Description

Malnutrition is a leading cause of death, contributing to nearly 45% of all deaths in children under the age of 5 years worldwide. In its most severe form, severe malnutrition remains prevalent globally affecting more than 45 million children. Severely malnourished children have a strongly increased risk of death from common infectious diseases. Updates in treatment protocols for severe malnutrition have been the most impactful intervention against childhood mortality.

Management of severely malnourished children hospitalized with critical illness is based on guidelines developed by the World Health Organization and consists of three main components: 1. Clinical stabilization 2. Treatment of underlying infections 3. Nutritional rehabilitation. Clinical stabilization includes administration of broad-spectrum antibiotics, fluid resuscitation (if needed) and providing a nutritional stabilization feed that is called 'F75'. F75 was designed in the 1990's assuming that severely malnourished children with infections are metabolically vulnerable and have a range of micronutrient disturbances. F75 aims to provide 95 kcal/kg/day and was not intended for weight gain since, during this initial period, children are actively fighting infections. Once clinically stabilized, on average after 3-5 days, children are transitioned from F75 to ready-to-use therapeutic foods (RUTF) that provide a substantially higher amount of protein and calories to promote rapid weight gain. Some children fail this transition and have to revert back to F75 for a period of time due to clinical deterioration or not tolerating the RUTF. Despite protocolized management of these highly vulnerable patients, mortality rates have remained high over the past decades and reported to range between 10-30%, depending on population, setting and duration of follow up.

Scientific evidence from the last decade has started to reform the approach to care for critically ill children in relation to feeding. Evidence shows that, during severe infection, the body enters a catabolic state, which is critical for immune function and pathogen clearance. Overfeeding during this phase may disrupt essential metabolic processes, including a process of cellular recycling called autophagy, which play a key role in fighting infections. Studies in both high- and low-resource settings have shown that limiting caloric intake in the early days of critical illness may improve clinical outcomes, including reducing the risk of infections and decreasing ICU stay durations.

No clinical trial has examined the optimal caloric intake for ill severely malnourished children in LMIC and the current F75 composition was only based on expert opinion. Our population and treatment settings are substantially different compared to high income settings. Children in LMIC are often wasted to a degree of severity not frequently observed in high resource settings. Severely malnourished children are thought to be at risk of refeeding syndrome, defined as an acute insulin response to rapid refeeding leading to electrolyte imbalances and hypoglycemia. In many LMIC, health resources are scarce and physician and nurse to patient ratios are low. Malnourished children are therefore managed using relatively protocolized but largely non-evidence-based approaches. This has led the World Health Organization (WHO) to press the scientific community to review of current practices. Intravenous fluid administration is often avoided due to the absence of fluid solutions, infusion pumps and lack of resources to monitor fluid intake. Parenteral nutrition is generally not available. Therefore, fluid and nutrition are mainly provided orally or through a nasogastric tube.

We aim to test the safety and tolerability of using lower caloric feeds during the initial clinical stabilization phase of acutely ill severely malnourished children. Reducing caloric intake has been shown to improve clinical outcomes of critically ill children with malnutrition in high resource setting. We propose that applying a similar strategy during the initial stabilization phase will improve survival of critically ill children with malnutrition in low resource settings. However, reducing caloric intake in these children may increase the risk of hypoglycemia. Therefore, we will conduct a randomized phase I clinical trial specifically designed to assess and minimize this risk. The potential benefits on childhood survival renders this trial ethically and clinically justified. Given current data, the use of lower caloric feeds should be evaluated in this vulnerable population. Conducting this safety phase-I trial will be a critical step before proceeding with an efficacy-focused trial powered for mortality.

The F50 and F35 feeds have been meticulously formulated for this trial. Their composition is identical to that of F75, with the only distinction being the reduction in calorie content with F50 aiming to provide 63kcal/kg/day and F35 aiming to provide 47kcal/kg/day. This ensures that the nutritional parameters and essential components remain consistent, while the lower calorie count aligns with the specific requirements of this trial. Once clinically stabilized, on average after 3-5 days, children are transitioned from F50 or F35 to RUTF that provide substantially higher amounts of protein and calories to promote rapid weight gain. This novel trial design will be used to ensure the highest level of safety. Once the optimal and safe reduction in calories is determined, we would be able to perform a large intervention trial whereby the provided feeds (i.e., standard F75 or a reduced calorie feed) can be randomized and tested for efficacy in reducing mortality. This work has the potential to radically change how we manage seriously ill severely malnourished children and reduce the mortality in the most vulnerable children globally.