When is enough, enough? Physiological responses to fluid resuscitation in sub-Saharan African adults with sepsis (360G-Wellcome-211098_Z_18_Z)

How are cardiovascular responses to intravenous fluid determined by causative pathogen, duration of illness and pre-existing cardiac disease in patients with sepsis in Malawi? Over 30 million people develop sepsis every year. The first six hours of treatment is critical, as in severe cases mortality is 25-50%, predominantly due to early cardiovascular compromise. In low income countries, intravenous fluids are used as primary supportive treatment. However, the three existing African trials describe higher mortality in those receiving higher fluid volumes, without any pathophysiological explanation. I will identify important mediators of treatment success in Africa examining biologically plausible candidates: 1) pathogen-specific effects; 2) sub-acute physiological compensation from late presentation; 3) existing cardiovascular pathology (related to rheumatic heart disease, HIV and hypertension). I will investigate cardiovascular dynamics in Malawian adults during sepsis resuscitation and unpick the causes of aberrant physiology by careful aetiological description, detailed cardiac and pulmonary ultrasound monitoring, and measures of tissue perfusion. I will investigate novel and existing mathematical models as predictors of specific adverse outcomes (pulmonary oedema, kidney injury, circulatory collapse), providing a theoretical underpinning for personalised fluid management, and the capacity to hypothesis-test alternative strategies for future clinical trials.