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Table 1 Animal models of acute lung injury evaluating the effects of treatment with local anticoagulant therapy.

From: Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations

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]
  1. 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