In the Fluid Expansion as Supportive Therapy (FEAST) trial, African children with shockrandomized to early rapid fluid resuscitation (20 to 40 ml/kg boluses) with normalsaline or 5% human albumin had a 3.3% increased absolute risk of death by 48 hourscompared with no-bolus controls [1]. Followingpublication, commentary papers, letters and discussion groups have speculated on reasonsfor this surprising result [2–7], given that bolus resuscitation is the gold standard forshock-management in well-resourced countries (albeit based on weak levels of evidence)[8].

FEAST was a pragmatic trial conducted in African hospitals without ventilationfacilities. It included children with shock caused by a heterogeneous group ofconditions including sepsis [9] and malaria[10] but excluded those withgastroenteritis and severe malnutrition [11].Consistency of adverse outcome was shown over all sites and in all possible subgroups,with no benefit of boluses observed for any working diagnosis [1], for any definition of shock [7, 12–14], or presence or absence of anemia or under-nutrition. Asreasons for harm caused by boluses remained unclear, we undertook further analyses toexplore possible mechanisms and modes of death in children randomized to bolusresuscitation versus control. We hypothesized that boluses may cause excess deaths fromneurological or respiratory events, particularly those relating to fluid overload. Weexplored the effect of boluses on 48-hour mortality according to signs and symptoms atenrolment (presentation syndrome, PS); predominant clinical syndrome in each patientprior to death (terminal clinical event, TCE); and changes in vital signs, measuredprospectively at pre-specified times.

In this paper, we have explored possible mechanisms for the excess death rate amongchildren randomized to receive rapid boluses of 20 to 40 ml/kg of 5% albumin or 0.9%saline fluid resuscitation compared with no-bolus controls. We found no evidence thatexcess 48-hour mortality associated with boluses differed by type of PS, by individualconstituent components of each syndrome, or by baseline hemoglobin level. Remarkably, inevery subgroup we examined, there was consistent evidence of harm by boluses.Paradoxically, the syndromes where most concern has been expressed over trial inclusion(respiratory or neurological alone and/or less severe shock criteria) not only had lowermortality overall, but also tended to have smaller differences between bolus andcontrol, although care must be taken with interpretation of smaller subgroups. The onlyexception was hypoxia, present in a quarter of children at admission, which surprisinglyappeared to be associated with significantly less harm from boluses. There appears to beno good rationale for this finding, which could have occurred by chance.

Even though this trial was conducted in settings with limited resources and no access tointensive care, the conduct of the trial complied to the highest standards of goodclinical practice including adherence to intervention strategy and completeness offollow-up, 100% source document monitoring and the robust and blinded methodology fordetermining PS and TCE. An intention-to-treat analysis with no need for imputation formissing data minimized the likelihood of bias and underpinned the magnitude andimportance of the unexpected findings of the trial and further analyses.

Noteworthy is that, consistent with global clinical experience, we observed a superiorresolution of impaired perfusion by one hour in the bolus arms compared with the controlarm. However, importantly, this did not translate into a superior outcome when comparedwith children with continued impaired perfusion: in both cases, boluses resulted inhigher mortality. Mortality excess with boluses among children with and without hypoxiaat baseline occurred to a similar extent irrespective of oxygen saturation status at onehour. Although de novo development of hypoxia at one hour was more common inthe bolus arms, it was not associated with a significant increase in 48-hour mortality -suggesting that, if fluid boluses were causing pulmonary edema (and hypoxia), this wasnot a unifying mechanism for increased mortality from boluses. Moreover, there waslittle evidence that fluid overload was the mechanism for excess deaths with bolusesfrom our analyses of neurological or respiratory TCEs. Overall, cardiovascular collapsewas the main TCE and contributed most substantially to the excess mortality in the bolusarms compared to control, peaking at 2 to 11 hours post-bolus. Whilst it is possiblethat subtle effects of fluid overload on the lungs or brain could have been missed, ourfindings do not lend support to this hypothesis, particularly as the ERC review processwas blind to randomization and used pre-specified TCE definitions.

A limitation of our trial was that we were unable to undertake invasive or point-of-carecontinuous monitoring to provide greater insight into TCEs, as in high-income intensivecare settings. However, the availability of patient-centered variables from our bedsideobservations and laboratory data from most children at baseline has enabled furthercharacterization of the trial participants into clinically relevant presentations (PS)in the context of where the trial was conducted. It has provided a more in-depthunderstanding of the spectrum of clinical groupings of children enrolled in the trialand the degree of adverse outcome fluid boluses had in these groups. Our bedsideobservations at pre-defined times following randomization, as well as adjudication ofcause of death by the ERC, blind to randomized arm and using pre-specified criteria(TCE), provide more speculative data but remain informative because they are largelyoperator-independent. These methodologies are central to the internal validity of ouranalysis, which sought to minimize systematic bias.

Whereas initial improvement in circulatory status following bolus resuscitation isconsistent with global clinical experience [8, 12, 19], the observation of excesssubsequent cardiovascular collapse and excess mortality, even in the early responders,was only made possible because of exemplary adherence to randomized allocation, and in atrial protocol in which further boluses were given to only (very few) childrendeveloping severe hypotension [12]. Thepossibility that fluid resuscitation lead to hemodilution [20, 21] in already anemic children, reducingoxygen delivery to the myocardium [22] andleading to ischemia and cardiac dysfunction, is largely ruled out by the lack ofheterogeneity in the TCEs by hemoglobin level, and by the analysis showing excess harmwith fluids across the whole range of hemoglobin values. These findings challenge thepresumption that early and rapid reversal of shock by fluid resuscitation translatesinto longer-term survival benefits [8, 23, 24] in settings where intensive carefacilities are not available. They do raise a possibility that rapid fluid resuscitationmay cause adverse effects on vascular hemodynamics and myocardial performance, drivingthe requirement for inotropic and pressor support. Rapid restoration of microcirculatoryperfusion may come at the expense of requiring other components of the sepsis bundle,including inotropes and ventilation. This possibility could be explored in futureclinical and preclinical research examining the natural history of shock in patientsmanaged by maintenance only (as in the control arm) and with fluid boluses.

Adverse effects of hyperchloremia, at the doses given in this trial, remaincontroversial [25–29].Intriguingly, the most deleterious effects of boluses were in those patients with severeacidosis at baseline, the group with the least a priori equipoise regarding thepotential benefits of fluid resuscitation - lending support to the notion of adverseeffects of the resuscitation fluids on acid-base equilibrium. Alternatively, this mayindicate lethal reperfusion injury [30] or asurge of cytokines [31] in cases with advancedshock. As previously suggested [1], shock may bean adaptive, time-dependent response sustaining children through a prolonged periodprior to hospital admission - only to die within hours of reperfusion.

Whatever the explanation, these findings raise important questions about thepathophysiological mechanisms of shock and goal-directed management, questioning whetherthe protocol-driven requirement for inotropes and vasoactive drugs has been driven, inpart, by aggressive fluid challenge [12]. The2008 Surviving Sepsis Campaign Guidelines, informed by a modified Delphi process, gradedthe pediatric recommendation (20 ml/kg boluses over 5 to 10 minutes up to 60 ml/kg) as2C, indicating a weak recommendation with low quality of evidence. The pediatric studieson which these recommendations were based included only two retrospective, observationalstudies of initial resuscitation volume on the outcome of children with putative sepsisfrom a single tertiary referral center, involving 34 and 91 children respectively[19, 24]. Theinclusion criteria for both studies were children who survived to intensive care unitadmission, but were inotrope-dependent and had pulmonary arterial catheters insitu. Higher initial fluid boluses and early shock reversal in 9 and 24 childrenin the two respective studies were associated with improved global outcome. However, thestudy design and the patient population had major limitations in terms of survivorshipbias and external validity to other settings. Other sources of evidence that werereferenced to inform fluid resuscitation guidelines include dengue shock. We suggestthese are largely irrelevant to the management of sepsis, because shock as acomplication of dengue occurs 7 to 10 days after fever defervescence, secondary to grossintravascular leakage leading to vomiting, abdominal pain, increasingly tenderhepatomegaly, narrow pulse pressure and hemoconcentration [32]. The American College of Critical Care Medicine guideline,and similar guidelines, nevertheless have been adopted by many countries worldwide wherepoint-of-care testing and intensive care facilities are available and are considered tobe best practice. These are now being recommended as standards of care for resource-poorsettings [33, 34];indicating that the FEAST trial had limited generalizability because the adverse effectsof fluid boluses were largely confined to children with malaria and/or anemia[33]. The data presented in the originalmanuscript [1], subsequence correspondence[7] and this detailed sub-analysisdefinitely counter this interpretation. A recent systematic review assessing theevidence base for fluid resuscitation in the treatment of children with shock due tosepsis or severe infection found only 13 pediatric trials. Whilst the majority of allrandomized evidence to date comes from the FEAST trial, they recommended thatimplementation of simple algorithms for children managed at hospitals with limitedresources to ensure identification of children who maybe potentially be harmed by fluidboluses [35]. The findings we report here raisequestions over the rates, volumes and types of solutions recommended in pediatricresuscitation protocols, most of which remain untested in clinical trials.

The results of the FEAST trial together with findings from these additional analysessuggest that rapid administration of fluid boluses increase the risk of subsequentcardiovascular collapse in children with shock, rather than increasing the risk of fatalfluid overload. The results suggest the need for further research to better understandthe pathophysiology of shock and its treatment, and the mechanisms whereby rapid fluidresuscitation increased mortality in African children.