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1.  Effect of Depth and Duration of Cooling on Deaths in the NICU Among Neonates With Hypoxic Ischemic Encephalopathy 
JAMA  2014;312(24):2629-2639.
Hypothermia at 33.5°C for 72 hours for neonatal hypoxic ischemic encephalopathy reduces death or disability to 44% to 55%; longer cooling and deeper cooling are neuroprotective in animal models.
To determine if longer duration cooling (120 hours), deeper cooling (32.0°C), or both are superior to cooling at 33.5°C for 72 hours in neonates who are full-term with moderate or severe hypoxic ischemic encephalopathy.
Arandomized, 2 × 2 factorial design clinical trial performed in 18 US centers in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network between October 2010 and November 2013.
Neonates were assigned to 4 hypothermia groups; 33.5°C for 72 hours, 32.0°C for 72 hours, 33.5°C for 120 hours, and 32.0°C for 120 hours.
The primary outcome of death or disability at 18 to 22 months is ongoing. The independent data and safety monitoring committee paused the trial to evaluate safety (cardiac arrhythmia, persistent acidosis, major vessel thrombosis and bleeding, and death in the neonatal intensive care unit [NICU]) after the first 50 neonates were enrolled, then after every subsequent 25 neonates. The trial was closed for emerging safety profile and futility analysis after the eighth review with 364 neonates enrolled (of 726 planned). This report focuses on safety and NICU deaths by marginal comparisons of 72 hours’ vs 120 hours’ duration and 33.5°C depth vs 32.0°C depth (predefined secondary outcomes).
The NICU death rates were 7 of 95 neonates (7%) for the 33.5°C for 72 hours group, 13 of 90 neonates (14%) for the 32.0°C for 72 hours group, 15 of 96 neonates (16%) for the 33.5°C for 120 hours group, and 14 of 83 neonates (17%) for the 32.0°C for 120 hours group. The adjusted risk ratio (RR) for NICU deaths for the 120 hours group vs 72 hours group was 1.37 (95% CI, 0.92–2.04) and for the 32.0°C group vs 33.5°C group was 1.24 (95% CI, 0.69–2.25). Safety outcomes were similar between the 120 hours group vs 72 hours group and the 32.0°C group vs 33.5°C group, except major bleeding occurred among 1% in the 120 hours group vs 3% in the 72 hours group (RR, 0.25 [95% CI, 0.07–0.91]). Futility analysis determined that the probability of detecting a statistically significant benefit for longer cooling, deeper cooling, or both for NICU death was less than 2%.
Among neonates who were full-term with moderate or severe hypoxic ischemic encephalopathy, longer cooling, deeper cooling, or both compared with hypothermia at 33.5°C for 72 hours did not reduce NICU death. These results have implications for patient care and design of future trials.
PMCID: PMC4335311  PMID: 25536254
2.  Sildenafil Exposure and Hemodynamic Effect after Fontan Surgery 
Determine sildenafil exposure and hemodynamic effect in children after Fontan single-ventricle surgery.
Prospective, dose-escalation trial.
Single-center, pediatric catheterization laboratory.
9 children post Fontan single-ventricle surgical palliation and undergoing elective cardiac catheterization: Median (range) age and weight: 5.2 years (2.5–9.4) and 16.3 kg (9.5–28.1). Five children (55%) were male, and 6/9 (67%) had a systemic right ventricle.
Catheterization and echocardiography performed before and immediately after single-dose intravenous sildenafil (0.25, 0.35, or 0.45 mg/kg over 20 minutes).
Peak sildenafil and des-methyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography.
Main Results
Maximum sildenafil concentrations ranged from 124–646 ng/ml and were above the in vitro threshold needed for 77% phosphodiesterase type-5 (PDE-5) inhibition in 8/9 children and 90% inhibition in 7/7 of children with doses ≥0.35 mg/kg. Sildenafil improved stroke volume (+22%, p=0.05) and cardiac output (+10%, p=0.01) with no significant change in heart rate in 8/9 children. Sildenafil also lowered systemic (-16%, p=0.01) and pulmonary vascular resistance index (PVRI) in all 9 children (median baseline PVRI 2.4 [range: 1.3, 3.7]; decreased to 1.9 [0.8, 2.7] WU x m2; p=0.01) with no dose-response effect. Pulmonary arterial pressures decreased (−10%, p=0.02) and pulmonary blood flow increased (9%, p=0.02). There was no change in myocardial performance index and no adverse events.
After Fontan surgery, sildenafil infusion acutely improves cardiopulmonary hemodynamics, increasing cardiac index. For the range of doses studied, exposure was within the acute safety range reported in adult subjects.
PMCID: PMC3887448  PMID: 24201857
single ventricle; sildenafil; Fontan; pulmonary hypertension; pulmonary vascular resistance; pharmacokinetics
3.  Characterization of the Population Pharmacokinetics of Ampicillin in Neonates Using an Opportunistic Study Design 
Although ampicillin is the most commonly used drug in neonates, developmental pharmacokinetic (PK) data to guide dosing are lacking. Ampicillin is primarily renally eliminated, and developmental changes are expected to influence PK. We conducted an open-label, multicenter, opportunistic, prospective PK study of ampicillin in neonates stratified by gestational age (GA) (≤34 or >34 weeks) and postnatal age (PNA) (≤7 or >7 days). Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effects modeling in NONMEM 7.2. Monte Carlo simulations were conducted to determine the probability of target attainment for the time in which the total steady-state ampicillin concentrations remained above the MIC (T>MIC) for 50%, 75%, and 100% of the dosing interval. A total of 142 PK samples from 73 neonates were analyzed (median [range] GA, 36 [24 to 41] weeks; PNA, 5 [0 to 25] days). The median ampicillin dose was 200 (100 to 350) mg/kg/day. Postmenstrual age and serum creatinine were covariates for ampicillin clearance (CL). A simplified dosing regimen of 50 mg/kg every 12 h for GA of ≤34 weeks and PNA of ≤7 days, 75 mg/kg every 12 h for GA of ≤34 weeks and PNA of ≥8 and ≤28 days, and 50 mg/kg every 8 h for GA of >34 weeks and PNA of ≤28 days achieved the prespecified surrogate efficacy target in 90% of simulated subjects. Ampicillin CL was associated with neonatal development. A simplified dosing regimen stratified by GA and PNA achieves the desired surrogate therapeutic target in the vast majority of neonates.
PMCID: PMC4068432  PMID: 24614374
4.  Comparative Effectiveness of Three Surfactant Preparations in Premature Infants 
The Journal of pediatrics  2013;163(4):955-960.e1.
To compare effectiveness of three surfactant preparations (beractant, calfactant, and poractant alpha) in premature infants for preventing three outcomes: (1) air leak syndromes; (2) death; and (3) bronchopulmonary dysplasia (BPD) or death (composite outcomes).
Study design
We conducted a comparative effectiveness study of premature infants admitted to 322 neonatal intensive care units in the U.S. from 2005–2010 who were treated with beractant, calfactant, or poractant alfa. We compared the incidence of air leak syndromes, death, and bronchopulmonary dysplasia (BPD) or death, adjusting for gestational age, antenatal steroids, discharge year, and small-for-gestational-age status.
51,282 infants received surfactant; 40% received beractant, 30% calfactant, and 30% poractant alfa. Median birth weight was 1435 g (interquartile range 966–2065); median gestational age was 30 weeks (27–33). On adjusted analysis, we observed a similar risk of air leak syndromes (calfactant vs. beractant odds ratio [OR]=1.17 [95% confidence interval: 0.95, 1.43]; calfactant vs. poractant OR=1.23 [0.98, 1.56]; beractant vs. poractant OR=1.06 [0.87, 1.29]), death (calfactant vs. beractant OR=1.14 [0.93, 1.39]; calfactant vs. poractant OR=0.98 [0.78, 1.23]; beractant vs. poractant OR=0.86 [0.72, 1.04]), and BPD or death (calfactant vs. beractant OR=1.08 [0.93, 1.26]; calfactant vs. poractant OR=1.19 [1.00, 1.41]; beractant vs. poractant OR=1.10 [0.96, 1.27]).
Beractant, calfactant, and poractant alfa demonstrated similar effectiveness in prevention of air leak syndromes, death, and BPD or death in premature infants when adjusted for site. Previously described differences in mortality between surfactants likely do not represent true differences in effectiveness but may relate to site variation in outcomes.
PMCID: PMC3779477  PMID: 23769501
beractant; calfactant; poractant alfa; premature infants; respiratory distress syndrome
5.  Evolving blood pressure dynamics for extremely preterm infants 
To examine changes in arterial blood pressure (ABP) after birth in extremely preterm infants.
Study Design
Prospective observational study of infants 230/7 – 266/7 weeks gestational age (GA). Antihypotensive therapy use and ABP measurements were recorded for the first 24 hours.
A cohort of 367 infants had 18,709 ABP measurements recorded. ABP decreased for the first three hours, reached a nadir at 4 – 5 hours, then increased at an average rate of 0.2 mmHg / hour. The rise in ABP from hour 4 – 24 was similar for untreated infants (n=164) and infants given any antihypotensive therapy (n=203), a fluid bolus (n=135), or dopamine (n=92). GA specific trends were similar. ABP tended to be lower as GA decreased, but varied widely at each GA.
Arterial blood pressure increased spontaneously over the first 24 postnatal hours for extremely preterm infants. The rate of rise in ABP did not change with antihypotensive therapy.
PMCID: PMC3982788  PMID: 24503912
Antihypotensive therapy; fluid bolus; dopamine
6.  Individual and Center-Level Factors Affecting Mortality Among Extremely Low Birth Weight Infants 
Pediatrics  2013;132(1):e175-e184.
To examine factors affecting center differences in mortality for extremely low birth weight (ELBW) infants.
We analyzed data for 5418 ELBW infants born at 16 Neonatal Research Network centers during 2006–2009. The primary outcomes of early mortality (≤12 hours after birth) and in-hospital mortality were assessed by using multilevel hierarchical models. Models were developed to investigate associations of center rates of selected interventions with mortality while adjusting for patient-level risk factors. These analyses were performed for all gestational ages (GAs) and separately for GAs <25 weeks and ≥25 weeks.
Early and in-hospital mortality rates among centers were 5% to 36% and 11% to 53% for all GAs, 13% to 73% and 28% to 90% for GAs <25 weeks, and 1% to 11% and 7% to 26% for GAs ≥25 weeks, respectively. Center intervention rates significantly predicted both early and in-hospital mortality for infants <25 weeks. For infants ≥25 weeks, intervention rates did not predict mortality. The variance in mortality among centers was significant for all GAs and outcomes. Center use of interventions and patient risk factors explained some but not all of the center variation in mortality rates.
Center intervention rates explain a portion of the center variation in mortality, especially for infants born at <25 weeks’ GA. This finding suggests that deaths may be prevented by standardizing care for very early GA infants. However, differences in patient characteristics and center intervention rates do not account for all of the observed variability in mortality; and for infants with GA ≥25 weeks these differences account for only a small part of the variation in mortality.
PMCID: PMC3691533  PMID: 23753096
mortality rates; outcome; NICU; preterm infants; extremely preterm infants
7.  Sildenafil exposure and hemodynamic effect after stage II single-ventricle surgery 
To determine sildenafil exposure and hemodynamic effect in children after stage II single-ventricle surgery.
Prospective, dose escalation trial.
Single-center, pediatric catheterization laboratory.
12 children post stage II single-ventricle surgical palliation and undergoing elective cardiac catheterization: median age 1.9 years (range: 0.8, 4.0), weight 11 kg (8, 13), 9 females, and 10 with a single right ventricle.
Catheterization and echocardiography performed before and immediately after single-dose intravenous sildenafil (0.125, 0.25, 0.35, or 0.45 mg/kg over 20 minutes).
Peak sildenafil and des-methyl sildenafil concentration, change in hemodynamic parameters measured by cardiac catheterization and echocardiography including indexed pulmonary vascular resistance, and myocardial performance.
Main Results
Maximum sildenafil concentrations ranged from 92–775 ng/ml and were above the in vitro threshold needed for 77% phosphodiesterase type-5 (PDE-5) inhibition in 80% of subjects and 90% inhibition in 80% of subjects with doses ≥0.35 mg/kg. Sildenafil lowered pulmonary vascular resistance index (PVRI) in all 12 subjects (median PVRI 2.2 [range: 1.6, 7.9]; decreased to 1.7 [1.2, 5.4] WU x m2; p<0.01) with no dose-response effect. Sildenafil improved pulmonary blood flow (+8% [0, 20], p=0.04) and saturations (+2% [0, 16], p=0.04) in those with baseline PVRI ≥2 WU x m2 (n=7). Change in saturations correlated inversely with change in PVRI (r2 = 0.74 p<0.01). Sildenafil also lowered mean blood pressure (−12% [−20, +10]; p=0.04). There was no change in cardiac index and no effect on myocardial performance. There were no adverse events.
Sildenafil demonstrated non-linear exposure with high inter-individual variability but was well tolerated and effectively lowered PVRI in all subjects. Sildenafil did not acutely improve myocardial performance or increase cardiac index.
PMCID: PMC3782306  PMID: 23823195
Single ventricle; sildenafil; bidirectional Glenn anastomosis; pulmonary hypertension; pulmonary vascular resistance; pharmacokinetics
8.  Use of Antihypotensive Therapies in Extremely Preterm Infants 
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
9.  Early Blood Gas Predictors of Bronchopulmonary Dysplasia in Extremely Low Gestational Age Newborns 
Aim. To determine among infants born before the 28th week of gestation to what extent blood gas abnormalities during the first three postnatal days provide information about the risk of bronchopulmonary dysplasia (BPD). Methods. We studied the association of extreme quartiles of blood gas measurements (hypoxemia, hyperoxemia, hypocapnea, and hypercapnea) in the first three postnatal days, with bronchopulmonary dysplasia, among 906 newborns, using multivariable models adjusting for potential confounders. We approximated NIH criteria by classifying severity of BPD on the basis of the receipt of any O2 on postnatal day 28 and at 36 weeks PMA and assisted ventilation. Results. In models that did not adjust for ventilation, hypoxemia was associated with increased risk of severe BPD and very severe BPD, while infants who had hypercapnea were at increased risk of very severe BPD only. In contrast, infants who had hypocapnea were at reduced risk of severe BPD. Including ventilation for 14 or more days eliminated the associations with hypoxemia and with hypercapnea and made the decreased risk of very severe BPD statistically significant. Conclusions. Among ELGANs, recurrent/persistent blood gas abnormalities in the first three postnatal days convey information about the risk of severe and very severe BPD.
PMCID: PMC4052060  PMID: 24959184
10.  Urinary tract infection concordance with positive blood and cerebrospinal fluid cultures in the neonatal intensive care unit 
Urinary tract infections (UTI) are common in the neonatal intensive care unit (NICU). Blood, urine, and cerebrospinal fluid (CSF) cultures are frequently obtained to evaluate for infection. We sought to determine the concordance between positive urine cultures and blood or CSF cultures.
Study design
Infants <121 days of age with a UTI admitted to 322 NICUs managed by the Pediatrix Medical Group from 1997–2010 were identified. UTIs were defined by isolation of a single pathogenic organism in a urine sample obtained by catheterization or suprapubic tap. The UTI was concordant if the same organism was identified in the blood or CSF within 3 days of the urine culture.
Of 5681 infants with a urine culture, 984 had 1162 UTIs. Nine hundred seventy-six UTIs (84%) had a blood culture collected within 3 days, and 127 (13%) were concordant. Of the 1162 UTIs, 77 (7%) had a CSF culture collected within 3 days, and 2 (3%) were concordant.
Collection of a urine culture in infants evaluated for late-onset sepsis is important. Concordance was observed in 13% of blood cultures and 3% of CSF cultures. These findings may be related to the initiation of empirical antimicrobial therapy before evaluation for disseminated infection or poor blood culture sensitivity.
PMCID: PMC3549035  PMID: 22935772
infant; sepsis
11.  Group B Streptococcus and Escherichia coli Infections in the Intensive Care Nursery in the Era of Intrapartum Antibiotic Prophylaxis 
Group B Streptococcus (GBS) and Escherichia coli (E. coli) cause serious bacterial infections (SBIs) and are associated with morbidity and mortality in newborn infants. Intrapartum antibiotic prophylaxis (IAP) reduces early-onset SBIs caused by GBS. The effect of IAP on late-onset SBIs caused by these organisms is unknown.
We examined all blood, urine, and cerebrospinal fluid culture results from infants admitted from 1997–2010 to 322 neonatal intensive care units managed by the Pediatrix Medical Group. We identified infants with positive cultures for GBS or E. coli and compared the incidence of early- and late-onset SBI for each organism in the time period before (1997–2001) and after (2002–2010) universal IAP recommendations.
We identified 716,407 infants with cultures, 2520 (0.4%) with cultures positive for GBS and 2476 (0.3%) with cultures positive for E. coli. The incidence of GBS early-onset SBI decreased between 1997–2001 and 2002–2010 from 3.5 to 2.6 per 1000 admissions, and the incidence for E. coli early-onset SBI remained stable (1.4 per 1000 admissions in both time periods). Over the same time period, the incidence of GBS late-onset SBI increased from 0.8 to 1.1 per 1000 admissions, and incidence of E. coli late-onset SBI increased from 2.2 to 2.5 per 1000 admissions.
In our cohort, the incidence of early-onset GBS SBI decreased, while the incidence of late-onset SBI for E. coli and GBS increased.
PMCID: PMC3572304  PMID: 23011013
infection; infant; sepsis; group B Streptococcus; Escherichia coli
12.  Systemic inflammation associated with mechanical ventilation among extremely preterm infants 
Cytokine  2012;61(1):315-322.
Little evidence is available to document that mechanical ventilation is an antecedent of systemic inflammation in preterm humans. We obtained blood on postnatal day 14 from 726 infants born before the 28th week of gestation and measured the concentrations of 25 inflammation-related proteins. We created multivariable models to assess the relationship between duration of ventilation and protein concentrations in the top quartile. Compared to newborns ventilated for fewer than 7 days (N=247), those ventilated for 14 days (N=330) were more likely to have elevated blood concentrations of pro-inflammatory cytokines (IL-1β, TNF-α), chemokines (IL-8, MCP-1), an adhesion molecule (ICAM-1), and a matrix metalloprotease (MMP-9), and less likely to have elevated blood concentrations of two chemokines (RANTES, MIP-1β), a matrix metalloproteinase (MMP-1), and a growth factor (VEGF). Newborns ventilated for 7-13 days (N=149) had systemic inflammation that approximated the pattern of newborns ventilated for 14 days. These relationships were not confounded by chorioamnionitis or antenatal corticosteroid exposure, and were not altered appreciably among infants with and without bacteremia. These findings suggest that two weeks of ventilation are more likely than shorter durations of ventilation to be accompanied by high blood concentrations of pro-inflammatory proteins indicative of systemic inflammation, and by low concentrations of proteins that might protect from inflammation-mediated organ injury.
PMCID: PMC3518391  PMID: 23148992
inflammation; ventilation; preterm infant; cytokine; chemokine
13.  Regional Variation in Late Preterm Births in North Carolina 
Late preterm (LPT) neonates (34 0/7th to 36 6/7th weeks' gestation) account for 70% of all premature births in the United States. LPT neonates have a higher morbidity and mortality risk than term neonates. LPT birth rates vary across geographic regions. Unwarranted variation is variation in medical care that cannot be explained by sociodemographic or medical risk factors; it represents differences in health system performance, including provider practice variation. The purpose of this study is to identify regional variation in LPT births in North Carolina that cannot be explained by sociodemographic or medical/obstetric risk factors.
We searched the NC State Center for Health Statistics linked birth-death certificate database for all singleton term and LPT neonates born between 1999 and 2006. We used multivariable logistic regression analysis to control for socio-demographic and medical/obstetric risk factors. The main outcome was the percent of late preterm birth in each of the six perinatal regions in North Carolina.
We identified 884,304 neonates; 66,218 (7.5%) were LPT. After multivariable logistic regression, regions 2 (7.0%) and 6 (6.6%) had the highest adjusted percent of LPT birth.
Analysis of a statewide birth cohort demonstrates regional variation in the incidence of LPT births among NC's perinatal regions after adjustment for sociodemographic and medical risk factors. We speculate that provider practice variation might explain some of the remaining difference. This is an area where policy changes and quality improvement efforts can help reduce variation, and potentially decrease LPT births.
PMCID: PMC3725330  PMID: 22350629
late preterm; preterm birth; unwarranted variation; practice variation
14.  Clinical prediction models for bronchopulmonary dysplasia: a systematic review and external validation study 
BMC Pediatrics  2013;13:207.
Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Very different models using clinical parameters at an early postnatal age to predict BPD have been developed with little extensive quantitative validation. The objective of this study is to review and validate clinical prediction models for BPD.
We searched the main electronic databases and abstracts from annual meetings. The STROBE instrument was used to assess the methodological quality. External validation of the retrieved models was performed using an individual patient dataset of 3229 patients at risk for BPD. Receiver operating characteristic curves were used to assess discrimination for each model by calculating the area under the curve (AUC). Calibration was assessed for the best discriminating models by visually comparing predicted and observed BPD probabilities.
We identified 26 clinical prediction models for BPD. Although the STROBE instrument judged the quality from moderate to excellent, only four models utilised external validation and none presented calibration of the predictive value. For 19 prediction models with variables matched to our dataset, the AUCs ranged from 0.50 to 0.76 for the outcome BPD. Only two of the five best discriminating models showed good calibration.
External validation demonstrates that, except for two promising models, most existing clinical prediction models are poor to moderate predictors for BPD. To improve the predictive accuracy and identify preterm infants for future intervention studies aiming to reduce the risk of BPD, additional variables are required. Subsequently, that model should be externally validated using a proper impact analysis before its clinical implementation.
PMCID: PMC3878731  PMID: 24345305
Prediction rules; Prognostic models; Calibration; Discrimination; Preterm infants; Chronic lung disease
15.  Safety and Effectiveness of Meropenem in Infants With Suspected or Complicated Intra-abdominal Infections 
The safety and effectiveness of meropenem in young infants with suspected or confirmed intra-abdominal infections were evaluated. was well tolerated in this cohort of critically-ill infants, and the majority of infants treated with meropenem (84%) met the definition of therapeutic success.
Background. Intra-abdominal infections are common in young infants and lead to significant morbidity and mortality. Meropenem is a broad-spectrum antimicrobial with excellent activity against pathogens associated with intra-abdominal infections. The purpose of this study was to determine the safety and effectiveness of meropenem in young infants with suspected or complicated intra-abdominal infections.
Methods. Preterm and term infants <91 days of age with suspected or confirmed intra-abdominal infections hospitalized in 24 neonatal intensive care units were studied in an open-label, multiple-dose study. Adverse events and serious adverse events were collected through 3 and 30 days following the last meropenem dose, respectively. Effectiveness was assessed by 3 criteria: death, bacterial cultures, and presumptive clinical cure score.
Results. Of 200 subjects enrolled in the study, 99 (50%) experienced an adverse event, and 34 (17%) had serious adverse events; no adverse events were probably or definitely related to meropenem. The most commonly reported adverse events were sepsis (6%), seizures (5%), elevated conjugated bilirubin (5%), and hypokalemia (5%). Only 2 of the serious adverse events were determined to be possibly related to meropenem (isolated ileal perforation and an episode of fungal sepsis). Effectiveness was evaluable in 192 (96%) subjects, and overall treatment success was 84%.
Conclusions. Meropenem was well tolerated in this cohort of critically ill infants, and the majority of infants treated with meropenem met the definition of therapeutic success.
Clinical Trials Registration. NCT00621192.
PMCID: PMC3491861  PMID: 22955430
16.  Predictors of Bronchopulmonary Dysplasia 
Clinics in perinatology  2012;39(3):585-601.
PMCID: PMC3443959  PMID: 22954271
bronchopulmonary dysplasia; predictors/risk factors; chronic lung disease; mechanical ventilation
18.  Feasibility Study of Early Blood Pressure Management in Extremely Preterm Infants 
The Journal of Pediatrics  2012;161(1):65-69.e1.
To assess the feasibility of a randomized placebo controlled trial (RCT) of blood pressure (BP) management for extremely preterm infants.
Study design
This was a prospective pilot RCT of infants 230/7 – 266/7 weeks gestation who had protocol-defined low BP in the first 24 postnatal hours. Enrolled infants were administered a study infusion (dopamine or placebo) and a study syringe medication (hydrocortisone or placebo).
Of the 366 infants screened, 119 (33%) had low BP, 58 (16%) met all entry criteria, and 10 (3%) were enrolled. 161 (44%) infants were ineligible because they received early indomethacin. Only 17% of eligible infants were enrolled. Problems with consent included insufficient time, parent unavailability, and physician unwillingness to enroll critically ill infants. Two infants were withdrawn from the study due to the potential risk of intestinal perforation with simultaneous administration of hydrocortisone and indomethacin.
This pilot RCT was not feasible due to low eligibility and consent rates. An RCT of BP management for extremely preterm infants may require a waiver of consent for research in emergency care. The frequent use of early indomethacin and the associated risk of intestinal perforation when used with hydrocortisone may limit future investigations to only inotropic medications.
PMCID: PMC3357442  PMID: 22336574
Extremely preterm infant; hypotension; hydrocortisone; dopamine; informed consent
19.  Approach to Infants Born at 22 to 24 Weeks’ Gestation: Relationship to Outcomes of More-Mature Infants 
Pediatrics  2012;129(6):e1508-e1516.
We sought to determine if a center’s approach to care of premature infants at the youngest gestational ages (22–24 weeks’ gestation) is associated with clinical outcomes among infants of older gestational ages (25–27 weeks’ gestation).
Inborn infants of 401 to 1000 g birth weight and 22 0/7 to 27 6/7 weeks’ gestation at birth from 2002 to 2008 were enrolled into a prospectively collected database at 20 centers participating in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Markers of an aggressive approach to care for 22- to 24-week infants included use of antenatal corticosteroids, cesarean delivery, and resuscitation. The primary outcome was death before postnatal day 120 for infants of 25 to 27 weeks’ gestation. Secondary outcomes were the combined outcomes of death or a number of morbidities associated with prematurity.
Our study included 3631 infants 22 to 24 weeks’ gestation and 5227 infants 25 to 27 weeks’ gestation. Among the 22- to 24-week infants, use of antenatal corticosteroids ranged from 28% to 100%, cesarean delivery from 13% to 65%, and resuscitation from 30% to 100% by center. Centers with higher rates of antenatal corticosteroid use in 22- to 24-week infants had reduced rates of death, death or retinopathy of prematurity, death or late-onset sepsis, death or necrotizing enterocolitis, and death or neurodevelopmental impairment in 25- to 27-week infants.
This study suggests that physicians’ willingness to provide care to extremely low gestation infants as measured by frequency of use of antenatal corticosteroids is associated with improved outcomes for more-mature infants.
PMCID: PMC3362905  PMID: 22641761
low-birth weight infant; NICUs; treatment; patient outcome assessment
20.  Pharmacokinetics of Moxifloxacin in an Infant with Mycoplasma hominis Meningitis 
Treatment of Mycoplasma hominis meningitis in infants is limited by a lack of consensus regarding therapy and limited pharmacokinetic data for agents to which M. hominis is susceptible. We report the successful treatment of a premature infant with M. hominis meningitis with doxycycline and moxifloxacin and provide a pharmacokinetic profile of moxifloxacin.
PMCID: PMC3358780  PMID: 22016080
meningitis; moxifloxacin; Mycoplasma hominis; infant; pharmacokinetic
21.  Patterns of blood protein concentrations of ELGANs classified by three patterns of respiratory disease in the first two postnatal weeks 
Pediatric research  2011;70(3):292-296.
We examined the association between elevated concentrations of 25 blood proteins in blood spots collected on postnatal days 1, 7, and 14 from infants < 28 weeks gestation who survived to 24 months and the risk of two patterns of early lung disease i.e., early and persistent pulmonary dysfunction (EPPD), and normal early pulmonary function followed by pulmonary deterioration (PD). 38% (N=347) of our cohort had PD, and 43% (N=383) had EPPD. On postnatal day 14, elevated concentrations of two proteins (RANTES and VEGF) were associated with reduced risk of PD. Similarly, the risk of EPPD was also reduced if three proteins had elevated concentrations on postnatal day 14 (RANTES, MMP-1, and VEGF). In contrast, the risk of EPPD was increased if on day 14 two proteins had elevated concentrations (IL-8 and ICAM-1). Inflammation might influence the risk of EPPD and PD, or be a consequence of lung damage or therapies to minimize lung dysfunction.
PMCID: PMC3152639  PMID: 21646942
22.  Characteristics of Patients Who Die of Necrotizing Enterocolitis 
Journal of Perinatology  2011;32(3):199-204.
Necrotizing enterocolitis is associated with high morbidity and mortality among infants admitted for intensive care. The factors associated with mortality and catastrophic presentation remain poorly understood.
To describe the factors associated with mortality in infants with necrotizing enterocolitis and to quantify the degree to which catastrophic presentation contributes to mortality in infants with necrotizing enterocolitis.
We performed a retrospective review of the Pediatrix's Clinical Data Warehouse (1997-2009) to compare the demographic, therapeutic and outcome characteristics of infants who survived NEC versus those who died. Associations were tested by bivariate and multivariate analysis.
In a total cohort of 560,227 infants, there were 2661 cases (17%) of surgically treated and 6460 (42%) of medically treated necrotizing enterocolitis; 1505 (16.5%) died. In multivariate analysis, the factors associated with death (P<0.01 in analysis) were lower estimated gestational age, lower birth weight, a need for assisted ventilation on the day of diagnosis of NEC, a need for vasopressors at the time of diagnosis, and Black race. Patients who received only ampicillin and gentamicin on the day of diagnosis were less likely to die.
Two thirds of NEC deaths occurred quickly (<7 days from diagnosis), with a median time of death of one day from time of diagnosis. Infants who died within 7 days of diagnosis had a higher birth weight, more often required vasopressors and more often were treated with high frequency ventilation at the time of diagnosis compared to patients who died at 7 or more days. Although mortality decreased with increasing gestational age, the proportion of deaths that occur within 7 days was relatively consistent (65-75 percent of the patients who died) across all gestational ages.
Mortality among infants who have necrotizing enterocolitis remains high and infants who die of necrotizing enterocolitis commonly (66%) die quickly. Most of the factors associated with mortality are related to immaturity, low birth weight and severity of illness.
PMCID: PMC3289772  PMID: 21593813
23.  Innovative clinical trial design for pediatric therapeutics 
Until approximately 15 years ago, sponsors rarely included children in the development of therapeutics. US and European legislation has resulted in an increase in the number of pediatric trials and specific label changes and dosing recommendations, although infants remain an understudied group. The lack of clinical trials in children is partly due to specific challenges in conducting trials in this patient population. Therapeutics in special populations, including premature infants, obese children and children receiving extracorporeal life support, are even less studied. National research networks in Europe and the USA are beginning to address some of the gaps in pediatric therapeutics using novel clinical trial designs. Recent innovations in pediatric clinical trial design, including sparse and scavenged sampling, population pharmacokinetic analyses and ‘opportunistic’ studies, have addressed some of the historical challenges associated with clinical trials in children.
PMCID: PMC3184526  PMID: 21980319
clinical trial simulation; opportunistic study; pediatrics; pharmacodynamics; pharmacokinetics; pharmacometrics; therapeutics
24.  Coagulase-negative Staphylococcal Infections in the Neonatal Intensive Care Unit 
Coagulase-negative staphylococci (CoNS) are the most commonly isolated pathogens in the neonatal intensive care unit (NICU). CoNS infections are associated with increased morbidity including neurodevelopmental impairment.
Describe the epidemiology of CoNS infections in the NICU. Determine mortality among infants with definite, probable, or possible CoNS infections.
We performed a retrospective cohort study of all blood, urine, and cerebrospinal fluid cultures from infants <121 postnatal days.
248 NICUs managed by the Pediatrix Medical Group from 1997 to 2009.
We identified 16,629 infants with 17,624 episodes of CoNS infection: 1734 (10%) definite, 3093 (17%) probable, and 12,797 (73%) possible infections. Infants with lower gestational age and birth weight had a higher incidence of CoNS infection. Controlling for gestational age, birth weight, and 5-minute Apgar score, infants with definite, probable, or possible CoNS infection had lower mortality—OR=0.74 (95% confidence interval; 0.61, 0.89), OR= 0.68 (0.59, 0.79), and OR=0.69 (0.63, 0.76)—compared to infants with negative cultures (P<0.001). No significant difference in overall mortality was found in infants with definite CoNS infection compared to those with probable or possible CoNS infection—OR=0.93 (0.75, 1.16) and OR=0.85 (0.70, 1.03), respectively.
CoNS infection was strongly related to lower gestational age and birth weight. Infants with clinical sepsis and culture-positive CoNS infection had lower mortality rates than infants with clinical sepsis and negative blood culture results. No difference in mortality between infants diagnosed with definite, probable, or possible CoNS infection was observed.
PMCID: PMC3238054  PMID: 21666399
nosocomial infection; infant; prematurity; Staphylococcus
25.  Prediction of Bronchopulmonary Dysplasia by Postnatal Age in Extremely Premature Infants 
Rationale: Benefits of identifying risk factors for bronchopulmonary dysplasia in extremely premature infants include providing prognostic information, identifying infants likely to benefit from preventive strategies, and stratifying infants for clinical trial enrollment.
Objectives: To identify risk factors for bronchopulmonary dysplasia, and the competing outcome of death, by postnatal day; to identify which risk factors improve prediction; and to develop a Web-based estimator using readily available clinical information to predict risk of bronchopulmonary dysplasia or death.
Methods: We assessed infants of 23–30 weeks' gestation born in 17 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network and enrolled in the Neonatal Research Network Benchmarking Trial from 2000–2004.
Measurements and Main Results: Bronchopulmonary dysplasia was defined as a categorical variable (none, mild, moderate, or severe). We developed and validated models for bronchopulmonary dysplasia risk at six postnatal ages using gestational age, birth weight, race and ethnicity, sex, respiratory support, and FiO2, and examined the models using a C statistic (area under the curve). A total of 3,636 infants were eligible for this study. Prediction improved with advancing postnatal age, increasing from a C statistic of 0.793 on Day 1 to a maximum of 0.854 on Day 28. On Postnatal Days 1 and 3, gestational age best improved outcome prediction; on Postnatal Days 7, 14, 21, and 28, type of respiratory support did so. A Web-based model providing predicted estimates for bronchopulmonary dysplasia by postnatal day is available at
Conclusions: The probability of bronchopulmonary dysplasia in extremely premature infants can be determined accurately using a limited amount of readily available clinical information.
PMCID: PMC3136997  PMID: 21471086
bronchopulmonary dysplasia; prematurity; low-birth-weight infant

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