Efficacy, Safety, and Tolerability of Methylprednisolone in Critically Ill Patients With the Hyperinflammatory Phenotype: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase II Trial
The goal of this clinical trial is to learn whether methylprednisolone improves outcomes in critically ill patients with a hyperinflammatory phenotype. It will also evaluate the safety of methylprednisolone at different doses. The main questions it aims to answer are: * Does methylprednisolone improve organ function compared with placebo? * Does methylprednisolone reduce the risk of mortality within 30 days? Researchers will compare high-dose methylprednisolone (160mg/d), low-dose methylprednisolone (80mg/d), and placebo (normal saline) to evaluate effectiveness and safety. Participants will: * Receive high-dose methylprednisolone, low-dose methylprednisolone, or placebo every 12 hours for the first 3 days * Be reassessed on Day 4 based on their inflammatory status If the hyperinflammatory phenotype persists, the treatment dose will be reduced by half and continued until Day 7 or ICU discharge, whichever occurs first If the patient transitions to a hypoinflammatory phenotype, the study treatment will be discontinued * Be monitored daily in the intensive care unit for organ function, inflammatory status, and need for organ support * Be followed for up to 30 days after randomization to assess survival and recovery
⁃ Participants must meet all of the following criteria:
• Age ≥18 years.
• Diagnosis of acute respiratory distress syndrome (ARDS) or sepsis.
⁃ ARDS will be defined according to standard criteria:
• acute onset within 1 week of a known clinical insult or new/worsening respiratory symptoms;
• bilateral pulmonary opacities on chest imaging (X-ray or CT) or bilateral B-lines and/or consolidation on lung ultrasound, not fully explained by effusion, atelectasis, or nodules;
• respiratory failure not fully explained by cardiac failure or fluid overload;
• hypoxemia defined as PaO₂/FiO₂ ≤300 mmHg or SpO₂/FiO₂ ≤315 (with SpO₂ ≤97%) under a minimum positive end-expiratory pressure (PEEP) of 5 cmH₂O.
⁃ Sepsis will be defined according to the Sepsis-3 criteria as suspected or confirmed infection with an acute increase in SOFA score ≥2 points, assuming a baseline SOFA score of 0 in patients without known prior organ dysfunction.
⁃ Sepsis-associated ARDS will be defined as ARDS occurring in patients with sepsis.
⁃ 3\. Receiving invasive mechanical ventilation. 4. Admission to the intensive care unit (ICU). 5. Hyperinflammatory phenotype, defined as a predicted probability ≥0.5 using a validated AI clinical classifier based on clinical data.
⁃ 6\. Randomization within 72 hours of ARDS or sepsis onset. 7. Provision of written informed consent by the patient or their legally authorized representative.