Glycaemia and upper gastrointestinal function in health and critical illness

Abstract

This thesis comprises four distinct but complementary chapters with a broad focus of glycaemia and upper gastrointestinal function in health and critical illness, encompassing four literature reviews, two epidemiological-observational and two interventional studies in the critically ill and three proof-of-principle studies in healthy volunteers. Hyperglycaemia occurs frequently in the critically ill, both in patients with diabetes, and in those with previously normal glucose tolerance. The literature is reviewed on the impact of dysglycaemia in the patient with sepsis, emphasising the interaction between acute dysglycaemia, chronic hyperglycaemia and outcomes (chapter 1.2). Observational studies were performed to estimate the prevalence of stress induced hyperglycaemia in the critically ill and to evaluate the subsequent risk of diabetes. I established that: (i) stress induced hyperglycaemia occurs in ~50% of patients, and (ii) peak blood glucose concentrations are associated with greater mortality in patients with adequate premorbid glycaemic control but not in those with chronic hyperglycaemia (chapter 1.3). In a large, state-wide retrospective observational study I established that stress induced hyperglycaemia doubles the risk for subsequent type 2 diabetes (chapter 1.4). Dysregulated enterohormone secretion is thought to mediate critical illness induced abnormalities of glycaemia and upper gastrointestinal function. A review of the literature is presented on the clinically relevant enterohormone disturbances (chapter 2.2). In a prospective comparative study of critically ill patients and healthy volunteers, I quantified gallbladder dysmotility in critical illness, a phenomenon that was independent of plasma concentrations of the enterohormone cholecystokinin (chapter 2.3). The therapeutic potential for the incretin enterohormones in the management of stress induced hyperglycaemia is reviewed in detail with a focus on glucagon-like peptide 1 (GLP-1) (chapter 3.2). Upper gastrointestinal function and glycaemia are inextricably linked and in healthy volunteer studies I examined the effect of GLP-1 on gastric emptying during extremes of glycaemia. I demonstrated that GLP-1 attenuated the acceleration of gastric emptying engendered by hypoglycaemia (chapter 3.3) and that the slowing of gastric emptying induced by hyperglycaemia is potentiated by GLP-1 (chapter 3.4). In a study investigating the islet cell effects of GLP-1 I demonstrated that intravenous pulsatile delivery of GLP-1 has an equivalent insulinotropic effect to continuous delivery in healthy volunteers (chapter 3.5). Prophylactic administration of proton pump inhibitors for the prevention of gastric stress related mucosal injury is widely prescribed yet has the potential to cause harm and has been inadequately evaluated in the critically ill. A review of the literature highlighting this paradox is presented in chapter 4.2. In a prospective, double-blind randomised, placebo-controlled trial I demonstrated that prophylactic administration of a proton pump inhibitor was neither superior nor inferior to placebo in preventing clinically significant upper gastrointestinal bleeding during critical illness (chapter 4.3). In summary, these studies have yielded a number of important insights including; the incidence of stress induced hyperglycaemia and the subsequent risk of diabetes, quantification of gallbladder motility in critical illness, the gastrokinetic effects of GLP-1 during extremes of glycaemia, the insulinotropic effects of pulsatile GLP-1 delivery, and an evaluation of stress ulcer prophylaxis in the critically ill.