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Levels of circulating norepinephrine and epinephrine before, during, and after cardiopulmonary bypass in man
Levels of circulating norepinephrine and epinephrine before, during, and after cardiopulmonary bypass in man Little information is available on the levels of circulating catecholamines during cardiac surgery. A study was undertaken to measure the serum levels of epinephrine and norepinephrine before, during, and after cardiopulmonary bypass in 16 patients. Sampling were drawn before induction, after intubation, before bypass, 2 and 8 minutes after initiation of the bypass, and 20 minutes after bypass. Thefindingsof this study show that the initiation of cardiopulmonary bypass was associated with a significant but transient fall in mean blood pressure accompanied by an increased secretion of adrenal epinephrine and norepinephrine. The cause of the observed hypotension may be due to an initial hemodilution of the circulating catecholamines by the 2 L. pump-priming solution. The secretion of adrenal catecholamines appears to be a compensatory response to the lowered blood pressure as indicated by the rapid return of the blood pressure in the ensuing minutes. Twenty minutes after bypass, both the blood pressure and serum catecholamine levels were observed to have returned to preinduction levels. Chee-Ken Tan, M.D., Silas N. Glisson, Ph.D., Adel A. El-Etr, M.D., and Kenkere B. Ramakrishnaiah, Ph.D., May wood. 111.
An the last few years a renewed interest in serum catecholamines has prompted several investigators to study the changes in serum norepinephrine (NE) and epinephrine (EPI) levels associated with the use of various anesthetics1-4 as well as with the use of extracorporeal circulation techniques. 5-8 The focus of this study concerns the serum NE and EPI changes occurring before, during, and after bypass, especially as they relate to a hypotensive response observed during the first few minutes of bypass with the use of narcotics. Methods To date, 16 patients who underwent cardiac surgery (Table I) requiring cardiopulmonary bypass have been studied. All patients were premedicated with diazepam (5 to 10 mg.) and morphine (5 to 10 mg.) intramuscuFrom the Department of Anesthesiology, Loyola University Stritch School of Medicine, 2160 South First Avenue, Maywood, 111. 60153. This work is supported in part by National Institutes of Health General Research Support Grant No. RR05368. Received for publication Aug. 1, 1975. Accepted for publication Feb. 17, 1976. 928
larly an hour before the operation. Two intravenous, indwelling Teflon catheters were inserted after the patient arrived in the operating room. The radial artery was cannulated percutaneously with a 20 gauge Teflon indwelling catheter. Blood pressure was displayed on an oscilloscope. Electrocardiographic leads were attached and displayed continuously on the oscilloscope. Central venous pressure, urine output, and tympanic temperature were monitored. After preoxygenation, anesthesia was induced with incremental doses of Pentothal (50 to 100 mg.) up to a total dose of 4 to 5 mg. per kilogram of body weight. Pancuronium (0.1 mg. per kilogram) or succinylcholine (1.0 to 1.5 mg. per kilogram) was given to facilitate endotracheal intubation, and thereafter incremental doses of pancuronium or d-tubocurarine were given as needed (Table II). Anesthesia was maintained with 50 per cent nitrous oxide-oxygen and narcotics (Table III). Pco 2 was kept at 35 to 40 torr by controlled ventilation. The extracorporeal system was primed with 2 L. of lactated Ringer's solution, 50 c.c. of 50 per cent glucose, and 50 mEq. of sodium bicarbonate. Blood samples were taken at frequent intervals for analysis of gases, pH, hematocrit levels, and electrolytes. Bypass
Volume 71 Number 6 June, 1976
flows were maintained at 40 to 70 ml. per kilogram per minute. Patients were cooled down to 28° C , except for one patient who underwent open mitral commissurectomy; in this patient normal body temperature was maintained. At the end of bypass, calcium chloride (400 to 1,000 mg.) was routinely given intravenously. No inotropic agents were given before, during, or after bypass. Arterial blood samples were drawn at six intervals: Period 1, before induction; Period 2, 5 minutes after intubation; Period 3, 20 minutes before bypass; Period 4, 2 minutes after initiation of bypass; Period 5, 8 minutes after initiation of bypass; and Period 6, 20 minutes after bypass. Serum NE and EPI were determined by a modification of the methods of Vendsalu9 and Haggendal.10 Basically, the method is as follows: Serum from 20 ml. heparinized blood samples was deproteinized with 4.0 normal perchloric acid containing EDTA* and ascorbic acid. NE and EPI were isolated and purified by passing the acidified serum through a 4.4 by 50 mm. column containing prebuffered (pH 6.5, Na+ form) BioRad AG W X-4 ion-exchange resin. After a 40 ml. water wash, elution of the NE and EPI was carried out with 2 normal hydrochloric acid. After conversion of NE and EPI to their respective fluorophores, the sample fluorescence was measured at 400/505 and 450/505 nm. in a spectrophotofluorometer equipped with an ellipsoidal mirror condensing system. Concentrations of NE and EPI were calculated by the method of simultaneous equations. It was found that the application of this method required at least 9 ml. of serum with a quantitative sensitivity of 450 pg.
929
Circulating catecholamines during cardiac surgery
Table I. Surgical procedures and sex distribution Type of surgery
No. of patients
Male
Female
Aorta-coronary anastomosis Valve replacement (mitral and aortic) Aorta-coronary anastomosis and ventricular aneurysmectomy Open commissurectomy
8
5
3
6
3
3
1
1
0
1
0
1
16
9
7
Totals
Table II. Kinds of muscle relaxant used for intubation and maintenance No. of patients
Muscle relaxant Pancuronium Succinylcholine and pancuronium Succinylcholine and d-tubocurarine
Table III. Anesthetic and narcotics used* No. of patients
Drug
16
Nitrous oxide and oxygen Innovar and Sublimaze Sublimaze Morphine
12 2 2
•Dosages: Innovar, 1 c.c. per 25 pounds; Sublimaze, 1 c.c. per 10 Kg.; morphine, 1 to 1.5 mg. per kilogram.
Results Blood pressure and body temperature. As can be seen in Table IV, the mean blood pressure was observed to increase 11 per cent (p < 0.001) from Period 2 to Period 3, followed by a significant fall in pressure (45 per cent) 2 minutes after initiation of bypass (Period 4). During the same time period (3 to 4) the body temperature cooled 2.5° C. Eight minutes after initiation of bypass (Period 5) the body temperature decreased an additional 2° C , while the mean blood pressure rose from 51 to 65 mm. Hg, both changes being significant (p < 0.001). Twenty minutes after bypass (Period 6) the body temperature had returned to the prebypass level (Period 3) and the blood pressure had returned to within 10 per cent of the Period 1 level (86 mm. Hg). *Ethylenediaminetetraacetic acid.
Serum NE and EPI. The mean levels of preanesthesia (Period 1) and postintubation (Period 2) serum NE were essentially the same (Table IV). At period 3, serum NE levels were observed to increase 20 per cent over those levels at Period 2. Two minutes after initiation of bypass (Period 4) serum NE levels were unchanged, although an 18 per cent fall in serum NE occurred over the next 6 minutes. At Period 6 the mean NE level was greater by 20 per cent than the NE level of Period 1. Although fluctuation in the mean values was observed, statistical analysis of the data indicate a lack of significant difference between any of the adjoining periods including Periods 1 and 6. In the case of the mean serum EPI levels, the response to cardiopulmonary bypass differed in some respects from that of NE. EPI levels increased by 30 per cent following intubation over the preinduction EPI
9 30
The Journal of Thoracic and Cardiovascular Surgery
Tan et al.
Table IV. Serum norepinephrine and epinephrine levels before, during, and after cardiopulmonary bypass* Period 1 Norepinephrine (/u.g/L. serum) Epinephrine (/ug/L. serum) Blood pressure (mm. Hg) p Value Temperature (tympanic- °C) p Value
Period 3
Period 2
Period 4
Period 6
Period 5
1.11 ± 0.37
0.99 ± 0.40
1.25 ± 0.35
1.30 ± 0.40
1.07 ± 0.30
1.33 ± 0.33
2.20 ± 0.21
2.98 ± 0.41
2.15 ± 0.45
1.60 ± 0.18
1.87 ± 0.26
2.66 ± 0.41
85.80 ± 3.8
82.90 ± 3.0 0.05
36.36 ± 0 . 1 7
92.10 ± 3.6
51.30 ± 3.1
0.001 36.32 + 0.17
0.001 35.91 ± 0.20
0.001 33.34 ± 0.45
0.001
78.10 ± 3.4
65.30 ± 3.0 0.02 31.19 ± 0.65 0.001
36.21 ± 0.14 0.001
* All values represent the mean ± standard error of the mean. Sample periods include: Period 1, preinduction; Period 2, 5 minutes postinmbation; Period 3, 20 minutes before bypass; Period 4, 2 minutes after initiation of bypass; Period 5, 8 minutes after initiation of bypass; Period 6, 20 minutes after bypass. Statistical analysis was done with the paired Student's t test and probabilities are shown between the periods paired.
levels (Table IV). This change was transient in nature, and by Period 3 the serum EPI had returned essentially to the preinduction (Period 1) level. Two minutes after bypass was initiated, EPI levels decreased an additional 26 per cent. Eight minutes after initiation of bypass, the decline in EPI had ceased and the serum EPI levels were observed to rise (1.60 to 1.87). This effect continued into Period 6 (after bypass), in which mean serum EPI levels were found to be 16 per cent above the preinduction (Period 1) level. Discussion In two previous studies5"6 in which serum NE and EPI levels were measured during cardiopulmonary bypass, an initial hypotensive response to the bypass was not reported. Examination of the methodology indicates that in these two studies the bypass pump was primed with heparinized whole blood and heparinized whole blood and dextran, respectively. In addition, the levels of NE and EPI in the blood used to prime the bypass pump were similar to those of the patient's own blood. In the present study the bypass pump is not primed with blood, and therefore the observed hypotensive response may reflect dilution of the patient's circulating serum catecholamines with the Ringer perfusate. Analysis of the data indicates that 2 and 8 minutes after bypass (Periods 4 and 5) the mean serum EPI and NE levels (micrograms per liter) are not significantly different from the prebypass levels. During this time the mean blood pressure fell by 45 per cent (Periods 3 and 4). If the hypotensive effect were due to a dilution of the circulating catecholamines, one would expect to see a decrease in the NE as well as the EPI levels. Since this was not the case, it would appear that the observed
hypotensive response is not due to hemodilution of catecholamines. Of particular interest with respect to the present findings is that the levels of circulating NE and EPI before, during, and after bypass seem to reflect the body's compensatory processes acting to restore the blood pressure to a near-normal level. The fact that NE and EPI levels (micrograms per liter) did not fall during Periods 4 and 5, the time when total blood volume is increased by some 2 L., indicates that these amines had to be added into the general circulation; the source is most probably the adrenals and sympathetic nerve terminal (i.e., saturation of the re-uptake process11). The questions remain as to whether NE and EPI are being added in response to an as yet undetected volume dilution of circulating NE and EPI or whether they are being added to compensate the hypotension. The direct cause of the observed hypotension remains unanswered, although it is now known that it occurs during the initial 2 minutes of bypass. Very early dilution of circulating catecholamines (less than 2 minutes), histamine release because of the cooled perfusate, or a mechanical effect are still the most probable causes for the hypotension and are now under investigation. We would like to thank Ms. Mary K. McGovern for technical assistance and Mr. Byron Bloor for assistance with computer analysis of the data. REFERENCES 1 Price, H. L., Linde, H. W . , Jones, R. E., Black, G. W., and Price, M. L.: Sympathoadrenal Responses to General Anesthesia in Man and Their Relation to Hemodynamics, Anesthesiology 20: 563, 1959. 2 Ngai, S. H . , Neff, N. H., and Costa, E.: The Effects of
Volume 71 Number 6 June, 1976
Cyclopropane and Halothane on the Biosynthesis of Norepinephrine In Vivo, Anesthesiology 31: 53, 1969. 3 Perry, L. B., Van Dyke, R. A., and Theye, R. A.: Sympathoadrenal and Hemodynamic Effects of Isoflurane, Halothane and Cyclopropane in Dogs, Anesthesiology 40: 465, 1974. 4 Roizen, M. F., Moss, J., Henry, D. P., and Kopin, I. M.: Effects of Halothane on Plasma Catecholamines, Anesthesiology 41: 432, 1974. 5 Replogle, R., Levy, M., DeWall, R. A., andLillehei, R. C : Catecholamine and Serotonin Response to Cardiopulmonary Bypass, J. THORAC. CARDIOVASC. SURG. 44:
638, 1962. 6 Anton, A. H., Gravenstein, J. S., and Wheat, M. W., Jr.: Extracorporeal Circulation and Endogenous Epinephrine and Norepinephrine in Plasma, Atrium and Urine in Man, Anesthesiology 25: 262, 1964.
Circulating catecholamines
during cardiac surgery
931
7 Stanley, T. H., Isern-Amaral, J., and Lathrop, G. D.: The Effects of Morphine Anesthesia on Urine Norepinephrine During and After Coronary Artery Surgery, in, Abstracts of Scientific Papers. American Society of Anesthesiologists Annual Meeting, pp. 209-210, 1974. 8 Bailey, D. R., Miller, E. D., Jr, Kaplan, J. A., Rogers, P. W.: The Renin-Angiotensin Aldosterone System During Cardiac Surgery With Morphine-Nitrous Oxide Anesthesia, Anesthesiology 42: 538, 1975. 9 Vendsalu, A.: Studies on Adrenaline and Noradrenaline in Human Plasma, Acta Physiol. Scand. 49: 1, 1960, (Suppl. 173). 10 Haggendal, J.: On the Use of Strong Exchange Resins for Determinations of Small Amounts of Catecholamines, Scand. J. Clin. Lab. Invest. 14: 537, 1962. 11 Ngai, S. H.: Plasma Catecholamines: Their Significance in Anesthesia, Anesthesiology 41: 429, 1974.
An the last few years a renewed interest in serum catecholamines has prompted several investigators to study the changes in serum norepinephrine (NE) and epinephrine (EPI) levels associated with the use of various anesthetics1-4 as well as with the use of extracorporeal circulation techniques. 5-8 The focus of this study concerns the serum NE and EPI changes occurring before, during, and after bypass, especially as they relate to a hypotensive response observed during the first few minutes of bypass with the use of narcotics. Methods To date, 16 patients who underwent cardiac surgery (Table I) requiring cardiopulmonary bypass have been studied. All patients were premedicated with diazepam (5 to 10 mg.) and morphine (5 to 10 mg.) intramuscuFrom the Department of Anesthesiology, Loyola University Stritch School of Medicine, 2160 South First Avenue, Maywood, 111. 60153. This work is supported in part by National Institutes of Health General Research Support Grant No. RR05368. Received for publication Aug. 1, 1975. Accepted for publication Feb. 17, 1976. 928
larly an hour before the operation. Two intravenous, indwelling Teflon catheters were inserted after the patient arrived in the operating room. The radial artery was cannulated percutaneously with a 20 gauge Teflon indwelling catheter. Blood pressure was displayed on an oscilloscope. Electrocardiographic leads were attached and displayed continuously on the oscilloscope. Central venous pressure, urine output, and tympanic temperature were monitored. After preoxygenation, anesthesia was induced with incremental doses of Pentothal (50 to 100 mg.) up to a total dose of 4 to 5 mg. per kilogram of body weight. Pancuronium (0.1 mg. per kilogram) or succinylcholine (1.0 to 1.5 mg. per kilogram) was given to facilitate endotracheal intubation, and thereafter incremental doses of pancuronium or d-tubocurarine were given as needed (Table II). Anesthesia was maintained with 50 per cent nitrous oxide-oxygen and narcotics (Table III). Pco 2 was kept at 35 to 40 torr by controlled ventilation. The extracorporeal system was primed with 2 L. of lactated Ringer's solution, 50 c.c. of 50 per cent glucose, and 50 mEq. of sodium bicarbonate. Blood samples were taken at frequent intervals for analysis of gases, pH, hematocrit levels, and electrolytes. Bypass
Volume 71 Number 6 June, 1976
flows were maintained at 40 to 70 ml. per kilogram per minute. Patients were cooled down to 28° C , except for one patient who underwent open mitral commissurectomy; in this patient normal body temperature was maintained. At the end of bypass, calcium chloride (400 to 1,000 mg.) was routinely given intravenously. No inotropic agents were given before, during, or after bypass. Arterial blood samples were drawn at six intervals: Period 1, before induction; Period 2, 5 minutes after intubation; Period 3, 20 minutes before bypass; Period 4, 2 minutes after initiation of bypass; Period 5, 8 minutes after initiation of bypass; and Period 6, 20 minutes after bypass. Serum NE and EPI were determined by a modification of the methods of Vendsalu9 and Haggendal.10 Basically, the method is as follows: Serum from 20 ml. heparinized blood samples was deproteinized with 4.0 normal perchloric acid containing EDTA* and ascorbic acid. NE and EPI were isolated and purified by passing the acidified serum through a 4.4 by 50 mm. column containing prebuffered (pH 6.5, Na+ form) BioRad AG W X-4 ion-exchange resin. After a 40 ml. water wash, elution of the NE and EPI was carried out with 2 normal hydrochloric acid. After conversion of NE and EPI to their respective fluorophores, the sample fluorescence was measured at 400/505 and 450/505 nm. in a spectrophotofluorometer equipped with an ellipsoidal mirror condensing system. Concentrations of NE and EPI were calculated by the method of simultaneous equations. It was found that the application of this method required at least 9 ml. of serum with a quantitative sensitivity of 450 pg.
929
Circulating catecholamines during cardiac surgery
Table I. Surgical procedures and sex distribution Type of surgery
No. of patients
Male
Female
Aorta-coronary anastomosis Valve replacement (mitral and aortic) Aorta-coronary anastomosis and ventricular aneurysmectomy Open commissurectomy
8
5
3
6
3
3
1
1
0
1
0
1
16
9
7
Totals
Table II. Kinds of muscle relaxant used for intubation and maintenance No. of patients
Muscle relaxant Pancuronium Succinylcholine and pancuronium Succinylcholine and d-tubocurarine
Table III. Anesthetic and narcotics used* No. of patients
Drug
16
Nitrous oxide and oxygen Innovar and Sublimaze Sublimaze Morphine
12 2 2
•Dosages: Innovar, 1 c.c. per 25 pounds; Sublimaze, 1 c.c. per 10 Kg.; morphine, 1 to 1.5 mg. per kilogram.
Results Blood pressure and body temperature. As can be seen in Table IV, the mean blood pressure was observed to increase 11 per cent (p < 0.001) from Period 2 to Period 3, followed by a significant fall in pressure (45 per cent) 2 minutes after initiation of bypass (Period 4). During the same time period (3 to 4) the body temperature cooled 2.5° C. Eight minutes after initiation of bypass (Period 5) the body temperature decreased an additional 2° C , while the mean blood pressure rose from 51 to 65 mm. Hg, both changes being significant (p < 0.001). Twenty minutes after bypass (Period 6) the body temperature had returned to the prebypass level (Period 3) and the blood pressure had returned to within 10 per cent of the Period 1 level (86 mm. Hg). *Ethylenediaminetetraacetic acid.
Serum NE and EPI. The mean levels of preanesthesia (Period 1) and postintubation (Period 2) serum NE were essentially the same (Table IV). At period 3, serum NE levels were observed to increase 20 per cent over those levels at Period 2. Two minutes after initiation of bypass (Period 4) serum NE levels were unchanged, although an 18 per cent fall in serum NE occurred over the next 6 minutes. At Period 6 the mean NE level was greater by 20 per cent than the NE level of Period 1. Although fluctuation in the mean values was observed, statistical analysis of the data indicate a lack of significant difference between any of the adjoining periods including Periods 1 and 6. In the case of the mean serum EPI levels, the response to cardiopulmonary bypass differed in some respects from that of NE. EPI levels increased by 30 per cent following intubation over the preinduction EPI
9 30
The Journal of Thoracic and Cardiovascular Surgery
Tan et al.
Table IV. Serum norepinephrine and epinephrine levels before, during, and after cardiopulmonary bypass* Period 1 Norepinephrine (/u.g/L. serum) Epinephrine (/ug/L. serum) Blood pressure (mm. Hg) p Value Temperature (tympanic- °C) p Value
Period 3
Period 2
Period 4
Period 6
Period 5
1.11 ± 0.37
0.99 ± 0.40
1.25 ± 0.35
1.30 ± 0.40
1.07 ± 0.30
1.33 ± 0.33
2.20 ± 0.21
2.98 ± 0.41
2.15 ± 0.45
1.60 ± 0.18
1.87 ± 0.26
2.66 ± 0.41
85.80 ± 3.8
82.90 ± 3.0 0.05
36.36 ± 0 . 1 7
92.10 ± 3.6
51.30 ± 3.1
0.001 36.32 + 0.17
0.001 35.91 ± 0.20
0.001 33.34 ± 0.45
0.001
78.10 ± 3.4
65.30 ± 3.0 0.02 31.19 ± 0.65 0.001
36.21 ± 0.14 0.001
* All values represent the mean ± standard error of the mean. Sample periods include: Period 1, preinduction; Period 2, 5 minutes postinmbation; Period 3, 20 minutes before bypass; Period 4, 2 minutes after initiation of bypass; Period 5, 8 minutes after initiation of bypass; Period 6, 20 minutes after bypass. Statistical analysis was done with the paired Student's t test and probabilities are shown between the periods paired.
levels (Table IV). This change was transient in nature, and by Period 3 the serum EPI had returned essentially to the preinduction (Period 1) level. Two minutes after bypass was initiated, EPI levels decreased an additional 26 per cent. Eight minutes after initiation of bypass, the decline in EPI had ceased and the serum EPI levels were observed to rise (1.60 to 1.87). This effect continued into Period 6 (after bypass), in which mean serum EPI levels were found to be 16 per cent above the preinduction (Period 1) level. Discussion In two previous studies5"6 in which serum NE and EPI levels were measured during cardiopulmonary bypass, an initial hypotensive response to the bypass was not reported. Examination of the methodology indicates that in these two studies the bypass pump was primed with heparinized whole blood and heparinized whole blood and dextran, respectively. In addition, the levels of NE and EPI in the blood used to prime the bypass pump were similar to those of the patient's own blood. In the present study the bypass pump is not primed with blood, and therefore the observed hypotensive response may reflect dilution of the patient's circulating serum catecholamines with the Ringer perfusate. Analysis of the data indicates that 2 and 8 minutes after bypass (Periods 4 and 5) the mean serum EPI and NE levels (micrograms per liter) are not significantly different from the prebypass levels. During this time the mean blood pressure fell by 45 per cent (Periods 3 and 4). If the hypotensive effect were due to a dilution of the circulating catecholamines, one would expect to see a decrease in the NE as well as the EPI levels. Since this was not the case, it would appear that the observed
hypotensive response is not due to hemodilution of catecholamines. Of particular interest with respect to the present findings is that the levels of circulating NE and EPI before, during, and after bypass seem to reflect the body's compensatory processes acting to restore the blood pressure to a near-normal level. The fact that NE and EPI levels (micrograms per liter) did not fall during Periods 4 and 5, the time when total blood volume is increased by some 2 L., indicates that these amines had to be added into the general circulation; the source is most probably the adrenals and sympathetic nerve terminal (i.e., saturation of the re-uptake process11). The questions remain as to whether NE and EPI are being added in response to an as yet undetected volume dilution of circulating NE and EPI or whether they are being added to compensate the hypotension. The direct cause of the observed hypotension remains unanswered, although it is now known that it occurs during the initial 2 minutes of bypass. Very early dilution of circulating catecholamines (less than 2 minutes), histamine release because of the cooled perfusate, or a mechanical effect are still the most probable causes for the hypotension and are now under investigation. We would like to thank Ms. Mary K. McGovern for technical assistance and Mr. Byron Bloor for assistance with computer analysis of the data. REFERENCES 1 Price, H. L., Linde, H. W . , Jones, R. E., Black, G. W., and Price, M. L.: Sympathoadrenal Responses to General Anesthesia in Man and Their Relation to Hemodynamics, Anesthesiology 20: 563, 1959. 2 Ngai, S. H . , Neff, N. H., and Costa, E.: The Effects of
Volume 71 Number 6 June, 1976
Cyclopropane and Halothane on the Biosynthesis of Norepinephrine In Vivo, Anesthesiology 31: 53, 1969. 3 Perry, L. B., Van Dyke, R. A., and Theye, R. A.: Sympathoadrenal and Hemodynamic Effects of Isoflurane, Halothane and Cyclopropane in Dogs, Anesthesiology 40: 465, 1974. 4 Roizen, M. F., Moss, J., Henry, D. P., and Kopin, I. M.: Effects of Halothane on Plasma Catecholamines, Anesthesiology 41: 432, 1974. 5 Replogle, R., Levy, M., DeWall, R. A., andLillehei, R. C : Catecholamine and Serotonin Response to Cardiopulmonary Bypass, J. THORAC. CARDIOVASC. SURG. 44:
638, 1962. 6 Anton, A. H., Gravenstein, J. S., and Wheat, M. W., Jr.: Extracorporeal Circulation and Endogenous Epinephrine and Norepinephrine in Plasma, Atrium and Urine in Man, Anesthesiology 25: 262, 1964.
Circulating catecholamines
during cardiac surgery
931
7 Stanley, T. H., Isern-Amaral, J., and Lathrop, G. D.: The Effects of Morphine Anesthesia on Urine Norepinephrine During and After Coronary Artery Surgery, in, Abstracts of Scientific Papers. American Society of Anesthesiologists Annual Meeting, pp. 209-210, 1974. 8 Bailey, D. R., Miller, E. D., Jr, Kaplan, J. A., Rogers, P. W.: The Renin-Angiotensin Aldosterone System During Cardiac Surgery With Morphine-Nitrous Oxide Anesthesia, Anesthesiology 42: 538, 1975. 9 Vendsalu, A.: Studies on Adrenaline and Noradrenaline in Human Plasma, Acta Physiol. Scand. 49: 1, 1960, (Suppl. 173). 10 Haggendal, J.: On the Use of Strong Exchange Resins for Determinations of Small Amounts of Catecholamines, Scand. J. Clin. Lab. Invest. 14: 537, 1962. 11 Ngai, S. H.: Plasma Catecholamines: Their Significance in Anesthesia, Anesthesiology 41: 429, 1974.