1 . In the large-dose group the remifentanil infusion rate was increased in 1.0 micro gram centered dot kg-1 centered dot min-1 increments to a maximum dose of 4 micro gram centered dot kg-1 centered dot min-1 . Bolus doses were given at 1-min intervals; rate increases were performed at 2-min intervals allowing for a maximum of five bolus doses and two infusion rate increases within a 5-min period for a given response. If signs of light anesthesia persisted after these maximum remifentanil dose adjustments, propofol 20 mg IV was given every minute until an adequate level of anesthesia was observed (propofol "rescue"). If episodes of light anesthesia persisted after the third propofol bolus, the propofol infusion rate was increased to 125 micro gram centered dot kg-1 centered dot min-1 until adequate anesthesia was present for 5 min after which the propofol infusion was decreased to 75 micro gram centered dot kg-1 centered dot min-1 .
Hypotension was defined as systolic blood pressure < 80 mm Hg or mean blood pressure < 60 mm Hg. Hypotension was treated with an increase in the IV fluid rate and a decrease in the remifentanil infusion to a rate midway between the current and previous rate. Continued hypotension was treated with a decrease in the propofol infusion rate to 50 micro gram centered dot kg-1 centered dot min-1 and intermittent IV bolus doses of phenylephrine or ephedrine. Bradycardia (heart rates < 60 bpm with hypotension or heart rates < 40 bpm lasting > 1 min) was treated with glycopyrrolate and/or ephedrine.
Approximately 15 min before the anticipated end of surgery, the propofol infusion was decreased by 50% and discontinued at the end of surgery. The remifentanil infusion was discontinued at the completion of surgery and an open-label analgesic infusion of remifentanil was begun. Initially the analgesic infusion of remifentanil was started at 0.05 micro gram centered dot kg-1 centered dot min-1 , but the protocol was later amended to start the analgesic infusion rate at 0.1 micro gram centered dot kg-1 centered dot min-1 . Neuromuscular blockade was reversed with neostigmine and glycopyrrolate 10 min before the remifentanil infusion was stopped. Patients were observed for the time to spontaneous ventilation and clinically adequate ventilation (respiratory rate >or=to 8 breaths/min and/or PETCO2 < 50 mm Hg). If adequate ventilation was not achieved within 10 min of starting the analgesic infusion of remifentanil, the infusion was stopped until the time of tracheal extubation. Patients were given naloxone if adequate ventilation was not present 5 min after stopping the analgesic infusion of remifentanil.
The primary efficacy end point was adequacy of anesthesia for endotracheal intubation. Secondary end points included patient responses to skin incision and other surgical stimuli 5 min after skin incision until the end of surgery. Patients were also evaluated as to the time to LOC and need for propofol rescue medication. Clinical adverse events were noted, including muscle rigidity (graded on a 0-3 scale from no rigidity to virtually impossible to ventilate), nausea and vomiting, and patient recall of operating room events (assessed on postoperative Day 1). Recovery from anesthesia was assessed as the time to return of spontaneous ventilation, time to adequate ventilation, time to extubation, time to response to verbal commands for eye opening and extremity lifting, and time to the first Aldrete score >or=to 9 [6]
Demographic characteristics were summarized by treatment group. The percentage of patients with responses to endotracheal intubation, surgical stimuli, or who required propofol rescue were compared between treatment groups using logistic regression. The average time of intraoperative responses was also determined as the quotient of the duration of responses and the duration of surgery. The percentage of intraoperative time without a response was determined as 1 - average time of intraoperative responses. Times to LOC and recovery were compared between treatment groups using a survival analysis model. Assessments of clinical adverse events were summarized by treatment groups. All statistical tests were two-sided, with significance considered for values of P < 0.05.
Results
One hundred seventy-eight patients were enrolled but 17 participated in an open-label, pilot portion of the study. Thus, 161 patients were randomized and included in the efficacy analyses. All demographic characteristics were similar between groups Table 1 .
Table 1: Demographic Information Including Number of Patients for Various Surgical Procedures
A comparison of the primary efficacy end point between the small- and large-dose remifentanil groups is presented in Figure 1 . Twenty-five percent of patients in the small-dose group responded to tracheal intubation compared to 6% in the large-dose group (P = 0.003). Seventeen (21%) and nine (11%) patients in the small-dose group responded to tracheal intubation with increases in systolic blood pressure and heart rate, respectively, compared with four (5%) and three (4%) patients in the large-dose group. A comparison of the secondary end points between the small- and large-dose remifentanil groups is listed in Table 2 ; 7% and 5% of patients in the small- and large-dose groups, respectively, had LOC after remifentanil, but before propofol administration. There were no significant differences, however, in the time to LOC between groups. The number of patients responding to skin incision or having responses to surgical stimuli 5 min after incision until the completion of surgery was small and similar in both groups. The percentage of the time free from responses was also similar between groups (92% and 93% of response-free time). The majority of patients in both groups (85%) had 75%-100% of their intraoperative time response free.
Figure 1: Percent of patients by remifentanil dosing group with response to laryngoscopy and tracheal intubation (primary efficacy end point). *P = 0.003 small-dose (low remifentanil) versus large-dose (high remifentanil) group.
Table 2: Secondary End-Point Results
A summary of remifentanil and propofol dose administration for each group is shown in Table 3 . The mean infusion rate of remifentanil at tracheal intubation and skin incision were different between groups as defined by the protocol. The weighted mean infusion rate of remifentanil from skin incision until the end of surgery and the duration of infusion were no different between groups. A comparable number of patients in both groups required remifentanil bolus dosing for predefined responses. Although not significant, when compared with the small-dose group, more patients in the large-dose group were managed without remifentanil infusion rate increases (large-dose group 61%; small-dose group 46%) or bolus dosing (large-dose group 58%; small-dose group 46%). The total dose of propofol, duration of infusion, and the infusion rate from skin incision to completion of surgery of propofol was no different between groups.
Table 3: Remifentanil and Propofol Dose Administration Summary
There were no differences between groups in baseline heart rate or arterial blood pressures Figure 2 . Compared with baseline, decreases in systolic blood pressure and heart rate were observed in both groups after anesthesia induction, prior to tracheal intubation, before skin incision, and from skin incision until the end of anesthesia. There were no differences between groups in these measurements during these periods. The maximum heart rate after tracheal intubation (mean +/- SD), bpm; minimum, maximum [min,max]) was significantly less (P = 0.012) in the large-dose group (68.5 +/- 14.8; 39,107) compared to the small-dose group (75.2 +/- 20.4; 43,142). The maximum systolic blood pressure after tracheal intubation (mean +/- SD, mm Hg; min,max) in the large-dose group (114.6 +/- 28.2; 77,212) was significantly less (P = 0.004) when compared with the small-dose group (125.2 +/- 34.3; 79,235).
Figure 2: Hemodynamic results (mean +/- SD) for each remifentanil dosing group at specified perioperative periods. Systolic blood pressure (SBP) and heart rate (HR) at all time points are significantly less (P < 0.001) compared with baseline awake measurements for both treatment groups except SBP (P = 0.004) and HR (P = 0.12) at intubation in the small-dose group. *P < 0.05 small-dose (low remifentanil) versus large-dose (high remifentanil) group.
Three patients in the small-dose group and four in the large-dose group received naloxone. Data from these seven patients were not included in the analysis of emergence times Table 4 . There was a failure to collect Aldrete scores for a period of 95 min in one patient and continued tracheal intubation and intensive care unit admission in another patient for unexpected surgical complications. Data from these two patients were excluded from analysis of times to response to verbal command, tracheal extubation, and first Aldrete score >or=to 9.
Table 4: Recovery Times (min) for Small- and Large-Dose Remifentanil Dosage Groups
Drug-related adverse events during induction of anesthesia occurred in 13% and 23% of the small- and large-dose groups of patients, respectively, while adverse events during maintenance occurred in 33% of the former and 39% of the latter group. The most common drug-related adverse events were hypotension during induction (small-dose 10%; large-dose 15%), hypotension (small-dose 27%; large-dose 30%), and bradycardia (small-dose 7%; large-dose 9%) during maintenance. Muscle rigidity occurred in 2% of the small-dose and 7% of the large-dose group patients during induction of anesthesia. There was one episode of intraoperative recall without pain. The patient with intraoperative recall was randomized to the small-dose group and reported hearing voices during surgery. In this patient, an IV infusion pump malfunction resulted in the interruption of the remifentanil infusion for 5-10 min; also, the propofol infusion rate was also decreased from 75 to 50 micro gram centered dot kg-1 centered dot min-1 at one point.
Discussion
Our results show that remifentanil 0.25-4 micro gram centered dot kg (-1 ) centered dot min-1 administered in a TIVA technique with propofol is an effective anesthetic regimen, allowing for rapid control of intraoperative stresses in a variety of inpatient surgical procedures. The attenuation of hemodynamic responses to tracheal intubation was best achieved with the 1 micro gram centered dot kg-1 centered dot min-1 infusion rate of remifentanil compared with the 0.5 micro gram centered dot kg-1 centered dot min-1 infusion rate. Twenty-five percent of patients receiving the small-dose infusion of remifentanil responded to endotracheal intubation compared with 6% of patients receiving the larger dose of remifentanil (P = 0.003). Equal control of intraoperative responses after endotracheal intubation was achieved in both groups as demonstrated by the lack of differences between groups in the number of bolus doses or infusion rate adjustments of remifentanil for light anesthesia from skin incision until the completion of surgery. Moreover, only a minority of patients in both groups (small-dose group 19% versus large-dose group 23%) required additional supplementation with propofol.
Regardless of the rate or duration of the remifentanil infusion, emergence from anesthesia was rapid (three to seven minutes) across a diverse surgical population. The design of this investigation required that the propofol infusion be decreased by 50% 15 minutes before the end of surgery, before starting an openlabel, analgesic remifentanil infusion at the end of surgery. Naloxone was given to 4%-5% of patients if adequate ventilation was not established in five minutes. In other similar studies, fewer remifentanil patients required naloxone compared with patients receiving alfentanil [7]
The short elimination half-life of remifentanil is independent of the duration of infusion and appears to make remifentanil well suited for rapid emergence from TIVA compared with other opioid/propofol combinations [1-5] [8] [8,9]
The infusion rate of propofol used in this study, 75 micro gram centered dot kg-1 centered dot min-1 , was less than that normally used for maintenance of anesthesia with nitrous oxide, and when combined with other opioids for a TIVA (100-150 micro gram centered dot kg-1 centered dot min-1 ) [10,11] [12] [8] -1 centered dot min-1 .
The most frequent drug-related adverse events in this study were transient hypotension and bradycardia. Decreases in arterial blood pressure and bradycardia have also been observed with other opioids [13-16] [17] 1 Propofol has many cardiovascular effects including hypotension [18-22] [19] [23]
In conclusion, when combined with propofol 75 micro gram centered dot kg-1 centered dot min-1 , remifentanil 1 micro gram/kg IV as a bolus followed by an infusion of 1.0 micro gram centered dot kg-1 centered dot min-1 effectively controls responses to tracheal intubation. After tracheal intubation, remifentanil 0.25-4.0 micro gram centered dot kg-1 centered dot min-1 with propofol effectively controlled intraoperative responses while allowing for rapid emergence from anesthesia.
The authors wish to gratefully acknowledge the following individuals for their participation in this study: University of Washington, Evan Kharasch, MD, PhD, Kathy Cox, William Nichols, MD; State University of New York, Enico Camporesi, MD, John Burnett, MD, Michael Hauser, MD, Andrew Sopchak, MD; Montefiore Medical Center, Ingrid Hollinger, MD, Philip Phillips, MD, Laurie Maysick, MD; Washington University, Kathy Martin-Bredahl, RN, Yifeng Ding, MD; Emory University, Robert Bastain, MD, Scott Kreger, MD; University of Utah, Kirk Miller, MD, Talmage Egan, MD, Katherine East, MS, Karen Kessler, RN, Barbara Gaylord, RN.
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