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Effect of ventilation on first-pass pulmonary retention of alfentanil and sufentanil in patients undergoing coronary artery surgery
British Journal of Anaesthesia 1994; 73: 458-463
Effect of ventilation on first-pass pulmonary retention of alfentanil and sufentanil in patients undergoing coronary artery surgery F. BOER, J. G. BOVILL, A. G. L. BURM AND A. HAK
Summary
Key words Analgesics opioid, alfentanil Ventilation, effects
Analgesics opioid, sufentanil
In addition to gas exchange, the lungs have important pharmacokinetic and metabolic functions [1-3]. The lungs metabolize a variety of amines, lipids, peptides, proteins and drugs. They act as a metabolic filter, modulating arterial concentrations of substances released or administered into the venous circulation. Furthermore, arterial concentrations of drugs administered i.v. may be modulated by first-pass lung uptake, followed by release of drug, even if no metabolism occurs in the lungs [4-6]. Opioids such as fentanyl, pethidine, sufentanil, and to a lesser extent alfentanil, undergo significant first-pass lung uptake [4,5]. We have studied previously the first-pass pulmonary extraction and retention of morphine, sufentanil and alfentanil [6]. With alfentanil, an initial extraction of 67 % of the administered dose was observed within 10 s of injection. Pulmonary retention of alfentanil was
Patients and methods The study was approved by the local Medical Ethics Committee and all patients gave informed consent. We studied 14 patients undergoing elective aortocoronary bypass surgery. Patients were excluded if they had unstable angina pectoris, poor left ventricular function, as assessed by preoperative angiography, valvular abnormalities or pulmonary disease. The effect of the type of ventilation on pulmonary uptake of the drugs was studied in two consecutive groups of patients; six patients in the sufentanil group and eight patients in the alfentanil group. In each patient, first-pass pulmonary retention of the opioid was studied during apnoea, IPPV and during IPPV with PEEP (lOmmHg). The order of the different ventilation types was varied randomly using coded envelopes. With three treatments there are six possible sequences and each sequence was represented in the sufentanil group (n = 6). In the alfentanil group (n = 8), each sequence was also represented and two sequences were studied twice. Premedication comprised lorazepam 3-5 mg orally, 90 min before arrival in the operating theatre. Patients who were receiving beta adrenoceptor blocking drugs, calcium entry blocking drugs and nitrates continued taking these medications until the morning of surgery. In the operating theatre, ECG electrodes were placed and a peripheral infusion was established. A pulse oximeter was connected for measurement of peripheral saturation. Under local anaesthesia a catheter was placed in a radial artery.
F. BOER, MD, J. G. BOVILL, MD, PHD, FFARCSI, A. G. L. BURM,
PHD, A. HAK, BSC, Department of Anaesthesiology, University Hospital Leiden, Postbox 9600, 2300 RC Leiden, The Netherlands. Accepted for publication: April 7, 1994.
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We have studied, in 14 patients undergoing elective aorto-coronary bypass surgery, the effect of the type of ventilation on pulmonary retention of alfentanil and sufentanil using a double indicator technique. Patients were allocated to one of two groups to receive either bolus doses of sufentanil 33.2 ug (n = 6) or alfentanil 654 ug (n = 8), mixed with indocyanine green. In each patient, pulmonary first-pass retention was studied during apnoea (during the 1-min study period), normoventilation and positive end-expiratory pressure (10 mm Hg) ventilation, the order of which was randomized. After sufentanil, mean (95% confidence interval) first-pass pulmonary retention was 50.9(41.760.1)% during apnoea, 50.8 (42.9-58.8)% during normoventilation and 54.4 (43.7-65.0)% during positive end-expiratory pressure ventilation. After alfentanil, first-pass pulmonary retention was 18.7(5.4-32.0)% during apnoea, 19.9(8.331.5)% during normoventilation and 16.6(5.627.6)% during positive end-expiratory pressure ventilation. First-pass pulmonary retention of alfentanil and sufentanil was not significantly affected by the type of ventilation. (Br. J. Anaesth. 1994; 73: 458-463)
9.2%, measured 30 s after injection. This result differs from that described by Taeger and co-workers [5], who found a median retention of alfentanil of 58.9%, 30 s after administration. Whereas in our study the patients were awake and breathing spontaneously, Taeger and co-workers investigated patients during anaesthesia and intermittent positive pressure ventilation (IPPV). It is possible that the use of IPPV contributed to the higher retention of alfentanil in their study. In this study we have examined the first-pass uptake of sufentanil and alfentanil during apnoea, IPPV without positive end-expiratory pressure (PEEP) and IPPV with PEEP in anaesthetized patients.
Pulmonary first-pass retention of opioids
and indocyanine green. The remaining solution was divided into three aliquots of 3 ml, each in a 5-ml syringe. The syringes were weighed before and after injection to allow calculation of the exact injected volume. From the measured opioid and indocyanine green concentrations in the administered solution and the injected volume, the doses administered were calculated. One minute before each bolus injection, an arterial blood sample was obtained for measurement of the concentrations of the test drug and indocyanine green. Immediately after injection of the test drugs, arterial blood samples were obtained at 1-s intervals for 60 s. Bloodflowingspontaneously from the radial artery cannula was diverted via an extension tube to a modified fraction collector containing 60 sampling tubes. Each tube contained heparin 40 ul (5000 u. ml"1). Individual tubes were exposed to the blood flow for 1 s. Blood sampling was continued until 60 s after injection, from each sample, 0.2 ml was separated for measurement of indocyanine green concentration, which was performed within 1 h of the study. The remaining portion of the whole blood sample was stored at —20 °C for opioid assay. After appropriate dilution, the concentration of indocyanine green was measured spectrographically at 805 nm. Alfentanil and sufentanil concentrations were measured by specific radioimmunoassay. The methods of measurement of indocyanine green and sufentanil concentrations have been reported previously [6]. The coefficient of variation of the present study of the indocyanine green measurement was 2.6-3.9% and that of sufentanil 5.5-7.4%. Details of the alfentanil assay are given in the appendix. CALCULATIONS
Extraction and retention were calculated as described by Geddes and colleagues [7] and Jorfeldt and colleagues [8]. The indocyanine green fraction vs time curve was taken as the reference curve representing zero uptake by the lungs. The curve was corrected for recirculation by log-linear extrapolation of the terminal part of the descending portion. The concentrations of indocyanine green and opioid in each sample were divided by the administered dose yielding dose-corrected quantities (from now on termed fractions FJQQ and FopM
.optoid
1 - F,, ^
xl00%
ICG
where FltOfAM and F,lOG = respective fractions at sampling time t. Retention was calculated as
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After induction of anaesthesia a pulmonary artery catheter was inserted via the internal jugular vein. Before and during induction of anaesthesia, an infusion of Haemaccel 500 ml was given to reduce the effect of PEEP ventilation on venous return and cardiac output, and this was followed by a slowly running infusing of glucose-saline 2.5%/0.45% until the experiment started. The total volume of glucose-saline administered to individual patients varied between 100 and 300 ml. Anaesthesia was induced with etomidate 0.3 mg kg"1 and either sufentanil 1 ng kg"1 (sufentanil group) or alfentanil 30 ug kg"1 (alfentanil group). Pancuronium 100 ug kg"1 was given for neuromuscular block. Anaesthesia was maintained with enflurane (inspired concentration 1.0-1.5%). After intubation of the trachea, the lungs were ventilated with an oxygen in air mixture (FiO2 = 0.5) by IPPV, using a Servo 900C ventilator (Siemens) with a ventilation frequency of 12 b.p.m. Minute volume was adjusted to maintain an end-expiratory carbon dioxide concentration of 4.5-5 %. The carbon dioxide concentration was measured with a Hewlett Packard type 17210A capnograph. Arterial oxygen and carbon dioxide partial pressures were measured in arterial blood samples obtained 2 min before and 2 min after injection of the study drugs. Airway pressure was measured using a Datex 2000A monitor with a pressure transducer connected to the side port of the swivel connector. The transducer was calibrated electronically immediately before the study. The study consisted of three periods of 6 min, separated by 4-min resting periods. During the last 1 min of each period, first-pass uptake was studied after a bolus injection of the study drug. When examining pulmonary retention during IPPV with or without PEEP, ventilation was maintained in that mode for the full 6-min period. When studying pulmonary retention during apnoea, normoventilation was applied in the 5 min preceding the 1 min of apnoea. Apnoea commenced 5 s before the bolus injection and was maintained throughout the 1-min sampling period. Three minutes after the start of each type of ventilation, cardiac output was measured by thermodilution, randomly over the ventilation cycle. Cardiac output was taken as the average of three measurements within 15% of each other. Central venous, pulmonary arterial and radial artery pressures were noted. One minute before measurement of pulmonary retention, an arterial blood sample was obtained for measurement of pH, P^co1 and Sa^. For measurement of first-pass pulmonary uptake, either alfentanil or sufentanil and indocyanine green were given via the right atrial port of the pulmonary artery catheter over 1 s, followed by a 10-s saline flush. The injectate was prepared by mixing 4 ml of alfentanil 500 ug ml"1 or 2 ml of sufentanil 50 ug ml"1 with indocyanine green 50 mg (Cardio-green, BBL Microbiology Systems, Becton Dickinson) in 4 ml of its solvent in a heparinized 10-ml syringe. Autologous blood was added to a total volume of 10 ml to prevent precipitation of indocyanine green. One millilitre of this solution was placed in a glass tube for later measurement of concentrations of opioid
459
British Journal of Anaesthesia
460 0.002 c •| 0.0015
E i 0.001 o <
0.0005
0
10
20 30 Time (s)
40
50
Figure 1 Arterial fraction vs time curves for indocyanine green (D) and sufentanil (O) after bolus injection of a mixture of the drugs in the right atrium. The fraction is the arterial blood concentration divided by the administered dose. The indocyanine green fraction curve was corrected for recirculation of the drug by log-linear extrapolation of the descending part of the curve.
Sufentanil No. of patients Height (cm) Weight (kg) Body surface area (m2) Medication (3 adrenoceptor blockers Nitrates Calcium entry blockers Diuretics
6
Alfentanil
CO =
DICG AUC ICG
Results are expressed as mean (SD) or mean (confidence interval of the mean). Data were analysed using analysis of variance with groups and type of ventilation as fixed factors and patients tested in these factors, followed by the Newman-Keuls range test, when applicable, or chi-square test. P < 0.05 was taken as statistically significant.
8
170.7(11.9) 73.5 (8.2) 1.86(0.15) 5/6 4/6 3/6 3/6
167.5 (9.7) 79.2(12.9) 1.93(0.22) 7/8 4/8 2/8 1/8
where AUC, = area under the fraction vs time curve up to time t (fig. 1). AUC was calculated by the linear trapezoidal rule. First-pass retention was denned as
Results The groups were comparable in height, weight, body surface area and preoperative medication (table 1). During the 5 min preceding the lung uptake study period, the groups were comparable in haemodynamic and arterial blood-gas values (table 2). In the sufentanil group, cardiac output measured by thermodilution or calculated from the indocyanine green concentration curve (table 3) was significantly lower during PEEP ventilation than during apnoea and IPPV. Within each group the opioid dose used
Table 2 Mean (SD) haemodynamic data and arterial blood-gas values, 2-3 min before injection of the mixture of indocyanine green and opioid. fGroup average with three observations per patient. * Statistically significant within-group difference (P < 0.05) Sufentanil Apnoea Heart rate (beat min"1) PCWP (mm Hg) Thermodilution cardiac output (litre min"1) Blood-gas values pH Pco 2 (kPa) Sao, (%)
Alfentanil Normoventilation
58 (8) 58(8) 8 (3) 9 (4) 4.48(0.56) 4.47(0.9)
PEEP ventilation
Sufentanil groupf
Apnoea
57.6 (6) 56(4) 8(4) 10(4) 3.55 (0.54)* 4.16(0.79)
7.42 (0.04) 7.42 (0.04) 7.41 (0.04) 5.4 (0.4) 5.4 (0.4) 5.4 (0.3) 100(1) 99(1) 99(1)
7.42 (0.04) 5.4 (0.4) 99(1)
Normoventilation
PEEP ventilation
Alfentanil groupf
61(8) 61(8) 61(7) 60(80 8(3) 10(4) 9(4) 8(3) 4.44 (0.87) 4.43(1.26) 3.68(1.12) 4.18(1.11)
7.38(7.39) 7.39(0.04) 7.38(0.04) 7.38(0.04) 5.8(0.5) 5.6(0.4) 5.6(0.4) 5.7(0.5) 99(1) 99(1) 99(1) 99(1)
Table 3 Mean (SD) indocyanine green (ICG) dose, opioid dose and cardiac output calculated from the indocyanine green concentration-time curve of the sufentanil and alfentanil group for each type of ventilation. fGroup average with three observations per patient. *Statistically significant within-group difference (P < 0.05) Sufentanil Apnoea
Alfentanil Normoventilation
PEEP ventilation
ICG dose (mg) 17.1(0.7) 17.8(1.7) 17.9(1.5) Opioid dose (ug) 33.5(2.7) 32.9(5.4) 33.1(5.8) Cardiac output 5.10(0.75) 5.11(1.38) 3.98(0.95)* (litre min"1)
Sufentanil groupf
Apnoea
17.6(1.3) 33.2(4.6) 4.73(1.13)
16.9(1.0) 17.0(0.6) 16.9(0.9) 16.9(0.8) 657(72) 655(69) 649(76) 654(69) 4.47(1.18) 4.17(1.70) 3.68(1.40) 4.11(1.40)
Normoventilation
PEEP ventilation
Alfentanil groupt
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Table 1 Patient data and preoperative medication in the two groups. Values are mean (SD) or proportion of the number of patients to the total number of patients in the study group
retention up to the time when 95 % of the total area under the indocyanine green curve was reached. Because possible recirculation of opioid was assumed to have occurred when recirculation of indocyanine green was observed, data from patients in whom recirculation occurred before 95 % of the AUC of indocyanine green was reached were not included in the calculation of extraction and retention. This did not occur in any of our patients. In addition to thermodilution cardiac output measurements, cardiac output was calculated also from the area under the curve and the dose of indocyanine green administered using the formula:
Pulmonary first-pass retention of opioids
461
Table 4 Mean (95 % confidence interval of the mean) pulmonary extraction and first-pass retention after bolus injection of alfentanil and sufentanil during apnoea, normoventilation and PEEP. The pivot point is the time from first appearance of drug in the arterial blood samples until the moment when extraction became zero. %n = 7, see text. -fGroup average with three observations per patient. *StarJstica]ly significant difference between sufentanil and alfentanil group (P < 0.05) Alfentanil
Sufentanil Apnoea 88.6 (77.1-100) First-pass retention (%) 50.9 (41.7-60.1) Pivot point (s) 27.3 (18.8-35.9) Peak extraction (%)
Normoventilation
PEEP ventilation
Sufentanil groupf
Apnoea
83.9 (79.1-88.7) 50.8 (42.9-58.8) 27.7 (19.9-35.5)
84.2 (75.2-93.2) 54.4 (43.7-65.0) 30.2 (21.8-38.6)
85.6* (81.5-89.7) 52.0* (47.8-56.3) 28.4 (24.7-32.1)
51.3 50.1 50.7 (41.9-60.7) (39.3-60.8) (35.2-66.3) 18.7 19.9 16.6 (5.4-32.0) (8.3-31.5) (5.6-27.6) 24.4$ 25.5 27.0 (21.4-27.4) (21.3-29.7) (21.7-32.3)
PEEP ventilation
Alfentanil
groupt 50.7* (44.8-56.6) 18.4* (12.6-24.2) 25.7 (23.5-27.9)
5? 80-I c o
60 40
i 20 Apnoea
IPPV
PEEP
Figure 2 First-pass pulmonary retention (percentage of the dose administered) of sufentanil after a fast bolus injection in six patients during anaesthesia with enflurane and with different types of ventilation during the first-pass retention study period of 1 min. Each patient is marked individually by a symbol. 100n
#
80-
I
60J 40
CD
a
20 0 -20 Apnoea
IPPV
PEEP
Figure 3 First-pass pulmonary retention (percentage of the dose administered) of alfentanil after a fast bolus injection in eight patients during anaesthesia with enflurane and with different types of ventilation during the first-pass retention study period of 1 min. Each patient is marked individually by a symbol.
for the retention study was comparable for each study period. Peak extraction and first-pass retention were significantly higher in the sufentanil group (table 4). Individual retention values for each ventilation type of the sufentanil and alfentanil groups are shown in figures 2 and 3, respectively. In both groups, peak extraction, first-pass retention and time to the pivot point, at which extraction becomes zero, were similar during each ventilation period. In one patient in the alfentanil group, during apnoea, extraction remained positive throughout the firstpass period and no pivot point could be detected. In
Discussion We have shown that first-pass pulmonary retention of sufentanil and alfentanil was not influenced by the type of ventilation in anaesthetized patients undergoing mechanical ventilation. We used the error mean square from the ANOVA table of first-pass retention to calculate the minimum detectable difference in first-pass retention in this study, as described by Zar [9]. In the sufentanil group, the ANOVA error mean square was 79.2 and (assuming a = 0.05, /? = 0.10) the within-group minimum detectable difference in first-pass retention was 17.0%. The ANOVA error mean square in the alfentanil group was 207.5 and the within-group minimum detectable difference in first-pass retention was 22.3%. The minimum detectable difference in first-pass retention in both groups was therefore small enough to allow detection of clinically significant changes in firstpass retention, if these occurred after changing the type of ventilation. The first-pass retention of sufentanil and alfentanil in this study was similar to that found in our previous study [6]. In that study, patients were investigated before induction of anaesthesia and they were breathing spontaneously. In these patients, pulmonary retention of sufentanil was 61.1 (95% confidence interval 51.3-70.9)% and that of alfentanil 10.1 (3.5-16.7)%. As first-pass retention in this study was similar to that of our previous study in which patients received only a single dose of opioid, it is unlikely that, in the context of the present study, the pulmonary system was saturable. Pulmonary retention of alfentanil in the present study, however, was lower than that reported by Taeger and coworkers [5] who studied patients during anaesthesia with enflurane and IPPV. In six patients who received alfentanil in their study median retention 30 s after administration was 58.8%. The median alfentanil retention in our patients who received alfentanil during IPPV was 19.8%. The differences between the three studies could be attributable to the drugs given for premedication or for anaesthesia, in
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two patients in the alfentanil group, first-pass retention was negative, although the indocyanine green and alfentanil concentration curves did not indicate that recirculation had occurred and loglinear extrapolation of the indocyanine green curve was straightforward.
100-,
c
Normoventilation
462
Compared with spontaneous ventilation, mechanical ventilation is associated with an increase in mean intrathoracic pressure. During PEEP ventilation, pulmonary capillaries partially collapse with higher PEEP values [18]. This could decrease the endothelial surface area available for exchange of drug molecules between blood and pulmonary tissue. In contrast, during apnoea, when intrathoracic pressure is low compared with positive pressure ventilation, there is least compression of pulmonary capillaries and thus possibly greater available endothelial area. Despite these observations, first-pass retention of sufentanil and alfentanil did not differ between types of ventilation. Possibly the effect of pressure ventilation on regional blood flow distribution is less important for opioid retention than it is for gas exchange. Redistribution of pulmonary blood flow to other parts of the lungs may outweigh the decrease in regional blood flow in the central parts of the lungs [19], leaving the available endothelial area relatively unchanged. Finally, uptake of sufentanil and alfentanil may not be limited by relatively small changes in the available endothelial area.
Ventilation-induced changes in pulmonary uptake and retention could also be caused by haemodynamic changes associated with mechanical ventilation. When higher magnitudes of PEEP are used, cardiac output decreases compared with normoventilation or spontaneous breathing, because of a decrease in venous return [20]. In the study, cardiac output (as measured by thermodilution) decreased significantly (—17%) during PEEP ventilation. Despite this decrease in cardiac output, first-pass retention of sufentanil and alfentanil remained constant. When changes in pulmonary blood flow are studied in isolation, neither a decrease in cardiac output nor diversion of cardiac output to one lung decreases pulmonary retention of alfentanil [21]. Appendix ALFENTANIL ASSAY Whole blood alfentanil concentrations were determined by radioimmunoassay. To 0.3 ml of whole blood, 1 ml of NaOH 0.1 mol litre"1 and 4 ml of n-heptane-isoamylalcohol were added and the solution was mixed for 10 min on a rotary mixer (Protherm type Cenco PT 1510). The solution was centrifuged for 10 mm at 4000 rpm (Heraeus Minifuge GL.) and the supernatant evaporated to dryness in a stream of dry nitrogen on a water bath at 60 °C. Then, 50 ul of absolute alcohol was added and the solution again vortexed. Thereafter, bovine serum albumin (Sigma no. A-7888 RIA grade) 450 ul in phosphate buffer (pH 7.5) was added and the rube was vortexed again. Then, 50 ul of the solution was added to 2 % bovine serum albumin 450 ul, vortexed and ['HJalfentanil Qanssen, Beerse, Belgium) added. After further vortexing, 100 ul of antiserum (Janssen, Beerse, Belgium) was added. The solution was left at room temperature for 2 h. Then, 500 ul of a NoritDextran suspension was added to each test tube and the solution incubated for 1 h. The solution was centrifuged (10 min, 4000 rpm, 20 °C), decanted into a new test tube and 4 ml of liquid scintillation cocktail (Ultima Gold, Packard) was added to the supernatant. Standard solutions, initial binding and antiserum free samples (to determine non-specific binding) were treated similarly. Scintillation was measured in a liquid scintillation analyser (Packard, Tricarb 2000 CA), measured as dpm. The detection limit of this assay was 0.5ugml~'. The average coefficients of variation of spiked concentrations of 40 and 100 ug ml"1 were 7.4 and 5.5 %. The initial binding was 45 % and the coefficient of non-specific binding was 0.76 % of total binding.
Acknowledgement This study was supported financially by the "Stichting de Drie Lichtcn".
References 1. Bahkle YS. Pharmacokinetic and metabolic properties of the lung. British Journal of Anaesthesia 1990; 65: 79-93. 2. Ryan US, Grantham CJ. Metabolism of endogenous and xenobiotic substances by pulmonary vascular endothelial cells. Pharmacology and Therapeutics 1989; 42: 235-250. 3. Nunn JF. Applied Respiratory Physiology, 3rd Edn. London: Butterworth, 1987; 284-293. 4. Roerig DL, Kotrly KJ, Vucins E, Ahlf SB, Dawson CA, Kampine JP. First pass uptake of fentanyl, meperidine and morphine in the human lung. Anesthesiology 1987; 67: 466-^72. 5. Taeger K, Weninger E, Schmelzer F, Adt M, Franke N, Peter K. Pulmonary kinetics of fentanyl and alfentanil in surgical patients. British Journal of Anaesthesia 1988; 61: 425-434. 6. Boer F, Bovill JG, Burm AGL, Mooren RAG. Uptake of sufentanil, alfentanil and morphine in the lungs of patients about to undergo coronary artery surgery. British Journal of Anaesthesia 1992; 68: 370-375. 7. Geddes DM, Nesbitt K, Traill T, Blackburn JP. First pass
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addition to factors such as mechanical ventilation. The various drugs could have altered pulmonary retention, as significant competition for pulmonary binding sites occurs between drugs [10,11]. Inhalation anaesthetic agents may also influence pulmonary uptake of drugs. Halothane increases the pulmonary retention of propranolol in dogs [12]. Pulmonary retention of lignocaine, on the other hand, was lower in patients during anaesthesia with fentanyl, droperidol and nitrous oxide in air, compared with healthy volunteers [11]. We are unaware of studies that have addressed the effect of enflurane on first-pass retention of drugs. Ventilation-induced changes in the pulmonary first-pass retention of opioids may be caused by changes in the pH of pulmonary arterial blood and lung tissue, changes in regional distribution of pulmonary blood flow or by changes in cardiac output and total pulmonary blood flow. IPPV is often associated with a change in the pH of pulmonary arterial blood as a result of relative hyperventilation. This may significantly increase pulmonary retention of drugs. Roth and Gillis [13, 14] observed that the removal of mescaline by isolated perfused rabbit lungs ventilated with room air was greater (76%) than when the lungs were inflated to a static volume (48%). When the lungs were ventilated with 95% air-5% carbon dioxide, removal of mescaline did not differ from that during static inflation. Increased mescaline removal during room air ventilation was associated with an increase in the pH of the effluent perfusate. When the pH of the medium that perfused the statistically inflated lungs was increased, removal of mescaline also increased. Similar pH-dependent changes in lung uptake have been observed with lignocaine, bupivacaine and etidocaine in vivo [15, 16] and in vitro [17]. In the present study, arterial pH and carbon dioxide partial pressure were similar during each type of ventilation. Therefore, if pH-related changes in pulmonary retention of alfentanil or sufentanil are important, they could not be shown in this study.
British Journal of Anaesthesia
Pulmonary first-pass retention of opioids
8. 9. 10. 11.
12.
13. 14.
uptake of 14C propranolol by the lung. Thorax 1979; 34: 810-813. Jorfeldt L, Lewis DH, Loefstroem JB. Post C. Lung uptake of lidocaine in healthy volunteers. Acta Anaesthesiologica Scandinavica 1979; 23: 567-574. Zar JH. Biostatistical Analysis, 2nd Edn. Englewood Cliffs, NJ: Prentice-Hall, 1984; 175. Roerig DL, Kotrly KJ, Ahlf SB, Dawson CA, Kampine JP. Effect of propranolol on the first-pass uptake of fentanyl in the human and rat lung. Anesthesiology 1989; 71: 62-68. Jorfeldt L, Lewis DH, Loefstrom JB, Post C. Lung uptake of lidocaine in man as influenced by anaesthesia, mepivacaine infusion or lung insufficiency. Ada Anaesthesiologica Scandinavica 1983; 27: 5-9. Pang JA, Williams TR, Blackburn JP, Butland RJA, Geddes DM. First-pass lung uptake of propranolol is enhanced in anaesthetized dogs. British Journal of Anaesthesia 1981; S3: 601-604. Roth RA, Gillis CN. Effect of ventilation on removal of 14Cmescaline by perfused rabbit lung. Biochemical Pharmacology 1977; 26: 1446-1448. Roth RA, Gillis CN. Effect of ventilation and pH on removal of mescaline and biogenic amines by rabbit lung. Journal of Applied Physiology 1978; 44: 553-558.
463 15. Post C, Eriksdotter-Behm K. Dependence of lung uptake of lidocaine in vivo on blood pH. Acta Pharmacologica el Toxicologica 1982; 51: 136-140. 16. Palazzo MGA, Kalso EA, Argiras E, Madgwick R, Sear JW. First pass lung uptake of bupivacaine: effect of acidosis in an intact rabbit lung model. British Journal of Anaesthesia 1991; 67: 759-763. 17. Post C, Andersson RGG, Ryrfeld A, Nilson E. Physicochemical modification of lidocaine uptake in rat lung tissue. Acta Pharmacologica et Toxicologica 1979; 44: 103-109. 18. Bindlcv L, Hedcnstierna G, Santesson J, Gottlieb I, Carvallhas A. Ventilation-perfusion distribution during inhalation anaesthesia. Acta Anaesthtsiologica Scandinavica 1981; 25: 360-371. 19. Hedenstierna G, White F, Mazzone FC, Wagner PD. Redistribution of pulmonary blood flow in the dog with positive end-expiratory pressure ventilation. Journal of Applied Physiology 1979; 46: 278-287. 20. Lcnfant C, Howell BJ. Cardiovascular adjustments in dogs during continuous pressure breathing. Journal of Applied Physiology 1960; 15: 425. 21. Boer F, Burm AGL, Bovill JG, Hak A. Effect of haemodynamics on pulmonary distribution of alfentanil in pigs. British Journal of Anaesthesia 1994; 72 (Suppl. 1): A162. Downloaded from http://bja.oxfordjournals.org/ at UQ Library on June 21, 2015
Effect of ventilation on first-pass pulmonary retention of alfentanil and sufentanil in patients undergoing coronary artery surgery F. BOER, J. G. BOVILL, A. G. L. BURM AND A. HAK
Summary
Key words Analgesics opioid, alfentanil Ventilation, effects
Analgesics opioid, sufentanil
In addition to gas exchange, the lungs have important pharmacokinetic and metabolic functions [1-3]. The lungs metabolize a variety of amines, lipids, peptides, proteins and drugs. They act as a metabolic filter, modulating arterial concentrations of substances released or administered into the venous circulation. Furthermore, arterial concentrations of drugs administered i.v. may be modulated by first-pass lung uptake, followed by release of drug, even if no metabolism occurs in the lungs [4-6]. Opioids such as fentanyl, pethidine, sufentanil, and to a lesser extent alfentanil, undergo significant first-pass lung uptake [4,5]. We have studied previously the first-pass pulmonary extraction and retention of morphine, sufentanil and alfentanil [6]. With alfentanil, an initial extraction of 67 % of the administered dose was observed within 10 s of injection. Pulmonary retention of alfentanil was
Patients and methods The study was approved by the local Medical Ethics Committee and all patients gave informed consent. We studied 14 patients undergoing elective aortocoronary bypass surgery. Patients were excluded if they had unstable angina pectoris, poor left ventricular function, as assessed by preoperative angiography, valvular abnormalities or pulmonary disease. The effect of the type of ventilation on pulmonary uptake of the drugs was studied in two consecutive groups of patients; six patients in the sufentanil group and eight patients in the alfentanil group. In each patient, first-pass pulmonary retention of the opioid was studied during apnoea, IPPV and during IPPV with PEEP (lOmmHg). The order of the different ventilation types was varied randomly using coded envelopes. With three treatments there are six possible sequences and each sequence was represented in the sufentanil group (n = 6). In the alfentanil group (n = 8), each sequence was also represented and two sequences were studied twice. Premedication comprised lorazepam 3-5 mg orally, 90 min before arrival in the operating theatre. Patients who were receiving beta adrenoceptor blocking drugs, calcium entry blocking drugs and nitrates continued taking these medications until the morning of surgery. In the operating theatre, ECG electrodes were placed and a peripheral infusion was established. A pulse oximeter was connected for measurement of peripheral saturation. Under local anaesthesia a catheter was placed in a radial artery.
F. BOER, MD, J. G. BOVILL, MD, PHD, FFARCSI, A. G. L. BURM,
PHD, A. HAK, BSC, Department of Anaesthesiology, University Hospital Leiden, Postbox 9600, 2300 RC Leiden, The Netherlands. Accepted for publication: April 7, 1994.
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We have studied, in 14 patients undergoing elective aorto-coronary bypass surgery, the effect of the type of ventilation on pulmonary retention of alfentanil and sufentanil using a double indicator technique. Patients were allocated to one of two groups to receive either bolus doses of sufentanil 33.2 ug (n = 6) or alfentanil 654 ug (n = 8), mixed with indocyanine green. In each patient, pulmonary first-pass retention was studied during apnoea (during the 1-min study period), normoventilation and positive end-expiratory pressure (10 mm Hg) ventilation, the order of which was randomized. After sufentanil, mean (95% confidence interval) first-pass pulmonary retention was 50.9(41.760.1)% during apnoea, 50.8 (42.9-58.8)% during normoventilation and 54.4 (43.7-65.0)% during positive end-expiratory pressure ventilation. After alfentanil, first-pass pulmonary retention was 18.7(5.4-32.0)% during apnoea, 19.9(8.331.5)% during normoventilation and 16.6(5.627.6)% during positive end-expiratory pressure ventilation. First-pass pulmonary retention of alfentanil and sufentanil was not significantly affected by the type of ventilation. (Br. J. Anaesth. 1994; 73: 458-463)
9.2%, measured 30 s after injection. This result differs from that described by Taeger and co-workers [5], who found a median retention of alfentanil of 58.9%, 30 s after administration. Whereas in our study the patients were awake and breathing spontaneously, Taeger and co-workers investigated patients during anaesthesia and intermittent positive pressure ventilation (IPPV). It is possible that the use of IPPV contributed to the higher retention of alfentanil in their study. In this study we have examined the first-pass uptake of sufentanil and alfentanil during apnoea, IPPV without positive end-expiratory pressure (PEEP) and IPPV with PEEP in anaesthetized patients.
Pulmonary first-pass retention of opioids
and indocyanine green. The remaining solution was divided into three aliquots of 3 ml, each in a 5-ml syringe. The syringes were weighed before and after injection to allow calculation of the exact injected volume. From the measured opioid and indocyanine green concentrations in the administered solution and the injected volume, the doses administered were calculated. One minute before each bolus injection, an arterial blood sample was obtained for measurement of the concentrations of the test drug and indocyanine green. Immediately after injection of the test drugs, arterial blood samples were obtained at 1-s intervals for 60 s. Bloodflowingspontaneously from the radial artery cannula was diverted via an extension tube to a modified fraction collector containing 60 sampling tubes. Each tube contained heparin 40 ul (5000 u. ml"1). Individual tubes were exposed to the blood flow for 1 s. Blood sampling was continued until 60 s after injection, from each sample, 0.2 ml was separated for measurement of indocyanine green concentration, which was performed within 1 h of the study. The remaining portion of the whole blood sample was stored at —20 °C for opioid assay. After appropriate dilution, the concentration of indocyanine green was measured spectrographically at 805 nm. Alfentanil and sufentanil concentrations were measured by specific radioimmunoassay. The methods of measurement of indocyanine green and sufentanil concentrations have been reported previously [6]. The coefficient of variation of the present study of the indocyanine green measurement was 2.6-3.9% and that of sufentanil 5.5-7.4%. Details of the alfentanil assay are given in the appendix. CALCULATIONS
Extraction and retention were calculated as described by Geddes and colleagues [7] and Jorfeldt and colleagues [8]. The indocyanine green fraction vs time curve was taken as the reference curve representing zero uptake by the lungs. The curve was corrected for recirculation by log-linear extrapolation of the terminal part of the descending portion. The concentrations of indocyanine green and opioid in each sample were divided by the administered dose yielding dose-corrected quantities (from now on termed fractions FJQQ and FopM
.optoid
1 - F,, ^
xl00%
ICG
where FltOfAM and F,lOG = respective fractions at sampling time t. Retention was calculated as
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After induction of anaesthesia a pulmonary artery catheter was inserted via the internal jugular vein. Before and during induction of anaesthesia, an infusion of Haemaccel 500 ml was given to reduce the effect of PEEP ventilation on venous return and cardiac output, and this was followed by a slowly running infusing of glucose-saline 2.5%/0.45% until the experiment started. The total volume of glucose-saline administered to individual patients varied between 100 and 300 ml. Anaesthesia was induced with etomidate 0.3 mg kg"1 and either sufentanil 1 ng kg"1 (sufentanil group) or alfentanil 30 ug kg"1 (alfentanil group). Pancuronium 100 ug kg"1 was given for neuromuscular block. Anaesthesia was maintained with enflurane (inspired concentration 1.0-1.5%). After intubation of the trachea, the lungs were ventilated with an oxygen in air mixture (FiO2 = 0.5) by IPPV, using a Servo 900C ventilator (Siemens) with a ventilation frequency of 12 b.p.m. Minute volume was adjusted to maintain an end-expiratory carbon dioxide concentration of 4.5-5 %. The carbon dioxide concentration was measured with a Hewlett Packard type 17210A capnograph. Arterial oxygen and carbon dioxide partial pressures were measured in arterial blood samples obtained 2 min before and 2 min after injection of the study drugs. Airway pressure was measured using a Datex 2000A monitor with a pressure transducer connected to the side port of the swivel connector. The transducer was calibrated electronically immediately before the study. The study consisted of three periods of 6 min, separated by 4-min resting periods. During the last 1 min of each period, first-pass uptake was studied after a bolus injection of the study drug. When examining pulmonary retention during IPPV with or without PEEP, ventilation was maintained in that mode for the full 6-min period. When studying pulmonary retention during apnoea, normoventilation was applied in the 5 min preceding the 1 min of apnoea. Apnoea commenced 5 s before the bolus injection and was maintained throughout the 1-min sampling period. Three minutes after the start of each type of ventilation, cardiac output was measured by thermodilution, randomly over the ventilation cycle. Cardiac output was taken as the average of three measurements within 15% of each other. Central venous, pulmonary arterial and radial artery pressures were noted. One minute before measurement of pulmonary retention, an arterial blood sample was obtained for measurement of pH, P^co1 and Sa^. For measurement of first-pass pulmonary uptake, either alfentanil or sufentanil and indocyanine green were given via the right atrial port of the pulmonary artery catheter over 1 s, followed by a 10-s saline flush. The injectate was prepared by mixing 4 ml of alfentanil 500 ug ml"1 or 2 ml of sufentanil 50 ug ml"1 with indocyanine green 50 mg (Cardio-green, BBL Microbiology Systems, Becton Dickinson) in 4 ml of its solvent in a heparinized 10-ml syringe. Autologous blood was added to a total volume of 10 ml to prevent precipitation of indocyanine green. One millilitre of this solution was placed in a glass tube for later measurement of concentrations of opioid
459
British Journal of Anaesthesia
460 0.002 c •| 0.0015
E i 0.001 o <
0.0005
0
10
20 30 Time (s)
40
50
Figure 1 Arterial fraction vs time curves for indocyanine green (D) and sufentanil (O) after bolus injection of a mixture of the drugs in the right atrium. The fraction is the arterial blood concentration divided by the administered dose. The indocyanine green fraction curve was corrected for recirculation of the drug by log-linear extrapolation of the descending part of the curve.
Sufentanil No. of patients Height (cm) Weight (kg) Body surface area (m2) Medication (3 adrenoceptor blockers Nitrates Calcium entry blockers Diuretics
6
Alfentanil
CO =
DICG AUC ICG
Results are expressed as mean (SD) or mean (confidence interval of the mean). Data were analysed using analysis of variance with groups and type of ventilation as fixed factors and patients tested in these factors, followed by the Newman-Keuls range test, when applicable, or chi-square test. P < 0.05 was taken as statistically significant.
8
170.7(11.9) 73.5 (8.2) 1.86(0.15) 5/6 4/6 3/6 3/6
167.5 (9.7) 79.2(12.9) 1.93(0.22) 7/8 4/8 2/8 1/8
where AUC, = area under the fraction vs time curve up to time t (fig. 1). AUC was calculated by the linear trapezoidal rule. First-pass retention was denned as
Results The groups were comparable in height, weight, body surface area and preoperative medication (table 1). During the 5 min preceding the lung uptake study period, the groups were comparable in haemodynamic and arterial blood-gas values (table 2). In the sufentanil group, cardiac output measured by thermodilution or calculated from the indocyanine green concentration curve (table 3) was significantly lower during PEEP ventilation than during apnoea and IPPV. Within each group the opioid dose used
Table 2 Mean (SD) haemodynamic data and arterial blood-gas values, 2-3 min before injection of the mixture of indocyanine green and opioid. fGroup average with three observations per patient. * Statistically significant within-group difference (P < 0.05) Sufentanil Apnoea Heart rate (beat min"1) PCWP (mm Hg) Thermodilution cardiac output (litre min"1) Blood-gas values pH Pco 2 (kPa) Sao, (%)
Alfentanil Normoventilation
58 (8) 58(8) 8 (3) 9 (4) 4.48(0.56) 4.47(0.9)
PEEP ventilation
Sufentanil groupf
Apnoea
57.6 (6) 56(4) 8(4) 10(4) 3.55 (0.54)* 4.16(0.79)
7.42 (0.04) 7.42 (0.04) 7.41 (0.04) 5.4 (0.4) 5.4 (0.4) 5.4 (0.3) 100(1) 99(1) 99(1)
7.42 (0.04) 5.4 (0.4) 99(1)
Normoventilation
PEEP ventilation
Alfentanil groupf
61(8) 61(8) 61(7) 60(80 8(3) 10(4) 9(4) 8(3) 4.44 (0.87) 4.43(1.26) 3.68(1.12) 4.18(1.11)
7.38(7.39) 7.39(0.04) 7.38(0.04) 7.38(0.04) 5.8(0.5) 5.6(0.4) 5.6(0.4) 5.7(0.5) 99(1) 99(1) 99(1) 99(1)
Table 3 Mean (SD) indocyanine green (ICG) dose, opioid dose and cardiac output calculated from the indocyanine green concentration-time curve of the sufentanil and alfentanil group for each type of ventilation. fGroup average with three observations per patient. *Statistically significant within-group difference (P < 0.05) Sufentanil Apnoea
Alfentanil Normoventilation
PEEP ventilation
ICG dose (mg) 17.1(0.7) 17.8(1.7) 17.9(1.5) Opioid dose (ug) 33.5(2.7) 32.9(5.4) 33.1(5.8) Cardiac output 5.10(0.75) 5.11(1.38) 3.98(0.95)* (litre min"1)
Sufentanil groupf
Apnoea
17.6(1.3) 33.2(4.6) 4.73(1.13)
16.9(1.0) 17.0(0.6) 16.9(0.9) 16.9(0.8) 657(72) 655(69) 649(76) 654(69) 4.47(1.18) 4.17(1.70) 3.68(1.40) 4.11(1.40)
Normoventilation
PEEP ventilation
Alfentanil groupt
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Table 1 Patient data and preoperative medication in the two groups. Values are mean (SD) or proportion of the number of patients to the total number of patients in the study group
retention up to the time when 95 % of the total area under the indocyanine green curve was reached. Because possible recirculation of opioid was assumed to have occurred when recirculation of indocyanine green was observed, data from patients in whom recirculation occurred before 95 % of the AUC of indocyanine green was reached were not included in the calculation of extraction and retention. This did not occur in any of our patients. In addition to thermodilution cardiac output measurements, cardiac output was calculated also from the area under the curve and the dose of indocyanine green administered using the formula:
Pulmonary first-pass retention of opioids
461
Table 4 Mean (95 % confidence interval of the mean) pulmonary extraction and first-pass retention after bolus injection of alfentanil and sufentanil during apnoea, normoventilation and PEEP. The pivot point is the time from first appearance of drug in the arterial blood samples until the moment when extraction became zero. %n = 7, see text. -fGroup average with three observations per patient. *StarJstica]ly significant difference between sufentanil and alfentanil group (P < 0.05) Alfentanil
Sufentanil Apnoea 88.6 (77.1-100) First-pass retention (%) 50.9 (41.7-60.1) Pivot point (s) 27.3 (18.8-35.9) Peak extraction (%)
Normoventilation
PEEP ventilation
Sufentanil groupf
Apnoea
83.9 (79.1-88.7) 50.8 (42.9-58.8) 27.7 (19.9-35.5)
84.2 (75.2-93.2) 54.4 (43.7-65.0) 30.2 (21.8-38.6)
85.6* (81.5-89.7) 52.0* (47.8-56.3) 28.4 (24.7-32.1)
51.3 50.1 50.7 (41.9-60.7) (39.3-60.8) (35.2-66.3) 18.7 19.9 16.6 (5.4-32.0) (8.3-31.5) (5.6-27.6) 24.4$ 25.5 27.0 (21.4-27.4) (21.3-29.7) (21.7-32.3)
PEEP ventilation
Alfentanil
groupt 50.7* (44.8-56.6) 18.4* (12.6-24.2) 25.7 (23.5-27.9)
5? 80-I c o
60 40
i 20 Apnoea
IPPV
PEEP
Figure 2 First-pass pulmonary retention (percentage of the dose administered) of sufentanil after a fast bolus injection in six patients during anaesthesia with enflurane and with different types of ventilation during the first-pass retention study period of 1 min. Each patient is marked individually by a symbol. 100n
#
80-
I
60J 40
CD
a
20 0 -20 Apnoea
IPPV
PEEP
Figure 3 First-pass pulmonary retention (percentage of the dose administered) of alfentanil after a fast bolus injection in eight patients during anaesthesia with enflurane and with different types of ventilation during the first-pass retention study period of 1 min. Each patient is marked individually by a symbol.
for the retention study was comparable for each study period. Peak extraction and first-pass retention were significantly higher in the sufentanil group (table 4). Individual retention values for each ventilation type of the sufentanil and alfentanil groups are shown in figures 2 and 3, respectively. In both groups, peak extraction, first-pass retention and time to the pivot point, at which extraction becomes zero, were similar during each ventilation period. In one patient in the alfentanil group, during apnoea, extraction remained positive throughout the firstpass period and no pivot point could be detected. In
Discussion We have shown that first-pass pulmonary retention of sufentanil and alfentanil was not influenced by the type of ventilation in anaesthetized patients undergoing mechanical ventilation. We used the error mean square from the ANOVA table of first-pass retention to calculate the minimum detectable difference in first-pass retention in this study, as described by Zar [9]. In the sufentanil group, the ANOVA error mean square was 79.2 and (assuming a = 0.05, /? = 0.10) the within-group minimum detectable difference in first-pass retention was 17.0%. The ANOVA error mean square in the alfentanil group was 207.5 and the within-group minimum detectable difference in first-pass retention was 22.3%. The minimum detectable difference in first-pass retention in both groups was therefore small enough to allow detection of clinically significant changes in firstpass retention, if these occurred after changing the type of ventilation. The first-pass retention of sufentanil and alfentanil in this study was similar to that found in our previous study [6]. In that study, patients were investigated before induction of anaesthesia and they were breathing spontaneously. In these patients, pulmonary retention of sufentanil was 61.1 (95% confidence interval 51.3-70.9)% and that of alfentanil 10.1 (3.5-16.7)%. As first-pass retention in this study was similar to that of our previous study in which patients received only a single dose of opioid, it is unlikely that, in the context of the present study, the pulmonary system was saturable. Pulmonary retention of alfentanil in the present study, however, was lower than that reported by Taeger and coworkers [5] who studied patients during anaesthesia with enflurane and IPPV. In six patients who received alfentanil in their study median retention 30 s after administration was 58.8%. The median alfentanil retention in our patients who received alfentanil during IPPV was 19.8%. The differences between the three studies could be attributable to the drugs given for premedication or for anaesthesia, in
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two patients in the alfentanil group, first-pass retention was negative, although the indocyanine green and alfentanil concentration curves did not indicate that recirculation had occurred and loglinear extrapolation of the indocyanine green curve was straightforward.
100-,
c
Normoventilation
462
Compared with spontaneous ventilation, mechanical ventilation is associated with an increase in mean intrathoracic pressure. During PEEP ventilation, pulmonary capillaries partially collapse with higher PEEP values [18]. This could decrease the endothelial surface area available for exchange of drug molecules between blood and pulmonary tissue. In contrast, during apnoea, when intrathoracic pressure is low compared with positive pressure ventilation, there is least compression of pulmonary capillaries and thus possibly greater available endothelial area. Despite these observations, first-pass retention of sufentanil and alfentanil did not differ between types of ventilation. Possibly the effect of pressure ventilation on regional blood flow distribution is less important for opioid retention than it is for gas exchange. Redistribution of pulmonary blood flow to other parts of the lungs may outweigh the decrease in regional blood flow in the central parts of the lungs [19], leaving the available endothelial area relatively unchanged. Finally, uptake of sufentanil and alfentanil may not be limited by relatively small changes in the available endothelial area.
Ventilation-induced changes in pulmonary uptake and retention could also be caused by haemodynamic changes associated with mechanical ventilation. When higher magnitudes of PEEP are used, cardiac output decreases compared with normoventilation or spontaneous breathing, because of a decrease in venous return [20]. In the study, cardiac output (as measured by thermodilution) decreased significantly (—17%) during PEEP ventilation. Despite this decrease in cardiac output, first-pass retention of sufentanil and alfentanil remained constant. When changes in pulmonary blood flow are studied in isolation, neither a decrease in cardiac output nor diversion of cardiac output to one lung decreases pulmonary retention of alfentanil [21]. Appendix ALFENTANIL ASSAY Whole blood alfentanil concentrations were determined by radioimmunoassay. To 0.3 ml of whole blood, 1 ml of NaOH 0.1 mol litre"1 and 4 ml of n-heptane-isoamylalcohol were added and the solution was mixed for 10 min on a rotary mixer (Protherm type Cenco PT 1510). The solution was centrifuged for 10 mm at 4000 rpm (Heraeus Minifuge GL.) and the supernatant evaporated to dryness in a stream of dry nitrogen on a water bath at 60 °C. Then, 50 ul of absolute alcohol was added and the solution again vortexed. Thereafter, bovine serum albumin (Sigma no. A-7888 RIA grade) 450 ul in phosphate buffer (pH 7.5) was added and the rube was vortexed again. Then, 50 ul of the solution was added to 2 % bovine serum albumin 450 ul, vortexed and ['HJalfentanil Qanssen, Beerse, Belgium) added. After further vortexing, 100 ul of antiserum (Janssen, Beerse, Belgium) was added. The solution was left at room temperature for 2 h. Then, 500 ul of a NoritDextran suspension was added to each test tube and the solution incubated for 1 h. The solution was centrifuged (10 min, 4000 rpm, 20 °C), decanted into a new test tube and 4 ml of liquid scintillation cocktail (Ultima Gold, Packard) was added to the supernatant. Standard solutions, initial binding and antiserum free samples (to determine non-specific binding) were treated similarly. Scintillation was measured in a liquid scintillation analyser (Packard, Tricarb 2000 CA), measured as dpm. The detection limit of this assay was 0.5ugml~'. The average coefficients of variation of spiked concentrations of 40 and 100 ug ml"1 were 7.4 and 5.5 %. The initial binding was 45 % and the coefficient of non-specific binding was 0.76 % of total binding.
Acknowledgement This study was supported financially by the "Stichting de Drie Lichtcn".
References 1. Bahkle YS. Pharmacokinetic and metabolic properties of the lung. British Journal of Anaesthesia 1990; 65: 79-93. 2. Ryan US, Grantham CJ. Metabolism of endogenous and xenobiotic substances by pulmonary vascular endothelial cells. Pharmacology and Therapeutics 1989; 42: 235-250. 3. Nunn JF. Applied Respiratory Physiology, 3rd Edn. London: Butterworth, 1987; 284-293. 4. Roerig DL, Kotrly KJ, Vucins E, Ahlf SB, Dawson CA, Kampine JP. First pass uptake of fentanyl, meperidine and morphine in the human lung. Anesthesiology 1987; 67: 466-^72. 5. Taeger K, Weninger E, Schmelzer F, Adt M, Franke N, Peter K. Pulmonary kinetics of fentanyl and alfentanil in surgical patients. British Journal of Anaesthesia 1988; 61: 425-434. 6. Boer F, Bovill JG, Burm AGL, Mooren RAG. Uptake of sufentanil, alfentanil and morphine in the lungs of patients about to undergo coronary artery surgery. British Journal of Anaesthesia 1992; 68: 370-375. 7. Geddes DM, Nesbitt K, Traill T, Blackburn JP. First pass
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addition to factors such as mechanical ventilation. The various drugs could have altered pulmonary retention, as significant competition for pulmonary binding sites occurs between drugs [10,11]. Inhalation anaesthetic agents may also influence pulmonary uptake of drugs. Halothane increases the pulmonary retention of propranolol in dogs [12]. Pulmonary retention of lignocaine, on the other hand, was lower in patients during anaesthesia with fentanyl, droperidol and nitrous oxide in air, compared with healthy volunteers [11]. We are unaware of studies that have addressed the effect of enflurane on first-pass retention of drugs. Ventilation-induced changes in the pulmonary first-pass retention of opioids may be caused by changes in the pH of pulmonary arterial blood and lung tissue, changes in regional distribution of pulmonary blood flow or by changes in cardiac output and total pulmonary blood flow. IPPV is often associated with a change in the pH of pulmonary arterial blood as a result of relative hyperventilation. This may significantly increase pulmonary retention of drugs. Roth and Gillis [13, 14] observed that the removal of mescaline by isolated perfused rabbit lungs ventilated with room air was greater (76%) than when the lungs were inflated to a static volume (48%). When the lungs were ventilated with 95% air-5% carbon dioxide, removal of mescaline did not differ from that during static inflation. Increased mescaline removal during room air ventilation was associated with an increase in the pH of the effluent perfusate. When the pH of the medium that perfused the statistically inflated lungs was increased, removal of mescaline also increased. Similar pH-dependent changes in lung uptake have been observed with lignocaine, bupivacaine and etidocaine in vivo [15, 16] and in vitro [17]. In the present study, arterial pH and carbon dioxide partial pressure were similar during each type of ventilation. Therefore, if pH-related changes in pulmonary retention of alfentanil or sufentanil are important, they could not be shown in this study.
British Journal of Anaesthesia
Pulmonary first-pass retention of opioids
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463 15. Post C, Eriksdotter-Behm K. Dependence of lung uptake of lidocaine in vivo on blood pH. Acta Pharmacologica el Toxicologica 1982; 51: 136-140. 16. Palazzo MGA, Kalso EA, Argiras E, Madgwick R, Sear JW. First pass lung uptake of bupivacaine: effect of acidosis in an intact rabbit lung model. British Journal of Anaesthesia 1991; 67: 759-763. 17. Post C, Andersson RGG, Ryrfeld A, Nilson E. Physicochemical modification of lidocaine uptake in rat lung tissue. Acta Pharmacologica et Toxicologica 1979; 44: 103-109. 18. Bindlcv L, Hedcnstierna G, Santesson J, Gottlieb I, Carvallhas A. Ventilation-perfusion distribution during inhalation anaesthesia. Acta Anaesthtsiologica Scandinavica 1981; 25: 360-371. 19. Hedenstierna G, White F, Mazzone FC, Wagner PD. Redistribution of pulmonary blood flow in the dog with positive end-expiratory pressure ventilation. Journal of Applied Physiology 1979; 46: 278-287. 20. Lcnfant C, Howell BJ. Cardiovascular adjustments in dogs during continuous pressure breathing. Journal of Applied Physiology 1960; 15: 425. 21. Boer F, Burm AGL, Bovill JG, Hak A. Effect of haemodynamics on pulmonary distribution of alfentanil in pigs. British Journal of Anaesthesia 1994; 72 (Suppl. 1): A162. Downloaded from http://bja.oxfordjournals.org/ at UQ Library on June 21, 2015