When people become seriously ill, their bodies can be affected in many ways beyond the original disease. One well-known complication in patients treated in intensive care units (ICUs) is the development of severe muscle weakness caused by damage to muscles and nerves. This condition is called critical illness-related weakness and includes disorders of the nerves (neuropathy), the muscles (myopathy), or both. These problems can make it difficult for patients to move, walk, or even breathe independently, and recovery can take months or longer.

So far, most research on this type of weakness has focused on patients who were treated in ICUs. However, many hospitalized patients outside the ICU-such as those admitted to internal medicine wards or semi-intensive care units-can also experience severe infections, organ failure, inflammation, prolonged bed rest, and metabolic stress. These are the same risk factors known to cause nerve and muscle damage in ICU patients. Despite this, weakness occurring outside the ICU is often overlooked, attributed simply to "deconditioning" or prolonged bed rest, and not properly investigated.

The CRI-WEAK-OUT study aims to better understand whether critical illness-related weakness also occurs in hospitalized patients who are not admitted to the ICU, how often it happens, how severe it is, and what factors increase the risk of developing it.

This is a prospective observational study, meaning that patients will be followed over time during and after their hospital stay, without changing their usual medical care. The study will include about 600 adult patients hospitalized for acute illnesses in non-ICU wards across several Italian hospitals. Half of the participants will have signs of organ failure during hospitalization, while the other half will serve as a comparison group without organ failure.

All participants will undergo careful clinical evaluations shortly after hospital admission and again before discharge. Doctors will assess muscle strength, level of disability, independence in daily activities, and overall frailty using standardized and widely accepted scales. Six months after discharge, patients will be contacted by phone to evaluate their recovery and quality of life.

If a patient develops new or worsening muscle weakness during hospitalization, more detailed tests will be performed. These include electrical tests of nerves and muscles to understand whether the weakness is caused mainly by nerve damage, muscle damage, or both. In a subgroup of patients, additional blood samples will be collected to measure substances linked to inflammation and nerve injury. These biological markers may help doctors recognize the condition earlier and predict recovery.

By collecting detailed clinical, electrical, and biological information, the study aims to answer several important questions:

• How common is critical illness-related weakness outside the ICU?
• Which patients are most at risk?
• How does this condition affect recovery and long-term independence?
• Can blood markers help identify patients with nerve or muscle damage? The results of the CRI-WEAK-OUT study may improve awareness of this under-recognized condition, promote earlier diagnosis, and help clinicians plan better prevention and rehabilitation strategies. Ultimately, this research could lead to improved care, faster recovery, and better quality of life for many hospitalized patients who currently experience unexplained weakness after acute illness.

Critical illness myopathy and neuropathy (CRIMYNE) is a spectrum of neuromuscular disorders that develop in patients with severe systemic illness and includes critical illness polyneuropathy, critical illness myopathy, and overlapping forms. These conditions are characterized by generalized symmetrical weakness involving limb and respiratory muscles and typically emerge during or after a prolonged critical illness. CRIMYNE is associated with prolonged mechanical ventilation, extended hospital stays, increased mortality, and long-term disability.

Although CRIMYNE has been primarily described in patients admitted to intensive care units (ICUs), many of the risk factors associated with its development-including systemic inflammation, sepsis, metabolic disturbances, hyperglycemia, prolonged immobilization, and multiorgan dysfunction-are also present in patients hospitalized in internal medicine wards or semi-intensive care settings. Despite this overlap, neuromuscular weakness related to acute illness in non-ICU patients remains poorly recognized and is often attributed to nonspecific causes such as general deconditioning or prolonged bed rest.

It is plausible that neuromuscular involvement similar to CRIMYNE may occur outside the ICU in patients experiencing acute illness with systemic stress and organ dysfunction. However, this condition may be underdiagnosed in non-ICU environments due to limited awareness, competing clinical priorities, and potentially milder clinical manifestations. A better understanding of the occurrence, clinical characteristics, and outcomes of CRIMYNE-like neuromuscular involvement in non-ICU hospitalized patients could improve recognition of this condition, facilitate earlier diagnosis, and support the development of preventive and rehabilitation strategies.

This study is a prospective cohort study including hospitalized adult patients admitted to non-ICU hospital units for acute medical conditions. Participants will be evaluated during hospitalization and followed longitudinally to investigate the occurrence of neuromuscular weakness compatible with CRIMYNE-like involvement.

Participants will undergo clinical evaluation at baseline, within 48 hours of hospital admission, and again near the time of discharge. Muscle strength, disability, and frailty will be assessed using standardized clinical scales. A follow-up evaluation will be performed six months after hospital discharge to assess functional outcomes and quality of life.

Patients who develop clinically significant muscle weakness during hospitalization will undergo electrophysiological evaluation to characterize possible neuromuscular involvement. Additional clinical data, laboratory values, comorbidities, and treatments during hospitalization will be collected from medical records to identify potential risk factors associated with the development of neuromuscular weakness.

In a subgroup of patients, blood samples will be collected to investigate biomarkers associated with peripheral nerve and muscle injury as well as systemic inflammation. These analyses will include measurement of neurofilament light chain and selected inflammatory markers. The aim of this exploratory component is to evaluate whether circulating biomarkers are associated with the development of neuromuscular involvement and with clinical outcomes.

By investigating the occurrence and characteristics of CRIMYNE-like neuromuscular involvement in patients hospitalized outside the ICU, this study aims to improve understanding of this potentially underrecognized complication of acute illness. The results may help identify patients at risk, support earlier recognition of neuromuscular weakness during hospitalization, and inform future preventive and therapeutic strategies.

Inclusion Criteria:

• Age ≥ 18 years
• Hospitalization for acute illness in a non-ICU unit
• For the critical illness cohort: presence of organ failure defined as a SOFA score ≥ 2 at admission or an increase (ΔSOFA) ≥ 2 during hospitalization
• For the control cohort: SOFA score < 2 throughout hospitalization
• Ability to provide written informed consent

Exclusion Criteria:

• History of peripheral neuropathy, myopathy, or other neuromuscular disorders (e.g., myasthenia gravis)
• Conditions affecting the lower limbs that prevent electrophysiological testing
• Delirium with agitation preventing clinical evaluation
• Coma or inability to assess muscle strength

Adult patients hospitalized for acute illness in non-ICU medical wards. Participants are classified into cohorts based on the presence or absence of organ failure during hospitalization, defined by the Sequential Organ Failure Assessment (SOFA) score.