Delirium is a sudden disturbance of cognition and consciousness consisting of a reduced ability to shift and sustain attention, impairment of memory and executive function, and fluctuating arousal levels with accompanying cortical slow wave activity in the electroencephalogram (EEG). Delirium occurs in 50‐80 per cent of critically ill patients, more than 34 per cent of cardiovascular surgical and 24 per cent of gastrointestinal surgical patients. It incurs a huge societal burden, in part due to its association with increased mortality and morbidity. Critically, delirium is bereft of therapies. It is important to understand how events such as delirium may accelerate cognitive decline, and the onset of dementia.
Tranexamic acid (TxA) is an antifibrinolytic agent used to reduce bleeding in many clinical settings, including cardiac surgery. Our group have found that there is a broader role of the fibrinolytic system outside haemostasis. Many components of the fibrinolytic system, including fibrin itself, have direct effects on immune function and inflammation, both stimulatory and inhibitory in nature.
Plasmin exerts pro‐inflammatory effects by processing and activating soluble factors and matrix metalloproteinases, as well as the release of inflammatory mediators, and induction of a tolerogenic phenotype in dendritic cells. In essence, plasmin is known to activate innate immunity, complement and drive Th1 responses that (1) accompany major surgery and (2) are associated with delirium.
Our recent work, has suggested that neuronal injury and inflammation are key pathogenic steps in the evolution of delirium. Both of these factors are driven by intraoperative blood loss, itself a strong predictor of delirium severity. Our recent extension of this work directly shows that BBB breakdown, as revealed by increases in cerebrospinal fluid (CSF) albumin (normalized to simultaneous changes in blood) occurs in delirious, but not nondelirious, subjects. Importantly this BBB remains evident for several days. Our data replicate similar data based on more limited perioperative measurements showing BBB breakdown as an important pathogenic mechanism of delirium. Other indirect evidence has been accumulating under the guise of plasma biomarkers that have been used to support this hypothesis. As an antifibrinolytic, TxA reduces blood loss and the consequent amplification of the inflammatory response by fibrin degradation products through the generation of plasmin.
This trial will provide important information about the use of TxA to prevent postoperative delirium, as well as providing novel information about the mechanisms of postoperative delirium.
Professor Paul Myles, Dr Mark Shulman, Alfred Hospital, Melbourne, Professor Robert Sanders, Dr Tim McCulloch, Royal Prince Alfred Hospital, NSW, Associate Professor Lisbeth Evered, Visiting Fellow, Weill Cornell Medicine, New York, Associate Professor Stefan Dieleman, Westmead Hospital, NSW.
The project was awarded $A70,000 through the ANZCA research grants program for 2022.