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Exploring mechanisms of excess mortality with early fluid resuscitation: insights from the FEAST trial
Kathryn Maitland1, Elizabeth C George, Jennifer A Evans
1Wellcome 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
Insights
Early fluid boluses in African children with severe febrile illnesses increased mortality. Cardiovascular collapse, not fluid overload, was the primary cause of excess deaths, prompting a re-evaluation of resuscitation fluid strategies.
Area of Science:
- Pediatric Critical Care Medicine
- Infectious Diseases
- Emergency Medicine
Background:
- Early rapid fluid resuscitation (boluses) in African children with severe febrile illnesses was associated with increased 48-hour mortality.
- The Fluid Expansion as Supportive Therapy (FEAST) trial investigated the impact of boluses on mortality in severely ill febrile children with shock.
- Hypotheses suggested fluid overload leading to neurological or respiratory events as potential causes for excess mortality.
Purpose of the Study:
- To explore the effect of fluid boluses on 48-hour all-cause mortality in African children with severe febrile illnesses.
- To analyze mortality based on clinical presentation, hemodynamic changes, and terminal clinical events.
- To investigate the specific causes of excess mortality associated with fluid bolus administration.
Main Methods:
- Analysis of 3,141 severely ill febrile children with shock from the FEAST trial, comparing bolus versus control groups.
- Utilized pre-defined presentation syndromes (PS) and predominant terminal clinical events.
- Employed landmark analyses and competing risks methods to assess early mortality and cumulative incidence of terminal events.
Main Results:
- Excess mortality with boluses was observed across all presentation syndromes, including severe acidosis/shock, respiratory, and neurological presentations.
- While shock resolved more frequently in the bolus group, excess mortality persisted in both responders and non-responders.
- Cardiovascular collapse was the predominant terminal clinical event in the bolus arm, rather than respiratory or neurological events, contrary to initial hypotheses.
Conclusions:
- Fluid boluses in this population increased mortality, with cardiovascular collapse being the main driver of excess deaths.
- Findings challenge the assumption that fluid overload is the primary mechanism for excess mortality.
- Re-evaluation of current guidelines for fluid resuscitation in pediatric shock is warranted, considering rate, composition, and volume.
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.
Trial Registration:
ISRCTN69856593.
