AND ANTIDIURETIC HORMONE RESPONSES TO STRESS IN CARDIAC SURGICAL PATIENTS

YASU OKA, SHIGEHARU WAKAYAMA, TSUTOMU OYAMA, Lou[s R. ORKIN, RONALD M. BECKER, M. DONALD BLAUFOX AND ROBERT W.M. FRATER

ABSTRACT The hormonal responses to anaesthesia and cardiac surgery were studied in patients undergoing valve or coronary bypass surgery. Marked increases in antidiuretic hormone levels as a result of surgical stress were seen, and were of approximately equal magnitude in both groups. Although both groups also showed marked increases in plasma cortisol levels in response to operations, this response appeared to be relatively bhmted in valve surgery patients, especially at the end of operation and in the intensive care unit. This blunted cortisol response may be a manifestation of exhaustion of adrenocortical reserves in valvular surgical patients whose sympathoadrenal system has already been chronically stimulatcd by a low output state. The important role of the neuroendocrine system in maintaining homeostasis postopera- tively has long been recognized; this relative cortisol deficiency may be aetiologically related to poor postoperative recovery in critically ill valvular surgery patients.

KEY WORDS: CARDIAC SURGERY, stress response.

A NUMBER OF INVESTIGATORSI-6 have indicated The present study was undertaken to evaluate that the function of the cardiovascular autonomic whether cortisol and antidiuretic hormone re- nervous system is altered in patients with val- sponses to stress are different in patients with vular heart disease. The loss of sympathetic coronary artery disease and valvular disease, as nervous system control associated with depletion we have previously found in regard to sympathe- of cardiac , when coupled with tic response. the impairment in parasympathetic cardiovas- cular regulation, limits the ability to augment MATERIALS AND METHODS cardiac output by increasing either stroke volume Twenty-two patients undergoing open heart or heart rate. These derangements of the auto- surgery were studied; 12 patients had coronary nomic nervous system may well play critical artery surgery (CAS) and ten had valvular sttr- roles in the limited cardiac response to stress in gery (VS). The patients were otherwise compa- these patients. rable except for a significantly lower ejection We have also reported studies 7-~~ of neuro- fraction in the VS group. (Table I). humoral and circulatory responses to stress in Premedication consisted of scopolamine cardiac surgical patients. Our studies generally (0.015 rag- kg -I) and morphine sulphate indicated that patients with coronary artery dis- (0.15 rag. kg-I for coronary patients or ease showed an excitatory sympathetic response 0.10 rag. kg -~ for valvular patients) intramuscu- to stress, while patients with valvular disease had larly, one hour before anaesthesia. Anaesthesia marginal or limited sympathetic response to was begun at 8-8:30 a.m. Induction was accom- stress. plished 3 mg d-tubocurarine and thiopentone so- Yasu Oka, M.D., Shigeharu Wakayama, M.D., dium 4-5 mg-kg -~ , followed by enflurane 0.5 to 2 Tsutomu Oyama, M.D., Louis R. Orkin, M.D., Ronald per cent and oxygen. The trachea was intubated M. Becker, M.D., M. Donald Blaufox, M.D., and Robert W.M. Frater, M.B., Ch.B. Department of with the aid of succinylcholine 1.5 mg. kg -L in- Anesthesiology, Cardiothoracic Surgery and Nuclear travenously and following topical application of Medicine. Albert Einstein College of Medicine, Bronx, lidocaine (4%-4ml). Anaesthesia was main- New York and Department of Anesthesiology, Uni- tained with enflurane 0.5 to 2 per cent with versity of Hirosaki, Hirosaki, Japan. oxygen, supplemented with either pancuronium Reprint requests to Dr. Oka at Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, or d-tubocurarine. Five per cent dextrose in New York, 10461. water was ad ministered at a rate of 10 ml. kg- n/hr 334 Canad. Anaesth. Soc. J., vol. 28, no. 4, July 1981 OKA, el al.: CORTISOL & ANTIDIURETIC RESPONSES TO STRESS 335

TABLE I osmolalities were measured by the freezing point PREOPERATIVE PATIENTCHARACTERISTICS depression method using an Osmette precision osmometer. Coronary Artery Valvular Surgery Surgery Arterial pressure (AP), right and left atrial pressures (RAP, LAP), heart rate (HR) and Patients No. 12 10 cardiac output (CO) were recorded. Pressures NYHA Class (11) 7 6 were measured and recorded continuously (Ill) 5 4 Age (Year) 59 + 10 59 4- 9 through a Statham transducer on a Hewlett- Ejection Fraction (%) 71 "r 18 58 + 11' Packard multichannel recorder (Model 775A). LVEDP (Torr) 16 q- 9 17 4- 7 Cardiac output was determined by dye dilution CPB lime (rain.) 154 + 85 144 _+ 63 technique using an Electronics for Medicine Mean + SD *P < 0.05. output computer (Model DTCCO). Systemic LVEDP: Left Ventricular end-diastolic pressure. vascular resistance (SVR) was calculated from CPB = Cardiopulmonary bypass. the output and pressure data. Intergroup data were analyzed using the uncorrelated t-test and until the start of cardiopulmonary bypass, and intragroup data were analyzed using the corre- thereafter reduced to 5ml-kg-t/hr. A conven- lated t-test. tional cardiopulmonary bypass (CPB) technique RESULTS using an Optiflo II (Cobe Laboratories) bubble oxygenator was employed and the patients were Coronary Artery Surgery Group cooled to 30~ C (oesophageal temperature) during Enflurane anaesthesia alone did not increase CPB. The prime solution consisted of albumin plama cortisol levels significantly. However, 500 ml and Normosol | 2000 ml. surgical stimulation provoked a significant rise of The study was divided into eight periods: l. cortisol from the control value of 11.0 4- 0.9 to Control (before induction of anaesthesia); 2. One 18.1 + 1.6p.g/100ml and this increase was sus- hour after induction of anaesthesia (before skin tained during CPB. After CPB there was a steady incision); 3. Thirty minutes after skin incision increase in plasma cortisol levels to a peak value (pre-CPB); 4. Fifteen minutes on CPB; 5. One (210 per cent of control, P < 0.01) in the ICU hour on CPB; 6. Thirty minutes offCPB; 7. End (Figure I). of operation and; 8. One hour postoperative in The control value of plasma ADH was 5.4 4- the intensive care unit. 0.7 ~tU/ml. Enflurane did not cause ADH release. The following were determined: Plasma cor- Plasma ADH rose significantly after surgical tisol and antidiuretic hormone (ADH) levels, stimulation (290 per cent of control, P< 0.01) and arterial and venous blood gases, serum osmolal- during CPB (> 300 per cent of control, P < 0.01). ity and electrolytes, urine output and osmolality. After CPB, the level declined but it stayed Plasma cortisol levels were determined by the significantly elevated compared with the control fluorimetric method of Rudd, et al.;~ the recov- value. In the ICU, it was 177 per cent of the ery rate was 102 per cent and the coefficient of control value. There were no significant changes variation (CV) was 1.5 per cent. Plasma ADH in plasma osmolality throughout the study. levels were measured by the radioimmunoassay Plasma sodium levels decreased significantly at method of Husain, et al.: ~z recovery rate was 74 the end of operation and plasma potassium de- per cent and CV was 11 per cent. Heparinized creased significantly during the first 15 minutes venous blood for ADH was immediately iced and on CPB. Urine output increased significantly centrifuged for 15 minutes at 4~ Extraction of during and after CPB in spite of high plasma A DH plasma samples was done using cold acetone and levels. Urine osmolality decreased, but not signi- petroleum ether. Dried plasma extracts were ficantly. stored at -20~ until assayed. Arginine Vaso- Haemodynamic changes are shown in Figure pressin (AVP) from Sigma Chemical Co. used as 2. There were no statistically significant changes a standard for ADH (I-125-AVP) was purchased in any variable except for a significant (P < 0.01, from New England Nuclear. The micropressor P < 0.05) decrease in MAP and SVR at pre-CPB unit (U) is the equivalent of about 2.5 pg of AVP. and during CPB. Cardiac index decreased signi- The packed cell volume (PCV) was measured by ficantly (P < 0.05) at the end of operation. the macrohaematocrit method and used to make There was no correlation between plasma cor- corrections for the haemodilution effect of tisol or ADH levels and changes in haemody- plasma cortisol and ADH levels. Serum and urine namic variables except after 15 minutes on CPB, 336 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL

PLASMA CORTISOL AND ADH LEVELS HEMODYNAMIC CHANGES Oc Dc

" .... * ,v

CO~TF~OL A~[S Pff CPB CPB P~SI [HO IrLI 3000 Ifil~ GPB 15MIH THR CPB SLIE5 IHR ~ 2000 . .. . S,pn,fIconl from r ".0-~ ".Ot S;onificonl Ifom c~onorv t "05 II ,.01

COH[ROL ANES PRE ;PB (;PB POST END FIGURE I Plasma Cortisol and ADH levels. Top, I HB CP8 l~ WIN I IfR (;P8 SURG plasma Cortisol levels in coronary artery and valvular surgical patients. Enflurane anaesthesia alone did not Significant from r e ".05 el r increase plasma levels significantly. Surgical stimula- Significanl from r 1" .05 t t ".OI tion (Pre CPB) provoked a significant rise of cortisol from the control valve and this increase was sustained FJrU~tE 2 Haemodynamic Changes. Changes in during and after CPB to a peak value in the ICU in both mean artieral pressure (MAP) cardiac index (CI) and groups. However, in general, the response in valvular systemic vascular resistance (SVR) in coronary artery surgical patients was blunted compared to that of and valvular surgical patients are shown. There were coronary artery surgical patients and a significant no statistically significant changes in any of those difference in plasma levels was noted at the end of variables except for significant decrease in MAP and operation and ICU periods. Bottom, plasma ADH SVR at pre and during CPB in both groups. At the end levels. The changes in ADH levels were identical in of operation, CI decreased significantly in coronary both groups and it rose significantly after surgical artery surgical patients associated with a significant stimulation and during CPB. After CPB, the level increase in SVR. declined but it stayed significantly elevated compared with the control value in both groups. DISCUSSION when MAP and SVR decreased significantly (P < 0.05) associated with increased ADH levels. During open heart surgery, patients are ex- posed to mechanical circulation, haemodilution Valvular Surgery Group and major surgical stress. The output of cortisol The control plasma cortisol level was 10.3 _ and ADH may be influenced by one or more of 1.0 lag/100 ml and it increased significantly to 14.8 these factors. Plasma cortisol is an indicator of 4- 1. I fag/100 ml after surgical stimulation. During the magnitude of adrenocortical response to CPB, the plasma cortisol levels did not increase stress. A typical pattern of cortisol response to further. The peak levels of cortisol were seen at surgical stress is a brisk rise from resting levels to the post CPB sampling time and had declined by a peak, with a subsequent return to normal values the end of operation and in the ICU. Haemody- within a few days. I3 However, the response of namic changes was similar to CAS group except plasma cortisol during CPB is not well defined that cardiac index decreased significantly at one although many studies have been done. Recent- hour of anaesthesia. ly, Taylor, et al. 14 reported that during CPB the cortisol response differs markedly from the typ- Coronary Artery Surgery Group vs Valvular ical response to surgical stress, with a marked fall Surgery Group in plasma cortisol levels at the onset of CPB. The plasma cortisol levels at the end of opera- Uozome, et al. is stated that these low levels of tion and in the ICU in the VS group were cortisol were probably caused by haemodilution. significantly lower (P < 0.05) than the levels at Taylor, et al. 16'17 suggested the existence of the same periods in coronary artery surgical adrenocortical hypofunction during non-pulsatile patients. The plasma ADH levels and all bio- CPB, due to reduced ACTH release. On the other chemical variables were identical to those in hand, Yokota, et al. ts reported that cortisol coronary patients. Haemodynamic variables did secretion could overcome the dilution effect after not differ significantly between the groups except 30 minutes on CPB and that the adrenal cortex that the MAP in valvular patients was signifi- preserved its responsiveness during CPB of less cantly lower (P < 0.05) compared to coronary than three hours; i.e. the cortisol response to a patients at the anaesthesia one hour, pre-CPB mechanical circulation during CPB was similar to and ICU periods. that occurring during surgical stress with a nor- OKA, el al.: CORTISOL & ANTIDIURETIC RESPONSES TO STRESS 337 real circulation. These investigators evaluated is commonly associated with low systemic vas- plasma cortisol levels in a heterogeneous groups cular resistance. The loss of pulsatile flow and of patients with congenital, valvular and coronary rapid decline in mean arterial pressure may be diseases. We evaluated the cortisol response to significant factors in ADH release, perhaps as an anaesthesia, surgery and CPB in two separate effort to maintain SVR. The circulatory stress of groups, one with coronary artery disease and the CPB seems to override the normal osmotic other with valvular disease. In the coronary regulation of ADH levels between 0.05 and patients we confirmed the slight fall in plasma 6.01.tU. 27,2s The ADH levels observed are con- cortisol levels during CPB as seen by Taylor, et sidered beyond the physiological range for an al. ~4 However, after CPB, the rise in cortisol antidiuretic effect on the kidney; thus paradoxic- levels typical of the usual response to surgery ally increased urine output may be related to the reappears,t9 The valvular surgical patients show changes in circulation.29 the same pattern but absolute levels were lower If ADH levels beyond the physiological range throughout operation. During the post CPB and are reflecting the stress reaction 24, there may be ICU periods, plasma cortisol levels were signifi- no difference in degree of stress caused by these cantly lower than in coronary artery surgical two operative procedures because ADH responses patients (Figure 1). The difference was not re- to surgical stimulation in both groups were lated to difference in serum electrolytes or car- identical. These observations of cortisol and diac output, which decreased significantly to the ADH responses suggest that the decline of the same extent in both groups. At this period, the plasma cortisol levels at the end of operation in only difference was mean arterial pressure in the valvular surgical patients may represent a rela- ICU, being significantly lower in valvular sur- tive exhaustion of adrenal cortical response, as gical patients than in coronary artery surgical the majority .of valvular surgical patients had patients (79.7 4- 9.0 vs 88.4 4- 9.2, P < 0.05) been under the stress of low output state and their Boucher 2~ demonstrated that during CPB adrenal sympatho-adrenal system had chronically been blood flow is increased and it is conceivable that stimulated. Together with the previously demon- the changes of blood flow and distribution in this strated derangement of the autonomic nervous gland might compromise its secretory reserve.~8 system in valvular cardiac patients, the compara- The control values for AD.H in these groups of tive cortisol deficiency may be related to relative- patients were slightly higher than the usual ly poor postoperative recovery seen in critically accepted values for healthy persons. 2~ This could ill valvular surgical patients, compared to that of be due to relative hypovolaemia in our patients patients undergoing coronary artery bypass sur- because of limitation of fluid intake and, in some gery. cases, chronic administration of diuretics. There ACKNOWLEDGEMENT was little change in plasma ADH following en- flurane anaesthesia in this study and this confirms We are deeply indebted to Hyo B. Lee for the the report of Oyama, et al.,19 that enflurane does technical assistance. not affect ADH release. This contrasts with the effects of other agents, such as dietbyl ether 2t REFERENCES and halothane2z which increase plasma ADH 1. BRAUNWALD,E., Editor. The Myocardium: Fail- levels during anaesthesia alone in man. The ADH ure and Infarction. New York: H.P. Publishing Co response to surgical stimulation demonstrated in page 59 (1974). these patients was also in agreement with reports 2. CHIDSAY, C.A., BRAUNWALD, E. & MORaOW, in the literature, z3 although the actual levels are A.G. Catecho[amine excretion and cardiac stores of norepinephrine in congestive heart failure. Am. lower in our patients. The extent of the ADH J. Med. 39:422 (1965). response may be related to the depth of anaes- 3. COVELL,J.W., CHIDSAY, C.A. ~r BRAUNWALD, E. thesia v* and the anaesthetics used. Simpson, et Reduction of the cardiac response to postgang- al. 25 reported that plasma ADH levels seen during lionic sympathetic nervice stimulation in experi- CPB under halothane anaesthesia were higher mental heart failure. Circulatory Research 19:51 (1966). than in those measured under narcotic anaesthe- 4. ECKBERG, D.L., DRABINSKY, M. & BRAUNWALD, sia. The volume of fluid administered is reported E. Defective cardiac parasympathetic control in to modify ADH release in general surgery;z6 patients with heart disease. New Eng. J. Med. 285: however, haemodilution does not appear to in- 877 (1971). 5. HIGGINS, C.B., VATNER, S.F., ECHBERG, D.L. & fluence ADH release significantly during CPB. 23 BRAUNWALD, E. Alterations in the baroreceptor The increase in ADH release seen at the onset reflex in conscious dogs with heart failure. J. Clin. of CPB is probably due to the hypotension which Invest. 51:715 (1972). 338 CANADIAN ANAESTHETISTS' SOCIETY JOURNAL

6. POOL, R.E., COVELL, J.W., LEVITT, M. GIBB, J. function during cardiopulmonary bypass. Brit. J. & BRAUNWALD. E. Reduction of cardiac tyrosine Sung. 63:161 (1976). bydroxylose activity in experimental congestive 18. YOKOTA, H., KAWASHIMA, Y., HASHIMOTO, S., heart failure. Its role in the depletion of cardiac MANABE, H., ONISHI, T., AONO, T. & MATSU- norepinephrine stores. Cir. Res. 20:349 (1967). MOTO, K. Plasma cortisol, luteinizing hormone 7. OKA, Y., LIN, Y.T., YEll, L,C., BECHER, R., (LH) and prolactin secretory responses to cardio- FRATER, R.W.M. & SPECTOR, S. Failure of mor- pulmonary bypass. Jour. Sung. Res. 23:196 (1977). phine to reduce mycardial O: demand 19. OYAMA, T,, TANIGUCHI, K., ISHIHARA, H., MAT- during coronary artery bypass surgery. Abstract, SUKE, A., MAEDA, A., MURAKAWA, T. & KUDO, Am. Soc. Aries. 511 (1977). T. Effects of enflurane anesthesia and surgery on 8. BASSELL, G., LIN, Y.T., OKA, Y. & FRATER, R. endocrine function in man. Brit. J. Anaesth. 51: Circulatory response to tracheal intubation in pa- 141 (1979). tients with coronary artery disease and valvular 20. BOUCHER, J.K., LLOYD, W.R. & EDMUNDS, H. diease. Bull. N. Y. Acad. Med. 51:842 (1978). Organ blood flow during pulsatile cardiopulmonary 9. OKA, Y., FRISllMAN, W., BECKER, R.M., KADlSH, bypass. J. Appl. Physiol. 36:86 (1974). A., STROM, J., MATSOMOTO, M., ORKIN, L.R. & 21. OVAMA, T. & KIMURA, K. Plasma levels of anti- FRATER, R.W.M. B-adrenoreceptor blockade and diuretic hormone in man during diethyl ether coronary surgery. Amer. Heart Jour. 99; 225 anaesthesia and surgery. Canad. Anaesth. Soc. J. (1980). 17:495 (1970). 10. FRATER, R.W.M., WAKAYAMA, S., OKA, Y., 22. OYAMA,T., SATO, K. & KIMURA, K. Plasmalevels BECKER, R.M., DESAI, P., OYAMA, T. & of antidiuretic hormone in man during halothane BLAUFOX. D. Pulsatile cardiopulmonary bypass? anaesthesia and surgery. Canad. Anaesth. Soc. J. Failure to influence hemodynamics and hormones. 18:614 (1971). Circulation 62(I) : 19 (1980). 23. PHILBIN, D.M. & COGGINS, C.H. Plasma vaso- II. RUDD, B.T., SIMPSON, P. & BROOKE, B.M. A new pressin levels during cardiopulmonary bypass with flurimetric method of plasma cortisol assay with a and without profound haemodilution. Canad. An- study of pituitary-adrenal function using Metya- aesth. Soc. J. 25:282 (1978). pone (SU 4885). Jour. of Endoc. 27:317 (1963). 24. PHILBIN, D.M. & COGGINS, C.H. Plasma antidiur- 12. HUSAIN, M.K., FERNANOO, N., SHAPtRO, M., etic hormone levels in cardiac surgical patients KAGAN, A. & GLICK, S.M. Radioimmunoassay of during morphine and halothane anesthesia. Anes- arginine in human plasma. Jour. Clin. thesiology 49:95 (1978). Endoc. Metab. 37:616 (1975). 25. ~IMPSON, P. & FORSLING, M, The effects of 13. COPE, C.L. Adrenal steroids and disease. Philadel- halothane on plasma vasopressln during cardlo- phia: J.B. Lippincott, page 197 (1972). pulmonary bypass. Clin. Endoc. 7:33 0977). 14. TAYLOR, R.M., JONES, J .V., WALKER, M.S., RAo, 26. ISHIMARA,H., ISHITA, K., OYAMA, T. • KUDO, T. S. & BAIN, W.H. The cortisol response during Effects of general anaesthesia on renal function heart-lung bypass. Circulation 54:20 (1976). and plasma ADH levels. Canad. Anaesth. Soc. J. 15. UOZONE, T., MANAGE, H., KAWASHIMA, Y., 25:312 (1978). YAMANUKA, Y., MONDEN, Y. & MATSUMOTO, K. 27. ROBERTSON, G.L. Vasopressin in osmotic regula- Plasma costisol, corticosterone and non-protein- tion in man. Annual Review of Medicinc 25:315 bound cortisol in extracorporeal circulation. Acta (1974). Endoc. 69:517 (1972). 28. MORAN, W.R., JR. & ZIMMERMANN, B. Mechan- 16. TAYOR, K.M., WRIGHT, G.S., REID, J.M., BAIN. ism of antidiuretic hormone (ADH) control of W.H., CAVES, P.K., WALTER, M.S. & GRAND, importance to the surgical patient. Surgery 62:639 J.K. Comparative studies of pulsatile and non- (1967). pulsatile flow during cardiopulmonary bypass. II. 29. PHILBIN, D.M., COGGINS, C.H., WILSON, N. & The effects of adrenal secretion of cortisol. J. SOKOLOSKI, J. Antidiuretic hormone levels during Thorac. Cardiovasc. Surg. 75:574 (1978). cardiopulmonary bypass. J. Thorac. Cardiovasc. 17. TAYLOR, K.M., BREMNER, W.F., GRAY, C.E., Surg. 73:145 (1977). RATCLIFFE, J.G. & BAIN, W.H. Anterior pituitary

R~SUM~ Les r~ponses hormonales ~ l'anesth~sie et fi la chirurgie ont fait l'objet de la pr6sente 6tude effeetu6e chez un groupe de malades soumis b. une chirirgie valvulaire ainsi que chez ceux d'un second groupe subissant une chirurgie coronarienne. On a observ6 une 616vation marqu6e de l'hormone anti-diur&ique secondaire au stress de la chirurgie et cette 616vation 6tait semblable chez les patients des deux groupes. Le taux du cortisol s'est 6galement 61ev~ chez les patients des deux groupes en r6ponse au stress chirurgical, mais cette r~ponse &ait att6nu6e chez les valvulaires, en particulier en fin d'intervention et darts la phase post- op6ratoire imm6diate. Une telle r6ponse chez les valvulaires pelt refl6ter l'~.puisement des r6serves adreno-corticales chez des patients dont le syst~me adreno-sympathique a 6t6 stimul ,a de faqon chronique par la pr6sence d'un bas d6bit cardiaque. Le r61e important du systeme neuro-endocrinien darts le maintien du l'homo6ostase post-op6ratoire est connu depuis longtemps; la d6ficience relative en cortisol pelt contribuer b. une 6volution post-op6ratoire difficile chez des patients en condition critique.