Nebulized Heparin in Severe Acute Respiratory Syndrome COVID-19 (NEBUHEPA)

Efficacy and Safety Study to Evaluate the Use of Nebulized Heparin in Patients With Severe Acute Respiratory Syndrome Covid-19 (SARS-CoV-2)

To evaluate the safety and efficacy of the use of inhalational heparin in patients with pulmonary compromise / pneumonia / SARS associated with COVID-19, laboratory with marked inflammation parameters, and prothrombotic state secondary to it (Fibrinogen, Ferritin and / or elevated D-Dimer) , from admission to hospitalization. The combination of inhalation heparin combined with prophylactic doses of LMWH could reduce the progression to severe forms of the disease, and consequently the need for intensive care units and mechanical ventilation.

The emergency of COVID-19 requires the urgent development of strategies to avoid the impact of the disease on our population, the saturation of the health system and the mortality of the disease. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, Hubei province, China and has subsequently spread to the world population. Factors associated with the development of SARS and its mortality include advanced age, lymphopenia, organ dysfunction, and bleeding disorders. Different manifestations have been described (deep vein thrombosis, pulmonary thromboembolism, digital ischemia and cerebral infarcts), and different mechanisms, such as the presence of antiphospholipid antibodies in COVID-19. There is evidence of the presence of a hypercoagulable state in the majority of deaths from SARS associated with COVID -19. Increased plasma D-dimer concentrations is a common finding and also appears to be an independent predictor of mortality. These patients and those who meet criteria for sepsis-induced coagulopathy (SIC) would benefit from anticoagulant therapy primarily with low molecular weight heparin (LMWH). Antithrombotic therapies have been used in clinical practice for almost a century. In clinical practice, unfractionated heparin (UFH) and heparin derivatives remain the predominant antithrombotic therapies administered parenterally. Heparin binds to antithrombin III (AT-III), a plasma glycoprotein, and to a small extent also to the heparin II cofactor. The result of this binding produces a conformational change and a strong increase in the inhibitory effect of thrombin, which becomes approximately 1000 times more potent than before. Other targets of heparin on coagulation are the inhibition or reduced activation of factors V, VIII and IX and the inhibition of thrombocyte function, due to a nonspecific binding of platelet factor IV. However, heparin is a drug not only with anticoagulant properties, it has many other properties (interaction with growth factors, regulation of cell proliferation and angiogenesis, modulation of proteases and antiproteases), making it an interesting subject of research in the field of inflammation, allergy and immunology, interstitial lung fibrosis and oncology. Inhalation of heparin produces local anti-inflammatory and antifibrotic effects . In addition, possible effects have been described to prevent viral infection, including coronaviridae . It was describes the capacity of SARS-CoV-2 S1 RBD to bind heparin. Such binding capacity is an important prerequisite for research related to the development of SARS-CoV-2 unfractionated heparin therapeutic inhalation Experimental studies of inhaled UFH in healthy subjects showed that doses of less than 32,000 IU of UFH through the lower respiratory tract were safe. In a prospective cohort study in young adults, Harenberg determined that the inhaled dose of LMWH had to be 10 times greater than that administered subcutaneously to achieve similar levels of anti-factor Xa assay. Considering the role of coagulopathy and inflammation in the induction of ventilator-induced lung injury, nebulized heparin improved lung function in ventilated patients, equivalent to the use of corticosteroids. It has also been compared with other interventions to stimulate the fibrinolysis or block coagulation to suppress the inflammatory response and reduce lung injury in adult acute respiratory distress syndrome .

Nebulized Heparin (UNF)5000 IU in Saline Solution1 ml every 8 hours plus Enoxaparine 40mg /d or 60mg/d, adjusted by BMI and calculated creatinine clearance . Device to nebulize without producing aerosolization: To nebulized heparin we have a modified a fullface snorkel mask, in which instead of the discharge valve a connector for the Venturi has been placed, and in the air outlet / inlet of the snorkel it has been adapted a connector made with 3D printing for the insertion of a disposable antiviral filter (filters commonly used in Mechanical Respiratory Assistance devices). The mask is made of materials that allow its sterilization with the STERRAT Hydrogen Peroxide plasma system, available at the institution.

Blood Gas criteria :PaO2 / FiO2 <200 (or the inability to maintain an SpO2 of at least 92% with a reservoir mask). Acute ventilatory failure (pH less than 7.35 with PaCO2 greater than 45 mmHg)

Inclusion Criteria: Persons over 18 years of age of any sex admitted with a diagnosis of a suspected case of COVID-19, in accordance with the definition of the Ministry of Health of the Nation (MSal) as of May 20, 2020, who present at the time of admission or in its evolution pulmonary infiltrates compatible with imaging studies (chest X-ray or chest CT) and at least one of the following biochemical parameters of systemic inflammation: D DIMER over 1.0 ug/dl Ferritin over 500 ng/ml Fibrinogen over 500 mg/dl Exclusion Criteria: Under 18 years old Pregnant women Known allergy to Heparin Participant in another clinical trial that is not approved for joint enrollment. APTT> 120 seconds, not due to anticoagulant therapy. Platelet count <20 x 109 per L Lung bleeding. Uncontrolled bleeding Advanced neurological impairment Advanced oncological disease

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