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Effect of blood transfusions on cognitive development in very low birth weight infants
Shah P, Cannon DC, Lowe JR, Phillips J, Christensen RD, Kamath-Rayne B, Rosenberg A, Wiedmeier S, Patel S, Winter S, et al
Journal of perinatology : official journal of the California Perinatal Association. 2021
Abstract
OBJECTIVE Preterm infants frequently receive red cell transfusions; however, the effect of transfusions on cognition is unclear. We evaluated the relationship between transfusions and cognitive outcomes in preterm infants enrolled in a randomized trial of erythropoiesis stimulating agents (ESAs). STUDY DESIGN Preterm infants were randomized to ESAs or placebo during initial hospitalization, and transfusions recorded. Children were evaluated using standard developmental tests of cognition at 18-22 months (56 ESA, 24 placebo) and 3.5-4 years (39 ESA, 14 placebo). RESULTS Cognitive scores at 18-22 months were inversely correlated with transfusion volume (p = 0.02). Among those receiving ≥1 transfusion, cognitive scores were significantly higher in the ESA-treated group (p = 0.003). At 3.5-4 years, transfusions were not correlated with cognitive scores. CONCLUSIONS In the placebo group, transfused children had lower cognitive scores than did non-transfused children at 18-22 months. In the ESA group, cognitive scores did not differ by transfusion status, suggesting ESAs might provide neuroprotection.
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2.
A randomized, masked, placebo-controlled study of darbepoetin alfa in preterm infants
Ohls RK, Christensen RD, Kamath-Rayne BD, Rosenberg A, Wiedmeier SE, Roohi M, Lacy CB, Lambert DK, Burnett JJ, Pruckler B, et al
Pediatrics. 2013;132((1):):e119-27.
Abstract
BACKGROUND A novel erythropoiesis stimulating agent (ESA), darbepoetin alfa (Darbe), increases hematocrit in anemic adults when administered every 1 to 3 weeks. Weekly Darbe dosing has not been evaluated in preterm infants. We hypothesized that infants would respond to Darbe by decreasing transfusion needs compared with placebo, with less-frequent dosing than erythropoietin (Epo). METHODS Preterm infants 500 to 1250 g birth weight and <=48 hours of age were randomized to Darbe (10 ug/kg, 1 time per week subcutaneously), Epo (400 U/kg, 3 times per week subcutaneously) or placebo (sham dosing) through 35 weeks' gestation. All received supplemental iron, folate, and vitamin E, and were transfused according to protocol. Transfusions (primary outcome), complete blood counts, absolute reticulocyte counts (ARCs), phlebotomy losses, and adverse events were recorded. RESULTS A total of 102 infants (946 +/- 196 g, 27.7 +/- 1.8 weeks' gestation, 51 +/- 25 hours of age at first dose) were enrolled. Infants in the Darbe and Epo groups received significantly fewer transfusions (P = .015) and were exposed to fewer donors (P = .044) than the placebo group (Darbe: 1.2 +/- 2.4 transfusions and 0.7 +/- 1.2 donors per infant; Epo: 1.2 +/- 1.6 transfusions and 0.8 +/- 1.0 donors per infant; placebo: 2.4 +/- 2.9 transfusions and 1.2 +/- 1.3 donors per infant). Hematocrit and ARC were higher in the Darbe and Epo groups compared with placebo (P = .001, Darbe and Epo versus placebo for both hematocrit and ARCs). Morbidities were similar among groups, including the incidence of retinopathy of prematurity. CONCLUSIONS Infants receiving Darbe or Epo received fewer transfusions and fewer donor exposures, and fewer injections were given to Darbe recipients. Darbepoetin and Epo successfully serve as adjuncts to transfusions in maintaining red cell mass in preterm infants.
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3.
Very low birth weight infants qualifying for a 'late' erythrocyte transfusion: does giving darbepoetin along with the transfusion counteract the transfusion's erythropoietic suppression?
Warwood TL, Lambert DK, Henry E, Christensen RD
Journal of Perinatology. 2011;31((Suppl 1):):S17-21.
Abstract
OBJECTIVE Red blood cell (RBC) transfusions can suppress erythropoiesis. On this basis, RBC transfusions administered to very low birth weight (VLBW) neonates potentially render them more likely to qualify for a subsequent transfusion.STUDY DESIGN We hypothesized that 'late' (>14 days after birth) RBC transfusions given to VLBW neonates result in a decrease in reticulocyte count persisting for at least 7 to 10 days. We also hypothesized that a single dose of darbepoetin given along with the transfusion would have the opposite effect, increasing the reticulocyte count for at least 7 to 10 days. To test this, we conducted a single-centered randomized trial with 20 VLBW neonates who, according to our transfusion guidelines, qualified for a late transfusion.RESULT VLBW infants about to receive a late RBC transfusion were randomized (1:1) to also receive vs not receive (controls) a single subcutaneous dose of darbepoetin (10 µgkg(-1)). Reticulocyte counts diminished significantly in the controls (a drop of 85±62 x 10(3) µl(-1) (mean±s.d.) at 7 to 10 days), but increased significantly in the darbepoetin recipients (an increase of 177±120 x 10(3) µl(-1) at 7 to 10 days, P<0.0001). At 7 to 10 days after the transfusion, hematocrits of the controls were 8.1±4.9 points above their pre-transfusion values and of the darbepoetin group were 12.4±2.7 points above their pre-transfusion values (P=0.033).CONCLUSION This was a limited-scope, single-centered, randomized trial intended to pilot-test a new concept in neonatal transfusion practice. Namely, we tested whether a late RBC transfusion suppressed reticulocytosis and whether a concomitant single dose of darbepoetin counteracted that suppression. Using the pilot data presented in this study, larger trials can now be designed to address meaningful clinical outcomes such as transfusion avoidance using this approach.
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4.
Single-dose darbepoetin administration to anemic preterm neonates
Warwood TL, Ohls RK, Wiedmeier SE, Lambert DK, Jones C, Scoffield SH, Neeraj G, Veng-Pedersen P, Christensen RD
Journal of Perinatology. 2005;25((11):):725-30.
Abstract
Objective: Darbepoetin is longer acting and more potent than recombinant erythropoietin (rEpo). In certain situations, preterm neonates might benefit from rEpo, and for such patients darbepoetin would require fewer doses at a lower cost. However, the proper dose and dosing interval have not been established. Study design: We performed a prospective trial in two level III Neonatal Intensive Care Units. Patients <32 weeks gestation at birth, with a birth weight (BW) <1500g, were eligible for participation if they were >21-days-old and had a hemoglobin (Hgb) concentration <=10. 5g/dl. In all, 12 were to receive a single subcutaneous (s. c. ) dose at either 1 or 4 mug/kg. Once before the dose was given, and at two preset intervals after, blood was obtained for immature reticulocyte fraction (IRF) and absolute reticulocyte count (ARC). Once before and at four preset intervals after, blood was obtained for pharmacokinetic studies. Results: The 12 subjects had BWs of 1129+/-245g (mean+/-SD), were 29. 2+/-1. 2 weeks gestation at delivery, and were 43+/-12 days old with an Hgb concentration of 9. 6+/-1. 0g/dl when the darbepoetin was given. Six received 1 mu;g/kg and six 4 mug/kg. The IRF increased (p<0. 05) as did the ARC (p<0. 05). The increases in IRF were somewhat greater among the 4 mug/kg recipients (P =0. 06). The highest recorded concentrations of drug occurred 6 to 12 hours after administration. The combined 6 and 12 hours values were 185+/-106mU/ ml in the 1 mug/kg group vs 597+/-238 in the 4 mug/kg group (p<0. 002). The t 1/2 was 26 hours (range 10 to 50). The biovailability-normalized clearance was 19ml/hour/kg (range 5 to 54). Conclusions: A single s. c. dose of darbepoetin given to preterm neonates accelerated effective erythropoiesis. The pharmacodynamic and pharmacokinetic findings suggest that darbepoetin dosing in neonates would require a higher unit dose/kg and a shorter dosing interval than are generally used for anemic adults. Copyright © 2011 Elsevier B. V. , Amsterdam. All Rights Reserved.
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5.
A randomized, double-blind, placebo-controlled trial of recombinant erythropoietin in treatment of the anemia of bronchopulmonary dysplasia
Ohls RK, Hunter DD, Christensen RD
Journal of Pediatrics. 1993;123((6):):996-1000.
Abstract
Because anemia in patients with bronchopulmonary dysplasia is characterized by inappropriately low serum concentrations of erythropoietin but increased in vitro sensitivity of erythroid progenitors to erythropoietin, we speculated that administration of human recombinant erythropoietin would correct this anemia. Fifteen infants with the anemia of bronchopulmonary dysplasia were randomly assigned to receive erythropoietin or placebo subcutaneously for 10 days. Changes in reticulocyte count, hematocrit, blood lactate concentration, neutrophil count, platelet count, heart rate, oxygen requirement, weight gain, and number of transfusions were assessed. In the 10 erythropoietin recipients (99 +/- 12 days of age), hematocrit values increased from 0.325 +/- 0.006 to 0.381 +/- 0.013 (mean +/- SEM; p < 0.005) and reticulocyte counts from 122 +/- 20 to 446 +/- 48 x 10(3)/microliters (p < 0.005); lactate values remained unchanged. In the five placebo recipients (91 +/- 12 days of age), hematocrits and reticulocyte counts remained unchanged, and lactate values increased from 0.73 +/- 0.14 to 1.34 +/- 0.25 mumol/gm (p < 0.05). During the 30 days after the treatment period, one erythropoietin recipient and four placebo recipients were given transfusions. Other measured variables remained unchanged in both groups. We conclude that erythropoietin is effective in treatment of the anemia of bronchopulmonary dysplasia.
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6.
Recombinant erythropoietin compared with erythrocyte transfusion in the treatment of anemia of prematurity
Ohls RK, Christensen RD
Journal of Pediatrics. 1991;119((5):):781-8.
Abstract
To assess the risks and benefits of erythropoietin versus erythrocyte transfusion in the treatment of the anemia of prematurity, we randomly assigned 19 anemic preterm infants (birth weight 988 +/- 227 gm; gestational age 27.6 +/- 1.2 weeks; age 41 +/- 15 days; all values mean +/- SD) to receive either transfusion or subcutaneously administered erythropoietin (200 units/kg every other day for 10 doses). In the 10 erythropoietin recipients, corrected reticulocyte counts increased from 2% +/- 1% to 7% +/- 2% (p less than 0.001) and hematocrits increased from 27% +/- 2% to 30% +/- 4% (p less than 0.05). In the nine infants who underwent transfusion, reticulocyte counts did not increase, but hematocrits increased from 28% +/- 4% to 41% +/- 2% after initial transfusion (p less than 0.001) and had decreased to 34% +/- 5% by day 20. Signs attributed to anemia (tachycardia, apnea with bradycardia, and poor weight gain) declined in both the erythropoietin recipients and those who underwent transfusion. However, five of nine infants who underwent transfusion had symptoms within 10 to 14 days and were given further transfusions. Marrow aspiration performed after 7 to 10 days of treatment showed that infants receiving erythropoietin had greater percentages of erythropoietic precursors (p less than 0.01), greater concentrations of mature erythroid progenitors (p less than 0.001), and higher cycling rates of erythroid progenitors (p less than 0.001). The percentage of mature stored neutrophils in marrow was lower in the erythropoietin group than in the transfusion group, resulting in an inverse myeloid/erythroid ratio (0.5:1 vs 6.2:1; p less than 0.001). After 20 days, absolute blood neutrophil counts were lower in the erythropoietin recipients (1.8 +/- 0.9 x 10(3) cells/microliters) than in the infants who underwent transfusion (3.9 +/- 1.9 x 10(3) cells/microliters; p less than 0.05). Administration of erythropoietin thus stimulated erythropoiesis and relieved signs attributed to anemia; the significance of the relative neutropenia remains to be determined. We conclude that erythropoietin administration offers promise as an alternative to erythrocyte transfusion in neonates with symptomatic anemia of prematurity.
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7.
A randomized, double-blind, placebo-controlled investigation of the safety of intravenous immune globulin administration to preterm neonates
Christensen RD, Hardman T, Thornton J, Hill HR
Journal of Perinatology. 1989;9((2):):126-30.
Abstract
Intravenous immune globulin (750 mg/kg), or an equivalent volume of a placebo, was administered during the first week of life, in a randomized trial, to 20 preterm neonates weighing 710 to 1800 g. A variety of laboratory and clinical values were measured serially and analyzed for possible untoward effects. Serum IgG levels were also determined serially. No differences in heart rate, respiratory rate, urine output, blood glucose, serum osmolality, BUN, SGPT, pH, blood gasses, serum electrolytes, total or direct bilirubin, blood leukocyte concentration, absolute neutrophil count, or blood platelet concentration were observed between the intravenous immune globulin (IVIG) and placebo recipients before or following IVIG administration. The red blood cell concentration of IVIG recipients diminished transiently and only slightly (P less than .05). Serum IgG levels increased from 503 +/- 162 mg/dL (X +/- SD) to 1492 +/- 201 mg/dL 15 minutes after the IVIG administration (P less than .001). After 8 days, serum IgG levels were still elevated, at 675 +/- 297 mg/dL. All patients randomized to receive the placebo experienced a diminution in serum IgG over this 8-day period (P less than .01). All 20 patients survived and none in either group had a documented nosocomial infection. This study suggests that IVIG can safely be administered to preterm neonates, resulting in serum IgG levels comparable to those of term infants.