Gastroenteritis aggressive versus slow treatment for rehydration (GASTRO): a phase II rehydration trial for severe dehydration: WHO plan C versus slow rehydration.

BACKGROUND: World Health Organization rehydration management guidelines (plan C) for severe dehydration are widely practiced in resource-poor settings, but never formally evaluated in a trial. The Fluid Expansion as a Supportive Therapy trial raised concerns regarding the safety of bolus therapy for septic shock, warranting a formal evaluation of rehydration therapy for gastroenteritis. METHODS: A multi-centre open-label phase II randomised controlled trial evaluated two rehydration strategies in 122 Ugandan/Kenyan children aged 60 days to 12 years with severe dehydration secondary to gastroenteritis. We compared the safety and efficacy of standard rapid rehydration using Ringer's lactate (100 ml/kg over 3 h (6 h if < 1 year), incorporating 0.9% saline boluses for children with shock (plan C) versus slower rehydration: 100 ml/kg Ringer's lactate over 8 h (all ages) without boluses (slow: experimental). The primary outcome was the frequency of serious adverse events (SAE) within 48 h including cardiovascular, respiratory and neurological complications. Secondary outcomes included clinical, biochemical and physiological measures of response to treatment by intravenous rehydration. RESULTS: One hundred twenty-two eligible children (median (IQR) age 8 (6-12) months) were randomised to plan C (n = 61) or slow (n = 61), with two (2%) lost to follow-up at day 7). Following randomisation mean (SD) time to start intravenous rehydration started was 15 min (18) in both arms. Mean (SD) fluid received by 1 hour was greater in plan C (mean 20.2 ml/kg (12.2) and 33.1 ml/kg (17) for children < 1 year and >- 1 year respectively) versus 10.4 ml/kg (6.6) in slow arm. By 8 hours volume received were similar mean (SD) plan C: 96.3 ml/kg (15.6) and 97.8 ml/kg (10.0) for children < 1 and ≥ 1 year respectively vs 93.2 ml/kg (12.2) in slow arm. By 48-h, three (5%) plan C vs two (3%) slow had an SAE (risk ratio 0.67, 95% CI 0.12-3.85, p = 0.65). There was no difference in time to the correction of dehydration (p = 0.9) or time to discharge (p = 0.8) between groups. Atrial natriuretic peptide levels rose substantially by 8 hours in both arms, which persisted to day 7. Day 7 weights suggested only 33 (29%) could be retrospectively classified as severely dehydration (≥ 10% weight loss). CONCLUSION: Slower rehydration over 8 hours appears to be safe, easier to implement than plan C. Future large trials with mortality as the primary endpoint are warranted. TRIAL REGISTRATION: ISRCTN67518332 . Date applied 31 August 2016.

Intravenous rehydration of malnourished children with acute gastroenteritis and severe dehydration: A systematic review.

Background: Rehydration strategies in children with severe acute malnutrition (SAM) and severe dehydration are extremely cautious. The World Health Organization (WHO) SAM guidelines advise strongly against intravenous fluids unless the child is shocked or severely dehydrated and unable to tolerate oral fluids. Otherwise, guidelines recommend oral or nasogastric rehydration using low sodium oral rehydration solutions. There is limited evidence to support these recommendations. Methods: We conducted a systematic review of randomised controlled trials (RCTs) and observational studies on 15 th June 2017 comparing different strategies of rehydration therapy in children with acute gastroenteritis and severe dehydration, specifically relating to intravenous rehydration, using standard search terms. Two authors assessed papers for inclusion. The primary endpoint was evidence of fluid overload. Results: Four studies were identified, all published in English, including 883 children, all of which were conducted in low resource settings. Two were randomised controlled trials and two observational cohort studies, one incorporated assessment of myocardial and haemodynamic function. There was no evidence of fluid overload or other fluid-related adverse events, including children managed on more liberal rehydration protocols. Mortality was high overall, and particularly in children with shock managed on WHO recommendations (day-28 mortality 82%). There was no difference in safety outcomes when different rates of intravenous rehydration were compared. Conclusions: The current 'strong recommendations' for conservative rehydration of children with SAM are not based on emerging evidence. We found no clinical trials providing a direct assessment of the current WHO guidelines, and those that were available suggested that these children have a high mortality and remain fluid depleted on current therapy. Recent studies have reported no evidence of fluid overload or heart failure with more liberal rehydration regimens. Clinical trials are urgently required to inform guidelines on routes and rates of intravenous rehydration therapy for dehydration in children with SAM.

Oral rehydration of malnourished children with diarrhoea and dehydration: A systematic review.

Background: Diarrhoea complicates over half of admissions to hospital with severe acute malnutrition (SAM). World Health Organization (WHO) guidelines for the management of dehydration recommend the use of oral rehydration with ReSoMal (an oral rehydration solution (ORS) for SAM), which has lower sodium (45mmols/l) and higher potassium (40mmols/l) content than old WHO ORS. The composition of ReSoMal was designed specifically to address theoretical risks of sodium overload and potential under-treatment of severe hypokalaemia with rehydration using standard ORS. In African children, severe hyponatraemia at admission is a major risk factor for poor outcome in children with SAM complicated by diarrhoea. We therefore reviewed the evidence for oral rehydration therapy in children with SAM. Methods: We conducted a systematic review of randomised controlled trials (RCTs) on 18 th July 2017 comparing different oral rehydration solutions in severely malnourished children with diarrhoea and dehydration, using standard search terms. The author assessed papers for inclusion. The primary endpoint was frequency of hyponatraemia during rehydration. Results: Six RCTs were identified, all published in English and conducted in low resource settings in Asia. A range of ORS were evaluated in these studies, including old WHO ORS, standard hypo-osmolar WHO ORS and ReSoMal. Hyponatraemia was observed in two trials evaluating ReSoMal, three children developed severe hyponatraemia with one experiencing convulsions. Hypo-osmolar ORS was found to have benefits in time to rehydration, reduction of stool output and duration of diarrhoea. No trials reported over-hydration or fatalities. Conclusions: Current WHO guidelines strongly recommend the use of ReSoMal based on low quality of evidence. Studies indicate a significant risk of hyponatraemia on ReSoMal in Asian children, none have been conducted in Africa, where SAM mortality remains high. Further research should be conducted in Africa to evaluate optimal ORS for children with SAM and to generate evidence based, practical guidelines.

Gastroenteritis Aggressive Versus Slow Treatment For Rehydration (GASTRO). A pilot rehydration study for severe dehydration: WHO plan C versus slower rehydration.

BACKGROUND: The World Health Organization (WHO) rehydration management guidelines (Plan C) for children with acute gastroenteritis (AGE) and severe dehydration are widely practiced in resource-poor settings, yet have never been formally evaluated in a clinical trial. A recent audit of outcome of AGE at Kilifi County Hospital, Kenya noted that 10% of children required high dependency care (20% mortality) and a number developed fluid-related complications. The fluid resuscitation trial, FEAST, conducted in African children with severe febrile illness, demonstrated higher mortality with fluid bolus therapy and raised concerns regarding the safety of rapid intravenous rehydration therapy. Those findings warrant a detailed physiological study of children's responses to rehydration therapy incorporating quantification of myocardial performance and haemodynamic changes.  Methods: GASTRO is a multi-centre, unblinded Phase II randomised controlled trial of 120 children aged 2 months to 12 years admitted to hospital with severe dehydration secondary to AGE. Children with severe malnutrition, chronic diarrhoea and congenital/rheumatic heart disease are excluded. Children will be enrolled over 18 months in 3 centres in Kenya and Uganda and followed until 7 days post-discharge. The trial will randomise children 1:1 to standard rapid rehydration using Ringers Lactate  (WHO plan 'C' - 100mls/kg over 3-6 hours according to age, plus additional 0.9% saline boluses for children presenting in shock) or to a slower rehydration regimen (100mls/kg given over 8 hours and without the addition of fluid boluses). Enrolment started in November 2016 and is on-going. Primary outcome is frequency of adverse events, particularly related to cardiovascular compromise and neurological sequelae.  Secondary outcomes focus on clinical, biochemical, and physiological measures related to assessment of severity of dehydration, and response to treatment by intravenous rehydration. DISCUSSION: Results from this pilot will contribute to generating robust definitions of outcomes (in particular for non-mortality endpoints) for a larger Phase III trial.