Long-Term Outcomes and Post-Intensive Care Syndrome: Investigating the Associations Between Metabolic Signatures and Physical Functioning in Critically Ill Patients

Long-Term Outcomes and Post-Intensive Care Syndrome: An Explorative, Prospective, Observational Cohort Study to Investigate the Associations Between Metabolic Signatures and Physical Functioning in Critically Ill Patients

Despite being young, healthy, and physically fit, some intensive care unit (ICU) patients experience significantly worse functional recovery after critical illness than older patients with multiple comorbidities although a poor precondition seems to be associated with worse ICU outcomes. This paradox highlights a fundamental gap in our understanding of the determinants of long-term recovery. While nonmodifiable factors such as age and pre-existing disease explain part of the variation, they cannot fully account for the wide heterogeneity in outcomes. Metabolic disturbances during critical illness, such as hypercatabolism, impaired muscle metabolism, nutritional deficits, systemic inflammation, and disruption of gut health, are likely to influence recovery trajectories, yet remain poorly characterized. Because these processes represent potentially modifiable targets, combining their evaluation with nonmodifiable patient characteristics is essential for unraveling the complex, multifactorial mechanisms underlying post-intensive care syndrome (PICS).

This explorative, prospective, observational study aims to investigate the associations between metabolic signatures during the acute phase of critical illness and PICS outcomes throughout the recovery trajectory of ICU survivors, with a primary focus on physical functioning. In addition, the study explores the longitudinal course of metabolic parameters from ICU admission up to 12 months post-discharge, and whether these signatures can help identify distinct recovery phenotypes.

Participants will be followed for 12 months, with study assessments at ICU admission, ICU discharge, and at 3-, 6-, and 12-months post-ICU admission.

Yearly, more than 70.000 patients are admitted to the intensive care unit (ICU) in the Netherlands. Although survival rates from critical illness have improved over the last decades, still patients suffer from profound weakness and functional impairments, collectively referred to as post-intensive care syndrome (PICS). PICS encompasses a cluster of long-lasting physical, cognitive, and mental health problems that have a severe impact on patients' quality of life. Studies investigating strategies to improve recovery after critical illness have shown limited effectiveness. This might be due to heterogeneous recovery trajectories observed among ICU survivors. Research has focussed on the associations between non-modifiable factors (e.g., age, sex and disease severity) and PICS outcomes. However, comprehensive assessment of potentially modifiable metabolic signatures (such as hypercatabolism, muscle metabolism, nutritional status, inflammatory response, and gut health) is lacking. These modifiable factors might be of interest as these likely shape the recovery trajectory of critical illness survivors. This approach, by combining the assessment of nonmodifiable factors together with potentially modifiable factors, is essential for understandiing the complex, multifactorial, pathophysiological mechanisms underlying PICS.

The TOPICS study aims to explore the associations between modifiable factors during critical illness (such as hypercatabolism, muscle metabolism, nutritional status, inflammatory response, and gut health), and physical and psychological functioning in ICU survivors. The main questions it aims to answer are:

1. What are the associations between metabolic signatures during the acute phase of critical illness and physical functioning 3-months post-ICU admission?
2. What are the associations between metabolic signatures during the acute phase of critical illness and physical functioning across different time points in the recovery phase?
3. What are the associations between metabolic signatures during the acute phase of critical illness and psychological functioning (cognitive functioning and mental health status) across different time points during the recovery phase?
4. What is the trajectory of PICS outcomes, quality of life and metabolic parameters during one year following ICU admission?
5. Can distinct patient phenotypes with different recovery trajectories be identified based on metabolic and physical functioning outcomes?

The study is a monocentre, longitudinal, explorative, prospective, observational study. Study measurements will be performed upon ICU admission, and in the recovery period (ICU discharge, 3-, 6-, and 12-months post-ICU admission). Study procedures include:

1. Completion of questionnaires on health-related quality of life, cognitive functioning, mental health status, and sleep quality.
2. Assessment of physical functioning.
3. Collection of blood samples.
4. Collection of fecal samples.
5. Assessment of dietary intake.

The study population will consist of 200 adult patients admitted to the ICU of Gelderse Vallei Hospital, Ede, with an expected ICU length of stay of ≥72 hours, or who receive invasive mechanical ventila-tion (IMV) or non-invasive ventilation (NIV) within 48 hours after ICU admission and are ex-pected to receive this ventilatory support (IMV or NIV) for ≥48 hours.

Inclusion Criteria:

• Age ≥ 18 years at time of ICU admission;
• Received ventilatory support (IMV or NIV) within 48 hours after ICU admission with an expected duration of ≥48 hours during ICU stay (irrespective of ICU length of stay); OR
• An expected ICU length of stay of ≥72 hours (irrespective of ventilatory support).

Exclusion Criteria:

• Concurrent participation in an intervention study with an anticipated therapeutic effect on PICS outcomes (physical functioning, cognitive functioning, or mental health status)
• Pre-admission diagnosis of a progressive neurological disease (e.g., Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive forms of multiple sclerosis)
• Participants with neurological paralysis significantly affecting leg function (e.g., spinal cord injury, multiple sclerosis)
• Patients receiving palliative care, with a life expectancy of <3 months (e.g., hospice care or equivalent)
• Patients who are moribund (i.e., in the final stages of a terminal illness, with imminent death expected)
• Anticipated logistical limitations during recovery phase (e.g., transfer to another hospital, no fixed abode);
• Deemed not suitable to participate based upon the judgement of the treating intensivist.