Time course of epigenetic, metabolic and endocrine alterations during critical illness
| ISRCTN | ISRCTN17621057 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN17621057 |
| Secondary identifying numbers | S58533 |
- Submission date
- 08/12/2015
- Registration date
- 09/12/2015
- Last edited
- 10/09/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Ongoing
- Condition category
- Other
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 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.
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 August 2025
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
Contact information
Public
Clinical Division and Laboratory of Intensive Care Medicine
Department Cellular and Molecular Medicine, KU Leuven
Herestraat 49
Leuven
3000
Belgium
Study information
| Study design | Single-center prospective observational cross-sectional study |
|---|---|
| Primary study design | Observational |
| Secondary study design | Cross sectional study |
| Study setting(s) | Hospital |
| Study type | Other |
| Participant information sheet | Not available in web format, please use contact details to request a patient information sheet |
| Scientific title | The dynamics of epigenetic, metabolic and endocrine alterations during critical illness: a prospective cross-sectional study |
| 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(s) | Medical Ethics Committee (Institutional Review Board) of the University Hospitals Leuven, 16/10/2015, ref: S58533 |
| 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 |
| Primary outcome measure | 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 study start date | 01/09/2015 |
| Overall study end date | 31/08/2025 |
Eligibility
| Participant type(s) | Mixed |
|---|---|
| Age group | Mixed |
| Sex | 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 |
| Total final enrolment | 374 |
| 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 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 (added 12/09/2018: patients who did receive chronic systemic treatment with glucocorticoids prior to ICU admission will be recruited separately to allow investigation of the impact of prior chronic systemic glucocorticoid treatment) 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 | 11/01/2017 |
| Recruitment end date | 03/09/2020 |
Locations
Countries of recruitment
- Belgium
Study participating centre
3000
Belgium
Sponsor information
University/education
c/o Professor Dr. Ir. Koenraad Debackere
Managing Director
University Administration and Central Services
Krakenstraat 3 - box 5500
Leuven
3000
Belgium
"ROR" |
https://ror.org/05f950310 |
|---|
Funders
Funder type
Government
No information available
No information available
Government organisation / Local government
- Alternative name(s)
- Research Foundation Flanders, Flemish Research Foundation, FWO
- Location
- Belgium
Results and Publications
| Intention to publish date | 31/08/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| Publication and dissemination plan | Planned publication in a high-impact peer reviewed journal, date to be confirmed later. |
| IPD sharing plan | Current IPD sharing plan as of 17/08/2023: The datasets generated during and/or analysed during the current study are not expected to be made available due to preserving patient confidentiality. Prof. Greet Van den Berghe will on request detail the restrictions and any conditions under which access to some data may be provided. Previous 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? |
|---|---|---|---|---|---|
| Interim results article | 15/05/2022 | 17/08/2023 | Yes | No |
Editorial Notes
10/09/2024: The contact confirmed the record is up to date.
17/08/2023: The following changes have been made:
1. The overall study end date was changed from 31/08/2023 to 31/08/2025 and the plain English summary was updated accordingly.
2. The intention to publish date was changed from 31/08/2024 to 31/08/2026.
3. The IPD sharing plan and summary were changed.
4. Publication reference added.
09/08/2021: The following changes have been made:
1. The recruitment end date has been changed from 31/08/2021 to 03/09/2020.
2. The intention to publish date has been added.
3. The total final enrolment number has been added.
01/09/2020: Recruitment to this study is no longer paused.
04/08/2020: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/08/2020 to 31/08/2021.
2. The overall trial end date was changed from 31/08/2022 to 31/08/2023.
05/05/2020: Due to current public health guidance, recruitment for this study has been paused.
27/09/2018: Publication and dissemination plan and IPD sharing statement added.
12/09/2018: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/03/2016 to 11/01/2017.
2. The recruitment end date was changed from 28/02/2019 to 31/08/2020.
3. The overall trial end date was changed from 28/02/2019 to 31/08/2022.
4. The exclusion criteria were updated.
