Remifentanil is a new micro-specific opioid receptor agonist currently under investigation. The interaction between opioids and volatile anesthetics is complex. Defining this interaction provides a basis for more rational dosing schemes when such combinations are used for anesthesia and allows the anesthetic potency of remifentanil relative to other opioids to be determined.
Two centers enrolled a total of 220 patients. Patients were randomized to receive a target concentration of remifentanil via a computer-assisted continuous infusion device of either 0.0, 0.5, 1.0, 1.5, 2.0, 4.0, 8.0, 16.0, and 32.0 ng/ml initiated before the administration of isoflurane. Patients were also stratified by groups 18-30, 31-55, and 56-65 yr. After induction of anesthesia with isoflurane the initial patient in each dose group was assigned an age-adjusted isoflurane concentration. The isoflurane concentration for each subsequent patient was adjusted according to the up/down technique until a minimum of 12 patients were enrolled in each group. Arterial blood samples for remifentanil whole blood concentrations were obtained. The patient was observed for purposeful movement for up to 1 min after skin incision. The minimum alveolar concentration (MAC) of isoflurane (0 ng/ml remifentanil group) and MAC reduction of isoflurane by remifentanil were determined.
The MAC of isoflurane alone was 1.3%. Remifentanil caused an exponential reduction in the MAC of isoflurane with 1.37 ng/ml remifentanil a 77% reduction and 32 ng/ml a 91% reduction of isoflurane MAC.
The MAC reduction of isoflurane by remifentanil is similar to that produced by other opioids. Although remifentanil was given at extremely high concentrations in the absence of isoflurane, it did not provide adequate anesthesia. A 50% isoflurane MAC reduction is produced by 1.37 ng/ml remifentanil whole blood concentration compared to previously published plasma concentrations of fentanyl of 1.67 ng/ml or sufentanil of 0.14 ng/ml.
THE minimum alveolar concentration necessary to prevent movement in 50% of patients (MAC) was defined originally by Eger et al. and has become the standard measure of volatile anesthetic potency. Opioids markedly reduce the concentrations of volatile anesthetic agents required to maintain anesthesia. [2–5]Evaluation of this reduction in the MAC of volatile anesthetic agents by opioids may be used as a comparison of relative opioid potency. [4,5].
Remifentanil is a novel synthetic micro-opioid receptor agonist. An ester linkage makes this 4-anilidopiperidine derivative susceptible to rapid metabolism by esterases in the blood and other tissues. Remifentanil has a rapid onset and offset of action and rapid blood-brain equilibration, properties that facilitate titration of dose according to effect. [7,8]Total clearance (250–300 l/h) is independent of dose, as is the volume of distribution (25–40 l). [9,10]The terminal half-life ranges from 10 to 21 min. [8–10].
Many of the original studies that attempted to quantify the MAC reduction of volatile anesthetic agents by opioids used a bolus dose technique for administering the opioid. [3,11,12]After a bolus dose, the opioid plasma concentration is continuously decreasing and there is a disequilibrium (hysteresis) between the plasma drug concentration and effect. [13,14]When defining drug effect and drug interactions, it is critical that both drugs have reached a steady biophase (effect compartment) concentration. The development of computer-assisted continuous infusion (CACI) devices enables (by compensating for ongoing drug distribution) the investigator to maintain a pseudo-steady state and allows for equilibration between the measured blood concentration and the biophase. This is particularly important when performing a MAC reduction study using a short-acting opioid such as remifentanil.
This study was undertaken to determine the MAC reduction by remifentanil of isoflurane in patients undergoing elective surgical procedures requiring general anesthesia. A CACI device was used to maintain a constant blood remifentanil concentration throughout the study period.
Materials and Methods
This was a two-center, open-label, randomized study conducted in ASA physical status 1–3 patients of both sexes. After institutional review board approval, informed written consent was obtained from a total of 220 patients between the ages of 18 and 65 yr. Patients scheduled for elective surgery under general anesthesia requiring at least a 2-inch skin incision, or abdominal laparoscopic surgery involving an incision of at least 1 inch, who were within 50% of ideal body weight for height, were included in the study. The following patients were excluded:(1) those in whom an inhalational induction was contraindicated;(2) those having any significant cardiovascular, respiratory, renal, or hepatic disease, as determined by their medical history, physical examination, a 12-lead electrocardiogram, and laboratory blood tests for hematology and serum chemistry;(3) those receiving medications known to affect MAC, or having a history of alcohol or drug abuse; and (4) women who were lactating or pregnant (as determined by history or a positive urine/serum pregnancy test).
Patients were randomly assigned to treatment groups to receive remifentanil via a CACI device to achieve a specified steady-state blood drug concentration of: 0, 0.5, 1, 1.5, 2, 4, 8, 16, and 32 ng/ml. The remifentanil infusion was started before the administration of isoflurane. The first patient randomized to each treatment group received a target end-tidal concentration of isoflurane thought to reflect MAC. If the first patient moved at skin incision, the next patient randomized to that treatment group received a 0.1% increase in the targeted end-tidal concentration of isoflurane. If the first patient didn't move at skin incision, the next patient randomized to the same treatment group received a 0.1% decrease in the targeted end-tidal concentration of isoflurane. This dosage adjustment procedure continued within each concentration group until twelve evaluable patients had been treated at each site. All patients had the inspired concentration of isoflurane adjusted to a predetermined, age-adjusted end-tidal isoflurane concentration. However, the number of patients within each target concentration group was not controlled to include an equal number of patients from each age range. The initial MAC estimations for the three age groups of 18–30 yr, 31–55 yr, and 56–65 yr, were 1.28%, 1.15%, and 1.05%, respectively. .
Patient monitoring consisted of a lead-II electrocardiogram, noninvasive blood pressure, pulse oximetry, temperature, capnography, and end-tidal isoflurane concentration. The patients breathed oxygen via a face mask and an infusion of remifentanil to the randomly allocated target blood concentration was begun. Isoflurane in increasing inspired concentrations was then administered to achieve loss of consciousness. Manual ventilation was provided as necessary to maintain adequate oxygenation and end-tidal carbon dioxide between 30 mmHg and 35 mmHg.
Remifentanil was administered via CACI. This is a target-controlled drug delivery system that enables the user to select a target drug concentration. The infusion rate administered is automatically determined and delivered based on previously derived pharmacokinetic parameters for the drug. The pharmacokinetic parameters of remifentanil that were used in CACI for this study are listed in Table 1.
After induction of anesthesia, 1 mg/kg succinylcholine was administered. Tracheal intubation was performed and the patients' lungs were mechanically ventilated. The inspired isoflurane concentration was adjusted to maintain the targeted end-tidal isoflurane concentration. End-tidal carbon dioxide was maintained between 30 mmHg and 35 mmHg and temperature above 35.5 degrees Celsius.
After tracheal intubation, a radial artery cannula was inserted and the first of a total of three arterial blood samples for remifentanil whole blood concentrations were taken. This was obtained at least 10 min before skin incision. Two more arterial blood samples were taken, before skin incision and 1 min after skin incision. For each blood sample, 5 ml arterial blood was collected into a Vacutainer (Becton Dickinson, Franklin Lake, NJ) with sodium heparin. This was inverted for mixing and transferred into a 20-ml polypropylene tube. Twenty microliters of 50% citric acid was added to each milliliter of collected blood, the tube capped and vigorously mixed for 10 s. The tube was then centrifuged, and the plasma was frozen at -20 degrees Celsius. Remifentanil whole blood concentrations were analyzed by gas chromatography high resolution mass spectrometry selected ion monitoring. The lower and upper limits of quantification were 0.1 ng/ml and 250 ng/ml, respectively, and the interday coefficient of variation for the assay was less than 11.5%.
Before skin incision, return of neuromuscular function was confirmed by providing a 4-s supramaximal tetanic stimulus at 50 Hz. After skin incision, determination of movement was made in the 1 min after incision, with movement defined as gross purposeful movement in response to incision. Coughing, chewing, or swallowing was not considered to be movement. If the patient moved, an intravenous hypnotic agent (thiopental or propofol) was administered. If the patient moved before skin incision (i.e., after the tetanic stimulus) but after the pseudo-steady state concentrations of both drugs had been achieved, the patient was also considered a mover and a blood sample for remifentanil concentration was immediately taken and an intravenous hypnotic was administered. A second sample was then taken 1 min after administration of the hypnotic.
After the final blood sampling, the remifentanil infusion was discontinued and anesthesia was maintained at the discretion of the attending anesthesiologist.
The data were analyzed using logistic regression to determine the probability of movement at remifentanil and isoflurane concentrations as previously described. Log (remifentanil) and log (isoflurane) were the major independent variables. Other independent variables tested included age, weight, gender, and ethnic origin. The MAC of isoflurane alone was estimated using logistic regression analysis of the response data in only the patients who did not receive remifentanil. The average of the remifentanil concentration in the last two blood samples was used in the response analysis.
The accuracy of CACI to achieve and maintain the targeted concentration was evaluated by calculating the performance error (bias) and median absolute performance error from the samples obtained. In addition, as the concentration of remifentanil was maintained stable over a period of time and the infusion rates required to achieve this were known, the effect of isoflurane on the clearance of remifentanil was determined.
A total of 220 patients were enrolled in the study. One hundred ninety-eight patients with a mean age of 39.3 (SD +/- 12.8) yr were included in the data analysis. All demographics including height, weight, age, and sex were similar across the different treatment groups. Adverse events that occurred during the infusion of remifentanil are listed in Table 2. Twenty-five patients did not receive remifentanil and were used to determine the MAC of isoflurane alone. A total of 173 patients were included in determining the MAC reduction of isoflurane by remifentanil. The number of crossovers and age distribution for each remifentanil target concentration is shown in Table 3. Three patients who received remifentanil and no isoflurane were excluded from the analysis as the log of 0 is indeterminable. Twelve patients were withdrawn from the study because of technical problems and seven were excluded from the data analysis for protocol violations. Technical problems included an inability to insert an arterial catheter before skin incision (n = 6), CACI pump failure (n = 1), no skin incision was made (n = 2), difficulty intubating the trachea (n = 1), and medical concerns unrelated to remifentanil administration (n = 2).
No age effect was seen on the MAC of isoflurane alone and this was determined as 1.3%. When data from the two sites were combined, logistic regression analysis of the isoflurane end-tidal concentration, the mean of the second and third remifentanil concentrations and movement/no movement found that patient age was not significant (P > 0.05) as an independent variable in the MAC reduction analysis. Figure 1illustrates the relationship between isoflurane and remifentanil concentrations of the pooled data for the move/no move response. The concavity of this relationship demonstrates the potentiation (synergism) of effect for the remifentanil/isoflurane combination. Using a MAC of 1.3% for isoflurane and the combined patient population data, a remifentanil concentration of 1.37 ng/ml resulted in a 50% reduction in isoflurane MAC. The maximum targeted remifentanil concentration of 32 ng/ml produced a 91% MAC reduction of isoflurane (Table 4).
The pharmacokinetic parameters of remifentanil used in CACI resulted in a positive performance error of 42% and a median absolute performance error of 37%. The positive bias indicates that the measured concentration was higher than the targeted concentration. As illustrated in Figure 2, CACI was able to maintain the measured remifentanil whole blood concentration remarkably stable during the administration of remifentanil.
The clearance of remifentanil for individual patients was determined using the CACI infusion rate and the average concentration of remifentanil during the period of skin incision. The mean clearances for the remifentanil ranged from 28 to 35 ml [dot] kg sup -1 [dot] kg sup -1 (Table 5). Linear regression analysis indicated that no relationship exists between remifentanil clearance and isoflurane concentration (P = 0.252).
In this study we determined the MAC reduction of isoflurane by remifentanil. The interaction that we observed was very similar to previously reported isoflurane MAC reduction studies with other potent micro agonists. [2,4,5]There was an initial steep decrease in isoflurane MAC (up to 70%) at relatively low remifentanil concentrations (2–4 ng/ml), and this was followed by a much flatter reduction in the MAC of isoflurane with 32 ng/ml, resulting in only a 90% isoflurane MAC reduction. A remifentanil whole blood concentration of 1.37 ng/ml resulted in a 50% reduction in the MAC of isoflurane.
The MAC reduction of isoflurane by remifentanil was determined using logistic regression analysis of the concentration and response to skin incision data. Using data from patients who did not receive remifentanil, the MAC of isoflurane alone was determined to be 1.3%. This value is similar to those reported in previous studies. At a remifentanil concentration of 1 ng/ml the MAC of isoflurane was reduced by 30–35%; at 2.0 ng/ml the MAC was reduced by just greater than 50%; and at 4 ng 65–70%. At concentrations greater than 4.0 ng/ml, there is limited further reduction in the MAC of isoflurane. In this study, because of the very evanescent nature of remifentanil's pharmacokinetics, we were able to administer the drug to extremely high concentrations, yet we were unable to reduce the MAC of isoflurane completely. Remifentanil, even at blood concentrations of 32 ng/ml, did not achieve a 100% reduction in the MAC of isoflurane. This finding is similar to data that exists for other opioids. [2,4,5,19]It supports the contention that remifentanil, like other pure micro receptor opioid agonists needs to be supplemented by another anesthetic agent.
Clinically, the isoflurane MAC reduction findings are important as to how remifentanil and isoflurane should be administered. The greatest reduction of isoflurane MAC is achieved at remifentanil concentrations of less than 4 ng/ml. Similar results are seen with fentanyl. To determine optimal dosing schemes when drugs are combined to achieve the anesthetic state, it is important to consider both their interaction in providing anesthesia, as well as the result of the combination in providing the most optimal (rapid) recovery. Fentanyl (plasma) and remifentanil (whole blood) concentrations of greater than 2 ng/ml result in significant respiratory depression. For a drug with a long context-sensitive halftime such as fentanyl, it would be most appropriate to maintain the fentanyl concentration between 1–2 ng/ml and titrate the isoflurane to provide adequate anesthesia. This would achieve the maximal MAC reduction of isoflurane from fentanyl without prolonging recovery due to respiratory depression from an opioid overdose. In contrast, remifentanil has an extremely short context-sensitive halftime (3 min), [8–10]which is even shorter than the time required for a 50% decrease in isoflurane concentration (9.5 min) after approximately 2 h of its administration. Thus, when combining remifentanil with isoflurane it may be more appropriate to maintain the isoflurane concentration slightly greater than MAC awake (i.e., 0.4–0.5%) and the remifentanil at higher concentrations, which are then titrated to achieve adequate anesthesia. As the t1/2 ke0 (time for a 50% equilibration between blood concentration and its effect site) for remifentanil is extremely short (1–1.5 min.), [8,9]depth of anesthesia can be rapidly titrated with remifentanil by administration of small bolus doses and adjustments in infusion rate. At isoflurane concentrations of 0.4–0.5%, remifentanil concentrations of 4–8 ng/ml (infusion rates of 0.15–0.30 micro gram/kg/min) are likely to be necessary for adequate anesthesia. From these concentrations of remifentanil it will take 3–12 min, as modeled by computer simulations, to decrease to less than 2 ng/ml.
Logistic analysis indicated that in addition to remifentanil and isoflurane concentrations, patient age was not a significant dependent variable in evaluating response to skin incision. Similarly, we did not demonstrate an effect of age on the MAC of isoflurane alone. The majority of the patients were in the 31–55-yr age range (Table 3), and thus, it is likely that these results are attributable to an inadequate distribution of patients across the entire age range, i.e. we had insufficient power to demonstrate an effect of age on the MAC and MAC reduction of isoflurane by remifentanil.
The relative potencies of opioid medications have been compared by various methods including hemodynamic changes, hormonal changes, electroencephalographic changes, respiratory depression, definition of the minimal effective analgesic concentration, and response to skin incision when combined with 66% nitrous oxide [28,29]or in terms of MAC reduction of volatile anesthetic agents. [4,5]It is important when comparing the potencies of different drugs that a reproducible and specific drug effect be used. Drug effects such as hemodynamic response, hormonal response, and electroencephalographic changes are not specific measures of opioid drug efficacy, and may vary with different surgical and anesthetic maneuvers. The primary measure of opioid efficacy is analgesia. Analgesia in the awake patient is a very subjective measure and thus results in great variability of opioid efficacy. The ability of an opioid to reduce the MAC of isoflurane provides a more objective measure of the analgesic efficacy of the opioid during anesthesia. A fentanyl blood concentration of between 0.5 and 1.67 ng/ml, an alfentanil blood concentration of 28.8 ng/ml, or a sufentanil concentration of 0.145 ng/ml decrease the MAC of isoflurane by 50%. [2,4,5]This suggests that remifentanil (whole blood concentration) is slightly more potent (1:1.2) than fentanyl (plasma concentration), and is about 70 times more potent than alfentanil (plasma concentration;Table 6). The potency of remifentanil established in this study is confirmed by other studies using different models which have determined its potency relative to alfentanil (plasma concentration) as 30–75 times greater. [7,26,31].
Remifentanil clearance (28–35 ml/min/kg) was consistent with previous estimates in healthy volunteers and anesthetized patients. [9,10]As expected, this clearance was unaltered by isoflurane.
The ability of the CACI infusion pump to achieve the targeted remifentanil concentration was assessed by the performance error of the observed and CACI-targeted remifentanil concentrations. The results indicated that the observed remifentanil concentrations were approximately 36% greater than the targeted concentration. This difference can be explained by comparing the pharmacokinetic parameters used in programming CACI and the clearance of remifentanil estimated in this patient population. The pharmacokinetic parameters were obtained from four subjects at the largest dose tolerated in a previous investigation. Using the central compartment volume (Vc 0.12 l/kg) and elimination rate constant (K10of 0.376 min sup -1) that were programmed into the CACI pump, the predicted clearance for this patient population would be 45 ml/min/kg, which is approximately 22–38% greater than that determined for these patients. This would account for the difference between the expected and observed remifentanil concentrations.
In conclusion, a 50% reduction in the MAC of isoflurane was produced by a remifentanil concentration of 1.37 ng/ml, indicating that remifentanil in the concentration domain is slightly more potent than fentanyl. Remifentanil concentrations greater than 4–8 ng/ml produced little further reduction in the MAC of isoflurane, with a maximum reduction of 91% at a concentration of 32 ng/ml. The clearance of remifentanil was not altered by isoflurane.