Nebulized anticoagulants in lung injury in critically ill patients-an updated systematic review of preclinical and clinical studies.

Pneumonia, inhalation trauma and acute respiratory distress syndrome (ARDS), typical causes of lung injury in critically ill patients, are all three characterized by dysregulated inflammation and coagulation in the lungs. Nebulized anticoagulants are thought to have beneficial effects as they could attenuate pulmonary coagulopathy and maybe even affect pulmonary inflammation. A systematic search of the medical literature was performed using terms referring to aspects of the condition ('pneumonia', 'inhalation trauma' and 'ARDS'), the intervention ('nebulized', 'vaporized', and 'aerosolized') and anticoagulants limited to agents that are commercially available and frequently given or tested in critically ill patients ['heparin', 'danaparoid', 'activated protein C' (APC), 'antithrombin' (AT) and 'tissue factor pathway inhibitor' (TFPI)]. The systematic search identified 16 articles reporting on preclinical studies and 11 articles reporting on human trials. All nebulized anticoagulants attenuate pulmonary coagulopathy in preclinical studies using various models for lung injury, but the effects on inflammation are less consistent. Nebulized heparin, danaparoid and TFPI, but not APC and AT also reduced systemic coagulation. Nebulized heparin in lung injury patients shows contradictory results, and there is concern over systemic side effects of this strategy. Future studies need to focus on the way to nebulize anticoagulants, as well as on efficient but safe dosages, and other side effects.

[1]  D. Foster,et al.  Outcomes Following the Use of Nebulized Heparin for Inhalation Injury (HIHI Study) , 2017, Journal of burn care & research : official publication of the American Burn Association.

[2]  T. van der Poll,et al.  Nebulized Recombinant Human Tissue Factor Pathway Inhibitor Attenuates Coagulation and Exerts Modest Anti-inflammatory Effects in Rat Models of Lung Injury. , 2017, Journal of aerosol medicine and pulmonary drug delivery.

[3]  D. Paterson,et al.  Is inhaled prophylactic heparin useful for prevention and management of pneumonia in ventilated ICU patients? , 2016, Journal of critical care.

[4]  J. Horn,et al.  Nebulized heparin for patients under mechanical ventilation: an individual patient data meta-analysis , 2016, Annals of Intensive Care.

[5]  B. Dixon,et al.  A Trial of Nebulised Heparin to Limit Lung Injury following Cardiac Surgery , 2016, Anaesthesia and intensive care.

[6]  A. Artigas,et al.  Effects of nebulized heparin on pulmonary inflammation in a rat model of acute lung injury , 2015 .

[7]  S. Matalon,et al.  Postexposure aerosolized heparin reduces lung injury in chlorine-exposed mice. , 2014, American journal of physiology. Lung cellular and molecular physiology.

[8]  S. Dissanaike,et al.  Does a Nebulized Heparin/N-acetylcysteine Protocol Improve Outcomes in Adult Smoke Inhalation? , 2014, Plastic and reconstructive surgery. Global open.

[9]  K. Colpaert,et al.  HEPBURN - investigating the efficacy and safety of nebulized heparin versus placebo in burn patients with inhalation trauma: study protocol for a multi-center randomized controlled trial , 2014, Trials.

[10]  D. Prough,et al.  Antithrombin Attenuates Vascular Leakage via Inhibiting Neutrophil Activation in Acute Lung Injury , 2013, Critical care medicine.

[11]  P. Tuinman,et al.  Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations , 2012, Critical Care.

[12]  Lian Yee Yip,et al.  Safety and potential anticoagulant effects of nebulised heparin in burns patients with inhalational injury at Singapore General Hospital Burns Centre. , 2011, Burns : journal of the International Society for Burn Injuries.

[13]  T. van der Poll,et al.  Nebulized Anticoagulants Limit Coagulopathy But Not Inflammation in Pseudomonas aeruginosa-Induced Pneumonia in Rats , 2011, Shock.

[14]  T. van der Poll,et al.  Pulmonary activation of coagulation and inhibition of fibrinolysis after burn injuries and inhalation trauma. , 2011, The Journal of trauma.

[15]  D. Angus,et al.  Immunotherapy in sepsis , 1992, Intensive Care Medicine.

[16]  B. Dixon,et al.  Nebulized heparin reduces levels of pulmonary coagulation activation in acute lung injury , 2010, Critical care.

[17]  B. Dixon,et al.  Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial , 2010, Critical care.

[18]  T. van der Poll,et al.  Nebulized anticoagulants limit pulmonary coagulopathy, but not inflammation, in a model of experimental lung injury. , 2010, Journal of aerosol medicine and pulmonary drug delivery.

[19]  T. van der Poll,et al.  Nebulized antithrombin limits bacterial outgrowth and lung injury in Streptococcus pneumoniae pneumonia in rats , 2009, Critical care.

[20]  V. Kuzkov,et al.  Inhaled aerosolised recombinant human activated protein C ameliorates endotoxin-induced lung injury in anaesthetised sheep , 2009, Critical care.

[21]  Andrew C. Miller,et al.  Influence of Nebulized Unfractionated Heparin and N-Acetylcysteine in Acute Lung Injury After Smoke Inhalation Injury , 2009, Journal of burn care & research : official publication of the American Burn Association.

[22]  B. Latenser.  Use of Inhaled Heparin/N-acetylcystine in Inhalation Injury: Does it help? , 2009 .

[23]  B. Dixon,et al.  A phase 1 trial of nebulised heparin in acute lung injury , 2008, Critical care.

[24]  H. Iwasaka,et al.  Danaparoid sodium inhibits systemic inflammation and prevents endotoxin-induced acute lung injury in rats , 2008, Critical care.

[25]  F. Menozzi,et al.  In vivo effect of adhesion inhibitor heparin on Legionella pneumophila pathogenesis in a murine pneumonia model , 2008, Intensive Care Medicine.

[26]  D. Prough,et al.  Combined anticoagulants ameliorate acute lung injury in sheep after burn and smoke inhalation. , 2008, Clinical science.

[27]  D. Prough,et al.  Aerosolized anticoagulants ameliorate acute lung injury in sheep after exposure to burn and smoke inhalation , 2007, Critical care medicine.

[28]  P. Reitsma,et al.  Inhalation of activated protein C inhibits endotoxin‐induced pulmonary inflammation in mice independent of neutrophil recruitment , 2006, British journal of pharmacology.

[29]  C. Roussos,et al.  Inhaled activated protein C attenuates lung injury induced by aerosolized endotoxin in mice. , 2006, Vascular pharmacology.

[30]  Arthur S Slutsky,et al.  Pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia—A review , 2006, Critical care medicine.

[31]  T. van der Poll,et al.  Protein C in pneumonia , 2005, Thorax.

[32]  T. van der Poll,et al.  Activation of coagulation and inhibition of fibrinolysis in the lung after inhalation of lipopolysaccharide by healthy volunteers , 2005, Thrombosis and Haemostasis.

[33]  M. Boermeester,et al.  Disturbed alveolar fibrin turnover during pneumonia is restricted to the site of infection , 2004, European Respiratory Journal.

[34]  Shigeaki Kobayashi,et al.  Temporal changes in pulmonary expression of key procoagulant molecules in rabbits with endotoxin-induced acute lung injury: elevated expression levels of protease-activated receptors , 2004, Thrombosis and Haemostasis.

[35]  D. Herndon,et al.  AEROSOLIZED TISSUE PLASMINOGEN INHIBITOR IMPROVES PULMONARY FUNCTION IN SHEEP WITH BURN AND SMOKE INHALATION , 2004, Shock.

[36]  T. van der Poll,et al.  Bidirectional Relation Between Inflammation and Coagulation , 2004, Circulation.

[37]  C. Esmon.  Crosstalk between inflammation and thrombosis. , 2004, Maturitas.

[38]  T. van der Poll,et al.  Disturbed alveolar fibrin turnover during pneumonia is associated with reduced activated protein C levels in lungs , 2004, Critical Care.

[39]  T. van der Poll,et al.  Thrombomodulin mutant mice with a strongly reduced capacity to generate activated protein C have an unaltered pulmonary immune response to respiratory pathogens and lipopolysaccharide. , 2004, Blood.

[40]  T. van der Poll,et al.  Local activation of coagulation and inhibition of fibrinolysis in the lung during ventilator associated pneumonia , 2004, Thorax.

[41]  M. Matthay,et al.  Protein C and thrombomodulin in human acute lung injury. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[42]  M. Matthay,et al.  Elevated levels of plasminogen activator inhibitor-1 in pulmonary edema fluid are associated with mortality in acute lung injury. , 2003, American journal of physiology. Lung cellular and molecular physiology.

[43]  T. Iba,et al.  [Disseminated intravascular coagulation]. , 2003, Nihon rinsho. Japanese journal of clinical medicine.

[44]  D. Herndon,et al.  Heparin Nebulization Attenuates Acute Lung Injury in Sepsis Following Smoke Inhalation in Sheep , 2002, Shock.

[45]  M. Carraway,et al.  Extrinsic coagulation blockade attenuates lung injury and proinflammatory cytokine release after intratracheal lipopolysaccharide. , 2002, American journal of respiratory cell and molecular biology.

[46]  S. Idell.  Endothelium and disordered fibrin turnover in the injured lung: Newly recognized pathways , 2002, Critical care medicine.

[47]  M. Dubick,et al.  Effects of heparin and lisofylline on pulmonary function after smoke inhalation injury in an ovine model. , 2002, Critical care medicine.

[48]  E. Gabazza,et al.  Activation of Protein C Pathway in the Airways , 2002, Lung.

[49]  E. Abraham.  Coagulation abnormalities in acute lung injury and sepsis. , 2000, American journal of respiratory cell and molecular biology.

[50]  C. Ruppert,et al.  Alveolar fibrin formation caused by enhanced procoagulant and depressed fibrinolytic capacities in severe pneumonia. Comparison with the acute respiratory distress syndrome. , 2000, American journal of respiratory and critical care medicine.

[51]  M. Matthay,et al.  The alveolar space is the site of intense inflammatory and profibrotic reactions in the early phase of acute respiratory distress syndrome. , 1999, Critical care medicine.

[52]  D. Loskutoff,et al.  Extrahepatic expression and regulation of protein C in the mouse. , 1998, The American journal of pathology.

[53]  T. van der Poll,et al.  Differential effects of anti-cytokine treatment on bronchoalveolar hemostasis in endotoxemic chimpanzees. , 1998, American journal of respiratory and critical care medicine.

[54]  K. Okajima.  Antithrombin prevents endotoxin-induced pulmonary vascular injury by inhibiting leukocyte activation. , 1998, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[55]  D. Herndon,et al.  Reduction in mortality in pediatric patients with inhalation injury with aerosolized heparin/N-acetylcystine [correction of acetylcystine] therapy. , 1998, Journal of Burn Care and Rehabilitation.

[56]  B. Crestani,et al.  Compartmentalized IL-8 and elastase release within the human lung in unilateral pneumonia. , 1996, American journal of respiratory and critical care medicine.

[57]  T. Fuchs-Buder,et al.  Time course of procoagulant activity and D dimer in bronchoalveolar fluid of patients at risk for or with acute respiratory distress syndrome. , 1996, American journal of respiratory and critical care medicine.

[58]  B. Crestani,et al.  Compartmentalized cytokine production within the human lung in unilateral pneumonia. , 1994, American journal of respiratory and critical care medicine.

[59]  E. de Benedetti,et al.  Procoagulant activity in bronchoalveolar fluids: no relationship with tissue factor pathway inhibitor activity. , 1992, Thrombosis research.

[60]  T. Martin,et al.  Serial abnormalities of fibrin turnover in evolving adult respiratory distress syndrome. , 1991, The American journal of physiology.

[61]  J. Hoidal,et al.  Alveolar epithelial cell plasminogen activator. Characterization and regulation. , 1990, The Journal of biological chemistry.

[62]  H. Chapman,et al.  Regulation of the procoagulant activity within the bronchoalveolar compartment of normal human lung. , 1988, The American review of respiratory disease.

[63]  R. Colman,et al.  Procoagulant activity in bronchoalveolar lavage in the adult respiratory distress syndrome. Contribution of tissue factor associated with factor VII. , 1987, The American review of respiratory disease.