Therapy Mortality after fluid bolus in African children with severe infection.
This review may be edited
Summary
Posted By:	Elizabeth Sweetman
E-Mail:	esweetman@med.usyd.edu.au
Posted Date:	19.03.2013
Title:	Mortality after fluid bolus in African children with severe infection.
Authors:	Maitland K, Kiguli S, Opoka RO, Engoru C, Olupot-Olupot P, Akech SO, Nyeko R, Mtove G, Reyburn H, Lang T, Brent B, Evans JA, Tibenderana JK, Crawley J, Russell EC, Levin M, Babiker AG, Gibb DM; FEAST Trial Group.
Reference:	N Engl J Med. 2011 Jun 30;364(26):2483-95.
Link:	Click here for a direct link to the paper. A password may be required for access to fulltext.
Abstract:	BACKGROUND: The role of fluid resuscitation in the treatment of children with shock and life-threatening infections who live in resource-limited settings is not established. METHODS: We randomly assigned children with severe febrile illness and impaired perfusion to receive boluses of 20 to 40 ml of 5% albumin solution (albumin-bolus group) or 0.9% saline solution (saline-bolus group) per kilogram of body weight or no bolus (control group) at the time of admission to a hospital in Uganda, Kenya, or Tanzania (stratum A); children with severe hypotension were randomly assigned to one of the bolus groups only (stratum B). All children received appropriate antimicrobial treatment, intravenous maintenance fluids, and supportive care, according to guidelines. Children with malnutrition or gastroenteritis were excluded. The primary end point was 48-hour mortality; secondary end points included pulmonary edema, increased intracranial pressure, and mortality or neurologic sequelae at 4 weeks. RESULTS: The data and safety monitoring committee recommended halting recruitment after 3141 of the projected 3600 children in stratum A were enrolled. Malaria status (57% overall) and clinical severity were similar across groups. The 48-hour mortality was 10.6% (111 of 1050 children), 10.5% (110 of 1047 children), and 7.3% (76 of 1044 children) in the albumin-bolus, saline-bolus, and control groups, respectively (relative risk for saline bolus vs. control, 1.44; 95% confidence interval [CI], 1.09 to 1.90; P=0.01; relative risk for albumin bolus vs. saline bolus, 1.01; 95% CI, 0.78 to 1.29; P=0.96; and relative risk for any bolus vs. control, 1.45; 95% CI, 1.13 to 1.86; P=0.003). The 4-week mortality was 12.2%, 12.0%, and 8.7% in the three groups, respectively (P=0.004 for the comparison of bolus with control). Neurologic sequelae occurred in 2.2%, 1.9%, and 2.0% of the children in the respective groups (P=0.92), and pulmonary edema or increased intracranial pressure occurred in 2.6%, 2.2%, and 1.7% (P=0.17), respectively. In stratum B, 69% of the children (9 of 13) in the albumin-bolus group and 56% (9 of 16) in the saline-bolus group died (P=0.45). The results were consistent across centers and across subgroups according to the severity of shock and status with respect to malaria, coma, sepsis, acidosis, and severe anemia. CONCLUSIONS: Fluid boluses significantly increased 48-hour mortality in critically ill children with impaired perfusion in these resource-limited settings in Africa. (Funded by the Medical Research Council, United Kingdom; FEAST Current Controlled Trials number, ISRCTN69856593.).
Are the Results Valid?
1. Was the assignment of patients to treatments randomized? ( Was allocation concealment maintained?)
	Yes. Opaque, sealed and consecutively numbered envelopes were used at each of the six participating clinical centres. Envelopes were opened in numerical order by a study clinician. Children eligible for inclusion without severe hypotension (STRATUM A) were randomised in a 1:1:1 ratio to; Saline-Bolus Group: Rapid volume expansion over 1 hour 20 ml per kg of 0.9% Saline Solution or Human-Albumin Group: Rapid volume expansion over 1 hour 20 ml per kg of 5% human albumin solution or Control Group: No bolus Children eligible for inclusion with severe hypotension (STRATUM B) (systolic BP of <50 mmHg in children younger than 12 months, <60 mmHg in children 1-5 years and <70 mmHg in children older than 5 years and up to 12 years were randomised in a 1:1 ratio to; Saline-Bolus Group: Rapid volume expansion over 1 hour 40 ml per kg of 0.9% Saline Solution or Human-Albumin Group: Rapid volume expansion over 1 hour 40 ml per kg of 5% human albumin solution *In Stratum A & B at 1 hour if impaired perfusion persisted; Saline-bolus and Human-Albumin Groups, not control group, received an additional 20 ml per kg bolus. *Control group children who developed severe hypotension were treated with a 40 mls per kg saline bolus. Please Note: In June 2010 (trial commenced 13th Jan 2009) boluses in STRATUM A were increased to 40 ml per kg in Saline and Human-Albumin Groups AND in STRATUM B boluses were increased to 60 ml per kg in Saline and Human-Albumin Groups.
2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?
2a. Was followup complete?
	Yes all randomised patients were accounted for in Figure 1, page 2486 and in the results section of this paper, pg 2487. There was no loss to follow up in STRATUM A patients, 29 patients in total and; 0.5% loss to follow up in STRATUM B, 17 patients in total (8 from Saline Group, 7 from Human Albumin Group & 2 from Control Group).
2b. Were patients analyzed in the groups to which they were randomized?
	Yes all patients were analysed in the groups to which they were randomised. The Study Protocol specified two primary comparisons for the primary outcome; 1. Saline Bolus vs Control and 2. Albumin Bolus vs Control
3. Were patients, health workers, and study personnel blind to treatment?
	Assessments of neurological function at 4 weeks were reviewed by an independent clinician unaware of treatment assignment.
4. Were the groups similar at the start of the trial?
	Groups appear to be similiar at Baseline (Table 1, page 2488 - 2489), no P values presented.
5. Aside from the experimental intervention, were the groups treated equally?
	Essentially yes. The authors note that in the children that had blood transfusions across the 3 study groups (1408 in total), control group patients received their blood transfusion marginally earlier than the saline-bolus or human-albumin bolus group. The volume of blood received by all 3 groups by 2 hours however, was similar across all groups.
What are the Results?
1. How large was the treatment effect?
	On the 5th Interim Analysis January 12th 2011, the independent DSMC recommended stopping enrolment due to safety concerns in the saline-bolus and albumin-bolus groups and also due to it being unlikely that the bolus strategy over the control strategy would be shown to be beneficial. 3141 patients of the 3600 sample size were enrolled when the trial was stopped. Primary Outcome - Death at 48 hours (from any cause); Saline bolus group 110 patients (10.5%) vs Control group 76 patients (7.3%) died ; RR of death 1.44, P = 0.01. (Table 2, pg. 2490) Albumin bolus group 111 patients (10.6%) vs Control group 76 patients (7.3%) ; RR of death 1.45, P = 0.008. (Table 2, pg. 2490)
2. How precise was the estimate of the treatment effect?
	Primary Outcome - Death at 48 hours (from any cause); Saline bolus vs Control Group (95% CI 1.09 - 1.90) Albumin bolus vs Control Group (95% CI 1.10 - 1.92)
Will the Results Help Me In Caring For My Patients?
1. Can the results be applied to my patient care?
	As children with severe malnutrition, gastroenteritis and non-infectious causes of shock were excluded, this study can likely generalise to children (aged 60 days to 12 years) with severe febrile illness and impaired perfusion without severe hypotension.
2. Were all clinically important outcomes considered?
	Yes, mortality is an important outcome however longer term mortality outcomes, 60 or 90 days, would be more convincing.
3. Are the likely treatment benefits worth the potential harms and costs?
	Saline or Albumin bolus vs Control (no bolus) caused harm in children with severe febrile illness and impaired perfusion but without severe hypotension.
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