Abstract
After myocardial infarction complicated by cardiogenic shock the inflammatory response is the result of an ischemic insult. Elevated procalcitonin levels, correlated to IL-6 levels, are triggered by bacterial toxins. In cardiac surgery with the use of cardiopulmonary bypass (CPB) hypoperfusion of the gut may result in a loss of barrier
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function and as a consequence bacterial endotoxins may enter the systemic circulation. Alkaline phosphatase is capable of detoxifying endotoxins and extracellular nucleotides. Based on the promising results of alkaline phosphatase in the attenuation of the inflammatory response in several studies we focused in this thesis on the effect of bovine Intestinal Alkaline Phosphatase (bIAP) on the inflammatory response in the field of cardiology and cardiac surgery. In chapter 2 of this thesis the proposed mechanism of endotoxin release during cardiac surgery with the use of CPB is discussed, followed by both material dependent and material independent measures taken throughout the years to diminish endotoxin release. In chapter 3 we investigated the effect of bIAP in myocardial infarction. Acute myocardial infarction (AMI) was induced in mice. BIAP was given intravenously. A single dose of bIAP reduced the production of the chymase mMCP-1 and diminished the systemic pro-inflammatory cytokine response in the acute phase after AMI . In chapter 4 a double blind, randomized, placebo-controlled study among a total of 63 patients undergoing coronary artery bypass grafting (CABG) with low till intermediate EuroSCORE is discussed. Bovine intestinal alkaline phosphatase or placebo was administered as an intravenous bolus followed by continuous infusion for 36 hours. Five patients in the placebo group displayed a significant TNFa response followed by an increase in plasma levels of IL-6 and IL-8. Such a TNFa response was not observed in the bIAP group, confirming the anti-inflammatory activity of bIAP. In chapter 5 we focused on alkaline phosphatase release. The intravenous administration of bIAP as a bolus followed by continuous infusion to patients undergoing elective CABG with CPB leads to an initial rise of plasma alkaline phosphatase levels followed by a significant increase of plasma alkaline phosphatase at about 4-6 hours post start of surgery. This second peak of alkaline phosphatase has an endogenous origin. The most likely source is liver type alkaline phosphatase. To exclude that aprotinin as possible anti-inflammatory agent was the eliciting factor in endogenous alkaline phosphatase release we performed a small study in patients undergoing CABG with the use of CPB, but without the use of aprotinin. This study is described in chapter 6. In this study it is demonstrated that the release of endogenous alkaline phosphatase is not induced by aprotinin, and that it is only induced by bolus bIAP followed by continuous infusion. In piglets bIAP was administered intravenously, intramuscularly or subcutaneously either as a single bolus or as repated bolus twice a day, with an interval of about 8 hours for 3 consecutive days. No endogenous alkaline phosphatase release could be demonstrated in piglet experiments which are described in chapter 7
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