Clinical Trial Summary
Critically ill patients show an acute phase characterized by systemic spread of the
inflammatory response, irrespectively of the cause of intensive care unit (ICU) admission,
and late sequelae, including ICU acquired muscle weakness (ICUAW) and neurocognitive
impairment. Mechanisms driving these late sequelae are unknown and there are no effective
therapies to date. PreMed4PICS hypothesis is that skeletal muscle pathogenetic phenotypes and
long-term sequelae in survivors to critical illness can be predicted at ICU admission in
peripheral blood samples by transcriptomic profiling of the acute systemic response. Our main
objective is to identify pathogenesis-dependent predictive signatures of muscle injury and
clinical outcomes such as ICUAW or cognitive impairment. A multicentric prospective
observational study will be conducted including adult patients admitted to the ICU and
followed up until 12 months after ICU discharge. This will allow for clinical subphenotyping,
sample acquisition and histopathological studies. To identify subphenotype-specific molecular
pathways involved in skeletal muscle recovery, single-nuclei RNAseq will be performed.
Massive sequencing of whole blood RNA and circulating microRNA at ICU admission will be
performed to identify transcriptomic signatures that result in quantitative scores predictive
of the outcomes of interest. All the findings will be confirmed in two validation cohorts.
Collectively, this project aims to characterize the molecular mechanisms leading to ICUAW
development and recovery, identifying therapeutic targets. The potential of a quantitative
approach to the acute inflammatory response to predict long-term sequelae in survivors of
critical illness will be validated.
The main objective of this project is to demonstrate that transcriptomic profiling of the
acute systemic inflammatory response in patients admitted to the ICU predicts the main
molecular pathways activated in the skeletal muscle at the onset of critical illness and
during recovery, and the long term post-ICU sequelae. To achieve this objective the following
specific aims have been established and organized into four work packages (WP) with specific
objectives:
WP1: Clinical subphenotying and sampling in a large cohort of critically ill patients.
WP1.1. To characterize clinical features of the acute response to critical illness in two
independents cohorts.
WP1.2. To evaluate long-term post-ICU sequelae after ICU discharge. WP1.3. To create a
biobanked collection of samples from critically-ill patients.
WP2: Pathogenetic subphenotyping of skeletal muscle injury and recovery in critically ill
patients.
WP2.1. To perform sn-RNAseq in muscle samples obtained at ICU admission and during the
recovery phase from patients with and without persistent postICU muscle weakness.
WP2.2. To identify local pathogenetic subphenotypes according to the mechanisms involved in
ICUAW development and recovery.
WP3: Transcriptomic profiling of peripheral whole blood during the acute response to critical
illness.
WP3.1. To massively sequence gene expression and c-miRNA in peripheral blood obtained at ICU
admission (discovery cohort).
WP3.2. To identify transcriptomic signatures in peripheral blood predictive of pathogenetic
muscular phenotypes and long-term post-ICU sequelae.
WP3.3. To characterize the acute inflammatory profiles in response to critical illness
according to the transcriptomic signatures.
