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1.  Population Pharmacokinetics of Intravenous Acyclovir in Preterm and Term Infants 
Background
Acyclovir is used to treat herpes infections in preterm and term infants; however, the influence of maturation on drug disposition and dosing requirements is poorly characterized in this population.
Methods
We administered intravenous acyclovir to preterm and term infants <31 days postnatal age and collected plasma samples. We performed a population pharmacokinetic analysis. The primary pharmacodynamic target was acyclovir concentration ≥3 mg/L for ≥50% of the dosing interval. The final model was simulated using infant data from a clinical database.
Results
The analysis included 28 infants (median 30 weeks gestation). Acyclovir pharmacokinetics was described by a 1-compartment model: clearance (L/h/kg) = 0.305 × (postmenstrual age [PMA]/31.3 weeks)3.02. This equation predicts a 4.5-fold increase in clearance from 25 to 41 weeks PMA. With proposed dosing, the pharmacodynamic target was achieved in 91% of infants: 20 mg/kg every 12 hours in infants <30 weeks PMA; 20 mg/kg every 8 hours in infants 30 to <36 weeks PMA; 20 mg/kg every 6 hours in infants 36–41 weeks PMA.
Conclusions
Acyclovir clearance increased with infant maturation. A dosing strategy based on PMA accounted for developmental changes in acyclovir disposition to achieve the surrogate pharmacodynamic target in the majority of infants.
doi:10.1097/01.inf.0000435509.75114.3d
PMCID: PMC3904301  PMID: 24346595
herpes simplex virus; preterm infants; acyclovir
2.  Comparative Effectiveness of Three Surfactant Preparations in Premature Infants 
The Journal of pediatrics  2013;163(4):955-960.e1.
Objective
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.
Results
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]).
Conclusions
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.
doi:10.1016/j.jpeds.2013.04.053
PMCID: PMC3779477  PMID: 23769501
beractant; calfactant; poractant alfa; premature infants; respiratory distress syndrome
3.  Risk of necrotizing enterocolitis in very-low-birth-weight infants with isolated atrial and ventricular septal defects 
Objective
Necrotizing enterocolitis (NEC) is associated with significant morbidity and mortality in premature infants. We sought to identify the frequency of NEC in very-low-birth-weight infants with isolated ventricular septal defects (VSD) or atrial septal defects (ASD) using a large multicenter database.
Methods
We identified a cohort of infants with birth weight <1500 g cared for in 312 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010. We examined the association between presence of an ASD or a VSD with development of NEC using logistic regression to control for small-for-gestational-age status, antenatal steroid use, antenatal antibiotic use, gestational age, sex, race, Apgar score at 5 minutes, and method of delivery.
Results
Of the 98,523 infants who met inclusion criteria, 1,904 (1.9%) had an ASD, 1943 (2.0%) had a VSD, and 146 (0.1%) had both. The incidence of NEC was 6.2% in infants without septal defects, 9.3% in those with an ASD, 7.8% in those with a VSD, and 10.3% in infants with both an ASD and a VSD. Compared to infants without septal defects, the adjusted odds ratios for developing NEC for each group—ASD alone, VSD alone, and ASD with VSD—were 1.26 (95% confidence interval 1.06–1.49), 1.27 (1.08–1.52), and 1.80 (1.03–3.12), respectively.
Conclusion
The presence of an ASD or a VSD was associated with NEC in this cohort of premature infants.
doi:10.1038/jp.2013.174
PMCID: PMC3969778  PMID: 24434778
necrotizing enterocolitis; atrial septal defect; ventricular septal defect
4.  Adverse Events Associated with Meropenem versus Imipenem/Cilastatin Therapy in a Large Retrospective Cohort of Hospitalized Infants 
Background
Carbapenems are commonly used in hospitalized infants despite a lack of complete safety data and associations with seizures in older children. We compared the incidence of adverse events in hospitalized infants receiving meropenem versus imipenem/cilastatin.
Methods
We conducted a retrospective cohort study of 5566 infants treated with meropenem or imipenem/cilastatin in neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2010. Multivariable conditional logistic regression was performed to evaluate the association between carbapenem therapy and adverse events, controlling for infant factors and severity of illness.
Results
Adverse events were more common with use of meropenem compared with imipenem/cilastatin (62.8/1000 infant days vs. 40.7/1000 infant days, P<0.001). There was no difference in seizures with meropenem vs. imipenem/cilastatin (adjusted odds ratio [OR] 0.96; 95% confidence interval 0.68, 1.32). The incidence of death, as well as the combined outcome of death or seizure, was lower with meropenem use—OR 0.68 (0.50, 0.88) and OR 0.77 (0.62, 0.95), respectively.
Conclusion
In this cohort of infants, meropenem was associated with more frequent but less severe adverse events when compared with imipenem/cilastatin.
doi:10.1097/INF.0b013e31828be70b
PMCID: PMC3708263  PMID: 23838776
meropenem; imipenem/cilastatin; adverse events; infant
5.  Intestinal Fatty-Acid Binding Protein and Metronidazole Response in Premature Infants 
Objectives
In premature infants with suspected intra-abdominal infection, biomarkers for treatment response to antimicrobial therapy are lacking. Intestinal fatty acid-binding protein (I-FABP) is specific to the enterocyte and is released in response to intestinal mucosal injury. I-FABP has not been evaluated as a surrogate marker of disease response to antimicrobial therapy. We examined the relationship between metronidazole exposure and urinary I-FABP concentrations in premature infants with suspected intra-abdominal infection.
Study design
We conducted an intravenous metronidazole pharmacokinetic study, collecting ≤3 urine samples per infant for I-FABP concentration measurements. We analyzed the relationship between I-FABP concentrations and measures of metronidazole exposure and pharmacokinetics, maturational factors, and other covariates.
Results
Twenty-six samples from 19 premature infants were obtained during metronidazole treatment. When analyzed without regard to presence of necrotic gastrointestinal disease, there were no significant associations between predictor variables and I-FABP concentrations. However, when the sample was limited to premature infants with necrotic gastrointestinal disease, an association was found between average predicted metronidazole concentration and I-FABP concentration (p=0.006).
Conclusion
While a predictive association between urinary I-FABP and metronidazole systemic exposure was not observed, the data suggest the potential of this endogenous biomarker to serve as a pharmacodynamic surrogate for antimicrobial treatment of serious abdominal infections in neonates and infants.
doi:10.3233/NPM-1477013
PMCID: PMC4225165  PMID: 25318626
necrotizing enterocolitis; biomarkers; pharmacokinetics; premature infants; antimicrobial agents
6.  Catheter Dwell Time and CLABSIs in Neonates With PICCs: A Multicenter Cohort Study 
Pediatrics  2013;132(6):e1609-e1615.
OBJECTIVE:
To determine whether the daily risk of central line–associated bloodstream infections (CLABSIs) increases over the dwell time of peripherally inserted central catheters (PICCs) in high-risk neonates.
METHODS:
Multicenter retrospective cohort including NICU patients with a PICC inserted between January 2005 and June 2010. We calculated incidence rates and used Poisson regression models to assess the risk of developing CLABSI as a function of PICC dwell time.
RESULTS:
A total of 4797 PICCs placed in 3967 neonates were included; 149 CLABSIs occurred over 89 946 catheter-days (incidence rate 1.66 per 1000 catheter-days). In unadjusted analysis, PICCs with a dwell time of 8 to 13 days, 14 to 22 days, and ≥23 days each had an increased risk of infection compared with PICCs in place for ≤7 days (P < .05). In adjusted analysis, the average predicted daily risk of CLABSIs after PICC insertion increased during the first 2 weeks after PICC insertion and remained elevated for the dwell time of the catheter. There was an increased risk of CLABSIs in neonates with concurrent PICCs (adjusted incidence rate ratio 2.04, 1.12–3.71). The incidence of Gram-negative CLABSIs was greater in PICCs with dwell times >50 days (incidence rate ratio 5.26, 2.40–10.66).
CONCLUSIONS:
The risk of CLABSIs increased during the 2 weeks after PICC insertion and then remained elevated until PICC removal. Clinicians should review PICC necessity daily, optimize catheter maintenance practices, and investigate novel CLABSI prevention strategies in PICCs with prolonged dwell times.
doi:10.1542/peds.2013-1645
PMCID: PMC3838533  PMID: 24218474
infection; catheter-related infections; NICU; central venous catheters; peripheral venous catheterization
7.  Early Administration of Oropharyngeal Colostrum to Extremely Low Birth Weight Infants 
Breastfeeding Medicine  2013;8(6):491-495.
Abstract
Background: Human milk reduces morbidities in extremely low birth weight (ELBW) infants. However, clinical instability often precludes ELBW infants from receiving early enteral feeds. This study compared clinical outcomes before and after implementing an oropharyngeal colostrum (COL) protocol in a cohort of inborn (born at our facility) ELBW infants.
Study Design: This is a retrospective cohort study of inborn ELBW infants admitted to the Duke Intensive Care Nursery from January 2007 to September 2011. In November 2010, we initiated a COL protocol for infants not enterally fed whose mothers were providing breastmilk. Infants received 0.1 mL of fresh COL to each cheek every 4 hours for 5 days beginning in the first 48 postnatal hours. We assessed demographics, diagnoses, feeding history, and mortality and for the presence of medical necrotizing enterocolitis (NEC), surgical NEC, and spontaneous perforation. Between-group comparisons were made using Fisher's exact test or Wilcoxon rank sum testing where appropriate.
Results: Of the 369 infants included, 280 (76%) were born prior to the COL protocol (Pre-COL Cohort [PCC]), and 89 (24%) were born after (COL Cohort [CC]). Mortality and the percentage of infants with surgical NEC and spontaneous perforations were statistically similar between the groups. The CC weighed an average (interquartile range) of 1,666 (1,399, 1,940) g at 36 weeks versus 1,380 (1,190, 1,650) g for the PCC (p<0.001). In a multivariable analysis with birth weight as a covariable, weight at 36 weeks was significantly greater (37 g; p<0.01).
Conclusions: Initiating oropharyngeal COL in ELBW infants in the first 2 postnatal days appears feasible and safe and may be nutritionally beneficial. Further research is needed to determine if early COL administration reduces neonatal morbidity and mortality.
doi:10.1089/bfm.2013.0025
PMCID: PMC3868273  PMID: 23805944
8.  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
9.  Developmental Pharmacokinetics of Piperacillin and Tazobactam Using Plasma and Dried Blood Spots from Infants 
Piperacillin-tazobactam is often given to infants with severe infection in spite of limited pharmacokinetics (PK) data. We evaluated piperacillin-tazobactam PK in premature and term infants of ages <61 days with suspected systemic infection. Infants received intravenous piperacillin-tazobactam (80 to 100 mg/kg of body weight every 8 h [q 8 h]) based on gestational and postnatal age. Sparse plasma samples were obtained after first and multiple doses. Drug concentrations were measured by tandem mass spectrometry. PK data were analyzed using population nonlinear mixed-effect modeling. Target attainment rates for the time unbound piperacillin concentrations remained above the MIC for 50% and 75% of the dosing interval at steady state were evaluated. Bias in population PK parameter estimates was assessed for dried blood spot (DBS) samples, and a comparability analysis was performed for DBS and plasma drug concentrations using linear regression. We obtained 128 plasma samples from 32 infants, median gestational age of 30 weeks (range, 23 to 40 weeks) and postnatal age of 8 days (range, 1 to 60). Piperacillin and tazobactam PK models included body weight (WT) and postmenstrual age (PMA) as covariates for clearance and WT for volume of distribution and were used to optimize dosing in infants. DBS drug concentrations were 50 to 60% lower than those in plasma, but when combined with plasma concentrations and a matrix effect, the data generated PK model parameters similar to those for plasma alone. With PMA-based dosing (100 mg/kg q 8 h, 80 mg/kg q 6 h, and 80 mg/kg q 4 h for PMA of ≤30, 30 to 35, and 35 to 49 weeks, respectively), 90% of simulated infants achieved the surrogate therapeutic target of time above the MIC (≤32 mg/liter) for 75% of the dosing interval.
doi:10.1128/AAC.02139-13
PMCID: PMC3993246  PMID: 24614369
10.  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
11.  Determining Population and Developmental Pharmacokinetics of Metronidazole Using Plasma and Dried Blood Spot Samples from Premature Infants 
Background
Limited pharmacokinetic (PK) data of metronidazole in premature infants has led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections.
Methods
We evaluated the PK of metronidazole using plasma and dried blood spot (DBS) samples from infants ≤32 weeks gestational age in an open-label, PK, multicenter (N=3) study using population PK modeling (NONMEM). Monte Carlo simulations (N=1000 virtual subjects) were used to evaluate the surrogate efficacy target. Metabolic ratios of parent and metabolite were calculated.
Results
Twenty-four premature infants (111 plasma and 51 DBS samples) were enrolled: median (range) gestational age at birth 25 (23–31) weeks, postnatal age 27 (1–82) days, postmenstrual age (PMA) 31 (24–39) weeks, and weight 740 (431–1466) g. Population clearance (CL, L/h/kg) was 0.038 × (PMA/30)2.45 and volume of distribution (L/kg) of 0.93. PK parameter estimates and precision were similar between plasma and DBS samples. Metabolic ratios correlated with CL.
Conclusion
Simulations suggested the majority of infants in the neonatal intensive care unit (>80%) would meet the surrogate efficacy target using PMA-based dosing.
doi:10.1097/INF.0b013e3182947cf8
PMCID: PMC3769518  PMID: 23587979
neonate; drug; pharmacokinetics; metronidazole; dried blood spots
12.  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
13.  Emperic Antifungal Therapy and Outcomes in Extremely-Low-Birth-Weight Infants with Invasive Candidiasis 
The Journal of Pediatrics  2012;161(2):264-269.e2.
Objective
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).
Results
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.
Conclusions
Emperic antifungal therapy was associated with increased survival without NDI. A prospective randomized trial of this strategy is warranted.
doi:10.1016/j.jpeds.2012.01.053
PMCID: PMC3380169  PMID: 22424952
Candida; neonate; mortality; neurodevelopmental impairment
14.  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
15.  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
16.  Effects of low-dose dopamine on urine output in normotensive very low birth weight neonates 
Objective
Determine effects of low-dose dopamine on urine output in very low birth weight premature neonates.
Study Design
Retrospective cohort study of all low-dose (3-5 μg/kg/min) dopamine infusions >24 hours duration in neonates ≤1500 g and ≤32 weeks gestation from August 2009 through September 2011. Linear regression was used to estimate the impact of covariates on urine output.
Results
We identified 91 episodes of low-dose dopamine use in 65 neonates. Increased urine output occurred with 64% of episodes. Low-dose dopamine use was associated with a 0.6 mL/kg/hr increase in urine output (p<0.001) and a 1.3 mL/kg/hr increase when baseline urine output was <1.5 mL/kg/hr (p<0.001). The improvement remained statistically significant after controlling for medications (diuretics and hydrocortisone) and fluid intake.
Conclusions
Low-dose dopamine use was associated with increased urine output in very low birth weight neonates.
doi:10.1038/jp.2013.20
PMCID: PMC4028044  PMID: 23448938
renal dose; dopamine; urine output
17.  Sublingual versus oral immunotherapy for peanut-allergic children: A retrospective comparison 
doi:10.1016/j.jaci.2013.02.017
PMCID: PMC3732569  PMID: 23534975
peanut allergy; sublingual immunotherapy; oral immunotherapy; food hypersensitivity; desensitization
18.  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
19.  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
20.  Sepsis in Young Infants with Congenital Heart Disease 
Early human development  2012;88(Suppl 2):S92-S97.
Background
We sought to describe the incidence, pathogen distribution, and mortality associated with blood culture-proven sepsis in young infants with congenital heart disease (CHD) admitted to a neonatal intensive care unit (NICU).
Methods
Cohort study of all blood cultures obtained from infants with CHD between 4 and 120 days of age cared for in250 NICUs managed by the Pediatrix Medical Group in the United States between 1996 and 2007.
Results
Of 11,638 infants with CHD, 656 (6%) had 821 episodes of sepsis: a cumulative incidence of 71/1000 admissions. Gram-positive organisms were the most common cause (64%), and coagulase-negative Staphylococcus and Staphylococcus aureus were the most frequently isolated species. On multivariable regression, infants with sepsis were more likely to die compared to infants with sterile blood cultures (odds ratio [OR] = 1.53 [95% confidence interval: 1.09, 2.13]). Infants with gram-negative bacteremia and candidemia were more likely to die than infants with sterile blood cultures (OR = 2.01 [1.20, 3.37], and OR = 3.18 [1.60, 6.34], respectively).
Conclusion
Infants with CHD have a high incidence of culture-proven sepsis, especially with staphylococcal organisms. Gram-negative bacteremia and candidemia are strongly associated with increased mortality in this group of young infants.
doi:10.1016/S0378-3782(12)70025-7
PMCID: PMC3513769  PMID: 22633525
infant; sepsis; infection; congenital heart disease; epidemiology; outcomes
21.  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
22.  Antibiotic Use and Misuse in the Neonatal Intensive Care Unit 
Clinics in Perinatology  2011;39(1):61-68.
Synopsis
Neonatal sepsis causes significant morbidity and mortality, especially in preterm infants. Consequently, clinicians are compelled to treat with empirical antibiotics at the first signs of suspected sepsis. Unfortunately, both broad-spectrum antibiotics and prolonged treatment with empirical antibiotics are associated with adverse outcomes including invasive candidiasis, increased antimicrobial resistance, necrotizing enterocolitis, late-onset sepsis, and death. Most common neonatal pathogens are susceptible to narrow-spectrum antibiotics. The choice of antibiotic and duration of empirical treatment are strongly associated with center-based rather than with individual patient risk factors, implying that these choices are modifiable across centers. Thus, clinicians should aim to treat with short courses of narrow-spectrum antibiotics whenever possible, choosing the appropriate antibiotics and treatment duration to balance the risks of potentially untreated sepsis against the adverse effects of treatment in infants with sterile cultures.
doi:10.1016/j.clp.2011.12.003
PMCID: PMC3285418  PMID: 22341537
neonatal intensive care unit; empirical; antibiotic; sepsis; infection
23.  Adaptation of a Post-Operative Handoff Communication Process for Children with Heart Disease: A Quantitative Study* 
Handoff communication is a point of vulnerability when valuable patient information can be inaccurate or omitted. In 2005 we implemented a protocol to improve the handoff process for children from the operating room to the intensive care unit after cardiac surgery. We performed a cross-sectional study of the present process to understand how users adapt a communication intervention over time. 29 handoff events were observed. Individuals required for the handoff were present at 97% of events. Content items averaged a 53% reporting rate. Some clinical information not specified in the protocol demonstrated a higher reporting rate, such as echocardiogram results (68%) and vascular access (79%). A mean of 2.3 environmental distractions per minute of communication were noted. Participant-directed adjustments in content reporting suggest that a facilitator in process improvement is user-centered innovation. Future handoff communication interventions should reduce nonessential distractions and incorporate a discussion of the anticipated patient course.
doi:10.1177/1062860610394342
PMCID: PMC3261576  PMID: 21701043
handoff; safety; communication; pediatric intensive care units; congenital heart defects; postoperative care
24.  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
25.  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

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