Abstract
During disseminated intravascular coagulation (DIC), the extrinsic tissue factor (TF)-dependent pathway has been implicated as the dominant route to thrombin generation and the production of IL-6 has been shown to correlate positively with the severity of sepsis-induced DIC. Pharmacological doses of AT have been shown to reduce mortality and morbidity in patients with DIC and there is increasing evidence to suggest that AT possesses anti-inflammatory properties in addition to its anticoagulant properties. In the present study, we have investigated the effect of AT on LPS-induced TF and IL-6 production in three different in vitro systems. Citrated whole blood. HUVECs and MNCs were stimulated with LPS for 4–6 h in the presence or absence of AT. TF activity was estimated by a TF-dependent clotting or chromogenic assay and IL-6 was measured by ELISA. Our results show a dose-dependent inhibition of TF and IL-6 production by AT, EC50 — ~36 and 20-35 iu/ml respectively in MNCs and HUVECs, but ~14 and <10 iu/ml in whole blood. Immuopurification experiments confirmed that the inhibitory activity was attributable to the AT and not to components that may have co-purified with the clinical product. In addition, up to 40 μM of hirudin, specific thrombin inhibitor, did not inhibit the production of TF and IL-6 in either of the three cell systems, suggesting that the observed inhibition by AT was not due solely to the inhibition of thrombin. Our investigation has shown that, apart from the inhibition of thrombin and other activated clotting factors, AT may also down-regulate the cellular expression of proinflammatory cytokines. Consequently, AT concentrates may have value in the treatment of sepsis-induced DIC.
Highlights
Ill patients requiring intensive care are at risk of iatrogenic ocular damage
Intensive Care Unit (ICU) management of critically ill patients often includes the requirement for tracheostomy and feeding access, most often a pecutaneous endoscopic gastrostomy (PEG)
Percutaneous tracheostomy is performed routinely in many medical intensive care unit (ICU) settings, in high risk surgical and trauma patients who often have unstable cervical spine injury and tissue edema, direct visualization of the cervical structures and trachea is imperative during tracheostomy
Summary
Ill patients requiring intensive care are at risk of iatrogenic ocular damage. We designed an experimental situation where external cardiac pressure conditions were controlled and adjusted to physiological extremes to mimic clinically relevant situations, while cardiac performance was assessed using left ventricular pressure–volume relationships (LVPVR) which are relatively preload and afterload independent This prospective, controlled study was undertaken to evaluate the response to therapy aimed at achieving supranormal cardiac and oxygen transport values (cardiac index >4.5 l/min/m2, oxygen delivery >600 l/min/m2, and oxygen consumption >170 l/min/m2) in patients older than 60 or with previous severe cardiorespiratory illnesses, who have undergone elective extensive ablative surgery planned for carcinoma or abdominal aortic aneurism. Whilst some human studies conducted in the critically ill and in high risk surgical patients have suggested that dopexamine may cause an increase in tonometrically measured gastric intra-mucosal pH (pHi) and an improvement in clinical outcome, this has not been confirmed in other randomised trials. In the present study the association of platelet function to inflammatory markers indicating disease severity was investigated
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