PEDIATRICS recent issues

Ambient Air Pollution: Health Hazards to Children

Ambient air pollution is produced by sources including vehicular traffic, coal-fired power plants, hydraulic fracturing, agricultural production, and forest fires. It consists of primary pollutants generated by combustion and secondary pollutants formed in the atmosphere from precursor gases. Air pollution causes and exacerbates climate change, and climate change worsens health effects of air pollution. Infants and children are uniquely sensitive to air pollution, because their organs are developing and they have higher air per body weight intake. Health effects linked to air pollution include not only exacerbations of respiratory diseases but also reduced lung function development and increased asthma incidence. Additional outcomes of concern include preterm birth, low birth weight, neurodevelopmental disorders, IQ loss, pediatric cancers, and increased risks for adult chronic diseases. These effects are mediated by oxidative stress, chronic inflammation, endocrine disruption, and genetic and epigenetic mechanisms across the life span. Natural experiments demonstrate that with initiatives such as increased use of public transportation, both air quality and community health improve. Similarly, the Clean Air Act has improved air quality, although exposure inequities persist. Other effective strategies for reducing air pollution include ending reliance on coal, oil, and gas; regulating industrial emissions; reducing exposure with attention to proximity of residences, schools, and child care facilities to traffic; and a greater awareness of the Air Quality Index. This policy reviews both short- and long-term health consequences of ambient air pollution, especially in relation to developmental exposures. It examines individual, community, and legislative strategies to mitigate air pollution.

Use of Probiotics in Preterm Infants

Probiotic products in the United States are available for use in the general category of dietary supplements, bypassing the rigor of the US Food and Drug Administration (FDA) approval process in safety, efficacy, and manufacturing standards. As a result, currently available probiotics lack FDA-approved drug labeling and cannot be marketed to treat or prevent disease in preterm infants, including necrotizing enterocolitis and late-onset sepsis. Despite lack of availability of a pharmaceutical-grade product, the number of preterm infants receiving probiotics in the United States and Canada is steadily increasing. According to recent reports from large collaborative databases in the United States, approximately 10% of extremely low gestational age neonates receive a probiotic preparation during their stay in the NICU, with wide variation in practice among units. In sum, more than 10 000 preterm infants have been enrolled in randomized clinical trials of probiotic supplementation worldwide. Methodologic differences among study protocols included different strains and combinations of therapy, masking of trials, and a priori definitions of the primary outcome measure. Large meta-analyses of these trials have demonstrated the efficacy of multiple-strain probiotics in reducing necrotizing enterocolitis and all-cause mortality, whereas the efficacy of single-strain probiotic preparations is less certain. In the absence of an appropriate medical-grade product in the United States, dietary supplement–grade probiotics, some of which have been the subject of recent recalls for contamination, are being prescribed. Given the lack of FDA-regulated pharmaceutical-grade products in the United States, conflicting data on safety and efficacy, and potential for harm in a highly vulnerable population, current evidence does not support the routine, universal administration of probiotics to preterm infants, particularly those with a birth weight of <1000 g.

Collaborative Care in the Identification and Management of Psychosis in Adolescents and Young Adults

Pediatricians are often the first physicians to encounter adolescents and young adults presenting with psychotic symptoms. Although pediatricians would ideally be able to refer these patients immediately into psychiatric care, the shortage of child and adolescent psychiatry services may sometimes require pediatricians to make an initial assessment or continue care after recommendations are made by a specialist. Knowing how to identify and further evaluate these symptoms in pediatric patients and how to collaborate with and refer to specialty care is critical in helping to minimize the duration of untreated psychosis and to optimize outcomes. Because not all patients presenting with psychotic-like symptoms will convert to a psychotic disorder, pediatricians should avoid prematurely assigning a diagnosis when possible. Other contributing factors, such as co-occurring substance abuse or trauma, should also be considered. This clinical report describes psychotic and psychotic-like symptoms in the pediatric age group as well as etiology, risk factors, and recommendations for pediatricians, who may be among the first health care providers to identify youth at risk.

Improving Inpatient Consult Communication Through a Standardized Tool

OBJECTIVES:

To increase the number of essential consult elements (ECEs) included in initial inpatient consultation requests between pediatric residents and fellows through implementation of a novel consult communication tool.

METHODS:

Literature review and previous needs assessment of pediatric residents and fellows were used to identify 4 specific ECEs. From February to June 2018, fellows audited verbal consult requests at a medium-sized, quaternary care children’s hospital to determine the baseline percentage of ECE components within consults. A novel consult communication tool containing all ECEs was then developed by using a modified situation-background-assessment-recommendation (SBAR) format. The SBAR tool was implemented over 3 plan-do-study-act cycles. Adherence to SBAR, inclusion of ECEs, and consult question clarity were tracked via audits of consult requests. A pre- and postintervention survey of residents and fellows was used to examine perceived miscommunication and patient care errors and overall satisfaction.

RESULTS:

The median percentage of consults containing ≥3 ECEs increased from 50% preintervention to 100% postintervention with consult question clarity increasing from 52% to 92% (P < .001). Overall perception of consult miscommunication frequency decreased (52% vs 18%; P < .01), although there was no significant change in resident- or fellow-reported patient errors. SBAR maintained residents’ already high consult satisfaction (96% vs 92%; P = .39) and increased fellows’ consult satisfaction (51% vs 91%; P < .001).

CONCLUSIONS:

Implementation of a standardized consult communication tool resulted in increased inclusion of ECEs. Use of the tool led to greater consult question clarity, decreased perceived miscommunication, and improved overall consult satisfaction.

Increasing Volume-Targeted Ventilation Use in the NICU

BACKGROUND:

In preterm infants who require mechanical ventilation (MV), volume-targeted ventilation (VTV) modes are associated with lower rates of bronchopulmonary dysplasia compared with pressure-limited ventilation. Bronchopulmonary dysplasia rates in our NICU were higher than desired, prompting quality improvement initiatives to improve MV by increasing the use of VTV.

METHODS:

We implemented and tested interventions over a 3-year period. Primary outcomes were the percentage of conventional MV hours when any-VTV mode was used and the percentage of conventional MV hours when an exclusively VTV mode was used. Exclusively VTV modes were modes in which all breaths were volume targeted. We evaluated outcomes during 3 project periods: baseline (May 2016–December 2016); epoch 1 (December 2016–October 2018), increasing the use of any-VTV mode; and epoch 2 (October 2018–November 2019), increasing the use of exclusively VTV modes.

RESULTS:

Use of any-VTV mode increased from 18 694 of 22 387 (83%) MV hours during baseline to 72 846 of 77 264 (94%) and 58 174 of 60 605 (96%) MV hours during epochs 1 and 2, respectively (P < .001). Use of exclusively VTV increased from 5967 of 22 387 (27%) during baseline to 47 364 of 77 264 (61%) and 46 091 of 60 605 (76%) of all conventional MV hours during epochs 1 and 2, respectively (P < .001). In statistical process control analyses, multiple interventions were associated with improvements in primary outcomes. Measured clinical outcomes were unchanged.

CONCLUSIONS:

Quality improvement interventions were associated with improved use of VTV but no change in measured clinical outcomes.

Diagnostic Stewardship of Endotracheal Aspirate Cultures in a PICU

BACKGROUND:

Clinicians commonly obtain endotracheal aspirate cultures (EACs) in the evaluation of suspected ventilator-associated infections. However, bacterial growth in EACs does not distinguish bacterial colonization from infection and may lead to overtreatment with antibiotics. We describe the development and impact of a clinical decision support algorithm to standardize the use of EACs from ventilated PICU patients.

METHODS:

We monitored EAC use using a statistical process control chart. We compared the rate of EACs using Poisson regression and a quasi-experimental interrupted time series model and assessed clinical outcomes 1 year before and after introduction of the algorithm.

RESULTS:

In the preintervention year, there were 557 EACs over 5092 ventilator days; after introduction of the algorithm, there were 234 EACs over 3654 ventilator days (an incident rate of 10.9 vs 6.5 per 100 ventilator days). There was a 41% decrease in the monthly rate of EACs (incidence rate ratio [IRR]: 0.59; 95% confidence interval [CI] 0.51–0.67; P < .001). The interrupted time series model revealed a preexisting 2% decline in the monthly culture rate (IRR: 0.98; 95% CI 0.97–1.0; P = .01), immediate 44% drop (IRR: 0.56; 95% CI 0.45–0.70; P = .02), and stable rate in the postintervention year (IRR: 1.03; 95% CI 0.99–1.07; P = .09). In-hospital mortality, hospital length of stay, 7-day readmissions, and All Patients Refined Diagnosis Related Group severity and mortality scores were stable. The estimated direct cost savings was $26 000 per year.

CONCLUSIONS:

A clinical decision support algorithm standardizing EAC obtainment from ventilated PICU patients was associated with a sustained decline in the rate of EACs, without changes in mortality, readmissions, or length of stay.

Remestemcel-L Therapy for COVID-19-Associated Multisystem Inflammatory Syndrome in Children

Multisystem inflammatory syndrome in children (MIS-C) is a serious postinfectious immune dysregulation associated with coronavirus disease 2019 that may present with severe and life-threatening cardiovascular dysfunction, hemodynamic instability, shock, and multisystem organ failure. Optimal treatment is unknown. Current standard of care consists of nonspecific anti-inflammatory and antithrombotic therapies. Interventions that target MIS-C’s distinctive clinical features and immunophenotype are indicated. Remestemcel-L, an investigational mesenchymal stromal cell therapy, is a promising candidate for treatment of MIS-C because of its beneficial anti-inflammatory, immunomodulatory, endothelial function and vascular stabilizing effects, which align well with the pathophysiology of MIS-C. Here, we present the first two patients with life-threatening MIS-C ever treated with remestemcel-L under an expanded access program. Both were previously healthy children without any indication of previous coronavirus disease 2019 infection or exposure. They presented with severe clinical illness including myocardial dysfunction, hemodynamic instability, hypotension, acute kidney injury, and shock. At the time of hospital admission, both had negative polymerase chain reaction (PCR) test results and positive serology results for severe acute respiratory syndrome coronavirus 2. Both children received standard of care MIS-C treatment. Although the patients showed some clinical improvement, left ventricular ejection fraction remained reduced and inflammatory biomarkers remained significantly elevated. When treated with two intravenous doses of remestemcel-L separated by 48 hours, rapid normalization of left ventricular ejection fraction, notable reductions in biomarkers of systemic and cardiac inflammation, and improved clinical status occurred. Neither child experienced adverse effects associated with remestemcel-L administration. This treatment appears promising as a novel immunomodulatory cellular therapy for children with clinically significant cardiovascular manifestations of MIS-C.

Compassionate Use of Remdesivir in Children With Severe COVID-19

OBJECTIVES:

Remdesivir shortens time to recovery in adults with severe coronavirus disease 2019 (COVID-19), but its efficacy and safety in children are unknown. We describe outcomes in children with severe COVID-19 treated with remdesivir.

METHODS:

Seventy-seven hospitalized patients <18 years old with confirmed severe acute respiratory syndrome coronavirus 2 infection received remdesivir through a compassionate-use program between March 21 and April 22, 2020. The intended remdesivir treatment course was 10 days (200 mg on day 1 and 100 mg daily subsequently for children ≥40 kg and 5 mg/kg on day 1 and 2.5 mg/kg daily subsequently for children <40 kg, given intravenously). Clinical data through 28 days of follow-up were collected.

RESULTS:

Median age was 14 years (interquartile range 7–16, range <2 months to 17 years). Seventy-nine percent of patients had ≥1 comorbid condition. At baseline, 90% of children required supplemental oxygen and 51% required invasive ventilation. By day 28 of follow-up, 88% of patients had a decreased oxygen-support requirement, 83% recovered, and 73% were discharged. Among children requiring invasive ventilation at baseline, 90% were extubated, 80% recovered, and 67% were discharged. There were 4 deaths, of which 3 were attributed to COVID-19. Remdesivir was well tolerated, with a low incidence of serious adverse events (16%). Most adverse events were related to COVID-19 or comorbid conditions. Laboratory abnormalities, including elevations in transaminase levels, were common; 61% were grades 1 or 2.

CONCLUSIONS:

Among 77 children treated with remdesivir for severe COVID-19, most recovered and the rate of serious adverse events was low.

Prospect of Direct Benefit in Pediatric Trials: Practical Challenges and Potential Solutions

Clinical research in pediatric patients is necessary to develop safe and effective medicines for children. US Food and Drug Administration (FDA) human subject protection regulations (21 Code of Federal Regulations 50, subpart D) require that, with limited exceptions, research in children that exceeds a defined level of risk must offer a prospect of direct benefit to the individual child that is sufficient to justify those risks. Growing attention to the merits of initiating pediatric clinical trials earlier in the drug and biological product development process has led the FDA to look more closely at the meaning of the regulatory term prospect of direct benefit. In collaboration with the FDA, the Duke-Margolis Center for Health Policy convened a workshop with leading experts in the fields of biomedical ethics, pediatric clinical research, and pediatric product development, as well as patient representatives, to discuss the FDA’s approach to characterizing prospect of direct benefit in the context of scientific advances in product development. Workshop topics included the extrapolation of adult efficacy data to children, use of nonclinical models of disease, use of modeling and simulation to support pediatric dosing, and reliance on biomarkers and surrogate end points in clinical research. Discussion from the workshop is provided herein to communicate the challenges that investigators, industry sponsors, regulators, and institutional review boards face when evaluating pediatric research and to outline several approaches to maximize prospect of direct benefit, minimize unnecessary risks and burden, and facilitate timely access to safe and effective medicines for children.

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