Ad e n o m a s of the anterior pituitary gland may present

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1 J Neurosurg 111: , 2009 Use of morning serum cortisol level after transsphenoidal resection of pituitary adenoma to predict the need for long-term glucocorticoid supplementation Clinical article *Ni c h o l a s F. Mar ko, M.D., 1 Vi v e k A. Go n u g u n t a, M.D., F.R.C.S., 1 Am i r H. Ham r a h i a n, M.D., 3 Al i Us m a n i, M.D., 4 Mar c R. May b e r g, M.D., 1,5 a n d Ro b e r t J. We i l, M.D. 1,2 1 Department of Neurosurgery, 2 Brain Tumor and Neuro-Oncology Center, 3 Department of Endocrinology, and 4 Department of Hospital Medicine, Cleveland Clinic, Cleveland, Ohio; and 5 Swedish Neurosciences Institute, Swedish Medical Center, Seattle, Washington Object. Accurate assessment of the hypothalamic-pituitary-adrenal (HPA) axis is critical for appropriate management of the disease in patients with pituitary adenoma after transsphenoidal resection. The authors examine the role of the morning total serum cortisol level in the early postoperative period as a predictor of long-term HPA function. Methods. Morning total serum cortisol was measured in 83 patients on postoperative Day 1 (or Day 2 if the patient received glucocorticoids during surgery) after transsphenoidal surgery for pituitary adenoma. These results were compared with those of definitive assays of HPA function performed at 1 3 months postoperatively, including cortrosyn/synacthen stimulation test (CST), insulin tolerance test (ITT), and metyrapone test (MTT). The ability of the early-postoperative morning cortisol level to predict HPA function was determined using standard confusion matrix calculations and receiver-operator control curve analysis. Results. The authors found that an early postoperative morning total cortisol level 15 μg/dl is a sensitive and accurate predictor of normal HPA function in the postoperative period (sensitivity 80.5%, specificity 66.7%, positive predictive value 96.9%). Conclusions. A morning total cortisol level 15 μg/dl in the early postoperative period after transsphenoidal surgery for pituitary adenomas is a good predictor of normal HPA function. This test has good sensitivity and accuracy and correlates well with the results of additional, definitive assays of HPA function (CST, ITT, and MTT) performed at 1 3 months postoperatively. Accordingly, it is the authors practice to avoid exogenous perioperative glucocorticoid supplementation in patients with normal preoperative HPA function and postoperative morning total cortisol levels 15 μg/dl 1 2 days after transsphenoidal pituitary adenomectomy. (DOI: / JNS081265) Ke y Wo r d s adrenal insufficiency hypothalamic-pituitary-adrenal axis transsphenoidal surgery Ad e n o m a s of the anterior pituitary gland may present with symptoms of mass effect, with systemic manifestations of hormone hypersecretion or deficiency, or after incidental identification on neuroimaging studies. Medical therapy is an initial therapeutic option for patients with prolactinomas, but resection via a transsphenoidal approach is often required for definitive Abbreviations used in this paper: CST = cortrosyn/synacthen stimulation test; HPA = hypothalamic-pituitary-adrenal; ITT = insulin tolerance test; MTT = metyrapone test; x 30, x 60 = mean value at 30 and 60 minutes. *Drs. Marko and Gonugunta contributed equally to this study. management of pituitary tumors. 18 Resection is safe and effective in the hands of an experienced neurosurgeon, and advances in anesthesia and microsurgical technique allow most patients to be discharged from the hospital within hours of surgery. Patients undergoing resection of pituitary adenomas require careful evaluation of the HPA axis function during the postoperative period because unrecognized adrenocorticotropic hormone deficiency may lead to fatigue, anorexia, nausea, vomiting, fever, hypotension, electrolyte and metabolic derangements, and possibly death. Several methods are currently used for assessing HPA axis function. The CST can be performed using either the 540 J Neurosurg / Volume 111 / September 2009

2 Morning serum cortisol level standard dose (250 μg) or a low dose (1 μg) of cortrosyn to stimulate measurable cortisol release. Both assays are acceptable for evaluating the HPA axis. 19 The low-dose CST is more sensitive but less specific compared with the standard-dose CST. 3,8,10,15,17,22 Neither is reliable for the diagnosis of acute adrenocorticotropic hormone deficiency within 2 weeks, 11,20 and therefore the utility of this assay during the immediate postoperative period is limited. The ITT is considered the gold standard assay for HPA axis function, and results of the overnight MTT closely resemble those of the ITT. 11,20,23 Both of these tests are cumbersome to perform, may be unpleasant for patients in that they must be performed immediately postoperatively, and carry some risk of serious adverse effects. We previously conducted a pilot study of 29 consecutive patients undergoing transsphenoidal pituitary surgery at our institution between January and December 2002 and demonstrated that a single serum cortisol level 15 μg/dl in the early postoperative period correlated well with longterm preservation of normal HPA axis function. 13 Based on these findings, we designed a study of patients undergoing transsphenoidal pituitary surgery for pituitary adenomas at our institution between January 2003 and December Our goal was to determine a threshold value for the earlymorning postoperative (< 48 hours) serum cortisol level that would reliably and accurately discriminate between patients with normal HPA axes and those with HPA axis dysfunction. Methods Patient Population All patients who underwent transsphenoidal pituitary adenomectomy between January 2003 and December 2005 were eligible. Patients undergoing transsphenoidal pituitary surgery for Cushing disease or for pituitary apoplexy, or those who received corticosteroids long term, were excluded from further analysis, as were patients in whom early postoperative morning cortisol levels were not checked or who failed to appear for the appropriate postoperative testing. This resulted in a cohort of 83 consecutive, eligible patients who composed the study group. Of the 83 patients, 46 (55%) were female and 37 (45%) were male. Ninety percent of tumors were macroadenomas, and most were nonsecretory. This study was approved by the Cleveland Clinic s Institutional Review Board. Patients with laboratory evidence of a normal HPA axis preoperatively were not given stress dose steroids at the time of surgery, whereas those with HPA dysfunction received a one-time dose of 100 mg hydrocortisone during the induction of general anesthesia. Early postoperative morning cortisol level was measured at 7 a.m. on postoperative Day 1 (12 22 hours after the conclusion of surgery) for patients who did not receive hydrocortisone with induction. Early postoperative morning cortisol was measured at 7 a.m. on postoperative Day 2 (24 36 hours after the conclusion of surgery) for patients given one dose of hydrocortisone at the time of surgery. Patients with an early postoperative morning cortisol level 15 µg/dl were discharged home on postoperative Days 1 2 J Neurosurg / Volume 111 / September 2009 without steroid supplementation. 1,14 Patients with levels < 15 µg/dl were started on hydrocortisone (20 mg each morning and 10 mg each evening) and were discharged on postoperative Days 1 2. The threshold of 15 µg/dl was chosen as a higher threshold, based on the literature and our experience, to ensure that we would be less likely to miss patients with adrenal insufficiency. 1,2,5 7,9,12,13,16,24 All patients were tested at 1 3 months postoperatively with a modified low-dose (25 μg) CST to evaluate HPA axis function. 4 In patients who received hydrocortisone after surgery, we held the evening dose the night before and the morning of testing. An adequate and sufficient response was defined as an absolute serum cortisol level of 18 μg/dl at either 30 or 60 minutes after stimulation. Patients with an adequate response would not receive steroid supplementation, and those who had been taking exogenous steroids after surgery would have their supplementation discontinued. Patients with an insufficient response to the CST were subsequently tested with either the ITT or the MTT for further evaluation of the HPA axis. In patients with an adequate response on these assays, steroid supplementation discontinued, whereas those with an inadequate response were continued on exogenous steroid supplementation. Patients who refused further testing were started or continued on steroids only if clinical symptoms were suggestive of hypocortisolism. This management algorithm is outlined in Fig. 1. Results Sixty-four patients (77%) had early postoperative morning cortisol levels 15 μg/dl (x = 27.4, σ = 15.6) and were therefore discharged home without steroid supplementation. Of these patients, 52 (81%) had sufficient response to the CST at their 1- to 3-month follow-up visit (x 30 = 24.6, x 60 = 24.8), whereas 12 (19%) had inadequate responses (x 30 = 15.7, x 60 = 11.9). The 12 patients with inadequate responses were offered further testing with ITT or MTT. Nine were found to have normal HPA axes; 1 was found to have an inadequate response and was started on steroid supplementation; and 2 refused ITT or MTT. Both of these patients were started empirically on glucocorticoids; 1 reported clinical improvement and remained on glucocorticoid therapy, whereas the other had no change in symptoms and discontinued therapy. Therefore, only 1 (1.6%) of 64 patients who had an early postoperative morning cortisol level 15 μg/dl had demonstrable evidence of HPA dysfunction requiring steroid supplementation. Nineteen patients (23%) had early postoperative morning cortisol levels < 15 μg/dl and were discharged on steroid supplementation. Of this group, 15 had normal CST results at follow-up (x 30 = 18.7, x 60 = 21.3), and their steroids were stopped. Four patients had abnormal CST results (x 30 = 11.4, x 60 = 10.7) and were continued on steroid supplementation. As mentioned above, only 2 of 83 patients elected not to complete definitive testing for HPA function in the outpatient setting after an abnormal result on the CST. The first patient had a postoperative Day 1 cortisol level of 27.3 μg/dl, but demonstrated an insufficient response to the CST (x 30 = 14.5, x 60 = 8.2). This patient refused ITT 541

3 N. F. Marko et al. Fig. 1. Algorithm showing management strategy based on postoperative cortisol levels. or MTT and elected to start exogenous steroid supplementation for symptom control. The second patient had a postoperative Day 1 cortisol level of 20.8 μg/dl, but had an insufficient response to a CST (x 30 = 16.4, x 60 = 12.6). This patient was asymptomatic and elected not to initiate exogenous steroid supplementation; he has remained asymptomatic over 3 years of follow-up care. Without definitive evidence of HPA function from ITT or MTT, these patients were categorized according to their steroid requirement for clinical symptom control. The first patient was therefore considered to have HPA dysfunction, and the second patient was considered to have normal HPA function. These data are summarized in Fig. 1. A receiver-operator control curve demonstrating the relationship of the true-positive rate to the false-positive rate was constructed (Fig. 2). 21 This curve suggests that cutoff values of 15.0 or even as low as 12.0 µg/dl may be reasonable threshold values for early postoperative cortisol levels predictive of normal HPA function. A summary of the confusion matrix values and derived indices at these two threshold levels is presented in Table 1. Discussion Accurate prediction of HPA axis function after transsphenoidal surgery is essential for proper postoperative management in patients with pituitary adenomas. Conservative management strategies for such patients in many centers involve several weeks of postoperative glucocorticoid supplementation, during which time outpatient endocrinological examination is conducted to assess HPA function, and steroid supplementation is discontinued after demonstration of a normal endogenous response. Complications associated with exogenous steroid use in the postoperative period, including impaired wound healing and difficulty with glycemic control, have prompted investigations into early predictors of normal HPA function that will decrease or eliminate the need for exogenous glucocorticoids in appropriate patients. Studies of cortisol levels during the week following surgery suggest that morning serum cortisol levels > 9 23 μg/dl on postoperative Days 3 7 may be predictive of normal long-term HPA axis function. 2,6,7,9,24 Fewer data are available regarding predictive levels of serum cortisol on postoperative Days 1 2, and these studies have been limited Fig. 2. Graph showing the receiver-operator control curve. Early postoperative serum cortisol levels (in µg/dl) for specific points are indicated above the curve. AUC = area under the curve. 542 J Neurosurg / Volume 111 / September 2009

4 Morning serum cortisol level TABLE 1: Confusion matrix values and derived calculation at selected cortisol levels in 83 patients treated via the transsphenoidal approach* Cortisol Level HPA Normal HPA Dysfunction < or 15.0 µg/dl (TP) 2 (FP) < (FN) 4 (TN) < or 12.0 µg/dl (TP) 3 (FP) < (FN) 3 (TN) * FN = false negative; FP = false positive; TN = true negative; TP = true positive. Sensitivity 80.5%; specificity 66.7%; positive predictive value 96.9%; negative predictive value 21.1%; false-positive rate 33.3%; accuracy 79.5%. Sensitivity 85.7%; specificity 50.0%; positive predictive value 95.7%; negative predictive value 21.4%; false-positive rate 50.0%; accuracy 83.1%. by small sample size, 12 reliance on multiple measures of cortisol levels, 16 and exclusion of patients with abnormal HPA axes. 16 The limitations in existing techniques for assessing HPA axis function in the immediate postoperative period, combined with the brief hospital stay for most patients undergoing resection of pituitary adenomas, has stimulated interest in an assay that would be predictive of HPA axis dysfunction and that could be safely and simply performed shortly after pituitary surgery. We investigated the role of a single measurement of the postoperative morning cortisol level (7 8 a.m. on postoperative Days 1 2) as a predictor for HPA function in patients undergoing transsphenoidal resection of pituitary adenomas. Our findings in 83 consecutive patients suggest that a total serum cortisol level 15 μg/dl on the morning of the 1st postoperative day (or the 2nd day if the patient received glucocorticoids during surgery) predicts normal postoperative HPA function, with a sensitivity of 80.5%, a specificity of 66.7%, a positive predictive value of 96.9%, a negative predictive value of 21.1%, and an accuracy of 79.5%. Lowering the cortisol threshold to 12 μg/dl optimizes the test accuracy at 83.1%, improves the sensitivity by 5.2% (to 85.7%), and slightly improves the negative predictive value (to 21.4%), at a cost of a 16.7% reduction (to 50%) in specificity. The selection between these thresholds is ultimately made according to the preference of the surgeon and the endocrinologist. These results suggest that withholding perioperative cortisol supplementation and using early postoperative morning serum cortisol levels can be done safely and serves as a simple, inexpensive, and useful test to discriminate accurately between the vast majority of patients who will not require exogenous steroid supplementation and those few who will. Conclusions We examined early postoperative morning total cortisol levels in 83 patients undergoing transsphenoidal J Neurosurg / Volume 111 / September 2009 resection of pituitary adenomas and demonstrated that levels 15 µg/dl are predictive of normal long-term HPA function. This test has good sensitivity and accuracy and correlates well with the results of additional, definitive assays of HPA function (CST, ITT, MTT) performed at 1 3 months postoperatively. Accordingly, we suggest that exogenous glucocorticoid supplementation in patients with total serum cortisol levels 15 µg/dl in the immediate postoperative period after transsphenoidal pituitary surgery is not necessary. Disclaimer The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. References 1. Arafah BM: Hypothalamic pituitary adrenal function during critical illness: limitations of current assessment methods. J Clin Endocrinol Metab 91: , Auchus RJ, Shewbridge RK, Shepherd MD: Which patients benefit from provocative adrenal testing after transsphenoidal pituitary surgery? Clin Endocrinol (Oxf) 46:21 27, Clark PM, Neylon I, Raggatt PR, Sheppard MC, Stewart PM: Defining the normal cortisol response to the short synacthen test: implications for the investigation of hypothalamic-pituitary disorders. 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5 N. F. Marko et al. 14. Hamrahian AH: Adrenal function in critically ill patients: how to test? When to treat? Cleve Clin J Med 72: , Hamrahian AH, El-Mallawany NK, Arafah BM: Evaluation and management of pituitary-adrenal function after pituitary surgery. Endocrinologist 9:16 24, Hout WM, Arafah BM, Salazar R, Selman W: Evaluation of the hypothalamic-pituitary-adrenal axis immediately after pituitary adenomectomy: is perioperative steroid therapy necessary? J Clin Endocrinol Metab 66: , Inder WJ, Hunt PJ: Glucocorticoid replacement in pituitary surgery: Guidelines for perioperative assessment and management. J Clin Endocrinol Metab 87: , Klibanski A, Zervas NT: Diagnosis and management of hormone secreting pituitary adenomas. N Engl J Med 324: , Mayenknecht J, Diederich S, Bahr V, Plockinger U, Oelkers W: Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab 83: , Mukherjee JJ, Castro JD, Kaltasas G, Afshar F, Grossman AB, Wass JA, et al: A comparison of the insulin tolerance/glucagon test with the short ACTH stimulation test in the assessment of the hypothalamo-pituitary-adrenal axis in the early post-operative period after hypophysectomy. Clin Endocrinol (Oxf) 47: 51 60, Sing T, Sander O, Beerenwinkel N, Lengauer T: ROCR: visualizing classifier performance in R. Bioinformatics 21: , Thaler LM, Blevins LS: The low dose (1-microg) adrenocorticotripin stimulation test in the evaluation of patients with suspected central adrenal insufficiency. J Clin Endocrinol Me tab 83: , Vance ML: Hypopituitarism. N Engl J Med 330: , Watts NB, Tindall G: Rapid assessment of corticotropin reserve after pituitary surgery. JAMA 259: , 1988 Manuscript submitted October 2, Accepted December 5, Please include this information when citing this paper: published online March 27, 2009; DOI: / JNS Address correspondence to: Robert Weil, M.D., Brain Tumor and Neuro-Oncology Center, The Neurological Institute, Cleveland Clinic, ND4-40 LRI, 9500 Euclid Avenue, Cleveland, Ohio weilr@ccf.org. 544 J Neurosurg / Volume 111 / September 2009