The role of gastrointestinal mucosal hypoperfusion in the pathogenesis of post-operative organ failure.

Multiple organ failure is the commonest cause of death in the intensive therapy unit. From a wide variety of stimuli, such as trauma or infection, an excessive and uncontrolled inflammatory response is thought to be the final common pathway in its pathogenesis. Major surgery is a significant pro-inflammatory stimulus that may be compounded by a failure to maintain an adequate blood supply to all organs. The purpose of this thesis was to explore the hypothesis that splanchnic hypoperfusion with subsequent activation of inflammatory pathways, possibly via translocation of endotoxin, occurs during major surgery and is associated with the development of post-operative organ failure. The gastrointestinal tonometer allows the assessment of splanchnic perfusion by calculation of the gastrointestinal intramucosal pH (pHi). In agreement with previous studies it was demonstrated that the development of a gastric intramucosal acidosis is common during major surgery and is a sensitive predictor of a poor outcome. By measuring descending aortic blood flow, using an oesophageal Doppler, the hypothesis was developed that occult hypovolaemia is a common cause of peri-operative splanchnic hypoperfusion. In another group of patients undergoing major surgery plasma components of the contact system and neutrophil elastase:1-antitrypsin complexes were measured. An association was demonstrated between peri-operative gut mucosal hypoperfusion, excessive activation of the contact system, increased neutrophil degranulation and the development of organ failure. The measurement of changes in endotoxin core antibodies were also used to examine the relationship between peri-operative gut mucosal hypoperfusion and exposure of patients to endotoxin. The results suggested that translocation from the gut lumen is not the sole source of endotoxin during the peri-operative period. The same results showed an unexpected association between exceptionally high levels of endotoxin antibodies and the maintenance of gut mucosal perfusion. Finally, in a prospective randomised study of patients undergoing elective cardiac surgery, it was demonstrated that per-operative plasma volume expansion reduces the incidence of gut mucosal hypoperfusion. This was associated with a significant reduction in post-operative morbidit