Comparison of alfentanil, fentanyl and sufentanil for total intravenous anaesthesia with propofol in patients undergoing coronary artery bypass surgery{dagger}

J. Ahonen1,*, K. T. Olkkola1, M. Hynynen2, T. Seppälä3, H. Ikävalko4, B. Remmerie5 and M. Salmenperä1

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


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We have studied the pharmacokinetics and pharmacodynamics of alfentanil, fentanyl and sufentanil together with propofol in patients undergoing coronary artery bypass graft surgery (CABG). Sixty patients (age 40–73 yr, 56 male) were assigned randomly to receive alfentanil, fentanyl or sufentanil and propofol. Plasma concentrations of these drugs and times for the plasma concentration to decrease by 50% (t50) and 80% (t80) after cessation of the infusion were determined. Times were recorded to awakening and tracheal extubation. Total dose and plasma concentrations of propofol were similar in all groups. Mean total doses of alfentanil, fentanyl and sufentanil were 443, 45 and 4.4 µg kg–1, respectively. Time to awakening did not differ significantly. In patients receiving fentanyl, the trachea was extubated on average 2 h later than in those receiving sufentanil and 3 h later than in those receiving alfentanil (P<0.05). The t80 of fentanyl was longer (P<0.05) than that of alfentanil or sufentanil, and there was a linear correlation between the t80 of the opioid and the time to tracheal extubation (r=0.51; P<0.01). However, the t50 values for these opioids were similar and did not correlate with recovery time. In conclusion, patients undergoing CABG and who were anaesthetized with fentanyl and propofol needed mechanical ventilatory support for a significantly longer time than those receiving alfentanil or sufentanil and propofol. On the basis of the interindividual variation observed, the time to tracheal extubation was most predictable in patients receiving alfentanil and most variable in patients receiving fentanyl, a finding which may be important if the patients are transferred to a step-down unit on the evening of the operation.

Br J Anaesth 2000; 85: 533–40.

Keywords: analgesics opioid, alfentanil; analgesics opioid, fentanyl; analgesics opioid, sufentanil; anaesthetics i.v., propofol; pharmacokinetics, alfentanil; pharmacokinetics, fentanyl; pharmacokinetics, sufentanil; pharmacokinetics, propofol


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Intravenous hypnotics and opioids play an important role in cardiac anaesthesia. For ‘fast-track’ recovery to be achieved, the patient must recover rapidly from the high plasma concentrations reached during cardiac anaesthesia. The interaction between opioids and propofol in reducing the Cp50 (the plasma concentration that will prevent a response in 50% of patients for a given stimulus) of propofol, and that between opioids and isoflurane in reducing minimum alveolar concentration (MAC) has been defined and is very similar for both propofol and isoflurane and the opioids. The initial decrease in Cp50 and MAC is very steep, but a plateau is reached above an opioid concentration equivalent to 250–400 ng ml–1 of alfentanil, 4–6 ng ml–1 of fentanyl or 0.4–0.6 ng ml–1 of sufentanil.1

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).


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The study design was double-blind and randomized for three groups. On the basis of our experience of time to tracheal extubation (which was regarded as the primary endpoint of recovery from the anaesthetic), it was calculated that 20 patients would be required in each group to demonstrate a 50% difference in time to tracheal extubation at a level of significance of P=0.05 and power of 80%. We obtained institutional approval to study 60 patients undergoing elective CABG. None of the patients, when presented with the informed consent form, refused to participate in the study. Exclusion criteria were left ventricular ejection fraction less than 40%, significant valvular dysfunction, renal or liver insufficiency, uncontrolled hypertension, treatment with any known inhibitor or inducer of the cytochrome P4503A enzymes,2 morbid obesity, anaesthesia duration more than 6 h, and reoperation due to any complication.

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 kg–1.

Our target plasma concentrations were 400 ng ml–1 for alfentanil, 6 ng ml–1 for fentanyl and 0.6 ng ml–1 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 kg–1) of alfentanil, fentanyl and sufentanil are approximately 10:1:0.1.3 4 The syringes containing alfentanil 500 µg ml–1, fentanyl 50 µg ml–1 or sufentanil 5 µg ml–1 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 3–5 min after insertion of the radial arterial cannula. Anaesthesia was induced with alfentanil 75 µg kg–1, fentanyl 7.5 µg kg–1 or sufentanil 0.75 µg kg–1, and propofol 1.0–1.5 mg kg–1. 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 kg–1 min–1 and alfentanil 1.5 µg kg–1 min–1, fentanyl 0.15 µg kg–1 min–1 or sufentanil 0.015 µg kg–1 min–1. The rate of opioid infusion was maintained unchanged until skin closure.

Before skin incision, a bolus dose of propofol 0.5 mg kg–1 was given, and the infusion rate was increased to 150 µg kg–1 min–1. Thereafter, the infusion rate of propofol was adjusted between 100 and 250 µg kg–1 min–1 in steps of 50 µg kg–1 min–1 to maintain the SAP between 90 and 130 mmHg. During CPB, the rate of propofol was allowed to fall to 50 µg kg–1 min–1. During the time when the infusion rate of propofol was being increased, a bolus dose of 0.5 mg kg–1 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 kg–1 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 kg–1 before initiation of CPB.

All surgical procedures were performed under moderate hypothermia (nasopharyngeal temperature 33–34°C). A cold crystalloid cardioplegic solution was used. During CPB, the pump flow rate was 2.4 l min–1 m–2 and perfusion pressure 50–80 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 kg–1 min–1 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 kg–1.

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 ml–1 and that for fentanyl was 0.1 ng ml–1. The intra-assay coefficient of variation for alfentanil was 11.1% at 110 ng ml–1 (n=8) and the day-to-day CV was 3.5% at 140 ng ml–1 (n=11). The intra-assay and day-to-day CVs for fentanyl were 5.0% at 5.8 ng ml–1 (n=5) and 6.6% at 2.0 ng ml–1 (n=13), respectively. Plasma concentrations of sufentanil were determined by radioimmunoassay.9 The limit of quantification for sufentanil was 0.020 ng ml–1. The intra-assay CVs for sufentanil were 7.3% at 0.041 ng ml–1 (n=2) and 2.7% at 0.544 ng ml–1 (n=2). The day-to-day CVs were 4.4% at 0.041 ng ml–1 (n=2) and 5.1% at 0.412 ng ml–1 (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 ml–1, the calibration curve was linear (r2=0.996) over the concentration range of 0.5–10 µg ml–1, and the intra-assay and day-to-day CVs were 0.6–5.4%. 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 (t1/2). The t50 and t80 values were determined by interpolation using the logarithmic plasma concentration–time profile for each patient. The elimination rate constant (kel) was determined by regression analysis of the log-linear part of the curve. The t1/2 was calculated from t1/2=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 concentration–time profile for each patient. For propofol, the area under the drug plasma concentration–time 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 4–5 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 {chi}2 test. The pharmacokinetic and pharmacodynamic parameters between the groups were compared by analysis of variance and a posteriori testing was done with Tukey’s 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).


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patient characteristics are shown in Table 1. Eight of the 60 patients who were initially enrolled had to be excluded because of violation of the study protocol, so eight additional patients were enrolled. One patient (alfentanil) was excluded because of improper delivery of the study drug, one patient (fentanyl) because infusion of diltiazem2 had been started, and two patients (alfentanil, sufentanil) because anaesthesia lasted more than 6 h. Two patients were excluded because of reinstitution of cardiopulmonary bypass (CPB) during the same sternotomy: one (alfentanil) because of uncontrolled bleeding from a posterior anastomosis, and one (sufentanil) because of bleeding from a tear in the pulmonary artery. One patient (fentanyl) underwent resternotomy because of bleeding, and one (fentanyl) had to be sedated with an infusion of propofol for a few hours after awakening because of failure to tolerate the endotracheal tube and inability to breathe spontaneously.


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Table 1 Preoperative characteristics (mean value (SD) or number of patients (n)). NYHA=New York Heart Association; MI=myocardial infarction; LV=left ventricle; ACE=angiotensin-converting enzyme. *Significant differences between groups (P<0.05)
 
The three groups were similar with respect to their characteristics (except for use of aspirin), premedication, severity of coronary artery disease, preanaesthetic SAP, duration of anaesthesia, duration of aortic cross-clamping and duration of CPB (Tables 1 and 2). At skin incision or sternotomy, five patients receiving alfentanil, 11 receiving fentanyl and four receiving sufentanil required one or two bolus doses of nitroglycerin because of hypertension.


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Table 2 Perioperative medication and surgical data (mean value (SD) or number of patients (n)). SAP=invasive systolic blood pressure; CPB=cardiopulmonary bypass; CK-MB=MB-fraction of creatine kinase; IU=international unit; ICU=intensive care unit; POD=postoperative day
 
Plasma concentration–time profiles of the opioids are presented in Figures 1 and 2. The mean plasma concentration of alfentanil at awakening was 44 (SD 13)% of that at the end of anaesthesia, that of fentanyl was 36 (13)% and that of sufentanil was 34 (7)%. At tracheal extubation, plasma concentrations of alfentanil, fentanyl and sufentanil were 18 (8)%, 20 (10)% and 17 (5)% of that at the end of anaesthesia, respectively (Table 3). Time to awakening did not differ significantly between the groups, whereas in patients receiving fentanyl, the trachea was extubated on average 2 h later (P<0.05) than in those receiving sufentanil and 3 h later (P<0.01) than in those receiving alfentanil (Fig. 3 and Table 3). On the basis of the interindividual variation observed, time to tracheal extubation was most predictable in patients receiving alfentanil and most variable in patients receiving fentanyl (Fig. 3). The t50 values of alfentanil, fentanyl and sufentanil did not differ significantly, nor did they correlate with recovery. However, the t80 of fentanyl was significantly (P<0.05) longer than those of alfentanil and sufentanil (Table 3), and the t80 of the opioid was significantly correlated with time to tracheal extubation in all groups (r=0.51; P<0.01). No differences between the groups were detected in PaCO2 before extubation or thereafter (Table 3), or in the consumption of morphine (Table 2). The t1/2 of fentanyl was significantly longer than that of sufentanil or alfentanil and the t1/2 of sufentanil was significantly longer (P<0.05) than that of alfentanil (Table 3). No linear correlation existed between the t1/2 values of the opioids and recovery.



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Fig 1 Plasma concentrations of alfentanil (A), fentanyl (B) and sufentanil (C) during anaesthesia for coronary artery bypass surgery (n=20, all groups). Sufentanil determinations were restricted because of limited resources for analysis.

 


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Fig 2 Plasma concentrations of alfentanil (A), fentanyl (B) and sufentanil (C) during and after coronary artery bypass surgery (n=20, all groups). Infusion=average duration of the anaesthetic.

 

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Table 3 Pharmacokinetic and pharmacodynamic values of alfentanil, fentanyl and sufentanil (mean (SD)). CANE=mean plasma concentration during anaesthesia; CAWA=plasma concentration at awakening, CEXT=plasma concentration at tracheal extubation. *Significantly different from patients receiving alfentanil or sufentanil (P<0.05). {dagger}Significantly different from that receiving alfentanil (P<0.05)
 


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Fig 3 Time to awakening (open circles) and tracheal extubation (filled circles) after alfentanil, sufentanil or fentanyl together with propofol (n=20, all groups).

 
Plasma concentration–time profiles of propofol are presented in Figure 4. The total dose, AUC, and t50 of propofol were similar in all three groups (Table 4). The short t50 of propofol did not correlate with recovery. Between the end of anaesthesia and awakening, the number of patients receiving bolus doses of propofol and the cumulative dose of propofol did not differ significantly between the groups (Table 2).



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Fig 4 Plasma concentrations of propofol in patients receiving alfentanil (A), fentanyl (B) and sufentanil (C) during and after coronary artery bypass surgery (n=20, all groups). Infusion=average duration of anaesthesia.

 

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Table 4 Pharmacokinetic values of propofol (mean (SD)). CAWA=plasma concentration at awakening
 
The amount of all crystalloids administered during CPB, urine excretion and bleeding until 24 h, CK-MB at 24 h, length of ICU stay and greatest weight gain during the hospital stay were similar in all three groups (Table 2).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The similar consumption and AUC of propofol in our CABG patients receiving alfentanil, fentanyl or sufentanil suggests that the opioid doses, selected on the basis of their equipotent electroencephalographic effects in volunteers3 4 were also equipotent with respect to clinical anaesthetic potency, which allows reliable comparison of recovery characteristics between the groups. A similar potency ratio was recently reported in CABG patients receiving fentanyl or sufentanil supplemented with isoflurane.12 In these patients, mean plasma concentrations of 7.3 ng ml–1 for fentanyl and 0.71 ng ml–1 for sufentanil were on the steep part of the concentration–response relationship, whereas those of 13.2 ng ml–1 and 1.25 ng ml–1, respectively, were on the plateau. This finding is in good agreement with the ceiling plasma concentrations targeted in our patients.1 In the present study, the t80 of fentanyl was significantly longer than those of alfentanil and sufentanil and there was a linear correlation between the t80 of the opioids and time to tracheal extubation. The t50 values of these opioids were similar and were not correlated with time to awakening or tracheal extubation. Compared with the opioids, propofol was cleared rapidly and probably did not influence recovery.

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 concentration–time 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


    Acknowledgements
 
We thank our cardiac surgeons for their cooperation, all the staff of the operating room and cardiac ICU for their aid during the anaesthesia and recovery of the patients, Carol Norris for revising the English, and the Janssen Research Foundation and Leiras Inc. for analysis of some blood samples.


    Footnotes
 
* Corresponding author: Department of Anaesthesia, Helsinki University Hospital, PO Box 340, FIN-00029 Hus, Finland Back


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Glass PSA. Pharmacokinetic and pharmacodynamic principles in providing ‘fast-track’ recovery. J Cardiothorac Vasc Anesth 1995; 9: 16–20[ISI][Medline]

2 Ahonen J, Olkkola KT, Salmenperä M, Hynynen M, Neuvonen P. Effect of diltiazem on midazolam and alfentanil disposition in patients undergoing coronary artery bypass grafting. Anesthesiology 1996; 85: 1246–52[ISI][Medline]

3 Scott JC, Ponganis KV, Stanski DR. EEG quantitation of narcotic effect: the comparative pharmacodynamics of fentanyl and alfentanil. Anesthesiology 1985; 62: 234–41[ISI][Medline]

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11 Wood M. Pharmacokinetics and principles of drug infusions in cardiac patients. In: Kaplan JA, ed. Cardiac Anaesthesia. Philadelphia: W. B. Saunders, 1999: chapter 20: 669–77

12 Thomson IR, Henderson BT, Singh K, Hudson RJ. Concentration–response relationship for fentanyl and sufentanil in patients undergoing coronary artery bypass grafting. Anesthesiology 1998; 89: 852–61[ISI][Medline]

13 Hughes MA, Glass PSA, Jacobs JR. Context-sensitive half-time in multi-compartment pharmacokinetic models for intravenous anaesthetic drugs. Anesthesiology 1992; 76: 334–41[ISI][Medline]

14 Keifer J, Glass P. Context-sensitive half-time and anesthesia: how does theory match reality? Curr Opin Anaesthesiol 1999; 12: 443–8

15 Hynynen M, Hynninen M, Soini H, Neuvonen PJ, Heinonen J. Plasma concentration and protein binding of alfentanil during high-dose infusion for cardiac surgery. Br J Anaesth 1994; 72: 571–6[Abstract]

16 Harris DNF, Bailey SM, Smith PLC, Taylor KM, Oatridge A, Bydder GM. Brain swelling after coronary artery bypass surgery. Lancet 1993; 342: 586–7

17 Schraag S, Mohl U, Hirsch M, Stolberg E, Georgieff M. Recovery from opioid anaesthesia: the clinical implication of context-sensitive half-times. Anesth Analg 1998; 86: 184–90[Abstract]

18 Vuyk J, Lim T, Engbers FHM, Burm AGL, Vletter AA, Bovill JG. The pharmacodynamic interaction of propofol and alfentanil during lower abdominal surgery in women. Anesthesiology 1995; 83: 8–22[ISI][Medline]

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