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Objective To characterize the safety of sildenafil in premature infants. Study design A phase I, open-label trial of sildenafil in premature infants receiving sildenafil per usual clinical care (cohort 1) or receiving a single IV dose of sildenafil (cohort 2). Safety was evaluated based on adverse events (AEs), transaminase levels, and mean arterial pressure monitoring. Results Twenty-four infants in cohort 1 (n = 25) received enteral sildenafil. In cohort 2, infants received a single IV sildenafil dose of 0.25 mg/kg (n = 7) or 0.125 mg/kg (n = 2). In cohort 2, there was one serious AE related to study drug involving hypotension associated with a faster infusion rate than specified by the protocol. There were no AEs related to elevated transaminases. Conclusion Sildenafil was well tolerated by the study population. Drug administration times and flush rates require careful attention to prevent infusion-related hypotension associated with faster infusions of IV sildenafil in premature infants. Clinical trial ClinicalTrials.gov Identifier: NCT01670136.

To characterize the association between hyperbilirubinemia and a failed newborn hearing screen in infants born at 22-32 weeks of gestation.We included infants with gestational ages of 22-32 weeks who were discharged from neonatal intensive care units in the US from 2002 to 2017 with available newborn hearing screen results obtained after 34 weeks postmenstrual age. We excluded infants with severe birth asphyxia or craniofacial abnormalities. We identified 95 672 infants from 313 neonatal intensive care units. We used multivariable logistic regression to examine the association between maximum total bilirubin at21 days postnatal age with failed hearing screen, adjusting for important demographic and clinical risk factors.The median gestational age and birth weight were 30 weeks (IQR, 28-32 weeks) and 1330 g (IQR, 1010-1630 g), respectively. The median maximum total bilirubin was 8.3 mg/dL (IQR, 6.7-10.0 mg/dL), and 5275 infants (6%) failed their newborn hearing screen. On adjusted analysis, each 1 mg/dL increase in maximum total bilirubin was associated with a small, but significant, increase in odds of a failed hearing screen (OR, 1.03; 95% CI, 1.02-1.04).An increased maximum total bilirubin level was independently associated with hearing screen failure. Further prospective studies are needed to understand whether this increased risk of hearing screen failure translates to increased risk of hearing loss.

OBJECTIVE: The management of early hypotension in extremely low gestational age neonates (ELGANs) varies greatly between centers. The objective of this study was to provide updated data on the use of vasoactive medications in ELGANs during the first postnatal week. STUDY DESIGN: We identified ELGANs (22-27 weeks gestational age) cared for at Pediatrix neonatal intensive care units from 2009-2018. We evaluated the frequency of exposure to vasoactive medications by gestational age, and compared use of vasoactive medications between 2 epochs (2009-2013 and 2014-2018). RESULTS: A total of 10 070/34 234 (29%) ELGANs received ≥1 vasoactive medication. Dopamine was the most frequently used vasoactive medication. The majority (83%) of treated ELGANs initiated therapy on postnatal day 0-1. Overall use of vasoactive medications was slightly lower in 2014-2018 than 2009-2013 (28% vs 31%, p

Objectives: Investigate characteristics of term infants culture-evaluated for early-onset sepsis (EOS) in neonatal intensive care units (NICUs), frequencies of organisms causing EOS, and factors associated with EOS. Study design: Using a cohort design, we identified term infants evaluated for EOS with blood, cerebrospinal fluid, or urine cultures in 326 NICUs (2011–2016). Using multivariable logistic regression, we investigated the association between EOS and demographic characteristics. Results: Of 142,410 infants, 1197 (0.8%) had EOS, most commonly caused by group B Streptococcus (GBS; 40.6%). Lower EOS risk was associated with low Apgar score, Cesarean delivery, small for gestational age, prenatal antibiotic exposure, and positive or unknown maternal GBS screening result. Increased risk was associated with prolonged rupture of membranes, maternal age

Objective Determine the associations between neonatal intensive care unit (NICU) medication safety practices, laboratory-based adverse events (lab-AEs), and death. Study design We combined data from a 2016 survey of Pediatrix NICUs on use of medication safety practices with 2014-2016 infant data. We grouped NICUs based on the number of safety practices used (≤5, 6-7, and 8-10) and evaluated the association between the number of safety practices used and lab-AEs and deaths using logistic regressions. Results Of the 94 NICUs included, 17% used ≤5 medication safety practices, 51% used 6-7, and 32% used 8-10. NICUs with more safety practices did not have a difference in lab-AEs or death. Conclusion In this cohort, the use of more medication safety practices was not associated with fewer lab-AEs or decreased death.

High doses of ampicillin are often used to achieve therapeutic drug concentrations in infants. A paradoxical antibiotic effect, often called the Eagle effect, occurs when increasing concentrations of antibiotic above a threshold results in decreased efficacy. It is unknown if infants treated with ampicillin are at risk for this paradoxical effect.We identified infants28 days of age with Escherichia coli, Enterococcus or Streptococcus agalactiae (group B streptococcus) bloodstream infections from 1997 to 2012 and previously included in an ampicillin pharmacokinetic (PK) modeling study. We compared the odds of death for ampicillin dose, estimated time above the minimum inhibitory concentration (TMIC) and PK parameters using separate logistic regression models. Adjusted logistic regression and Poisson models were used to calculate the odds of prolonged bacteremia ≥3 days and the duration of bacteremia, respectively, for dose, TMIC and multiple PK parameters.Among 1272 infants meeting inclusion criteria, odds of death 7 or 30 days after the positive blood culture were not consistent with a paradoxical effect across any of the dosing regimens or PK parameters evaluated. The odds of prolonged bacteremia was lowest at the lowest dose category and the lowest daily dose category but not associated with the area-under-the-concentration time curve from 0 to 24 hours, or the maximum or minimum concentrations at steady state. TMIC of ≥50% of the dosing interval was associated with decreased duration of bacteremia and odds of prolonged bacteremia.It is unlikely that a paradoxical antibiotic effect will have a clinical correlate when ampicillin is used for neonatal bacteremia. A TMIC ≥50% decreased both duration of bacteremia and odds of prolonged bacteremia.

BACKGROUND We sought to compare meropenem and fluconazole dosing in the neonatal intensive care unit with recommendations based on published pharmacokinetic (PK) studies in infants. METHODS We performed an observational cohort study of infants

BACKGROUND Clinical trials for antibiotics designed to treat hospital-acquired and ventilator-associated bacterial pneumonias (HABP/VABP) are hampered by making these diagnoses in a way that is acceptable to the United States Food and Drug Administration and consistent with standards of care. We examined laboratory and clinical features that might improve pediatric HABP/VABP trial efficiency by identifying risk factors predisposing children to HABP/VABP and describing the epidemiology of pediatric HABP/VABP. METHODS We prospectively reviewed the electronic medical records of patients

Background: Furosemide is commonly used off-label in the neonatal intensive care unit (NICU), but current dosing practices vary widely. Objectives: To describe dosing practices including route, dose, and duration of exposure to furosemide in a large number of community and tertiary NICUs across North America. Method: Using the Pediatrix Medical Group Clinical Data Warehouse, we identified infants who received ≥1 dose of furosemide between 1997 and 2016. We excluded infants with incomplete dosing data. We calculated average daily furosemide dose, cumulative dose, total days of exposure, and maximum daily dose. We compared dosing between infants born at Results: A total of 18,572 infants had complete dosing data. The median (interquartile value) postnatal age at first exposure was 11 days (4, 26), the median maximum daily dose was 1.0 mg/kg (0.97, 1.6), the median average daily dose was 1.0 mg/kg (0.88, 1.1), and the median cumulative dose was 2.0 mg/kg (1.0, 4.5). The median total duration of exposure was 2 days (1, 4). A total of 177 (1%) infants received ≥4 mg/kg/day of furosemide. Infants born p < 0.001. Conclusions: Most infants received short courses of furosemide within the labeled dosing parameters. Further studies are needed to assess the safety and efficacy of furosemide in the NICU.

OBJECTIVE Obstetric studies often report neonatal morbidity as a composite score. Composite scores can simplify data analysis when multiple outcomes of interest are present and allows researchers to conduct smaller, more manageable trials. The Hassan scale is a neonatal morbidity composite scale that assigns high scores to infants with multiple morbidities and low scores to infants without or with single morbidities. The objective of this study was to validate the association between scores on the Hassan scale and neonatal intensive care unit (NICU) length of stay STUDY DESIGN: We conducted a cohort study of all infants born between 22 and 366/7 weeks' gestation and cared for within 419 neonatal units in the Pediatrix Medical Group between 1997 and 2018. Each infant was assigned a Hassan's score based on the number of neonatal morbidity events that occurred during the delivery hospitalization. The association between Hassan's scores and neonatal length of stay was evaluated using linear regression. Multivariable models were constructed to determine if the Hassan score was independently associated with neonatal length of stay. RESULTS There were 760,037 infants included. The median (interquartile range [IQR]) gestational age of delivery was 34 (31, 35) weeks and the median (IQR) birth weight at delivery was 2,000 (1,503, 2,430) g. The median length of stay for infants discharged home was 17 (10-33) days. A Hassan's score was able to be assigned to 699,206 (92%) patients. Neonatal morbidities included in the Hassan scale were more common among infants born earlier in gestation. On adjusted analysis, the Hassan scale was found to be independently associated with neonatal length of stay (p

Objective To provide up-to-date medication prescribing patterns in US neonatal intensive care units (NICUs) and to examine trends in prescribing patterns over time. Study design We performed a cohort study of 799 016 infants treated in NICUs managed by the Pediatrix Medical Group from 2010 to 2018. We used 3 different methods to report counts of medication: exposure, courses, and days of use. We defined the change in frequency of medication administration by absolute change and relative change. We examined the Food and Drug Administration (FDA) package insert for each medication to determine whether a medication was labeled for use in infants and used PubMed to search for pharmacokinetics (PK) studies. Results The most frequently prescribed medications included ampicillin, gentamicin, caffeine citrate, poractant alfa, morphine, vancomycin, furosemide, fentanyl, midazolam, and acetaminophen. Of the top 50 medications used in infants with extremely low birth weight, only 20 (40%) are FDA-labeled for use in infants; of the 30 that are not labeled for use in infants, 13 (43%) had at least 2 published PK studies. The medications with the greatest relative increase in use from 2010 to 2018 included dexmedetomidine, clonidine, rocuronium, levetiracetam, atropine, and diazoxide. The medications with the greatest relative decrease in use included tromethamine acetate, pancuronium, chloral hydrate, imipenem + cilastatin, and amikacin. Conclusion Trends of medication use in the NICU change substantially over time. It is imperative to identify changes in medication use in the NICU to better inform further prospective studies.

BACKGROUND: In premature infants, complicated intra-abdominal infections (cIAIs) are a leading cause of morbidity and mortality. Although universally prescribed, the safety and effectiveness of commonly used antibiotic regimens has not been established in this population. METHODS: Infants ≤33 weeks gestational age and 4) 30 days after study drug completion. RESULTS: 180 infants (128 randomized [R], 52 non-randomized [NR]) were enrolled: 63 in group 1 (45 R, 18 NR), 47 in group 2 (41 R, 6 NR), and 70 in group 3 (42 R, 28 NR). Thirty-day mortality was 8%, 7%, and 9% in groups 1, 2, and 3, respectively. There were no differences in safety outcomes between antibiotic regimens. After adjusting for treatment group and gestational age, mortality rates through end of follow-up were 4.22 (95% confidence interval [CI] 1.39–12.13), 4.53 (95% CI 1.21–15.50), and 4.07 (95% CI 1.22–12.70) for groups 1, 2, and 3, respectively. CONCLUSIONS: Each of the antibiotic regimens are safe in premature infants with cIAI. CLINICAL TRIAL REGISTRATION: NCT0199499

The objectives describe the frequency that inadequate oral feeding (IOF) is the reason why moderately preterm (MPT) infants remain hospitalized and its association with neonatal morbidities. Prospective study using the NICHD Neonatal Research Network MPT Registry. Multivariable logistic regression was used to describe associations between IOF and continued hospitalization at 36 weeks postmenstrual age (PMA). A total of 6017 MPT infants from 18 centers were included. Three-thousand three-seventy-six (56%) remained hospitalized at 36 weeks PMA, of whom 1262 (37%) remained hospitalized due to IOF. IOF was associated with RDS (OR 2.02, 1.66–2.46), PDA (OR 1.86, 1.37–2.52), sepsis (OR 2.36, 95% 1.48–3.78), NEC (OR 16.14, 7.27–35.90), and BPD (OR 3.65, 2.56–5.21) compared to infants discharged and was associated with medical NEC (OR 2.06, 1.19–3.56) and BPD (OR 0.46, 0.34–0.61) compared to infants remaining hospitalized for an alternative reason. IOF is the most common barrier to discharge in MPT infants, especially among those with neonatal morbidities.

Objective: Pharmacokinetic (PK) data to guide cefazolin dosing in premature infants is virtually non-existent. Therefore, we aimed to characterize cefazolin PK in infants aged ≤32 weeks of gestation at birth. Study Design: We conducted a prospective, open-label PK and safety study of cefazolin in infants ≤32 weeks gestation from a University Medical Center. We administered intravenous cefazolin and collected both timed and scavenged blood samples. We analyzed data using non-linear mixed effect modeling and simulated several dosage regimens to achieve target concentrations against methicillin-susceptible Staphylococcus aureus. Results: We analyzed 40 samples from 9 infants and observed that premature infants had lower clearance and greater volume of distribution for cefazolin compared to older children. The median (range) individual Bayesian estimates were 0.03 L/h/kg (0.01-0.08) for clearance and 0.39 L/kg (0.31-0.52) for volume. Conclusion: Simulations suggested reduced cefazolin dosing based on postmenstrual age achieve target concentrations and potentially reduce unnecessary exposure.

Author(s): Greenberg, Rachel G; Chowdhury, Dhuly; Hansen, Nellie I; Smith, P Brian; Stoll, Barbara J; Sanchez, Pablo J; Das, Abhik; Puopolo, Karen M; Mukhopadhyay, Sagori; Higgins, Rosemary D; Cotten, C Michael; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network | Abstract: BackgroundProlonged early antibiotics in extremely premature infants may have negative effects. We aimed to assess prevalence and outcomes of provision of prolonged early antibiotics to extremely premature infants in the absence of culture-confirmed infection or NEC.MethodsCohort study of infants from 13 centers born without a major birth defect from 2008-2014 who were 401-1000 grams birth weight, 22-28 weeks gestation, and survived ≥5 days without culture-confirmed infection, NEC, or spontaneous intestinal perforation. We determined the proportion of infants who received prolonged early antibiotics, defined as ≥5 days of antibiotic therapy started at ≤72 h of age, by center and over time. Associations between prolonged early antibiotics and adverse outcomes were assessed using multivariable logistic regression.ResultsA total of 5730 infants were included. The proportion of infants receiving prolonged early antibiotics varied from 30-69% among centers and declined from 49% in 2008 to 35% in 2014. Prolonged early antibiotics was not significantly associated with death (adjusted odds ratio 1.17 [95% CI: 0.99-1.40], p = 0.07) and was not associated with NEC.ConclusionsThe proportion of extremely premature infants receiving prolonged early antibiotics decreased, but significant center variation persists. Prolonged early antibiotics were not significantly associated with increased odds of death or NEC.

Objective To characterize the association between gentamicin dosing, duration of treatment, and ototoxicity in hospitalized infants. Study design This retrospective cohort study conducted at 330 neonatal intensive care units (2002-2014) included inborn infants exposed to gentamicin with available hearing screen results, and excluded infants with incomplete dosing data and major congenital anomalies. Our primary outcome was the final hearing screen result performed during hospitalization: abnormal (failed or referred for further testing in one or both ears) or normal (bilateral passed). The 4 measures of gentamicin exposure were highest daily dose, average daily dose, cumulative dose, and cumulative duration of exposure. We fitted separate multivariable logistic regression models adjusted for demographics, comorbidities, and other clinical events. Results A total of 84 808 infants met inclusion/exclusion criteria; median (25th, 75th percentile) gestational age and birth weight were 35 weeks (33, 38) and 2480 g (1890, 3184), respectively. Failed hearing screens occurred in 3238 (3.8%) infants; failed screens were more likely in infants of lower gestational age and birth weight, who had longer hospital lengths of stay, higher rates of morbidities, and were small for gestational age. Median highest daily dose, average daily dose, and cumulative dose were 4.0 mg/kg/day (3.0, 4.0), 3.8 mg/kg/day (3.0, 4.0), and 12.1 mg/kg (9.1, 20.5), respectively. Median cumulative duration of exposure was 3 days (3, 6). In adjusted analysis, gentamicin dose and duration of therapy were not associated with hearing screen failure. Conclusions Gentamicin dosing and duration of treatment were not associated with increased odds of failed hearing screen at the time of discharge from initial neonatal intensive care unit stay.

Background Therapeutic hypothermia reduces the risk of death, or moderate to severe neurodevelopmental impairment (NDI) in term infants with hypoxic-ischemic encephalopathy (HIE). Reports of its safety and efficacy in preterm infants are scarce. Objective Report short and long-term outcomes of preterm infants with HIE who received therapeutic hypothermia. Methods A retrospective cohort analysis of all preterm infants Results 30 infants with a median gestational age and birthweight of 35 weeks' (range; 33–35) and 2575 g (1850–4840) and a median first postnatal blood pH of 6.81 (6.58–7.14). Complications included coagulopathy (50%), early clinical seizures (43.3%), arterial hypotension (40%), persistent metabolic acidosis (37%) and thrombocytopenia (20%). Four infants died before or soon after discharge (18.2%). Eighteen surviving infants (69.2%) had follow up data; 7 of them had moderate to severe NDI (38.9%). Cognitive, motor and language mean composite BSID III scores were 84 (54–110), 83 (46–118), and 78 (46–112). Death or moderate to severe NDI occurred in 11/22 (50%) infants with known outcomes. Conclusion Large randomized trials on efficacy and safety are needed in this highly vulnerable population as the incidence of complications and the combined outcome of death and NDI is concerning.

Background At very high doses, furosemide is linked to ototoxicity in adults, but little is known about the risk of hearing loss in premature infants exposed to furosemide. Aims Evaluate the association between prolonged furosemide exposure and abnormal hearing screening in premature infants. Study design Using propensity scoring, infants with prolonged (≥28 days) exposure to furosemide were matched to infants never exposed. The matched sample was used to estimate the impact of prolonged furosemide exposure on the probability of an abnormal hearing screen prior to hospital discharge. Subjects A cohort of infants 501–1250 g birth weight and 23–29 weeks gestational age discharged home from 210 neonatal intensive care units in the United States (2004–2013). Outcome measures We defined abnormal hearing screen as a result of either “fail” or “refer” for either ear. Results Altogether, 1020 infants exposed to furosemide for ≥28 days were matched to 790 unique infants never exposed, yielding a total of 1042 matches due to sampling with replacement and propensity score ties. Matching resulted in a population similar in baseline characteristics. After adjusting for covariates, the proportion of infants with an abnormal hearing screen in the furosemide-exposed group was not significantly higher than the never-exposed group (absolute difference 3.0% [95% CI −0.2–6.2%], P = 0.07). Conclusions Prolonged furosemide exposure was associated with a positive, but not statistically significant, difference in abnormal hearing screening in premature infants. Additional studies with post-hospital discharge audiology follow-up are needed to further evaluate the safety of furosemide in this population.

Adverse drug events are common in critically ill children and often result from systemic or target organ drug exposure. Methods of drug dosing and titration that consider pharmacokinetic alterations may improve our ability to optimally dose critically ill patients and reduce the risk for drug-related adverse events. To demonstrate this possibility, we explored the exposure-response relationship between midazolam and delirium in critically ill children. We retrospectively examined electronic health records (EHRs) of critically ill children

BACKGROUND AND OBJECTIVES: Despite the neonatal opioid withdrawal syndrome (NOWS) epidemic in the United States, evidence is limited for pharmacologic management when first-line opioid medications fail to control symptoms. The objective with this study was to evaluate outcomes of infants receiving secondary therapy with phenobarbital compared with clonidine, in combination with morphine, for the treatment of NOWS. METHODS: We performed a retrospective cohort study of infants with NOWS from 30 hospitals. The primary outcome measures were the length of hospital stay, duration of opioid treatment, and peak morphine dose. Outcomes were compared by group by using analysis of variance and multivariable linear regression controlling for relevant confounders. RESULTS: Of 563 infants with NOWS treated with morphine, 32% (n = 180) also received a secondary medication. Seventy-two received phenobarbital and 108 received clonidine. After adjustment for covariates, length of hospital stay was 10 days shorter, and, in some models, duration of morphine treatment was 7.5 days shorter in infants receiving phenobarbital compared with those receiving clonidine, with no difference in peak morphine dose. Infants were more likely to be discharged from the hospital on phenobarbital than clonidine (78% vs 29%, P < .0001). CONCLUSIONS: Among infants with NOWS receiving morphine and secondary therapy, those treated with phenobarbital had shorter length of hospital stay and shorter morphine treatment duration than clonidine-treated infants but were discharged from the hospital more often on secondary medication. Further investigation is warranted to determine if the benefits of shorter hospital stay and shorter duration of morphine therapy justify the possible neurodevelopmental consequences of phenobarbital use in infants with NOWS.

BACKGROUND AND OBJECTIVES: Variation in pediatric medical care is common and contributes to differences in patient outcomes. Site-to-site variation in the characteristics and care of infants with neonatal opioid withdrawal syndrome (NOWS) has yet to be quantified. Our objective was to describe site-to-site variation in maternal-infant characteristics, infant management, and outcomes for infants with NOWS. METHODS: Cross-sectional study of 1377 infants born between July 1, 2016, and June 30, 2017, who were ≥36 weeks’ gestation, with NOWS (evidence of opioid exposure and NOWS scoring within the first 120 hours of life) born at or transferred to 1 of 30 participating hospitals nationwide. Site-to-site variation for each parameter within the 3 domains was measured as the range of individual site-level means, medians, or proportions. RESULTS: Sites varied widely in the proportion of infants whose mothers received adequate prenatal care (31.3%–100%), medication-assisted treatment (5.9%–100%), and prenatal counseling (1.9%–75.5%). Sites varied in the proportion of infants with toxicology screening (50%–100%) and proportion of infants receiving pharmacologic therapy (6.7%–100%), secondary medications (1.1%–69.2%), and nonpharmacologic interventions including fortified feeds (2.9%–90%) and maternal breast milk (22.2%–83.3%). The mean length of stay varied across sites (2–28.8 days), as did the proportion of infants discharged with their parents (33.3%–91.1%). CONCLUSIONS: Considerable site-to-site variation exists in all 3 domains. The magnitude of the observed variation makes it unlikely that all infants are receiving efficient and effective care for NOWS. This variation should be considered in future clinical trial development, practice implementation, and policy development.

BACKGROUND: Metronidazole is frequently used off-label in infants with complicated intra-abdominal infections (cIAI) to provide coverage against anaerobic organisms, but its safety and efficacy in this indication are unknown. METHODS: In the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections (SCAMP) open-label multicenter trial infants ≥34 weeks gestation at birth and 4. A blinded adjudication committee reviewed all safety events of special interest. RESULTS: Fifty-five infants were included; median gestational age was 36 weeks (range: 34–41) and postnatal age was 7 days (0–63). The most common additional antibiotics received included gentamicin, piperacillin-tazobactam, ampicillin, and vancomycin. Only one adverse event, a candidal rash, was identified to be potentially caused by metronidazole administration. One infant died of cardiopulmonary failure, which was deemed unrelated to metronidazole. The most common events of special interest included feeding intolerance in 18 (33%) infants, and exploratory laparotomy in 10 (18%) requiring intestinal anastomosis in 7 (13%) infants. There was one (2%) intestinal stricture. Fifty-three infants (96%) achieved overall therapeutic success, 54 (98%) were alive through 30 days post-study therapy, and 54 (98%) had 30-day clinical cure score >4. CONCLUSIONS: In a cohort of late pre-term and term infants with cIAIs, combination antibiotic therapy that included metronidazole was safe, and therapeutic success was high.

BACKGROUND: Invasive candidiasis is an important cause of sepsis in extremely low birth weight infants (ELBW

BACKGROUND: Dexmedetomidine is increasingly used off-label in infants and children with cardiac disease during cardiopulmonary bypass (CPB) and in the postoperative period. Despite its frequent use, optimal dosing of dexmedetomidine in the setting of CPB has not been identified but is expected to differ from dosing in those not supported with CPB. This study had the following aims: (1) characterize the effect of CPB on dexmedetomidine clearance (CL) and volume of distribution (V) in infants and young children; (2) characterize tolerance and sedation in patients receiving dexmedetomidine; and (3) identify preliminary dosing recommendations for infants and children undergoing CPB. We hypothesized that CL would decrease, and V would increase during CPB compared to pre- or post-CPB states. METHODS: Open-label, single-center, opportunistic pharmacokinetics (PK) and safety study of dexmedetomidine in patients ≤36 months of age administered dexmedetomidine per standard of care via continuous infusion. We analyzed dexmedetomidine PK data using standard nonlinear mixed effects modeling with NONMEM software. We compared model-estimated PK parameters to those from historical patients receiving dexmedetomidine before anesthesia for urologic, lower abdominal, or plastic surgery; after low-risk cardiac or craniofacial surgery; or during bronchoscopy or nuclear magnetic resonance imaging. We investigated the influence of CPB-related factors on PK estimates and used the final model to simulate dosing recommendations, targeting a plasma concentration previously associated with safety and efficacy (0.6 ng/mL). We used the Wilcoxon rank sum test to evaluate differences in dexmedetomidine exposure between infants with hypotension or bradycardia and those who did not develop these adverse events. RESULTS: We collected 213 dexmedetomidine plasma samples from 18 patients. Patients had a median (range) age of 3.3 months (0.1–34.0 months) and underwent CPB for 161 minutes (63–394 minutes). We estimated a CL of 13.4 L/h/70 kg (95% confidence interval, 2.6–24.2 L/h/70 kg) during CPB, compared to 42.1 L/h/70 kg (95% confidence interval, 38.7–45.8 L/h/70 kg) in the historical patients. No specific CPB-related factor had a statistically significant effect on PK. A loading dose of 0.7 μg/kg over 10 minutes before CPB, followed by maintenance infusions through CPB of 0.2 or 0.25 μg/kg/h in infants with postmenstrual ages of 42 or 92 weeks, respectively, maintained targeted concentrations. We identified no association between dexmedetomidine exposure and selected adverse events (P = .13). CONCLUSIONS: CPB is associated with lower CL during CPB in infants and young children compared to those not undergoing CPB. Further study should more closely investigate CPB-related factors that may influence CL. (Anesth Analg 2019;129:1519–28)

As advances in neonatal intensive care increase the survival of extremely premature infants, the at-risk population for necrotizing enterocolitis (NEC) continues to rise. Although racial health disparities in preterm births have been well documented, large-scale studies exploring racial differences in NEC outcomes are lacking. Here, we conduct a study of racial health disparities in NEC using a nationally representative multicenter cohort. Infants ≤1500 g birth weight and ≤30 weeks gestational age admitted in the first week after birth to neonatal intensive care units in the Pediatrix Medical group from 1997 to 2015 were included. Multivariable logistic regression was used to determine the adjusted odds ratio (AOR) of risk factors related to NEC and associated mortality. Of the 126,089 (45% non-Hispanic White, 27% non-Hispanic Black, and 19% Hispanic) infants who met the inclusion criteria, 8796 (7%) developed NEC. On multivariable analysis, non-Hispanic Black and Hispanic infants had higher odds of developing NEC (AOR 1.31, 95% confidence interval (CI) [1.24–1.39], p

Objective Pulmonary hypertension causes substantial morbidity and mortality in infants. Although Food and Drug Administration approved to treat pulmonary arterial hypertension in adults, sildenafil is not approved for infants. We sought to describe sildenafil exposure and associated diagnoses and outcomes in infants. Study Design Retrospective cohort of neonates discharged from more than 300 neonatal intensive care units from 2001 to 2016. Results Sildenafil was administered to 1,336/1,161,808 infants (0.11%; 1.1 per 1,000 infants); 0/35,977 received sildenafil in 2001 versus 151/90,544 (0.17%; 1.7 per 1,000 infants) in 2016. Among infants Conclusion The use of sildenafil has increased since 2001. Exposed infants were commonly diagnosed with BPD. Further studies evaluating dosing, safety, and efficacy of sildenafil are needed.

OBJECTIVE: To evaluate the association between furosemide exposure and patent ductus arteriosus (PDA) in a large, contemporary cohort of hospitalized very low birth weight (VLBW) infants. STUDY DESIGN: Using the Pediatrix Medical Group Clinical Data Warehouse, we identified all inborn VLBW infants

Objective We conducted a detailed survey to identify medication safety practices among a large network of United States neonatal intensive care units (NICUs). Methods We created a 53-question survey to assess 300 U.S. NICU's demographics, medication safety practices, adverse drug event (ADE) reporting, and ADE response plans. Results Among the 164 (55%) NICUs that responded to the survey, more than 85% adhered to practices including use of electronic health records, computerized physician order entry, and clinical decision support; fewer reported adopting barcoding, formal safety surveys, and formal culture training; 137 of 164 (84%) developed at least one NICU-specific order-set with a median of 10 order-sets. Conclusion Among our survey of 164 NICUs, we found that many safety practices remain unused. Understanding safety practice variation is critical to prevent ADEs and other negative infant outcomes. Future efforts should focus on linking safety practices identified from our survey with ADEs and infant outcomes.

PURPOSE: Inguinal hernias are common in premature infants, but there is substantial variation with regards to timing of repair. We sought to quantify and explain this variation. METHODS: Cohort study of infants

Background Lumbar puncture (LP) is the gold standard for diagnosing meningitis; however it is unknown whether early LP (≤ 3 days of life) is associated with increased risk of intraventricular hemorrhage (IVH) in very low birth weight (VLBW) infants. Objective To determine whether early LP in VLBW infants is associated with severe IVH. Methods VLBW infants from a cohort of 1,158,789 infants discharged from 382 neonatal intensive care units (1997–2015) were enrolled. Exclusion criteria: infants with major congenital anomalies, outborns, died/transferred prior to day of life 3, and those who had an LP performed only after day of life 3. Logistic regression was used to determine the association between early LP and the incidence of severe IVH (IVH grades 3/4) by 28 days of life for each day of life from day 0 (birth) to day 3, adjusting for clinical covariates. Results 106,461 infants were included: 754 received an LP on Day-0, 640 on Day-1, 559 on Day-2 and 483 on Day-3. Severe IVH occurred in 4% (4130/104,025) of the infants in the no LP group and 9% (217/2436) of the LP group. Severe IVH was higher for infants with early LP: adjusted OR (95% confidence interval) = 2.64 (1.96–3.54) on Day-0; 2.21 (1.61–3.04) on Day-1; 1.55 (1.03–2.34) on Day-2; and 2.25 (1.50–3.38) on Day-3. Conclusions Early LP was associated with severe IVH in VLBW infants by 28 days of life. LP is either a surrogate for an unrecognized factor or is itself associated with an increased risk of IVH.

Objective To assess frequency of preoperative hematologic testing in a tertiary care pediatric emergency department (PED) and how often these values predict clinical outcome or change management decisions. Methods Single-center retrospective cohort study in a tertiary-care children's hospital PED. Patients 0–18 years old, presenting between July 1, 2009-July 1, 2011, ultimately undergoing a surgical procedure within 48 h of presentation were included. Patients were defined as having “preoperative” hematologic assessment if these studies were performed solely because the child was going to the operative suite. Patients who met trauma team activation criteria, underwent neurosurgical procedures, or had laboratory studies performed prior to PED arrival were excluded. The primary outcome was the prevalence of preoperative laboratory assessment. Results 528 children were included, of whom 301 (57%) underwent preoperative hematologic laboratory evaluations. Of these 301 patients, 115 (38%) had abnormal hematologic parameters, and only 3 (1%) of these patients had their perioperative management changed. One additional child had intraoperative bleeding that required blood products but did not undergo preoperative hematologic assessment. All four children had medical histories that would have identified their risk for perioperative bleeding events. Conclusion Preoperative hematologic laboratory assessment occurs frequently in children initially cared for in a tertiary care pediatric emergency department who subsequently undergo operative interventions. Although age-based abnormal hematologic values are often found, rarely are these abnormalities clinically significant. This study suggests that children cared for in a PED without a history concerning for an increased risk of perioperative bleeding does not require preoperative hematologic assessment.

Micafungin is used off-label in the United States to treat invasive candidiasis in neonates. We used an established pharmacokinetic model to determine micafungin exposures for 46 courses in 39 hospitalized infants. In this small cohort of infants, micafungin exposure was not associated with laboratory markers of liver toxicity, death, or failure of microbiological clearance.

BackgroundThe relationship between sildenafil dosing, exposure, and systemic hypotension in infants is incompletely understood.ObjectivesThe aim of this study was to characterise the relationship between predicted sildenafil exposure and hypotension in hospitalised infants.MethodsWe extracted information on sildenafil dosing and clinical characteristics from electronic health records of 348 neonatal ICUs from 1997 to 2013, and we predicted drug exposure using a population pharmacokinetic model.ResultsWe identified 232 infants receiving sildenafil at a median dose of 3.2 mg/kg/day (2.0, 6.0). The median steady-state area under the concentration–time curve over 24 hours (AUC24,SS) and maximum concentration of sildenafil (Cmax,SS,SIL) were 712 ng×hour/ml (401, 1561) and 129 ng/ml (69, 293), respectively. Systemic hypotension occurred in 9% of the cohort. In multivariable analysis, neither dosing nor exposure were associated with systemic hypotension: odds ratio=0.96 (95% confidence interval: 0.81, 1.14) for sildenafil dose; 0.87 (0.59, 1.28) for AUC24,SS; 1.19 (0.78, 1.82) for Cmax,SS,SIL.ConclusionsWe found no association between sildenafil dosing or exposure with systemic hypotension. Continued assessment of sildenafil’s safety profile in infants is warranted.

Background:Late-onset sepsis (LOS) is an important cause of death and neurodevelopmental impairment in premature infants. The purpose of this study was to assess overall incidence of LOS, distribution of LOS-causative organisms and center variation in incidence of LOS for extremely premature infants

BackgroundIn very low birth weight infants, persistence of a patent ductus arteriosus results in morbidity and mortality. Therapies to close the ductus are effective, but clinical outcomes may depend on the accuracy of diagnosis and the timing of administration. The objective of the present study was to characterise the association between early echocardiography, therapy for patent ductus arteriosus, and outcomes in very low birth weight infants.MethodsThis retrospective cohort study used electronic health record data on inborn infants of gestational age ⩽28 weeks and birth weight ResultsThis study included a total of 48,551 infants with a median gestational age of 27 weeks (interquartile range 25, 28) and birth weight 870 g (706, 1050). Early echocardiography – that is, performed during days of life 2 to 6 – was performed in 15,971/48,551 (33%) infants, and patent ductus arteriosus was diagnosed in 31,712/48,551 (65%). The diagnosis was more common in infants who had undergone early echocardiography (14,549/15,971 [91%] versus 17,163/32,580 [53%], pConclusionsEarly echocardiography was associated with an increased diagnosis of patent ductus arteriosus, but not with decreased mortality.

Despite limited pharmacokinetic (PK) data, dexmedetomidine is increasingly being used off-label for sedation in infants. We aimed to characterize the developmental PK changes of dexmedetomidine during infancy. In this open-label, single-center PK study of dexmedetomidine in infants receiving dexmedetomidine per clinical care, ≤10 blood samples per infant were collected. A set of structural PK models and residual error models were explored using nonlinear mixed-effects modeling in NONMEM. Covariates including postmenstrual age (PMA), serum creatinine, and recent history of cardiac surgery requiring cardiopulmonary bypass were investigated for their influence on PK parameters. Univariable generalized estimating equation models were used to evaluate the association of hypotension with dexmedetomidine concentrations. A total of 89 PK samples were collected from 20 infants with a median PMA of 44 weeks (range, 33-61). The median maximum dexmedetomidine infusion dose during the study period was 1.8 μg/(kg·h) (0.5-2.5), and 16/20 infants had a maximum dose >1 μg/(kg·h). A 1-compartment model best described the data. Younger PMA was a significant predictor of lower clearance. Infants with a history of cardiac surgery had ∼40% lower clearance compared to those without a history of cardiac surgery. For infants with PMA of 33 to 61 weeks and body weight of 2 to 6 kg, the estimated clearance and volume of distribution were 0.87 to 2.65 L/(kg·h) and 1.5 L/kg, respectively. No significant associations were found between dexmedetomidine concentrations and hypotension. Infants with younger PMA and recent cardiac surgery may require relatively lower doses of dexmedetomidine to achieve exposure similar to older patients and those without cardiac surgery.

Acyclovir is used to treat herpes simplex virus disease in infants. Treatment with high-dose acyclovir, 60 mg/kg/d, is recommended; however, the safety of this dosage has not been assessed in the past 15 years, and this dosage is not currently approved for infants by the US Food and Drug Administration.We included infants with neonatal herpes simplex virus disease treated with ≥14 days of intravenous acyclovir starting in the first 120 days of life admitted to 1 of 42 neonatal intensive care units managed by the Pediatrix Medical Group between 2002 and 2012. We determined the frequency and proportion of infants with clinical and laboratory adverse events (AEs) as well as the number and proportion of infant days with laboratory AEs occurring during acyclovir exposure.We identified 89 infants during the study period with 1658 days of acyclovir exposure. Almost all received high-dose acyclovir therapy (79/89, 89%). The most common clinical AEs were hypotension and seizure, both occurring in 9% of infants. Thrombocytopenia was the most common laboratory AE occurring in 25% of infants and on 9% of infant-days. Elevated creatinine occurred in 2% of infants and 0.2% of infant-days and no infants developed renal failure requiring dialysis. Overall, 45% of infants had ≥1 AE.In this cohort of infants treated during the high-dose acyclovir era, AEs were common but usually not severe. Many of the AEs reported in this cohort may be related to the underlying infection rather than due to acyclovir exposure.

BackgroundData reported during the past 5 years indicate that rates of survival have increased among infants born at the borderline of viability, but less is known about how increased rates of survival among these infants relate to early childhood neurodevelopmental outcomes.MethodsWe compared survival and neurodevelopmental outcomes among infants born at 22 to 24 weeks of gestation, as assessed at 18 to 22 months of corrected age, across three consecutive birth-year epochs (2000-2003 [epoch 1], 2004-2007 [epoch 2], and 2008-2011 [epoch 3]). The infants were born at 11 centers that participated in the National Institute of Child Health and Human Development Neonatal Research Network. The primary outcome measure was a three-level outcome - survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, or death. After accounting for differences in infant characteristics, including birth center, we used multinomial generalized logit models to compare the relative risk of survival without neurodevelopmental impairment, survival with neurodevelopmental impairment, and death.ResultsData on the primary outcome were available for 4274 of 4458 infants (96%) born at the 11 centers. The percentage of infants who survived increased from 30% (424 of 1391 infants) in epoch 1 to 36% (487 of 1348 infants) in epoch 3 (P

Patients with systemic right ventricles frequently experience progressive heart failure and conduction abnormalities leading to abnormal ventricular activation. Activation delay-induced mechanical dyssynchrony can contribute to ventricular failure and is identified by a classic strain pattern of paradoxical opposing wall motion that is an excellent predictor of response to cardiac resynchronization therapy in adults with left bundle branch block. The specific aims of this study were to compare right ventricular (RV) mechanics in an adult systemic right ventricle population versus control subjects, evaluate the feasibility of this RV strain pattern analysis, and determine the frequency of the classic pattern.Young adults (n = 25) with d-transposition of the great arteries, status post Mustard or Senning palliation (TGA-MS), were ambispectively enrolled and compared with healthy young adults (n = 30) who were prospectively enrolled. All subjects were imaged using novel three-apical view (18-segment) RV longitudinal speckle-tracking strain analysis (EchoPAC) and electrocardiographic data.Patients with TGA-MS had diminished RV global peak systolic strain compared with control subjects (-12.0 ± 4.0% vs -23.3 ± 2.3%, P .001). Most patients with TGA-MS had intrinsic or left ventricular paced right bundle branch block. A classic pattern was present in 11 of 25 subjects (44%), but this pattern would have been missed in four of 11 based only on the RV four-chamber (six-segment) model. Only three subjects underwent cardiac resynchronization therapy. Both subjects who had the classic pattern responded to cardiac resynchronization therapy, whereas the one nonresponder did not have the classic pattern.Systemic right ventricles demonstrated decreased function and increased mechanical dyssynchrony. The classic pattern of activation delay-induced mechanical dyssynchrony was frequently seen in this TGA-MS population and associated with activation delays. This comprehensive RV approach demonstrated incremental value.

Quantify the risk of treatment for retinopathy of prematurity (ROP) among infants meeting current U.S. screening guidelines. Among infants ≤1500 g birth weight or ≤30 weeks gestation screened for ROP from 2006–2015, we developed a risk prediction model to identify infants treated for ROP. We applied our model to a separate infant cohort discharged in 2016. Seventy-five thousand eight hundred and twenty one infants met inclusion criteria; 2306 (3%) were treated for ROP. Infants with several risk factor combinations (no ventilator support or oxygen on postnatal day 28, no history of necrotizing enterocolitis, and no intraventricular hemorrhage) were at low risk of ROP. Applied to 6127 infants discharged in 2016, our model had 97.9% sensitivity, 63.3% specificity, positive predictive value of 4.0%, and negative predictive value of 99.9%. Large numbers of infants at low risk of developing ROP are required to undergo screening. Refining current ROP guidelines may reduce unnecessary examinations.

Objective To assess site variability and concomitant respiratory support related to the timing of caffeine discontinuation, and compare clinical characteristics of infants who discontinued caffeine before vs. within the last week of hospitalization. Study design Cohort study of 81,110 infants

Following publication of the original article [1], the authors notified us that they would like to acknowledge Anjali Gupta for her contribution to the background for this systematic review.

OBJECTIVE: To characterize the dosing and safety of off-label caffeine citrate in a contemporary cohort of extremely premature infants. STUDY DESIGN: We used electronic health records (2010–2013) from four neonatal intensive care units to identify infants of ≤28 weeks’ gestational age (GA) exposed to caffeine citrate. Safety outcomes included: death, bronchopulmonary dysplasia, necrotizing enterocolitis, spontaneous intestinal perforation, intraventricular hemorrhage, patent ductus arteriosus ligation, seizures, and arrhythmias. We used multivariable logistic regression to evaluate the association of caffeine citrate exposure with clinical events. RESULTS: Of 410 infants with a median (interquartile range [IQR]) GA of 26 (24–27) weeks, 95% received caffeine citrate for >10 days. Infants received a median (IQR) daily dose of 8 (5–10) mg/kg/day. Incidences of clinical events on day of caffeine citrate exposure were: death 2%, patent ductus arteriosus ligation 12%, and medical and surgical necrotizing enterocolitis 5% and 4%, respectively. Bronchopulmonary dysplasia occurred in 37% of infants and was not associated with caffeine dose. Increased caffeine citrate dose was associated with lower odds of patent ductus arteriosus ligation and necrotizing enterocolitis. CONCLUSIONS: Caffeine citrate was used in extremely premature infants at younger gestation, at higher doses, and for longer durations than recommended on the drug label. Increased caffeine citrate exposure, dose or therapy duration, was not associated with increased risk of necrotizing enterocolitis.

Fluconazole is used to treat hematogenous Candida meningoencephalitis in preterm and term infants. To characterize plasma and central nervous system exposure, an adult fluconazole physiologically-based pharmacokinetic (PBPK) model was scaled to infants, accounting for age dependencies in glomerular filtration and metabolism. The model was optimized using 760 plasma samples from 166 infants (median postmenstrual age (range) 28 weeks (24-50)) and 27 cerebrospinal fluid (CSF) samples from 22 infants (postmenstrual age 28 weeks (24-33)). Simulations evaluated achievement of the surrogate efficacy target of area under the unbound concentration-time curve ≥ 400 mg • hour/L over the dosing interval in plasma and CSF using dosing guidelines. Average fold error of predicted concentrations was 0.73 and 1.14 for plasma and CSF, respectively. Target attainment in plasma and CSF was reached faster after incorporating a loading dose of 25 mg/kg. PBPK modeling can be useful in exploring CNS kinetics of drugs in children.

OBJECTIVE: Characterize frequency and volume of blood draws and transfusions in extremely low birth weight infants in the first 10 weeks of life. STUDY DESIGN: We included infants with a birth weight

BACKGROUND: Gastrostomy tube (G-tube) placement is a long-term alternative to oral or nasogastric feeding for premature infants, who cannot safely feed orally or need supplemental nutrition for adequate growth. MATERIALS AND METHODS: We compared daily weight changes for G-tube infants 14 and 30 days pre- and post-placement, excluding the first 7 days post–G-tube insertion, were compared. Infants

OBJECTIVE: To evaluate how frequently surfactant is used off-label in preterm infants. STUDY DESIGN: We conducted a retrospective cohort analysis of prospectively collected administrative data between 2005 and 2015 from 348 neonatal intensive care units in the United States. We quantified off-label administration of poractant alfa, calfactant, or beractant in inborn infants

Objective To describe the variation in surgical gastrostomy tube (SGT) placement in premature infants among neonatal intensive care units (NICUs) in the United States. Study Design We identified 8,781 premature infants discharged from 114 NICUs in the Pediatrix Medical Group from 2010 to 2012. The outcome of interest was SGT placement prior to discharge home from an NICU. Unadjusted proportions and adjusted risk estimates were calculated to quantify variation observed among individual NICUs. Results SGT placement occurred in 360 of 8,781 (4.1%) of infants. Across NICUs, any gastrostomy tube placement ranged from none in 45 NICUs up to 19.6%. Adjusted risk estimates for factors associated with SGT placement included gestational age at birth (odds ratio [OR]: 0.7/week, 95% confidence interval[CI]: [0.65, 0.75]), small for gestational age status (OR: 2.78 [2.09, 3.71]), administration of antenatal steroids (OR: 0.69 [0.52, 0.92]), Hispanic ethnicity (OR: 0.54 [0.37, 0.78]), and higher 5-minute Apgar scores (7–10, OR: 0.54 [0.37, 0.79]). Conclusion Individual NICU center has a strong clinical effect on the probability of SGT placement relative to other medical factors. Future work is needed to understand the cause of this variation and the degree to which it represents over or under use of gastrostomy tubes.

Ticarcillin–clavulanate covers a broad spectrum of pathogens that are common in premature infants. In infants 90% of simulated infants. For highly resistant organisms (minimum inhibitory concentration 32 μg/mL), increased dosing frequency or extended infusion are necessary.

Furosemide is a potent loop diuretic commonly and variably used by neonatologists to improve oxygenation and lung compliance in premature infants. There are several safety concerns with use of furosemide in premature infants, specifically the risk of sensorineural hearing loss (SNHL), and nephrocalcinosis/nephrolithiasis (NC/NL). We conducted a systematic review of all trials and observational studies examining the association between these outcomes with exposure to furosemide in premature infants. We searched MEDLINE, EMBASE, CINAHL, and clinicaltrials.gov. We included studies reporting either SNHL or NC/NL in premature infants (