Aerosolized anticoagulants ameliorate acute lung injury in sheep after exposure to burn and smoke inhalation
ABSTRACT Acute lung injury is a detrimental complication for victims of burn accidents. Airway obstruction plays an important role in pulmonary dysfunction in these patients. In this study, we tested the hypothesis that aerosolized anticoagulants will reduce the degree of airway obstruction and improve pulmonary function in sheep with severe combined burn and smoke inhalation injury by preventing the formation of airway fibrin clots.
Prospective, randomized, controlled, experimental animal study.
Investigational intensive care unit at a university hospital.
Adult female sheep.
After 7 days of surgical recovery, sheep were given a cutaneous burn (40% of total body surface, third degree) and insufflated with cotton smoke (48 breaths, <40 degrees C) under halothane anesthesia. After injury, sheep were placed on ventilators and resuscitated with lactated Ringer's solution. Sheep were randomly divided into five groups: sham, noninjured and nontreated (n = 6); control, injured and aerosolized with saline (n = 6); recombinant human antithrombin (rhAT) + heparin, injured and aerosolized with rhAT (290 units for each) and heparin (10,000 units for each) (n = 6); rhAT, injured and aerosolized with rhAT alone (290 units for each; n = 5); and heparin, injured and aerosolized with heparin alone (10,000 units for each; n = 5). rhAT and heparin were aerosolized every 4 hrs, starting at 2 hrs postinjury.
Cardiopulmonary hemodynamics were monitored during a 48-hr experimental time period. Control sheep developed multiple signs of acute lung injury. This pathophysiology included decreased pulmonary gas exchange and lung compliance, increased pulmonary edema, and extensive airway obstruction. These variables were stable in sham animals. The aerosolization of rhAT or heparin alone did not significantly improve deteriorated pulmonary gas exchange. However, aerosolization of these anticoagulants in combination significantly attenuated all the observed pulmonary pathophysiology.
The results provide definitive evidence that aerosolized rhAT and heparin in combination may be a novel treatment strategy for pulmonary pathology in burn victims with smoke inhalation injury.
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ABSTRACT: Diese Übersichtsarbeit beschreibt die Pathophysiologie und mögliche Therapieansätze für das akute Lungenversagen [„acute lung injury“ (ALI) und „acute respiratory distress syndrome“ (ARDS)] bei Schwerbrandverletzten mit Inhalationstrauma. Ursächlich führen die Verlegung der Atemwege, die erhöhte transvaskuläre Flüssigkeitsverschiebung und der Verlust der hypoxisch pulmonalen Vasokonstriktion zu einem Abfall der arteriellen Oxygenierung. Die kardiopulmonale Funktionseinschränkung wird durch Sauerstoff- und Stickstoffradikale verursacht. Hierbei spielt Stickstoffmonoxid (NO), das durch die induzierbare und die konstitutiven Isoformen der Stickstoffmonoxidsynthase (NOS) produziert wird, eine zentrale Rolle. In aktuellen Studien rückt die neuronale NOS in den Fokus des NO-Pathomechanismus. Stickstoffmonoxid verbindet sich in einer schnellen Reaktion mit dem Sauerstoffradikal Superoxid und bildet das höchst toxische Peroxynitrit. Die Bildung reaktiver NO-Radikale führt zu einer Aktivierung der Poly-(ADP-ribose-)Polymerase, einem Enzym, das durch Ribosylierung an der Regulation nukleärer Transkriptionsfaktoren beteiligt ist und im Fall einer Überaktivierung zu der Entwicklung des ARDS beiträgt. Des Weiteren spielt die bronchiale Zirkulation durch den Transport von aktivierten polymorphkernigen neutrophilen Granulozyten aus den Atemwegen in das Lungenparenchym eine wesentliche Rolle in der Pathogenese des ALI/ARDS. Durch experimentelle Studien konnte eine Verbesserung des pulmonalen Gasaustausches durch Reduktion des bronchialen Blutflusses erreicht werden. This review article describes the pathophysiological aspects of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), induced by combined burn and smoke inhalation and examines various therapeutic approaches. The injury results in a fall in arterial oxygenation as a result of airway obstruction, increased pulmonary transvascular fluid flux and loss of hypoxic pulmonary vasoconstriction. The changes in cardiopulmonary function are mediated by reactive oxygen and nitrogen species. Nitric oxide (NO) is generated by both inducible and constitutive isoforms of nitric oxide synthase (NOS). Recently, neuronal NOS emerged as a major component within the pathogenesis of ARDS. NO rapidly combines with the oxygen radical superoxide to form reactive and highly toxic nitrogen species such as peroxynitrite. The control of NO formation involves poly(ADP-ribose) polymerase and its ability to up-regulate the activity of nuclear transcription factors through ribosylation. In addition, present data support a major role of the bronchial circulation in the injury, as blockage of bronchial blood flow will also minimize the pulmonary injury. Current data suggest that cytotoxins and activated cells are formed in the airway and carried to the parenchyma.Der Anaesthesist 08/2009; 58(8):805-812. DOI:10.1007/s00101-009-1560-x · 0.74 Impact Factor
Article: Copyright[Show abstract] [Hide abstract]
ABSTRACT: "Copyright is the branch of Intellectual Property Law that governs works of expression such as books, paintings and songs, and the expressive aspects of computer programs. Intellectual products such as these have a partially public goods character: they are largely inexhaustible and nonexcludable. Intellectual Property Law responds to inexcludability by giving producers legal rights to exclude nonpayers from certain usages of their intellectual products. The goal is to provide incentives for new production at fairly low transaction costs. However, the copyright owner will charge a price above marginal cost and this, coupled with the inexhaustibility of most copyrighted products, creates deadweight loss. Various copyright doctrines (such as the idea/expression dichotomy, the limited duration of the copyright ownership term and the doctrine of 'fair use') work to reduce deadweight loss and other costs within a larger structure that creates incentives. Copyright Law, unlike Patent Law, gives owners rights only against those who actually copy the work. This limitation, too, may serve to reduce both transaction costs and deadweight loss. Empirically it is unclear how successful copyright has been in creating incentives for production, reducing transaction costs and keeping deadweight costs low."
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ABSTRACT: Despite recent advances in supportive care, acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are clinical entities with high morbidity and high mortality. In systemic inflammation, like sepsis, uncontrolled host defense can lead to systemic activation of coagulation on the one hand, and attenuation of fibrinolysis on the other. In ALI/ARDS similar but local disturbances in fibrin turnover occur, leading to excessive alveolar fibrin deposition compromising pulmonary integrity and function. Therapies in patients with sepsis have specifically focused on coagulation disturbances. Evidence from preclinical and clinical investigations suggests pharmacologically targeting pulmonary "coagulopathy" could be of benefit to patients with ALI/ARDS as well. Recent animal studies have demonstrated that administration of heparins, activated protein C (APC), Antithrombin (AT), Tissue factor Factor VIIa (TF-FVIIa) pathway inhibitors, plasminogen activators (PA) and thrombomodulin (TM) can attenuate pulmonary coagulopathy and reduce lung injury and/or improve oxygenation. Some of these studies have also shown anti-inflammatory effects of treatment targeting at coagulation. To date there are no published studies that have specifically studied the effects of anticoagulants on ALI/ARDS however there are ongoing clinical trials. A solid base has to be provided by preclinical studies to justify clinical studies on new pharmacologic therapies for ALI/ARDS. In this systematic literature review we give an overview of the models for ALI/ARDS that have been used so far on the topic of pulmonary coagulopathy and focus on the pharmacological interventions that have been evaluated with these models. Finally, the applicability of the different approaches for future research on this subject will be discussed.Current Medicinal Chemistry 03/2008; 15(6):588-595. DOI:10.2174/092986708783769696 · 3.85 Impact Factor