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Inhaled Anticoagulation Regimens for the Treatment of Smoke Inhalation–Associated Acute Lung Injury: A Systematic Review*

Miller, Andrew C. MD1,2; Elamin, Elamin M. MD, MSc3; Suffredini, Anthony F. MD1

doi: 10.1097/CCM.0b013e3182a645e5
Review Articles

Objective: Inhaled anticoagulation regimens are increasingly being used to manage smoke inhalation–associated acute lung injury. We systematically reviewed published and unpublished preclinical and clinical trial data to elucidate the effects of these regimens on lung injury severity, airway obstruction, ventilation, oxygenation, pulmonary infections, bleeding complications, and survival.

Data Sources: PubMed, Scopus, EMBASE, and Web of Science were searched to identify relevant published studies. Relevant unpublished studies were identified by searching the Australian and New Zealand Clinical Trials Registry, World Health Organization International Clinical Trials Registry Platform, Cochrane Library,,, Current Controlled Trials, and Google.

Study Selection: Inclusion criteria were any preclinical or clinical study in which 1) animals or subjects experienced smoke inhalation exposure, 2) they were treated with nebulized or aerosolized anticoagulation regimens, including heparin, heparinoids, antithrombins, or fibrinolytics (e.g., tissue plasminogen activator), 3) a control and/or sham group was described for preclinical studies, and 4) a concurrent or historical control group described for clinical studies. Exclusion criteria were 1) the absence of a group treated with a nebulized or aerosolized anticoagulation regimen, 2) the absence of a control or sham group, and 3) case reports.

Data Extraction: Ninety-nine potentially relevant references were identified. Twenty-seven references met inclusion criteria including 19 preclinical references reporting 18 studies and eight clinical references reporting five clinical studies.

Data Synthesis: A systematic review of the literature is provided. Both clinical and methodological diversity precluded combining these studies in a meta-analysis.

Conclusions: The high mortality associated with smoke inhalation–associated acute lung injury results from airway damage, mucosal dysfunction, neutrophil infiltration, airway coagulopathy with cast formation, ventilation-perfusion mismatching with shunt, and barotrauma. Inhaled anticoagulation regimens in both preclinical and clinical studies improve survival and decrease morbidity without altering systemic markers of clotting and anticoagulation. In some preclinical and clinical studies, inhaled anticoagulants were associated with a favorable effect on survival. This approach appears sufficiently promising to merit a well-designed prospective study to validate its use in patients with severe smoke inhalation–associated acute lung injury requiring mechanical ventilation.

Supplemental Digital Content is available in the text.

1Department of Critical Care Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.

2Department of Internal Medicine, Division of Pulmonary, Allergy, and Critical Care, University of Pittsburgh Medical Center, Pittsburgh, PA.

3Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, James A. Haley Veteran’s Hospital and University of South Florida, Tampa, FL.

* See also p. 474.

All authors contributed to all stages of manuscript planning, research, preparation, and revision.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Supported, in part, by the Intramural Research Program of the Clinical Center, National Institutes of Health, and the Veterans Administration Hospital.

Dr. Elamin received support for travel from SuperDimension. Dr. Suffredini received support for article research from the National Institutes of Health. Dr. Miller disclosed that he does not have any potential conflicts of interest.

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© 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins