Association between congenital heart disease and parenteral nutrition-associated liver disease in neonates: A retrospective cohort study.

OBJECTIVE: Infants receiving parenteral nutrition (PN) are at increased risk of PN-associated liver disease (PNALD), which can lead to hepatic fibrosis. Congenital heart disease (CHD) represents a risk factor for hepatic fibrosis, so this study sought to better understand whether infants with CHD were at elevated risk of PNALD when receiving long-term PN. STUDY DESIGN: This study includes a retrospective cohort of infants at a level IV neonatal intensive care unit from 2010 to 2020 who received long-term PN during the first 8 weeks of life. A time-varying Cox survival model was used to model risk of PNALD between infants with and without CHD, adjusted for demographics, surgical intervention, and PN exposure, using a 5000-iteration bootstrap estimation. Secondary analyses evaluated risk against discrete CHD diagnoses, and sensitivity analysis was performed on the magnitude and quantity of direct bilirubin laboratory measurements making up the PNALD definition. RESULTS: Neonates with CHD were found to be at higher risk for PNALD during or soon after long-term PN exposure. A pattern of increasing association strength with increasing bilirubin threshold suggests infants with CHD may also experience higher degrees of injury. CONCLUSIONS: This work offers a step in understanding how diagnoses can be factored into neonate PN prescription. Future work will explore modifications in lipid profiles and timing to mitigate risk in patients with CHD.

Challenges in management of refractory pain and sedation in infants.

The survival of preterm infants continues to improve, along with an increased in neonatal intensive care unit (NICU) management of chronic infants who are medically complex infants who have prolonged hospital stays, sometimes up until 2 years of age. Despite advances in neonatal and infant care, the management of pain and sedation in chronic NICU patients continues to be a challenge. Challenges such as development of appropriate pain, sedation, and withdrawal scales along with unfamiliarity of the NICU care team with pediatric disease states and pharmacotherapy complicate management of these patients. Opioid induced hyperalgesia (OIH) and delirium may play a large role in these refractory cases, yet are often not considered in the NICU population. Drug therapy interventions such as gabapentin, ketamine, risperidone, and others have limited data for safety and efficacy in this population. This article summarizes the available literature regarding the evidence for diagnosis and management of infants with refractory pain and sedation along with the challenges that clinicians face when managing these patients.

Corticosteroid response predicts bronchopulmonary dysplasia status at 36 weeks in preterm infants treated with dexamethasone: A pilot study.

IMPORTANCE: A major barrier to therapeutic development in neonates is a lack of standardized drug response measures that can be used as clinical trial endpoints. The ability to quantify treatment response in a way that aligns with relevant downstream outcomes may be useful as a surrogate marker for new therapies, such as those for bronchopulmonary dysplasia (BPD). OBJECTIVE: To construct a measure of clinical response to dexamethasone that was well aligned with the incidence of severe BPD or death at 36 weeks' postmenstrual age. DESIGN: Retrospective cohort study. SETTING: Level IV Neonatal Intensive Care Unit. PARTICIPANTS: Infants treated with dexamethasone for developing BPD between 2010 and 2020. MAIN OUTCOME(S) AND MEASURE(S): Two models were built based on demographics, changes in ventilatory support, and partial pressure of carbon dioxide (pCO2 ) after dexamethasone administration. An ordinal logistic regression and regularized binary logistic model for the composite outcome were used to associate response level to BPD outcomes defined by both the 2017 BPD Collaborative and 2018 Neonatal Research Network definitions. RESULTS: Ninety-five infants were treated with dexamethasone before 36 weeks. Compared to the baseline support and demographic data at the time of treatment, changes in ventilatory support improved ordinal model sensitivity and specificity. For the binary classification, BPD incidence was well aligned with risk levels, increasing from 16% to 59%. CONCLUSIONS AND RELEVANCE: Incorporation of response variables as measured by changes in ventilatory parameters and pCO2 following dexamethasone administration were associated with downstream outcomes. Incorporating drug response phenotype into a BPD model may enable more rapid development of future therapeutics.

Exploring Residency Program Directors, Preceptors, and Residents' Intentions to Participate in Multicenter Pediatric Pharmacy Resident Research Projects.

OBJECTIVE: The purpose was to explore preceptors, residency program directors (RPDs), and residents' beliefs and intentions in participating in multicenter pediatric resident research projects (PRRPs). METHODS: This exploratory qualitative study used the theory of planned behavior to explore beliefs, attitudes, and intentions toward participation in a multicenter PRRP. Two focus groups were formed: RPDs/preceptors and pharmacy residents. The primary objective was to identify attitudes/salient beliefs, subjective norms, and perceived behavioral controls regarding participation in multicenter PRRPs. The secondary objectives included identifying potential barriers and mitigation strategies for multicenter PRRPs. Descriptive statistics and a thematic analysis were performed. RESULTS: The 2 focus groups included 24 participants: RPDs/preceptors (n = 16) and pharmacy residents (n = 8). The RPD/preceptor group had a mean of 7.4 ± 5.4 years of research experience; all residents had prior research experience as students. Participants shared and contrasted their salient beliefs, subjective norms, and perceived behavioral control beliefs about logistical challenges, networking, mentoring, sample size, collaboration, workload, shared responsibilities for data collection and the institutional review board application, and resources associated with participation in multicenter PRRPs. Other items that participants felt were important were discussion of authorship order and dedicated research time for residents. CONCLUSIONS: Participants provided favorable comments toward multicenter PRRPs but acknowledged some barriers. The resident, preceptor, and RPD intention to participate in multi-center PRRPs is very likely if they perceive this as an opportunity for increased networking and mentorship, increased likelihood of publication, enhanced research skill experience, and shared resources and responsibilities.

A Pilot Evaluation of the Possible Association of Metronidazole With Neurodevelopmental Outcomes in Premature Neonates.

OBJECTIVE: Metronidazole is recommended as a first-line treatment of necrotizing enterocolitis (NEC) in neonates. Metronidazole-associated neurotoxicity has been reported, but long-term neurodevelopmental effects in neonates have not been explored. The primary objective was to evaluate the relationship of cumulative metronidazole dose with each Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) composite score in neonates with NEC. Secondary objectives included comparison of seizure rates, mean Bayley-III scores, and neurodevelopmental impairment defined as 2 of 3 Bayley-III composite scores ≤ 79 or 1 score ≤ 70 between the metronidazole exposed and non-exposed groups. METHODS: This multisite, retrospective cohort study compared infants with a birth weight < 1500 grams between January 1, 2011, and December 31, 2016, who developed stage 2 or greater NEC or spontaneous intestinal perforation and were followed up at a developmental clinic visit at approximately 1 year of age. Patients were excluded if admitted >72 hours of life, had congenital neurodevelopmental anomalies, hypoxic ischemic encephalopathy, grade III or IV intraventricular hemorrhage, or seizures prior to treatment of NEC. Included patients were stratified into 2 groups based on metronidazole exposure versus no metronidazole. Data were assessed using descriptive and inferential statistical techniques, using SAS 9.4. RESULTS: Forty-one patients were included. Seven patients received metronidazole and 34 patients were in the non-metronidazole group. The only statistical difference noted between groups was for gestational age, with the non-exposed group being more premature. There was no statistical difference in Bayley-III scores, seizure rates, or neurodevelopmental impairment between groups. CONCLUSION: No differences in neurodevelopmental outcomes were found between those with and without metronidazole exposure. Further studies are needed to validate our results.

Using quality improvement to implement consensus guidelines for postnatal steroid treatment of preterm infants with developing bronchopulmonary dysplasia.

OBJECTIVE: Achieve over 90% adherence to consensus guidelines on use of postnatal steroids (PNS) in preterm infants for bronchopulmonary dysplasia (BPD) within 6 months. METHODS: A multidisciplinary team formulated and implemented consensus guidelines using the Plan-Do-Study-Act method of quality improvement. Outcome measure was rate of compliance to guidelines, process measure was age of starting PNS treatment, and balancing measure was rate of repeat steroid courses. RESULTS: Retrospective application of guidelines to preceding 10 months showed mean baseline compliance rate of 71% (n = 42). After implementation, compliance escalated to a mean rate of 96% within 6 months. Rate of PNS treatment ≤ 30 days of life increased from 50 to 80%, while rate of repeat PNS was unchanged. CONCLUSIONS: Compliance with new guidelines for PNS treatment of BPD was quickly attained using simple quality improvement interventions. Further study is needed to evaluate effects of these guidelines on clinical outcomes.

Improving Recognition and Reporting of Adverse Drug Reactions in the NICU: A Quality Improvement Project.

Adverse drug reactions (ADRs) are under-recognized and under-reported in the Neonatal Intensive Care Unit (NICU) population, with up to 95% of all ADRs not reported. Compared with non-elderly adults, pediatric patients are 3 times more likely to experience an ADR, with varying rates from 0.6% to 16.8%. The Children's Mercy NICU has an ADR rate of 0.29% (2015). This high rate presents an opportunity to increase recognition and reporting, and improve characterization of ADRs in the NICU. METHODS: The primary aim of this quality improvement project was for 70% of patients who received specified medications (indomethacin, dexmedetomidine, fentanyl, lorazepam, dexamethasone, or hydrocortisone) in the first 3 months of age to be assessed daily for ADRs. We selected these medications due to the frequency of use and well-understood ADR associations. For each ADR recognized, the Naranjo score, was calculated and compared with the neonatal-specific Du score to assess the effectiveness of ADR characterization. RESULTS: Implementation occurred on May 15, 2017. We completed 3 PDSA cycles over 1 year. The bedside monitoring tool was utilized 83% of the time. Twenty-eight potential ADRs were identified, far exceeding the number reported before implementation. The Du score appeared to better characterize ADRs compared with the Naranjo score. CONCLUSIONS: Use of a bedside monitoring tool improves ADR detection. We experienced challenges with consistently identifying patients on target drugs and getting the tool to the bedside. Application of the Du score for ADR classification in neonates appears to be more appropriate than the use of the Naranjo.

Extended course of prednisolone in infants with severe bronchopulmonary dysplasia.

BACKGROUND: There are few published data on the efficacy and safety of prednisolone in preterm infants with bronchopulmonary dysplasia (BPD). AIMS: To describe the use of chronic prednisolone therapy in a population of infants with severe BPD, examine potential benefits on respiratory status, and document potential effects on growth. STUDY DESIGN: Single-center retrospective cohort study. SUBJECTS: Preterm infants who had received ≥30 days of prednisolone for the treatment of severe BPD. OUTCOME MEASURES: Weekly changes in Pulmonary Severity Score (PSS), as well as weekly changes in weight, length, and head circumference during prednisolone therapy. RESULTS: Forty-three infants (mean birth weight 729 g; mean gestational age 26 weeks) were identified. The average age at start of prednisolone treatment was 42.5 ±â€¯5.9 weeks; while the median duration and median cumulative dose of prednisolone therapy were 67 (IQR 57-107) days and 61.3 (IQR 39.9-93.3) mg/kg, respectively. PSS decreased after 1 week of prednisolone therapy (mean difference, 0.19; 95% Cl, 0.01 to 0.37; p = 0.03). No further reduction in PSS was noted despite continued treatment. Length z-scores decreased after 4 weeks of continued treatment (mean difference 0.6; 95% CI 0.01 to 1.1; P = 0.04), while weight and head circumference did not change. CONCLUSIONS: In one of the first reports on prednisolone therapy for severe BPD, we describe that long-term prednisolone is associated with modest short-term improvement in PSS, but impairs linear growth. Our results suggest a risk-benefit profile of prednisolone that does not favor long-term use in infants with severe BPD.

Current status of lipid emulsions in the prevention of intestinal failure-associated liver disease.

PURPOSE OF REVIEW: The current review provides a summary of available lipid products and discusses current literature and the limitations to the use of various lipid products for treatment and prevention of intestinal failure-associated liver disease (IFALD) in pediatric patients dependent on parenteral nutrition. RECENT FINDINGS: Improvements in markers of cholestasis and liver function have been seen with minimizing soybean lipid, fish oil lipid, and mixed fish oil-containing lipid emulsions. Soybean-based lipid products are thought to be the biggest contributor to development of IFALD. Mixed fish oil-containing lipid emulsions are most promising for minimizing and improving IFALD. SUMMARY: Several types of lipid-based products are available for parenteral nutrition. Newer products like the mixed fish oil-containing-based lipid emulsions, that closely mimic the lipid composition provided by enteral feeding, may impact prevention and treatment of IFALD. Limitations exist in the current literature regarding mixed fish oil-containing-based emulsions, as many of the studies were designed to show efficacy with regard to growth, not prevention or treatment of IFALD. Based on available literature, it is reasonable to make some recommendations with regard to product selection for lipid provision.

Acidity of Enteral Feeding Tube Aspirate in Neonates: Do pH Values Meet the Cutoff for Predicting Gastric Placement?

BACKGROUND: Enteral feeding tubes (EFTs) are commonly used in neonatal practice, but complications from tube misplacement remain a concern. Measuring the pH of EFT aspirate is a recommended method to evaluate EFT placement. A pH value of ≤5.5 is considered predictive of gastric placement. Using this method in infants has been questioned. It is unclear whether infants can produce adequate gastric acid to achieve a pH 5 or less and whether feedings and medications influence pH. PURPOSE: To report EFT aspirate pH values in infants and to evaluate factors potentially influencing pH values. METHODS: A retrospective descriptive study was conducted with 1024 infants with 6979 pH values. Demographic and clinical data were collected including type of EFT, pH of gastric aspirate, feeding method, time of last feeding, and administration of acid suppression medications. The frequency of measured pH values of 5 or less was calculated for each covariate. FINDINGS/RESULTS: The majority (97.51%) of pH values were 5 or less. Orogastric tubes, continuous feeding, a 4-hour or more feeding interval, exposure to medications (proton pump inhibitor, histamine-2 receptor antagonist, or multiple medications) were associated with an increased likelihood of pH values of more than 5. However, with each study variable the majority of pH values were 5 or less. IMPLICATIONS FOR PRACTICE: These findings suggest EFT pH, a recommended method to evaluate the likelihood of gastric placement, can be successfully used in the neonatal population. IMPLICATIONS FOR RESEARCH: Future research should prospectively evaluate EFT pH in infants when compared with clinically indicated radiographs. Other factors that might influence pH should be explored including severity of illness, feeding type, and other medications.

Acute Post-Tracheostomy Clinical Decompensations in Infants-Are There Predictive Markers?

OBJECTIVE: To report on the population of infants receiving a tracheostomy, identify acute post-tracheostomy clinical decompensations, and seek predictive markers associated with acute complications following the placement of a tracheostomy. STUDY DESIGN: Retrospective deidentified clinical data was provided by the Infant Pulmonary Data Repository at Children's Mercy Hospital, Kansas City. Data from infants undergoing tracheostomy from January 1, 2008 through September 30, 2016 were divided into one of two study groups based on clinical correlations: (1) no acute decompensations within 72 hours post-tracheostomy or (2) acute clinical decompensation defined as sustained escalation of respiratory care within the 72 hours following tracheostomy. RESULTS: Thirty-four percent of infants undergoing tracheostomy during this period developed acute post-tracheostomy clinical decompensations. Elevated pre-tracheostomy positive end expiratory pressure, mean airway pressure, and echocardiogram findings suggestive of pulmonary hypertension (PH) or ventricular dysfunction were associated with acute post-tracheostomy clinical decompensations. Additionally acute post-tracheostomy clinical decompensation was associated with higher rate of death prior to discharge. CONCLUSION: Infants requiring higher respiratory support and infants with PH or ventricular dysfunction are at risk of acute post-tracheostomy clinical decompensation, thus identifying these patients may lead to better pre-tracheostomy counseling and potentially targeted treatments to decrease this risk.

Comparison of Arginine Hydrochloride and Acetazolamide for the Correction of Metabolic Alkalosis in Pediatric Patients.

Metabolic alkalosis is a common acid-base disturbance occurring in critically ill pediatric patients. Acetazolamide and arginine hydrochloride are pharmacologic agents used at our institution for patients refractory to first-line therapy or those unable to tolerate fluid replacement. The objective of this retrospective review was to determine if a course of arginine hydrochloride or acetazolamide was more effective at correcting metabolic alkalosis within a 24-hour period. Patients included received a course of acetazolamide or arginine hydrochloride for metabolic alkalosis with a repeat metabolic panel 18-30 hours after treatment initiation. Exclusion criteria consisted of previous treatment with either drug within 24 hours or a documented metabolic disorder. Efficacy was determined by proportion of patients achieving resolution of metabolic alkalosis (treatment success: serum CO2 <30 mmol/L and Cl >96 mmol/L). Additionally, mean change in serum bicarbonate and chloride concentrations was assessed. Thirty-four patients met inclusion criteria, 19 patients received acetazolamide and 15 patients received arginine hydrochloride. Treatment success was similar in patients receiving acetazolamide and arginine hydrochloride (37% vs. 7%, P = 0.053). Correction of serum bicarbonate was observed in more patients treated with acetazolamide (42% vs. 7%, P = 0.047). Both groups had a similar increase in mean serum chloride concentration (5.7 ± 5.3 vs. 4.4 ± 4.4 mmol/L, P = 0.458). Mean decrease in serum bicarbonate concentration was equivalent between groups (5.6 ± 5.2 vs. 2.8 ± 4.7, mmol/L, P = 0.110). Acetazolamide and arginine hydrochloride appear to be equally effective in correcting metabolic alkalosis in critically ill pediatric patients.

Survey results: characterization of direct thrombin inhibitor use in pediatric patients.

OBJECTIVES: The objective of this multicenter survey is to characterize the use of direct thrombin inhibitors (DTIs) in the pediatric population. The results of this survey may be used to design a prospective multicenter study with the ultimate goal of developing a dosing/titration recommendation for the use of DTIs in the pediatric population. METHODS: This is a multicenter, descriptive study to survey hospitals around the country regarding the use of DTIs (argatroban, bivalirudin, and lepirudin) in the pediatic population. Institutional review board approval was obtained. The survey consisted of 42 questions and was designed utilizing Survey Monkey. The survey was emailed to members of the Pediatric Pharmacy Advocacy Group. Listserv members who responded to the survey within 4 weeks of when the survey was emailed were included in the study. Descriptive statistics were performed utilizing Microsoft Excel 2007. RESULTS: Responses were obtained from 56 institutions from 29 states in the United States. Multiple agents are available on formulary with argatroban being the most common (~80%). The large majority of institutions (41.1%) utilize DTIs 2 to 4 times a year with an additional 33.9% utilizing them less than twice a year. There is no consistent approach to dosing and titration amongst pediatric institutions. CONCLUSIONS: There are a wide variety of methods used by pediatric institutions with regard to dosing and titration of DTIs. Recently published prospective studies and package insert updates should help guide practitioners toward a more consistent approach to dosing of these high-risk medications.

Retrospective evaluation of antithrombin III supplementation in neonates and infants receiving enoxaparin for treatment of thrombosis.

BACKGROUND: Thromboembolic events are occurring at increasing rates in neonates and infants. At Children's Mercy Hospitals and Clinics, antithrombin III (AT3) concentrates are often used in combination with enoxaparin to supplement physiologically low AT3 levels. Theoretically, AT3 enhances the anticoagulant activity of enoxaparin and results in decreased time to therapeutic anti-Xa levels. No data exist on use of AT3 for this indication. PROCEDURE: This retrospective study compared time to therapeutic anti-Xa levels in patients <1 year of age receiving enoxaparin with AT3 (Group 1) and without AT3 (Group 2) for treatment of thrombosis. Primary objective was to compare time to therapeutic anti-Xa levels (0.5-1 U/ml) between groups. Secondary objectives included comparison of the initial and therapeutic dose of enoxaparin, enoxaparin dose changes, AT3 supplementation, and level monitoring. Bleeding events and cost were also evaluated. Statistical tests included Schuirmann's two one-sided tests for equivalence and general linear models/logistic regression for independent effects of age, critical illness, and timing of AT3. RESULTS: Mean time to therapeutic anti-Xa levels were not equivalent between Groups 1 and 2 (80.7 vs. 65.2 hours; P = 0.28). Initial enoxaparin dose and number of dose changes were equivalent. Group 1 required higher doses of enoxaparin to achieve therapeutic anti-Xa levels. Age, critical illness, and timing of AT3 had no effect on time to therapeutic anti-Xa levels. Bleeding events were not equivalent between Groups 1 and 2 (14.3% vs. 3.9%; P = 0.55). CONCLUSION: Supplementation with AT3 did not decrease time to therapeutic anti-Xa levels, added significant cost, and was associated with increased bleeding events.

Safety and efficacy of two potassium cocktail formulations for treatment of neonatal hyperkalemia.

BACKGROUND: A consensus has not been established for the standard treatment of hyperkalemia in the neonatal population. Most treatment regimens include a dextrose/insulin infusion. Additional agents used include calcium, sodium bicarbonate, polystyrene sulfonate, and albuterol. This study assessed the safety and efficacy of a potassium cocktail (k-cocktail) containing dextrose, insulin, calcium gluconate, and sodium lactate for treatment of neonatal hyperkalemia. OBJECTIVE: To determine whether modifications to a potassium cocktail formulation, based on a prior quality improvement project, resulted in a decrease in the incidence of hyperglycemia and acidosis associated with its use, and to evaluate the effectiveness of the k-cocktail in lowering serum potassium levels and the incidence of adverse effects. METHODS: We conducted a retrospective cohort study of neonates with hyper-kalemia who received 2 k-cocktail formulations (group 1 [n = 13], original formulation, dextrose:insulin 5:1; group 2 [n = 26], modified formulation, dextrose: insulin 3.3:1). Group 2 subjects were matched 2:1 by gestational age and birth weight with those in group 1. Variables related to safety and effectiveness of therapy were assessed by medical record review. The following tests were used to assess group differences: χ(2), Fisher exact, 2-tailed t-tests, and mixed linear models. RESULTS: The incidence of hyperglycemia during the modified k-cocktail infusion in group 2 decreased from 76.9% to 21.7% (p = 0.001). Serum blood glucose concentrations increased during the infusion, on average, for group 1 infants and were unchanged during the infusion for those in group 2. The incidence of acidosis during the infusion was similar between groups (group 1 [76.9%] vs group 2 [68.2%]; p = 0.58). No significant adverse events were observed. Serum potassium concentrations decreased similarly in both groups. CONCLUSIONS: An intravenous infusion including a dextrose:insulin ratio of 3.3:1, compared with a higher ratio, results in less hyperglycemia and appears to be as effective in decreasing potassium concentrations in newborns.

Dexmedetomidine for opioid and benzodiazepine withdrawal in pediatric patients.

PURPOSE: The published literature on the use of dexmedetomidine as an adjunct to sedation and analgesia in the management of pediatric narcotic withdrawal was reviewed. SUMMARY: Pediatric narcotic withdrawal syndromes are reported to be increasingly frequent in pediatric intensive care units. A number of tools specifically designed for assessment of withdrawal in newborns and infants are in current use, including the widely used Finnegan Scoring System. A limited number of studies and case reports suggest that dexmedetomidine, an α(2)-receptor agonist with a mechanism of action similar to that of clonidine but with greater α(2)-receptor specificity, might have a role in the treatment of pediatric withdrawal (by blunting withdrawal symptoms without causing respiratory depression and by permitting shorter narcotic tapering schedules) and also in the prevention of pediatric narcotic withdrawal (by reducing narcotic requirements). Potential adverse effects associated with dexmedetomidine use in pediatric patients are generally associated with use of bolus doses and mainly involve central nervous system effects (e.g., hypotension, bradycardia), with no hemodynamic manifestations. When bolus doses are used, strategies described in published reports entail a loading dose of 0.5-1.0 µg/kg administered over 5-10 minutes, followed by a continuous infusion at 0.1-1.4 µg/kg/hr for a period of 1-16 days. More research is needed to define the optimal use of dexmedetomidine in the management of pediatric narcotic withdrawal. CONCLUSION: A limited body of published evidence from retrospective studies and case reports suggests a potential role for dexmedetomidine as an adjunct therapy to provide sedation and analgesia to reduce narcotic withdrawal symptoms in pediatric patients.