Monitoring vascular endothelial function by microdialysis in septic patients.

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Background: Sepsis and the systemic inflammatory response syndrome (SIRS) characterises up to 80% of critical illness in children. The fundamental pathophysiological features underpinning sepsis/septic shock (and SIRS) are changes to the vascular endothelium, which include:1) increased permeability to fluid and protein ("leaky") and, 2) increased activation ("sticky"). Therefore, monitoring the permeability of the vascular endothelium should inform clinicians about the stage and severity of sepsis and assist in clinical decision making regards fluid resuscitation and fluid balance management. Positive fluid balance i s a poor prognostic sign, but without clear science, opinion on fluid management in septic shock i s divided. We recently published data which confirms a direct role for Eph/ephrin signalling in endothelial leakage both in a mouse gut ischaemia/reperfusion injury model and in vitro in TNF-a induced vascular leakage in human umbilical venous endothelial cells. Hypotheses: That vascular endothelial function can be monitored in the intensive care unit by: (a) quantifying interstitial protein levels by microdialysis; and (b) measuring plasma levels of Eph/ephrins as endothelial activation markers. Aims: The aim of this project is to determine whether it is feasible to monitor the integrity of the vascular endothelium in critically-ill children by: a) using microdialysis to quantify interstitial protein levels; and (b) measuring plasma levels of Eph/ephrin proteins as endothelial activation biomarkers. Objectives: Our experiments are designed to improve monitoring of vascular endothelial activation and integrity, in order to guide rational fluid therapy and thereby, reduce ventilator bed days and lower mortality. Methods: In previous experiments in paediatric cardiac surgical patients, we have tested the feasibility of monitoring interstitial protein, fluid and cytokines. In these experiments, we will prospectively identify infants and children admitted to the paediatric intensive care unit (PICU) of Lady Cilento Children’s Hospital (LCCH) with sepsis/septic shock. Briefly, a microdialysis catheter (CMA60) will be inserted subcutaneously into the forearm of septic children (n = 100), and perfused with electrolyte solution and the dialysate collected for protein and cytokine determination. Serial routine blood tests will be analysed for biomarkers of endothelial activation. Approximately 100 infants and children are admitted annually with sepsis/septic shock to LCCH PICU, and are treated according to the paediatric Surviving Sepsis Guidelines. Control patients will be healthy children (n = 20) undergoing routine elective surgery at LCCH. Significance: We will introduce new diagnostic test to identify endothelial activation and a new tool (i.e. microdialysis) for monitoring vascular endothelial integrity. This may improve supportive care in the ICU and result in reduced ventilator days,

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