Clinical trial NCT01937884
Conditions: Acute Respiratory Failure With Hypoxia Malnutrition
Sponsor: University of Arizona
Start date: 2013-08-01; Completion date: 2018-08-01
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Optimal delivery of nutritional support during critical illness is central to appropriate intensive care unit management, and yet fundamental gaps in knowledge exist regarding timing, route, dose, and type of nutritional support for critically ill infants and children. Understanding how to optimize nutritional support during pediatric critical illness is important because even brief periods of malnutrition in infancy result in permanent negative effects on long-term neurocognitive development. Optimized nutrition support is a way to improve morbidity for survivors of pediatric critical illness. Parenteral nutrition (PN) supplementation could improve long-term neurocognitive outcome for pediatric critical illness by preventing acute malnutrition, but has unknown effects on intestinal barrier function; a proposed mechanism for late sepsis and infectious complications during critical illness.

While randomized controlled trials (RCT) support early PN in premature infants and late PN in critically ill adults, the optimal time to begin PN is unknown for critically ill infants and children. Acute malnutrition may develop within 48 hours of admission in critically ill infants and children, and repleted energy stores are predictive of survival. And yet, due to concerns for PN-associated infectious morbidity, current PICU standard of care is to supplement with PN only in children who fail to enterally feed, as late as 7 days into their admission. Delays in nutrition may have long-term effects on cognitive outcome in older infants and children. In premature infants, PN begun within hours of birth results in improved 18-month neurocognitive outcome without an increase in infectious complications. An RCT is needed to determine if early PN in critically ill infants and children prevents acute malnutrition and improves short and long-term outcomes of PICU hospitalization.

The central hypothesis of this proposal is that optimized early protein and calorie delivery will improve nutritional outcomes and intestinal barrier function for critically ill infants and children. The overall purpose of this study is to evaluate the efficacy and safety of early PN as a supplement to enteral nutrition to improve nutritional delivery, nutritional outcomes, and intestinal barrier function for infants and children with acute respiratory failure who are mechanically ventilated in the pediatric intensive care unit.

Detailed description:

Arms: arm 1: Patients receive supplemental parenteral nutrition within 12 hours of enrollment. Titrated with enteral nutrition to achieve target goal calories and protein. arm 2: Patients receive supplemental parenteral nutrition 96 hours after enrollment. Titrated with enteral nutrition to achieve target goal calories and protein.
Interventions: intervention 1: Parenteral Nutrition
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
Supplemental Parenteral Nutrition in Pediatric Respiratory Failure 
SUPPER Study 
Manual of Operations 
03.06.2017 
NCT: NCT01937884 
 
 
 
 
PI: Katri V. Typpo, MD, MPH 
University of Arizona 
Pediatric Critical Care Medicine 
1501 N. Campbell Ave. Tucson, AZ 85724-5073 
 
 
Project Summary 
 
Acute hypoxemic respiratory failure (AHRF) accounts for 10% of all pediatric intensive care unit (PICU) 
admissions.  Nutritional support is central to appropriate PICU management of AHRF, and yet 
fundamental gaps in knowledge exist regarding best practice for timing, route, dose, and type of 
nutrition. Optimized nutritional support during pediatric critical illness is important because even brief 
periods of malnutrition in infancy result in permanent negative effects on neurocognitive 
development, an outcome with lifelong impact. Parenteral nutrition (PN) supplementation could 
improve long-term neurocognitive outcome for pediatric AHRF by preventing acute malnutrition, but 
has unknown effects on intestinal barrier function; a proposed mechanism for late sepsis and 
infectious complications during critical illness.  
 
In this research protocol we will randomize mechanically ventilated infants and children with AHRF 
who can be enterally fed and do not have a baseline intestinal disorder to early vs standard care PN.  
PN will be in combination with early EN to provide nearly immediate and constant goal calories and 
protein over the first week of mechanical ventilation in the early PN arm.  We want to examine the 
impact of a combined early EN + PN approach on intestinal barrier functions and nutritional 
biomarkers in children with AHRF.  The central hypothesis of this study is that combined early EN and 
PN support will improve both nutritional outcome and intestinal barrier function for critically ill infants 
and children with AHRF.  The overall goals of this project are to evaluate the efficacy and safety of an 
early PN strategy to improve nutritional delivery, nutritional outcomes, and intestinal barrier function 


2 
 
for children with AHRF in the PICU when used in combination with early EN. These goals will be 
addressed in 2 specific aims:  
 
Aim 1: Perform a prospective, single-blind, randomized pilot trial to determine the effect of early PN 
supplementation of EN versus late PN supplementation of EN in children with a functional 
gastrointestinal tract to meet measured resting energy expenditure on nutritional indices for infants 
and children with AHRF.  
 
Aim 2a:  Determine the effect of early combined EN + PN on intestinal barrier function in children 
with AHRF.  
Aim 2b: Identify patient, disease, and treatment factors, which act as effect modifiers for non-
invasive markers of intestinal barrier function for children with AHRF.  
Aim 2c: (Exploratory) Determine the influence of EN +/- PN on the intestinal microbiome in children 
with AHRF.  
 
This proposal is innovative, because will evaluate the extent to which early combined enteral and 
parenteral nutrition improves delivery of daily and cumulative goal calories, protein, and indices of 
nutrition (Aim 1), while monitoring for potential negative consequences of early PN on intestinal 
barrier function (Aim 2).  This proposal is significant, because it is expected to improve our 
understanding of optimal timing for parenteral nutritional support and define the effect of route and 
dose of nutrition, patient, disease, and treatment characteristics on intestinal barrier function. By 
understanding how patient, disease, and treatment factors impact intestinal barrier function during 
pediatric AHRF, we may be able individualize dose of enteral nutrition to protect against gut barrier 
dysfunction and promote new strategies to reduce septic morbidity; meeting the goals of NIH Healthy 
People 2020.    
 
 
 


3 
 
Timeline of Interventions 
 
 
 
 
Screening and Eligibility 
 
Screening is to take place twice daily (~8am and ~5pm) for newly intubated patients that meet 
inclusion criteria.  All screened patients will receive a study ID.  Enter the patient on the SUPPER 
Enrollment log for study ID.  Complete the SUPPER Screening form for all screened patients.  If the 
patient does not meet eligibility, complete the SUPPER Enrollment log and the Supper Screening form 
and place the Screening form in the study binder under Completed Screenings.  If the patient meets all 
inclusion criteria, with no exclusion criteria, the patient is eligible and the family may be approached 
for consent. If unsure whether an individual patient can be enrolled in the SUPPER study, please call 
the University of Arizona PI.  
 
Inclusion Criteria-  
Intent: To identify PICU patients who have Acute Hypoxemic Respiratory Failure and who will receive 
early enteral feeding.  
Inclusion Criteria 
1. Admitted to study hospital pediatric intensive care unit (PICU), 
2. One month to 16 years of age, 
3. Exhibits Acute Hypoxemic Respiratory Failure as defined as: 
1 month-16yrs,
With AHRF,
On enteral feeds, 
enrolled within 
24hrs of 
admission/
ventilation.
Randomized to 
Early 
Parenteral 
Nutrition
Randomized to 
Late Parenteral 
Nutrition
Day 1
Start PN 
Supplementation
First 24 Hrs. 4 sample collections
Day 2 
2 sample 
collections
Day 3-7
Daily sample collections
First 24 Hrs. 4 Sample 
collections
Day 5
Start PN 
Supplementation
Day 5 
4 sample collections
Day 3 & 4
Daily sample 
collections
Day 6 & 7
Daily sample 
collection
Day 1 or 2
Metabolic Cart 
Testing
Day 1 or 2
Metabolic Cart 
Testing
Day 5 or 6
Metabolic Cart 
Testing
Day 5 or 6
Metabolic Cart 
Testing
Enteral Nutrition
Enteral Nutrition
Day 1
Sugar Test
Day 5
Sugar Test
Day 1
Sugar Test
Day 5
Sugar Test
Day 2 
2 sample 
collections


4 
 
a. PaO2/FiO2 ≤ 300 or SpO2/FiO2 ≤ 260 
b. No evidence of left ventricular systolic dysfunction 
c. Mechanically ventilated,  
4. Require enteral tube feeding for nutrition, 
5. Anticipate placement of central venous line within 48 hours of intubation.  
 
Exclusion Criteria 
Intent: To exclude patients with a baseline intestinal disorder (which would alter biomarkers of 
intestinal barrier function), or who have contraindications to premixed PN solutions or sugar 
permeability testing.  
Patients will be excluded if at screening they have one or more of the following: 
1. Premature infants and neonates < 37 weeks corrected gestational age, 
2. Transfer patient from an outside facility and mechanically ventilated for >24 hours, 
3.  Receiving parenteral nutrition for > 24 hours, 
4. Known allergy to lactulose or mannitol, 
5. Pregnant, 
6. Thoracic trauma, abdominal trauma, and/or active intracranial bleeding,   
7. Anuric renal failure  
8. Previous bowel resection and/or short gut syndrome, inflammatory bowel disease, or any 
patient without a functional gastrointestinal tract. 
9. Cannot be enterally fed within 24 hours of admission according to the admitting physician, 
10. On extracorporeal membrane oxygenation (ECMO), 
11. Expected survival <24 hours or limitations to aggressive ICU care (DNR),  
12. Receiving active CPR when admitted to the PICU, 
13. A pre-existing bronchopleural fistula, 
14. At goal enteral feeds at time of screening, 
15. Previously enrolled and randomized into this protocol, 
16. Actively enrolled in another clinical trial, which at the discretion of the PI would conflict with 
this study. 
 
Consent and Assent 
 
This project involves both infants and children up through the age of 16 and is categorized as 45 CFR 
§46.405, greater than minimal risk with potential benefit, and requires parental consent.  Approach for 
consent must be within 24 hours of PICU admission or initiation of mechanical ventilation.  Document 
consent approach on the Supper Screening form and whether parental consent was obtained on the 
SUPPER Enrollment log.  Original parental consent forms are to be filed in the patient study file.  Make 
two copies of the parental consent form, one for the family and one for bedside.  Note in the patient 
medical record that patient was enrolled in the SUPPER Study.   
 
Patients ≥8 years of age are to be approached for assent if the patient is extubated, no longer under 
the influence of sedatives and analgesics, and the patient is actively receiving early or late parenteral 
nutrition per study.  If no assent obtained because the patient is sedated and unable to participate in 
the assent process, document this on the assent form and keep in patient study file. If the child does 
not provide assent once able to cooperate with assent, the intervention is discontinued at that point.  
All data obtained prior to assent will be utilized.  File original assent forms with original parental 


5 
 
consent form in the patient study file and document assent on the SUPPER Enrollment form.  Make 
two copies of the assent form, one for the family and one for bedside. 
 
 
Randomization 
 
Randomization takes place within 48 hours of PICU admission or initiation of mechanical ventilation.  
Patients are blocked randomized by age and pre-existing acute or chronic malnutrition (based on 
admission weight for age BMI z score) to either early or late parenteral nutrition (PN) supplementation. 
There are 9 randomization stratifications (see table below).  Randomization cards are pre-generated; 
random sequence was created using a random generator with atmospheric noise at random.org.  BMI 
z-score is derived from one of two websites.  If <2 years of age, use 
www.emmes.cpm/study/ped/resources/htwtcalc.htm; if ≥2 years of age, use 
www.stokes.chop.edu/web/zscore/index/php.  
 
 
1month to <3 years 
3-10 years of age 
11-16 years of age 
BMI z score < -1 and >-2 
(Low) 
A1 
B1 
C1 
BMI z score    -1 to +1 
(Normal) 
A2 
B2 
C2 
BMI z score > +1 and < +2 
(High) 
A3 
B3 
C3 
 
 
 
        
To randomize a successfully consented patient, use age and BMI z score to determine which 
randomization block the patient should be in.  Choose the first randomization envelope in the pack.  
The envelope will have a card stating the intervention arm.  Record the patient’s study ID, patient age, 
BMI z-score, name of study personnel randomizing, and date/time of randomization on the card, and 
staple to the SUPPER Screening Form.  Document date, time and study intervention randomized on the 
patient’s SUPPER Screening form and SUPPER Enrollment Log. 
 
Once randomized, email the study PI the patient’s study ID, age BMI z score, date and time of 
randomization, and assigned intervention. 
    
Patient Kits and Supplies 
 
Each successfully enrolled and randomized patient will have a patient study file.  This file will contain 
all forms for that patient.  SUPPER Study Sample Kits have been provided for the collection of blood, 
and stool for this study.  One kit is to be used per patient.   
 
 
 
 


6 
 
Early Parenteral Nutrition Supplementation (EPN) 
Supplies, Medications, and Forms to have on hand when starting:   
SUPPER Tablet with SUPPER Titration 
Supplemental PN (Baxter Clinimix for patients 1 year of age and older; in-house custom PN for infants 1 
month and <1 year) 
SUPPER Patient Study Binder 
SUPPER Sample Kit  
Tape measure to perform mid upper arm circumference 
 
Once randomized to Early Parenteral Nutrition (EPN), patients are to be started on the PN intervention 
within 2 hours of randomization.  Patients randomized to EPN will receive enteral nutrition with 
supplemental PN for 168 hours.  Calorie goal and titration of PN/IL are according to the SUPPER 
Titration Tool.   If at any point the clinical team feels that it is unsafe to continue PN, discontinue PN 
immediately and record this as a protocol violation. Ensure appropriate monitoring of blood glucose 
after abrupt discontinuation of PN. Reducing the hourly rate of PN to achieve clinically indicated fluid 
restriction is also acceptable for the study protocol.  All attempts should be made, and the study 
protocol is designed to avoid fluid overload as a result of PN.  The SUPPER Titration Tool does not allow 
PN to exceed MIVF rates. Obtain mid upper arm circumference.  
 
Prior to EPN Hour 0, set up SUPPER Tablet at bedside.  Open the SUPPER Titration and enter all of the 
patient demographics, formula, TPN, and fluid information at the top.  Calculate Schofield 100% BMR 
(height/weight).  Rates for EN, PN, Lipids, and remaining available hourly fluids will populate.  Print 
SUPPER Titration for bedside and study binder and review with the bedside nurse.  A new SUPPER 
Titration Tool will need to be created for any change in formula kcal content, calorie goal, or new total 
fluid order (such as in the case of fluid restriction).  As EN feeds are advanced, PN and Lipids decrease.  
If EN is held or reduced, titrate PN and Lipids according to SUPPER Titration sheet.  Choice of PN is 
based on patient age.  If the patient is 1 year of age or older, patients will receive Baxter Clinimix.  
Patients between 1 month of age and <1 year of age will receive in-house custom PN. The early EN 
guideline in place for clinical use at CHOP will be used to increase enteral feeds.  The goal should be to 
reach full enteral feeds within 48 hours of initiating EN.  
 
The SUPPER Algorithm uses Schofield’s equation to calculate the initial kcal/day goal.  Patients are to 
initially receive a max of 75% of calorie goal and 1.5 gm/kg/day protein for the first 24 hours.  Patients 
will receive 100-120% of MREE (or 100-120% of Schofield predicted BMR in the setting of no MREE) 
and 2-3gm/kg/day protein with combined PN and EN by study day 2, not to exceed 1600mL/M2/day in 
fluids (See Table at end of MOO).  If there is >20% discrepancy between the unit dietician’s usual 
practice for determination of kcals/day for a given patient and the Schofield predicted BMR, please call 
the U of A PI to discuss altering the individual patient’s kcal goal during the 7-day study intervention.  
The bedside nurse will titrate PN to maintain calorie goal and protein every 4 hours with the aid of the 
SUPPER Titration Sheet in place of usual total IVF orders.  As patient tolerates increased EN, PN and IL 
are decreased. In this manner, in the Early PN arm, the patient’s delivered calories and protein remain 
constant, although the route of delivery changes as enteral feeds advance.  
 
 
 


7 
 
 
0 
Hour 
12 
Hour 
24 
Hour 
48 
Hour 
72 
Hour 
96 
Hour 
120 
Hour 
144 
Hour 
168 
Hour 
Blood 
Sample 
2mLs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fecal 
Samples  
(if patient 
has stool) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Metabolic 
Cart (REE) 
Occurs Between 0 hour and 48 
hours (DCMC Only) 
 
Occurs Between 96 
hours and 144 hours 
(DCMC Only) 
 
   
Before initiation of EPN, collect 0 hour blood sample.  This may be collected within 4 hours prior to 
beginning EPN to coordinate with clinical laboratory sample collection.  Continue with timed sample 
collections as shown in the table above, using the time of EPN initiation as the starting point.  All 
samples may be collected ± 2 hours from target time.  If patient has continuous vasoactive infusions 
and the infusion has been titrated within the last hour of the time of sample collection, wait at least 1 
hour from time of last vasoactive infusion change. (For example, sample collection is to be drawn at 
8:00am, and vasoactive infusion was titrated last at 7:30am, wait until 8:30am for sample collection).  
Where ever possible, match sample collection with clinical labs to reduce line access and risk of 
infection.  For clinical variables recorded on the sample collection log use clinical data obtained within 
the hour prior to sample collection.  (i.e. if sample collection is at 0805, record CVP from the clinical 
record between 0705-0805.) 
 
While writing initial orders for EN/PN, also include orders for PINI.  This includes albumin, c-reactive 
protein, fibrinogen, transferrin, and prealbumin.  If these values are not already available pre-
randomization, then obtain within 4 hours of randomization.  
 
If the care team decides the patient does not require artificial nutrition and/or central access lines are 
no longer needed, PN regimen is to be discontinued. 
 
 
After Initiation of EPN: 
 
SUPPER Pre-Admit Questionnaire and SUPPER Baseline Form 
 
Once the patient has been initiated on EPN, retrieve the SUPPER Pre-Admit Questionnaire from the 
patient study file.  SUPPER Pre-Admit Questionnaire should be completed within 24 hours of 
randomization.  Ideally, study personnel should sit with family and complete the questionnaire to assist 
the family with any questions and ensure that questionnaire is successfully completed. 
 
Using the patient’s medical record, complete the SUPPER Baseline Form.  Include only information 
prior to time of randomization.  For variables with multiple values, choose that which is closest to 
randomization.        


8 
 
 
SUPPER Daily Data Collection and SUPPER EN/PN Tracking Log 
 
SUPPER Daily Data Collection forms are provided for each of the intervention days and can be found in 
the patient’s study file.  For variables with multiple values use value closest to 8:00am, unless 
otherwise noted.  For Day 0 Daily Data Collection, only use post randomization information.  These 
forms do not need to be completed in real time if normal bedside charting clearly provides required 
information, but we recommend completing them the day after they occur (ex: Day 0 completed on 
Day 1). 
 
Due to frequent collection of study labs, it is recommended to speak with bedside nurse at these times 
to gather information about possible adverse events or signs of feeding intolerance.  SUPPER study labs 
may be delayed by 1-2 hours, if necessary, to ensure that blood collection occurs at a time when 
vasoactive infusions have not been titrated for 1 hour.   
 
Using nutrition charting and tracking of in/out fluids, complete a SUPPER EN/PN Tracking Log for each 
study day. 
 
Metabolic Cart Testing (University of Arizona only) 
 
Within the first 48 hours of the intervention, the patient’s Resting Energy Expenditure (REE) is to be 
tested using the site’s available metabolic cart.  Print at least two copies of the REE results; one for the 
patient study file and one for the patient’s medical record.  Attending physician caring for the patient 
should be updated on REE results.  Record REE results on the SUPPER Sample log and file in the 
patient’s study file.  Repeat REE between Hour 96 and 144 of the intervention. 
 
Prescribed kcal/day from the REE maybe different than the calculated kcal/day goal from the SUPPER 
Titration.  If it is different, enter the new Measured REE kcal/day in the space provided.  The SUPPER 
Titration sheet will utilize this new goal and adjust EN, PN, and Lipid rates accordingly.   
 
At Hour 96 document PINI.  This includes albumin, C - reactive protein, fibrinogen, transferrin, and 
prealbumin.   
 
Discharge and Follow Up 
 
Prior to patient PICU discharge, complete the SUPPER Contact Form with the parent/guardian.  This 
form will be used for the 28 Day Vitals check if patient is not in the hospital or deceased. 
 
There are 5 key sections to the SUPPER Discharge Form, Extubation, PICU Discharge, Hospital 
Discharge, Early Cessation, and 28 Day Vitals and Patient Death.  Complete each of these sections as 
they occur.   
 
To assess 28 Day Vitals first check to see if the patient is still hospitalized or if the patient died while 
hospitalized.  If patient is not hospitalized, use the SUPPER Contact form to contact the patient’s 
parents/guardians.  Three attempts should be made to contact the parents/guardians.  If the third 
attempt is unsuccessful, attempt to contact the patient’s primary care physician.  If the patient has not 


9 
 
been seen by the primary care physician since hospitalization, assess vital status from county death 
records.  If you can successful contact either the patient’s parents/guardians or primary care physician 
obtain information on whether the patient’s condition is better, the same, or worse from condition at 
discharge.  Also obtain information on whether the patient was readmitted to the hospital on or before 
28 Days. 
 
Late Parenteral Nutrition Supplementation (LPN) 
 
Supplies and forms for have on hand after randomization. 
SUPPER Tablet with SUPPER Titration 
SUPPER Patient Study Binder 
SUPPER Sample Kit 
Tape measure to measure mid upper arm circumference 
 
Once randomized to Late Parenteral Nutrition (LPN), patients are to be started on EN within 2 hours of 
randomization if not already started.  Patients randomized to LPN will receive enteral nutrition for 168 
hours and supplemental PN if not reaching 80% goal feeds starting at Hour 96 for a total of 72 hours.  
Calorie goal and titration of feeds are according to the SUPPER Titration. Obtain mid upper arm 
circumference.  
 
Prior to LPN Hour 0, set up SUPPER Tablet at bedside.  Open the SUPPER Titration and enter all of the 
patient demographics, formula, and fluid information at the top.  Rates for EN and remaining fluids will 
populate.  Print SUPPER Titration for bedside and study binder and review with the bedside nurse. 
 
The SUPPER Titration uses Schofield’s equation to calculate the initial kcal/day goal.  Patients are to 
initially receive a max of 75% of calorie goal and 1.5gm/kg/day protein for the first 24 hours.  Patients 
will receive 100-120% of MREE and 2-3gm/kg/day protein with combined EN by study day 2, not to 
exceed 1600mL/M2/day in fluids.  As the patient can tolerate, EN is to be escalated every 4 hours to full 
kcal/day goal.    
 
The LPN intervention starts with the initiation of enteral feeds.  Initiation of EN should take place 
within 2 hours of randomization if the patient was not already on EN.  Within 2 hours of 
randomization, collect 0 hour blood sample and continue with timed sample collections as shown in 
the table below using the time of LPN initiation as the starting point.  All samples may be collected ± 2 
hours from target time.  Where ever possible, match sample collection with clinical labs to reduce line 
access and risk of infection. 
 
While writing initial orders for EN also document PINI.  This includes albumin, C - reactive protein, 
fibrinogen, transferrin, and prealbumin.  If these values are not already available pre-randomization, 
then obtain within 4 hours of randomization. 
 
 
 
 
 


10 
 
 
0 
Hour 
12 
Hour 
24 
Hour 
48 
Hour 
72 
Hour 
96 
Hour 
120 
Hour 
144 
Hour 
168 
Hour 
Blood 
Sample 
2mLs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fecal 
Samples  
(if patient 
has stool) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Metabolic 
Cart (REE) 
Occurs Between 0 hour and 48 
hours (DCMC Only) 
 
Occurs Between 96 
hours and 144 hours 
(DCMC Only) 
 
   
 
SUPPER Pre-Admit Questionnaire and SUPPER Baseline Form 
 
Once LPN is initiated and 0 hour sample is collected, retrieve the SUPPER Pre-Admit Questionnaire 
from the patient study file.  SUPPER Pre-Admit Questionnaire should be completed within 24 hours of 
randomization.  Ideally, study personnel should sit with family and complete the questionnaire to assist 
the family with any questions and ensure that questionnaire is successfully completed. 
 
Using the patient’s medical record, complete the SUPPER Baseline Form.  Include only information 
prior to time of randomization.  For variables with multiple values, choose that which is closest to 
randomization. 
 
SUPPER Daily Data Collection and SUPPER EN/PN Tracking Log 
 
SUPPER Daily Data Collection forms are provided for each of the intervention days and can be found in 
the patient’s study file.  For variables with multiple values use value closest to 8:00am, unless 
otherwise noted.  For Day 0 Daily Data Collection, only use post randomization information.  These 
forms do not need to be completed in real time if normal bedside charting clearly provides required 
information, but we recommend completing them the day after they occur (ex: Day 0 completed on 
Day 1). 
 
Due to frequent collection of study labs, it is recommended to speak with bedside nurse at these times 
to gather information about possible adverse events or signs of feeding intolerance.  Supper study labs 
may be delayed by 1-2 hours, if necessary, to ensure that blood collection occurs at a time when 
vasoactive infusions have not been titrated for 1 hour.  Data on the daily sample collection forms (vital 
signs and clinical data) are to be collected as the most recent vital sign in the hour PRIOR to blood 
sample collection.  
 
Using nutrition charting and tracking of in/out fluids, complete a SUPPER EN/PN Tracking Log for each 
study day. 
 
 


11 
 
Metabolic Cart Testing  
 
Within the first 48 hours of the intervention, the patient’s Resting Energy Expenditure (REE) is to be 
tested using the site’s available metabolic cart.  Print at least two copies of the REE results; one for the 
patient study file and one for the patient’s medical record.  Attending physician should be updated on 
REE results.  Record REE results on the SUPPER Sample log and file in the patient’s study file.  Repeat 
REE between Hour 96 and 144 of the intervention. 
 
Prescribed kcal/day from the REE maybe different than the calculated kcal/day goal from the SUPPER 
Titration.  If it is different, enter the new Measured REE kcal/day in the space provided.  The SUPPER 
Titration sheet will utilize this new goal and adjust EN rates accordingly. 
 
At Hour 96 record PINI.  This includes albumin, C - reactive protein, fibrinogen, transferrin, and 
prealbumin.   
 
Initiation of PN at Hour 96 
 
At hour 96, late supplemental PN is initiated if the patient is not meeting 80% of calorie goal on EN 
feeds alone.  Choice of PN is based on patient age.  If patient is 1 year of age or older, patients will 
receive Baxter Clinimix E 5/15.  Patients between 1 month of age and 1 year of age will receive in-
house custom PN.  Enter PN/EN doses into SUPPER Titration, and start tracking PN on the PN/EN 
Hourly Log with first PN entry under the hour PN is initiated.  The bedside nurse will titrate PN to 
maintain calorie goal and protein every 4 hours with the aid of the SUPPER Titration Sheet.  As patient 
tolerates increased EN, PN is decreased.  
 
If the care team decides the patient does not require artificial nutrition and/or central access lines are 
no longer needed, PN regiment is to be discontinued, or foregone if before 96 hours. 
 
Discharge and Follow Up 
 
Prior to patient PICU discharge, complete the SUPPER Contact Form with the parent/guardian that 
provided consent for this study.  This form will be used for the 28 Day Vitals check if patient is not in 
the hospital or deceased. 
 
There are 5 key sections to the SUPPER Discharge Form, Extubation, PICU Discharge, Hospital 
Discharge, Early Cessation, and 28 Day Vitals and Patient Death.  Complete each of these sections as 
they occur.   
 
To assess 28 Day Vitals, first check to see if the patient is still hospitalized or if the patient died while 
hospitalized.  If patient is not hospitalized, use the SUPPER Contact Form to contact the patient’s 
parents/guardians.  Three attempts should be made to contact the parents/guardians.  If the third 
attempt is unsuccessful, attempt to contact the patient’s primary care physician.  If the patient has not 
been seen by the primary care physician since hospitalization, assess vital status from county death 
records.  If you can successful contact either the patient’s parents/guardians or primary care physician 
obtain information on whether the patient’s condition is better, the same, or worse from condition at 


12 
 
discharge.  Also obtain information on whether the patient was readmitted to the hospital on or before 
28 Days. 
 
Subject Withdrawal 
 
Subjects may withdraw from the study at any time.  Should the patient or the patient’s 
parents/guardians wish to withdraw, note the date, time, and reason for withdrawal on the SUPPER 
Discharge Form.  If the patient is receiving supplemental PN when they wish to withdraw from the 
study, review the risks associated with abrupt discontinuation of PN, and advise that the patient will 
require blood sugar monitored 2-3 times over a 24 hour period to ensure they do not develop 
hypoglycemia.  Ask parents/guardians if we may continue to collect information from the medical 
record without continuing any study procedures for outcome analysis.  If they gave permission to bank 
samples for future research, ensure this has not changed. 
 
Data Collection and Entry into REDCap 
Prior to starting the study, sites will provide a written plan on how and from what system data is 
obtained.  This is to assist with consistency of source of information, and to provide a guide for data 
monitoring.  For instance, if vitals and medications are found in different applications of the medical 
record system, it should be noted where source documentation is obtained. 
 
Data is to be collected onto the provided SUPPER study forms from source documentation.  All data 
forms are to be kept in the patient’s study file and the file kept in a secure location.  Study personnel at 
each site will have a username and password to REDCap.  REDCap is serviced and maintained by the 
University of Arizona’s Clinical and Translational Sciences Research Center (CATS) Informatics Core.  All 
SUPPER data should be entered into REDCap no later than 2 week from Study Day 7.  SUPPER 
Enrollment Log information from the previous week should be entered every Monday when ever 
possible.      
 
Sample Collection 
 
Each patient will have a max of 11 blood samples and 8 stool samples.  Blood samples are to be taken 
from indwelling catheters placed for clinical care.  Stool samples will be collected from diapers, or in 
older patients, bed pans.  Each blood sample collected will amount to 2mLs for a total of 22mLs. 
  
Collect samples per the sample collection table provided and coordinate these samples collections so 
that they are obtained when clinical labs are being obtained.  SUPPER Sample Kits are labeled for each 
sample collection and have either a 4mL purple top EDTA tube or a sterile double swab.  For each 
blood collection tube, there are 5 red-capped aliquots. 
 
Blood Samples 
• From the patient’s indwelling catheter, draw 2mLs of blood per unit protocol and place into the 
provided EDTA tube. 
• Gentle invert EDTA tube 3 times to mix preservative. 
• Place sample tube on ice after collection or store at 4⁰C.  


13 
 
• Within 4 hours of collection, spin blood samples at 3600 RPM for 15 minutes in 4⁰C refrigerated 
centrifuge (if available).  The specific technique standard for separating plasma by a site’s 
central laboratory is also acceptable. 
• Using a micropipette, pipette 250µL of plasma into each of the 5 red capped aliquots. 
• Complete labels with patient Study ID, date, and time of collection and place labels on 
collection tube and aliquots. 
• Freeze collection tube and 5 aliquots upright at -80⁰C in provided boxes.  Use Box 1 for serum 
and blood pellet.  Label each box with the patient Study ID.   
 
Stool samples 
• Collect stool samples using provided double swap sample container (preservative free) from the 
patients diaper, or from bedpan.  It is acceptable to have urine in the same diaper.  
• Place sample tube on ice after collection or store at 4⁰C. 
• Freeze at -80⁰C within 4 hours of collection. Use Box 2 for stool samples tubes. 
 
All samples must remain frozen until ready for shipping.    
 
Shipping 
Timing of shipping is to be quarterly or after collection of all samples for 4 patients, whichever is first.  
Contact the site PI or research coordinator the day prior to shipping to obtain FedEX label and to notify 
that shipment is coming. 
 
Directions for Shipping Samples to University of Arizona 
• Place collection boxes in large biohazard bags. All bags should fit in one large shipping box. 
• Label the bag with Study ID. 
• Obtain dry ice and package these samples in the large insulated shipping box. 
• Using provided shipping labels, ship these samples to: 
Katri Typpo, MD 
1501 N. Campbell Ave. 
Pediatric Critical Care, Room 3354 
Tucson, Arizona 85724-5073 
 
Protocol Deviations 
 
In the event of protocol deviations, deviations must be recorded on the SUPPER Protocol Deviation Log 
and on the SUPPER Daily Data Collection form for the day the protocol deviation took place.  There are 
six protocol deviation categories. 
1. EN Feeds paused for >2 hours; one exception is if feeds are stopped for 4hr pre and post 
extubation. 
2. PN not administered per protocol 
3. Metabolic cart not done per protocol (Not a violation at CHOP) 
4. 2 Sugar Test not done per protocol (Not a violation at CHOP) 
5. Blood sample collection not done per protocol 
6. Other 


14 
 
Describe the deviation with as much detail as possible on the SUPPER Protocol Deviation Log.  Protocol 
deviations that result in the harm of the patient, others, or indicate that the patient or others may be at 
increased risk of harm must be reported to study PI within 24 hours of knowledge of the deviation. 
 
Serious, Unexpected, and Expected Adverse Events Definitions 
The study subjects are mechanically ventilated, critically ill infants and children with acute respiratory failure and 
as such are known to have mortality rates of 8-22%.  We do not anticipate any serious adverse events 
specifically related to the short-term use of study PN formulations, performance of the metabolic cart, or to 
blood and urine sampling, but will report standard adverse events.  All serious, unexpected, or unanticipated 
problems that are potentially related to study procedures will be reported to the PI, local IRB, the medical 
monitor, he DSMB and study sponsor within 24 hours.  SAE’s and AE’s will be reported up to and including 14 
days after study enrollment.  Ongoing SAE’s and AE’s will be followed until resolved.  A 28-day AE, SAE follow up 
form will be included in subject monitoring for 28-day vital status. The medical monitor will determine if the 
serious adverse event is potentially related to study procedures. 
 
For safety monitoring, all adverse and serious adverse events are to be recorded and tracked.  In addition to 
local site reporting for adverse events and serious adverse events, following guidelines are to be followed for 
this study. 
 
Serious Adverse Event is any of the events listed below: 
1. Death within 28 days of enrollment 
2. Cardiopulmonary arrest 
3. Operation or re-operation 
4. Any other event that is not listed in the Expected Adverse Events, that increased risk and/or harm to the 
patient, may increase hospital length of stay, or require treatment.  
 
If one of these events occurs, the medical monitor and PI within 24 hours of knowledge of the event.  These 
events are also recorded on the SUPPER Adverse Event Log.  A chart review of events leading up to the SAE will 
be required to determine relatedness to the study. 
 
Expected Adverse Events 
1. Aspiration of tube feeding 
2. Unplanned extubation or need for reintubation 
3. Pneumothorax 
4. Desaturation < 85% 
5. Pulmonary embolus 
6. Catheter associated thrombosis 
7. Healthcare acquired infections (Catheter associated blood stream infection, ventilator associated 
pneumonia, catheter associated urinary tract infection) as defined by the hospital infection prevention 
8. Readmission to the pediatric intensive care unit 
9. Cholestatic jaundice 
10. Hyperglycemia (blood glucose >250 mg/dL) 
11. Hypoglycemia (blood glucose <60 mg/dL) 
12. Hyperammonemia 
13. Acute Kidney Failure 
 
If an adverse event occurs, it is to be noted on the SUPPER Adverse Event Log and the SUPPER Daily Data 
Collection form for the day the event occurred.  All adverse events will be reviewed weekly by Dr. Katri 
Typpo to ensure study patient safety. 
  


15 
 
Report A/E and SAE per local IRB regulations as needed and required. 
 
Data and Safety Monitoring Plan 
 
Should study subjects have adverse events related to study interventions in Aim 1 or Aim 2 we will report these 
to the local and primary IRB and the Safety Officer (K Typpo). The DCMC study coordinator will produce 
Administrative Reports quarterly to describe study progress to include: accrual, subject demographics, and 
subject status. Reports will also describe adherence to inclusion/exclusion criteria, and protocol deviations. 
Safety reports will also be generated quarterly, or if enrollment exceeds expectations, at least with every 10 
patients enrolled, list frequencies of adverse events, serious adverse events, safety outcomes, deaths, and 
disease or treatment specific events in blinded groups for review. These reports will be reviewed internally for 
ongoing quality control and then presented to the Safety Officer, DSMB, and IRB. The Safety Officer will review 
these quarterly reports to ensure good clinical care and identify any potential trends.  The Safety Officer may 
request interim reports and analysis between meetings or prior to the scheduled interim analysis when 
necessary. Clinicians will be blinded to the safety monitoring data, as exposure to emerging trends may 
influence enrollment and care, biasing the study.  This is designed as a single-blinded study so that the treating 
physician and investigative team are aware of group assignment in the event of electrolyte abnormalities, loss of 
central venous access, and related to feasibility of blinding PN. Our safety officer will also review charts for 
randomized subjects to ensure that no adverse events are attributable to the study intervention, this is in 
addition to review by the study PI.  
 
Interim Safety Analysis 
 
After 40 patients are enrolled, the Safety Officer and biostatistician blinded to group intervention will examine 
the safety endpoints stratified by TPN group, blinded into group A and group B.  By utilizing the REDCap 
database, we are able to lock the database during this safety evaluation.  We will trigger additional safety 
evaluations (e.g., more frequent or using an independent clinical panel) analysis if mortality rates (or other 
safety outcomes) in either arm are statistically different based on the previously mentioned safety reports, or 
statistically different from historical controls.  Furthermore, since safety outcomes are not always powered for 
“statistical significance”, these safety evaluations will also be examined in a more qualitative fashion, with error 
being on the side of overly conservative (e.g., any possible difference in safety outcomes).  If there is any doubt 
then an independent panel of clinicians will be convened; if this group decides that there is an unacceptable 
difference in the two treatment arms then Aim 1 data collection will terminate prior to completing enrollment.  
Specifically, if either treatment group has significantly increased incidence of hospital acquired infections, 
increased utilization of dialysis, increased duration of mechanical ventilation, or mortality, then the independent 
panel can ask for unblinded data.  If after data are presented data in an unblinded manner, the independent 
panel believes that safety concerns are unbalanced between the two arms then the study described in Aim 1 will 
be discontinued. Aim 2 data and sample collection will continue as planned but in patients on usual care for 
timing of EN and PN. 
A DSMB was convened for this study as part of the Data Safety Monitoring Plan:  
 
DSMB responsibilities 
The first responsibility of the DSMB will be to approve the final protocol of the clinical study so that the 
study/studies can begin enrolling patients.  In this case, the Supper study is ongoing and the DSMB will provide 
approval for continuing enrollment.  After initial review of the study protocol and consent documents, and at 
periodic intervals during the course of the study, the DSMB responsibilities are to: 
 
• 
Provide input to assist the investigators in protecting the safety of study participants; 
• 
Provide input to the investigators on major changes to the research protocol, informed consent 
documents and plans for data and safety monitoring; 


16 
 
• 
Provide input to the investigators on the progress of the study, including periodic assessments 
of the data quality and timeliness, participant recruitment, accrual and retention, participant 
risk vs benefit, performance of the study sites, and other factors that may affect study 
outcomes; 
• 
Review areas of concern regarding the performance of individual sites and provide comment to 
the investigators on actions to be considered regarding sites that perform unsatisfactorily; 
• 
Consider factors external to the study when relevant information becomes available, such as 
scientific or therapeutic developments that may have an impact on the safety of the participants 
or the ethics of the study; 
• 
Provide input to the investigators on modification of the study protocol or possible early 
termination of the study because of attainment of study objectives, safety concerns, low 
likelihood of showing a benefit of the intervention, or inadequate performance (such as 
enrollment and retention problems); 
• 
If appropriate, review the interim analysis of efficacy in accordance with stopping rules which 
are clearly defined in the protocol and have the concurrence of the DSMB; 
 
Statistical Analysis Plan:  
 
Aim 1. We will assess differences between cumulative percent of goal energy and protein by study arm. We 
will report means and standard deviations as standard descriptive statistics. We will compare means between 
study arms with the Student’s t tests as we expect cumulative percent of goal energy and protein to have 
normal distributions. Results will be considered significant at p<0.05. Relationships between cumulative 
energy and protein delivered with clinical characteristics, mid upper arm circumference changes, and weight 
for age z scores will be reported by Pearson’s correlation coefficient. 
 
Aim 2. We will assess differences between FABP2, claudin 3, citrulline, lactulose/mannitol ratios, and by study 
arm. Descriptive plots: serum biomarker (y-variable) over time (x–variable) will be fit, with 
linear and smoothing splines. Plots are qualitative. Splines allow examination of possible nonlinear 
relationships and can be used to specify nonlinear or change-point models. We utilize one-way repeated 
measures ANOVA with the intestinal barrier assays as continuously measured outcomes and time (1,2,3,5, 
and 7 days) as explanatory variables. If the slope of the serum biomarkers is linear, then change in the slope 
over time will be calculated using a linear mixed effects model with an AR(1) variance-covariance structure. 
The variance-covariance structure allows for measurements taken closer together to be more similar than 
those farther apart in time, and adjusts the standard errors for this correlation. If the relationship between the 
serum biomarker is not linear in time, then change-point or nonlinear mixed effects models will be used. Aim 
Multivariable regression analysis will evaluate possible effect modification, or mediation, for non-invasive 
measures of intestinal epithelial barrier function. Effect modifiers are the interactions with PN group; mediators 
are those variables that could have a potential additive effect with the PN group. Additionally we will assess 
any potential confounding that might be present by assessing the change in the parameter estimate for the PN 
group effect. Potential modifiers, mediators, and confounders, include clinical variables, center effects, and 
severity of illness. We will test associations between measures of intestinal function and clinical variables, 
severity of illness, as well as dose and route of nutrition. With 40 subjects total, we will be able to include up to 
4 possible predictors; therefore, if effect modifiers are warranted, model simplification will be necessary. If the 
study is stopped early the analysis plan may be modified due to small sample size.