The online version of this article (doi:10.1186/cc9286) contains supplementary material, which is available to authorized users.
St. Vincent's Hospital has applied for a patent relating to nebulized heparin, and BD and RS could benefit from this application. The other authors declare that they have no competing interests.
BD and RS participated in the study design, data gathering, interpretation, statistical analysis, and writing the first draft and all revisions of the manuscript. MJS participated in the study design, laboratory analysis, interpretation, and writing the first draft and all revisions of the manuscript. JBF participated in the study design. DJC and JDS participated in the study design and revisions of the manuscript. All authors read and approved the final manuscript.
Prolonged mechanical ventilation has the potential to aggravate or initiate pulmonary inflammation and cause lung damage through fibrin deposition. Heparin may reduce pulmonary inflammation and fibrin deposition. We therefore assessed whether nebulized heparin improved lung function in patients expected to require prolonged mechanical ventilation.
Fifty patients expected to require mechanical ventilation for more than 48 hours were enrolled in a double-blind randomized placebo-controlled trial of nebulized heparin (25,000 U) or placebo (normal saline) 4 or 6 hourly, depending on patient height. The study drug was continued while the patient remained ventilated to a maximum of 14 days from randomization.
Nebulized heparin was not associated with a significant improvement in the primary end-point, the average daily partial pressure of oxygen to inspired fraction of oxygen ratio while mechanically ventilated, but was associated with improvement in the secondary end-point, ventilator-free days amongst survivors at day 28 (22.6 ± 4.0 versus 18.0 ± 7.1, treatment difference 4.6 days, 95% CI 0.9 to 8.3, P = 0.02). Heparin administration was not associated with any increase in adverse events.
Nebulized heparin was associated with fewer days of mechanical ventilation in critically ill patients expected to require prolonged mechanical ventilation. Further trials are required to confirm these findings.
The Australian Clinical Trials Registry (ACTR-12608000121369).
Additional file 1:Supplement. A table of medication. (DOC 56 KB)13054_2010_8779_MOESM1_ESM.DOC
Authors’ original file for figure 113054_2010_8779_MOESM2_ESM.tiff
Authors’ original file for figure 213054_2010_8779_MOESM3_ESM.tiff
Authors’ original file for figure 313054_2010_8779_MOESM4_ESM.tiff
Authors’ original file for figure 413054_2010_8779_MOESM5_ESM.tiff
Gajic O, Dara SI, Mendez JL, Adesanya AO, Festic E, Caples SM, Rana R, St Sauver JL, Lymp JF, Afessa B, Hubmayr RD: Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med 2004, 32: 1817-1824. 10.1097/01.CCM.0000133019.52531.30 CrossRefPubMed
Kollef M, Pittet D, Sanchez Garcia M, Chastre J, Fagon JY, Bonten M, Hyzy R, Fleming TR, Fuchs H, Bellm L, Mercat A, Manez R, Martinez A, Eggimann P, Daguerre M, Luyt CE: A randomized double-blind trial of iseganan in prevention of ventilator-associated pneumonia. Am J Respir Crit Care Med 2006, 173: 91-97. 10.1164/rccm.200504-656OC CrossRefPubMed
Determann RM, Royakkers A, Wolthuis EK, Vlaar AP, Choi G, Paulus F, Hofstra JJ, de Graaff MJ, Korevaar JC, Schultz MJ: Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit Care 2010, 14: R1. 10.1186/cc8230 PubMedCentralCrossRefPubMed
Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network N Engl J Med 2000, 342: 1301-1308. 10.1056/NEJM200005043421801
Dixon B, Opeskin K, Stamaratis G, Nixon I, Yi M, Newcomb AE, Rosalion A, Zhang Y, Santamaria JD, Campbell DJ: Pre-operative heparin reduces pulmonary microvascular fibrin deposition following cardiac surgery. Thromb Res 2010, in press.
Taylor FB Jr, Emerson TE Jr, Jordan R, Chang AK, Blick KE: Antithrombin-III prevents the lethal effects of Escherichia coli infusion in baboons. Circ Shock 1988, 26: 227-235. PubMed
Cox CS Jr, Zwischenberger JB, Traber DL, Traber LD, Haque AK, Herndon DN: Heparin improves oxygenation and minimizes barotrauma after severe smoke inhalation in an ovine model. Surg Gynecol Obstet 1993, 176: 339-349. PubMed
Darien BJ, Fareed J, Centgraf KS, Hart AP, MacWilliams PS, Clayton MK, Wolf H, Kruse-Elliott KT: Low molecular weight heparin prevents the pulmonary hemodynamic and pathomorphologic effects of endotoxin in a porcine acute lung injury model. Shock 1998, 9: 274-281. 10.1097/00024382-199804000-00007 CrossRefPubMed
Weber JR, Angstwurm K, Rosenkranz T, Lindauer U, Freyer D, Burger W, Busch C, Einhaupl KM, Dirnagl U: Heparin inhibits leukocyte rolling in pial vessels and attenuates inflammatory changes in a rat model of experimental bacterial meningitis. J Cereb Blood Flow Metab 1997, 17: 1221-1229. 10.1097/00004647-199711000-00011 CrossRefPubMed
Dixon B: The role of microvascular thrombosis in sepsis. Anaesth Intensive Care 2004, 32: 619-629. PubMed
Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Penzes I, Kubler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM: Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 2001, 286: 1869-1878. 10.1001/jama.286.15.1869 CrossRefPubMed
Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, Beale R, Svoboda P, Laterre PF, Simon S, Light B, Spapen H, Stone J, Seibert A, Peckelsen C, De Deyne C, Postier R, Pettila V, Artigas A, Percell SR, Shu V, Zwingelstein C, Tobias J, Poole L, Stolzenbach JC, Creasey AA: Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 2003, 290: 238-247. 10.1001/jama.290.2.238 CrossRefPubMed
Levi M, Levy M, Williams MD, Douglas I, Artigas A, Antonelli M, Wyncoll D, Janes J, Booth FV, Wang D, Sundin DP, Macias WL: Prophylactic heparin in patients with severe sepsis treated with drotrecogin alfa (activated). Am J Respir Crit Care Med 2007, 176: 483-490. 10.1164/rccm.200612-1803OC CrossRefPubMed
Hofstra JJ, Vlaar AP, Cornet AD, Dixon B, Roelofs JJ, Choi G, van der Poll T, Levi M, Schultz MJ: Nebulized anticoagulants limit pulmonary coagulopathy, but not inflammation, in a model of experimental lung injury. J Aerosol Med Pulm Drug Deliv 2010, 23: 105-111. 10.1089/jamp.2009.0779 CrossRefPubMed
Determann RM, Wolthuis EK, Choi G, Bresser P, Bernard A, Lutter R, Schultz MJ: Lung epithelial injury markers are not influenced by use of lower tidal volumes during elective surgery in patients without preexisting lung injury. Am J Physiol Lung Cell Mol Physiol 2008, 294: L344-350. 10.1152/ajplung.00268.2007 CrossRefPubMed
Coalson JJ, Benjamin B, Archer LT, Beller B, Gilliam CL, Taylor FB, Hinshaw LB: Prolonged shock in the baboon subjected to infusion of E. coli endotoxin. Circ Shock 1978, 5: 423-437. PubMed
Cooper JR Jr, Abrams J, Frazier OH, Radovancevic R, Radovancevic B, Bracey AW, Kindo MJ, Gregoric ID: Fatal pulmonary microthrombi during surgical therapy for end-stage heart failure: possible association with antifibrinolytic therapy. J Thorac Cardiovasc Surg 2006, 131: 963-968. 10.1016/j.jtcvs.2006.01.005 CrossRefPubMed
Jantsch H: Incidence and prognostic significance of pulmonary artery thromboses in patients with acute respiratory failure. Wien Klin Wochenschr Suppl 1989, 179: 3-15. PubMed
Bertuglia S, Colantuoni A: Protective effects of leukopenia and tissue plasminogen activator in microvascular ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2000, 278: H755-761. PubMed
- Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial
Marcus J Schultz
James B Fink
John D Santamaria
Duncan J Campbell
- BioMed Central
Neu im Fachgebiet AINS
Meistgelesene Bücher aus dem Fachgebiet AINS
Mail Icon II