The pediatric exclusivity program has been successful in encouraging drug studies in children. However, the dissemination of these results in the peer-reviewed literature is limited. Mechanisms to more widely disperse this information through publication warrant further evaluation.

Objective This pilot study assesses the degree of hemolysis induced by cardiopulmonary bypass (CPB) and determines its association with acute kidney injury (AKI) in pediatric patients. Further, it evaluates the degree to which the use of urinary biomarkers neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C correlate with the presence of AKI and hemolysis following CPB. Design Prospective observational study Setting A 13-bed pediatric cardiac intensive care unit in a university hospital Patients Children undergoing cardiac surgery with the use of CPB Interventions None Measurements and Main Results Blood and urine samples were obtained at multiple time points before and after CPB. Hemolysis was assessed by measuring levels of plasma hemoglobin and haptoglobin. AKI was defined as a doubling in serum creatinine from preoperative baseline and by using the pediatric-modified RIFLE criteria. Urinary NGAL and Cystatin C levels were measured. A total of 40 patients (range: 3 days to 4.8 years) were enrolled. Plasma hemoglobin levels increased markedly on separation from CPB with a concurrent decrease in haptoglobin. This was associated with an increase in protein oxidation in the plasma. Hemolysis was more evident in younger patients with a longer duration of bypass and in those requiring a blood-primed circuit. 40% of patients had a doubling in serum creatinine and 88% of patients developed acute kidney injury when defined by the pediatric-modified RIFLE criteria. Controlling for CPB time, persistently elevated levels of plasma hemoglobin were associated with a 5 fold increase in AKI. Further, urinary NGAL measured 2 hours after separation from CPB was associated with AKI and with elevations in plasma hemoglobin. Conclusions CPB in pediatric patients results in significant hemolysis, which is associated with the development of AKI. The biomarker NGAL correlates with both AKI and hemolysis in this population.

Physicians working in the world of competitive sports face unique ethical challenges, many of which center around conflicts of interest. Team-employed physicians have obligations to act in the club’s best interest while caring for the individual athlete. As such, they must balance issues like protecting versus sharing health information, as well as issues regarding autonomous informed consent versus paternalistic decision-making in determining whether an athlete may compete safely. Moreover, the physician has to deal with an athlete’s decisions about performance enhancement and return to play, pursuit of which may not be in the athlete’s long-term best interests but may benefit the athlete and team in the short term. These difficult tasks are complicated by the lack of evidence-based standards in a field influenced by the lure of financial gains for multiple parties involved. In this article, we review ethical issues in sports medicine with specific attention paid to American professional football.

Purpose We evaluated the prevalence of cardiovascular abnormalities and the efficacy and safety of enzyme replacement therapy (ERT) in patients with late onset Pompe disease. Methods Ninety patients were randomized 2:1 to ERT or placebo in a double-blind protocol. Electrocardiograms (ECG) and echocardiograms were obtained at baseline and scheduled intervals over the 78-week study period. Baseline cardiovascular abnormalities, and efficacy and safety of ERT were described. Three pediatric patients were excluded. Results Eighty-seven patients were included. Median age was 44 years; 51% were male. At baseline, a short PR interval was present in 10%, 7% had decreased left ventricular systolic function, and 5% had elevated left ventricular mass on echocardiogram (all in mild range). There was no change in cardiovascular status associated with ERT. No significant safety concerns related to ERT were identified. Conclusions Although some patients with late onset Pompe disease had abnormalities on baseline ECG or echocardiogram, those classically seen in infantile Pompe disease, such as significant ventricular hypertrophy, were not noted. Cardiovascular parameters were not impacted by ERT and there were no cardiovascular safety concerns. The cardiovascular abnormalities identified may be related to Pompe disease or other comorbid conditions.

Objective Supraventricular tachycardia (SVT) is the most common arrhythmia in infants. Infants are typically treated with antiarrhythmic medications, but there is a lack of evidence guiding management, thus exposing infants to risks of both inadequate therapy and medication adverse events. We used data from a large clinical database to better understand current practices in SVT management, safety of commonly used medications, and outcomes of hospitalized infants treated for SVT. Methods This retrospective data analysis included all infants discharged from Pediatrix Medical Group neonatal intensive care units between 1998 and 2012 with a diagnosis of SVT who were treated with antiarrhythmic medications. We categorized infants by presence of congenital heart disease other than patent ductus arteriosus. Medications were categorized as abortive, acute, or secondary prevention therapies. We used descriptive statistics to describe medication use, adverse events, and outcomes including SVT recurrence and mortality. Results A total of 2848 infants with SVT were identified, of whom 367 (13%) had congenital heart disease. Overall, SVT in-hospital recurrence was high (13%), and almost one fifth of our cohort (18%) experienced an adverse event. Mortality was 2% in the overall cohort and 6% in the congenital heart disease group (p<0.001). Adenosine was the most commonly used abortive therapy, but there was significant practice variation in therapies used for acute treatment and secondary prevention of SVT. Conclusion and Practice Implication Significant variation in SVT treatment and suboptimal outcomes warrant future clinical trials to determine best practices in treating SVT in infants.

Infants are therapeutic orphans. Many drugs used in infants are used “off-label”, increasing the risk of drug toxicity and suboptimal efficacy in this vulnerable population. This knowledge gap in clinical pharmacology is partly attributed to challenges associated with conducting clinical trials in infants. Consequently, there is a need for novel and efficient study designs more suited to this population. Available literature describing the use of minimal-risk approaches to characterize the pharmacokinetics (PK) of drugs in infants was critically reviewed. Population PK approach with sparse sampling was found to be well established. Other, more recent alternatives, like dried blood spots sampling, opportunistic design, and the use of non-blood matrices are promising strategies with an increasing number of applications in infants. Physiologically based pharmacokinetic modeling provides valuable insight in drug disposition but still needs more prospective validation. Increasing experience with these methods provides understanding of their strengths and limitations and will help improve the design of future PK studies in infants.

Abstract-Historically, drugs prescribed for children have not been studied in pediatric populations. Since 1997, however, a 6-month extension of marketing rights is granted if manufacturers conduct Food and Drug Administration-defined pediatric trials. In nearly half of the drugs studied, there were unexpected results in dosing, safety, or efficacy compared with adult studies, including failure of half of the antihypertensive dose-response trials, which are pivotal for deriving dosing recommendations. We sought to define design elements that might have contributed to these trial failures by combining patient-level data from 6 dose-ranging antihypertensive efficacy trials completed for pediatric exclusivity and submitted to the Food and Drug Administration from 1998 to 2005. We evaluated dosing, primary end point, and other components to assess underlying reasons for failure to show efficacy in children. Of 6 trials examined, 3 showed a dose response; 3 did not. Eligibility criteria were similar across studies, as were subject demographics. Successful studies showed large differences in doses, with little or no overlap between low, medium, and high doses; failed trials used narrow dose ranges with considerable overlap. Successful trials also provided pediatric formulations and used reduction in diastolic, not systolic, blood pressure as the primary end point. Careful attention to pediatric pharmacology and selection of primary end points can improve trial performance. We found poor dose selection, lack of acknowledgement of differences between adult and pediatric populations, and lack of pediatric formulations to be associated with failures. More importantly, our ability to combine data across trials allowed us to evaluate and potentially improve trial design.

Objective To characterize administration of sedatives, analgesics, and paralytics in a large cohort of mechanically ventilated, premature infants. Study design Retrospective cohort study including all infants <1500 g birth weight and <32 weeks gestational age mechanically ventilated at 348 Pediatrix Medical Group neonatal intensive care units (NICU) from 1997–2012. The primary outcome is the proportion of mechanically ventilated days in which infants were administered drugs of interest. Multivariable logistic regression was used to evaluate the predictors of administration of drugs of interest. Results We identified 85,911 mechanically ventilated infants. Infants received a drug of interest (opioids, benzodiazepines, other sedatives, and paralytics) on 433,587/1,305,413 (33%) of mechanically ventilated infant-days. The administration of opioids increased during the study period from 5% of infant-days in 1997 to 32% in 2012. The administration of benzodiazepines increased during the study period from 5% of infant-days in 1997 to 24% in 2012. Use of paralytics and other drugs remained ≤1% throughout the study period. Predictors of drug administration included younger gestational age, small for gestational age status, male sex, major congenital anomaly, older postnatal age at intubation, exposure to high frequency ventilation, exposure to inotropes, more recent year of discharge, and NICU site. Conclusion Administration of opioids and benzodiazepines in mechanically ventilated premature infants increased over time. Because infant characteristics were unchanged, site-specific differences in practice likely explain our observations. Increased administration over time is concerning given limited evidence of benefit and potential for harm.