• Newton Opiyo, Elizabeth Molyneux, David Sinclair, Paul Garner, and Mike English.
• Health Services Unit, KEMRI-Wellcome Trust Research Programme, Nairobi, Kenya.
• BMJ Open. 2014 Apr 30; 4 (4): e004934.

ObjectiveTo evaluate the effects of intravenous fluid bolus compared to maintenance intravenous fluids alone as part of immediate emergency care in children with severe febrile illness and signs of impaired circulation in low-income settings.DesignSystematic review of randomised controlled trials (RCTs), and observational studies, including retrospective analyses, that compare fluid bolus regimens with maintenance fluids alone. The primary outcome measure was predischarge mortality.Data Sources And SynthesisWe searched PubMed, The Cochrane Library (to January 2014), with complementary earlier searches on, Google Scholar and Clinical Trial Registries (to March 2013). As studies used different clinical signs to define impaired circulation we classified patients into those with signs of severely impaired circulation, or those with any signs of impaired circulation. The quality of evidence for each outcome was appraised using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Findings are presented as risk ratios (RRs) with 95% CIs.ResultsSix studies were included. Two were RCTs, one large trial (n=3141 children) from a low-income country and a smaller trial from a middle-income country. The remaining studies were from middle-income or high-income settings, observational, and with few participants (34-187 children).Severely Impaired CirculationThe large RCT included a small subgroup with severely impaired circulation. There were more deaths in those receiving bolus fluids (20-40 mL/kg/h, saline or albumin) compared to maintenance fluids (2.5-4 mL/kg/h; RR 2.40, 95% CI 0.84 to 6.88, p=0.054, 65 participants, low quality evidence). Three additional observational studies, all at high risk of confounding, found mixed effects on mortality (very low quality evidence).Any Signs Of Impaired CirculationThe large RCT included children with signs of both severely and non-severely impaired circulation. Overall, bolus fluids increased 48 h mortality compared to maintenance fluids with an additional 3 deaths per 100 children treated (RR 1.45, 95% CI 1.13 to 1.86, 3141 participants, high quality evidence). In a second small RCT from India, no difference in 72 h mortality was detected between children who received 20-40 mL/kg Ringers lactate over 15 min and those who received 20 mL over 20 min up to a maximum of 60 mL/kg over 1 h (147 participants, low quality evidence). In one additional observational study, resuscitation consistent with Advanced Paediatric Life Support (APLS) guidelines, including fluids, was not associated with reduced mortality in the small subgroup with septic shock (very low quality evidence).Signs Of Impaired Circulation, But Not Severely ImpairedOnly the large RCT allowed an analysis for children with some signs of impaired circulation who would not meet the criteria for severe impairment. Bolus fluids increased 48 h mortality compared to maintenance alone (RR 1.36, 95% CI 1.05 to 1.76, high quality evidence).ConclusionsPrior to the publication of the large RCT, the global evidence base for bolus fluid therapy in children with severe febrile illness and signs of impaired circulation was of very low quality. This large study provides robust evidence that in low-income settings fluid boluses increase mortality in children with severe febrile illness and impaired circulation, and this increased risk is consistent across children with severe and less severe circulatory impairment.

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