Gastroenteritis: rehydration for children with severe acute malnutrition (GASTRO-SAM)

Children with severe acute malnutrition (SAM) who are admitted to a hospital in Africa frequently (>50%) have diarrhoea (3 watery stools/day). The outcome in such children when they managed in accordance to World Health Organization (WHO) SAM treatment guideline is very poor with over 20% dying during hospital admission. One standard treatment of diarrhoea that causes dehydration is 'rehydration' therapy either by using a drip (intravenous) for those who have developed severe dehydration, where approximately 10% or more of the body weight has been lost from watery diarrhoea. The other treatment is oral rehydration salt (ORS) solutions which is given to those with less severe dehydration or as a follow-on rehydration treatment for children after they have received their drip (intravenous) treatment. However, the WHO guidelines for SAM children with severe dehydration recommend restriction of intravenous therapy only to cases with late stage advanced shock (where the blood pressure is low) and focus exclusively on the use of low sodium (salt) oral rehydration solutions (ORS) for fear of causing heart failure and giving too much salt (sodium). Therefore, for children requiring ORS guidelines recommend a low sodium ORS called ReSoMal. These guidelines are very controversial since they are based on expert opinion, and do not have the relevant clinical studies or clinical trials to back up the evidence to support these recommendations.

Owing to the very poor outcomes, we therefore aim to evaluate in a clinical trial called GASTROSAM whether the usual standard treatment that is given to children who are well nourished is better and safer that the intravenous and oral rehydration recommended treatments for SAM children with diarrhoea. We will conduct a small trial that will test whether it is safe to give intravenous rehydration for SAM children with severe dehydration of 100mls/kg (the equivalent volume to replace what has been lost) which is currently recommended for children without malnutrition. We will do this in two ways by either infusing the fluid rapidly (over 3- 5 hours), or more slowly (over 8 hours) and compare this to what is currently being recommended (which largely recommends to treat this with oral rehydration salts and only to start drip treatment if shock occurs). We will also test whether the standard ORS (with a higher amount of sodium) given for children without severe malnutrition is safer and has less harmful effects that the current ORS called ReSoMal which has a much lower sodium content and has in the past has been shown to result in children developing very low sodium levels which can cause harm. The results of the trial will help us design a much larger trial in which we aim to compare rapid rehydration versus slower rehydration in all children who are admitted to hospital irrespective of their nutritional status (i.e. well-nourished and malnourished). We are currently conducting another small trial called GASTRO in children with severe diarrhoea who do not have malnutrition comparing rapid (standard recommended treatment) versus slower rehydration as the outcomes even for children who are not malnourished is also very poor. The data from this trial will also help us design a future large trial.

Children hospitalised with severe acute malnutrition (SAM) are frequently complicated (>50%) by diarrhoea (3 watery stools/day) which is accompanied by poor outcomes (case fatality 21%). Rehydration guidelines for SAM are exceptionally conservative and controversial, as they rely upon expert opinion, recommending restriction of intravenous (iv) to cases with advanced shock and exclusive use of low sodium oral rehydration solutions (ORS) for fear of fluid and/or sodium overload. We aim to evaluate standard (non-SAM) liberal strategies for both iv and oral rehydration in SAM children with diarrhoea. The Phase II trial will generate feasibility, safety and preliminary data on survival to 7 days and 28 days of rehydration strategies incorporating two strata for management of (A) severe dehydration comparing both rates of rehydration and volume of iv replacement and (B) the composition of ORS for children with some dehydration (and post iv-rehydration) designed as a factorial trial.
The two major questions to be addressed are
(1) In Stratum A involving SAM children with clinical signs of severe dehydration (~10% loss) whether 'liberal' rehydration strategy using 100mls/kg of isotonic Ringers Lactate with either (i) standard WHO Plan C for rapid rehydration over 3-5 hours (incorporating boluses for shock) versus (ii) slower fixed rate of intravenous rehydration over 8 hours (and no boluses) are safer and result in better outcomes versus (iii) current WHO SAM guidelines recommending oral rehydration with low-sodium ReSoMal and restricting iv to those with advanced shock only (15 ml/kg bolus (plus one repeat).
(2) In Stratum B in children with diarrhoea with clinical signs of 'some dehydration' and follow on treatment post-intravenous rehydration whether oral rehydration with (i)WHO standard oral rehydration solution (ORS) for non-SAM results in less hyponatraemia and less adverse outcomes than (ii) current recommendation advocating low sodium (ReSoMal) ORS.

The direct beneficiaries will be African children hospitalised with severe malnutrition, but in the broader context research and progress in this area will have wider downstream benefits, especially for the current epidemics of cholera. Children with malnutrition with severe dehydration due to diarrhoea are current 'denied' intravenous fluids, except of a very small group with advanced shock- who have a very high mortality. These are based on fears that the malnourished heart is at risk of heart failure. The guidelines have not changed in nearly two decades since they were first published with the grave warnings about the risks of intravenous fluid replacement and sodium overload. Emerging data from clinical studies in African children have found the heart to be proportionately smaller (in proportionate to general muscle mass of the child) with no evidence of pump failure or adverse response to fluid rehydration. Furthermore, this stance may also be having profound implications for cholera management, where similarly SAM children are denied iv rehydration under current guidelines since they do not differentiate between cholera and non-cholera mamagement. Furthermore, there are wider implications to children with stable chronic undernutrition, temporally fulfilling anthropometric criteria for severe malnutrition during an acute life-threatening diarrhoea due to 10% loss of body weight (severe dehydration). Following iv rehydration and for children some dehydration WHO recommends low-sodium RESOMAL. However, this only made at a single source (Nutriset, France), thus infrequently available and poorly implemented.

There is an urgent need to reappraise these recommendations; since they lack any relevant studies and have largely ignored published data contradicting these opinions and therefore most clinicians are fearful of use of intravenous fluids owing to the very strongly worded warnings about the potential harm. Demonstrating that intravenous rehydration is safe in children with SAM will be an important achievement and may even result in some guideline changes permitting intravenous rehydration for SAM children with cholera. A trial conducted in Indian using rapid intravenous therapy in SAM children in cholera showed this was safe, but this was not taken into consideration in the updated 2013 SAM guidelines. Nor were the data emerging from Africa showing the diarrhoea was not 'of trivial consequence' and that signs of severe dehydration identified high risk groups, with guidelines continuing to suggest these were 'unreliable' and indicated lack of fat mass rather than true signs of severe dehydration. As a result many children are not identified even for oral rehydration. Moreover, the 2013 guidelines also ignore the only trial of ReSoMal comparing to ORS with higher sodium content. The trial showed superior potassium correction but noted that a higher number of children receiving ReSoMal developed severe hyponatraemia with one child developing hyponatraemic seizures. By examining both elements of rehydration in a single trial, if we were to demonstrate that treatments guidelines that guide rehydration for non-malnourished are safe and have less adverse outcomes compared to the ones currently recommended for SAM, this will be an important development. This will also pave the way for a much larger trial comparing rates of intravenous rehydration with mortality as an endpoint and guideline review specifically relating to the current strong recommendations that intravenous therapy should be avoided and that sodium-rich ORS solutions are not harmful.