Characterisation and Novel Treatment of Several Causes of Mortality in Critical Illness

Abstract

Three critical care syndromes form the main foci of this thesis: sepsis; delirium; and severe trauma. Research methods used to investigate the pathogenesis and novel treatments of these syndromes include clinical trials, observational studies, and preclinical models. In several instances, a complete research programme is presented. For example: • in the investigation of delirium, in which observational studies and empirical assessments of clinical measurement tools led to a pilot study and then the definitive 15-hospital clinical trial (Dexmedetomidine to Lessen ICU Agitation: DahLIA) comparing dexmedetomidine to placebo as a treatment for this condition; and • in the assessment of a haemodynamic protocol-guided treatment algorithm for septic shock, in which practice surveys and reviews of trial methodologies preceded three harmonised international clinical trials subsequently subjected to definitive meta-analysis. Other research programmes that are still in progress are also presented. For example: • the Cryopreserved vs. Liquid Platelets (CLIP) trial; • a programme that has developed a novel preclinical model of acute traumatic coagulopathy, in parallel with clinical trials of resuscitation in trauma such as the 1400-patient Pre-hospital Anti-fibrinolytics for Traumatic Coagulopathy and Haemorrhage (PATCH) trial; and • a research programme testing a protocolised approach to sedation, including the 4000-patient definitive Sedation Practice in Intensive Care Evaluation (SPICE) trial. A substantial part of this thesis includes collaborative applications of trial and observational methodologies to other critical care topics, including advanced-care planning, nutrition, oxygen delivery, lactate concentration, anaemia, coagulopathy, and the effects of gender and race. Research methodology is constantly evolving, and contributions to this process are outlined along with examples of research translation into practice through both policy and education.