Research Progress of Nebulized Heparin for Acute Lung Injury
HU Bin1,2, CHEN Gui-liang3*, WANG Hao2
1. School of Pharmacy, Fudan University, Shanghai 201203, China; 2. Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203, China; 3. Shanghai Institute for Food and Drug Control, Shanghai 201203, China
Abstract��It is widely recognized that alveolar fibrin deposition is a hallmark of acute lung injury. The inhaled anticoagulation regimens are employed to manage acute lung injury with the goal of improving lung function by decreasing airways fibrin deposition and obstruction.Inhalation administration may improve local biological availability and efficacy and lower the risk of systemic bleeding complications. Heparin is the most widely used anticoagulant in clinic. The author performed a systematic review of international preclinical studies and clinical trials of nebulized heparin for acute lung injury induced by smoke inhalation, severe infection and mechanical ventilation in animals and humans. It was demonstrated that nebulized heparin is a very prospective regimen in the treatment of acute lung injury.
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HU Bin, CHEN Gui-liang, WANG Hao. Research Progress of Nebulized Heparin for Acute Lung Injury. Chinese Pharmaceutical Journal, 2017, 52(4): 258-262.
ENKHBAATA P, HERNDON D N, TRABER D L. Use of nebulized heparin in the treatment of smoke inhalation injury [J]. J Burn Care Res, 2009, 30(1):159-162.
SCHULTZ M J, HAITSMA J J, ZHANG H, et al. Pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia��a review [J]. Crit Care Med, 2006, 34(3):871-877.
DIXON B, SCHULTZ M J, SMITH R, et al. Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients:a randomized controlled trial [J]. Crit Care, 2010, 14(5):R180.
SUTER P M. Nebulised heparin:a new approach to the treatment of acute lung injury? [J]. Crit Care, 2008, 12(4):170.
HOFSTRA J J, CORNET A D, DE ROOY B F, et al. Nebulized antithrombin limits bacterial outgrowth and lung injury in Streptococcus pneumoniae pneumonia in rats [J]. Crit Care, 2009, 13(5):R145.
MURAKAMI K, MCGUIRE R, COX R A, et al. Heparin nebulization attenuates acute lung injury in sepsis following smoke inhalation in sheep [J]. Shock, 2002, 18(3):236-241.
WANG Z Y, WU S N, ZHU X. The effects of three dosages of nebulized unfractioned heparin on alveolar coagulation and tissue inflammation injury in endotoxin-induced acute lung injury rat model[J]. Chin Crit Care Med(�й�Σ�ز�����ҽѧ), 2012, 24(10):612-615.
BENDSTRUP K E, CHAMBERS C B, JENSEN J I, et al. Lung deposition and clearance of inhaled (99m)Tc-heparin in healthy volunteers [J]. Am J Respir Crit Care Med, 1999, 160(5 Pt 1):1653-1658.
BENDSTRUP K E, GRAM J, JENSEN J I. Effect of inhaled heparin on lung function and coagulation in healthy volunteers [J]. Eur Respir J, 2002, 19(4):606-610.
MILLER A C, ELAMIN E M, SUFFREDINI A F. Inhaled anticoagulation regimens for the treatment of smoke inhalation-associated acute lung injury:a systematic review [J]. Crit Care Med, 2014, 42(2):413-419.
DESAI M H, MLCAK R, RICHARDSON J, et al. Reduction in mortality in pediatric patients with inhalation injury with aerosolized heparin/acetylcystine therapy [J]. J Burn Care Rehabil, 1998, 19(3):210-212.
MLCAK R P. Aerosolized heparin/N acetylcystine treatment of smoke inhalation injury in 596 burned children:a 15 year review, 1990-2005 [C]. 2005 Shanghai:6th International Heparin in Burns Symposium.
KASHEFI N S, NATHAN J I, DISSANAIKE S. Does a nebulized heparin/n-acetylcysteine protocol improve outcomes in adult smoke inhalation? [J]. Plast Reconstr Surg Glob Open, 2014, 2(6):e165.
ENKHBAATA P,MURAKAMI K, WESTPHAL M,et al. Combined antithrombin and heparin nebulization improves pulmonary function in sheep with burn and smoke inhalation:96 [J]. Crit Care Med, 2004, 12(32):A24.
SALIBAJR M J. Heparin in the treatment of burns:a review [J]. Burns, 2001, 27(4):349-358.
COX C J, ZWISCHENBERGER J B, TRABER D L, et al. Heparin improves oxygenation and minimizes barotrauma after severe smoke inhalation in an ovine model [J]. Surg Gynecol Obstet, 1993, 176(4):339-349.
BROWN M, DESAI M, TRABER L D, et al. Dimethylsulfoxide with heparin in the treatment of smoke inhalation injury [J]. J Burn Care Rehabil, 1988, 9(1):22-25.
TANG H T, CHEN Y L. Heparin improves oxygenation and minimizes barotrauma after severe smoke inhalation in an ovine model[J]. Foreign Med Sci(Trauma Surg Sect)(����ҽѧ:��������ƻ�������ֲ�), 1994, 15(1):53.
ENKHBAATA P, ESECHIE A, WANG J, et al. Combined anticoagulants ameliorate acute lung injury in sheep after burn and smoke inhalation [J]. Clin Sci (Lond), 2008, 114(4):321-329.
ENKHBAATA P, COX R A, TRABER L D, et al. Aerosolized anticoagulants ameliorate acute lung injury in sheep after exposure to burn and smoke inhalation [J]. Crit Care Med, 2007, 35(12):2805-2810.
TASAKI O, MOZINGO D W, DUBICK M A, et al. Effects of heparin and lisofylline on pulmonary function after smoke inhalation injury in an ovine model[J]. Crit Care Med, 2002, 30(3):637-643.
OURIQUE A F, CHAVES P S, SOUTO G D, et al. Redispersible liposomal-n-acetylcysteine powder for pulmonary administration:development, in vitro characterization and antioxidant activity [J]. Eur J Pharm Sci, 2014, 65:174-182.
KALLET R H. Adjunct therapies during mechanical ventilation:airway clearance techniques, therapeutic aerosols, and gases [J]. Respir Care, 2013, 58(6):1053-1073.
CUZZOCREA S, MAZZON E, DUGO L, et al. Protective effects of n-acetylcysteine on lung injury and red blood cell modification induced by carrageenan in the rat [J]. Faseb J, 2001, 15(7):1187-1200.
MILLER A C, RIVERO A, ZIAD S, et al. Influence of nebulized unfractionated heparin and n-acetylcysteine in acute lung injury after smoke inhalation injury [J]. J Burn Care Res, 2009, 30(2):249-256.
RIVERO A, ELAMIN E, NGUYEN V, et al. Can nebulized heparin and n-acetylcysteine reduce acute lung injury after inhalation lung insult? [J]. Chest, 2007, 132(S4):565.
YIP L Y, LIM Y F, CHAN H N. Safety and potential anticoagulant effects of nebulised heparin in burns patients with inhalational injury at Singapore General Hospital Burns Centre [J]. Burns, 2011, 37(7):1154-1160.
ELSHARNOUBY N M, EID H E, ABOU E N, et al. Heparin/n-acetylcysteine:an adjuvant in the management of burn inhalation injury:a study of different doses [J]. J Crit Care, 2014, 29(1):182. e1-182e4.
CHOPRA A, BURKEY B, CALAMAN S. A case report of clinically significant coagulopathy associated with aerosolized heparin and acetylcysteine therapy for inhalation injury [J]. Burns, 2011, 37(7):e73-e75.
HOLT J, SAFFLE J R, MORRIS S E, et al. Use of inhaled heparin/n-acetylcystine in inhalation injury:does it help? [J]. J Burn Care Res, 2008, 29(1):192-195.
MONAGLE K, RYAN A, HEPPONSTALL M, et al. Inhalational use of antithrombotics in humans:review of the literature [J]. Thromb Res, 2015, 136(6):1059-1066.
GLAS G J, MULLER J, BINNEKADE J M, 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 [J]. Trials, 2014, 15:91.
WANG Z Y, YANG B X, ZHU X, et al. Effect of inhalation of aerosolized unfractioned heparin on peri-alveolar coagulability and inflammatory response in endotoxin-induced acute lung injury rat model[J]. Chin Crit Care Med(�й�Σ�ز�����ҽѧ), 2011, 23(4):239-242.
DIXON B, SANTAMARIA J D, CAMPBELL D J. A phase 1 trial of nebulised heparin in acute lung injury [J]. Crit Care, 2008, 12(3):R64.
WANG Z Y, WU S N, ZHU Z Z, et al. Inhaled unfractionated heparin improves abnormalities of alveolar coagulation, fibrinolysis and inflammation in endotoxemia-induced lung injury rats [J]. Chin Med J(Engl)(�л�ҽѧ��־Ӣ�İ�), 2013, 126(2):318-324.
DIXON B, SCHULTZ M J, HOFSTRA J J, et al. Nebulized heparin reduces levels of pulmonary coagulation activation in acute lung injury [J]. Crit Care, 2010, 14(5):445.
XIE N L, CAO X, YAN S J, et al. Effect of low molecular weight heparin nebulization at different dose on acute lung injury / acute respiratory distress syndrome[J]. Chin J Lung Dis (Electronic Edition) (�л��β�������־:���Ӱ�), 2014, 7(2):182-185.
GAO S W. Research of low weight heparin nebulization at different dose on acute lung injury/acute respiratory distress sgndrome[J]. Mod J Integr Tradit Chin West Med (�ִ�����ҽ�����־), 2014, 23(22):2481-2482.
TUINMAN P R, DIXON B, LEVI M, et al. Nebulized anticoagulants for acute lung injury - a systematic review of preclinical and clinical investigations [J]. Crit Care, 2012, 16(2):R70.