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CHANGES IN PLASMA VASOPRESSIN CONCENTRATION IN ASSOCIATION WITH CORONARY ARTERY SURGERY OR THYMECTOMY
Br. J. Anaesth. 1986, 58, 1273-1277
CHANGES IN PLASMA VASOPRESSIN CONCENTRATION IN ASSOCIATION WITH CORONARY ARTERY SURGERY OR THYMECTOMY
The aetiology of postoperative hypertension following cardiopulmonary bypass (CPB), particularly when used during myocardial revascularization, remains obscure, although the reninangiotensin system, and vasopressin, have been implicated. A previous investigation (Hawkins et al., 1986) failed to demonstrate any consistent pattern of change in plasma renin activity. However, in all patients plasma vasopressin concentration increased significantly after sternotomy and remained so for up to 6 h into the postoperative period. This release of vasopressin was stimulated not only by CPB but also by the events which preceded bypass. Vasopressin is released rapidly after a trigger stimulus and has a circulating half-life of about 8 min (Fabian et al., 1969). As the purpose of this second study was to determine the stimuli to vasopressin release, the only non-cardiac operation routinely performed through a median sternotomy, thymectomy, was chosen for comparison. Sampling times were chosen to follow surgical events by 3 min. If the interval between samples was more than 15 min, a new baseline sample was taken. PATIENTS AND METHODS
Two groups of patients were studied: 14 undergoing elective coronary artery surgery, and eight having a median sternotomy for thymectomy. ANNE KNIGHT, M.D., F.F.A.R.CS., W. AVELTNG, M.A., M.B., B.CHIR., F.F.A.R.CS. (Department of Anaesthesia); MARY
FORSLING, B.SC., PH.D. (Department of Physiology); TOM TREASURE, M.D., M J . , F.R.CS., M. F. STURRIDGE, M J . , F.R.CS.
(Cardiothoracic Unit); The Middlesex Hospital and Medical School, Mortimer Street, London W I N 8AA. L. LOH, F.F.A.R.Cs. (and M. F. S.), The National Hospitals for Nervous Diseases, Queen Square, WC1. Correspondence to T . T .
SUMMARY Plasma vasopressin concentrations in 14 patients undergoing coronary artery surgery were compared with those in eight patients undergoing thymectomy. Vasopressin concentrations increased similarly in both groups on sternotomy. A second, and more marked increase was noted in the patients requiring cardiopulmonary bypass. Haemodynamic stimuli could be responsible in both groups and might explain both the similarities and the differences between the groups.
Coronary artery surgery
Twelve men and two women, aged between 40 and 73 yr (mean 54) were included in the study. All had normal renal and hepatic function; patients with poor left ventricular function (ejection fraction < 30%) were excluded. Preoperative medication included beta-adrenoceptor blockers (« = 9), diuretics (n = 5), isosorbide, persantin, nifedipine and nitrates. Premedication was with diazepam 10-20 mg by mouth, followed 1 h later by papaveretum •15-20 mg and hyoscine 0.3-0.4 mg i.m. A cannula was inserted to the radial artery under local anaesthesia and monitoring was instituted with a cardioscope and an automatic arterial pressure monitor (Dinamap). Anaesthesia was induced with papaveretum and thiopentone. The dose of opioid administered was standardized to total 1 mg kg"1 divided between the premedicant and the induction doses. After induction, the right internal jugular vein was cannulated and a catheter inserted to the bladder. The ECG, arterial pressure, central venous pressure and temperature were displayed throughout the procedure, and arterial blood-gas ten-
Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on September 3, 2015
A. KNIGHT, M. FORSLING, T. TREASURE, W. AVELING, L. LOH AND M. F. STURRIDGE
BRITISH JOURNAL OF ANAESTHESIA
1274 sions, plasma concentrations of sodium and potassium, and urine volume, were measured regularly. Pancuronium was administered to provide neuromuscular blockade. Anaesthesia was maintained with nitrous oxide in oxygen supplemented with halothane before bypass if the systolic arterial pressure increased above 150 mm Hg. The technique of bypass included a single right atrial cannula and arterial return to the ascending aorta; a bubble oygenator (Harvey or Bentley), primed with 1500 ml of lactated Ringer's solution; a roller pump (Stockert or Gambro) used in the pulsatile mode; arterial flow of 2.4 litre min"1 m~*; and whole body cooling to 28 °C. During bypass the patient received lorazepam 4 mg and additional doses of pancuronium. Subsequent doses of opioid were withheld during bypass until all sampling was completed. Mean arterial pressure on bypass was kept between 90 and 50 mm Hg with phentolamine or metaraminol. During aortic cross-clamping the myocardium was protected with St Thomas's Hospital cardioplegic solution and topical cooling with saline at 4°C. Twelve samples for the measurement of vasopressin concentration were taken from the arterial
line, usually 3 min after each possible stimulus under investigation during the preparatory part of the operation and, then, before going onto bypass; after 3, 15 and 30 min of bypass; and, finally, 2 h after bypass (table I). Plasma and urine were collected for osmolality measurements after induction, during bypass and 2 h after bypass.
Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on September 3, 2015
Thymectomy Patients (« = 8) were all female, aged 18-52 yr (mean 32 yr), suffering from myasthenia gravis, and all were receiving treatment with anticholinesterases. They were premedicated with papaveretum and hyoscine. In the anaesthetic room 4% cocaine solution was applied to the nasal mucosa, anaesthesia was induced with thiopentone, suxamethonium was administered and the trachea intubated with a Portex nasal tube to permit longterm management. Anaesthesia was maintained with nitrous oxide, oxygen and halothane; spontaneous ventilation resumed at the end of the procedure. The sternotomy incision was identical to that used for cardiac surgery, but the pericardium was not opened. The ECG and end-tidal Pco a concentration were monitored throughout the procedure, and arterial pressure was measured
TABLE I. Mean changes (SEM) in heart rate (HR), mean arterial pressure (AP) and central venous pressure (CVP) during coronary artery surgery and thymectomy Thymectomy
Coronary artery graft
Code 1 2 3 4 5 6 7 8 9 10 11 12
Event Pre-induction Intubation + 3min Leg incis. + 3 min Chest inHfi + 3min Saw + 3 min Retraction + 3min Peric. tract + 3 min Heparin (CPB-3) Bypass + 3min Bypass + 15 min Bypass + 30 min 2 h post CPB
HR (beat min"1)
AP (mmHg)
61 (3.7) 81(5.1)
93 (4.2) 92 (7.8)
74(3.9)
83 (4.3)
6 (1.1)
73(4.8)
90 (4.3)
6 (13)
74(3.8) 75 (3.7)
100 (4.2) 93 (6.4)
4 (2.7) 5 (13)
72 (3.4) 83 (3.5)
69 (6.2) 87 (3.5)
9 (1.8) 5 (1.4)
—
49 (3.6)
3 (1.1)
—
50 (3.9)
1 (1.2)
—
62 (4.1)
3 (1.0)
100 (3.1)
5 (0.8)
94 (4.3)
CVP (mmHg) —
HR (beat min"1)
AP (mmHg)
Pre-induction Intubation + 3min
79 (9.2) 96 (7.6)
88 (5.0) 98 (6.0)
Chest incis. + 3 min Saw + 3 min Retraction
65 (3.5)
77(3.7)
72 (4.8) 66 (4.3)
86(7.1) 77 (5.7)
Sternotomy + 15 min
65(3.1)
76 (6.8)
Sternotomy + 30 min
68 (4.0)
73 (4.3)
Postop.
68 (2.3)
89 (3.8)
Event
+ 3min
PLASMA VASOPRESSIN CONCENTRATION IN CORONARY SURGERY
1275
TABLE II. Mean plasma and urine composition (SEM) before and after coronary artery surgery and thymectomy Before op. Coronary artery graft Plasma osmolality (mosm litre"1) Plasma sodium (mmol litre"1) Urine flow (ml h"1) Urine osmolality (mosm litre"1) Thymectomy Plasma osmolality (mosm litre"1)
282 136 77 527
(1.5) (0.9) (14.8) (60)
280 (4.0)
During CPB 285(1.1) 137 (0.9) 139 (30.4) 492 (58)
After op. 284(1.9) 135(1.5) 176 (47.8) 390 (22) 280(8.1)
Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on September 3, 2015
drugs) had more stable heart rates and arterial pressures with similar but less marked changes on intubation and sternotomy. Plasma sodium concentration and osmolality (table II) were constant. The cardiac patients produced copious volumes of urine without mannitol or diuretics, in spite of high circulating concentrations of vasopressin. Plasma vasopressin concentrations are presented in a semilogarithmic plot in figures 1 and 2. In the coronary artery bypass patients, the median increased significantly from an initial value of 1.2 to 5.6 pmol litre"1 after intubation. It increased more markedly on sternotomy to reach a peak of 48 pmol litre"1 after retraction of the pericardium. Thereafter, the tendency for the vasopressin concentration to decrease was reversed after the initiation of cardiopulmonary bypass, when the maximum values were achieved in all patients, with a median value of 123 pmol litre"1—a 100-fold increase over the preinduction values. Concentrations remained increased (34 pmol RESULTS litre"1) in the postoperative period. Inspection of the vasopressin data from the The pattern of the changes in heart rate and arterial pressure during the coronary artery patients undergoing thymectomy indicates that operations (n = 14) (table I) were as would be the stimulus of sternotomy produced a vasopressin predicted from clinical experience. Mean heart response which was similar to that observed in the rate for the group increased by 20 beat min"1 on cardiac surgery group (24 and 30 pmol litre"1), intubation despite beta-adrenoceptor blockade, while comparison of the two plots suggests that decreased thereafter to an intermediate value, but the release of vasopressin in response to pericardial increased significantly again in the postoperative traction and to CPB was superimposed upon this. period. Arterial pressure increased during the splitting of the sternum, decreased significantly DISCUSSION during retraction of the pericardium and was increased in the postoperative period, when 11 of Stimuli which provoke the release of vasopressin the 14 patients (79%) required nitroprusside to include hypotension (aterial and venous), pain control hypertension. Both arterial and central and "surgical stress", decreases in plasma osmovenous pressures decreased abruptly on the lality, and other less well evaluated factors such as institution of cardiopulmonary bypass. morphine and hypoxia. In this study the most Patients undergoing thymectomy (who were marked changes in vasopressin concentration not in receipt of beta-adrenoceptor blocking were clearly related to haemodynamic factors. automatically at 1-min intervals (Dinamap). Plasma osmolality was determined before and after surgery. Plasma vasopressin concentration was assayed in samples (n = 7) drawn from a peripheral vein 3 min after intubation, skin incision, sternal splitting, sternal retraction, 15 and 30 min after stemotomy and, finally, in the recovery room (table I). All specimens for vasopressin assay were collected into precooled heparinized plastic tubes and the separated plasma was stored at 20 °C before the measurement of the vasopressin concentration by immunoassay. Since vasopressin is not metabolized in the lungs (Lansome, 1974) it was believed reasonable to compare venous and arterial samples. No correction was made for haemodUution on bypass because it is probably the concentration at the end organ that is important rather than the total amount of hormone released.
BRITISH JOURNAL OF ANAESTHESIA
1276
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Event FIG. 1. Plasma vasopressin concentrations during coronary artery surgery, plotted logarithmically. The numbers refer to the events listed in table I. Statistical significance of the changes: * P < 0 . 0 5 ; **P<0.01.
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Event FIG. 2. Plasma vasopressin, plotted logarithmically, during thymectomy. The numbers refer to the events listed in table I. Statistical significance of the changes: *P < 0.05.
Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on September 3, 2015
20
PLASMA VASOPRESSIN CONCENTRATION IN CORONARY SURGERY
vasopressin on the renal microcirculation. On the other hand, it has been shown that cooling does not influence the release of vasopressin from the pituitary (Thomson, Thompson and Forsling, 1980). Hypoxia, a known cause of vasopressin release (Forsling and Aziz, 1983) can be excluded as a possible aetiological factor in producing the increases in plasma vasopressin concentration because oxygenation was well maintained during bypass and in the postoperative period. Morphine has been reported both to stimulate (Lightman and Forsling, 1980) and to inhibit (Woods et al., 1983) the release of vasopressin. In view of the large doses (1 mg kg"1) give to the cardiac patients, it is not possible to exclude some influence, but it cannot be responsible for the short-term responses seen. Therefore, it seems likely that vasopressin was released, in both groups, in response to hypotensive and hypovolaemic haemodynamic changes. REFERENCES Fabian, M. L., Forsling, M. L., Jones, J. J., and Pryer, J. S. (1969). The clearance and antidiuretic potency of neurohypophyseal hormones in man and their plasma binding and stability. J. Physiol. (Lond.), 204, 653. Forsling, M. L. (1982). Antidiuretic Hormone, p. 44. Montreal: Eden Press. Aziz, L. A. (1983). The vasopressin response to hypoxia and the effect of aminergic and opioid antagonists. J. Endocrinol., 99, 77. Frater, R. W. M., Wakayama, S., Oka, Y., Becker, R. M., Desai, P., Oyama, T., and Blaufox, M. D. (1980). Pulsatile cardiopulmonary bypass: failure to influence haemodynamics or hormones. Circulation, 62 (Suppl. I), 19. Hawkins, S., Forsling, M., Treasure, T., and Aveling, W. (1986). Changes in pressor hormone concentrations in association with coronary artery surgery. Rerun and Vasopressin Responses. Br.J. Anaesth., 58, 1267. Lansome, H. D. (1974). Metabolism of neurohypophyseal hormones; in Handbook of Physiology (eds E. Knobil and W. F. Sawyer), Section 7, Vol IV, part 1, p. 287. Washington: American Physiological Society. Levine, F. H., Philbin, D. M., Kono, K., Coggins, C. H., Emerson, C. W., Austen, W. G., and Buckley, M. J. (1981). Plasma vasopressin levels and urinary sodium excretion during cardiopulmonary bypass with and without pulsatile flow. Arm. Thorac. Surg., 32, 63. Lightman, S. L., and Forsling, M. L. (1980). Evidence for endogenous opioid control of vasopressin release in man. J. Clm. Endocrinol. Metab., 50, 569. Thomson, E. M., Thompson, G. E., and Forsling, M. L. (1980). The effect of cold exposure on fluid balance, circulating vasopressin concentration and milk secretion in the goat. Pfluegers Arch., 383, 241. Woods, W. G. A., Forsling, M. L-, Sturridge, M. F., Bennett, P. J., and LeQuesne, L. P. (1983). Vasopressin release and arterial pressure during cardiac surgery. Br. J. Surg., 20, 302.
Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on September 3, 2015
The abrupt decreases in arterial and right atrial pressures on the institution of bypass (table I) were associated with the highest concentrations of vasopressin, values which were more than seven times those at the nearest equivalent stage during thymectomy. Since the effects of atrial emptying and arterial hypotension (Forsling, 1982) on vasopressin release are well established, we must conclude that such mechanisms explain our findings, although the very high concentrations of vasopressin attained are greater than those previously demonstrated to be caused by circulatory effects in man. However, this observation may indicate the severity of the circulatory changes which occur in the course of cardiopulmonary bypass. Apart from sensitivity to mean pressure, baroreceptors also respond to pulse pressure. There is some evidence (Levine et al., 1981) that the increase in vasopressin concentration is attentuated by the use of pulsatile bypass (our routine practice), although other work (Frater et al., 1980) suggests that this effect is not significant. The lesser, but still substantial, increase in vasopressin concentration on sternotomy, which was similar in the two groups, remains to be explained. One simple explanation would be that the pain of sawing the sternum is the trigger stimulus and, indeed, in patients undergoing thymectomy who did not receive beta-adrenoceptor blocking agents, the mean heart rate increased from 65 beatmin" 1 (SEM 3.5) to 72 beatmin" 1 (SEM 4.8), suggesting activation of the sympathetic nervous system. At the same time, intrathoracic venous pressure (table I) tended to decrease as the sternum was split, and we postulate that this may at least be a contributory factor. The plasma osmolality and sodium concentration do not change during or after bypass and, therefore, can have no influence on the release of vasopressin (table II). The vasopressin concentrations were considerably greater than those which normally produce maximal antidiuresis. It is interesting to speculate, therefore, why such large volumes of urine were produced after cardiac surgery in the absence of diuretic therapy. Although it may be attributable to the solute load, which was equivalent to 2500 ml of isotonic electrolyte solution, there must be some other factor which acts on the kidney to reduce the response to vasopressin. Possible contributing factors are the effects of intraoperative cooling on renal medullary gradients and the direct effect of
1277
CHANGES IN PLASMA VASOPRESSIN CONCENTRATION IN ASSOCIATION WITH CORONARY ARTERY SURGERY OR THYMECTOMY
The aetiology of postoperative hypertension following cardiopulmonary bypass (CPB), particularly when used during myocardial revascularization, remains obscure, although the reninangiotensin system, and vasopressin, have been implicated. A previous investigation (Hawkins et al., 1986) failed to demonstrate any consistent pattern of change in plasma renin activity. However, in all patients plasma vasopressin concentration increased significantly after sternotomy and remained so for up to 6 h into the postoperative period. This release of vasopressin was stimulated not only by CPB but also by the events which preceded bypass. Vasopressin is released rapidly after a trigger stimulus and has a circulating half-life of about 8 min (Fabian et al., 1969). As the purpose of this second study was to determine the stimuli to vasopressin release, the only non-cardiac operation routinely performed through a median sternotomy, thymectomy, was chosen for comparison. Sampling times were chosen to follow surgical events by 3 min. If the interval between samples was more than 15 min, a new baseline sample was taken. PATIENTS AND METHODS
Two groups of patients were studied: 14 undergoing elective coronary artery surgery, and eight having a median sternotomy for thymectomy. ANNE KNIGHT, M.D., F.F.A.R.CS., W. AVELTNG, M.A., M.B., B.CHIR., F.F.A.R.CS. (Department of Anaesthesia); MARY
FORSLING, B.SC., PH.D. (Department of Physiology); TOM TREASURE, M.D., M J . , F.R.CS., M. F. STURRIDGE, M J . , F.R.CS.
(Cardiothoracic Unit); The Middlesex Hospital and Medical School, Mortimer Street, London W I N 8AA. L. LOH, F.F.A.R.Cs. (and M. F. S.), The National Hospitals for Nervous Diseases, Queen Square, WC1. Correspondence to T . T .
SUMMARY Plasma vasopressin concentrations in 14 patients undergoing coronary artery surgery were compared with those in eight patients undergoing thymectomy. Vasopressin concentrations increased similarly in both groups on sternotomy. A second, and more marked increase was noted in the patients requiring cardiopulmonary bypass. Haemodynamic stimuli could be responsible in both groups and might explain both the similarities and the differences between the groups.
Coronary artery surgery
Twelve men and two women, aged between 40 and 73 yr (mean 54) were included in the study. All had normal renal and hepatic function; patients with poor left ventricular function (ejection fraction < 30%) were excluded. Preoperative medication included beta-adrenoceptor blockers (« = 9), diuretics (n = 5), isosorbide, persantin, nifedipine and nitrates. Premedication was with diazepam 10-20 mg by mouth, followed 1 h later by papaveretum •15-20 mg and hyoscine 0.3-0.4 mg i.m. A cannula was inserted to the radial artery under local anaesthesia and monitoring was instituted with a cardioscope and an automatic arterial pressure monitor (Dinamap). Anaesthesia was induced with papaveretum and thiopentone. The dose of opioid administered was standardized to total 1 mg kg"1 divided between the premedicant and the induction doses. After induction, the right internal jugular vein was cannulated and a catheter inserted to the bladder. The ECG, arterial pressure, central venous pressure and temperature were displayed throughout the procedure, and arterial blood-gas ten-
Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on September 3, 2015
A. KNIGHT, M. FORSLING, T. TREASURE, W. AVELING, L. LOH AND M. F. STURRIDGE
BRITISH JOURNAL OF ANAESTHESIA
1274 sions, plasma concentrations of sodium and potassium, and urine volume, were measured regularly. Pancuronium was administered to provide neuromuscular blockade. Anaesthesia was maintained with nitrous oxide in oxygen supplemented with halothane before bypass if the systolic arterial pressure increased above 150 mm Hg. The technique of bypass included a single right atrial cannula and arterial return to the ascending aorta; a bubble oygenator (Harvey or Bentley), primed with 1500 ml of lactated Ringer's solution; a roller pump (Stockert or Gambro) used in the pulsatile mode; arterial flow of 2.4 litre min"1 m~*; and whole body cooling to 28 °C. During bypass the patient received lorazepam 4 mg and additional doses of pancuronium. Subsequent doses of opioid were withheld during bypass until all sampling was completed. Mean arterial pressure on bypass was kept between 90 and 50 mm Hg with phentolamine or metaraminol. During aortic cross-clamping the myocardium was protected with St Thomas's Hospital cardioplegic solution and topical cooling with saline at 4°C. Twelve samples for the measurement of vasopressin concentration were taken from the arterial
line, usually 3 min after each possible stimulus under investigation during the preparatory part of the operation and, then, before going onto bypass; after 3, 15 and 30 min of bypass; and, finally, 2 h after bypass (table I). Plasma and urine were collected for osmolality measurements after induction, during bypass and 2 h after bypass.
Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on September 3, 2015
Thymectomy Patients (« = 8) were all female, aged 18-52 yr (mean 32 yr), suffering from myasthenia gravis, and all were receiving treatment with anticholinesterases. They were premedicated with papaveretum and hyoscine. In the anaesthetic room 4% cocaine solution was applied to the nasal mucosa, anaesthesia was induced with thiopentone, suxamethonium was administered and the trachea intubated with a Portex nasal tube to permit longterm management. Anaesthesia was maintained with nitrous oxide, oxygen and halothane; spontaneous ventilation resumed at the end of the procedure. The sternotomy incision was identical to that used for cardiac surgery, but the pericardium was not opened. The ECG and end-tidal Pco a concentration were monitored throughout the procedure, and arterial pressure was measured
TABLE I. Mean changes (SEM) in heart rate (HR), mean arterial pressure (AP) and central venous pressure (CVP) during coronary artery surgery and thymectomy Thymectomy
Coronary artery graft
Code 1 2 3 4 5 6 7 8 9 10 11 12
Event Pre-induction Intubation + 3min Leg incis. + 3 min Chest inHfi + 3min Saw + 3 min Retraction + 3min Peric. tract + 3 min Heparin (CPB-3) Bypass + 3min Bypass + 15 min Bypass + 30 min 2 h post CPB
HR (beat min"1)
AP (mmHg)
61 (3.7) 81(5.1)
93 (4.2) 92 (7.8)
74(3.9)
83 (4.3)
6 (1.1)
73(4.8)
90 (4.3)
6 (13)
74(3.8) 75 (3.7)
100 (4.2) 93 (6.4)
4 (2.7) 5 (13)
72 (3.4) 83 (3.5)
69 (6.2) 87 (3.5)
9 (1.8) 5 (1.4)
—
49 (3.6)
3 (1.1)
—
50 (3.9)
1 (1.2)
—
62 (4.1)
3 (1.0)
100 (3.1)
5 (0.8)
94 (4.3)
CVP (mmHg) —
HR (beat min"1)
AP (mmHg)
Pre-induction Intubation + 3min
79 (9.2) 96 (7.6)
88 (5.0) 98 (6.0)
Chest incis. + 3 min Saw + 3 min Retraction
65 (3.5)
77(3.7)
72 (4.8) 66 (4.3)
86(7.1) 77 (5.7)
Sternotomy + 15 min
65(3.1)
76 (6.8)
Sternotomy + 30 min
68 (4.0)
73 (4.3)
Postop.
68 (2.3)
89 (3.8)
Event
+ 3min
PLASMA VASOPRESSIN CONCENTRATION IN CORONARY SURGERY
1275
TABLE II. Mean plasma and urine composition (SEM) before and after coronary artery surgery and thymectomy Before op. Coronary artery graft Plasma osmolality (mosm litre"1) Plasma sodium (mmol litre"1) Urine flow (ml h"1) Urine osmolality (mosm litre"1) Thymectomy Plasma osmolality (mosm litre"1)
282 136 77 527
(1.5) (0.9) (14.8) (60)
280 (4.0)
During CPB 285(1.1) 137 (0.9) 139 (30.4) 492 (58)
After op. 284(1.9) 135(1.5) 176 (47.8) 390 (22) 280(8.1)
Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on September 3, 2015
drugs) had more stable heart rates and arterial pressures with similar but less marked changes on intubation and sternotomy. Plasma sodium concentration and osmolality (table II) were constant. The cardiac patients produced copious volumes of urine without mannitol or diuretics, in spite of high circulating concentrations of vasopressin. Plasma vasopressin concentrations are presented in a semilogarithmic plot in figures 1 and 2. In the coronary artery bypass patients, the median increased significantly from an initial value of 1.2 to 5.6 pmol litre"1 after intubation. It increased more markedly on sternotomy to reach a peak of 48 pmol litre"1 after retraction of the pericardium. Thereafter, the tendency for the vasopressin concentration to decrease was reversed after the initiation of cardiopulmonary bypass, when the maximum values were achieved in all patients, with a median value of 123 pmol litre"1—a 100-fold increase over the preinduction values. Concentrations remained increased (34 pmol RESULTS litre"1) in the postoperative period. Inspection of the vasopressin data from the The pattern of the changes in heart rate and arterial pressure during the coronary artery patients undergoing thymectomy indicates that operations (n = 14) (table I) were as would be the stimulus of sternotomy produced a vasopressin predicted from clinical experience. Mean heart response which was similar to that observed in the rate for the group increased by 20 beat min"1 on cardiac surgery group (24 and 30 pmol litre"1), intubation despite beta-adrenoceptor blockade, while comparison of the two plots suggests that decreased thereafter to an intermediate value, but the release of vasopressin in response to pericardial increased significantly again in the postoperative traction and to CPB was superimposed upon this. period. Arterial pressure increased during the splitting of the sternum, decreased significantly DISCUSSION during retraction of the pericardium and was increased in the postoperative period, when 11 of Stimuli which provoke the release of vasopressin the 14 patients (79%) required nitroprusside to include hypotension (aterial and venous), pain control hypertension. Both arterial and central and "surgical stress", decreases in plasma osmovenous pressures decreased abruptly on the lality, and other less well evaluated factors such as institution of cardiopulmonary bypass. morphine and hypoxia. In this study the most Patients undergoing thymectomy (who were marked changes in vasopressin concentration not in receipt of beta-adrenoceptor blocking were clearly related to haemodynamic factors. automatically at 1-min intervals (Dinamap). Plasma osmolality was determined before and after surgery. Plasma vasopressin concentration was assayed in samples (n = 7) drawn from a peripheral vein 3 min after intubation, skin incision, sternal splitting, sternal retraction, 15 and 30 min after stemotomy and, finally, in the recovery room (table I). All specimens for vasopressin assay were collected into precooled heparinized plastic tubes and the separated plasma was stored at 20 °C before the measurement of the vasopressin concentration by immunoassay. Since vasopressin is not metabolized in the lungs (Lansome, 1974) it was believed reasonable to compare venous and arterial samples. No correction was made for haemodUution on bypass because it is probably the concentration at the end organ that is important rather than the total amount of hormone released.
BRITISH JOURNAL OF ANAESTHESIA
1276
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Event FIG. 1. Plasma vasopressin concentrations during coronary artery surgery, plotted logarithmically. The numbers refer to the events listed in table I. Statistical significance of the changes: * P < 0 . 0 5 ; **P<0.01.
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Event FIG. 2. Plasma vasopressin, plotted logarithmically, during thymectomy. The numbers refer to the events listed in table I. Statistical significance of the changes: *P < 0.05.
Downloaded from http://bja.oxfordjournals.org/ at University of California, Santa Barbara on September 3, 2015
20
PLASMA VASOPRESSIN CONCENTRATION IN CORONARY SURGERY
vasopressin on the renal microcirculation. On the other hand, it has been shown that cooling does not influence the release of vasopressin from the pituitary (Thomson, Thompson and Forsling, 1980). Hypoxia, a known cause of vasopressin release (Forsling and Aziz, 1983) can be excluded as a possible aetiological factor in producing the increases in plasma vasopressin concentration because oxygenation was well maintained during bypass and in the postoperative period. Morphine has been reported both to stimulate (Lightman and Forsling, 1980) and to inhibit (Woods et al., 1983) the release of vasopressin. In view of the large doses (1 mg kg"1) give to the cardiac patients, it is not possible to exclude some influence, but it cannot be responsible for the short-term responses seen. Therefore, it seems likely that vasopressin was released, in both groups, in response to hypotensive and hypovolaemic haemodynamic changes. REFERENCES Fabian, M. L., Forsling, M. L., Jones, J. J., and Pryer, J. S. (1969). The clearance and antidiuretic potency of neurohypophyseal hormones in man and their plasma binding and stability. J. Physiol. (Lond.), 204, 653. Forsling, M. L. (1982). Antidiuretic Hormone, p. 44. Montreal: Eden Press. Aziz, L. A. (1983). The vasopressin response to hypoxia and the effect of aminergic and opioid antagonists. J. Endocrinol., 99, 77. Frater, R. W. M., Wakayama, S., Oka, Y., Becker, R. M., Desai, P., Oyama, T., and Blaufox, M. D. (1980). Pulsatile cardiopulmonary bypass: failure to influence haemodynamics or hormones. Circulation, 62 (Suppl. I), 19. Hawkins, S., Forsling, M., Treasure, T., and Aveling, W. (1986). Changes in pressor hormone concentrations in association with coronary artery surgery. Rerun and Vasopressin Responses. Br.J. Anaesth., 58, 1267. Lansome, H. D. (1974). Metabolism of neurohypophyseal hormones; in Handbook of Physiology (eds E. Knobil and W. F. Sawyer), Section 7, Vol IV, part 1, p. 287. Washington: American Physiological Society. Levine, F. H., Philbin, D. M., Kono, K., Coggins, C. H., Emerson, C. W., Austen, W. G., and Buckley, M. J. (1981). Plasma vasopressin levels and urinary sodium excretion during cardiopulmonary bypass with and without pulsatile flow. Arm. Thorac. Surg., 32, 63. Lightman, S. L., and Forsling, M. L. (1980). Evidence for endogenous opioid control of vasopressin release in man. J. Clm. Endocrinol. Metab., 50, 569. Thomson, E. M., Thompson, G. E., and Forsling, M. L. (1980). The effect of cold exposure on fluid balance, circulating vasopressin concentration and milk secretion in the goat. Pfluegers Arch., 383, 241. Woods, W. G. A., Forsling, M. L-, Sturridge, M. F., Bennett, P. J., and LeQuesne, L. P. (1983). Vasopressin release and arterial pressure during cardiac surgery. Br. J. Surg., 20, 302.
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The abrupt decreases in arterial and right atrial pressures on the institution of bypass (table I) were associated with the highest concentrations of vasopressin, values which were more than seven times those at the nearest equivalent stage during thymectomy. Since the effects of atrial emptying and arterial hypotension (Forsling, 1982) on vasopressin release are well established, we must conclude that such mechanisms explain our findings, although the very high concentrations of vasopressin attained are greater than those previously demonstrated to be caused by circulatory effects in man. However, this observation may indicate the severity of the circulatory changes which occur in the course of cardiopulmonary bypass. Apart from sensitivity to mean pressure, baroreceptors also respond to pulse pressure. There is some evidence (Levine et al., 1981) that the increase in vasopressin concentration is attentuated by the use of pulsatile bypass (our routine practice), although other work (Frater et al., 1980) suggests that this effect is not significant. The lesser, but still substantial, increase in vasopressin concentration on sternotomy, which was similar in the two groups, remains to be explained. One simple explanation would be that the pain of sawing the sternum is the trigger stimulus and, indeed, in patients undergoing thymectomy who did not receive beta-adrenoceptor blocking agents, the mean heart rate increased from 65 beatmin" 1 (SEM 3.5) to 72 beatmin" 1 (SEM 4.8), suggesting activation of the sympathetic nervous system. At the same time, intrathoracic venous pressure (table I) tended to decrease as the sternum was split, and we postulate that this may at least be a contributory factor. The plasma osmolality and sodium concentration do not change during or after bypass and, therefore, can have no influence on the release of vasopressin (table II). The vasopressin concentrations were considerably greater than those which normally produce maximal antidiuresis. It is interesting to speculate, therefore, why such large volumes of urine were produced after cardiac surgery in the absence of diuretic therapy. Although it may be attributable to the solute load, which was equivalent to 2500 ml of isotonic electrolyte solution, there must be some other factor which acts on the kidney to reduce the response to vasopressin. Possible contributing factors are the effects of intraoperative cooling on renal medullary gradients and the direct effect of
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