The ACTH test fails to diagnose adrenal insufficiency and augments cytokine production in sepsis.

Summary

In septic mouse models, the ACTH stimulation test erroneously labels most animals as adrenal insufficient, including those with intact stress responses. Moreover, ACTH provokes lethal cytokinemia and increases mortality, indicating the test can be harmful in sepsis and may have confounded prior steroid trial interpretations.

Key Findings

• In septic mice, the ACTH test classified most animals as adrenal insufficient even when adrenal stress responses were intact.
• ACTH stimulation markedly increased inflammatory cytokines to lethal levels and moderately raised mortality.
• Findings indicate fundamental flaws in the ACTH test for diagnosing RAI/CIRCI and suggest it may have confounded prior glucocorticoid trial outcomes.

Clinical Implications

Clinicians should be cautious in using ACTH stimulation to guide steroid therapy in sepsis; alternative, non-provocative biomarkers and functional assessments are needed to identify true corticosteroid insufficiency without amplifying inflammation.

Limitations

• Preclinical animal data may not fully translate to humans.
• Dosing, timing, and physiological differences limit direct clinical extrapolation.

Future Directions

Develop and validate non-provocative diagnostics for CIRCI in sepsis; observational human studies assessing biomarker-based adrenal function without ACTH; re-analyze steroid trials excluding ACTH-based selection to test benefit in true insufficiency.