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ItemThe Haemodynamic Effects of Mannitolcontaining Intravenous Paracetamol: A Pilot ProgramChiam, Elizabeth Ann ( 2019)The haemodynamic effects of intravenous paracetamol: overview of clinical significance In households worldwide, paracetamol is an over-the-counter drug synonymous with its safety and efficacy for its antipyretic (fever relieving) and analgesic (pain relieving) properties. It is readily available to the public in both enteral (oral) and rectal formulations. In the hospital setting, with 100% bioavailability and ease of administration, the intravenous (IV) formulation of paracetamol is an attractive option for patients undergoing major surgery and the critically ill, where oral and rectal administration may be challenging. Studies have found IV paracetamol is often used in multimodal postoperative pain management and has been shown to improve pain, opioid consumption and overall patient satisfaction in the postoperative setting for both major and minor surgeries. As such, IV paracetamol is one of the most commonly ordered medications for surgery and critical care patients. However, there is a paucity of evidence-based research surrounding its safety profile in these patient subgroups. Emerging clinical data suggests it may have the propensity to produce hypotension in surgical patients and the critically ill. Intraoperative hypotensive events have been associated with morbidity and longer hospital stays. Additionally, maintenance of haemodynamic stability is a requirement for a patient to be discharged from intensive care. Despite the concern of such a significant, and potentially underreported side effect, the current corpus of science relating to the haemodynamic effects of IV paracetamol is limited. It is also worth noting an underappreciated excipient of IV paracetamol is mannitol. Mannitol is added to the IV paracetamol formulation as a stabilizing compound but is present in quantities close to 4% in the majority of IV paracetamol formulations available. Recent advances in invasive and non-invasive haemodynamic monitoring have allowed for the accurate measurement of variables that determine blood pressure, namely cardiac output and systemic vascular resistance. For this thesis, state-of-the-art haemodynamic monitoring will be used to quantify the haemodynamic impact of IV paracetamol by measuring the fundamental components of blood pressure. In order to understand the effects of IV paracetamol on blood pressure and the potential for mannitol to play a role in any haemodynamic alterations, this thesis will aim to investigate the haemodynamic effects of IV paracetamol by means of a comprehensive paracetamol program. This program will be specifically tailored to examine these effects in patient subgroups of varying baseline haemodynamic stability. This comprehensive paracetamol haemodynamic program involves the following: Stage 1 – Literature review: Comprehensive literature review to identify, evaluate and critically analyse the current knowledge base of the haemodynamic effects of IV paracetamol. Stage 2 – STUDY 1 Healthy volunteer study: To assess the haemodynamic effects of IV paracetamol in a healthy, normotensive population. Stage 2 – STUDY 2 Cardiac surgery patients (preoperative) study: To assess the haemodynamic effects of IV paracetamol in patients with pre-existing cardiac disease. Stage 2 – STUDY 3 Cardiac surgery patients (postoperative) study: To assess the haemodynamic effects of IV paracetamol in patients who have undergone major surgery and who are at greater risk of haemodynamic instability. Stage 2 – STUDY 4 Chronic liver disease patients study: To assess the haemodynamic effects of IV paracetamol in patients with pre-existing derangements of their systemic vascular system (similar to shock). It is hoped that this thesis will synthesize high quality results to add to the growing body of evidence that IV paracetamol may cause hypotension. Analyzing the haemodynamic effects in such different patient populations, may offer insight as to which individuals may be at greater risk of developing hypotension after the administration of IV paracetamol.