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.
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.
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.
To investigate associations between nucleated red blood cell (NRBC) count in neonates with hypoxic-ischemic encephalopathy (HIE), acute perinatal sentinel events, and neurodevelopmental outcomes and ...to examine the mechanism(s) causing elevated counts.
We included newborn infants with HIE treated with therapeutic hypothermia with ≥3 NRBC counts during their neonatal intensive care unit hospitalization and neurodevelopmental evaluations at a mean of 24 ± 6 months.
Ninety-five of 152 infants who met our study criteria (63%) had a normal NRBC count after birth, defined as ≤95th percentile of the upper reference interval, and the other 57 (37%) had an elevated count. Documented sentinel events during labor resulting in emergency delivery (eg, acute abruption) (n = 79) were associated with a normal NRBC count (OR, 257; 95% CI, 33-1988). Of the 152 infants evaluated, 134 (88%) survived to discharge. The odds of surviving were 3-fold greater (OR, 3.0; 95% CI, 1.1-8.3) when the first NRBC count was normal than when it was elevated. Normal counts were moderately predictive of infants without neurodevelopmental impairment at a 2-year evaluation (P < .001). NRBC half-life was longer in infants with an elevated NRBC count compared with those with a normal count (60 hours vs 39 hours; P < .01).
In infants with HIE, a normal NRBC count after birth was associated with acute intrapartum events necessitating emergent delivery. Normal counts were modestly predictive of a better prognosis. We speculate that the elevated NRBC counts at birth resulted from hypoxia that occurred earlier or chronically. Impaired clearance of NRBCs from the blood might be one mechanistic explanation for the high counts.
Exogenous mesenchymal stromal cells (MSCs) ameliorate experimental bronchopulmonary dysplasia. Moreover, data from term-born animal models and human tracheal aspirate-derived cells suggest altered ...mesenchymal signaling in the pathophysiology of neonatal lung disease. We hypothesized that hyperoxia, a factor contributing to the development of bronchopulmonary dysplasia, perturbs human lung-resident MSC function. Mesenchymal cells were isolated from human fetal lung tissue (16-18 wk of gestation), characterized and cultured in conditions resembling either intrauterine (5% O
) or extrauterine (21% and 60% O
) atmospheres. Secretome data were compared with MSCs obtained from term umbilical cord tissues. The human fetal lung mesenchyme almost exclusively contains CD146
MSCs expressing SOX-2 and OCT-4, which secrete elastin, fibroblast growth factors 7 and 10, vascular endothelial growth factor, angiogenin, and other lung cell-protecting/-maturing proteins. Exposure to extrauterine atmospheres
leads to excessive proliferation, reduced colony-forming ability, alterations in the cell's surface marker profile, decreased elastin deposition, and impaired secretion of factors important for lung growth. Conversely, umbilical cord-derived MSCs abundantly secreted factors that impaired lung MSCs are unable to produce. Oxygen-impaired human fetal lung MSC function may contribute to disrupted repair capacity and arrested lung growth. Exogenous MSCs may act by triggering the signaling pathways lost by impaired endogenous lung mesenchymal cells.
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