Dynamics of the stress response in acute and prolonged critical illness

ISRCTN	ISRCTN14587520
DOI	https://doi.org/10.1186/ISRCTN14587520
Secondary identifying numbers	S58941

Submission date: 04/07/2016
Registration date: 07/07/2016
Last edited: 23/08/2022

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Other

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

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

Contact information

Prof Greet Van den Berghe
Scientific

Herestraat 49
Leuven
3000
Belgium

Phone	+32 (0)16 34 40 21
Email	greet.vandenberghe@kuleuven.be

Study information

Study design	Randomized double-blind placebo-controlled crossover study
Primary study design	Interventional
Secondary study design	Randomised cross over trial
Study setting(s)	Hospital
Study type	Other
Participant information sheet	Not available in web format, please use the contact details to request a patient information sheet
Scientific title	The dynamics of the ACTH and cortisol response to CRH stimulation during critical illness: a randomized, double-blind, placebo-controlled crossover study
Study acronym	DACAR
Study objectives	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(s)	Ethics Committee (Institutional Review Board) of the University Hospitals Leuven, 23/03/2016, ref: S58941
Health condition(s) or problem(s) studied	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
Pharmaceutical study type(s)
Phase	Not Applicable
Drug / device / biological / vaccine name(s)
Primary outcome measure	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 study start date	20/01/2016
Completion date	10/05/2018

Eligibility

Participant type(s)	Mixed
Age group	Adult
Lower age limit	18 Years
Sex	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
Key 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
Key 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
Date of first enrolment	30/08/2016
Date of final enrolment	08/05/2018

Locations

Countries of recruitment

Belgium

Study participating centre

University Hospitals Leuven (UZ Leuven)

Herestraat 49
Leuven
3000
Belgium

Sponsor information

Katholieke Universiteit Leuven (Belgium)
University/education

Professor Koenraad Debackere
Managing Director
University Administration and Central Services
Krakenstraat 3 - box 5500
Leuven
3000
Belgium

Phone	+32 (0)16 32 41 67
Email	koenraad.debackere@kuleuven.be
"ROR"	https://ror.org/05f950310

Funders

Funder type

Government

Methusalem (long term structural funding by the Flemish Government, Belgium)

No information available

Fonds Wetenschappelijk Onderzoek
Government organisation / Local government

Alternative name(s): Research Foundation Flanders, Flemish Research Foundation, FWO
Location: Belgium

Results and Publications

Intention to publish date	10/05/2019
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
Publication and dissemination plan	Planned publication in a high-impact peer reviewed journal.
IPD sharing plan	The data sharing plans for the current study are unknown and will be made available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article	results	01/12/2018		Yes	No
Protocol file	version 1.3	05/07/2016	23/08/2022	No	No

Additional files

32292 Protocol v1.3 05July2016.pdf

Editorial Notes

23/08/2022: The following changes were made to the trial record:
1. Uploaded protocol (not peer-reviewed) as an additional file.
2. The recruitment start date was changed from 01/07/2016 to 30/08/2016.
05/11/2018: Publication reference added.
10/07/2018: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/03/2018 to 08/05/2018.
2. The overall trial end date was changed from 30/04/2018 to 10/05/2018.
18/10/2017: Internal review.
13/10/2017: Publication and dissemination plan and IPD sharing statement added.
11/10/2017: The following changes were made to the trial record:
1. The recruitment end date was changed from 30/06/2017 to 31/03/2018.
2. The overall trial end date was changed from 31/07/2017 to 30/04/2018.