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Randomized Controlled Trial
, 44 (12), 2048-2058

ACTH and Cortisol Responses to CRH in Acute, Subacute, and Prolonged Critical Illness: A Randomized, Double-Blind, Placebo-Controlled, Crossover Cohort Study

Affiliations
Randomized Controlled Trial

ACTH and Cortisol Responses to CRH in Acute, Subacute, and Prolonged Critical Illness: A Randomized, Double-Blind, Placebo-Controlled, Crossover Cohort Study

Bram Peeters et al. Intensive Care Med.

Abstract

Purpose: Low 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.

Methods: This randomized, double-blind, placebo-controlled crossover cohort study, compared ACTH responses to 100 µg 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 135 min and AUC responses to placebo were subtracted from those to CRH.

Results: Patients had normal mean ± SEM plasma ACTH concentrations (25.5 ± 1.6 versus 24.8 ± 3.6 pg/ml in healthy subjects, P = 0.54) but elevated free cortisol concentrations (3.11 ± 0.27 versus 0.58 ± 0.05 µg/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 ± 848 pg/mL min versus 4120 ± 688 pg/mL min in healthy subjects; P = 0.77), whereas those in the subacute (2333 ± 387 pg/mL min, P = 0.01) and prolonged phases (2441 ± 685 pg/mL min, 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.

Keywords: ACTH; CRH; Cortisol; Hypothalamus; Pituitary; Septic shock.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
Flowchart of the study participants and study design. a Flowchart of the study participants. b Randomization into crossover subgroups. ICU denotes intensive care unit. *Blood sample
Fig. 2
Fig. 2
Plasma ACTH, total and free cortisol concentrations after CRH or placebo injection over time in ICU. Data are shown as mean ± SEM on a logarithmic scale. ICU denotes intensive care unit
Fig. 3
Fig. 3
Incremental a ACTH, b total cortisol and c free cortisol responses to CRH and placebo in 3 patient cohorts. The AUC hormone responses to placebo were subtracted from the AUC hormone responses to CRH and indicate the incremental hormone responses. Data are shown as mean ± SEM on a logarithmic scale. ICU denotes intensive care unit. The horizontal blue-shaded areas represent the mean ± SEM incremental hormone responses from the 20 healthy subjects. *P ≤ 0.05, **P ≤ 0.01, and ***P ≤ 0.0001 for the comparisons with healthy subjects. The numerical P values are those for the comparisons between patient cohorts
Fig. 4
Fig. 4
Incremental ACTH responses to CRH and placebo in 3 patient cohorts, in a survivors and non-survivors, b patients with and without sepsis, and c patients with and without septic shock. The AUC ACTH responses to placebo were subtracted from the AUC ACTH responses to CRH and indicate the incremental ACTH responses. Data are shown as mean ± SEM on a logarithmic scale. ICU denotes intensive care unit. The horizontal blue-shaded areas represent the mean ± SEM incremental hormone responses from the 20 healthy subjects. The numerical P values are those for the comparisons between patient groups

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