Current Controversies in the Management of the Anemia of Prematurity
Section snippets
Transfusion Studies
Newer, more restrictive transfusion guidelines have been evaluated in randomized, controlled trials (RCTs) over the past two decades. The ability of critically ill adults and children to adapt to lower hemoglobin levels has recently been evaluated, and studies have sought to determine the safety and efficacy of more restrictive transfusion guidelines.5
Adult and Pediatric Transfusion Studies
Studies evaluating transfusion guidelines in critically ill adults have significantly changed transfusion practices over the last decade.6, 7, 8, 9 The largest of these was the Transfusion Requirements in Critical Care trial, a RCT involving 838 critically ill adults.10 The investigators determined whether a restrictive approach to transfusions was equivalent to a liberal strategy. In patients who were less acutely ill, the mortality rates were lower in the restrictive group (8.7% versus
Neonatal Transfusion Practices
Similar to transfusion practices in adult critically ill patients, neonatal transfusion practices have changed significantly in the last 30 years. In the 1970s and 1980s, a common approach to neonatal transfusion was to maintain the hematocrit at or above 40%. Blood losses due to laboratory draws were carefully monitored, and blood was replaced in the form of packed red cell transfusions when the total volume reached 10 mL/kg.5 Many neonatal intensive care units modified their transfusion
Neonatal Transfusion Studies
Bifano was the first to evaluate neonatal transfusion guidelines in prospective fashion. They randomized 50 infants with birth weights of 650 to 1000 g to two groups, a high hematocrit strategy (>32%) and a low hematocrit strategy (<30%).15 In the high group, the hematocrit was maintained with Epo and transfusions, while in the “low” group the hematocrit was maintained by transfusions only. Statistically significant differences in hematocrit were achieved by the second week of the study and
Phlebotomy Losses
ELBW infants are among the most highly transfused group of patients, in part due to the phlebotomy losses occurring in the first weeks of life. Strategies to decrease phlebotomy losses include microsampling, batching of blood labs, cord blood sampling for immediate postnatal labs such as type and cross-match, removing central lines as soon as possible, ordering labs judiciously, careful monitoring of phlebotomy losses, and the use of blood-testing devices operated at the bedside or point of
Red Cell Growth Factors
Red cell growth factors such as human recombinant Epo have been extensively studied as a treatment for a variety of anemias. In vitro and in vivo studies determined that the anemia of prematurity was primarily a result of low endogenous Epo production. Clinical trials have evaluated the administration of Epo to preterm infants to treat anemia of prematurity. Recent studies have focused on the administration of Epo in the first weeks of life to alleviate the anemia caused by excessive phlebotomy
Randomized Epo Trials
The results of initial studies evaluating Epo administration to preterm infants were highly variable due to numerous methodological problems, including a lack of randomization, small sample size, and use of different Epo protocols regarding dosage, route of administration, onset, and duration of treatment. Despite these limitations, these early studies provided helpful information, demonstrating that the response to Epo was dose related.32 Studies in the 1990s that employed adequate dosing
Darbepoetin
Darbepoetin alfa, a biologically modified, long-acting version of Epo, was approved in 2001 by the US Food and Drug Administration for the treatment of anemia of chronic renal failure. Darbepoetin contains 5 N-linked oligosaccharide chains along the 165 amino acid backbone, which do not alter its biologic activity or tertiary structure, but increase the half-life. Single-dose darbepoetin pharmacokinetics35, 36 showed that neonates had a shorter half-life, a larger volume of distribution, and
Epo and Retinopathy of Prematurity
In addition to its hematopoietic properties, Epo is also a vascular growth factor. Retrospective analyses and meta-analyses have raised concerns about an association between retinopathy of prematurity (ROP) and Epo administration. Epo plays a role in the developing human eye, where Epo concentrations have been measured that exceed serum concentrations.41 However, no RCTs published in peer-reviewed journals have reported an increased incidence of ROP in Epo-treated groups. A Cochrane Review of
Epo and Neuroprotection
The risks versus benefits of Epo administration to preterm infants continue to be evaluated in RCTs. One benefit currently being investigated involves the potential neuroprotective effect of Epo in the developing preterm infant. Numerous animal studies over the past 15 years suggest a neuroprotective effect of Epo43 and pilot studies suggest that high-dose Epo is safe in ELBW infants.44 Our group was the first to publish a relationship between elevated serum Epo concentrations and improved
Summary
It is likely that Epo administration in combination with restrictive transfusion guidelines and a multi-factorial approach to minimize red cell blood loss will have the greatest impact in reducing transfusion requirements in preterm and term neonates, regardless of the etiology of their anemia. Research continues on identifying a clear marker for transfusion need, on refining dosing strategies of red cell growth factors, and on evaluating potential neuroprotective benefits of Epo
References (45)
- et al.
Minimizing donor blood exposure in the neonatal intensive care unitCurrent trends and future prospects
Clin Perinatol
(1995) - et al.
Early treatment with erythropoietin beta ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g
J Pediatr
(2002) Why, when and how should we provide red cell transfusions to neonates?
- et al.
Efficacy of red blood cell transfusion in the critically ill
Crit Care Clin
(2004) - et al.
Changing patterns of red blood cell transfusion in very low birth weight infants
J Pediatr
(1996) - et al.
Changing practices of red blood cell transfusions in infants with birth weights less than 1000 g
J Pediatr
(2000) The physiologic impact of anemia in the neonate
Clin Perinatol
(1995)- et al.
Relationship between determinants of oxygen delivery and respiratory abnormalities in preterm infants with anemia
J Pediatr
(1992) - et al.
Lactic acid as a predictor for erythrocyte transfusion in healthy preterm infants with anemia of prematurity
J Pediatr
(1993) - et al.
Myocardial, erythropoietic, and metabolic adaptations to anemia of prematurity in infants with bronchopulmonary dysplasia
J Pediatr
(1998)