Importantly, in our study there are some limitations. This is a retrospective analysis of clinical data obtained from electronic patient records, and therefore there is the potential for selection bias in those individuals undergoing short Synacthen testing. We do not have accurate data on the dose and duration of exposure to glucocorticoids, and therefore we are unable to answer questions that relate to cumulative exposure that might predict AI. However, this does represent the largest analysis of this kind published to date. Our data extend to approximately 4 years of follow-up and therefore it is not possible to say whether further recovery of the HPA axis may occur after this time point. The algorithm that we have proposed is designed to guide and help the clinician, but is only derived from this data set and has not been tested or validated in other cohorts. As a result, it is important that individual clinicians use their discretion and clinical judgment in the frequency and interpretation of dynamic assessments of HPA axis function. b) if an extension notice has been served under section 35A of the 2001 Act, the period of 18 months following the creation of the tenancy.” We conducted the study following the guidelines outlined in the declaration of Helsinki. This study was approved by the Institutional Ethics Committee of King Faisal Specialist Hospital & Research Centre and a waiver for the need for informed consent was granted. 3.1 Local SST protocol and interpretation Adrenal insufficiency (AI) is classified according to a primary adrenal cause or as a consequence of central AI [which can be divided into secondary AI (SAI) and tertiary AI (TAI)] ( 1). SAI is caused by the loss of corticotroph cell function, most frequently by pituitary tumors and/or their subsequent treatment including surgery and radiotherapy ( 2). By contrast, TAI occurs due to suppression of corticotroph function following exogenous glucocorticoid (GC) therapy and is a major unmet clinical need with 0.5% to 2% of the population taking exogenous GC therapy to treat a variety of inflammatory diseases ( 3). Hypothalamic-pituitary-adrenal axis suppression by exogenous GCs has been associated with adrenal crisis in patients treated with systemic, inhaled, intra-articular and topical GCs ( 4, 5) and is related to the cumulative exposure (determined by a combination of the duration of therapy and the dose and relative potency of GC used). However, there is considerable interindividual variability in the response to GCs and as such any consensus to what defines the level of exposure required to cause AI is difficult. Abbreviations: ACTH = adrenocorticotropic hormone, ANOVA = analysis of variance, HPA = hypothalamic-pituitary-adrenal, ITT = insulin tolerance test, SST = short Synacthen test.

Other indications (autoimmune disease, hyponatremia, vomiting, weight loss, hyperkalemia, hypoglycemia, hypotension, collapse, fatigue)We have therefore undertaken a retrospective analysis of repeat SSTs performed in patients with potentially reversible causes of AI to determine if there are features of the SST results (basal, 30-minute, or delta cortisol) that might both guide a strategy for repeat testing and in addition help to identify groups of patients in whom HPA axis function is likely (or unlikely) to be restored. Materials and Methods Patient selection The patients’ characteristics are presented in Table 1, including the relevant clinical indications as well as the number and timing of the SSTs performed. A total of 776 subjects were recruited, all with potentially reversible causes of AI. A subgroup analysis was performed in 110 patients with AI secondary to treatment with suppressive doses of glucocorticoids. Kaplan-Meier plots estimating time to recovery of HPA axis function in 110 patients with AI due to exposure to suppressive doses of glucocorticoid therapy stratified by (a) basal (0-min) cortisol of the same test, (b) 30-min cortisol, and (c) delta cortisol (30-min – basal cortisol) of their initial SST. (d) ROC curve analysis to determine the ability of the characteristics of the initial SST to predict eventual recovery of adrenal function. We used frequency measures and percentages to describe physicians' common practices and attitudes toward the test protocols. We used chi-square tests to analyze the associations between the indications of SST with physicians' specialties and grades. Our study included patients who underwent standard dose of SST alone. We therefore cannot advocate if one test is superior to the other. Our institutional practice allows the clinicians to use their discretion in the choice of the standard dose for SST. However, different studies have shown conflicting results. An earlier meta-analysis by Dorin et al [19] and a more recent study by Ospina et al [20] have both shown that the standard and the low dose SST perform well and have similar diagnostic accuracy. Another meta-analysis by Kazlauskaite et al [12] showed that the diagnostic value of LDSST was superior to the standard dose SST. These studies contrast with that of Kazlauskaite et al who had different inclusion criteria; they excluded 12 studies that were included in Dorin's earlier meta-analysis and included 3 new studies. A more recent study, involving 804 patients who had either a low dose or standard dose SST, reported that both tests were comparable for differentiating Addison's disease. [15]

In the pituitary disease group of patients with SAI, 57% of patients with nonfunctioning pituitary tumors and 44% of patients who underwent pituitary surgery subsequently passed the SST. This is significantly higher than one would have expected and has major potential implications for clinical practice. Although untreated or unrecognized AI confers the risk of adrenal crisis and increased morbidity and mortality, it has also become increasingly evident that morbidity and mortality are increased in patients with AI taking replacement GC ( 10–16). The mortality excess is largely due to increased cardiovascular deaths ( 15), most likely from subtle but prolonged increase in either dose of GC replacement and/or a noncircadian mode of replacement, effectively leading to mild Cushing syndrome ( 17). Impaired quality of life is a further major issue that again appears to be related to AI but also GC exposure ( 18, 19). The realization that many patients with established SAI might recover endogenous adrenal function and thereby avoid lifelong GC replacement is clearly important. The test does not require hospital admission but please note the contraindications and precautions. No dietary preparation is required. Current or recent steroid therapy may make result interpretation difficult. Preparations should be made in advance to combat any anaphylactic reaction that may occur after the injection of Synacthen.Proposed flow chart for the use of SST in patients with potentially reversible causes of AI. *Random morning cortisol was measured between 9 and 12 am and at least 18 h after the last dose of glucocorticoid. All SSTs were performed between 9 and 12 am, at least 18 hours after the most recent dose of glucocorticoids. Individual clinicians determined the frequency of repeat testing on a case-by-case basis. Patients taking the oral contraceptive pill or other estrogen replacement were required to stop the treatment at least 6 weeks before the test. Blood was sampled for serum cortisol at baseline and after 30 minutes: baseline serum cortisol levels were measured prior to injection of 250 μg Synacthen (Questcor Operations Limited, Dublin, Ireland, for Siemens assays; Alliance Pharmaceuticals, Chippenham, United Kingdom, and Sigma-tau Pharmaceutical, Rome, Italy, for Roche assays) intramuscularly or intravenously. The 30-minute response to intramuscular or intravenous Synacthen has been shown to be equivalent ( 18). After administration of Synacthen, the patients were observed for 15 minutes for signs of any allergic reaction. The interpretation of the SST is based on the 30-minute serum cortisol where an adequate response to Synacthen was defined as >450 nmol/L for Siemens ADVIA Centaur ( 19), as >550 nmol/L for the Roche Generation I Modular System (tests done before February 2016) ( 19), and as >450 nmol/L for the Roche Generation II Modular System (tests done after February 2016). The incremental response to Synacthen was calculated as: delta cortisol = [30-minute – 0-minute cortisol]. Statistical methods Our survey results showed similarities and differences between our single center 1 and the multicenter national practice.

If eviction proceedings have been raised in relation to a tenancy which is a short SST on any of the antisocial behaviour grounds but an eviction decree is not granted by the courts, the tenancy becomes an SST with effect from: Cho et al. investigated [4] over 200 healthy individuals to define the normal thresholds for serum cortisol levels upon stimulation in dynamic studies; however, they used an RIA instead of the traditional fluorometric assay, used in earlier studies. [1] Following an ITT, the 95 th percentile of the peak serum cortisol was 15 μg/dL (414 nmol/L), which was proposed to be the reference level for healthy volunteers. The study participants also underwent either a low dose (1 μg) or standard dose (250 μg) SST. All those who underwent the low dose SST had serum cortisol level >18 μg/dL (497 nmol/L) while those who underwent the standard-dose SST had serum cortisol ≥20 μg/dL (550 nmol/L). The use of this threshold as the standard dose SST was therefore suggested. [4] They also measured cortisol levels with 2 different RIAs and found that the results correlated with each other.Send all samples to the laboratory with one completed request form giving clinical details, any relevant drugs (especially steroid treatment) and stating that a Synacthen test has been done. The short Synacthen test is a test of adrenal insufficiency which can be used as a screening procedure in the non-critically ill patient. The test is based on the measurement of serum cortisol before and after an injection of synthetic ACTH (also known as tetracosactrin). As our study was a retrospective analysis, we collected data on all protocols adopted by the clinicians. We defined a normal response as a stimulated cortisol value ≥550 nmol/L achieved at 30 or 60 minutes or at both time points. An abnormal response referred to a stimulated cortisol value <550 nmol/L. Primary adrenal insufficiency was defined when the patient had an inadequate response (ie, cortisol <550 nmol/L with corresponding elevated ACTH levels when ACTH results were available). Secondary adrenal insufficiency was defined by an inadequate response (ie, cortisol <550 nmol/L with corresponding low ACTH levels when ACTH results were available). 3.2 Statistical analysis Short Synacthen test (SST) involves measuring the baseline, 30-, and 60-minute serum cortisol levels, after injecting 250 μg of synthetic adrenocorticotropic hormone or Synacthen (ACTH). This study aimed to review the current clinical practice of performing SST to establish a standardized test protocol and to additionally test the hypothesis regarding performing the 60-minute cortisol test alone and the dependence of overall SST result on baseline cortisol level. As well as the utility of the peak cortisol value post-SST, the authors highlight the importance of the delta cortisol to predict future recovery of AI. It is perhaps not surprising that in a group of patients with suppressed adrenal function post exogenous GC therapy as opposed to a “normal” population being evaluated for adrenal sufficiency, the incremental change in cortisol was clinically useful. However, it is important to stress that the SST in this context has yet to be validated against the ITT; Kane et al. ( 25) in a small series of GC treated rheumatology patients highlighted differences between the performance of the SST and ITT in patients with TAI; 8/22 patients failing the SST but passed the ITT.

http://www.pathology.leedsth.nhs.uk/dnn_bilm/Misc/Syntheticglucocorticoidsandcortisolassays.aspx Further information In almost all cases in our study, clinicians reviewed the baseline cortisol level obtained on the day of the SST after the entire SST results were available. This made the use of the baseline cortisol measurement performed on the day of the test questionable. However, as a standalone screening test to identify patients at risk, it will have a more discriminatory role, and might reduce the need for performing SST unnecessarily in those with a robust baseline cortisol level. Ensure that you have read the contraindications and precautions as given in the Synacthen product information sheet. Having done so it is the responsibility of the investigating medical officer to decide whether it is safe to proceed with this investigation. This test is not recommended if pituitary problems are suspected. An endocrine referral is required in this situation as alternate stimulation tests may be necessary. Contraindications and Precautions Where the tenancy is a short SST on any of the antisocial behaviour grounds and the landlord has served a notice of proceedings for recovery of possession of the tenancy on the tenant within 12 months of creation of the tenancy (or 18 months in cases where an extension notice has been served following creation of the short SST), [42] and either the notice:Patients >14 years who underwent SST from January 2010 to December 2017 were included. Pearson's chi-square cross-tabulation was used to identify individuals with inconsistent 30- and 60-minute serum cortisol test results. Logistic regression analysis was performed to predict normal responses based on the baseline cortisol value. Clinicians have been using SST with increasing frequency because of its ease; it is now replacing ITT for the assessment of adrenal reserve. Approximately 50% of surveyed clinicians were using SST to assess the HPA axis in 1996, which was in sharp contrast to only 25% in 1988. [5,9] SST provides an excellent clinical tool to test the HPA axis and has several advantages including relative ease and simplicity, lower cost, and accurate assessment of cortisol secretion. However, a wide variation occurs with the time points used for measuring cortisol levels after ACTH injection. For instance, some clinicians use the 30- and 60-minute serum cortisol level measurements, while some prefer either the 30-minute or the 60-minute serum cortisol measurements alone. Further, some clinicians measure the baseline serum cortisol before ACTH injection while others omit it. Give the 250 ug of Synacthen by either intravenous (i.v.) or intramuscular (i.m.) injection (there is no difference in cortisol response between i.v. and i.m. administration). Send both blood samples to the laboratory at ambient temperature. If unavoidable can be refrigerated overnight. Required information Section 37(1A) of the 2001 Act defines the “relevant period” for the purposes of conversion to an SST as follows: