Introduction
Biological rationale: pathophysiology of COVID-19
Infection, inflammation and coagulopathy
Hyaline membrane formation
Microvascular thrombosis
Mucus exudates and DNA NETs
Biological rationale: effects of nebulised UFH
Anti-viral effects
Anti-inflammatory effects
Anti-coagulant effects
Mucolytic effects
Pre-clinical and clinical evidence in lung injury
Dosage (Timing) | Species | Model (Sacrifice) | Nebulizer | Outcomes | Side effects | Reference |
---|---|---|---|---|---|---|
Animal models of acute lung injury treated with nebulised heparin | ||||||
1000 IU/kg (30min before injury and every 6h) | Rat | it. Streptococcus pneumoniae (40h) | Aeroneb Pro Nebulizer | ↓ Pulmonary coagulation | NR | Hofstra et al, 2009 [104] |
1000 IU/kg (30min before, 6h and 12h after injury) | Rat | iv. LPS (7.5 mg/kg) (16h) | Aeroneb Pro Nebulizer | ↓ Coagulation | NR | Hofstra et al, 2010 [105] |
1000 IU/kg (30min before injury and every 6h) | Rat | it. Pseudomonas aeruginosa (16h) | Aeroneb Pro Nebulizer | = | NR | Cornet et al, 2011 [106] |
Dose NR (5 min after injury) | Mouse | inh. Chlorine (400 ppm for 30min) (6h) | AirLife Brand Misty Max 10 | ↓ Decreased inflammation | No side effects | Zarogiannis et al, 2014 [107] |
1000 IU/kg (4h and 8h after injury or 30min before, 4h and 8h after injury) | Rat | it. LPS (10μg/g) (24h) | Aeroneb Pro Nebulizer | ↓ Pulmonary coagulation and inflammation | NR | Chimenti et al, 2017 [80] |
Animal models of acute lung injury treated with nebulised heparin and combined with another treatment | ||||||
10000 IU (1h after injury, every 4h) | Sheep | Smoke inh. and it. Pseudomonas aeruginosa (24h) | AirLife Brand Misty Max 10 | ↓ Lung injury and airways obstruction ↑ PaO2 | No side effects | Murakami et al, 2002 [108] |
10000 IU (30min after injury, every 4h for 24h) or combined with intravenous 10 mg/kg/h lisofylline | Sheep | Smoke inh. (48h) | AirLife Brand Misty Max 10 | ↓ Need for MV ↑ PaO2 | No side effects | Tasaki et al, 2002 [109] |
10000 IU (2h after injury, every 4h) or combined with nebulized 290 IU recombinant antithrombin | Sheep | Cutaneous burn and smoke inh. (48h) | AirLife Brand Misty Max 10 | Combination: ↓ Pulmonary inflammation and airways obstruction ↑ PaO2 | No side effects | Enkhbataar et al, 2007 [110] |
10000 IU (1h after injury, every 4h) combined with intravenous 0.34 mg/kg/h recombinant antithrombin | Sheep | Cutaneous burn and smoke inh. (48h) | AirLife Brand Misty Max 10 | ↓ Inflammation, oedema, airways obstruction ↑ PaO2 | No side effects | Enkhbataar et al, 2008 [111] |
10000 IU (2h after injury, every 4h) combined with intravenous 6 IU/kg/h recombinant antithrombin (from 1h after injury until the end of the study) and nebulized 2 mg tissue plasminogen inhibitor (4h after injury, every 4h) | Sheep | Cutaneous burn and smoke inh. (48h) | AirLife Brand Misty Max 10 | ↓ Lung injury, oedema and airways obstruction ↑ PaO2 | No side effects | Rehberg et al, 2014 [112] |
1000 IU/kg (4h, 12h and 28h after injury) combined with nebulized 500 IU/kg antithrombin (4h and 28h after injury) | Rat | it. HCl and LPS (30 μg/g) (72h) | Aeroneb Pro Nebulizer | ↓ Pulmonary coagulation and inflammation | No side effects | Camprubí-Rimblas et al, 2020 [113] |
Dosage (Timing) | Patients | n | Nebulizer | Outcomes | Reference |
---|---|---|---|---|---|
Clinical studies of acute respiratory distress syndrome with nebulised heparin | |||||
50000-400000 IU/day (two days) | MV ARDS Open-label phase 1 trial | 16 | Aeroneb Pro Nebulizer | ↓systemic coagulation (↓ pulmonary coagulation, 400000 IU) | Dixon et al, 2008 [114] |
25000 IU (every 4h or 6h, max 14 days) | > 48h MV RCT | 50 | Aeroneb Pro Nebulizer | ↓systemic coagulation ↑ Free days MV | Dixon et al, 2010 [100] |
5000 IU (four times a day until cease MV or discharge from the UCI) | > 48h MV Phase 2 RCT | 214 | Aeroneb Pro Nebulizer | = | Bandeshe et al, 2016 [115] |
50000 IU (one day) | Elective cardiac surgery RCT | 40 | Aeroneb Pro Nebulizer | ↓ alveolar dead space fraction and tidal volumes | Dixon et al, 2016 [101] |
25000 IU (every 6h, 10 days) | MV ARDS RCT | 256 | Aeroneb Pro Nebulizer | ↓Lung injury ↑ 60 day survivors at home | Dixon et al, 2020 (submitted for publication) |
Clinical studies of acute respiratory distress syndrome with nebulised heparin and combined with another treatment | |||||
5000 IU combined with N-acetylcysteine and bronchodilator (every 4h for 7 days) | Burn patients paediatric Retrospective | 90 (children) | NR | ↓atelectasis, reintubation and mortality | Desai et al, 1999 [116] |
5000 IU combined N-acetylcystine and bronchodilator (every 4h for 7 days) | Burn patients Retrospective | 150 (children/adults) | NR | = | Holt et al, 2008 [117] |
10000 IU combined N-acetylcystine and bronchodilator (every 4h for 7 days) | Burn patients Retrospective | 30 | NR | ↓ lung injury ↓ mortality ↑ oxygenation | Miller et al, 2009 [118] |
5000 IU combined N-acetylcystine and bronchodilator (every 4h for 7 days) | Burn patients Retrospective | 63 | NR | = | Yip et al, 2011 [119] |
5000 IU combined N-acetylcystine and bronchodilator (every 4h for 7 days) | Burn patients Retrospective | 40 | NR | = | Kashefi et al, 2014 [120] |
10000 IU combined N-acetylcystine and bronchodilator (every 4h for 7 days) | Burn patients Retrospective | 72 | NR | ↑ free days MV | McIntire et al, 2017 [121] |
25000 IU (every 4h for 14 days) | Burn patients RCT (terminated, insufficient recruitment of patients and high costs associated with the purchase and blinding of study medication) | 160 | Aeroneb Pro Nebulizer | Not available | Glas et al, 2014 [122] |
Clinical studies of COVID-19 with nebulised heparin | |||||
25000 IU (every 6h for 10 days) | SARS CoV 2 infection, on MV | RCT ACTRN: 12620000517976 | Aeroneb Pro Nebulizer | On-going | Dixon et al, 2020 [123] |
25000 IU (every 6h up to 21 days) | SARS CoV 2 infection, pre-ICU | RCT EudraCT: 2020-001736-95 | Aeroneb Pro Nebulizer | On-going | ACCORD-2 (NHS UK) |