The Journal of Bioscience and Medicine 3, 1 (2013) Article

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1 The Journal of Bioscience and Medicine 3, 1 (2013) Article Early postoperative serum cortisol measurements guide management in a steroid-sparing protocol and predict need for long-term steroid replacement after resection of pituitary s Andrew S. Little, MD 1* ; Mark E. Oppenlander, MD 1 ; Laura Knecht, MD 2 ; Daniel Duick, MD 3 ; William L. White, MD 1 1 Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph s Hospital and Medical Center, Phoenix, Arizona 2 Department of Medicine, St. Joseph s Hospital and Medical Center, Phoenix, Arizona 3 Research, Barrow Neurological Institute, St. Joseph s Hospital and Medical Center, Phoenix, Arizona * Corresponding author: Andrew S. Little, MD; c/o Neuroscience Publications, Barrow Neurological Institute, 350 West Thomas Road, Phoenix, AZ (Tel: (602) ; Fax: (602) ; neuropub@chw.edu) Received: 12 January 2012, Accepted: 19 September 2012, Published: 15 February 2013 Abstract: Background: The utility of postoperative serum cortisol levels in predicting long-term hypothalamic-pituitary -adrenal (HPA) axis function after resection of pituitary s is not well elucidated. Objectives: We evaluated the utility of postoperative Day 2 morning serum cortisol levels for stratifying patients in a steroid-sparing management protocol after resection of pituitary s and for predicting long-term HPA axis function. After surgery 112 patients with pituitary s and normal preoperative adrenal function were managed using a steroid-sparing protocol. Morning postoperative Day 2 cortisol levels were determined for all patients. Those with levels greater than 10 mcg/dl were discharged without steroid supplementation. The ability of postoperative cortisol to predict long-term HPA axis function was assessed by comparing the test results to whether patients required steroid replacement at one year. Findings: Sixty-eight (61%) patients had postoperative cortisol values greater than 10 mcg/dl and were discharged home without steroid coverage, and 44 (39%) were given steroid coverage until definitive testing was performed. Thirteen (12%) patients required chronic steroid replacement. Steroids were subsequently initiated in two patients who were discharged without them, one for minor symptoms and one for failing stimulation testing. With a threshold of 10 mcg/dl, positive predictive value of the diagnostic test was 97% and its specificity was 86%. By increasing the threshold to12 mcg/dl, these values improved to 98% and 93%, respectively. Conclusions: An early postoperative serum cortisol level greater than 12 mcg/dl is a good predictor of adequate long-term HPA axis function after pituitary resection and can be used safely to guide steroid replacement immediately after surgery. A cortisol cutoff of 12 mcg/dl would allow half of the patients in this cohort to be spared perioperative steroids. KEYWORDS: pituitary, serum cortisol, transsphenoidal surgery DOI: /jbm Page 18 C ortisol deficiency is a potentially serious complication of pituitary resection. To prevent an adrenal crisis, it is common practice to empirically cover all patients after surgery until definitive hypothalamic-pituitary-adrenal (HPA) axis testing can be performed and steroids weaned. Because exogenous steroids have numerous adverse effects such as hyperglycemia, causing difficulties with wound healing, infection, and weight

2 gain, some centers have investigated steroid-sparing protocols intended to identify promptly patients with normal adrenal function who do not need supplemental steroids. A simple test that predicts which patients are likely to be steroid deficient may help limit the number of patients who unnecessarily receive exogenous glucocorticoids and provide clinicians with important prognostic information. Several studies have examined the utility of postoperative serum cortisol measurements for predicting the need for longterm supplementation (1-4). Early postoperative serum cortisol measurement has the advantages of being widely available, inexpensive, and easy to perform. In contrast, formal cosyntropin stimulation and insulin tolerance testing is more expensive, time consuming, and may require inpatient admission (5-8). Because of these issues, serum cortisol levels obtained within the first week of surgery may serve as a surrogate for more complicated tests. Preliminary guidelines for the interpretation of postoperative serum cortisol measurements have been proposed (9) but are based on studies limited by a small sample and heterogeneous patient population. At our institution, we instituted a steroid-sparing protocol in 2003 that utilized serum cortisol levels obtained 2 days after surgery to determine which patients required steroid coverage. Based on our experience, we chose a cortisol threshold of 10 mcg/dl to guide treatment until formal testing was completed 1 to 2 months after surgery. Patients with serum cortisol levels greater than 10 mcg/dl were discharged without steroid coverage whereas patients with cortisol level less than 10 mcg/dl received steroid supplementation. The primary aims of this study were to investigate utility of early postoperative serum cortisol measurements for predicting long-term cortisol deficiency and to determine if they were useful in selecting patients who could be discharged safely without glucocorticoid coverage. This work could supplement other work in this area by providing an analysis of a larger and more homogeneous population of patients than has previously been reported. Methods Study population One hundred twelve patients (54 males, 58 females) with pituitary s, not on preoperative steroid supplementation, and no history suggestive of hypocortisolemia who underwent transsphenoidal surgery between January 2003 and June 2007 were included in the analysis. The analysis excluded patients taking preoperative glucocorticoid supplementation, functioning s, or prior radiotherapy. The mean age of patients was 55 years (range years). The most common presenting symptoms (Table 1) were headache (71 patients) and visual field complaints (61 patients). Eight patients (7%) had undergone prior surgery. The mean coronal height of the tumors was 17 mm (range 11 to 47 mm). Perioperative steroid management The management of patients during their immediate postoperative hospitalization was standardized. Stress-dose dexamethasone was administered at the induction of anesthesia (4 mg), on the night of surgery (2 mg) and on the morning of postoperative Day (POD) 1 (2 mg). At 8 am on POD 2, serum cortisol levels (POD2 cortisol) were determined. Patients with a level less than 10 mcg/dl received prednisone (5 mg daily) coverage until they could undergo formal outpatient adrenal testing. Patients with morning serum cortisol levels greater than 10 mcg/dl were discharged without replacement steroids and counseled on symptoms of cortisol deficiency. Evaluation of POD 2 cortisol testing This study was approved by the St. Joseph s Hospital and Medical Center Institutional Review Board, but was restricted to reviewing data at affiliated sites. Consequently, data on the preoperative and postoperative formal HPA axis evaluation performed by unaffiliated consulting endocrinologists were unavailable for review. These restrictions affected our study design. To determine the utility of POD 2 cortisol level as a diagnostic test for predicting long-term HPA axis function, we compared the results to whether patients required steroid replacement therapy at 1 year (the gold standard) rather than to adrenocorticotropic hormone stimulation results. Patients not on steroid supplementation were considered to have adequate HPA axis function, and patients on supplementation were considered to be adrenally insufficient. Sensitivity, specificity, positive predictive value, and negative predictive value were determined for various cut-off values for POD 2 cortisol. A true positive was defined as a patient who had a serum cortisol level greater than the cutoff value and who was not taking steroid replacement at one year. A false positive was defined as a patient who had a POD 2 cortisol greater than the cutoff value and a deficient HPA axis at 1 year indicated by taking steroid supplementation. Statistical analysis was completed utilizing SPSS (version 14.0) by a doctorally trained biostatistician. Results Of the 112 patients, 44 (39%) had POD 2 cortisol levels less than 10 mcg/dl and were discharged home on steroid replacement. Sixty-eight (61%) had cortisol levels greater than 10 mcg/dl and were discharged without glucocorticoids (Fig. 1). DOI: /jbm Page 19

3 operating curve (ROC) analysis was performed, and the area under the curve was 0.80 (95% confidence limit ), which is considered good. The analysis suggested a cutoff of 10 mcg/dl. Table 2: Characteristics of POD 2 Cortisol Testing POD 2 Cortisol Value (mcg/dl) Positive Predictive Value % Specificity % Figure 1. Treatment algorithm based on the results of postoperative Day (POD) 2 morning serum cortisol levels. Used with permission from Barrow Neurological Institute One year after surgery, 14 patients (13%) were on chronic steroid replacement and 98 (87%) were not. No deaths or serious adverse events occurred in the 68 patients who received no steroid coverage after discharge. However, two patients needed steroids initiated during the follow-up period. One patient (POD 2 cortisol of 12 mcg/dl) complained of fatigue 8 weeks after surgery; his symptoms resolved with the initiation of prednisone and he remained on prednisone at one year) Formal stimulation testing results were not available for this patient. The other patient (70-year-old female, cortisol 12.5 mcg/dl) was asymptomatic but was placed on replacement steroids after failing definitive assessment of the HPA axis 3 months after surgery. Neither of these patients had preoperative stimulation testing, but 0800 cortisol levels were greater than 15 mcg/dl. Table 1: Presenting symptoms of 112 patients with pituitary s Symptom n (%) Chiasmopathy 61 (54) Extraocular Movement Deficits 15 (13) Headache 71 (63) Apoplexy 13 (12) Abnormal Menses 10 (9) Incidental 17 (15) The sensitivity, specificity, negative predictive value, and positive predictive value of POD 2 cortisol were calculated for various cut-offs (Table 2). POD 2 cortisol > 10 mcg/dl had a high positive predictive value (97%) and specificity (86%). Adjusting the cutoff to12 mcg/dl increased the positive predictive value of the test to 98% and the specificity to 93%. A receiver DOI: /jbm Page Discussion Patients undergoing resection of pituitary s are routinely supplemented with glucocorticoids on hospital discharge to prevent Addisonian crises until a formal assessment of their pituitary function can be obtained. Because exogenous steroids have adverse effects, several investigators have examined strategies to improve stratification who should receive postoperative steroids and who should not to minimize risks associated with overtreatment with glucocorticoids. Several studies have suggested that morning postoperative serum cortisol levels may have a role in stratifying immediate postoperative patients (Table 3) (1-3). Inder et al. reviewed the literature and proposed patient management guidelines (9). They suggested that cortisol levels higher than 16 mcg/dl (450 nm) predict normal long-term functioning of the HPA axis and eliminate the need for steroid coverage. Patients with levels less than 16 mcg/dl may be cortisol deficient and should receive steroid coverage until definitive testing is obtained. In a prospective observational study in 83 patients, Marko et al. further investigated the utility of early postoperative cortisol testing (2). They determined that cortisol levels greater than 15 mcg/dl are good predictors of normal function and correlate well with definitive testing. Compared to definitive assays of HPA function performed several months after surgery, the positive predictive value and sensitivity of the test were 96.9% and 80.5%, respectively. In a subsequent publication, they reviewed 100 patients who underwent cortisol measurements 1 to 3 hours after surgery and reported positive predictive value and sensitivity of 99% and 98% for a cortisol cutoff of 15 mcg/dl. Consequently, they propose withholding steroid coverage in patients with cortisol lev-

4 Table 3: Summary of studies evaluating morning cortisol levels after resection. CST: Cortrosyn stimulation test, ITT: insulin tolerance test, MTT: metyrapone test, and HPA: hypothalamic-pituitary adrenal Reference Study Population No. Patients Routine postoperative steroid coverage protocol Watts and Tindall 35 1 to 2 days of hydrocorti- (1988)(3) sone Courtney et al. (2000)(5) Marko et al. (2009)(2) Marko et al. (2010) (10) Current Study Nonfunctioning els greater than 15 mcg/dl (10). The main limitations of these prior reports are that they review cohorts heterogeneous with respect to preoperative HPA axis function and secretory status of the tumor. For example, the series by Marko et al. (2), Courtney et al. (5), and Watts et al. (3) included patients with preoperative adrenal suppression. Because the role of postoperative cortisol assessment may be different in such patients, we focused on patients not requiring steroid supplementation and those with nonsecreting tumors. Doing so may clarify recommendations for this cohort. Furthermore, the addition of a large series to the overall experience may improve the power to detect infrequent adverse events related to withholding steroid replacement. Finally, the threshold for steroid supplementation recommended by other groups (<15 mcg/dl) was more stringent than what we employ. Our study was therefore an opportunity to gather comparative clinical data to refine the risks and benefits of different steroid-sparing protocols. Developing management recommendations based on postoperative cortisol levels involves balancing the risks of overtreating patients with normal HPA axis function and undertreating those with adrenal insufficiency. In this clinical circumstance, the positive predictive value is the most important diagnostic test parameter because it describes the likelihood that a patient with a POD 2 cortisol above the threshold for whom steroids have been withheld has an intact HPA axis long-term. Specificity is also an important characteristic because it describes the likelihood that all patients needing steroid supplementation were correctly identified. Our study offers the opportunity to fine-tune current recommendations based on postoperative cortisol values. We learned that the positive predictive value (100%) and specificity (100%) of the serum cortisol assay is excellent at DOI: /jbm Page or 6 days of hydrocortisone Postoperative cortisol draw Day 2 or 3 Gold standard comparison ITT 5 to 7 days after surgery Study Recommendation > 9 mcg/dl Day 6 or 7 ITT at 6 weeks Cortisol > 16 mcg/dl predicts normal HPA axis 83 No steroids given routinely Day 1 or 2 CST/ITT/MTT at 1-3 months > 15 mcg/dl 100 No steroids given routinely Day 0 CST at 1 month > 15 mcg/dl day of dexamethasone Day 2 Steroid dependency at 1 year > mcg/dl cortisol levels of 15 mcg/dl or greater. However, using 15 mcg/ dl as a trigger would have resulted in overtreating a proportion of patients who ultimately proved to have normal HPA axis function. For example, if a threshold of 15 mcg/dl instead of 10 mcg/dl had been used, 18 patients would have been treated unnecessarily to protect two patients who were modestly cortisol deficient (1 patient with minor symptoms and 1 with no symptoms but who failed follow-up provocative testing) and safely managed as outpatients. A threshold of either 10 mcg/ dl (positive predictive value 97% and specificity 86%) or 12 mcg/dl (positive predictive value 98% and specificity 93%) may represent better practical thresholds. Given these findings, we suggest that patients with POD 2 morning cortisol levels greater than 10 mcg/dl to 12 mcg/dl be observed after discharge without steroid coverage with appropriate counseling on the symptoms of adrenal insufficiency. Patients with levels less than 12 mcg/dl should receive steroid coverage until definitive HPA axis testing is performed. This protocol provides the opportunity to spare steroid coverage in about half of the patients. Several aspects of this study deserve further comment. While our study has demonstrated that postoperative morning serum cortisol levels are clinically useful for predicting which patients will not require steroid replacement, one important limitation is that it does not predict which patients will need steroid supplementation. This point reinforces the concept that cortisol levels are a useful screening test but not a confirmatory test to replace provocative assays. The negative predictive value of cortisol testing is poor in our hands because the pituitary gland may have capacity to recover after surgery and because we supplemented with perioperative dexamethasone. Dexamethasone has a half-life of 48 to 72 hours and may suppress cortisol levels on Day 2. Using a perioperative steroid with a shorter half-life such as hydrocortisone or no steroid at

5 all may improve some of the testing parameters; dexamethasone suppression of POD2 cortisol might misclassify patients as being adrenal insufficient. Next, we selected whether patients required glucocorticoid supplementation or not rather than use the results of stimulation testing as a gold standard for this study because of the limitations of our IRB approval. Furthermore, we did not perform stimulation testing in all patients preoperatively or postoperatively. Some might argue that stimulation testing allows for better identification of patients with partial adrenal deficiency, but our methodology provides a practical way to score patients who follow-up with the community endocrinologists not affiliated with our center. Preoperative morning cortisol levels and need for steroid supplementation were used as surrogate markers for endocrine status because they are inexpensive and easy assessments. We do not believe that all patients require preoperative stimulation testing because it would be unnecessarily costly and time-consuming in patients whose history raises no concerns, who have significant normal gland, or who have not had apoplexy. Conclusions This study demonstrates that a steroid-sparing protocol guided by POD 2 morning cortisol measurements in patients with adequate preoperative HPA axis function who have undergone transsphenoidal resection of pituitary is safe. Our data suggest that early postoperative serum cortisol levels are useful for determining which patients do not require postoperative steroid replacement and in predicting endocrine function at one year. While we had previously used a cortisol level of 10 mcg/dl as a threshold for supplementation, these data suggest that a threshold of 12 mcg/dl improves the positive predictive value of the test and limits the number of patients overtreated with steroids. Patients with morning serum cortisol values less 12 mcg/dl should receive glucocorticoid supplementation until definitive HPA axis testing is performed, while patients with levels greater than 12 mcg/dl can be discharged without steroids and followed clinically for symptoms of cortisol deficiency. Using the serum cortisol assay to guide management provides the opportunity to spare steroid coverage in more than half of these patients after surgery. Acknowledgments necessary? J Clin Endocrinol Metab. 1988;66(6): Marko NF, Gonugunta VA, Hamrahian AH, Usmani A, Mayberg MR, Weil RJ. Use of morning serum cortisol level after transsphenoidal resection of pituitary to predict the need for long-term glucocorticoid supplementation. J Neurosurg. 2009;111(3): Watts NB, Tindall GT. Rapid assessment of corticotropin reserve after pituitary surgery. JAMA. 1988;259(5): Wentworth JM, Gao N, Sumithran KP, Maartens NF, Kaye AH, Colman PG, Ebeling PR. Prospective evaluation of a protocol for reduced glucocorticoid replacement in transsphenoidal pituitary adenomectomy: prophylactic glucocorticoid replacement is seldom necessary. Clin Endocrinol (Oxf). 2008;68(1): Courtney CH, McAllister AS, McCance DR, Bell PM, Hadden DR, Leslie H, Sheridan B, Atkinson AB. Comparison of one week 0900 h serum cortisol, low and standard dose synacthen tests with a 4 to 6 week insulin hypoglycaemia test after pituitary surgery in assessing HPA axis. Clin Endocrinol (Oxf). 2000;53(4): 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. Clin Endocrinol (Oxf). 1998;49 (3): Dokmetas HS, Colak R, Kelestimur F, Selcuklu A, Unluhizarci K, Bayram F. A comparison between the 1-microg adrenocorticotropin (ACTH) test, the short ACTH (250 microg) test, and the insulin tolerance test in the assessment of hypothalamo-pituitary-adrenal axis immediately after pituitary surgery. J Clin Endocrinol Metab. 2000;85 (10): Dickstein G. High-dose and low-dose cosyntropin stimulation tests for diagnosis of adrenal insufficiency. Ann Intern Med. 2004;140(4): Inder WJ, Hunt PJ. Glucocorticoid replacement in pituitary surgery: guidelines for perioperative assessment and management. J Clin Endocrinol Metab. 2002;87(6): Marko NF, Hamrahian AH, Weil RJ. Immediate postoperative cortisol levels accurately predict postoperative hypothalamic-pituitary-adrenal axis function after transsphenoidal surgery for pituitary tumors. Pituitary. 2010;13(3): The authors thank Pamela Goslar, PhD for assistance with statistical analysis. References 1. Hout WM, Arafah BM, Salazar R, Selman W. Evaluation of the hypothalamic-pituitary-adrenal axis immediately after pituitary adenomectomy: is perioperative steroid therapy DOI: /jbm Page 22