Reduction in Cortisol Inactivation is Part of the Adrenal Stress Response to Cardiac and Noncardiac Pediatric Surgery: A Prospective Study Using Gas Chromatography-Mass Spectrometry Analysis

Abstract

We examined the hypothesis that major cardiac surgery triggers a more intense adrenal stress response than less intensive noncardiac surgery, which then alters cortisol inactivation. Urinary excretion rates of glucocorticoid metabolites were determined before and after surgery using gas chromatography-mass spectrometry in 29 children undergoing scheduled major cardiac surgery and 17 control children undergoing conventional noncardiac surgery in a prospective observational study. Excretion rates of glucocorticoid metabolites were summed and corrected for creatinine excretion to calculate cortisol production rates (mg/mmol creatinine/m² body surface area). Precursor/product ratios from individual metabolites were calculated to characterize cortisol inactivation (11β-hydroxysteroid dehydrogenase). Postoperatively, median cortisol production rates increased in both groups (MCS: from 2.7 to 9.3; controls: from 2.7 to 5.8; p<0.001) with no significant difference between groups (p=0.12). Ratios of cortisol to cortisone metabolites, indicating the overall activity of 11β-hydroxysteroid dehydrogenase, increased postoperatively in both groups (p<0.001). In conclusion, surgery resulted in a distinct postoperative increase in cortisol production. In contrast to our hypothesis, children undergoing major cardiac surgery did not show an increased adrenal stress response compared to children undergoing conventional surgery. Furthermore, the reduction in cortisol inactivation appears to be an essential part of the stress response to pediatric surgery in general.

Key words

11β-hydroxysteroid dehydrogenase - glucocorticoid - precursor/product ratio

• References

• 1 Boyle Jr EM, Pohlman TH, Johnson MC, Verrier ED. Endothelial cell injury in cardiovascular surgery: the systemic inflammatory response. Ann Thorac Surg 1997; 63: 277-284
• 2 Rossaint J, Berger C, Van Aken H, Scheld HH, Zahn PK, Rukosujew A, Zarbock A. Cardiopulmonary bypass during cardiac surgery modulates systemic inflammation by affecting different steps of the leukocyte recruitment cascade. PLoS One 2012; 7: e45738
• 3 Munck A, Guyre PM, Holbrook NJ. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev 1984; 5: 25-44
• 4 Dotsch J, Wagner R, Groschl M, Schoof E, Harig F, Scharf J, Singer H, Katz N, Blum WF, Doerr HG, Rascher W. Cardiopulmonary bypass surgery does not further increase elevated serum leptin concentrations after major surgery. Pediatr Crit Care Med 2001; 2: 36-39
• 5 Modan-Moses D, Ehrlich S, Kanety H, Dagan O, Pariente C, Esrahi N, Lotan D, Vishne T, Barzilay Z, Paret G. Circulating leptin and the perioperative neuroendocrinological stress response after pediatric cardiac surgery. Crit Care Med 2001; 29: 2377-2382
• 6 Gajarski RJ, Stefanelli CB, Graziano JN, Kaciroti N, Charpie JR, Vazquez D. Adrenocortical response in infants undergoing cardiac surgery with cardiopulmonary bypass and circulatory arrest. Pediatr Crit Care Med 2010; 11: 44-51
• 7 Alvarez Kindelan A, Perez Navero JL, Ibarra de la Rosa I, Concha Ruiz M, Montilla Lopez P, Romanos Lezcano A. Relationship between hemodynamic changes and blood hormone concentrations after cardiac surgery in children with congenital heart disease. Crit Care Med 1994; 22: 1754-1761
• 8 Wald EL, Preze E, Eickhoff JC, Backer CL. The effect of cardiopulmonary bypass on the hypothalamic-pituitary-adrenal axis in children. Pediatr Crit Care Med 2011; 12: 190-196
• 9 Vogeser M, Felbinger TW, Roll W, Jacob K. Cortisol metabolism in the postoperative period after cardiac surgery. Exp Clin Endocrinol Diabetes 1999; 107: 539-546
• 10 Vogeser M, Groetzner J, Kupper C, Briegel J. The serum cortisol:cortisone ratio in the postoperative acute-phase response. Horm Res 2003; 59: 293-296
• 11 Caulfield MP, Lynn T, Gottschalk ME, Jones KL, Taylor NF, Malunowicz EM, Shackleton CH, Reitz RE, Fisher DA. The diagnosis of congenital adrenal hyperplasia in the newborn by gas chromatography/mass spectrometry analysis of random urine specimens. J Clin Endocrinol Metab 2002; 87: 3682-3690
• 12 Kraan GP, Dullaart RP, Pratt JJ, Wolthers BG, Drayer NM, De Bruin R. The daily cortisol production reinvestigated in healthy men. The serum and urinary cortisol production rates are not significantly different. J Clin Endocrinol Metab 1998; 83: 1247-1252
• 13 Heckmann M, Hartmann MF, Kampschulte B, Gack H, Boedeker RH, Gortner L, Wudy SA. Assessing cortisol production in preterm infants: do not dispose of the nappies. Pediatr Res 2005; 57: 412-418
• 14 Lema G, Vogel A, Canessa R, Jalil R, Carvajal C, Becker P, Jaque MP, Fajardo C, Urzua J. Renal function and cardiopulmonary bypass in pediatric cardiac surgical patients. Pediatric nephrology 2006; 21: 1446-1451
• 15 Anand KJ, Sippell WG, Schofield NM, Aynsley-Green A. Does halothane anaesthesia decrease the metabolic and endocrine stress responses of newborn infants undergoing operation?. Br Med J (Clin Res Ed) 1988; 296: 668-672
• 16 Anand KJ, Sippell WG, Aynsley-Green A. Randomised trial of fentanyl anaesthesia in preterm babies undergoing surgery: effects on the stress response. Lancet 1987; 1: 62-66
• 17 Anand KJ, Hickey PR. Halothane-morphine compared with high-dose sufentanil for anesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med 1992; 326: 1-9
• 18 Wilkinson JD, Pollack MM, Ruttimann UE, Glass NL, Yeh TS. Outcome of pediatric patients with multiple organ system failure. Crit Care Med 1986; 14: 271-274
• 19 Lacour-Gayet F, Clarke D, Jacobs J, Comas J, Daebritz S, Daenen W, Gaynor W, Hamilton L, Jacobs M, Maruszsewski B, Pozzi M, Spray T, Stellin G, Tchervenkov C, Mavroudis C. Aristotle Committee . The Aristotle score: a complexity-adjusted method to evaluate surgical results. Eur J Cardiothorac Surg 2004; 25: 911-924
• 20 Quattropani C, Vogt B, Odermatt A, Dick B, Frey BM, Frey FJ. Reduced activity of 11 beta-hydroxysteroid dehydrogenase in patients with cholestasis. J Clin Invest 2001; 108: 1299-1305
• 21 Shackleton CHL. Mass spectrometry in the diagnosis of steroid-related disorders and in hypertension research. J Steroid Biochem Mol Biol 1993; 45: 127-140
• 22 Ulick S, Levine LS, Gunczler P, Zanconato G, Ramirez LC, Rauh W, Rosler A, Bradlow HL, New MI. A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J Clin Endocrinol Metab 1979; 49: 757-764
• 23 Walker EA, Ahmed A, Lavery GG, Tomlinson JW, Kim SY, Cooper MS, Ride JP, Hughes BA, Shackleton CH, McKiernan P, Elias E, Chou JY, Stewart PM. 11beta-Hydroxysteroid Dehydrogenase Type 1 Regulation by Intracellular Glucose 6-Phosphate Provides Evidence for a Novel Link between Glucose Metabolism and Hypothalamo-Pituitary-Adrenal Axis Function. J Biol Chem 2007; 282: 27030-27036
• 24 Anand KJ, Aynsley-Green A. Measuring the severity of surgical stress in newborn infants. Journal of pediatric surgery 1988; 23: 297-305
• 25 Levine A, Cohen D, Zadik Z. Urinary free cortisol values in children under stress. J Pediatr 1994; 125: 853-857
• 26 Roth-Isigkeit AK, Dibbelt L, Schmucker P. Blood levels of corticosteroid-binding globulin, total cortisol and unbound cortisol in patients undergoing coronary artery bypass grafting surgery with cardiopulmonary bypass. Steroids 2000; 65: 513-520
• 27 Vogeser M, Felbinger TW, Kilger E, Roll W, Fraunberger P, Jacob K. Corticosteroid-binding globulin and free cortisol in the early postoperative period after cardiac surgery. Clin Biochem 1999; 32: 213-216
• 28 Kerrigan JR, Veldhuis JD, Leyo SA, Iranmanesh A, Rogol AD. Estimation of daily cortisol production and clearance rates in normal pubertal males by deconvolution analysis. J Clin Endocrinol Metab 1993; 76: 1505-1510
• 29 Linder BL, Esteban NV, Yergey AL, Winterer JC, Loriaux DL, Cassorla F. Cortisol production rate in childhood and adolescence. J Pediatr 1990; 117: 892-896
• 30 Paisley AN, Rowles SV, Brandon D, Trainer PJ. A subnormal peak cortisol response to stimulation testing does not predict a subnormal cortisol production rate. J Clin Endocrinol Metab 2009; 94: 1757-1760
• 31 Duncan HP, Cloote A, Weir PM, Jenkins I, Murphy PJ, Pawade AK, Rogers CA, Wolf AR. Reducing stress responses in the pre-bypass phase of open heart surgery in infants and young children: a comparison of different fentanyl doses. Br J Anaesth 2000; 84: 556-564
• 32 Jeschke MG, Williams FN, Finnerty CC, Rodriguez NA, Kulp GA, Ferrando A, Norbury WB, Suman OE, Kraft R, Branski LK, Al-Mousawi AM, Herndon DN. The effect of ketoconazole on post-burn inflammation, hypermetabolism and clinical outcomes. PLoS One 2012; 7: e35465
• 33 Fuster D, Escher G, Vogt B, Ackermann D, Dick B, Frey BM, Frey FJ. Furosemide inhibits 11beta-hydroxysteroid dehydrogenase type 2. Endocrinology 1998; 139: 3849-3854
• 34 Vis JC, Duffels MG, Winter MM, Weijerman ME, Cobben JM, Huisman SA, Mulder BJ. Down syndrome: a cardiovascular perspective. J Intellect Disabil Res 2009; 53: 419-425
• 35 Murdoch JC, Giles CA, Grant JK, Ratcliffe JG. Hypothalamic-pituitary-adrenocortical function in adults with Down’s syndrome. J Ment Defic Res 1979; 23: 157-162
• 36 Annane D, Maxime V, Ibrahim F, Alvarez JC, Abe E, Boudou P. Diagnosis of adrenal insufficiency in severe sepsis and septic shock. American journal of respiratory and critical care medicine 2006; 174: 1319-1326