Safety of Withholding Perioperative Hydrocortisone for Patients With Pituitary Adenomas With an Intact Hypothalamus-Pituitary-Adrenal Axis

Abstract

ImportancePituitary adenoma is the second most common primary brain tumor. Perioperative hydrocortisone has been used for decades to avoid postoperative adrenal insufficiency. Recent studies suggest that withholding perioperative hydrocortisone may be safe for patients with an intact hypothalamus-pituitary-adrenal (HPA) axis.ObjectiveTo assess the safety of withholding hydrocortisone during the perioperative period of pituitary adenoma surgery for patients with an intact HPA axis.Design, Setting, and ParticipantsA parallel-group, triple-masked, noninferiority randomized clinical trial was conducted at Peking Union Medical College Hospital from November 1, 2020, to January 31, 2022, among 436 patients aged 18 to 70 years with an intact HPA axis undergoing surgery for pituitary adenomas.InterventionsHydrocortisone supplementation protocol (intravenous and subsequent oral hydrocortisone, using a taper program) or no-hydrocortisone protocol.Main Outcomes and MeasuresThe primary outcome was the incidence of new-onset adrenal insufficiency (morning cortisol level, <5 μg/dL with adrenal insufficiency–related symptoms) during the perioperative period (on the day of operation and the following 2 days). The secondary outcome was the incidence of adrenal insufficiency in postoperative month 3. Analysis was on an intention-to-treat basis.ResultsOf the 436 eligible patients, 218 were randomly assigned to the hydrocortisone group (136 women [62.4%]; mean [SD] age, 45.4 [13.0] years) and 218 to the no-hydrocortisone group (128 women [58.7%]; mean [SD] age, 44.5 [13.8] years). All patients completed 3-month postoperative follow-up. The incidence of new-onset adrenal insufficiency during the perioperative period was 11.0% (24 of 218; 95% CI, 6.9%-15.2%) in the no-hydrocortisone group and 6.4% (14 of 218; 95% CI, 3.2%-9.7%) in the hydrocortisone group, with a difference of 4.6% (95% CI, −0.7% to 9.9%), meeting the prespecified noninferiority margin of 10 percentage points. The incidence of adrenal insufficiency at the 3-month follow-up was 3.7% (8 of 218) in the no-hydrocortisone group and 3.2% (7 of 218) in the hydrocortisone group (difference, 0.5%; 95% CI, −3.0% to 3.9%). Incidences of new-onset diabetes mellitus (1 of 218 [0.5%] vs 9 of 218 [4.1%]), hypernatremia (9 of 218 [4.1%] vs 21 of 218 [9.6%]), hypokalemia (23 of 218 [10.6%] vs 34 of 218 [15.6%]), and hypocalcemia (6 of 218 [2.8%] vs 19 of 218 [8.7%]) were lower in the no-hydrocortisone group than in the hydrocortisone group. Lower preoperative morning cortisol levels were associated with higher risks of the primary event (<9.3 µg/dL; odds ratio, 3.0; 95% CI, 1.5-5.9) and the secondary event (<8.8 µg/dL; odds ratio, 7.8; 95% CI, 2.6-23.4) events.Conclusions and RelevanceThis study found that withholding hydrocortisone was safe and demonstrated noninferiority to the conventional hydrocortisone supplementation regimen regarding the incidence of new-onset adrenal insufficiency among patients with an intact HPA axis undergoing pituitary adenomectomy.Trial RegistrationClinicalTrials.gov Identifier: NCT04621565

Basal cortisol in relation to metyrapone confirmation in predicting adrenal insufficiency after pituitary surgery

“…A recent, triple-masked, randomized clinical trial showed that the incidence of new-onset adrenal insufficiency directly after surgery was 11% (95% CI 6.9-15.2%) in the non-hydrocortisone group compared to 6.4% (95% CI 3.2-9.7%) in the hydrocortisone group which did not reach statistical significance. In a subgroup analysis of patients with a BMI < 25.5 kg/m 2 there was a significant difference in post-operative adrenal insufficiency [16]. In this study the reduction of hydrocortisone related complication of diabetes together with incidence of new-onset hypokalemia, hypernatremia and hypocalcemia was reduced by withholding hydrocortisone whereas incidence of hyponatremia was significantly increased by withholding treatment.…”

“…In all of our patients, hydrocortisone was administered perioperatively (50 mg one hour before surgery and two subsequent dosages of 50 mg that same day, 75 mg intravenously on POD1, 20 mg orally on POD2) including those without preoperative adrenal insufficiency. Perioperative glucocorticoid supplementation has been the standard of care for a long period of time [16]. There is, however, debate whether this protocol is still necessary [1].…”

Identifying hormones and other perioperative risk factors for postoperative delirium after endoscope‐assisted transsphenoidal pituitary adenoma resection: A retrospective, matched cohort study

“…Therefore, perioperative glucocorticoid supplementation has long been a routine practice for patients with pituitary adenomas (Hattori et al., 2021 ; Molitch, 2017 ). A recent randomized clinical trial indicated that withholding hydrocortisone was safe and noninferior to the conventional hydrocortisone supplementation regimen regarding the incidence of new‐onset adrenal insufficiency among patients with an intact hypothalamic‒pituitary‒adrenal axis undergoing pituitary adenomectomy (Guo et al., 2022 ). However, researchers did not take postoperative delirium into consideration in their study.…”

From Genes to Therapy: Pituitary Adenomas in the Era of Precision Medicine

“…The main objective of these therapies is to attain biochemical control, and treatment risks vary based on the specific medication. Considering that these therapies might be prolonged or indefinite, understanding patient tolerability is essential [14].…”

“…Furthermore, some pituitary adenomas may overproduce one or more hormones, resulting in hormonal imbalances that affect body functions, even when the tumors are small. Importantly, pituitary adenomas can occur in individuals of any age [14].…”