Intravenous fluid for adults with sepsis in sub-Saharan Africa: developing the design of an randomised controlled trial

Severe infections are a major global health problem, and are the leading cause of admission to hospital. The sources of infections are variable, but are commonly the lungs (pneumonia) and the gut (gastroenteritis). The body's usual protective responses should contain and destroy the bacteria or microbes causing infection. However, these responses can often become damaging: this is sepsis, and it is life threatening. During sepsis, a complex mix of abnormalities cause problems throughout the body, including with the immune system, breathing, blood circulation and kidneys. The flow of blood through vital organs can be compromised, causing further organ failure. Many patients die in the first few hours, before antibiotics have a chance to work. Improving early supportive care of patients with sepsis has been associated with significant improvements in patients' survival, but it is not certain which interventions work.
Much focus has been on early aggressive treatment with intravenous fluids, in order to raise low blood pressure and to improve blood supply to vital organs. However, fluids can cause "waterlogging" of the lungs (pulmonary oedema), of the kidneys (worsening kidney function), and other organs. This is particularly damaging where there are no intensive care facilities to "rescue" the patient. A large, well conducted trial in in sub-Saharan Africa showed that intravenous fluid given quickly for sepsis caused children to die. We do not know if the same could be expected in adults: current clinical guidelines for adults emphasise quick fluid "boluses" to try to bring blood pressure back to normal.

* What this development proposal would lead to
We believe that a randomised controlled trial of intravenous fluids in adults should answer the question: "In sub-Saharan Africa, which is the better treatment for sepsis: 1) quick, larger volume fluids given to try bring blood pressure back to normal or; 2) slower fluid given to prevent dehydration, but not designed to "correct" blood pressure.

* Objectives
Before this type of trial could start, we have to define carefully who should be enrolled, how many patients we could expect, and how they should be monitored during treatment. This development grant proposal will examine each of these areas, by systematically reviewing existing knowledge, and by collecting data from a representative sub-Saharan African hospital (Blantyre, Malawi).

* Why the trial is needed now and why in Malawi?
New guidelines for the diagnosis and management of sepsis have been published using data from US hospitals and Intensive Care Units. These used no data from Low Income settings, yet are promoted as internationally useful. Their generalisability to sub-Saharan Africa is poor, and the region must develop and act on clinical evidence which is relevant to areas with younger patient groups, high rates of HIV, and low healthcare spending.

* Stakeholders
Acute infection is a national research priority, and we will ensure that the Malawi Ministry of Health and the College of Medicine (University) have input into the design and chosen outcomes. We will also engage the public and clinical stakeholders to ensure that the trial will be acceptable and appropriate to the healthcare setting. We will build on expertise in Applied Health Research (CAHRD network), develop South-South collaborative networks, and enhance North-South support in trials design (Co-I: DM).

Sepsis is a life threatening organ dysfunction caused by a dysregulated host response to infection. Globally, there are 31.5m cases per year; in-hospital mortality in Malawi is 22-50%. Supportive therapy is key to good outcomes. Intravenous (iv) fluids are used to support a cardiovascular system compromised by peripheral vasodilatation, insufficient cardiac output, and leakage of fluid to the interstitium. While fluids can raise blood pressure, they do not counter the circulatory dysfunction. In high incomes settings, aggressive intravenous fluid (and intensive care [ICU]) management is associated with reduced mortality (OR 0.64).

However, potentially beneficial adaptive responses to hypotension are abolished by high volumes of fluid, leading to acute respiratory distress syndrome, and worsening kidney function. This becomes apparent where ICU is not available. In LMIC, the only relevant trial in adults was stopped early due to high mortality. An uncontrolled Ugandan implementation study suggested benefit, but no dose-response effect above 1 litre in the first 6 hours (cf: 4.9l in a US study). Worryingly, the FEAST study from sub-Saharan Africa showed higher mortality in children treated with more aggressive fluid therapy.

A randomised clinical trial of iv fluid treatment strategy in adults is warranted, comparing conservative therapy versus a blood-pressure-target-driven approach. This development proposal will: 1) determine current practice and inform study protocols; 2) refine inclusion criteria and demonstrate feasibility of recruitment.

Using standard clinical pathways, and leveraging existing research structures, we will identify septic patients in the emergency department, intensively record their baseline and dynamic physiological responses and fluid administration over the first 6 hours, and record outcomes. A systematic review of fluid administration in research and clinical practice in LMIC will be performed.

The major impact of this study will be the design of a definitive trial: a multicentre randomised controlled trial of intravenous fluids in sepsis relevant to sub-Saharan Africa would be the first of its kind, and as such would have widespread relevance at multiple levels: individual clinicians prescribing and patients receiving treatment; hospital administration in organising workflow for septic patients; governmental health policy, including cost-effectiveness data; international (WHO) policy and recommendations. A number of other immediate impacts should be expected to accrue from the development proposal.

* Clinical impact including public involvement
Clinical impact will be felt by engagement with medical training in the host hospital, and through incorporation of local nurses and clinicians into the research team. As an inherent part of the project, we will strengthen communication between primary care and secondary emergency facilities, using the existing channels and initiatives (such as the MLW "Chipatala robot" project for triage). Public engagement as detailed in "Engagement, communication and dissemination" will aim to promote early health-seeking behaviour for people with suspected infection. We will establish a dialogue with healthcare users to improve the integration of clinical research into the emergency department, and to maximise the acceptability of future large scale projects, particularly with respect to emergency consent.

* Enhancing research infrastructure impact
By focussing on research training in a supportive and well-established research environment, we will support Malawi to become a leading regional centre for investigation of acute medical care and sepsis in adults. The project impact will offer excellent value for money due to a close relationship with existing sepsis projects, and the clinical laboratory at MLW and CoM. Trials management advice is available from within our team, and will support the development of the local Clinical Research Support Unit.

* Policy and decision making impact
Existing connections with MLW partners strengthen decision making in health central government through knowledge synthesis and Health Economics expertise. We will make use of MLW commitment to developing an Evidence Informed Decision-making Centre (EvIDeNCe), and a national Evidence Informed Decision-making Network with key national stakeholders (EvIDeNt). These activities will allow early input of high-level stakeholders in a definitive trial. Internationally, our group is represented on the Global Intensive Care Working Group at the European Society of Intensive Care Medicine. This group have previously published guidelines on sepsis treatment in low-resource-settings; data from the project will inform future revisions of this guidance.
Sepsis is high on the international agenda, but due to its perception as a process rather than a disease, it is not visible or well represented on Global Burden of Disease estimates. We will raise this profile at international conferences, and in peer-reviewed journals.