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1.  Individual and Center-Level Factors Affecting Mortality Among Extremely Low Birth Weight Infants 
Pediatrics  2013;132(1):e175-e184.
OBJECTIVE:
To examine factors affecting center differences in mortality for extremely low birth weight (ELBW) infants.
METHODS:
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.
RESULTS:
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.
CONCLUSIONS:
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.
doi:10.1542/peds.2012-3707
PMCID: PMC3691533  PMID: 23753096
mortality rates; outcome; NICU; preterm infants; extremely preterm infants
2.  Pharmacokinetics and Tolerability of Single-Dose Daptomycin in Young Infants 
Background
Daptomycin is approved for the treatment of complicated skin and skin structure infections and Staphylococcus aureus bacteremia. We sought to characterize daptomycin single-dose pharmacokinetics and tolerability in young infants.
Methods
Subjects <120 days of age with suspected systemic infections were eligible for inclusion. Each subject was given a single 6 mg/kg intravenous dose of daptomycin. An average of 4 post-dose concentrations per infant was obtained.
Results
Data from 20 infants are presented. Median gestational age at birth and postnatal age were 32 weeks (range 23, 40) and 3 days (1, 85), respectively. The median area under the concentration curve at 24 hours, volume of distribution, total body clearance, and half-life of daptomycin were 262.4 mg*h/L (166.7, 340.2), 0.21 L/kg (0.11, 0.34), 0.021 L/hr/kg (0.016, 0.034), and 6.2 hours (3.7, 9.0), respectively. No adverse events related to daptomycin were observed, including changes in creatine phosphokinase concentrations.
Conclusions
Daptomycin clearance in young infants was similar to that in 2–6-year-olds and higher than that observed in adolescents and adults.
doi:10.1097/INF.0b013e31825d2fa2
PMCID: PMC3421038  PMID: 22627869
daptomycin; complicated skin and skin structure infections; Staphylococcus aureus; pharmacokinetics
3.  Urinary tract infection concordance with positive blood and cerebrospinal fluid cultures in the neonatal intensive care unit 
Objective
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.
Results
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.
Conclusion
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.
doi:10.1038/jp.2012.111
PMCID: PMC3549035  PMID: 22935772
infant; sepsis
4.  Duration of empirical antibiotic therapy for infants suspected of early-onset sepsis 
Current opinion in pediatrics  2013;25(2):167-171.
Purpose of review
Clinicians’ adherence to AAP and CDC Guidelines to prevent Group B Streptococcal (GBS) early onset sepsis (EOS) have reduced GBS EOS. While evidence-based testing and empirical antibiotic initiation is likely saving lives, clinicians have less compelling data to guide duration of empirically initiated antibiotics when cultures remain sterile and clinical signs resolve quickly. Our purpose is to review current opinions and evidence influencing clinicians’ choices for duration of empirically initiated antibiotics in newborns with sterile cultures.
Recent findings
Retrospective cohort studies indicate potential for harm with longer duration of empirical antibiotics for EOS when cultures are sterile. Cohort studies indicate timing of widely used tests used to estimate EOS risk affects their predictive value, and tests acquired 24 – 48 hours postnatally may provide reassurance for safe discontinuation.
Summary
Every day clinicians caring for thousands of neonates in the US stop antibiotics which were started empirically to treat EOS on the first postnatal day. Evidence is lacking to support a universal approach to decisions on duration of empirical antibiotics when cultures remain sterile. Reviewing predictive value relative to timing of laboratory testing can help clinicians develop locally appropriate antimicrobial duration decision-making guidelines.
doi:10.1097/MOP.0b013e32835e01f6
PMCID: PMC3596444  PMID: 23407181
empirical antibiotics; early onset sepsis
5.  Perinatal Factors Associated with Poor Neurocognitive Outcome in Early School Age Congenital Diaphragmatic Hernia Survivors 
Journal of pediatric surgery  2013;48(4):730-737.
Objective
Determine predictors of neurocognitive outcome in early school age congenital diaphragmatic hernia (CDH) survivors.
Study design
Prospective study of infants with CDH at Duke University Medical Center. Neurocognitive delay (NCD) at school age (4 to 7 years) was defined as a score < 80 in any of the following areas: Verbal Scale IQ, Performance Scale IQ, Expressive Language, or Receptive Language. Logistic regression, Fisher’s exact, and the Wilcoxon rank sum test were used to examine the relationship between NCD at early school age and 6 demographic and 18 medical variables.
Results
Of 43 infants with CDH, twenty seven (63%) survived to hospital discharge, and 16 (59%) returned for school age testing at a median age of 4.9 years. Seven (44%) of the children evaluated had NCD. Patch repair (p=0.01), extracorporeal membrane oxygenation (ECMO; p=0.02), days on ECMO (p=0.01), days of mechanical ventilation (p=0.049), and post-operative use of inhaled nitric oxide (p=0.02) were found to be associated with NCD at early school age.
Conclusions
CDH survivors are at risk for neurocognitive delay persisting into school age. Perinatal factors such as patch repair and ECMO treatment may aid in identifying CDH survivors at high risk for continued learning difficulties throughout childhood.
doi:10.1016/j.jpedsurg.2012.09.026
PMCID: PMC3734202  PMID: 23583126
hernia, diaphragmatic; follow-up studies; neurobehavioral manifestations; growth & development; infant nutrition disorders
6.  Group B Streptococcus and Escherichia coli Infections in the Intensive Care Nursery in the Era of Intrapartum Antibiotic Prophylaxis 
Background
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.
Methods
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.
Results
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.
Conclusions
In our cohort, the incidence of early-onset GBS SBI decreased, while the incidence of late-onset SBI for E. coli and GBS increased.
doi:10.1097/INF.0b013e318275058a
PMCID: PMC3572304  PMID: 23011013
infection; infant; sepsis; group B Streptococcus; Escherichia coli
7.  Risk Factors for Invasive Candidiasis in Infants >1500 g Birth Weight 
Background
We describe the incidence, risk factors, and outcomes of invasive candidiasis in infants >1500 g birth weight.
Methods
We conducted a retrospective cohort study of infants >1500 g birth weight discharged from 305 NICUs in the Pediatrix Medical Group from 2001–2010. Using multivariable logistic regression, we identified risk factors for invasive candidiasis.
Results
Invasive candidiasis occurred in 330/530,162 (0.06%) infants. These were documented from positive cultures from ≥1 of these sources: blood (n=323), cerebrospinal fluid (n=6), or urine from catheterization (n=19). Risk factors included day of life >7 (OR 25.2; 95% CI 14.6–43.3), vaginal birth (OR 1.6 [1.2–2.3]), exposure to broad-spectrum antibiotics (OR 1.6 [1.1–2.4]), central venous line (OR 1.8 [1.3–2.6]), and platelet count <50,000/mm3 (OR 3.7 [2.1–6.7]). All risk factors had poor sensitivities, low positive likelihood ratios, and low positive predictive values. The combination of broad-spectrum antibiotics and low platelet count had the highest positive likelihood ratio (46.2), but the sensitivity of this combination was only 4%. Infants with invasive candidiasis had increased mortality (OR 2.2 [1.3–3.6]).
Conclusions
Invasive candidiasis is uncommon in infants >1500 g birth weight. Infants at greatest risk are those exposed to broad-spectrum antibiotics and with platelet counts of <50,000/mm3.
doi:10.1097/INF.0b013e3182769603
PMCID: PMC3578110  PMID: 23042050
candidiasis; candidemia; neonates; neonatal intensive care unit
8.  Sports Medicine and Ethics 
Physicians working in the world of competitive sports face unique ethical challenges, many of which center around conflicts of interest. Team-employed physicians have obligations to act in the club’s best interest while caring for the individual athlete. As such, they must balance issues like protecting versus sharing health information, as well as issues regarding autonomous informed consent versus paternalistic decision-making in determining whether an athlete may compete safely. Moreover, the physician has to deal with an athlete’s decisions about performance enhancement and return to play, pursuit of which may not be in the athlete’s long-term best interests but may benefit the athlete and team in the short term. These difficult tasks are complicated by the lack of evidence-based standards in a field influenced by the lure of financial gains for multiple parties involved. In this article, we review ethical issues in sports medicine with specific attention paid to American professional football.
doi:10.1080/15265161.2013.828114
PMCID: PMC3899648  PMID: 24024796
sports medicine; ethics; conflict of interest; sports; football; athletes
9.  Regional Variation in Late Preterm Births in North Carolina 
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1007/s10995-012-0945-7
PMCID: PMC3725330  PMID: 22350629
late preterm; preterm birth; unwarranted variation; practice variation
10.  Isoflurane for Life-Threatening Bronchospasm – A 15 Year Single-Center Experience 
Respiratory care  2012;57(11):10.4187/respcare.01605.
Introduction
Children with severe bronchospasm requiring mechanical ventilation may become refractory to conventional therapy. In these critically ill patients, isoflurane is an inhaled anesthetic agent available in some centers to treat bronchospasm. We hypothesized that isoflurane is safe and would lead to improved gas exchange in children with life-threatening bronchospasm refractory to conventional therapy.
Methods
A retrospective review was conducted and included mechanically ventilated children treated with isoflurane in a quaternary pediatric intensive care unit for life-threatening bronchospasm from 1993–2007. Demographic, blood gas, ventilator and outcome data were collected.
Results
Thirty-one patients with a mean age of 9.5 years (range; 0.4 – 23 years) were treated with isoflurane from 1993–2007. Mean time to initiation of isoflurane after intubation was 13 hours (0–120 hours) and the mean maximum isoflurane dose was 1.1 % (0.3 – 2.5%). Mean duration of isoflurane administration was 54.5 hours (1 – 181), with a total mean duration of mechanical ventilation of 252 hours (33.3 – 1454.5). Isoflurane led to significant improvement in pH and pCO2 within four hours of initiation (p ≤ 0.001). Complications during isoflurane administration included hypotension requiring vasoactive infusions in 24 (77%), arrhythmia in 3 (10%), neurologic side effects in 3 (10%), and pneumothorax in 1 (3%) patient.
Conclusions
Isoflurane led to improvement in pH and pCO2 within four hours in this series of mechanically ventilated patients with life-threatening bronchospasm. The majority of patients in this series developed hypotension, but there was a low incidence of other side effects related to isoflurane administration. Isoflurane appears to be an effective therapy in patients with life-threatening bronchospasm refractory to conventional therapy. However, further investigation is warranted given the uncertain overall impact of isoflurane in this context.
doi:10.4187/respcare.01605
PMCID: PMC3825849  PMID: 22417969
asthma; bronchospasm; mechanical ventilation; inhaled anesthetics; isoflurane; pediatric intensive care unit
11.  Very low birth weight neonates who survive early-onset sepsis do not have an increased risk of developing late-onset sepsis 
Early human development  2012;88(11):905-909.
SUMMARY
Background
Very low birth weight neonates (≤1500 g, VLBWs) have a high rate of infection and distinct baseline immune function compared with more mature populations. In critically ill children and adults, sepsis increases subsequent infection risk. It is unknown whether sepsis modifies the risk of subsequent infection in VLBWs.
Methods
We conducted a retrospective cohort study of VLBWs ≤32 weeks gestation at birth cared for in 312 neonatal intensive care units in the United States from 1997–2011 (n=103,376). Early-onset sepsis (EOS, culture-positive only) and late-onset sepsis (LOS, culture-positive or clinical) cases were identified. Cox proportional hazards models were used to control for clinical variables between neonates with and without EOS to determine if EOS modified risk of LOS, necrotizing enterocolitis (NEC), or death.
Results
LOS occurred in 12,112/102,317 (11.8%) neonates without EOS and in 133/1059 (12.6%) of those with EOS. After adjustment for clinical variables, the risk of LOS was not different between neonates with or without a history of EOS (hazard ratio [HR]=0.92; 95% confidence interval [CI] 0.74, 1.16). EOS increased the risk of 120-day mortality (HR=1.78; 95% CI 1.49, 2.13).
Conclusions
In contrast to findings in children and adults, EOS was not associated with an increased risk of LOS in this cohort. Age-specific investigations are needed to determine if post-sepsis immunologic alterations are present.
doi:10.1016/j.earlhumdev.2012.07.009
PMCID: PMC3462255  PMID: 22840605
preterm; neonate; sepsis; immunoparalysis
13.  Pharmacokinetics and Safety of Fluconazole in Young Infants Supported with Extracorporeal Membrane Oxygenation 
Background
Candida infections are a leading cause of infectious disease-related death in infants supported with extracorporeal membrane oxygenation (ECMO). The ECMO circuit can alter drug pharmacokinetics (PK), thus standard fluconazole dosing in children on ECMO may result in suboptimal drug exposure. This study determined the PK of fluconazole in infants on ECMO.
Methods
Infants <120 days old received either intravenous fluconazole prophylaxis (25 mg/kg once a week) or treatment (12 mg/kg daily) while on ECMO. Paired plasma samples were collected pre- and post-oxygenator around doses 1 and 2 to calculate PK indices and describe oxygenator extraction. A 1-compartment model was fit to the data using non-linear regression. Surrogate pharmacodynamic targets for efficacy were evaluated.
Results
Ten infants were enrolled. After dose 1 (n=9), the median clearance was 17 mL/kg/h, the median volume of distribution was 1.5 L/kg, and the median exposure in the first 24 hours (AUC0–24) was 322 h*mg/L. After multiple doses (n=7), the median clearance was 22 mL/kg/h, the median volume of distribution was 1.9 L/kg, and the AUC0–24 was 352 h*mg/L. After dose 1, 78% of infants achieved the prophylaxis target, while only 11% achieved the therapeutic target. Oxygenator extraction of fluconazole was minimal (−2.0%, standard deviation 15.0), and extraction was not correlated with age of the ECMO circuit (rho= − 0.05). There were no adverse events related to fluconazole.
Conclusions
Infants on ECMO had higher volume of distribution but similar clearance when compared with historical controls not on ECMO. In infants on ECMO, a fluconazole dose of 25 mg/kg weekly provides adequate exposure for prophylaxis against Candida infections. However, higher doses may be needed for treatment.
doi:10.1097/INF.0b013e31825d3091
PMCID: PMC3444624  PMID: 22627870
fluconazole; Candida; extracorporeal membrane oxygenation; pharmacokinetics; infants
15.  Recent Advances in the Detection of Neonatal Candidiasis 
Neonatal candidiasis is serious and often fatal. Blood culture, the standard for diagnosis, has a sensitivity of 50% or less, and isolate speciation and susceptibility takes several days. This review explores recent advances in Candida detection using various diagnostic strategies.
doi:10.1007/s12281-010-0002-1
PMCID: PMC2864036  PMID: 20454602
16.  Use of the Complete Blood Cell Count in Early-Onset Neonatal Sepsis 
Background
Early-onset sepsis is an important cause of morbidity and mortality in neonates, and its diagnosis remains challenging. The complete blood cell count and differential have been previously evaluated as diagnostic tools for early-onset sepsis in small, single-center reports. We evaluated the diagnostic accuracy of the complete blood count and differential in early-onset sepsis in a large, multicenter population of neonates admitted to the neonatal intensive care unit.
Methods
Using a cohort of 166,092 neonates with suspected early-onset sepsis with cultures admitted to 293 neonatal intensive care units, we calculated odds ratios and receiver operating characteristic curves for complete blood cell count indices and prediction of a positive culture. We determined sensitivity, specificity, and likelihood ratios for various commonly used cut-off values from the complete blood cell count.
Results
Low white blood cell counts, low absolute neutrophil counts, and high immature-to-total neutrophil ratios were associated with increasing odds of infection (highest odds ratios: 5.38, 6.84, and 7.97, respectively). Specificity and negative predictive values were high (73.7–99.9% and >99.8%). However, sensitivities were low (0.3–54.5%) for all complete blood cell count indices analyzed.
Conclusion
Low white blood cell count, absolute neutrophil count, and high immature-to-total neutrophil ratio were associated with increasing odds of infection, but no complete blood cell count-derived index possesses the sensitivity to rule out reliably early-onset sepsis in neonates.
doi:10.1097/INF.0b013e318256905c
PMCID: PMC3399972  PMID: 22531231
neonatal; early-onset sepsis; blood cell count
17.  Use of the Complete Blood Cell Count in Late-Onset Neonatal Sepsis 
Background
Late-onset sepsis is an important cause of morbidity and mortality in infants. Diagnosis of late-onset sepsis can be challenging. The complete blood cell count and differential have been previously evaluated as diagnostic tools for late-onset sepsis in small, single-center reports.
Objective
We evaluated the diagnostic accuracy of the complete blood count and differential in late-onset sepsis in a large multicenter population.
Study design
Using a cohort of all infants with cultures and complete blood cell count data from a large administrative database, we calculated odds ratios for infection, as well as sensitivity, specificity, positive and negative predictive values, and likelihood ratios for various commonly used cut-off values.
Results
High and low white blood cell counts, high absolute neutrophil counts, high immature-to-total neutrophil ratios, and low platelet counts were associated with late-onset sepsis. Associations were weaker with increasing postnatal age at the time of the culture. Specificity was highest for white blood cell counts <1000/mm3 and >50,000/mm3 (>99%). Positive likelihood ratios were highest for white blood cell counts <1000/mm3 (4.1) and platelet counts <50,000/mm3 (3.5).
Conclusion
No complete blood count index possessed adequate sensitivity to reliably rule out late-onset sepsis in this population.
doi:10.1097/INF.0b013e31825691e4
PMCID: PMC3399981  PMID: 22531232
neonatal; late-onset sepsis; blood cell count
18.  Safety and Effectiveness of Indomethacin versus Ibuprofen for Treatment of the Patent Ductus Arteriosus 
American journal of perinatology  2009;27(5):425-429.
Objective
Compare the rates of medical closure of the PDA and complications (renal dysfunction, necrotizing enterocolitis, spontaneous intestinal perforation, and intraventricular hemorrhage) between infants treated with indomethacin and ibuprofen.
Study Design
A retrospective comparative cohort study of infants treated with indomethacin or ibuprofen for symptomatic patent ductus arteriosus at Duke University Medical Center between November 2005 and November 2007.
Result
We identified 65 infants that received indomethacin and 57 that received ibuprofen. The rate of survival without surgical ductal ligation was 62% (40/65) in the indomethacin group and 58% (33/57) in the ibuprofen group, P=0.71. The rate of the composite of complications (death, necrotizing enterocolitis, or intestinal perforation) was 40% (26/65) in the indomethacin group and 32% (18/57) in the ibuprofen group, P=0.35. There was no significant difference between groups in elevation of serum creatinine during treatment.
Conclusion
In clinical practice, ibuprofen appears to be as effective as indomethacin for closure of patent ductus arteriosus with similar complication rates. The decision to use one agent over the other should be based on dose schedule preference and the currently published clinical trials until more safety and effectiveness data are available.
doi:10.1055/s-0029-1243371
PMCID: PMC2877168  PMID: 20013605
Ibuprofen; Indomethacin; Patent Ductus Arteriosus; Neonates; Nonsteroidal antiinflammatory drug
19.  Approach to Infants Born at 22 to 24 Weeks’ Gestation: Relationship to Outcomes of More-Mature Infants 
Pediatrics  2012;129(6):e1508-e1516.
OBJECTIVE:
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).
METHODS:
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.
RESULTS:
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.
CONCLUSIONS:
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.
doi:10.1542/peds.2011-2216
PMCID: PMC3362905  PMID: 22641761
low-birth weight infant; NICUs; treatment; patient outcome assessment
20.  Methicillin-Resistant Staphylococcus aureus Colonization in the Neonatal Intensive Care Unit Increases Total Hospital Costs 
Methicillin-resistant Staphylococcus aureus (MRSA) infections are increasing in neonatal intensive care units. We determined the economic impact of isolating and cohorting MRSA colonized neonates on total hospital cost at a 49 bed, level III-IV Neonatal Intensive Care Unit.
doi:10.1086/596610
PMCID: PMC2756112  PMID: 19222371
MRSA; newborn; length of stay
21.  Safety of Placebo Controls in Pediatric Hypertension Trials 
Hypertension  2008;51(4):829-833.
Many clinical trials, including those in pediatric populations, use a placebo arm for medical conditions for which there are readily available therapeutic interventions. Several short-term efficacy trials of antihypertensive medications performed in response to Food and Drug Administration-issued written requests have used a placebo arm; whether the use of a placebo arm is safe in children with hypertension is unknown. We sought to define the rates of adverse events in 10 short-term antihypertensive trials in order to determine whether these trials resulted in increased risk to pediatric patients receiving placebo. We combined patient-level data from 10 antihypertensive efficacy trials performed in pediatric patients that were submitted to the Food and Drug Administration from 1998–2005. We determined the number and type of all adverse events reported during the placebo-controlled portion of the clinical trials and compared these numbers between the patients who received placebo and those who received active drug. Among the 1707 children in the 10 studies, we observed no differences in the rates of adverse events reported between the patients who received placebo and those who received active drug. Only 5 patients suffered a serious adverse event during the trials; none were thought by the investigators to be related to study drug, and only 1 occurred in a patient receiving placebo. Short-term antihypertensive trials in carefully selected populations of hypertensive children can be safely accomplished with the use of a placebo-control arm.
doi:10.1161/HYPERTENSIONAHA.107.104950
PMCID: PMC2755192  PMID: 18285612
pediatric drug therapy; hypertension; placebo-controlled clinical trials; adverse events; medical ethics
22.  Safety Monitoring of Drugs Receiving Pediatric Marketing Exclusivity 
Pediatrics  2008;122(3):e628-e633.
Objective
The Food and Drug Administration (FDA) Modernization Act provided for an additional 6-month period of marketing exclusivity to companies that perform pediatric drug trials in response to an FDA-issued written request. Because many safety concerns cannot be detected until after the introduction of a product to a larger and more diverse market, the Best Pharmaceuticals for Children Act required the FDA to report to the Pediatric Advisory Committee (PAC) on adverse events occurring during the 1-year period after granting pediatric exclusivity. We sought to describe the PAC’s recommendations made in response to safety reviews informed by data from the FDA’s Adverse Event Reporting System in 67 drugs granted exclusivity.
Patients and Methods
PAC meetings and data presented by the FDA for all drugs were reviewed from June 2003 through April 2007. We divided the drugs into 2 groups: those that were returned to routine adverse event monitoring and those that had specific PAC recommendations.
Results
Forty-four (65.7%) drugs were returned to routine monitoring for adverse events. The PAC, sometimes working with other advisory committees, recommended label changes for 12 (17.9%) drugs, continued monitoring for 10 (14.9%), production of MedGuides for 9 (13.4%), and an update on label changes resulting from discussions with the sponsor for 1 (1.5%) drug. Some drugs had more than 1 action. Several of the adverse events revealed during this process were rare and life-threatening.
Conclusions
Safety monitoring during the early post-marketing period is crucial to detect rare, serious, or pediatric-specific adverse events. Fortunately, the majority of drugs given exclusivity had no adverse events of a frequency or severity that prevented a return to routine adverse event monitoring.
doi:10.1542/peds.2008-0585
PMCID: PMC2561901  PMID: 18762496
pediatric drug safety; Pediatric Advisory Committee; adverse event reporting; drug labeling
23.  Antifungal Therapy and Outcomes in Infants with Invasive Candida Infections 
Background
Invasive candidiasis is a leading cause of mortality and morbidity in neonatal intensive care units. Treatment recommendations are limited by a lack of comparative outcomes data.
Methods
We identified all infants ≤120 days of age with positive blood, urine, or cerebrospinal fluid cultures for Candida sp. who received amphotericin B deoxycholate, fluconazole, amphotericin B lipid products, or combination therapy admitted to 1 of 192 neonatal intensive care units in the United States between 1997 and 2003. Primary outcome measures included overall mortality and therapeutic failure (combined outcome of duration of infection >7 days, need for additional antifungal therapy, or death prior to discharge). We compared outcomes by antifungal therapy using logistic regression, controlling for gestational age, day of life at start of antifungal therapy, delay in therapy, and site of infection.
Results
Overall, 138/730 (19%) infants died. On multivariable logistic regression, we observed higher overall mortality for infants receiving amphotericin B lipid products compared with infants receiving amphotericin B deoxycholate (OR 1.96 [95% CI: 1.16, 3.33]; p=0.01) or fluconazole (OR 2.39 [1.18, 4.83]; p=0.02).
Conclusions
Infants treated with amphotericin B lipid products had higher mortality than infants treated with either amphotericin B deoxycholate or fluconazole. This finding may be related to inadequate penetration of amphotericin B lipid products into the kidneys, inappropriate dosing in premature infants, or unknown differences in acuity of illness in infants treated with amphotericin B lipid products.
doi:10.1097/INF.0b013e3182467a72
PMCID: PMC3329577  PMID: 22189522
invasive candidiasis; infants; amphotericin B deoxycholate; fluconazole; amphotericin B lipid products
24.  Neonatal fungal infections: when to treat? 
Early human development  2012;88(Suppl 2):S6-S10.
Candida infections are a major cause of morbidity and mortality in neonatal intensive care units. Mortality following Candida bloodstream infections is as high as 40%, and neurodevelopmental impairment is common among survivors. Because invasive fungal infections are common and extremely difficult to diagnose, empirical treatment with antifungal therapy should be considered in high-risk, low-birth-weight infants who fail to quickly respond to empirical antibacterial treatment. Risk factors to consider when deciding to administer empirical antifungal therapy include: prior exposure to third-generation cephalosporins, extreme prematurity, and presence of central venous catheters.
doi:10.1016/S0378-3782(12)70004-X
PMCID: PMC3512570  PMID: 22633516
neonatal intensive care unit; empirical; Candida; infection; antifungal therapy
25.  Early and Late Onset Sepsis in Very-Low-Birth-Weight Infants from a Large Group of Neonatal Intensive Care Units 
Early human development  2012;88(Suppl 2):S69-S74.
Background
Very-low-birth-weight (VLBW, <1500 g birth weight) infants are at high risk for both early- and late-onset sepsis. Prior studies have observed a predominance of gram-negative organisms as a cause of early-onset sepsis and gram-positive organisms as a cause of late-onset sepsis. These reports are limited to large, academic neonatal intensive care units (NICUs) and may not reflect findings in other units. The purpose of this study was to determine the risk factors for sepsis, the causative organisms, and mortality following infection in a large and diverse sample of NICUs.
Methods
We analyzed the results of all cultures obtained from VLBW infants admitted to 313 NICUs from 1997 to 2010.
Results
Over 108,000 VLBW infants were admitted during the study period. Early-onset sepsis occurred in 1032 infants, and late-onset sepsis occurred in 12,204 infants. Gram-negative organisms were the most commonly isolated pathogens in early-onset sepsis, and gram-positive organisms were most commonly isolated in late-onset sepsis. Early- and late-onset sepsis were associated with increased risk of death controlling for other confounders (odds ratio 1.45 [95% confidence interval 1.21, 1.73], and OR 1.30 [95% CI 1.21, 1.40], respectively).
Conclusions
This is the largest report of sepsis in VLBW infants to date. Incidence for early-onset sepsis and late-onset sepsis has changed little over this 14-year period, and overall mortality in VLBW infants with early- and late-onset sepsis is higher than in infants with negative cultures.
doi:10.1016/S0378-3782(12)70019-1
PMCID: PMC3513766  PMID: 22633519
early-onset sepsis; late-onset sepsis; very-low-birth-weight infants

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