Lay title
Optimising and targeting oxygen treatment in sick children: The COAST trial
What is the problem?
Although oxygen is a basic element of hospital care, there are no relevant studies to guide which level of oxygen saturation or the best method of how to administer it (low flow or high flow) to improve outcome. In practice many children in low-income countries do not receive oxygen, despite being recommended, owing to the lack of its availability due to the high cost, or supplies that are unpredictable (erratic delivery of cylinders or electricity to power oxygen concentrators) resulting in mismatch between supply and demand. The outcomes of children in sub-Saharan Africa with pneumonia, remains poor with an in-hospital mortality 9-10% (for those with oxygen saturations between 80% and 92%) and 26-30% case fatality for those with oxygen saturations <80%, indicating that the current recommendations and/or management strategies are not working in practice.
What questions are we trying to answer?
COAST has been designed to identify which children would benefit from receiving oxygen and what would be the best delivery method. Although oxygen is a basic element of hospital care, this therapy is costly and supplies are inadequate and erratic in African hospitals.
COAST will address two related questions of oxygen therapy and one about nutrition supplementation:
1. Who to give oxygen too?
We will examine whether or not giving oxygen improves outcomes for children who have a moderately low level of oxygen it is not certain what the best level to provide oxygen is and whether this results in a better outcome – so half of the children will receive oxygen and the other half will not. Children with severe hypoxia (<80%) will all receive oxygen as we are more confident about the benefits of oxygen in this group.
2. How best to give oxygen?
For children receiving oxygen, we will compare whether giving oxygen at a higher flow compared with a lower flow (routine care) improves outcomes. High flow oxygen provides extra pressure to the airways to prevent them from collapsing after every exhalation. This helps reduce the effort of breathing, which is vital when lung infections can often lead to respiratory exhaustion and ultimately respiratory failure in critically sick children with limited access to relevant life support i.e. mechanical ventilation (the majority of hospitals in Africa).
3. Nutritional Support
To establish whether supplementary feeding for 56-days (8 weeks) using Ready to Use Therapeutic Feeds (RUTF) in all children versus usual standard care will improve outcome at 90-days.
Where is the study taking place?
The study will take place in 5 hospitals in 2 African countries Kilifi County Hospital and Coast Provincial General Hospital (Kenya) and Mulago (Kampala) Mbale and Soroti Hospitals in Uganda.

COAST overarching objective is to address the key research gaps in the therapeutic use of oxygen in resource-limited setting in order to provide a better evidence base for future management guidelines. The trial has been designed to address the poor outcomes of children in sub-Saharan Africa, which are associated with high rates of in-hospital mortality 9-10% (for those with oxygen saturations between 80% and 92%) and 26-30% case fatality for those with oxygen saturations <80%, indicating that the current recommendations and/or management strategies are not working in practice.

Despite over two decades of investment by WHO technologies group aimed at improving systems for delivering oxygen it appears not to have been afforded a high enough priority at both a global and a country level. Although oxygen is a basic element of hospital care, the poor implementation of current treatment recommendations also stems from the lack of availability in many hospitals, or it cannot be used routinely due to unpredictable supply, faulty cylinders or limitations and interruptions of the electricity supply. This has resulted in mismatch between supply of, and demand for, oxygen in many rural hospitals in developing countries. Whilst the health burden of hypoxia, including morbidity, hospital admission and death have been realised, its potential economic burden for treating children with conditions leading to hypoxia is substantial. As a result there are major gaps between current treatment policies and implementation. These largely stem from the lack of relevant research to inform clinical management; consequently current treatment recommendations are based on weak evidence. Systematic and policy reviews have indicated the need for formal evaluation of the hypoxaemia threshold for which oxygen should be targeted and how best to administer oxygen.

COAST aims to provide the relevant evidence for policy makers and health services by evaluating key elements of an integrated management strategy in African hospitals on the basis of clinical effectiveness and costs.

COAST is a randomised controlled trial designed to provide the evidence for the most clinically-effective and cost-efficient targeted use of oxygen as a life-saving treatment with respect to the optimal oxygen saturation threshold for treatment and mode of delivery in 4200 African children, aged 2 months to 12 years, presenting to hospital with respiratory distress complicated by hypoxia (defined as oxygen saturation (SaO₂)< 92%). 

Children will be enrolled at admission to hospital over 2 years from 5 sites in 2 countries (Uganda and Kenya) and followed for 28 days.  The trial has a pragmatic design, to ensure this encompasses a spectrum of high-risk children, identified largely by clinical criteria, so that the results are applicable to health services in Africa, with limited access to health technologies.

Primary objectives

To establish whether:

·       liberal oxygenation will decrease mortality compared with permissive hypoxia (usual care); and

·       high flow oxygen delivery will decrease mortality compared with low flow oxygen delivery (usual care).

Secondary objectives

The secondary objectives of COAST are:

·       to assess the effectiveness in the speed and success of recovery from the initial respiratory failure;

·       to assess safety and quality of life;

·       to determine long-term effects of the delivery strategies; and

·       to identify whether the additional costs of each of the interventions are proportionate to the health benefits and to inform future widespread implementation in terms of value for money.

The trial will have two randomisations:

R1: For children with a baseline SaO₂<92% but ≥80%, randomisation to liberal oxygenation delivered by either high flow or low flow versus a more conservative strategy (control: no oxygen)

R2: For children with a baseline SaO₂<80% and for those randomised to liberal oxygenation for R1, high flow versus low flow delivery (routine care)

R1 addresses the question of what threshold to give oxygen in children with hypoxia (above a threshold of SaO₂≥80%); R2 addresses how best to give oxygen all receiving to oxygen. For R1, a cut off of <92% assesses a range of saturations that would be consistent with international recommendations for use of oxygen in sick children - providing important additional data about those at a higher threshold than currently recommended by WHO. Children randomised to control will receive low flow oxygen if they ever develop severe hypoxia (SaO₂<80%). All randomisations will be open.