Erythropoietin and darbepoetin use in the NICU

Introduction

Premature infants receive a greater number of transfusions and are exposed to a greater number of donors compared to any other hospitalized population. Transfusion guidelines are now used in many neonatal units; however, the search for the most appropriate transfusion guidelines continues. Recently, two of the largest randomized controlled trials (RCTs) to date enrolled over 2800 extremely low birth weight (ELBW) infants and showed similar 2-year outcomes between those infants transfused using liberal (higher) hematocrit strategies compared to restrictive (lower) hematocrit strategies ^, (see Chapter 10 ). Despite these efforts, the fact remains that in the smallest preterm infants there is a positive correlation between the amount of blood removed for laboratory evaluation and the volume of blood replaced via red cell transfusion ( Fig. 9.1 ). When restrictive transfusion guidelines are applied, greater phlebotomy losses (and lower hematocrits) are tolerated before transfusions are ordered. The use of red cell growth factors provides increased red cell mass, thereby delaying the need for transfusions even further, resulting in lower total transfusion volumes.

Erythropoiesis stimulating agents

Erythropoiesis stimulating agents (ESAs) to improve red cell mass have been studied for over 40 years. ESAs such as erythropoietin (Epo) and darbepoetin (Darbe) have proven successful in decreasing transfusion number, transfusion volume, and donor exposures in adults, children, and the smallest, most critically ill infants. Epo, a 34-kD glycoprotein whose gene is located on the long arm of chromosome 7, was first purified in the 1970s by Goldwasser and Miyake, who isolated 8 mg of Epo from 2500 L of urine from patients with aplastic anemia. Epo is made up of a 165–amino acid backbone chain with four carbohydrate groups attached (three N-linked carbohydrates and one O-linked carbohydrate). The Epo gene was cloned in 1985 and soon thereafter approved by the US Food and Drug Administration in 1989 for adults with anemia due to end stage renal disease (ESRD). Studies performed in the pediatric population expanded the use of Epo to stimulate red cell production and decrease transfusions in children with ESRD.

Amgen, the company that originally marketed and produced Epo, recognized a direct relationship between Epo’s sialic acid–containing carbohydrate content and the serum half-life. They altered 5 of the 165 amino acids to produce two additional N-linked carbohydrate sites, resulting in a 37-kD biologically modified ESA, darbepoetin alfa (Darbe), trade named Aranesp. Studies confirmed the longer serum half-life and greater biologic activity of Darbe. Clinical trials in adults with ESRD reported adequate hematopoietic responses when Darbe was administered every 1 to 4 weeks.

Preterm ESA studies

Interest in administering Epo to preterm infants began in the late 1980s. Initial studies in the early 1990s evaluated Epo doses that were effective in adults, but were lower than doses required for preterm infants, given the differences in clearance and volume of distribution that were not identified until later in the 1990s (see Pharmacokinetics).

Maier et al. were one of the first European neonatal investigative groups to publish a large multicenter RCT on Epo in very low birth weight (VLBW) infants. Investigators reported improved hematocrits and decreased transfusions in infants weighing less than 1500 g who received subcutaneous (SC) Epo, 250 units/kg three times weekly, starting by day 3 of life. Numerous randomized trials (reviewed previously) in Europe, Australia, New Zealand, the United States, and South America followed, evaluating different dosing regimens and lengths of treatment. To varying degrees, depending on dosing and the population studied, Epo administration stimulated erythropoiesis and decreased transfusion number and volume.

By the mid-1990s researchers identified nonhematopoietic effects of ESAs. Over the next 10 years they determined that ESAs in animal models were protective in the developing brain, suggesting the possibility that they might be of benefit to very premature infants at risk for intraventricular hemorrhage (IVH), hypoxic-ischemic injury, and developmental delay. Neuroprotective mechanisms of ESAs included decreased neuronal apoptosis, decreased inflammation, promotion of oligodendrocyte differentiation and maturation, and improved white matter survival. Based on preliminary in vitro evaluations of Darbe dose effects on marrow progenitors and our previous work comparing Epo concentrations to cognitive outcome, we designed a multicenter, randomized, placebo-controlled study of Darbe and Epo administration to preterm infants to evaluate both hematopoietic and neuroprotective effects of ESAs. Infants with birth weights 500 to 1250 g and 48 hours or less of age were randomized to Darbe (10 μg/kg, 1x/week SC), Epo (400 units/kg, 3x/week SC), or placebo (sham dosing) through 35 weeks corrected gestation. All infants were transfused according to a restrictive protocol and received supplemental iron, folate, and vitamin E. Transfusions, complete blood counts, absolute reticulocyte counts (ARC), phlebotomy losses, common neonatal morbidities, and adverse effects were recorded. We powered the study for two primary outcomes. The primary outcome for the hospital phase of the study was number of transfusions, while the primary outcome for the follow-up phase of the study was cognitive composite score on the Bayley Scales of Infant Development, Third Edition (Bayley III). We hypothesized that infants receiving Epo or Darbe would have decreased transfusions during hospitalization and improved cognitive outcomes at 18 to 22 months corrected age compared to the placebo group.

Hospital outcomes

Infants in the Epo and Darbe groups received significantly fewer transfusions (p=0.015) and were exposed to fewer donors (p=0.044) than the placebo group (Darbe: 1.2±2.4 transfusions and 0.7±1.2 donors/infant; Epo: 1.2±1.6 transfusions and 0.8±1.0 donors/infant; placebo: 2.4±2.9 transfusions and 1.2±1.3 donors/infant). Transfusions and donor exposures were reduced by 50% in ESA-treated infants compared to placebo-treated infants. Hematocrit and ARC were higher in the Darbe and Epo groups compared to placebo (p=0.001, Darbe and Epo vs. placebo for both hematocrit and ARC). Morbidities were similar among groups, including the incidence of retinopathy of prematurity (ROP). We concluded that infants receiving ESAs received fewer transfusions and fewer donor exposures, with fewer injections given to Darbe recipients. Importantly, 56% of VLBW infants in the ESA group remained transfusion free during their neonatal intensive care unit (NICU) stay.