Nebulized Anticoagulants Limit Pulmonary Coagulopathy, But Not Inflammation, in a Model of Experimental Lung Injury

Hofstra, Jorrit J.; Vlaar, Alexander P.J.; Cornet, Alexander D.; Dixon, Barry; Roelofs, Joris J. T. H.; Choi, Goda; Poll, Tom van der; Levi, Marcel; Schultz, Marcus J.

doi:10.1089/jamp.2009.0779

Cited by 39 publications

(65 citation statements)

References 27 publications

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“…In studies reporting on pulmonary coagulation markers, nebulized heparin was found to have a markedly anticoagulant effect in the lungs in the presence of pulmonary infection (35,36) or lung injury (49). In studies reporting on pulmonary inflammation, nebulized heparin also inhibited pulmonary inflammation in the presence of pulmonary infection (35,36) or lung injury (43,44), and in two studies using an inhalation trauma model (40,41).…”

Section: Heparinmentioning

confidence: 95%

“…Nebulized APC attenuated pulmonary coagulopathy in studies using pulmonary infection models (35,36) and studies using lung injury models (47,49). Nebulized APC was associated with anti-inflammatory effects in two out of the three studies in animals with lung injury (47,48), but not in studies in animals with a pulmonary infection (35,36).…”

Section: Apcmentioning

confidence: 97%

“…An effect of nebulized heparin on systemic coagulation was reported in one study using a lung injury model (49), but not in studies using pulmonary infection models (36,49) or inhalation trauma models (38)(39)(40)(41)(42). None of these studies, however, showed systemic bleeding.…”

Section: Heparinmentioning

confidence: 98%

“…None of the studies of nebulized danaparoid reported on physiologic parameters. Nebulized danaparoid was found to have a systemic anticoagulant effect during pulmonary infection (35) and lung injury (49). None of these studies, however, showed systemic bleedings.…”

Section: Danaparoidmentioning

confidence: 99%

“…Nebulized danaparoid also had clear anticoagulant effects in the lungs in studies using pulmonary infection models (35,36) or lung injury model (49). An anti-inflammatory effect of nebulized danaparoid was only found in a study using a lung injury model (45).…”

Section: Danaparoidmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Heparinmentioning

confidence: 95%

Section: Apcmentioning

confidence: 97%

Section: Heparinmentioning

confidence: 98%

Section: Danaparoidmentioning

confidence: 99%

Section: Danaparoidmentioning

confidence: 99%

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

et al. 2017

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Restoration of Alveolar Epithelial Function as a Therapeutic Strategy for Acute Lung Injury

Herrero

Sanchez

Lorente

2013

Annual Update in Intensive Care and Emergency Medicine 2013

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Nebulized C1-Esterase Inhibitor does not Reduce Pulmonary Complement Activation in Rats with Severe Streptococcus Pneumoniae Pneumonia

Beer

Lagrand

Glas

et al. 2016

Cell Biochem Biophys

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Complement activation plays an important role in the pathogenesis of pneumonia. We hypothesized that inhibition of the complement system in the lungs by repeated treatment with nebulized plasma-derived human C1-esterase inhibitor reduces pulmonary complement activation and subsequently attenuates lung injury and lung inflammation. This was investigated in a rat model of severe Streptococcus pneumoniae pneumonia. Rats were intra–tracheally challenged with S. pneumoniae to induce pneumonia. Nebulized C1-esterase inhibitor or saline (control animals) was repeatedly administered to rats, 30 min before induction of pneumonia and every 6 h thereafter. Rats were sacrificed 20 or 40 h after inoculation with bacteria. Brochoalveolar lavage fluid and lung tissue were obtained for measuring levels of complement activation (C4b/c), lung injury and inflammation. Induction of pneumonia was associated with pulmonary complement activation (C4b/c at 20 h 1.24 % [0.56–2.59] and at 40 h 2.08 % [0.98–5.12], compared to 0.50 % [0.07–0.59] and 0.03 % [0.03–0.03] in the healthy control animals). The functional fraction of C1-INH was detectable in BALF, but no effect was found on pulmonary complement activation (C4b/c at 20 h 0.73 % [0.16–1.93] and at 40 h 2.38 % [0.54–4.19]). Twenty hours after inoculation, nebulized C1-esterase inhibitor treatment reduced total histology score, but this effect was no longer seen at 40 h. Nebulized C1-esterase inhibitor did not affect other markers of lung injury or lung inflammation. In this negative experimental animal study, severe S. pneumoniae pneumonia in rats is associated with pulmonary complement activation. Repeated treatment with nebulized C1-esterase inhibitor, although successfully delivered to the lungs, does not affect pulmonary complement activation, lung inflammation or lung injury.

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Nebulized Anticoagulants Limit Pulmonary Coagulopathy, But Not Inflammation, in a Model of Experimental Lung Injury

Abstract: In conclusion, local treatment with APC, AT, heparin, or danaparoid attenuate pulmonary coagulopathy, but not inflammation, in rats with endotoxemia-induced lung injury.

Cited by 39 publications

References 27 publications

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

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

Restoration of Alveolar Epithelial Function as a Therapeutic Strategy for Acute Lung Injury

Nebulized C1-Esterase Inhibitor does not Reduce Pulmonary Complement Activation in Rats with Severe Streptococcus Pneumoniae Pneumonia

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