The association between diuretic class exposures and enteral electrolyte use in infants developing grade 2 or 3 bronchopulmonary dysplasia in United States children's hospitals.

OBJECTIVE: To evaluate the association between chronic diuretic exposures and enteral electrolyte use in infants developing severe bronchopulmonary dysplasia (sBPD). STUDY DESIGN: Retrospective longitudinal cohort study in infants admitted to United States children's hospitals. We identified diuretic exposures and measured enteral NaCl and KCl use during pre-defined exposure risk-interval days. We used mixed-effects logistic regression to model the association between diuretic exposures and electrolyte use. RESULTS: We identified 442,341 subject-days in 3252 infants. All common diuretic classes and class combinations were associated with increased NaCl and KCl use. Thiazide monotherapy was associated with greater electrolyte use than loop monotherapy. The addition of potassium-sparing diuretics was associated with a limited reduction in KCl use compared to thiazide monotherapy. CONCLUSIONS: Chronic diuretic exposures are associated with increased NaCl and KCl use. Presumptions about the relative impact of different diuretic classes on electrolyte derangements may be inaccurate and require further study.

Sedation Practices of Neonates Receiving Extracorporeal Membrane Oxygenation.

Neonatal sedation practices during extracorporeal membrane oxygenation (ECMO) are not well described and no universal guidelines exist. Current literature describes types of medications used in adult and pediatric ECMO patients, but to our knowledge no data is published on neonatal specific median daily dose requirements or descriptions of sedation practices. The objective of this study is to examine the types and median doses of sedation utilized and to describe sedation practices for neonatal patients requiring ECMO support. This study was a descriptive, retrospective analysis of sedation practices in a single center newborn/infant intensive care unit (N/IICU) from 2012 to 2016. Subjects included all neonates who required ECMO support in the N/IICU for >24 hours. Data were collected from 87 patients and showed the median daily dose of opioids converted to intravenous morphine equivalents was 1.2, 2.0, and 3.4 mg/kg on ECMO days 1, 7, and 14, respectively. The most commonly used continuous medication infusions included morphine, midazolam, and hydromorphone. Dexmedetomidine was used in eight patients and ketamine in two patients. Doses of opioids and sedatives typically escalated over time. Pain scores did not correlate with sedation or analgesic administrations.

Medication use in infants with severe bronchopulmonary dysplasia admitted to United States children's hospitals.

OBJECTIVE: To identify the number of cumulative medication exposures and most frequently used medications in infants with severe BPD. STUDY DESIGN: We performed a retrospective cohort study in infants with severe BPD admitted to United States children's hospitals. We measured cumulative medication exposures in individual subjects and between-center variation after adjustment for infant characteristics. We then identified the specific medications and therapeutic classes with the highest rates of use. RESULTS: In 3252 subjects across 43 hospitals, we identified a median (interquartile range) of 30 (17-45) cumulative medication exposures per infant. The adjusted mean number of medication exposures varied between centers (p < 0.0001), with a range of 22-50. Diuretics and furosemide were the most frequently prescribed therapeutic class and specific medication for the management of severe BPD. CONCLUSIONS: Infants with severe BPD are exposed to alarming number of medications of unclear efficacy and safety, with marked variation between center.

Identifying and treating intrinsic PEEP in infants with severe bronchopulmonary dysplasia.

RATIONALE: Infants with severe bronchopulmonary dysplasia (sBPD) and airway obstruction may develop dynamic hyperinflation and intrinsic positive end-expiratory pressure (PEEPi ), which impairs patient/ventilator synchrony. OBJECTIVES: To determine if PEEPi is present in infants with sBPD during spontaneous breathing and if adjusting ventilator PEEP improves patient/ventilator synchrony and comfort. METHODS: Interventional study in infants with sBPD. PEEPi measured by esophageal pressure (Pes) and pneumotachometer, during pressure-supported breaths. PEEP i defined as the difference between Pes at start of the inspiratory effort minus Pes at onset of inspiratory flow. The set PEEP was adjusted to minimize PEEP i . "Best PEEP" was the setting with minimal wasted efforts (WE), an inspiratory effort seen on the Pes waveform without a corresponding ventilator breath. FiO 2 and SpO 2 measured pre- and post-PEEP adjustment. Sedation requirements evaluated 72 hours preprocedure and postprocedure. RESULTS: Twelve infants were assessed (gestational age, 24.9 ± 1.4 weeks; study age, 48.8 ± 1.5 weeks, postmenstrual age). Mean baseline ventilator PEEP was 16.4 cm H2 O (14-20 cm H 2 O). Eight infants required an increase, one, a reduction, and three, no change in the set PEEP. For the eight infants requiring an increase in set PEEP, there was an 18.9% reduction in WE and a reduction in FiO 2 (0.084 ± 0.058) requirements in the subsequent 24 hours. Conditional sedation was reduced in five infants postprocedure. No adverse events occurred during testing. CONCLUSION: PEEPi is measurable in infants with sBPD with concurrent esophageal manometry and flow-time tracings without the need for pharmacological paralysis. In those with PEEP i , increasing ventilator PEEP to offset PEEP i improves synchrony.

Improved growth and developmental activity post tracheostomy in preterm infants with severe BPD.

OBJECTIVES: To examine growth, sedation needs, and participation in developmental activities before and after tracheostomy among infants with severe bronchopulmonary dysplasia. METHODS: Retrospective analysis of infants born at <32 weeks' gestation or birth weights <1500 g with severe BPD who underwent tracheostomy placement between January 1, 2010 and December 31, 2016 in a quaternary referral newborn and infant intensive care unit. Changes in growth parameters and frequency/type of participation in physical therapy sessions performed during the 4-weeks before tracheostomy and 4-weeks after the first tracheostomy tube change were compared. RESULTS: A total of 72 patient were included in the study. Average weekly gain in weight, length, and head circumference were significantly higher during the 4-week period after compared to before tracheostomy. The most significant change occurred for linear growth (0.71 ± 0.40 cm/wk pre vs 0.97 ± 0.48 cm/wk pre, P < 0.001). Median Z score improved for weight (pre -1.42 [-3,10, -0.33] vs post -0.91 [-2.7, 0.27], P < 0.001), length (pre -3.07 [-4.39, -1.31] vs post -1.95 [-3.83, -0.93], P < 0.001) and weight-to-length ratio (pre 1.66 [0.58, 2.55] vs post 1.32 [0.17, 2.2], P = 0.02). Participation in developmental therapies significantly improved post tracheostomy (pre vs post: 5.2 ± 2.9 vs 8.7 ± 4.3 sessions performed over 4 weeks, P < 0.0001). Physical therapy sessions more often promoted developmental skill acquisition after tracheostomy compared to facilitating physiologic stability before tracheostomy. Daily sedation requirements decreased post tracheostomy. CONCLUSIONS: Tracheostomy was associated with improved proportional growth and increased participation in activities promoting developmental skill acquisition and reduced daily sedation requirements in preterm infants with severe BPD.

Treprostinil Improves Persistent Pulmonary Hypertension Associated with Congenital Diaphragmatic Hernia.

OBJECTIVE: To evaluate the effect of continuous treprostinil in infants with severe pulmonary hypertension associated with congenital diaphragmatic hernia (CDH) on specific markers of pulmonary hypertension severity and to report the safety and tolerability of treprostinil. STUDY DESIGN: We conducted a retrospective cohort study of infants with CDH-associated pulmonary hypertension treated with treprostinil from January 2011 to September 2016. Severity of pulmonary hypertension was assessed by echocardiogram and serum B-type natriuretic peptide (BNP) by using time points before initiation and 24 hours, 1 week, and 1 month after treprostinil initiation. Fisher exact tests, Wilcoxon-rank sum tests, and mixed-effects models were used for analysis. RESULTS: Seventeen patients were treated with treprostinil for a median of 54.5 days (IQR 44.3-110 days). Compared with the concurrent CDH population (n = 147), infants treated with treprostinil were more likely to require extracorporeal support (76.5% vs 25.2%, P < .0001), to have a longer hospital stay (144 vs 60 days, P < .0001), and to need longer mechanical ventilator support (76.5 vs 30.9 days, P < .0001). Following treprostinil initiation, there was a significant reduction in BNP at 1 week (1439 vs 393 pg/mL, P < .01) and 1 month (1439 vs 242 pg/mL, P = .01). Severity of pulmonary hypertension by echocardiogram improved at 1 month (OR 0.14, CI 95% 0.04-0.48, P = .002). Despite these improvements, overall mortality remained high (35%). There were no adverse events related to treprostinil, including no hypotension, hypoxia, or thrombocytopenia. CONCLUSIONS: In this cohort, treprostinil use was associated with improved severity of pulmonary hypertension assessed by echocardiogram and decreased BNP, with no significant side effects.

Determinants of Severe Metabolic Bone Disease in Very Low-Birth-Weight Infants with Severe Bronchopulmonary Dysplasia Admitted to a Tertiary Referral Center.

OBJECTIVE: Nonrespiratory comorbidities are common among preterm infants with severe bronchopulmonary dysplasia (BPD) referred to tertiary perinatal centers. We evaluated the incidence, severity, and risk factors for metabolic bone disease (MBD) in this population. STUDY DESIGN: We conducted a retrospective cohort study of all infants born ≤ 1,500 g who were diagnosed with severe BPD in our single, tertiary referral center between September 2010 and October 2012. MBD severity was classified by serial radiography. RESULTS: Among the 83 infants diagnosed with severe BPD, 26 (31%) developed severe MBD (rickets). Male gender and lower gestational age and birth weight were associated with increased odds of severe MBD. After adjustment for these potential confounders, cytomegalovirus infection, postnatal growth restriction, surgical necrotizing enterocolitis, and blood culture confirmed sepsis were associated with increased odds of severe MBD. The cumulative duration of therapy with furosemide, hydrocortisone, and prednisolone each correlated with significantly greater probability of severe MBD. CONCLUSIONS: Severe MBD was common in this referral-based cohort with severe BPD. The high incidence in this population is likely explained by the coexistence of multiple exposures and comorbidities associated with bone demineralization.

Short-Term Safety of Zoledronic Acid in Young Patients With Bone Disorders: An Extensive Institutional Experience.

CONTEXT: Zoledronic acid (ZA) is increasingly used in young patients with bone disorders. However, data related to the safety of ZA administration in this population are limited. OBJECTIVE: The study aimed to characterize the short-term safety profile of ZA and identify risk factors for ZA-related adverse events (AEs) in young patients. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective chart review of inpatients and outpatients less than 21 years old who received at least one ZA infusion between July 2010 and January 2014 at The Children's Hospital of Philadelphia. RESULTS: Eighty-one patients (56% male; median age, 12 y; age at first infusion, 0.5 to 20 y) with diverse skeletal disorders received a total of 204 infusions. The most common indications were osteoporosis (33% of cohort) and osteogenesis imperfecta (27.2%). The median ZA dose was 0.025 mg/kg (interquartile range, 0.025-0.05); the median dosing interval was 6 months (range, 1 to 25.6 mo). AEs were mild and more common after the first ZA infusion in patients with no previous bisphosphonate exposure: hypophosphatemia (25.2% of infusions), acute phase reactions (19.1%), and hypocalcemia (16.4%). Symptomatic hypocalcemia requiring iv calcium occurred after two infusions. ZA dose was significantly associated with hypophosphatemia, but not other AEs. Hypocalcemia was more common in patients with high bone turnover as assessed by preinfusion alkaline phosphatase levels. AEs were not associated with diagnosis, baseline serum calcium, or calcium/calcitriol supplementation. CONCLUSION: Acute AEs related to ZA infusion in youths are common, occur principally after the first ZA infusion in bisphosphonate-naive patients, and are typically mild and easily managed. Future prospective studies are needed to determine the potential long-term risks, as well as benefits, of ZA therapy in the pediatric population.

New antifungal and antiviral dosing.

Neonatal fungal and viral infections are associated with mortality and neurologic impairment among survivors. Advances in pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobial medications have led to improved dosing guidance for neonates. This article discusses the basic PK/PD properties and dosing of the most common antifungal and antiviral medications used in neonates.

Calcitriol treatment in metabolic bone disease of prematurity with elevated parathyroid hormone: A preliminary study.

OBJECTIVE: To describe the association of calcitriol treatment with the change in parathyroid hormone (PTH) and biochemical markers of bone disease in infants with metabolic bone disease of prematurity (MBD) and secondary hyperparathyroidism. STUDY DESIGN: This retrospective chart review examined serum intact PTH, serum calcium (Ca), serum phosphorus (P), serum alkaline phosphatase (APA), urine calcium/creatinine (UCa/Cr), and tubular reabsorption of phosphate (TRP) in 32 infants prior to and following calcitriol treatment for MBD with PTH >100 pg/ml. 25-hydroxyvitamin D concentrations were recorded. RESULTS: Following calcitriol treatment, PTH decreased from median (min/max) 220 (115/593) to 25 (3/259) pg/ml, p < 0.001; Ca increased from 9.9 (8.9/10.7) to 10.3 (9.7/11.3) mg/dl, p < 0.001; P increased from 4.3 (2.7/6.4) to 5.4 (2.9/7.4) mg/dl, p = 0.001; and TRP increased from 81 (59/98) to 91.5 (78/98) %, p = 0.03. APA did not differ pre-treatment: 616 (209/1193) vs. post-treatment 485 (196/1229) U/L, p = 0.12. Vitamin D deficiency was not present. Hypercalcemia with hypercalciuria occurred in 3/32 subjects, all normalized after dose reduction. CONCLUSION: Improvements in MBD markers and lack of serious adverse effects suggest calcitriol may be a treatment option in infants with MBD and secondary hyperparathyroidism.

Safety of rotavirus vaccine in the NICU.

BACKGROUND AND OBJECTIVE: Rotavirus vaccination is discouraged during hospitalization given concerns regarding live attenuated virus transmission, although recommended upon discharge. Infants should have vaccination initiated by 104 days of age or they become age-ineligible. Our institution believed the known risk of severe disease in unvaccinated infants outweighed the theoretical risk of transmission. We routinely administer RotaTeq (RV5) to age-eligible hospitalized infants on enteral feeds. The objective of this study was to determine the safety of RV5 vaccination among vaccinated (VI) and unvaccinated infants (UVI) within the NICU. METHODS: A retrospective review identified VI between 2008 and 2010, and UVI geographically located near VI within 15 days of vaccination. We screened for gastrointestinal symptoms among UVI by using an electronic medical record query (trigger tool) to identify infants with orders for bowel rest, abdominal imaging, and antibiotics. Trigger-positive infants had full chart review. RESULTS: Most VI (76%) were either asymptomatic (25% [24 of 96]) or symptomatic but unchanged from baseline (51% [49 of 96]) postvaccination. Although 24% of VI had clinical status changes postvaccination, none were directly attributed to RV5. Among 801 neighboring UVI, 10 (1.2%) had clinical status changes, none directly attributed to RV5, but mostly bacterial sepsis or preexisting gastrointestinal pathology. Two UVI underwent stool analysis; both negative for rotavirus. CONCLUSIONS: RV5 was well tolerated in hospitalized infants, with most postvaccination symptoms attributed to preexisting symptoms. UVI seemed to have a low risk of symptomatic transmission. Inpatient administration ensures that age-eligible infants are vaccinated regardless of hospital duration. Prospective evaluation of safety and transmissibility is needed.

Medication absorption considerations in patients with postpyloric enteral feeding tubes.

PURPOSE: The gastrointestinal absorption sites of medications administered via postpyloric enteral feeding tubes were examined. SUMMARY: Many issues must be considered when administering medications via the postpyloric route, including interactions with enteral feeds, additional toxicities, and the concern of whether the medication will be absorbed. Despite the potential clinical significance of this information, data regarding the gastrointestinal site of absorption for most medications are lacking. Gastrointestinal absorption sites for all drugs for which requests for information on absorption sites were received at our institution since 2008 (n = 124) were evaluated by reviewing the package insert, consulting tertiary references, conducting primary literature searches, or contacting the drug manufacturer. Seventy (56.5%) of the 124 drugs reviewed had information available regarding the site of absorption. Just 2 drugs required acid for absorption and thus should be administered only through the stomach, while 2 other drugs were found to bind extensively to tubing and should not be administered in this manner. For 3 drugs, increased absorption may occur when they are administered directly into the small bowel. Seven medications had decreased absorption when administered directly to the small bowel, and 10 drugs were clearly not absorbed when administered through either the duodenal or the jejunal route. CONCLUSION: The implications of absorption site should be considered for all patients receiving medications via postpyloric feeding tubes. Several medications cannot be administered through alternative routes because gastric acid is needed for their absorption, the medications may bind to the tubing, or drug absorption is altered at the intestinal site.

Cinacalcet monotherapy in neonatal severe hyperparathyroidism: a case study and review.

CONTEXT: Neonatal severe hyperparathyroidism (NSHPT) is a severe form of familial hypocalciuric hypercalcemia characterized by severe hypercalcemia and skeletal demineralization. In most cases, NSHPT is due to biallelic loss-of-function mutations in the CASR gene encoding the calcium-sensing receptor (CaSR), but some patients have heterozygous mutations. Conventional treatment consists of iv saline, bisphosphonates, and parathyroidectomy. OBJECTIVE: The aim of this project was to characterize the molecular basis for NSHPT in an affected newborn and to describe the response to monotherapy with cinacalcet. METHODS: Clinical and biochemical features were monitored as cinacalcet therapy was initiated and maintained. Genomic DNA was obtained from the proband and parents. The CASR gene was amplified by PCR and sequenced directly. RESULTS: The patient was a full-term male who developed hypotonia and respiratory failure soon after birth. He was found to have multiple fractures and diffuse bone demineralization, with a marked elevation in serum ionized calcium (1.99 mmol/L) and elevated serum levels of intact PTH (1154 pg/mL); serum 25-hydroxyvitamin D was low, and fractional excretion of calcium was reduced. The serum calcium level was not reduced by iv saline infusion. Based on an extensive family history of autosomal dominant hypercalcemia, a diagnosis of NSHPT was made, and cinacalcet therapy was initiated with a robust and durable effect. Molecular studies revealed a heterozygous R185Q missense mutation in the CASR in the patient and his father, whereas normal sequences for the CASR gene were present in the patient's mother. CONCLUSIONS: We describe the first use of cinacalcet as monotherapy for severe hypercalcemia in a newborn with NSHPT. The rapid and durable response to cinacalcet suggests that a trial of calcimimetic therapy should be considered early in the course of NSHPT.

Levetiracetam for treatment of neonatal seizures.

Neonatal seizures are often refractory to treatment with initial antiseizure medications. Consequently, clinicians turn to alternatives such as levetiracetam, despite the lack of published data regarding its safety, tolerability, or efficacy in the neonatal population. We report a retrospectively identified cohort of 23 neonates with electroencephalographically confirmed seizures who received levetiracetam. Levetiracetam was considered effective if administration was associated with a greater than 50% seizure reduction within 24 hours. Levetiracetam was initiated at a mean conceptional age of 41 weeks. The mean initial dose was 16 ± 6 mg/kg and the mean maximum dose was 45 ± 19 mg/kg/day. No respiratory or cardiovascular adverse effects were reported or detected. Levetiracetam was associated with a greater than 50% seizure reduction in 35% (8 of 23), including seizure termination in 7. Further study is warranted to determine optimal levetiracetam dosing in neonates and to compare efficacy with other antiseizure medications.

Intravenous levetiracetam in critically ill children with status epilepticus or acute repetitive seizures.

OBJECTIVE: Intravenous (IV) levetiracetam (LEV) is approved for use in patients older than 16 years and may be useful in critically ill children, although there is little data available regarding pharmacokinetics. We aim to investigate the safety, an appropriate dosing, and efficacy of IV LEV in critically ill children. DESIGN: We describe a cohort of critically ill children who received IV LEV for status epilepticus, including refractory or nonconvulsive status, or acute repetitive seizures. RESULTS: There were no acute adverse effects noted. Children had temporary cessation of ongoing refractory status epilepticus, termination of ongoing nonconvulsive status epilepticus, cessation of acute repetitive seizures, or reduction in epileptiform discharges with clinical correlate. CONCLUSIONS: IV LEV was effective in terminating status epilepticus or acute repetitive seizures and well tolerated in critically ill children. Further study is needed to elucidate the role of IV LEV in critically ill children.