The prevalence of platelet activating factor acetylhydrolase single nucleotide polymorphisms in relationship to necrotizing enterocolitis in Northwest Louisiana infants

PURPOSE: Studies documented that platelet activating factor (PAF) and the enzyme platelet activating factor acetylhydrolase (PAFAH) play a very important role in the pathogenesis of neonatal necrotizing enterocolitis (NEC). In this retrospective, case-controlled pilot study, the authors investigated the prevalence of single nucleotide polymorphisms (Ile198Thr and Ala379Val) of the PAFAH gene. SUBJECTS AND METHODS: We screened 570 blood samples from both Caucasian and African-American preterm infants in the Northwest Louisiana population for the above mentioned PAFAH gene polymorphisms. Out of 570 infants, 36 had stage I or II NEC based on diagnostic coding, the International Classification of Diseases, 9th revision, Clinical Modification, 2009 (ICD-9-CM). The remaining infants without an ICD-9-CM diagnosis of NEC were recruited as control population. The DNA was isolated and restriction fragment length polymorphism microplate polymerase chain reaction assay was performed. RESULTS: Variants of the PAFAH gene polymorphism (Ile198Thr and Ala379Val) frequencies were not significantly different between the infants with NEC and the control group (P value of 0.26 by either multiple logistic regression analysis or the Cochran-Mantel-Haenszel test). CONCLUSIONS: This is the first study of its kind in exploring the relationship between NEC and single nucleotide polymorphisms in the coding genes of the enzyme PAFAH. Our preliminary data demonstrated that adjusted for the effect of race, PAFAH polymorphisms (Ile198Thr and Ala379Val) have no significant effect on NEC

Time to First Blood Glucose Determination and Administration of Intravenous Glucose at Birth in Extremely Low Birth Weight Infants

Background: Extremely low birth weight (ELBW) infants are prone to hypoglycemia unless intravenous glucose is administered within an hour (golden hour) of life. These infants often require resuscitation at birth, but monitoring and intervention for hypoglycemia may be delayed. Objectives: (1) Study the time to first blood glucose determination and IV glucose administration at birth in ELBW infants, (2) determine the incidence of hypoglycemia, \u3c47mg/dl, and severe hypoglycemia, \u3c40mg/dl, at admission, (3) determine risk factors for hypoglycemia, and (4) compare clinical outcomes at discharge between hypoglycemic and euglycemic infants. Methods: 244 ELBW (≤1000g birth weight) infants born during Jan 2017- Feb 2020 at the Regional One Health NICU, Memphis, TN were included in the study. Data collected included maternal and infant clinical, demographic, and outcomes at discharge, along with time to first blood glucose determination and IV glucose administration (bolus and/or IV infusion). Blood glucose was measured using the iStat® method at bedside. Data were analyzed for risk factors for hypoglycemia and severe hypoglycemia. Outcomes at discharge of infants who were hypoglycemic or severely hypoglycemic on first blood glucose determination were compared to euglycemic (≥47mg/dl) infants. Results:Gestational age was 26.2 ±2.4 weeks; birth weight 739 ±161g. The median time (IQR) to first glucose determination was 56 (45-73) min, and the median time for initiation of IV fluids with dextrose or giving bolus dextrose was 88 (60-120) min. Within the golden hour, only 59% of all infants had their first blood glucose determination, and 24% had IV glucose administered, (Figure). 123 infants (50%) had hypoglycemia, and 91(37%) had severe hypoglycemia (\u3c40mg/dL). There was no difference between euglycemic and hypoglycemic infants in time to blood glucose determination or IV glucose infusion. Caesarean delivery, intrauterine growth restriction (IUGR), and maternal β-blocker medications use increased the risk for hypoglycemia and severe hypoglycemia (all p Conclusion(s): Incidence of hypoglycemia on admission is high among ELBW infants, and administration of IV glucose is delayed beyond an hour of life in majority of these infants. All ELBW infants need to be screened for hypoglycemia and provided iv glucose within an hour after birt

Hyperglycemia During the First Three Days of Life Increases the Risk of Retinopathy of Prematurity in Extremely Low Birth Weight Infants

Background: The association between hyperglycemia and ROP has been inconsistent in previous studies. Extremely low birth weight (ELBW) infants are at high risk for ROP. They also experience hypoglycemia initially and hyperglycemia while receiving IV glucose infusion. The effect of initial hypoglycemia on hyperglycemia associated ROP risk is unknown. Objective: To study the effect of initial hypoglycemia and subsequent hyperglycemia during the first three days of life on the incidence of ROP and severe ROP in ELBW (birth weight ≤1000g) infants. Methods: Clinical and demographic data were collected from 227 ELBW infants born during the years 2017-2019 at the Regional One Health NICU, Memphis, TN. All blood glucose determinations done during the first 72 hours were collected from these infants along with maternal and neonatal demographic and clinical information. The infants were divided into four groups based on hypoglycemia at birth and subsequent hyperglycemia during the first 72 hours; group I: all the blood glucose levels were between 47-125mg/dl (euglycemia group); group II: initial hypoglycemia (\u3c47mg/dl) and with treatment became euglycemic; group III: initial hypoglycemia and at least one episode of hyperglycemia (\u3e125mg/dl) later on; group IV: initial euglycemia followed by at least one episode of hyperglycemia. Incidence of ROP and severe ROP (stage III or greater) was compared between the groups after adjusting for gestational age. Results: Clinical and outcomes data are presented in the table. The mean blood sugar levels during each day for the first 72 hours are presented in the figure. ROP incidence was lowest in infants who were euglycemic throughout the first 72 hours of life and no severe ROP was seen in this group. Infants who were hypoglycemic initially without experiencing hyperglycemia later appear to have higher incidence of ROP though it was not statistically different after adjusting for gestational age. Infants who were euglycemic at birth and became hyperglycemic later had increased incidence of ROP even after adjusting for gestational age; they also had the highest incidence of severe ROP. Mortality did not statistically differ between the groups. Comparing combined groups 1 &2 vs. 3 &4 showed no difference in ROP [aOR 1.5 (082-2.84)]. Conclusions: Hyperglycemia during the first three days of life without hypoglycemia at birth increases the risk for ROP. Hypoglycemia at birth appears to confound the risk of hyperglycemia associated ROP in ELBW infants

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams

Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants

Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide.

ObjectiveTo assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD).Study designExtremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction.ResultsA total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA &lt;26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks.ConclusionLate treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing.Trial registrationClinicalTrials.gov: NCT01022580

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

ObjectiveTo determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control).Study designCaregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys).ResultsInfants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM.ConclusionTreatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity.Trial registrationClinicalTrials.gov: NCT01022580

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

ObjectiveTo determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control).Study designCaregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys).ResultsInfants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM.ConclusionTreatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity.Trial registrationClinicalTrials.gov: NCT01022580