Remifentanil (GI87084B) is a new, esterase-metabolized mu-selective opioid receptor agonist. Its context-sensitive half-time [1] [2-4] [5]
Methods
This open-label study was approved by the institutional review boards of the Massachusetts General (Site 1) and Northwestern Memorial (Site 2) Hospitals. All participants gave written, informed consent. Subjects (28 at Site 1, 23 at Site 2) were male or female, ASA physical status I or II, aged 18-65 yr, within 30% of ideal body weight for height, and scheduled for inpatient surgery of at least 1-h duration. Females were either postmenopausal, surgically sterile, or undergoing hysterectomy. Patients were excluded if they had a history of hepatitis, a family history of pseudocholinesterase deficiency, treatment with a parenteral opioid within the week prior to surgery, chronic therapy with any psychoactive medication, clinically significant ethanol abuse, recent drug abuse, or heavy tobacco use. Also excluded were patients undergoing neurosurgical, cardiothoracic, or major vascular surgical procedures.
Patients were not premedicated. Lactated Ringer's solution was infused through a peripheral intravenous (IV) catheter, and standard monitors were applied. All patients had a radial artery catheter for blood sampling. After anesthetic induction with propofol (2 mg/kg IV), ventilation was controlled with 67% nitrous oxide in oxygen. Supplemental bolus doses of propofol were given as needed prior to skin incision (i.e., in response to any indicator of light anesthesia).
After an initial arterial blood sample was taken (at least 1 min after the initial bolus dose of propofol), vecuronium 0.08 mg/kg was given, followed by remifentanil 1 micro gram/kg IV. An infusion of remifentanil was immediately started at either 0.05, 0.1, 0.3, 0.6, or 1.0 micro gram centered dot kg-1 centered dot min-1 . These dose groups were studied in order, starting with the lowest initial infusion rate. At least six subjects were studied at each infusion rate. At the completion of the study it was clear that, at Site 1, some patients had a substantial analgesic effect at the lowest rate (0.05 micro gram centered dot kg (-1 ) centered dot min-1 ), hence two more groups were added at Site 1 (n = 4 per group) using initial infusion rates of 0.0125 and 0.025 micro gram centered dot kg-1 centered dot min-1 , and two more patients were studied at an initial infusion rate of 0.05 micro gram centered dot kg-1 centered dot min-1 . At Site 2, eight additional patients were studied at an initial infusion rate of 0.05, 0.1, 0.3, or 0.6 micro gram centered dot kg-1 centered dot min-1 (n = 2 per group).
The trachea was intubated at least 5 min after starting the remifentanil infusion, and surgical incision occurred at least 10 min after intubation. Responses were measured in an all-or-none fashion: A response to incision or subsequent surgical stimuli could be autonomic (tearing, sweating, >15% increase in systolic pressure or >20% increase in heart rate from the preoperative baseline) or somatic (movement or coughing). Baseline values for heart rate and blood pressure were defined as the mean of the lowest two values obtained prior to induction of anesthesia.
The response to incision was assessed at the initial remifentanil infusion rate. The dose of remifentanil could be increased twice (by 50%) if a response occurred. Any additional responses were treated by administration of isoflurane.
One objective of this pilot study was to estimate the ED50 of remifentanil for ablation of the response to skin incision when the predicted blood level of remifentanil would be approaching steady state [2,3]
Vecuronium was administered as needed to maintain suppression of two to three twitches on the train-of-four monitor. Complete paralysis was avoided to permit observation of patient movement, if it occurred. Neuromuscular block was reversed with neostigmine and glycopyrrolate, if necessary, prior to skin closure. Nitrous oxide and the remifentanil infusion were discontinued simultaneously with the placement of the last skin suture, and the patients' lungs were ventilated with 100% oxygen. The time was recorded from the termination of the remifentanil infusion until each patient responded to voice, breathed spontaneously, and was tracheally extubated. A patient was given postoperative analgesic therapy only when he or she complained of pain.
At baseline, before incision, at the end of surgery, and at the resumption of spontaneous ventilation, an arterial blood sample was obtained for determination of the blood remifentanil concentration. Blood samples were immediately mixed with acetonitrile to stop esterase activity. Remifentanil was then extracted by the addition of methylene chloride. The organic phase was removed and stored at -70 degrees C. Determination of remifentanil concentrations was by high resolution gas chromatographic mass spectrometry, and a central laboratory analyzed the samples from both study sites. The detection limit of remifentanil in blood was 0.1 ng/mL [6]
Preoperatively, and on the first postoperative day, each patient had an electrocardiogram, urinalysis, and blood tests to assess renal, hepatic, and hematologic function. Each was interviewed regarding his or her perioperative experience, and was specifically asked about recall of any intraoperative events.
Differences between dose groups were assessed by one-way analysis of variance. P < 0.05 was considered statistically significant. ED50 values were determined by logistic regression using SAS statistical software (version 6.07; SAS Institute, Cary, NC) and the procedure PROBIT.
Results
Mean age and weight were consistent among the dose groups. The distribution of patients by gender was not uniform among the dose groups (25% males in the two lowest dose groups, and up to 90% males in the higher dose groups). The duration of anesthesia (listed in Table 1 ) did not differ among groups.
Table 1: Emergence Times as a Function of the Final Infusion Rate of Remifentanil
The concentration of remifentanil in blood at the time of skin incision is shown in Figure 1 . These concentrations increased linearly as the infusion rate of remifentanil increased.
Figure 1: The blood concentration of remifentanil (ng/mL) at the time of skin incision as a function of the initial infusion rate of remifentanil. Each point represents the remifentanil concentration for a single patient. Skin incision occurred at least 15 min after beginning the remifentanil infusion in all patients (mean +/- SEM, 28 +/- 1.6 min). Blood concentrations were not determined in patients receiving the two lowest initial infusion rates.
Incision occurred at least 15 min (mean time +/- SEM 27.4 +/- 1.2 min) after beginning the infusion of remifentanil. Figure 2 shows the dose of remifentanil versus the probability of response to skin incision. The two study sites differed significantly: the ED50 values were 0.020 micro gram centered dot kg-1 centered dot min-1 (95% confidence interval 0-0.046 micro gram centered dot kg-1 centered dot min-1 ) and 0.087 micro gram centered dot kg-1 centered dot min-1 (95% confidence interval not estimable) at Sites 1 and 2, respectively.
Figure 2: The percentage of patients not responding to incision as a function of the initial infusion rate of remifentanil. The individual data points show the percentage of patients not responding at the two study sites, and the two dashed lines indicate the dose-response relationships predicted by logistic regression analysis of the data. The ED50 values for the abolition of the response to incision are 0.020 micro gram centered dot kg-1 centered dot min-1 and 0.087 micro gram centered dot kg-1 centered dot min-1 at Sites 1 and 2, respectively.
(Figure 3 ) shows the probability of response to surgical stimuli at or after skin incision. All patients responded to surgery at remifentanil infusion rates less than 0.1 micro gram centered dot kg-1 centered dot min-1 . The ED50 for remifentanil-mediated abolition of all surgical responses was 0.52 micro gram centered dot kg-1 centered dot min-1 (95% confidence interval 0.16-0.88 micro gram centered dot kg-1 centered dot min-1 ).
Figure 3: The percentage of patients not responding to all surgical stimuli as a function of the initial infusion rate of remifentanil. The dashed line indicates the dose-response relationship predicted by logistic regression analysis of the data. The ED50 value for the abolition of the response to surgical stimulation is 0.52 micro gram centered dot kg-1 centered dot min-1 .
Repeated responses to surgical stimuli which required administration of isoflurane occurred more commonly at infusion rates less than 0.3 micro gram centered dot kg-1 centered dot min-1 Table 1 . Only 3 of 21 patients given remifentanil at a final infusion rate of 0.3 micro gram centered dot kg-1 centered dot min (-1 ) or greater required isoflurane.
(Table 1 ) also lists the times until spontaneous ventilation, responsiveness to voice, extubation, and requirement for first postoperative analgesic as a function of the infusion rate at the end of the anesthetic. The median times to spontaneous ventilation, responsiveness, and extubation for all doses combined were 3 min, 3 min, and 4 min, respectively. No patient required more than 10 min to breathe spontaneously, and no patient required naloxone. Most patients (92%) complained of pain and received fentanyl, meperidine, or morphine within a median time of 21 min after remifentanil discontinuation. Figure 4 shows the remifentanil blood concentrations at two times: final suture placement and occurrence of spontaneous ventilation. In the time that elapsed between these two blood samples (mean times 3.2-7.4 min across dose groups), the blood concentrations of remifentanil decreased markedly. Blood concentrations measured at spontaneous ventilation increased slightly as a function of final infusion rate.
Figure 4: The blood concentrations of remifentanil (ng/mL) at the time of skin closure and spontaneous ventilation as a function of the final infusion rate of remifentanil. Each bar represents the mean +/- SEM. The mean times (in minutes) between skin closure and spontaneous ventilation are shown above each pair of bars.
One intraoperative adverse event was deemed likely to be causally related to the study medication. A patient who had been taking metoprolol 100 mg twice daily for hypertension experienced severe bradycardia (heart rate 30-35 bpm) and systolic hypotension (<70 mm Hg) after induction of anesthesia with propofol and within 2 min of the initiation of remifentanil at 0.3 micro gram centered dot kg-1 centered dot min-1 but prior to intubation. The bradycardia and hypotension responded to treatment with atropine, ephedrine, and a brief phenylephrine infusion. Remifentanil was continued during his surgery with no further intraoperative problems.
No patient had any postoperative laboratory abnormality or electrocardiogram alteration which was believed to be causally related to remifentanil. In addition, no patient described recall of any intraoperative events when questioned on the first postoperative day.
Discussion
Remifentanil was successfully used as part of an anesthetic regimen that included propofol induction followed by nitrous oxide maintenance. Infusion rates of 0.1 micro gram centered dot kg-1 centered dot min-1 or greater suppressed the autonomic and somatic responses to incision in the majority of patients. Larger infusion rates, up to 2 micro gram centered dot kg-1 centered dot min-1 , were well tolerated and successfully prevented the responses to subsequent surgical stimuli. Most patients receiving remifentanil at 0.6 micro gram centered dot kg-1 centered dot min-1 and greater appeared to have adequate analgesia intraoperatively because they had no significant changes in their heart rates or blood pressures compared to preoperative baseline. Approximately one third of these patients did respond, however, by moving during the surgical procedure, and some opened their eyes to voice command. These patients were unpremedicated, the doses of muscle relaxant were relatively small, and nitrous oxide was the only other drug given during most of the anesthetic. No patients had intraoperative recall.
Remifentanil appeared pharmacologically similar to fentanyl and other potent mu agonists. Decreases in heart rate were common, although they were severe enough to require treatment in only one patient who was taking a large dose of metoprolol. Hypotension and bradycardia after coadministration of beta blockers and opioids are well known occurrences. Chest wall rigidity due to remifentanil has been described [2]
Remifentanil may possess a larger margin of safety than other opioid analgesics in terms of rapid recovery, even after a high-dose infusion. While the final infusion rate was varied 80-fold from 0.025 micro gram centered dot kg-1 centered dot min-1 to 2.0 micro gram centered dot kg-1 centered dot min-1 , and the duration of anesthesia ranged from 1.0 to 6.8 h, spontaneous ventilation, responsiveness to voice, and extubation occurred within a few minutes in most cases. Recall that the remifentanil infusion was continued until surgery was completely finished.
(Figure 1 ) shows no unexpected variability in remifentanil pharmacokinetics, and the steady-state blood concentration was well predicted as a function of the infusion rate.
The differences in ED50s between study sites are not easily explained. Apart from pharmacokinetics, we can expect a three- to fivefold variability among subjects in the pharmacodynamic effects of opioid agonists [7]
The reportedly short context-sensitive half-time of remifentanil was clinically apparent in the present study because the patients emerged rapidly from anesthesia, the concentrations of remifentanil decreased rapidly after termination of the infusion, and most patients required postoperative analgesia within a median time of 21 min after remifentanil discontinuation. Since we wished to evaluate the speed of emergence, longeracting opioids were not administered prior to discontinuing remifentanil. The administration of a longeracting opioid near the end of anesthesia would be a reasonable option when remifentanil is used clinically in patients who are expected to have postoperative pain. Alternatively, the patient might be transported to the postanesthesia care unit with remifentanil infusing at a lower, analgesic rate.
The blood concentration of remifentanil measured at the time of spontaneous ventilation rose slightly at higher final infusion rates. We believe that this reflects the administration of supplemental propofol and isoflurane intraoperatively rather than the development of tolerance. Residual remifentanil may not have been the limiting factor in recovery of spontaneous ventilation in this anesthetic regimen.
In a previous study, the pharmacokinetics of remifentanil were not greatly influenced by patient gender, weight, or age [3] [8,9]
Remifentanil appears to be useful as the opioid component of a balanced anesthetic when rapid emergence is desirable. Furthermore, remifentanil may be administered in relatively large doses and still permit the trachea to be extubated within a short time after the procedure.
The authors are grateful to Drs. Randal L. Batenhorst, Anthony W. Fox, and Keith Muir for their helpful comments and critical review of the manuscript.
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