Postoperative day 1 versus postoperative day 5 morning cortisol for predicting an intact hypothalamic-pituitary axis: A cohort analysis
- Department of Neurosurgery, University of Alabama, Birmingham, United States.
- Joe DiMaggio Children’s Hospital, Hollywood, Fla., United States.
- Erlanger Neurosurgery and Spine, Chattanooga, TN., United States.
- Department of Medicine in Endocrinology, Diabetes and Nutrition, Boston Medical Center, Boston MA, United States.
- Department of Medicine, Endocrinology Division, University of Alabama, Birmingham, United States.
Department of Neurosurgery, University of Alabama, Birmingham, United States.
DOI:10.25259/SNI-105-2019Copyright: © 2019 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Esther Dupepe, Daxa Patel, Joseph Miller, Ivania Rizo, Tom Brooks Vaughan, Kristen Riley. Postoperative day 1 versus postoperative day 5 morning cortisol for predicting an intact hypothalamic-pituitary axis: A cohort analysis. 07-Jun-2019;10:91
How to cite this URL: Esther Dupepe, Daxa Patel, Joseph Miller, Ivania Rizo, Tom Brooks Vaughan, Kristen Riley. Postoperative day 1 versus postoperative day 5 morning cortisol for predicting an intact hypothalamic-pituitary axis: A cohort analysis. 07-Jun-2019;10:91. Available from: https://surgicalneurologyint.com/?post_type=surgicalint_articles&p=9357
Background:A reliable standard for evaluating postoperative hypothalamic-pituitary-axis (HPA) function following transsphenoidal pituitary surgery (TSS) could reduce hospital stays and unnecessary prolonged steroid therapy. We retrospectively examined the predictive role of morning cortisol levels on long-term HPA function to develop an institutional protocol. Here, we report the results of this analysis, which is the first to report the predictive strength of multiple variables (i.e., timing of measurement and values of serum cortisol cutoffs) within the same cohort.
Methods:A retrospective chart review was performed in 183 patients at a single institution from 2007 to 2012. 67 patients met inclusion criteria. The predictive value of postoperative day (POD) 1 and POD 5 morning cortisol for HPA function as determined by 1 ug cosyntropin stimulation test was evaluated using standard confusion matrix calculations and receiver-operator control curve analysis.
Results:In our cohort, an early POD 5 serum morning cortisol ≥15 ug/dl predicted an intact HPA axis with 100% specificity, 51% sensitivity, and a positive predictive value (PPV) of 100%. A POD 1 serum cortisol ≥25 ug/dl was needed to achieve a specificity of 100% and PPV of 100% to predict an intact HPA axis with a sensitivity of 30%. A POD 1 serum cortisol ≥18 ug/dl predicted an intact HPA axis with 33.3% specificity, PPV of 90.9%, and a sensitivity of 51.3%.
Conclusion:A POD 5 morning cortisol level ≥15 ug/dl is an excellent predictor of normal postoperative HPA function in patients undergoing TSS for pituitary adenoma.
Keywords: Hypothalamic-pituitary axis, Postoperative cortisol, Transsphenoidal adenomectomy
Transsphenoidal pituitary surgery (TSS) for pituitary adenomas is a fairly frequent necessity as a treatment modality of pituitary adenomas that are causing visual deficits and threatening vision or are hypersecretory. Hospital stays for this surgery can be brief and often patients can discharge within 24–48 h of the procedure which challenges physicians with assessing the hypothalamic-pituitary-adrenal axis (HPA) in a short span of time to avoid prolonging hospital length of stay.
The most commonly performed traditional tests to assess the HPA axis are the low dose (1 μg) or high dose (250 μg) 1 ug cosyntropin stimulation tests (CSTs). However, these tests cannot be performed with any reliability acutely after surgery or any form of pituitary injury because it takes 2–4 weeks for the adrenal glands to atrophy from a lack of ACTH stimulation. The insulin tolerance test is the gold standard test of the HPA axis because it stimulates the entire axis and, therefore, does not require waiting 2–4 weeks to perform. However, it is cumbersome and associated with some risk and, therefore, impractical to perform in the immediate postoperative period.
Due to the limitations of available tests, a variety of methods have been proposed to rapidly assess the HPA axis after surgery; however, there is no current gold standard and pituitary centers use a variety of methods. The critical issue is balancing the adverse effects and risk to patients of prolonged glucocorticoid exposure before definitive CST can be performed versus the potentially catastrophic risk of missing a case of central adrenal insufficiency if the screening test in the postoperative period is inaccurate.
Due to the possibility for a fatal outcome with missed adrenal insufficiency, our institution historically utilized a conservative approach with empiric postoperative glucocorticoid coverage until a definitive assessment was performed 4–6 weeks postsurgery.[
There are other published protocols involving the utilization of an immediate POD 1 or day 5 cortisol values in the assessment of the HPA axis but none assessing multiple time points and cutoff values in a single population.[
We reviewed data from all patients who underwent endoscopic transsphenoidal surgery for pituitary adenoma at the University of Alabama at Birmingham between August 2007 and March 2012. This resulted in a total of 183 patients. Patients taking long-term exogenous steroids or who underwent TSS for Cushing’s disease or pituitary apoplexy or who received stress dose corticosteroids perioperative or postoperative due to nasal flap were excluded from the study. A total of 67 patients met inclusion criteria.
All patients in our cohort group received 0.5 mg of dexamethasone in the operating room before start endoscopic transsphenoidal pituitary adenomectomy. A 0800 am serum cortisol level was drawn on POD 1. Regardless of the 0800 am serum cortisol, patients were started on hydrocortisone (HC) 10 mg once a day. A serum cortisol was checked again as an outpatient at 0800 on POD 5. Patients were instructed to hold their dose of HC until after this laboratory was drawn on POD 5. If both POD 1 and POD 5 0800 am cortisol were ≥18 ug/dl, then HC was discontinued. If either POD 1 or POD 5 0800 am cortisol was <18 ug/dl, then HC was continued. The patients who were continued on HC were scheduled for follow-up approximately 4 weeks postoperatively for a low-dose (1 ug) CST. Before the CST, HC was tapered from 10 mg/day to 5 mg/day and then held on the day of CST. During the CST, serum total cortisol levels were assayed at baseline and 30 min postinjection. Patients who had a serum cortisol ≥18 ug/dl at 30 min postinjection were deemed to have an adequate and sufficient response and were taken off of HC. This management algorithm is outlined in
The ability of POD 1 and POD 5 cortisol to predict HPA function was determined using standard confusion matrix calculations and receiver-operator control curve analysis. Analyses were performed using both a serum cortisol ≥18 ug/dl and ≥15 ug/dl.
Twenty-one of the 67 patients who met inclusion criteria had a POD 1 and POD 5 0800 am cortisol ≥18 ug/dL and, therefore, did not continue HC after the results from POD 5 were received. Forty-six patients had either POD 1 or POD 5 or both 0800 am cortisol <18 ug/dL. One patient did not follow-up at our institution. Two of the 46 patients with a POD 1 <18 ug/dL but POD 5 0800 am cortisol ≥18ug/dL and were not continued on HC.
Forty-three patients were continued on HC and had a CST after approximately 4 weeks. Forty patients passed the CST and three patients had a serum cortisol <18 ug/dl at 30 min postinjection. These three patients were continued on long-term HC [
In our cohort, an early POD 5 serum morning cortisol ≥15 ug/dl predicted an intact HPA axis with 100% specificity, 51% sensitivity, and positive predictive value (PPV) of 100%. POD 5 serum morning cortisol ≥18 ug/dl also predicted an intact HPA axis with 100% specificity and PPV. A POD 1 serum cortisol ≥25 ug/dl was needed to achieve a specificity and PPV of 100% with a sensitivity of 30%. A POD 1 serum cortisol ≥18 ug/dl predicted an intact HPA axis with only 33.3% specificity, PPV of 90.9%, and a sensitivity of 51.3%. A POD 1 cortisol ≥15 ug/dl predicted an intact HPA axis with 69.2% sensitivity, 33.3% specificity, and 93.1% PPV. These data are presented in
Physicians are faced with balancing the risk of unnecessary exposure to glucocorticoids compared to the potentially fatal risk of missing a case of central adrenal insufficiency when deciding to continue patients on glucocorticoid treatment postoperatively. A reliable standard for evaluating HPA function in the immediate postoperative period would enable clinicians to choose treatment strategies that minimize the risk to individual patients. However, there is no current gold standard for assessing the function of the HPA axis in the immediate postoperative period. Our study aimed to assess the utility of POD 1 and POD 5 serum cortisol measurements for this purpose.
The gold standard for assessing HPA function is the insulin tolerance test. However, adverse side effects (e.g., myocardial ischemia, seizures, and arrhythmias) make this test undesirable in many patient populations including postoperative and elderly patients.[
A variety of protocols have been proposed to assess function in the early postoperative period, but controversy persists in key aspects of each protocol.[
Proposed morning serum cortisol cutoff values indicative of intact HPA function range from >8 μg/dL to >18 μg/dL.[
In respect to the timing of morning serum cortisol measurements, earlier literature supports using values on POD 3–7[
Our study aimed to address both areas of key controversy by assessing multiple cutoff values at time points of both POD 1 and 5. We used the low-dose cosynotropin stimulation after 4–6 weeks for definitive testing. In doing so, this is the first study to report results for multiple variables in regard to timing and cutoff values within the same study cohort allowing for direct comparisons.
We found that POD 5 values (both >18 and >15 ug/dl) were better predictors of a functional HPA with a specificity and PPV of 100%. Furthermore, two of 23 patients (8.7%) with a POD 1 cortisol ≥18 ug/dl ultimately failed the CST, which calls into question the safety of using this time point to make treatment decisions and suggests that early POD 1 measurements are less reliable indicators of an intact HPA than POD 5 measurements. This is consistent with the results reported by Manuylova et al. In their series, 9 of 32 (28%) patients with an initial POD 1 cortisol ≥14 ug/dl went onto have POD 6 cortisol <14 ug/dl.[
This contrasts with the findings of earlier studies. Marko et al. reported POD 1 serum cortisol levels >15 ug/dL corresponding to an intact HPA with 80.5% sensitivity, 66.7% specificity, and 96.9% PPV.[
Jayasena et al. also used intraoperative coverage although preoperative function was unknown in their population.[
Our findings are limited by our small sample size, which is similar to other reported studies. In addition, it is difficult to compare our findings to other studies that use dissimilar protocols, specifically with respect to intraoperative steroid coverage. All patients included in our study received 0.5 mg dexamethasone intraoperatively and it is possible that these patients represent a unique subset compared to patients with known normal function who do not receive intraoperative steroid coverage. We feel it is unlikely that the intraoperative steroid dose administered (0.5 mg dexamethasone) altered the utility of POD 1 versus POD 5 morning cortisol values but recommend that future studies take this into consideration and address this potential limitation through the use of uniform protocols and subset analysis to further delineate if these two groups are truly distinct. A large multicenter study with uniform protocols is needed to address the limitations identified in our study.
Given the potentially serious consequences of failing to recognize patients with an impaired HPA, screening tests with 100% PPV should be used when deciding which patients require replacement steroids. In our cohort, 8.7% of patients with POD 1 cortisol >18 ug/dl failed CST while POD 5 cortisol >15 and 18 ug/dl predicted a functional HPA with 100% specificity and PPV. A POD 5 morning cortisol level ≥15 ug/dl is an excellent predictor of normal postoperative HPA function.
1. Arraez MA. Assessment of postoperative hypocortisolism after pituitary surgery: When and how?. World Neurosurg. 2013. 80: 495-7
2. Auchus RJ, Shewbridge RK, Shepherd MD. Which patients benefit from provocative adrenal testing after transsphenoidal pituitary surgery?. Clin Endocrinol (Oxf). 1997. 46: 21-7
3. Courtney CH, McAllister AS, McCance DR, Bell PM, Hadden DR, Leslie H. 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: 431-6
4. Cozzi R, Lasio G, Cardia A, Felisati G, Montini M, Attanasio R. Perioperative cortisol can predict hypothalamus-pituitary-adrenal status in clinically non-functioning pituitary adenomas. J Endocrinol Invest. 2009. 32: 460-4
5. Dorin RI, Qualls CR, Crapo LM. Diagnosis of adrenal insufficiency. Ann Intern Med. 2003. 139: 194-204
6. Inder WJ, Hunt PJ. Glucocorticoid replacement in pituitary surgery: Guidelines for perioperative assessment and management. J Clin Endocrinol Metab. 2002. 87: 2745-50
7. Jayasena CN, Gadhvi KA, Gohel B, Martin NM, Mendoza N, Meeran K. Day 5 morning serum cortisol predicts hypothalamic-pituitary-adrenal function after transsphenoidal surgery for pituitary tumors. Clin Chem. 2009. 55: 972-7
8. Kozyra EF, Wax RS, Burry LD. Can 1 g of cosyntropin be used to evaluate adrenal insufficiency in critically ill patients?. Ann Pharmacother. 2005. 39: 691-8
9. Magnotti M, Shimshi M. Diagnosing adrenal insufficiency: Which test is best--the 1-microg or the 250-microg cosyntropin stimulation test?. Endocr Pract. 2008. 14: 233-8
10. Manuylova E, Calvi LM, Vates GE, Hastings C, Shafiq I. Morning serum cortisol level after transsphenoidal surgery for pituitary adenoma predicts hypothalamic-pituitary-adrenal function despite intraoperative dexamethasone use. Endocr Pract. 2015. 21: 897-902
11. Marko NF, Gonugunta VA, Hamrahian AH, Usmani A, Mayberg MR, Weil RJ. Use of morning serum cortisol level after transsphenoidal resection of pituitary adenoma to predict the need for long-term glucocorticoid supplementation. J Neurosurg. 2009. 111: 540-4
12. 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: 249-55
13. McLaughlin N, Cohan P, Barnett P, Eisenberg A, Chaloner C, Kelly DF. Early morning cortisol levels as predictors of short-term and long-term adrenal function after endonasal transsphenoidal surgery for pituitary adenomas and rathke’s cleft cysts. World Neurosurg. 2013. 80: 569-75
14. Oelkers W. Adrenal insufficiency. N Engl J Med. 1996. 335: 1206-12
15. Rothwell PM, Lawler PG. Prediction of outcome in intensive care patients using endocrine parameters. Crit Care Med. 1995. 23: 78-83