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

Abstract

BackgroundEarly 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.MethodsPre-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.ResultsOf 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.ConclusionsExcess 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.Trial registrationISRCTN69856593

Unintended Consequences: Fluid Resuscitation Worsens Shock in an Ovine Model of Endotoxemia

“…This was reflected in a statistically significant difference in between the groups in the repeated measures linear regression analysis and differences between groups at both 9 and 12 hours post resuscitation. This result has some parallels to the exploratory analysis of increased mortality seen in the landmark FEAST trial 26 . In the post hoc analysis of the excess mortality the authors noted that the largest contributor to the excess mortality seen with fluid resuscitation was delayed cardiovascular collapse occurring between 2-11 hours.…”

“…In a secondary analysis of the FEAST trial authors demonstrated that the excess mortality in the FR arms was due to delayed cardiovascular collapse, a potentially novel mechanism of harm 12 . Consequently, we aimed to examine the effectiveness of FR in the treatment of septic shock in an animal model of endotoxemia.…”

What is the evidence base for fluid resuscitation in acute medicine?

“…12 A reanalysis of this study suggested that cardiovascular collapse was linked to the increased mortality rather than respiratory failure due to pulmonary oedema. 13 Despite the lack of high-quality IV fluid trials in developed world populations, there is a signal of harm including complications noted in one in five patients in the NHS. 14 Consistent with this, observational studies performed in an intensive care setting have found associations between a positive fluid balance and increased mortality in inflammatory conditions and AKI.…”

Singapore Paediatric Resuscitation Guidelines 2016

“…(2)(3)(4)(51)(52)(53) The Fluid Expansion as Supportive Therapy (FEAST) study indicated that, while fl uid management is important in paediatric life support, it needs to be judiciously administered. (51,52) The recommended initial resuscitation fl uid of choice in infants and children remains as isotonic crystalloids. (54,55) If the patients show signs of inadequate systemic perfusion, they may benefi t from a bolus of 20 mL/kg of an isotonic crystalloid.…”