Exploring mechanisms of excess mortality with early fluid resuscitation: insightsfrom the FEAST trial

Background Early rapid fluid resuscitation (boluses) in African children with severe febrileillnesses increases the 48-hour mortality by 3.3% compared with controls (nobolus). We explored the effect of boluses on 48-hour all-cause mortality byclinical presentation at enrolment, hemodynamic changes over the first hour, andon different modes of death, according to terminal clinical events. We hypothesizethat boluses may cause excess deaths from neurological or respiratory eventsrelating to fluid overload. Methods Pre-defined presentation syndromes (PS; severe acidosis or severe shock,respiratory, neurological) and predominant terminal clinical events(cardiovascular collapse, respiratory, neurological) were described by randomizedarm (bolus versus control) in 3,141 severely ill febrile children with shockenrolled in the Fluid Expansion as Supportive Therapy (FEAST) trial. Landmarkanalyses were used to compare early mortality in treatment groups, conditional onchanges in shock and hypoxia parameters. Competing risks methods were used toestimate cumulative incidence curves and sub-hazard ratios to compare treatmentgroups in terms of terminal clinical events. Results Of 2,396 out of 3,141 (76%) classifiable participants, 1,647 (69%) had a severemetabolic acidosis or severe shock PS, 625 (26%) had a respiratory PS and 976(41%) had a neurological PS, either alone or in combination. Mortality wasgreatest among children fulfilling criteria for all three PS (28% bolus, 21%control) and lowest for lone respiratory (2% bolus, 5% control) or neurological(3% bolus, 0% control) presentations. Excess mortality in bolus arms versuscontrol was apparent for all three PS, including all their component features. Byone hour, shock had resolved (responders) more frequently in bolus versus controlgroups (43% versus 32%, P <0.001), but excess mortality with boluseswas evident in responders (relative risk 1.98, 95% confidence interval 0.94 to4.17, P = 0.06) and 'non-responders' (relative risk 1.67, 95% confidenceinterval 1.23 to 2.28, P = 0.001), with no evidence of heterogeneity( P = 0.68). The major difference between bolus and control arms wasthe higher proportion of cardiogenic or shock terminal clinical events in bolusarms (n = 123; 4.6% versus 2.6%, P = 0.008) rather than respiratory (n =61; 2.2% versus 1.3%, P = 0.09) or neurological (n = 63, 2.1% versus1.8%, P = 0.6) terminal clinical events. Conclusions Excess mortality from boluses occurred in all subgroups of children. Contrary toexpectation, cardiovascular collapse rather than fluid overload appeared tocontribute most to excess deaths with rapid fluid resuscitation. These resultsshould prompt a re-evaluation of evidence on fluid resuscitation for shock and are-appraisal of the rate, composition and volume of resuscitation fluids. Trial registration ISRCTN69856593