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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. Clinicaltrials.gov identifier: NCT04695392.

OBJECTIVES:. To evaluate the link between early acute respiratory failure and functional morbidity in survivors using the plasma biomarkers interleukin-8, interleukin-1 receptor antagonist, thrombomodulin, and plasminogen activator inhibitor-1. We hypothesized that children with acute respiratory failure with higher levels of inflammation would have worse functional outcomes at discharge, as measured by Pediatric Overall Performance Category. DESIGN:. Secondary analysis of the Genetic Variation and Biomarkers in Children with Acute Lung Injury (R01HL095410) study. SETTING:. Twenty-two PICUs participating in the multisite clinical trial, Randomized Evaluation of Sedation Titration for Respiratory Failure (U01 HL086622) and the ancillary study (Biomarkers in Children with Acute Lung Injury). SUBJECTS:. Children 2 weeks to 17 years requiring invasive mechanical ventilation for acute airways and/or parenchymal lung disease. Patients with an admission Pediatric Overall Performance Category greater than 3 (severe disability, coma, or brain death) were excluded. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Among survivors, 387 patients had no worsening of Pediatric Overall Performance Category at discharge while 40 had worsening functional status, defined as any increase in Pediatric Overall Performance Category from baseline. There was no significant relationship between worsening of Pediatric Overall Performance Category and interleukin-8 or plasminogen activator inhibitor-1 on any day. There was no significant relationship between interleukin-1 receptor antagonist, or thrombomodulin, and worsening Pediatric Overall Performance Category on day 1. Plasma interleukin-1 receptor antagonist and thrombomodulin were significantly elevated on days 2 and 3 in those with worse functional status at discharge compared with those without. In multivariable analysis, interleukin-1 receptor antagonist and thrombomodulin were associated with a decline in functional status on days 2 and 3 after adjustment for age and highest oxygenation index. However, after adjusting for age and cardiovascular failure, only day 2 thrombomodulin levels were associated with a worsening in Pediatric Overall Performance Category. CONCLUSIONS:. Higher levels of interleukin-1 receptor antagonist or thrombomodulin following intubation were associated with worse Pediatric Overall Performance Category scores at hospital discharge in children who survive acute respiratory failure. These data suggest that persistent inflammation may be related to functional decline.