Drug-induced HPA axis alterations during acute critical illness: a multivariable association study

Critical illness is hallmarked by low plasma ACTH in the face of high plasma cortisol. We hypothesized that frequently used drugs could play a role by affecting the hypothalamic-pituitary-adrenal axis.

Observational association study.

A total of 156 medical-surgical critically ill patients.

Plasma concentrations of ACTH and total/free cortisol were quantified upon ICU admission and throughout the first 3 ICU days. The independent associations between drugs administered 24 h prior to ICU admission and plasma ACTH and cortisol concentrations upon ICU admission were quantified with use of multivariable linear regression analyses.

Upon ICU admission, compared with healthy subjects, patients had low mean±SEM plasma ACTH concentrations (2·7 ± 0·6 pmol/l vs 9·0 ± 1·6 pmol/l, P < 0·0001) in the face of unaltered total plasma cortisol (336·7 ± 30·4 nmol/l vs 300·8 ± 16·6 nmol/l, P = 0·3) and elevated free plasma cortisol concentrations (41·4 ± 5·5 nmol/l vs 5·5 ± 0·8 nmol/l, P = 0·04). Plasma ACTH concentrations remained low (P < 0·001) until day 3, whereas plasma (free) cortisol concentrations steeply increased and remained high (P < 0·001). No independent correlations with plasma ACTH were found. In contrast, the total admission plasma cortisol concentration was independently and negatively associated with the cumulative opioid (P = 0·001) and propofol (P = 0·02) dose, the use of etomidate (P = 0·03), and positively with the cumulative dobutamine dose (P = 0·0007).

Besides the known suppressive effect of etomidate, opioids and propofol may also suppress and dobutamine increases plasma cortisol in a dose-dependent manner. The observed independent associations suggest drug effects not mediated centrally via ACTH, but rather peripherally by a direct or indirect action on the adrenal cortex.