Froghi, Farid; (2025) Effect of fluid administration and endothelial injury on organ function in liver ischaemia-reperfusion injury and acute pancreatitis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The presence of systemic inflammatory response syndrome (SIRS) in hospital settings is linked to increased mortality and morbidity. Deaths primarily result from the progression of SIRS to severe shock and multi-organ dysfunction (MOD) in later disease stages. This thesis explores the pathological processes of SIRS in liver ischemia-reperfusion (IR) injury and acute pancreatitis, emphasising the role of goal-directed fluid therapy (GDFT) and endothelial glycocalyx (GCX) injury in organ dysfunction. The COLT study evaluated the feasibility of GDFT using a stroke-volume optimisation protocol in 60 patients undergoing liver transplantation. GDFT was found to be feasible (94% consent rate) and safe in cirrhotic patients. The mean (SD) volume of IV crystalloid administered to the GDFT group during the 12-h study period was higher (3968 ml GDFT vs. 2510 ml SC group, p=0.002). A secondary analysis of hemodynamic parameters and end-organ function revealed no significant differences despite the GDFT group receiving more crystalloids. Damage to the endothelial GCX was observed after reperfusion with a significant rise in circulating syndecan-1 (SDC-1) levels from baseline in all patients (baseline 124.7 ng/ml ±65.2 vs. reperfusion 6000ng/ml ±3216.4, p<0.0001). The GAP trial examined the feasibility of GDFT in 50 patients with acute pancreatitis patients within the first 48 hours of hospital admission. Both groups received similar volumes of IV fluids (GDFT 5465 ml, SC 5211 ml). The GDFT group showed lower heart rate, blood pressure, and respiratory rate, with improved oxygen saturations. There was no evidence of difference in complications of AP (GDFT 24%, SC 32%) or in the duration of stay in intensive care (GDFT 0 (0), SC 0.7 (3) days). Length of hospital stay was 5 (2.9) days in GDFT and 6.3 (7.6) in SC groups. Ward-based GDFT is feasible and shows a signal of possible efficacy in AP in this early-stage study. A detailed analysis of endothelial GCX injury was conducted during organ retrieval, ischemic preservation, and reperfusion of the graft. The key findings of this study were the differences in circulating and urinary SDC-1 levels in DBD and DCD donors. DCD donors tend to have higher circulating SDC-1 levels during the retrieval surgery as well as high SDC-1 levels in the transport fluid after cold ischaemic preservation, indicating a higher insult to the endothelial GCX. Significant correlations were found between circulating markers of GCX injury at 6- and 12-hours post-reperfusion and post-operative graft function and complications. Patients who had persistent SDC-1 >400 at 12h post=operatively had increased number of complications, grade >4 complications by Clavien-Dindo (p=0.002), and deaths (n=2/12). Sulodexide (SDX), a drug shown to be protective of GCX in other disease processes, was tested in a murine model of warm liver IR injury. The drug improved liver microcirculation. There was an increase in flow parameters between SDX IR and PBS IR at reperfusion (, p<0.001) and pretermination (, p<0.05). SDX significantly reduced tissue oedema as demonstrated by a reduction in Evan’s blue extravasation in tissues but did not affect the immune response or liver function. In conclusion, addressing endothelial GCX injury and implementing GDFT may improve outcomes in patients with SIRS, particularly in the contexts of liver transplantation and acute pancreatitis.

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