Restore Resilience in Critically Ill Children
Phase: NA
Conditions: Acute Respiratory Distress Syndrome
Sponsor: University of Pennsylvania

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RESTORE RESILIENCE IN CRITICALLY ILL CHILDREN – R2 
 
 
Principal Investigators  
Martha A. Q. Curley, PhD, RN, FAAN 
University of Pennsylvania 
School of Nursing 
Claire M. Fagin Hall, 418 Curie Boulevard - #425 
Philadelphia, PA 19104-4217 USA 
Phone: 215.573.9449 
curley@nursing.upenn.edu 
 
Athena Zuppa, MD 
Children’s Hospital of Philadelphia 
Anesthesiology and Critical Care 
34th and Civic Center Blvd 
Philadelphia, PA 19104 
Phone: 215-590-1924 
zuppa@email.chop.edu 
 
Sapna R. Kudchadkar, MD 
Johns Hopkins University School of Medicine 
Charlotte R. Bloomberg Children's Center 
1800 Orleans Street, Suite 6318B 
Baltimore, MD 21287 
Phone: (410) 814-1218 
skudcha1@jhmi.edu 
 
Funding Sponsor 
 
National Institute of Child Health and Human Development 
National Institute of Health, Rockville, MD 20847 
 
1-800-370-2943 
 
IRB Number 
 
 
828061 
NIH Grant Number 
 
R21-HD093369-01 
 
Initial version 
 
 
8/17/17 
Version 2: 
 
 
11/3/2017 
Version 3: 
 
 
12/13/2017 
Version 4: 
 
 
1/2/2018 
Version 5: 
 
 
2/12/2020 
Version 6: 
 
 
7/28/2020 
Version 7: 
 
 
9/18/2020 
 

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Study Summary 
 
Title 
RESTORE Resilience in Critically Ill Children – R2 
Short Title 
R2  
IRB Number 
828061 
Methodology 
A prospective cohort study with a convenience sample of patients admitted to 
the PICU at two study sites. 
Study Duration 
Study participation will be completed at PICU discharge or PICU Day 28, 
whichever occurs first. 
Study Center(s) 
This is two-site study, CHOP & Johns Hopkins. 
Objectives 
The study design will allow investigators to describe usual care in each PICU 
and identify the facilitating and restraining factors impacting the 
implementation of R2 at each PICU. The purpose of this pilot study is to 
improve the care, environment, daily routine and sleep patterns of children in 
the PICU. The goal of this study is to learn what can be improved to support a 
critically ill child’s healing and circadian rhythms. 
Number of Subjects 
Each site will enroll 10 baseline (control) subjects and 20 intervention subjects. 
Main Inclusion and 
Exclusion Criteria 
Inclusion Criteria: PICU admission at one of the study sites in which 
elements of R2 are typically but sporadically implemented; Between the ages 6 
months and 18 years at the time of enrollment; Intubated and mechanically 
ventilated within the last 48 hours; acute lung disease is the primary reason for 
intubation; ≤4 nights in the hospital (≤2 nights in PICU); Parental/Guardian 
provides primary care for child;  
Exclusion Criteria:  ; child has a baseline cognitive dysfunction ≥4, measured 
by the Pediatric Cerebral Performance Category (PCPC); Transferred to the 
PICU from another hospital unit/ward ≥4 days (≥2 nights in the PICU); 
admitted with an uncontrolled seizure disorder, cerebral hypertension, 
neuromuscular respiratory failure, ventilator dependence (excluding BiPAP or 
CPAP at night); history of inability to tolerate bolus;. 
enteral feeds; the presence of any of the following within 24 hours of 
admission: modal pain scores > 4; persistent hypotension/hypertension 
unresponsive to standard therapies; use of High Frequency Oscillatory 
Ventilation or Extracorporeal Membrane Oxygenation; administered melatonin 
within the past week or have active do-not-resuscitate plans. 
Intervention  
 
 
During the intervention phase the following will occur: 1) parents will complete 
the Child's Daily Routine and Sleep Survey, 2) cycled day-night lighted and 
modulation of sound will be provided to match the child’s routine (provided by 
the parent), 3) the subjects sedation will be managed using the RESTORE 
process that is standard care at both sites, 4) night fasting with bolus enteral 
daytime feedings will be administered per child's routine feeding schedule 
(unless contraindicated), 5) the PICU Up! program will be implemented, 6) the 
number of nurses assigned to care for the subjects will be limited, and 7) 
parents will be asked to complete a paper or electronic diary during the child's 
PICU stay to track the day's events, their thoughts, or questions they may 
have for the care team. 

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Statistical 
Methodology 
Descriptive statistics will be calculated, including means, standard deviations, 
medians, and interquartile ranges for continuous variables and frequency 
counts and percentages for categorical variables. Data will be examined for 
skewness, outliers, and systematic missing data. For non-normal continuous 
outcomes, we will consider data transformations or nonparametric methods, as 
appropriate. Our primary analysis will compare the circadian activity ratio 
post-extubation between Baseline Phase and Intervention Phase patients 
using t-tests or Wilcoxon rank-sum tests, as appropriate. Secondary analyses 
will use linear regression to control for variables that could be associated with 
outcomes, such as patient severity or age group. Analysis of secondary 
outcomes will use t-tests or Wilcoxon rank-sum tests for continuous variables 
and Fisher’s exact tests for categorical variables. Regression methods (linear, 
logistic, proportional hazards) will be used to assess the effects of covariates 
on secondary outcomes. Though we do not anticipate differences due to 
gender, race/ethnicity, or center, we will assess main effects and possible 
effect modification due to these factors using regression methods. Data 
analyses will be performed using SAS® or similar statistical packages. 
Data and Safety 
Monitoring Plan  
This PI and data coordinating site (Children’s Hospital Boston) will be 
responsible for data quality and safety of all subjects. 
 
Background and Study Rationale 
This is a research study and will be conducted in full accordance with all applicable University of 
Pennsylvania Research Policies and Procedures and all applicable Federal and state laws and 
regulations as applicable. 
1 
Introduction 
Maintaining a child’s circadian rhythm during their critical illness may strengthen their resilience and, in 
the very least, not burden a child’s already compromised state. Optimizing CR during critical illness has 
been shown to be feasible and safe, improve patient-important outcomes, and is therefore now 
recommended as one of the best practices and priorities among adult ICUs. Although each R2 element is 
currently practiced in 58 PICUs, the R2 bundle has not been systemically implemented or tested. The first 
step in a paradigm shift is to ensure there is supporting evidence for the planned change in care. 
Therefore, a systematic approach is urgently needed to optimize the healing milieu in the PICU and 
characterize the functional changes that occur as a result of disrupted circadian rhythms in PICU 
survivors.  Our interprofessional team believes that PICU care and environments can be modulated to 
sustain a child’s circadian rhythm (CR), support their physiological resilience and enhance their capacity 
to heal. The recent completion of the RESTORE clinical trial (HL086622, PI Curley) provides evidence 
that critically ill children can be safely managed in a more awake state. Pilot work on PICU Up! (PI: 
Kudchadkar), an intervention promoting early progressive exercise and mobility in critically ill children, 
supports its safety and feasibility. We believe that more awake, responsive and active children who 
receive CR-restoring interventions may derive benefit. Our team, with expertise in pediatric critical care 
nursing, medicine, sleep, and pharmacology intends to shift the current PICU paradigm from potentially 
toxic to healing for the most vulnerable of patients. It is hypothesized that patients managed per 
RESTORE resilience will experience a more restorative circadian rhythm evidenced by an improved 
temporal sleep-wake pattern than patients receiving usual care. The overall aim of this study is to pilot 
test an individualized bundle of clinical care, RESTORE resilience (R2), in pediatric patients on 
mechanical ventilation for acute respiratory failure.   
1.1 
Background and Relevant Literature  
Each year, more than 250,000 infants and children in the US receive care in a PICU, and more than 
100,000 are supported on mechanical ventilation (MV). (8) With improved mortality, the focus of PICU 
care has shifted to patient and family morbidity and improvement in quality of life. (9-11) In adults, we 

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know that disruptions in CR may impair mentation, immunity, autonomic function, endocrine activity, 
hormonal signaling, and ultimately healing.(12-15) As acuity of illness increases, circadian rhythmicity 
may be abolished.(16,17) Causes of circadian disruption may be environmental or internal to the 
patient.(18) For example, inadequate daytime illumination and increases in nocturnal light, coupled with 
sudden and frequent peaks in noise with high baseline noise levels, negatively impact both sleep onset 
and sleep continuity in the ICU. Intrinsic causes of circadian disruption include critical illness itself and the 
patient’s experiences with distress and pain. Moreover, melatonin is integral to the maintenance of 
circadian rhythms and regulation of sleep, and derangements in melatonin secretion among adult ICU 
patients are associated with sleep disturbances. (12,16,18-24) In pediatrics, sleep recommendations are 
age-based and reflect neurologic maturation.(25-29) While we know that sleep quality is poor in the PICU, 
data regarding the clinical effects of sleep disturbances in critically ill children are severely lacking.(25,30-
32) Thus, it is not surprising that a recent survey of pediatric intensivists revealed that the vast majority of 
PICUs do not have protocols in place for sleep promotion.(33) Currently, PICUs are implementing 
delirium screening with little data to support interventions for delirium prevention. This practice is 
disconcerting because CR/sleep disruption is a known contributor to ICU delirium. (13,34) Without data 
on the physical and psychological benefits of sleep in sick children, long-established hospital routines will 
continue to disrupt circadian rhythms in critically ill children. 
2 
Study Objectives 
The first step in this program of research is to pilot-test RESTORE resilience (R2), a 7-item individualized 
bundle that we hypothesize will restore CR in critically ill children using a pre-posttest design. Two 
separate PICUs will each enroll 10 baseline subjects followed by 20 intervention subjects, 6 months to 18 
years of age, who are intubated and mechanically ventilated for acute respiratory failure. Specifically, as 
soon as possible after PICU admission, parents will be interviewed to create an individualized 
chronotherapeutic bundle to include (1) focused effort to replicate the child’s pre-hospitalization daily 
routine (bedtime/wake time, bedtime/arousal routine, nap time, feeding schedule, active periods), (2) 
cycled day-night lighting and modulation of sound to match the child’s routine, (3) minimal yet effective 
sedation using a nurse-implemented goal-directed sedation plan (RESTORE), (4) night fasting with bolus 
enteral daytime feedings, (5) early, developmentally-appropriate, progressive exercise and mobility (PICU 
Up!), (6) continuity in nursing care, and (7) parent diaries. The overall objective of this study is to pilot-test 
an intervention that can be implemented in any PICU that will improve sleep-wake patterns with 
restoration/maintenance of circadian rhythms in critically ill children with acute respiratory failure. Results 
of this pilot study will be used to inform the design of an adequately powered multicenter randomized trial 
of R2. 
 
2.1 
Primary Objective 
• 
Circadian activity ratio (daytime activity/total 24-hr activity) after endotracheal extubation. 
2.2 
Secondary Objectives (if applicable) 
• 
Salivary melatonin levels on PICU day two and five  
• 
Nighttime EEG slow-wave activity during endotracheal intubation with EMG and EOG 
• 
R2 feasibility, adherence, system barriers   
• 
Levels of patient comfort: PICU days free of pain, agitation, delirium, iatrogenic withdrawal  
• 
PICU exposure to sedative medications (total dose and length of exposure)  
• 
Time to physiological stability (time on vasoactive medication, duration of mechanical ventilation, 
PICU and hospital length of stay)  
• 
Parent perception of being well-cared-for  
 

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3 
Investigational Plan  
3.1 
General Design 
The study design is a two-phase prospective cohort study. Consecutive subjects will be enrolled into the 
Baseline Phase and then the Intervention Phase in two separate PICUs: Children’s Hospital of 
Philadelphia and Johns Hopkins Children’s Center.  
3.2 
Allocation to Interventional Group [if applicable] 
Following the baseline phase, all subjects will be enrolled in the intervention phase.  No randomization or 
subject group allocation will occur.   
3.3 
Study Measures 
All patients will be enrolled within 24 hours of PICU admission. Using medical records, patient monitoring 
and environmental monitoring, the following data will be collected for this study. 
 
Baseline and Intervention Phase: 
1) Patient comfort will be measured using the following scale, as applicable: 
a. Pain assessed using either the Face, Legs, Activity, Cry, Consolability (FLACC) scale in 
nonverbal children 0 to 6 years of age, the individualized numeric rating scale (INRS) in 
nonverbal cognitively impaired children age 6 and older, or the Wong-Baker Faces Pain 
Scale (WBFPS) in verbal children age 3 and older. All pain scales range 0-10 with higher 
scores indicating more pain.  
b. Level of sedation in intubated patients is assessed using the State Behavioral Scale 
(SBS).71 SBS scores range from -3 (unresponsive) to +2 (agitated).  
c. In patients receiving neuromuscular blockade, pain/agitation is judged to be present by 
the bedside nurse when a patient demonstrates a ≥20% increase in heart rate or blood 
pressure when stimulated.  
d. Delirium is assessed using either the Cornell Assessment for Pediatric Delirium (CAPD), 
or the preschool/pediatric CAM instruments; all are rapid bedside screeners for delirium 
in hospitalized children.  
e. Patients weaning from ≥5 days of sedation are monitored for IWS using the Withdrawal 
Assessment Tool-1 (WAT-1). The WAT-1 scale ranges 0-12 with higher scores indicating 
more withdrawal symptoms.  
f. 
Percentage of total ICU days with no pain, agitation, delirium, or IWS will be monitored 
and reported. 
2) Child's Daily Routine and Sleep Survey – completed at enrollment by a parent  
3) Exposure to sedative medications – per medical record 
4) The duration of time between the start and stop of all vasoactive medications, from endotracheal 
intubation to successful endotracheal extubation, from PICU admission to PICU discharge, and 
from hospital admission to hospital discharge – per medical record 
5) Light and noise monitoring - recorded continuously using Quietyme technology 
6) EEG, EOG and EMG monitoring for up to 72 hours- EEG will consist of 2 central leads in addition 
to EOG and EMG (1 lead each on outer corner of the eye and one on the chin). 
7) Actigraphy monitoring (placed on wrist or ankle at enrollment) – recorded continuously 
8) Saliva Samples – collected with an oral swab eight times across two days (Day 2 & Day 5) 
9) Activity Log – completed by parent or nurse daily to record patient activities (such as sleep, 
feeding, etc)  
 
Intervention Phase: 
1) 
The local investigator(s) or designee will round separately on each enrolled subject daily and 
complete the R2 bundle adherence form 
2) 
Child's Daily Routine and Sleep Survey – completed at enrollment by a parent  
3) 
The provision of cycled day-night lighted and modulation of sound to match the child’s routine 
(provided by the parent) 
4) 
Minimum but effective sedation administered per RESTORE process – per medical records 

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5) 
Night fasting with bolus enteral daytime feedings per child's routine feeding schedule (unless 
contraindicated) – per medical records and activity log 
6) 
Documentation of one of three physical activities within the PICU Up! program implemented 
7) 
The number of nurses assigned to care for the subject – per activity log 
8) 
Parent diary entries – paper or electronic  
 
Within 48 hours of patient PICU discharge; specifically, after transfer to an inpatient unit: 
• Parents will be contacted to complete the Family-Centered Care Scale (FCCS) 
o Completed in person if still hospitalized or over the phone or electronically (using a 
REDCap database) 
o A 7-item measure of parents’ experiences with nursing care and perceptions of being 
well-cared for during a PICU stay 
3.4 
Study Endpoints  
3.4.1 Primary Study Endpoint 
The study endpoint will be PICU discharge or PICU day 28, whichever occurs first.  
4 
Study Population and Duration of Participation  
The target population for this study is pediatric patients admitted to the PICU between the ages of 6 
months and 18 years who are intubated and mechanically ventilated for acute airways or parenchymal 
disease, and are expected to be intubated for more than 24 hours. 
4.1 
Duration of Study Participation  
Subject participation will last until PICU discharge or Day 28, whichever occurs first. 
4.2 
Total Number of Subjects and Sites  
No subjects will be enrolled at Penn.  Two sites, Children’s hospital of Philadelphia and Johns Hopkins 
Children’s Center, will each enroll 30 subjects who provide full usable data (10 baseline/control and 20 
intervention).   
4.3 
Inclusion Criteria 
The following is a list of study inclusion criteria:  
• 
PICU admission at one of the study sites in which elements of R2 are typically but sporadically 
implemented 
• 
Transferred to the PICU from another hospital unit/ward with ≤4 nights in the hospital (≤2 nights in 
PICU) 
• 
Between the ages 6 months and 18 years at the time of enrollment (has not had their 18th 
birthday) 
• 
Intubated and mechanically ventilated for acute airway or parenchymal disease within last 48 
hours  
• 
Expected to be intubated for more than 12 hours past enrollment 
• 
Parent/Guardian providing consent, provides primary care for subject 
4.4 
Exclusion Criteria 
The following is a list of exclusionary criteria for this study: 
• 
A baseline cognitive dysfunction, measured by the Pediatric Cerebral Performance Category 
(PCPC ≥4)  
• 
A history of an uncontrolled seizure disorder (seizure within past 3 months), cerebral 
hypertension, neuromuscular respiratory failure, ventilator dependence (excluding BiPAP or 
CPAP at night)  
• 
A history of inability to tolerate bolus enteral feeds (full J-Tube fed patients) 

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• 
The presence of any of the following within 24 hours of admission:  
o 
Modal pain scores greater than 4 
o 
Persistent hypotension/hypertension unresponsive to standard therapies 
o 
Use of High Frequency Oscillatory Ventilation or Extracorporeal Membrane Oxygenation 
• 
Administered melatonin within the past week 
• 
Has an active do-not-resuscitate plan 
  
4.5 
Subject Recruitment  
Subjects for this study will be recruited via daily PICU admission logs.  Consecutive patients admitted to 
the PICU at each of the study sites will be reviewed for eligibility (based on medical record) and if eligible 
invited to participate. After verifying the patient's eligibility status, the patient’s legal guardian or parent(s) 
will be introduced to the research team by a member of the patients care team and informed consent will 
be requested from the parent or legal guardian. Recruitment will end when 60 subjects are enrolled. 
  
4.6 
Vulnerable Populations:  
This study involves children.  At the time of enrollment, the patient’s legal guardian/parents will be 
introduced to the research team by a member of the patient’s care team and informed consent will be 
requested from the parent or legal guardian. Due to existing medical conditions (e.g. sedation, 
mechanical ventilation) minor assent will not be obtained. Although not directly targeted, mentally 
disabled persons, economically or educationally disadvantaged persons, and/or employees or students of 
the University of Pennsylvania or other involved institutions will not be denied enrollment and any special 
protections and/or additional safeguards will be undertaken in order to protect the rights and welfare of 
these subjects from coercion or undue influence as appropriate. 
5 
Study Procedures  
Following informed consent, during the baseline phase, all patient care will be managed at the discretion 
of the clinical care team.  The study will not provide care recommendations or changes to treatment 
during the baseline phase.   
 
The following procedures will occur daily during the Baseline and Intervention Phases: 
• 
Completion of the Child’s Daily Routine and Sleep Survey 
• 
Patient Activity Log completed by parent or nurse  
• 
Light and noise monitoring within the patient room using Quietyme technology 
• 
Patient EEG monitoring (4 leads) for first 72 hours following enrollment 
• 
Patient actigraphy monitoring (placed on wrist or ankle)  
The following activity will occur twice during the study - on Day 2 and Day 5  
1) Saliva Samples – an oral swab will be collected a total of eight times per day/2 days (16 total) 
a. A small cotton swab (Salimetrics, Inc, PA) will be placed under the child’s tongue for 60-
90 seconds then inserted into a storage tube 
 
In addition to those listed above, the following procedures will only occur during the Intervention Phase: 
• 
Use the Child’s Daily Routine and Sleep survey data to replicate the child’s pre-hospitalization 
daily routine (bedtime/wake time, bedtime/arousal routine, nap time, feeding schedule, active 
periods) modulate the PICU environment and child activity 
• 
Window shades and ambient lighting will be modified to provide day/night cycling per child’s 
routine 
• 
Light and sound will be modified throughout the day to match the child’s preference and parent 
reporting 

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• 
Sedation managed per RESTORE principles within the PICU’s standard of care.  
• 
Enteral feeding will be provided during the day according to the child’s routine 
• 
Physical therapy and progressive mobility/exercise will be implemented per the PICU Up! 
program 
• 
The PICU charge nurse will limit the number of nurses assigned to care for the subject  
• 
Parents will be asked to complete daily diary entries via paper or electronic format 
5.1 
Screening  
Screening activities will take place daily at 10am +/- 2 H for this study.  The research coordinator will 
review the medical records of all PICU admissions within the past 24 hours for demographic and clinical 
condition to determine initial eligibility.  The research coordinator will confirm each potential patient’s 
eligibility with the patient’s care team and attending physician.  Upon confirmation of eligibility the clinical 
team will introduce the patient’s parent/legal guardian to the study and the research coordinator.  For 
parents/legal guardians interested in participation, informed consent will be obtained.   
 
The following table provides a review of the data collection timeline for this study: 
 
Measurement 
Screening 
Day 1 
Day 2 & 
Day 5 
Daily 
PICU 
Discharge 
Demographic Data 
X 
X 
 
 
 
PCPC/POPC score 
X 
X 
 
 
 
Medical History 
X 
X 
 
 
 
PRISM III  
 
X 
 
 
 
Child’s Daily Routine and 
Sleep Survey 
 
X 
 
 
 
Salivary Swab 
 
 
X 
 
 
Ventilation Status, sedative 
medications, 
neuromuscular blockades, 
extubation readiness test 
 
 
 
X 
 
Pain, Sedation, Delirium 
Scores 
 
 
 
X 
 
WAT-1 Iatrogenic 
Withdrawal Syndrome 
assessment 
 
 
 
Weaning 
phase 
 
Enteral nutrition 
pattern/volume 
 
 
 
X 
 
Occupational/Physical/Child 
life therapy 
 
 
 
X 
 
Sound/Light monitoring 
 
 
 
X 
 
EEG monitoring 
 
 
 
X (3 days) 
 
Ankle/wrist Actigraphy 
 
 
 
X 
 
Activity Log 
 
 
 
X 
 
Parent Diary 
 
 
 
X 
 
Family Centered Care 
Scale (FCCS) 
 
 
 
 
X 
 
5.1.1 End of Study Visit 
None required     
5.2 
Subject Withdrawal  
Subjects may withdraw from the study at any time without impact to their care.  They may also be 
discontinued from the study at the discretion of the Investigator for lack of adherence to intervention or 

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study procedures or visit schedules, AEs, or due to a change in medical history (e.g. develop an 
exclusionary medical condition or medication).  The Investigator may also withdraw subjects who violate 
the study plan, to protect the subject for reasons related to safety or for administrative reasons.  It will be 
documented whether or not each subject completes the study. Subjects who withdraw early will have one 
final visit to collect final evaluations and assess adverse events.   
5.2.1 Data Collection and Follow-up for Withdrawn Subjects 
Subjects who withdraw consent to participate in the study will be seen for one final study visit. During this 
visit they will be asked for permission to assess their survival status via medical records.   
6 
Statistical Plan 
The study design will allow multiple comparisons; specifically baseline to intervention group and cross-
unit comparisons. The specific aim of the study is to pilot test RESTORE resilience, an individualized 
chronotherapeutic bundle, in pediatric patients supported on mechanical ventilation for acute respiratory 
failure in the PICU. The study design is a two-phase prospective cohort study. Subjects will be 
consecutively enrolled into the Baseline Phase and then into the Intervention Phase in two separate 
PICUs. Each unit will enroll 10 baseline subjects followed by 20 intervention subjects (total: 20 baseline 
subjects and 40 intervention subjects). Outcome variables are designed to be as objective as possible 
since it is not possible to blind the assessor to treatment phase. 
6.1 
Sample Size and Power Determination 
This study is not powered for effect.  As a pilot study we are only interested in evaluating the feasibility of 
implementing all elements of the RESTORE-resilience intervention (see below). 
6.2 
Statistical Methods 
For purposes of this pilot study, we assume that subjects managed per R2 will exhibit maintain circadian 
rhythmicity and demonstrate an improved sleep-wake pattern, as evidenced by increased circadian 
activity ratio (daytime activity/total 24-hr activity) post-extubation, compared to those managed per usual 
care. Preliminary data from current studies in the PICU suggest that 50% of activity occurs during the 
nighttime hours in the PICU. We anticipate that the R2 intervention will result in a decrease in nighttime 
activity to 30% of total activity. This pilot study is exploratory to determine preliminary estimates in 
order to develop power calculations for a future trial. 
6.3 
Control of Bias and Confounding  
To avoid bias all eligible subjects will be consecutively approached for consent and we will use objective 
biological endpoints.  
6.3.1 Baseline Data 
Baseline and demographic characteristics will be summarized by standard descriptive statistics (including 
mean and standard deviation for continuous variables such as age and standard percentages for 
categorical variables such as gender). 
6.3.2 Analysis of Primary Outcome of Interest 
Analysis of the primary outcome: Average circadian activity ratio, defined as daytime activity/total 24-hr 
activity, after extubation as demonstrated by actigraphy. Daytime will be defined as 7 am -7 pm. Validated 
in infants and children, actigraphs capture activity counts in 1-minute epochs which can be compared 
between daytime and nighttime hours as a marker of circadian rhythm. Because activity levels vary 
between patients (i.e., a child with cerebral palsy and/or muscle weakness will not produce the same 
activity amplitude as a healthy child), the circadian activity ratio provides a method of normalizing the data 
to account for each patient’s baseline amplitude. Increases in the daily circadian activity ratio would 
suggest improvement in day-night rest-activity patterns and sleep consolidation over time. 

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7 
Safety and Adverse Events 
All enrolled subjects are critically ill and no additional study-related risk is anticipated. This section 
provides the safety management plans for the study if one were to occur. The MPIs will be responsible for 
ensuring the safety of participants on a daily basis. The MPI and the study coordinators will meet bi-
weekly to review current status of the protocol. The bi-weekly meetings will assess the safety of the 
patients enrolled on the study. 
7.1 
Definitions 
7.1.1 Adverse Event 
Patients will be monitored for the occurrence of events defined as any undesirable experience or 
unanticipated benefit. Patients will be monitored daily to determine whether an event has occurred. All 
adverse events will be recorded on an adverse event case report form. Serious adverse events (death, 
life threatening, new serious or permanent disability) will be reported within 24 hours to the MPI team 
within 72 hours to the Institutional Review Board (IRB). Recommended protocol modifications will be 
implemented immediately. A description of all undesirable experiences or unanticipated benefits will be 
recorded on the case report form. In addition, the required interventions, patient’s condition after the 
event, an estimate of the extent of injury, and prevention strategies will be reported. The relationship of 
the study protocol to the event will be classified by a consensus of the bedside team as follows:  
• 
Not related: The event is clearly related to factors such as the subject’s clinical state, not with 
therapeutic interventions associated with the study protocol.  
• 
Remote: The event was most likely related to factors such as the subject’s clinical state, not with 
therapeutic interventions associated with the study protocol. 
• 
Possible: The event follows a reasonable temporal sequence from the implementation of the 
protocol and/or is consistent with known events related to the protocol but is possibly related to 
factors such as the subject’s clinical state.  
• 
Probable: The event follows a reasonable temporal sequence from the implementation of the 
protocol and/or is consistent with known events related to the protocol and cannot be reasonably 
explained by factors such as the subject’s clinical state.  
• 
Highly Probable: The event follows a reasonable temporal sequence from the implementation of 
the protocol and/or is consistent with known events related to the implementation of the protocol 
and cannot be reasonably explained by factors such as the subject’s clinical state. In addition, the 
event occurs immediately following the implementation of the protocol, or improves when 
discontinuing the protocol, or reappears on the repeat implementation of the protocol. 
7.1.2 Serious Adverse Event 
The severity of an adverse event in both phases is defined as a qualitative assessment of the degree of 
intensity of an adverse event as determined by a consensus of the bedside team as follows:  
• 
Mild: Does not impact (in anyway) the patient’s course of illness.  
• 
Moderate: Impacts the subject’s course of illness but is not life-threatening or incapacitating.  
• 
Severe: Fatal, life threatening, permanently disabling; severely incapacitating; requires/prolongs 
inpatient hospitalization.  
The principal investigators will immediately follow-up on all serious events on a case-by-case basis. All 
adverse events will be summarized and reviewed on a monthly basis. 
 
7.2 
Recording of Adverse Events 
At each contact with the subject, the investigator will seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events will be recorded 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results will be 
recorded in the CRF. 
 

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All adverse events occurring during the study period will be recorded.  All study related SAE's will be 
reported to the IRB in writing by the MPI within 24 hours of the event. The following guidelines will be 
followed: 1) A letter will summarize any adverse events or events that occurred, the patient's name will 
not be included. The event outcome will be described. 2) An original and 3 sets of documents including 
the letter, any communication from the study team, and all supporting documents will be provided. The 
clinical course of each event will be followed until resolution, stabilization, or until it has been determined 
that the study intervention or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period will be followed up to determine the final outcome.  Any serious adverse 
event that occurs after the study period and is considered to be possibly related to the study intervention 
or study participation will be recorded and reported. 
7.3 
Relationship of AE to Study  
Following discussion with the attending physician and clinical care team, review of the medical records 
and any applicable CRFs, the PI will determine the relationship and classification of all AEs. 
7.4 
Reporting of Adverse Events and Unanticipated Problems 
The Investigator will promptly notify the Penn IRB of all on-site unanticipated, Adverse Events that are 
related to the research activity. Other unanticipated problems related to the research involving risk to 
subjects or others will also be reported promptly. Written reports will be filed within HS-ERA within 10 
working days.  
 
All adverse events that are previously undescribed, or serious and study-related are subject to expedited 
reporting. The NIH will be notified (by telephone, fax, or writing) as soon as possible but no later than 7 
calendar days after first knowledge by investigator that a case qualifies, followed by as complete a report 
as possible within 8 additional calendar days. The NIH report will include:  
• 
Patient details: initials, subject number, gender, age and/or DOB, weight, and height. 
• 
Intervention that resulted in AE or SAE  
• 
Other treatments (same as above) for all other concomitant medicinal products.  
• 
Details of the SAE: description of the event (signs and symptoms/diagnosis); why this is 
considered serious (criteria); onset and duration of the event; dechallenge/ rechallenge 
information; setting.  
• 
Outcome: information on recovery and any sequelae; specific treatments/tests and results; cause 
of death; autopsy or post mortem reports.  
• 
Reporter - name, profession, address, and phone number. 
• 
Determinants of causality - temporal (time) association, known AEs, subject's current state of 
health, response to dosage change, concomitant medications, other therapies the subject is 
undergoing. 
 
7.4.1 Follow-up Report 
If an AE has not resolved at the time of the initial report and new information arises that changes the 
investigator’s assessment of the event, a follow-up report including all relevant new or reassessed 
information (e.g., concomitant medication, medical history) will be submitted to the IRB.  
7.4.2 Data and Safety Monitoring Plan 
A DSMB will not be required for this study. The PI will monitor this study. Local investigators will contact 
Dr. Curley immediately, should any unanticipated problems occur. Patients will be monitored for the 
occurrence of events defined as any undesirable experience or unanticipated benefit. Patients will be 
monitored daily to determine whether an event has occurred.  
 

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8 
Study Administration, Data Handling and Record Keeping 
8.1 
Confidentiality 
 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  The parental permission form 
for this study informs the parent/subject of the following:  
• 
What protected health information (PHI) will be collected in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PH.  
 
After providing informed consent/parental permission/assent, the subject will be assigned a unique case 
number. This number will be used to label all private research information, including clinical assessments 
and saliva swabs. Original signed informed consent forms will be kept in a locked cabinet in a private 
office. All data and photographs will be entered directly into a password-protected database that will be 
maintained on a password-protected network drive. Access to the server is through a password-protected 
account that allows access to data collected only to the investigator and their designees. Consent logs 
and other research records will be kept for 7 years after the primary paper is published for audit purposes. 
At that time, they may be destroyed under the direction of the Principal Investigator. Results will only be 
reported in aggregate form. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts will be made to obtain permission 
to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study period. 
8.2 
Data Collection and Management  
The Data Coordinating Center (DCC) will work with the MPI team to develop a web-based Data 
Management System (DMS) using the REDCap electronic data capture system. According to 
programmed workflow logic, the DMS will generate electronic Case Report Forms as needed for each 
patient (e.g., daily forms, study discharge form). The DMS allows for the data to be viewed in real time by 
the DCC staff and certified data entry personnel at the clinical sites. Many automated logic and range 
checks and cross-form validations will be programmed to ensure data quality, and audit trails will be 
maintained.  
 
The DCC will work with each clinical center to ensure that database training and certification is obtained 
by all new staff and that data are entered, data queries are resolved, and data-related questions are 
answered promptly.  
 
The DCC will transfer electronic data files as needed in a secure and confidential manner. The DCC will 
also create reports as needed by the NIH, for study quality review (e.g., monthly protocol adherence 
reports), and for review as needed by our Data and Safety Monitoring Plan. 
 
Confidentiality will be maintained throughout the study in the following ways: 
 
1) All data will be de-identified then stored in the secure REDCap database or in the Excel 
database, as appropriate.  
2) Specimens will be de-identified and stored in lockable research freezers, and each participant will 
be assigned a unique identification number. 
3) A master list (linking PHI to study ID) will be housed separately from all data forms (both paper 
and electronically).  The master list will be maintained by the PI and stored in a password 
protected file within Excel on computers on accessible by the study team and password 
protected.   

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8.3 
Records Retention 
Study records will be retained per applicable NIH and Penn IRB requirements.  Records will be stored in 
locked cabinets, in locked offices only accessible to the study team. 
9 
Study Monitoring, Auditing, and Inspecting 
9.1 
Study Monitoring Plan 
The study MPIs will be responsible for ensuring the ongoing quality and integrity of the research study.   
9.2 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
10 
Ethical Considerations 
10.1 
Risks 
Privacy and Confidentiality: Strict measures will be taken to ensure participant privacy and confidentiality. 
All data will be de-identified then stored in the secure REDCap database or in the Excel database, as 
appropriate. Specimens will be de-identified and stored in lockable research freezers, and each 
participant will be assigned a unique identification number. The master list linking identification numbers 
to identifying information will be stored separately from the study database. All personally identifiable 
information will be kept strictly confidential and stored in an encrypted document, on a dedicated research 
server only accessible by the research team.  
Risk associated with EEG and ankle/wrist monitoring includes irritation at the site and will be minimized 
by scheduled assessments of the sites, and removal of the device if irritation or redness occurs.  
 
The major components of RESTORE are a standard of care in each PICU. The current study is testing 
the feasibility of implementing the entire 7-item bundle of activities/clinical care within a PICU, it is not 
testing each item within the bundle.  Risk associated with over and /or under sedation will be minimized 
by hourly assessment of goal SBS attainment with the subject is intubated. 
 
Risks associated with bolus feed included gastro-esophageal reflux and aspiration. However, children 
who are at risk for reflux and aspiration will be excluded from the study. Children who have clinical signs 
of aspiration will be removed from study. Reflux precautions including head of bed at 300 will be 
implemented when appropriate.  
 
Risks from progressive mobility include inadvertent tube/catheter dislodgement. However, these risks are 
minimized since the care models at both Johns Hopkins and CHOP have incorporated progressive 
mobility as part of the standard of care, and are well trained with this intervention. Children at high risk for 
tube and or catheter dislodgment will not participate in this activity.   
10.2 
Benefits 
10.3 
Risk Benefit Assessment 
No direct benefit from study participation is expected.  Participation may result in the improvement in the 
environment, daily routine and sleep patterns of children during a stay in the PICU. The findings from this 
study will increase clinical knowledge regarding the care of critically ill children and how best to preserve 
and/or restore a child’s circadian rhythm.  The possible benefits of this study outweigh the risks to 
participation. We expect these results will contribute to education of pediatric health providers, care of all 

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pediatric patients with acute respiratory failure, and future studies evaluating the effects of environment 
and care. 
10.4 
Informed Consent Process / HIPAA Authorization  
 
All parents/legal guardians of the potential subjects for this study will be provided a consent form 
describing this study providing sufficient information for subjects to make an informed decision about their 
participation in this study.  This consent form will be approved by the Penn IRB for this study.  The formal 
consent of a subject, using the IRB-approved consent form, will be obtained before that subject 
undergoes any study procedure.  The parent/legal guardian, will sign the consent form, and the 
investigator-designated research professional obtaining the consent. Subjects will be consented by the 
study Principal Investigator, or appropriate designee. Potential subjects will review the consent form in 
detail with the person designated to consent (either PI or CRC) and have the ability to take the consent 
home for further review.  
 
In the event of a health pandemic we will use telephone consent and obtain an electronic signature on the 
R2 parental permission form. This will only be used if parents are prevented from accompanying their 
child in the hospital because of a pandemic.  If ever necessary, we would help the site use an existing e-
signature software account or create a new one. 
 
Participants will be informed that their participation in all aspects of the proposed study is entirely 
voluntary, and that they are free to withdraw at any time. The consent process, which will follow an item-
by-item reading of the IRB-approved consent form, will include an explanation of the study, its voluntary 
nature, compensation, and the risks and benefits of participation. Consent forms will be written at no 
higher than a 6th grade reading level. All participants will be given the opportunity to ask questions and 
decline participation. Assent cannot be obtained because children of assenting age will be intubated and 
sedated. The completed consent document will be signed and dated by the individual obtaining consent, 
and a copy will be provided to the participating family. Signed consent forms will be stored in a locked 
cabinet. Should participants become intolerant of the study, their participation will be discontinued. 
Contact information for study PI and the study team will be included on consent forms to allow 
participants to ask questions or raise concerns about the study at any time. Should any specific concerns 
arise, the study team would intervene to address problems including, if needed, a change or 
discontinuation of study procedures. The study team and IRB will be informed of any concerns, and the 
NIH will be informed of any adverse events associated with the study. 
11 
Study Finances 
11.1 
Funding Source 
This study is financed through a grant from the US National Institute of Health- National Institute of Child 
Health and Human Development. 
11.2 
Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on Conflicts of 
Interest Related to Research.  
11.3 
Subject Stipends or Payments 
There are no subject payments or stipends for participation in this study.  
12 
Publication Plan 
A publication committee will be created to oversee study publications, and publication authorship based 
on the relative contributions of investigators and staff. 
 

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13 
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