Modelling cardiovascular responses during treatment for sepsis – a data-rich longitudinal analysis to determine what mediates the harm from aggressive fluid resuscitation in Malawi

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%. In low income countries, intravenous fluids are used as primary supportive treatment. However, the three existing African randomised trials describe higher mortality in those receiving higher fluid volumes, without a definitive pathophysiological explanation (pulmonary oedema and cardiovascular collapse have both been implicated).

Hypotheses: We will test mediators of fluid resuscitation success in sepsis in Africa, examining biologically plausible hypotheses: 1) pathogen-specific effects (with special interest in tuberculosis); 2) sub-acute physiological compensation from late presentation; 3) existing cardiovascular pathology (related to rheumatic heart disease, HIV and hypertension).

Methods: We 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 (echocardiography and baseline and serial measures of fluid responsiveness by passive leg raise), and measures of tissue perfusion (sidestream dark field imaging of the buccal mucosa).

Inclusion criteria: adult patients attending Queen Elizabeth Central Hospital, Malawi; suspected infection with at least 1 of: temperature <35°C or ≥38°C; history of fever, night sweats or rigors in the preceding week; cardiovascular instability (defined as systolic hypotension<100 or tachycardia>110).

Follow-up: intensive first 24 hours, 48 hour review and day 28 outcome determination.

Analysis and implications: Using both existing computational models (open source CVSim), and novel longitudinal mathematical models, we will examine the 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.

Where does the project lie on the Translational Pathway?

T1 – Basic Research, T2 – Human/Clinical Research

Expected Outputs

High impact publications are expected, and the project is expected to yield results which have policy relevance (including clinical guidelines for the treatment of critically unwell patients). Significant funding opportunities are available in this area (sepsis and critical care), and the specialised skills have very broad applicability (longitudinal models, understanding the practical application of models to aberrant physiology).

Training Opportunities

Training in interpretation of echocardiography and other clinical tests

Quantitative modelling, especially longitudinal analysis.

Skills Required

Biomedical or statistical background, with a keen interest in quantitative science applied in a biological setting.  Ideally, an understanding of data manipulation and "R" software

Key Publications associated with this project

Wheeler I, Price C, Sitch A, Banda P, Kellett J, Nyirenda M, Rylance J. Early warning scores generated in developed healthcare settings are not sufficient at predicting early mortality in Blantyre, Malawi: a prospective cohort study. PLoS One. 2013; 8(3): e59830. PMC3612104

Lewis MJ, Abouyannis M, Katha G, Nyirenda M, Chatsika G, Feasey NA, Rylance J. Population incidence and mortality of sepsis in an urban African setting 2013-2016. under review. 2019.

Levin M, Cunnington AJ, Wilson C, Nadel S, Lang HJ, Ninis N, McCulloch M, Argent A, Buys H, Moxon CA, Best A, Nijman RG, Hoggart CJ. Effects of saline or albumin fluid bolus in resuscitation: evidence from re-analysis of the FEAST trial. The lancet Respiratory medicine. 2019; 7(7): 581-93. PMC6593355

Lewis JM, Feasey NA, Rylance J. Aetiology and outcomes of sepsis in adults in sub-Saharan Africa: a systematic review and meta-analysis. Critical Care. 2019; 23(1): 212.

Guarracino F, Bertini P, Pinsky MR. Cardiovascular determinants of resuscitation from sepsis and septic shock. Crit Care. 2019; 23(1): 118. PMC6466803

Now Accepting Applications 

CLOSING DATE FOR APPLICATIONS: Application Portal closes: Wednesday 9th February 2022 (12:00 noon UK time)

Shortlisting complete by: End Feb/early March 2022

Interviews by: Late March/early April 2022

For more information on Eligibility, funding and how to apply please visit the MRC DTP/CASE pages