Population Pharmacokinetic Analysis and Dose Regimen Optimization in Japanese Infants with an Extremely Low Birth Weight.
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SUBMITTER: Sasano H
PROVIDER: S-EPMC8092535 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ImportanceCycled (intermittent) phototherapy (PT) might adequately control peak total serum bilirubin (TSB) level and avoid mortality associated with usual care (continuous PT) among extremely low-birth-weight (ELBW) infants (401-1000 g).ObjectiveTo identify a cycled PT regimen that substantially reduces PT exposure, with an increase in mean peak TSB level lower than 1.5 mg/dL in ELBW infants.Design, setting, and participantsThis dose-finding randomized clinical trial of cycled PT vs continuous PT among 305 ELBW infants in 6 US newborn intensive care units was conducted from March 12, 2014, to November 14, 2018.InterventionsTwo cycled PT regimens (≥15 min/h and ≥30 min/h) were provided using a simple, commercially available timer to titrate PT minutes per hour against TSB level. The comparator arm was usual care (continuous PT).Main outcomes and measuresMean peak TSB level and total PT hours through day 14 in all 6 centers and predischarge brainstem auditory-evoked response wave V latency in 1 center. Mortality and major morbidities were secondary outcomes despite limited power.ResultsConsent was requested for 452 eligible infants and obtained for 305 (all enrolled) (mean [SD] birth weight, 749 [152] g; gestational age, 25.7 [1.9] weeks; 81 infants [27%] were multiple births; 137 infants [45%] were male; 112 [37%] were black infants; and 107 [35%] were Hispanic infants). Clinical and demographic characteristics of the groups were similar at baseline. After a preplanned interim analysis of 100 infants, the regimen of 30 min/h or more was discontinued, and the study proceeded with 2 arms. Comparing 128 infants receiving PT of 15 min/h or more with 128 infants receiving continuous PT among those surviving to 14 days, mean peak TSB levels were 7.1 vs 6.4 mg/dL (adjusted difference, 0.7; 95% CI, 0.4-1.1 mg/dL) and mean total PT hours were 34 vs 72 (adjusted difference, -39; 95% CI, -45 to -32). Wave V latency adjusted for postmenstrual age was similar in 37 infants receiving 15 min/h or more of PT and 33 infants receiving continuous PT: 7.42 vs 7.32 milliseconds (difference, 0.10; 95% CI, -0.11 to 0.30 millisecond). The relative risk for death was 0.79 (95% CI, 0.40-1.54), with a risk difference of -4.5% (95% CI, -10.9 to 2.0). Morbidities did not differ between groups.Conclusions and relevanceCycled PT can substantially reduce total PT with little increase in peak TSB level. A large, randomized trial is needed to assess whether cycled PT would increase survival and survival without impairment in small, preterm infants.Trial registrationClinicalTrials.gov Identifier: NCT01944696.
| S-EPMC7186919 | biostudies-literature
Project description:ObjectiveTo determine if selected pro-inflammatory and anti-inflammatory cytokines and/or mediators of inflammation reported to be related to the development of cerebral palsy (CP) predict neurodevelopmental outcome in extremely low birth weight infants.Study designInfants with birth weights ?1000 g (n = 1067) had blood samples collected at birth and on days 3 ± 1, 7 ± 1, 14 ± 3, and 21 ± 3 to examine the association between cytokines and neurodevelopmental outcomes. The analyses were focused on 5 cytokines (interleukin [IL] 1?; IL-8; tumor necrosis factor-?; regulated upon activation, normal T-cell expressed, and secreted (RANTES); and IL-2) reported to be most predictive of CP in term and late preterm infants.ResultsIL-8 was higher on days 0-4 and subsequently in infants who developed CP compared with infants who did not develop CP in both unadjusted and adjusted analyses. Other cytokines (IL-12, IL-17, tumor necrosis factor-?, soluble IL r?, macrophage inflammatory protein 1?) were found to be altered on days 0-4 in infants who developed CP.ConclusionsCP in former preterm infants may, in part, have a late perinatal and/or early neonatal inflammatory origin.
| S-EPMC3215787 | biostudies-literature
Project description:Prophylactic indomethacin reduces severe intraventricular hemorrhage but may increase spontaneous intestinal perforation (SIP) in extremely low birth weight (ELBW) infants. Early feedings improve nutritional outcomes but may increase the risk of SIP. Despite their benefits, use of these therapies varies largely by physician preferences in part because of the concern for SIP.This was a cohort study of 15,751 ELBW infants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network from 1999 to 2010 who survived beyond 12 hours after birth. The risk of SIP was compared between groups of infants with and without exposure to prophylactic indomethacin and early feeding in unadjusted analyses and in analyses adjusted for center and for risks of SIP.Among infants exposed to prophylactic indomethacin, the risk of SIP did not differ between the indomethacin/early-feeding group compared with the indomethacin/no-early-feeding group (adjusted relative risk [RR] 0.74, 95% confidence interval [CI] 0.49-1.11). The risk of SIP was lower in the indomethacin/early-feeding group compared with the no indomethacin/no-early-feeding group (adjusted RR 0.58, 95% CI 0.37-0.90, P = .0159). Among infants not exposed to indomethacin, early feeding was associated with a lower risk of SIP compared with the no early feeding group (adjusted RR 0.53, 95% CI 0.36-0.777, P = .0011).The combined or individual use of prophylactic indomethacin and early feeding was not associated with an increased risk of SIP in ELBW infants.
| S-EPMC4533280 | biostudies-other
Project description:It is unclear whether aggressive phototherapy to prevent neurotoxic effects of bilirubin benefits or harms infants with extremely low birth weight (1000 g or less).We randomly assigned 1974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy. The primary outcome was a composite of death or neurodevelopmental impairment determined for 91% of the infants by investigators who were unaware of the treatment assignments.Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 vs. 9.8 mg per deciliter [120 vs. 168 micromol per liter], P<0.01) but not the rate of the primary outcome (52% vs. 55%; relative risk, 0.94; 95% confidence interval [CI], 0.87 to 1.02; P=0.15). Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26%, vs. 30% for conservative phototherapy; relative risk, 0.86; 95% CI, 0.74 to 0.99). Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24% and 23%, respectively (relative risk, 1.05; 95% CI, 0.90 to 1.22). In preplanned subgroup analyses, the rates of death were 13% with aggressive phototherapy and 14% with conservative phototherapy for infants with a birth weight of 751 to 1000 g and 39% and 34%, respectively (relative risk, 1.13; 95% CI, 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.Aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment. The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy. This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth. (ClinicalTrials.gov number, NCT00114543.)
| S-EPMC2821221 | biostudies-literature
Project description:BackgroundAlthough the overall quality of high-risk neonatal care has improved recently, there is still concern about a difference in the quality of care when comparing off-hour births and regular-hour births. Moreover, there are no data in Korea regarding the impact of time of birth on mortality and morbidities in preterm infants.MethodsA total of 3,220 infants weighing < 1,000 g and born at 23-34 weeks in 2013-2017 were analyzed based on the Korean Neonatal Network data. Mortality and major morbidities were analyzed using logistic regression according to time of birth during off-hours (nighttime, weekend, and holiday) and regular hours. The institutes were sub-grouped into hospital group I and hospital group II based on the neonatal intensive care unit (NICU) care level defined by the mortality rates of < 50% and ≥ 50%, respectively, in infants born at 23-24 weeks' gestation.ResultsThe number of births during regular hours and off-hours was similar. In the total population and hospital group I, off-hour births were not associated with increased neonatal mortality and morbidities. However, in hospital group II, increased early mortality was found in the off-hour births when compared to regular-hour births.ConclusionEfforts to improve the overall quality of NICU are required to lower the early mortality rate in off-hour births. Also, other sensitive indexes for the evaluation of quality of NICU care should be further studied.
| S-EPMC8021978 | biostudies-literature
Project description:OBJECTIVE:Characterize frequency and volume of blood draws and transfusions in extremely low birth weight infants in the first 10 weeks of life. STUDY DESIGN:We included infants with a birth weight?<1000?g born 23 0/7-29 6/7 weeks gestational age (GA) and with a length of stay??10 weeks, admitted between 2014 and 2016 to a single neonatal intensive care unit. RESULTS:Of 54 infants, median (25th, 75th percentile) GA and birth weight were 25 weeks (24, 26) and 665?g (587, 822), respectively. Median number of blood draws per infant decreased from 57 (49, 65) in week 1 to 12 (8, 22) in week 10. Median volume of blood extracted was 83?mL (70, 97), and median number of blood transfusions was 8 (5, 10). CONCLUSIONS:This cohort experienced a high number and volume of blood draws. Draw frequency and transfusions decreased over the first 10 weeks of life.
| S-EPMC7331095 | biostudies-literature
Project description:OBJECTIVE:The goal was to develop multivariate logistic regression models for the outcome of bronchopulmonary dysplasia and/or death at postmenstrual age of 36 weeks by using clinical and cytokine data from the first 28 days. METHODS:For 1067 extremely low birth weight infants in the Neonatal Research Network of the National Institute of Child Health and Human Development, levels of 25 cytokines were measured in blood collected within 4 hours after birth and on days 3, 7, 14, and 21. Stepwise regression analyses using peak levels of the 25 cytokines and 15 clinical variables identified variables associated with bronchopulmonary dysplasia/death. Multivariate logistic regression analysis was performed for bronchopulmonary dysplasia/death by using variables selected through stepwise regression. Similar analyses were performed by using average cytokine values from days 0 to 21, days 0 to 3, and days 14 to 21. RESULTS:Of 1062 infants with available data, 606 infants developed bronchopulmonary dysplasia or died. On the basis of results from all models combined, bronchopulmonary dysplasia/death was associated with higher concentrations of interleukin 1beta, 6, 8, and 10 and interferon gamma and lower concentrations of interleukin 17, regulated on activation, normal T cell expressed and secreted, and tumor necrosis factor beta. Compared with models with only clinical variables, the addition of cytokine data improved predictive ability by a statistically significant but clinically modest magnitude. CONCLUSIONS:The overall cytokine pattern suggests that bronchopulmonary dysplasia/death may be associated with impairment in the transition from the innate immune response mediated by neutrophils to the adaptive immune response mediated by T lymphocytes.
| S-EPMC2903210 | biostudies-literature
Project description:Infants born prematurely, particularly extremely low birth weight infants (ELBW) have altered gut microbial communities. Factors such as maternal health, gut immaturity, delivery mode, and antibiotic treatments are associated with microbiota disturbances, and are linked to an increased risk of certain diseases such as necrotising enterocolitis. Therefore, there is a requirement to optimally characterise microbial profiles in this at-risk cohort, via standardisation of methods, particularly for studying the influence of microbiota therapies (e.g. probiotic supplementation) on community profiles and health outcomes. Profiling of faecal samples using the 16S rRNA gene is a cost-efficient method for large-scale clinical studies to gain insights into the gut microbiota and additionally allows characterisation of cohorts were sample quantities are compromised (e.g. ELBW infants). However, DNA extraction method, and the 16S rRNA region targeted can significantly change bacterial community profiles obtained, and so confound comparisons between studies. Thus, we sought to optimise a 16S rRNA profiling protocol to allow standardisation for studying ELBW infant faecal samples, with or without probiotic supplementation.Using ELBW faecal samples, we compared three different DNA extraction methods, and subsequently PCR amplified and sequenced three hypervariable regions of the 16S rRNA gene (V1 + V2 + V3), (V4 + V5) and (V6 + V7 + V8), and compared two bioinformatics approaches to analyse results (OTU and paired end). Paired shotgun metagenomics was used as a 'gold-standard'.Results indicated a longer bead-beating step was required for optimal bacterial DNA extraction and that sequencing regions (V1 + V2 + V3) and (V6 + V7 + V8) provided the most representative taxonomic profiles, which was confirmed via shotgun analysis. Samples sequenced using the (V4 + V5) region were found to be underrepresented in specific taxa including Bifidobacterium, and had altered diversity profiles. Both bioinformatics 16S rRNA pipelines used in this study (OTU and paired end) presented similar taxonomic profiles at genus level.We determined that DNA extraction from ELBW faecal samples, particularly those infants receiving probiotic supplementation, should include a prolonged beat-beating step. Furthermore, use of the 16S rRNA (V1 + V2 + V3) and (V6 + V7 + V8) regions provides reliable representation of ELBW microbiota profiles, while inclusion of the (V4 + V5) region may not be appropriate for studies where Bifidobacterium constitutes a resident microbiota member.
| S-EPMC5668952 | biostudies-literature
Project description:Acute kidney injury (AKI) is a common event in the neonatal intensive care unit (NICU), especially in extremely-low-birth-weight (ELBW) infants. This cohort study investigated the incidence of and risk factors for AKI in ELBW infants and their overall survival at the postmenstrual age (PMA) of 36 weeks.All ELBW infants admitted to our NICU between January 2010 and December 2013 were enrolled. Those who died prior to 72 hours of life, had congenital renal abnormality, or had only one datum of the serum creatinine (SCr) level after the first 24 hours of life were excluded. The criteria used for the diagnosis of AKI was set according to the modified neonatal KDIGO AKI definition.AKI occurred in 56% of 276 infants. Specifically, stage 1, stage 2, and stage 3 AKI occurred in 30%, 17%, and 9% of ELBW infants, respectively. High-frequency ventilation support (adjusted odds ratio [OR]: 3.4, 95% confidence interval [CI]: 1.78-6.67, p< 0.001), the presence of patent ductus arteriosus (adjusted OR: 4.3, 95% CI: 2.25-8.07, p < 0.001), lower gestational age (adjusted OR for gestational age: 0.7, 95% CI: 0.58-0.83, < 0.001), and inotropic agent use (adjusted OR: 2.6, 95% CI: 1.31-5.21, p = 0.006) were independently associated with AKI. Maternal pre-eclampsia was a protective factor (adjusted OR: 0.4, 95% CI: 0.14-0.97, p = 0.044). Infants with AKI had higher mortality before the PMA of 36 weeks with an adjusted hazard ratio (HR) of 5.34 (95% CI: 1.21-23.53, p = 0.027). Additionally, infants with stage 3 AKI had a highest HR of 10.60, 95% CI: 2.09-53.67, p = 0.004).AKI was a very common event (56%) in ELBW infants and was associated with a lower GA, high-frequency ventilation support, the presence of PDA, and inotropic agent use. AKI reduced survival of ELBW infants before the PMA of 36 weeks.
| S-EPMC5673227 | biostudies-literature
Project description:To develop a length of stay (LOS) model for extremely low birth weight (ELBW) infants.We included infants from the California Perinatal Quality Care Collaborative with birth weight 401 to 1000?g who were discharged to home. Exclusion criteria were congenital anomalies, surgery and death. LOS was defined as days from admission to discharge. As patients who died or were transferred to lower level of care were excluded, we assessed correlation of hospital mortality rates and transfers to risk-adjusted LOS.There were 2012 infants with median LOS 79 days (range 23 to 219). Lower birth weight, lack of antenatal steroids and lower Apgar score were associated with longer LOS. There was negligible correlation between risk-adjusted LOS and hospital mortality rates (r=0.0207) and transfer-out rates (r=0.121).Particularly because ELBW infants have extended hospital stays, identification of unbiased and informative risk-adjusted LOS for these infants is an important step in benchmarking best practice and improving efficiency in care.
| S-EPMC3815522 | biostudies-literature