A Pilot Study of Nebulized Heparin for Prevention of Ventilator Induced Lung Injury: Comparative Effects with an Inhaled Corticosteroid

Farzin Ghiasi, Mohsen Sadeghian, Mohammad Emami, Babak Ali Kiaie, Sarah Mousavi, Farzin Ghiasi, Mohsen Sadeghian, Mohammad Emami, Babak Ali Kiaie, Sarah Mousavi

Abstract

Background: Ventilator-induced lung injury (VILI) is a side effect of mechanical ventilation. Lung inflammation and pulmonary activation of coagulation are induced by mechanical stress. Clinical and preclinical studies show that heparin possesses anti-inflammatory properties. Therefore, we assessed the effects of nebulized heparin in VILI.

Methods: Sixty critically ill adult patients who require mechanical ventilation for more than 48 h were included in this prospective, nonrandomized controlled study. Patients received nebulized heparin (10,000 U every 6 h) for 5 days. The matched control group received nebulized budesonide as routine practice in our center. This study assessed changes in partial pressure of oxygen to inspired fraction of oxygen ratio (PaO2/FiO2) and rapid shallow breathing index (RSBI) during the study as primary endpoints.

Results: The average daily PaO2/FiO2 ratio was not statistically significant between both groups (187 ± 11.6 vs. 171 ± 11.6, P = 0.35). The RSBI also did not differ between groups (P = 0.58). Heparin administration was associated with a higher number of ventilator-free days among survivors but not significantly (7.7 ± 10.6 vs. 5.1 ± 8, 95% confidence interval - 2.2-7.5, P = 0.28). Successful weaning from mechanical ventilation was higher in the heparin group (P = 0.42). We did not observe any serious or increased adverse effects from nebulized heparin.

Conclusion: The results of this study show that the overall effectiveness of nebulized heparin is at least as comparable with a potent corticosteroid (budesonide). Heparin could be a safe and effective modality for patients who at risk of VILI.

Keywords: Heparin; mechanical ventilation; nebulizer.

Conflict of interest statement

There are no conflicts of interest.

Figures

Figure 1
Figure 1
Changes in PaO2/FiO2 ratio over the first 5 days of the study
Figure 2
Figure 2
Rate of weaning and freedom from mechanical ventilation

References

    1. Wunsch H, Linde-Zwirble WT, Angus DC, Hartman ME, Milbrandt EB, Kahn JM, et al. The epidemiology of mechanical ventilation use in the United States. Crit Care Med. 2010;38:1947–53.
    1. Saddy F, Sutherasan Y, Rocco PR, Pelosi P. Ventilator-associated lung injury during assisted mechanical ventilation. Semin Respir Crit Care Med. 2014;35:409–17.
    1. Beitler JR, Malhotra A, Thompson BT. Ventilator-induced lung injury. Clin Chest Med. 2016;37:633–46.
    1. Bhatia M, Zemans RL, Jeyaseelan S. Role of chemokines in the pathogenesis of acute lung injury. Am J Respir Cell Mol Biol. 2012;46:566–72.
    1. Curley GF, Laffey JG, Zhang H, Slutsky AS. Biotrauma and ventilator-induced lung Injury: Clinical implications. Chest. 2016;150:1109–17.
    1. Cabrera-Benítez NE, Valladares F, García-Hernández S, Ramos-Nuez Á, Martín-Barrasa JL, Martínez-Saavedra MT, et al. Altered profile of circulating endothelial-derived microparticles in ventilator-induced lung injury. Crit Care Med. 2015;43:e551–9.
    1. Hughes KT, Beasley MB. Pulmonary manifestations of acute lung injury: More than just diffuse alveolar damage. Arch Pathol Lab Med. 2017;141:916–22.
    1. Rasmussen BS, Maltesen RG, Pedersen S, Kristensen SR. Early coagulation activation precedes the development of acute lung injury after cardiac surgery. Thromb Res. 2016;139:82–4.
    1. Bowler SD, Smith SM, Lavercombe PS. Heparin inhibits the immediate response to antigen in the skin and lungs of allergic subjects. Am Rev Respir Dis. 1993;147:160–3.
    1. Bissonnette EY, Tremblay GM, Turmel V, Pirotte B, Reboud-Ravaux M. Coumarinic derivatives show anti-inflammatory effects on alveolar macrophages, but their anti-elastase activity is essential to reduce lung inflammation in vivo. Int Immunopharmacol. 2009;9:49–54.
    1. Hofstra JJ, Vlaar AP, Cornet AD, Dixon B, Roelofs JJ, Choi G, et al. Nebulized anticoagulants limit pulmonary coagulopathy, but not inflammation, in a model of experimental lung injury. J Aerosol Med Pulm Drug Deliv. 2010;23:105–11.
    1. Tuinman PR, Dixon B, Levi M, Juffermans NP, Schultz MJ. Nebulized anticoagulants for acute lung injury - A systematic review of preclinical and clinical investigations. Crit Care. 2012;16:R70.
    1. Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res. 2008;122:743–52.
    1. Ludwig RJ. Therapeutic use of heparin beyond anticoagulation. Curr Drug Discov Technol. 2009;6:281–9.
    1. Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. Anti-inflammatory effects of heparin and its derivatives: A Systematic review. Adv Pharmacol Sci. 2015;2015:507151.
    1. Poterucha TJ, Libby P, Goldhaber SZ. More than an anticoagulant: Do heparins have direct anti-inflammatory effects? Thromb Haemost. 2017;117:437–44.
    1. Mohammad RS, El-Maraghi SK, El-Sorougi WM, Sabri SM, Mohammad MF. Role of nebulized heparin inhalation on mechanically ventilated critically ill patients. Egypt J Bronchology. 2016;10:179.
    1. Fan E, Villar J, Slutsky AS. Novel approaches to minimize ventilator-induced lung injury. BMC Med. 2013;11:85.
    1. Köhler D. Aerosolized heparin. J Aerosol Med. 1994;7:307–14.
    1. Bendstrup KE, Newhouse MT, Pedersen OF, Jensen JI. Characterization of heparin aerosols generated in jet and ultrasonic nebulizers. J Aerosol Med. 1999;12:17–25.
    1. Dixon B, Schultz MJ, Hofstra JJ, Campbell DJ, Santamaria JD. Nebulized heparin reduces levels of pulmonary coagulation activation in acute lung injury. Crit Care. 2010;14:445.
    1. Dixon B, Schultz MJ, Smith R, Fink JB, Santamaria JD, Campbell DJ, et al. Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: A randomized controlled trial. Crit Care. 2010;14:R180.
    1. Wilson MR, Takata M. Inflammatory mechanisms of ventilator-induced lung injury: A time to stop and think? Anaesthesia. 2013;68:175–8.
    1. Tang BM, Craig JC, Eslick GD, Seppelt I, McLean AS. Use of corticosteroids in acute lung injury and acute respiratory distress syndrome: A systematic review and meta-analysis. Crit Care Med. 2009;37:1594–603.
    1. Festic E, Carr GE, Cartin-Ceba R, Hinds RF, Banner-Goodspeed V, Bansal V, et al. Randomized clinical trial of a combination of an inhaled corticosteroid and beta agonist in patients at risk of developing the acute respiratory distress syndrome. Crit Care Med. 2017;45:798–805.
    1. Ju YN, Yu KJ, Wang GN. Budesonide ameliorates lung injury induced by large volume ventilation. BMC Pulm Med. 2016;16:90.
    1. Glas GJ, Serpa Neto A, Horn J, Cochran A, Dixon B, Elamin EM, et al. Nebulized heparin for patients under mechanical ventilation: An individual patient data meta-analysis. Ann Intensive Care. 2016;6:33.
    1. Dixon B, Santamaria JD, Campbell DJ. A phase 1 trial of nebulised heparin in acute lung injury. Crit Care. 2008;12:R64.

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