BACKGROUND—Bronchopulmonary dysplasia and emphysema are life-threatening diseases resulting from impaired alveolar development or alveolar destruction. Both conditions lack effective therapies. ...Angiogenic growth factors promote alveolar growth and contribute to alveolar maintenance. Endothelial colony-forming cells (ECFCs) represent a subset of circulating and resident endothelial cells capable of self-renewal and de novo vessel formation. We hypothesized that resident ECFCs exist in the developing lung, that they are impaired during arrested alveolar growth in experimental bronchopulmonary dysplasia, and that exogenous ECFCs restore disrupted alveolar growth.
METHODS AND RESULTS—Human fetal and neonatal rat lungs contain ECFCs with robust proliferative potential, secondary colony formation on replating, and de novo blood vessel formation in vivo when transplanted into immunodeficient mice. In contrast, human fetal lung ECFCs exposed to hyperoxia in vitro and neonatal rat ECFCs isolated from hyperoxic alveolar growth–arrested rat lungs mimicking bronchopulmonary dysplasia proliferated less, showed decreased clonogenic capacity, and formed fewer capillary-like networks. Intrajugular administration of human cord blood–derived ECFCs after established arrested alveolar growth restored lung function, alveolar and lung vascular growth, and attenuated pulmonary hypertension. Lung ECFC colony- and capillary-like network-forming capabilities were also restored. Low ECFC engraftment and the protective effect of cell-free ECFC-derived conditioned media suggest a paracrine effect. Long-term (10 months) assessment of ECFC therapy showed no adverse effects with persistent improvement in lung structure, exercise capacity, and pulmonary hypertension.
CONCLUSIONS—Impaired ECFC function may contribute to arrested alveolar growth. Cord blood–derived ECFC therapy may offer new therapeutic options for lung diseases characterized by alveolar damage.
We previously reported decreased transfusions and donor exposures in preterm infants randomized to Darbepoetin (Darbe) or erythropoietin (Epo) compared with placebo. As these ...erythropoiesis-stimulating agents (ESAs) have shown promise as neuroprotective agents, we hypothesized improved neurodevelopmental outcomes at 18 to 22 months among infants randomized to receive ESAs.
We performed a randomized, masked, multicenter study comparing Darbe (10 μg/kg, 1×/week subcutaneously), Epo (400 U/kg, 3×/week subcutaneously), and placebo (sham dosing 3×/week) given through 35 weeks' postconceptual age, with transfusions administered according to a standardized protocol. Surviving infants were evaluated at 18 to 22 months' corrected age using the Bayley Scales of Infant Development III. The primary outcome was composite cognitive score. Assessments of object permanence, anthropometrics, cerebral palsy, vision, and hearing were performed.
Of the original 102 infants (946 ± 196 g, 27.7 ± 1.8 weeks' gestation), 80 (29 Epo, 27 Darbe, 24 placebo) returned for follow-up. The 3 groups were comparable for age at testing, birth weight, and gestational age. After adjustment for gender, analysis of covariance revealed significantly higher cognitive scores among Darbe (96.2 ± 7.3; mean ± SD) and Epo recipients (97.9 ± 14.3) compared with placebo recipients (88.7 ± 13.5; P = .01 vs ESA recipients) as was object permanence (P = .05). No ESA recipients had cerebral palsy, compared with 5 in the placebo group (P < .001). No differences among groups were found in visual or hearing impairment.
Infants randomized to receive ESAs had better cognitive outcomes, compared with placebo recipients, at 18 to 22 months. Darbe and Epo may prove beneficial in improving long-term cognitive outcomes of preterm infants.
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).
Preterm infants 500 to 1250 g birth weight and ≤48 hours of age were randomized to Darbe (10 μg/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.
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.
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.
To identify neonates with “severe anemia at birth”, defined by a hemoglobin/hematocrit within the first six hours after birth that plotted below the 1st percentile according to gestational age. For ...each patient, we retrospectively determined whether caregivers recognized the anemia within the first 24 hours after birth, and the probable cause and outcome.
A retrospective cohort analysis of Intermountain Healthcare population-based data from neonates born between January 2011 and December 2020 who had a hemoglobin or hematocrit, measured within the first six hours after birth, below the 1st percentile lower reference interval (hematocrit ∼35% in near-term/term neonates).
From 299,927 live births, we identified 344 with severe anemia at birth. In 191 (55.5%) the anemia was recognized by caregivers during the first 24 hoursAnemia was more likely to be recorded as a problem (85%) if the hemoglobin was 2 g/dL or more below the 1st percentile (P<0.001). The lowest hemoglobin values occurred among those where hemorrhage was the probable cause (P<0.013 vs. hemolysis and P<0.001 vs. hypoproduction, mixed cause, or indeterminant.) Treatment was given to 39.5%. Retrospective review suggested that mixed mechanisms, particularly hemorrhagic plus hemolytic, occurred more commonly than was recognized at the time of occurrence.
Severe anemia at birth often went unrecognized on the first day of life. Algorithm-directed retrospective reviews commonly identified causes that were not listed in the medical record. We postulate that earlier recognition and more accurate diagnoses would be facilitated by an electronic medical record-associated hemoglobin/hematocrit gestational age nomogram.
We previously reported improved neurodevelopmental outcomes at 2 years among infants treated with the erythropoiesis-stimulating agents (ESAs) darbepoetin alfa (darbepoetin) or erythropoietin. Here ...we characterize 4-year outcomes.
Former preterm infants randomly assigned to receive darbepoetin (10 μg/kg, once per week), erythropoietin (400 U/kg, 3 times/week), or placebo through 35 weeks' postconceptual age were evaluated at 3.5 to 4 years of age. For comparison, healthy children formerly delivered full term (term controls TCs) were also recruited. All participants were assessed by using measures of full-scale IQ (FSIQ) and general language from the Wechsler Preschool and Primary Scale of Intelligence, Third Edition, and an overall measure of executive function, on the basis of tests evaluating inhibitory control and spatial working memory. Rates of neurodevelopmental impairment were compared across groups.
Multivariate analysis of variance compared children randomly assigned to ESAs (n = 39), placebo (n =14), and TCs (n = 24). FSIQ and performance IQ were significantly higher in the ESA group than in the placebo group (FSIQ: 91.1 ± 17.5 vs 79.2 ± 18.5, P = .036; performance IQ: 93.0 ± 17.0 vs 79.5 ± 19.5, P = .018). Follow-up analyses revealed that the children receiving ESAs performed better than those who received placebo on executive function tasks. The ESA group's performance was below that of TCs, but the results did not reach significance on executive function. The incidence of neurodevelopmental impairment was greater in the placebo group than in the ESA group.
ESA-treated infants had better cognitive outcomes and less developmental impairment at 3.5 to 4 years of age compared with placebo-treated infants. ESAs show promise in improving long-term cognitive outcomes of infants born prematurely.
To evaluate whether implementing more restrictive neonatal intensive care unit (NICU) platelet transfusion guidelines following the Platelets for Neonatal Transfusion - Study 2 randomized controlled ...trial (transfusion threshold changed from 50 000/μL to 25 000/μL for most neonates) was associated with fewer NICU patients receiving a platelet transfusion, without adversely affecting outcomes.
Multi-NICU retrospective analysis of platelet transfusions, patient characteristics, and outcomes during 3 years before vs 3 years after revising system-wide guidelines.
During the first period, 130 neonates received 1 or more platelet transfusions; this fell to 106 during the second. The transfusion rate was 15.9/1000 NICU admissions in the first period vs 12.9 in the second (P = .106). During the second period, a smaller proportion of transfusions was administered when the platelet count was in the 50 000–100 000/μL range (P = .017), and a larger proportion when it was <25 000/μL (P = .083). We also saw a fall in the platelet counts that preceded the order for transfusion from 43 100/μL to 38 000/μL (P = .044). The incidence of adverse outcomes did not change.
Changing platelet transfusion guidelines in a multi-NICU network to a more restrictive practice was not associated with a significant reduction in number of neonates receiving a platelet transfusion. The guideline implementation was associated with a reduction in the mean platelet count triggering a transfusion. We speculate that further reductions in platelet transfusions can safely occur with additional education and accountability tracking.
A few patients in neonatal intensive care units (NICU) receive numerous platelet transfusions. These patients can become refractory, defined as transfusions of ≥10 mL/kg failing to increase the ...platelet count by at least 5,000/µL. Causes of, and best treatments for, platelet transfusion refractoriness in neonates have not been defined.
Multi-NICU multiyear retrospective analysis of neonates receiving >25 platelet transfusions.
Eight neonates received 29 to 52 platelet transfusions. All eight were blood group O. Five had sepsis, four were very small for gestational age, four had bowel resections, two Noonan syndrome, two had cytomegalovirus infection. All eight had some (19-73%) refractory transfusions. Many (2-69%) of the transfusions were ordered when the platelet count was >50,000/µL. Higher posttransfusion counts occurred after ABO-identical transfusions (
= 0.026). Three of the eight had late NICU deaths related to respiratory failure; all five survivors had severe bronchopulmonary dysplasia requiring tracheostomy for prolonged ventilator management.
Neonates who are high users of platelet transfusions appear to be at high risk for poor outcomes, especially respiratory failure. Future studies will examine whether group O neonates are more likely to develop refractoriness and whether certain neonates would have a higher magnitude of posttransfusion rise if they received ABO-identical donor platelets.
· Many of the platelet transfusions given in the NICU are given to a small subset of patients.. · Refractoriness to platelet transfusions is common among these very high recipients.. · Neonates who are high users of platelet transfusions appear to be at high risk for poor outcomes..
To understand better those factors relevant to the increment of rise in platelet count following a platelet transfusion among thrombocytopenic neonates STUDY DESIGN: We reviewed all platelet ...transfusions over 6 six years in our multi-NICU system. For every platelet transfusion in 8 neonatal centers we recorded: 1) platelet count before and after transfusion; 2) time between completing the transfusion and follow-up count; 3) transfusion volume (mL/kg); 4) platelet storage time; 5) sex and age of platelet donor; 6) gestational age at birth and post-natal age at transfusion; and magnitude of rise as related to: 7) pre-transfusion platelet count; 8) method of enhancing transfusion safety (irradiation vs. pathogen reduction); 9) cause of thrombocytopenia; and 10) donor/recipient ABO group.
We evaluated 1,797 platelet transfusions administered to 605 neonates (median one/recipient, mean three, range 1-52). The increment was not associated with gestational age at birth, postnatal age at transfusion, or donor sex or age. The rise was marginally lower: 1) with consumptive vs. hypoproductive thrombocytopenia (p<0.001); 2) after pathogen reduction (p<0.01); 3) after transfusing platelets with a longer storage time (p<0.001); and 4) among group O neonates receiving platelets from non-group O donors (p<0.001). Eighty-seven neonates had severe thrombocytopenia (<20,000/μL). Among these infants, poor increments and death were associated with the cause of the thrombocytopenia.
The magnitude of post-transfusion rise was unaffected by most variables we studied. However, the increment was lower in neonates with consumptive thrombocytopenia, after pathogen reduction, with longer platelet storage times, and when not ABO matched.