- Email: [email protected]
Blood Concentrations of Enflurane Before, During, and After Hypothermic Cardiopulmonary Bypass
Blood Concentrations of Enflurane Before, During, and After Hypothermic Cardiopulmonary Bypass C. Roger Goucke, FANZCA,* L. Peter Hackett, MRSC,† P. Hugh Barrett, PhD,‡ and Kenneth. F. Ilett, PhD§ Objective: The purpose of this study was to determine blood concentrations of enflurane delivered via a membrane oxygenator during hypothermic cardiopulmonary bypass (CPB) with changes in the input enflurane concentration and temperature and to characterize the pharmacokinetics of enflurane washout during and after CPB. Design: Blood enflurane concentrations were measured by gas chromatography before, during, and after CPB by using mean delivered enflurane concentrations of 0.5% v/v (group 1, n ⴝ 5), 0.8% (group 2, n ⴝ 7), and 1% (group 3, n ⴝ 14). Setting: The investigation was performed in a teaching hospital setting. Participants: Twenty-six patients undergoing cardiac surgery requiring hypothermic CPB. Interventions: Variations in input enflurane concentration in different patients plus blood sampling from the arterial side of the circuit for enflurane assay.
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OLATILE ANESTHETIC AGENTS (VAAs) are commonly used in general anesthesia to induce and maintain hypnosis, analgesia, amnesia, and muscle relaxation. They can be administered during cardiopulmonary bypass (CPB) to minimize the risk of awareness, control systemic blood pressure and myocardial oxygen consumption, and improve myocardial function in the postischemic state.1-4 Although no longer widely used, enflurane was a commonly used VAA for cardiac surgery. This study was undertaken because of the potential of enflurane to cause dose-dependent cardiovascular depression.5 In the absence of many of the usual clinical signs to guide the dose of VAA and the paucity of information on the kinetics of these agents during CPB, the amount of VAA administered while on CPB is based on non-CPB experience. The objectives of this study were to determine how blood concentrations of enflurane change when delivered via a membrane oxygenator during hypothermic CPB and to characterize the pharmacokinetics of enflurane washout on bypass.
From the *Department of Anaesthesia, Sir Charles Gairdner Hospital, Nedlands, WA, Australia; †Clinical Pharmacology and Toxicology Laboratory, Path West Laboratory Medicine, Nedlands, WA, Australia; ‡Medicine Unit, Royal Perth Hospital, and §Pharmacology and Anaesthesiology Unit, School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia. Supported by grants from the Sir Charles Gairdner Research Committee and the US National Institutes of Health (NIH/NIBIB Grant P41 EB-001975). P.H.B. is a fellow of the National Health and Medical Research Council of Australia. Address reprint requests to C. Roger Goucke, FANZCA, Department of Anaesthesia, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia, Australia. E-mail: [email protected] © 2007 Elsevier Inc. All rights reserved. 1053-0770/07/2102-0010$32.00/0 doi:10.1053/j.jvca.2006.08.009 218
Measurements and Main Results: Median (25th and 75th percentiles) pre-CPB blood enflurane concentrations were 48 (25-50) mg/L, 52 (47-56) mg/L, and 115 (90-143) mg/L in groups 1 (0.5% v/v), 2 (0.8% v/v), and 3 (1% v/v), respectively. During hypothermia (28°C) corresponding enflurane concentrations were 44 (31-53) mg/L, 56 (45-62) mg/L, and 145 (109-203) mg/L, respectively. For groups 1 and 2, there were no significant changes in blood enflurane compared with the corresponding pre-CPB value. However, for group 3, cooling resulted in a significant increase (p ⴝ 0.006) in blood enflurane. In all groups, enflurane concentrations after rewarming were similar to those in the pre-CPB period. Conclusions: It is concluded that exposure to enflurane concentrations greater than 0.8% during CPB can result in high blood concentrations. © 2007 Elsevier Inc. All rights reserved. KEY WORDS: enflurane, pharmacokinetics, hypothermic cardiopulmonary bypass METHODS After University of Western Australia Human Rights Committee approval and written informed consent, 26 patients undergoing cardiac surgery requiring hypothermic CPB were studied. Sequential, consenting patients receiving anesthesia for cardiac sugery while the first author was the anesthesiologist were studied. There were no specific exclusion criteria. All patients received premedication with oral lorazepam, 2 mg, intramuscular morphine, 7.5 to 10 mg, and promethazine, 12.5 mg. Anesthesia was induced with midazolam, 40 to 60 g/kg, and fentanyl, 20 g/kg. After induction, anesthesia was maintained with enflurane (Ethrane; Abbott Australasia Pty Ltd, Botany, NSW, Australia). A second dose of fentanyl, 10 g/kg, was given at commencement of rewarming on CPB. Tracheal intubation and muscle paralysis were facilitated with pancuronium, 100 g/kg. Before CPB, enflurane was delivered in the anesthetic circuit from a recently calibrated (Australian/New Zealand Standard 4059:1996) vaporizer (Ohmeda Enfluratec; BOC Healthcare, North Ryde, NSW, Australia). The vaporizer was standardized against a Poet II gas analyzer (POET II Criticare Systems Incorporated, Waukesha, WI) that had been calibrated by using an International Standards Organisation– certified calibration gas. The vaporizer was tested at 2% v/v enflurane and an oxygen flow of 5 L/min and accepted provided it was within ⫾0.1% of the expected value. During CPB, enflurane was delivered into the oxygen inlet of the membrane oxygenator from the same vaporizer (group 1, n ⫽ 5 [0.5% v/v]; group 2, n ⫽ 7 [0.8%], and group 3, n ⫽ 14 [1%]). Group 3 had 2 subgroups: group 3A (n ⫽ 7) in which the enflurane was delivered throughout the operation and group 3B (n ⫽ 7) in which enflurane was stopped at the time of rewarming so that “washout” characteristics could be studied. In the latter patients, anesthesia was maintained with a propofol (50-60 mg/kg/h) intravenous infusion. Before CPB, anticoagulation was achieved with 400 U/kg of heparin. Nonpulsatile hypothermic CPB with alpha-stat acid-base management was instituted by using a Capiox-E oxygenator (Terumo Corporation, Tokyo, Japan). A Stockert CAPS Heart Lung Machine with flows of 2.4 L/min/m2 was used for blood circulation (Stockert Instruments GmbH, Munich, Germany). Oxygen gas flow was adjusted (1.5-3 L/min) to maintain a ventilation/perfusion ratio of 0.6. The pump prime consisted of 2.4 L of Hartmann’s solution with additional crystalloid to maintain reservoir volume. Cooling commenced after initiation of CPB and cross-clamping of the aorta occurred within 5 minutes of instituting
Journal of Cardiothoracic and Vascular Anesthesia, Vol 21, No 2 (April), 2007: pp 218-223
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Table 1. Group Characteristics for Patients Undergoing CPB on Enflurane Variable
Group 1 (0.5 % v/v)
Group 2 (0.8% v/v)
Groups 3A plus B (1% v/v)
Number and sex Age (y) Weight (kg) Body mass index Pump prime volume (L) Cardioplegia volume (L) Supplemental crystalloid volume (L)
4 M/1 F 74 (72-76) 77 (66-89) 25.6 (24.5-26.7) 2.4 (2.0-2.4) 1.1 (0.2-2.0) 2.0 (0.5-3.5)
4 M/3 F 62 (53-70) 72 (63-81) 27.5 (26.0-29.0) 2.4 (2.0-2.8) 1.2 (0.2-2.2) 2.4 (1.5-3.3)
9 M/5 F 65 (59-71) 76 (68-84) 26.4 (24.1-28.7) 2.3 (2.2-2.4) 1.2 (0.8-2.6) 1.9 (1.5-2.3)
NOTE. Data as mean (95% confidence interval). Abbreviations: M, male; F, female.
CPB. Blood cardioplegia via antegrade and retrograde routes was used. Arterial blood samples (EDTA) were taken for enflurane analysis 5 to 10 minutes before and during CPB. The samples were placed on ice, transported to the laboratory at the end of the operation, and analyzed immediately. Enflurane in EDTA-anticoagulated blood was quantified by gas chromatography using halothane (Fluothane; AstraZeneca Pty Ltd, North Ryde, NSW, Australia) as an internal standard. After equilibration of standards and unknown samples at 48°C for 90 minutes in sealed vials, aliquots of headspace gas were injected into a gas chromatograph (Varian Model 3700; Varian Inc, Palo Alto, CA) by using a Chromosorb 101 column (2 m ⫻ 4 mm ID), an oven temperature of 160°C, a N2 flow of 30 mL/min, and a flame ionization detector. Retention times for enflurane and halothane were 1.7 and 2.9 minutes, respectively. Standard curves for enflurane had correlation coefficients of ⬎0.998. Intraday relative standard deviations ranged from 1.1% to 4.9%, whereas interday values ranged from 8.7% to 11.2%. The linear trapezoidal rule6 was used to calculate the area under the blood enflurane concentration-time curve (AUC28) during the period when the patients were cooled to 28°C. Average enflurane concentration was estimated as AUC28/time at 28°C. Data are summarized as mean (95% confidence interval) or median (25th and 75th percentiles). Differences between groups were investigated by using a paired t test or 1-way analysis of variance (ANOVA) on ranks with Dunns’s test (SigmaStat 3.1; SPSS Inc, Chicago, IL). To explore the pharmacokinetics of enflurane, a 2-compartment model was developed by using the SAAM II program (SAAM Institute, Seattle, WA) and data from patients in group 3B. The model consisted of a central compartment (#1; blood) and an extravascular compartment (#2). Fractional rate constants between compartments (k12 and k21) and the elimination rate constant (k10, from the central compartment) were all assumed to be first order. The differential equations describing the model are: dq1 dt dq2 dt
⫽ ⫺(k10⫹k12)q1 ⫹ k21q2 ⫹ u1共t兲 ⫽ ⫺k21q2 ⫹ k12q1
where q1 and q2 are the masses of enflurane in the central and extravascular compartments, respectively, and u1 (t) is the input of enflurane into the central compartment. The model provided for 2 square-wave inputs of enflurane into the central compartment, one that simulated enflurane administration via the lungs and one that simulated input via the oxygenator. Half-lives (t1/2␣ and t1/2) and steady-state volume of distribution (Vss) for the model were obtained by using standard equations.7 Several studies have shown a relationship between changes in temperature and enflurane solubility in blood,8,9 such that a 5% change in solubility is observed with each degree change in temperature. This relationship was incorporated into the model so that blood concentra-
tion was a function of the mass of enflurane in the central compartment and temperature: Enflurane ⫽ q1
Solubility V1
Solubility ⫽ 关1⫹共共Temp共0兲 ⫺ linear(Temp(t)))0.05)] where V1 is volume of distribution for the central compartment, Temp(0) is body temperature at the start of CPB, and linear(Temp(t)) is a linear interpolation of the temperature values at time (t) during CPB. RESULTS
Patients in all 3 groups were of similar age, body weight, and body mass index (Table 1). Pump prime, cardioplegia, and supplemental crystalloid volumes used were also similar across the 3 groups. Time from induction of anesthesia to start of CPB varied between 45 and 60 minutes. Eighteen patients received coronary artery grafts, 5 had coronary artery grafts plus valve replacement, and 3 patients received valve replacements alone. Blood enflurane concentrations and corresponding nasopharyngeal temperatures for patients in group 1 (0.5%), group 2 (0.8%), and groups 3A and 3B (1% ) during CPB are shown in Figure 1. Median pre-CPB blood enflurane concentrations were 48 (25-50) mg/L, 52 (47-56) mg/L, and 115 (90-143) mg/L in groups 1, 2, and 3A plus 3B, respectively. One-way ANOVA on ranks with Dunn’s test indicated that blood enflurane concentrations in group 1 and group 2 were significantly lower (q ⫽ 3.8 and q ⫽ 3.4, respectively; p ⬍ 0.05) than in group 3. Patients were cooled to approximately 28°C and maintained at this temperature for a mean of 29 (19-40) minutes. Median blood enflurane concentrations while at 28°C were 44 (31-53) mg/L, 56 (45-61) mg/L, and 145 (109-203) mg/L in groups 1, 2, and 3A plus 3B, respectively. For groups 1 and 2 , there were no significant changes in blood enflurane at 28°C compared with the corresponding pre-CPB value (Fig 1A and B). However, for patients in group 3 (Fig 1C and D), cooling to 28°C resulted in a significant (paired t ⫽ 3.2, p ⫽ 0.006) mean increase of 14.2 mg/L (95% confidence interval, 4.8-23.8) in blood enflurane concentration compared with the corresponding pre-CPB concentration. In addition, a 1-way ANOVA on ranks (Dunn’s test) comparing the average enflurane concentrations at 28°C across all groups showed significantly higher concentrations in groups
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GOUCKE ET AL
Fig 1. Blood enflurane concentration (upper panel) and nasopharyngeal temperature (lower panel) for patients receiving (A) 0.5% v/v enflurane (group 1), (B) 0.8% v/v enflurane (group 2), (C) 1% v/v enflurane (group 3A), and (D) 1% v/v enflurane with washout of anesthetic starting at the time of rewarming (group 3B). Data for individual patients are indicated by the different symbols. CPB commenced at zero hours.
3A and B combined compared with either group 1 (q ⫽ 3.7, p ⬍ 0.05) or group 2 (q ⫽ 3.3, p ⬍ 0.05). When the patients were rewarmed to 35°C to 37°C, median blood enflurane decreased to concentrations similar to those seen in the preCPB period: 39 (28-50) mg/L for group 1, 49 (43-55) mg/L for group 2, and 125 (86-137) mg/L for group 3. The washout characteristics of enflurane during CPB (group 3b) were also investigated (Fig 1D). To gain insight into the enflurane input concentration-dependent changes in blood enflurane during CPB, the concentration-time data were subjected to pharmacokinetic analysis. In preliminary investigations (data
not shown), the enflurane blood concentration-time data were fitted to 1- and 2-compartment models with zero-order input and first-order distribution and elimination rate constants. A 2-compartment model with first-order elimination from the central compartment (rate constant k10) was the most parsimonious model that explained the data. The use of a MichaelisMenten elimination term instead of the first-order rate constant (k10) was attempted but could not be justified on the basis of the Akaike Information Criterion value for the model.10 The pharmacokinetic descriptors for the model are summarized in Table 2. The washout phase was characterized as a biexponential
BLOOD ENFLURANE DURING CPB
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Figure 1.
decay in blood enflurane concentrations with mean initial (␣) and terminal () t1/2 values of 1.3 minutes and 111 minutes, respectively. DISCUSSION
The most important result of this study is that, after the administration of enflurane (1% v/v) throughout CPB, a 26% increase in median blood enflurane concentration occurred between the pre-CPB levels and those taken during CPB. Although VAAs are commonly used as part of the anesthetic technique for cardiac surgery, their pharmacokinetics and pharmacodynamics during CPB are poorly understood. The main justification for use was a reduction in the incidence of awareness; however, the cardioprotective effects shown by the newer
(Cont’d)
agents add support to their continued use. The concentration of VAA delivered is usually determined empirically. With the trend toward offering cardiac surgery to patients with lower ejection fractions and reduced cardiac reserve, knowledge of the disposition of VAAs during CPB remains an area of interest. Until a well-validated measure of level of consciousness during all stages of CPB is available, it is likely that empirical concentrations of VAA will continue to be used to minimize the risk of awareness. The pre-CPB data showing a mean enflurane level of 118 (95-139) mg/L for patients receiving 1% enflurane are consistent with the range in previous reports (44-144 mg/L).11,12 Equilibrated pre-CPB blood enflurane concentrations were significantly higher at 1% enflurane than at 0.5% or 0.8%. When
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Table 2. Pharmacokinetic Parameter Estimates for Enflurane During Washout Patient
k10 (/h)
k12 (/h)
k21 (/h)
V1 (L)
Vss (L)
1 2 3 4 5 6 7 Mean (95% CI)
4.58 7.65 15.88 10.39 7.11 23.18 3.03 7.02 (5.02-15.49)
3.41 26.87 18.65 13.80 9.11 31.82 30.48 19.16 (11.01-27.31)
1.01 0.84 1.67 0.38 0.31 1.86 0.80 0.98 (0.54-1.42)
3.57 3.39 4.22 3.77 2.98 1.59 2.24 3.11 (2.43-3.79)
15.7 111.2 51.3 140.1 89.3 28.9 87.5 74.8 (41.6-108.1)
Abbreviation: CI, confidence interval.
these patients were cooled to 28°C, blood enflurane concentration increased significantly in the 1% group but was essentially unchanged in patients receiving 0.5% or 0.8% enflurane. However, at all 3 input concentrations, the enflurane levels measured after rewarming was completed were similar to those in the pre-CPB period. These data show that the decrease in temperature during CPB is an important factor in the increase in blood enflurane observed at 1% enflurane input. The washout studies at 1% enflurane are important because they show that enflurane is very rapidly removed from the blood. These data also suggest that washout of enflurane could be used at the time of rewarming to minimize the possibility of cardiovascular depression. Apart from the vaporizer setting and specific vaporizer characteristics, other factors that determine the amount of VAA in blood during CPB are those that affect the kinetics of tissue uptake and release.13 These include the amount of VAA in the tissues before CPB (influenced by the patient’s cardiac output), characteristics of the VAA such as increased solubility in blood during hypothermia,8 decreased solubility in crystalloid,14 fresh gas flow rate, pump flow rate, oxygenator efficiency, temperature, duration of CPB, and pre-bypass administration of the VAA. Other factors, such as the volume of pump prime, cardioplegia, urine production, nonscavenged surgical blood loss, and evaporation from the surgical site, also may influence VAA blood levels. In the present study, the input concentration dependence of pre-CPB blood enflurane is unlikely to be attributable to between-patient differences in hemodynamics because all patients were selected on the same basis. However, a group order effect cannot be excluded because the groups were accrued sequentially. Because the patients were similar, input concentration dependence is simply a result of the different doses adminis-
tered via the vaporizer. The mean ratio of k12/k21 (19.6) was consistent with the expected tissue accumulation of enflurane and with the mean t1/2␣ and t1/2 values of 1.3 and 111 minutes, respectively. The mean volume of the central compartment (3.1 L) was compatible with the anticipated initial distribution of volatile anesthetics into the vascular system.13 The greater accumulation of enflurane during the cooling phase of CPB in the patients who received an input concentration of 1% compared with 0.5% or 0.8% enflurane suggests that the disposition of drug may be saturable at the higher level. Zhou and Liu15 have shown that enflurane has a very high partition coefficient into fat (95.3), and, therefore, it cannot be excluded that the observed increase in blood enflurane was related to decreased perfusion of fat. Nevertheless, the mechanism underlying the increase in blood enflurane during cooling is unclear. Although temperature appears to be important, the enflurane input concentration dependence suggests that the membrane oxygenator itself also may be involved. However, the microporous polypropylene type of membrane used has been shown to allow excellent passage of VAAs.16 Increased blood enflurane concentration during CPB could be detrimental to cardiac function,5,17 as well as causing increased carbon monoxide production,18 increased free radical concentrations, and disruption of cellular antioxidant protective mechanisms.19,20 Therefore, it is suggested that enflurane input concentrations should be kept at or below 0.8% v/v. However, there is also strong support for the use of related VAAs during CPB because of their cardioprotective properties.3,4,21 Although enflurane is no longer the VAA of choice for CPB, similar studies are needed for the newer agents such as isoflurane and sevoflurane, which have similar physicochemical and pharmacokinetic properties.
REFERENCES 1. Ranta S, Jussila J, Hynynen M: Recall of awareness during cardiac anaesthesia: Influence of feedback information to the anaesthesiologist. Acta Anaesth Scand 40:554-560, 1996 2. Rodig G, Wild K, Behr R, et al: Effects of desflurane and isoflurane on systemic vascular resistance during hypothermic cardiopulmonary bypass. J Cardiothorac Vasc Anesth 11:54-57, 1997 3. Julier K, da Silva R, Garcia C, et al: Preconditioning by sevoflurane decreases biochemical markers for myocardial and renal dysfunction in coronary artery bypass graft surgery: A doubleblinded, placebo-controlled, multicenter study. Anesthesiology 98: 1315-1327, 2003
4. De Hert SG, Van der Linden PJ, Cromheecke S, et al: Cardioprotective properties of sevoflurane in patients undergoing coronary surgery with cardiopulmonary bypass are related to the modalities of its administration. Anesthesiology 101:299-310, 2004 5. Calverley RK, Smith NT, Prys-Roberts C, et al: Cardiovascular effects of enflurane anesthesia during controlled ventilation in man. Anesth Analg 57:619-628, 1978 6. Thomann P: Non-compartmental analysis methods manual in TopFit 2.0. Pharmacokinetic and pharmacodynamic data analysis system for the PC. Edited by Heinzel G, Woloszcak R, Thomann P. Stuttgart, Germany, Gustav Fischer, 1993
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7. Wagner JG: Linear compartmental models, in Wagner JG, Hamilton IL (eds): Fundamentals of Clinical Pharmacokinetics. Hamilton, IL, Drug Intelligence Publications, 1975 8. Eger RR, Eger EI: Effect of temperature and age on the solubility of enflurane, halothane, isoflurane, and methoxyflurane in human blood. Anesth Analg 64:640-642, 1985 9. Lockwood GG, Sapsed-Byrne SM, Smith MA: Effect of temperature on the solubility of desflurane, sevoflurane, enflurane and halothane in blood. Br J Anaesth 79:517-520, 1997 10. Akaike H: Information theory and an extension of the maximum likelihood principle, in Petrov BN, Tsahkadsor CF (eds): 2nd International Symposium on Information Theory. Armenia, USSR, USSR Academy of Sciences, 1971 11. Ise H, Kudo K, Jitsufuchi N, et al: Simple and rapid determination of enflurane in human tissues using gas chromatography and gas chromatography-mass spectrometry. J Chromatog B Biomed Sci Appl 698:97-102, 1997 12. Corall IM, Knights KM, Strunin L: Enflurane (Ethrane) anaesthesia in man. Metabolism and effects on biochemical and haematological variables. Br J Anaesth 49:881-885, 1977 13. Dale O, Brown BRJ: Clinical pharmacokinetics of the inhalational anaesthetics. Clin Pharmacokinet 12:145-167, 1987 14. Feingold A: Crystalloid hemodilution, hypothermia, and halothane blood solubility during cardiopulmonary bypass. Anesth Analg 56:622-626, 1977
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15. Zhou J-X, Liu J: The effect of temperature on solubility of volatile anesthetics in human tissues. Anesth Analg 93:234-238, 2001 16. Wiesenack C, Wiesner G, Keyl C, et al: In vivo uptake and elimination of isoflurane by different membrane oxygenators during cardiopulmonary bypass. Anesthesiology 97:133-138, 2002 17. Ciofolo MJ, Reiz S: Circulatory effects of volatile anesthetic agents. Minerva Anestesiol. 65:232-238, 1999 18. Keijzer C, Perez RS, De Lange JJ: Carbon monoxide production from five volatile anesthetics in dry sodalime in a patient model: halothane and sevoflurane do produce carbon monoxide: Temperature is a poor predictor of carbon monoxide production. BMC Anesthesiol 5:1-7, 2005 19. Turkan H, Bukan N, Sayal A, et al: Effects of halothane, enflurane, and isoflurane on plasma and erythrocyte antioxidant enzymes and trace elements. Biol Trace Elem Res 102:105-112, 2004 20. Zhou YF, Zhao KM, Chen QL: [Effects of enflurane on myocardial reperfusion injury during cardiac surgery with cardiopulmonary bypass]. Zhejiang Da Xue Xue Yi Xue Ban 32:227-230, 2003 21. De Hert SG, Van der Linden PJ, Cromheecke S, et al: Choice of primary anesthetic regimen can influence intensive care unit length of stay after coronary surgery with cardiopulmonary bypass. Anesthesiology 101:9-20, 2004
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OLATILE ANESTHETIC AGENTS (VAAs) are commonly used in general anesthesia to induce and maintain hypnosis, analgesia, amnesia, and muscle relaxation. They can be administered during cardiopulmonary bypass (CPB) to minimize the risk of awareness, control systemic blood pressure and myocardial oxygen consumption, and improve myocardial function in the postischemic state.1-4 Although no longer widely used, enflurane was a commonly used VAA for cardiac surgery. This study was undertaken because of the potential of enflurane to cause dose-dependent cardiovascular depression.5 In the absence of many of the usual clinical signs to guide the dose of VAA and the paucity of information on the kinetics of these agents during CPB, the amount of VAA administered while on CPB is based on non-CPB experience. The objectives of this study were to determine how blood concentrations of enflurane change when delivered via a membrane oxygenator during hypothermic CPB and to characterize the pharmacokinetics of enflurane washout on bypass.
From the *Department of Anaesthesia, Sir Charles Gairdner Hospital, Nedlands, WA, Australia; †Clinical Pharmacology and Toxicology Laboratory, Path West Laboratory Medicine, Nedlands, WA, Australia; ‡Medicine Unit, Royal Perth Hospital, and §Pharmacology and Anaesthesiology Unit, School of Medicine and Pharmacology, University of Western Australia, Crawley, WA, Australia. Supported by grants from the Sir Charles Gairdner Research Committee and the US National Institutes of Health (NIH/NIBIB Grant P41 EB-001975). P.H.B. is a fellow of the National Health and Medical Research Council of Australia. Address reprint requests to C. Roger Goucke, FANZCA, Department of Anaesthesia, Sir Charles Gairdner Hospital, Nedlands 6009, Western Australia, Australia. E-mail: [email protected] © 2007 Elsevier Inc. All rights reserved. 1053-0770/07/2102-0010$32.00/0 doi:10.1053/j.jvca.2006.08.009 218
Measurements and Main Results: Median (25th and 75th percentiles) pre-CPB blood enflurane concentrations were 48 (25-50) mg/L, 52 (47-56) mg/L, and 115 (90-143) mg/L in groups 1 (0.5% v/v), 2 (0.8% v/v), and 3 (1% v/v), respectively. During hypothermia (28°C) corresponding enflurane concentrations were 44 (31-53) mg/L, 56 (45-62) mg/L, and 145 (109-203) mg/L, respectively. For groups 1 and 2, there were no significant changes in blood enflurane compared with the corresponding pre-CPB value. However, for group 3, cooling resulted in a significant increase (p ⴝ 0.006) in blood enflurane. In all groups, enflurane concentrations after rewarming were similar to those in the pre-CPB period. Conclusions: It is concluded that exposure to enflurane concentrations greater than 0.8% during CPB can result in high blood concentrations. © 2007 Elsevier Inc. All rights reserved. KEY WORDS: enflurane, pharmacokinetics, hypothermic cardiopulmonary bypass METHODS After University of Western Australia Human Rights Committee approval and written informed consent, 26 patients undergoing cardiac surgery requiring hypothermic CPB were studied. Sequential, consenting patients receiving anesthesia for cardiac sugery while the first author was the anesthesiologist were studied. There were no specific exclusion criteria. All patients received premedication with oral lorazepam, 2 mg, intramuscular morphine, 7.5 to 10 mg, and promethazine, 12.5 mg. Anesthesia was induced with midazolam, 40 to 60 g/kg, and fentanyl, 20 g/kg. After induction, anesthesia was maintained with enflurane (Ethrane; Abbott Australasia Pty Ltd, Botany, NSW, Australia). A second dose of fentanyl, 10 g/kg, was given at commencement of rewarming on CPB. Tracheal intubation and muscle paralysis were facilitated with pancuronium, 100 g/kg. Before CPB, enflurane was delivered in the anesthetic circuit from a recently calibrated (Australian/New Zealand Standard 4059:1996) vaporizer (Ohmeda Enfluratec; BOC Healthcare, North Ryde, NSW, Australia). The vaporizer was standardized against a Poet II gas analyzer (POET II Criticare Systems Incorporated, Waukesha, WI) that had been calibrated by using an International Standards Organisation– certified calibration gas. The vaporizer was tested at 2% v/v enflurane and an oxygen flow of 5 L/min and accepted provided it was within ⫾0.1% of the expected value. During CPB, enflurane was delivered into the oxygen inlet of the membrane oxygenator from the same vaporizer (group 1, n ⫽ 5 [0.5% v/v]; group 2, n ⫽ 7 [0.8%], and group 3, n ⫽ 14 [1%]). Group 3 had 2 subgroups: group 3A (n ⫽ 7) in which the enflurane was delivered throughout the operation and group 3B (n ⫽ 7) in which enflurane was stopped at the time of rewarming so that “washout” characteristics could be studied. In the latter patients, anesthesia was maintained with a propofol (50-60 mg/kg/h) intravenous infusion. Before CPB, anticoagulation was achieved with 400 U/kg of heparin. Nonpulsatile hypothermic CPB with alpha-stat acid-base management was instituted by using a Capiox-E oxygenator (Terumo Corporation, Tokyo, Japan). A Stockert CAPS Heart Lung Machine with flows of 2.4 L/min/m2 was used for blood circulation (Stockert Instruments GmbH, Munich, Germany). Oxygen gas flow was adjusted (1.5-3 L/min) to maintain a ventilation/perfusion ratio of 0.6. The pump prime consisted of 2.4 L of Hartmann’s solution with additional crystalloid to maintain reservoir volume. Cooling commenced after initiation of CPB and cross-clamping of the aorta occurred within 5 minutes of instituting
Journal of Cardiothoracic and Vascular Anesthesia, Vol 21, No 2 (April), 2007: pp 218-223
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Table 1. Group Characteristics for Patients Undergoing CPB on Enflurane Variable
Group 1 (0.5 % v/v)
Group 2 (0.8% v/v)
Groups 3A plus B (1% v/v)
Number and sex Age (y) Weight (kg) Body mass index Pump prime volume (L) Cardioplegia volume (L) Supplemental crystalloid volume (L)
4 M/1 F 74 (72-76) 77 (66-89) 25.6 (24.5-26.7) 2.4 (2.0-2.4) 1.1 (0.2-2.0) 2.0 (0.5-3.5)
4 M/3 F 62 (53-70) 72 (63-81) 27.5 (26.0-29.0) 2.4 (2.0-2.8) 1.2 (0.2-2.2) 2.4 (1.5-3.3)
9 M/5 F 65 (59-71) 76 (68-84) 26.4 (24.1-28.7) 2.3 (2.2-2.4) 1.2 (0.8-2.6) 1.9 (1.5-2.3)
NOTE. Data as mean (95% confidence interval). Abbreviations: M, male; F, female.
CPB. Blood cardioplegia via antegrade and retrograde routes was used. Arterial blood samples (EDTA) were taken for enflurane analysis 5 to 10 minutes before and during CPB. The samples were placed on ice, transported to the laboratory at the end of the operation, and analyzed immediately. Enflurane in EDTA-anticoagulated blood was quantified by gas chromatography using halothane (Fluothane; AstraZeneca Pty Ltd, North Ryde, NSW, Australia) as an internal standard. After equilibration of standards and unknown samples at 48°C for 90 minutes in sealed vials, aliquots of headspace gas were injected into a gas chromatograph (Varian Model 3700; Varian Inc, Palo Alto, CA) by using a Chromosorb 101 column (2 m ⫻ 4 mm ID), an oven temperature of 160°C, a N2 flow of 30 mL/min, and a flame ionization detector. Retention times for enflurane and halothane were 1.7 and 2.9 minutes, respectively. Standard curves for enflurane had correlation coefficients of ⬎0.998. Intraday relative standard deviations ranged from 1.1% to 4.9%, whereas interday values ranged from 8.7% to 11.2%. The linear trapezoidal rule6 was used to calculate the area under the blood enflurane concentration-time curve (AUC28) during the period when the patients were cooled to 28°C. Average enflurane concentration was estimated as AUC28/time at 28°C. Data are summarized as mean (95% confidence interval) or median (25th and 75th percentiles). Differences between groups were investigated by using a paired t test or 1-way analysis of variance (ANOVA) on ranks with Dunns’s test (SigmaStat 3.1; SPSS Inc, Chicago, IL). To explore the pharmacokinetics of enflurane, a 2-compartment model was developed by using the SAAM II program (SAAM Institute, Seattle, WA) and data from patients in group 3B. The model consisted of a central compartment (#1; blood) and an extravascular compartment (#2). Fractional rate constants between compartments (k12 and k21) and the elimination rate constant (k10, from the central compartment) were all assumed to be first order. The differential equations describing the model are: dq1 dt dq2 dt
⫽ ⫺(k10⫹k12)q1 ⫹ k21q2 ⫹ u1共t兲 ⫽ ⫺k21q2 ⫹ k12q1
where q1 and q2 are the masses of enflurane in the central and extravascular compartments, respectively, and u1 (t) is the input of enflurane into the central compartment. The model provided for 2 square-wave inputs of enflurane into the central compartment, one that simulated enflurane administration via the lungs and one that simulated input via the oxygenator. Half-lives (t1/2␣ and t1/2) and steady-state volume of distribution (Vss) for the model were obtained by using standard equations.7 Several studies have shown a relationship between changes in temperature and enflurane solubility in blood,8,9 such that a 5% change in solubility is observed with each degree change in temperature. This relationship was incorporated into the model so that blood concentra-
tion was a function of the mass of enflurane in the central compartment and temperature: Enflurane ⫽ q1
Solubility V1
Solubility ⫽ 关1⫹共共Temp共0兲 ⫺ linear(Temp(t)))0.05)] where V1 is volume of distribution for the central compartment, Temp(0) is body temperature at the start of CPB, and linear(Temp(t)) is a linear interpolation of the temperature values at time (t) during CPB. RESULTS
Patients in all 3 groups were of similar age, body weight, and body mass index (Table 1). Pump prime, cardioplegia, and supplemental crystalloid volumes used were also similar across the 3 groups. Time from induction of anesthesia to start of CPB varied between 45 and 60 minutes. Eighteen patients received coronary artery grafts, 5 had coronary artery grafts plus valve replacement, and 3 patients received valve replacements alone. Blood enflurane concentrations and corresponding nasopharyngeal temperatures for patients in group 1 (0.5%), group 2 (0.8%), and groups 3A and 3B (1% ) during CPB are shown in Figure 1. Median pre-CPB blood enflurane concentrations were 48 (25-50) mg/L, 52 (47-56) mg/L, and 115 (90-143) mg/L in groups 1, 2, and 3A plus 3B, respectively. One-way ANOVA on ranks with Dunn’s test indicated that blood enflurane concentrations in group 1 and group 2 were significantly lower (q ⫽ 3.8 and q ⫽ 3.4, respectively; p ⬍ 0.05) than in group 3. Patients were cooled to approximately 28°C and maintained at this temperature for a mean of 29 (19-40) minutes. Median blood enflurane concentrations while at 28°C were 44 (31-53) mg/L, 56 (45-61) mg/L, and 145 (109-203) mg/L in groups 1, 2, and 3A plus 3B, respectively. For groups 1 and 2 , there were no significant changes in blood enflurane at 28°C compared with the corresponding pre-CPB value (Fig 1A and B). However, for patients in group 3 (Fig 1C and D), cooling to 28°C resulted in a significant (paired t ⫽ 3.2, p ⫽ 0.006) mean increase of 14.2 mg/L (95% confidence interval, 4.8-23.8) in blood enflurane concentration compared with the corresponding pre-CPB concentration. In addition, a 1-way ANOVA on ranks (Dunn’s test) comparing the average enflurane concentrations at 28°C across all groups showed significantly higher concentrations in groups
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Fig 1. Blood enflurane concentration (upper panel) and nasopharyngeal temperature (lower panel) for patients receiving (A) 0.5% v/v enflurane (group 1), (B) 0.8% v/v enflurane (group 2), (C) 1% v/v enflurane (group 3A), and (D) 1% v/v enflurane with washout of anesthetic starting at the time of rewarming (group 3B). Data for individual patients are indicated by the different symbols. CPB commenced at zero hours.
3A and B combined compared with either group 1 (q ⫽ 3.7, p ⬍ 0.05) or group 2 (q ⫽ 3.3, p ⬍ 0.05). When the patients were rewarmed to 35°C to 37°C, median blood enflurane decreased to concentrations similar to those seen in the preCPB period: 39 (28-50) mg/L for group 1, 49 (43-55) mg/L for group 2, and 125 (86-137) mg/L for group 3. The washout characteristics of enflurane during CPB (group 3b) were also investigated (Fig 1D). To gain insight into the enflurane input concentration-dependent changes in blood enflurane during CPB, the concentration-time data were subjected to pharmacokinetic analysis. In preliminary investigations (data
not shown), the enflurane blood concentration-time data were fitted to 1- and 2-compartment models with zero-order input and first-order distribution and elimination rate constants. A 2-compartment model with first-order elimination from the central compartment (rate constant k10) was the most parsimonious model that explained the data. The use of a MichaelisMenten elimination term instead of the first-order rate constant (k10) was attempted but could not be justified on the basis of the Akaike Information Criterion value for the model.10 The pharmacokinetic descriptors for the model are summarized in Table 2. The washout phase was characterized as a biexponential
BLOOD ENFLURANE DURING CPB
221
Figure 1.
decay in blood enflurane concentrations with mean initial (␣) and terminal () t1/2 values of 1.3 minutes and 111 minutes, respectively. DISCUSSION
The most important result of this study is that, after the administration of enflurane (1% v/v) throughout CPB, a 26% increase in median blood enflurane concentration occurred between the pre-CPB levels and those taken during CPB. Although VAAs are commonly used as part of the anesthetic technique for cardiac surgery, their pharmacokinetics and pharmacodynamics during CPB are poorly understood. The main justification for use was a reduction in the incidence of awareness; however, the cardioprotective effects shown by the newer
(Cont’d)
agents add support to their continued use. The concentration of VAA delivered is usually determined empirically. With the trend toward offering cardiac surgery to patients with lower ejection fractions and reduced cardiac reserve, knowledge of the disposition of VAAs during CPB remains an area of interest. Until a well-validated measure of level of consciousness during all stages of CPB is available, it is likely that empirical concentrations of VAA will continue to be used to minimize the risk of awareness. The pre-CPB data showing a mean enflurane level of 118 (95-139) mg/L for patients receiving 1% enflurane are consistent with the range in previous reports (44-144 mg/L).11,12 Equilibrated pre-CPB blood enflurane concentrations were significantly higher at 1% enflurane than at 0.5% or 0.8%. When
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Table 2. Pharmacokinetic Parameter Estimates for Enflurane During Washout Patient
k10 (/h)
k12 (/h)
k21 (/h)
V1 (L)
Vss (L)
1 2 3 4 5 6 7 Mean (95% CI)
4.58 7.65 15.88 10.39 7.11 23.18 3.03 7.02 (5.02-15.49)
3.41 26.87 18.65 13.80 9.11 31.82 30.48 19.16 (11.01-27.31)
1.01 0.84 1.67 0.38 0.31 1.86 0.80 0.98 (0.54-1.42)
3.57 3.39 4.22 3.77 2.98 1.59 2.24 3.11 (2.43-3.79)
15.7 111.2 51.3 140.1 89.3 28.9 87.5 74.8 (41.6-108.1)
Abbreviation: CI, confidence interval.
these patients were cooled to 28°C, blood enflurane concentration increased significantly in the 1% group but was essentially unchanged in patients receiving 0.5% or 0.8% enflurane. However, at all 3 input concentrations, the enflurane levels measured after rewarming was completed were similar to those in the pre-CPB period. These data show that the decrease in temperature during CPB is an important factor in the increase in blood enflurane observed at 1% enflurane input. The washout studies at 1% enflurane are important because they show that enflurane is very rapidly removed from the blood. These data also suggest that washout of enflurane could be used at the time of rewarming to minimize the possibility of cardiovascular depression. Apart from the vaporizer setting and specific vaporizer characteristics, other factors that determine the amount of VAA in blood during CPB are those that affect the kinetics of tissue uptake and release.13 These include the amount of VAA in the tissues before CPB (influenced by the patient’s cardiac output), characteristics of the VAA such as increased solubility in blood during hypothermia,8 decreased solubility in crystalloid,14 fresh gas flow rate, pump flow rate, oxygenator efficiency, temperature, duration of CPB, and pre-bypass administration of the VAA. Other factors, such as the volume of pump prime, cardioplegia, urine production, nonscavenged surgical blood loss, and evaporation from the surgical site, also may influence VAA blood levels. In the present study, the input concentration dependence of pre-CPB blood enflurane is unlikely to be attributable to between-patient differences in hemodynamics because all patients were selected on the same basis. However, a group order effect cannot be excluded because the groups were accrued sequentially. Because the patients were similar, input concentration dependence is simply a result of the different doses adminis-
tered via the vaporizer. The mean ratio of k12/k21 (19.6) was consistent with the expected tissue accumulation of enflurane and with the mean t1/2␣ and t1/2 values of 1.3 and 111 minutes, respectively. The mean volume of the central compartment (3.1 L) was compatible with the anticipated initial distribution of volatile anesthetics into the vascular system.13 The greater accumulation of enflurane during the cooling phase of CPB in the patients who received an input concentration of 1% compared with 0.5% or 0.8% enflurane suggests that the disposition of drug may be saturable at the higher level. Zhou and Liu15 have shown that enflurane has a very high partition coefficient into fat (95.3), and, therefore, it cannot be excluded that the observed increase in blood enflurane was related to decreased perfusion of fat. Nevertheless, the mechanism underlying the increase in blood enflurane during cooling is unclear. Although temperature appears to be important, the enflurane input concentration dependence suggests that the membrane oxygenator itself also may be involved. However, the microporous polypropylene type of membrane used has been shown to allow excellent passage of VAAs.16 Increased blood enflurane concentration during CPB could be detrimental to cardiac function,5,17 as well as causing increased carbon monoxide production,18 increased free radical concentrations, and disruption of cellular antioxidant protective mechanisms.19,20 Therefore, it is suggested that enflurane input concentrations should be kept at or below 0.8% v/v. However, there is also strong support for the use of related VAAs during CPB because of their cardioprotective properties.3,4,21 Although enflurane is no longer the VAA of choice for CPB, similar studies are needed for the newer agents such as isoflurane and sevoflurane, which have similar physicochemical and pharmacokinetic properties.
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4. De Hert SG, Van der Linden PJ, Cromheecke S, et al: Cardioprotective properties of sevoflurane in patients undergoing coronary surgery with cardiopulmonary bypass are related to the modalities of its administration. Anesthesiology 101:299-310, 2004 5. Calverley RK, Smith NT, Prys-Roberts C, et al: Cardiovascular effects of enflurane anesthesia during controlled ventilation in man. Anesth Analg 57:619-628, 1978 6. Thomann P: Non-compartmental analysis methods manual in TopFit 2.0. Pharmacokinetic and pharmacodynamic data analysis system for the PC. Edited by Heinzel G, Woloszcak R, Thomann P. Stuttgart, Germany, Gustav Fischer, 1993
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7. Wagner JG: Linear compartmental models, in Wagner JG, Hamilton IL (eds): Fundamentals of Clinical Pharmacokinetics. Hamilton, IL, Drug Intelligence Publications, 1975 8. Eger RR, Eger EI: Effect of temperature and age on the solubility of enflurane, halothane, isoflurane, and methoxyflurane in human blood. Anesth Analg 64:640-642, 1985 9. Lockwood GG, Sapsed-Byrne SM, Smith MA: Effect of temperature on the solubility of desflurane, sevoflurane, enflurane and halothane in blood. Br J Anaesth 79:517-520, 1997 10. Akaike H: Information theory and an extension of the maximum likelihood principle, in Petrov BN, Tsahkadsor CF (eds): 2nd International Symposium on Information Theory. Armenia, USSR, USSR Academy of Sciences, 1971 11. Ise H, Kudo K, Jitsufuchi N, et al: Simple and rapid determination of enflurane in human tissues using gas chromatography and gas chromatography-mass spectrometry. J Chromatog B Biomed Sci Appl 698:97-102, 1997 12. Corall IM, Knights KM, Strunin L: Enflurane (Ethrane) anaesthesia in man. Metabolism and effects on biochemical and haematological variables. Br J Anaesth 49:881-885, 1977 13. Dale O, Brown BRJ: Clinical pharmacokinetics of the inhalational anaesthetics. Clin Pharmacokinet 12:145-167, 1987 14. Feingold A: Crystalloid hemodilution, hypothermia, and halothane blood solubility during cardiopulmonary bypass. Anesth Analg 56:622-626, 1977
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15. Zhou J-X, Liu J: The effect of temperature on solubility of volatile anesthetics in human tissues. Anesth Analg 93:234-238, 2001 16. Wiesenack C, Wiesner G, Keyl C, et al: In vivo uptake and elimination of isoflurane by different membrane oxygenators during cardiopulmonary bypass. Anesthesiology 97:133-138, 2002 17. Ciofolo MJ, Reiz S: Circulatory effects of volatile anesthetic agents. Minerva Anestesiol. 65:232-238, 1999 18. Keijzer C, Perez RS, De Lange JJ: Carbon monoxide production from five volatile anesthetics in dry sodalime in a patient model: halothane and sevoflurane do produce carbon monoxide: Temperature is a poor predictor of carbon monoxide production. BMC Anesthesiol 5:1-7, 2005 19. Turkan H, Bukan N, Sayal A, et al: Effects of halothane, enflurane, and isoflurane on plasma and erythrocyte antioxidant enzymes and trace elements. Biol Trace Elem Res 102:105-112, 2004 20. Zhou YF, Zhao KM, Chen QL: [Effects of enflurane on myocardial reperfusion injury during cardiac surgery with cardiopulmonary bypass]. Zhejiang Da Xue Xue Yi Xue Ban 32:227-230, 2003 21. De Hert SG, Van der Linden PJ, Cromheecke S, et al: Choice of primary anesthetic regimen can influence intensive care unit length of stay after coronary surgery with cardiopulmonary bypass. Anesthesiology 101:9-20, 2004