losartan-potassium and Bronchopulmonary-Dysplasia

Recombinant erythropoietin (rEPO) has erythropoiesis and anti-inflammatory properties that might help reduce lung injury in preterm infants.. To conduct a systematic review and meta-analysis to evaluate the possible role of rEPO in altering the risk of bronchopulmonary dysplasia (BPD).. PubMed, EMBASE, Web of Science, and the Cochrane Library databases were searched to identify randomized controlled trials (RCTs) that evaluated the effects of rEPO for the prevention of BPD in preterm infants.. Fourteen studies (3199 infants) were included. Our results could not demonstrate a significant effect of rEPO on the incidence of BPD36 (risk ratio [RR]: 0.97, 95% confidence interval [CI]: 0.87-1.09, p = 0.63, I. Our results suggest that rEPO does not affect the risk of developing BPD in preterm infants. Adequately powered RCTs are required to further confirm these findings.

Topics: Bronchopulmonary Dysplasia; Enterocolitis, Necrotizing; Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature; Sepsis

Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia. Darbepoetin (Darbe) and EPO are currently available ESAs.. To assess the effectiveness and safety of late initiation of ESAs, between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm or low birth weight infants.. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 5 June 2018), Embase (1980 to 5 June 2018), and CINAHL (1982 to 5 June 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.. Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) or low birth weight (< 2500 grams) neonates.. We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of the evidence.. We include 31 studies (32 comparisons) randomising 1651 preterm infants. Literature searches in 2018 identified one new study for inclusion. No new on-going trials were identified and no studies used darbepoetin.Most included trials were of small sample size. The meta-analysis showed a significant effect on the use of one or more RBC transfusions (21 studies (n = 1202); typical risk ratio (RR) 0.72, 95% confidence interval (CI) 0.65 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 66%; RD I² = 58%). The quality of the evidence was very low. We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant (typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants). There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%).Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). The quality of the evidence was very low.Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was no heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). The quality of the evidence was very low.There were no significant differences in other clinical outcomes including mortality and necrotising enterocolitis. For the outcomes of mortality and necrotising enterocolitis, the quality of the evidence was moderate. Long-term neurodevelopmental outcomes were not reported.. Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (mL/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment, to prevent donor exposure, is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.

Topics: Age Factors; Anemia, Neonatal; Bronchopulmonary Dysplasia; Cause of Death; Drug Administration Schedule; Erythrocyte Transfusion; Erythropoietin; Hematinics; Hospital Mortality; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity; Time Factors

Erythropoietin (EPO) plays an important role in the development and maturation of the gastrointestinal tract. Recombinant EPO (rEPO) has been used to prevent anemia of prematurity. The gastrointestinal trophic effects of EPO may reduce feeding intolerance and necrotizing enterocolitis (NEC) in preterm neonates. The aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the effects of rEPO on clinical outcomes such as feeding intolerance, stage II or higher NEC, any stage NEC, sepsis, retinopathy of prematurity, and bronchopulmonary dysplasia in preterm neonates. Twenty-five RCTs (intravenous: 13; subcutaneous: 10; enteral: 2; n = 4025) were eligible for inclusion. Meta-analysis of data from 17 RCTs (rEPO compared with placebo) with the use of a fixed-effects model showed no significant effect of rEPO on stage II or higher NEC (RR: 0.87; 95% CI: 0.64, 1.19; P = 0.39). Meta-analysis of data from 25 RCTs (rEPO compared with placebo) showed that rEPO significantly decreased the risk of any stage NEC [cases/total sample: 120/2058 (5.83%) compared with 146/1967 (7.42%); RR: 0.77; 95% CI: 0.61, 0.97; P = 0.03]. Only one RCT reported on time to full feedings. Meta-analysis of data from 15 RCTs showed a significant reduction in late-onset sepsis after rEPO administration (RR: 0.81; 95% CI: 0.71, 0.94; P = 0.004). Meta-analysis of 13 RCTs showed no significant effect of rEPO on mortality, retinopathy of prematurity, and bronchopulmonary dysplasia. Prophylactic rEPO had no effect on stage II or higher NEC, but it reduced any stage NEC, probably by reducing feeding intolerance, which is often labeled as stage I NEC. Adequately powered RCTs are required to confirm these findings.

Topics: Bronchopulmonary Dysplasia; Enterocolitis, Necrotizing; Erythropoietin; Gastrointestinal Tract; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Retinopathy of Prematurity; Sepsis

Acute kidney injury (AKI) and disordered fluid balance are common in premature neonates; a positive fluid balance dilutes serum creatinine, and a negative fluid balance concentrates serum creatinine, both of which complicate AKI diagnosis. Correcting serum creatinine for fluid balance may improve diagnosis and increase diagnostic accuracy for AKI.. To determine whether correcting serum creatinine for fluid balance would identify additional neonates with AKI and alter the association of AKI with short-term and long-term outcomes.. This study was a post hoc cohort analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT), a phase 3, randomized clinical trial of erythropoietin, conducted at 19 academic centers and 30 neonatal intensive care units in the US from December 2013 to September 2016. Participants included extremely premature neonates born at less than 28 weeks of gestation. Data analysis was conducted in December 2022.. Diagnosis of fluid-corrected AKI during the first 14 postnatal days, calculated using fluid-corrected serum creatinine (defined as serum creatinine multiplied by fluid balance [calculated as percentage change from birth weight] divided by total body water [estimated 80% of birth weight]).. The primary outcome was invasive mechanical ventilation on postnatal day 14. Secondary outcomes included death, hospital length of stay, and severe bronchopulmonary dysplasia (BPD). Categorical variables were analyzed by proportional differences with the χ2 test or Fisher exact test. The t test and Wilcoxon rank sums test were used to compare continuous and ordinal variables, respectively. Odds ratios (ORs) and 95% CIs for the association of exposure with outcomes of interest were estimated using unconditional logistic regression models.. A total of 923 premature neonates (479 boys [51.9%]; median [IQR] birth weight, 801 [668-940] g) were included, of whom 215 (23.3%) received a diagnosis of AKI using uncorrected serum creatinine. After fluid balance correction, 13 neonates with AKI were reclassified as not having fluid-corrected AKI, and 111 neonates previously without AKI were reclassified as having fluid-corrected AKI (ie, unveiled AKI). Therefore, fluid-corrected AKI was diagnosed in 313 neonates (33.9%). Neonates with unveiled AKI were similar in clinical characteristics to those with AKI whose diagnoses were made with uncorrected serum creatinine. Compared with those without AKI, neonates with unveiled AKI were more likely to require ventilation (81 neonates [75.0%] vs 254 neonates [44.3%] and have longer hospital stays (median [IQR], 102 [84-124] days vs 90 [71-110] days). In multivariable analysis, a diagnosis of fluid-corrected AKI was associated with increased odds of adverse clinical outcomes, including ventilation (adjusted OR, 2.23; 95% CI, 1.56-3.18) and severe BPD (adjusted OR, 2.05; 95% CI, 1.15-3.64).. In this post hoc cohort study of premature neonates, fluid correction increased the number of premature neonates with a diagnosis of AKI and was associated with increased odds of adverse clinical outcomes, including ventilation and BPD. Failing to correct serum creatinine for fluid balance underestimates the prevalence and impact of AKI in premature neonates. Future studies should consider correcting AKI for fluid balance.. ClinicalTrials.gov Identifier: NCT01378273.

Topics: Acute Kidney Injury; Birth Weight; Bronchopulmonary Dysplasia; Cohort Studies; Creatinine; Erythropoietin; Humans; Infant, Newborn; Infant, Newborn, Diseases; Male; Neuroprotection; Retrospective Studies

Extremely low gestational age neonates are at risk of disorders of fluid balance (FB), defined as change in fluid weight over a specific period. Few data exist on the association between FB and respiratory outcomes in this population.. To describe FB patterns and evaluate the association of FB with respiratory outcomes in a cohort of extremely low gestational age neonates.. This study is a secondary analysis of the Preterm Erythropoietin Neuroprotection Trial (PENUT), a phase 3 placebo-controlled randomized clinical trial of erythropoietin in extremely premature neonates conducted in 30 neonatal intensive care units in the US from December 1, 2013, to September 31, 2016. This analysis included 874 extremely premature neonates born at 24 to 27 weeks' gestation who were enrolled in the PENUT study. Secondary analysis was performed in November 2021.. Primary exposure was peak FB during the first 14 postnatal days. The FB was calculated as percent change in weight from birth weight (BW) as a surrogate for FB.. The primary outcome was mechanical ventilation on postnatal day 14. The secondary outcome was a composite of severe bronchopulmonary dysplasia (BPD) or death.. A total of 874 neonates (449 [51.4%] male; mean [SD] BW, 801 [188] g; 187 [21.4%] Hispanic, 676 [77.3%] non-Hispanic, and 11 [1.3%] of unknown ethnicity; 226 [25.9%] Black, 569 [65.1%] White, 51 [5.8%] of other race, and 28 [3.2%] of unknown race) were included in this analysis. Of these 874 neonates, 458 (52.4%) received mechanical ventilation on postnatal day 14, and 291 (33.3%) had severe BPD or had died. Median peak positive FB was 11% (IQR, 4%-20%), occurring on postnatal day 13 (IQR, 9-14). A total of 93 (10.6%) never decreased below their BW. Neonates requiring mechanical ventilation at postnatal day 14 had a higher peak FB compared with those who did not require mechanical ventilation (15% above BW vs 8% above BW, P < .001). On postnatal day 3, neonates requiring mechanical ventilation were more likely to have a higher FB (5% below BW vs 8% below BW, P < .001). The median time to return to BW was shorter in neonates who received mechanical ventilation (7 vs 8 days, P < .001) and those with severe BPD (7 vs 8 days, P < .001). After adjusting for confounding variables, for every 10% increase in peak FB during the first 14 postnatal days, there was 103% increased odds of receiving mechanical ventilation at postnatal day 14 (adjusted odds ratio, 2.03; 95% CI, 1.64-2.51).. In this secondary analysis of a randomized clinical trial, peak FB was associated with mechanical ventilation on postnatal day 14 and severe BPD or death. Fluid balance in the first 3 postnatal days and time to return to BW may be potential targets to help guide management and improve respiratory outcomes.. ClinicalTrials.gov Identifier: NCT01378273.

Topics: Bronchopulmonary Dysplasia; Erythropoietin; Female; Gestational Age; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Male; Respiration, Artificial

To investigate the safety and short term outcome of high dose recombinant human erythropoietin (rhEpo) given shortly after birth and subsequently over the first 2 days for neuroprotection to very preterm infants.. Randomized, double masked phase II trial. Preterm infants (gestational age 26 0/7-31 6/7 weeks) were given rhEpo (nt = 229; 3000 U/kg body weight) or NaCl 0.9% (nc = 214) intravenously at 3, 12-18, and 36-42 hours after birth.. There were no relevant differences between the groups for short-term outcomes such as mortality, retinopathy of prematurity, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. At day 7-10, we found significantly higher hematocrit values, reticulocyte, and white blood cell counts, and a lower platelet count in the rhEpo group.. Early high-dose rhEpo administration to very premature infants is safe and causes no excess in mortality or major adverse events.. ClinicalTrials.gov: NCT00413946.

Topics: Bronchopulmonary Dysplasia; Developmental Disabilities; Dose-Response Relationship, Drug; Double-Blind Method; Enterocolitis, Necrotizing; Erythropoietin; Europe; Hematocrit; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Infant, Premature; Intracranial Hemorrhages; Leukocyte Count; Leukomalacia, Periventricular; Neuroprotective Agents; Platelet Count; Recombinant Proteins; Reticulocyte Count; Retinopathy of Prematurity; Sepsis

To determine whether treatment with recombinant human erythropoietin (r-HuEPO) reduces transfusion requirements in premature neonates at risk of having bronchopulmonary dysplasia and requiring multiple transfusions.. A double-blind, randomized, controlled trial.. Fifty-five infants appropriate in weight for gestational age (less than 1250 gm birth weight) who, at 10 days of age, were predicted to have a greater than 75% probability of having bronchopulmonary dysplasia. This criterion had previously been shown to identify infants requiring multiple transfusions. Twenty-seven infants were randomly assigned to receive r-HuEPO therapy and 28 to a control group. r-HuEPO was administered in a dosage of 20 U/kg body weight, subcutaneously, three times a week for 6 weeks. Control infants received sham treatment.. Infants treated with r-HuEPO required significantly fewer transfusions than control infants during their entire hospital stay (mean 3.48 +/- 1.58 vs 5.68 +/- 2.30; p = 0.0001) and had a higher mean reticulocyte count (p < or = 0.0005) and a higher mean hemoglobin concentration (p < or = 0.005) during the treatment period. At follow-up, 4 months after term, there were no significant differences between the groups in mean reticulocyte count (p = 0.86) or mean hemoglobin concentration (p = 0.56). However, two infants in each group had low serum ferritin values indicative of depleted iron stores.. Treatment with r-HuEPO effectively stimulated erythropoiesis in premature infants at high risk of having bronchopulmonary dysplasia and requiring multiple transfusions; the result was a reduction in transfusion requirements. This treatment, together with other strategies to reduce the need for transfusions, is appropriate in this population. Unrelated to r-HuEPO treatment, these infants may be at risk of having iron deficiency later in infancy.

Topics: Bronchopulmonary Dysplasia; Double-Blind Method; Erythrocyte Transfusion; Erythropoietin; Female; Humans; Infant, Newborn; Male; Recombinant Proteins

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.

Topics: Anemia; Bronchopulmonary Dysplasia; Double-Blind Method; Erythropoietin; Female; Hematocrit; Humans; Infant; Infant, Newborn; Leukocyte Count; Male; Recombinant Proteins; Reticulocyte Count

Topics: Animals; Animals, Newborn; Apoptosis; Bronchopulmonary Dysplasia; Cell Movement; Cell Proliferation; Chemokine CXCL12; Disease Models, Animal; Endothelium, Vascular; Erythropoietin; Lung; Mesenchymal Stem Cells; Mice; Neovascularization, Physiologic; Receptors, CXCR4; Vascular Endothelial Growth Factor A

Erythropoietin treatment is associated with a reduction in moderate to severe bronchopulmonary dysplasia in preterm infants. A regional retrospective study.. To determine whether premature infants treated with erythropoietin (Epo) in the neonatal period for anemia had a lower incidence of bronchopulmonary dysplasia (BPD), defined as oxygen need at 36 weeks postmenstrual age, and lower rehospitalization rates in the first year of life than infants not exposed.. Retrospective study of a population of infants born at 23 to 32 weeks gestational age, between January 2009 and December 2014, with birthweight ≤1500 g. Patient characteristics, and risk factors for BPD were compared between patients who received erythropoietin, and those not exposed. To examine the association between the outcomes of BPD at 36 weeks PMA, rehospitalization, and erythropoietin treatment, we performed a propensity score (PS) analysis using inverse probability of treatment weighted (IPTW) approach. For comparison, we conducted a logistic regression adjusting for the same covariates used to generate PS using the original population.. The study population included 1821 preterm infants: 928 received Epo and 893 did not. Epo treatment was associated with a reduction in BPD (18.8% versus 25.9%, p < 0.01) at 36 weeks PMA and reduced median length of stay with lowest BPD rate with Epo initiation before 2 weeks of age. There was no difference in rehospitalization rates in the first year of life.. Erythropoietin treatment was associated with a reduction in BPD but not in rehospitalization rate in the first year of life.

Topics: Bronchopulmonary Dysplasia; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Length of Stay; Male; Patient Readmission

The aim of this study is to optimize the timing of erythropoietin gene modified mesenchymal stem cells (EPO-MSCs) transplantation for bronchopulmonary dysplasia (BPD). Three weeks post-operation, the results indicated that the damage of airway structure and apoptosis were significantly decreased, the proliferation was increased in three EPO-MSCs transplantation groups as compared with BPD mice. Moreover, the inflammation cytokines were improvement in early EPO-MSCs injection mice than in BPD mice, but there was no significant difference between late injection and BPD groups. Furthermore, the protein expression ratio of p-p38/p38MAPK was down-regulation in early mice but not in late transplantation mice. Our findings suggest that EPO-MSCs maybe attenuate BPD injury in early than in late administration by inhibiting inflammation response through down-regulation of the p38MAPK signalling pathway.

Topics: Animals; Apoptosis; Bronchopulmonary Dysplasia; Cell Proliferation; Disease Models, Animal; Erythropoietin; Gene Expression Regulation; Humans; Infant, Newborn; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; p38 Mitogen-Activated Protein Kinases; Signal Transduction

The substantial risk of iron overload is not routinely monitored in most of the neonatal intensive care units (NICUs) in Japan; however, blood transfusion is an essential strategy for successfully treating preterm low-birth-weight infants.. The aim of this study was to investigate the iron status and clinical features of infants with a birth weight of <1,500 g, i.e. very-low-birth-weight infants (VLBWIs).. This prospective observational study enrolled 176 (82.6%) patients from a total of 213 VLBWIs admitted to our NICU from 2009 to 2014. Clinical information was collected including maternal records and infant morbidity and treatment. Management strategies including enteral iron supplementation, erythropoietin administration and blood transfusion were allowed according to the consensus in Japan. The hematological status was surveyed from birth to 12 postnatal weeks of age. The iron status was determined according to serum iron, unbound iron-binding capacity and serum ferritin. The definition of hyperferritinemia was set as a value of ≥500 ng/ml.. Twenty-four (13.6%) infants displayed hyperferritinemia. A multiple logistic analysis selected 3 associated factors of hyperferritinemia: surgical ligation for patent ductus arteriosus, sepsis and moderate or severe states of bronchopulmonary dysplasia. We also verified that the value of ferritin was significantly correlated with those of aspartate transaminase, creatine kinase and C-reactive protein according to a multilinear regression analysis. After excluding the ferritin data of these outliers, we did not observe any factors associated with hyperferritinemia.. Hyperferritinemia might be associated with oxygen radical diseases and susceptibility to infection.

Topics: Birth Weight; Bronchopulmonary Dysplasia; C-Reactive Protein; Ductus Arteriosus, Patent; Erythropoietin; Female; Ferritins; Gestational Age; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Iron Metabolism Disorders; Iron Overload; Japan; Logistic Models; Male; Multivariate Analysis; Prospective Studies; Sepsis

To explore the association between concentrations of endogenous erythropoietin (EPO) in blood the first 2 weeks of life and neonatal disorders in extremely low gestational age newborns (ELGANs).. Prospective cohort study.. Neonatal care units at 14 participating hospitals in the USA.. 867 children born before the 28th week of gestation from the ELGAN study cohort.. EPO blood concentrations were measured on postnatal days 1, 7 and 14. The following neonatal characteristics and disorders were registered: blood gases, early and late respiratory dysfunction, pulmonary deterioration, retinopathy of prematurity (ROP), necrotising enterocolitis (NEC) and bronchopulmonary dysplasia (BPD). We calculated the gestational age-adjusted ORs for having each disorder associated with an EPO blood concentration in the highest or lowest quartile, compared with infants whose EPO concentration was in the middle two quartiles on the corresponding day.. Newborns whose day-1 EPO was in the highest quartile were at increased risk for early and persistent respiratory dysfunction during the first 2 weeks of life, and NEC requiring surgery. The lowest EPO quartile on day 1 was associated with a decreased risk of moderate BPD. The association between low EPO and decreased risk of respiratory complications persisted on day 7. On day 14, being in the highest EPO quartile was associated with increased risk of ROP, and BPD not requiring ventilation assistance.. EPO blood concentrations in extremely preterm newborns during the first 2 weeks of life convey information about increased risks of bowel, lung and retinal diseases.

Topics: Bronchopulmonary Dysplasia; Enterocolitis, Necrotizing; Erythropoietin; Gestational Age; Humans; Infant, Extremely Premature; Infant, Premature, Diseases; Prospective Studies; Respiratory Distress Syndrome, Newborn; Retinopathy of Prematurity; Risk Factors; Time Factors

The aim of the present study is to investigate the protection effects of bone marrow mesenchymal stem cells (MSCs) in combination with EPO against hyperoxia-induced bronchopulmonary dysplasia (BPD) injury in neonatal mice. BPD model was prepared by continuous high oxygen exposure, 1×106 bone marrow MSCs and 5000U/kg recombinant human erythropoietin (EPO) were injected respectively. Results showed that administration of MSCs, EPO especially MSCs+EPO significant attenuated hyperoxia-induced lung damage with a decrease of fibrosis, radical alveolar counts and inhibition of the occurrence of epithelial-mesenchymal transition (EMT). Furthermore, MSCs+EPO co-treatment more significantly suppressed the levels of transforming growth factor-β1(TGF-β1) than MSCs or EPO alone. Collectively, these results suggested that MSCs, EPO in particular MSCs+EPO co-treatment could promote lung repair in hyperoxia-induced alveoli dysplasia injury via inhibition of TGF-β1 signaling pathway to further suppress EMT process and may be a promising therapeutic strategy.

Topics: Animals; Bronchopulmonary Dysplasia; Cells, Cultured; Combined Modality Therapy; Disease Models, Animal; Epithelial-Mesenchymal Transition; Erythropoietin; Female; Fibrosis; Humans; Hyperoxia; Mesenchymal Stem Cell Transplantation; Mice; Mice, Inbred C57BL; Pulmonary Alveoli; Recombinant Proteins; Signal Transduction; Transforming Growth Factor beta1

Bronchopulmonary dysplasia (BPD) is the most common type of chronic lung disease in infancy, for which no effective therapy is currently available. The aim of the present study was to investigate the effect of treatment with bone marrow mesenchymal stem cells (BMSCs) in combination with recombinant human erythropoietin (rHuEPO) on BPD‑induced mouse lung injury, and discuss the underlying mechanism. The BPD model was established by the exposure of neonatal mice to continuous high oxygen exposure for 14 days, following which 1x106 BMSCs and 5,000 U/kg rHuEPO were injected into the mice 1 h prior to and 7 days following exposure to hyperoxia. The animals received four treatments in total (n=10 in each group). After 14 days, the body weights, airway structure, and levels of matrix metalloproteinase‑9 (MMP‑9) and vascular endothelial growth factor (VEGF) were detected using histological and immunohistochemical analyses. The effect on cell differentiation was observed by examining the presence of platelet endothelial cell adhesion molecule (PECAM) and VEGF using immunofluorescence. Compared with the administration of BMSCs alone, the body weight, airway structure, and the levels of MMP‑9 and VEGF were significantly improved in the BMSCs/rHuEPO group. The results of the present study demonstrated that the intravenous injection of BMSCs significantly improved lung damage in the hyperoxia‑exposed neonatal mouse model. Furthermore, the injection of BMSCs in combination with intraperitoneal injection of rHuEPO had a more marked effect, compared with BMSCs alone, and the mechanism may be mediated by the promoting effects of BMSCs and EPO. The results of the present study provided information, which may assist in future clinical trials.

Topics: Animals; Antigens, CD; Bronchopulmonary Dysplasia; Cell Culture Techniques; Combined Modality Therapy; Disease Models, Animal; Erythropoietin; Immunophenotyping; Lung Injury; Matrix Metalloproteinase 9; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Mice; Vascular Endothelial Growth Factor A

Topics: Bronchopulmonary Dysplasia; Erythropoietin; Female; Humans; Infant, Extremely Low Birth Weight; Infant, Extremely Premature; Male

Despite advances in clinical care, the incidence of bronchopulmonary dysplasia (BPD) remains high in premature infants. Erythropoietin (EPO) is used for the treatment of anemia of prematurity (AOP) to decrease blood transfusion needs. EPO has been shown to mobilize circulating endothelial progenitor cells and to enhance lung repair in animal models.. To determine whether EPO treatment for AOP was associated with a reduced incidence of BPD in premature infants.. This retrospective study was performed on all live-born neonates with birth weights from 500 to 1,500 g and gestational age (GA) from 22 to 32 weeks admitted from 1994 to 2002. Infants who received EPO and those who did not receive EPO were compared for incidence of BPD and other morbidities.. Of 478 patients, 297 received EPO before 36 weeks' postmenstrual age (group 1) and 181 did not receive EPO (group 2). Group 1 was of similar birth weight but lower GA than group 2. The incidence of BPD was lower in group 1 than group 2 (26 vs. 36%, p = 0.03); after adjusting for significant risk factors, the adjusted odds ratio for BPD was 0.50 (95% CI 0.32, 0.79), p = 0.0028. The BPD rate was much lower when EPO was initiated before 4 weeks of age (16%) as compared to later initiation (44%).. This study shows an association between EPO treatment and reduced incidence of BPD in preterm infants, particularly when EPO treatment was initiated within the first 4 weeks of life.

Topics: Birth Weight; Bronchopulmonary Dysplasia; California; Erythropoietin; Female; Gestational Age; Humans; Incidence; Infant; Infant, Extremely Low Birth Weight; Infant, Extremely Premature; Infant, Newborn; Injections, Subcutaneous; Male; Oxygen; Retrospective Studies; Treatment Outcome

To study the effect of recombinant human erythropoietin (rhEPO) on apoptosis following hyperoxic lung injury in neonatal rats.. Ninety-six neonatal Sprague-Dawley rats were randomly divided into four groups: air-exposed control, air-exposed rhEPO-treated, hyperoxia-exposed placebo (95% oxygen), and hyperoxia-exposed rhEPO-treated. rhEPO (800 U/kg) was administered 2, 4, and 6 days after air or hyperoxia exposure. The rats were sacrificed 3, 7 and 14 days after air or hyperoxia exposure for the assessment of lung histological changes by hematoxylin and eosin staining (n=8 each time point). p-JNK levels were measured by Western blot. Lung cell apoptosis was evaluated by TUNEL assay.. Compared with the air-exposed control group, inflammatory cell infiltration was found at 3 days and increased obviously at 7 days, and widening of the alveolar septa was observed, the number of alveoli decreased and normal alveolarization disappeared at 14 days after hyperoxia exposure in the hyperoxia-exposed placebo group. rhEPO treatment alleviated significantly the hyeroxia-induced alterations in lung pathology. P-JNK protein levels and the number of apoptosis cells decreased significantly in the hyperoxia-exposed rhEPO-treated compared with those in the hyperoxia-exposed placebo group.. rhEPO may reduce apoptosis and thus provide a protective effect against hyperoxic lung injury in neonatal rats. JNK signal pathway may be involved in the protective mechanism.

Topics: Animals; Animals, Newborn; Apoptosis; Bronchopulmonary Dysplasia; Erythropoietin; Female; Humans; Hyperoxia; Infant, Newborn; JNK Mitogen-Activated Protein Kinases; Lung; Male; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Hypertension is an uncommon but significant problem in high-risk neonates and infants, and the spectrum of potential causes is broad. Here, we describe an extremely premature infant (birth weight, 728 g; gestational age, 27 weeks) with multiple complications and hypertension. During admission, umbilical artery catheters were used for a period of time, and he suffered from respiratory distress syndrome, intraventricular hemorrhage, pulmonary hemorrhage, patent ductus arteriosus, pericardial effusion, heart failure, repeated sepsis, anemia, thrombocytopenia, chronic lung disease, and progressive liver damage. He was treated with multiple medications, including erythropoietin, indomethacin, epinephrine, dopamine, aminophylline, multiple antibiotics, amphotericin B, and total parenteral nutrition. Hypertension was first noted when he was 41 days old, with spontaneous remission. It then recurred, reaching higher than 100 mmHg when he was almost 4 months old. After stopping erythropoietin, hypertension subsided for a short period of time and went up again. Multiple factor-related hypertension in this premature infant was considered. Related literature on hypertension in premature infants is reviewed. In conclusion, multiple factors can influence blood pressure and may induce hypertension in high-risk premature infants. Thus, blood pressure should be closely monitored in high-risk premature infants. Judicious use of all medications and interventions are crucial to decrease the incidence of hypertension in high-risk premature infants.

Topics: Bronchopulmonary Dysplasia; Ductus Arteriosus, Patent; Erythropoietin; Humans; Hypertension; Infant, Newborn; Infant, Premature; Male

The effects of anemia of prematurity during bronchopulmonary dysplasia (BPD) as well as on the metabolic and erythropoietic functions were determined before and after a transfusion. Fourteen anemic (Hb range: 65-88 gm/L), oxygen dependent (fraction of inspired oxygen < or = 35%), nonventilated, preterm infants with BPD were studied at a postnatal age of 6 +/- 2 weeks.. Cardiac output, heart rate, mean velocity of circumferential fiber shortening, shortening fraction (SF), and stroke volume were assessed by pulsed and continuous wave Doppler echocardiography. Values for resting oxygen consumption, carbon dioxide production, and energy expenditure were obtained by indirect calorimetry. The affinity of oxygenated hemoglobin was determined by a blood oxygen dissociation analyzer.. An increased hemoglobin level resulted in a suppression of erythropoietin secretion (p < 0.001), whereas heart rate, cardiac output, stroke volume, and SF decreased (p < 0.05). Weight gain before and after transfusion were similar. Plasma lactate levels decreased from 1.6 +/- 0.3 to 1.2 +/- 0.3. Oxygen consumption, carbon dioxide production, and energy expenditure were not affected.. Anemia of prematurity and BPD increase heart rate, cardiac output, stroke volume, and SF. These hemodynamic compensatory responses are normalized by transfusion.

Topics: Adaptation, Physiological; Anemia, Neonatal; Blood Transfusion; Bronchopulmonary Dysplasia; Echocardiography, Doppler; Erythropoietin; Hemodynamics; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; Myocardium; Oxygen Consumption; Oxygen Inhalation Therapy

In seven patients with bronchopulmonary dysplasia and anemia, we evaluated the mechanisms causing the anemia. All had a normocytic, normochromic, hyporegenerative anemia (mean hematocrit 26%; range 21% to 30%). The low hematocrit values seemed physiologically significant because mean (+/- SD), heart rates fell after transfusion (162 +/- 7 to 149 +/- 9 beats/min; p less than 0.005), as did blood lactate concentrations (1.2 +/- 0.3 mumol/gm blood before vs 0.5 +/- 0.3 after transfusion; p less than 0.05). Anemia could not be explained by blood withdrawal or deficiency of vitamin E, folate, or iron. No dyserthropoietic or megaloblastic changes were observed. No erythroid regenerative response was seen in the marrow; however, when recombinant erythropoietic growth factors were added to marrow cells in tissue culture, erythroid cell growth in vitro was normal. In contrast to patients with the "anemia of chronic disorders," these patients had a normal or increased number of marrow sideroblasts and increased serum transferrin saturation. Serum concentrations of erythropoietin were low for patients with anemia (range 11.4 to 47.1 mU/ml); yet the in vitro sensitivity of bone marrow erythroid progenitors (colony-forming units--erythroid) to recombinant erythropoietin was increased (p less than 0.001). We conclude that the anemia in these patients was the result of deficient production of erythropoietin, and we speculate that administration of recombinant erythropoietin would correct the anemia.

Topics: Anemia; Bilirubin; Bone Marrow Examination; Bronchopulmonary Dysplasia; Cells, Cultured; Erythroid Precursor Cells; Erythropoietin; Female; Ferritins; Heart Rate; Hematocrit; Humans; Infant; Infant, Newborn; Lactates; Lactic Acid; Male; Recombinant Proteins; Stem Cells; Transferrin; Vitamin E