Can nebulised HepArin Reduce morTality and time to Extubation in patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT): Protocol and statistical analysis plan for an investigator-initiated international meta-trial of prospective randomised clinical studies.

There is significant interest in the potential for nebulised unfractionated heparin (UFH), as a novel therapy for patients with COVID-19 induced acute hypoxaemic respiratory failure requiring invasive ventilation. The scientific and biological rationale for nebulised heparin stems from the evidence for extensive activation of coagulation resulting in pulmonary microvascular thrombosis in COVID-19 pneumonia. Nebulised delivery of heparin to the lung may limit alveolar fibrin deposition and thereby limit progression of lung injury. Importantly, laboratory studies show that heparin can directly inactivate the SARS-CoV-2 virus, thereby prevent its entry into and infection of mammalian cells. UFH has additional anti-inflammatory and mucolytic properties that may be useful in this context. METHODS AND INTERVENTION: The Can nebulised HepArin Reduce morTality and time to Extubation in Patients with COVID-19 Requiring invasive ventilation Meta-Trial (CHARTER-MT) is a collaborative prospective individual patient data analysis of on-going randomised controlled clinical trials across several countries in five continents, examining the effects of inhaled heparin in patients with COVID-19 requiring invasive ventilation on various endpoints. Each constituent study will randomise patients with COVID-19 induced respiratory failure requiring invasive ventilation. Patients are randomised to receive nebulised heparin or standard care (open label studies) or placebo (blinded placebo-controlled studies) while under invasive ventilation. Each participating study collect a pre-defined minimum dataset. The primary outcome for the meta-trial is the number of ventilator-free days up to day 28 day, defined as days alive and free from invasive ventilation.

Compliance Phenotypes in Early Acute Respiratory Distress Syndrome before the COVID-19 Pandemic.

Rationale: A novel model of phenotypes based on set thresholds of respiratory system compliance (Crs) was recently postulated in context of coronavirus disease (COVID-19) acute respiratory distress syndrome (ARDS). In particular, the dissociation between the degree of hypoxemia and Crs was characterized as a distinct ARDS phenotype.Objectives: To determine whether such Crs-based phenotypes existed among patients with ARDS before the COVID-19 pandemic and to closely examine the Crs-mortality relationship.Methods: We undertook a secondary analysis of patients with ARDS, who were invasively ventilated on controlled modes and enrolled in a large, multinational, epidemiological study. We assessed Crs, degree of hypoxemia, and associated Crs-based phenotypic patterns with their characteristics and outcomes.Measurements and Main Results: Among 1,117 patients with ARDS who met inclusion criteria, the median Crs was 30 (interquartile range, 23-40) ml/cm H2O. One hundred thirty-six (12%) patients had preserved Crs (≥50 ml/cm H2O; phenotype with low elastance ["phenotype L"]), and 827 (74%) patients had poor Crs (<40 ml/cm H2O; phenotype with high elastance ["phenotype H"]). Compared with those with phenotype L, patients with phenotype H were sicker and had more comorbidities and higher hospital mortality (32% vs. 45%; P < 0.05). A near complete dissociation between PaO2/FiO2 and Crs was observed. Of 136 patients with phenotype L, 58 (43%) had a PaO2/FiO2 < 150. In a multivariable-adjusted analysis, the Crs was independently associated with hospital mortality (adjusted odds ratio per ml/cm H2O increase, 0.988; 95% confidence interval, 0.979-0.996; P = 0.005).Conclusions: A wide range of Crs was observed in non-COVID-19 ARDS. Approximately one in eight patients had preserved Crs. PaO2/FiO2 and Crs were dissociated. Lower Crs was independently associated with higher mortality. The Crs-mortality relationship lacked a clear transition threshold.