title: Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial.
abstract: BACKGROUND
  Early rapid fluid resuscitation (boluses) in African children with severe febrile illnesses increases the 48-hour mortality by 3.3% compared with controls (no bolus). We explored the effect of boluses on 48-hour all-cause mortality by clinical presentation at enrolment, hemodynamic changes over the first hour, and on different modes of death, according to terminal clinical events. We hypothesize that boluses may cause excess deaths from neurological or respiratory events relating 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 randomized arm (bolus versus control) in 3,141 severely ill febrile children with shock enrolled in the Fluid Expansion as Supportive Therapy (FEAST) trial. Landmark analyses were used to compare early mortality in treatment groups, conditional on changes in shock and hypoxia parameters. Competing risks methods were used to estimate cumulative incidence curves and sub-hazard ratios to compare treatment groups in terms of terminal clinical events.
  
  
  RESULTS
  Of 2,396 out of 3,141 (76%) classifiable participants, 1,647 (69%) had a severe metabolic acidosis or severe shock PS, 625 (26%) had a respiratory PS and 976 (41%) had a neurological PS, either alone or in combination. Mortality was greatest 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 versus control was apparent for all three PS, including all their component features. By one hour, shock had resolved (responders) more frequently in bolus versus control groups (43% versus 32%, P <0.001), but excess mortality with boluses was evident in responders (relative risk 1.98, 95% confidence interval 0.94 to 4.17, P = 0.06) and 'non-responders' (relative risk 1.67, 95% confidence interval 1.23 to 2.28, P = 0.001), with no evidence of heterogeneity (P = 0.68). The major difference between bolus and control arms was the higher proportion of cardiogenic or shock terminal clinical events in bolus arms (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% versus 1.8%, P = 0.6) terminal clinical events.
  
  
  CONCLUSIONS
  Excess mortality from boluses occurred in all subgroups of children. Contrary to expectation, cardiovascular collapse rather than fluid overload appeared to contribute most to excess deaths with rapid fluid resuscitation. These results should prompt a re-evaluation of evidence on fluid resuscitation for shock and a re-appraisal of the rate, composition and volume of resuscitation fluids.
  
  
  BACKGROUND
  ISRCTN69856593.
authors.affiliation: Wellcome Trust Centre for Clinical Tropical Medicine, Department of Paediatrics, Faculty of Medicine, St Marys Campus, Norfolk Place, Imperial College, London W2 1PG, UK. Kathryn.maitland@gmail.com
authors.forename: Kathryn
authors.initials: K
authors.lastname: Maitland
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: George
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Evans
authors.forename: Sarah
authors.initials: S
authors.lastname: Kiguli
authors.forename: Peter
authors.initials: P
authors.lastname: Olupot-Olupot
authors.forename: Samuel O
authors.initials: SO
authors.lastname: Akech
authors.forename: Robert O
authors.initials: RO
authors.lastname: Opoka
authors.forename: Charles
authors.initials: C
authors.lastname: Engoru
authors.forename: Richard
authors.initials: R
authors.lastname: Nyeko
authors.forename: George
authors.initials: G
authors.lastname: Mtove
authors.forename: Hugh
authors.initials: H
authors.lastname: Reyburn
authors.forename: Bernadette
authors.initials: B
authors.lastname: Brent
authors.forename: Julius
authors.initials: J
authors.lastname: Nteziyaremye
authors.forename: Ayub
authors.initials: A
authors.lastname: Mpoya
authors.forename: Natalie
authors.initials: N
authors.lastname: Prevatt
authors.forename: Cornelius M
authors.initials: CM
authors.lastname: Dambisya
authors.forename: Daniel
authors.initials: D
authors.lastname: Semakula
authors.forename: Ahmed
authors.initials: A
authors.lastname: Ddungu
authors.forename: Vicent
authors.initials: V
authors.lastname: Okuuny
authors.forename: Ronald
authors.initials: R
authors.lastname: Wokulira
authors.forename: Molline
authors.initials: M
authors.lastname: Timbwa
authors.forename: Benedict
authors.initials: B
authors.lastname: Otii
authors.forename: Michael
authors.initials: M
authors.lastname: Levin
authors.forename: Jane
authors.initials: J
authors.lastname: Crawley
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Babiker
authors.forename: Diana M
authors.initials: DM
authors.lastname: Gibb
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D005334:Fever / Q000401:mortality* / Q000628:therapy*; D005440:Fluid Therapy / Q000009:adverse effects* / Q000379:methods*; D006801:Humans; D007223:Infant; D008297:Male; D009026:Mortality; D012151:Resuscitation