Division of Clinical and Molecular Endocrinology, Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio.
J Clin Endocrinol Metab. 2020 Mar 1;105(3). doi: 10.1210/clinem/dgaa042.
Perioperative glucocorticoid therapy for patients with adrenal insufficiency (AI) is currently based on anecdotal reports, without supporting pharmacokinetic data.
We determined the half-life, clearance, and volume of distribution of 2 consecutive intravenously (IV)-administered doses of hydrocortisone (15 or 25 mg every 6 hours) to 22 dexamethasone-suppressed healthy individuals and used the data to develop a novel protocol to treat 68 patients with AI who required surgical procedures. Patients received 20 mg of hydrocortisone orally 2 to 4 hours before intubation and were started on 25 mg of IV hydrocortisone every 6 hours for 24 hours and 15 mg every 6 hours during the second day. Nadir cortisol concentrations were repeatedly measured during that period.
In healthy individuals, cortisol half-life was longer when the higher hydrocortisone dose was administered (2.02 ± 0.15 vs 1.81 ± 0.11 hours; P < 0.01), and in patients with AI, the half-life was longer than in healthy individuals given the same hydrocortisone dose. In both populations, the cortisol half-life increased further with the second hormone injection. Prolongation of cortisol half-life was due to decreased hydrocortisone clearance and an increase in its volume of distribution. Nadir cortisol levels determined throughout the 48 postoperative hours were within the range of values and often exceeded those observed perioperatively in patients without adrenal dysfunction.
Cortisol pharmacokinetics are altered in the postoperative period and indicate that lower doses of hydrocortisone can be safely administered to patients with AI undergoing major surgery. The findings of this investigation call into question the current practice of administering excessive glucocorticoid supplementation during stress.
目前，针对肾上腺功能不全（AI）患者的围手术期糖皮质激素治疗是基于轶事报道，而没有支持的药代动力学数据。
我们测定了 22 例地塞米松抑制的健康个体连续 2 次静脉（IV）给予氢化可的松（每 6 小时 15 或 25mg）的半衰期、清除率和分布容积，并利用这些数据制定了一种新的方案来治疗需要手术的 68 例 AI 患者。患者在插管前 2 至 4 小时口服 20mg 氢化可的松，并在 24 小时内每 6 小时静脉给予 25mg 氢化可的松，第 2 天每 6 小时给予 15mg。在此期间，反复测量皮质醇的最低值。
在健康个体中，给予较高剂量的氢化可的松时，皮质醇半衰期更长（2.02±0.15 比 1.81±0.11 小时；P<0.01），而 AI 患者的半衰期比给予相同剂量氢化可的松的健康个体更长。在这两种人群中，皮质醇半衰期在接受第二次激素注射后进一步延长。皮质醇半衰期的延长是由于氢化可的松清除率降低和分布容积增加所致。在整个 48 小时的术后期间，皮质醇的最低值处于范围内，并且在没有肾上腺功能障碍的患者围手术期期间经常超过这些值。
皮质醇的药代动力学在术后期间发生改变，表明在接受大手术的 AI 患者中可以安全地给予较低剂量的氢化可的松。这一发现质疑了目前在应激期间给予过度糖皮质激素补充的做法。
