Plain English Summary
Background and study aims
When we are stressed, the concentration of a hormone called ACTH in the blood rises. This, in turn, increases the amount of stress-hormone cortisol released from the adrenal gland. However, in intensive care unit (ICU) patients this stress response seems to be different. Our research group recently showed that during critical illness high blood levels of cortisol are, to a large extent, due to a decrease in the amount of cortisol broken down in the body, rather than an increase in the amount of the hormone made. These high cortisol levels could in their turn stop the release of ACTH by what is called ‘negative feedback inhibition’. However, it remains unknown whether and to what extent the high cortisol levels in ICU patients evoke feedback-inhibition at certain regions in the brain, and whether and how this effect evolves with the duration of critical illness. As such, documenting a change in ACTH and/or cortisol response to the injection of CRH (another hormone of the brain) over time could be highly informative to understand illness evolution and might open perspectives for new treatment strategies.
Who can participate?
Adult patients (age 18 or over) at the medical and surgical ICU. Healthy individuals are recruited to match with the patient group.
What does the study involve?
Participants are randomly allocated to receive an injection of either CRH or salt water, and blood samples are taken. The next day, each participant receives the other injection, and blood samples are taken again.
What are the possible benefits and risks of participating?
There will be no immediate benefits or risks for participants in the study
Where is the study run from?
Five ICUs of the University Hospitals of Leuven (Belgium)
When is the study starting and how long is it expected to run for?
July 2016 to April 2018
Who is funding the study?
1. Methusalem (long term structural funding by the Flemish Government, Belgium)
2. Research Foundation - Flanders (FWO) (Belgium) to the KU Leuven
Who is the main contact?
Prof. Dr Greet Van den Berghe
greet.vandenberghe@med.kuleuven.be
Trial website
Contact information
Type
Scientific
Primary contact
Prof Greet Van den Berghe
ORCID ID
Contact details
Herestraat 49
Leuven
3000
Belgium
+32 (0)16 34 40 21
greet.vandenberghe@kuleuven.be
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
S58941
Study information
Scientific title
The dynamics of the ACTH and cortisol response to CRH stimulation during critical illness: a randomized, double-blind, placebo-controlled crossover study
Acronym
DACAR
Study hypothesis
We hypothesize that the sustained increased plasma cortisol concentrations during critical illness could exert negative feedback inhibition on the central components of the HPA axis, causing decreased CRH and/or ACTH synthesis and/or release. Such central inhibition might contribute to the observed low plasma ACTH concentrations and the increased incidence of absolute adrenal insufficiency in the prolonged phase of critical illness.
Ethics approval
Ethics Committee (Institutional Review Board) of the University Hospitals Leuven, 23/03/2016, ref: S58941
Study design
Randomized double-blind placebo-controlled crossover study
Primary study design
Interventional
Secondary study design
Randomised cross over trial
Trial setting
Hospitals
Trial type
Other
Patient information sheet
Not available in web format, please use the contact details to request a patient information sheet
Condition
Critical illness
Intervention
The trialists will study unique patients from different time cohorts, with an increasing duration of critical illness, in order to have three sets of patients who represent three different time points in the course of critical illness. After informed consent, each patient from each cohort will be randomized into two crossover study groups for the order of receiving CRH (test) or placebo injection. Consecutive patients will be randomly assigned to ‘first placebo’ or ‘first CRH’ using blinded envelopes, stratified according to the three ‘time in ICU’ cohorts.
Intervention type
Drug
Phase
Not Applicable
Drug names
Primary outcome measures
ACTH and cortisol responses to exogenous CRH/placebo in relation with available baseline demographic and clinical outcome data, collected during ICU stay. Quantification of plasma ACTH and cortisol will be done during 2 consecutive mornings from 10.45-13.00h, after receiving an alternate injection of CRH or placebo each morning, in the acute phase (ICU day 3-6), the intermediate phase (ICU day 7-16) and prolonged phase (ICU day 17-28) of critical illness.
Secondary outcome measures
Secondary endpoints (clinical parameters and treatment information) will be collected during their stay in ICU
Overall trial start date
20/01/2016
Overall trial end date
30/04/2018
Reason abandoned
Eligibility
Participant inclusion criteria
For patients:
1. Critically ill patients at the surgical or medical intensive care units, with ongoing intensive care dependency, a stable condition for at least 48h, and an expected stay in ICU for at least 48h
2. Age ≥18 years
For healthy volunteers:
1. Age-, gender- and BMI-matched to the included patients
Participant type
Mixed
Age group
Adult
Gender
Both
Target number of participants
Recruitment of patients will continue until the preset number of 40 patients is reached in the 3 patient cohorts, and 20 healthy matched volunteers will be studied
Participant exclusion criteria
For patients:
1. Predisposing factors of adrenal insufficiency
1.1. Cerebral disease with intracranial hypertension threatening the neuroendocrine system
1.2. Pituitary disorders including (pan)hypopituitarism
1.3. Known adrenal disease (Cushing’s syndrome or Addison’s disease)
1.4. Chronic treatment with glucocorticoids, other steroids or anti-steroid chemotherapy within the last 3 months
1.5. IV administration of glucocorticoids within the last 72 hours
1.6. Use of etomidate within the last 72 hours
1.7. Use of azoles within the last 7 days
1.8. Other drugs predisposing to adrenal insufficiency: phenytoin, rifampicin, glitazones, imipramin, phenothiazine, phenobarbital
2. Patients known to be pregnant or nursing
3. No arterial line or central venous catheter in place
4. Ethical restrictions
4.1. Moribund
4.2. Declined participation
For healthy volunteers:
1. Recent history of treatment with HPA-axis interfering drugs
Recruitment start date
01/07/2016
Recruitment end date
31/03/2018
Locations
Countries of recruitment
Belgium
Trial participating centre
University Hospitals Leuven (UZ Leuven)
Herestraat 49
Leuven
3000
Belgium
Sponsor information
Organisation
Katholieke Universiteit Leuven (Belgium)
Sponsor details
Professor Koenraad Debackere
Managing Director
University Administration and Central Services
Krakenstraat 3 - box 5500
Leuven
3000
Belgium
+32 (0)16 32 41 67
koenraad.debackere@kuleuven.be
Sponsor type
University/education
Website
Funders
Funder type
Government
Funder name
Methusalem (long term structural funding by the Flemish Government, Belgium)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
Fonds Wetenschappelijk Onderzoek
Alternative name(s)
Research Foundation Flanders, Flemish Research Foundation, FWO
Funding Body Type
government organisation
Funding Body Subtype
government non-federal
Location
Belgium
Results and Publications
Publication and dissemination plan
Planned publication in a high-impact peer reviewed journal.
IPD sharing statement
The data sharing plans for the current study are unknown and will be made available at a later date.
Intention to publish date
30/04/2019
Participant level data
To be made available at a later date
Results - basic reporting
Publication summary