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1.  Medication use in the neonatal intensive care unit 
American journal of perinatology  2013;31(9):811-822.
We provide an update on medication use in infants admitted to the neonatal intensive care unit (NICU) in the United States and examine how use has changed over time.
Study Design
We performed a retrospective review (2005–2010) of a large prospectively collected administrative database.
Medications most commonly administered during the study period were ampicillin, gentamicin, caffeine citrate, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant (56–681 exposures per 1000 infants). Those with the greatest relative increase in use included azithromycin, sildenafil, and milrinone. Medications with the greatest relative decrease in use included theophylline, metoclopramide, and doxapram.
Medication use in the NICU has changed substantially over time, and only 35% of the most commonly prescribed medications are FDA-approved in infants.
PMCID: PMC4061287  PMID: 24347262
pharmacotherapy; trends over time
2.  No Survival Benefit with Empirical Vancomycin Therapy for Coagulase-negative Staphylococcal Bloodstream Infections in Infants 
Coagulase-negative Staphylococcus (CoNS) is the most common cause of bloodstream infections (BSI) in hospitalized infants. CoNS BSI is most reliably treated with vancomycin; however, concerns about side effects and promoting resistance often delay empirical vancomycin therapy until culture results become available.
All infants with CoNS BSI discharged from 348 neonatal intensive care units managed by the Pediatrix Medical Group from 1997–2012 were identified. Empirical vancomycin therapy was defined as vancomycin exposure on the day of the first positive blood culture. Delayed vancomycin therapy was defined as vancomycin exposure 1–3 days after the first positive blood culture. We used multivariable logistic regression with random effects for site to evaluate the association between the use of empirical vancomycin therapy vs. delayed vancomycin therapy and 30-day mortality, controlling for gestational age, small-for-gestational age status, postnatal age on the day of the first positive culture, oxygen requirement, ventilator support, and inotropic support on the day the first positive culture was obtained.
Of the 4364 infants with CoNS BSI, 2848 (65%) were treated with empirical vancomycin. The median postnatal age at first positive culture was 14 days (interquartile range: 9, 21). Unadjusted 30-day mortality was similar for infants treated with empirical vancomycin and infants treated with delayed vancomycin therapy (166/2848 [6%] vs. 69/1516 [4%]; p=0.08). There was no significant difference in 30-day mortality on multivariable analysis (odds ratio: 1.14 [0.84, 1.56]). The median duration of bacteremia was 1 day longer for infants with delayed vancomycin therapy (4 days [interquartile range 2, 6] vs. 3 days [2, 5]; p<0.0001).
The median duration of bacteremia was 1 day longer in infants with CoNS BSI who received delayed vancomycin therapy. Despite this finding, empirical vancomycin therapy for CoNS BSI was not associated with improved mortality.
PMCID: PMC4357312  PMID: 25760564
late-onset sepsis; NICU
3.  Dosing in neonates: Special considerations in physiology and trial design 
Pediatric research  2014;77(0):2-9.
Determining the right dose for drugs used to treat neonates is critically important. Neonates have significant differences in physiology affecting drug absorption, distribution, metabolism, and elimination that makes extrapolating dosages from adults and older children inappropriate. In spite of recent legislative efforts requiring drug studies in this population, most drugs given to neonates remain insufficiently studied. Many ethical and logistical concerns make designing studies in this age group difficult. Fortunately, specialized analytical techniques, such as the use of dried blood spots, scavenged sampling, population pharmacokinetics analyses, and sparse sampling, have helped investigators better define doses that maximize efficacy and safety. Through the use of these methods, successful clinical trials have resulted in recent changes to drug dosing in this population.
PMCID: PMC4268272  PMID: 25268145
4.  Anaerobic Antimicrobial Therapy After Necrotizing Enterocolitis in VLBW Infants 
Pediatrics  2015;135(1):e117-e125.
To evaluate the effect of anaerobic antimicrobial therapy for necrotizing enterocolitis (NEC) on clinical outcomes in very low birth weight (≤1500 g) infants.
We identified very low birth weight infants with NEC from 348 US NICUs from 1997 to 2012. Anaerobic antimicrobial therapy was defined by antibiotic exposure on the first day of NEC. We matched (1:1) infants exposed to anaerobic antimicrobial therapy with infants who were not exposed by using a propensity score stratified by NEC severity (medical and surgical). The primary composite outcome was in-hospital death or intestinal stricture. We assessed the relationship between anaerobic antimicrobial therapy and outcome by using a conditional logistic regression on the matched cohort.
A total of 1390 infants exposed to anaerobic antimicrobial therapy were matched with 1390 infants not exposed. Mean gestational age and birth weight were 27 weeks and 946 g, respectively, and were similar in both groups. We found no significant difference in the combined outcome of death or strictures, but strictures as a single outcome were more common in the anaerobic antimicrobial therapy group (odds ratio 1.73; 95% confidence interval, 1.11–2.72). Among infants with surgical NEC, mortality was less common with anaerobic antimicrobial therapy (odds ratio 0.71; 95% confidence interval, 0.52–0.95).
Anaerobic antimicrobial therapy was not associated with the composite outcome of death or strictures but was associated with an increase in intestinal strictures. This higher incidence of intestinal strictures may be explained by the fact that death is a competing outcome for intestinal strictures, and mortality was slightly lower in the anaerobic cohort. Infants with surgical NEC who received anaerobic antimicrobial therapy had lower mortality.
PMCID: PMC4279070  PMID: 25511117
necrotizing enterocolitis; very low birth weight infants; anaerobes; antibiotics; mortality; intestinal strictures
5.  Baseline Urinary Glucose Tetrasaccharide Concentrations in Patients with Infantile- and Late-Onset Pompe Disease Identified by Newborn Screening 
JIMD Reports  2015;19:67-73.
Purpose: The urinary glucose tetrasaccharide, Glcα1-6Glcα1-4Glcα1-4Glc (Glc4), is a biomarker of glycogen accumulation and tissue damage and is elevated in patients with Pompe disease. We report baseline urinary Glc4 concentrations for patients with classic infantile-onset or late-onset Pompe disease, and those with a pseudodeficiency of acid alpha-glucosidase (GAA), identified through newborn screening (NBS) in Taiwan.
Methods: Infants identified through NBS with (1) classic infantile-onset Pompe disease (NBS-IOPD) (n = 7) defined as patients with evidence for hypertrophic cardiomyopathy by EKG, X-ray, and echocardiogram, (2) a late-onset phenotype (NBS-LOPD) (n = 13) defined as patients without evidence for cardiomyopathy, (3) a GAA pseudodeficiency (n = 58), and (4) one patient with LOPD diagnosed in infancy due to family history were consented to the study. Four infants diagnosed after the onset of clinical symptoms (CLIN-IOPD) were included for comparison. Glc4 concentrations in dried urine samples on filter paper were determined using tandem mass spectrometry.
Results: Baseline Glc4 concentrations were at or above the 90th centile of the age-matched reference range for the NBS-IOPD cohort. The median Glc4 level for this group was lower than that of the CLIN-IOPD group, although not at the level of significance (p = 0.07), but was significantly higher than that of the NBS-LOPD group (p < 0.05). Baseline Glc4 was not elevated for the NBS-LOPD and GAA pseudodeficiency cohorts and remained low for late-onset patients that did not require treatment before the age of three years.
Conclusion: Baseline urinary Glc4 is elevated in neonates with infantile-onset Pompe disease identified through NBS.
Electronic supplementary material
The online version of this chapter (doi:10.1007/8904_2014_366) contains supplementary material, which is available to authorized users.
PMCID: PMC4501239  PMID: 25681082
Biomarker; Glucose tetrasaccharide; Newborn screening; Pompe disease; Tandem mass spectrometry
6.  Rifampin Use and Safety in Hospitalized Infants 
American journal of perinatology  2015;32(6):565-570.
To examine the use and safety of rifampin in hospitalized infants.
Study Design
Observational study of clinical and laboratory adverse events among infants exposed to rifampin from 348 neonatal intensive care units managed by the Pediatrix Medical Group between 1997 and 2012.
2500 infants received 4279 courses of rifampin; mean gestational age was 27 weeks (5th, 95th %tile; 23, 36) and mean birth weight was 1125 g (515, 2830). Thrombocytopenia (121/1000 infant days) and conjugated hyperbilirubinemia (25/1000 infant days) were the most common laboratory adverse events. The most common clinical adverse events were medical necrotizing enterocolitis (64/2500 infants, 3%) and seizure (60/2500 infants, 2%).
The overall incidence of adverse events among infants receiving rifampin appears low; however, additional studies to further evaluate safety and dosing of rifampin in this population are needed.
PMCID: PMC4433596  PMID: 25594217
rifampin; broad-spectrum antibiotic; infectious disease; neonatal intensive care unit
7.  Late-Onset Bloodstream Infections in Hospitalized Term Infants 
The epidemiology and incidence of late-onset bloodstream infections (BSIs) in premature infants has been described, but studies describing late-onset BSI in term infants are sparse. We sought to describe the pathogens, incidence, risk factors, and mortality of late-onset BSI in hospitalized term infants.
A cohort study was conducted of infants ≥37 weeks gestational age and ≤120 days old discharged from Pediatrix Medical Group neonatal intensive care units from 1997–2010. We examined all cultures obtained from day of life (DOL) 4–120 and used multivariable regression to assess risk factors for late-onset BSI.
We found a total of 206,019 infants cared for between DOL 4 and 120, and the incidence of late-onset BSI was 2.7/1000 admissions. We identified Gram-positive organisms in 64% of the cultures and Gram-negative organisms in 26%. We found a decreased risk of late-onset BSI in infants with the following characteristics: small for gestational age, delivery by Cesarean section, antenatal antibiotic use, and discharged in the later years of the study. Late-onset BSI increased the risk of death after controlling for confounders (odds ratio 8.43 [95% confidence interval 4.42, 16.07]).
Our data highlight the importance of late-onset BSI in hospitalized term infants. We identified Gram-positive organisms as the most common pathogen, and late-onset BSI was an independent risk factor for death.
PMCID: PMC4160433  PMID: 24618934
sepsis; infant; term birth; infection
8.  Adverse Events Associated with Meropenem versus Imipenem/Cilastatin Therapy in a Large Retrospective Cohort of Hospitalized Infants 
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.
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.
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.
In this cohort of infants, meropenem was associated with more frequent but less severe adverse events when compared with imipenem/cilastatin.
PMCID: PMC3708263  PMID: 23838776
meropenem; imipenem/cilastatin; adverse events; infant
9.  The Epidemiology and Diagnosis of Invasive Candidiasis Among Premature Infants 
Clinics in perinatology  2014;42(1):105-117.
Invasive candidiasis is a leading infectious cause of morbidity and mortality in premature infants. Improved recognition of modifiable risk factors and antifungal prophylaxis have contributed to the recent decline in the incidence of this infection among infants. Invasive candidiasis typically occurs in the first six weeks of life and presents with non-specific signs of sepsis. Definitive diagnosis relies on growth of Candida in blood culture or cultures from other normally sterile sites, but this may identify fewer than half of cases. Improved diagnostics are needed to guide initiation of antifungal therapy in premature infants.
PMCID: PMC4328135  PMID: 25677999
neonatal candidiasis; Candida; premature infants; risk factors
10.  Trends in Caffeine Use and Association between Clinical Outcomes and Timing of Therapy in Very-Low-Birth-Weight Infants 
The Journal of pediatrics  2014;164(5):992-998.e3.
To examine the effect of early initiation of caffeine therapy on neonatal outcomes and characterized the use of caffeine therapy in very-low-birth-weight (VLBW) infants.
Study design
We analyzed a cohort of 62,056 VLBW infants discharged between 1997 and 2010 who received caffeine. We compared outcomes between infants receiving early caffeine therapy (initial dose <3 days of life) and late caffeine therapy (initial dose ≥3 days of life) through propensity scoring using baseline and early clinical variables. The primary outcome was the association between the timing of caffeine initiation and the incidence of bronchopulmonary dysplasia (BPD) or death.
We propensity score-matched 29,070 VLBW infants in a 1:1 ratio. Of infants receiving early caffeine therapy, 3681 (27.6%) died or developed BPD compared with 4591 (34.0%) infants receiving late caffeine therapy (odds ratio [OR]=0.74; 99% confidence interval 0.69–0.80). The incidence of BPD was lower in infants receiving early caffeine (early, 23.1%; late, 30.7%; OR=0.68; 0.63–0.73), and the incidence of death was higher (early, 4.5%; late, 3.7%; OR=1.23; 1.05–1.43). Infants receiving early caffeine therapy had decreased treatment of a patent ductus arteriosus (OR=0.60; 0.55–0.65) and a shorter duration of mechanical ventilation (mean difference of 6 days; P<0.001).
Early caffeine initiation is associated with a decreased incidence of BPD. Randomized trials are needed to determine the efficacy and safety of early caffeine prophylaxis in VLBW infants.
PMCID: PMC3992195  PMID: 24461786
methylxanthines; outcomes; bronchopulmonary dysplasia; chronic lung disease; premature infants; neonatal care
12.  Changes in the Incidence of Candidiasis in Neonatal Intensive Care Units 
Pediatrics  2014;133(2):236-242.
Neonatal invasive candidiasis is associated with significant morbidity and mortality. We describe the association between invasive candidiasis and changes in use of antifungal prophylaxis, empirical antifungal therapy, and broad-spectrum antibacterial antibiotics over time.
We examined data from 709 325 infants at 322 NICUs managed by the Pediatrix Medical Group from 1997 to 2010. We determined the cumulative incidence of invasive candidiasis and use of antifungal prophylaxis, broad-spectrum antibacterial antibiotics, and empirical antifungal therapy by year.
We identified 2063 (0.3%) infants with 2101 episodes of invasive candidiasis. Over the study period, the annual incidence of invasive candidiasis decreased from 3.6 episodes per 1000 patients to 1.4 episodes per 1000 patients among all infants, from 24.2 to 11.6 episodes per 1000 patients among infants with a birth weight of 750–999 g, and from 82.7 to 23.8 episodes per 1000 patients among infants with a birth weight <750 g. Fluconazole prophylaxis use increased among all infants with a birth weight <1000 g (or <1500 g), with the largest effect on birth weights <750 g, increasing from 3.8 per 1000 patients in 1997 to 110.6 per 1000 patients in 2010. The use of broad-spectrum antibacterial antibiotics decreased among all infants from 275.7 per 1000 patients in 1997 to 48.5 per 1000 patients in 2010. The use of empirical antifungal therapy increased over time from 4.0 per 1000 patients in 1997 to 11.5 per 1000 patients in 2010.
The incidence of invasive candidiasis in the NICU decreased over the 14-year study period. Increased use of fluconazole prophylaxis and empirical antifungal therapy, along with decreased use of broad-spectrum antibacterial antibiotics, may have contributed to this observation.
PMCID: PMC3904270  PMID: 24446441
invasive candidiasis; fluconazole prophylaxis; premature infants
13.  Safety of Sildenafil in Infants* 
In view of the recent U.S. Food and Drug Administration’s warning against the use of sildenafil in pediatric patients, we aimed to provide an updated overview of the dosing and safety of sildenafil in infants and to explore the relevance of the present safety concerns to the infant population.
Data Source
The National Library of Medicine PubMed and Cochrane Database of Systematic Reviews were searched using the following terms: Sildenafil AND (infant OR infants OR newborn OR newborns OR child OR children OR childhood OR pediatric OR pediatrics OR paediatric OR paediatrics).
Study Selection
Studies presenting original clinical data regarding the dosing, use, or safety of sildenafil in infants with pulmonary hypertension would be included.
Data Extraction
Of the 49 included studies, case reports and case series were the most common type of publications (n = 25). The identified trials included 625 children, with more than 140 infants. Persistent pulmonary hypertension of the newborn and pulmonary hypertension associated with other conditions were the most common underlying diagnoses.
There is currently no evidence of serious adverse event in infants exposed to sildenafil. Present safety concerns regarding the use of sildenafil in pediatric patients should be further explored before being applied to infant population. Sildenafil remains a valuable option for the treatment of pulmonary hypertension in young infants. Prospective studies should be designed in such a way that they include a safety assessment to evaluate potential adverse outcomes of sildenafil therapy in this population.
PMCID: PMC4709254  PMID: 24583505
adverse events; infants; off-label; pulmonary hypertension; safety; sildenafil
14.  Diuretic exposure in premature infants from 1997–2011 
Diuretics are often prescribed off-label to premature infants, particularly to prevent or treat bronchopulmonary dysplasia (BPD). We examined their use and safety in this group.
Study Design
Retrospective cohort study of infants <32 weeks gestation and <1500 g birth weight exposed to diuretics in 333 neonatal intensive care units from 1997–2011. We examined use of acetazolamide, amiloride, bumetanide, chlorothiazide, diazoxide, ethacrynic acid, furosemide, hydrochlorothiazide, mannitol, metolazone, or spironolactone combination. Respiratory support and FiO2 on the first day of each course of diuretic use were identified.
Thirty-seven percent (39,357/107,542) of infants were exposed to at least 1 diuretic; furosemide was the most commonly used (93% with ≥1 recorded dose), followed by spironolactone, chlorothiazide, hydrochlorothiazide, bumetanide, and acetazolamide. Seventy-four percent were exposed to 1 diuretic at a time, 19% to 2 diuretics simultaneously, and 6% to 3 diuretics simultaneously. The most common combination was furosemide/spironolactone, followed by furosemide/chlorothiazide and chlorothiazide/spironolactone. Many infants were not receiving mechanical ventilation on the first day of each new course of furosemide (47%), spironolactone (69%), chlorothiazide (61%), and hydrochlorothiazide (68%). Any adverse event occurred on 42 per 1000 infant-days for any diuretic and 35 per 1000 infant-days for furosemide. Any serious adverse event occurred in 3.8 for any diuretic and 3.2 per 1000 infant-days for furosemide. The most common laboratory abnormality associated with diuretic exposure was thrombocytopenia.
Despite no FDA indication and little safety data, over one third of premature infants in our population were exposed to a diuretic, many with minimal respiratory support.
PMCID: PMC4223004  PMID: 24801161
bronchopulmonary dysplasia; diuretic; safety; drug
15.  Safety of milrinone use in neonatal intensive care units 
Early human development  2014;91(1):31-35.
Milrinone use in the neonatal intensive care unit has increased over the last 10 years despite a paucity of published safety data in infants. We sought to determine the safety of milrinone therapy among infants in the neonatal intensive care unit.
We conducted a retrospective data analysis, identifying all infants exposed to milrinone discharged from 322 neonatal intensive care units managed by the Pediatrix Medical Group from 1997–2010. We identified adverse events (AEs) during milrinone exposure. The unit of observation for clinical AEs was the first course of milrinone and for laboratory AEs was an infant-day of exposure to milrinone.
Overall, 1446 of 716,821 (0.2%) infants received milrinone for a total of 6894 infant-days. The proportion of infants exposed to milrinone increased from 0 in 1997 to 4/1000 infant cases in 2010. Persistent pulmonary hypertension (40%) was the most commonly reported diagnosis at the start of milrinone administration. Overall, 606/1446 (42%) of infants had at least 1 clinical AE recorded during milrinone therapy. Hypotension requiring pressors and thrombocytopenia (<100,000/mm3) were the most commonly reported clinical and laboratory AEs, respectively. Death was reported in 8% of infants during the first course of milrinone therapy.
Among infants hospitalized in the neonatal intensive care unit, there was an increase in the use of milrinone over the past 13 years. The safety, dosing, and efficacy of milrinone in infants should be determined in prospective clinical trials.
PMCID: PMC4302030  PMID: 25460254
milrinone; infants; safety; adverse events; neonatal intensive care unit; persistent pulmonary hypertension
16.  Population Pharmacokinetics of Intravenous Acyclovir in Preterm and Term Infants 
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.
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.
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.
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.
PMCID: PMC3904301  PMID: 24346595
herpes simplex virus; preterm infants; acyclovir
17.  Clinical outcomes in very low birth weight infants with major congenital heart defects 
Early human development  2014;90(12):791-795.
The combination of major congenital heart disease (CHD) and prematurity is associated with poor prognosis, but previous studies have not fully characterized morbidity and mortality in this population. We conducted a retrospective cohort study of very low birth weight (VLBW) infants with major CHD to describe outcomes, including mortality, over time.
We included all infants <1500 g birth weight with major CHD discharged from Pediatrix Medical Group neonatal intensive care units from 1997–2012. We report incidences of major CHD in VLBW infants and compare mortality and morbidity by infant birth weight, type of major CHD, and time period.
Of 105,539 VLBW infants, 299 (0.3%) were diagnosed with 15 different major CHDs. Coarctation of the aorta (n=67, 22%), atrioventricular septal defect (n=58, 19%), and tetralogy of Fallot (n=53, 18%) were the most common major CHDs identified. Overall mortality was 163/299 (55%). Mortality was ≥70% for 10 lesions and <30% for isolated aortic valve stenosis (6/30, 20%). Mortality in infants with major CHD did not significantly change over time: 76/133 (57%) in 1997–2005, 49/95 (52%) in 2006–2009, and 38/71 (54%) in 2010–2012 (p=0.70). The majority of infants suffered ≥1 comorbidity or died (218/299, 73%).
Major CHD is associated with high morbidity and mortality. While mortality varies by lesion, overall survival and incidence of major morbidity have not improved over time.
PMCID: PMC4312193  PMID: 25463822
prematurity; very low birth weight; congenital heart defect; morbidity; mortality
18.  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
19.  Risk of necrotizing enterocolitis in very-low-birth-weight infants with isolated atrial and ventricular septal defects 
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.
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.
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.
The presence of an ASD or a VSD was associated with NEC in this cohort of premature infants.
PMCID: PMC3969778  PMID: 24434778
necrotizing enterocolitis; atrial septal defect; ventricular septal defect
20.  Between-Hospital Variation in Treatment and Outcomes in Extremely Preterm Infants 
The New England journal of medicine  2015;372(19):1801-1811.
Between-hospital variation in outcomes among extremely preterm infants is largely unexplained and may reflect differences in hospital practices regarding the initiation of active lifesaving treatment as compared with comfort care after birth.
We studied infants born between April 2006 and March 2011 at 24 hospitals included in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Data were collected for 4987 infants born before 27 weeks of gestation without congenital anomalies. Active treatment was defined as any potentially lifesaving intervention administered after birth. Survival and neurodevelopmental impairment at 18 to 22 months of corrected age were assessed in 4704 children (94.3%).
Overall rates of active treatment ranged from 22.1% (interquartile range [IQR], 7.7 to 100) among infants born at 22 weeks of gestation to 99.8% (IQR, 100 to 100) among those born at 26 weeks of gestation. Overall rates of survival and survival without severe impairment ranged from 5.1% (IQR, 0 to 10.6) and 3.4% (IQR, 0 to 6.9), respectively, among children born at 22 weeks of gestation to 81.4% (IQR, 78.2 to 84.0) and 75.6% (IQR, 69.5 to 80.0), respectively, among those born at 26 weeks of gestation. Hospital rates of active treatment accounted for 78% and 75% of the between-hospital variation in survival and survival without severe impairment, respectively, among children born at 22 or 23 weeks of gestation, and accounted for 22% and 16%, respectively, among those born at 24 weeks of gestation, but the rates did not account for any of the variation in outcomes among those born at 25 or 26 weeks of gestation.
Differences in hospital practices regarding the initiation of active treatment in infants born at 22, 23, or 24 weeks of gestation explain some of the between-hospital variation in survival and survival without impairment among such patients. (Funded by the National Institutes of Health.)
PMCID: PMC4465092  PMID: 25946279
21.  Comparative effectiveness of digoxin and propranolol for supraventricular tachycardia in infants 
Supraventricular tachycardia (SVT) is the most common arrhythmia in infants, and antiarrhythmic medications are frequently used for prophylaxis. The optimal prophylactic antiarrhythmic medication is unknown, and prior randomized trials have been underpowered. We used data from a large clinical registry to compare efficacy and safety of digoxin and propranolol for infant SVT prophylaxis. We hypothesized that SVT recurrence is less common on digoxin compared with propranolol.
Retrospective cohort study.
Pediatrix Medical Group neonatal intensive care units.
Infants discharged from 1998–2012 with SVT treated with digoxin or propranolol. We excluded infants discharged prior to completing 2 days of therapy, those with Wolff-Parkinson-White syndrome, structural heart defects (except atrial/ventricular septal defects and patent ductus arteriosus), and those started on multi-drug therapy.
We used Cox proportional hazards to evaluate SVT recurrence, defined as need for adenosine or electrical cardioversion while exposed to digoxin vs. propranolol, controlling for infant characteristics, inotropic support, supplemental oxygen, and presence of a central line.
We identified 342 infants exposed to digoxin and 142 infants exposed to propranolol. The incidence rate of treatment failure was 6.7/1000 infant-days of exposure to digoxin and 15.4/1000 infant-days of exposure to propranolol. On multivariable analysis, treatment failure was higher on propranolol compared with digoxin (hazard ratio=1.97 [95% confidence interval: 1.05, 3.71]). Hypotension was more frequent during exposure to digoxin versus propranolol (39.4 versus 11.1/1000 infant-days, p<0.001). There was no difference in frequency of other clinical adverse events.
Digoxin was associated with fewer episodes of SVT recurrence but more frequent hypotension in hospitalized infants relative to propranolol.
PMCID: PMC4221410  PMID: 25072477
supraventricular tachycardia; infants; digoxin; propranolol
22.  Vancomycin Cerebrospinal Fluid Pharmacokinetics in Children with Cerebral Ventricular Shunt Infections 
This study described the cerebrospinal fluid (CSF) exposure of vancomycin in 8 children prescribed intravenous vancomycin therapy for cerebral ventricular shunt infection. Vancomycin CSF concentrations ranged from 0.06 to 9.13 mg/L and the CSF: plasma ratio ranged from 0 to 0.66. Two children out of three with a staphylococcal CSF infection had CSF concentrations > minimal inhibitory concentration at the end of the dosing interval.
PMCID: PMC4209191  PMID: 24776517
vancomycin; pharmacokinetics; cerebrospinal fluid; children; cerebral shunt
23.  Population Pharmacokinetics of Micafungin in Neonates and Young Infants▿  
Micafungin is an echinocandin with potent activity against Candida spp. Hematogenous Candida meningoencephalitis (HCME) is a frequent complication of disseminated Candida infection in premature infants. A preclinical model of HCME suggests that micafungin may be an effective agent for this syndrome, but relatively high weight-based dosages are required. This prompted the further study of the safety and pharmacokinetics (PK) of micafungin in infants. Here, we describe the population pharmacokinetics of micafungin in 47 infants with a proven or presumptive diagnosis of disseminated candidiasis, who received 0.75, 1.5, 3, 7, 10, and 15 mg/kg of micafungin. The drug was infused daily, and samples were taken in the first dosing interval and at steady state. Serum concentrations were measured using high-performance liquid chromatography (HPLC). Data were modeled using an allometric pharmacokinetic model using a three-fourths scaling exponent for clearance and parameters normalized to a 70-kg adult. Drug exposures were estimated using Monte Carlo simulation. Optimal sampling times were determined using D-optimal design theory. The fit of the allometric model to the data was highly acceptable. The pharmacokinetics of micafungin were linear. The weight-normalized estimates of clearance and volume of distribution approximated those previously described for adults. The original population parameter values could be recapitulated in the Monte Carlo simulations. A dosage of 10 mg/kg/day resulted in 82.6% of patients with areas under the concentration-time curve (AUCs) that are associated with near-maximal decline in fungal burden within the central nervous system (CNS).
PMCID: PMC2876406  PMID: 20308367
24.  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
25.  A systematic review of randomized controlled trials for the prevention of bronchopulmonary dysplasia in infants 
Bronchopulmonary dysplasia (BPD) is the most common cause of pulmonary morbidity in premature infants and is associated with life-long morbidities. Developing drugs for the prevention of BPD would improve public health. We sought to determine characteristics of favorable randomized controlled trials (RCTs) of drugs for BPD prevention.
Evidence review
We searched MEDLINE and EMBASE from 1992–2014 using the MeSH terms “BPD” and “respiratory distress syndrome, newborn.” We included a Cochrane Library search to ensure inclusion of all available RCTs. We identified RCTs with BPD as a primary or secondary outcome and determined the definition of BPD used by the study. We determined whether a phase I or phase II study—to determine drug safety, efficacy, or optimal dose—was performed prior to the RCT. Finally, we searched the Cochrane Library for meta-analyses for each drug and used the results of available meta-analyses to define a favorable versus unfavorable RCT.
We identified 2026 articles; 47 RCTs met our inclusion criteria encompassing 21 drugs; 5 of the drugs reduced the incidence of BPD. We found data from phase I or II studies for 16 of the drugs, but only 1 demonstrated a reduction of BPD.
Conclusions and relevance
The majority of the drugs studied in RCTs failed to reduce the incidence of BPD. Performing early-phase studies prior to phase III trials might provide necessary information on drugs and drug doses capable of preventing BPD, thus informing the development of future RCTs.
PMCID: PMC4152555  PMID: 25010224
bronchopulmonary dysplasia; randomized controlled trials; infant; newborn; FDA; labeling

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