Effects of Part D Star Ratings on racial and ethnic disparities in health care costs.

Background: Racial/ethnic minorities are less likely than non-Hispanic White (White) patients to be included in the Medicare Part D Star Ratings measure assessment due to the restrictive inclusion criteria for the measures. Objective: This paper examined the effects of racial/ethnic disparities in the measure assessment in Part D Star Ratings on disparities in healthcare costs among patients with Alzheimer's disease and related dementias (ADRD). Methods: This cross-sectional study analyzed 2017 Medicare data. Proportions of Beneficiaries with ADRD were categorized into the included and excluded groups based on the inclusion criteria for the calculation of medication adherence measures in Star Ratings. Outcomes included costs for medications, physician visits, emergency room (ER) visits, and total costs. A generalized linear model was employed to compare costs across racial/ethnic groups. To explore the differential disparities in healthcare costs between the 2 groups, interaction terms between dummy variables for being excluded from the measure calculation and racial/ethnic minorities were included in the models. Results: The patterns of racial/ethnic disparities in healthcare costs found in this study were generally consistent with expectations, with some exceptions. For example, compared with White patients, in the hyperlipidemia cohort, the physician visit cost for Black patients among the included group was 31% lower (cost ratio or CR = 0.69, 95% CI = 0.67-0.72); in the hypertension cohort, the hospitalization cost for Blacks among the excluded group was 15% higher (CR = 1.15, 95% CI = 1.12-1.19). More importantly, exclusion from measurement assessments was associated with differential cost disparities. For example, compared with individuals included in the measure assessment for hypertension, the Black-White disparities in costs for hospitalization and total healthcare were 30% higher (CR = 1.30, 95% CI = 1.26-1.34), and 10% higher (CR = 1.10; 95% CI = 1.08-1.12), respectively, among the excluded group. Conclusions: Medicare Part D Star Ratings may be associated with aggravated racial/ethnic disparities in healthcare costs in the Medicare Part D population.

Concomitant Ceftriaxone and Intravenous Calcium Therapy in Infants.

OBJECTIVE: To determine if increased mortality could be detected with the administration of ceftriaxone and IV calcium in infants through an analysis of a large repository of electronic health records. METHODS: Patients were split into 3 groups: 1) neonates, 2) infants, and 3) infants <1 year whose age was not specified. Deaths were classified into mutually exclusive categories based on the administration and timing of ceftriaxone and IV calcium. Crude death rates were calculated, and logistic regression modeling was used to calculate adjusted relative odds of death with associated covariates. RESULTS: A total of 259,149 infants were identified. Of 79,038 neonates, the proportion of patients that received ceftriaxone and IV calcium within 48 hours who died was 3.8%, compared with 1.95% (IV calcium), 0.3% (ceftriaxone), 1.54% (IV fluids), and 2.03% (parenteral nutrition). For 102,456 infants, the proportions of deaths were 5.47% (ceftriaxone and IV calcium within 48 hours), 0.45% (IV calcium), 0.15% (ceftriaxone), 0.39% (IV fluids), and 5.5% (parenteral nutrition). Multivariate analysis showed increased odds of death in infants who received ceftriaxone and IV calcium within 48 hours, regardless of age, and propensity score-matched analysis showed a more than 2-fold increased risk for death. CONCLUSIONS: The increased risk for death following ceftriaxone and IV calcium administration was noted not only in neonates, but among older infants as well.

Identifying the "Blip on the Radar Screen": Leveraging Big Data in Defining Drug Safety and Efficacy in Pediatric Practice.

The immense amount of electronic health data (pharmacy and administrative claims, electronic health records, and clinical registries) that is being generated every day in the care of patients has the potential to be leveraged for improving clinical decisions at the point of care, uncovering or validating drug efficacy and drug safety. The potential use of big data for improving safe and effective use of medications is especially important in children because of their low drug exposure relative to adults. Electronic health data is collected primarily for clinical or billing purposes and not for research purposes. The major steps involved in data acquisition, extraction, aggregation, analysis, modeling, and interpretation are discussed. It is important to understand the limitation of big data and utilize appropriate study design and statistical methods. Possible applications are presented along with specific examples of how big data has been used in drug research to find that blip on the radar screen that may give an efficacy or safety signal that can lead to further investigation.

Lipid Injectable Emulsion Survey With Gap Analysis.

BACKGROUND: Lipid injectable emulsion (ILE) is an integral part of parenteral nutrition (PN), providing energy and essential fatty acids. With recent consensus recommendations for PN, clinical guidelines for ordering and preparation of PN, the U.S. Food and Drug Administration approval of new ILE products, and revised ILE labeling to include a 1.2-micron filter, a gap in current practice knowledge was apparent. MATERIALS AND METHODS: The American Society for Parenteral and Enteral Nutrition PN Safety Committee surveyed clinicians on how ILE products are prescribed, prepared, and administered to patients from neonates to adults. RESULTS: The results of this survey conducted in late 2016 found a wide variation in practice, particularly across patient age groups. CONCLUSION: These findings demonstrate the need for ongoing dissemination and education on standardized safe practices for ILE use.

Calprotectin: Clinical Applications in Pediatrics.

As seen over the past 20 years, calprotectin has evolved as a novel, non-invasive biomarker of gastrointestinal (GI) inflammation. We present this review of calprotectin in pediatrics. This article will focus on studies using calprotectin concentrations from different body fluids to monitor inflammation in different disease states and conditions. The ultimate goal of our group is to lay down a foundation as we consider using calprotectin prospectively as a marker of intestinal inflammation that could lead to further testing and possibly a marker of preparedness for feeding. We surveyed all published studies in English of calprotectin in neonates, infants, children, and adolescents through February 2014. We will discuss calprotectin's basic properties and analysis such as characteristics, identification, presence in body fluids, and maturational development. In addition, calprotectin's use in inflammatory diseases exploring both GI and non-GI conditions will be evaluated and compared with other serum markers presently available. Finally, a summary of our findings and discussion of future work that could be undertaken in order to render calprotectin as a more useful monitoring tool to the medical research community will complete the review.

Pediatric drug development programs for type 2 diabetes: A review.

Considerable progress has been made in pediatric drug development. Despite these gains there remain certain therapeutic areas where a high percentage of drugs approved for use in adults do not gain approval for use in children. Lack of sufficient US Food and Drug Administration (FDA)-approved labeling correlates with diminished therapeutic efficacy and increased risk for adverse drug reactions. Despite the increasing prevalence and important clinical challenge with pediatric type 2 diabetes mellitus (T2DM), only 1 drug (metformin) of the first 4 T2DM drugs to complete testing in children gained FDA approval. This analysis reviews 4 pediatric drug development programs for orally administered antidiabetic agents that have undergone FDA review and discusses factors influencing failure to meet specified end points for approval. Recommendations to guide future study are also provided.

Recent new drug approvals, part 2: drugs undergoing active clinical studies in children.

The objective of this 2-part review is to provide information about drugs that have been recently approved by the US Food and Drug Administration. Part 1 reviewed recently approved drugs with pediatric indications. Part 2 reviews drugs recently approved only in adults and have published or ongoing studies in children.

Retrospective evaluation of enoxaparin dosing in patients 48 weeks' postmenstrual age or younger in a neonatal intensive care unit.

BACKGROUND: Enoxaparin is the anticoagulant of choice in neonates because of the ease of administration, predictable pharmacokinetics, and reduced adverse effects when compared to heparin. The Chest guidelines recommend that therapy in patients younger than 2 months should be initiated with enoxaparin 1.5 mg/kg administered subcutaneously twice daily. This starting dosage may be inadequate, leading to a delay in achieving therapeutic anti-factor Xa plasma concentrations. OBJECTIVE: To determine an enoxaparin dose for neonatal patients that achieves a therapeutic anti-factor Xa plasma concentration and compare that dose to the recommended enoxaparin dose per published guidelines for this patient population. METHODS: The study was designed as a single-center chart review. Eligible patients were identified by pharmacy anticoagulation records or a search of the electronic medical record for enoxaparin orders. Patients must have received enoxaparin subcutaneously twice daily and have had a postmenstrual age of 48 weeks or younger. Patients diagnosed with renal failure and those receiving prophylactic doses of enoxaparin were excluded. RESULTS: The mean (SD) initial dose of enoxaparin was 1.4 (0.3) mg/kg subcutaneously twice daily, resulting in 27 of 33 patients (81.8%) having a subtherapeutic anti-factor Xa concentration. A mean enoxaparin dose of 2.0 (0.5) mg/kg was required to achieve a therapeutic anti-factor Xa plasma concentration (p < 0.001). Patients born prematurely required a higher enoxaparin dose (2.2 [0.5] mg/kg) than did those born at full-term gestation (1.8 [0.4] mg/kg; p < 0.05). CONCLUSIONS: For patients 48 weeks' postmenstrual age or younger who are treated in a neonatal intensive care unit, a higher initial dose of enoxaparin than that suggested by the Chest guidelines is required to attain a therapeutic antifactor Xa plasma concentration. Premature neonates require a larger starting dose of enoxaparin than do infants born at full-term gestation.

Recent new drug approvals. Part 1: drugs with pediatric indications.

This two-part review provides information about drugs that have been recently approved by the Food and Drug Administration and focuses on drugs approved with pediatric indications or approved in adults with active pediatric studies. Information was obtained from the product labeling and selected published studies. Part 1 reviews recently approved drugs with labeled pediatric indications, and Part 2 will review recent drug approvals in adults that have potential use in pediatrics and have active studies.

Enteral fish oil for treatment of parenteral nutrition-associated liver disease in six infants with short-bowel syndrome.

STUDY OBJECTIVE: To evaluate the use of enteral fish oil for the treatment of parenteral nutrition-associated liver disease (PNALD). DESIGN: Retrospective case series. SETTING: Pediatric academic hospital and outpatient clinic. PATIENTS: Six parenteral nutrition-dependent infants with short-bowel syndrome and PNALD. MEASUREMENTS AND MAIN RESULTS: The six infants received supplementation with enteral fish oil, and treatment was evaluated over a 12-week period. The PNALD, as reflected by elevated total bilirubin levels, completely reversed in four of the six infants within a mean ± SD of 5 ± 2.6 weeks (range 2-8 wks) after initiation of the enteral fish oil supplementation. In addition, improvement in enteral feedings occurred after starting enteral fish oil therapy. CONCLUSION: Enteral fish oil may be an effective adjunctive treatment option for infants with PNALD, particularly for those infants with PNALD who are tolerating some amount of enteral nutrition as the result of an adequate amount of small bowel.

A tandem mass spectrometry assay for the simultaneous determination of acetaminophen, caffeine, phenytoin, ranitidine, and theophylline in small volume pediatric plasma specimens.

BACKGROUND: Acetaminophen, caffeine, phenytoin, ranitidine, and theophylline are widely used in pediatric pharmacotherapy, but only very limited information is available on the pharmacokinetics of these medications in premature neonates. As pharmacokinetic studies in this population are hampered by limitations in the number and volume of plasma samples, we developed an LC-MS/MS assay for the simultaneous determination of these medications in small volume human plasma specimens for pharmacokinetic evaluations in neonates. METHODS: Sample preparation was performed by protein precipitation with methanol after addition of internal standard to 50 microl of plasma specimen. After chromatographic separation on a C18 column using gradient elution, analytes were detected using a triple quadrupole mass spectrometer that was operated in positive ion mode with electrospray ionization. RESULTS: All 5 analytes could be simultaneously quantified in human plasma. The linear quantification range comprised 12.2 to 25,000 ng/ml for acetaminophen, phenytoin, and ranitidine, 24.4 to 25,000 ng/ml for theophylline, and 48.8 to 25,000 ng/ml for caffeine with accuracies ranging from 87.5 to 115.0%. The intra-day and inter-day precision (%CV) was between 2.8 and 11.8% and 4.5 and 13.5%, respectively. CONCLUSIONS: An accurate, sensitive, and reliable LC-MS/MS method was developed and validated to simultaneously quantify 5 drugs frequently used in neonatal pharmacotherapy.

Elevated tobramycin concentrations following endotracheal administration in a premature infant.

The following case report describes a 1-month-old, 34-week-gestation premature neonate who had compromised renal function. The neonate received endotracheally administered tobramycin (300 mg every 12 hours) via a PARI PLUS reusable nebulizer to treat a documented Gram-negative tracheostomy infection. The patient also received systemic tobramycin (2.5 mg/kg intravenously every 18 hours). The tobramycin serum concentration obtained 45 hours after the last intravenous dose and 11.5 hours after the second nebulized dose was 17.6 mg/L. The tobramycin nebulizations were stopped.

Relative bioavailability of carnitine supplementation in premature neonates.

BACKGROUND: Carnitine is an important nutrient in the infant diet. We compared total plasma carnitine concentrations in premature neonates supplemented with carnitine via parenteral and enteral nutrition. METHODS: This is a post hoc analysis of plasma total carnitine concentrations and carnitine intake in neonates randomized in a previous study to receive 20 mg/kg/d carnitine supplementation over 8 weeks. Neonates received l-carnitine initially via parenteral nutrition (PN). When neonates were fed enterally, oral supplementation of l-carnitine was given in divided doses with each feeding. RESULTS: Sixteen neonates (27 +/- 2 weeks gestation; 2.9 +/- 1.0 days postnatal age at enrollment; 965.6 +/- 279.1 g birth weight) are included. Concentrations were below reference range (31.1-60.5 nmol/mL) at baseline and exceeded reference range from week 1 through the last study period. Concentrations were not different from week 1 (108 +/- 49) through weeks 4 (87 +/- 34) and 8 (83 +/- 31). Carnitine intakes and concentrations were compared in neonates receiving 100% parenteral carnitine at week 1 (n = 6) and 100% enteral carnitine at week 8 (n = 8). Concentrations at week 1 (100.1 +/- 27.9) were not different (p = .19) from week 8 (78.6 +/- 29.3); an estimate of relative bioavailability was 78.6%. Bioavailability with paired analysis of neonates (n = 5) receiving 100% parenteral carnitine at week 1 and 100% enteral carnitine at week 8 was 83.7% +/- 41.2% (30.1%-140.6%). CONCLUSIONS: Parenteral and enteral supplementation of 20 mg/kg/d carnitine results in plasma total carnitine concentrations that exceed the reference range. Concentrations are not different between parenteral to enteral supplementation, suggesting that enteral carnitine is well absorbed when given daily in divided doses with enteral feedings.

Carnitine supplementation in premature neonates: effect on plasma and red blood cell total carnitine concentrations, nutrition parameters and morbidity.

BACKGROUND & AIMS: Carnitine may be considered conditionally essential in the neonatal population. The purpose of this study was to evaluate the effects of long-term carnitine supplementation on total carnitine status and morbidity in premature neonates. METHODS: In this prospective, randomized, placebo-controlled, double-blinded study, premature neonates received carnitine supplementation (20mg/kg/day) or placebo. Plasma (nmol/ml) and red blood cell (RBC) (nmol/mg hemoglobin) total carnitine concentrations, 24-h nitrogen excretion, intake and weight, and respiratory, gastroesophageal, and infectious morbidity were assessed. RESULTS: Twenty-nine neonates (13 placebo, 16 carnitine; 27+/-2 weeks gestation; 976+/-259g birthweight) were studied for up to 8 weeks. Plasma total carnitine concentrations exceeded the reference range in the carnitine group (weeks 1-8); however, concentrations did not reach reference range until week 4 in the placebo group. RBC total carnitine concentrations increased, but remained below reference range in both the carnitine (weeks 1-6) and placebo (weeks 1-8) groups. Carnitine group neonates regained their birthweight more rapidly than placebo group neonates (day of life 11.8+/-6 vs. 16.9+/-6.3, P=0.034). In addition, percent periodic breathing calculated from cardiopulmonary trend monitor data (weeks 1-8) was lower in the carnitine group (0.4+/-0.9 vs. 1.4+/-1.9, P=0.014). There was no difference with respect to other markers of respiratory, gastroesophageal and infectious morbidity or nitrogen balance. CONCLUSIONS: Carnitine supplementation at 20mg/kg/day results in increased plasma and RBC total carnitine concentrations, has a positive effect on catch-up growth, and may improve periodic breathing in premature neonates.

Beta2-adrenergic receptor polymorphisms in African American children with status asthmaticus.

BACKGROUND: The beta2-adrenergic receptor plays a central role in the bronchodilator response to beta2-agonists in patients with asthma. Genetic polymorphisms within the gene coding for this receptor influence responsiveness of the receptor. A number of these polymorphisms differ in frequency in the African American and white populations. OBJECTIVE: To determine the frequency of specific beta2-adrenergic receptor polymorphisms in African American children with status asthmaticus and to examine whether a specific genotype is associated with the clinical response to therapy. DESIGN: Cohort of African American children diagnosed with status asthmaticus. SETTING: Tertiary care children's hospital. PATIENTS: A total of 31 African American children with status asthmaticus. INTERVENTION: Blood samples were obtained from children at admission. Genotypes were determined by polymerase chain reaction amplification and restriction enzyme digestion. MAIN OUTCOME MEASURES: The requirement for admission to the pediatric intensive care unit, need for mechanical ventilation, institution of various therapies, and length of stay. RESULTS: The genotypes of the polymorphic sites at amino acid positions 16 and 27 in the beta2-adrenergic receptor were determined. There were no significant differences between the various genotypes in the percentage of children requiring pediatric intensive care unit admission, mechanical ventilation, terbutaline treatment, or length of stay. However, in children heterozygous for Glu at position 27 of the beta2-adrenergic receptor, the percentage of patients requiring aminophylline treatment, in addition to beta2-agonist therapy, was significantly higher than that seen in patients homozygous for Gln at that position (5/10 [50%] vs. 1/21 [5%], respectively; p = .002). CONCLUSIONS: African American children with status asthmaticus who have the Gln/Glu genotype at amino acid position 27 of the beta2-adrenergic receptor may benefit from aminophylline treatment in addition to beta2-agonist therapy.

Insulin dynamics predict body mass index and z-score response to insulin suppression or sensitization pharmacotherapy in obese children.

OBJECTIVE: To assess the use of oral glucose tolerance testing (OGTT) to predict efficacy of insulin sensitization (metformin) or suppression (octreotide) because insulin resistance and insulin hypersecretion may impact pharmacotherapeutic efficacy in obese children. STUDY DESIGN: Forty-three and 24 obese children, with and without central nervous system (CNS) insult, underwent OGTT. Insulin sensitivity was expressed as composite insulin sensitivity index (CISI), and secretion as corrected insulin response (CIRgp). Those without CNS insult received metformin (weight-based dosing) for 6 to 16 months. Those with CNS insult received octreotide SQ 15 microg/kg/d for 6 months. Body mass index (BMI) and z-score responses were modeled using CIRgp and CISI. RESULTS: Metformin: With CIRgp and CISI = 1, BMI z-score in white children declined by 0.23 over the first 4 months (P < .001), and by 0.14 over the next year (P = .33). Each 2-fold increase in CIRgp or CISI attenuated BMI z-score reduction, but with wide uncertainty (P = .24). Black children exhibited little response. Octreotide: With CIRgp and CISI = 1, BMI z-score decreased by 0.23 in the first 4 months (P = .052). Efficacy was dependent on an interaction between CIRgp and CISI (P = .051). CONCLUSIONS: Efficacy of metformin was predicted by pretreatment insulin resistance. Efficacy of octreotide was predicted by insulin hypersecretion and sensitivity.

Single- and multiple-dose pharmacokinetics of pioglitazone in adolescents with type 2 diabetes.

This study assessed the single- and multiple-dose pharmacokinetics of 3 doses (15 mg, 30 mg, and 45 mg) of pioglitazone in 36 adolescents with type 2 diabetes. Blood samples were obtained over a 48-hour interval after the first dose (day 1) and over a 72-hour interval after the last dose (day 15) of pioglitazone and were assayed for pioglitazone and active metabolites (M-III and M-IV). Pioglitazone systemic exposure increased dose dependently but was less than dose proportional during multiple dosing. The median peak pioglitazone concentration occurred at 2 hours. The mean half-life was 8 to 9 hours for pioglitazone and 24 to 32 hours for M-III and M-IV, with similar values at each dose level. During multiple dosing, accumulation for pioglitazone was negligible, but it reached 2.5- to 3.0-fold for M-III and M-IV. The sustained total serum concentration of active compounds during multiple dosing provides the basis for once-daily dose administration of pioglitazone in adolescents.

Changing requirements for evaluation of pharmacologic agents.

Children sadly have been excluded from some of the therapeutic advances that have marked pharmaceutical drug development during the past 100 years. Most drugs in use today lack Food and Drug Administration approval for use in children or are restricted to certain pediatric age groups, predominantly older than 12 years. Only a few of the new drugs approved each year have pediatric indications and dosing guidelines described in the drug labeling information. However, many of these drugs are used in children. The lack of suitable information places children at risk for over- or underdosing, and there is a lack of suitable dosage forms, which can result in improper drug administration. This lack of information on the safe and effective use of drugs in the most vulnerable patients--infants and neonates--is of greatest concern. Recent changes in the regulations that govern drug development has dramatically increased the number of drugs that undergo testing in children. This article reviews new laws that govern drug testing in children and the use of children in therapeutic research.

Pharmacokinetics of sumatriptan nasal spray in children.

The authors studied the pharmacokinetics of sumatriptan nasal spray after a single dose in children migraineurs outside of migraine attack. Seventeen subjects (9 females) ages 6 to 11 years were given one dose of sumatriptan nasal spray based on age and weight; children 6 to 8 years of age weighing 25 kg and children ages 9 to 11 years of age weighing 40 kg received 20 mg (n = 4). Plasma sumatriptan concentrations were determined in serial blood samples obtained over 8 hours. Pharmacokinetic analysis included both noncompartmental and population modeling methods. The pharmacokinetic parameter estimates (geometric mean [95% confidence interval]) following 5, 10, and 20 mg sumatriptan were, respectively, as follows: maximum concentration = 8.1 ng/mL (3.6-18.4), 10.8 ng/mL (7.7-15.4), and 12.3 ng/mL (7.6-19.9); half-life = 1.4 hours (1.2-1.8), 1.7 hours (1.4-2.0), and 1.7 hours (1.3-2.3); and AUC = 27.8 ng*h/mL (9.7-79.8), 42.4 ng*h/mL (30.6-58.8), and 49.2 ng*h/mL (32.9-73.7). The median time to maximum concentration for all groups was 2 hours. Population pharmacokinetic modeling included pooled data from this study and from an adolescent study (n = 16). Clearance (CL/F) was 197 L/h for a 30-kg child with between-subject variability of 28%, and the volume of distribution was 751 L, normalized for an 11-year-old child with variability of 43%. The covariate analysis showed that volume increases with age and clearance increases with body size. The absorption was complex, often displaying double-peak plasma concentrations, with a rapid absorption phase and a delayed and rate-limited absorption phase. The dosing scheme based on age and weight resulted in maximal concentrations (C(max)) and systemic exposure (AUC) that were comparable to those observed in adolescents and adults treated with 20 mg. The age- and weight-adjusted dosing scheme appears to an appropriate initial dosing regimen for children with migraine headache. Appropriate safety and efficacy trials will need to be completed in children prior to recommending its use in children.