A major cause of morbidity and mortality in cardiovascular surgery is excessive bleeding post- operatively, which is commonly managed by pharmacologically modifying clot degradation (fibrinolysis), through inhibition of plasmin activity (PLact). However, the only FDA approved and most commonly used inhibitor of PLact in cardiovascular surgery, while effective in reducing post-operative bleeding, was associated with extravascular effects and ultimately led to FDA withdrawal. The likely mechanisms for these adverse events include highly variable dosing regimens and inhibition of enzyme pathways other than PLact (off target effects). As a consequence, a significant void in approaches for haemostatic control following cardiovascular surgery has developed. Presently, a class of pharmacological compounds called lysine analogues is being used clinically in an "off label" status to modify PLact in the context of cardiovascular surgery. The effective dosing strategy of these lysine analogues to selectively modify PLact is unknown, and therefore clinical dosing algorithms for these compounds remain empirical. The technology and product to be developed in this application directly addresses this problematic issue and clinical need by providing a means to continuously monitor PLact during and following cardiovascular surgery. Through the use of microdialysis and microfluidics, the specific aims of this development project are (1) to complete calibration studies of a prototype and validated method to specifically and continuously measure PLact following administration of a prototypical lysine analogue;(2) to complete and construct a refined prototype that can be easily used in the setting of cardiovascular surgery;(3) to demonstrate the application and utility of this validated prototype in a large animal model of cardiopulmonary bypass. The outcomes from the technology refinement and animal testing will be a complete system that can be easily deployed in the cardiovascular surgical setting for continuously monitoring PLact. The clinical benefit from this project will be a means to individualize dosing strategies of antifibrinolytics such as lysine analogues and thereby maximizing haemostatic control and minimizing off target effects. The marketing/technology transfer benefit is a companion diagnostic that can be easily coupled to existing and future pharmacological compounds targeting the fibrinolytic cascade in cardiovascular surgery.
In the United States alone, almost 2 million adults and children require open heart surgery. While the overall outcomes from these cardiac surgical procedures is excellent, one of the factors that can cause a difficult early recovery from cardiac surgery is excessive bleeding in the early post-surgical period. Bleeding in the post cardiac surgical period can require blood transfusions, administration of factors that can enhance blood clotting, and may even require re-operation. Since blood transfusions and blood product administration is associated with a set of intrinsic risks and complications, is costly, and can be in short supply, alternative strategies to improve blood clotting following cardiac surgery have been pursued. One of these strategies is to prevent the breakdown of a blood clot following cardiac surgery by inhibiting the activity of an enzyme called plasmin. However, up to now, it has not been possible to directly and continuously measure plasmin activity in the cardiac surgery setting and in the intensive care unit. The technology and product to be developed in this application directly addresses this problematic issue and clinical need by providing a means to continuously monitor plasmin activity during and following cardiac surgery. The clinical benefit from this project will be to provide a means to individualize dosing strategies of drugs currently used to reduce blood loss following cardiac surgery. As a consequence, millions of patients that may be at risk for significant post-surgical bleeding will directly benefit from the development of this technology.
|DeSantis, Stacia M; Toole, J Matthew; Kratz, John M et al. (2011) Early postoperative outcomes and blood product utilization in adult cardiac surgery: the post-aprotinin era. Circulation 124:S62-9|
|Reust, Daryl L; Dixon, Jennifer A; McKinney, Richard A et al. (2011) Continuous localized monitoring of plasmin activity identifies differential and regional effects of the serine protease inhibitor aprotinin: relevance to antifibrinolytic therapy. J Cardiovasc Pharmacol 57:400-6|
|Reust, Daryl L; Reeves, Scott T; Abernathy 3rd, James H et al. (2010) Temporally and regionally disparate differences in plasmin activity by tranexamic acid. Anesth Analg 110:694-701|
|Reust, Daryl L; Reeves, Scott T; Abernathy 3rd, James H et al. (2010) Interstitial plasmin activity with epsilon aminocaproic acid: temporal and regional heterogeneity. Ann Thorac Surg 89:1538-45|