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Kathryn Maitland, an author of a study protocol published on Wellcome Open Research, talks about gastroenteritis and the importance of the Phase II GASTRO trial to monitor children’s responses to rehydration therapy.

Gastroenteritis is the second biggest cause of death in children under 5 years, after acute respiratory illnesses, with the vast majority occurring in low resource settings including sub-Saharan Africa. A large multi-continent study of gastroenteritis (GEMS) found that children hospitalised with gastroenteritis with dehydration are eight and half more times more likely to die than other causes, with one third of these deaths occurring within a week of hospitalisation. This indicates that current management strategies are not working in practice.

Gastroenteritis is the second biggest cause of death in children under 5 years

Standard management of gastroenteritis complicated by severe dehydration, referred to as WHO Plan C, is to give the approximate volume estimated to have been lost, which is about 10% of body weight over 3 hours or 6 hours in children under 1 year using saline solutions given by an intravenous (iv) drip. This equates to almost one and half times the circulating blood volume in a short space of time. Yet, these recommendations have not been tested in a clinical trial and emerging data suggests that outcome remains poor.

In 2011, a trial of fluid resuscitation in children with shock due to severe infection (FEAST), demonstrated that this widely recommended treatment was harmful, with a 3.3% higher mortality in children randomised to fluid bolus therapy than in the maintenance only no-bolus control. The excess mortality appeared to be related to cardiovascular collapse rather than fluid overload. This has raised concerns regarding the safety of rapid intravenous rehydration therapy in other illnesses, such as acute gastroenteritis, which was not included in this trial.

Our study protocol on Wellcome Open Research is part of GASTRO,  a Phase II safety and efficacy trial comparing current standard WHO plan C rapid rehydration protocol with a strategy that aims to give a slower rehydration regimen using the same total volume (100ml/kg of Ringers Lactate) over 8 hours, irrespective of age. The trial is being conducted in three centres in Kilifi County Hospital, Kenya; Mbale and Soroti Regional Referral Hospitals, Uganda and will include 120 children (60 in each treatment group). The trial started enrolment in early 2017 and is due to complete later this year.

The benefit of a pilot trial

We have designed GASTRO as a multisite study to increase generalisability

Phase II trials are an important step to examine the feasibility, acceptability and safety of new or existing treatments with primary outcomes based on mechanisms of action (e.g. rehydration) and for safety rather than mortality, since this would require a substantially larger trial.

Phase II evaluation also provides important data on outcomes to inform the design and sample size for definitive Phase III trial evaluation. We have designed GASTRO as a multisite study to increase generalisability, since past experience has shown that promising research emerging from single-centre Phase II trials may partly contribute to their lack of reproducibility in Phase III trials.

The challenges

When carrying out work on this Phase II trial we faced some challenges. The first was related to staff training and confidence in ensuring and documenting accurate fluid balance. In usual practice the ability to control the precise volume and rate that a fluid is given by a drip is difficult, particularly without the assistance of gauged fluid burettes and/or infusion pumps, which are rarely in use or available.

Staffing levels limit the ability to monitor and record fluid volumes

Furthermore, staffing levels limit the ability to monitor and record fluid volumes infused and fluid output, e.g., urine and stool purging rates. Prior to initiating the study in Uganda, it was clear that WHO Plan C was not being strictly adhered owing to the complexity of the standard protocol.

For example, the rates of rehydration are split into two phases with an initial ultra-rapid rehydration phase followed by a phase of slower rehydration. This is further complicated by the time over which this is recommended to be given and the volume administered in the ultra-rapid rehydration phase which differs for children aged under one year and those over.

Despite the clinical teams being very familiar with clinical trials involving fluid administration the complexity of the WHO protocol necessitated substantial pre- and peri-trial training and close monitoring during the trial.

Many children, owing to severe dehydration, were misclassified as severely malnourished

Finally, gastroenteritis is related to the seasonal rains. In 2017, Kenya and Uganda experienced their worst drought for a decade, therefore restricting recruitment into GASTRO. In addition, many children, owing to severe dehydration, were misclassified as severely malnourished who were excluded from the trial since WHO recommendations strongly advise against iv rehydration in the majority of children with severe malnutrition and gastroenteritis. Following oral rehydration many were reclassified as undernourished and could have been eligible for recruitment.

Open peer review

I am a great believer in open peer review. This encourages fair and justifiable positive and negative peer review, that is published at the time of the manuscript to ensure a transparent review process.