Trial reportIntensive care medicine2018
ACTH and cortisol responses to CRH in acute, subacute, and prolonged critical illness: a randomized, double-blind, placebo-controlled, crossover cohort study.
Trial report in Intensive care medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
25 citing papers in PubMed, 2 syntheses or guidelines pooled it, 39 citations in OpenAlex.
- Corticosteroids for treating sepsis in children and adults.The Cochrane database of systematic reviews · 2025Pooled it
- Corticosteroids for treating sepsis in children and adults.The Cochrane database of systematic reviews · 2019Pooled it
- Corticotropin-stimulated steroid profiles to predict shock development and mortality in sepsis: From the HYPRESS study.Critical care (London, England) · 2022Trial
- Persisting neuroendocrine abnormalities and their association with physical impairment 5 years after critical illness.Critical care (London, England) · 2021Trial
- Impact of prenatal LPS on sepsis-related neurobiological outcomes.Metabolic brain disease · 2026Article
- Tears and saliva as alternative matrices for minimally invasive assessment of acute stress and pain in sheep.Frontiers in veterinary science · 2026Article
- Cortisol Testing in Septic Shock: An Evaluation of Diagnostic Performance and Predictors of Corticosteroid Use in a Middle Eastern Cohort.Diagnostics (Basel, Switzerland) · 2025Article
- Muscle weakness after critical illness: unravelling biological mechanisms and clinical hurdles.Critical care (London, England) · 2025Review
- Critical illness-related corticosteroid insufficiency: latest pathophysiology and management guidelines.Acute and critical care · 2024Article
- Plasma aldosterone response to ACTH stimulation test for diagnosis of primary aldosteronism: a cross-sectional study.BMC endocrine disorders · 2024Article
- The Hypothalamus-pituitary-adrenocortical Response to Critical Illness: A Concept in Need of Revision.Endocrine reviews · 2023Article
- Cerebrospinal fluid levels of hypothalamic-pituitary-adrenal axis hormones in MCI and dementia due to Alzheimer's disease: a systematic review.Dementia & neuropsychologia · 2023Review
- Four-Compartment Diffusion Model of Cortisol Disposition: Comparison With 3 Alternative Models in Current Clinical Use.Journal of the Endocrine Society · 2022Article
- Critical Illness-induced Corticosteroid Insufficiency: What It Is Not and What It Could Be.The Journal of clinical endocrinology and metabolism · 2022Review
- CIRMI-a new term for a concept worthy of further exploration: a narrative review.Annals of translational medicine · 2022Review
- Sepsis-Induced Brain Dysfunction: Pathogenesis, Diagnosis, and Treatment.Oxidative medicine and cellular longevity · 2022Review
- Adrenal function/dysfunction in critically ill patients: a concise narrative review of recent novel insights.Journal of anesthesia · 2021Review
- Acute Cortisol Profile Associations With Cognitive Impairment After Severe Traumatic Brain Injury.Neurorehabilitation and neural repair · 2021Article
- Sepsis and Cerebral Dysfunction: BBB Damage, Neuroinflammation, Oxidative Stress, Apoptosis and Autophagy as Key Mediators and the Potential Therapeutic Approaches.Neurotoxicity research · 2021Review
- Glucocorticoids and the Brain after Critical Illness.Endocrinology · 2021Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
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 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.
resultsPatients 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.
conclusionsSuppressed 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.