Condition category
Not Applicable
Date applied
08/12/2015
Date assigned
09/12/2015
Last edited
09/12/2015
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Plain English Summary

Background and study aims
Critically ill patients suffer from vital organ failure, undergo remarkable endocrine (hormonal) and metabolic changes, and frequently develop muscle weakness. Patients who survive a critical illness often face continuing debilitating physical and psychological problems after their stay in an intensive care unit (ICU). The exact mechanisms leading to the changes that occur during a critical illness and the long-term consequences that follow remain largely unknown. Recent data has shown that disturbances in stress responses (how the body responds to a stressful situation) may play a crucial role. Furthermore, there is evidence to suggest that changes in what genes are switched on or off (epigenetics) may also be involved in causing the long-term consequences of critical illness. For a long time, it has been known that critical illness has a remarkable time course. In that regard, hormonal changes during a prolonged critical illness differ from those present in the acute (short term) phase of critical illness. So far, however, the dynamics of the metabolic, hormonal and epigenetic changes during a stay in ICU have not been thoroughly studied. In view of finding the right timing for starting certain treatments (interventions) in critically ill patients, this is nevertheless crucial. Indeed, insight in when epigenetic, metabolic and endocrine changes develop may identify a “time window of opportunity” for future interventions and may to an important extent contribute to the planning of future intervention studies. The aim of this study is to map the time course of the epigenetic, metabolic and endocrine changes during critical illness (i.e. find out when these changes happen). In the intensive care units of the University Hospitals of Leuven we will, once a week, collect blood, mouth mucosa (inside of the mouth), hair and urine samples as well as a muscle and fat biopsy from adult patients. In this way, human samples will be obtained at different stages of a critical illness, from the acute phase of illness until recovery. The results will be compared with demographically matched controls (people who are not critically ill). The levels of stress hormones and how they are being used by the body and any epigenetic changes will be studied and there will be tests looking at muscle function.

Who can participate?
Adults in ICU and matched controls. The matched control group is made up of volunteers who have not been critically ill but have similar health issues.

What does the study involve?
Biological samples are collected from both patients and controls in order to look at epigenetic, metabolic and endocrine changes that occur during a critical illness. This includes the sampling of blood, mouth mucosa, hair, urine, and/or muscle and fat biopsies. These analyses will be complemented with muscle force measurement (checking the strength of the muscles) and electrophysiological tests (testing heart function).

What are the possible benefits and risks of participating?
There is no direct personal benefit for the participating patients, but they can contribute to obtaining new information on the impact of critical illness. This can be important in the future for the treatment of critically ill patients during and after ICU stay and can provide new medical insight. There is no risk to participating.

Where is the study run from?
Five intensive care units (ICUs) at the University Hospital of Leuven (Belgium)

When is the study starting and how long is it expected to run for?
September 2015 to February 2019

Who is funding the study?
1. Methusalem program funded by the Flemish Government through the University of Leuven
2. European Research Council Advanced Grant from the Ideas Programme of the European Union’s Seventh Framework Programme
3. Research Foundation-Flanders (FWO) Belgium

Who is the main contact?
Professor Greet Van den Berghe

Trial website

Contact information

Type

Public

Primary contact

Prof Greet Van den Berghe

ORCID ID

Contact details

Clinical Division and Laboratory of Intensive Care Medicine
Department Cellular and Molecular Medicine
KU Leuven
Herestraat 49
Leuven
3000
Belgium

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

S58533

Study information

Scientific title

The dynamics of epigenetic, metabolic and endocrine alterations during critical illness: a prospective cross-sectional study

Acronym

CROSS

Study hypothesis

Critically ill patients suffer from vital organ failure, are characterized by remarkable endocrine and metabolic alterations, and frequently develop muscle weakness. Patients who survive critical illness are often confronted with sustained debilitating physical and psychological problems after ICU stay, including persistent muscle weakness and long-term neurocognitive impairment. This condition is referred to as “the legacy of critical illness”. The exact pathophysiology of these alterations during critical illness and the legacy of critical illness remain largely unknown. The aim of this study is to gain insight in the pathophysiology of critical illness and its long-term consequences. As primary objective, we will study in detail in preset time windows of ICU stay the time course of the epigenetic, metabolic and endocrine alterations that develop in response to critical illness and to unravel potential underlying processes involved in these changes. Secondary objectives include a reanalysis of the time course of the alterations described in the primary objective as well as a longitudinal analysis of within-subjects changes in time for those patients who participate multiple times.

Ethics approval

Medical Ethics Committee (Institutional Review Board) of the University Hospitals Leuven, 16/10/2015, ref: S58533

Study design

Single-center prospective observational cross-sectional study

Primary study design

Observational

Secondary study design

Cross sectional study

Trial setting

Hospitals

Trial type

Other

Patient information sheet

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

Condition

Critical illness

Intervention

Biological samples will be collected from patients and controls after informed consent in order to perform the detailed studies as described. This includes the sampling of blood, mouth mucosa, hair, urine, and/or muscle and fat biopsies. These analyses will be complemented with muscle force measurement and electrophysiological tests. The data obtained from these analyses will be correlated with available demographic and clinical data.

Intervention type

Other

Phase

Drug names

Primary outcome measures

To study in detail, in preset time windows of ICU stay, the time course of the epigenetic, metabolic and endocrine alterations that develop in response to critical illness and to unravel potential underlying processes involved in these changes

Secondary outcome measures

1. Reanalysis of the time course of the alterations described in the primary objective
2. Within-subjects longitudinal analysis of changes for those patients who participate multiple times

Overall trial start date

01/09/2015

Overall trial end date

28/02/2019

Reason abandoned

Eligibility

Participant inclusion criteria

1. Patients:
All adult/senior patients at the surgical and medical intensive care units are eligible

2. Controls:
A control group of volunteers who have not been critically ill, but have similar comorbidities as the critically ill patients will be recruited to match demographically with the patient group

Participant type

Mixed

Age group

Mixed

Gender

Both

Target number of participants

Patient recruitment will continue until preset sample numbers (120 per group for blood analyses and 60 per group for biopsy analyses) will have been obtained in four groups based on time in ICU within the first 28 days time window with a comparable distribution of ICU admission categories. At that time, recruitment of patients in a fifth group (> day 28) will also stop. In addition, we will recruit controls who never stayed in the ICU until 120 matched controls have been included for blood analyses and 60 for biopsy analyses

Participant exclusion criteria

1. Patients:
1.1. General:
1.1.1. Age younger than 18 years
1.1.2. Readmission to ICU (unless within 48 hrs)
1.1.3. Declined participation
1.1.4. DNR code
1.1.5. Patients with HIV
1.1.6. Chronic systemic treatment with glucocorticoids prior to ICU admission
1.2. Blood sampling: absence of arterial line
1.3. Mouth mucosa sampling: normal mouth mucosa not accessible (e.g. post-tumor resection)
1.4. Neuromuscular evaluation:
1.4.1. General:
1.4.1.1. Patients with neuromuscular disorders identified prior to ICU admission / unable to walk without assistance (wheelchair, walking stick, arm support) prior to ICU admission
1.4.1.2. Patients with a neuromuscular disorder as reason for ICU admission
1.4.2. Muscle biopsy: increased bleeding risk
1.4.2.1. Platelet count below 50000/mm3 and/or PT below 40%
1.4.2.2. Known coagulation disorders
1.4.2.3. Use of anti-coagulation or thrombolytic agents
1.4.3. Muscle force by MRC sum score:
1.4.3.1. No muscle biopsy
1.4.3.2. Patient not awake/cooperative (*)
1.4.4. Hand grip strength
1.4.4.1. No muscle biopsy
1.4.4.2. Patients not awake/cooperative (*)
1.4.4.4. Medical Research Council (MRC) score for forearm flexion or wrist extension below 3
1.4.5. Electromyography / nerve conduction studies / direct muscle stimulation
1.4.5.1. No muscle biopsy
(*) patients who give a biopsy but are not awake/cooperative at the time of sampling will be screened for awakening/cooperation up until two days later for MRC sum scoring and hand grip strength
1.5. Fat biopsy: increased bleeding risk:
1.5.1. Platelet count below 50000/mm3 and/or PT below 40%
1.5.2. Known coagulation disorders
1.5.3. Use of anti-coagulation or thrombolytic agents

2. Controls:
2.1. General
2.1.1. Age younger than 18 years
2.1.2. Previous ICU stay (except coronary care unit stay)
2.2. Blood sampling: known severe coagulation disorders (e.g. hemophilia)
2.3. Mouth mucosa sampling: normal mouth mucosa not accessible (e.g. post-tumor resection)
2.4. Muscle and fat biopsy:
2.4.1. Controls with acute or chronic neuromuscular disorders or unable to walk without assistance (wheelchair, walking stick, arm support) will be excluded for muscle biopsy
2.4.2. Increased risk of bleeding:
2.4.2.1. Known coagulation disorders
2.4.2.2. Use of anti-coagulation
2.5. Muscle force / electrophysiology / direct muscle stimulation: no muscle biopsy

Recruitment start date

01/03/2016

Recruitment end date

28/02/2019

Locations

Countries of recruitment

Belgium

Trial participating centre

KU Leuven University Hospital
Leuven
3000
Belgium

Sponsor information

Organisation

KU Leuven

Sponsor details

c/o Professor Dr. Ir. Koenraad Debackere
Managing Director
University Administration and Central Services
Krakenstraat 3 - box 5500
Leuven
3000
Belgium

Sponsor type

University/education

Website

Funders

Funder type

Government

Funder name

Methusalem program funded by the Flemish Government through the University of Leuven (METH08/07 and METH14/06)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

European Research Council Advanced Grant from the Ideas Programme of the European Union’s Seventh Framework Pogramme (AdvG-2012-321670)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Research Foundation-Flanders (FWO) Belgium

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Intention to publish date

Participant level data

Not expected to be available

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes