Early volume expansion for prevention of morbidity and mortality in very preterm infants.

BACKGROUND: Reduced perfusion of organs such as the brain, heart, kidneys and the gastrointestinal tract may lead to acute dysfunction and be associated with permanent injury. Various strategies have been used to provide cardiovascular support to preterm infants including inotropes, corticosteroids and volume expansion.

OBJECTIVES: In very preterm infants, does early volume expansion reduce morbidity and mortality. If volume expansion is effective, what type of volume expansion is most effective.

SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. See Review Group details for more information. This was supplemented by additional searches of the Oxford Database of Perinatal Trials, and updated search performed of the Cochrane Central Register of Controlled Trials (CENTRAL, Cochrane Library Issue 1, 2004), MEDLINE (1996-January 2004), EMBASE (1980-January 2004), previous reviews including cross references (all articles referenced), abstracts and conferences (Perinatal Society of Australia and New Zealand, and Pediatric Academic Societies and American Academy of Pediatrics meetings 1998-2003).

SELECTION CRITERIA: Randomised trials of early volume expansion with normal saline, fresh frozen plasma, albumin, plasma substitutes or blood compared to no treatment or another form of volume expansion in preterm infants < 32 weeks gestation or < 1500g were included. Volume expansion was defined as at least 10 mls/kg given in the first 72 hours of life.

DATA COLLECTION AND ANALYSIS: Standard methods of the Neonatal Review Group with use of relative risk (RR), risk difference (RD) and weighted mean difference (WMD). The fixed effects model using RevMan 4.1 was used for meta-analysis. Data from individual studies were only eligible for inclusion if a least 80% of infants were reported for that outcome.

MAIN RESULTS: Seven studies were included. Five studies, four with data for mortality, compared volume to no treatment. Most studies enrolled very preterm infants on the basis of gestation or birthweight. Two studies comparing different types of volume expansion enrolled very preterm infants with hypotension. No study enrolled infants on the basis of low blood flow. One study examined the effect of volume expansion on blood flow but in normotensive very preterm infants. Comparing volume and no treatment, 4 studies with a total of 940 very preterm infants reported no significant difference in mortality (RR 1.11, 95% CI 0.88, 1.40). The large NNNI 1996 study reported no significant difference in severe disability (RR 0.80, 95% CI 0.52, 1.23), cerebral palsy (RR 0.76, 95% CI 0.48, 1.20) and combined death or severe disability (RR 1.00, 95% CI 0.80, 1.24). Although one small study (Beverley 1985) reported reduced P/IVH with volume expansion, this was not supported by any other study. No significant difference was reported in grade 3-4 P/IVH and combined death or grade 3-4 P/IVH. One study (NNNI 1996) reported no significant difference in the incidence of hypotension. The finding of decreased necrotising enterocolitis and increased sepsis in infants who received fresh frozen plasma compared to a gelatin-based plasma substitute or no treatment in one study should be treated with caution. No significant differences in mortality or disability were found in this study. Comparing albumin and saline in hypotensive infants, one study (Lynch 2002) reported a significant increase in mean BP and reduced incidence of treatment failure (persistent hypotension). The other study (So 1997) and the meta-analysis of the two studies found no significant difference in treatment failure (RR 0.75, 95% CI 0.53, 1.06) or in any other clinical outcome.

REVIEWERS' CONCLUSIONS: There is no evidence from randomised trials to support the routine use of early volume expansion in very preterm infants without cardiovascular compromise. There is insufficient evidence to determine whether infants with cardiovascular compromise benefit from volume expansion. There is insufficient evidence to determine what type of volume expansion should be used in preterm infants (if at all) or for the use of early red cell transfusions. The significance of the finding of a significant increase in blood pressure in hypotensive preterm infants in one trial comparing albumin and saline is unclear, but the overall meta-analyses found no other significant clinical benefit in using albumin compared to saline.