Survival of critically ill patients has improved, resulting in a growing population of chronically critically ill (CCI) individuals with prolonged organ dysfunction, mechanical ventilation, and high morbidity. While nutritional guidelines during the acute phase are well established, evidence on protein intake in CCI patients is limited. Inflammation may influence metabolic responses and clinical outcomes, highlighting the need for prospective studies.

The MetaChronic Study is a single-center, prospective cohort designed to describe metabolic trajectories and evaluate the effect of protein intake on outcomes in critically ill adults. Resting energy expenditure will be measured by serial indirect calorimetry, protein and caloric intake will be recorded weekly, and inflammation will be assessed using C-reactive protein (CRP) and procalcitonin. Secondary objectives include subgroup analyses, assessment of protein delivery routes, and exploration of interactions between protein intake, caloric intake, and inflammation.

This single-center, longitudinal observational study enrolls critically ill adults who require invasive mechanical ventilation (IMV) for at least 48 hours and remain in the Intensive Care Unit (ICU) for more than 7 days. Participants are followed in-hospital for up to 42 days after ICU admission, unless discharged, deceased, or unable to continue accurate nutritional monitoring due to transition to oral feeding for nutritional purposes. The final assessment occurs on Day 90 after onset of critical illness, when functional status is evaluated using the Portuguese validated version of the EuroQol 5-Dimension Questionnaire (EQ-5D), administered either by telephone or in person depending on patient location.

Baseline characterization includes:

• Demographic information (age, sex)
• Pre-ICU hospitalization days
• Nutritional risk assessed with the modified Nutrition Risk in the Critically Ill (NUTRIC) score (without interleukin-6)
• Category of critical illness (septic with/without abdominal surgery, trauma with/without head injury, neurocritical, and other categories)
• Severity upon ICU admission measured by the Simplified Acute Physiology Score II (SAPS II)

Metabolic assessment is performed using serial indirect calorimetry beginning on Day 7 of ICU stay and repeated one to three times per week up to Day 42 or until hospital discharge. Feasibility requires absence of air leaks in the respiratory system. For patients on invasive mechanical ventilation (IMV), measurements follow device requirements (fraction of inspired oxygen < 70% and positive end-expiratory pressure < 12 cmH₂O); for spontaneous ventilation, measurements are obtained in canopy mode at FiO₂ 21%. Weekly metabolic values are calculated as the average of available measurements.

Protein intake is recorded according to routine clinical practice and quantified weekly after Day 7, expressed in grams (g) per kilogram of adjusted body weight per day (g/kg/day). Protein delivered as amino acids is converted to grams of protein using a standard factor (100 g hydrolyzed protein = 83 g amino acids). Total caloric intake is also quantified weekly, including enteral and parenteral nutrition as well as non-nutritional caloric sources such as glucose-containing solutions and propofol.

Inflammatory status is assessed weekly using C-reactive protein (CRP) and procalcitonin measurements.

Patients are monitored according to routine clinical practice, and comparative analyses will evaluate outcomes according to protein intake achieved during the second week of ICU stay (>1.3 vs. ≤1.3 g/kg/day). Outcomes include:

• Duration of invasive mechanical ventilation (days)
• Days alive and out of the ICU to Day 90 (days)
• Days alive and out of the hospital to Day 90 (days)
• Need for tracheostomy (Yes/No); if yes, possibility of decannulation (Yes/No)
• Duration of tracheostomy (days)
• Mortality at 28 days, in ICU, in-hospital, and at 90 days
• Number of infections to Day 30 (defined as the number of infectious agents, not deemed colonization, in biological samples obtained per local standard practice)
• Discharge destination (institution/home)
• Functional outcome at Day 90 assessed using the EuroQol 5-Dimension Questionnaire (EQ-5D)

Inclusion Criteria:

• Adult critically ill patients admitted to Intensive Care Unit > 7 days
• Invasive mechanical ventilation (IMV) > 48 hours

Exclusion Criteria:

• Active oncological disease
• Neuromuscular diseases
• Confirmed or predicted Glasgow Coma Score < 10 at 14 days in Intensive Care Unit
• Pregnant women

The study will include adult critically ill patients admitted to intensive care who meet the eligibility criteria described.

Individual participant data (IPD) to be shared include: de-identified demographic and clinical variables (age, sex, diagnosis, severity scores), nutritional data (caloric and protein intake, feeding route), indirect calorimetry results, inflammatory markers (C-reactive protein, procalcitonin), and outcome variables (ICU/hospital length of stay, mortality).

Beginning 3 months after publication and ending 2 years after the publication of results

De-identified individual participant data and supporting documents (protocol, analysis plan, CRFs) will be made available as supplementary material to the publication and can also be shared with qualified researchers upon reasonable request. Access requires submission of a research proposal and signing a data use agreement to ensure confidentiality and compliance with ethical regulations.