Selective Use of Steroid Replacement After Adrenalectomy Lessons from 331 Consecutive Cases

PAPER Selective Use of Steroid Replacement After Adrenalectomy Lessons From 331 Consecutive Cases

Wen T. Shen, MD; James Lee, MD; Electron Kebebew, MD; Orlo H. Clark, MD; Quan-Yang Duh, MD

Hypothesis: Only selected patients require steroid re- tomy. Of the 57 patients requiring steroid replacement, placement therapy following adrenalectomy. 52 had Cushing syndrome and 5 had bilateral pheochromocytomas. The 52 patients with Cushing syndrome in- Design: Retrospective review. cluded 16 with pituitary tumors who had failed pituitary resection and/or medical therapy, 14 with unilateral Settings: University tertiary care center and veterans’ adrenal adenomas, 9 with ectopic corticotropin- hospital. secreting tumors who had failed resection and/or medical therapy, 7 with incidentalomas and subclinical Cush- Patients: A total of 331 patients who underwent adre- ing syndrome, 4 with macronodular hyperplasia, and 2 nalectomy by 1 surgeon (Q.-Y.D.) between April 1, 1993, with adrenocortical carcinoma. No patients undergoing and August 31, 2005. unilateral adrenalectomy for non-Cushing adrenal disease required steroid replacement. Four (7%) of the 57 Interventions: Laparoscopic, open, and hand-assisted patients receiving steroid replacement had episodes of adrenalectomy. Steroid replacement therapy was administered using a standardized hydrocortisone taper pro- acute adrenocortical insufficiency following operation and tocol. required increased steroid supplementation. There were no cases of acute adrenocortical insufficiency in the 274 Main Outcome Measures: Indications for adrenal- patients who did not receive steroid replacement. ectomy, operative approach, requirement for postoperative steroid replacement, and episodes of acute adreno- Conclusions: Steroid replacement therapy after adre- cortical insufficiency. nalectomy should be reserved for patients with Cushing syndrome (overt or subclinical) and patients undergo- Results: Of the 331 adrenalectomies, 304 were laparo- ing bilateral adrenalectomy. Patients undergoing adre- scopic, 23 were open, and 4 were hand assisted. There nalectomy for unilateral non-Cushing adrenal tumors do were 299 unilateral adrenalectomies and 32 bilateral ad- not require postoperative steroid replacement. renalectomies performed. Fifty-seven (17%) of the 331 patients required steroid replacement after adrenalec- Arch Surg. 2006;141:771-776

HE PRACTICE OF PROVIDING roid replacement needed to provide ad- perioperative glucocorti- equate coverage for perioperative stress; coid replacement therapy to the concept and practice of administer- prevent adrenal insuffi- ing supraphysiologic, or “stress-dose,” ste- ciency in patients receiv- roids has been called into question by sev- ing steroids for inflammatory conditions eral investigators,5-8 and new guidelines for T 1,2 is well established. Since the early 1950s steroid-dependent patients undergoing op- when the first articles3,4 describing the dan- erations have been proposed and used.5-8 gers of postoperative adrenal insuffi- Another population of patients who may ciency in steroid-dependent patients were require perioperative steroid supplementa- published, the standard of care has been tion consists of patients undergoing adre- to treat these patients with physiologic or nalectomy for the spectrum of primary ad- Author Affiliations: supraphysiologic doses of steroids dur- renal tumors or, less commonly, adrenal Department of Surgery, ing the perioperative period. Within the metastases or extra-adrenal hypersecre- University of California, past 2 decades, there has been consider- tory conditions. However, few published San Francisco. able debate regarding the amount of ste- guidelines exist for identifying precisely

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 RESULTS Table 1. Comparison of Patients Who Required Postoperative Steroid Supplementation vs Patients Who Did Not Require Postoperative Steroids Between April 1, 1993, and August 31, 2005, 331 patients underwent adrenalectomy by 1 surgeon (Q.-Y.D.) Patients Patients Requiring Not Requiring at the University of California, San Francisco, or one of Postoperative Postoperative its affiliated institutions. Of these 331 patients, 304 un- Steroids Steroids derwent laparoscopic adrenalectomy, 23 underwent open Characteristic (n = 57) (n = 274) adrenalectomy, and 4 underwent hand-assisted laparo- Episodes of adrenal insufficiency, No. 4 0* scopic adrenalectomy. Of the 23 open adrenalectomies, Infectious complications, No. 4 0* 4 were initially attempted laparoscopically but were con- Length of hospital stay, mean ± SEM, d 2.6 ± 0.3 1.5 ± 0.1* verted to open adrenalectomy because of difficult dis- section or intraoperative findings that may have been in- PϽ.05. * dicative of malignancy. The indications for operation for the 331 patients included aldosteronomas in 108 patients, pheochromocytomas in 71 patients (including bi- which patients undergoing adrenalectomy require peri- lateral pheochromocytomas in 5 patients), Cushing syn- operative steroids. Not all patients undergoing adrenalec- drome in 52 patients, nonfunctioning cortical adenomas tomy are at risk for postoperative adrenal insufficiency, and in 34 patients, isolated adrenal metastases in 29 pa- unnecessary steroid administration is associated with a host tients, adrenocortical carcinoma (not causing Cushing of deleterious effects, including poor wound healing, blood syndrome) in 5 patients, and a virilizing adrenal tumor glucose level abnormalities, and other metabolic derange- in 1 patient. The remaining 31 patients who underwent ments. We therefore reviewed our experience with pa- adrenalectomy during this period had other types of uni- tients who underwent adrenalectomy during the past de- lateral nonfunctioning adrenal tumors (including my- cade, with the goal of identifying which patients required elolipomas, adrenal cysts, and adrenal hemorrhages). perioperative steroid replacement. We aimed to provide ra- Fifty-seven (17%) of 331 patients required steroid re- tional guidelines for the administration of steroids in pa- placement following adrenalectomy; the remaining 274 tients undergoing adrenalectomy and to highlight the sub- patients did not require or receive any form of postop- groups of patients who are at highest risk for postoperative erative steroid supplementation. The 57 patients receiv- adrenal insufficiency. ing steroids included 52 patients with Cushing syndrome and 5 with bilateral pheochromocytomas who underwent bilateral adrenalectomies. All of the 52 pa- METHODS tients with Cushing syndrome were diagnosed preoperatively by biochemical testing either because of clini- We reviewed the medical records of all of the patients who un- cal features of hypercortisolism or as part of the routine derwent adrenalectomy by 1 surgeon (Q.-Y.D.) between April workup of an incidentally discovered adrenal mass. The 1, 1993, and August 31, 2005. Patients who underwent open, cause of glucocorticoid excess in the 52 patients with laparoscopic, or hand-assisted adrenalectomy were included. The clinical presentation and indications for operation were re- Cushing syndrome included functioning pituitary tu- corded for each patient. All of the operations were performed mors in 16 patients who had failed pituitary resection at the University of California, San Francisco, Medical Center, and/or medical therapy; functioning unilateral adrenal the San Francisco Veterans Affairs Medical Center, the Uni- cortical adenomas in 14 patients; ectopic corticotropin- versity of California, San Francisco/Mt Zion Medical Center, secreting tumors in 9 patients who had failed resection or the San Francisco General Hospital. and/or medical therapy; subclinical Cushing syndrome All of the patients requiring postoperative steroid supple- in 7 patients who had been diagnosed during biochemi- mentation were identified, and their indications for and dura- cal workup of an incidentaloma; bilateral adrenal mac- tion of steroid therapy were recorded. Steroid supplementa- ronodular hyperplasia in 4 patients; and functioning ad- tion was administered using a standardized protocol established renocortical carcinoma in 2 patients. The 5 patients with in conjunction with medical endocrinologists at our institution. Postoperative complications were noted, including all epi- bilateral pheochromocytomas included 3 with multiple sodes of adrenal insufficiency requiring additional steroid supple- endocrine neoplasia type 2A or 2B, 1 with Osler-Weber- mentation and any complications related to hypercortisolism Rendu syndrome, and 1 with neurofibromatosis. (including wound infections and other infectious complica- A comparison of postoperative complications in pa- tions). Episodes of adrenal insufficiency following operation tients who received steroid supplementation and pa- were documented by either serum or urinary testing in patients who did not receive steroids is provided in Table 1. tients with symptoms or signs of hypocortisolism. The dura- The 57 patients who underwent steroid replacement in- tion of hospitalization was recorded. In our practice, all of the cluded 4 who required additional steroid therapy be- patients are seen for follow-up by the surgeon between 2 and cause of signs and symptoms of addisonian crisis. Infec- 4 weeks after operation. If there are no persistent postopera- tious complications developed in 4 patients undergoing tive problems, subsequent follow-up is with the patient’s endocrinologist or primary care physician. Episodes of delayed steroid replacement therapy: 2 patients developed wound adrenal insufficiency, tumor recurrence, or other long-term com- infections in trocar sites, necessitating bedside incision plications either were reported directly to the surgeon or were and drainage; 1 patient developed a subphrenic abscess identified during record reviews and follow-up telephone calls requiring drainage by interventional radiology; and 1 pa- to referring physicians for this study. tient developed severe postoperative pneumonia and a

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Table 2. Clinical Features of 4 Patients With Acute Adrenal Insufficiency After Adrenalectomy Despite Glucocorticoid Replacement

Time After Symptoms of Age, y/Sex Diagnosis Operation Operation Adrenal Insufficiency Outcome 66/F Cushing syndrome, ectopic Laparoscopic bilateral 2 d Fever, nausea, failure to thrive Improved,5dinhospital corticotropin-secreting adrenalectomy tumor 51/F Cushing syndrome, pituitary Laparoscopic bilateral 3 d Hypotension, shock requiring Improved,9dinhospital adenoma adrenalectomy intensive care unit care 43/F Subclinical Cushing Laparoscopic right 1 y Fatigue, nausea, dizziness Improved, but recurrent episode syndrome, incidentaloma adrenalectomy during steroid taper during treatment for gallstones 1 y later 40/M Cushing syndrome, bilateral Laparoscopic bilateral 2 y Diarrhea, nausea, vomiting Improved, no repeat macronodular adrenalectomy hospitalization hyperplasia

urinary tract infection with subsequent extended hospi- tive steroid supplementation was 2.6±0.3 days. The talization. In comparison, of the 274 patients who did mean±SEM length of postoperative hospitalization for not receive perioperative steroid replacement, only 1 de- the 274 patients who did not require steroid supplemen- veloped an infectious complication after adrenalectomy tation was 1.5±0.1 days (P=.002). (PϽ.001). Of the patients who underwent steroid replacement, 1 with adrenocortical carcinoma developed local recurrence requiring reoperation. One patient with COMMENT multiple endocrine neoplasia type 2B and bilateral pheochromocytomas developed local recurrence requiring reoperation and died several months later of metastatic med- In this study, we reviewed the clinical presentations and ullary thyroid carcinoma. There was 1 postoperative death postoperative outcomes of 331 consecutive patients who in a patient with an ectopic corticotropin-secreting tu- underwent adrenalectomy during a 12-year period, and we mor who underwent emergent operation after develop- identified factors that determined the requirement for peri- ing acute multisystem failure despite aggressive medi- operative steroid supplementation. The results of this in- cal therapy; this patient developed uncontrollable vestigation suggest that only patients with preoperatively postoperative bleeding and died 1 day after operation. diagnosed Cushing syndrome (either overt or subclini- The clinical features of the 4 patients who developed cal) and patients undergoing bilateral adrenalectomy re- postoperative adrenal insufficiency despite glucocorticoid quire perioperative steroid supplementation. In addition, replacement are listed in Table 2. These 4 patients who patients receiving steroids for other medical conditions (eg, required additional steroid supplementation included 2 asthma, inflammatory bowel disease, rheumatoid arthri- patients who developed hypocortisolism in the immedi- tis) need to receive steroid coverage after adrenalectomy ate postoperative period and 2 patients who presented sev- as they would with any operation. Patients undergoing uni- eral months to years after their operations. The 2 imme- lateral adrenalectomy for non-Cushing adrenal tumors do diate cases of addisonian crisis included 1 patient with not require perioperative steroid supplementation. The only pituitary Cushing syndrome who became critically hypo- cases of postoperative addisonian crisis that we encoun- tensive and required transfer to the intensive care unit on tered during this 12-year study period were in patients with postoperative day 3 as well as 1 patient with an ectopic Cushing syndrome. Overall, 4 (1%) of 331 patients under- corticotropin-secreting tumor who developed fever, nau- going adrenalectomy at our institution had an episode of sea, and failure to thrive on postoperative day 2. Both of postoperative hypocortisolism; this result is similar to that these patients improved after additional supplemental reported in other single-institution studies9 of patients un- steroid therapy. The 2 cases of delayed addisonian crisis dergoing adrenalectomy. We also found that patients re- included 1 patient with macronodular hyperplasia who quiring perioperative steroid supplementation are at higher had severe gastrointestinal distress 2 years after his bilat- risk for postoperative infectious complications and have a eral adrenalectomy as well as 1 patient with subclinical significantly longer hospital stay than patients who do not Cushing syndrome who became acutely fatigued, nause- require steroids. ated, and dizzy while attempting to wean off of steroids 1 In our practice, perioperative steroid replacement is year after her adrenalectomy. These 2 patients with de- administered according to a standardized protocol that layed symptoms of hypocortisolism showed improvement was established with assistance from the medical endo- after additional supplemental steroid therapy; the patient crinologists at our institution. The protocol calls for 100 with subclinical Cushing syndrome had another episode mg of intravenous hydrocortisone to be given prior to of addisonian crisis while being treated for cholecystitis operation, followed by 100 mg of intravenous hydrocor- 2yearsafterheradrenalectomyandrequiredincreaseddoses tisone every 8 hours for 1 day or an equivalent daily dose of steroids during this period. of oral prednisone, then a subsequent rapid 3-day taper The mean±SEM length of hospitalization after adre- to a maintenance dose of 25 mg twice daily of intrave- nalectomy in the 57 patients who required periopera- nous hydrocortisone or an equivalent dose of oral pred-

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 nisone until the patient is seen in follow-up. Patients who tients is dependent on patient history, extent of operation, undergo bilateral adrenalectomy will require lifelong ste- and clinician judgment. roid supplementation whereas those with Cushing syndrome who undergo unilateral adrenalectomy can usu- ally be tapered off of all steroids within 6 months to 1 Accepted for Publication: April 13, 2006. year.10-14 In our practice, the referring endocrinologist or Correspondence: Quan-Yang Duh, MD, San Francisco primary care physician determines the final tapering regi- Veterans Affairs Medical Center, 4150 Clement St, San men for patients weaning off of steroids; all of the pa- Francisco, CA 94121 ([email protected]). tients undergo repeat biochemical testing to confirm the Previous Presentation: This paper was presented at the integrity of the hypothalamic-pituitary axis prior to dis- 77th Annual Meeting of the Pacific Coast Surgical Asso- continuing steroid therapy. It is important to note that ciation; February 19, 2006; San Francisco, Calif; and is patients with Cushing syndrome may develop signs and published after peer review and revision. The discus- symptoms of hypocortisolism months and even years af- sions that follow this article are based on the originally ter their adrenalectomy; 2 of the 4 patients with postop- submitted manuscript and not the revised manuscript. erative adrenal insufficiency in this study group presented within 1 to 2 years after operation. REFERENCES Patients with subclinical Cushing syndrome repre- sent an interesting subgroup of our study population. 1. Jabbour SA. Steroids and the surgical patient. Med Clin North Am. 2001;85:1311- Subclinical Cushing syndrome is defined by autono- 1317. mous secretion of glucocorticoids without overt clinical 2. Krasner AS. Glucocorticoid-induced adrenal insufficiency. JAMA. 1999;282: 671-676. manifestations of Cushing syndrome. We identified 7 pa- 3. Fraser CG, Preuss FS, Bigford WD. Adrenal atrophy and irreversible shock as- tients with this condition; these patients had inciden- sociated with cortisone therapy. JAMA. 1952;149:1542-1543. tally discovered adrenal masses and no clinical features 4. Lewis L, Robinson RF, Yee J, Hacker LA, Eisen G. Fatal adrenal cortical insuffi- of hypercortisolism but were found to have elevated cor- ciency precipitated by surgery during prolonged continuous cortisone treatment. Ann Intern Med. 1953;39:116-126. tisol secretion on biochemical workup of their inciden- 5. Brown CJ, Buie WD. Perioperative stress dose steroids: do they make a difference? talomas. These patients with subclinical Cushing syn- J Am Coll Surg. 2001;193:678-686. drome are at risk for postoperative addisonian crisis and 6. Glowniak JV, Loriaux DL. A double-blind study of perioperative steroid require- should receive steroid supplementation; 1 patient with ments in secondary adrenal insufficiency. Surgery. 1997;121:123-129. subclinical Cushing syndrome in our study had 2 epi- 7. Salem M, Tainsh RE Jr, Bromberg J, Loriaux DL, Chernow B. Perioperative glucocorticoid coverage: a reassessment 42 years after emergence of a problem. sodes of postoperative hypocortisolism despite steroid re- Ann Surg. 1994;219:416-425. 15,16 placement. Other investigators have reported cases 8. Levy A. Perioperative steroid cover. Lancet. 1996;347:846-847. of fatal adrenal insufficiency in patients with subclinical 9. Poulose BK, Holzman MD, Lao OB, Grogan EL, Goldstein RE. Laparoscopic ad- Cushing syndrome who did not receive glucocorticoid renalectomy: 100 resections with clinical long-term follow-up. Surg Endosc. 2005; 19:379-385. supplementation after adrenalectomy. As the frequency 10. Zeiger MA, Fraker DL, Pass HI, et al. Effective reversibility of the signs and symp- of incidentalomas continues to rise in conjunction with toms of hypercortisolism by bilateral