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

Worldwide, an estimated 2.5 billion cases of acute gastroenteritis occur annually in children under 5 years. In this age group, gastroenteritis is the second biggest cause of mortality (after acute respiratory illnesses) [1, 2]. The vast majority of deaths occur in low resource settings in South Asia and sub-Saharan Africa. A large case-control study, Global Enteric Multicentre study of gastroenteritis (GEMS), conducted in Africa and Asia showed that children with moderate/severe gastroenteritis seeking care at health centres are 8.5 times more likely to die than non-gastroenteritis controls [3, 4]. A third of the fatalities occurred < 7 days following enrolment—indicating that current treatment strategies may not be working in practice and/or are poorly implemented [5].

The World Health Organization (WHO) has produced guidance on the management of dehydration in children with diarrhoea, largely based on expert opinion [6, 5]. In children (without severe malnutrition), oral rehydration solution (ORS) is recommended for children with diarrhoea with some dehydration, defined as two or more of the following: restlessness/irritability, sunken eyes, drinks eagerly/thirsty and/ or skin pinch goes back slowly (plan B). Intravenous fluids are recommended for resuscitation of children with severe dehydration, defined as the presence of two or more of the following clinical features: sunken eyes, skin pinch goes back very slowly ≥ 2 seconds (s), lethargy and/or inability to drink (under the protocol called ‘plan C’), using 100 ml/kg of Ringer’s lactate or 0.9% saline [6]. This is the approximate volume estimated to have been lost in children with 10% dehydration and is recommended to be given over 3 h (or 6 h in children < 1 year). Plan C consists of two steps in which the volume and rate of infusion are different and also differ by age group (< 1 year and ≥ 1 year). In Step 1 30 ml/kg over 30 min (or 1 h if < 1 year) and then in Step 2 70 ml/kg over 2.5 h (or 5 h if < 1 year). For children presenting with shock (defined as the presence of all three of weak and fast pulse, temperature gradient and capillary refilling time > 3 s), WHO also recommends initial fluid boluses given for shock (i.e. up to 3 boluses of 20 ml/kg of normal (0.9%) saline given as rapidly as possible) followed directly by Step 2, i.e. 90–130 ml/kg. These management guidelines are recommended in resource-poor settings, despite no formal testing in a clinical trial [7]. A review of the evidence underpinning WHO management guidelines in 2012, with regard to shock and rehydration management, focused principally on the type of fluid for resuscitation but did not consider the rate or volume [5].

In this clinical trial involving 122 children with severe dehydration due to gastroenteritis, we have shown that a simpler protocol involving slower rehydration with 100 ml/kg over 8-h irrespective of age was as safe as the 2-stage age-specific WHO plan C protocol. Correction of dehydration and time to tolerate oral fluids and time to discharge was similar in both arms. Overall, mortality in this phase II trial was substantially lower (3.3%) than previous reports [4, 11] and few other adverse events were recorded.

One of the additional objectives of the trial was to assess adherence to the rehydration protocol and other challenges for implementation rehydration. Whilst current management guidelines (WHO plan C) are thought to be widely practiced in African hospitals, it became apparent when conducting the training for the clinical trial that clinicians prior to the trial were not routinely able to adhere to plan C for a number of reasons. First, the administration of accurate volume and rates of infusion were found to be challenging to hospitals where gauged burettes or infusion sets are routinely unavailable. Second, the two-step plan C involving a fast infusion followed by slower intravenous replacement at two different rates and volumes for two age groups were confusing and thus difficult to recall and implement accurately in practice [18]. Finally, the WHO treatment guideline for the child with severe dehydration presenting with shock [6] is rather opaque on whether fluid boluses (20 ml/kg of normal saline given as fast as possible and repeated up to two times if shock persists) are given in addition to rehydration (thus, the maximum volume a child could receive would be 160 ml/kg) in 4–6 h. We found initially navigating and executing the plan C guideline a challenge to teach and implement, yet the trial teams, as a result of recurrent training throughout the trial, were able to demonstrate adherence to the guideline in the study arm.

In the design of the trial, when considering secondary outcomes, we aimed to use guideline recommendations for assessing the reversal of dehydration. First, we aimed to check on whether the clinical signs for severe dehydration accurately predict the degree of dehydration. We based this on the gold standard looking at the percentage change in weight from admission to day 7, rather than weight at discharge since this time point has not been reliable previously [19, 20]. We found that although the trial was targeting children that were assumed to have 10% or more dehydration, our data suggests this was present in only 33 (29%), with 30 (26%) having a deficit of > 5- < 10% and nearly half with only modest deficit (1–5%). There have been several systematic reviews covering the issue of the specificity of all the available dehydration scores; nearly all perform poorly in practice [21] including the WHO scoring. Of note during initial rehydration, at 8-h most children remained clinically dehydrated, based on the same signs, but were not re-prescribed intravenous rehydration (even though it is recommended to start plan C again). In order to address the lack of specificity of these signs we added two additional parameters that are also considered as rehydration goals and/or adverse consequences. We selected time to pass urine as a more reliable marker of perfusion (as it is specified or required as an endpoint for management of shock or hydration status). We also included dysnatraemia, as this has been used in a number of other clinical trials as a safety endpoint (defined as a sodium level outside the normal range (135-145 mmol/L) [7]. However, we found, on stored samples, batch-analysed at the end of the trial, that quite a number had haemolysis (noted at the time of storage in – 80 °C freezers) and many had extreme sodium and chloride values at admission and 8 h which could not be rechecked for verification. We thus excluded samples with visual evidence of haemolysis (that also had extreme potassium values) and those with extreme values (sodium > 240 mmol/L and creatinine (< 20 mmol/L). However, we do note that severe hypernatraemia can also cause rhabdomyolysis, which would also result in similar findings as haemolysis (as well as dark urine) [22]. Discussions with local trial teams indicated that intravenous access for cannulation and blood draws were exceptionally difficult owing to the extreme volume depletion in many children. Moreover, our finding of exceptionally high sodium level (and chlorides) in some children is consistent with hypernatraemic dehydration, and with a history of parents rehydrating children with high-sugar energy fizzy drinks (containing 54–62 g glucose/500 ml). This practice has been reported on by previously as being a major risk factor for hypernatraemic dehydration, as well as young infants receiving only breast milk [5]. Hypertonic or hypernatraemic dehydration (defined as a sodium level > 150 mmol/L) occurs when water loss is much greater than sodium loss and usually often presents with different clinical signs (‘doughy’ skin in an irritable child and full fontanelle in an infant) [23] and is generally recommended to be managed using a separate slow rehydration protocol [24]. The current WHO rehydration Plan C protocol recommends that children with severe isotonic or hypotonic dehydration receive fast rehydration to restore intracellular sodium and water losses but makes no recommendations for rehydration of children with hypernatraemic dehydation. The most conservative estimate, when most haemolysed and extreme values were excluded, suggests that 26% of children with gastroenteritis in Eastern Uganda present with hypernatraemic dehydration (sodium > 150 mmol/L). Nevertheless, outcomes for both arms were similar with few children developing neurological complications (one of the risks of hypertonic dehydration) [23, 25] and mortality was much lower that pre-trial estimates [11]. On the whole sodium levels tended to normalise by 8- and 24-h in those presenting with hyponatraemia, normonatraemia and hypernatraemia, with little difference between the study arms (Fig. 5).

One other challenge we met was incomplete data on time to pass urine. During the consent process, we asked parents whether we were able to catheterize children; however, by 24 h, we only had data on 54/122 patients (44%) that had passed urine despite most having resolved features of dehydration and tolerating oral fluids and feeds (Fig. 3). We suggest that this was due to the fact that parents did not accept urinary catheterization (not specifically recorded in the case report form) but consented to enrolment into the trial. Alternative approaches to an 8-hourly assessment of urine output included estimating urine output from weighing nappies (diapers) or the use of urine collections bags (specifically in females) were not viable options in children with on-going diarrhoeal losses.

One hypothesis, to explain the excess mortality and mode of death observed in the FEAST trial is that cardiovascular collapse may occur as a result of right atrial stretch following aggressive fluid loading, and could be predicted by myocardial performance indices, raised ANP (atrial natriuretic peptide) [26] and subsequent urinary sodium excretion. ANP is a cardiac hormone that is released in response to atrial stretch [27]. In an ovine model of sepsis, a 14-fold rise in ANP levels was seen in experimental endotoxaemia and further rise with fluid resuscitation [28] but not in the control (no bolus arm). However, in that study, the rise was transient and peaked just after volume loading with a fluid bolus before declining. In contrast, the ANP profile in this cohort of dehydrated children rose from admission to 8 h and remained persistently high at day 7.

BNP is released in response to ventricular stretch and has been shown to have diuretic, natriuretic and vasodilator properties in published literature [16] . A study by Westerlind et al. (2008), reported the highest ANP and BNP values in children with systolic dysfunction and volume overload [29]. It has also been reported to be high in conditions such as sepsis [30, 31]. Price et al. (2006) reported a higher risk of hospitalisation and mortality in children with systolic dysfunction and elevated BNP levels [32]. In this cohort, BNP levels were highest at admission in both groups with severe dehydration, which was not accounted for by high creatinine level in this with high BNP, then decreased over the first 8-h despite fluid administration, but later increased at 24 h. Troponin I is a marker of cardiac muscle injury independent of volume status. Soldin et al. (1999) reported higher levels of troponin in children under-1 year [33]. The levels of troponin were normal and comparable in both groups. Whilst there was a rise in troponin following fluid administration at 8 h, 24 h and day 7, values were still within normal ranges and did not indicate cardiac injury.

The strength of our trial is that it includes an unselected population (except the exclusion of children with severe malnutrition, who are managed under a separate guideline [6, 34]), good adherence to protocol, and completeness of follow up. These factors plus the close clinical monitoring of children may have resulted in the low overall mortality in contrast to previous reports [11]. The low mortality (3.3%) together with the lack of other volume-specific complications indicates that slower rehydration is at least as safe as current Plan C.

The limitations include our inability to show surrogates of rehydration (time to pass urine in many of the children as routine catheterization was impractical and not acceptable to parents) and sodium endpoint (dysnatraemia at 8 h) was compromised by the high number of children with high sodium levels on admission, which we were not able to repeat as these were not done real-time but on batch processing of stored plasma at the end of the trial. Further observational studies, in Uganda in particular, are required to verify, using fresh sample analysis, whether children admitted with severe gastroenteritis frequently have hypernatraemic dehydration and whether these children had a history of taking sugary drinks. If true, then there would be a public health imperative to ensure populations are aware of and understand the risks of such practices.

In this phase II trial, we have shown that slow rehydration over 8 h is as safe as WHO Plan C resulting in similar surrogate markers of patient outcome (resolution of dehydration signs, time to tolerate oral fluids and time to discharge) and no evidence of increase of adverse events (including mortality and fluid-volume related event). Training throughout the trial was required to reinforce adherence to the more complicated 2-step WHO plan C protocol. We suggest further large multicentre trials should test slow rehydration, as per GASTRO protocol, against Plan C with mortality as an endpoint.