Mortality risk over time after early fluid resuscitation in African children
Elizabeth C George1, Sarah Kiguli2, Peter Olupot Olupot3
1Medical Research Council Clinical Trials Unit (MRC CTU) at UCL, Institute of Clinical Trials and Methodology, UCL, London, UK. elizabeth.george@ucl.ac.uk.
Insights
Fluid boluses in African children with severe febrile illness did not immediately increase mortality risk. However, the risk reduction was slower in children receiving fluid boluses compared to those who did not.
Area of Science:
- Pediatric critical care medicine
- Infectious diseases
- Clinical trials
Background:
- African children hospitalized with severe febrile illness face high mortality rates.
- The Fluid Expansion As Supportive Therapy (FEAST) trial indicated increased mortality with fluid boluses, but the timing and mechanism were unclear.
Purpose of the Study:
- To analyze the temporal relationship between fluid bolus administration and mortality risk in African children with severe febrile illness.
- To investigate the underlying mechanisms of increased mortality associated with fluid boluses in this population.
Main Methods:
- A post hoc retrospective analysis of the FEAST trial data was conducted.
- Flexible parametric models were used to compare mortality risk changes after randomization in children receiving fluid boluses (albumin or saline) versus no bolus.
- Analysis considered overall mortality and specific terminal clinical events (cardiogenic, neurological, respiratory, other).
Main Results:
- Mortality risk peaked early post-randomization in both bolus and no-bolus groups.
- While peak risk was similar, the decline in mortality risk was significantly slower in the bolus group for up to 4 days post-randomization.
- This delayed risk reduction was most evident in deaths attributed to cardiogenic causes.
Conclusions:
- The increased mortality risk associated with fluid boluses was not immediate but resulted from a slower decline in risk over several days.
- Modest fluid bolus administration appeared to impede the natural rate of mortality risk reduction rather than causing acute harm.
- Findings suggest a need to re-evaluate fluid resuscitation strategies in febrile illnesses in African children.
Background:
African children hospitalised with severe febrile illness have a high risk of mortality. The Fluid Expansion As Supportive Therapy (FEAST) trial (ISCRTN 69856593) demonstrated increased mortality risk associated with fluid boluses, but the temporal relationship to bolus therapy and underlying mechanism remains unclear.
Methods:
In a post hoc retrospective analysis, flexible parametric models were used to compare change in mortality risk post-randomisation in children allocated to bolus therapy with 20-40 ml/kg 5% albumin or 0.9% saline over 1-2 h or no bolus (control, 4 ml/kg/hour maintenance), overall and for different terminal clinical events (cardiogenic, neurological, respiratory, or unknown/other).
Results:
Two thousand ninety-seven and 1041 children were randomised to bolus vs no bolus, of whom 254 (12%) and 91 (9%) respectively died within 28 days. Median (IQR) bolus fluid in the bolus groups received by 4 h was 20 (20, 40) ml/kg and was the same at 8 h; total fluids received in bolus groups at 4 h and 8 h were 38 (28, 43) ml/kg and 40 (30, 50) ml/kg, respectively. Total fluid volumes received in the control group by 4 h and 8 h were median (IQR) 10 (6, 15) ml/kg and 10 (10, 26) ml/kg, respectively. Mortality risk was greatest 30 min post-randomisation in both groups, declining sharply to 4 h and then more slowly to 28 days. Maximum mortality risk was similar in bolus and no bolus groups; however, the risk declined more slowly in the bolus group, with significantly higher mortality risk compared to the no bolus group from 1.6 to 101 h (4 days) post-randomisation. The delay in decline in mortality risk in the bolus groups was most pronounced for cardiogenic modes of death.
Conclusions:
The increased risk from bolus therapy was not due to a mechanism occurring immediately after bolus administration. Excess mortality risk in the bolus group resulted from slower decrease in mortality risk over the ensuing 4 days. Thus, administration of modest bolus volumes appeared to prevent mortality risk declining at the same rate that it would have done without a bolus, rather than harm associated with bolus resulting from a concurrent increased risk of death peri-bolus administration.
Trial Registration:
ISRCTN69856593. Date of registration 15 December 2008.
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