Nebulised Heparin as a Treatment for COVID-19

Scientific Rationale and a Call for Randomised Evidence

Frank M. P. van Haren; Clive Page; John G. Laffey; Antonio Artigas; Marta Camprubi-Rimblas; Quentin Nunes; Roger Smith; Janis Shute; Mary Carroll; Julia Tree; Miles Carroll; Dave Singh; Tom Wilkinson; Barry Dixon

Disclosures

Crit Care. 2020;24(454) 

In This Article

Abstract and Introduction

Abstract

Nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale and warrants urgent investigation of its therapeutic potential, for COVID-19-induced acute respiratory distress syndrome (ARDS). COVID-19 ARDS displays the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. Patients infected with SARS-CoV-2 who manifest severe disease have high levels of inflammatory cytokines in plasma and bronchoalveolar lavage fluid and significant coagulopathy. There is a strong association between the extent of the coagulopathy and poor clinical outcomes.

The anti-coagulant actions of nebulised UFH limit fibrin deposition and microvascular thrombosis. Trials in patients with acute lung injury and related conditions found inhaled UFH reduced pulmonary dead space, coagulation activation, microvascular thrombosis and clinical deterioration, resulting in increased time free of ventilatory support. In addition, UFH has anti-inflammatory, mucolytic and anti-viral properties and, specifically, has been shown to inactivate the SARS-CoV-2 virus and prevent its entry into mammalian cells, thereby inhibiting pulmonary infection by SARS-CoV-2. Furthermore, clinical studies have shown that inhaled UFH safely improves outcomes in other inflammatory respiratory diseases and also acts as an effective mucolytic in sputum-producing respiratory patients. UFH is widely available and inexpensive, which may make this treatment also accessible for low- and middle-income countries.

These potentially important therapeutic properties of nebulised UFH underline the need for expedited large-scale clinical trials to test its potential to reduce mortality in COVID-19 patients.

Introduction

In December 2019, a novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) emerged in China and has since spread globally. A large proportion of patients admitted to hospital for coronavirus disease 2019 (COVID-19) develop acute respiratory distress syndrome (ARDS) criteria according to the Berlin definition.[1–3] ARDS is an acute inflammatory lung injury, associated with increased pulmonary vascular permeability, increased lung weight and loss of aerated lung tissue, affecting 23% of mechanically ventilated critically ill patients. The hospital mortality of ARDS is estimated between 35 and 46% depending on ARDS severity.[4,5] However, the death rate in COVID-19 patients with ARDS appears to be higher, up to 66%.[2] It has been suggested that COVID-19 pneumonia-associated ARDS is a specific disease or perhaps a specific phenotype of ARDS, whose distinctive features are severe hypoxaemia initially associated with relatively well-preserved lung mechanics.[6,7] A possible explanation for such severe hypoxaemia occurring in compliant lungs is the loss of lung perfusion regulation and hypoxic vasoconstriction. In addition, COVID-19 ARDS patients have higher plasma markers of coagulation, such as D-dimers, increased prothrombin time and a lower platelet count.[2,8–12] Endothelial dysfunction and microvascular thrombosis could therefore also explain the specific pulmonary findings in severe COVID-19—high dead space and impaired oxygenation in the absence of significant decrease in pulmonary compliance. Post-mortem studies and lung biopsies of SARS-CoV-2 patients with ARDS indeed demonstrated pulmonary fibrin deposition with hyaline membranes in the alveolar spaces and extensive pulmonary microvascular thrombi.[13–15]

Pulmonary disease severity is also related to an aggressive host inflammatory response to SARS-CoV-2 infection, with release of an uncontrolled cytokine storm inflicting damage to other organs including the cardiac, hepatic and renal systems.[16]

In this focused review, we present the biological and scientific rationale for the use of nebulised UFH for COVID-19 pneumonia and ARDS in hospitalised patients and make a call for an urgent, global approach to the investigation of its therapeutic potential for this devastating condition.

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