Effects and Safety of Infusion of Low-Doses of Methylprednisolone in Early ALI and ARDS in Children

Phase II, Randomized, Placebo-Controlled, Double-Blind Clinical Trial to Evaluate the Effects and Safety of Infusion of Low-Doses of Methylprednisolone in Early ALI and ARDS in Children

The purpose of this study is to investigate the effects of prolonged low-dose methylprednisolone infusion on pulmonary function (LIS and ventilation-free days), extra pulmonary organ function (PMODS score), inflammatory markers - RCP (Reactive C Protein), IL6 (Interleukine 6), TNFα (Tumor Necrosis Factor), IL8 (Interleukine 8), IL10 (Interleukine 10) and length of Pediatric Intensive Care Unit (PICU) stay in early ALI/ARDS in children.

Scientific background. Dysregulated systemic inflammation - characterized by protracted elevation of inflammatory cytokines in the circulation - is a key pathogenetic mechanism for morbidity and mortality in ALI/ARDS, and is associated with tissue insensitivity and/or resistance to inappropriately elevated endogenous glucocorticoids. In one study, prolonged methylprednisolone treatment of ARDS patients resulted in rapid and sustained reduction in circulating and pulmonary levels of pro-inflammatory cytokines, chemokines, and procollagen.

Preliminary work. Two recent metanalysis evaluating the use of low doses of corticosteroids in acute lung injury/ARDS in adults reported a significant physiological improvement, a sizable reduction in duration of mechanical ventilation and ICU length of stay and reduction in mortality.

Hypothesis. We hypothesized that prolonged administration of low doses of methylprednisolone in pediatric ALI/ARDS is safe and downregulates systemic inflammation and leads to earlier resolution of pulmonary and extra pulmonary organ dysfunction and a reduction in duration of mechanical ventilation and ICU stay.

Objective. To investigate the effects of prolonged low-dose methylprednisolone infusion on pulmonary function (LIS and ventilation-free days), extra pulmonary organ function (PMODS score), inflammatory markers - RCP (Reactive C Protein), IL6 (Interleukine 6), TNFα (Tumor Necrosis Factor), IL8 (Interleukine 8), IL10 (Interleukine 10) and length of Pediatric Intensive Care Unit (PICU) stay in early ALI/ARDS in children.

Study design. Prospective randomized, placebo-controlled, double-blind clinical trial.

Inclusion Criteria:

• Diagnosis of ALI/ARDS within the first 72 hours based on all of the following criteria:

  • Respiratory failure requiring mechanical ventilation - via endotracheal intubation or noninvasive positive pressure ventilation;
  • Acute onset of bilateral pulmonary densities on chest radiograph in the context of appropriate predisposing injury or illness with no evidence of left ventricular failure;
  • Ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2:FiO2 ) ≤ 300 (criteria for ALI) or 200 (criteria for ARDS) with FiO2 ≥ 0,5 and PEEP = 5 cmH2O.

• To sign the Informed Consent to participate.

Exclusion Criteria:

• ALI/ARDS with more than 72 hours of diagnosis
• Failure to obtain written informed consent to participate in the study;
• Condition requiring > 0.5mg/Kg/day of prednisone equivalent (i.e., acute asthma or bronchopulmonary dysplasia)
• Patients enrolled in another experimental (interventional) protocol within the past 30 days, which might adversely impact on the results of this study as determined by the investigators;
• Primary or secondary neuromuscular dysfunction
• Patients using aminoglycosides combined with neuromuscular blockers
• Cardiopulmonary arrest within 7 days or anytime during present hospitalization prior to enrollment;
• Irreversible cessation of all brain function;
• Immunosuppression, including HIV+ status, history of bone marrow or solid organ transplantation, current malignancy, neutropenia, receiving cytotoxic therapy for any reason, and acute burn injury;
• Severe chronic liver disease (Child-Pugh Class C score > 10 points).