title: Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations.
abstract: BACKGROUND
  Data from interventional trials of systemic anticoagulation for sepsis inconsistently suggest beneficial effects in case of acute lung injury (ALI). Severe systemic bleeding due to anticoagulation may have offset the possible positive effects. Nebulization of anticoagulants may allow for improved local biological availability and as such may improve efficacy in the lungs and lower the risk of systemic bleeding complications.
  
  
  METHODS
  We performed a systematic review of preclinical studies and clinical trials investigating the efficacy and safety of nebulized anticoagulants in the setting of lung injury in animals and ALI in humans.
  
  
  RESULTS
  The efficacy of nebulized activated protein C, antithrombin, heparin and danaparoid has been tested in diverse animal models of direct (for example, pneumonia-, intra-pulmonary lipopolysaccharide (LPS)-, and smoke inhalation-induced lung injury) and indirect lung injury (for example, intravenous LPS- and trauma-induced lung injury). Nebulized anticoagulants were found to have the potential to attenuate pulmonary coagulopathy and frequently also inflammation. Notably, nebulized danaparoid and heparin but not activated protein C and antithrombin, were found to have an effect on systemic coagulation. Clinical trials of nebulized anticoagulants are very limited. Nebulized heparin was found to improve survival of patients with smoke inhalation-induced ALI. In a trial of critically ill patients who needed mechanical ventilation for longer than two days, nebulized heparin was associated with a higher number of ventilator-free days. In line with results from preclinical studies, nebulization of heparin was found to have an effect on systemic coagulation, but without causing systemic bleedings.
  
  
  CONCLUSIONS
  Local anticoagulant therapy through nebulization of anticoagulants attenuates pulmonary coagulopathy and frequently also inflammation in preclinical studies of lung injury. Recent human trials suggest nebulized heparin for ALI to be beneficial and safe, but data are very limited.
authors.affiliation: Department of Intensive Care Medicine and Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, Meibergdreef 9, Amsterdam, 1105 AZ, The Netherlands. p.r.tuinman@amc.uva.nl
authors.forename: Pieter R
authors.initials: PR
authors.lastname: Tuinman
authors.forename: Barry
authors.initials: B
authors.lastname: Dixon
authors.forename: Marcel
authors.initials: M
authors.lastname: Levi
authors.forename: Nicole P
authors.initials: NP
authors.lastname: Juffermans
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy*; D000280:Administration, Inhalation; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage*; D006801:Humans; D009330:Nebulizers and Vaporizers
chemical_list: D000925:Anticoagulants