In FEAST stratum A, 3,141 children were randomized between 13 January 2009 and 13January 2011 (1,050 albumin-bolus, 1,047 saline-bolus, 1,044 control) (Figure 1). Baseline characteristics were similar across arms and median agewas 24 months (interquartile range 13 to 38 months). Overall, 2,398 (76%) had impairedconsciousness (including 457 (15%) with unarousable coma), 1,172 (37%) had convulsionsand 2,585 (83%) had respiratory distress. Plasmodium falciparum malariaparasitemia was present in 1,793 out of 3,123 (57%); severe anemia (hemoglobin <5g/dl) in 987 out of 3,054 (32%); 1,070 out of 2,079 (52%) had a base deficit >8mmol/L; 1,159 out of 2,981 (39%) had a lactate level >5mmol/l; 126 out of 1,070(12%) had bacteremia (positive blood culture); and 10 out of 292 (3%) had meningitis(positive cerebrospinal fluid culture).
Of the 3,141 children in stratum A, 2,396 (76%) could be classified into a single PSor a combination; 633 (20%) cases had missing base excess (589) or lactate (32) orblood pressure (12), thus precluding classification to shock or acidosis PS, but halfof these had additional respiratory and/or neurological presentations (Figure 2a,b; Table S1 in Additional file 1). In112 children (4%), information was missing on two or more PS. Of the 2,396 childrenwith full information, 1,647 (69%) had severe metabolic acidosis or severe shock, 625(26%) had respiratory presentations and 976 (41%) had neurological presentations,alone or in combination. The distribution of PS was balanced across randomized arms(Table S1 in Additional file 1).
Mortality by presenting syndrome
Mortality was greatest among children fulfilling criteria for all three PS (28%bolus, 21% control) and combined shock or acidosis and respiratory presentations(19% bolus, 18% control). The greatest differences in mortality between bolus andcontrol groups was among those with all three PS (n = 205) and those with severeshock or acidosis PS alone (n = 698; 10% bolus, 3% control). These two groupsrepresented 37% (898 out of 2,396) of classifiable cases. Mortality was lowest forrespiratory presentation alone (2% bolus, 5% control) or neurological presentationalone (3% bolus, 0% control) (Figure 2a). A small number,363 out of 2,396 (15%), had only FEAST entry criteria; three children died in thisgroup (2% bolus; 0% control).
We found no evidence that the excess 48-hour mortality in bolus arms versus thecontrol arm differed by PS (Figure 3) or by individualclinical components of each PS (Figures 4, 5 and 6) (all P-values for heterogeneity≥0.2). The exception was hypoxia (oxygen saturations <92%), present in856 children (27%) at admission. As expected, hypoxia was a strong predictor ofhigher subsequent mortality, but there was statistically significant evidence thatthe excess mortality with boluses was greater in the subgroup without hypoxia atpresentation (bolus versus control, relative risk (RR) 1.94, 95% confidenceinterval (CI) 1.31 to 2.89) than in the subgroup with hypoxia (RR 1.13, 95%CI 0.79to 1.16; heterogeneity P = 0.04, Figure 4). This isalso demonstrated with oxygen saturation as a continuous variable in Figure S2 inAdditional file 1. Conversely, and as reportedpreviously, the degree of anemia at admission had no significant impact on theeffect of boluses on overall mortality [1, 7], excess harm being evident in the bolus armsversus control across the whole range of baseline hemoglobin values (Figure S3 inAdditional file 1).
Terminal clinical events
In stratum A, 345 out of 3,141 children (11%) died; of these, 297 deaths (86%)occurred within 48 hours. Primary working diagnoses, recorded by clinicians andreported previously , included malaria 142(48%), pneumonia or respiratory etiology 41 (14%); septicemia 27 (9%), anemia 27(9%), meningitis 15 (5%), encephalitis 7 (2%), other diagnosis 12 (4%) andinsufficient information 26 (9%). The ERC adjudicated 265 single and 32 (11%)combined TCEs: 247 (83%) were judged to have a primary cardiogenic, respiratory orneurological TCE .
A cardiovascular or shock TCE was the most frequent overall (n = 123 (41%));neurological and respiratory TCEs occurred in 63 children (21%) and 61 children(20.5%) respectively (Figure 7); in 18 children the TCE wasunknown. As expected, TCE generally aligned with PS (Table S2 in Additional file1).
Terminal clinical event-specific mortality by randomization arm
The major difference between bolus and control arms was the higher proportion ofdeaths adjudicated as having a cardiogenic or shock TCE in bolus arms, 96 (4.6%)compared with 27 (2.6%) in the control arm (sub-hazard ratio 1.79, 95%CI 1.17 to2.74, P = 0.008, Figure 7). This difference waseven greater when 39 modes of death in 39 children who died in the first hour(when bolus administration was incomplete) were excluded (79 (3.8%) compared with19 (1.8%) respectively of modes of death were cardiogenic (sub-hazard ratio 2.09,95%CI 1.27 to 3.45, P = 0.004)). Of note, and as expected, 25 out of 39early deaths (64%) were cardiogenic.
We found no evidence for increased risk of neurological events (putative 'cerebraledema') with boluses: there were 44 neurological TCEs in bolus arms (2.1%) versus19 (1.8%) in the control arm (P = 0.6). Respiratory TCEs (putative'pulmonary edema') were marginally more common in bolus arms: 47 (2.2%) versus 14(1.3%); P = 0.09 (Figure 7). No significantdifferences were found between albumin or saline boluses for any TCE.
The cumulative incidence of death by TCE for all children by bolus versus controlarms is shown in Figure 7, where, for clarity, single andcombined TCEs are redistributed so that cardiogenic and neurological TCEs areincluded with cardiogenic alone, and neurological and respiratory (largelyterminal lung aspiration in a comatose child) are included with neurologicalalone. Cumulative incidence for individual and combined TCE categories is shown inFigure S4a,b in Additional file 1.
Terminal clinical events according to bolus volume, malaria status andhemoglobin
The effect of a bolus had similar patterns on TCEs in children receiving 20 ml/kgand 40 ml/kg (that is, before and after the protocol amendment), among childrenwith and without malaria, and in those with and without severe anemia. In allgroups, cardiogenic TCEs accounted for the greatest excess in mortality in thebolus versus control groups, with no evidence of heterogeneity (allP-values >0.1) (Tables S3a,b,c in Additional file 1).
Changes in hemodynamics, vital status and laboratory parameters over time
Box and whisker plots of individual bedside vital status observations, includingheart rate, respiratory rate oxygen saturation, consciousness level andhypoglycemia (blood glucose <3 mmol/L) showed improvement over time, with fewdifferences between bolus and control arms (Figure S1 in Additional file 1). The exception was the composite measure of impairedperfusion (first box and whiskers plot in panel in Figure S1 in Additional file1), which by one hour had resolved more frequently inthe bolus than control arms; 43% of bolus-recipients had no sign of impairedperfusion compared with only 32% in the control arm (P ≤0.001).
Hemodynamic responses and changes in oxygen status at one hour
The mortality at 48 hours was significantly higher among 1,881 children withpersistent impaired perfusion (see analysis section for definition) at one hour(non-responders) compared with 1,198 responders (shock-resolution) (10% versus 4%,P <0.001, Table S4a in Additional file 1). However, despite greater improvements in perfusion in the bolus armat one hour, excess mortality in bolus versus control arms was evident innon-responders (RR 1.67, 95%CI 1.23 to 2.28, P = 0.001) as well asresponders (RR 1.98, 95%CI 0.94 to 4.17, P = 0.06), with no evidence thatthese were different (heterogeneity P = 0.68, Table S4a in Additionalfile 1).
Children with baseline hypoxia who remained hypoxic at one hour had increased riskof subsequent mortality compared with those whose hypoxia resolved (18% versus 7%,P <0.001, Table S4b in Additional file 1). There was no evidence to indicate that boluses were associated withincreased mortality in the children with persistent hypoxia compared with controlchildren (RR 0.71, 95%CI 0.43 to 1.18). Among children whose hypoxia had resolvedby one hour, the RR of mortality for bolus versus control was 1.45 (95%CI 0.73 to2.85, heterogeneity P = 0.1, Table S4b in Additional file 1).
A total of 175 out of 2144 children without hypoxia at baseline (8%) developedhypoxia by one hour and, as expected, had higher mortality compared with those whodid not develop hypoxia (15% versus 5%, bottom panel of Table S4b in Additionalfile 1). Slightly more children in the bolus arms thanin the control arm (129 (9%) versus 46 (7%)) developed hypoxia by one hour.However, excess risk of death in the bolus versus control arms was observed amongboth children who developed hypoxia (RR 1.96, 95%CI 0.71 to 5.39) and those whoremained non-hypoxic (RR 2.64, 95%CI 1.53 to 4.54). Thus, overall, there was noevidence that development of de novo hypoxia by one hour impacted on theexcess mortality in fluid bolus versus control arms (P-value forheterogeneity = 0.63, Table S4b in Additional file 1).