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Ten Years on: Safety of Short Synacthen Tests in Assessing Adrenocorticotropin Deficiency in Clinical Practice

Metabolic Unit, Western General Hospital, Edinburgh, United Kingdom EH4 2XN

Address all correspondence and requests for reprints to: Dr. P. L. Padfield, Department of Endocrinology, Western General Hospital, Edinburgh, United Kingdom EH4 2XN. E-mail: paul.padfield{at}luht scot.nhs.uk.

Abstract

Since 1988, when a retrospective study of patients attending this unit was published, we have advocated the use of the short synacthen test (SST) as the primary screening investigation to detect ACTH deficiency. However, others have published comparisons of SST and insulin tolerance tests that suggest a significant false negative rate with SST, leading to concern that some patients who pass the SST are in danger from the clinical consequences of ACTH deficiency.

To address this, we audited biochemical results and clinical outcome in 63 patients who did not have ACTH deficiency detected (i.e. who passed the test) by SST after pituitary surgery.

Twelve of the 63 patients who passed a SST after pituitary surgery became ACTH-deficient later as diagnosed by SST: 4 within the first year, 2 of whom had received postoperative radiotherapy (3 had symptoms of tiredness and 1 was admitted to the hospital with a viral infection); 8 in yr 3–5, 7 of whom had received postoperative radiotherapy (all had either no symptoms or symptoms of tiredness alone). Thus, the predictive value of the SST in excluding ACTH deficiency is approximately 97% (2 of 63 patients who initially passed the SST were found to be ACTH-deficient within 12 months without having received postoperative radiotherapy). Only 1 patient was ill enough to require hospital admission.

Setting the risk of false negatives with SST against the morbidity and manpower implications associated with insulin tolerance tests, SST remains the primary screening test for ACTH deficiency in our practice. However, a high index of clinical suspicion to detect false negative results must be maintained.

THERE HAS BEEN much debate over the last 20 yr as to which is the most appropriate screening test of ACTH deficiency. The short synacthen test (SST) is cheaper, safer, and less unpleasant for the patient than the insulin tolerance test (ITT). Consequently, the use of the SST as a screening investigation for ACTH deficiency is popular among UK endocrinologists, with two surveys, 6 yr apart, demonstrating an increase from 24% in 1988 to 50% in 1994 (1, 2).

In 1988, a study from this unit compared 70 paired SST and ITT results in patients with pituitary disease (1). We advocated the use of the SST as the primary screening investigation to detect ACTH deficiency (1). Furthermore, this retrospective audit showed that a measurement of 0900-h plasma cortisol of more than 400 nM is predictive of an intact hypothalamic-pituitary-adrenal (HPA) axis (1), and many others have confirmed this (3, 4, 5, 6, 7, 8). However, different conclusions have been drawn from more recent studies that compared the SST with the ITT in the setting of ACTH deficiency, using various ‘pass’ levels of plasma cortisol (5, 9, 10, 11, 12, 13, 14); a normal cortisol response to a SST can be found in patients with a subnormal response to ITT. This has led to concern that the SST may not demonstrate whether the patient would have an adequate response in a stressful situation, notwithstanding that even the ITT may not be 100% sensitive and specific for ACTH deficiency (10, 15).

In the present study, we have taken a different pragmatic approach. Rather than comparing the SST with a so-called gold standard ITT in patients with known ACTH deficiency, we have examined the predictive value of postoperative SST for clinical outcome among all patients undergoing pituitary surgery, including those with and without ACTH deficiency. We have also reexamined the value of measurement of 0900-h plasma cortisol in the immediate postoperative period. This enabled us to examine whether the perceived dangers of undiagnosed ACTH deficiency translate into an unacceptable risk in the clinical scenario in which the test is commonly used.

Subjects and Methods

Patients who had pituitary surgery from March 1989 to February 1999 were traced, using the hospital diagnostic coding system (see Fig. 1). One hundred fifty-three operations in 143 patients were identified. Thirty patients, who had 33 operations, were excluded. Thus, information on 120 operations was obtained from 113 patients’ case notes.

View larger version (30K): [in this window] [in a new window]   Figure 1. Numbers of patients and operations assessed and clinical outcome, in the first postoperative year, in those patients passing SST postoperatively.

The recommended protocol after pituitary surgery throughout this period was that: hydrocortisone [20 mg (morning) and 10 mg (afternoon)] be administered for 48 h from the day of surgery; 0900-h plasma cortisol be measured before the hydrocortisone dose on the third postoperative day; hydrocortisone replacement therapy be continued, in the same regimen, only if 0900-h plasma cortisol was less than 400 nM; and all patients reattend for a SST 4–6 wk postoperatively.

The SST was carried out at varying times of the day by Metabolic Unit nursing staff. Hydrocortisone was omitted on the morning of the test. Blood was collected for measurement of plasma cortisol before and 30 min after im injection of 250 µg 1–24 corticotrophin. Plasma cortisol was measured as follows: from 1989 to August 1994, by a manual competitive RIA (Amerlex M; Amersham Biosciences UK Ltd., Bucks, UK); from July 1994 to May 1999, by a competitive nonisotopic, automated assay (TDX Analyser; Abbott Laboratories Ltd., Berks, UK); and from May 1999 to date, by an automated competitive magnetic separation assay (Immuno 1 Analyser, Bayer plc, Newbury, UK). The criterion for a pass cortisol level for the SST has changed over the years, as the assays have become more specific and hence have generated consistently lower values. Based on extrapolation from the assay used before 1989, for which the peak cortisol cut-off to infer ACTH deficiency was 550 nM (1), the cut-off was adjusted in 1994 to 520 nM and in 1999 to 460 nM. The incremental change after ACTH has never been used in our diagnostic criteria. Because SSTs were performed at all times of the working day, we did not evaluate predictions from the basal cortisol measurement before ACTH administration. At lower cortisol concentrations, the bias in the assay is less pronounced, so that a 0900-h plasma cortisol more than 400 nM has always been taken to indicate intact ACTH secretion 3 d after pituitary surgery.

Statistics

Data are presented as median (range). We used clinical outcome as the gold standard for ACTH deficiency. Terms denoting test outcome were defined as: a false negative result, when either 0900-h cortisol was more than 400 nM or the SST was passed in the setting of ACTH deficiency; a false positive result, when response to a test was subnormal in the setting of an intact HPA axis; the false negative rate, as the percentage of false negative results in patients with known ACTH deficiency; the false positive rate, as the percentage of false positive results in patients diagnosed as having an intact HPA axis; the predictive value of the test to exclude ACTH deficiency, as the percentage of true negative results in patients diagnosed as having an intact HPA axis by the same test; and the predictive value of the test to diagnose ACTH deficiency, as the percentage of true positive results in patients diagnosed as having ACTH deficiency by the same test.

Results

Of the 113 patients identified, 72 were male. The diagnoses of the patients are as follows: nonfunctioning pituitary adenoma (n = 70), acromegaly (n = 30), craniopharyngioma (n = 4), macroprolactinoma (n = 5), microprolactinoma (n = 1), pituitary cyst (n = 1), meningioma (n = 1), toxoplasmosis (n = 1). The median age at operation was 54 (range, 17–80) yr; 71.7% (81 of 113) of patients received radiotherapy post pituitary surgery. The patients had a total of 485 yr of follow-up after each operation, with a median of 2 (<1–10) yr.

See Fig. 1. Of the 120 operations, 89 operations in 89 patients were assessed postoperatively by the SST. SST was performed at a median of 47 (range, 10–188) d.

Of the remaining 31 operations (24 patients): there was no testing of the HPA axis after 21 operations (14 patients) because of documented long standing or preoperative ACTH deficiency, and the patients remained on hydrocortisone replacement; the HPA axis was assessed by an ITT after 3 operations (3 patients) and 0900-h plasma cortisol levels after 3 operations (3 patients); the relevant information on 4 operations (4 patients) was missing from the case notes.

0900-h Cortisol measurement

See Fig. 1 and Table 1. None of the 89 patients became unwell during the immediate postoperative period. After 30 operations, there was a third-day postoperative 0900-h plasma cortisol of less than 400 nM, and these patients were maintained on hydrocortisone until further assessment. Eleven of these patients passed the SST; however, one of these patients went on to develop signs of ACTH deficiency during the first year after the operation, requiring hydrocortisone replacement (see case 1). There were, therefore, 10 false positive results for third-day postoperative 0900-h plasma cortisol of less than 400 nM. One patient not maintained on hydrocortisone postoperatively borderline-failed the SST at 40 d (plasma cortisol, 208 nM at 0 min and 458 nM at 30 min; the SST was in 1997, so the 30-min plasma cortisol pass level was defined as 520 nM). Another patient not maintained on hydrocortisone postoperatively also passed the SST postoperatively but went on to develop signs of ACTH deficiency during the first year after the operation, requiring hydrocortisone replacement (see case 2). There were, therefore, 2 false negative results for third-day postoperative 0900-h plasma cortisol of less than 400 nM.

SST

The postoperative SST was passed after 69 operations (3 of the patients had been previously ACTH-deficient) and failed after 20 operations (5 of whom were previously ACTH-deficient). Thus, new ACTH deficiency in the postoperative period occurred in 18.5%. Borderline results in the SST (with 30-min plasma cortisol levels of more than 400 nM) were achieved after 9 operations: 4 of these patients were retested and passed; the other 5 were not retested and remained on hydrocortisone.

See Tables 1 and 2. Sixty-three patients who passed the postoperative SST have undergone at least 1 yr of follow-up [median, 3 (range, 1–10) yr]. Twelve of these 63 subsequently became ACTH-deficient, as diagnosed by SST. All apart from 1 patient (see case 2) either had no symptoms or had symptoms of tiredness alone. Only 4 of the 63 patients who passed a postoperative SST developed ACTH deficiency within the first year of follow-up. However, 2 of the 4 patients who developed ACTH deficiency had received radiotherapy and may have developed ACTH deficiency as a consequence. There were, therefore, 2 false negative results for the postoperative SST.

These four cases represent the potentially most important group in whom the postoperative SST did not detect ACTH deficiency. Their case histories were as follows.

Case 1

The patient complained of tiredness at initial postoperative assessment at 71 d but passed a SST (plasma cortisol, 308 nM at 0 min and 554 nM at 30 min; the SST was in 1994, so the 30-min plasma cortisol pass level was defined as 520 nM). The patient was rechecked at 87 d as a precaution when he failed a SST (206 nM and 476 nM, respectively). The patient had remained on hydrocortisone in the initial postoperative period.

Case 2

The patient had initial postoperative assessment at 53 d, when he passed a SST (plasma cortisol, 521 nM at 0 min and 631 nM at 30 min; the SST was in 1990, so the 30-min cortisol pass level was defined as 550 nM). At 72 d, the patient was admitted to the hospital with a chest infection, SST was repeated and passed (514 nM and 764 nM, respectively), and hydrocortisone was started as a precaution and converted to dexamethasone on discharge. SST was rechecked at 134 d, after 24 h off dexamethasone, and failed (231 nM, 395 nM); 0900-h plasma cortisol on the third postoperative day had also not detected ACTH deficiency in this patient. It should be noted that, because of the prolonged duration of HPA axis suppression of dexamethasone, 24 h may have been inadequate time to allow accurate assessment of the HPA axis.

Cases 3 and 4

Patients had initial postoperative assessment at 31 and 28 d, respectively, when they passed the SST (380 nM, 667 nM; 417 nM, 762 nM, respectively; both SSTs were performed in 1990, so the 30-min plasma cortisol pass level was defined as 550 nM). At the annual review, they complained of tiredness (318 d and 332 d, respectively), when both failed SSTs (111 nM, 358 nM, 89 nM, and 325 nM, respectively). Both cases had received radiotherapy within 5 months of pituitary surgery; 0900-h plasma cortisol on the third postoperative day had also not detected ACTH deficiency in these patients.

Discussion

The ITT has been used as the gold standard for assessing the function of the HPA axis, since its value was first demonstrated in the 1960s (16, 17, 18). It is, however, an expensive, uncomfortable, and dangerous test. The ITT is also contraindicated in certain patients (e.g. ischemic heart disease, cerebrovascular disease, epilepsy) (8). With chronic ACTH deficiency, the adrenal cortex undergoes atrophy and fails to respond to exogenous ACTH (19). Consequently, the SST has been used to assess the integrity of the HPA axis (1, 5, 20, 21, 22). However, despite an excellent correlation between peak plasma cortisol levels achieved in the SST and ITT, some discrepancies have been reported, with potentially serious consequences (5, 6, 9, 10, 11, 12, 13, 14, 21, 23, 24, 25).

One explanation for false negative results with the SST, when compared with the ITT, is that mild adrenocortical atrophy may provide a pass cortisol level response when exposed to the supraphysiological dose of 250 µg, at least 1000 times the dose required for maximal adrenal stimulation, used in the SST (26). It has been argued that a low-dose (1 µg) synacthen test is more sensitive than the 250-µg SST in the setting of ACTH deficiency (6, 25, 27), but the low-dose test has not been subjected to a pragmatic analysis of predicting clinical outcome, as is presented here for the high-dose test. The discrepancies in sensitivity and specificity found between the ITT and SST are also partly explained by the wide variations, between studies, in the pass cortisol level. Two recent reports suggested raising the lower pass cortisol level to 600 nM to increase the sensitivity of the SST (5, 10). This would, however, risk raising the number of falsely subnormal results, resulting in unnecessary treatment with hydrocortisone (13, 28). In our audit, a lower pass cortisol level of 600 nM would increase sensitivity of the SST to detect ACTH deficiency from 91% to 96% but would decrease specificity as new ACTH deficiency postoperatively would increase from 18.5% to 28%. Unless an auxiliary test (e.g. an ITT) is to be performed after a screening SST, it would be more appropriate to choose the pass cortisol level on the basis of an acceptable predictive value for excluding ACTH deficiency in patients with pituitary disease. With our cut-offs, the predictive value of the SST to exclude ACTH deficiency was 97%, which we believe is sufficient to avoid using ITT routinely.

Another reason for the discrepancies between the two tests is the different interpretation of SST results, i.e. using peak and increment rather than the +30-min plasma cortisol level. The peak and incremental cortisol are higher in the SST than with the ITT, suggesting that +60-min plasma cortisol should not be used or at least should be evaluated with another threshold (28). Our practice is to measure plasma cortisol at +30 min. There are also reports suggesting that the ITT itself is not 100% sensitive (10, 15). Intraindividual reproducibility of cortisol response to the ITT in normal men is good (29, 30); however, in men with hypopituitarism, it can vary by 41.6% (3.5–92.7%) (30). Although these discrepancies were not sufficient to alter choice of initiation of glucocorticoid therapy, this produces concerns that the ITT itself may occasionally inadequately identify partial ACTH deficiency.

Auditing a group of patients who have recently undergone pituitary surgery, after which pituitary function may change, is a test of the safety of the SST. It has been reported that the SST may induce false negative cortisol responses shortly after pituitary surgery (11, 13, 31). However, many of the studies performed the SST within 2 wk of surgery, so that ACTH deficiency may not have been sufficiently prolonged to result in adrenal atrophy (11, 12, 13, 31). Dokemetas et al. (2000) also found that five patients who had subnormal cortisol responses to ITTs in the first 7 d postoperatively were not subnormal at 3 months postoperatively and suggested that this was attributable to transient dysfunction of the HPA axis post pituitary surgery (12). In our audit, SSTs were performed at 6.7 wk postoperatively (<2–27). However, despite the written protocol, three patients were tested within 2 wk of the operation. Although these patients have remained well, we do not advocate using the SST less than 4 wk after surgery. The two patients who eventually went on to fail the SST in the first year, having passed it originally, were tested at 7 and 11 wk postoperatively. It has been suggested that 0900-h plasma cortisol level may be a predictor of whether further evaluation of the HPA axis by dynamic testing is necessary (3, 4, 5, 6, 7, 8). We found that a 0900-h plasma cortisol level less than 400 nM is 91% sensitive and 85% specific for diagnosing ACTH deficiency, defined by a SST and clinical outcome. This is in keeping with the original study from this unit (1) and other studies post pituitary surgery (3, 12, 13) and in more heterogeneous groups of patients with pituitary disease (7, 32). We continue to use 400 nM as our indicator of an intact HPA axis post pituitary surgery. Despite the recent recommendation that further dynamic testing of the HPA axis is not necessary if the basal plasma cortisol postoperatively is either less than 100 nM (indicative of ACTH deficiency) or more than 450 nM (indicative of an intact HPA axis) (13), we continue to use a dynamic test to further assess HPA function in all patients. This is both to reduce unnecessary long-term hydrocortisone replacement and, more importantly, to limit the number of false negative results (two in our audit).

Routine use of glucocorticoid replacement post pituitary surgery, although it can prevent adrenal insufficiency in patients with temporary or permanent corticotroph cell damage, may also cause suppression of ACTH secretion and frustrate postoperative evaluation of HPA integrity (33). This is unavoidable, given that early dynamic testing of the HPA axis is not reliable because ACTH deficiency that is demonstrated in the early postoperative period may not be permanent (12). Our protocol of continuing hydrocortisone in those with a postoperative 0900-h cortisol of less than 400 nM limits the numbers requiring glucocorticoids in the immediate postoperative period while maintaining patient safety.

The sensitivity of the SST was 91%, and the predictive value of the SST to exclude ACTH deficiency was 97%. This is in concordance with the original study, which found the SST to have a sensitivity of 90% and a predictive value of 98% for excluding ACTH deficiency (1). It is not possible, from this retrospective study, to ascertain specificity of the SST and predictive value to diagnose ACTH deficiency because of being unable to predict false positive SST results. Stewart et al. (1) found the predictive value of the SST to diagnose ACTH deficiency to be 50%, with a false positive rate of 15%. The development of new ACTH deficiency in our patients was 18.5%. One study reported the incidence of ACTH deficiency, post pituitary surgery, in the region of 8% (34). This suggests a significant false positive rate for the SST, resulting in inappropriate glucocorticoid replacement. The recording of additional pituitary hormone deficits would have clarified the situation. However, this suggests, as above, that our cut-offs for the SST in this clinical setting are in favor of high sensitivity at the expense of specificity. The option to perform an ITT in those that have failed the SST has been previously recommended, to reduce the number of patients remaining on long-term hydrocortisone (1).

In summary, these data confirm the use of 0900-h plasma cortisol in the immediate postoperative period and reassure that the SST is safe to use in the assessment of ACTH deficiency after pituitary surgery in clinical practice. Although the predictive value of the SST to exclude ACTH deficiency is similar to that found in the studies comparing the ITT and SST, this does not seem to expose patients to the potential devastating consequences of ACTH deficiency if reasonable clinical vigilance is maintained. However, it is essential that clinical awareness of symptoms of hypocortisolemia remains, to minimize the impact of occasional false negatives.

Footnotes

Abbreviations: HPA, Hypothalamic-pituitary-adrenal; ITT, insulin tolerance test; SST, short synacthen test.

Received June 25, 2002.

Accepted February 2, 2003.

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