Dynamic pituitary-adrenal interactions in response to cardiac surgery.

Objectives: To characterize the dynamics of the pituitary-adrenal interaction during the course of coronary artery bypass grafting both on and off pump. Since our data pointed to a major change in adrenal responsiveness to adrenocorticotropic hormone, we used a reverse translation approach to investigate the molecular mech-anisms underlying this change in a rat model of critical illness.Design: Clinical studies: Prospective observational study. Animal studies: Controlled experimental study.Setting: Clinical studies: Cardiac surgery operating rooms and critical care units. Animal studies: University research laboratory.Subjects: Clinical studies: Twenty, male patients. Animal studies: Adult, male Sprague-Dawley rats.Interventions: Clinical studies: Coronary artery bypass graft—both on and off pump. Animal studies: Injection of either lipopolysac-charide or saline (controls) via a jugular vein cannula.Measurements and Main Results: Clinical studies: Blood sam-ples were taken for 24 hours from placement of the first venous access. Cortisol and adrenocorticotropic hormone were mea-sured every 10 and 60 minutes, respectively, and corticosteroid-binding globulin was measured at the beginning and end of the 24-hour period and at the end of operation. There was an initial rise in both levels of adrenocorticotropic hormone and cortisol to supranormal values at around the end of surgery. Adrenocor-ticotropic hormone levels then returned toward preoperative val-ues. Ultradian pulsatility of both adrenocorticotropic hormone and cortisol was maintained throughout the perioperative period in all individuals. The sensitivity of the adrenal gland to adrenocortico-tropic hormone increased markedly at around 8 hours after sur-gery maintaining very high levels of cortisol in the face of “basal” levels of adrenocorticotropic hormone. This sensitivity began to return toward preoperative values at the end of the 24-hour sam-pling period. Animal studies: Adult, male Sprague-Dawley rats were given either lipopolysaccharide or sterile saline via a jugular vein cannula. Hourly blood samples were subsequently collected for adrenocorticotropic hormone and corticosterone measure-ment. Rats were killed 6 hours after the injection, and the adrenal glands were collected for measurement of steroidogenic acute regulatory protein, steroidogenic factor 1, and dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 messenger RNAs and protein using real-time quantitative polymerase chain reaction and Western immunoblotting, respec-tively. Adrenal levels of the adrenocorticotropic hormone receptor (melanocortin type 2 receptor) messenger RNA and its accessory protein (melanocortin type 2 receptor accessory protein) were also measured by real-time quantitative polymerase chain reac-tion. In response to lipopolysaccharide, rats showed a pattern of