- Email: [email protected]
Isoflurane elimination via a bubble oxygenator during extra circulation
Isoflurane
Elimination Via a Bubble Oxygenator Extracorporeal Circulation
Susan L. Price, MD, David L. Brown,
MD, Randall L. Carpenter,
MD, Jashvant
During
D. Unadkat,
PhD,
and Sondra S. Crosby, PharmD It has been suggested that inhalational anesthetics should be discontinued at least 15 minutes prior to termination of extracorporeal circulation (ECC) to avoid myocardial depression. However, data regarding elimination of inhalation agents via a bubble oxygenator from hypothermic, hemodiluted patients have not been previously reported. The washout of isoflurane (ISF) from ten cardiac surgical patients using mass spectrometry was studied. The mean baseline oxygenator exhaust concentration of ISF was 0.85% prior to termination of ECC. Oxygenator
I
NHALATIONAL anesthetics are frequently used during extracorporeal circulation (ECC) to provide anesthesia and amnesia, and to aid in controlling blood pressure. Inhalational agents, however, depress myocardial contractility’.* and thus may impair the ability to wean from ECC. To minimize the risk of significant myocardial depression, it has been recommended that inhalational anesthetics should be discontinued at least 15 minutes prior to the termination of ECC.3 This fifteen-minute interval should, theoretically, provide adequate time for anesthetics to be eliminated from the heart and minimize depression of contractility. However, this estimate is presumably based on pharmacokinetic data obtained in healthy patients in whom anesthetics are eliminated via the lungs. These estimates may not be accurate for patients during ECC when anesthetics are eliminated via the bubble oxygenator, and when this elimination may be altered by hypothermia and hemodilution. This study defines the oxygenator washout curve for isoflurane (ISF) during ECC in adults. METHODS Following approval of the institutional review board, ten consecutive adult cardiac surgery patients undergoing ECC with moderate hypothermia (range: 25°C to 28°C) and hemodilution (range, 19% to 29% hematocrit; mean, 240/o), in whom ISF was used during the anesthetic, were studied. Nine patients underwent coronary artery bypass grafting, while one had aortic valve replacement performed. The eight male and two female patients ranged in age from 42 to 79 years (mean, 66 years), in weight from 52 to 98 kg (mean, 78 kg), and in height from 157 to 180 cm (mean, 172 cm). Preoperative left ventricular ejection fractions ranged from 32% to 70% (mean, 55%). All of the patients received a combined inhalational
concentration of ISF decreased to less than 0.05% in 8.8 + 2.5 minutes. Eight of ten patients had ISF washout curves best characterized by a one-compartment model, with a mean time constant of 1.94 minutes. Therefore, 95% washout of ISF should occur in 5.8 minutes (three time constants). It is suggested that ISF may be used closer to the termination of ECC than previously recommended without fear of significant myocardial depression. e 1988 by Grune & Stratton, Inc.
and narcotic anesthetic technique. Two of the patients received sufentanil, while the remainder received fentanyl (greater than 50 rg/kg). In addition to the narcotics, all patients received intravenous (IV) benzodiazepines and ISF via a calibrated vaporizer (Forane Vaporizer, Ohio Medical Products, Madison, WI) into the bubble oxygenator (Bentley-10, American Bentley, American Hospital Supply Corporation, Irvine, CA) during ECC. Seven patients also received ISF prior to the institution of ECC. All patients were similarly managed with crystalloid hemodilution, crystalloid cardioplegia, and aortic cross-clamping. Fresh oxygen flow into the oxygenator was adjusted to produce normocarbia (PaCO, uncorrected) during hypothermic ECC and was progressively increased during patient rewarming (in a ratio of 1.5 to 1.7 0, flow/cardiac output). Cardiac index was maintained at approximately 1.5 L/min during hypothermia and increased to 2.0 to 2.2 L/min during rewarming. Immediately preceding aortic crossclamp removal, baseline measurements of temperature, hematocrit, and oxygenator exhaust ISF concentration were recorded. ISF was discontinued when the aortic cross-clamp was removed. Oxygenator exhaust gases were sampled at the oxygenator exhaust port. A 500-mL dead-space reservoir was attached to the exhaust port, beyond the sampling site to prevent contamination of exhaust gases with room air (Fig 1). ISF and nitrogen (NJ partial pressures in oxygenator exhaust gases were measured by mass spectrometry (System for Anesthesia and Respiratory Analysis [SARA], Allegheny International Medical From the Department of Anesthesiology, Virginia Mason Medical Center: the Department of Anesthesiology and the Multidisciplinary Pain Center, University of Washington &hool of Medicine; and the Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle. This material was presented in part at the Annual Meeting of the Society of Cardiovascular Anesthesia, Montreal, April 1986. Address reprint requests to David L. Brown, MD, Virginia Mason Medical Center, PO Box 900. Seattle, WA 98111. o 1988 by Grune & Stratton, Inc. OSSS-6296/88/0201-0009$03.00/0
Journal of Cardiothoracic Anesthesia, Vol2, No 1 (February), 1988: pp 41-44
41
42
PRICE ET AL
Mass Spectrometer
,
Vaoorizer
Arterial
Blood
Bubble Fig 1. The mass spectrometry sampling was carried out via a 6DD-mL deadspace reservoir added to the bubble-oxygenator exhaust port.
Technology, St Louis, MO) at 1, 2, 3,4, 6, 8, 10, 12, and 16 minutes after discontinuing ISF. The reservoir volume was sufficient to prevent contamination of the exhaust gas samples with room air as evidenced by the fact that nitrogen was not detected in the samples. The ratio of F,/FAo was used to define the washout of anesthetic. FA is the exhaust concentration of anesthetic at each measurement interval; FAo is the exhaust concentration of anesthetic obtained immediately prior to discontinuing the anesthetic administration. Multi-exponential (multicompartment) models of the form
2.1%, Table 1). The mean minimum alveolar concentration (MAC) hours of ISF were 0.58 hours and 0.61 hours for pre-ECC and intraECC use, respectively, with total mean MAC hours prior to washout determinations of 1.19 hours. Oxygenator exhaust concentrations of ISF decreased rapidly (Fig 2) and were less than 0.05% in 8.8 2 2.5 minutes. In eight of ten patients, the isoflurane washout curve was “best fit” with a one-compartment model, with a mean time constant of 1.94 + 0.76 minutes. In the other two patients a two-compartment model provided the “best fit.” The terminal portion of the washout curve could not be identified due to limitations in the sensitivity of the mass spectrometer (ie, concentrations ~0.05%). During ECC, the mean arterial pressures ranged from 50 to 83 mmHg. In no patient did the mean arterial pressure rise more than 10 mmHg following discontinuation of the ISF. There was no evidence of intraoperative recall on postoperative evaluation.
were fit to the washout data using least-squares analysis4 For each data set, the model having the greatest number of compartments (highest n) that significantly decreased the residual sum of squares when compared with the model having one less compartment (n - 1) was considered to provide the “best fit” (P < .05, F-ratio test).’ RESULTS
The mean exhaust concentration of ISF immediately prior to discontinuing the anesthetic administration (FAO) was 0.85% (range, 0.42% to Table 1. Individual Patient Values for Oxygenator and F,/F,,
Ratios 1,2.3,4,6,8,10,
Baseline Concentrations
F,/FAo Patient NO.
of ISF IF,,)
in Percent,
and 12 Minutes After ISF Was Discontinued Ratio
Minutes FA0
1
2.1
1
0.46
2
3
4
6
0.24
0.09
0.06
0.03
0
8
10
2
0.85
0.64
0.21
0.15
0.13
0.09
0.06
0
3
1.05
0.54
0.15
0.14
0.11
0.07
0.05
0
4
0.93
0.82
0.4 1
0.29
0.18
0.12
0.09
0
5
0.47
0.55
0.19
0.15
0.13
0
6
0.80
0.30
0.14
0.11
0.06
0
7
0.42
0.54
0.31
0.17
0.14
0
8
0.52
0.61
0.37
0.27
0.23
0.19
0.13
0.08
9
0.60
0.77
0.33
0.23
0.18
0.12
0.08
0
10
0.80
0.79
0.51
0.32
0.21
0.16
0.10
0.08
12
0 0
43
ISOFLURANE ELIMINATION VIA BUBBLE OXYGENATOR
1.0 -I 900
.750
.150 Fig 2. Actual and predicted onecompartment model of ISF washout curves from one individual (patient no. 2). Key: F,,, measured isoflurane concentration; Fl,,, baseline measured isoflurane concentration: X (dashed line). predicted isoflurane F&/F,, ratios for patient no. 2; 0 (solid line), actual isoflurane F,/F,, ratios for patient no. 2
0.00
DISCUSSION
The isoflurane washout curve for the bubble oxygenator is best described by a onecompartment model with a time constant of approximately two minutes. During the early washout period, the decline in the oxygenator exhaust partial pressure should reflect washout of anesthetic from both the gas volume in the oxygenator and washout from the vessel-rich group. Washout of the gas volume in the oxygenator should be very rapid, with a predicted time constant of 0.16 minutes (an average blood volume of 0.8 L, and a fresh gas flow of 5 L/min). The observed time constant of two minutes must, therefore, be largely determined by washout of the vessel-rich group. Consequently, it is believed that this time constant is primarily determined by the rate of elimination from the vessel-rich group. If this reasoning is correct, the ISF partial pressure in the oxygenator exhaust gases provides a useful estimation of myocardial partial pressures. The absolute partial pressure of anesthetic in the myocardium is dependent on the myocardial blood flow and the tissue-blood partition coefficient. It is difficult to predict what effect ECC and coronary artery bypass grafting will
1
2
3
4
6
8
Time (minutes)
have on myocardial blood flow in patients with diseased coronary arteries. However, the use of aortic cross-clamping during ECC limits the amount of ISF delivered to the myocardium; thus myocardial partial pressures of ISF were probably significantly lower than would be otherwise predicted from the blood partial pressures. Although blood levels of ISF were not quantitated, the gas and blood flowing through the oxygenator would be expected to reach equilibrium; thus, the oxygenator exhaust concentration should reflect the blood partial pressure. Nussmeier et al have demonstrated this in an in vitro investigation of isoflurane elimination via a bubble oxygenator.6 Pump flow (cardiac index) and oxygenator Q2 flow will also affect the speed of ISF washout from the blood, but would not be expected to affect the equilibration of blood and gas in the range of flows used in this study. Tissue:blood partition coefficients would be affected by both hemodilution and hypothermia. Data on the effect of hemodilution and hypothermia on tissue solubilities of inhaled anesthetics are not available. However, data regarding the effects these factors have on blood:gas solubilities are available. The effect of hematocrit on the ISF
44
PRICE ET AL
blood:gas partition coefficient is complex. Lerman et al demonstrated that as hematocrit decreased, the blood:gas partition coefficient increased, indicating a greater blood solubility at lower hematocrits.’ Their data were produced in vitro by altering the proportion of red cells and plasma. Since solubility has been found to correlate positively with concentrations of serum albumin and triglycerides8 the blood:gas partition coefficient would be expected to increase with hemodilution carried out with plasma. On the other hand, crystalloid hemodilution will have the opposite effect, since the water:gas partition coefficient, 0.61, (at 37V) is less than the blood:gas partition coefficient, 1.4 (at 37°C).9 Feingold calculated that during crystalloid hemodilution with the hematocrit decreasing from 40% to 20% there would be a 30% decrease in blood:gas partition coefficient.” Hypothermia can be expected to have the opposite effect on ISF blood solubility. Eger and Eger showed that the blood:gas partition coefficient for ISF increased from 1.46 at 37°C to 1.96 at 30°C.” The rate of change (% change in solubility per “C increase) was -4.36% per “C. They determined the rate of change in healthy patients and suggested it might even be less in hemodiluted patients. Feingold documented the opposing effects of hypothermia and crystalloid hemodilution on the blood:gas partition coefficient for halothane in patients undergoing cardiac surgery.” He also calculated a predicted net change in blood:gas solubility for ISF when hematocrit and temperature decreased from 40% to 20% and 37OC to 28OC, respectively, of + 2%. Although data regarding the effects of
hemodilution and hypothermia on tissue solubilities are not available, the net effect on tissue:blood partition would not be large. Even in the worst case, for example, if hemodilution had no effect on tissue solubility and hypothermia increased tissue solubility by 30%, tissue:blood solubilities would not be expected to increase more than about 30%. It is suggested that at the initiation of the present ISF measurements, while the patients were still moderately hypothermic (28°C) and hemodilute (24% hematocrit), that the two factors largely cancelled each other. As rewarming occurred, however, the solubility of ISF decreased allowing a relatively more rapid washout of the drug. Multicompartmental modeling of the washout curves suggests that the patientoxygenator unit acted as if one compartment were involved. It is speculated that additional compartments in eight of the ten patients were unable to be defined due to limitations in the sensitivity of the mass spectrometer. This study demonstrates that during hypothermic, hemodiluted ECC for adult cardiac surgical patients, ISF washout through a bubble oxygenator occurs rapidly, to clinically unmeasurable exhaust gas levels (~0.05% ISF in 8.8 k 2.5 min). The exhaust concentrations of ISF can be used to approximate the washout curve of anesthetic from the blood and myocardial tissue. Using the time constant of 1.94 minutes, 95% washout of ISF would be accomplished in 5.82 minutes, suggesting that ISF may be used closer to the termination of ECC than previously recommended without fear of significant myocardial depression as a result of ISF administration.
REFERENCES 1. Kemmotsu 0, Hashimoto Y, Shimosato S: Inotropic effects of isoflurane on mechanics of contraction in isolated cat papillary muscles from normal and failing hearts. Anesthesiology 39:470-477, 1973 2. Brown BR, Crout JR: A comparative study of the effects of five general anesthetics on myocardial contractility: I. Isometric conditions. Anesthesiology 34:236-245, 1971 3. Wailer JL, Kaplan JA, Jones EL: Anesthesia for coronary revascularization, in Kaplan JA (ed): Cardiac Anesthesia, vol 1, New York, Grune & Stratton, 1979, p 269 4. Dixon WJ (ed): BMPD statistical software, 1983. Berkeley, University of California, 1983, pp 290-314 5. Boxenbaum HG, Riegelman S, Elashoff RM: Statistical estimations in pharmacokinetics. J Pharmacokinet Biopharm 2:123-148, 1974 6. Nussmeier NA, Cohen NA, Moskowitz GJ, et al: Uptake and elimination of isoflurane via bubble oxygenators.
Sot Cardiovascular Anesthesia 9th Abstracts, Palm Desert, CA, 1987, p 89
Annual
Meeting
7. Lerman J, Gregory GA, Eger EI: Hematocrit and the solubility of volatile anesthetics in blood. Anesth Analg 63:911-914, 1984 8. Lerman J, Gregory GA, Willis MM, et al: Age and solubility of volatile anesthetics in blood. Anesthesiology 61:139-143, 1984 9. Wade JG, Stevens WC: Isoflurane: Anesthetic the eighties? Anesth Analg 60:666-682, 1981
for
10. Feingold A: Crystalloid hemodilution, hypothermia, and halothane blood solubility during cardiopulmonary bypass. Anesth Analg 561622-626, 1977 Il. 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
Elimination Via a Bubble Oxygenator Extracorporeal Circulation
Susan L. Price, MD, David L. Brown,
MD, Randall L. Carpenter,
MD, Jashvant
During
D. Unadkat,
PhD,
and Sondra S. Crosby, PharmD It has been suggested that inhalational anesthetics should be discontinued at least 15 minutes prior to termination of extracorporeal circulation (ECC) to avoid myocardial depression. However, data regarding elimination of inhalation agents via a bubble oxygenator from hypothermic, hemodiluted patients have not been previously reported. The washout of isoflurane (ISF) from ten cardiac surgical patients using mass spectrometry was studied. The mean baseline oxygenator exhaust concentration of ISF was 0.85% prior to termination of ECC. Oxygenator
I
NHALATIONAL anesthetics are frequently used during extracorporeal circulation (ECC) to provide anesthesia and amnesia, and to aid in controlling blood pressure. Inhalational agents, however, depress myocardial contractility’.* and thus may impair the ability to wean from ECC. To minimize the risk of significant myocardial depression, it has been recommended that inhalational anesthetics should be discontinued at least 15 minutes prior to the termination of ECC.3 This fifteen-minute interval should, theoretically, provide adequate time for anesthetics to be eliminated from the heart and minimize depression of contractility. However, this estimate is presumably based on pharmacokinetic data obtained in healthy patients in whom anesthetics are eliminated via the lungs. These estimates may not be accurate for patients during ECC when anesthetics are eliminated via the bubble oxygenator, and when this elimination may be altered by hypothermia and hemodilution. This study defines the oxygenator washout curve for isoflurane (ISF) during ECC in adults. METHODS Following approval of the institutional review board, ten consecutive adult cardiac surgery patients undergoing ECC with moderate hypothermia (range: 25°C to 28°C) and hemodilution (range, 19% to 29% hematocrit; mean, 240/o), in whom ISF was used during the anesthetic, were studied. Nine patients underwent coronary artery bypass grafting, while one had aortic valve replacement performed. The eight male and two female patients ranged in age from 42 to 79 years (mean, 66 years), in weight from 52 to 98 kg (mean, 78 kg), and in height from 157 to 180 cm (mean, 172 cm). Preoperative left ventricular ejection fractions ranged from 32% to 70% (mean, 55%). All of the patients received a combined inhalational
concentration of ISF decreased to less than 0.05% in 8.8 + 2.5 minutes. Eight of ten patients had ISF washout curves best characterized by a one-compartment model, with a mean time constant of 1.94 minutes. Therefore, 95% washout of ISF should occur in 5.8 minutes (three time constants). It is suggested that ISF may be used closer to the termination of ECC than previously recommended without fear of significant myocardial depression. e 1988 by Grune & Stratton, Inc.
and narcotic anesthetic technique. Two of the patients received sufentanil, while the remainder received fentanyl (greater than 50 rg/kg). In addition to the narcotics, all patients received intravenous (IV) benzodiazepines and ISF via a calibrated vaporizer (Forane Vaporizer, Ohio Medical Products, Madison, WI) into the bubble oxygenator (Bentley-10, American Bentley, American Hospital Supply Corporation, Irvine, CA) during ECC. Seven patients also received ISF prior to the institution of ECC. All patients were similarly managed with crystalloid hemodilution, crystalloid cardioplegia, and aortic cross-clamping. Fresh oxygen flow into the oxygenator was adjusted to produce normocarbia (PaCO, uncorrected) during hypothermic ECC and was progressively increased during patient rewarming (in a ratio of 1.5 to 1.7 0, flow/cardiac output). Cardiac index was maintained at approximately 1.5 L/min during hypothermia and increased to 2.0 to 2.2 L/min during rewarming. Immediately preceding aortic crossclamp removal, baseline measurements of temperature, hematocrit, and oxygenator exhaust ISF concentration were recorded. ISF was discontinued when the aortic cross-clamp was removed. Oxygenator exhaust gases were sampled at the oxygenator exhaust port. A 500-mL dead-space reservoir was attached to the exhaust port, beyond the sampling site to prevent contamination of exhaust gases with room air (Fig 1). ISF and nitrogen (NJ partial pressures in oxygenator exhaust gases were measured by mass spectrometry (System for Anesthesia and Respiratory Analysis [SARA], Allegheny International Medical From the Department of Anesthesiology, Virginia Mason Medical Center: the Department of Anesthesiology and the Multidisciplinary Pain Center, University of Washington &hool of Medicine; and the Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle. This material was presented in part at the Annual Meeting of the Society of Cardiovascular Anesthesia, Montreal, April 1986. Address reprint requests to David L. Brown, MD, Virginia Mason Medical Center, PO Box 900. Seattle, WA 98111. o 1988 by Grune & Stratton, Inc. OSSS-6296/88/0201-0009$03.00/0
Journal of Cardiothoracic Anesthesia, Vol2, No 1 (February), 1988: pp 41-44
41
42
PRICE ET AL
Mass Spectrometer
,
Vaoorizer
Arterial
Blood
Bubble Fig 1. The mass spectrometry sampling was carried out via a 6DD-mL deadspace reservoir added to the bubble-oxygenator exhaust port.
Technology, St Louis, MO) at 1, 2, 3,4, 6, 8, 10, 12, and 16 minutes after discontinuing ISF. The reservoir volume was sufficient to prevent contamination of the exhaust gas samples with room air as evidenced by the fact that nitrogen was not detected in the samples. The ratio of F,/FAo was used to define the washout of anesthetic. FA is the exhaust concentration of anesthetic at each measurement interval; FAo is the exhaust concentration of anesthetic obtained immediately prior to discontinuing the anesthetic administration. Multi-exponential (multicompartment) models of the form
2.1%, Table 1). The mean minimum alveolar concentration (MAC) hours of ISF were 0.58 hours and 0.61 hours for pre-ECC and intraECC use, respectively, with total mean MAC hours prior to washout determinations of 1.19 hours. Oxygenator exhaust concentrations of ISF decreased rapidly (Fig 2) and were less than 0.05% in 8.8 2 2.5 minutes. In eight of ten patients, the isoflurane washout curve was “best fit” with a one-compartment model, with a mean time constant of 1.94 + 0.76 minutes. In the other two patients a two-compartment model provided the “best fit.” The terminal portion of the washout curve could not be identified due to limitations in the sensitivity of the mass spectrometer (ie, concentrations ~0.05%). During ECC, the mean arterial pressures ranged from 50 to 83 mmHg. In no patient did the mean arterial pressure rise more than 10 mmHg following discontinuation of the ISF. There was no evidence of intraoperative recall on postoperative evaluation.
were fit to the washout data using least-squares analysis4 For each data set, the model having the greatest number of compartments (highest n) that significantly decreased the residual sum of squares when compared with the model having one less compartment (n - 1) was considered to provide the “best fit” (P < .05, F-ratio test).’ RESULTS
The mean exhaust concentration of ISF immediately prior to discontinuing the anesthetic administration (FAO) was 0.85% (range, 0.42% to Table 1. Individual Patient Values for Oxygenator and F,/F,,
Ratios 1,2.3,4,6,8,10,
Baseline Concentrations
F,/FAo Patient NO.
of ISF IF,,)
in Percent,
and 12 Minutes After ISF Was Discontinued Ratio
Minutes FA0
1
2.1
1
0.46
2
3
4
6
0.24
0.09
0.06
0.03
0
8
10
2
0.85
0.64
0.21
0.15
0.13
0.09
0.06
0
3
1.05
0.54
0.15
0.14
0.11
0.07
0.05
0
4
0.93
0.82
0.4 1
0.29
0.18
0.12
0.09
0
5
0.47
0.55
0.19
0.15
0.13
0
6
0.80
0.30
0.14
0.11
0.06
0
7
0.42
0.54
0.31
0.17
0.14
0
8
0.52
0.61
0.37
0.27
0.23
0.19
0.13
0.08
9
0.60
0.77
0.33
0.23
0.18
0.12
0.08
0
10
0.80
0.79
0.51
0.32
0.21
0.16
0.10
0.08
12
0 0
43
ISOFLURANE ELIMINATION VIA BUBBLE OXYGENATOR
1.0 -I 900
.750
.150 Fig 2. Actual and predicted onecompartment model of ISF washout curves from one individual (patient no. 2). Key: F,,, measured isoflurane concentration; Fl,,, baseline measured isoflurane concentration: X (dashed line). predicted isoflurane F&/F,, ratios for patient no. 2; 0 (solid line), actual isoflurane F,/F,, ratios for patient no. 2
0.00
DISCUSSION
The isoflurane washout curve for the bubble oxygenator is best described by a onecompartment model with a time constant of approximately two minutes. During the early washout period, the decline in the oxygenator exhaust partial pressure should reflect washout of anesthetic from both the gas volume in the oxygenator and washout from the vessel-rich group. Washout of the gas volume in the oxygenator should be very rapid, with a predicted time constant of 0.16 minutes (an average blood volume of 0.8 L, and a fresh gas flow of 5 L/min). The observed time constant of two minutes must, therefore, be largely determined by washout of the vessel-rich group. Consequently, it is believed that this time constant is primarily determined by the rate of elimination from the vessel-rich group. If this reasoning is correct, the ISF partial pressure in the oxygenator exhaust gases provides a useful estimation of myocardial partial pressures. The absolute partial pressure of anesthetic in the myocardium is dependent on the myocardial blood flow and the tissue-blood partition coefficient. It is difficult to predict what effect ECC and coronary artery bypass grafting will
1
2
3
4
6
8
Time (minutes)
have on myocardial blood flow in patients with diseased coronary arteries. However, the use of aortic cross-clamping during ECC limits the amount of ISF delivered to the myocardium; thus myocardial partial pressures of ISF were probably significantly lower than would be otherwise predicted from the blood partial pressures. Although blood levels of ISF were not quantitated, the gas and blood flowing through the oxygenator would be expected to reach equilibrium; thus, the oxygenator exhaust concentration should reflect the blood partial pressure. Nussmeier et al have demonstrated this in an in vitro investigation of isoflurane elimination via a bubble oxygenator.6 Pump flow (cardiac index) and oxygenator Q2 flow will also affect the speed of ISF washout from the blood, but would not be expected to affect the equilibration of blood and gas in the range of flows used in this study. Tissue:blood partition coefficients would be affected by both hemodilution and hypothermia. Data on the effect of hemodilution and hypothermia on tissue solubilities of inhaled anesthetics are not available. However, data regarding the effects these factors have on blood:gas solubilities are available. The effect of hematocrit on the ISF
44
PRICE ET AL
blood:gas partition coefficient is complex. Lerman et al demonstrated that as hematocrit decreased, the blood:gas partition coefficient increased, indicating a greater blood solubility at lower hematocrits.’ Their data were produced in vitro by altering the proportion of red cells and plasma. Since solubility has been found to correlate positively with concentrations of serum albumin and triglycerides8 the blood:gas partition coefficient would be expected to increase with hemodilution carried out with plasma. On the other hand, crystalloid hemodilution will have the opposite effect, since the water:gas partition coefficient, 0.61, (at 37V) is less than the blood:gas partition coefficient, 1.4 (at 37°C).9 Feingold calculated that during crystalloid hemodilution with the hematocrit decreasing from 40% to 20% there would be a 30% decrease in blood:gas partition coefficient.” Hypothermia can be expected to have the opposite effect on ISF blood solubility. Eger and Eger showed that the blood:gas partition coefficient for ISF increased from 1.46 at 37°C to 1.96 at 30°C.” The rate of change (% change in solubility per “C increase) was -4.36% per “C. They determined the rate of change in healthy patients and suggested it might even be less in hemodiluted patients. Feingold documented the opposing effects of hypothermia and crystalloid hemodilution on the blood:gas partition coefficient for halothane in patients undergoing cardiac surgery.” He also calculated a predicted net change in blood:gas solubility for ISF when hematocrit and temperature decreased from 40% to 20% and 37OC to 28OC, respectively, of + 2%. Although data regarding the effects of
hemodilution and hypothermia on tissue solubilities are not available, the net effect on tissue:blood partition would not be large. Even in the worst case, for example, if hemodilution had no effect on tissue solubility and hypothermia increased tissue solubility by 30%, tissue:blood solubilities would not be expected to increase more than about 30%. It is suggested that at the initiation of the present ISF measurements, while the patients were still moderately hypothermic (28°C) and hemodilute (24% hematocrit), that the two factors largely cancelled each other. As rewarming occurred, however, the solubility of ISF decreased allowing a relatively more rapid washout of the drug. Multicompartmental modeling of the washout curves suggests that the patientoxygenator unit acted as if one compartment were involved. It is speculated that additional compartments in eight of the ten patients were unable to be defined due to limitations in the sensitivity of the mass spectrometer. This study demonstrates that during hypothermic, hemodiluted ECC for adult cardiac surgical patients, ISF washout through a bubble oxygenator occurs rapidly, to clinically unmeasurable exhaust gas levels (~0.05% ISF in 8.8 k 2.5 min). The exhaust concentrations of ISF can be used to approximate the washout curve of anesthetic from the blood and myocardial tissue. Using the time constant of 1.94 minutes, 95% washout of ISF would be accomplished in 5.82 minutes, suggesting that ISF may be used closer to the termination of ECC than previously recommended without fear of significant myocardial depression as a result of ISF administration.
REFERENCES 1. Kemmotsu 0, Hashimoto Y, Shimosato S: Inotropic effects of isoflurane on mechanics of contraction in isolated cat papillary muscles from normal and failing hearts. Anesthesiology 39:470-477, 1973 2. Brown BR, Crout JR: A comparative study of the effects of five general anesthetics on myocardial contractility: I. Isometric conditions. Anesthesiology 34:236-245, 1971 3. Wailer JL, Kaplan JA, Jones EL: Anesthesia for coronary revascularization, in Kaplan JA (ed): Cardiac Anesthesia, vol 1, New York, Grune & Stratton, 1979, p 269 4. Dixon WJ (ed): BMPD statistical software, 1983. Berkeley, University of California, 1983, pp 290-314 5. Boxenbaum HG, Riegelman S, Elashoff RM: Statistical estimations in pharmacokinetics. J Pharmacokinet Biopharm 2:123-148, 1974 6. Nussmeier NA, Cohen NA, Moskowitz GJ, et al: Uptake and elimination of isoflurane via bubble oxygenators.
Sot Cardiovascular Anesthesia 9th Abstracts, Palm Desert, CA, 1987, p 89
Annual
Meeting
7. Lerman J, Gregory GA, Eger EI: Hematocrit and the solubility of volatile anesthetics in blood. Anesth Analg 63:911-914, 1984 8. Lerman J, Gregory GA, Willis MM, et al: Age and solubility of volatile anesthetics in blood. Anesthesiology 61:139-143, 1984 9. Wade JG, Stevens WC: Isoflurane: Anesthetic the eighties? Anesth Analg 60:666-682, 1981
for
10. Feingold A: Crystalloid hemodilution, hypothermia, and halothane blood solubility during cardiopulmonary bypass. Anesth Analg 561622-626, 1977 Il. 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