Towards the treatment of toxic thoracic duct lymph

Abstract

Background: Multiple organ dysfunction syndrome (MODS) is the result of persistent end-organ dysfunction, which can result from a range of acute diseases. The gut-lymph concept describes the pathophysiological events precipitating MODS as a result of hypotension with subsequent profound splanchnic vasoconstriction, which causes gut injury and a change in the composition of gut lymph. This toxic lymph then returns to the systemic circulation via the thoracic duct (TD) to mediate further end-organ dysfunction. The gut-lymph concept requires clinical translation from largely animal-based studies to improve outcomes for patients with MODS. Aims and methodologies: The aims and methodologies of this thesis were (1) through three systematic reviews on the anatomy of the terminal TD, previous TD interventions and radiological interventions for chylothorax, to improve the knowledge base to conduct further clinical translational studies; (2) to gain surgical access to the TD to assess the compositional change of TD lymph with the introduction of enteral feeding; (3) to optimise a method of enriching extracellular vesicles in TD lymph; and (4) to develop a method of minimally invasive TD cannulation. Results: (1) The terminal TD is highly anatomically variable, with only 72% of patients having a single terminal duct. Previous TD interventions were generally underpowered, observational and noncomparative in design. The overall clinical success rate for radiological interventions for chylothorax is 51.6%. (2) With the introduction of enteral feeding, inflammatory cytokines and D-lactate, increased Limulus amoebocyte lysate endotoxin and intestinal fatty-acid binding protein in TD lymph were among other compositional changes consistent with the gut-lymph concept. (3) Density gradient centrifugation followed by ultracentrifugation enabled the identification of extracellular vesicles in TD lymph. (4) A method of antegrade opacification and guidewire access step followed by retrograde percutaneous TD cannulation was identified. Conclusions: The foundations for the translation of the gut-lymph concept into clinical practice have been laid down in this thesis. A trial of the efficacy of external TD lymph drainage in MODS is now possible with a minimally invasive method of TD cannulation.