December 20, 2018

Intensive Care Medicine journal

EJRC – Article Review


ACTH & Cortisol responses to CRH in critically ill patients


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

Critically ill patients usually show a low level of adrenocorticotropic hormone (ACTH), particularly during severe infections. This finding has been attributed to hypothalamus and/or pituitary damage due to inflammation or hypoperfusion. Additionally, negative feedback exerted by high circulating free cortisol caused by a decreased level of cortisol binding protein (CBP) and a reduced cortisol turnover.

This study by Peeters et al investigated the mechanism which leads to the low ACTH levels in intensive care unit (ICU), by the administration of a single dose of 100μg corticotropin-releasing hormone (CRH), in 20 healthy subjects and 120 patients divided in three groups. The three groups were divided according to the ICU length of stay defined as acute (3-6 days), subacute (7-16 days) and prolonged (17-28 days). The response to CRH variably affected the low level of ACTH. In hypothalamus damage, CRH would cause a prolonged increase in ACTH level while in pituitary injury, ACTH would be suppressed and no response to CRH could be recorded. The ACTH response would be normal in early phases and lowered in prolonged phase of illness.

Pooled patients and healthy subjects showed similar ACTH levels, lower CBG and albumin, and and an increase of total and free cortisol. ACTH response to CRH administration showed a decrease related to the duration of illness. Incremental response of total cortisol was significantly lower and free cortisol equal compared to healthy subjects irrespective of length of stay in ICU but they tended to decrease in subacute and prolonged phases.

This study strongly supports the mechanism of a negative feedback of (free) cortisol on ACTH level and suggests a potential use of CRH to reactivate ACTH synthesis in order to prevent adrenal insufficiency.

Take-home message

  • Low level of ACTH in critically ill patients is due to a negative feedback exerted by (free)cortisol.
  • CRH may be used to protect long-stay ICU patients against adrenocortical atrophy and dysfunction.

This article review was prepared and submitted by ESICM NEXT member Maria Vargas, Department of Neurosciences, Reproductive & Odontostomatological Sciences, University of Naples, Italy, on behalf of the ESICM Journal Review Club


1) Peeters B et al. ACTH and cortisol responses to CRH in acute, subacute, and prolonged critical illness: a randomized, double-blind, placebo-controlled, crossover cohort study.

2) Annane D. The role of ACTH and corticosteroids for sepsis and septic shock: an update. Front Endocrinol (Lausanne) 7:70.

3) Boonen E, Vervenne H, Meersseman P, et al. Reduced cortisol metabolism during critical illness. N Engl J Med 368:1477–1488

4) Boonen E, Langouche L, Janssens T, et al. Impact of duration of critical illness on the adrenal glands of human intensive care patients. J Clin Endocrinol Metab 99:4214–4222

5) Schulte HM, Chrousos GP, Avgerinos P, et al. The corticotropin-releasing hormone stimulation test: a possible aid in the evaluation of patients with adrenal insufficiency. J Clin Endocrinol Metab 58:1064–1067


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