Critical care medicine
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To review the complex interactions of markers of genetic susceptibility for critical illness and acute lung injury. These may affect the responses of critically ill patients to acute lung injury and acute respiratory distress syndrome and may affect outcome. ⋯ The search for an association between functional variants of a gene and clinical phenotype may help to identify key pathophysiological processes of disease. In the future, we will know much about which therapy is best for each individual patient in the intensive care unit.
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Critical care medicine · Apr 2003
ReviewSelective pulmonary vasodilation in acute respiratory distress syndrome.
Acute respiratory distress syndrome (ARDS) is characterized by a marked maldistribution of pulmonary perfusion in favor of nonventilated, atelectatic areas of the lungs, and it is the main cause of pulmonary right-to-left shunting and hypoxemia. Therapeutic interventions to selectively influence pulmonary perfusion in ARDS became feasible with the introduction of inhaled nitric oxide, which provided a means not only to reduce pulmonary hypertension, but also to improve matching of ventilation to perfusion and, thus, hypoxemia. Clinical studies in ARDS subsequently demonstrated that the combination of inhaled nitric oxide with other interventions, such as positive end-expiratory pressure and prone positioning, yielded beneficial and additive effects on arterial oxygenation. ⋯ Ongoing research aims to augment the effectiveness of vasodilators with specific inhibitors of phosphodiesterases or by combination with intravenous vasoconstrictors. Consequently, several alternative ways to selectively modulate pulmonary vascular tone in patients with ARDS may be available in the near future. Cost-benefit analysis of these therapeutic options will largely determine their future perspective.
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To review the role of coagulation and of single nucleotide polymorphisms of coagulation factors in acute lung injury. ⋯ Exuberant coagulation relative to anticoagulation and fibrinolysis in the lung and the systemic circulation are important in the pathophysiology of acute lung injury. In the early stages of acute lung injury, fibrin is deposited in the alveoli, and fibrin in the alveoli increases the inflammatory response. Sepsis, trauma, and aspiration are risk factors for acute lung injury. They are also potent stimuli for increased coagulation because inflammatory stimuli activate coagulation and proinflammatory cascades. There is "cross-talk" amplification of the coagulation and inflammatory cascades. Inflammatory mediators activate coagulation. Tumor necrosis factor-alpha, interleukin-1, and interleukin-6 increase tissue factor and inhibit fibrinolysis, thereby activating the extrinsic pathway. Conversely, intravascular coagulation induces an inflammatory response. Coagulation of blood in vitro increases the production of tumor necrosis factor-alpha, interleukin-1, and interleukin-8 by monocytes. Factor Xa, alpha-thrombin, and fibrin increase synthesis of interleukin-6 and interleukin-8. Genetic predisposition could increase the tendency to intravascular and intraalveolar coagulation. Single nucleotide polymorphisms and single nucleotide polymorphism haplotypes of coagulation factor genes increase coagulation and impair anticoagulation and fibrinolysis, which could tip the balance in favor of coagulation. For example, procoagulant and antifibrinolytic single nucleotide polymorphisms in the promoter and coding regions have been reported for alpha-thrombin, fibrinogen, factor V, protein C, endothelial protein C receptor, and plasminogen activator inhibitor-1. Single nucleotide polymorphisms of protein C, factor V (e.g., factor V Leiden), and plasminogen activator inhibitor-1 are associated with an increased risk of deep venous thrombosis, pulmonary emboli, acute myocardial infarction, and stroke. These and other single nucleotide polymorphisms could be associated with increased risk of coagulation relative to anticoagulation/fibrinolysis in the vascular spaces and airspaces of the lung, thus increasing the risk of acute lung injury in patients with sepsis, trauma, aspiration, and other precursors of acute lung injury.
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Critical care medicine · Apr 2003
ReviewCoagulation, fibrinolysis, and fibrin deposition in acute lung injury.
To review: a) the role of extravascular fibrin deposition in the pathogenesis of acute lung injury; b) the abnormalities in the coagulation and fibrinolysis pathways that promote fibrin deposition in the acutely injured lung; and c) the pathways that contribute to the regulation of the fibrinolytic system via the lung epithelium, including newly recognized posttranscriptional and urokinase-dependent pathways. Another objective was to determine how novel anticoagulant or fibrinolytic strategies may be used to protect against acute inflammation or accelerated fibrosis in acute lung injury. ⋯ Disordered coagulation and fibrinolysis promote extravascular fibrin deposition in acute lung injury. It is this deposition that characterizes acute lung injury and repair. Expression of uPA, uPAR, and PAI-1 by the lung epithelium, as well as the ability of uPA to induce other components of the fibrinolytic system, involves posttranscriptional regulation. These pathways may contribute to disordered fibrin turnover in the injured lung. The success of anticoagulant or fibrinolytic strategies designed to reverse the abnormalities of local fibrin turnover in acute lung injury supports the inference that abnormalities of coagulation, fibrinolysis, and fibrin deposition have a critical role in the pathogenesis of acute lung injury.