FULL TITLE: A randomised trial of fluid resuscitation strategies in African children with severe febrile illness and clinical evidence of impaired perfusion
Short Title: Fluid Expansion As Supportive Therapy in critically ill African children
International Trial registration number: ISRCTN 69856593
A 3-arm randomised open comparative trial of fluid resuscitation strategies:
(1) Immediate volume resuscitation with normal (0.9%) saline;
(2) Immediate volume expansion with 5% human albumin solution (HAS);
(3) Control: no immediate volume expansion.
In hospitals throughout sub-Saharan Africa, mortality from malaria and other severe infections in childhood remains at 15-30%, with over 50% of deaths occurring within 24 hours of admission. Currently, antimalarial and antimicrobial drugs are the mainstay of treatment, with little consideration being given to the use of adjunctive supportive therapies. There is considerable debate about the degree to which intravascular volume depletion (hypovolaemia) contributes to the pathophysiology of malaria and other severe infections, and clinical practice varies widely across the continent. To resolve the continuing uncertainty, this multi-centre randomised clinical trial will evaluate different fluid resuscitation strategies in children presenting to hospital with severe febrile illness and clinical evidence of impaired perfusion, with the intention of generating data of practical value to clinicians working in resource-poor settings in Africa.
Primary Endpoint: In-hospital mortality at 48 hours after randomisation.
Secondary Endpoints: Mortality at 4 weeks, neurological sequelae at 4 weeks and 24 weeks, episodes of hypotensive shock within 48 hours of randomisation, adverse events related to fluid resuscitation (pulmonary oedema, intracranial hypertension or severe allergic reaction to those receiving albumin).
The total sample size is 3,600 children.
Children aged >60 days and <12 years with severe febrile illness (impaired consciousness or respiratory distress) plus clinical evidence of impaired perfusion.
Children with the following conditions will be excluded: severe acute malnutrition; gastroenteritis; chronic renal failure, pulmonary oedema and other conditions in which volume expansion is contraindicated; non-infectious causes of severe illness; children who have already received an isotonic volume expander during the current illness.
3,600 eligible children will be randomly assigned in a ratio of 1:1:1 to one of three fluid management arms:
(1) Rapid volume expansion with 40mls/kg intravenous 0.9% saline;
(2) Rapid volume expansion with 40mls/kg 5% human albumin solution (HAS);
(3) Maintenance fluids with no volume expansion (control arm).
Children will be reassessed at 1, 4, 8, 24 and 48 hours, and further fluid boluses will be given in strict accordance with the protocol. Children will receive a maximum of 100mls/kg in 24 hours of fluid boluses. The small number of eligible children that are anticipated to have hypotensive shock (severe hypotension plus impaired perfusion) at the time of admission (n=144) will be randomly allocated in a ratio of 1:1 to rapid volume expansion with either saline or HAS.
Children will be clinically assessed at 1, 4, 8, 24 and 48 hours. Neurological assessments will be carried out at 4 weeks and, for those with sequelae at 4 weeks, at 24 weeks from the time of randomisation. Follow-up neurological assessments will be carried out by a clinician or nurse who is blind to treatment allocation.
The trial will enrol over 24 months and started in January 2009.