Pulsatile activation of the hypothalamic-pituitary-adrenal axis during major surgery

To examine the response of the hypothalamic-pituitary-adrenal (HPA) axis to severe surgical stress, we measured the immunoreactive plasma levels of corticotropin-releasing hormone (CRH), corticotropin, cortisol, arginine-vasopressin (AVP), atrial natriuretic factor (ANF), neuropeptide Y (NPY), interleukin-1 (IL-1), IL-6, interferon gamma (INF), and tumor necrosis factor-alpha (TNF-α) in eight patients with Zollinger-Ellison syndrome (ZES) or mediastinal parathyroid carcinoma, all undergoing major surgery with a standardized anesthetic technique. Blood samples were drawn the morning before surgery, every 10 to 30 minutes throughout surgery (average, 308.7 ± 15 minutes), and every morning for the next 4 postoperative days (POD). During surgery, plasma CRH concentrations were slightly but not significantly elevated compared with those before surgery and with those of the next 4 POD. However, the values were within the normal range (<2.2 pmol/L) and showed 8.9 ± 0.6 pulses (one pulse every 34.7 ± 1.6 minutes). Plasma corticotropin, on the other hand, was quite elevated, but was also released in a pulsatile fashion during the surgical procedure (one pulse every 36.7 ± 1.6 minutes). Most of these secretory episodes of corticotropin were temporally related to those of CRH. Corticotropin returned to basal levels on the first POD and remained so for all 4 POD. Plasma cortisol concentrations increased steadily during surgery and remained elevated the first POD. Cortisol showed 6.2 ± 1.1 pulses during the operative sampling period (one pulse every 71.8 ± 13 minutes). Plasma AVP concentrations were also markedly elevated during surgery, but individual secretory pulses were not detected. Like cortisol, plasma AVP returned to basal values the second POD. ANF plasma levels were slightly increased during the first 120 minutes of surgery, but returned to normal values thereafter. The plasma concentrations of NPY, a peptide presumably coreleased with catecholamines and capable of releasing glucocorticoids from the adrenal cortex, were slightly, although not significantly, increased during the first half of the surgical procedure and were normal thereafter. Of the cytokines examined, IL-1 had significant increases of its plasma concentrations in six patients, IL-6 in three patients, and TNF-α in five of eight patients, with no correlations to each other, corticotropin, or cortisol. In conclusion, during major surgical stress, the plasma levels of glucocorticoids increase steadily, sustained by the pulsatile release of CRH and corticotropin and increased levels of AVP. The marked pulsatility of corticotropin secretion seen in major surgery contrasts to the mild, constant elevations of corticotropin seen in less traumatic surgery, such as neck exploration. No consistent or universal elevations of cytokines were observed either during or after the operative procedure.