FEAST: Fluid Boluses in Critically Ill African Children (2011)

“In critically ill children with impaired perfusion in a resource-limited setting in Africa, fluid boluses significantly increased 48-hour mortality.”

  • The FEAST Trial Investigators

1. Publication Details

  • Trial Title: Mortality after Fluid Bolus in African Children with Severe Infection
  • Citation: Maitland K, Kiguli S, Opoka RO, et al. Mortality after fluid bolus in African children with severe infection. N Engl J Med. 2011;364(26):2483-2495. DOI: 10.1056/NEJMoa1101549
  • Published: June 30, 2011, in The New England Journal of Medicine
  • Author: Kathryn Maitland, F.R.C.P.C.H., Ph.D.
  • Funding: The UK Medical Research Council.

2. Keywords

  • Sepsis, Shock, Fluid Resuscitation, Pediatrics, Resource-Limited Setting, Randomized Controlled Trial

3. The Clinical Question

  • In critically ill children in Africa with severe febrile illness and impaired perfusion (Population), does rapid fluid resuscitation with an albumin or saline bolus (Intervention) compared to no bolus (maintenance fluids only) (Comparison) reduce 48-hour mortality (Outcome)?

4. Background and Rationale

  • Existing Knowledge: At the time, international guidelines for the management of pediatric shock, largely developed in high-income countries, strongly recommended rapid and aggressive fluid resuscitation with large-volume boluses as a life-saving intervention.
  • Knowledge Gap: These guidelines had never been tested in a rigorous randomized controlled trial in the resource-limited settings of Africa, where the causes of shock (e.g., malaria, severe anemia) and the available supportive care (e.g., lack of mechanical ventilation) were very different.
  • Proposed Hypothesis: The authors hypothesized that a strategy of early fluid bolus administration would be superior to a strategy of no bolus in reducing short-term mortality in this patient population.

5. Study Design and Methods

  • Design: A multicenter, prospective, open-label, randomized, controlled trial with a factorial design (used to test the effectiveness of interventions).
  • Setting: 6 hospitals in 3 African countries (Kenya, Tanzania, and Uganda).
  • Trial Period: Enrollment ran from June 2009 to January 2011.
  • Population:
    • Inclusion Criteria: Children aged 60 days to 12 years with a severe febrile illness and clinical evidence of impaired perfusion (e.g., prolonged capillary refill time, tachycardia, altered consciousness).
    • Exclusion Criteria: Included severe malnutrition, gastroenteritis, or conditions requiring immediate surgery.
  • Intervention: Patients were randomized to one of three groups:
  • Albumin Bolus: A rapid bolus of 5% albumin (20-40 ml/kg).
  • Saline Bolus: A rapid bolus of 0.9% saline (20-40 ml/kg).
  • Control (No Bolus): No fluid bolus was given; patients received maintenance intravenous fluids only.
  • Control: The no-bolus group served as the control.
  • Management Common to Both Groups: All patients received standard care for their underlying illness, including antibiotics and antimalarials as appropriate.
  • Power and Sample Size: The authors calculated that a sample size of 3600 patients would be required to have 90% power to detect a 4% absolute risk reduction in mortality. (Power is a study’s ability to find a real difference between treatments if one truly exists; 90% power means the study had a 90% chance of detecting the specified effect, which is considered very high).
  • Outcomes:
    • Primary Outcome: All-cause mortality at 48 hours.
    • Secondary Outcomes: Included mortality at 4 weeks and the incidence of neurologic sequelae.

6. Key Results

  • Enrollment and Baseline: 3141 children were randomized. The groups were well-matched at baseline.
  • Trial Status: The trial was stopped early by the data and safety monitoring board after an interim analysis showed a significant increase in mortality in the fluid-bolus groups.
  • Primary Outcome: 48-hour mortality was significantly higher in both fluid-bolus groups compared to the control group. 10.6% of children in the albumin-bolus group and 10.5% in the saline-bolus group died, compared with only 7.3% in the control (no-bolus) group (p=0.01).
  • Secondary Outcomes: The increased mortality in the bolus groups was sustained at 4 weeks. There was no significant difference in neurologic outcomes among survivors.
  • Adverse Events: The primary adverse event was death, which was significantly more common in the fluid-bolus groups.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a chi-square test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the proportions of death between the three groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death at 48 hours for bolus vs. no bolus: 1.45 (95% CI, 1.13 to 1.86; P-value: 0.003).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the combined result as 1.45.
      • Clinical Meaning: The RR of 1.45 means that children who received a fluid bolus (either albumin or saline) had a 45% higher relative risk of dying at 48 hours compared to the no-bolus group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 1.13 to 1.86.
      • Clinical Meaning: Since this entire range is above the line of no effect (1.0), it confirms that the result is highly statistically significant and demonstrates a clear signal of harm.
    • P-value: The p-value of 0.003 is well below the 0.05 threshold, indicating the result is highly statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Increase (ARI):
      • Formula: ARI = (Risk in Intervention Group) – (Risk in Control Group)
      • Calculation: ARI = 10.5% (average of bolus groups) – 7.3% = 3.2%.
      • Clinical Meaning: For every 100 children treated with a fluid bolus, about 3 additional deaths occurred.
    • Number Needed to Harm (NNH):
      • Formula: NNH = 1 / ARI
      • Calculation: NNH = 1 / 0.032 = 31.
      • Clinical Meaning: You would only need to treat 31 children with a fluid bolus to cause one additional death.
  • Subgroup Analyses: The harm was consistent across all pre-specified subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized controlled design provided high-quality evidence on a critical public health question.
  • Generalizability: The pragmatic design across six diverse hospitals in three African countries makes the findings highly generalizable to similar resource-limited settings.
  • Statistical Power: The enormous sample size provided definitive power to detect a difference, ultimately revealing a clear signal of harm.
  • Patient-Centered Outcomes: The primary outcome of 48-hour mortality is a robust, objective, and highly relevant endpoint.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was open-label, which introduces a risk of performance bias.
  • External Validity (Generalizability): The findings are specific to the resource-limited settings of sub-Saharan Africa, where the causes of shock and the availability of advanced supportive care (like mechanical ventilation) are very different from high-income countries. The results should not be directly extrapolated to pediatric ICUs in high-resource settings.
  • Other: The trial was stopped early for harm, which was ethically necessary.

10. Conclusion of the Authors

  • The authors concluded that in critically ill children with severe infection in a resource-limited setting, fluid boluses significantly increased 48-hour mortality.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial that completely overturned the existing international guidelines for pediatric fluid resuscitation. It provided definitive evidence that a practice considered standard of care in high-income countries was actively harmful in a different patient population and clinical context.
  • Specific Recommendations:
    • Patient Selection: For critically ill children with severe febrile illness and impaired perfusion in resource-limited settings.
    • Actionable Intervention: Do not administer rapid, large-volume fluid boluses.
    • Expected Benefit: Avoiding this therapy prevents one additional death for every 31 children treated.
  • What This Trial Does NOT Mean: This trial does NOT mean that all fluid administration is harmful. It specifically tested rapid bolus therapy. It also does NOT mean that the findings are directly applicable to children in high-resource settings with access to full intensive care support.
  • Implementation Caveats: The key takeaway is the critical importance of context in evidence-based medicine. A “one-size-fits-all” global guideline for fluid resuscitation is not appropriate.

12. Context and Related Studies

  • Building on Previous Evidence: The FEAST trial (2011) was designed to test a fundamental tenet of modern resuscitation that had been extrapolated from high-resource settings but never proven in a resource-limited context.
  • Influence on Subsequent Research: The shocking and definitive results of this trial led to an immediate change in WHO and other international guidelines for the management of pediatric shock in resource-limited settings. It has spurred a great deal of research into the pathophysiology of shock in these populations and the potential harms of fluid overload.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: The precise mechanism by which fluid boluses caused harm in this population is still not fully understood, though theories include rapid fluid shifts causing pulmonary edema and cardiac dysfunction in the context of severe anemia and malaria.
  • Future Directions: Future research is focused on developing and testing more appropriate, context-specific resuscitation strategies for children in resource-limited settings.

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was of the highest relevance, testing a universally recommended intervention in a vulnerable population where it had never been properly studied.
  • Methods: The large, multicenter, pragmatic RCT design was of high quality and appropriate for the question. The main methodological weakness is the open-label design, but the primary outcome of mortality is objective and unlikely to be biased.
  • Results: The study reported a statistically significant and clinically profound increase in harm (NNH of 31) for its primary outcome. The finding was so clear and robust that the trial was stopped early.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in global health and evidence-based medicine, serving as a powerful example of the dangers of extrapolating evidence from one clinical context to another without rigorous local validation. Its findings are highly applicable to similar resource-limited settings.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
Scroll to Top