1University Central Hospital, Helsinki, Finland. 2Jorvi Hospital, Espoo, Finland. 3Department of Biomedicine, University of Helsinki, Helsinki, Finland. 4Bioanalytics, Research & Development, Leiras Inc., Turku, Finland. 5Janssen Research Foundation, Beerse, Belgium
Accepted for publication: April 28, 2000
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Abstract |
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Br J Anaesth 2000; 85: 53340.
Keywords: analgesics opioid, alfentanil; analgesics opioid, fentanyl; analgesics opioid, sufentanil; anaesthetics i.v., propofol; pharmacokinetics, alfentanil; pharmacokinetics, fentanyl; pharmacokinetics, sufentanil; pharmacokinetics, propofol
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Introduction |
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In planning fast-track recovery from a cardiac procedure that is associated with very intense stimuli, it is prudent to administer the opioids to achieve these ceiling concentrations and then titrate the hypnotic or volatile anaesthetic as needed during the procedure.1 Studies using this method and comparing alfentanil, fentanyl and sufentanil together with propofol are lacking. Therefore, we have studied the pharmacokinetics and pharmacodynamics of these three opioids in total intravenous anaesthesia (TIVA) with propofol in patients undergoing coronary artery bypass graft surgery (CABG).
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Methods |
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Routine medication was terminated the evening before surgery, except for beta blockers and long-acting nitrates, which were given concomitantly with the premedication. Aspirin was halted 1 week before surgery. Two hours before induction of anaesthesia, the patients received orally administered lorazepam 40 µg kg1.
Our target plasma concentrations were 400 ng ml1 for alfentanil, 6 ng ml1 for fentanyl and 0.6 ng ml1 for sufentanil. The dosage of alfentanil was adjusted from that of our previous study;2 fentanyl and sufentanil were administered on the assumption that equipotent doses (mg kg1) of alfentanil, fentanyl and sufentanil are approximately 10:1:0.1.3 4 The syringes containing alfentanil 500 µg ml1, fentanyl 50 µg ml1 or sufentanil 5 µg ml1 were prepared by our hospital pharmacy just before induction of anaesthesia. The basic infusion rate of propofol was chosen to avoid intraoperative awareness5 and the infusion rate could be increased over a wide range to prevent arousal in response to noxious stimulation.6 All the staff in the operating room and in the intensive care unit (ICU) remained unaware of the randomization code of the patients.
Before induction of anaesthesia, peripheral venous and radial arterial cannulae were inserted. The systolic arterial blood pressure (SAP) was recorded 35 min after insertion of the radial arterial cannula. Anaesthesia was induced with alfentanil 75 µg kg1, fentanyl 7.5 µg kg1 or sufentanil 0.75 µg kg1, and propofol 1.01.5 mg kg1. The induction dose of propofol was given concomitantly with the opioid within 3 min in order to mask the different onset time of alfentanil compared with those of fentanyl and sufentanil.3 4 All patients received ephedrine 10 mg at the beginning of induction to avoid hypotension.7 At the beginning of induction, continuous infusions were started of propofol 100 µg kg1 min1 and alfentanil 1.5 µg kg1 min1, fentanyl 0.15 µg kg1 min1 or sufentanil 0.015 µg kg1 min1. The rate of opioid infusion was maintained unchanged until skin closure.
Before skin incision, a bolus dose of propofol 0.5 mg kg1 was given, and the infusion rate was increased to 150 µg kg1 min1. Thereafter, the infusion rate of propofol was adjusted between 100 and 250 µg kg1 min1 in steps of 50 µg kg1 min1 to maintain the SAP between 90 and 130 mmHg. During CPB, the rate of propofol was allowed to fall to 50 µg kg1 min1. During the time when the infusion rate of propofol was being increased, a bolus dose of 0.5 mg kg1 was always given. Outside the range of the propofol infusion rate, haemodynamic control was provided by bolus doses of nitroglycerin 0.05 mg, ephedrine 5 mg or norepinephrine 5 µg. Rocuronium 1 mg kg1 was given for muscle paralysis, with additional bolus doses as needed. After endotracheal intubation, the lungs were ventilated with a mixture of oxygen in air. All patients received a slow injection of tranexamic acid 20 mg kg1 before initiation of CPB.
All surgical procedures were performed under moderate hypothermia (nasopharyngeal temperature 3334°C). A cold crystalloid cardioplegic solution was used. During CPB, the pump flow rate was 2.4 l min1 m2 and perfusion pressure 5080 mmHg. Before separation from CPB, all patients were rewarmed (nasopharyngeal temperature 37°C, bladder temperature 36°C) and an infusion of epinephrine 0.04 µg kg1 min1 was started. After surgery, the patients were warmed actively with a forced-air warmer until awake. In case of gagging on the intubation tube or agitation, the patient was sedated with a bolus dose of propofol 20 mg. The time to awakening was defined as the time to the return of appropriate responses to the command Move your right and left arm and your legs and to the question Do you feel any pain?. Ketorolac 20 mg was administered intravenously 60 min after the end of anaesthesia and 6 and 14 h thereafter. After awakening, additional analgesia was provided by intravenous bolus doses of morphine 0.05 mg kg1.
Separation from mechanical ventilation was initiated when the patient was awake and calm. We used the same weaning protocol and extubation criteria as in our previous study with CABG patients:2 according to the end-tidal carbon dioxide concentration (E'CO2) and the arterial carbon dioxide tension (PaCO2), mandatory ventilations were reduced, allowing the E'CO2 and the PaCO2 to increase to 7% and 6.5 kPa, respectively. Simultaneously, with increasing spontaneous ventilatory rate, the mandatory ventilation was reduced until the patient was breathing in the presence of 5 cm H2O of continuous positive airway pressure. Extubation criteria were as follows: the patient was breathing on continuous positive airway pressure (FIO2 <0.40) with the ventilation rate less than 20; arterial oxygen tension was more than 9.8 kPa; and PaCO2 was less than 6.5 kPa. The PaCO2 was recorded just before extubation and 30 min thereafter. In every patient, the postoperative care, the weaning process and tracheal extubation were performed by the same anaesthetist (J.A.).
To determine drug plasma concentrations, arterial blood samples were drawn before induction of anaesthesia, 10 min after induction, every 30 min thereafter until initiation of CPB, 15 min after initiation of CPB (from the CPB circuit), at the end of CPB (from the CPB circuit), every 30 min thereafter until skin closure, and at the end of anaesthesia (skin closure). After anaesthesia, blood samples were drawn every 30 min for 3 h, every 60 min for an additional 3 h, and at 12, 15, 18, 21 and 24 h. Plasma concentrations of alfentanil, fentanyl and propofol were determined for all samples. Sufentanil determinations had to be restricted because of the limitation of resources for analysis (before induction, 10 min thereafter, at the end of anaesthesia, and thereafter from all samples until 15 h).
Plasma concentrations of alfentanil and fentanyl were determined by capillary column gas-liquid chromatography.8 Tioridazine was used as the internal standard. The sensitivity of the method for alfentanil was 10 ng ml1 and that for fentanyl was 0.1 ng ml1. The intra-assay coefficient of variation for alfentanil was 11.1% at 110 ng ml1 (n=8) and the day-to-day CV was 3.5% at 140 ng ml1 (n=11). The intra-assay and day-to-day CVs for fentanyl were 5.0% at 5.8 ng ml1 (n=5) and 6.6% at 2.0 ng ml1 (n=13), respectively. Plasma concentrations of sufentanil were determined by radioimmunoassay.9 The limit of quantification for sufentanil was 0.020 ng ml1. The intra-assay CVs for sufentanil were 7.3% at 0.041 ng ml1 (n=2) and 2.7% at 0.544 ng ml1 (n=2). The day-to-day CVs were 4.4% at 0.041 ng ml1 (n=2) and 5.1% at 0.412 ng ml1 (n=2). Plasma concentrations of propofol were determined by high-performance liquid chromatography.10 Thymol was used as the internal standard. The limit of quantification for propofol was 0.5 µg ml1, the calibration curve was linear (r2=0.996) over the concentration range of 0.510 µg ml1, and the intra-assay and day-to-day CVs were 0.65.4%. Plasma concentrations of alfentanil and fentanyl were determined at the Department of Biomedicine, University of Helsinki, those of sufentanil at the Janssen Research Foundation, and those of propofol at Bioanalytics, Research and Development, Leiras Inc.
The pharmacokinetics of alfentanil, fentanyl and sufentanil were characterized by the time after cessation of the infusion for the drug plasma concentration to decrease by 50% (t50) and 80% (t80), and by the terminal elimination half-life (t). The t50 and t80 values were determined by interpolation using the logarithmic plasma concentrationtime profile for each patient. The elimination rate constant (kel) was determined by regression analysis of the log-linear part of the curve. The t
was calculated from t
=ln 2/kel. In every patient, the mean plasma concentration of alfentanil, fentanyl or sufentanil during anaesthesia was calculated from the samples drawn at 10 min and at the end of anaesthesia. The plasma concentrations of the opioid at time of awakening and at tracheal extubation were interpolated from the logarithmic plasma concentrationtime profile for each patient. For propofol, the area under the drug plasma concentrationtime profile (AUC) during anaesthesia was calculated using the logarithmic trapezoidal rule. The t50 for propofol was determined, as was the plasma concentration of propofol at time of awakening. The t80 for propofol could not be determined, since this concentration remained below the detection limit. At the time of extubation, propofol was not detectable.
CABG with CPB is associated with profound physiological changes that may alter the pharmacokinetics of intravenous anaesthetics.11 Therefore, we recorded the amount of all crystalloids administered during CPB, urine excretion and bleeding until 24 h, and the greatest weight gain during the hospital stay. Furthermore, we recorded the fraction of MB creatine kinase (CK-MB) at 24 h. The day of discharge to the ward was noted. We do not have a step-down unit, and the patients were transferred to the ward according to the routine policy of our cardiac ICU, which handles 1500 adult surgical patients a year. Because many patients were transferred to other hospitals after 45 days and these hospitals have different criteria for home readiness, the length of hospital stay was not recorded.
Statistical analysis
Results are expressed as mean and SD. Patient characteristics were compared by analysis of variance and the 2 test. The pharmacokinetic and pharmacodynamic parameters between the groups were compared by analysis of variance and a posteriori testing was done with Tukeys test. The Pearson product-moment correlation coefficient was used to investigate the relationship between t50 and t80 for the opioids and t50 for propofol and for time to awakening and tracheal extubation. All the data were analysed with Systat for Windows, version 5.0 (Systat, Evanston, IL, USA).
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Results |
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Discussion |
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In our patients, the observed 50 and 80% decrement times differed from the modelled context-sensitive decrement times for these three opioids.13 14 The elimination of fentanyl was faster than predicted and no differences were detected between alfentanil and sufentanil. However, instead of a computer-controlled infusion scheme to reach the target concentrations,13 we chose the clinically more widely used loading dose followed by a zero-order infusion, and in contrast to the model13 we determined the t50 and t80 values of the drugs by interpolation using the logarithmic plasma concentrationtime profile for each patient. Furthermore, the complex effect of CPB on the pharmacokinetics of intravenous anaesthetics11 probably explains, at least in part, the differences between the modelled and observed values. In our patients receiving alfentanil or fentanyl, the loading dose followed by a zero-order infusion resulted in a stable plasma concentration of the opioid until the initiation of CPB. Thereafter, the plasma concentrations of these opioids decreased slightly. However, during CPB the unbound fraction of the opioid is increased,15 and in clinical practice the infusion rate of the opioid is not increased to keep the total plasma concentrations stable.
Time to awakening did not differ significantly. The t50 values of the opioids and that of propofol were not correlated with times to awakening and tracheal extubation. In patients having conventional CABG with CPB, time to awakening can also be affected by factors not associated with the anaesthetics. For instance, brain swelling after surgery16 may influence recovery. In the present study, the relative decrease in drug plasma concentration up to the time of tracheal extubation was approximately 80% for all three opioids. After TIVA with propofol in patients undergoing general surgery lasting for about 5 h, the relative decrease in drug plasma concentration up to the time of tracheal extubation was 48% for alfentanil and 62% for sufentanil. Unfortunately, the t50 values of the opioids and propofol were not determined.17 Again, factors not related to the anaesthetic, such as brain swelling and changes in homeostasis, may explain the obvious difference between patients undergoing general surgery and CABG with CPB. The sensitivity of the time to extubation as a measure of recovery from the opioid effect was probably improved by our rigorous weaning and extubation protocol, which was also used in our previous study with CABG patients.2 The postoperative care, the weaning process, and the tracheal extubation of the patients were performed by the same anaesthetist. There were no differences between the groups in PaCO2 values just before and after extubation.
Drug interactions can influence the times needed to return to consciousness and spontaneous ventilation. In female patients undergoing lower abdominal surgery, a pharmacodynamic interaction between propofol and alfentanil reduced the alfentanil requirement. On the other hand, alfentanil decreased the plasma concentration of propofol associated with the return of consciousness.18 Because the consumption and the plasma concentrations of propofol were similar in our study groups, it can be concluded that alfentanil, fentanyl and sufentanil were administered in equipotent doses. Because the decrease in the plasma concentration of propofol after anaesthesia was also similar and rapid in all three groups, it is plausible that the pharmacodynamic interaction between propofol and the opioids did not influence recovery. Propofol inhibits dose-dependently the oxidative metabolism of alfentanil and sufentanil in vitro.19 However, although the dosage of alfentanil in the present study was based on our previous study using alfentanil without propofol,2 plasma concentrations of alfentanil remained lower than predicted. Moreover, elimination of alfentanil in the present study was similar to that observed after anaesthesia with infusions of alfentanil and midazolam supplemented with isoflurane.2 Although clinical studies with sufentanil are lacking, it is unlikely that the pharmacokinetic interaction between propofol and the opioids would have affected our patients recovery.
Theoretically, the observed differences in times to awakening and tracheal extubation could have been affected by pharmacokinetic or pharmacodynamic interactions between lorazepam and the opioids. Alfentanil, fentanyl and sufentanil are metabolized in the liver by the enzyme cytochrome P450 3A4.20 21 Lorazepam, however, is metabolized by hepatic conjugation to glucuronic acid, which is a non-microsomal reaction and is not affected by changes in cytochrome P450 activity.22 Furthermore, because alfentanil, fentanyl and sufentanil are equivalent µ-agonists, it is plausible that lorazepam potentiates the effects of the opioids on the central nervous system in a similar manner.23
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Acknowledgements |
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Footnotes |
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References |
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