Using the Neonatal Intensive Care Unit Wisely: A National Survey of Clinicians Regarding Practices for Lower-Acuity Care.

OBJECTIVE: The objective of this study was to document the practices and preferences of neonatal care stakeholders regarding location and duration of care for newborns with low illness acuity. STUDY DESIGN: We developed a survey instrument that comprised 14 questions across 2 global scenarios and 7 specific clinical conditions. The latter included apnea of prematurity, gestational age for neonatal intensive care unit admission, jaundice, neonatal opioid withdrawal, thermoregulation, and sepsis evaluation. Respondents reported their current practice and preferences for an alternative approach. We administered the survey to individuals in the membership email distribution lists of the American Academy of Pediatrics Section on Neonatal-Perinatal Medicine, the National Association of Neonatal Nurses, and the Vermont Oxford Network. RESULTS: Of 2284 respondents, 53% believed that infants were, in general, admitted to a higher level of care than was required, and only 13% reported that the level of care was too low. Length of stay was perceived to be generally too long by 46% of respondents and too short by 21%. Across 10 specific clinical questions, there was substantial variability in current practice and up to 35% of respondents reported discordance between current and preferred practice. These respondents preferred a lower level of care in 8 of 10 scenarios. CONCLUSIONS: A multidisciplinary sample of US clinicians reported significant variation in the level and duration of care for infants with low illness acuity. Among individuals reporting discordance between current and preferred practice, a majority believed that current management could be accomplished in a lower level of care location.

Variation in United States COVID-19 newborn care practices: results of an online physician survey.

BACKGROUND: Newborn care practices that best promote the health and well-being of mother-infant dyads after birth while minimizing transmission of COVID-19 were uncertain at the onset of the COVID-19 pandemic. OBJECTIVE: Examine variation in COVID-19 newborn care practices among U.S. birth hospitals and by hospital characteristics (U.S. census region, highest level of neonatal level of care, and Baby-Friendly hospital status). STUDY DESIGN: We surveyed physicians via American Academy of Pediatrics email listservs and social media between 5/26/2020-6/8/2020. Physicians identified the birth hospital in which they provided newborn care and their hospital's approach to obstetrical and newborn care related to COVID-19. Chi-square tests were used to examine variation in hospital practices by U.S. census region, highest level of neonatal care, and Baby-Friendly hospital status. RESULTS: Four hundred thirty three physicians responded from 318 hospitals across 46 states. Variation in care of SARS-CoV-2 positive mother-infant dyads was greatest for approaches to location of newborn care (31% separation, 17% rooming-in, and 51% based on shared-decision making), early skin-to-skin care (48% prohibited/discouraged, 11% encouraged, and 40% based on shared-decision making) and direct breastfeeding (37% prohibited/discouraged, 15% encouraged, and 48% based on shared-decision making). Among presumed uninfected dyads, 59% of hospitals discharged at least some mother-infant dyads early. We found variation in practices by U.S. census region. CONCLUSION: Approaches to newborn care and breastfeeding support for mother-infant dyads with positive SARS-CoV-2 testing differed across U.S. birth hospitals during the COVID-19 pandemic. Early discharge of presumed uninfected mother-infant dyads was common.

Effectiveness of Dual Medication Therapy (Oral Acetaminophen and Oral Ibuprofen) for the Management of Patent Ductus Arteriosus in Extremely Premature Infants: A Feasibility Trial.

OBJECTIVE: The study aimed to evaluate the efficacy of dual medication therapy (DMT) with oral acetaminophen and oral ibuprofen for the closure of a hemodynamically significant patent ductus arteriosus (hsPDA). STUDY DESIGN: In a prospective case-control cohort study (July 2017-May 2019), infants <29 weeks' gestational age and birth weight <1,000 g at ≤14 postnatal days with hsPDA and ratio of the smallest ductal diameter to the ostium of the left pulmonary artery diameter >0.5 were eligible. Infants received 10 mg/kg oral ibuprofen followed by two additional doses of 5 mg/kg at 24 and 48 hours after the initial ibuprofen dose and concomitant treatment with 15 mg/kg oral acetaminophen every 6 hours for 3 days (12 doses). Success of PDA treatment was defined as a small or absent PDA as ascertained by echocardiographic measurements. The p-values of comparisons were adjusted for multiple comparisons to preserve an error rate of 5%. RESULTS: Overall, 20 infants received oral DMT and 11 infants received intravenous single medication therapy (SMT) with ibuprofen. The rates of successful PDA treatment following the first treatment in DMT and SMT groups were not statistically different (11/20 [55%] vs. 4/11 [36%], p = 0.46). However, DMT significantly decreased PDA size (mean difference = 0.54 mm, 95% confidence interval [CI]: 0.21-0.96, adjusted p-value = 0.0002) and PDA/LPA ratio (mean difference = 0.27, 95% CI: 0.10-0.47, adjusted p-value = 0.0004). We observed no evidence of hematologic, hepatic, or renal impairment. CONCLUSION: DMT achieved a greater degree of PDA closure than SMT and did not result in abnormalities in hepatic and renal profile. KEY POINTS: · No consensus on optimal medication for PDA treatment is available.. · Dual oral medication therapy (ibuprofen and acetaminophen) could be an effective alternative treatment for PDA.. · Dual oral medication therapy (ibuprofen and acetaminophen) may have a better safety profile than currently approved medications such as intravenous indomethacin and intravenous ibuprofen..

Improving Outcomes through a Neonatal Abstinence Syndrome Collaborative in Maryland.

OBJECTIVES: A statewide Maryland Perinatal Neonatal Quality Collaborative, facilitated by the Maryland Patient Safety Center (MPSC), identified the three specific, measurable, attainable, relevant, and time-limited (SMART) aims to improve outcomes of neonatal abstinence syndrome (NAS) care as follows: (1) to reduce hospital length of stay (LOS), (2) to reduce interhospital transfers, and (3) to reduce 30-day readmission rates of infants with NAS. STUDY DESIGN: The Maryland collaborative developed a bundle of best practices for care of infants with NAS. MPSC partnered with Vermont Oxford Network (VON) to utilize the VON NAS toolkit and provided its standardized NAS educational curriculum to address the three objectives for participating birthing hospitals. Efforts began in quarter 4 (Q4) of 2016 and continued for 2 years. Thirty-one of Maryland's 32 delivery hospitals (97%) participated in the 2-year collaborative. Additionally, one specialty pediatric hospital with an NAS unit participated in the group learnings. Participating facilities implemented components of the MPSC NAS bundle and provided their staff caring for infants with NAS and their mothers access to the VON standardized educational curriculum. MPSC partnered with VON to conduct two audits of implementation of policies and procedures in Q1 of 2016 and Q3 of 2018. The Maryland Department of Health supplied quarterly aggregate hospital information on LOS, interhospital transfers, and 30-day readmissions of infants with a discharge diagnosis of the International Classification of Disease, 10th Revision (ICD-10), P96.1. RESULTS: Among term infants with NAS with total hospital stay greater than 5 days, we observed a nonsignificant reduction in both mean and median LOS of 1.5 days. In this same group, the rate of interhospital transfers fell significantly from 20.1% in 2016 to 13.8 and 11.0% in 2017 and 2018, respectively. CONCLUSION: The best practice bundle created by the Maryland collaborative was associated with a reduction in the percentage of infants with NAS who required interhospital transfer, thereby reducing family disruption. KEY POINTS: · A state NAS collaborative engaged 97% of delivery hospitals in education and standardization of care.. · The collaborative witnessed a 1.5-day decrease in length of stay, similar to that observed in other state collaboratives.. · The unique outcome of our collaborative was a 50% decrease in the rate of interhospital transfer..

Charge Nurses Taking Charge, Challenging the Culture of Culture-Negative Sepsis, and Preventing Central-Line Infections to Reduce NICU Antibiotic Usage.

OBJECTIVE: We aimed to reduce our monthly antibiotic usage rate (AUR, days of treatment per 1,000 patient-days) in the neonatal intensive care unit (NICU) from a baseline of 330 (July 2015-April 2016) to 200 by December 2018. STUDY DESIGN: We identified three key drivers as follows: (1) engaging NICU charge nurses, (2) challenging the culture of culture-negative sepsis, and (3) reducing central-line associated bloodstream infections (CLABSI). Our main outcome was AUR. The percentage of culture-negative sepsis that was treated with antibiotics for >48 hours and CLABSI was our process measure. We used hospital cost/duration of hospitalization and mortality as our balancing measures. RESULTS: After testing several plan-do-study-act (PDSA) cycles, we saw a modest reduction in AUR from 330 in the year 2016 to 297 in the year 2017. However, we did not find a special-cause variation in AUR via statistical process control (SPC) analysis (u'-chart). Thereafter, we focused our efforts to reduce CLABSI in January 2018. As a result, our mean AUR fell to 217 by December 2018. Our continued efforts resulted in a sustained reduction in AUR beyond the goal period. Importantly, cost of hospitalization and mortality did not increase during the improvement period. CONCLUSION: Our sequential quality improvement (QI) efforts led to a reduction in AUR. We implemented processes to establish a robust antibiotic stewardship program that included antibiotic time-outs led by NICU charge nurses and a focus on preventing CLABSI that were sustained beyond the QI period. KEY POINTS: · This is a quality improvement project to reduce antibiotic usage in NICU.. · Charge nurses should take charge to reduce infections in NICU.. · Central line infections should be reduced to decrease antibiotic usage..

Electrophysiological effects and clinical utility of propafenone in children.

AIM: This retrospective case series study sought to describe the safety and clinical effectiveness of propafenone for the control of arrhythmias in children with and without CHD or cardiomyopathy. METHODS: We reviewed baseline characteristics and subsequent outcomes in a group of 63 children treated with propafenone at 2 sites over a 15-year period Therapy was considered effective if no clinically apparent breakthrough episodes of arrhythmias were noted on the medication. RESULTS: Sixty-three patients (29 males) were initiated on propafenone at a median age of 2.3 years. CHD or cardiomyopathy was noted in 21/63 (33%). There were no significant differences between demographics, clinical backgrounds, antiarrhythmic details, side effect profiles, and outcomes between children with normal hearts and children with CHD or cardiomyopathy. Cardiac depression at the initiation of propafenone was more common amongst children with CHD or cardiomyopathy compared to children with normal hearts. Systemic ventricular function was diminished in 15/63 patients (24%) prior to starting propafenone and improved in 8/15 (53%) of patients once better rhythm control was achieved. Other than one child in whom medication was stopped due to gastroesophageal reflux, no other child experienced significant systemic or cardiac side effects during treatment with propafenone. Propafenone achieved nearly equal success in controlling arrhythmias in both children with normal hearts and children with congenital heart disease or cardiomyopathy (90% versus 86%, p = 0.88). CONCLUSION: Propafenone is a safe and effective antiarrhythmic medication in children.

Blood metabolomics in infants enrolled in a dose escalation pilot trial of budesonide in surfactant.

BACKGROUND: The pathogenesis of BPD includes inflammation and oxidative stress in the immature lung. Corticosteroids improve respiratory status and outcome, but the optimal treatment regimen for benefit with low systemic effects is uncertain. METHODS: In a pilot dose escalation trial, we administered ≤5 daily doses of budesonide in surfactant to 24 intubated premature infants (Steroid And Surfactant in ELGANs (SASSIE)). Untargeted metabolomics was performed on dried blood spots using UPLC-MS/MS. Tracheal aspirate IL-8 concentration was determined as a measure of lung inflammation. RESULTS: Metabolomics data for 829 biochemicals were obtained on 121 blood samples over 96 h from 23 infants receiving 0.025, 0.05, or 0.1 mg budesonide/kg. Ninety metabolites were increased or decreased in a time- and dose-dependent manner at q ≤ 0.1 with overrepresentation in lipid and amino acid super pathways. Different dose response patterns occurred, with negative regulation associated with highest sensitivity to budesonide. Baseline levels of 22 regulated biochemicals correlated with lung inflammation (IL-8), with highest significance for sphingosine and thiamin. CONCLUSIONS: Numerous metabolic pathways are regulated in a dose-dependent manner by glucocorticoids, which apparently act via distinct mechanisms that impact dose sensitivity. The findings identify candidate blood biochemicals as biomarkers of lung inflammation and systemic responses to corticosteroids. IMPACT: Treatment of premature infants in respiratory failure with 0.1 mg/kg intra-tracheal budesonide in surfactant alters levels of ~11% of detected blood biochemicals in discrete time- and dose-dependent patterns. A subset of glucocorticoid-regulated biochemicals is associated with lung inflammatory status as assessed by lung fluid cytokine concentration. Lower doses of budesonide in surfactant than currently used may provide adequate anti-inflammatory responses in the lung with fewer systemic effects, improving the benefit:risk ratio.

Consequences of the SARS-CoV-2 pandemic in the perinatal period.

PURPOSE OF REVIEW: To provide an update on the consequences of severe acute respiratory syndrome (SARS)-CoV-2 infection on the health and perinatal outcomes of pregnant women and their infants. RECENT FINDINGS: The severity of SARS-CoV-2 infection is greater in pregnant compared to nonpregnant women as measured by rates of admission to intensive care units, mechanical ventilation, mortality, and morbidities including myocardial infarction, venous thromboembolic and other thrombotic events, preeclampsia, preterm labor, and preterm birth. The risk of transmission from mother-to-infant is relatively low (1.5-5%) as quantitated by neonatal SARS-CoV-2 testing. Infants appear to be at higher risk of testing positive for SARS-CoV-2 if the mother has tested positive within 1 week of delivery or is herself symptomatic at the time of maternity admission. The rate of positivity is not higher in infants who room in with the mother compared to infants who are initially separated and cared for in a SARS-CoV-2-free environment. Infants who test positive in the hospital have no or mild signs of disease, most of which may be attributable to prematurity, and rarely require readmission for clinical signs consistent with COVID-19. SUMMARY: Pregnant women should take precautions to avoid infection with SARS-CoV-2. Infants born to mothers who test positive for SARS-CoV-2 can receive normal neonatal care in-hospital with their mothers if mother and staff adhere to recommended infection control practices.

Neurodevelopmental Outcomes of Neonates Randomized to Morphine or Methadone for Treatment of Neonatal Abstinence Syndrome.

OBJECTIVE: To evaluate the effects of pharmacologic treatment of neonatal abstinence syndrome on neurodevelopmental outcome from a randomized, controlled trial. STUDY DESIGN: Eight sites enrolled 116 full-term newborn infants with neonatal abstinence syndrome born to mothers maintained on methadone or buprenorphine into a randomized trial of morphine vs methadone. Ninety-nine infants (85%) were evaluated at hospital discharge using the NICU Network Neurobehavioral Scale. At 18 months, 83 of 99 infants (83.8%) were evaluated with the Bayley Scales of Infant and Toddler Development-Third Edition and 77 of 99 (77.7%) with the Child Behavior Checklist (CBCL). RESULTS: Primary analyses showed no significant differences between treatment groups on the NICU Network Neurobehavioral Scale, Bayley Scales of Infant and Toddler Development-Third Edition, or CBCL. However in post hoc analyses, we found differences by atypical NICU Network Neurobehavioral Scale profile on the CBCL. Infants receiving adjunctive phenobarbital had lower Bayley Scales of Infant and Toddler Development-Third Edition scores and more behavior problems on the CBCL. In adjusted analyses, internalizing and total behavior problems were associated with use of phenobarbital (P = .03; P = .04), maternal psychological distress (measured by the Brief Symptom Inventory) (both P < .01), and infant medical problems (both P = .02). Externalizing problems were associated with maternal psychological distress (P < .01) and continued maternal substance use (P < .01). CONCLUSIONS: Infants treated with either morphine or methadone had similar short-term and longer term neurobehavioral outcomes. Neurodevelopmental outcome may be related to the need for phenobarbital, overall health of the infant, and postnatal caregiving environment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958476.

Dose-escalation trial of budesonide in surfactant for prevention of bronchopulmonary dysplasia in extremely low gestational age high-risk newborns (SASSIE).

BACKGROUND: Initial trials of lung-targeted budesonide (0.25 mg/kg) in surfactant to prevent bronchopulmonary dysplasia (BPD) in premature infants have shown benefit; however, the optimal safe dose is unknown. METHODS: Dose-escalation study of budesonide (0.025, 0.05, 0.10 mg/kg) in calfactatant in extremely low gestational age neonates (ELGANs) requiring intubation at 3-14 days. Tracheal aspirate (TA) cytokines, blood budesonide concentrations, and untargeted blood metabolomics were measured. Outcomes were compared with matched infants receiving surfactant in the Trial Of Late SURFactant (TOLSURF). RESULTS: Twenty-four infants with mean gestational age 25.0 weeks and 743 g birth weight requiring mechanical ventilation were enrolled at mean age 6 days. Budesonide was detected in the blood of all infants with a half-life of 3.4 h. Of 11 infants with elevated TA cytokine levels at baseline, treatment was associated with sustained decrease (mean 65%) at all three dosing levels. There were time- and dose-dependent decreases in blood cortisol concentrations and changes in total blood metabolites. Respiratory outcomes did not differ from the historic controls. CONCLUSIONS: Budesonide/surfactant had no clinical respiratory benefit at any dosing levels for intubated ELGANs. One-tenth the dose used in previous trials had minimal systemic metabolic effects and appeared effective for lung-targeted anti-inflammatory action.

Retrospective Analysis of Short-Term Respiratory Outcomes of Three Different Steroids Used in Clinical Practice in Intubated Preterm Infants.

OBJECTIVE: This study aimed to compare short-term respiratory outcomes of three steroids (dexamethasone, hydrocortisone, and methylprednisolone) to facilitate extubation by improving respiratory status in preterm infants. STUDY DESIGN: This is a retrospective, single-center, cohort study of 98 intubated preterm infants ≤346/7 weeks' gestation, admitted to a 64-bed, level III neonatal intensive care unit at the Women & Children's Hospital of Buffalo, Buffalo, NY, between 2006 and 2012, who received a short course of low-dose steroids for lung disease after first week of life. RESULTS: Study infants received dexamethasone (34%), hydrocortisone (44%), or methylprednisolone (22%) based on clinical team preference. By day 7 after initiation of steroids, extubation occurred in 59, 44, and 41%, respectively, in infants on dexamethasone, hydrocortisone, and methylprednisolone (p = 0.3). The mean respiratory severity score (RSS = fraction of inspired oxygen × mean airway pressure), a quantitative measure of respiratory status, decreased by 44% for all infants and by 59% in the dexamethasone group by day 7. CONCLUSION: Steroids improved short-term respiratory outcomes in all infants (RSS and extubation); by day 7, dexamethasone treatment was associated with the greatest decrease in RSS. Additional prospective, randomized trials of short-course low-dose steroids are warranted to substantiate these findings to guide clinical decision making and in evaluating differential steroid effects on long-term neurodevelopmental outcomes.

Assessing the Burden of Neonatal Abstinence Syndrome: Validation of ICD-9-CM Data, Florida, 2010-2011.

CONTEXT: On October 1, 2015, the United States transitioned from using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) to ICD-10-CM. Continuing to monitor the burden of neonatal abstinence syndrome (NAS) after the transition presently requires use of data dependent on ICD-9-CM coding to enable trend analyses. Little has been published on the validation of using ICD-9-CM codes to identify NAS cases. OBJECTIVE: To assess the validity of hospital discharge data (HDD) from selected Florida hospitals for passive NAS surveillance, based on ICD-9-CM codes, which are used to quantify baseline prevalence of NAS. DESIGN: We reviewed infant and maternal data for all births at 3 Florida hospitals from 2010 to 2011. Potential NAS cases included infants with ICD-9-CM discharge codes 779.5 and/or 760.72 in linked administrative data (ie, HDD linked to vital records) or in unlinked HDD and infants identified through review of neonatal intensive care unit admission logs or inpatient pharmacy records. Confirmed infant cases met 3 clinician-proposed criteria. Sensitivity and positive predictive value were calculated to assess validity for the 2 ICD-9-CM codes, individually and combined. RESULTS: Of 157 confirmed cases, 134 with 779.5 and/or 760.72 codes were captured in linked HDD (sensitivity = 85.4%) and 151 in unlinked HDD (sensitivity = 96.2%). Positive predictive value was 74.9% for linked HDD and 75.5% for unlinked HDD. For either HDD types, the single 779.5 code had the highest positive predictive value (86%), lowest number of false positives, and good to excellent sensitivity. CONCLUSIONS: Passive surveillance using ICD-9-CM code 779.5 in either linked or unlinked HDD identified NAS cases with reasonable validity. Our work supports the use of ICD-9-CM code 779.5 to assess the baseline prevalence of NAS through 2015.

Rifampin Pharmacokinetics and Safety in Preterm and Term Infants.

Rifampin is active against methicillin-resistant staphylococcal species and tuberculosis (TB). We performed a multicenter, prospective pharmacokinetic (PK) and safety study of intravenous rifampin in infants of <121 days postnatal age (PNA). We enrolled 27 infants; the median (range) gestational age was 26 weeks (23 to 41 weeks), and the median PNA was 10 days (0 to 84 days). We collected 102 plasma PK samples from 22 of the infants and analyzed safety data from all 27 infants. We analyzed the data using a population PK approach. Rifampin PK was best characterized by a one-compartment model; drug clearance increased with increasing size (body weight) and maturation (PNA). There were no adverse events related to rifampin. Simulated weight and PNA-based intravenous dosing regimens administered once daily (<14 days PNA, 8 mg/kg; ≥14 days PNA, 15 mg/kg) in infants resulted in comparable exposures to adults receiving therapeutic doses of rifampin against staphylococcal infections and TB. (This study has been registered at ClinicalTrials.gov under identifier NCT01728363.).

Glucose Gel in Infants at Risk for Transitional Neonatal Hypoglycemia.

OBJECTIVE: To evaluate whether glucose gel as a supplement to feedings in infants admitted to the newborn nursery at risk for neonatal hypoglycemia (NH) reduces the frequency of transfer to a higher level of care for intravenous dextrose treatment. STUDY DESIGN: We revised our newborn nursery protocol for management of infants at risk for NH to include use of 40% glucose gel (200 mg/kg). Study population included late preterm, small and large for gestational age infants, and infants of diabetic mothers. We compared outcomes before (4/1/14-3/31/15: Year 1) and after (4/1/15-3/31/16: Year 2) initiation of the revised protocol. Our prospective primary outcome was transfer to the neonatal intensive care unit (NICU) for treatment with a continuous infusion of dextrose. RESULTS: NICU transfer for management of NH fell from 8.1% in Year 1 (34 of 421 at-risk infants screened) to 3.7% in Year 2 (14 of 383 at-risk infants screened). Rate of exclusive breastfeeding increased from 6% in Year 1 to 19% in Year 2. Hospital charges for the study population decreased from 801,276 USD to 387,688 USD in Year 1 and Year 2, respectively. CONCLUSION: Our study supports the adjunctive use of glucose gel to reduce NICU admissions and total hospitalization expense.

The Randomized, Controlled Trial of Late Surfactant: Effects on Respiratory Outcomes at 1-Year Corrected Age.

OBJECTIVE: To determine the effects of late surfactant on respiratory outcomes determined at 1-year corrected age in the Trial of Late Surfactant (TOLSURF), which randomized newborns of extremely low gestational age (≤28 weeks' gestational age) ventilated at 7-14 days to late surfactant and inhaled nitric oxide vs inhaled nitric oxide-alone (control). STUDY DESIGN: Caregivers were surveyed in a double-blinded manner at 3, 6, 9, and 12 months' corrected age to collect information on respiratory resource use (infant medication use, home support, and hospitalization). Infants were classified for composite outcomes of pulmonary morbidity (no PM, determined in infants with no reported respiratory resource use) and persistent PM (determined in infants with any resource use in ≥3 surveys). RESULTS: Infants (n = 450, late surfactant n = 217, control n = 233) were 25.3 ± 1.2 weeks' gestation and 713 ± 164 g at birth. In the late surfactant group, fewer infants received home respiratory support than in the control group (35.8% vs 52.9%, relative benefit [RB] 1.28 [95% CI 1.07-1.55]). There was no benefit of late surfactant for No PM vs PM (RB 1.27; 95% CI 0.89-1.81) or no persistent PM vs persistent PM (RB 1.01; 95% CI 0.87-1.17). After adjustment for imbalances in baseline characteristics, relative benefit of late surfactant treatment increased: RB 1.40 (95% CI 0.89-1.80) for no PM and RB 1.24 (95% CI 1.08-1.42) for no persistent PM. CONCLUSION: Treatment of newborns of extremely low gestational age with late surfactant in combination with inhaled nitric oxide decreased use of home respiratory support and may decrease persistent pulmonary morbidity. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Population Pharmacokinetics of Fluconazole in Premature Infants with Birth Weights Less than 750 Grams.

Fluconazole is an effective agent for prophylaxis of invasive candidiasis in premature infants. The objective of this study was to characterize the population pharmacokinetics (PK) and dosing requirements of fluconazole in infants with birth weights of <750 g. As part of a randomized clinical trial, infants born at <750 g birth weight received intravenous (i.v.) or oral fluconazole at 6 mg/kg of body weight twice weekly. Fluconazole plasma concentrations from samples obtained by either scheduled or scavenged sampling were measured using a liquid chromatography-tandem mass spectrometry assay. Population PK analysis was conducted using NONMEM 7.2. Population PK parameters were allometrically scaled by body weight. Covariates were evaluated by univariable screening followed by multivariable assessment. Fluconazole exposures were simulated in premature infants using the final PK model. A population PK model was developed from 141 infants using 604 plasma samples. Plasma fluconazole PK were best described by a one-compartment model with first-order elimination. Only serum creatinine was an independent predictor for clearance in the final model. The typical population parameter estimate for oral bioavailability in the final model was 99.5%. Scavenged samples did not bias the parameter estimates and were as informative as scheduled samples. Simulations indicated that the study dose maintained fluconazole troughs of >2,000 ng/ml in 80% of simulated infants at week 1 and 59% at week 4 of treatment. Developmental changes in fluconazole clearance are best predicted by serum creatinine in this population. A twice-weekly dose of 6 mg/kg achieves appropriate levels for prevention of invasive candidiasis in extremely premature infants.

Randomized Trial of Late Surfactant Treatment in Ventilated Preterm Infants Receiving Inhaled Nitric Oxide.

OBJECTIVE: To assess whether late surfactant treatment in extremely low gestational age (GA) newborn infants requiring ventilation at 7-14 days, who often have surfactant deficiency and dysfunction, safely improves survival without bronchopulmonary dysplasia (BPD). STUDY DESIGN: Extremely low GA newborn infants (GA ≤28 0/7 weeks) who required mechanical ventilation at 7-14 days were enrolled in a randomized, masked controlled trial at 25 US centers. All infants received inhaled nitric oxide and either surfactant (calfactant/Infasurf) or sham instillation every 1-3 days to a maximum of 5 doses while intubated. The primary outcome was survival at 36 weeks postmenstrual age (PMA) without BPD, as evaluated by physiological oxygen/flow reduction. RESULTS: A total of 511 infants were enrolled between January 2010 and September 2013. There were no differences between the treated and control groups in mean birth weight (701 ± 164 g), GA (25.2 ± 1.2 weeks), percentage born at GA <26 weeks (70.6%), race, sex, severity of lung disease at enrollment, or comorbidities of prematurity. Survival without BPD did not differ between the treated and control groups at 36 weeks PMA (31.3% vs 31.7%; relative benefit, 0.98; 95% CI, 0.75-1.28; P = .89) or 40 weeks PMA (58.7% vs 54.1%; relative benefit, 1.08; 95% CI, 0.92-1.27; P = .33). There were no between-group differences in serious adverse events, comorbidities of prematurity, or severity of lung disease to 36 weeks. CONCLUSION: Late treatment with up to 5 doses of surfactant in ventilated premature infants receiving inhaled nitric oxide was well tolerated, but did not improve survival without BPD at 36 or 40 weeks. Pulmonary and neurodevelopmental assessments are ongoing. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580.

Efficacy of recombinant human granulocyte colony stimulating factor in very-low-birth-weight infants with early neutropenia.

BACKGROUND/PURPOSE: Neutropenia is a risk factor for nosocomial infections (NI) in very-low-birth-weight (VLBW) infants. Although recombinant human granulocyte colony stimulating factor (rhG-CSF) increases the neutrophil counts in neutropenic VLBW infants, its long-term efficacy for early neutropenia (EN) remains unknown. METHODS: In this case-controlled study, charts of VLBW recipients of rhG-CSF for EN (total neutrophil count <1.5 × 10(9)/L during first 7 days) were reviewed and compared to gestational age, total neutrophil count, and birth weight matched infants unexposed to rhG-CSF. RESULTS: Twenty-seven infants were identified in each group. Mortality and morbidity did not differ between the two groups. Rate of NI (16/27 vs. 4/27, p = 0.002, odds ratio = 8.36) as well as the total number of episodes of NI (22 vs. 4, p = 0.007) were higher in rhG-CSF (+) group than in the rhG-CSF (-) group. CONCLUSION: Our experience does not show benefit in empirical use of rhG-CSF in preventing NI in VLBW infants with EN.

Clinical care for opioid-using pregnant and postpartum women: the role of obstetric providers.

We review clinical care issues that are related to illicit and therapeutic opioid use among pregnant women and women in the postpartum period and outline the major responsibilities of obstetrics providers who care for these patients during the antepartum, intrapartum, and postpartum periods. Selected patient treatment issues are highlighted, and case examples are provided. Securing a strong rapport and trust with these patients is crucial for success in delivering high-quality obstetric care and in coordinating services with other specialists as needed. Obstetrics providers have an ethical obligation to screen, assess, and provide brief interventions and referral to specialized treatment for patients with drug use disorders. Opioid-dependent pregnant women often can be treated effectively with methadone or buprenorphine. These medications are classified as pregnancy category C medications by the Food and Drug Administration, and their use in the treatment of opioid-dependent pregnant patients should not be considered "off-label." Except in rare special circumstances, medication-assisted withdrawal during pregnancy should be discouraged because of a high relapse rate. Acute pain management in this population deserves special consideration because patients who use opioids can be hypersensitive to pain and because the use of mixed opioid-agonist/antagonists can precipitate opioid withdrawal. In the absence of other indications, pregnant women who use opioids do not require more intense medical care than other pregnant patients to ensure adequate treatment and the best possible outcomes. Together with specialists in pain and addiction medicine, obstetricians can coordinate comprehensive care for pregnant women who use opioids and women who use opioids in the postpartum period.