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Hypoxic-ischemic encephalopathy (HIE) remains a significant source of long-term neurodevelopmental impairment despite overall improvements in survival without disability in neonates who undergo therapeutic hypothermia. Each phase in the evolution of hypoxic-ischemic injury presents potential pharmacologic targets for neuroprotective agents. Melatonin is a promising emerging therapy for early phases of ischemic injury, but utility is currently limited by the lack of pharmaceutical-grade products. Magnesium has been extensively studied for its neuroprotective effects in the preterm population. Studies in neonates with HIE have produced mixed outcomes. Erythropoietin use in HIE with or without therapeutic hypothermia appears to be safe and may provide additional benefit. Dexmedetomidine, N-acetylcysteine, xenon, and topiramate all have promising animal data, but need additional human trials to elucidate what role they may play in HIE. Frequent review of existing literature is required to ensure provision of evidence-based pharmacologic agents for neuroprotection following HIE.

Objective To investigate if preterm neonates developed systemic hypertension after intravitreal bevacizumab for retinopathy of prematurity. Methods Patients who received treatment between January 1, 2011 and January 31, 2019 were eligible for inclusion. Patients with pre-existing hypertension, congenital eye disease, or who were discharged within 72 h of treatment were excluded. Charts were reviewed for baseline data, co-morbidities, and the development of systemic hypertension within 4 weeks post treatment. Results After exclusions, 64 patients were analyzed. New-onset systemic hypertension was identified in 44 (69%) infants. There were no statistical differences in the demographic characteristics or presence of co-morbidities between the hypertensive and non-hypertensive groups. Of those who developed hypertension, the majority presented within the first week post treatment (55%). Conclusions The majority of infants who received intravitreal bevacizumab developed new-onset systemic hypertension after treatment. Further studies may explore hypertension as a potential side effect of bevacizumab in the neonatal population.

Background: In the adult population, a high rate of discrepancies exists between provider-performed and pharmacist-performed medication histories. Limited data exist regarding pharmacist-performed medication histories in hospitalized pediatric patients. Objective: Identify the incidence and severity of discrepancies in medication histories performed by practitioners compared with pharmacists in the pediatric population. Methods: After institutional review board approval, a retrospective analysis of pediatric patients admitted to inpatient pediatric units in a tertiary hospital was performed. The primary endpoint of the study was the percentage of provider-performed medication histories with any discrepancies compared with the pharmacist-performed medication history. Secondary endpoints included the number and type of discrepancies and the discrepancy’s potential risk of patient harm. Results: A total of 101 subjects were included. Nineteen patients (18.8%) had at least one medication discrepancy. Missing medications accounted for the majority of the discrepancies. Advance practice providers performed a small number of the initial medication histories (5%) and had at least one discrepancy for each history performed. The percentages of Grades 1, 2, and 3 discrepancies were 57.2%, 17.1%, and 25.7%, respectively. Medications with the most frequent discrepancies included anticonvulsants, antihistamines, and histamine receptor antagonists. Limitations include the retrospective nature of the study and lower than expected discrepancy rate. Conclusion: In this study, 18.8% of pediatric patients had a discrepancy between medication histories. Missing medications accounted for the largest amount of discrepancies. A large percentage of discrepancies had the potential to cause patient harm.

What is known and objective As the global adoption of ENFit-compatible syringes becomes more widespread, it is important for syringe users to understand the risk of dosing inaccuracy for both the oral and enteral routes of use. Describing the risk of dosing inaccuracy specifically related to route of use is important to the end users' understanding of the clinical impact of device changes. The objective of this study was to compare the performance of female design ENFit low dose tip (LDT) syringes when used for enteral medication administration to the syringe performance during oral administration conditions. Methods This study was a secondary analysis of a prospective study conducted at the University of Florida Health Shands Hospital in conjunction with the University of Florida College of Pharmacy. Dosing variance (DV) up to 10% for low-risk medications and DV up to 5% is the target for high-risk medication administration is considered acceptable. The primary outcome was the frequency of administration volumes exceeding 10% of the expected amount when using the ENFit LDT syringe for both oral and enteral medication administration. Secondarily, the performance of standard ENFit syringes and the frequencies of DV exceeding 5 and 10% were also evaluated in the same conditions. Results and discussion A total of 264 tests were evaluated (ENFit LDT, n = 210; ENFit standard tip, n = 54). Using the LDT syringe for the enteral route resulted in statistically significant higher rates of unacceptable dosing variance >10% when compared to the oral application (26.9% vs 12.9%, P = .01). The frequency of LDT syringe DV >5% was significantly greater than >10% variance, regardless of oral or enteral use. Standard ENFit syringes had overall fewer tests with unacceptable dosing variance and showed no difference in performance between applications. What is new and conclusions This study raises additional clinical concerns specifically related to the enteral use of ENFit LDT syringes within commonly accepted dosing variance ranges. Enteral and oral application of LDT syringes yield unacceptably high rates of dosing variance for high risk medications with narrow therapeutic index.

WHAT IS KNOWN AND OBJECTIVE The International Organization for Standardization (ISO) created enteral device specifications to reduce tubing misconnections. The Global Enteral Device Supplier Association (GEDSA) supports a female design: standard and low dose tip (LDT). Concerns include increased complexity of use with adapters, dosing accuracy and workflow. No peer-reviewed studies have evaluated dosing accuracy of the complete female system with adapters. The objective of this study was to compare dosing accuracy of the female design to legacy syringes. METHODS An in vitro study was conducted at the University of Florida College of Pharmacy pharmaceutics laboratory. Assessments were completed for syringe size, dispense methods and volumes, and adapters when applicable. A gravimetric scale and specific gravity were used to calculate administration volumes. The primary outcome was frequency administration volume exceeded 10% expected amount. RESULTS AND DISCUSSION A total of 576 tests were performed. The LDT resulted in significantly higher rates of unacceptable dosing variance compared to legacy (21.2% vs 7.4%, P = 0.003). Variance exceeding 10% occurred more frequently with LDT 0.5 and 1 mL syringes, medication cup dispensing (liquid or tablet) and inappropriate LDT adapter use. Unapproved adapter processes compared to FDA-approved processes held a higher likelihood of unacceptable dosing variance (28% vs 7.4%, P

Hypoxic-ischemic encephalopathy (HIE) produces a high rate of long-term neurodevelopmental disability in survivors. Therapeutic hypothermia dramatically improves the incidence of intact survival, but does not eliminate adverse outcomes. The ideal provision of sedation and treatment of seizures during therapeutic hypothermia represent therapeutic targets requiring optimization in practice. Physiologic stress from therapeutic hypothermia may obviate some of the benefits of this therapy. Morphine is commonly utilized to provide comfort, despite limited empiric evidence supporting safety and efficacy. Dexmedetomidine represents an interesting alternative, with preclinical data suggesting direct efficacy against shivering during induced hypothermia and neuroprotection in the setting of HIE. Pharmacokinetic properties must be considered when utilizing either agent, with safety dependent on conservative dosing and careful monitoring. HIE is the leading cause of neonatal seizures. Traditional therapies, including phenobarbital, fosphenytoin, and benzodiazepines, control seizures in the vast majority of neonates. Concerns about the acute and long-term effects of these agents have led to the exploration of alternative anticonvulsants, including levetiracetam. Unfortunately, levetiracetam is inferior to phenobarbital as first-line therapy for neonatal seizures. Considering both the benefits and risks of traditional anticonvulsant agents, treatment should be limited to the shortest duration indicated, with maintenance therapy reserved for neonates at high risk for recurrent seizures.

OBJECTIVES This study aimed to determine whether there are differences in the incidence of metabolic bone disease (MBD) between preterm neonates first exposed to diuretics prior to 2 weeks of life versus those exposed after 2 weeks. METHODS This study was a retrospective analysis of premature neonates born at a tertiary care center between 2011 and 2015 who received either furosemide or chlorothiazide. The primary outcome was incidence of MBD. Secondary outcomes included growth, electrolyte disturbances, oxygen requirement, and length of stay. RESULTS A total of 147 patients were included. Early initiation (n = 90) and late initiation (n = 57) arms were balanced with respect to birth weight and gestational age. There was no difference in incidence of MBD in the early group (76%) versus the late group (65%; p = 0.164). Stratification by cumulative dose showed incidence of 85% in patients receiving ≥8 mg/kg of furosemide, compared with 68% and 64% of those in the CONCLUSIONS Timing of diuretic initiation did not affect incidence of MBD. Increased cumulative furosemide exposure may be associated with higher incidence. Patients first exposed to diuretics within 2 weeks of life are at higher risk for electrolyte abnormalities and reduced growth velocity.

Feeding intolerance, poor oral feeding skills, and retching are common symptoms seen in medically complex infants with a history of abdominal disorders and surgical interventions, such as gastrostomy tube placement and Nissen fundoplication. Visceral hyperalgesia may play a role in the underlying pathophysiology. We report the use of orally administered gabapentin in 3 infants with presumed visceral hyperalgesia presenting as poor tolerance of enteral and oral feeds. Retching and outward discomfort associated with feeds was resolved within 2 to 3 days of initiation of therapy. Full oral feeds were obtained in all 3 patients within 3 to 4 months of starting gabapentin without changing adjunctive medications or therapies. After attainment of full oral feeds, all patients were successfully weaned off gabapentin over a month, with no notable side effects, signs of withdrawal, or impact on ability to feed by mouth.

Bevacizumab is a human monoclonal immunoglobulin G1 antibody to vascular endothelial growth factor indicated in several adult diseases. Emerging literature and expert opinion support the off-label use of intravitreal bevacizumab in the treatment of retinopathy of prematurity (ROP), a common disease process seen in premature neonates. One of the most common side effects of systemic therapy in adults is hypertension; however, this has not been well described in infants receiving bevacizumab for ROP. In this report, we review a case of a former 25-week premature infant treated for stage 3 ROP with administration of intravitreal bevacizumab. The immediate posttreatment course was uncomplicated; however, at 10 days posttreatment, he developed new-onset systemic hypertension. In addition, neuroimaging revealed new areas of vasogenic edema, which improved over time. To the best of our knowledge and after a review of the literature, neither of these effects has been described in neonates after intravitreal bevacizumab for ROP.

Hypoxic-ischemic encephalopathy (HIE) is a significant cause of morbidity and mortality in neonates. Therapeutic hypothermia reduces the risk of death or disability. Providing optimal sedation while neonates are undergoing therapeutic hypothermia is likely beneficial but may present therapeutic challenges. There are limited data describing the use of dexmedetomidine for sedation in patients undergoing therapeutic hypothermia. The objective of this study is to evaluate the efficacy and short-term safety of dexmedetomidine infusion for sedation in term neonates undergoing therapeutic hypothermia for HIE.

OBJECTIVES To determine the percentage of patients with >10% reduction in heparin infusion rate within 48 hours of antithrombin III (ATIII) administration. Secondary objectives include the achievement of therapeutic anticoagulation and determining the days of subtherapeutic infusion prior to supplementation. METHODS Retrospective chart review of 12 patients younger than 18 years of age who received ATIII concentrate supplementation while on continuous heparin infusion. Specific indications for heparin infusion therapy included extracorporeal membrane oxygenation (ECMO), treatment of thrombus, and post implantation of ventricular assist device(s). RESULTS From time of heparin initiation to ATIII supplementation, patients spent a mean 4.9 ± 2.6 days of subtherapeutic infusion and required uptitration from a mean of 15.3 ± 4.4 units/kg/hr to a mean rate of 40.7 ± 9.5 units/kg/hr. 58.3% of the patients (n = 7) had a ≥10% reduction from the baseline heparin infusion rate within 48 hours of ATIII administration. Those patients considered responders (≥10% reduction from baseline rate) had a slightly higher mean baseline antithrombin level (76.3% ± 22.0% vs. 58.6% ± 2.7% in non-responders, p = 0.1) and were administered comparable doses of ATIII. ATIII supplementation did appear to increase the time of therapeutic anticoagulation within the 48 hours. CONCLUSIONS Administration of ATIII is associated with >10% decrease in heparin requirements in more than half of the patients identified. In those patients deemed non-responders, there was a trend towards lower baseline antithrombin serum levels. Further studies are warranted to determine if the lack of response in some patients is due to inadequate dosing of ATIII or any patient-related factors.

OBJECTIVES: To determine if computerized provider order entry (CPOE) implementation impacts the time it takes for preterm neonates to reach their parenteral macronutrient goals.METHODS: Retrospective review of neonates RESULTS: Goal PN was achieved by 12/47 (25.5%) intervention vs. 2/44 (4.5%) control group infants (p < 0.05). This goal was attained in 10.8 ± 7.5 days in the intervention group and 10 ± 4.2 days in the control group (p = 0.90). Goal protein was reached by 74.5% of CPOE patients vs. 36.4% of controls, p < 0.05. Lipid goals were achieved by 98% vs. 100% (p = 0.33) of patients and were attained at an average of 1.5 ± 0.8 days vs. 2.0 ± 1.1 days (p < 0.05). Abnormal serum electrolyte values occurred more frequently in the control group (0.79 vs. 1.12/day PN). Adjustments by a verification pharmacist were required in 5.6% of CPOE compared with 30.4% of control group orders (p < 0.05).CONCLUSIONS: CPOE parenteral nutrition increased the proportion of preterm neonates attaining overall macronutrient goals. With CPOE, protein goals were reached by more patients and goal lipids were achieved faster. This system also decreased the number of pharmacist interventions during verification of PN orders and appeared to positively impact the incidence of serum electrolyte disturbances.

Objective: To describe a case of dexmedetomidine use for sedation in a 24-week gestational age premature neonate. Case Summary: A 9-day-old, 24-week gestational age male neonate on high-frequency oscillatory mechanical ventilation was experiencing severe agitation refractory to high-dose intravenous narcotics and benzodiazepines. Since the infant's respiratory stability was reliant on adequate sedation, he was given dexmedetomidine after several days of suboptimal response to escalation of standard agents. Treatment prior to dexmedetomidine included continuous-infusion fentanyl 10 μg/kg/h, intravenous lorazepam 0.6 mg/kg every 4 hours, intermittent doses of both lorazepam and midazolam as needed, and a single bolus dose of phenobarbital. The patient calmed markedly during the dexmedetomidine loading dose infusion and remained adequately sedated while the drug was continued. The dexmedetomidine infusion allowed weaning of mechanical ventilation settings and eventual extubation of the infant, as well as rapid tapering of other sedative medications. The maximum dexmedetomidine infusion rate was 0.7 μg/kg/h, and total duration of therapy was 19 days. No significant adverse effects were directly attributed to dexmedetomidine use during this time. Discussion: Dexmedetomidine is a novel α2-agonist approved for short-term sedation in mechanically ventilated adults. Data describing its use in pediatric and neonatal patients continue to emerge. The prolonged use of dexmedetomidine in very-low-birth-weight neonates has not been described in the literature. Conclusions: Dexmedetomidine was an effective sedative and analgesic in a 24-week gestational age neonate treated for refractory agitation while on mechanical ventilation. Based on its documented efficacy for pain and sedation and its favorable adverse effect profile, dexmedetomidine warrants further study as first-line or adjunct therapy with narcotics for sedation in ventilated newborns.

Objective: To describe a case of tramadol withdrawal in a neonate and treatment with clonidine after exposure to long-term maternal use of high-dose tramadol. Case Summary: A 34-week gestational age neonate displayed symptoms of tramadol withdrawal within 48 hours of delivery. Due to a confusing initial clinical picture, including presumed congenital Chlamydia, questionable seizures, and an original report of maternal use of ketorolac (Toradol), diagnosis was delayed until day of life 5. Symptoms included jitteriness, myoclonic movements, and irritability. Upon further questioning of the mother, it was revealed that she was actually taking tramadol 600–800 mg daily. The infant was placed on maintenance therapy with oral clonidine (from 1 to 3 μg/kg orally every 3 hours) until discontinuation on day of life 11. After 3 days off treatment, he began to display symptoms of withdrawal again. Clonidine was restarted at 1 μg/kg orally every 8 hours and he was discharged home on maintenance clonidine therapy at 18 days postnatal age. A 7-day tapering regimen was initiated 2 weeks after discharge, and no further withdrawal symptoms occurred. Discussion: Few published articles are available to guide clinicians on the clinical course and treatment strategies for tramadol dependence and withdrawal. In neonates, the reports are particularly sparse. Traditional agents used in neonatal opioid withdrawal are narcotics (morphine, tincture of opium, methadone), benzodiazepines (diazepam, lorazepam), and phenobarbital. Clonidine use for neonatal abstinence syndrome from narcotics has been shown to be effective alone or in combination with agents such as other opiates and chloral hydrate. Potential benefits of clonidine therapy include shorter duration of therapy, reduced withdrawal symptoms, and decreased length of hospital stay. Conclusions: Withdrawal can be prolonged in infants exposed to maternal tramadol use. Clonidine may be a safe and effective option for managing symptoms of neonatal tramadol abstinence.

OBJECTIVE To compare the efficacy and safety of dexmedetomidine and fentanyl for sedation in mechanically ventilated premature neonates. METHODS This was a retrospective, observational case-control study in a level III neonatal intensive care unit. Forty-eight premature neonates requiring mechanical ventilation were included. Patients received fentanyl (n=24) or dexmedetomidine (n=24) for pain or sedation. Each group also received fentanyl and lorazepam boluses as needed for agitation. The primary outcomes were efficacy and frequency of acute adverse events associated with each drug. Days on mechanical ventilation, stooling patterns, feeding tolerance, and neurologic outcomes were also evaluated. RESULTS There were no significant differences in baseline demographics between the dexmedetomidine and fentanyl patients. Patients in the dexmedetomidine group required less adjunctive sedation and had more days free of additional sedation in comparison to fentanyl (54.1% vs. 16.5%, p CONCLUSIONS Dexmedetomidine was safe and effective for sedation in the premature neonates included in this study. Prospective randomized-controlled trials are needed before routine use of dexmedetomidine can be recommended.