Nebulised heparin for patients with or at risk of acute respiratory distress syndrome: a multicentre, randomised, double-blind, placebo-controlled phase 3 trial

Abstract

Background Mechanical ventilation in intensive care for 48 h or longer is associated with the acute respiratory distress syndrome (ARDS), which might be present at the time ventilatory support is instituted or develop afterwards, predominantly during the first 5 days. Survivors of prolonged mechanical ventilation and ARDS are at risk of considerably impaired physical function that can persist for years. An early pathogenic mechanism of lung injury in mechanically ventilated, critically ill patients is inflammation-induced pulmonary fibrin deposition, leading to thrombosis of the microvasculature and hyaline membrane formation in the air sacs. The main aim of this study was to determine if nebulised heparin, which targets fibrin deposition, would limit lung injury and thereby accelerate recovery of physical function in patients with or at risk of ARDS.Methods The Can Heparin Administration Reduce Lung Injury (CHARLI) study was an investigator-initiated, multicentre, double-blind, randomised phase 3 trial across nine hospitals in Australia. Adult intensive care patients on invasive ventilation, with impaired oxygenation defined by a PaO 2 /FiO 2 ratio of less than 300, and with the expectation of invasive ventilation beyond the next calendar day were recruited. Key exclusion criteria were heparin allergy, pulmonary bleeding, and platelet count less than 50 X 10⁹/L. Patients were randomly assigned 1:1, with stratification by site and using blocks of variable size and random seed, via a web-based system, to either unfractionated heparin sodium 25 000 IU in 5 mL or identical placebo (sodium chloride 0•9% 5 mL), administered using a vibrating mesh membrane nebuliser every 6 h to day 10 while invasively ventilated. Patients, clinicians, and investigators were masked to treatment allocation. The primary outcome was the Short Form 36 Health Survey Physical Function Score (out of 100) of survivors at day 60. Prespecified secondary outcomes, which are exploratory, included development of ARDS to day 5 among at-risk patients, deterioration of the Murray Lung Injury Score (MLIS) to day 5, mortality at day 60, residence of survivors at day 60, and serious adverse events. Analyses followed the intention-to-treat principle. There was no imputation of missing data. The trial is registered with the Australian and New Zealand Clinical Trials Register, number ACTRN12612000418875 .

Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 By Disrupting The Spike-ACE2 interaction

“…Given the half-life of pixatimod in mice is 38h ( 34 ), compared to 141h in human ( 13 ), future studies should adopt repeat-dose schedules to identify the optimal schedule in models of SARS-CoV-2 infection. We also suggest that direct intranasal delivery of pixatimod would be worth investigation, in view of recent positive data on the delivery of nebulized heparin for treatment of ARDS ( 36 ) which has significance for potential application of heparin in COVID-19 treatment (21).…”

Nebulized Heparin for Post-COVID-19-Related Hypoxia

“…Its safety and usefulness were also confirmed at the early phase of COVID-19 infection. 12 Using such cheap and safe drugs during such challenging pandemic and a global risk of economic crises is of paramount importance (even in developed countries). So, it seems that nebulized UFH treatment is safe and effective in reducing O 2 need at Table 1 Pre-and post-nebulized unfractionated heparin (UFH) treatment days cases' oxygen saturation and need Days Nebulized UFH…”

Combinations of drugs might increase the survival chances of COVID-19 patients: Literature review till date

“…A trial was conducted by Dixon et.al in 252 patients with or at risk of acute respiratory distress syndrome (ARDS) while on Mechanical ventilation in intensive care unity [2131]. Dixon et.al wanted to see if Nebulised heparin can target fibrin deposition and limit the lung injury.…”