Anaesth Intens Care (1992), 20, 191-195
Uptake of Enflurane and Isoflurane During Spontaneous and Controlled Ventilation J. P. BENGTSON,* A. BENGTSSONt AND O. STENGVISTt Department of Anaesthesia and Intensive Care, Sahlgren Hospital, University of Goteborg, GOteborg, Sweden SUMMARY
The uptake of enflurane and of isoflurane were studied in forty patients during anaesthesia with nitrous oxide using either spontaneous or controlled ventilation. A Douglas bag method was used in combination with low fresh gas flows to a circle system and constant end-tidal anaesthetic concentration. The mean enflurane uptake rates were between 24 and 14 ml. 70 kg-I.min- I between 10 and 60 minutes. Corresponding isoflurane uptake rates were between 15 and 8 ml. 70 kg- I.min- 1. The initial uptake rates were lower than expected from "the square root of time concept". During spontaneous ventilation, the anaesthetic uptake rates were similar or even higher than corresponding rates during controlled ventilation in spite of lower minute ventilation volumes.
Key Words: ANAESTHETICS, VOLATILE: enflurane uptake, isoflurane uptake
The uptake rate of nitrous oxide is inversely proportional to the square root of time. 1 Other anaesthetic vapours have been assumed to follow this empirical rule, and the square root of time concept has been applied in the delivery of anaesthetics to closed systems. 2 Anaesthetic uptake is a product of three factors: solubility, cardiac output and the alveolar to venous partial pressure difference. 3 The blood/gas partition coefficient describes the relative affinity of anaesthetic for the two phases. At 37"C the blood/gas partition coefficients for nitrous oxide, isoflurane and enflurane are 0.47, 1.4 and 1.8 respectively. Cardiac output decreases during anaesthesia with controlled ventilation and enflurane 4 but is maintained 5 or even increased 6 during isoflurane anaesthesia. Nitrous oxide has little effect on cardiac output when used alone. 7,8 Nitrous oxide is known to increase the initial uptake rates of any gas given concomitantly.9,10 Alterations in ventilation will produce greater changes in anaesthetic uptake with more soluble agents. 3,11 Isoflurane and even more so, enflurane are respiratory depressants and therefore decrease delivery of anaesthetic to the alveoli, if the inspired °M.D., Ph.D., Associate Professor. tM.D., Ph.D., Associate Professor. tM.D., Ph.D., Associate Professor. Address for Reprints: J. B. Bengtson, M.D., Ph.D., Department of Anaesthesia and Intensive Care, Sahlgren Hospital, University of Giitebors, 5-413 45 Gotebors, Sweden. Accepted for publication October
20, 1991
Anaesthesia and Intensive Care, Vol. 20, No. 2, May, 1992
concentration is constant, during spontaneous ventilation. 12,13 Modern anaesthetic gas analysers permit continuous monitoring of end-tidal concentrations of anaesthetic gases. Almost independently of the breathing system used, it is possible to keep the end-tidal concentration at a desired level. Theoretically, this servo-control of end-tidal concentration eliminates the effect of ventilation on anaesthetic uptake. 14 The aim of this investigation was to study the uptake rates of enflurane and isoflurane during spontaneous and controlled ventilation during constant end-tidal anaesthetic concentrations. PATIENTS AND METHODS In order to minimize influence of gas losses through the surgical wound, knee arthroscopy patients with an ASA classification I or 11 were selected for the study. Forty patients were randomized after informed consent to one of four groups (Table I). A circle absorber system (Monosorb, SiemensElema, Solna, Sweden) with a graded standing bellows was used. A mixing box was inserted upstream from the absorption canister. The total volume of the circle system was 4.5 litres. Inspiratory oxygen and nitrous oxide and endtidal carbon dioxide concentrations were measured between the Y-piece and the endotracheal tube with a sampling analyser (Multi cap, Datex Instrumentarium OY, Helsinki, Finland). End-
192
J. P. BENGTSON ET AL. TABLE 1 Experimental design
Group
Anaesthetic
ET-anaesth Ventilation %
ES EC
Enflurane Enflurane
1.20 1.20
IS IC
Isoflurane Isoflurane
0.85 0.85
Spontaneous Controlled, ET CO 2 4.5% Spontaneous Controlled, ET C0 2 4.5%
tidal concentrations of enflurane and isoflurane were measured with a Datex Normac. Expiratory minute ventilation was measured between the endotracheal tube and the Y-piece with an Ohmeda 5420 Volume Monitor (Ohmeda, BOC Health Care Division). This monitor has a turbine vane transducer sensor with a stated tidal volume accuracy of ±8% or ±40 ml within the interval 200 to 3000 ml. Sampling gas from the gas analysers was returned to the circle system after a uni-directional valve prior to the absorption canister. Excess gas was collected every ten minutes in a noncompliant mylar plastic bag connected to the excess valve. The gas pressure in the bag was measured during the collection period. When the pressure had increased from -0.2 to 1.5 cm H 20, the bag contained a volume of 660 ml of gas (ATPS at 22°C). The excess gas flow could thereby be calculated. The gas contained in the plastic bag was then analysed with the Multicap and the Normac for gas concentration. Knowing the gas flows entering the circle system and leaving the system through the excess valve, one can calulate the patient gas uptake rates assuming constant anaesthetic concentrations in the circle system. The maximal change in circle system concentrations of enflurane and isoflurane was 0.2 vol% per ten minutes. Therefore, the calculation of patient uptake rate was simplified to VAn = VfgAn-VexcAn: i.e., the patient anaesthetic gas uptake (VAn) equals anaesthetic fresh gas flow (V fgAn) minus anaesthetic excess gas flow (VexcAn) per minute. All volumes are corrected to STPD. Room temperature was 21-23°C during the entire investigation. System check and calibrations The circle system was tested for leaks before and after each anaesthetic. In all cases, the leak was found to be less than 50 mllmin at a pressure of 30 cm H 20. Two vaporizers, one for enflurane and one for isoflurane, were used during the entire study. These
vaporizers were calibrated using the different fresh gas flows, oxygen-nitrous oxide mixtures, and dial settings employed in the study. The oxygen and nitrous oxide flowmeters were calibrated with a Calibration Analyzer RT-200 (Timeter International Inc., Lancaster, PA 17601, U.S.A.). These flowmeters were also checked against filling times of the plastic bag used for the collection of excess gas. There was no detectable gas diffusion from the sampling bag during ten-minute observation periods. In repeated laboratory bench tests, the excess volume flow was measured employing different fresh gas flows, gas compositions and breathing frequencies. The maximal systematic error in mean was ±4% of the excess gas flow. The Multicap analyser was calibrated before and after each studied patient with certified calibration gas containing 3.0% carbon dioxide, 31 % oxygen, 59% nitrous oxide and 7% nitrogen (AGA GAS AB, Stockholm, Sweden). The Multicap was also calibrated with 100% oxygen and 100% nitrous oxide. The anaesthetic agent monitor was calibrated according to the manufacturer's recommendations with calibration gas from Datex and AGA. The displayed readings from the Normac were within 0.05 vol% of the calibration gases delivered. Anaesthesia The patients were premedicated with intravenous midazolam 1.0 mg. Preoxygenation with ten litres per minute was used for about one minute. Anaesthesia was induced with thiopentone 4 to 5 mg per kilogram body weight. No atropine was used. The patients received succinylcholine 1.0 mg per kg for endotracheal intubation. Tracheal spray oflignocaine was used just before intubation. After intubation, the flows of fresh gas to the circle system were 1.5 litres of oxygen and 3.5 litres of nitrous oxide per minute for six minutes. The inhalation agent used was delivered by a conventional vaporizer outside the circuit to the end-tidal concentration desired. During the first six minutes after induction of anaesthesia, ventilation was controlled so that an end-tidal carbon dioxide concentration of 4.5% was obtained. Either enflurane or isoflurane was used with an end-tidal concentration maintained at 1.20 or 0.85%. The cuff pressures of the endotracheal tubes were kept between 20 and 30 cm H 20. After six minutes, spontaneous ventilation was resumed in two of the groups. Six minutes after intubation, low-flow anaesthesia was started. The fresh gas flow of oxygen was set according to body weight. Patients with a body weight of less than 70 kg received 250 ml oxygen per minute. For patients weighing Anaesthesia and Intensive Care. Vol. 20, No. 2, May, 1992
193
UPTAKE OF ENFLURANE AND ISOFLURANE c:
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MINUTES FIGURE 1.-Enflurane uptake rates, ml vapour. 70 kg-I. min- 1 ±SD. Spontaneous ventilation - open circles, controlled ventilation, closed circles. The values in this study are compared to the calculated ones employing Lowe's formula (VAn = f X MAC X BIG part.coeff. X C.O. X t-0.5. This equation assumes a constant alveolar concentration and a known cardiac output, or if unknown approximated to 0.2.kg-0.75 ) dashed-dotted line.
70-100 kg, 350 ml 02/min was used, and 500 ml 02/ min was used for a body weight of more than 100 kg. The fresh gas flow of nitrous oxide was adjusted to maintain an inspired oxygen concentration of 30%, resulting in an inspired nitrous oxide concentration of 65 to 69%. If the bellows was sinking, the oxygen fresh gas flow was increased by 50 ml/min. Either enflurane or isoflurane was used with an end-tidal concentration maintained at 1.20 or 0.85% respectively. If the anaesthetic depth needed to be increased during the course of anaesthesia, thiopentone 50 mg was given intravenously. With the exception of succinylcholine for endotracheal intubation, no muscle relaxant was used. Statistics Results are expressed as means±SD. Differences between groups at any given time were analysed with one-way analysis of variance (ANOYA) and Fisher's PLSD test. Statistical significance was assumed for values of P < 0.05. The study was approved by the Ethics Committee of University of Gbteborg. RESULTS
The patients had a mean age of 36 years, a mean length of 177 cm, and a mean weight of78 kg. There were 29 men and 11 women. Additional doses of thiopentone were given to two to four patients in each group due to coughing or movement of extremities. The anaesthetic uptake rates were normalized by weight to 70 kilograms. There were no statistically significant differences in uptake between spontaneous and controlled ventilation, regardless Anaesthesia and Intensive Care, Vol. 20, No. 2, May, 1992
'"
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FIGURE 2,-Isoflurane uptake rates, ml vapour. 70 kg- 1 min- 1 ±SD. Spontaneous ventilation - open circles, controlled ventilation - closed circles, Calculated uptake according to Lowe's formula - dashed-dotted line.
of vaporized agent used. At 10 minutes, the mean enflurane uptake was 22 and 24 ml. 70 kg-1.min- 1in Group ES and Group EC, respectively (Figure 1). At 30 minutes corresponding uptake rates were 18 and 16 ml. 70 kg-1.min- 1. The isoflurane uptake at 10 minutes was 15 and 11 ml. 70 kg-1.min- 1 in Group IS and IC, respectively (Figure 2). From 20 to 60 minutes, the isoflurane uptake rate was relatively stable, about 9 ml. 70 kg-1.min- 1 in both groups. In Figures 1 and 2, the uptake rates in this study are compared with the ones expected f~om the square root of time model. 2 The mean time
for start of surgery was between 20 and 25 minutes in all the groups. The mean expiratory ventilation volumes at 10 minutes were 1.5 and 5.8 litres.70 kg-1.min- 1 in Groups ES and EC, and 2.2 and 5.2 litres.70 kg-I. min- 1 in Groups IS and IC, respectively. At 30 minutes the mean expiratory ventilation volumes were 4.0, 5.5, 5.8 and 5.4 litres.70 kg-1.min- 1 in Groups ES, EC, IS and IC, respectively. DISCUSSION
Anaesthetic uptake is usually expressed by the ratio of alveolar to inspired anaesthetic concentration (FA/FI),3,15-17 This ratio gives wash-in curves with the relative uptake rates when comparing different anaesthetic gases. For quantitative estimations of uptake rates, other methods must be used. Fick's equation (UL = Q(Ca-Cv) i.e. uptake from lungs equals cardiac output multiplied by the arterio-venous content difference) has been used in the study of isoflurane uptake rates. 1S Analogous to oxygen uptake measurements, non-rebreathing systems employing inspired and expired volumes 19 and closed circuit techniques 20 have been used for estimations of anaesthetic uptake. A recurrent finding is large intra- and interindividual variations in uptake rates of vaporized agents. 21 ,22
194
J. P. BENGTSON ET AL.
The current view is based on the uptake rates of nitrous oxide found by Severinghaus (VN20 = 1000. t-0 . 5) with the assumption that the inverse relationship between uptake and square root of time is also applicable to other gases and vapours. The quantitative calculations of the respective uptake rates are based on the blood/gas partition coefficient and the alveolar concentration used. 2 Models for anaesthetic uptake are based on some assumptions such as alveolar concentration equals arterial concentration, there is no metabolism or diffusion of the gas used, the partition coefficient remains constant independently of concentration and that cardiac output does not depend on the concentration used. In the present study, the anaesthetic uptake rates of the square root of time concept could not be confirmed. Thus, if unit doses according to Lowe's formula were to be injected in a closed circuit system, the amount of liquid anaesthetic would not correspond to the patient's uptake rate. In the groups with spontaneous ventilation, the uptake rates of enflurane and isoflurane were lower than anticipated during the first twenty minutes. With controlled ventilation, the anaesthetic uptake tended to be even lower and did not reach the anticipated uptake rates until after about 45 minutes. In another investigation using the Fick method, 18 the isoflurane uptake rate decreased only 10% between 30 and 60 minutes. In a study on enflurane uptake using controlled ventilation with a closed circuit and a constant end-tidal concentration of 2.0%, Westenskow et al. 21 found mean uptake rates similar to ours if the differences in end-tidal concentration (2.0 vs 1.20%) and body size (1.22 vs l.94 m 2 ) are taken into account. Our study supported the theoretical assumption that a constant end-tidal concentration of enflurane or isoflurane eliminates the effect of different minute ventilation volumes on uptake. 14 In conclusion, the initial uptake rates of enflurane and isoflurane were lower than expected from the square root of time concept. There were no significant differences in anaesthetic uptake rates between spontaneous and controlled ventilation in spite of lower minute ventilation volumes during spontaneous ventilation. ACKNOWLEDGEMENTS Financial support was provided by AGA AB Medical Research Fund. REFERENCES 1. Severinghaus JW. The rate of uptake of nitrous oxide in man. J Clin Invest 1954; 33:1183-1189. 2. Lowe HJ, Ernst EA. The quantitative practice of anesthesia. Williams & Wilkins, Baltimore 1981; 67-97.
3. Eger El 11. Anesthetic uptake and action. Williams & Wilkins, Baltimore 1974; 77-145. 4. Calverley RK, Smith NT, Prys-Roberts C, Eger El n, Jones CW. Cardiovascular effects of enflurane anesthesia during controlled ventilation in man. Anesth Analg 1978; 57:619-628. 5. Stevens WC, Cromwell TH, Halsey MJ, Eger El n, Shakespeare TF, Bahlman SH. The cardiovascular effects of a new inhalational anesthetic, Forane, in human volunteers at constant arterial carbon dioxide tension. Anesthesiology 1971; 35:8-16. 6. Dolan WM, Stevens WC, Eger El II et al. The cardiovascular and respiratory effects of isofluranenitrous oxide anaesthesia. Can Anaesth Soc J 1974; 21:557-568. 7. Eisele JH, Smith NT. Cardiovascular effects of 40 per cent nitrous oxide in man. Anesth Ana1g 1972; 51 :956-963. 8. Kawamura R, Stanley TH, English JB, Hill GE, Liu WS, Webster LR. Cardiovascular responses to nitrous oxide exposure for two hours in man. Anesth Analg 1980; 59:93-99. 9. Epstein RM, Rackow H, Salanitre E, Wolf GL. Influence of the concentration effect on the uptake of anesthetic mixtures: the second gas effect. Anesthesio10gy 1964; 25:364-371. 10. Stoelting RK, Eger El n. An additional explanation for the second gas effect: A concentrating effect. Anesthesiology 1969; 30:273-277. 11. Yamamura H, Wakasugi B, Okuma Y, Maki K. The effects of ventilation on the absorption and elimination of inhalational anaesthetics. Anaesthesia 1963; 18:427-438. 12. Fourcade HE, Stevens WC, Larson P et al. The ventilatory effects of Forance, a new inhaled anesthetic. Anesthesiology 1971; 35:26-31. 13. Calverley RK, Smith NT, Jones CW, Prys-Roberts C, Eger El 11. Ventilatory and cardiovascular effects of enflurane anesthesia during spontaneous ventilation in man. Anesth Ana1g 1978; 57:610-618. 14. Lockwood GG, White DC. Effect of ventilation and cardiac output on the uptake of anaesthetic agents from different breathing systems: a theoretical study. Br J Anaesth 1991; 66:519-526. 15. Cromwell TH, Eger El n, Stevens WC, Dolan WM. Forane uptake, excretion and blood solubility in man. Anesthesiology 1971; 35:401-408. 16. Torri G, Damia G, Fabiani ML, Frova G. Uptake and elimination of enflurane in man. A comparative study between enflurane and halothane. Br J Anaesth 1972; 44:789-794. 17. Dwyer R, Fee JPH, C1arke RSJ. End-tidal concentration of halothane and isoflurane during induction of anaesthesia in young and elderly patients. Br J Anaesth 1990; 64:36-41. 18. Schmidt H, Dudziak R. Uptake and elimination of isoflurane in man. In: Bennetts FE, ed. Enflurane, Isoflurane, 8th World Congress of Anaesthesiologists, Selected Proceedings. New York: Biomedical Information Corporation, 1984; 51-59. 19. Virtue R, Sherrill DL, Swanson GD. Uptake of nitrous oxide by man. Can Anaesth Soc J 1982; 29:424-427. Anaesthesia and Intensive Care, Vo/. 20, No. 2, May, 1992
UPTAKE OF ENFLURANE AND ISOFLURANE 20. O'Callaghan AC, Hawes DW, Ross JAS, White DC, Wloch RT. Uptake of isoflurane during clinical anaesthesia. Br J Anaesth 1983; 55:1061-1064. 21. Westenskow DR, Jordan WS, Hayes JK. Uptake of enflurane: a study of the variability between patients. Br J Anaesth 1983; 55:595-601. 22. Eger El, Guadagni NP. Halothane uptake in man at constant alveolar concentration. Anesthesiology 1963; 24:299-304.
Anaesthesia and Intensive Care, Vo/. 20, No. 2, May, 1992
195
Uptake of Enflurane and Isoflurane During Spontaneous and Controlled Ventilation J. P. BENGTSON,* A. BENGTSSONt AND O. STENGVISTt Department of Anaesthesia and Intensive Care, Sahlgren Hospital, University of Goteborg, GOteborg, Sweden SUMMARY
The uptake of enflurane and of isoflurane were studied in forty patients during anaesthesia with nitrous oxide using either spontaneous or controlled ventilation. A Douglas bag method was used in combination with low fresh gas flows to a circle system and constant end-tidal anaesthetic concentration. The mean enflurane uptake rates were between 24 and 14 ml. 70 kg-I.min- I between 10 and 60 minutes. Corresponding isoflurane uptake rates were between 15 and 8 ml. 70 kg- I.min- 1. The initial uptake rates were lower than expected from "the square root of time concept". During spontaneous ventilation, the anaesthetic uptake rates were similar or even higher than corresponding rates during controlled ventilation in spite of lower minute ventilation volumes.
Key Words: ANAESTHETICS, VOLATILE: enflurane uptake, isoflurane uptake
The uptake rate of nitrous oxide is inversely proportional to the square root of time. 1 Other anaesthetic vapours have been assumed to follow this empirical rule, and the square root of time concept has been applied in the delivery of anaesthetics to closed systems. 2 Anaesthetic uptake is a product of three factors: solubility, cardiac output and the alveolar to venous partial pressure difference. 3 The blood/gas partition coefficient describes the relative affinity of anaesthetic for the two phases. At 37"C the blood/gas partition coefficients for nitrous oxide, isoflurane and enflurane are 0.47, 1.4 and 1.8 respectively. Cardiac output decreases during anaesthesia with controlled ventilation and enflurane 4 but is maintained 5 or even increased 6 during isoflurane anaesthesia. Nitrous oxide has little effect on cardiac output when used alone. 7,8 Nitrous oxide is known to increase the initial uptake rates of any gas given concomitantly.9,10 Alterations in ventilation will produce greater changes in anaesthetic uptake with more soluble agents. 3,11 Isoflurane and even more so, enflurane are respiratory depressants and therefore decrease delivery of anaesthetic to the alveoli, if the inspired °M.D., Ph.D., Associate Professor. tM.D., Ph.D., Associate Professor. tM.D., Ph.D., Associate Professor. Address for Reprints: J. B. Bengtson, M.D., Ph.D., Department of Anaesthesia and Intensive Care, Sahlgren Hospital, University of Giitebors, 5-413 45 Gotebors, Sweden. Accepted for publication October
20, 1991
Anaesthesia and Intensive Care, Vol. 20, No. 2, May, 1992
concentration is constant, during spontaneous ventilation. 12,13 Modern anaesthetic gas analysers permit continuous monitoring of end-tidal concentrations of anaesthetic gases. Almost independently of the breathing system used, it is possible to keep the end-tidal concentration at a desired level. Theoretically, this servo-control of end-tidal concentration eliminates the effect of ventilation on anaesthetic uptake. 14 The aim of this investigation was to study the uptake rates of enflurane and isoflurane during spontaneous and controlled ventilation during constant end-tidal anaesthetic concentrations. PATIENTS AND METHODS In order to minimize influence of gas losses through the surgical wound, knee arthroscopy patients with an ASA classification I or 11 were selected for the study. Forty patients were randomized after informed consent to one of four groups (Table I). A circle absorber system (Monosorb, SiemensElema, Solna, Sweden) with a graded standing bellows was used. A mixing box was inserted upstream from the absorption canister. The total volume of the circle system was 4.5 litres. Inspiratory oxygen and nitrous oxide and endtidal carbon dioxide concentrations were measured between the Y-piece and the endotracheal tube with a sampling analyser (Multi cap, Datex Instrumentarium OY, Helsinki, Finland). End-
192
J. P. BENGTSON ET AL. TABLE 1 Experimental design
Group
Anaesthetic
ET-anaesth Ventilation %
ES EC
Enflurane Enflurane
1.20 1.20
IS IC
Isoflurane Isoflurane
0.85 0.85
Spontaneous Controlled, ET CO 2 4.5% Spontaneous Controlled, ET C0 2 4.5%
tidal concentrations of enflurane and isoflurane were measured with a Datex Normac. Expiratory minute ventilation was measured between the endotracheal tube and the Y-piece with an Ohmeda 5420 Volume Monitor (Ohmeda, BOC Health Care Division). This monitor has a turbine vane transducer sensor with a stated tidal volume accuracy of ±8% or ±40 ml within the interval 200 to 3000 ml. Sampling gas from the gas analysers was returned to the circle system after a uni-directional valve prior to the absorption canister. Excess gas was collected every ten minutes in a noncompliant mylar plastic bag connected to the excess valve. The gas pressure in the bag was measured during the collection period. When the pressure had increased from -0.2 to 1.5 cm H 20, the bag contained a volume of 660 ml of gas (ATPS at 22°C). The excess gas flow could thereby be calculated. The gas contained in the plastic bag was then analysed with the Multicap and the Normac for gas concentration. Knowing the gas flows entering the circle system and leaving the system through the excess valve, one can calulate the patient gas uptake rates assuming constant anaesthetic concentrations in the circle system. The maximal change in circle system concentrations of enflurane and isoflurane was 0.2 vol% per ten minutes. Therefore, the calculation of patient uptake rate was simplified to VAn = VfgAn-VexcAn: i.e., the patient anaesthetic gas uptake (VAn) equals anaesthetic fresh gas flow (V fgAn) minus anaesthetic excess gas flow (VexcAn) per minute. All volumes are corrected to STPD. Room temperature was 21-23°C during the entire investigation. System check and calibrations The circle system was tested for leaks before and after each anaesthetic. In all cases, the leak was found to be less than 50 mllmin at a pressure of 30 cm H 20. Two vaporizers, one for enflurane and one for isoflurane, were used during the entire study. These
vaporizers were calibrated using the different fresh gas flows, oxygen-nitrous oxide mixtures, and dial settings employed in the study. The oxygen and nitrous oxide flowmeters were calibrated with a Calibration Analyzer RT-200 (Timeter International Inc., Lancaster, PA 17601, U.S.A.). These flowmeters were also checked against filling times of the plastic bag used for the collection of excess gas. There was no detectable gas diffusion from the sampling bag during ten-minute observation periods. In repeated laboratory bench tests, the excess volume flow was measured employing different fresh gas flows, gas compositions and breathing frequencies. The maximal systematic error in mean was ±4% of the excess gas flow. The Multicap analyser was calibrated before and after each studied patient with certified calibration gas containing 3.0% carbon dioxide, 31 % oxygen, 59% nitrous oxide and 7% nitrogen (AGA GAS AB, Stockholm, Sweden). The Multicap was also calibrated with 100% oxygen and 100% nitrous oxide. The anaesthetic agent monitor was calibrated according to the manufacturer's recommendations with calibration gas from Datex and AGA. The displayed readings from the Normac were within 0.05 vol% of the calibration gases delivered. Anaesthesia The patients were premedicated with intravenous midazolam 1.0 mg. Preoxygenation with ten litres per minute was used for about one minute. Anaesthesia was induced with thiopentone 4 to 5 mg per kilogram body weight. No atropine was used. The patients received succinylcholine 1.0 mg per kg for endotracheal intubation. Tracheal spray oflignocaine was used just before intubation. After intubation, the flows of fresh gas to the circle system were 1.5 litres of oxygen and 3.5 litres of nitrous oxide per minute for six minutes. The inhalation agent used was delivered by a conventional vaporizer outside the circuit to the end-tidal concentration desired. During the first six minutes after induction of anaesthesia, ventilation was controlled so that an end-tidal carbon dioxide concentration of 4.5% was obtained. Either enflurane or isoflurane was used with an end-tidal concentration maintained at 1.20 or 0.85%. The cuff pressures of the endotracheal tubes were kept between 20 and 30 cm H 20. After six minutes, spontaneous ventilation was resumed in two of the groups. Six minutes after intubation, low-flow anaesthesia was started. The fresh gas flow of oxygen was set according to body weight. Patients with a body weight of less than 70 kg received 250 ml oxygen per minute. For patients weighing Anaesthesia and Intensive Care. Vol. 20, No. 2, May, 1992
193
UPTAKE OF ENFLURANE AND ISOFLURANE c:
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MINUTES FIGURE 1.-Enflurane uptake rates, ml vapour. 70 kg-I. min- 1 ±SD. Spontaneous ventilation - open circles, controlled ventilation, closed circles. The values in this study are compared to the calculated ones employing Lowe's formula (VAn = f X MAC X BIG part.coeff. X C.O. X t-0.5. This equation assumes a constant alveolar concentration and a known cardiac output, or if unknown approximated to 0.2.kg-0.75 ) dashed-dotted line.
70-100 kg, 350 ml 02/min was used, and 500 ml 02/ min was used for a body weight of more than 100 kg. The fresh gas flow of nitrous oxide was adjusted to maintain an inspired oxygen concentration of 30%, resulting in an inspired nitrous oxide concentration of 65 to 69%. If the bellows was sinking, the oxygen fresh gas flow was increased by 50 ml/min. Either enflurane or isoflurane was used with an end-tidal concentration maintained at 1.20 or 0.85% respectively. If the anaesthetic depth needed to be increased during the course of anaesthesia, thiopentone 50 mg was given intravenously. With the exception of succinylcholine for endotracheal intubation, no muscle relaxant was used. Statistics Results are expressed as means±SD. Differences between groups at any given time were analysed with one-way analysis of variance (ANOYA) and Fisher's PLSD test. Statistical significance was assumed for values of P < 0.05. The study was approved by the Ethics Committee of University of Gbteborg. RESULTS
The patients had a mean age of 36 years, a mean length of 177 cm, and a mean weight of78 kg. There were 29 men and 11 women. Additional doses of thiopentone were given to two to four patients in each group due to coughing or movement of extremities. The anaesthetic uptake rates were normalized by weight to 70 kilograms. There were no statistically significant differences in uptake between spontaneous and controlled ventilation, regardless Anaesthesia and Intensive Care, Vol. 20, No. 2, May, 1992
'"
~ 20
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FIGURE 2,-Isoflurane uptake rates, ml vapour. 70 kg- 1 min- 1 ±SD. Spontaneous ventilation - open circles, controlled ventilation - closed circles, Calculated uptake according to Lowe's formula - dashed-dotted line.
of vaporized agent used. At 10 minutes, the mean enflurane uptake was 22 and 24 ml. 70 kg-1.min- 1in Group ES and Group EC, respectively (Figure 1). At 30 minutes corresponding uptake rates were 18 and 16 ml. 70 kg-1.min- 1. The isoflurane uptake at 10 minutes was 15 and 11 ml. 70 kg-1.min- 1 in Group IS and IC, respectively (Figure 2). From 20 to 60 minutes, the isoflurane uptake rate was relatively stable, about 9 ml. 70 kg-1.min- 1 in both groups. In Figures 1 and 2, the uptake rates in this study are compared with the ones expected f~om the square root of time model. 2 The mean time
for start of surgery was between 20 and 25 minutes in all the groups. The mean expiratory ventilation volumes at 10 minutes were 1.5 and 5.8 litres.70 kg-1.min- 1 in Groups ES and EC, and 2.2 and 5.2 litres.70 kg-I. min- 1 in Groups IS and IC, respectively. At 30 minutes the mean expiratory ventilation volumes were 4.0, 5.5, 5.8 and 5.4 litres.70 kg-1.min- 1 in Groups ES, EC, IS and IC, respectively. DISCUSSION
Anaesthetic uptake is usually expressed by the ratio of alveolar to inspired anaesthetic concentration (FA/FI),3,15-17 This ratio gives wash-in curves with the relative uptake rates when comparing different anaesthetic gases. For quantitative estimations of uptake rates, other methods must be used. Fick's equation (UL = Q(Ca-Cv) i.e. uptake from lungs equals cardiac output multiplied by the arterio-venous content difference) has been used in the study of isoflurane uptake rates. 1S Analogous to oxygen uptake measurements, non-rebreathing systems employing inspired and expired volumes 19 and closed circuit techniques 20 have been used for estimations of anaesthetic uptake. A recurrent finding is large intra- and interindividual variations in uptake rates of vaporized agents. 21 ,22
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The current view is based on the uptake rates of nitrous oxide found by Severinghaus (VN20 = 1000. t-0 . 5) with the assumption that the inverse relationship between uptake and square root of time is also applicable to other gases and vapours. The quantitative calculations of the respective uptake rates are based on the blood/gas partition coefficient and the alveolar concentration used. 2 Models for anaesthetic uptake are based on some assumptions such as alveolar concentration equals arterial concentration, there is no metabolism or diffusion of the gas used, the partition coefficient remains constant independently of concentration and that cardiac output does not depend on the concentration used. In the present study, the anaesthetic uptake rates of the square root of time concept could not be confirmed. Thus, if unit doses according to Lowe's formula were to be injected in a closed circuit system, the amount of liquid anaesthetic would not correspond to the patient's uptake rate. In the groups with spontaneous ventilation, the uptake rates of enflurane and isoflurane were lower than anticipated during the first twenty minutes. With controlled ventilation, the anaesthetic uptake tended to be even lower and did not reach the anticipated uptake rates until after about 45 minutes. In another investigation using the Fick method, 18 the isoflurane uptake rate decreased only 10% between 30 and 60 minutes. In a study on enflurane uptake using controlled ventilation with a closed circuit and a constant end-tidal concentration of 2.0%, Westenskow et al. 21 found mean uptake rates similar to ours if the differences in end-tidal concentration (2.0 vs 1.20%) and body size (1.22 vs l.94 m 2 ) are taken into account. Our study supported the theoretical assumption that a constant end-tidal concentration of enflurane or isoflurane eliminates the effect of different minute ventilation volumes on uptake. 14 In conclusion, the initial uptake rates of enflurane and isoflurane were lower than expected from the square root of time concept. There were no significant differences in anaesthetic uptake rates between spontaneous and controlled ventilation in spite of lower minute ventilation volumes during spontaneous ventilation. ACKNOWLEDGEMENTS Financial support was provided by AGA AB Medical Research Fund. REFERENCES 1. Severinghaus JW. The rate of uptake of nitrous oxide in man. J Clin Invest 1954; 33:1183-1189. 2. Lowe HJ, Ernst EA. The quantitative practice of anesthesia. Williams & Wilkins, Baltimore 1981; 67-97.
3. Eger El 11. Anesthetic uptake and action. Williams & Wilkins, Baltimore 1974; 77-145. 4. Calverley RK, Smith NT, Prys-Roberts C, Eger El n, Jones CW. Cardiovascular effects of enflurane anesthesia during controlled ventilation in man. Anesth Analg 1978; 57:619-628. 5. Stevens WC, Cromwell TH, Halsey MJ, Eger El n, Shakespeare TF, Bahlman SH. The cardiovascular effects of a new inhalational anesthetic, Forane, in human volunteers at constant arterial carbon dioxide tension. Anesthesiology 1971; 35:8-16. 6. Dolan WM, Stevens WC, Eger El II et al. The cardiovascular and respiratory effects of isofluranenitrous oxide anaesthesia. Can Anaesth Soc J 1974; 21:557-568. 7. Eisele JH, Smith NT. Cardiovascular effects of 40 per cent nitrous oxide in man. Anesth Ana1g 1972; 51 :956-963. 8. Kawamura R, Stanley TH, English JB, Hill GE, Liu WS, Webster LR. Cardiovascular responses to nitrous oxide exposure for two hours in man. Anesth Analg 1980; 59:93-99. 9. Epstein RM, Rackow H, Salanitre E, Wolf GL. Influence of the concentration effect on the uptake of anesthetic mixtures: the second gas effect. Anesthesio10gy 1964; 25:364-371. 10. Stoelting RK, Eger El n. An additional explanation for the second gas effect: A concentrating effect. Anesthesiology 1969; 30:273-277. 11. Yamamura H, Wakasugi B, Okuma Y, Maki K. The effects of ventilation on the absorption and elimination of inhalational anaesthetics. Anaesthesia 1963; 18:427-438. 12. Fourcade HE, Stevens WC, Larson P et al. The ventilatory effects of Forance, a new inhaled anesthetic. Anesthesiology 1971; 35:26-31. 13. Calverley RK, Smith NT, Jones CW, Prys-Roberts C, Eger El 11. Ventilatory and cardiovascular effects of enflurane anesthesia during spontaneous ventilation in man. Anesth Ana1g 1978; 57:610-618. 14. Lockwood GG, White DC. Effect of ventilation and cardiac output on the uptake of anaesthetic agents from different breathing systems: a theoretical study. Br J Anaesth 1991; 66:519-526. 15. Cromwell TH, Eger El n, Stevens WC, Dolan WM. Forane uptake, excretion and blood solubility in man. Anesthesiology 1971; 35:401-408. 16. Torri G, Damia G, Fabiani ML, Frova G. Uptake and elimination of enflurane in man. A comparative study between enflurane and halothane. Br J Anaesth 1972; 44:789-794. 17. Dwyer R, Fee JPH, C1arke RSJ. End-tidal concentration of halothane and isoflurane during induction of anaesthesia in young and elderly patients. Br J Anaesth 1990; 64:36-41. 18. Schmidt H, Dudziak R. Uptake and elimination of isoflurane in man. In: Bennetts FE, ed. Enflurane, Isoflurane, 8th World Congress of Anaesthesiologists, Selected Proceedings. New York: Biomedical Information Corporation, 1984; 51-59. 19. Virtue R, Sherrill DL, Swanson GD. Uptake of nitrous oxide by man. Can Anaesth Soc J 1982; 29:424-427. Anaesthesia and Intensive Care, Vo/. 20, No. 2, May, 1992
UPTAKE OF ENFLURANE AND ISOFLURANE 20. O'Callaghan AC, Hawes DW, Ross JAS, White DC, Wloch RT. Uptake of isoflurane during clinical anaesthesia. Br J Anaesth 1983; 55:1061-1064. 21. Westenskow DR, Jordan WS, Hayes JK. Uptake of enflurane: a study of the variability between patients. Br J Anaesth 1983; 55:595-601. 22. Eger El, Guadagni NP. Halothane uptake in man at constant alveolar concentration. Anesthesiology 1963; 24:299-304.
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