Infant feeding and criticality in children.

BACKGROUND: Data support the protective effects of human breast milk (HBM) feeding in acute illness but little is known about the impact of HBM feeding on the criticality of infants. AIM: To explore the relationship between early HBM feeding and severity of illness and recovery in critically ill children requiring intubation and mechanical ventilation for acute respiratory failure (ARF). STUDY DESIGN: Prospective cohort study of mothers of patients aged 1-36 months who participated in the acute and follow-up phases of the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial. Participants completed a survey describing HBM dose fed during their infant's first month of life. RESULTS: Of 138 patients, 70 (51%) received exclusive HBM feedings (90%-100% total feeds) and 68 (49%) did not. We found no group differences in severity of illness on paediatric intensive care unit (PICU) admission or severity of paediatric acute respiratory distress syndrome (PARDS) within the first 24-48 h of intubation/mechanical ventilation (Pediatric Risk of Mortality [PRISM] III-12 score median: 5 vs. 5, p = .88; moderate/severe PARDS: 53% vs. 54%, p = .63). While median time to recovery from ARF was reduced by 1 day in patients who received exclusive HBM feedings, the difference between groups was not statistically significant (median 1.5 vs. 2.6 days, hazard ratio 1.40 [95% confidence interval, 0.99-1.97], p = .06). CONCLUSIONS: Human breast milk dose was not associated with severity of illness on PICU admission in children requiring mechanical ventilation for ARF. RELEVANCE TO CLINICAL PRACTICE: Data support the protective effects of HBM during acute illness and data from this study support a clinically important reduction in time to recovery of ARF. Paediatric nurses should continue to champion HBM feeding to advance improvements in infant health.

Protocol for the Prone and Oscillation Pediatric Clinical Trial (PROSpect).

OBJECTIVES: Respiratory management for pediatric acute respiratory distress syndrome (PARDS) remains largely supportive without data to support one approach over another, including supine versus prone positioning (PP) and conventional mechanical ventilation (CMV) versus high-frequency oscillatory ventilation (HFOV). DESIGN: We present the research methodology of a global, multicenter, two-by-two factorial, response-adaptive, randomized controlled trial of supine versus PP and CMV versus HFOV in high moderate-severe PARDS, the Prone and Oscillation Pediatric Clinical Trial (PROSpect, www.ClinicalTrials.gov, NCT03896763). SETTING: Approximately 60 PICUs with on-site extracorporeal membrane oxygenation support in North and South America, Europe, Asia, and Oceania with experience using PP and HFOV in the care of patients with PARDS. PATIENTS: Eligible pediatric patients (2 wk old or older and younger than 21 yr) are randomized within 48 h of meeting eligibility criteria occurring within 96 h of endotracheal intubation. INTERVENTIONS: One of four arms, including supine/CMV, prone/CMV, supine/HFOV, or prone/HFOV. We hypothesize that children with high moderate-severe PARDS treated with PP or HFOV will demonstrate greater than or equal to 2 additional ventilator-free days (VFD). MEASUREMENTS AND MAIN RESULTS: The primary outcome is VFD through day 28; nonsurvivors receive zero VFD. Secondary and exploratory outcomes include nonpulmonary organ failure-free days, interaction effects of PP with HFOV on VFD, 90-day in-hospital mortality, and among survivors, duration of mechanical ventilation, PICU and hospital length of stay, and post-PICU functional status and health-related quality of life. Up to 600 patients will be randomized, stratified by age group and direct/indirect lung injury. Adaptive randomization will first occur 28 days after 300 patients are randomized and every 100 patients thereafter. At these randomization updates, new allocation probabilities will be computed based on intention-to-treat trial results, increasing allocation to well-performing arms and decreasing allocation to poorly performing arms. Data will be analyzed per intention-to-treat for the primary analyses and per-protocol for primary, secondary, and exploratory analyses. CONCLUSIONS: PROSpect will provide clinicians with data to inform the practice of PP and HFOV in PARDS.

Design and rationale of the Post-Intensive Care Syndrome - paediatrics (PICS-p) Longitudinal Cohort Study.

INTRODUCTION: As paediatric intensive care unit (PICU) mortality declines, there is growing recognition of the morbidity experienced by children surviving critical illness and their families. A comprehensive understanding of the adverse physical, cognitive, emotional and social sequelae common to PICU survivors is limited, however, and the trajectory of recovery and risk factors for morbidity remain unknown. METHODS AND ANALYSIS: The Post-Intensive Care Syndrome - paediatrics Longitudinal Cohort Study will evaluate child and family outcomes over 2 years following PICU discharge and identify child and clinical factors associated with impaired outcomes. We will enrol 750 children from 30 US PICUs during their first PICU hospitalisation, including 500 case participants experiencing ≥3 days of intensive care that include critical care therapies (eg, mechanical ventilation, vasoactive infusions) and 250 age-matched, sex-matched and medical complexity-matched control participants experiencing a single night in the PICU with no intensive care therapies. Children, parents and siblings will complete surveys about health-related quality of life, physical function, cognitive status, emotional health and peer and family relationships at multiple time points from baseline recall through 2 years post-PICU discharge. We will compare outcomes and recovery trajectories of case participants to control participants, identify risk factors associated with poor outcomes and determine the emotional and social health consequences of paediatric critical illness on parents and siblings. ETHICS AND DISSEMINATION: This study has received ethical approval from the University of Pennsylvania Institutional Review Board (protocol #843844). Our overall objective is to characterise the ongoing impact of paediatric critical illness to guide development of interventions that optimise outcomes among children surviving critical illness and their families. Findings will be presented at key disciplinary meetings and in peer-reviewed publications at fixed data points. Published manuscripts will be added to our public study website to ensure findings are available to families, clinicians and researchers. TRIALS REGISTRATION NUMBER: NCT04967365.

Whole blood transcriptomics identifies subclasses of pediatric septic shock.

BACKGROUND: Sepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles. METHODS: The subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses. RESULTS: Patients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells and less diverse T cell receptor repertoires. CONCLUSIONS: Two subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences. Trial Registration This is a secondary analysis of data generated as part of the observational CAF-PINT ancillary of the HALF-PINT study (NCT01565941). Registered March 29, 2012.

Whole Blood Transcriptomics Identifies Subclasses of Pediatric Septic Shock.

Background: Sepsis is a highly heterogeneous syndrome, that has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles. Methods: The subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA-sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses. Results: Patients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells, and less diverse T-Cell receptor repertoires. Conclusions: Two subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences. Trial Registration: This is a secondary analysis of data generated as part of the observational CAF PINT ancillary of the HALF PINT study (NCT01565941). Registered 29 March 2012.

Risk Factors for Positive Post-Traumatic Stress Disorder Screening and Associated Outcomes in Children Surviving Acute Respiratory Failure: A Secondary Analysis of the Randomized Evaluation of Sedation Titration for Respiratory Failure Clinical Trial.

OBJECTIVES: To identify risk factors and outcomes associated with a positive post-traumatic stress disorder (PTSD) screen following pediatric acute respiratory failure treated with invasive mechanical ventilation. DESIGN: Nonprespecified secondary analysis of a randomized clinical trial. SETTING: Thirty-one U.S. PICUs. PATIENTS: Children in the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) trial (NCT00814099, ClinicalTrials.gov ) over 8 years old who completed PTSD screening 6 months after discharge. INTERVENTIONS: RESTORE sites were randomized to a targeted, nurse-directed sedation strategy versus usual care. MEASUREMENTS AND MAIN RESULTS: PTSD screening was completed by 102 subjects using the Child Post-Traumatic Stress Disorder Symptom Scale; a score of greater than or equal to 11 was considered screening positive for PTSD. Cognitive status was categorized using Pediatric Cerebral Performance Category; health-related quality of life (HRQL) was evaluated using child-reported Pediatric Quality of Life Inventory, Version 4.0. Thirty-one children (30%) screened positive for PTSD. Children with a positive screen endorsed symptoms in all categories: reexperiencing, avoidance, and hyperarousal. Most endorsed that symptoms interfered with schoolwork ( n = 18, 58%) and happiness ( n = 17, 55%). Screening positive was not associated with RESTORE treatment group. In a multivariable logistic model adjusting for age, sex, and treatment group, screening positive was independently associated with lower median income in the family's residential zip code (compared with income ≥ $80,000; income < $40,000 odds ratio [OR], 32.8; 95% CI, 2.3-458.1 and $40,000-$79,999 OR, 15.6; 95% CI, 1.3-182.8), renal dysfunction (OR 5.3, 95% CI 1.7-16.7), and clinically significant pain in the PICU (OR, 8.3; 95% CI, 1.9-35.7). Children with a positive screen experienced decline in cognitive function and impaired HRQL more frequently than children with a negative screen. CONCLUSIONS: Screening positive for PTSD is common among children following acute respiratory failure and is associated with lower HRQL and decline in cognitive function. Routine PTSD screening may be warranted to optimize recovery.

Impact of tight glycemic control and hypoglycemia after pediatric cardiac surgery on neurodevelopmental outcomes at three years of age: Findings from a randomized clinical trial.

BACKGROUND: Studies examining the impact of randomization As per standard instruction, city is required for affiliations; however, this information is missing in affiliation 6. Please check if the provided city is correct and amend if necessary. to tight glycemic control (TGC) and resultant hypoglycemia on later neurodevelopmental outcomes have produced mixed results. Our study examined this association in children undergoing cardiac surgery. METHODS: Participants who were enrolled in the Safe Pediatric Euglycemia after Cardiac Surgery (SPECS) trial returned for neurodevelopmental (ND) follow-up between 30 to 42.5 months of age. ND outcomes were assessed using the Bayley Scales of Infant and Toddler Development, Third Edition. ND scores were compared between the TGC and standard care treatment groups and between patients with moderate to severe and no to mild hypoglycemia. As a secondary analysis, to increase sample size and power, we combined the three-year-old assessments with previously collected assessments done at < 30 months of age to further examine differences between groups longitudinally. RESULTS: Among the 269 participants who completed neurodevelopmental evaluation (in-person testing or questionnaires) at three years of age (follow-up rate, 31%), there were no statistically significant differences in ND outcomes according to treatment group or hypoglycemia status. In the combined analysis of all evaluations (from 9 to 42.5 months of age), we found no treatment group differences. However, in these longitudinal analyses, children who experienced moderate to severe hypoglycemia had lower scores on the Bayley-III cognitive and motor domains compared to children with no to mild hypoglycemia. CONCLUSIONS: For infants undergoing cardiac surgery, there was no impact of tight glycemic control on neurodevelopmental outcomes. Moderate to severe hypoglycemia was associated with worse ND outcomes in longitudinal analyses. TRIAL REGISTRATION: ClinicalTrials.gov NCT00443599. Registered: November 2016.

Nursing Care at End of Life in Pediatric Intensive Care Unit Patients Requiring Mechanical Ventilation.

BACKGROUND: Parents' perceptions of critical care during the final days of their child's life shape their grief for decades. Little is known about nursing care needs of children actively dying in the pediatric intensive care unit (PICU). OBJECTIVES: To examine associations between patient characteristics, circumstances of death, and nursing care requirements for children who died in the PICU. METHODS: A secondary analysis of the data set from the Randomized Evaluation of Sedation Titration for Respiratory Failure trial was conducted. RESULTS: This analysis included 104 children; 67 died after withdrawal of life-sustaining treatments; 21, after failed resuscitation; and 16, after brain death. Patients had a median age of 7.5 years, were cognitively appropriate, and were intubated for acute respiratory failure. Daily pain and sedation scores indicated patients' comfort was well managed (mean pain scores: modal, 0; peak, 2; mean sedation scores: modal, -2; peak, -1). Patients with longer PICU stays more often experienced pain and agitation on the day of death. Illness trajectory (acute, complex chronic condition, or cancer) was associated with pain scores (P = .04). Specifically, children with cancer had higher pain scores than children with acute illness trajectories (P = .01). Many patients (62%) had no change in critical care devices in their last days of life (median, 5 devices). Patterns of pain, sedation, comfort medications, and nursing care requirements did not differ by circumstances of death. CONCLUSION: Children with cancer and longer PICU stays may need comprehensive comfort management. Invasive devices left in place during withdrawal of life support may have inhibited parents' ability to connect with their child. Future research should incorporate parents' perspectives.

Association of Acute Respiratory Failure in Early Childhood With Long-term Neurocognitive Outcomes.

Importance: Approximately 23 700 US children undergo invasive mechanical ventilation for acute respiratory failure annually, with unknown long-term effects on neurocognitive function. Objective: To evaluate neurocognitive outcomes of children who survive pediatric intensive care unit (PICU) hospitalization for acute respiratory failure compared with their biological siblings. Design, Setting, and Participants: Prospective sibling-matched cohort study conducted at 31 US PICUs and associated neuropsychology testing centers. Patients were 8 years or younger with a Pediatric Cerebral Performance Category score of 1 (normal) before PICU admission and less than or equal to 3 (no worse than moderate neurocognitive dysfunction) at PICU discharge, excluding patients with a history of neurocognitive deficits or who were readmitted and underwent mechanical ventilation. Biological siblings were aged 4 to 16 years at testing, with Pediatric Cerebral Performance Category score of 1 and no history of mechanical ventilation or general anesthesia. A total of 121 sibling pairs were enrolled from September 2, 2014, to December 13, 2017, and underwent neurocognitive testing starting March 14, 2015. The date of the final follow-up was November 6, 2018. Exposures: Critical illness and PICU treatment for acute respiratory failure. Main Outcomes and Measures: The primary outcome was IQ, estimated by the age-appropriate Vocabulary and Block Design subtests of the Wechsler Intelligence Scale. Secondary outcomes included measures of attention, processing speed, learning and memory, visuospatial skills, motor skills, language, and executive function. Evaluations occurred 3 to 8 years after hospital discharge. Results: Patients (n = 121; 55 [45%] female patients) underwent PICU care at a median (IQR) age of 1.0 (0.2-3.2) years, received a median (IQR) of 5.5 (3.1-7.7) days of invasive mechanical ventilation, and were tested at a median (IQR) age of 6.6 (5.4-9.1) years. Matched siblings (n = 121; 72 [60%] female siblings) were tested at a median (IQR) age of 8.4 (7.0-10.2) years. Patients had a lower mean estimated IQ than matched siblings (101.5 vs 104.3; mean difference, -2.8 [95% CI, -5.4 to -0.2]). Among secondary outcomes, patients had significantly lower scores than matched siblings on nonverbal memory (mean difference, -0.9 [95% CI, -1.6 to -0.3]), visuospatial skills (mean difference, -0.9 [95% CI, -1.8 to -0.1]), and fine motor control (mean difference, -3.1 [95% CI, -4.9 to -1.4]) and significantly higher scores on processing speed (mean difference, 4.4 [95% CI, 0.2-8.5]). There were no significant differences in the remaining secondary outcomes, including attention, verbal memory, expressive language, and executive function. Conclusions and Relevance: Among children, survival of PICU hospitalization for respiratory failure and discharge without severe cognitive dysfunction was associated with significantly lower subsequent IQ scores compared with matched siblings. However, the magnitude of the difference was small and of uncertain clinical importance.

Early Neuromuscular Blockade in Moderate-to-Severe Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: The use of neuromuscular blocking agents (NMBAs) in pediatric acute respiratory distress syndrome (PARDS) is common but unsupported by efficacy data. We sought to compare the outcomes between patients with moderate-to-severe PARDS receiving continuous NMBA during the first 48 hours of endotracheal intubation (early NMBA) and those without. DESIGN: Secondary analysis of data from the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) clinical trial, a pediatric multicenter cluster randomized trial of sedation. SETTING: Thirty-one PICUs in the United States. PATIENTS: Children 2 weeks to 17 years receiving invasive mechanical ventilation (MV) for moderate-to-severe PARDS (i.e., oxygenation index ≥ 8 and bilateral infiltrates on chest radiograph on days 0-1 of endotracheal intubation). INTERVENTIONS: NMBA for the entire duration of days 1 and 2 after intubation. MEASUREMENTS AND MAIN RESULTS: Among 1,182 RESTORE patients with moderate-to-severe PARDS, 196 (17%) received early NMBA for a median of 50.0% ventilator days (interquartile range, 33.3-60.7%). The propensity score model predicting the probability of receiving early NMBA included high-frequency oscillatory ventilation on days 0-2 (odds ratio [OR], 7.61; 95% CI, 4.75-12.21) and severe PARDS on days 0-1 (OR, 2.16; 95% CI, 1.50-3.12). After adjusting for risk category, early use of NMBA was associated with a longer duration of MV (hazard ratio, 0.57; 95% CI, 0.48-0.68; p < 0.0001), but not with mortality (OR, 1.62; 95% CI, 0.92-2.85; p = 0.096) compared with no early use of NMBA. Other outcomes including cognitive, functional, and physical impairment at 6 months post-PICU discharge were similar. Outcomes did not differ when comparing high versus low NMBA usage sites or when patients were stratified by baseline Pao2/Fio2 less than 150. CONCLUSIONS: Early NMBA use was associated with a longer duration of MV. This propensity score analysis underscores the need for a randomized controlled trial in pediatrics.

School and Work Absences After Critical Care Hospitalization for Pediatric Acute Respiratory Failure: A Secondary Analysis of a Cluster Randomized Trial.

Importance: Patients who survive pediatric critical illness and their caregivers commonly experience physical, emotional, and cognitive sequelae. However, the rate and duration of school absence among patients and work absence among their caregivers are unknown. Objective: To determine the rates and duration of school absence among children who survived hospitalization with acute respiratory failure and work absence among their caregivers. Design, Setting, and Participants: The Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) cluster randomized trial included 2449 children from 31 sites to protocolized sedation (intervention) vs usual care (control) from June 6, 2009, to December 2, 2013. In total, 1360 children survived hospitalization and were selected for follow-up at 6 months after pediatric intensive care unit (PICU) discharge, which was completed from January 12, 2010, to April 13, 2015. This secondary analysis was conducted from July 1, 2020, to September 30, 2021. Exposures: PICU hospitalization for acute respiratory failure, including invasive mechanical ventilation. Main Outcomes and Measures: Postdischarge assessments with caregivers of eligible participants at 6 months after PICU discharge, including questions about school and work absence. Risk factors associated with longer absence from school and work were identified. Results: Postdischarge assessments were completed for 960 children who survived treatment for acute respiratory failure, of whom 443 (46.1%) were girls and 517 (53.9%) were boys; 509 of 957 (53.2%) were non-Hispanic White. Median age was 1.8 years (IQR, 0.4-7.9 years). In total, 399 children (41.6%) were enrolled in school, of whom 279 (69.9%) missed school after discharge. Median duration of postdischarge absence was 9.1 days (IQR, 0-27.9 days) among all children enrolled in school and 16.9 days (IQR, 7.9-43.9 days) among the 279 children with postdischarge absence. Among 960 primary caregivers, 506 (52.7%) were employed outside the home, of whom 277 (54.7%) missed work. Median duration of postdischarge work absence was 2 days (IQR, 0-10 days) among all employed primary caregivers, and 8 days (IQR, 4-20 days) among the 277 caregivers who missed work after discharge. The odds of postdischarge school absence and greater duration of absence increased for children 5 years or older (compared with 0-4 years, odds ratios [ORs] for 5-8 years, 3.20 [95% CI, 1.69-6.05] and 2.09 [95% CI, 1.30-3.37], respectively; ORs for 9-12 years, 2.49 [95% CI, 1.17-5.27] and 2.32 [95% CI, 1.30-4.14], respectively; and ORs for 13-18 years, 2.37 [95% CI, 1.20-4.66] and 1.89 [95% CI, 1.11-3.24], respectively) and those with a preexisting comorbidity (ORs, 1.90 [95% CI, 1.10-3.29] and 1.76 [95% CI, 1.14-2.69], respectively). Conclusions and Relevance: In this secondary analysis of a cluster randomized trial, 2 in 3 children hospitalized for acute respiratory failure missed school after discharge, for a median duration of nearly 2 weeks. In addition, more than half of primary caregivers missed work after discharge. The magnitude of school absenteeism suggests that children may be at increased risk for lower educational achievement, economic hardship, and poor health outcomes in adulthood.

Study protocol for a two-center test of a nurse-implemented chronotherapeutic restoring bundle in critically ill children: RESTORE Resilience (R2).

Often, pediatric intensive care environments are not conducive to healing the sick. Critically ill children experience disruptions in their circadian rhythms, which can contribute to delayed recovery and poor outcomes. We aim to test the hypothesis that children managed via RESTORE Resilience (R2), a nurse-implemented chronotherapeutic bundle, will experience restorative circadian rhythms compared to children receiving usual care. In this two-phased, prospective cohort study, two separate pediatric intensive care units in the United Sates will enroll a total of 20 baseline subjects followed by 40 intervention subjects, 6 months to less than 18 years of age, requiring invasive mechanical ventilation. During the intervention phase, we will implement the R2 bundle, which includes: (1) a focused effort to replicate the child's pre-hospitalization daily routine, (2) cycled day-night lighting and sound modulation, (3) minimal yet effective sedation (RESTORE), (4) nighttime fasting with bolus enteral daytime feedings, (5) early progressive mobility (PICU Up!), (6) continuity in nursing care, and (7) parent diaries. Our primary outcome is circadian activity ratio post-extubation. We hypothesize that children receiving R2 will experience restored circadian rhythms as evidenced by decreased nighttime activity while in the PICU. Our exploratory outcomes include salivary melatonin levels; electroencephalogram (EEG) slow-wave activity; R2 feasibility, adherence, and system barriers; levels of patient comfort; exposure to sedative medications; time to physiological stability; and parent perception of being well cared for. This paper describes the design, rationale, and implementation of R2. CLINICALTRIALSGOV IDENTIFIER: NCT04695392.

Performance of an Electronic Decision Support System as a Therapeutic Intervention During a Multicenter PICU Clinical Trial: Heart and Lung Failure-Pediatric Insulin Titration Trial (HALF-PINT).

BACKGROUND: The use of electronic clinical decision support (CDS) systems for pediatric critical care trials is rare. We sought to describe in detail the use of a CDS tool (Children's Hospital Euglycemia for Kids Spreadsheet [CHECKS]), for the management of hyperglycemia during the 32 multicenter Heart And Lung Failure-Pediatric Insulin Titration trial. RESEARCH QUESTION: In critically ill pediatric patients who were treated with CHECKS, how was user compliance associated with outcomes; and what patient and clinician factors might account for the observed differences in CHECKS compliance? STUDY DESIGN AND METHODS: During an observational retrospective study of compliance with a CDS tool used during a prospective randomized controlled trial, we compared patients with high and low CHECKS compliance. We investigated the association between compliance and blood glucose metrics. We describe CHECKS and use a computer interface analysis framework (the user, function, representation, and task analysis framework) to categorize user interactions. We discuss implications for future randomized controlled trials. RESULTS: Over a 4.5-year period, 658 of 698 children were treated with the CHECKS protocol for ≥24 hours with a median of 119 recommendations per patient. Compliance per patient was high (median, 99.5%), with only 30 patients having low compliance (<90%). Patients with low compliance were from 16 of 32 sites, younger (P = .02), and less likely to be on inotropic support (P = .04). They were more likely to be have been assigned randomly to the lower blood glucose target (80% vs 48%; P < .001) and to have spent a shorter time (53% vs 75%; P < .001) at the blood glucose target. Overrides (classified by the user, function, representation, and task analysis framework), were largely (89%) due to the user with patient factors contributing 29% of the time. INTERPRETATION: The use of CHECKS for the Heart And Lung Failure-Pediatric Insulin Titration trial resulted in a highly reproducible and explicit method for the management of hyperglycemia in critically ill children across varied environments. CDS systems represent an important mechanism for conducting explicit complex pediatric critical care trials. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01565941, registered March 29 2012; https://clinicaltrials.gov/ct2/show/NCT01565941?term=HALF-PINT&draw=2&rank=1.

The Impact of Preintubation Noninvasive Ventilation on Outcomes in Pediatric Acute Respiratory Distress Syndrome.

OBJECTIVES: There is evidence that noninvasive ventilation decreases the need for invasive mechanical ventilation. However, children with pediatric acute respiratory distress syndrome who fail noninvasive ventilation may have worse outcomes than those who are intubated without exposure to noninvasive ventilation. Our objective was to evaluate the impact of preintubation noninvasive ventilation on children with pediatric acute respiratory distress syndrome. DESIGN: Secondary analysis of data from the Randomized Evaluation of Sedation Titration for Respiratory Failure trial. SETTING: Thirty-one PICUs in the United States. PATIENTS: Children 2 weeks to 17 years old with pediatric acute respiratory distress syndrome receiving invasive mechanical ventilation, excluding those admitted with tracheostomies. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 2,427 subjects receiving invasive mechanical ventilation, preintubation noninvasive ventilation was used in 995 (41%). Compared with subjects without preintubation noninvasive ventilation use, subjects with preintubation noninvasive ventilation use were more likely to have a history of seizures (10% vs 8%; p = 0.04) or cancer (11% vs 6%; p < 0.001) and have moderate or severe pediatric acute respiratory distress syndrome by the end of their first full day of invasive mechanical ventilation (68% vs 60%; p < 0.001). Adjusting for age, severity of illness on PICU admission, and baseline functional status, preintubation noninvasive ventilation use resulted in longer invasive mechanical ventilation duration (median 7.0 vs 6.0 d), longer PICU (10.8 vs 8.9 d), and hospital (17 vs 14 d) lengths of stay, and higher 28-day (5% vs 4%) and 90-day (8% vs 5%) inhospital mortalities (all comparisons p < 0.001). Longer duration of noninvasive ventilation before intubation was associated with worse outcomes. CONCLUSIONS: In children with pediatric acute respiratory distress syndrome, preintubation noninvasive ventilation use is associated with worse outcomes when compared with no preintubation noninvasive ventilation use. These data can be used to inform the design of clinical studies to evaluate best noninvasive ventilation practices in children with pediatric acute respiratory distress syndrome.

Association of Race and Ethnicity with Sedation Management in Pediatric Intensive Care.

Rationale: Racial disparities in pain management have been previously reported for children receiving emergency care.Objectives: To determine whether patient race or ethnicity is associated with the broader goal of pain management and sedation among pediatric patients mechanically ventilated for acute respiratory failure.Methods: Planned secondary analysis of RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure). RESTORE, a cluster-randomized clinical trial conducted in 31 U.S. pediatric intensive care units, compared protocolized sedation management (intervention arm) with usual care (control arm). Participants included 2,271 children identified as non-Hispanic white (white, n = 1,233), non-Hispanic Black (Black, n = 502), or Hispanic of any race (Hispanic, n = 536).Results: Within each treatment arm, neither opioid nor benzodiazepine selection, nor cumulative dosing, differed significantly among race and ethnicity groups. Black patients experienced fewer days with an episode of pain (compared with white patients in the control arm and with Hispanic patients in the intervention arm) and experienced less iatrogenic withdrawal syndrome (compared with white patients in either arm or with Hispanic patients in the intervention arm). The percentage of days awake and calm while intubated was not significantly different in pairwise comparisons by race and ethnicity groups in either the control arm (median: white, 75%; Black, 71%; Hispanic, 75%) or the intervention arm (white, 86%; Black, 88%; Hispanic, 85%).Conclusions: Across multiple measures, our study found scattered differences in sedation management among critically ill Black, Hispanic, and white children that did not consistently favor any group. However, racial disparities related to implicit bias cannot be completely ruled out.Clinical trial registered with clinicaltrials.gov (NCT00814099).

Timing of Antibiotic Administration in Pediatric Sepsis.

OBJECTIVES: Antibiotic administration within 1 hour of hypotension has been shown to reduce mortality. It is unknown whether antibiotics before hypotension in children who eventually meet criteria for septic shock improves outcomes. This study assesses whether antibiotic timing from the time of meeting criteria for sepsis in children with septic shock impacts morbidity and mortality. METHODS: This is a retrospective study of children 18 years or younger presenting to a tertiary free-standing children's hospital emergency department with sepsis that subsequently progressed to septic shock and were admitted to an intensive care unit from 2008 to 2012. The time when the patient met criteria for sepsis to the time of first antibiotic administration was assessed and correlated with patient morbidity and mortality. RESULTS: Among 135 children (median age, 13.1 years), 34 (25%) were previously healthy, whereas 49 (36%) had 2 or more medical comorbidities. Twenty-seven children (20%) had positive blood cultures, 17 (13%) had positive urine cultures, and 34 (25%) had chest x-ray findings that were interpreted as pneumonia. Among the 42 (31%) with antibiotics within 1 hour from criteria for sepsis, there was higher mortality (4/42 vs 0/93, P = 0.009), more organ dysfunction, longer time on a vasoactive infusion, and increased intensive care unit and hospital lengths of stay (all P < 0.05). CONCLUSIONS: Children with criteria for sepsis who subsequently progressed to septic shock who received antibiotics within 1 hour of meeting sepsis criteria had increased mortality, length of stay, and organ dysfunction.

Outcomes Associated With Multiple Organ Dysfunction Syndrome in Critically Ill Children With Hyperglycemia.

OBJECTIVES: Patterns and outcomes of multiple organ dysfunction syndrome are unknown in critically ill children with hyperglycemia. We aimed to determine whether tight glycemic control to a lower vs. higher range influenced timing, duration, or resolution of multiple organ dysfunction syndrome as well as characterize the clinical outcomes of subgroups of multiple organ dysfunction syndrome in children enrolled in the Heart And Lung Failure-Pediatric INsulin Titration trial. DESIGN: Planned secondary analysis of the multicenter Heart And Lung Failure-Pediatric INsulin Titration trial. SETTING: Thirty-five PICUs. PATIENTS: Critically ill children with hyperglycemia who received the Heart And Lung Failure-Pediatric INsulin Titration protocol from 2012 to 2016. INTERVENTIONS: Randomization to a lower versus higher glucose target group. MEASUREMENTS AND MAIN RESULTS: Of 698 patients analyzed, 48 (7%) never developed multiple organ dysfunction syndrome, 549 (79%) had multiple organ dysfunction syndrome without progression, 32 (5%) developed new multiple organ dysfunction syndrome, and 69 (10%) developed progressive multiple organ dysfunction syndrome. Of those whose multiple organ dysfunction syndrome resolved, 192 (34%) experienced recurrent multiple organ dysfunction syndrome. There were no significant differences in the proportion of multiple organ dysfunction syndrome subgroups between Heart And Lung Failure-Pediatric INsulin Titration glucose target groups. However, patients with new or progressive multiple organ dys function syndrome had fewer ICU-free days through day 28 than those without new or progressive multiple organ dysfunction syndrome, and progressive multiple organ dysfunction syndrome patients had fewer ICU-free days than those with new multiple organ dysfunction syndrome: median 25.1 days for never multiple organ dysfunction syndrome, 20.2 days for multiple organ dysfunction syndrome without progression, 18.6 days for new multiple organ dysfunction syndrome, and 0 days for progressive multiple organ dysfunction syndrome (all comparisons p < 0.001). Patients with recurrent multiple organ dysfunction syndrome experienced fewer ICU-free days than those without recurrence (median, 11.2 vs 22.8 d; p < 0.001). CONCLUSIONS: Tight glycemic control target range was not associated with differences in the proportion of new, progressive, or recurrent multiple organ dysfunction syndrome. New or progressive multiple organ dysfunction syndrome was associated with poor clinical outcomes, and progressive multiple organ dysfunction syndrome was associated with worse outcomes than new multiple organ dysfunction syndrome. In future studies, new multiple organ dysfunction syndrome and progressive multiple organ dysfunction syndrome may need to be considered separately, as they represent distinct subgroups with different, potentially modifiable risk factors. Patients with recurrent multiple organ dysfunction syndrome represent a newly characterized, high-risk group which warrants attention in future research.

Risk Factors for Functional Decline and Impaired Quality of Life after Pediatric Respiratory Failure.

Rationale: Poor outcomes of adults surviving critical illness are well documented, but data in children are limited.Objectives: To identify factors associated with worse postdischarge function and health-related quality of life (HRQL) after pediatric acute respiratory failure.Methods: We assessed functional status at baseline, discharge, and 6 months after pediatric ICU discharge and HRQL 6 months after discharge in 2-week- to 17-year-olds mechanically ventilated for acute respiratory failure in the RESTORE (Randomized Evaluation of Sedation Titration for Respiratory Failure) trial. We assessed HRQL via Infant and Toddler Quality of Life Questionnaire-97 (<2 yr old) or Pediatric Quality of Life Inventory (≥2 yr old). We categorized patients with normal baseline function as having impaired HRQL if scores were greater than 1 SD below mean norms for Infant and Toddler Quality of Life Questionnaire-97 growth and development or Pediatric Quality of Life Inventory total score.Measurements and Main Results: One-fifth (n = 192) of 949 patients declined in function from baseline to postdischarge; 20% (55/271) had impaired growth and development; 19% (64/343) had impaired HRQL. In multivariable analyses, decline in function was associated with baseline impaired function, prematurity, cancer, respiratory failure etiology, ventilation duration, and clonidine (odds ratio [OR] = 2.14; 95% confidence interval [CI] = 1.22-3.76). Independent predictors of impaired growth and development included methadone (OR = 2.27; 95% CI = 1.18-4.36) and inadequate pain management (OR = 2.94; 95% CI = 1.39-6.19). Impaired HRQL was associated with older age, non-white or Hispanic race, cancer, and inadequate sedation management (OR = 3.15; 95% CI = 1.74-5.72).Conclusions: Postdischarge morbidity after respiratory failure is common and associated with admission factors, exposure to critical care therapies, and pain and sedation management.

Short-Term Adverse Outcomes Associated With Hypoglycemia in Critically Ill Children.

OBJECTIVES: Previous studies report worse short-term outcomes with hypoglycemia in critically ill children. These studies relied on intermittent blood glucose measurements, which may have introduced detection bias. We analyzed data from the Heart And Lung Failure-Pediatric INsulin Titration trial to determine the association of hypoglycemia with adverse short-term outcomes in critically ill children. DESIGN: Nested case-control study. SETTING: Thirty-five PICUs. A computerized algorithm that guided the timing of blood glucose measurements and titration of insulin infusion, continuous glucose monitors, and standardized glucose infusion rates were used to minimize hypoglycemia. PATIENTS: Nondiabetic children with cardiovascular and/or respiratory failure and hyperglycemia. Cases were children with any hypoglycemia (blood glucose < 60 mg/dL), whereas controls were children without hypoglycemia. Each case was matched with up to four unique controls according to age group, study day, and severity of illness. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 112 (16.0%) of 698 children who received the Heart And Lung Failure-Pediatric INsulin Titration protocol developed hypoglycemia, including 25 (3.6%) who developed severe hypoglycemia (blood glucose < 40 mg/dL). Of these, 110 cases were matched to 427 controls. Hypoglycemia was associated with fewer ICU-free days (median, 15.3 vs 20.2 d; p = 0.04) and fewer hospital-free days (0 vs 7 d; p = 0.01) through day 28. Ventilator-free days through day 28 and mortality at 28 and 90 days did not differ between groups. More children with insulin-induced versus noninsulin-induced hypoglycemia had zero ICU-free days (35.8% vs 20.9%; p = 0.008). Outcomes did not differ between children with severe versus nonsevere hypoglycemia or those with recurrent versus isolated hypoglycemia. CONCLUSIONS: When a computerized algorithm, continuous glucose monitors and standardized glucose infusion rates were used to manage hyperglycemia in critically ill children with cardiovascular and/or respiratory failure, severe hypoglycemia (blood glucose < 40 mg/dL) was uncommon, but any hypoglycemia (blood glucose < 60 mg/dL) remained common and was associated with worse short-term outcomes.