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MAC reduction of isoflurane by sufentanil
British Journal of Anaesthesia 1994; 72: 42^16
MAC reduction of isoflurane by sufentanil M. D. BRUNNER, P. BRAITHWAITE, R. JHAVERI, A. I. MCEWAN, D. K. GOODMAN, L. R. SMITH AND P. S. A. GLASS
PATIENTS AND METHODS
SUMMARY
KEY WORDS Anaesthetics, volatile: isoflurane, minimum alveolar concentration. Analgesics, opioid: sufentanil. Potency, minimum alveolar concentration.
The minimum alveolar concentration necessary to prevent movement in 50 % of patients (MAC) was defined originally by Eger, Saidman and Brandstater [1] and has become the standard measure of anaesthetic potency. The MAC of the potent volatile anaesthetics are reduced by increasing plasma concentrations of opioids [2—5]; the degree by which MAC is reduced may be used as a measure of opioid potency [2]. The MAC of isoflurane is reduced by 50% with a plasma fentanyl concentration of 1.67 ng ml"1 (95% confidence limits 1.11, 2.38 ng ml"1) [2]. The MAC reduction of isoflurane produced by sufentanil in humans has not previously been determined. The purpose of this study was to quantify the MAC reduction of isoflurane by sufentanil in humans, when both drugs had reached a steady concentration and had equilibrated with the effect site. By comparing the MAC reduction of isoflurane by sufentanil with that obtained for fentanyl, the relative potency of sufentanil to fentanyl could be defined.
This study was approved by the Duke Institutional Review Board. We studied 76 ASA I and II unpremedicated patients aged between 18 and 60 yr. All patients gave written informed consent. We excluded patients if they were pregnant, taking medication known to alter MAC (psychotropics or opioids), those in whom an inhalation induction was contraindicated (hiatus hernia, obesity, oesophageal reflux) and those in whom any sudden movement would be dangerous (patients having surgery on the head or neck). The patients were allocated randomly to receive a target plasma concentration of sufentanil 0 (group A), 0.1 (group B), 0.3 (group C) or 0.6 (group D) ng ml"1. Within each sufentanil group, the patients were further allocated randomly to receive isoflurane to five different predetermined end-tidal concentrations (fig. 1). On arrival of the patient at the operating theatre, an intravenous cannula was sited and routine monitoring started. Sufentanil was administered using computer assisted continuous infusion (CACI)—a
1.8-1 „
1.6-
S 1-2-I c 1-0 .2 0.8 -
1 0.6 I 0.4 UJ
0.20
0.1 0.3 0.6 Target sufentanil concn (ng ml )
FIG. 1. The patient randomization scheme. End-tidal isoflurane concentrations for each subject in each of the targeted sufentanil concentration groups.
M. D. BRUNNER, M.B., B.S., F.R.C.A.; R. JHAVERI, M.B., B.S., F.F.A.R.C.S.I.; D.K.GOODMAN, B.S.; L. R. SMITH, PH.D.; P. S. A. GLASS, M.B., CH.B., F.F.A.(S.A.).; Department of Anes-
thesia, Duke University Medical Center, Durham, North Carolina 27710, U.S.A. P. BRAITHWAITE, M.B., CH.B., F.F.A.R.C.S.I., De-
partment of Anaesthesia, The Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF. A. I. MCEWAN, M.B., CH.B.,
F.R.C.A., Department of Anaesthesia, St George's Hospital, Blackshaw Road, Tooting, London SW17 0QT. Accepted for Publication: August 3, 1993. Correspondence to P. S. A. Glass.
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We have shown previously that a plasma fentanyl concentration of 1.67 ng m/~' reduced the MAC of isoflurane by 50%. By comparing equal degrees of MAC reduction by sufentanil, we may determine the potency ratio of these opioids. Seventy-six patients were allocated randomly to receive predetermined infusions of sufentanil, and end-tidal concentrations of isoflurane in oxygen. Blood samples were obtained 10 min after the start of the infusion, and just before and after skin incision. Any purposeful movement by the patient was recorded. The MAC reduction of isoflurane produced by sufentanil was obtained using a logistic regression model. A sufentanil plasma concentration of 0.145 ng ml-1 (95% confidence limits 0.04, 0.26 ng mt1) resulted in a 50% reduction in the MAC of isoflurane. At a plasma concentration greater than 0.5 ng mt1, sufentanil exhibited a ceiling effect. (Br. J. Anaesth. 1994; 72: 42-46)
ISOFLURANE MAC AND SUFENTANIL
Pr [no movement] = 1/1+exp where Xt = measured plasma sufentanil concentration ; Xt = expired isoflurane concentration; /? = regression intercept parameter; /?, = sufentanil par-
ameter; /?2 = isoflurane regression parameter; pit = regression parameter for the product of the measured sufentanil and expired isoflurane concentrations (interaction parameter). MAC was determined by setting the probability of no movement to 0.5 and solving for isoflurane as a function of the measured sufentanil concentration: The estimate of variability in Xt was derived using statistical differentials [9]. The parameters of the model are given in the Appendix. RESULTS
We enrolled 76 patients in the study. Ten patients were excluded from subsequent analysis because measured plasma concentrations of sufentanil before and after incision were not within 30 % or 0.05 ng ml"1 of each other. Thus the results of 66 patients are presented (mean age 38.3 yr (range 19—60 yr); mean weight 74.2 kg (range 43-116 kg); 42 males). 2.0!
Infusion + 10 min FIG. 2. Measured plasma concentrations of sufentanil taken 10 min after the initiation of infusion and before and after skin incision.
2.0-1
Sufentanil concn (ng ml FIG. 3. MAC reduction of isoflurane by increasing concentrations of sufentanil: solid line = maximum likelihood (logistic regression) solution; dashed lines = 95% confidence interval of isoflurane MAC. + = No movement; — = movement, n = 66.
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pharmacokinetic model-driven infusion device [6, 7]. Sufentanil was started in patients in groups B, C and D at their randomized target plasma concentration. The target concentration entered into CACI was maintained for at least 20 min before skin incision. At the same time, a gaseous induction of anaesthesia was performed with increasing concentrations of isoflurane in oxygen. After loss of consciousness, suxamethonium 1.5 mg kg"1 i.v. was given and the trachea intubated. The lungs were ventilated mechanically and the inspired concentration of isoflurane manipulated to achieve the predetermined end-tidal isoflurane concentration. This was measured using a Puritan Bennett Anaesthetic Agent Monitor 222. Before each use, the monitor was switched on for 30 min to allow it to warm up, and a two-point calibration with a standard calibration gas was performed. The endtidal isoflurane concentration was kept constant for a minimum of 15 min before incision. Venous blood samples, to determine plasma sufentanil were taken from an indwelling i.v. cannula in the arm contralateral to that receiving the sufentanil infusion, for measurements of plasma sufentanil concentration. This cannula was used only for obtaining blood samples and was placed after the patient was asleep. The samples were obtained 10 min after the start of the sufentanil infusion, just before, and 1 min after skin incision to ensure that the plasma concentration of sufentanil was constant throughout the study. The samples were immediately placed on ice. The plasma was separated soon after and kept frozen at — 70 °C until required for analysis using a previously described radioimmunoassay (RIA) technique [8]. The lower limit of detection for this assay was 0.1 ng ml"1. For the smaller serum concentrations of sufentanil, a sorbent extraction procedure was performed to enhance the specificity and sensitivity of the assay. The lower limit of detection for the enhanced assay was 0.02 ng ml"1. The assay was linear over the range of 20-80% binding, with intra- and intersample coefficients of variation of 6.4 and 13.6 %. Before skin incision, a peripheral nerve stimulator was used to ensure that full recovery of neuromuscular function had occurred after the suxamethonium. For 1 min after incision, the patients were observed for any purposeful movement which did not include chewing on the tube, swallowing or coughing [9]. To ensure that a steady plasma concentration was maintained, patients were included only if the difference between their measured sufentanil concentrations before and after incision were less than 30%, or within 0.05 ng ml"1. The pre-incision concentration of sufentanil was used within the model. The MAC and MAC reduction of isoflurane by sufentanil was obtained using a logistic regression model [2]:
43
BRITISH JOURNAL OF ANAESTHESIA
44 No movement
7K
Movement
1.8 1.2 1.4 1.6 Expired isoflurane (%) FIG. 4. Isoflurane end-tidal concentration at which patients did or did not move when only isoflurane was administered. Upward tick = patient who did not move; downward tick = patient who did move. The MAC was calculated as 1.4% (95% confidence interval: 0.66%, 2.13%).
0.8
1.0
TABLE I. MAC and MAC reduction of isoflurane with increasing concentrations of sufentanil
MAC of isoflurane (95% Cl)
Isoflurane MAC reduction
(%)
(%)
0.0 0.1 0.2 0.5 1.0 1.4
1.40(0.66,2.13) 0.83(0.54, 1.12) 0.59(0.36,0.81) 0.33 (0.22, 0.44) 0.21 (0.08,0.34) 0.17(0.01,0.33)
44.2 60.4 77.8 85.9 88.6
The measured plasma concentrations of sufentanil tended to be greater than the target concentration. However, the measured sufentanil concentration in each individual remained relatively constant between 10 min, before and after incision (fig. 2). The preincision concentrations of sufentanil used in the analysis of the MAC reduction were from 0 to 1.39 ng ml"1. The MAC reduction of isoflurane produced by sufentanil is presented in figure 3. In the patients studied, the MAC of isoflurane alone was 1.4% (95% confidence interval (CI) 0.6, 2.37%) (fig. 4). Sufentanil O.lngm]- 1 produced a 44.2% MAC reduction (table I). Increasing the sufentanil plasma concentration to 0.5 ng ml"1 resulted in a 77.8 % reduction in isoflurane MAC. Sufentanil concentrations greater than 0.5 ng ml"1 produced a limited further reduction in MAC. The maximum MAC reduction over the concentrations studied (up to l ^ n g m T 1 ) was 88.6%. A 50% reduction in the MAC of isoflurane was produced by a sufentanil concentration of 0.145 ng ml"1 (95% confidence limits 0.04, 0.26 ng ml-1). DISCUSSION
The aim of this study was to determine the extent of the MAC reduction of isoflurane by sufentanil in humans with both drugs at a steady concentration and equilibrated with the effect site. By comparing the plasma concentrations that produced an equal MAC reduction (50%), we have established the potency of sufentanil as 11.5 times greater than that of fentanyl. The CACI device which we used in this study consists of a microprocessor programmed with a pharmacokinetic model interfaced with an infusion pump [6, 7]. A pharmacokinetic model is used to
By using CACI in this study, we were able to infuse sufentanil to a predetermined target plasma concentration. Equilibrium between the plasma and the effect site concentration of sufentanil occurred as the infusion was maintained for 20 min before skin incision. Sufentanil exhibits hysteresis when given as a bolus, such that the observed effect lags behind the plasma concentration. The half-life for the plasma and effect compartment to reach equilibrium (7^*°°) in the case of sufentanil is 6.2 (SD 2.8) min [17]. Thus the 20-min (3 x 7j*<»>) infusion before surgical skin incision compensated for this hysteresis. The desired end-tidal isoflurane concentration was maintained for at least 15 min before incision to allow the alveolar and brain concentrations of isoflurane to reach equilibrium [18]. In this study we showed that sufentanil markedly altered the MAC of isoflurane. The initial decrease in isoflurane MAC with increasing sufentanil plasma concentration was steep. However, at a plasma concentration greater than 0.5 ng ml"1, sufentanil exhibited a ceiling effect in its ability to reduce the MAC of isoflurane. This observation is in agreement with the MAC reduction of halothane produced by sufentanil in rats [19] and of enflurane in dogs [19]. In the latter study, a plasma concentration of 48 (8) ng ml"1 produced a maximum MAC reduction of 70.5 (5.7)%, which was not statistically greater than the MAC reduction of 56.5 (7.3) % produced by sufentanil 0.92 (0.19) ng ml-1. Fentanyl, in dogs, causes a greater MAC reduction in isoflurane than enflurane [21, 22]. This may be because enflurane has cerebral excitatory effects. Therefore, the greater degree of MAC reduction of isoflurane in humans, than that of enflurane in dogs by sufentanil (85.9% vs 56% with sufentanil approximately 1 ng ml-1), may be caused by differences both in the volatile anaesthetic and between
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Sufentanil concentration (ng ml"1)
derive the infusion rate to deliver a drug to a preset plasma concentration. This infusion rate is communicated electronically to the infusion pump. At frequent intervals, the current predicted plasma concentration is compared with the target concentration and a new infusion rate calculated. The first such model, the BET scheme, was described in 1968 [11] and led to the development of other models expressed either as multiexponential equations or compartment models [12, 13]. The BET model was first used clinically in 1981 by Schwilden [14], who used a computer to control an infusion pump. The accuracy of CACI for various opioids and pharmacokinetic models has been evaluated [6, 15], although this has not been done for sufentanil. We used the pharmacokinetic parameters published by Bovill and colleagues [16]. In this study, using these pharmacokinetic parameters, we found a performance error of 60 %. These values do not describe fully the accuracy of the sufentanil pharmacokinetic model used, as only a limited number of samples was obtained in each patient. Of greater importance for this study was that the sufentanil concentration was maintained steady so that plasma and effect compartment equilibration occurred. Figure 2 illustrated that CACI was able to maintain a constant plasma concentration in the patients studied.
ISOFLURANE MAC AND SUFENTANIL
The minimal effective analgesic concentration (MEAC) is a primary measure of efficacy in patients. The relative potency of sufentanil to fentanyl based on MEAC is 1:15 [33, 34]. MEAC, although a good
measure of opioid effect, demonstrates marked interpatient variability, with up to five-fold differences between patients [33-36]. It is also a subjective measurement of opioid effect and thus may not be the ideal measure to establish relative potency. Sufentanil is 12 times more potent than fentanyl, based on the IC60 (plasma concentration to produce 50% of the maximal EEG effect) [17]. Although equilibration between plasma and effect site was obtained in this study, the EEG is not a specific measure of opioid effect [37]. As the determination of MAC involves a specific clinical end-point, namely purposeful movement by the patient on skin incision, it has become the gold standard used to describe the potency of volatile anaesthetic gases. Similarly, the reduction of MAC produced by opioids is a specific, objective and reproducible measure of opioid drug effect, allowing for the determination of the potency of sufentanil. The relative potency of fentanyl to sufentanil based on the IC50 (1:12) is similar to the relative potency determined by MAC reduction (1:11.5). This would tend to support the IC50 as a measure of opioid effect for these two opioids.
APPENDIX The parameter estimates were :#, = 1.9995(P < 0.05),/?, = 0.6700 (/><0.72), & = -1.3368 (/><0.16) and /?„ = -11.3722 (P < 0.02), overall model chi-square = 17.276 (3 df, P < 0.0006). Because of the large interaction term, direct interpretation of /?, and fSt is difficult. However, even though these are not significant, they are included because of the significant interaction. This model was adequate for prediction—the area under the receiver operating curve [10] was 0.803.
REFERENCES 1. Eger El, Saidman LJ, Brandstater B. Minimum alveolar anesthetic concentration: A standard of anesthetic potency. Antsthtsiology 1965; 26: 756-763. 2. McEwan AI, Smith C, Dyar O, Goodman D, Smith LR, Glass PSA. Isoflurane minimum alveolar concentration reduction by fentanyl. Anesthesiology 1993; 78: 864-869. 3. Saidman LJ, Eger El n. Effect of nitrous oxide and of narcotic premedication on the alveolar concentration of halothane required for anesthesia. Anesthesiology 1964; 25: 302-306. 4. Munson ES, Saidman LJ, Eger El II. Effects of nitrous oxide and morphine on the minimum anesthetic concentration of fluroxene. Anesthesiology 1965; 26: 134-139. 5. Sebel PS, Glass PSA, Fletcher JE, Murphy MR, Gallagher C, Quill T. Reduction of MAC of desflurane with fentanyl. Anesthesiology 1992; 76: 52-59. 6. Glass PSA, Jacobs JR, Smith LR, Ginsberg B, Quill TJ, Bai SA, Reves JG. Pharmacokinetic model-driven infusion of fentanyl: Assessment of accuracy. Anesthesiology 1990; 73: 1082-1090. 7. Glass PSA, Jacobs JR, Reves JG. Intravenous drug delivery systems. In: Miller RD, ed. Anesthesia. New York, Churchill Livingstone Inc., 1990; 367-388. 8. Michials M, Hcndriks R, Hoykants J. Radioimmunoassay of the new opiate and analgesics alfentanil and sufentanil. Preliminary pharmacokinetic profile in man. Journal of Pharmacy and Pharmacology 1983; 35: 88-93. 9. Ku HH. Notes on the use of propagation of error formulas. Journal of Research of the National Bureau of Standards—C. Engineering and Instrumentation 1966; 70C: 263-273. 10. Hanley JA, McNeil J. The meaning and use of the area under a receiver operating curve (ROC). Radiology 1982; 143: 29-36. 11. Kruger-Thiemer E. Continuous intravenous infusion and
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species. Similarly, the values for the MAC reduction of isofiurane produced by sufentanil may not necessarily hold true for interactions between sufentanil and other volatile anaesthetic gases. Similar ceiling effects on MAC reduction have been demonstrated for fentanyl [2] and alfentanil, although with very large concentrations of alfentanil (QOOngml-1) [23] a 100% reduction in isoflurane MAC was achieved. However, when alfentanil was studied, thiopentone was used for induction, which may have influenced the results. We failed to show a 100% reduction in isoflurane MAC by sufentanil, but very great plasma concentrations of sufentanil were not used. Clinically, the implications of our findings are that a substantial reduction in isoflurnae requirements may be achieved with small plasma concentrations of sufentanil (0.1-0.5 ng ml"1). Increasing the plasma concentration of sufentanil to anything much greater than 0.5 ng ml"1 results in only minimal further reductions in isoflurane requirement. In addition, side effects (rigidity or respiratory depression) are more likely to occur with greater sufentanil concentrations. A plasma concentration of sufentanil 0.15 ng ml"1 may be achieved with a manual infusion consisting of an initial loading dose of 0.15 jig kg"1 (given over 1 min), followed by a continuous infusion of 0.003 (ig kg"1 min"1. A 0.5-ugkg"1 loading dose and an infusion of 0.008 ug kg"1 min"1 would provide a sufentanil plasma concentration of 0.5 ng ml"1. In a previous study by one of the authors using the exact same methodology, a 50 % MAC reduction in isoflurane was achieved with fentanyl 1.67 ng ml"1 (95% confidence limits 1.11, 2.38 ng ml"1) [2]. In this study, a 50% MAC reduction of isoflurane was produced by a sufentanil concentration of 0.145 ng ml"1 (95% confidence limits 0.04, 0.26 ng ml"1). Thus the relative potency of sufentanil to fentanyl based on their ability to reduce MAC is 11.5:1. Many attempts have been made to define the relative potencies of the different opioids. Sufentanil has been found to be three to 10 times more potent than fentanyl, based on the dose requirements using haemodynamic changes [24-26], hormonal [26] and EEG [28-30] responses during surgery as a guide to anaesthetic depth, and by the dose requirements •during a nitrous oxide-opioid technique [31]. Because of differences in pharmacokinetics between individuals [32], the same dose can result in different plasma concentrations. Also, there is significant hysteresis between plasma concentration and the resultant biophase concentration after a bolus dose of sufentanil [17]. Therefore it is less appropriate to base relative potency on dose-response studies. It is important when comparing the potencies of different drugs that a reproducible and specific drug effect be used. Drug effects such as haemodynamic and EEG changes are not specific measures of opioid drug effect, and may vary with different surgical and anaesthetic manoeuvres. The primary measure of the efficacy of an opioid is analgesia.
45
BRITISH JOURNAL OF ANAESTHESIA
46
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multicompartment accumulation. European Journal of Pharmacology 1968; 4: 317-324. Alvis JM, Reves JG, Govier AV, Mcnkhaus PG, Henling CE, Spain JA, Bradley E. Computer assisted continuous infusions of fentanyl during cardiac anesthesia: comparison with a manual method. Anesthesiology 1985; 63: 41-49. White M, Kenny GNC. Intravenous propofol anaesthesia using a computerized infusion system. Anaesthesia 1990; 45: 204-209. Schwilden H. A general method for calculating the dosage scheme in linear pharmacokinetics. European Journal of Clinical Pharmacology 1981; 20: 379-386. Ausems ME, Stanski DR, Hug CC jr. An evaluation of the accuracy of pharmacokinetic data for the computer assisted infusion of alfentanil. British Journal of Anaesthesia 1985; 57: 1217-1225. Bovill JG, Sebel PS, Blackburn CL, Oei-Lim V, Heykants JJ. The pharmacokinetics of sufentanil in surgical patients. Anesthesiology 1984; 61: 502-506. Scon JC, Cooke JE, Stanski DR. Elcctroencephalographic quantitation of opioid effect: Comparative pharmacodynamics of fentanyl and sufentanil. Anesthesiology 1991; 74: 34-^12. Quasha AL, Egcr IE, Tinker JH. Determination and application of MAC. Anesthesiology 1980; 53: 315-334. Hecker BR, Lake CL, DiFazio CA, Moscicki JC, Engle JS. The decrease of the minimum alveolar anesthetic concentration produced by sufentanil in rats. Anesthesia and Analgesia 1983; 62: 987-990. Hall RI, Murphy MR, Hug CC jr. The enflurane sparing effect of sufentanil in dogs. Anesthesiology 1987; 67: 518-525. Murphy MR, Hug CC jr. The anesthetic potency of fentanyl in terms of its reduction of enflurane MAC. Anesthesiology 1982; 57: 485-488. Murphy MR, Hug CC jr. Efficacy of fentanyl in reducing isoflurane MAC; antagonism by naloxone and nalbuphine. Anesthesiology 1983; 53 (3A): A338. Westmoreland C, Sebel PS, Gropper A, Hug CC jr. Reduction of isoflurane MAC by fentanyl or alfentanyl. Anesthesiology 1992; 77 (3A): A394. Shupak RC, Harp JR. Comparison between high-dose sufentanil—oxygen and high-dose fentanyl—oxygen for ncuroanaesthesia. British Journal of Anaesthesia 1985; 57: 375-381. de Lange S, Boscoe MJ, Stanley TH, Pace N. Comparison of sufentanil-O, and fentanyl-O, for coronary artery surgery. Anesthesiology 1982; 56: 112-118. Van de Walle J, Lauwers P, Ariaensen H. Double blind
MAC reduction of isoflurane by sufentanil M. D. BRUNNER, P. BRAITHWAITE, R. JHAVERI, A. I. MCEWAN, D. K. GOODMAN, L. R. SMITH AND P. S. A. GLASS
PATIENTS AND METHODS
SUMMARY
KEY WORDS Anaesthetics, volatile: isoflurane, minimum alveolar concentration. Analgesics, opioid: sufentanil. Potency, minimum alveolar concentration.
The minimum alveolar concentration necessary to prevent movement in 50 % of patients (MAC) was defined originally by Eger, Saidman and Brandstater [1] and has become the standard measure of anaesthetic potency. The MAC of the potent volatile anaesthetics are reduced by increasing plasma concentrations of opioids [2—5]; the degree by which MAC is reduced may be used as a measure of opioid potency [2]. The MAC of isoflurane is reduced by 50% with a plasma fentanyl concentration of 1.67 ng ml"1 (95% confidence limits 1.11, 2.38 ng ml"1) [2]. The MAC reduction of isoflurane produced by sufentanil in humans has not previously been determined. The purpose of this study was to quantify the MAC reduction of isoflurane by sufentanil in humans, when both drugs had reached a steady concentration and had equilibrated with the effect site. By comparing the MAC reduction of isoflurane by sufentanil with that obtained for fentanyl, the relative potency of sufentanil to fentanyl could be defined.
This study was approved by the Duke Institutional Review Board. We studied 76 ASA I and II unpremedicated patients aged between 18 and 60 yr. All patients gave written informed consent. We excluded patients if they were pregnant, taking medication known to alter MAC (psychotropics or opioids), those in whom an inhalation induction was contraindicated (hiatus hernia, obesity, oesophageal reflux) and those in whom any sudden movement would be dangerous (patients having surgery on the head or neck). The patients were allocated randomly to receive a target plasma concentration of sufentanil 0 (group A), 0.1 (group B), 0.3 (group C) or 0.6 (group D) ng ml"1. Within each sufentanil group, the patients were further allocated randomly to receive isoflurane to five different predetermined end-tidal concentrations (fig. 1). On arrival of the patient at the operating theatre, an intravenous cannula was sited and routine monitoring started. Sufentanil was administered using computer assisted continuous infusion (CACI)—a
1.8-1 „
1.6-
S 1-2-I c 1-0 .2 0.8 -
1 0.6 I 0.4 UJ
0.20
0.1 0.3 0.6 Target sufentanil concn (ng ml )
FIG. 1. The patient randomization scheme. End-tidal isoflurane concentrations for each subject in each of the targeted sufentanil concentration groups.
M. D. BRUNNER, M.B., B.S., F.R.C.A.; R. JHAVERI, M.B., B.S., F.F.A.R.C.S.I.; D.K.GOODMAN, B.S.; L. R. SMITH, PH.D.; P. S. A. GLASS, M.B., CH.B., F.F.A.(S.A.).; Department of Anes-
thesia, Duke University Medical Center, Durham, North Carolina 27710, U.S.A. P. BRAITHWAITE, M.B., CH.B., F.F.A.R.C.S.I., De-
partment of Anaesthesia, The Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF. A. I. MCEWAN, M.B., CH.B.,
F.R.C.A., Department of Anaesthesia, St George's Hospital, Blackshaw Road, Tooting, London SW17 0QT. Accepted for Publication: August 3, 1993. Correspondence to P. S. A. Glass.
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We have shown previously that a plasma fentanyl concentration of 1.67 ng m/~' reduced the MAC of isoflurane by 50%. By comparing equal degrees of MAC reduction by sufentanil, we may determine the potency ratio of these opioids. Seventy-six patients were allocated randomly to receive predetermined infusions of sufentanil, and end-tidal concentrations of isoflurane in oxygen. Blood samples were obtained 10 min after the start of the infusion, and just before and after skin incision. Any purposeful movement by the patient was recorded. The MAC reduction of isoflurane produced by sufentanil was obtained using a logistic regression model. A sufentanil plasma concentration of 0.145 ng ml-1 (95% confidence limits 0.04, 0.26 ng mt1) resulted in a 50% reduction in the MAC of isoflurane. At a plasma concentration greater than 0.5 ng mt1, sufentanil exhibited a ceiling effect. (Br. J. Anaesth. 1994; 72: 42-46)
ISOFLURANE MAC AND SUFENTANIL
Pr [no movement] = 1/1+exp where Xt = measured plasma sufentanil concentration ; Xt = expired isoflurane concentration; /? = regression intercept parameter; /?, = sufentanil par-
ameter; /?2 = isoflurane regression parameter; pit = regression parameter for the product of the measured sufentanil and expired isoflurane concentrations (interaction parameter). MAC was determined by setting the probability of no movement to 0.5 and solving for isoflurane as a function of the measured sufentanil concentration: The estimate of variability in Xt was derived using statistical differentials [9]. The parameters of the model are given in the Appendix. RESULTS
We enrolled 76 patients in the study. Ten patients were excluded from subsequent analysis because measured plasma concentrations of sufentanil before and after incision were not within 30 % or 0.05 ng ml"1 of each other. Thus the results of 66 patients are presented (mean age 38.3 yr (range 19—60 yr); mean weight 74.2 kg (range 43-116 kg); 42 males). 2.0!
Infusion + 10 min FIG. 2. Measured plasma concentrations of sufentanil taken 10 min after the initiation of infusion and before and after skin incision.
2.0-1
Sufentanil concn (ng ml FIG. 3. MAC reduction of isoflurane by increasing concentrations of sufentanil: solid line = maximum likelihood (logistic regression) solution; dashed lines = 95% confidence interval of isoflurane MAC. + = No movement; — = movement, n = 66.
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pharmacokinetic model-driven infusion device [6, 7]. Sufentanil was started in patients in groups B, C and D at their randomized target plasma concentration. The target concentration entered into CACI was maintained for at least 20 min before skin incision. At the same time, a gaseous induction of anaesthesia was performed with increasing concentrations of isoflurane in oxygen. After loss of consciousness, suxamethonium 1.5 mg kg"1 i.v. was given and the trachea intubated. The lungs were ventilated mechanically and the inspired concentration of isoflurane manipulated to achieve the predetermined end-tidal isoflurane concentration. This was measured using a Puritan Bennett Anaesthetic Agent Monitor 222. Before each use, the monitor was switched on for 30 min to allow it to warm up, and a two-point calibration with a standard calibration gas was performed. The endtidal isoflurane concentration was kept constant for a minimum of 15 min before incision. Venous blood samples, to determine plasma sufentanil were taken from an indwelling i.v. cannula in the arm contralateral to that receiving the sufentanil infusion, for measurements of plasma sufentanil concentration. This cannula was used only for obtaining blood samples and was placed after the patient was asleep. The samples were obtained 10 min after the start of the sufentanil infusion, just before, and 1 min after skin incision to ensure that the plasma concentration of sufentanil was constant throughout the study. The samples were immediately placed on ice. The plasma was separated soon after and kept frozen at — 70 °C until required for analysis using a previously described radioimmunoassay (RIA) technique [8]. The lower limit of detection for this assay was 0.1 ng ml"1. For the smaller serum concentrations of sufentanil, a sorbent extraction procedure was performed to enhance the specificity and sensitivity of the assay. The lower limit of detection for the enhanced assay was 0.02 ng ml"1. The assay was linear over the range of 20-80% binding, with intra- and intersample coefficients of variation of 6.4 and 13.6 %. Before skin incision, a peripheral nerve stimulator was used to ensure that full recovery of neuromuscular function had occurred after the suxamethonium. For 1 min after incision, the patients were observed for any purposeful movement which did not include chewing on the tube, swallowing or coughing [9]. To ensure that a steady plasma concentration was maintained, patients were included only if the difference between their measured sufentanil concentrations before and after incision were less than 30%, or within 0.05 ng ml"1. The pre-incision concentration of sufentanil was used within the model. The MAC and MAC reduction of isoflurane by sufentanil was obtained using a logistic regression model [2]:
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BRITISH JOURNAL OF ANAESTHESIA
44 No movement
7K
Movement
1.8 1.2 1.4 1.6 Expired isoflurane (%) FIG. 4. Isoflurane end-tidal concentration at which patients did or did not move when only isoflurane was administered. Upward tick = patient who did not move; downward tick = patient who did move. The MAC was calculated as 1.4% (95% confidence interval: 0.66%, 2.13%).
0.8
1.0
TABLE I. MAC and MAC reduction of isoflurane with increasing concentrations of sufentanil
MAC of isoflurane (95% Cl)
Isoflurane MAC reduction
(%)
(%)
0.0 0.1 0.2 0.5 1.0 1.4
1.40(0.66,2.13) 0.83(0.54, 1.12) 0.59(0.36,0.81) 0.33 (0.22, 0.44) 0.21 (0.08,0.34) 0.17(0.01,0.33)
44.2 60.4 77.8 85.9 88.6
The measured plasma concentrations of sufentanil tended to be greater than the target concentration. However, the measured sufentanil concentration in each individual remained relatively constant between 10 min, before and after incision (fig. 2). The preincision concentrations of sufentanil used in the analysis of the MAC reduction were from 0 to 1.39 ng ml"1. The MAC reduction of isoflurane produced by sufentanil is presented in figure 3. In the patients studied, the MAC of isoflurane alone was 1.4% (95% confidence interval (CI) 0.6, 2.37%) (fig. 4). Sufentanil O.lngm]- 1 produced a 44.2% MAC reduction (table I). Increasing the sufentanil plasma concentration to 0.5 ng ml"1 resulted in a 77.8 % reduction in isoflurane MAC. Sufentanil concentrations greater than 0.5 ng ml"1 produced a limited further reduction in MAC. The maximum MAC reduction over the concentrations studied (up to l ^ n g m T 1 ) was 88.6%. A 50% reduction in the MAC of isoflurane was produced by a sufentanil concentration of 0.145 ng ml"1 (95% confidence limits 0.04, 0.26 ng ml-1). DISCUSSION
The aim of this study was to determine the extent of the MAC reduction of isoflurane by sufentanil in humans with both drugs at a steady concentration and equilibrated with the effect site. By comparing the plasma concentrations that produced an equal MAC reduction (50%), we have established the potency of sufentanil as 11.5 times greater than that of fentanyl. The CACI device which we used in this study consists of a microprocessor programmed with a pharmacokinetic model interfaced with an infusion pump [6, 7]. A pharmacokinetic model is used to
By using CACI in this study, we were able to infuse sufentanil to a predetermined target plasma concentration. Equilibrium between the plasma and the effect site concentration of sufentanil occurred as the infusion was maintained for 20 min before skin incision. Sufentanil exhibits hysteresis when given as a bolus, such that the observed effect lags behind the plasma concentration. The half-life for the plasma and effect compartment to reach equilibrium (7^*°°) in the case of sufentanil is 6.2 (SD 2.8) min [17]. Thus the 20-min (3 x 7j*<»>) infusion before surgical skin incision compensated for this hysteresis. The desired end-tidal isoflurane concentration was maintained for at least 15 min before incision to allow the alveolar and brain concentrations of isoflurane to reach equilibrium [18]. In this study we showed that sufentanil markedly altered the MAC of isoflurane. The initial decrease in isoflurane MAC with increasing sufentanil plasma concentration was steep. However, at a plasma concentration greater than 0.5 ng ml"1, sufentanil exhibited a ceiling effect in its ability to reduce the MAC of isoflurane. This observation is in agreement with the MAC reduction of halothane produced by sufentanil in rats [19] and of enflurane in dogs [19]. In the latter study, a plasma concentration of 48 (8) ng ml"1 produced a maximum MAC reduction of 70.5 (5.7)%, which was not statistically greater than the MAC reduction of 56.5 (7.3) % produced by sufentanil 0.92 (0.19) ng ml-1. Fentanyl, in dogs, causes a greater MAC reduction in isoflurane than enflurane [21, 22]. This may be because enflurane has cerebral excitatory effects. Therefore, the greater degree of MAC reduction of isoflurane in humans, than that of enflurane in dogs by sufentanil (85.9% vs 56% with sufentanil approximately 1 ng ml-1), may be caused by differences both in the volatile anaesthetic and between
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Sufentanil concentration (ng ml"1)
derive the infusion rate to deliver a drug to a preset plasma concentration. This infusion rate is communicated electronically to the infusion pump. At frequent intervals, the current predicted plasma concentration is compared with the target concentration and a new infusion rate calculated. The first such model, the BET scheme, was described in 1968 [11] and led to the development of other models expressed either as multiexponential equations or compartment models [12, 13]. The BET model was first used clinically in 1981 by Schwilden [14], who used a computer to control an infusion pump. The accuracy of CACI for various opioids and pharmacokinetic models has been evaluated [6, 15], although this has not been done for sufentanil. We used the pharmacokinetic parameters published by Bovill and colleagues [16]. In this study, using these pharmacokinetic parameters, we found a performance error of 60 %. These values do not describe fully the accuracy of the sufentanil pharmacokinetic model used, as only a limited number of samples was obtained in each patient. Of greater importance for this study was that the sufentanil concentration was maintained steady so that plasma and effect compartment equilibration occurred. Figure 2 illustrated that CACI was able to maintain a constant plasma concentration in the patients studied.
ISOFLURANE MAC AND SUFENTANIL
The minimal effective analgesic concentration (MEAC) is a primary measure of efficacy in patients. The relative potency of sufentanil to fentanyl based on MEAC is 1:15 [33, 34]. MEAC, although a good
measure of opioid effect, demonstrates marked interpatient variability, with up to five-fold differences between patients [33-36]. It is also a subjective measurement of opioid effect and thus may not be the ideal measure to establish relative potency. Sufentanil is 12 times more potent than fentanyl, based on the IC60 (plasma concentration to produce 50% of the maximal EEG effect) [17]. Although equilibration between plasma and effect site was obtained in this study, the EEG is not a specific measure of opioid effect [37]. As the determination of MAC involves a specific clinical end-point, namely purposeful movement by the patient on skin incision, it has become the gold standard used to describe the potency of volatile anaesthetic gases. Similarly, the reduction of MAC produced by opioids is a specific, objective and reproducible measure of opioid drug effect, allowing for the determination of the potency of sufentanil. The relative potency of fentanyl to sufentanil based on the IC50 (1:12) is similar to the relative potency determined by MAC reduction (1:11.5). This would tend to support the IC50 as a measure of opioid effect for these two opioids.
APPENDIX The parameter estimates were :#, = 1.9995(P < 0.05),/?, = 0.6700 (/><0.72), & = -1.3368 (/><0.16) and /?„ = -11.3722 (P < 0.02), overall model chi-square = 17.276 (3 df, P < 0.0006). Because of the large interaction term, direct interpretation of /?, and fSt is difficult. However, even though these are not significant, they are included because of the significant interaction. This model was adequate for prediction—the area under the receiver operating curve [10] was 0.803.
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species. Similarly, the values for the MAC reduction of isofiurane produced by sufentanil may not necessarily hold true for interactions between sufentanil and other volatile anaesthetic gases. Similar ceiling effects on MAC reduction have been demonstrated for fentanyl [2] and alfentanil, although with very large concentrations of alfentanil (QOOngml-1) [23] a 100% reduction in isoflurane MAC was achieved. However, when alfentanil was studied, thiopentone was used for induction, which may have influenced the results. We failed to show a 100% reduction in isoflurane MAC by sufentanil, but very great plasma concentrations of sufentanil were not used. Clinically, the implications of our findings are that a substantial reduction in isoflurnae requirements may be achieved with small plasma concentrations of sufentanil (0.1-0.5 ng ml"1). Increasing the plasma concentration of sufentanil to anything much greater than 0.5 ng ml"1 results in only minimal further reductions in isoflurane requirement. In addition, side effects (rigidity or respiratory depression) are more likely to occur with greater sufentanil concentrations. A plasma concentration of sufentanil 0.15 ng ml"1 may be achieved with a manual infusion consisting of an initial loading dose of 0.15 jig kg"1 (given over 1 min), followed by a continuous infusion of 0.003 (ig kg"1 min"1. A 0.5-ugkg"1 loading dose and an infusion of 0.008 ug kg"1 min"1 would provide a sufentanil plasma concentration of 0.5 ng ml"1. In a previous study by one of the authors using the exact same methodology, a 50 % MAC reduction in isoflurane was achieved with fentanyl 1.67 ng ml"1 (95% confidence limits 1.11, 2.38 ng ml"1) [2]. In this study, a 50% MAC reduction of isoflurane was produced by a sufentanil concentration of 0.145 ng ml"1 (95% confidence limits 0.04, 0.26 ng ml"1). Thus the relative potency of sufentanil to fentanyl based on their ability to reduce MAC is 11.5:1. Many attempts have been made to define the relative potencies of the different opioids. Sufentanil has been found to be three to 10 times more potent than fentanyl, based on the dose requirements using haemodynamic changes [24-26], hormonal [26] and EEG [28-30] responses during surgery as a guide to anaesthetic depth, and by the dose requirements •during a nitrous oxide-opioid technique [31]. Because of differences in pharmacokinetics between individuals [32], the same dose can result in different plasma concentrations. Also, there is significant hysteresis between plasma concentration and the resultant biophase concentration after a bolus dose of sufentanil [17]. Therefore it is less appropriate to base relative potency on dose-response studies. It is important when comparing the potencies of different drugs that a reproducible and specific drug effect be used. Drug effects such as haemodynamic and EEG changes are not specific measures of opioid drug effect, and may vary with different surgical and anaesthetic manoeuvres. The primary measure of the efficacy of an opioid is analgesia.
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