Table 1.
Animal models of acute lung injury evaluating the effects of treatment with local anticoagulant therapy.
| Drug (dose) | Animal | Lung injury model and nebulizer | Effect parameter, observed effect and safety | Reference |
|---|---|---|---|---|
| Rh-APC (12.5 μg/h) | mice | Mechanical ventilation Aeroneba |
Rh-APC attenuated pulmonary inflammation, improved oxygenation, and prevented endothelial dysfunction. Rh-APC did not increase pulmonary bleeding. |
Maniatis [32] |
| Rh-APC (48 μg/kg/h) | sheep | i.v. LPS Servo Ultrab |
Rh-APC improved oxygenation and increased aerated lung volume; EVLW was unaffected. Rh-APC did not cause systemic bleeding. |
Waerhaug [33] |
| Rh-APC (2 × 25 or 100 μg) and repeated dosing | mice | i.t. LPS Aeroneb Proa |
Rh-APC attenuated pulmonary coagulation and inflammation; Rh-APC improved lung function. No differences between single and repeated dosing. Effects on systemic coagulation or systemic bleeding were not reported. |
Slofstra [34] |
| Rh-APC (4 mg/3 mL) | mice | i.t. LPS DeVilbissc |
Rh-APC attenuated pulmonary inflammation, decreased VCAM-1 upregulation and prevented changes in histopathology. Effects on systemic coagulation or systemic bleeding were not reported. |
Kotanidou [35] |
| Rh-APC (5,000 μg/kg) Heparin (1,000 U/kg) Plasma-derived human AT (500 IU/kg) Danaparoid (250 E/kg) |
Rats |
S. pneumoniae pneumonia Aeroneb Proa |
All agents attenuated pulmonary coagulation. Plasma-derived human AT also attenuated pulmonary inflammation, bacterial outgrowth and changes in histopathology. Only danaparoid affected systemic coagulation. Systemic bleeding was not reported |
Hofstra [36] |
| Rh-APC (5,000 μg/kg) Heparin (1,000 U/kg) Plasma-derived human AT (500 IU/kg) Danaparoid (250 E/kg) |
Rats | i.v. LPS Aeroneb Proa |
All agents attenuated pulmonary coagulation; pulmonary inflammation and histopathology were not affected. Heparin and danaparoid affected systemic coagulation. Systemic bleeding was not reported |
Hofstra [37] |
| Heparin (5 μg) i.t. | mice |
Legionella pneumonia No nebulizer used |
Heparin improved survival and decreased pulmonary inflammation, bacterial outgrowth, Legionella adherence and endothelial permeability. Effects on systemic coagulation or systemic bleeding were not reported. |
Ader [40] |
| Heparin (10,000 IU/4 h) AT (290 IU) or a combination |
sheep | burn and smoke inhalation Nebulizer not stated |
Combination therapy improved hemodynamics and P/F ratio; airway obstruction and wet-to-dry weight decreased. Systemic clotting time was unaffected. Systemic bleeding was not reported. |
Enkhbaater [38] |
| Combination therapy of Heparin (10,000 IU/4 h) and plasma-derived human AT i.v. (0.34 mg/kg/h) | sheep | burn and smoke inhalation Nebulizer not stated |
Heparin + plasma-derived human AT improved P/F ratio; central venous pressure, airway obstruction and wet-to-dry weight decreased. Systemic levels of AT were elevated. Systemic bleeding was not reported. |
Enkhbaatar [39] |
| Heparin (10,000 IU/4 h) or Heparin i.v. (5,300 U/kg/23 h) |
sheep | burn and smoke inhalation + P. aeruginosa pneumonia Airlife Mistyd |
Nebulization of heparin improved hemodynamics and P/F ratio; airway obstruction, wet-to-dry weight and changes in histopathology were decreased. Systemic clotting time was unaffected with nebulized heparin. Systemic bleeding was not reported. |
Murakami [41] |
| Heparin (10,000 IU/4h) and/or Lisofylline i.v. (10 mg/kg/h after bolus 20 mg/kg) |
sheep | burn and smoke inhalation Nebulizer not stated |
Combination therapy decreased the need of mechanical ventilation, P(A-a)O2 and pulmonary shunt fraction; wet-to-dry weight and changes in histopathology were unaffected. Effects on systemic coagulation and systemic bleeding were not reported. |
Tasaki [42] |
Drugs delivered intravenously (i.v.) and intratracheally (i.t.) are described in the table See original manuscript for details. aAerogen, Galway, Ireland. bSiemens-Elema AB, Solna, Sweden. cHealth Care Worldwide, Somerset, PA, USA. dAllegiance Healthcare, McGaw Park, IL, USA. AT, antithrombin; EVLW, extravascular lung water; LPS, lipopolysaccharide; P/F, PaO2/FiO2; Rh-APC, recombinant human-activated protein C; VCAM-1, vascular cell adhesion molecule 1