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1.  Growth Requirements of the Meningococcus 
Journal of Bacteriology  1942;43(6):757-761.
PMCID: PMC373642  PMID: 16560537
2.  Definitions of cardiovascular insufficiency and relation to outcomes in critically ill newborn infants 
American journal of perinatology  2015;32(11):1024-1030.
We previously reported on the overall incidence, management and outcomes in infants with cardiovascular insufficiency (CVI). However, there are limited data on the relationship of the specific different definitions of CVI to short term outcomes in term and late preterm newborn infants.
To evaluate how 4 definitions of CVI relate to short term outcomes and death.
Study Design
The previously reported study was a multicenter, prospective cohort study of 647 infants ≥ 34 weeks gestation admitted to a Neonatal Research Network (NRN) newborn intensive care unit (NICU) and mechanically ventilated (MV) during their first 72 hours. The relationship of five short term outcomes at discharge and 4 different definitions of CVI were further analyzed.
All 4 definitions were associated with greater number of days on MV & days on O2. The definition using a threshold blood pressure (BP) measurement alone was not associated with days to full feeding, days in the NICU or death. The definition based on treatment of CVI was associated with all outcomes including death.
The definition using a threshold BP alone was not consistently associated with adverse short term outcomes. Using only a threshold BP to determine therapy may not improve outcomes.
PMCID: PMC4689139  PMID: 25825962
blood pressure; cardiovascular insufficiency; outcomes; newborn; infant
3.  Incidence, management and outcomes of cardiovascular insufficiency in critically ill term and late preterm newborn infants 
American journal of perinatology  2014;31(11):947-956.
To characterize the incidence, management and short term outcomes of cardiovascular insufficiency (CVI) in mechanically ventilated newborns, evaluating 4 separate pre-specified definitions.
Study Design
Multicenter, prospective cohort study of infants ≥34 weeks gestational age (GA) and on mechanical ventilation during the first 72 hours. CVI was prospectively defined as either (1) mean arterial pressure (MAP)
Of 647 who met inclusion criteria, 419 (65%) met ≥1 definition of CVI. Of these, 98% received fluid boluses, 36% inotropes and 17% corticosteroids. Of treated infants, 46% did not have CVI as defined by a MAP < GA ± signs of inadequate perfusion. Inotrope therapy was associated with increased mortality (11.1% vs. 1.3%; P < 0.05).
More than half of the infants met at least one definition of CVI. However, almost half of the treated infants met none of the definitions. Inotropic therapy was associated with increased mortality. These findings can help guide the design of future studies of CVI in newborns.
PMCID: PMC4127379  PMID: 24515617
blood pressure; cardiovascular insufficiency; mechanical ventilation; inotrope; fluid bolus; glucocorticoid; outcomes; newborn
Pediatrics  2013;131(6):e1865-e1873.
To investigate the relationships among blood pressure (BP) values, antihypotensive therapies, and in-hospital outcomes to identify a BP threshold below which antihypotensive therapies may be beneficial.
Prospective observational study of infants 230/7 to 266/7 weeks’ gestational age. Hourly BP values and antihypotensive therapy use in the first 24 hours were recorded. Low BP was investigated by using 15 definitions. Outcomes were examined by using regression analysis controlling for gestational age, the number of low BP values, and illness severity.
Of 367 infants enrolled, 203 (55%) received at least 1 antihypotensive therapy. Treated infants were more likely to have low BP by any definition (P < .001), but for the 15 definitions of low BP investigated, therapy was not prescribed to 3% to 49% of infants with low BP and, paradoxically, was administered to 28% to 41% of infants without low BP. Treated infants were more likely than untreated infants to develop severe retinopathy of prematurity (15% vs 8%, P = .03) or severe intraventricular hemorrhage (22% vs 11%, P < .01) and less likely to survive (67% vs 78%, P = .02). However, with regression analysis, there were no significant differences between groups in survival or in-hospital morbidity rates.
Factors other than BP contributed to the decision to use antihypotensive therapies. Infant outcomes were not improved with antihypotensive therapy for any of the 15 definitions of low BP investigated.
PMCID: PMC3666108  PMID: 23650301
extremely preterm infant; antihypotensive therapy; blood pressure; hypotension
Pediatric research  2013;74(6):721-729.
Myo-inositol given to preterm infants with respiratory distress has reduced death, increased survival without bronchopulmonary dysplasia (BPD) and reduced severe retinopathy of prematurity (ROP) in 2 randomized trials. Pharmacokinetic (PK) studies in extremely preterm infants are needed prior to efficacy trials.
Infants of 23–29 weeks gestation were randomized to a single intravenous (IV) dose of inositol at 60 or 120 mg/kg or placebo. Over 96 h, serum levels (sparse sampling population PK) and urine inositol excretion were determined. Population PK models were fit using a nonlinear mixed effects approach. Safety outcomes were recorded.
A 1-compartment model that included factors for endogenous inositol production, allometric size based on weight, gestational age (GA) strata and creatinine clearance fit the data best. The central volume of distribution was 0.5115 l/kg, the clearance 0.0679 l/kg/h, endogenous production 2.67 mg/kg/h and the half life 5.22 h when modeled without the covariates. During the first 12 h renal inositol excretion quadrupled in the 120 mg/kg group, returning to near baseline after 48 h. There was no diuretic side-effect. No significant differences in adverse events occurred between the 3 groups (p > 0.05).
A single compartment model accounting for endogenous production satisfactorily described the PK of IV inositol.
PMCID: PMC3962781  PMID: 24067395
The Journal of Pediatrics  2012;161(2):264-269.e2.
To assess the impact of emperic antifungal therapy of invasive candidiasis on subsequent outcomes in premature infants.
Study design
This was a cohort study of infants ≤1000 g birth weight cared for at Neonatal Research Network sites. All infants had at least 1 positive culture for Candida. Emperic antifungal therapy was defined as receipt of a systemic antifungal on the day of or the day before the first positive culture for Candida was drawn. We created Cox proportional hazards and logistic regression models stratified on propensity score quartiles to determine the effect of emperic antifungal therapy on survival, time to clearance of infection, retinopathy of prematurity, bronchopulmonary dysplasia, end-organ damage, and neurodevelopmental impairment (NDI).
136 infants developed invasive candidiasis. The incidence of death or NDI was lower for infants who received emperic antifungal therapy (19/38, 50%) compared with those who had not (55/86, 64%; odds ratio=0.27 [95% confidence interval 0.08–0.86]). There was no significant difference between the groups for any single outcome or other combined outcomes.
Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.
PMCID: PMC3380169  PMID: 22424952
Candida; neonate; mortality; neurodevelopmental impairment
Current guidelines, initially published in 1995, recommend antenatal corticosteroids for mothers with preterm labor from 24–34 weeks gestational age, but not before 24 weeks because of lack of data. However, many infants born before 24 weeks are provided intensive care now.
To determine if antenatal corticosteroids are associated with improvement in major outcomes in infants born at 22 and 23 weeks.
Design, Setting, Participants
Data for this cohort study were collected prospectively on 401–1000 gram inborn infants (N=10,541) of 22–25 weeks gestation born between 1993–2009 at 23 academic perinatal centers in the United States. Certified examiners unaware of exposure to antenatal corticosteroids performed follow-up examinations on 4,924 (86.5%) of the infants born in 1993–2008 who survived to 18–22 months. Logistic regression models generated adjusted odds ratios, controlling for maternal and neonatal variables.
Main Outcome Measures
Mortality and neurodevelopmental impairment at 18–22 months corrected age
Death or neurodevelopmental impairment at 18–22 months was lower for infants whose mothers received antenatal corticosteroids born at 23 weeks (antenatal corticosteroids, 83.4% vs no antenatal corticosteroids, 90.5%; adjusted odds ratio 0.58; 95% CI, 0.42–0.80), at 24 weeks (antenatal corticosteroids, 68.4% vs no antenatal corticosteroids, 80.3%; adjusted odds ratio 0.62; 95% CI, 0.49–0.78), and at 25 weeks (antenatal corticosteroids, 52.7% vs no antenatal corticosteroids, 67.9%; adjusted odds ratio 0.61; 95% CI, 0.50–0.74) but not at 22 weeks (antenatal corticosteroids, 90.2% vs no antenatal corticosteroids, 93.1%; adjusted odds ratio 0.80; 95% CI, 0.29–12.21). Death by 18–22 months, hospital death, death/intraventricular hemorrhage/periventricular leukomalacia, and death/necrotizing enterocolitis were significantly lower for infants born at 23, 24, and 25 weeks gestational age if the mothers had received antenatal corticosteroids but the only outcome significantly lower at 22 weeks was death/necrotizing enterocolitis (antenatal corticosteroids, 73.5% vs no antenatal corticosteroids, 84.5%; adjusted odds ratio 0.54; 95% CI, 0.30–0.97).
Among infants born at 23–25 weeks gestation, use of antenatal corticosteroids compared to non-use was associated with a lower rate of death or neurodevelopmental impairment at 18–22 months.
PMCID: PMC3565238  PMID: 22147379
prematurity; infant mortality; neonatal intensive care; neurodevelopmental impairment; lung maturation; limits of viability
Pediatrics  2011;127(5):817-826.
Guidelines for prevention of group B streptococcal (GBS) infection have successfully reduced early onset (EO) GBS disease. Study results suggest that Escherichia coli is an important EO pathogen.
To determine EO infection rates, pathogens, morbidity, and mortality in a national network of neonatal centers.
Infants with EO infection were identified by prospective surveillance at Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Network centers. Infection was defined by positive culture results for blood and cerebrospinal fluid obtained from infants aged ≤72 hours plus treatment with antibiotic therapy for ≥5 days. Mother and infant characteristics, treatments, and outcomes were studied. Numbers of cases and total live births (LBs) were used to calculate incidence.
Among 396 586 LBs (2006–2009), 389 infants developed EO infection (0.98 cases per 1000 LBs). Infection rates increased with decreasing birth weight. GBS (43%, 0.41 per 1000 LBs) and E coli (29%, 0.28 per 1000 LBs) were most frequently isolated. Most infants with GBS were term (73%); 81% with E coli were preterm. Mothers of 67% of infected term and 58% of infected preterm infants were screened for GBS, and results were positive for 25% of those mothers. Only 76% of mothers with GBS colonization received intrapartum chemoprophylaxis. Although 77% of infected infants required intensive care, 20% of term infants were treated in the normal newborn nursery. Sixteen percent of infected infants died, most commonly with E coli infection (33%).
In the era of intrapartum chemoprophylaxis to reduce GBS, rates of EO infection have declined but reflect a continued burden of disease. GBS remains the most frequent pathogen in term infants, and E coli the most significant pathogen in preterm infants. Missed opportunities for GBS prevention continue. Prevention of E coli sepsis, especially among preterm infants, remains a challenge.
PMCID: PMC3081183  PMID: 21518717
neonatal sepsis; group B streptococcal disease; Escherichia coli infection
To determine association of anemia and RBC transfusions with NEC in preterm infants.
Study Design
111 preterm infants with NEC ≥ Stage 2a were compared with 222 matched controls. 28 clinical variables, including hematocrit and RBC transfusions were recorded. Propensity scores and multivariate logistic regression models were created to examine effects on the risk of NEC.
Controlling for other factors, lower hematocrit was associated with increased odds of NEC [OR 1.10, p =0.01]. RBC transfusion has a temporal relationship with NEC onset. Transfusion within 24h (OR=7.60, p=0.001) and 48h (OR=5.55, p=0.001) has a higher odds of developing NEC but this association is not significant by 96h (OR= 2.13, p =0.07), post transfusion
Anemia may increase the risk of developing NEC in preterm infants. RBC transfusions are temporally related to NEC. Prospective studies are needed to better evaluate the potential influence of transfusions on the development of NEC.
PMCID: PMC3234132  PMID: 21273983
transfusion related gut injury; hematocrit
Pediatrics  2010;126(4):e865-e873.
Invasive candidiasis is a leading cause of infection-related morbidity and mortality in extremely low-birth-weight (<1000 g) infants. We quantify risk factors predicting infection in high-risk premature infants and compare clinical judgment with a prediction model of invasive candidiasis.
The study involved a prospective observational cohort of infants <1000 g birth weight at 19 centers of the NICHD Neonatal Research Network. At each sepsis evaluation, clinical information was recorded, cultures obtained, and clinicians prospectively recorded their estimate of the probability of invasive candidiasis. Two models were generated with invasive candidiasis as their outcome: 1) potentially modifiable risk factors and 2) a clinical model at time of blood culture to predict candidiasis.
Invasive candidiasis occurred in 137/1515 (9.0%) infants and was documented by positive culture from ≥ 1 of these sources: blood (n=96), cerebrospinal fluid (n=9), urine obtained by catheterization (n=52), or other sterile body fluid (n=10). Mortality was not different from infants who had positive blood culture compared to those with isolated positive urine culture. Incidence varied from 2–28% at the 13 centers enrolling ≥ 50 infants. Potentially modifiable risk factors (model 1) included central catheter, broad-spectrum antibiotics (e.g., third-generation cephalosporins), intravenous lipid emulsion, endotracheal tube, and antenatal antibiotics. The clinical prediction model (model 2) had an area under the receiver operating characteristic curve of 0.79, and was superior to clinician judgment (0.70) in predicting subsequent invasive candidiasis. Performance of clinical judgment did not vary significantly with level of training.
Prior antibiotics, presence of a central catheter, endotracheal tube, and center were strongly associated with invasive candidiasis. Modeling was more accurate in predicting invasive candidiasis than clinical judgment.
PMCID: PMC3045840  PMID: 20876174
Candidiasis; premature infant; risk factors
Pediatrics  2010;126(3):443-456.
This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA).
Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22–28 weeks) and very low birth weight (401–1500 g) who were born at network centers between January 1, 2003, and December 31, 2007.
Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at ≤ 12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respiratory distress syndrome, 46% patent ductus arteriosus, 16% severe intraventricular hemorrhage, 11% necrotizing enterocolitis, and 36% late-onset sepsis. The new severity-based definition of bronchopulmonary dysplasia classified more infants as having bronchopulmonary dysplasia than did the traditional definition of supplemental oxygen use at 36 weeks (68%, compared with 42%). More than one-half of infants with extremely low GAs had undetermined retinopathy status at the time of discharge. Center differences in management and outcomes were identified.
Although the majority of infants with GAs of ≥24 weeks survive, high rates of morbidity among survivors continue to be observed.
PMCID: PMC2982806  PMID: 20732945
extremely low gestation; very low birth weight; morbidity; death
Pediatrics  2009;123(2):674-681.
The purpose of this work was to evaluate therapy for patent ductus arteri-osus as a risk factor for death or neurodevelopmental impairment at 18 to 22 months, bronchopulmonary dysplasia, or necrotizing enterocolitis in extremely low birth weight infants.
We studied infants in the National Institute of Child Health and Human Development Neonatal Research Network Generic Data Base born between 2000 and 2004 at 23 to 28 weeks’ gestation and at <1000-g birth weight with patent ductus arteriosus. Patent ductus arteriosus therapy was evaluated as a risk factor for outcomes in bivariable and multivariable analyses.
Treatment for subjects with patent ductus arteriosus (n = 2838) included 403 receiving supportive treatment only, 1525 treated with indomethacin only, 775 with indomethacin followed by secondary surgical closure, and 135 treated with primary surgery. Patients who received supportive therapy for patent ductus arteriosus did not differ from subjects treated with indomethacin only for any of the outcomes of interest. Compared with indomethacin treatment only, patients undergoing primary or secondary surgery were smaller and more premature. When compared with indomethacin alone, primary surgery was associated with increased adjusted odds for neurodevelopmental impairment and bronchopulmonary dysplasia in multivariable logistic regression. Secondary surgical closure was associated with increased odds for neurodevelopmental impairment and increased adjusted odds for bronchopulmonary dysplasia but decreased adjusted odds for death. Risk of necrotizing enterocolitis did not differ among treatments. Indomethacin prophylaxis did not significantly modify these results.
Our results suggest that infants treated with primary or secondary surgery for patent ductus arteriosus may be at increased risk for poor short- and long-term outcomes compared with those treated with indomethacin. Prophylaxis with indomethacin in the first 24 hours of life did not modify the subsequent outcomes of patent ductus arteriosus therapy.
PMCID: PMC2752886  PMID: 19171637
patent ductus arteriosus; bronchopulmonary dysplasia; necrotizing enterocolitis; neurodevelopmental impairment; therapy ductus arteriosus
Journal of Clinical Investigation  1968;47(7):1664-1671.
The effect of cholestyramine on the fecal excretion of bile acids and neutral sterols was measured in a hypercholesterolemic patient on a low fat, high polyunsaturated fatty acid-containing diet after the intravenous injection of cholesterol-4-14C. A significant (16%) lowering of serum cholesterol concentration was accompanied by a 3.2-fold increase in fecal bile acid excretion but no change in neutral sterol output. The increased bile acid loss was adequate to account for the observed fall in serum cholesterol level. The implications of these findings were discussed.
PMCID: PMC297323  PMID: 5658594
Journal of Clinical Investigation  1968;47(7):1517-1534.
Fecal bile acid and neutral sterol excretion rates were determined in five healthy young men when serum cholesterol changes were induced by isocaloric substitution of an unsaturated (safflower oil) for a saturated fat (butter). The isotope balance method was used after the intravenous injection of cholesterol-4-14C. A feces extraction method is presented which permits essentially complete separation of fecal neutral sterols and bile acids.
There was a significant increase in the total excretion of the fecal end products of cholesterol metabolism from 966 ± 42 mg/day on saturated fat to 1147 ± 45 mg/day on unsaturated fat, and the increase was equally distributed between the neutral sterol and bile acid fractions. With the substitution of dietary fats, regardless of the sequence of their feeding, there was a 28% reduction in serum cholesterol concentration during ingestion of the unsaturated fat. There were reciprocal changes in serum cholesterol levels and fecal steroid excretion with the substitution of one type of fat for the other. The changes in plasma cholesterol content were more than adequately balanced by the reciprocal changes in fecal cholesterol end product excretion.
The findings in this study agree with several previous reports in supporting the hypothesis that the hypocholesteremic action of dietary unsaturated fatty acids is associated with an increase in the fecal loss of bile acids and neutral sterols.
PMCID: PMC297311  PMID: 5658585
Synthesis of cholesterol from acetate in the rat was studied after injection of triton WR-1339, both in the whole animal and by the liver slice technique. Synthesis appeared to be increased 3-fold 24 hours after the injection. It was depressed after 72 hours, concurrently with a rise in the cholesterol concentration in the liver and its fall towards normal in the blood. When triton was injected into cholesterol-fed animals, or when their bile ducts were ligated, cholesterol synthesis was faster than in the untreated, normally fed controls, despite, in some instances, an elevated concentration of cholesterol in the liver.
PMCID: PMC2136468  PMID: 13233448
The effect on cholesterol synthesis of ligation of the common bile duct was studied in the rat. The bile ducts of rats were ligated; 24 to 48 hours later, estimates of the rate of cholesterol synthesis were made, either by injection of labelled water or acetate into the intact animal, or by incubation of slices or homogenates of the liver in the presence of 1-C14-acetate. These various criteria all indicated that cholesterol synthesis was increased following ligation of the bile duct. The average ratios of the rate of synthesis in the experimental animals to that in the controls were as follows: 1. Synthesis from C14-carboxyl-labelled acetate: (a) in the intact rat fed ad libitum, 19; (b) in liver slices from the fasted rat, 23; (c) in liver slices from the rat fed ad libitum, 4; (d) in cell-free homogenates from the fasted rat, >27; (e) in cell-free homogenates from the rat fed ad libitum, 17. 2. Synthesis from tritium-labelled water in the intact rat fed ad libitum, 4.
PMCID: PMC2136318  PMID: 13118062

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