Condition category
Not Applicable
Date applied
11/11/2014
Date assigned
30/12/2014
Last edited
17/12/2015
Prospective/Retrospective
Retrospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

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 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 stops the release of ACTH by what is called ‘negative feedback inhibition’. It is possible that when circulating ACTH levels remain low for too long, the patients adrenal glands may become affected, resulting in a condition called ‘relative adrenal failure’. We want to investigate how circulating cortisol and ACTH levels change over time in ICU patients. We will also look at how the adrenal glands respond to an extra stimulation by ACTH. This will allow us to gain further insights in the recovery of ACTH and cortisol levels in the blood as well as what leads to relative adrenal failure.

Who can participate?
Adult patients that have been in ICU for at least 7 days. Healthy individuals will be recruited to match with the patient group.

What does the study involve?
To investigate the changes in ACTH and cortisol during critical illness, urine samples and blood samples are collected daily from critically ill patients from day 7 until day 28 of their ICU stay. A test that stimulates the production of ACTH (ACTH stimulation test) is performed weekly. In patients staying more than 28 days, an additional blood sample, urine sample and ACTH stimulation test is taken weekly until the patient is discharged from the ICU. On the last day in ICU an additional blood sample is collected. After discharge from ICU to a regular ward, a final blood sample and ACTH stimulation test are taken on day 7 after discharge from the ICU or on the day of discharge from the hospital before day 7.

What are the possible benefits and risks of participating?
There will be no immediate benefits or risks for participants in the study. Taking a small amount of blood on day 7 after discharge from the ICU may cause mild pain, bruises or minimal bleeding.

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?
December 2014 to November 2015

Who is funding the study?
Methusalem (long term structural funding by the Flemish Government, Belgium), 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

University Hospitals Leuven (UZ Leuven)
Head Laboratory of Intensive Care Medicine
Department Cellular and Molecular Medicine
University of Leuven (KU Leuven)
Herestraat 49
Leuven
3000
Belgium
+32 (0) 16344021
greet.vandenberghe@med.kuleuven.be

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

S57249

Study information

Scientific title

On the dynamics of the hypothalamus-pituitary-adrenal axis response to prolonged critical illness: a prospective observational study

Acronym

Dynamic Adrenal Study (DAS)

Study hypothesis

Recently it was shown that during critical illness reduced cortisol metabolism contributes to hypercortisolism while cortisol production is only mildly elevated, if at all [Boonen et al., NEJM 2013]. Maintaining high circulating cortisol levels could suppress ACTH secretion via negative feedback inhibition. It remains unknown whether/when ACTH secretion recovers in ICU patients and whether/when the continuously suppressed circulating ACTH during prolonged critical illness is causing adrenal insufficiency. Also, the use of a single ACTH stimulation test for the diagnosis of adrenal failure in this condition is highly debated, because it is poorly reproducible in critically ill patients and may simply reflect the degree of negative feedback inhibition exerted by the cortisol that is not broken down. Therefore our primary objective is to characterize the time course of the HPA-axis changes and the response to exogenous ACTH during prolonged critical illness and upon recovery. Our secondary objective is to address the causes/consequences of these changes.

Ethics approval

Ethics Committee (Institutional Review Board) of the University Hospitals Leuven, 30/10/2014, ref: ML11107

Study design

Observational cohort study

Primary study design

Observational

Secondary study design

Cohort study

Trial setting

Hospitals

Trial type

Other

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Critical illness

Intervention

To evaluate the evolution of the HPA-axis alterations during critical illness, 24h-urine collection samples and blood samples (4 ml) will be collected daily in critically ill patients from day 7 until day 28 of their ICU stay to determine evolution of ACTH and cortisol plasma concentrations and urine cortisol metabolites. A short ACTH-stimulation test (injection of 250 μg Synacthen®) will be performed weekly. In patients staying more than 28 days, a minority of the ICU population, an additional blood sample (4 ml), 24 h urine collection and ACTH-stimulation test will be taken weekly until ICU discharge or death. On the last day in ICU an additional blood sample (4 ml) will be collected to quantify plasma ACTH and cortisol concentrations at recovery/death. After discharge from the ICU, a final blood sample and ACTH stimulation test will be taken on day 7 post-ICU or on the day of discharge in patients discharged from the hospital before day 7.

Intervention type

Phase

Not Applicable

Drug names

Primary outcome measures

1. Determination of the evolution of ACTH and cortisol plasma concentrations and urine cortisol metabolites during prolonged critical illness and upon recovery, in comparison with ACTH and cortisol plasma concentrations of healthy volunteers.
2. To characterize the time course of the response to exogenous ACTH during prolonged critical illness and upon recovery, in comparison with response to exogenous ACTH in healthy volunteers.

Secondary outcome measures

Further mechanistic analyses using clinical and laboratory parameters.

Overall trial start date

01/12/2014

Overall trial end date

31/07/2017

Reason abandoned

Eligibility

Participant inclusion criteria

For patients:
1. Critically ill patients admitted for ≥7 days to one of the five ICUs from two departments (medical and surgical) in the University Hospitals Leuven
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

At least 542 patients (not receiving exogenous steroids) staying more than 7 days at the ICU and 20 healthy matched volunteers

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. Treatment with glucocorticoids, other steroids or anti-steroid chemotherapy within the last 3 months
1.5. Use of etomidate within the last 72 hours
1.6. Other drugs predisposing to adrenal insufficiency: azoles, phenytoin, rifampicin, glitazones, imipramin, phenothiazine, phenobarbital
2. No arterial line in place
3. Ethical restrictions:
3.1. Moribund
3.2. Declined participation

For healthy volunteers:
1. Recent history of treatment with HPA-axis interfering drugs

Recruitment start date

01/12/2014

Recruitment end date

31/07/2017

Locations

Countries of recruitment

Belgium

Trial participating centre

University Hospitals Leuven (UZ Leuven)
Herestraat 49
Leuven
3000
Belgium

Sponsor information

Organisation

KU Leuven

Sponsor details

Professor Koenraad Debackere
Managing Director
University Administration and Central Services
Krakenstraat 3 - box 5500
Leuven
Leuven
3000
Belgium
+32 16 32 41 67
koenraad.debackere@kuleuven.be

Sponsor type

Research organisation

Website

www.kuleuven.be

Funders

Funder type

Government

Funder name

Methusalem (long term structural funding by the Flemish Government, Belgium), Research Foundation - Flanders (FWO) (Belgium)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

To be confirmed at a later date

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

17/12/2015: The sponsor has been updated from Research Foundation - Flanders (FWO) (Belgium) to KU Leuven (Belgium). 04/12/2015: The recruitment end date and overall trial end date were updated from 30/11/2015 to 31/07/2017.