A Master Protocol Template for Pediatric ARDS Studies.

BACKGROUND: Pediatric ARDS is associated with significant morbidity and mortality. High-quality data from clinical trials in children are limited due to numerous barriers to their design and execution. Here we describe the collaborative development of a master protocol as a tool to address some of these barriers and support the conduct of pediatric ARDS studies. METHODS: Using PubMed, we performed a literature search of randomized controlled trials (RCTs) in pediatric ARDS to characterize the current state and evaluate potential benefit of harmonized master protocols. We used a multi-stakeholder, collaborative, and team science-oriented process to develop a master protocol template with links to common data elements (CDEs) for pediatric ARDS trials. RESULTS: We identified 11 RCTs that enrolled between 14-200 total subjects per trial. Interventions included mechanical ventilation, prone positioning, corticosteroids, and surfactant. Studies displayed significant heterogeneity in ARDS definition, design, inclusion and exclusion criteria, and reported outcomes. Mortality was reported in 91% of trials and ventilator-free days in 73%. The trial heterogeneity made pooled analysis unfeasible. These findings underscore the need for a method to facilitate combined analysis of future trials through standardization of trial elements. As a potential solution, we developed a master protocol, iteratively revised with input from a multidisciplinary panel of experts and organized into 3 categories: instructions and general information, templated language, and a series of text options of common pediatric ARDS trial scenarios. Finally, we linked master protocol sections to relevant CDEs previously defined for pediatric ARDS and captured in a series of electronic case report forms. CONCLUSIONS: The majority of pediatric ARDS trials identified were small and heterogeneous in study design and outcome reporting. Using a master protocol template for pediatric ARDS trials with CDEs would support combining and comparing pediatric ARDS trial findings and increase the knowledge base.

Nonpulmonary Treatments for Pediatric Acute Respiratory Distress Syndrome: From the Second Pediatric Acute Lung Injury Consensus Conference.

OBJECTIVES: To provide an updated review of the literature on nonpulmonary treatments for pediatric acute respiratory distress syndrome (PARDS) from the Second Pediatric Acute Lung Injury Consensus Conference. DATA SOURCES: MEDLINE (Ovid), Embase (Elsevier), and CINAHL Complete (EBSCOhost). STUDY SELECTION: Searches were limited to children with PARDS or hypoxic respiratory failure focused on nonpulmonary adjunctive therapies (sedation, delirium management, neuromuscular blockade, nutrition, fluid management, transfusion, sleep management, and rehabilitation). DATA EXTRACTION: Title/abstract review, full-text review, and data extraction using a standardized data collection form. DATA SYNTHESIS: The Grading of Recommendations Assessment, Development, and Evaluation approach was used to identify and summarize evidence and develop recommendations. Twenty-five studies were identified for full-text extraction. Five clinical practice recommendations were generated, related to neuromuscular blockade, nutrition, fluid management, and transfusion. Thirteen good practice statements were generated on the use of sedation, iatrogenic withdrawal syndrome, delirium, sleep management, rehabilitation, and additional information on neuromuscular blockade and nutrition. Three research statements were generated to promote further investigation in nonpulmonary therapies for PARDS. CONCLUSIONS: These recommendations and statements about nonpulmonary treatments in PARDS are intended to promote optimization and consistency of care for patients with PARDS and identify areas of uncertainty requiring further investigation.

Changes in the Use of Invasive and Noninvasive Mechanical Ventilation in Pediatric Asthma: 2009-2019.

Rationale: Despite lower overall hospitalization rates for asthma in recent years, there has been an increase in the number of pediatric patients receiving intensive care management in the United States. Objectives: To investigate how the use of invasive and noninvasive mechanical ventilation for asthma has changed in the context of an evolving cohort of critically ill pediatric patients with asthma. Methods: We analyzed children admitted to intensive care units for asthma from 2009 through 2019 in the Virtual Pediatric Systems database. Regression analyses were used to evaluate how respiratory support interventions, mortality, and patient characteristics have changed over time. Odds ratios were calculated to determine how patient characteristics were associated with respiratory support needs. Stratified analyses were performed to determine how changing practice patterns may have differed between patient subgroups. Results: There were 67,614 admissions for 56,727 patients analyzed. Intubation occurred in 4.6% of admissions and decreased from 6.9% to 3.4% over time (P < 0.001), whereas noninvasive ventilation as the maximal respiratory support increased from 8.9% to 20.0% (P < 0.001). Over time, the cohort shifted to include more 2- to 6-year-olds and patients of Asian/Pacific Islander or Hispanic race/ethnicity. Although intubation decreased and noninvasive ventilation increased in all subgroups, the changes were most pronounced in the youngest patients and slightly less pronounced for obese patients. Conclusions: In pediatric asthma, use of intubation has halved, whereas use of noninvasive ventilation has more than doubled. This change in practice appears partially related to a younger patient cohort, although other factors merit exploration.

Evaluating the association between obesity and discharge functional status after pediatric injury.

BACKGROUND: Children with obesity frequently have functional impairment after critical illness. Although obesity increases morbidity risk after trauma, the association with functional outcomes in children is unknown. OBJECTIVE: To evaluate the association of weight with functional impairment at hospital discharge in children with serious injuries. METHODS: This secondary analysis of a multicenter prospective study included children <15 years old with a serious injury. Four weight groups, underweight, healthy weight, overweight, and obesity/severe obesity were defined by body mass index z-scores. The functional status scale (FSS) measured impairment across six functional domains before injury and at hospital discharge. New domain morbidity was defined as a change ≥2 points. The association between weight and functional impairment was determined using logistic regression adjusting for demographics, physiological measures, injury details, presence of a severe head injury, and physical abuse. RESULTS: Although most patients discharged with good/unchanged functional status, new domain morbidity occurred in 74 patients (17%). New FSS domain morbidity occurred in 13% of underweight, 14% of healthy weight, 15% of overweight, and 26% of obese/severe obese patients. Compared to healthy weight patients, those with obesity had more frequent new domain morbidity (p = 0.01), while the other weight groups had similar morbidity. However, after adjustment for confounders, weight was not associated with new functional morbidity at discharge. CONCLUSION: Patients with obesity have greater frequency of new domain morbidity after a serious injury; however, after accounting for injury characteristics, weight group is not independently associated with new functional morbidity at hospital discharge after injury in children. LEVEL OF EVIDENCE: III.

Respiratory Dysfunction Criteria in Critically Ill Children: The PODIUM Consensus Conference.

CONTEXT: Respiratory dysfunction is a component of every organ failure scoring system developed, reflecting the significance of the lung in multiple organ dysfunction syndrome. However, existing systems do not reflect current practice and are not consistently evidence based. OBJECTIVE: We aimed to review the literature to identify the components of respiratory failure associated with outcomes in children, with the purpose of developing an operational and evidence-based definition of respiratory dysfunction. DATA SOURCES: Electronic searches of PubMed and Embase were conducted from 1992 to January 2020 by using a combination of medical subject heading terms and text words to define respiratory dysfunction, critical illness, and outcomes. STUDY SELECTION: We included studies of critically ill children with respiratory dysfunction that evaluated the performance of metrics of respiratory dysfunction and their association with patient-centered outcomes. Studies in adults, studies in premature infants (≤36 weeks' gestational age), animal studies, reviews and commentaries, case series with sample sizes ≤10, and studies not published in English in which we were unable to determine eligibility criteria were excluded. DATA EXTRACTION: Data were abstracted into a standard data extraction form. RESULTS: We provided binary (no or yes) and graded (no, nonsevere, or severe) definitions of respiratory dysfunction, prioritizing oxygenation and respiratory support. The proposed criteria were approved by 82% of members in the first round, with a score of 8 of 9 (interquartile range 7-8). LIMITATIONS: Exclusion of non-English publications, heterogeneity across the pediatric age range, small sample sizes, and incomplete handling of confounders are limitations. CONCLUSIONS: We propose definitions for respiratory dysfunction in critically ill children after an exhaustive literature review.

Association of patient weight status with plasma surfactant protein D, a biomarker of alveolar epithelial injury, in children with acute respiratory failure.

AIMS AND OBJECTIVES: Alveolar epithelial injury is a key determinant of acute respiratory failure (ARF) severity. Plasma surfactant protein D (SP-D), a biomarker of alveolar epithelial injury, is lower in obese adults with ARF compared to their lean peers. We aimed to determine if children with ARF have similar variance in plasma SP-D associated with their weight status on admission. METHODS: Plasma SP-D was measured on days 0, 1, or 2 in children (1-18 years) with ARF enrolled in the genetic variation and biomarkers in children with acute lung injury and RESTORE studies. Weight classification (underweight, normal, overweight, and obese) was based on body mass index or weight-for-height z-scores. Associations between weight group and SP-D on each day were tested. RESULTS: Inclusion criteria were met in 212 subjects, 24% were obese. There were no differences among weight groups in SP-D levels on days 0 and 1. However, on day 2, there was a statistically significant linear trend for lower SP-D levels as weight increased in both the univariate analysis (P = .02) and when adjusting for age, ethnicity, and diagnosis of pediatric acute respiratory distress syndrome (P = .05). CONCLUSIONS: Obesity was associated with lower plasma SP-D levels on day 2 of ARF. This finding may be explained by altered ARF pathogenesis in obese individuals or a reduced incidence of ventilator-induced lung injury.

Design and Rationale for Common Data Elements for Clinical Research in Pediatric Critical Care Medicine.

OBJECTIVES: Common data elements are a combination of a precisely defined question paired with a specified set of responses. Common data elements contribute to the National Institutes of Health-supported principle of Findable, Accessible, Interoperable, and Reusableness of research data. Routine use of Common data elements and standardized definitions within pediatric critical care research are likely to promote collaboration, improve quality, and consistency of data collection, improve overall efficiency of study or trial setup, and facilitate cross-study comparisons, meta-analysis, and merging of study cohorts. The purpose of this Pediatric Critical Care Medicine Perspective is to establish a road map for the development of multinational, multidisciplinary consensus-based common data elements that could be adapted for use within any pediatric critical care subject area. METHODS: We describe a multistep process for the creation of "core domains" of research (e.g. patient outcomes, health-related conditions, or aspects of health) and the development of common data elements within each core domain. We define a tiered approach to data collection based on relevance of each common data element to future studies and clinical practice within the field of interest. Additionally, we describe the use of the Delphi methods to achieve consensus of these common data element documents using an international, multidisciplinary panel of experts.

Evaluation of the Association of Early Elevated Lactate With Outcomes in Children With Severe Sepsis or Septic Shock.

OBJECTIVE: The aim of the study was to assess the association of initial lactate (L0) with mortality in children with severe sepsis. METHODS: This prospective cohort study included 74 patients younger than 18 years with severe sepsis admitted to the pediatric intensive care unit (PICU) of a tertiary, academic children's hospital with lactate measured within 3 hours of meeting severe sepsis or septic shock. The primary outcome was in-hospital mortality. The secondary outcomes included PICU and hospital length of stay. RESULTS: Although overall mortality was 10.5% (n = 18), patients with L0 measured (n = 72) had a higher mortality (16% vs 6%, P = 0.03) and higher median PRISM-III risk of mortality scores (P = 0.02) than those who did not. Median L0 was no different between nonsurvivors and survivors (3.6 mmol/L [interquartile range, 2.0-9.0] in nonsurvivors vs 2.3 mmol/L [interquartile range, 1.4-3.5] in survivors, P = 0.11). However, L0 was independently associated with PRISM-III score (coefficient, 1.12; 95% confidence interval, 0.4-1.8; P = 0.003) with an increase in mean PRISM-III score of 1.12 U for every 1 mmol/L increase in L0, with L0 accounting for 12% of the variability in PRISM-III scores between patients. There was no association between L0 and PICU or hospital length of stay. CONCLUSIONS: Although our single center study did not demonstrate that an elevated early lactate is associated with mortality in pediatric severe sepsis, L0 did correlate strongly with PRISM-III, the most robust measure of mortality risk in pediatrics. Therefore, early lactate measurement may be important as an early biomarker of disease severity. These data should be validated in a larger, multicenter, prospective study.

Variability in Pediatric Ideal Body Weight Calculation: Implications for Lung-Protective Mechanical Ventilation Strategies in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: No gold standard for ideal body weight determination in children exists. We aimed to compare four methods of ideal body weight calculation and determine level of agreement between methods and impact of measurement variance on tidal volumes prescribed in mechanically ventilated pediatric acute respiratory distress syndrome. DESIGN: Post hoc analysis of four multicenter pediatric acute respiratory distress syndrome studies. SETTING: Twenty-six academic PICUs. PATIENTS: Five hundred eighty-nine patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ideal body weight was calculated by four common methods: National Center for Health Statistics, McLaren, Moore, and body mass index, and compared in three ways: 1) determine the proportion of the cohort for which each method could successfully calculate ideal body weight; 2) compare the level of agreement between the ideal body weight methods by Bland-Altman analysis; and 3) evaluate the difference in tidal volume when 6 mL/kg ideal body weight was prescribed. We a priori defined the better method to be one that could calculate ideal body weight in most subjects, had good agreement with other methods, and led to a lower tidal volume. Only 55% could have ideal body weight measured by all four methods. National Center for Health Statistics, McLaren, and Moore methods could calculate ideal body weight in greater than or equal to 90%, whereas body mass index method was successful in only 61% because of no body mass index validation in less than 2-year-olds. In comparing each method to the others, there was great variance, particularly in greater than or equal to 10-year-olds. This variance was greatest between Moore and body mass index methods with greater than or equal to 10 kg difference in ideal body weight in some subjects. The McLaren method had the best agreement with all other methods, and yielded similar prescribed tidal volume in 2- to 10-year-olds and lower tidal volume in greater than or equal to 10 years old. CONCLUSIONS: There is substantial variation in calculated ideal body weight among four commonly used methods, particularly in adolescents. Since varying ideal body weight may lead to discrepancies in pediatric acute respiratory distress syndrome care, a standard approach to ideal body weight measurement is needed. We recommend the McLaren method to calculate ideal body weight in children with pediatric acute respiratory distress syndrome until a gold standard method is validated.

Long-Term Pulmonary Function and Quality of Life in Children After Acute Respiratory Distress Syndrome: A Feasibility Investigation.

OBJECTIVES: To determine the feasibility of pulmonary function and quality of life evaluations in children after acute respiratory distress syndrome. DESIGN: A prospective follow-up feasibility study. SETTING: A tertiary PICU. PATIENTS: Children less than 18 years old with acute respiratory distress syndrome admitted between 2000 and 2005. INTERVENTION: Pulmonary function testing and patient and parental quality of life surveys approximately 12-month after acute respiratory distress syndrome. MEASUREMENTS AND MAIN RESULTS: One hundred eighty patients met acute respiratory distress syndrome criteria; 37 (20%) died, 90 (51%) declined participation, 28 (16%) consented but did not return, and 24 (13%) returned for follow-up visit. Twenty-three patients completed quality of life testing and 17 completed pulmonary functions. Clinical characteristics of those who returned were no different from those who did not except for age (median age, 4.9 vs 1.8 yr). One-third had mild to moderate pulmonary function deficits. Quality of life scores were marginal with general health perception, physical functioning, and behavior being areas of concern. These scores were lower than scores in children with chronic asthma. Parental quality of life assessments report lower scores in single-parent homes but no differences were noted by race or parental employment status. CONCLUSIONS: Valuable information may be discerned from acute respiratory distress syndrome patients who return for follow-up evaluation. In this pilot study, up to one-third of children with acute respiratory distress syndrome exhibit pulmonary function deficits and 12-month postillness quality of life scores are lower than in children with chronic asthma. Parental perceptions of postillness quality of life may be negatively impacted by socioeconomic constraints. Long-term follow of children with acute respiratory distress syndrome is feasible and bears further investigation.

Poor Adherence to Lung-Protective Mechanical Ventilation in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: To determine the frequency of low-tidal volume ventilation in pediatric acute respiratory distress syndrome and assess if any demographic or clinical factors improve low-tidal volume ventilation adherence. DESIGN: Descriptive post hoc analysis of four multicenter pediatric acute respiratory distress syndrome studies. SETTING: Twenty-six academic PICU. PATIENTS: Three hundred fifteen pediatric acute respiratory distress syndrome patients. MEASUREMENTS AND MAIN RESULTS: All patients who received conventional mechanical ventilation at hours 0 and 24 of pediatric acute respiratory distress syndrome who had data to calculate ideal body weight were included. Two cutoff points for low-tidal volume ventilation were assessed: less than or equal to 6.5 mL/kg of ideal body weight and less than or equal to 8 mL/kg of ideal body weight. Of 555 patients, we excluded 240 for other respiratory support modes or missing data. The remaining 315 patients had a median PaO2-to-FIO2 ratio of 140 (interquartile range, 90-201), and there were no differences in demographics between those who did and did not receive low-tidal volume ventilation. With tidal volume cutoff of less than or equal to 6.5 mL/kg of ideal body weight, the adherence rate was 32% at hour 0 and 33% at hour 24. A low-tidal volume ventilation cutoff of tidal volume less than or equal to 8 mL/kg of ideal body weight resulted in an adherence rate of 58% at hour 0 and 60% at hour 24. Low-tidal volume ventilation use was no different by severity of pediatric acute respiratory distress syndrome nor did adherence improve over time. At hour 0, overweight children were less likely to receive low-tidal volume ventilation less than or equal to 6.5 mL/kg ideal body weight (11% overweight vs 38% nonoverweight; p = 0.02); no difference was noted by hour 24. Furthermore, in the overweight group, using admission weight instead of ideal body weight resulted in misclassification of up to 14% of patients as receiving low-tidal volume ventilation when they actually were not. CONCLUSIONS: Low-tidal volume ventilation is underused in the first 24 hours of pediatric acute respiratory distress syndrome. Age, Pediatric Risk of Mortality-III, and pediatric acute respiratory distress syndrome severity were not associated with improved low-tidal volume ventilation adherence nor did adherence improve over time. Overweight children were less likely to receive low-tidal volume ventilation strategies in the first day of illness.

Impact of Weight Extremes on Clinical Outcomes in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: To determine whether weight extremes impact clinical outcomes in pediatric acute respiratory distress syndrome. DESIGN: Post hoc analysis of a cohort created by combining five multicenter pediatric acute respiratory distress syndrome studies. SETTING: Forty-three academic PICUs worldwide. PATIENTS: A total of 711 subjects prospectively diagnosed with pediatric acute respiratory distress syndrome. INTERVENTION: Subjects more than 2 years were included and categorized by Center for Disease Control and Prevention body mass index z score criteria: underweight (< -1.89), normal weight (-1.89 to +1.04), overweight (+1.05 to +1.64), and obese (≥ +1.65). Subjects were stratified by direct versus indirect lung injury leading to pediatric acute respiratory distress syndrome. The primary outcome was in-hospital mortality. In survivors, secondary analyses included duration of mechanical ventilation and ICU length of stay. MEASUREMENTS AND MAIN RESULTS: A total of 331 patients met inclusion criteria; 12% were underweight, 50% normal weight, 11% overweight, and 27% obese. Overall mortality was 20%. By multivariate analysis, body mass index category was independently associated with mortality (p = 0.004). When stratified by lung injury type, there was no mortality difference between body mass index groups with direct lung injury; however, in the indirect lung injury group, the odds of mortality in the obese were significantly lower than normal weight subjects (odds ratio, 0.11; 95% CI, 0.02-0.84). Survivors with direct lung injury had no difference in the duration of mechanical ventilation or ICU length of stay; however, those with indirect lung injury, the overweight required longer duration of mechanical ventilation than other groups (p < 0.001). CONCLUSIONS: These data support the obesity paradox in pediatric acute respiratory distress syndrome. Obese children with indirect lung injury pediatric acute respiratory distress syndrome have a lower risk of mortality. Importantly, among survivors, the overweight with indirect lung injury requires longer duration of mechanical ventilation. Our data require prospective validation to further elucidate the pathobiology of this phenomenon.