International Survey on High– and Low–Dose Synacthen Test and Assessment of Accuracy in Preparing Low–Dose Synacthen

Alexandra S. Cross; E. Helen Kemp; Anne White; Leanne Walker; Suzanne Meredith; Pooja Sachdev; Nils P. Krone; Richard J. Ross; Neil P. Wright; Charlotte J. Elder


Clin Endocrinol. 2018;88(5):744-751. 

In This Article

Abstract and Introduction


Objective The short synacthen test (SST) is widely used to assess patients for adrenal insufficiency, but the frequency and protocols used across different centres for the low–dose test (LDT) are unknown. This study aimed to survey centres and test the accuracy of ten different synacthen preparation strategies used for the LDT.

Methods Members of 6 international endocrine societies were surveyed regarding diagnostic tests used for adrenal insufficiency, and in particular the SST. Synacthen was diluted for the LDT and concentrations measured using a synacthen ELISA.

Results Survey responses were received from 766 individuals across 60 countries (52% adult, 45% paediatric endocrinologists). The SST is used by 98% of centres: 92% using high–dose (250 μg), 43% low–dose and 37% both. Ten low–dose dilution methods were assessed and variation in synacthen concentration was demonstrated with intramethod coefficients of variation (CV) ranging from 2.1% to 109%. The method using 5% dextrose as a diluent was the least variable (CV of 2.1%). The variation in dilution methods means that the dose of synacthen administered in a LDT may vary between 0.16 and 0.81 μg.

Conclusions The high–dose SST is the most popular diagnostic test of adrenal insufficiency, but up to 72% of paediatric endocrinologists use a LDT. There is considerable variation observed both within and between low–dose synacthen dilution methods creating considerable risk of inaccurate dosing and thereby invalid results.


The use of the ACTH stimulation test, or short synacthen test (SST), has been growing in popularity,[1,2] and is the most widely used investigation of adrenocortical function in some countries.[3] It is increasingly being considered increasingly as the "standard" for the diagnosis of adrenal insufficiency.[4–6] The SST mimics the ACTH stimulus to the adrenal cortex and involves administration of either high–dose supraphysiological 250 μg or low–dose physiological, usually 1 μg, synacthen. Both the high– and low–dose tests are used in clinical practice, and results of meta–analyses do not show significant superiority of 1 test over the other.[7–11] Worldwide clinician preference for adrenal function testing and the popularity of the high– and low–dose SST are unknown. We report the results of an international survey, of both paediatric and adult endocrinologists, to assess current practice.

One form of diagnostic–grade synacthen is commercially available, manufactured in 250 μg/mL ampoules, necessitating large dilutions if administration of a low dose is required. A British survey of paediatric endocrinologists in 2012 reported that, amongst the 82% of respondents who use the low–dose test, 14 different dilution methods were used.[3] These varied in the amount of synacthen utilised for the initial dilution (0.1–1 mL), the volume of the diluent (10 mL–1 L), the diluent type (5% dextrose and 0.9% saline) and the number of dilution steps (1, 2 or 3) employed to prepare the required concentration.[3]

There is a paucity of literature on the accuracy or reproducibility of making up low–dose synacthen. The majority of related work pertains to the analysis of adsorptive losses on glass and plastic equipment during the dilution process, with losses proportionate to the length of the plastic device used for administration.[12–14] We addressed this important clinical issue in an in vitro study and reported the accuracy and reliability of making up 1 μg doses of synacthen by ten of the different methods currently in use.