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. 2012 Dec 12;16(2):R70.
doi: 10.1186/cc11325.

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

Pieter R Tuinman  1 , Barry Dixon, Marcel Levi, Nicole P Juffermans, Marcus J Schultz
Affiliations

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

Pieter R Tuinman et al. Crit Care. .

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.

Method: 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.

Conclusion: 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.

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Figures

Figure 1
Figure 1
Schematic and simplified presentation of coagulation, fibrinolysis and anticoagulant pathways. The coagulation cascade is started through activation of tissue factor (TF)-factor VII (FVIIa) complex. Several coagulation factors accelerate the conversion of prothrombin to thrombin. Activated protein C (APC) can inactivate coagulation factors Va and VIIIa. Antithrombin (AT) serves to block the action of multiple coagulation factors (for example, Xa and IIa). Tissue factor pathway inhibitor (TFPI) inhibits stepwise the activation of coagulation factors. The fibrinolytic system is designed to degrade clots and fibrin degradation products (FDP) are formed. The main inhibitor of the plasminogen activators is plasminogen activator inhibitor type 1 (PAI-1). +: stimulating effect; -: inhibiting effect. Adapted and modified from Tuinman et al. [59].
Figure 2
Figure 2
Prisma flow diagram showing the search strategy and selection process.
See this image and copyright information in PMC

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