ACTH and cortisol responses to CRH in acute, subacute, and prolonged critical illness: a randomized, double-blind, placebo-controlled, crossover cohort study

PurposeLow plasma ACTH in critically ill patients may be explained by shock/inflammation-induced hypothalamus-pituitary damage or by feedback inhibition exerted by elevated plasma free cortisol. One can expect augmented/prolonged ACTH-responses to CRH injection with hypothalamic damage, immediately suppressed responses with pituitary damage, and delayed decreased responses in prolonged critical illness with feedback inhibition.MethodsThis randomized, double-blind, placebo-controlled crossover cohort study, compared ACTH responses to 100 mu g IV CRH and placebo in 3 cohorts of 40 matched patients in the acute (ICU-day 3-6), subacute (ICU-day 7-16) or prolonged phase (ICU-day 17-28) of critical illness, with 20 demographically matched healthy subjects. CRH or placebo was injected in random order on two consecutive days. Blood was sampled repeatedly over 135min and AUC responses to placebo were subtracted from those to CRH.ResultsPatients had normal meanSEM plasma ACTH concentrations (25.5 +/- 1.6 versus 24.8 +/- 3.6pg/ml in healthy subjects, P=0.54) but elevated free cortisol concentrations (3.11 +/- 0.27 versus 0.58 +/- 0.05 mu g/dl in healthy subjects, P<0.0001). The order of the CRH/placebo injections did not affect the ACTH responses, hence results were pooled. Patients in the acute phase of illness had normal mean +/- SEM ACTH responses (5149 +/- 848pg/mLmin versus 4120 +/- 688pg/mLmin in healthy subjects; P=0.77), whereas those in the subacute (2333 +/- 387pg/mLmin, P=0.01) and prolonged phases (2441 +/- 685pg/mLmin, P=0.001) were low, irrespective of sepsis/septic shock or risk of death.Conclusions Suppressed ACTH responses to CRH in the more prolonged phases, but not acute phase, of critical illness are compatible with feedback inhibition exerted by elevated free cortisol, rather than by cellular damage to hypothalamus and/or pituitary.