Protocol

Protocol
This trial protocol has been provided by the authors to give readers additional information about their work.
Protocol for: Fivez T, Kerklaan D, Mesotten D, et al. Early versus late parenteral nutrition in critically ill children.
N Engl J Med 2016;374:1111-22. DOI: 10.1056/NEJMoa1514762
This supplement contains the following items:
1. Original protocol, final protocol, summary of changes.

2. Original statistical analysis plan, final statistical analysis plan, summary of changes
Protocols
For the KU Leuven:
1. Initial protocol (incl. original statistical analysis plan) 3
2. Summary of all amendments 36
3. Most recent protocol (incl. most recent statistical analysis plan) 42
For the Erasmus Universiteit Rotterdam:

5. Summary of all amendments 133
6. Most recent protocol (incl. most recent statistical analysis plan) 138
For Stollery Children’s Hospital Edmonton:

Ethical approvals
For the KU Leuven:
8. Ethical approval of the initial protocol 224
9. Ethical approval of the most recent protocol 228
For the Erasmus Universiteit Rotterdam:

11. Ethical approval of the most recent protocol 244
For Stollery Children’s Hospital Edmonton:

13. Trails paper (Final published protocol and statistical analysis plan) 260
1. Initial protocol (incl. original statistical analysis plan) -
KU Leuven
Versienummer 1
14-02-2012
Impact of Early Parenteral Nutrition Completing Enteral Nutrition

in Paediatric Critically Ill Patients
STUDY PROTOCOL
TABLE OF CONTENTS
SYNOPSIS OF STUDY RATIONALE ......................................................................... 2

I. PROTOCOL SYNOPSIS .................................................................................... 3
II. INTRODUCTION ................................................................................................ 6
III. KEY STUDY OBJECTIVES ................................................................................ 7
IV. STUDY POPULATION ........................................................................................ 7
V. STUDY TIMETABLE .......................................................................................... 8
VI. STUDY PROCEDURES ..................................................................................... 8
VII. INVESTIGATIONAL PRODUCTS .................................................................... 12
VIII. OUTCOME MEASURES .................................................................................. 12
IX. ADVERSE EVENTS ......................................................................................... 13
X. STATISTICAL ANALYSES .............................................................................. 14
XI. ADMINISTRATIVE AND LEGAL ASPECTS ................................................... 15
XII. STUDY PERSONNEL ...................................................................................... 16
Appendix 1: Protocol Enterale Voeding PICU ...................................................... 17
Appendix 2: STRONGkids Protocol....................................................................... 18
Appendix 3: Informed Consent .............................................................................. 19
Appendix 4: Sepsis Criteria op de PICU ............................................................... 21
Appendix 5: Flow Chart .......................................................................................... 22
Appendix 6: Voorschriftbladen TPN ............................................................ ..........23
Appendix 7: Glycemie controle op de PICU………………………………………….27
References……………………………….………………………………………………...31
SYNOPSIS OF STUDY RATIONALE
The PEPaNIC-study is an investigator-initiated, non-commercial, multi-centre randomized controlled, parallel

group clinical trial. The study intervention is to withhold parenteral nutrition (PN) during the first week of
intensive care stay in critically ill paediatric patients. The administration of enteral nutrition will be guided by
the same early enteral feeding protocol in both study groups. It will be the first multi-centre RCT on nutrition
in critically ill children and will meet an urgent scientific need looking at short-term and long-term effects of
PN in critically ill children. The study will also include a full health economy analysis.
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I. PROTOCOL SYNOPSIS
Protocol Title: Impact of Early Parenteral Nutrition Completing Enteral Nutrition in Pediatric Critically Ill
Patients
Principal Leading principal investigator:
Investigators: Prof. Dr. Greet Van den Berghe
Principal Investigators for the KULeuven:
Prof. Dr. Dieter Mesotten

Prof. Dr. Dirk Vlasselaers
Dr. Lars Desmet
Prof. Ilse Vanhorebeek
Dr. Tom Fivez
Principal Investigators for the Erasmus Universiteit, Rotterdam:

Prof. Dr. Dick Tibboel
Dr. Koen Joosten
Dr. Sascha Verbruggen
Trial Centres: University Hospitals of the KU Leuven, Belgium & the University Hospital of the
Erasmus Universiteit Rotterdam, the Netherlands
Type of the trial: Investigator-Initiated, Non-Commercial Study
Test Preparation: Parenteral nutrition completing enteral nutrition versus enteral nutrition
Reference Drug: Smoflipid or Intralipid 20% and pharmacy-prepared parenteral nutrition or Oli-Clinomel
Posology and Intravenous administration according to calculated caloric needs.
method of
administration:
Patient Population: Children with critical illness and a STRONGkids score of 2 points or more (cfr appendix
2)
Method of Clinical follow up, laboratory analyses and ultrasonography
evaluation:
Number of patients: 1440
Duration of patient 3 à 3.5 years
recruitment:
Study Duration: 4 years (excluding a study on long term effects and excluding the mechanistic studies)
Study Design: A multicentre, open-label, randomized, parallel group efficacy, safety and tolerability
study
Sample size: 720 per study arm
Primary endpoint: The incidence of new infections and the time to alive discharge from ICU up to 90 days
post-randomization.
Secondary - Mortality up to 90 days post-randomization.

endpoints: - Time to final (alive) weaning from mechanical respiratory support
up to 90 days post-randomization.
- Time to final (alive) discharge from hospital up to 90 days post-randomization.
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- The Incidence of hypoglycaemia during ICU stay up to 90 days post-randomization.
- The presence or absence of new kidney injury during intensive care
- The presence of abnormal liver function tests during intensive care
- Time to alive discharge up to 90 days post-randomization.
- The need for haemodynamic support during intensive care stay
- The duration of antibiotic treatment during ICU stay up to 90 days post-randomization.
- Number of readmissions to the PICU up to 90 days post-randomization.
- Amount of calories delivered during ICU stay up to 90 days post-randomization.
- C-reactive protein concentrations during ICU stay up to 90 days post-randomization.
- Structural differences in muscle tissue during ICU stay
- Biochemical, metabolic, immunological, inflammatory and (epi)genetic markers on
blood samples up to 4 years post-randomization.
- Functional and neurocognitive development up to 4 years post-randomization.
Inclusion / Exclusion Inclusion criteria:
Criteria:
All Patients admitted to the PICU with a STRONGkids score higher or equal to 2 upon
ICU admission.
Exclusion criteria:
- Patients with a DNR code at the time of ICU admission.

- Patients expected to die within 12 hours (=moribund patients).
- Patient readmitted to ICU after randomization to the PEPaNIC trial (except when < 48
hours after the initial discharge and still in the intervention window of the first 7 days)
- Patients already enrolled in another outcome RCT.
- Patients transferred from another paediatric intensive care after a stay of more than 7
days
- Patients suffering from ketoacidotic or hyperosmolar coma on admission.
- Patients suffering from Short Bowel Syndrome on home PN or other conditions that
require home PN
- Patients suspicious or established inborn metabolic diseases requiring specific diet
- STRONGkids score lower than 2 on ICU admission.
- Premature Newborns ( 37 weeks gestational age upon admission in the PICU)
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Concomitant No restriction; as indicated clinically
medications allowed:
Blinding: Open label during intensive care (blinded thereafter). All
investigators/outcome assessors not directly involved in the clinical care will
be blinded to study treatment allocation
Statistical methods: A consort diagram will be reported. All analyses will be performed on a full
intention-to-treat basis. The data file will be finalised 90 days after inclusion
of the last patient.
To assess compliance with the study protocol, the amounts of PN and EN
actually given in the two study groups during the intervention window of 7
days will be reported as absolute numbers and percentages of target
calories.
Discrete variables will be summarised by frequencies and percentages and
analysed by (exact) Chi- square test or logistic regression analysis.
Continuous variables will be summarised by use of either mean or standard
deviations (SD) or median and interquartile range as appropriate and
compared using Student’s t-test or Mann-Whitney-U test, as appropriate.
Time to event analysis will be performed by Cox proportional hazard
analysis.
All outcomes will be analysed in an uncorrected manner as well as
corrected for risk factors (type and severity of illness, age, on admission
nutritional status and risk scores). Also the following a priori defined
subgroup analyses will be performed: patients after cardiac surgery as
compared with all other patients; patients with and without sepsis upon
admission; patients with a contra-indication for enteral feeding on admission
or not. For all endpoints, differences will be considered statistically
significant whenever the p-value is lower than 0.05 without correction for
multiple testing.
Laboratory tests: Will be performed by Labo Intensieve Geneeskunde KU Leuven.

The laboratory tests performed in the context of daily clinical care will be
performed by the Leuven University Hospitals Laboratorium Geneeskunde
and at the central laboratory of the Erasmus MC in Rotterdam
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II. INTRODUCTION
We have recently shown that withholding PN during the first week of critical illness (Late PN) is beneficial in
comparison with the early supplementation of insufficient enteral nutrition (EN) with PN (Early PN) in critically
ill adults [1]. The benefits of Late PN mainly encompassed a decrease in the incidence of new infections in
the ICU, a shortening of the stay in the ICU and hospital, and a reduction in healthcare costs. These findings
put pressure on the current guidelines by the European Society of Parenteral & Enteral Nutrition (ESPEN),
which recommend the practice of Early PN in critically adults [2].
The detrimental impact of the practice of Early PN in critically ill adults has alerted the clinical community that
also the guidelines for nutritional strategy in paediatric critically ill patients are merely based on expert
opinion. Not only is Early PN current practice in most PICUs, it is also often more aggressively promoted [3,
4]. This is further evidenced by the presence of national governmental healthcare programmes that include
the success rate for reaching nutritional goals as a quality benchmark [5].
A widely held assumption is that in children, nutrition not only serves the maintenance of body tissues. It also
allows them to grow, which is particularly important during infancy and adolescence, when the fast growth
makes healthy children vulnerable to caloric restriction [6, 7]. Therefore, in the current European and
American guidelines for nutrition in hospitalised children, PN is recommended to prevent/correct malnutrition
and to sustain appropriate growth when enteral nutrient supply is insufficient [2, 8]. Based upon indirect
calorimetric measurements there seems to be evidence for a hypometabolic phase, lasting longer in children
compared to adults in ICU. Based on these measurements the authors emphasize the possible danger of
overfeeding the critical ill child. [11,12,13,14,15]
This strengthens further the recommendations of a 2009 Cochrane systematic review [10] that multi-centre
randomised studies of nutritional support in critically ill children during the first week of critical illness should
include a control arm in which no nutritional support is administered or hypocaloric goals for nutritional
support are used.
We aim to evaluate whether the current practice of Early PN in critically ill children really provides clinical
benefits over a strategy of withholding PN during the first 7 days in the PICU. The evaluation will be done in
a multi-centre RCT performed in two large, expert, tertiary, referral PICUs. The study will be sufficiently
statistically powered to detect differences in clinically relevant outcome variables (the rate of new infections
and the length of stay in the ICU). The trial will also be able to detect a doubling or halving of the mortality
rate with a respectable statistical power.
The results of this RCT will provide, for the first time, high quality evidence for practice guidelines for nutrition
in critically ill children. It will answer the question whether Early PN is beneficial, harmful or neutral in
comparison with the new therapy of withholding PN during the first week of critical illness.
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III. KEY STUDY OBJECTIVES
3.1. The key objective of this clinical study is to test the hypothesis that in critically ill children, a strategy
aimed at a late delivery of full caloric support, using only EN, results in shorter ICU and hospital stay and
less morbidity as compared to a strategy aimed at early delivery of full caloric support, using a combination
of EN and PN (in conditions preventing hyperglycemia and overfeeding). The null hypothesis is that there will
be no difference in the primary outcome measures (length of stay in the PICU and the incidence of new
infections) between the two strategies. As a safety endpoint, mortality will be monitored.
3.2. The secondary objective is to define which underlying mechanisms may explain the eventual benefits of
a late delivery of full caloric support during critical illness
3.2.1. by studying the effects of treatment allocation on nitrogen balance, structural and volumetric
echographic muscle and subcutaneous adipose tissue evaluation.
3.2.2. by studying the effects of treatment allocation on metabolic, endocrine, inflammatory and
(epi)genetic markers in the blood of critically ill children.
3.2.3. by studying the effects of treatment allocation on the “innate immune response” and pathways
of inflammation (TLR4 signaling and other pathways).
3.2.4. by studying long-term physiological and neurocognitive rehabilitation
IV. STUDY POPULATION
On admission patients will undergo nutritional screening with the STRONGkids nutritional risk score. This is
a scoring system developed to detect the presence of malnutrition and the risk of developing malnutrition in
the hospital (appendix 2).
4.1. Inclusion Criteria
All patients admitted to the PICU with a STRONGkids score higher or equal to 2 upon ICU admission.
4.2. Exclusion criteria

- Patient readmitted to ICU after randomization to the PEPaNIC trial (except when < 48 hours after the initial
discharge and still in the intervention window of the first 7 days)
- Patients already enrolled in another intervention RCT.
- Patients transferred from another paediatric intensive care after a stay of more than 7 days
- Patients suffering from Short Bowel Syndrome on home PN or other conditions that require home PN
- Premature Newborns (37 weeks gestational age upon admission in the PICU)
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4.3. Readmissions to the ICU
Patients readmitted to the ICU within 48 hours of discharge and still within the intervention window (i.e. 7
days) will receive the nutrition-schedule they were assigned to during their initial ICU admission. Patients
readmitted later than 48 hours after the initial ICU discharge will be fed at the discretion of the attending
physician.
4.4. Withdrawal of patients from the study
When a patient or legal representative withdraws consent during ICU stay, the patient will go on to be
clinically followed up without his data being analyzed in the study. A separate patient log will register all
patients withdrawn from the study.
End-of-care decisions in patients for whom further intensive care is considered to be futile will be taken in
consensus by a group of two senior ICU physicians and the referring specialist, all blinded to study treatment
allocation.
V. STUDY TIMETABLE
The start of patient inclusion is planned for 1 May 2012. The last inclusion is planned before 1 September
2015. Data interpretation and publication will take 12 months. The study on long-term rehabilitation outcome
will start two years (± 1 year) after the discharge of the first patient.
VI. STUDY PROCEDURES
6.1. Written informed consent
Written informed consent (see consent form in appendix 3) will be obtained from the patient or the closest
family member or legal guardian. For planned PICU admissions after elective procedures, informed consent
will be asked beforehand. For emergency PICU admissions, treatment allocation will be done after
assessment of the patient for eligibility by the attending physician within the time frame of two hours. If
eligible, the patient will be randomised into the study and informed consent will be asked within the time
frame of 24 hours (deferred informed consent) as a nutritional regimen has to be initiated on admission. A
duplicate of the signed informed consent will be given to the patient or the closest family member or legal
guardian. The patient’s referring physician will also be informed about the patient’s participation.
The family member or the patient can withdraw from the trial, at any time, without impact on his treatment or
penalty.
The study protocol and consent forms will be approved by the Institutional Review Board of the Katholieke
Universiteit Leuven School of Medicine, Belgium and of the Erasmus University Rotterdam, The
Netherlands.
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6.2. Randomization
The study will use a prospective, randomized, controlled, parallel-group design. On admission patients will
be randomly assigned to receive EN combined with early PN or only EN. At ICU admission, consecutive
patients will be randomly assigned to one of these two treatment groups using a centralized computer
randomisation. Randomisation will be done in a 1:1 ratio in permuted blocks of 10 and stratified according to
primary diagnostic category on admission:
I Medical-ICU admissions (infectious or non-infectious): (a) respiratory (b) cardiac (c) renal (d)
haematological/oncological (e) gastro-intestinal/hepatic (f) neurological (g) other.
II Surgical-ICU admissions (elective or urgent) according to referral discipline (a) cardiac surgery (b) solid
organ transplants (c) pulmonary/oesophageal surgery (d) abdominal surgery (e) neurosurgery (f)
trauma/orthopaedic surgery (g) burns (more than 20% BSA is burned and/or patient requires ventilation)
Patients with sepsis upon admission will be labeled based on 1992 ACCP/SCCM consensus conference with
adaptations for the pediatric population. (cfr appendix 4)
6.3. Feeding schedules
For the purpose of this clinical study the day starts at 7:00 am.
a. Randomized interventions
a.1. Early PN (control arm of the study)
KULeuven protocol
Upon admission to PICU patients receive a mixture of glucose 30% and Vaminolact® (Fresenius, Sweden)
in equal amounts, comprising 150 mg/ml glucose and 4.7 mg/ml nitrogen. For patients who require fluid
restriction, total fluid intake is 50 ml/m2/h on day 1 and 2, and 60 ml/m2/h on day 3. Patients not requiring
fluid restriction receive 100 ml/kg/day for the first 10 kg bodyweight, 50 ml/kg for the next 10 kg, and 20 ml/kg
for the bodyweight over 20 kg.
For all patients on intravenous (IV) nutrition, and within the fluid limitation described above, lipids [Smoflipid®
(20g/100ml) Fresenius, Sweden] are added at the end of day 2 at 4:00 am, initially at a dose of 1.5 g/kg/day
for all patients weighing less than 20kg and at a dose of 1 g/kg/d for all patients weighing more than 20kg,
increasing to a maximum of 3 g/kg/day on day 3 for all patients weighing less than 20kg and to a maximum
of 2g/kg/d for patients weighing more than 20kg. At the end of day 3 at 4:00 am, a pharmacy-prepared PN
preparation is administered (weekdays), unless adequate enteral nutritional intake is expected. During
weekends and public holidays Smoflipid will be continued at the maximum rate until the pharmacy-prepared
PN preparation is available.
Pharmacy-prepared PN contains a mixture of glucose 50% and Smoflipid covering respectively 60- 70% and
40-30% of calculated energy target and a 2 g/kg protein intake, according to age, by Vaminolact®. If the
body weight is above 6 kg, Vaminolact® is replaced by Vamin 18®. Any enterally delivered energy is taken
9
into account daily to reduce the energy delivered by PN. Glucose-containing solutions to dissolve
medications will not be taken into account.
When EN covers 80% of the optimal calculated caloric needs, PN is stopped. When the patient starts to take
oral nutrition, the PN and/or EN is reduced to 50% and eventually stopped. Whenever enteral or oral intake
falls below 50% of calculated caloric needs, the PN is restarted.
Erasmus MC protocol
Patients will receive a continuous glucose infusion (< 30 kg; 4-6 mg/kg/min, > 30 kg; 2-4 mg/kg/min). From
day 2 onwards the glucose intake will increase for all children on IV nutrition to 8.3 mg/kg/min (5-a10 kg), 6.9
mg/kg/min (10-30 kg) and 4 mg/kg/min (> 30 kg). Primene® (Baxter) (5.5 – 5.7 mg/ml nitrogen) will be added
from day 2 onward, initially at a dose of 12.5 ml/kg/day (<10 kg) and 10 ml/kg/day (10-30 kg), increasing to
25 ml/kg/day (<10 kg) and 20 ml/kg/day (10-30 kg). Also from day 2 onwards, Intralipid® (Baxter) will be
added initially at a dose of 10 ml/kg/day (<10 kg) and 7.5 ml/kg/day (10-30 kg), increasing to 20 and 15
ml/kg/day respectively. Children > 30 kg on IV nutrition on day 2 onwards will be provided with Oliclinomel
N5 (5.2 mg/ml nitrogen, 115 mg/ml glucose) for central lines or Oliclinomel N4 (4.0 mg/ml nitrogen, 75 mg/ml
glucose) for peripheral lines, initially at a dose of 24 ml/kg/day and on day 3 increasing to 48 ml/kg/day. Any
enterally delivered energy is taken into account twice daily to reduce the energy delivered by PN. When EN
covers 80% of optimal calculated caloric needs, PN is stopped. When the patient starts to take oral nutrition,
the PN and/or EN is reduced and eventually stopped. Whenever enteral or oral intake falls below 50% of
calculated caloric needs, the PN is restarted.
a.2. Late PN (intervention arm of the study)
Both in Leuven and Rotterdam, patients randomised to the “late PN” group will receive a mixture of Glucose
5% and NaCl 0.9% at, respectively, 60% and 40% of the total flow rate that is required to obtain optimal
hydration taking into account the volume of EN that is being delivered. If enteral feeding of at least 80% of
the calculated calories is not possible after 7 days in ICU, PN, as specified above, is initiated on day 8.
When the glycaemia falls spontaneously below 50 mg/dl, the standard glucose of 5% in the late PN group
will be switched to 10% glucose until glycaemia is above 80 mg/dl. At this point the infusion of glucose 10%
will be stopped and switched again to glucose 5%.
The volumes of PN and EN to be given according to the treatment group are calculated by the patient data
management system (PDMS). These calculations are based on the nutritional intake during the previous
day. The amount of protein and glucose administered during the previous day, as well as the target, will be
displayed by the PDMS to further guide the prescription of nutrients. Glucose-containing medication
solutions will not be included in this calculation.
b. Common strategy for attempting early enteral nutrition in both study arms
Enteral feeding will start 6 hrs after admission in the PICU and will be done according protocol (cfr appendix
1) Trace elements and minerals (AddamelNovum, Fresenius) and vitamins (Cernevit, Baxter) will be
administered daily IV to all patients from day 2 at 4:00 pm. IV substitution will be stopped in patients
receiving at least 80% of their caloric needs of EN. According to the protocol vitamin K (KonakionRoche)
will be given weekly.
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6.4. Baseline assessment and data collection
At baseline, data on demographic and clinical characteristics of the patients are obtained. Disease-specific
risk scores (such as the Risk-Adjustment in Congenital Heart Surgery or RACHS score) are calculated, co-
morbidities and known use of important medications prior to admission are noted: these comprise, among
others, the presence of congenital disease or syndrome, gestational age at birth, gender, ethnicity, paediatric
risk scores, presence/history of cancer, diabetes mellitus, kidney failure, liver failure, chronic heart failure
and sepsis upon admission. In addition, we record the need for and the number of days of mechanical
ventilatory support, of mechanical and pharmacological haemodynamic support, of renal replacement
therapies, days on antibiotics and days requiring a central line.
All medications received by the patients during ICU stay are registered. Every day the amount of kilocalories,
lipids, proteins, carbohydrates delivered by either PN or EN are calculated from the PDMS in an automated
manner and entered into the case record form (CRF). Of the gastric residual volume discarded, half of the
volume will be considered to be EN and half gastric secretions. The duration (in min) and cause of
interruption of delivery of EN will be recorded. Digestive intolerance will be registered as vomiting, tracheal
aspiration of enteral feeding (defined 8), diarrhea, and gastric residue above 5ml/kg (see appendix for
definitions). Tube displacement or obstruction will be labeled as mechanical complications. Occlusion and
dislodging of central venous catheters will be recorded as mechanical complications. Pneumothorax,
hemothorax and arterial puncture will be recorded as clinical complications. Number of ICU days with a
central line in situ will be noted
Blood samples are taken upon ICU admission and daily at 06:00h until discharge from ICU or death. Upon
admission three extra blood samples will be taken; namely two yellow SST-5 tubes each containing 3,5
milliliter blood and 1 blue CTAD tube of 1,8 milliliter blood.
During the following days until the patient has left the PICU we will daily take an extra yellow SST-5 tube
(containing 3,5 milliliter blood) and an extra blue CTAD tube (containing 1,8 milliliter blood) for further
analyses.
A subset of the samples will be immediately stored on ice for future endocrine measurements. Processed
serum and plasma as well as the spun-down blood cells will be frozen and stored.
Analyses on the 06:00h sample will include routine clinical chemistry, hematology (Hgb, WBC, TC), and
markers of inflammation (CRP), liver function ALT, AST, ALP, GGT, bilirubin total/direct. A number of
metabolic, hormonal and inflammatory study analyses will be performed on selected days.
The latter include coagulation & fibrinolysis tests, cytokines and markers of oxidative stress. Also on selected
days urine (5 tubes of 5 mL out of 24 hours’ urine collection) will be stored for further evaluation (e.g. cortisol
metabolites, NGAL).
All whole blood glucose levels are measured on arterial blood using a blood gas analyser on each ICU and
are registered for later calculation of glucose metrics ( cfr appendix 7).
11
All new infections of the lungs, the blood stream, the urinary tract and wounds are recorded by an infectious
disease specialist. Bacteraemia is further classified by responsible pathogen and as catheter-related blood
stream infection versus other bacteraemia.
For mechanistic and exploratory studies, ultrasound evaluation of the skeletal muscle and subcutaneous
adipose tissue will be performed. Furthermore, as far as practically feasible, every patient is approached just
prior to hospital discharge, to complete a validated, semi- structured child health questionnaire (Functional
Independence Measure (WEEFIM), Health Utilities Index (HUI) and Child Health Questionnaire (CHQ)).
Additionally the patient will undergo a full neurocognitive testing by a qualified paediatric psychologist. For
the long-term study these analyses will be repeated at different time intervals after hospital discharge.
VII. INVESTIGATIONAL PRODUCTS
The study intervention is to postpone the administration of PN complementing EN with one week. The
control group will receive standard therapy, i.e. PN with or without lipids or electrolytes within one week. In
appendix, the summary of product characteristics files for the different preparations are included.
VIII. OUTCOME MEASURES
8.1. Primary outcome
The primary outcome measures of this study will be the incidence of new infections and the time to alive
discharge from ICU.
In order to accurately and objectively assess duration of ICU stay, which is often influenced by non-patient
related factors such as bed availability on regular wards, patients will be defined ‘dischargeable from ICU’
when they are no longer in need of vital organ system support.
8.2. Secondary outcome
- Death (ICU, hospital, 90-day mortality):

- Time to final (alive) weaning from mechanical respiratory support: patients still on mechanical respiratory
support at closing of the data file (90 days after last patient inclusion) will be censored at that time point. ICU
non-survivors will be censored beyond the longest duration of mechanical respiratory support of the
survivors.
- Time to final (alive) discharge from hospital: patients still in the hospital at closing of the data file (90 days
after last patient inclusion) will be censored at that time point.
- Kidney failure: Proportion of patients in need for renal replacement therapy (RRT) during ICU stay;
distribution of duration of RRT (for those patients requiring RRT); proportion of patients with a post-
randomisation diagnosis of new kidney injury/failure (defined by modified Risk, Injury, Failure, Loss, and
End-stage Kidney (RIFLE) classification criteria as a plasma creatinine doubling or more during ICU stay) in
both treatment groups. In addition, the duration of a score RIFLE 2 will be used as a marker of time to
recovery of kidney damage.
- Liver dysfunction: Proportion of patients during the time window of the intervention and during the whole
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ICU stay presenting with cholestatic or cytolytic liver dysfunction will be compared.
- Need for pharmacological or mechanical haemodynamic support during ICU stay, and its duration. In
addition, time to final (alive) weaning from all pharmacological or mechanical haemodynamic support in ICU
will be analysed, with ICU non-survivors censored beyond the longest duration of pharmacological or
mechanical haemodynamic support of the survivors and censoring time of patients still on such support at
closing of the data file (90 days after last patient inclusion) over both treatment groups.
- The duration of treatment with antibiotics of infected patients
- Number of readmissions to the PICU
- Inflammation: Effect of the intervention on inflammation will be analysed by comparing the distribution of
the highest value reached during ICU stay and changes from baseline to the highest value and by
comparing time profiles of daily C-Reactive Protein values.
- Episodes of hypoglycemic events (defined as glycaemia < 40 mg/dL) per patient ICU-stay
- Amount and type of calories delivered
- Child health questionnaire scores (WEEFIM, HUI, CHQ) and neurocognitive testing at hospital discharge in
both treatment groups will be compared.
- The presence of volumetric and structural echographic differences in muscle tissue and subcutaneous
adipose tissue.
- Use of intensive care resources will be analyzed by health economy analysis.
8.3. Complications possibly related to nutrition management
In order to monitor the quality of the enteral and parenteral nutrition management during the study we will
register all known complications possibly related to them. These complications should not be considered as
adverse events since the study intervention is to withhold parenteral feeding during one week. These known
complications of parenteral feeding will not be reported to the sponsor until the end of the trial.
*Complications possibly related to enteral feeding

Digestive intolerance: either vomiting, tracheal aspiration of enteral feeding (defined in 7), diarrhea, or gastric
residue above 5ml/kg, abdominal distention (see appendix for definitions).
Complicated insertion of feeding tubes: nasal bleeding
Mechanical complications Feeding tube displacement or obstruction
*Complications possibly related to parenteral feeding

Mechanical complications Occlusion and dislodging of central venous catheters
Clinical complications: pneumothorax, hemothorax and arterial puncture, central line replacement due to
suspicion of catheter-related blood stream infections
IX. ADVERSE EVENTS
Hypoglycemia (< 40 mg/dL) resistant to iv glucose administration will be considered as a serious

adverse event. This adverse event will be reported to the sponsor.
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X. STATISTICAL ANALYSES
10.1. Sample size
The sample size (N=1440, 720 per arm) is calculated in order to detect, with at least 80% power (one- tailed;
the two-tailed power is 70%) and 95% certainty, a reduction in PICU infections from 20% to 15% and, with at
least 90% power (2-tailed) and 95% certainty, a reduction in mean duration of stay in PICU of 1 day. With
this sample size, and for safety reasons, also any substantial impact on mortality (increase or decrease with
an absolute +/- 2%, although unexpected taken the adult data), can be excluded with a power of around 62-
75% depending on the true mortality in the total population. We plan to calculate the true power of the study
for detection of any eventual smaller differences in these outcomes.
We anticipate that 3-3.5 years will be needed to take this study to completion, provided informed consent will
be at least 80%. To face worse recruitment, we anticipate requiring 4 years to complete the clinical study
(excluding long term follow up) and 1 more year to process samples and data.
10.2. Efficacy variables and analysis
All analyses will be done on intention to treat basis. The analyses will be performed on the whole set of
patients and by subgroups of patients based on the primary diagnostic categories used as prognostic factors
for stratification and on septic/non-septic groups of patients.
A consort diagram will be reported. The data file will be finalised 90 days after inclusion of the last patient. To
assess compliance with the study protocol, the amounts of PN and EN actually given in the two study groups
during the intervention window of 7 days will be reported as absolute numbers and percentages of target
calories. Discrete variables will be summarised by frequencies and percentages and analysed by (exact)
Chi- square test or logistic regression analysis. Continuous variables will be summarised by use of either
mean or standard deviations (SD) or median and interquartile range as appropriate and compared using
Student’s t-test or Mann-Whitney-U test, as appropriate. Time to event analysis will be performed by Cox
proportional hazard analysis. All outcomes will be analysed in an uncorrected manner as well as (jointly)
corrected for risk factors (type and severity of illness, age, on admission nutritional status and risk scores). A
priori defined subgroup analyses will be performed for patients admitted to ICU after cardiac surgery as
compared with all other patients; for patients with and without sepsis upon admission; for patients with
contra-indications for EN on admission or not. For all endpoints, differences will be considered statistically
significant whenever the p-value is lower than 0.05 without correction for multiple testing.
10.3. Safety variables and analysis
The safety analyses will be done on the whole set of patients and by subgroups of patients based on the
primary diagnostic categories used as prognostic factors for stratification and on septic/non-septic groups of
patients.
14
10.4. Interim Analysis
For safety reasons, an interim analysis of ICU mortality and hospital mortality will be performed after the first
720 patients with stopping boundaries predefined by the DMC to allow early study termination if one of the
intervention groups would appear clearly inferior.
XI. ADMINISTRATIVE AND LEGAL ASPECTS
Electronic data collection will be used. Data will be collected in an anonymous, CRF, unambiguously linked
to the source file. The sponsor will provide direct access to the CRF, the source data and the study master
file for monitoring, Independent Ethics committee review and regulatory inspection. The sponsor will
establish a data-monitoring committee. The sponsor appointed one monitor (PW). The monitor will verify that
the trial is performed in accordance to the protocol as described in the European Medicine Agency’s “Note
for guidance on good clinical practice CPMP/ICH/135/95.” as well as the Declaration of Helsinki. Monitoring
will be performed and will be reported following the sponsor’s SOPs. No fault insurance is covered by Amlin
Corporate Insurance.
Publication policy and financing will be addressed in separate agreements.
15
XII. STUDY PERSONNEL
A list of all study personnel and investigators will be updated in the study master file.
All investigators not directly involved in the patients care will be blinded to treatment allocation:
Statisticians
Microbiologists
Pathologists
….
16
Appendix 1
Protocol Enterale Voeding op de PICU
<10 kg start aan 1 ml/kg/u en verder opdrijven met 1 ml/kg om de 6 tot 12u
>10 kg start aan 0,5ml/kg/u en verder opdrijven met 1ml/kg om de 6 tot 12u
Kleine zuigeling:
alternatief schema: 6-8 keer voeden per dag en dit startend aan 3ml/kg per voeding
verder op te drijven volgens tolerantie
Voedingen:
<1 jaar: start met standaard formule dewelke het kind reeds kreeg
>1 jaar: Nutrini (1kcal/ml)
Absolute Contra indicaties:

- Ileus
- Necrotiserende enterocolitis
- Darmischemie
Relatieve Contra indicatie:

- Abdominale Heelkunde
- Haemodynamische instabiliteit
- Aspiratie risico
- Gastro-intestinale bloeding
Maagresidu
- gedefinieerd als >5ml/kg, dit wordt niet terug gegeven aan patiënt
- 50% wordt gerekend als zijnde sondevoeding, 50% als verteringssappen
- geen gebruik van prokinetica
Diarree
- Etiologie?
Osmotisch => reductie sondevoeding of stop sondevoeding
Infectieus => Clostridium uitsluiten; er wordt geen Motilium gebruikt op de PICU
17
Appendix 2 STRONGkids
18
Adressogram
Appendix 3
Informed consent formulier : PEPaNIC
Geachte Mevrouw,
Geachte Heer,
Een van de opdrachten van een universitair ziekenhuis bestaat erin niet alleen hoogstaande
medische zorgen te geven aan de patienten, maar ook constant de huidige
behandelingstechnieken kritisch te evalueren en eventueel aan te passen aan de nieuwe
inzichten.
Na uitgebreide heelkundige ingrepen en tijdens ernstige kritieke ziekte zijn kinderen soms
niet in staat zich normaal te voeden. De patiënten worden dan gevoed via een maagsonde.
Deze voeding via de maagsonde voldoet soms pas na enkele dagen of weken aan de
behoeften. Tot voor kort was het niet duidelijk vanaf wanneer ze best wordt aangevuld met
voeding via het veneuze infuus.
Recent werd er in de dienst Intensieve Geneeskunde van de Universitaire Ziekenhuizen
Leuven via een grootschalig onderzoek aangetoond bij volwassen patiënten dat het laattijdig
opstarten van aanvullende veneuze voeding de overlevingskansen van deze patienten
duidelijk verbeterden. Ook de risico’s op complicaties namen duidelijk af in vergelijking met
de patiënten waarbij de veneuze voeding vroegtijdig werd opgestart.
De vraag stelt zich of er met deze behandeling ook bij kritiek zieke kinderen gunstige
effecten kunnen bekomen worden. Dit willen wij nu bestuderen bij kinderen tussen 0 en 17
jaar. We vragen daarom uw toestemming om uw kind aan het onderzoek te laten
deelnemen.
Indien U uw toestemming verleent zal uw kind tijdens het verblijf op de intensieve
zorgenafdeling ingedeeld worden in een groep waarbij de veneuze voeding laatijdig wordt
opgestart of in een groep waarbij we de huidige manier van werken toepassen, namelijk het
vroegtijdig starten van aanvullende veneuze voeding. Om de resultaten van het onderzoek
niet te beïnvloeden, wordt de indeling in één van de twee groepen door toevalstrekking
bepaald. Uw kind zal verder dezelfde maximale zorgen krijgen; het deelnemen aan de studie
verandert niets aan de verdere behandeling.
Om deze behandeling goed te kunnen bestuderen hebben we dagelijks een kleine
hoeveelheid bloed nodig, die zal worden afgenomen samen met de klassieke bloednames
die nodig zijn om de ziektetoestand van uw kind nauwkeurig op te volgen. De bloedname
veroorzaakt geen pijn of ongemak gezien ze gebeurt via het buisje dat reeds in het bloedvat
is aangebracht om continu de bloeddruk te meten. Op verschillende tijdstippen tijdens het
verblijf zullen er eveneens volstrekt pijnloze echografieën gemaakt worden ter evaluatie van
de spiermassa en het subcutaan vetweefsel.
Uiteraard staat het U volledig vrij om voor deelname aan deze studie te kiezen en behoudt U
ten allen tijde het recht om deelname aan de studie stop te zetten. De studie brengt geen
enkele bijkomende kosten met zich mee.
19
Gegevens en resultaten van dit onderzoek kunnen gebruikt worden voor publicatie in
wetenschappelijke tijdschriften doch zonder dat persoonlijke gegevens worden vermeld en
met volledige waarborg van de anonimiteit.
In de hoop op uw medewerking te kunnen rekenen, danken wij U bij voorbaat,
Prof Dr Dieter Mesotten Prof Dr Greet Van den Berghe

Dr Tom Fivez Diensthoofd
Prof Dr Dirk Vlasselaers
Dr Lars Desmet
Ik, ondergetekende, heb de nodige inlichtingen gekregen betreffende het onderzoek

“vroegtijdig versus laattijdig opstarten van aanvullende intraveneuze voeding” en
stem ermee in dat mijn kind hieraan deelneemt.
Naam patiënt:
………………………………………………………………………………………..
Naam en relatie tot de patiënt
………………………………………………………………………………………..
Handtekening(en) : …………………………………………………………………………..
Leuven, ….. / ……./ 201…
Naam Arts:…………………………………………………………………………………
Handtekening:……………………………………………………………………………..
Datum:……………………………………………………………………………………...
Een duplicaat van het IC werd aan de tegenpartij overhandigd
20
Appendix 4
SIRS
1. Temperature >38°C rectal or <36°C rectal
2. Heart rate > 90th percentile for age
3. Respiratory rate > 90th percentile for age or hyperventilation to PaCO2<32mmHg
4. Wbc count >12000cells/mm3 or <4000
àpresence of at least 2criteria, representing an acute change from baseline and in the absence of
other known causes for these changes
SEPSIS = SIRS secondary to a systemic infection
SEVERE SEPSIS
Sepsis + any one of the following
1. Glasgow coma scale <15( in the absence of CNS disease)
2. Arterial blood lactate > 1.6 mmol/l or venous blood lactate > 2.2 mmol/l
3. Urine output < 1ml/kg /hour for 2 consecutive hours with a urine catheter in place
SEPTIC SHOCK
Sepsis with hypotension (2 distinct measurements of BP < 3th percentile for age) after administration
of 20 ml/kg crystalloid or colloid, + any one of the following
1. Requirement for inotropic or vasopressor effect (excluding dopamine >6microgram/kg/min)
Based on 1992 ACCP/SCCM consensus conference with adaptations for the pediatric population
21
Appendix 5
At admission: determine STRONGkids

include if ³ 2 and no exclusion criteria randomize with sealed
envelopes
Early PN completing EN EN only

start Glucose 30% and start Glucose 5% en NaCl
Vaminolactat according 0,9% according protocol
protocol
! start EN within 6 hrs start EN within 6 hrs

after admission after admission
Start Smoflipid at day2 “unblinded placebo”
at 4:00 am according
protocol
If patient able to eat
Start TPN at day 3 at
4:00 am according
protocol Oral nutrition + 50% of
TPN volume based on parenteral regimen until
EN delivered the intake > 50% caloric target
previous day
Oral nutrition <50% caloric target
If patient able to eat
If 7 days after admission EN

Oral nutrition + 50% of delivery < 80% of calculated
parenteral regimen until needs, add TPN to meet caloric
intake of >50% caloric target needs on the 8th day
Oral nutrition < 50% caloric

target
Stop TPN as soon as 80% of

caloric needs are met with EN
Formula for caloric needs

Energy intake
0-10 kg bodyweight : 100 kcal/kg/day
10-20 kg bodyweight : 1000 kcal/day + (50 kcal/kg/day for weight over 10 kg)
> 20 kg bodyweight : 1500 kcal/day + (20 kcal/kg/day for weight over 20 kg)
Protein target
0-10 kg bodyweight : 1.5-3 g/kg/day
10-20 kg bodyweight : 1-3 g/kg/day
> 20 kg bodyweight : 1-2 g/kg/day
22
Appendix 6
TPN VOORSCHRIFT voor tot en met 5 kg

E NKEL VOORSCHRIFTEN DIE VOOR 14 UUR IN DE APOTHEEK ZIJN WORDEN NOG DEZELFDE DAG UITGEVOERD .
Gewicht patiënt: G = ………………………

Lengte in cm: L = ………………………
Lichaamsopp in m²: M = ………………………
(zie nomogram)
Totaal vocht per 24 uur (vochtbeperking)
dag 1 : 40 x M x 24 = ………………… ml
dag 2 : 50 x M x 24 = ………………… ml
dag 3+ : 60 x M x 24 = ………………… ml
Totaal vocht per 24 uur (géén vochtbeperking)
100 ml/kg/dag: 100 ml x G = ………………… ml (= T)
Totaal Aminozuuropl. per 24u (Vaminolact®) = A

2 g/kg/dag = 30 ml x G = …………(= A) ml x 0.27 = ……………… kcal
Totaal koolhydraten per 24u (Glucose 50 %) = G
(100 kcal x G) – kcal AZ –kcal vet = …………..kcal gl kcal gl x 0.5 = ………………(= G) ml
Addamel. (0.25 ml/kg/dag) = ………………(= M) ml

(bilirubine > 2 mg % : stop Addamel)
Cernevit®: 1 ml = ………………(= N) ml
Konakion 2mg 1/week
Totaal vet per 24 u: Smoflipid 20% = S

3 g/kg/dag = 15 ml x G = …………(=V)ml x2 = ……………… kcal
Apotheek:
Eindvolume zonder vet =T-V =……………….. ml (dit moet minimaal = A+G+M (+N))
VOOR DE APOTHEEK: binair mengsel + vet apart Overvolume (primen leidingen) = 25 ml (bij binair +vetmengsel)
Versie 11-08-2009 Naam, handtekening en RIZIV – nummer arts
23
TPN VOORSCHRIFT voor van 6 tot en met 11 kg

(zie nomogram)
dag 1 : 40 x M x 24 = ………………… ml
dag 2 : 50 x M x 24 = ………………… ml
dag 3 : 60 x M x 24 = ………………… ml
dag 4+ : 80 x M x 24 = ………………… ml
100 ml/kg/dag: 100 ml x G = ………………… ml (= T)
Totaal Aminozuuropl. per 24u (Vamin® 18) = A
2 g/kg/dag = 17,5 ml x G = ………….(=A) ml x 0,46 = ……………… kcal
(100 kcal x G) – kcal AZ – kcal vet =………………kcal gl kcal gl x 0,5 = ……………(=G) ml
Addamel (0.25 ml/kg/dag) = ……………… (= M) ml

Cernevit®: 1 ml = …………….. (= N) ml
Konakion 2 mg 1/week
Totaal vet per 24 u (Smoflipid® 20 %) = S

3 g/kg/dag = 15 ml x G = …………(=V) ml x2 = ……………… kcal
Apotheek:
VOOR DE APOTHEEK: binair mengsel + vet apart Overvolume (primen leidingen) = 25 ml (bij binair + vetmengsel)
24

(zie nomogram)
dag 1 : 40 x M x 24 = ………………… ml
dag 2 : 50 x M x 24 = ………………… ml
dag 3 : 60 x M x 24 = ………………… ml
vanaf dag 4: geen vochtbeperking
Totaal kcal per 24 uur (volgens gewicht)

tot 10 kg: 100 kcal per kg
tot 20 kg : 1000 kcal + 50 kcal per kg voor kg> 10kg
Totaal kcal = ………………… kcal
Totaal vocht indien geen vochtbeperking !

Totaal vocht = totaal kcal in ml = ………………… ml (=T)
2 g/kg/dag = 17,5 ml x G = …………(= A) ml x 0,46 = ………………kcal
totaal kcal – kcal AZ – kcal vet =……………kcal gl kcal gl x 0.5 = ……………(=G) ml

Addamel (0.25 ml/kg/dag, max 5 ml) = ……………(= M) ml
Cernevit®:2.5 ml = …………....(= N) ml
Konakion 5mg 1/week

3 g/kg/dag = 15 ml x G = …………(= V) ml x2 = ……………… kcal
Apotheek:
Eindvolume zonder vet = T-V = ……………….ml (dit moet minimaal = A+ G + M(+N))
25
TPN VOORSCHRIFT voor van 21 tot 40 kg

(zie nomogram)

dag 1 : 40 x M x 24 = ………………… ml
dag 2 : 50 x M x 24 = ………………… ml
dag 3 : 60 x M x 24 = ………………… ml
Totaal vocht per 24 uur (volgens gewicht)
tot 20 kg: 1000 kcal + 50 kcal per kg voor kg > 10 kg
> 20 kg: 1500 kcal + 20 kcal per kg voor kg > 20 kg
Totaal vocht indien geen vochtbeperking
Totaal vocht = totaal kcal in ml = ………………… ml T

2 g/kg/dag = 17,5 ml x G = ……….. = (A) ml x 0,46 = ……………… kcal

totaal kcal – kcal AZ – kcal vet = ……… kcal x 0,5 = ………………(= G) ml
Addamel. (0.25 ml/kg/dag, max 10 ml) = ………………(= M) ml
Cernevit®: 2.5 ml = ………………(= N) ml
Konakion 10mg 1/week

2 g/kg/dag = 10 ml x G = ………….. = (V)ml x2 = ……………… kcal
Apotheek:
Eindvolume zonder vet =T-V =……………….. ml (dit moet minimaal = A+G+M +(N))
VOOR DE APOTHEEK:binair mengsel + vet apart Overvolume (primen leidingen) = 25 ml (bij binair + vetmengsel)
26
Appendix 7
GLYCEMIEBELEID BIJ
KINDEREN OP ITE TE
GASTHUISBERG
In 2001 werd een strikt glycemiebeleid opgenomen in de basiszorg bij volwassen patiënten op
de dienst intensieve geneeskunde (N Engl J Med 2001; 345:1359-67). Het significant verschil
in mortaliteit en morbiditeit ten gevolge van een strikte glycemiecontrole werd in 2009 ook
bij kinderen aangetoond (Lancet 2009; 373(9663):547-56). Daarom passen we ook bij
kinderen een strikt glycemiebeleid toe.
De fysiologische glycemiewaarde verschilt volgens de leeftijd van het kind. Om een
onderscheid te maken tussen de leeftijdsgroepen werd er geopteerd om deze populatie in 2
groepen op te delen, nl. de groep jonger dan 1 jaar en de groep tussen 1 jaar en 16 jaar. Beide
groepen hebben eigen glycemiestreefwaarden. (figuur 1).
Leeftijd Ondergrens Bovengrens Streefwaarde
0 tot 1 jaar 50 mg/dl 80 mg/dl 65 mg/dl

Figuur 1
Wat volgt zijn richtlijnen, dit is geen algoritme. Er wordt van de verpleegkundige verwacht
zelf anticiperende beslissingen te nemen in het streven naar normoglycemie.
Concreet dienen de volgende richtlijnen te worden gevolgd:
 De streefwaarden van elke leeftijdsgroep wordt in acht genomen.
 Het insuline-infuus
o Insuline wordt opgelost in NaCl 0,9% en steeds toegediend met een
spuitdrijver en een harde leiding.
o Bij voorkeur op een centrale veneuze katheter.
o Er worden geen bolussen insuline toegediend.
o Het insuline-infuus moet zo dicht mogelijk bij de patiënt geplaatst worden:
iedere aanpassing van het debiet moet zo snel mogelijk bij de patiënt
toekomen.
 Op welk lumen van de centrale katheter mag het insulinee-infuus geplaatst worden?
o Kan en mag op het lumen met het glucose-infuus geplaatst worden.
o Mag eventueel samen met continue infusen met inotropica.
o Mag niet op het lumen dat gebruikt wordt voor bolusinjectie.
27
 De concentratie van het insuline-infuus is afhankelijk van het gewicht van de patiënt
(figuur 2).
 Er wordt gestart met insulinetoediening indien de glycemiewaarde de bovengrens
overschrijdt.
 Bij grote overschrijding van de bovengrens wordt een hoger startdebiet gekozen.
Concentratie Startdebiet
insuline-infuus glyc > bovengrens glyc > 2x
Gewicht
(opgelost in NaCl bovengrens
0,9%)
< 15 kg 10 IE / 50 ml 0,5 ml/kg LG/u 1 ml/kg LG/u
15 kg – 30 kg 20 IE / 50 ml 0,25 ml/kg LG/u 0,5 ml/kg LG/u
>30 kg 50 IE / 50 ml 0,1 ml/kg LG/u 0,2 ml/kg LG/u

Figuur 2
 Bij strikt glycemiebeleid is een frequente controle van de glycemie noodzakelijk
o De glycemie wordt gemeten op onverdund arterieel bloed via het VAMP-
systeem.
o Bepaal steeds wanneer mogelijk de glycemie op de bloedgasanalyser.
o Bij het opstarten en bij iedere aanpassing van het insuline-infuus dient er
binnen het uur een controle glycemie genomen te worden.
o De controlefrequentie van de glycemie is minimum 1 maal om de 4 uur.
 De controle van de glycemie tot binnen de fysiologische grenzen is noodzakelijk.
o Telkens wanneer de glycemie buiten de streefwaarden valt, hoe minimaal
ook, moet er per uur glycemiecontrole uitgevoerd worden tot de glycemie
weer binnen de grenzen is.
o Dit geldt nog meer indien de glycemie een grote correctie nodig heeft en het
insuline-infuus fors moet worden verhoogd. Dan moet je binnen het uur een
nieuwe glycemiecontrole uitvoeren ter preventie van hypoglycemie.
o Indien de glycemie fors daalt en weer binnen de grenzen komt, moet je het
insuline-infuus opnieuw verlagen om hypoglycemie te vermijden.
 Bij een lage glycemiewaarde wordt, afhankelijk van de waarde, het insuline-infuus
verminderd of gestopt.
 Bij hypoglycemie wordt glucose IV (1 ml glucose 50%/ kg LG) (50% = 500mg/ml)
toegediend (fig.3).
STOP insuline
Leeftijd Streefwaarde STOP insuline
geef gluc 50% (1 ml/kg)
0 tot 1 jaar 65 mg/dl < 50 mg/dl < 30 mg/dl

Figuur 3
28
 Bij ontslag van het kind naar de kamer moeten volgende handelingen gebeuren:
o Het insuline-infuus moet 2 uur voor ontslag gestopt zijn.
o Er moet een controle van de glycemie gebeuren na het stoppen van het
insuline-infuus.
o Een kind gaat NOOIT met een insuline-infuus naar de kamer.
Bijkomende aandachtspunten
 Insuline in een 50 ml spuit voor spuitdrijver is stabiel gedurende 24 uur.
 Indien bij kinderen het insuline-infuus aan een laag debiet loopt (< 1 ml/u) is het
van imperatief belang dat je de leiding met het insuline-infuus op het lumen met
glucose-infuus laat lopen. Zo hebben kleine aanpassingen van het insuline infuus (bv.
0,1ml/u) bij deze patiënten ook onmiddellijk effect.
 Door de toediening van insuline daalt het kaliumgehalte in het bloed. Het is van
belang om het kaliumgehalte via de bloedgassen op te volgen bij elk
glycemiecontrole.
 Aandachtspunten bij een lieskatheter : aangezien het kind met de beentjes beweegt,
bestaat de kans dat de katheter even afknikt. Het gevaar bestaat dat er een
discontinuïteit is in de toediening van Actrapid. Het opnieuw doorgankelijk worden
van het lumen kan een bolustoediening Actrapid veroorzaken met hypoglycemie als
gevolg. Om hypoglycemie te vermijden raden we aan het insuline-infuus en het
glucose-infuus op hetzelfde lumen te plaatsen.
 Bij staalname via de centraal veneuze katheter moet er eveneens een onverdund
bloedstaal genomen worden dat niet gecontamineerd is met glucose. De volgende
maatregelen moeten genomen worden:
o Sluit steeds de kraan van het andere lumen af om contaminatie te vermijden.
o Aspireer voldoende bloed vóór de staalname (tot 4 maal de dode ruimte
tussen het insteekpunt en het afnamepunt.)
o Spoel na met 1 à 2 ml NaCl 0,9%.
o Enkel met toelating van een senior supervisor.
 Iedere patiënt heeft zijn eigen insulinegevoeligheid. In de eerste postoperatieve

fase kan dit resulteren in insulineresistentie. Dit heeft tot gevolg dat er hoge dosissen
insuline nodig zijn om de glycemie op punt te stellen. Verhoog uw controlefrequentie
naar minimum 1 maal om de 2 uur. Dit is noodzakelijk omdat de insulineresistentie
afneemt na een bepaalde tijd en bijgevolg de glycemie plots fors kan dalen.
 Hou steeds rekening met:
o Het gewicht van het kind voor de concentratie van het insuline-infuus
o De toediening van corticoïden
o De aanpassingen van het vochtbeleid en dus de calorieën-intake
o Stress
o Koorts
o Gepland onderzoek of ingreep.
 Wanneer wordt het protocol gestopt?
o Indien de arteriële katheter van het kind verwijderd wordt of onbruikbaar is
(en er geen medische indicatie is om opnieuw een arteriële katheter te
plaatsen).
29
o Indien er geen reflux is op de centrale veneuze katheter, de afname zeer
moeilijk verloopt of er op geen enkele manier een betrouwbare glycemie kan
gecontroleerd worden.
o Wanneer het kind intermittent eet en drinkt.
In deze gevallen is er overeen gekomen dat men het insulineprotocol moet stoppen,
d.w.z. dat het insuline-infuus gestopt moet worden.
30
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inflammatory response syndrome and sepsis. ANN Surg. 2001 Apr;223(4):581-7.
13. Rachel M. Taylor, MSc; Paul Cheeseman, PhD; Victor Preedy, DSc et al.Can energy
expenditure be predicted in critically ill children?Pediatr Crit Care Med 2003; 4:176 –180)
31
14. Christine M. Hardy, MS, RD, CNSD; Johanna Dwyer, DSc, RD; Linda K. Snelling, MD et al.
Pitfalls in Predicting Resting Energy Requirements in Critically Ill Children: A Comparison of
Predictive Methods to Indirect Calorimetry Nutrition in Clinical Practice 17:182–189, June
2002
15. Christine M. Hardy Framson, PhD, RD, CNSD; Neal S. LeLeiko, MD, PhD; Gerard E. Dallal,
PhD et al. Energy expenditure in critically ill children. Pediatr Crit Care Med 2007; 8:264 –267
32
2. Summary of all amendments to the protocol -
KU Leuven
Amendment protocol VN2
Overview of changes made in protocol VN 2 compared with VN 1
P4 Exclusion criteria was added

Patient readmitted to ICU after randomization to the PEPaNIC trial (except when < 48 hours after the
initial discharge).
“still in the intervention window of the first 7 day” is deleted as a readmission within 48 hours will be
classified as a post hoc inappropriate discharge .
P7
Same adaptation as on page 4.
P8
Study Timetable
“after discharge of the first patient” was replaced by “after admission of the first patient”
P9
Randomization:
The amount of stratification categories for stratification are diminished as we think that the high amount
of stratification categories could create bias.
P9
The following sentence was added: “Children weighing more than 40kg will receive adult parenteral
nutrition.”
P11
“Digestive intolerance” was replaced by “Problematic digestive intolerance”
To limit the amount of blood taken from children weighing less than 10 kg the following was added:
“namely two yellow SST-5 tubes each containing 5 milliliter blood and 1 blue CTAD tube of 2,7 milliliter
blood. During the following days until the patient has left the PICU we will daily take an extra yellow SST-
5 tube (containing 5 milliliter blood) and an extra blue CTAD tube (containing 2,7 milliliter blood) for further
analyses. When the child weighs less than 10 kg than we the SST-5 tube is replaced by an SST-3,5 tube
(containing 3,5 milliliter blood).”
Amendment protocol VN3
Overview of changes made in protocol VN 3 compared with VN 2
P4: the following was added

- Patients with an age of 17 years or older
- Patients who do not need a central venous catheter within the first hours after PICU- admission.
P7: same adaptation as on page 4
P8: Study Timetable was adapted

“The patient inclusion started on 18 June 2012 in Leuven and on 13 September 2012 in Rotterdam. A
statistical repowering of the study will be done after the inclusion of patient number 480. If required, more
study sites will be included in the PEPaNIC trial. The last inclusion is planned before 1 May 2015. Data
interpretation and publication will take 12 months. The study on long-term rehabilitation outcome will start
four months after admission of the first patient.”
P9: “Bedside nurses and doctors will not know the block size” was added

Blood samples are taken upon ICU admission and daily at 06:00h until discharge from ICU or death. If
the patient is staying in the PICU longer than 16 days, blood samples will be taken every four days and a
final sample at discharge. Upon admission three extra blood samples will be taken; namely two yellow
SST-5 tubes(BD Vacutainer SST II Advance ref 367955) each containing 5 milliliter blood and 1 purple
EDTA tube (BD Vacutainer K2E 3,6mg ref 38841) of 2 milliliter blood.
(containing 5 milliliter blood) and an extra purple EDTA(BD Vacutainer K2E 3,6mg ref 38841) (containing
2 milliliter blood) for further analyses. When the child weighs less than 10 kg than we the SST-5 tube is
replaced by an SST-3,5 tube(BD Vacutainer SST II Advance ref 367957) (containing 3,5 milliliter blood).
A subset of the samples will be immediately stored on ice and processed in a cold chain for future
endocrine measurements.
All (suspected) new infections of the lungs, the blood stream, the urinary tract and wounds are recorded
in the patient data file by the bedside senior intensive care specialists. New infections or suspected new
infections will be scored, based on the administered antibiotics, by blinded infectious disease specialists.
For the long-term study this questionnaire will be repeated at different time intervals after inclusion in the
PEPaNIC study (4 months,2 year, 4 years). Long-term follow-up at 2 years will also include a clinical
paediatric examination and neurocognitive testing by a qualified paediatric psychologist. Follow-up at 4
years after inclusion will consist of the questionnaire, the clinical paediatric examination and a full
neurocognitive testing.

- Child health questionnaire scores (HUI, CHQ, PEDI-NL, SDQ), reflecting the state of the child before
hospital admission will be compared in both treatment groups.

We plan to re calculate the power of the study, based on the incidence of new infections, in the control
group after inclusion of patient number 480. If required, additional study sites will be included.

DMC meetings for safety analyses will be held after the discharge of patient 250, 750, and 1250:
i. ICU mortality (in 2 blinded study groups; when differences are significant, the board will call for
unblinding).
ii. Proportion of patients requiring mechanical ventilation for more than 7 days (only aggregated data
of both groups) in comparison with those from the previous annual reports of the department.
iii. Hypoglycaemia (<40 mg/dL or 2.2 mmol/L; no SAE) (in 2 blinded study groups; when differences are
significant, the board will call for unblinding).
iv. SAE: Therapy resistant hypoglycemia (in 2 blinded study groups; when differences are significant,
the board will call for unblinding).

“Op verschillende tijdstippen tijdens het verblijf zullen er eveneens volstrekt pijnloze echografieën
gemaakt worden ter evaluatie van de spiermassa en het onderhuids vetweefsel. Het zou kunnen dat we
over enkele jaren Uw kind uitnodigen voor een vrijblijvende opvolgconsultatie. Om een beter inzicht te
krijgen in de evolutie van uw kind na hospitalisatie op intensieve zorgen, zullen we op regelmatige
tijdstippen een vragenlijst opsturen.”
P20: An English and French informed consent was added.

3. Most recent protocol (incl. most recent statistical analysis plan) -
KU Leuven
Versienummer 3
05-02-2013

STUDY PROTOCOL
TABLE OF CONTENTS

I. PROTOCOL SYNOPSIS .................................................................................... 3
II. INTRODUCTION ................................................................................................ 6
III. KEY STUDY OBJECTIVES ................................................................................ 7
IV. STUDY POPULATION ........................................................................................ 7
VI. STUDY PROCEDURES ..................................................................................... 8
VII. INVESTIGATIONAL PRODUCTS .................................................................... 12
VIII. OUTCOME MEASURES .................................................................................. 12
IX. ADVERSE EVENTS ......................................................................................... 13
XI. ADMINISTRATIVE AND LEGAL ASPECTS ................................................... 15
XII. STUDY PERSONNEL ...................................................................................... 16
References……………………………….………………………………………………...31

2
Patients
Principal Investigators for the KU Leuven:

Dr. Lars Desmet
Dr. Tom Fivez

Dr. Koen Joosten
Dr. Sascha Verbruggen
Trial Centres: University Hospitals of the KU Leuven, Belgium & the University Hospital of the
Erasmus Universiteit Rotterdam, the Netherlands
Test Preparation: Parenteral nutrition completing enteral nutrition versus enteral nutrition
Reference Drug: Smoflipid or Intralipid 20% and pharmacy-prepared parenteral nutrition or Oli-Clinomel
Posology and Intravenous administration according to calculated caloric needs.
method of
administration:
Patient Population: Children with critical illness and a STRONGkids score of 2 points or more (cfr appendix
2)
evaluation:
Duration of patient 3 à 3.5 years
recruitment:
study
post-randomization.

3
- Structural differences in muscle tissue during ICU stay
Criteria:
All Patients admitted to the PICU with a STRONGkids score higher or equal to 2 upon
ICU admission.
Exclusion criteria:

hours after the initial discharge)
- Patients already enrolled in another outcome RCT.
- Patients transferred from another paediatric intensive care after a stay of more than 7
days
require home PN
- Patients who do not need a central venous catheter within the first hours after PICU-
admission
4
intention-to-treat basis. The data file will be finalised 90 days after inclusion
calories.
Discrete variables will be summarised by frequencies and percentages and
analysed by (exact) Chi- square test or logistic regression analysis.
Continuous variables will be summarised by use of either mean or standard
analysis.
All outcomes will be analysed in an uncorrected manner as well as
multiple testing.
Laboratory tests: Will be performed by Labo Intensieve Geneeskunde KU Leuven.

and at the central laboratory of the Erasmus MC in Rotterdam
5
II. INTRODUCTION
A widely held assumption is that in children, nutrition not only serves the maintenance of body tissues. It also
allows them to grow, which is particularly important during infancy and adolescence, when the fast growth
makes healthy children vulnerable to caloric restriction [6, 7]. Therefore, in the current European and
American guidelines for nutrition in hospitalised children, PN is recommended to prevent/correct malnutrition
randomised studies of nutritional support in critically ill children during the first week of critical illness should
include a control arm in which no nutritional support is administered or hypocaloric goals for nutritional
support are used.
a multi-centre RCT performed in two large, expert, tertiary, referral PICUs. The study will be sufficiently
6

discharge)
- Patients who do not need a central venous catheter within the first hours after PICU-admission.
- Patients transferred from another paediatric intensive care after a stay of more than 7 days
7
physician.
clinically followed up without his data being analyzed in the study. A separate patient log with minimal data
will register all patients withdrawn from the study.
allocation.
V. STUDY TIMETABLE
The patient inclusion started on 18 June 2012 in Leuven and on 13 September 2012 in Rotterdam. A
four months after admission of the first patient.
Written informed consent (see consent form in appendix 3) will be obtained from the patient or the closest
family member or legal guardian. For planned PICU admissions after elective procedures, informed consent
will be asked beforehand. For emergency PICU admissions, treatment allocation will be done after
assessment of the patient for eligibility by the attending physician within the time frame of two hours. If
eligible, the patient will be randomised into the study and informed consent will be asked within the time
frame of 24 hours (deferred informed consent) as a nutritional regimen has to be initiated on admission. A
duplicate of the signed informed consent will be given to the patient or the closest family member or legal
guardian. The patient’s referring physician will also be informed about the patient’s participation.
The family member or the patient can withdraw from the trial, at any time, without impact on his treatment or
penalty.
Netherlands.
8
6.2. Randomization
randomisation. Randomisation will be done in a 1:1 ratio in permuted blocks of 10 and stratified according to
I Medical-ICU admissions (≤1 year or >1 year): (a) neurologic, (b) other
II Surgical-ICU admissions (≤1 year or >1 year): (a) cardiac surgery, (b) other
Bedside nurses and doctors will not know the block size.
KULeuven protocol
PN preparation is available. Children weighing more than 40kg will receive adult parenteral nutrition.
9
Erasmus MC protocol
Both in Leuven and Rotterdam, patients randomised to the “late PN” group will receive a mixture of Glucose
will be given weekly.
10
volume will be considered to be EN and half gastric secretions. The duration and cause of interruption of
delivery of EN will be recorded. Problematic digestive intolerance will be registered as vomiting, tracheal
Blood samples are taken upon ICU admission and daily at 06:00h until discharge from ICU or death. If the
patient is staying in the PICU longer than 16 days, blood samples will be taken every four days and a final
sample at discharge. Upon admission three extra blood samples will be taken; namely two yellow SST-5
tubes(BD Vacutainer SST II Advance ref 367955) each containing 5 milliliter blood and 1 purple EDTA tube
(BD Vacutainer K2E 3,6mg ref 38841) of 2 milliliter blood.
(containing 5 milliliter blood) and an extra purple EDTA(BD Vacutainer K2E 3,6mg ref 38841) (containing 2
milliliter blood) for further analyses. When the child weighs less than 10 kg than we the SST-5 tube is
replaced by an SST-3,5 tube(BD Vacutainer SST II Advance ref 367957) (containing 3,5 milliliter blood).
A subset of the samples will be immediately stored on ice and processed in a cold chain for future endocrine
measurements. Processed serum and plasma as well as the spun-down blood cells will be frozen and
stored.
Analyses on the 06:00h sample will include routine clinical chemistry, hematology (Hgb, WBC, TC), and
markers of inflammation (CRP), liver function ALT, AST, ALP, GGT, bilirubin total/direct. A number of
metabolic, hormonal and inflammatory study analyses will be performed on selected days.
The latter include coagulation & fibrinolysis tests, cytokines and markers of oxidative stress. Also on selected
days urine (5 tubes of 5 mL out of 24 hours’ urine collection) will be stored for further evaluation (e.g. cortisol
metabolites, NGAL).
All whole blood glucose levels are measured on arterial blood using a blood gas analyser on each ICU and
are registered for later calculation of glucose metrics (cfr appendix 7).
adaptations for the pediatric population. (cfr appendix 4)
11
All (suspected) new infections of the lungs, the blood stream, the urinary tract and wounds are recorded in
the patient data file by the bedside senior intensive care specialists. New infections or suspected new
Bacteraemia is further classified by responsible pathogen and as catheter-related blood stream infection
versus other bacteraemia.
adipose tissue will be performed. Furthermore, as far as practically feasible, every patient is approached just
prior to hospital discharge, to complete a validated, semi- structured child health questionnaire (HUI, CHQ,
PEDI-NL, SDQ).).
PEPaNIC study (4 months,2 year, 4 years). Long-term follow-up at 2 years will also include a clinical
paediatric examination and neurocognitive testing by a qualified paediatric psychologist. Follow-up at 4 years
after inclusion will consist of the questionnaire, the clinical paediatric examination and a full neurocognitive
testing.
control group will receive standard therapy, i.e. PN with or without lipids or electrolytes within one week. In
discharge from ICU.
when they are no longer in need of vital organ system support.

survivors.
randomisation diagnosis of new kidney injury/failure (defined by modified Risk, Injury, Failure, Loss, and
12
will be analysed, with ICU non-survivors censored beyond the longest duration of pharmacological or
- Inflammation: Effect of the intervention on inflammation will be analysed by comparing the distribution of
comparing time profiles of daily C-Reactive Protein values.
- Child health questionnaire scores (HUI, CHQ, PEDI-NL, SDQ), reflecting the state of the child before
adipose tissue.


Clinical complications: pneumothorax, hemothorax and arterial puncture, central line replacement due to
suspicion of catheter-related blood stream infections
IX. ADVERSE EVENTS
13
Hypoglycemia (< 40 mg/dL) resistant to iv glucose administration will be considered as a serious
adverse event. This adverse event will be reported to the sponsor.
10.1. Sample size
75% depending on the true mortality in the total population. We plan to re calculate the power of the study,
based on the incidence of new infections, in the control group after inclusion of patient number 480. We
anticipate that 3-3.5 years will be needed to take this study to completion, provided informed consent will be
at least 80%. If required, additional study sites will be included. To face worse recruitment, we anticipate
requiring 4 years to complete the clinical study (excluding long term follow up) and 1 more year to process
samples and data.
A consort diagram will be reported. The data file will be finalised 90 days after inclusion of the last patient. To
calories. Discrete variables will be summarised by frequencies and percentages and analysed by (exact)
Chi- square test or logistic regression analysis. Continuous variables will be summarised by use of either
proportional hazard analysis. All outcomes will be analysed in an uncorrected manner as well as (jointly)
patients.
14
i. ICU mortality (in 2 blinded study groups; when differences are significant, the board will call for unblinding).
ii. Proportion of patients requiring mechanical ventilation for more than 7 days (only aggregated data of both
groups) in comparison with those from the previous annual reports of the department.
iv. SAE: Therapy resistant hypoglycemia (in 2 blinded study groups; when differences are significant, the
board will call for unblinding).
will be performed and will be reported following the sponsor’s SOPs. No fault insurance is covered by Fortis
Corporate Insurance NV. A copy of the insurance policy is included.
Publication policy and financing will be addressed in separate agreements.
15
Statisticians
Microbiologists
Pathologists
….
16
Appendix 1
Kleine zuigeling:
Voedingen:

- Ileus
- Darmischemie

- Aspiratie risico
Maagresidu
Diarree
- Etiologie?
17
18
Adressogram
Informed consent formulier : PEPaNIC Versienummer 3

17-12-2012
Geachte Mevrouw,
Geachte Heer,
medische zorgen te geven aan de patiënten, maar ook constant de huidige
inzichten.
Na uitgebreide heelkundige ingrepen en tijdens ernstige kritieke ziekte zijn patiënten soms
opstarten van aanvullende veneuze voeding de overlevingskansen van deze patiënten
duidelijk verbeterde. Ook de risico’s op complicaties namen duidelijk af in vergelijking met de
patiënten waarbij de veneuze voeding vroegtijdig werd opgestart.
deelnemen.
zorgenafdeling ingedeeld worden in een groep waarbij de veneuze voeding laattijdig wordt
bepaald. Uw kind zal verder dezelfde maximale zorgen krijgen. Het deelnemen aan de studie
de spiermassa en het onderhuids vetweefsel. Het zou kunnen dat we over enkele jaren Uw
19
kind uitnodigen voor een vrijblijvende opvolgconsultatie. Om een beter inzicht te krijgen in de
evolutie van uw kind na hospitalisatie op intensieve zorgen, zullen we op regelmatige
tijdstippen een vragenlijst opsturen.
De superioriteit van een van beide voedingsschema's is nog nooit aangetoond bij kinderen.
Een theoretisch risico zou kunnen zijn dat de bloedsuikerwaarde iets lager zou kunnen zijn
wanneer de voeding laattijdig wordt opgestart. Echter, deze bloedsuikerwaarde wordt continu
opgevolgd en onmiddellijk gecorrigeerd zo deze afwijkend is.
te allen tijde het recht om deelname aan de studie stop te zetten. De studie brengt geen
enkele bijkomende kosten met zich mee. Gegevens en resultaten van dit onderzoek kunnen
gebruikt worden voor publicatie in wetenschappelijke tijdschriften doch zonder dat
persoonlijke gegevens worden vermeld en met volledige waarborg van de anonimiteit.
Conform de Belgische wet inzake experimenten op de menselijke persoon van 7 mei 2004 is
de opdrachtgever van het onderzoek zelfs foutloos, aansprakelijk voor alle schade die de
deelnemer en/of zijn rechthebbenden oplopen en die rechtstreeks dan wel onrechtstreeks
verband houdt met de proef. De opdrachtgever heeft een verzekering afgesloten die deze
aansprakelijkheid dekt. Indien U schade zou oplopen ten gevolge van uw deelname aan
deze studie zal die schade bijgevolg worden vergoed conform de Belgische wet inzake
experimenten op de menselijke persoon van 7 mei 2004.
Deze studie werd goedgekeurd door de Commissie Medische Ethiek van UZ/KU Leuven.
Deze goedkeuring mag echter niet beschouwd worden als een aanzet tot deelname aan de
studie.
Prof Dr Dieter Mesotten Prof Dr Greet Van den Berghe

Senior-assistent Prof Dr Dirk Vlasselaers
Dr Lars Desmet
20
“vroegtijdig versus laattijdig opstarten van aanvullende intraveneuze voeding” en stem ermee
in dat mijn kind hieraan deelneemt.
Naam patiënt:
………………………………………………………………………………………..
………………………………………………………………………………………..
Handtekening(en) : …………………………………………………………………………..
Leuven, ….. / ……./ 201…
Naam Arts:…………………………………………………………………………………
Handtekening:……………………………………………………………………………..
Datum:……………………………………………………………………………………...
Een duplicaat van het IC werd aan de patiënt of aan een van de ouders overhandigd.
21
Adressogram
INTENSIVE CARE MEDICINE
Informed consent document: PEPaNIC Version number 1

05-02-2013
Dear Madam,
Dear Sir,
Besides providing high quality patient care, one of the duties of an academic teaching
hospital is to critically evaluate the current medical standard and to update it according to
new insights.
Your child has been admitted to the ICU. During this period your child is not able to be
normally fed. Therefore children are fed through a gastric tube, which we call enteral feeding.
Sometimes this enteral feeding is insufficient during the first days or weeks. Then the caloric
deficit will be managed by the administration of intravenous feeding. However, the optimal
timing to start supplementary intravenous feeding in critically ill children is unknown.
In adults, a large controlled randomized trial from the Dept Intensive Care Medicine of the
University Hospitals Leuven has shown that withholding the intravenous feeding during the
first week of critical illness improves the outcome of critically ill adults. Also the risk of
complications was smaller when the administration of intravenous feeding was delayed.
It is yet not known whether delaying intravenous feeding is also beneficial for children in the
ICU aged 0 to 17 years.
Hence, we are asking you to consent your child participating in a research study to help us
learn more about nutrition during critical illness, such as the optimal timing to start
intravenous nutrition and the long-term effects of it. In the future, this information will help
doctors to optimize nutritional support in children during the first week of critical illness.
If you consent your child participating, he/she will be randomized to either the intervention
group or the control group of the study. Randomization is like flipping a coin; this means that
your child has an equal chance of being in the intervention group or the control group. This
study will not affect any of the other treatments or care given by the doctors and nurses to
your child. The intervention group will receive fewer calories during the first week of critical
illness and intravenous feeding will not be started in this period. The control group will
receive the normal intravenous feeding according to the current practice in our ICU. Neither
you nor your physician can choose which group your child is randomized to. This blinding is
necessary to fairly test the intervention.
22
To further evaluate and examine the effects of the nutritional regimens, we will need a small
amount of blood (two teaspoons). This will be taken daily during ICU-stay, together with the
daily routine blood samples. The blood draw will not cause any pain or discomfort as all
children have already a line in the blood vessels for continuous blood pressure
measurement. On a few occasions during the ICU-stay we will also do an ultrasound
examination of the muscle mass and the subcutaneous fat tissue. To get a better insight into
your child’s evolution after hospitalization in the ICU, we will send you a regularly a
questionnaire to fill out.
In a few years’ time we may also invite your child for a non-committal follow-up consultation.
Superiority of one of the nutritional regimens has not yet been proven in children. There may
be a small risk of hypoglycaemia in the intervention group, when intravenous feeding is
delayed. However blood glucose levels are frequently checked and directly treated when
abnormal.
Participation in the study is fully voluntary. If you agree to participate, you are free to
withdraw your child from the research study at any time. The study will not result in additional
costs to you. The data and the results of this study may be used for a publication in scientific
journals. However, we warrant that your child’s name will not be disclosed outside the
research clinic and that any report published as a result of this study will not identify your
child’s name.
The Participating Site and Investigator will perform their part of the Study fully in accordance
with the terms of the Protocol, any implementation in national law of the applicable national
law (Belgian Law relating to experiments on human persons dated May 7, 2004 and the Law
of December 19, 2008 on the acquisition and use of human biological material), and apply
and adhere to the ICH GCP Guidelines. Furthermore the Parties agree to comply with
applicable laws, regulations and rules (including the Declaration of Helsinki (2008) and the
internal rules and guidelines of the University or Hospital where they perform the Study
and/or their employer), as well as with the ethical rules applicable to the medical profession
in their country of residence. Parties also agree that they will make all required disclosures
and obtain all approvals with respect to their engagement hereunder as required by
applicable laws, regulations and rules, including without limitation any required notification to
the relevant ethics committee, government agency or employer.
This study was approved by the Ethics Committee of the University Hospitals Leuven / KU
Leuven. This approval should not be regarded as a stimulus to participate in the study.
Hoping on your participation, we would already like to thank you in anticipation,
Prof. dr. Dieter Mesotten Prof. dr. Greet Van den Berghe
Consultant Intensive Care Medicine Head Intensive Care Medicine
Dr. Tom Fivez Prof. dr. Dirk Vlasselaers

Fellow Intensive Care Medicine Consultant Intensive Care Medicine
Dr. Lars Desmet

Consultant Intensive Care Medicine
23
Patient’s Name:
………………………………………………………………………………………..
Name and relation to the patient:
………………………………………………………………………………………..
Signature : …………………………………………………………………………..
Leuven, ….. / ……./ 201…
Name Doctor:…………………………………………………………………………………
Signature:……………………………………………………………………………..
Date:……………………………………………………………………………………...
A copy of this consent has been given to the patient or to the parents.
24
Adressogram
Formulaire d’information et de consentement éclaire:

PEPaNIC
Version 1 (05-02-2013)
Madame,
Monsieur,
La mission première d’un hôpital universitaire consiste non seulement à prodiguer les
meilleurs soins à ses patients, mais aussi à continuellement évaluer et améliorer les
thérapies actuelles afin de pouvoir assurer une médecine de référence, à la pointe
du progrès et des développements technologiques et scientifiques.
Après une intervention chirurgicale et pendant une maladie grave ou critique, le
patient est parfois dans l’impossibilité de se nourrir normalement. Généralement, on
a alors recours à l’alimentation par sonde gastrique. Hélas, ce n’est souvent qu’après
quelques jours ou quelques semaines que ce type d’alimentation n’atteint l’apport
calorique souhaité. On peut alors y ajouter l’alimentation parentérale, qui elle, est
introduite directement dans le sang par voie veineuse (perfusion). Toutefois, jusqu’à
peu, il n’était pas clair quand commencer ce type d’alimentation supplémentaire.
Récemment, nous avons démontré, qu’une instauration plus tardive du support
nutritionnel par voie parentérale, était avantageuse pour l’adulte gravement malade.
Ceci se traduisait en une réduction du nombre d’infections ainsi qu’une réduction de
la durée de séjour, en réanimation et à l’hôpital. La question se pose maintenant, si
cette stratégie aura aussi ces mêmes effets favorables chez les enfants en
réanimation. Ceci est le sujet de cette étude clinique dans laquelle nous voulons
inclure les patients entre 0 et 17 ans.
Nous vous demandons l’autorisation de laisser participer votre enfant à cette étude.
Si vous consentez à ce que votre enfant prenne part à cette étude, il (elle) sera
assigné(e) dans soit le groupe d’enfants qui reçoivent ’tardivement’ l’alimentation par
perfusion, soit le groupe d’enfants qui reçoivent conformément aux habitudes
actuelles, une nutrition complémentaire intraveineuse précoce. Dans cette étude
randomisée, les participants sont répartis de façon aléatoire (par tirage au sort) dans
le groupe témoin (alimentation parentérale précoce) et le groupe expérimental
(alimentation parentérale plus tardive). Tous les autres soins sont maximaux et
identiques dans les deux groupes. Participer à cette étude n’altérera en aucun cas la
prise en charge médicale de votre enfant.
Afin de pouvoir étudier les effets de cette stratégie, nous avons besoin d’une petite
quantité de sang, qui sera prise en même temps que les prises de sang journalières
classiques, nécessaires pour suivre l’évolution de votre enfant. Cette prise de sang
est indolore puisqu’elle s’effectue par le cathéter qui a été placé afin de pouvoir
mesurer continuellement la tension artérielle. Pendant le séjour en soins intensifs, on
effectuera plusieurs échographies, qui sont, elles aussi, indolores, afin de pouvoir
évaluer la masse musculaire et le tissu adipeux sous-cutané. Il se peut également
25
que votre enfant soit invité ultérieurement (dans quelques années) pour une
consultation de suivi.
Jusqu’à présent, on n’a pu démontrer la supériorité d’une des deux stratégies de
nutrition chez les enfants. En théorie, un risque accru d’hypoglycémie (taux sanguin
de glucose trop bas) pourrait se poser quand la nutrition parentérale est administrée
plus tardivement. Cependant, le taux sanguin de glucose est contrôlé
continuellement, ce qui nous permet de le corriger immédiatement s’il s’avère
aberrant.
Evidemment, vous êtes libre de participer. Vous pouvez à tout moment vous
soustraire à l'étude, sans en donner de raison et sans que soit altérée la prise en
charge médicale et les soins prodigués.
Cette étude ne vous apporte pas de frais supplémentaires. Les résultats analysés
peuvent faire l'objet de publications scientifiques. Toutefois, la confidentialité des
données et des résultats de cette étude est assurée.
Conformément à la Loi relative aux expérimentations sur la personne humaine du 7

mai 2004, le promoteur assume, même sans faute, la responsabilité du dommage
causé au participant ou à ses ayants droit, dommage lié de manière directe ou
indirecte à l'expérimentation. Le promoteur a préalablement contracté une assurance
couvrant cette responsabilité ainsi que celle de tout intervenant à l'expérimentation,
indépendamment de la nature des liens existants entre l'intervenant, le promoteur et
le participant.
Cet essai clinique a été approuvé par le Comité d'Ethique de la recherche UZ/KU
Leuven. Néanmoins, cette approbation ne doit pas être considérée comme
encouragement à la participation à cette étude.
Nous espérons pouvoir compter sur votre participation, et vous remercions d’avance,
Prof.dr. Dieter Mesotten Prof.dr. Greet Van den Berghe

Service de Soins Intensifs Chef de Service de Soins
Intensifs
Dr. Tom Fivez Prof.dr. Dirk Vlasselaers

Senior-assistant Dr. Lars Desmet
Service de Soins Intensifs
26
Nom du patient:
………………………………………………………………………………………..
Nom et relation avec le patient
………………………………………………………………………………………..
Signature : …………………………………………………………………………..
Leuven, ….. / ……./ 201…
Nom Docteur:…………………………………………………………………………………
Signature:……………………………………………………………………………..
Date:……………………………………………………………………………………...
Un doublon de l’IC a été remis au patient ou à un des parents.
Appendix 4
SIRS
27
àpresence of at least 2criteria, representing an acute change from baseline and in the absence of
other known causes for these changes
SEVERE SEPSIS
SEPTIC SHOCK
Appendix 5
Appendix 6
28

(zie nomogram)
dag 1 : 40 x M x 24 = ………………… ml
dag 2 : 50 x M x 24 = ………………… ml
dag 3+ : 60 x M x 24 = ………………… ml
100 ml/kg/dag: 100 ml x G = ………………… ml (= T)


Konakion 2mg 1/week

Apotheek:
29

(zie nomogram)
dag 1 : 40 x M x 24 = ………………… ml
dag 2 : 50 x M x 24 = ………………… ml
dag 3 : 60 x M x 24 = ………………… ml
dag 4+ : 80 x M x 24 = ………………… ml
100 ml/kg/dag: 100 ml x G = ………………… ml (= T)

Cernevit®: 1 ml = …………….. (= N) ml

Apotheek:
30

(zie nomogram)
dag 1 : 40 x M x 24 = ………………… ml
dag 2 : 50 x M x 24 = ………………… ml
dag 3 : 60 x M x 24 = ………………… ml



Cernevit®:2.5 ml = …………....(= N) ml
Konakion 5mg 1/week

Apotheek:
31

(zie nomogram)

dag 1 : 40 x M x 24 = ………………… ml
dag 2 : 50 x M x 24 = ………………… ml
dag 3 : 60 x M x 24 = ………………… ml


Cernevit®: 2.5 ml = ………………(= N) ml

Apotheek:
32
Appendix 7
GLYCEMIEBELEID BIJ
KINDEREN OP ITE TE
GASTHUISBERG
bij kinderen aangetoond (Lancet 2009; 373(9663):547-56). Daarom passen we ook bij

Figuur 1
zelf anticiperende beslissingen te nemen in het streven naar normoglycemie.
toekomen.
33
(figuur 2).
overschrijdt.
insuline-infuus glyc > bovengrens glyc > 2x
Gewicht
0,9%)

Figuur 2
systeem.
 De controle van de glycemie tot binnen de fysiologische grenzen is noodzakelijk.
nieuwe glycemiecontrole uitvoeren ter preventie van hypoglycemie.
 Bij hypoglycemie wordt glucose IV (1 ml glucose 50%/ kg LG) (50% = 500mg/ml)
toegediend (fig.3).
STOP insuline
geef gluc 50% (1 ml/kg)

Figuur 3
34
insuline-infuus.
glycemiecontrole.

o Stress
o Koorts
plaatsen).
35
References
36
17.
2011;27(2):133-137.
11. George Briassoulis, Shekhar Venkataramanand Ann Thompson. Cytokines and Metabolic
expenditure be predicted in critically ill children?Pediatr Crit Care Med 2003; 4:176 –180)
2002
37
PhD et al. Energy expenditure in critically ill children. Pediatr Crit Care Med 2007; 8:264 –267
38
Erasmus Universiteit Rotterdam
PEPaNIC/ 38772 PEPaNIC
Paediatric Early versus late

Parenteral Nutrition In Critical illness
- PEPaNIC
(April 2012)
PROTOCOL TITLE ‘Paediatric Early versus late Parenteral Nutrition In Critical illness’
Protocol ID PEPaNIC - NL
Short title PEPaNIC
Version 3
Date 22-04-2012
Coordinating investigator/project Prof. Dr. G Van Den Berghe, Katholieke

leader Universiteit, Leuven, Belgium
Principal investigator(s) (in Erasmus MC – Sophia Children’s Hospital

Dutch:
Prof. Dr. D Tibboel
hoofdonderzoeker/uitvoerder)
Dr. SCAT Verbruggen
Multicenter research: per site
Dr. KFM Joosten
Katholieke Universiteit, Leuven, Belgium
Prof. Dr. G Van Den Berghe
Prof. Dr. D. Mesotten
Prof. I Vanhorenbeek
Dr. L Desmet
Dr. T Fivez
Sponsor (in Dutch: Investigator Initiated

verrichter/opdrachtgever)
Independent physician(s) Prof. Dr. IKM Reiss, Neonatology, Erasmus MC –

Sophia Children’s Hospital
Laboratory sites <if applicable> Laboratory Paediatrics,

Erasmus MC –Sophia, Rotterdam
Laboratory Intensive Care Medicine, University

Hospital Leuven, Belgium
Pharmacy <if applicable> Erasmus MC – Sophia (Rotterdam site)
University Hospital Leuven (Leuven site)

PROTOCOL SIGNATURE SHEET
Name Signature Date
For non-commercial research, Prof. Dr. D. Tibboel

Head of Department:
Head of department,
Pediatric ICU
Coordinating Investigator/Project leader Dr. KFM Joosten
Dr. SCAT Verbruggen

Principal Investigator:
TABLE OF CONTENTS
1. INTRODUCTION AND RATIONALE .............................................................................. 9

2. OBJECTIVES ................................................................................................................11
3. STUDY DESIGN ...........................................................................................................14
4. STUDY POPULATION ..................................................................................................17
4.1 Population Base .....................................................................................................17
4.2 Inclusion criteria .....................................................................................................17
4.3 Exclusion criteria ....................................................................................................17
4.4 Sample size calculation ..........................................................................................17
5. TREATMENT OF SUBJECTS .......................................................................................19
5.1 Investigational treatment ........................................................................................19
5.2 Use of co-intervention (if applicable) ......................................................................24
5.3 Escape medication (if applicable) ...........................................................................24
6. INVESTIGATIONAL MEDICINAL PRODUCT ................................................................24
7. METHODS ....................................................................................................................25
7.1 Study parameters/endpoints...................................................................................25
7.1.1 Main study parameter/endpoint .......................................................................25
7.1.2 Secondary study parameters/endpoints ..........................................................25
7.1.3 Other study parameters ...................................................................................30
7.2 Randomisation, blinding and treatment allocation ..................................................31
7.3 Study procedures ...................................................................................................31
7.4 Withdrawal of individual subjects ............................................................................35
7.4.1 Specific criteria for withdrawal (if applicable) ...................................................35
7.5 Replacement of individual subjects after withdrawal ...............................................35
7.6 Follow-up of subjects withdrawn from treatment .....................................................35
7.7 Premature termination of the study.........................................................................35
8. SAFETY REPORTING ..................................................................................................36
8.1 Section 10 WMO event ..........................................................................................38
8.2 Adverse and serious adverse events ......................................................................38
8.2.1 Suspected unexpected serious adverse reactions (SUSAR) ...........................39
8.2.2 Annual safety report ........................................................................................39
8.3 Follow-up of adverse events...................................................................................40
8.4 Data Safety Monitoring Board (DSMB) ...................................................................40
9. STATISTICAL ANALYSIS .............................................................................................41
9.1 Descriptive statistics ...............................................................................................41
9.2 Univariate analysis .................................................................................................42
9.3 Multivariate analysis ...............................................................................................42

9.4 Interim analysis ......................................................................................................44
10. ETHICAL CONSIDERATIONS...................................................................................45
10.1 Regulation statement .............................................................................................45
10.2 Recruitment and consent........................................................................................45
10.3 Objection by minors or incapacitated subjects (if applicable) ..................................45
10.4 Benefits and risks assessment, group relatedness .................................................46
10.5 Compensation for injury .........................................................................................46
10.6 Incentives ...............................................................................................................46
11. ADMINISTRATIVE ASPECTS AND PUBLICATION ..................................................47
11.1 Handling and storage of data and documents ........................................................47
11.2 Amendments ..........................................................................................................47
11.3 Annual progress report ...........................................................................................47
11.4 End of study report .................................................................................................47
11.5 Public disclosure and publication policy..................................................................48
12. REFERENCES ..........................................................................................................49
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS
ABR ABR form, General Assessment and Registration form, is the application
form that is required for submission to the accredited Ethics Committee (In
Dutch, ABR = Algemene Beoordeling en Registratie)
AE Adverse Event
AR Adverse Reaction
CA Competent Authority
CCMO Central Committee on Research Involving Human Subjects; in Dutch:
Centrale Commissie Mensgebonden Onderzoek
CV Curriculum Vitae
DSMB Data Safety Monitoring Board
EU European Union
EudraCT European drug regulatory affairs Clinical Trials
GCP Good Clinical Practice
IB Investigator’s Brochure
IC Informed Consent
IMP Investigational Medicinal Product
IMPD Investigational Medicinal Product Dossier
METC Medical research ethics committee (MREC); in Dutch: medisch ethische
toetsing commissie (METC)
(S)AE (Serious) Adverse Event
SPC Summary of Product Characteristics (in Dutch: officiële productinfomatie
IB1-tekst)
Sponsor The sponsor is the party that commissions the organisation or performance
of the research, for example a pharmaceutical
company, academic hospital, scientific organisation or investigator. A party
that provides funding for a study but does not commission it is not
regarded as the sponsor, but referred to as a subsidising party.
SUSAR Suspected Unexpected Serious Adverse Reaction
Wbp Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens)
WMO Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen
Version 3: 22-04-2012 6 of 51
SUMMARY
Rationale: It has recently been shown in a large randomized study in adult ICU patients that
the early PN caused an increase of morbidity (infections and increased length of stay on the
ICU). Such a study is warranted also in critically ill children of different age groups, as PN
has been associated with increased incidence of complications, such as (line) infections,
hyperglycemia and hepatic steatosis. It has not been studied whether early PN, when enteral
feeding is insufficient, influences the outcome of critically ill children.
Objective: The ultimate aim of this project is to answer the question whether insufficient EN
should or should not be supplemented with PN early in the disease course of critical illness in
children. The scientific objectives of the study are the following: 1) Performing the first well-
designed and sufficiently powered, multicentre RCT to test the effects of early PN
supplementation on the health of critically ill children. 2) ) Performing an economic evaluation
study, investigating the costs and cost-effectiveness, during hospitalisation of early versus
late PN supplementation. 3) Starting to unravel potential mechanisms that underlie any
difference in acute and long term outcome with early or late PN supplementation by studying
metabolic, endocrine, inflammatory and (epi.)genetic markers.
Study design: This study is a large, two-centre, non-blinded, randomized, controlled study.
Consecutive patients are randomly assigned to one of the two treatment study groups using
a digital system with central, computerised randomisation. Randomisation – in a one to one
allocation ratio - is performed per centre and using permuted blocks of 10 per diagnostic
stratum. The block size remains unknown to bed-side physicians and nurses, responsible for
patient recruitment and therapy assignment.
Study population: Critically ill children (0 – 18 yrs), with nutritional risk score
(STRONGkids® see appendix) 2 or more, who are not able to take oral nutrition and are
expected to stay in PICU for more than 24h are eligible for inclusion. Exclusion criteria are a
“do not resuscitate” code at the time of PICU admission, expected death within 12 hours, re-
admission to the PICU after previously being randomised to the PEPaNIC trial, transfer from
another PICU after a stay of more than seven days, ketoacidotic or hyperosmolar coma on
admission or inborn metabolic diseases requiring specific diet, premature newborns (<37
weeks gestational age), patients on Total Parenteral Nutrition for >7 days prior to inclusion,
short bowel syndrome or other conditions which required home-PN.
Intervention: The “early PN” strategy will be the nutritional management currently applied in
the participating centres, acting as “control”. The “late PN” strategy comprises initiation of this
strategy only after day 7 in PICU, patients will receive a mixture of Glucose 5% and NaCl
0.9% at, respectively, 60% and 40% of the total flow rate that is required to obtain standard
optimal hydration taking into account the volume of EN that is being delivered. If enteral
Version 3: 22-04-2012 7 of 51
feeding of at least 80% of the calculated calories is not possible after 7 days in ICU, PN, as
specified above, is initiated on day 8.
Main study parameters/endpoints: We will compare “early PN” with “late PN” in paediatric
ICU patients at risk of developing malnutrition in the ICU. The primary focus of the PEPaNIC
study is clinical outcome, more specifically the acquisition of new ICU infections, the
dependency on intensive medical care and convalescence from critical illness.
Nature and extent of the burden and risks associated with participation, benefit and
group relatedness: The burden is expected to be minimal as it will only entail additional
blood draws, which will be taken from clinical lines or in addition to pricks for clinical purpose.
The long-term follow up will be held as part of already organised follow-up outdoor clinics
and which are developed to help children and their parents to recover physically, emotionally
and socially after ICU admissions. For mechanistic and exploratory studies, muscle strength
testing and an ultrasound evaluation of the skeletal muscle and adipose tissue compartments
will be performed. Furthermore, as far as practically feasible, every patient is approached just
prior to hospital discharge, to complete a validated, semi-structured child health
questionnaire (Functional Independence Measure (WEEFIM), Health Utilities Index (HUI)
and Child Health Questionnaire (CHQ)).
The risk in participating to the study and being randomized to the "late PN' group are
negligible, and specifically compass an increased risk of developing hypoglycemia and/or
underfeeding. However, safety measures will be taken to further decrease these risks.
GROUP relatedness: This study was already performed in adult ICU patients. However, the
results of this study should NOT be translated one-on-one to the pediatric patient, as critically
ill children of different age groups have different metabolic and nutritional issues. Therefore,
this study deserves to be repeated in our population of critically ill children.
Version 3: 22-04-2012 8 of 51
1. INTRODUCTION AND RATIONALE
It has recently been shown that withholding parenteral nutrition (PN.) during the first week of
critical illness (Late PN) is beneficial in comparison with the early supplementation of
insufficient enteral nutrition (EN) with PN (Early PN) in critically ill adults (1). The benefits of
Late PN mainly encompassed a decrease in the incidence of new infections in the ICU, a
shortening of the stay in the ICU and hospital, and a reduction in healthcare costs. These
findings put pressure on the current guidelines by the European Society of Parenteral &
Enteral Nutrition (ESPEN.), which recommend the practice of Early PN in critically adults (2).
These current medical practice and expert panels advocate the early supplementation by
PN. This is based on the premise that PN is probably beneficial, and if not, harmless. This
contrasts strongly with the findings of the study in adult critically ill patients where it has been
shown that this early supplementation by PN is not providing benefit and is actually causing
harm to patients by increasing the morbidity and delaying recovery.
The detrimental impact of the practice of Early PN in critically ill adults has alerted the clinical
community that also the guidelines for nutritional strategy in paediatric critically ill patients are
merely based on expert opinion. Not only is Early PN current practice in most paediatric
ICUs, it is also often more aggressively promoted (3, 4). This is further evidenced by the
presence of national governmental healthcare programs that include the success rate for
reaching nutritional goals as a quality benchmark (5). Therefore critically ill children may be
exposed to risk by the aggressive feeding protocols, which were previously deemed innocent
or even beneficial. We and others have shown recently that current aggressive feeding
protocols with early high protein and lipid intakes, not only fail to achieve anabolism, but have
potential negative side effects, such as increased risk of developing hyperglycemia,
dyslipidemia and insulin resistance (6, 7). Furthermore, there is currently no evidence of
beneficence of early supplementation of parenteral nutrition, although this is practiced in
multiple PICU’s according current guidelines. PN has been associated with increased
incidence of complications, such as (line) infections, hyperglycemia and hepatic steatosis.
Furthermore, it is well recognized that the quality of current PN solutions lack sufficient
scientific basis and are potentially harmful (8). Therefore, it is unclear whether an early
supplementary intervention of parenteral nutrition to try and decrease catabolism in critically
ill children outweighs the potential harm of such therapy. Furthermore, recent studies have
suggested a negative role of early aggressive nutrition in the interference of autophagy of
cellular damage in critically ill patients, a process that may protect against infectious
diseases and hyperinflammation (9-11). Children are in the early phase of their life when the
fundaments of metabolism are developing. Therefore, it cannot be excluded that the
aggressive nutritional support given to critically ill children has repercussions on the long run,
Version 3: 22-04-2012 9 of 51
until later in their adult life. And thus, such a study deserves to be performed in a population
of critically ill children.
In our study we aim to evaluate whether the current practice of Early PN in critically ill
children really provides clinical benefits over a strategy of withholding PN during the first 7
days in the paediatric ICU. The evaluation will be done in a multicentre randomized
controlled trial performed in two large expert tertiary referral paediatric ICUs. The study will
be statistically sufficiently powered to detect differences in clinically relevant outcome
variables (the rate of new infections and the length of stay in the ICU). The trial will also be
able to detect a doubling or halving of the mortality rate with a respectable statistical power
(details on statistical power are given in the description further on). The results of this
randomized controlled trial will provide, for the first time, high quality evidence for practice
guidelines for nutrition in critically ill children. It will answer the question whether Early PN is
beneficial, harmful or neutral in comparison with the new therapy of withholding PN during
the first week of critical illness. In weighing this evidence for current nutritional practice, this
study will take into account 1) the short-term as well as the long-term health effects of the
feeding protocols, 2) costs, and cost-effectiveness and 3) some insights into the underlying
mechanisms of the observed clinical differences.
Version 3: 22-04-2012 10 of 51
2. OBJECTIVES
The ultimate aim of this project is to answer the question whether insufficient EN should or
should not be supplemented with PN early in the disease course of critical illness in children.
The scientific objectives of the study are divided into 3 main work-packages (WP 1-3) and
are the following:
- WP1: Performing and completing the first well-designed and sufficiently powered,
multicentre RCT to test the effects of early PN supplementation on the health of
critically ill children. The short-term outcome analysis, as well as a substantial part of
the long-term follow-up, will be completed within the time frame of the study.
- WP2: an economic evaluation, in which costs and cost-effectiveness will be
investigated of early versus late PN supplementation during hospitalization.
- WP3: Starting to unravel potential mechanisms that underlie any difference in acute
and long term outcome with early or late PN supplementation by studying metabolic,
endocrine, inflammatory and (epi.)genetic markers in the blood of critically ill children
included in the study.
Primary Objective:
The primary focus of the PEPaNIC study is clinical outcome, more specifically the acquisition
of new ICU infections, the dependency on intensive medical care and convalescence from
critical illness, this is part of WP1.
The primary efficacy endpoints for this RCT are the incidence of new infections and the time
to discharge alive from ICU. We expect to see a decrease in secondary infections from 20%
to 15%, which is based on a previous study in critically ill children in Leuven (12) and on
retrospective data in critically ill children who were admitted for at least four days in the
PICU, Rotterdam.
Number of patients with new infections and types of infection will be assessed by numbers
and percentages, and the duration of any antibiotics therapy initiated after randomisation for
those patients requiring antibiotics will be analysed by non-parametrical tests. As the time of
ICU discharge to the regular ward may be affected by the availability of beds on the regular
wards, which could induce bias, we a priori decided to analyse “time to discharge from ICU”
as “time to ready for discharge from ICU”. A patient is considered “ready for discharge” as
soon as all clinical conditions for ICU discharge have been fulfilled (no longer in need for vital
organ support). Time to discharge alive from ICU will be reported by Kaplan-Meier plots, with
ICU non-survivors censored beyond the longest ICU stay of survivors and censoring time of
patients still in the ICU at closing of the data file (90 days after last patient inclusion) over
both treatment groups. The impact of “late PN” versus “early PN” will be analysed, with and
Version 3: 22-04-2012 11 of 51
without correction for age, nutritional status and risk categories and type and severity of
illness, by Cox proportional hazard analysis. The distribution of the actual time to discharge
from ICU will be reported for ICU-survivors and ICU-non-survivors separately. In view of the
time window of the randomised intervention in ICU, also the proportion of patients staying
beyond 8 days in ICU will be reported. Analyses on blood and urine for the primary clinical
analyses include routine chemistry, haematology, and markers of inflammation. Further
epigenetic, metabolic, endocrine and inflammatory measurements on stored samples in the
context of mechanistic analyses will be planned. All new infections of the lungs, the blood
stream, the urinary tract and wounds are recorded by an infectious disease specialist. A
nosocomial infection is defined as a localized or systemic condition 1) that results from
adverse reaction to the presence of an infectious agent(s) or its toxin(s) and 2) that was not
present or incubating at the time of admission to the PICU. The information used to
determine the presence and classification of an infection should be a combination of clinical
findings and results of laboratory and other tests. Definitions various types of proven and
suspected infections will be used according to clinical, laboratory evidence and/or supportive
data. WHO definitions for nosocomial infections will be used (13).
WHO definitions for nosocomial infections (13).
Version 3: 22-04-2012 12 of 51
Clinical evidence is derived from direct observation of the infection site or review of other
pertinent sources of data, such as the patient’s chart. Laboratory evidence includes results of
cultures, antigen or antibody detection tests, or microscopic visualization. Supportive data
are derived from other diagnostic studies, such as x-ray, ultrasound, computed tomography
(CT) scan, magnetic resonance imaging (MRI), radiolabel scan, endoscopic procedure,
biopsy, or needle aspiration. It will be recorded during the entire ICU period until discharge,
death or until day 90 of admittance.
Bacteraemia is further classified by responsible pathogen and as catheter-related blood
Secondary Objectives:
WP2. Performing an economic evaluation study, investigating the effects of early versus late
PN supplementation during hospitalization.
WP3. Starting to unravel potential mechanisms that underlie any difference in acute and
long-term outcome with early or late PN supplementation by studying metabolic, endocrine,
inflammatory and (epi.)genetic markers in the blood of critically ill children included in the
study.
Version 3: 22-04-2012 13 of 51
3. STUDY DESIGN
This study is a large, two-centre, non-blinded, randomized, controlled study. The study
intervention will last for a maximum of 7 days per patient, and the entire study (final patient
completed study) is anticipated to last 4 years, excluding the long-term follow-up, the health-
economic analysis and the completion of the mechanistic studies. (See figure)
The “early PN” strategy will be the nutritional management currently applied in the
participating centres, acting as “control”.
The “late PN” strategy comprises initiation of this strategy only after day 7 in PICU.
Timeline of the entire study

Work package 1 (WP1)
The first milestone (M1) of the study will be the start of the large RCT in the centre of the
coordinating investigator/project leader in Leuven, closely followed by our center at Erasmus
MC-Sophia. The study will continue in parallel in both centers until patient number 720 will
have left the ICU. At that time point, a safety interim analysis will be performed (milestone
M2). Three possible scenarios are foreseen depending on the result of this analysis:
1. The interim analysis shows harm by “Late PN” and the clinical study will be prematurely
stopped (“no go” decision).
2. The data safety monitoring board requests a new safety interim analysis because of
reasonable doubt about the safety of “Late PN”. In that case, the study will continue in both
centers under very strict monitoring, and planning of additional safety interim analyses if
necessary, until the end of the study (either when completed or when prematurely stopped).
3. The study will be continued in both centers as planned, without further interim analyses,
until all 1440 patients have been included.
In all three scenarios the end of the study will be milestone 3 (M3). Together with the
finalization and cross-check of the clinical database and the writing of the corresponding
manuscript of the short-term clinical outcome, this will constitute deliverable 1 (D1). Hence,
D1 is guaranteed irrespective of premature interruption of the study. In view of the outcome
results of the adult EPaNIC study, such premature interruption will rather be unlikely. The
Version 3: 22-04-2012 14 of 51
applicants have extensive experience in the management of large RCTs, including in

critically ill children, and handling and monitoring of the corresponding large clinical
databases. This invaluable experience will be key to successful accomplishment of this
ambitious study.

The fourth milestone (M4) will be targeted for before the end of the clinical study and consists
of the setup of appropriate template database structures for import of the data that will be
needed for the health economy analysis. This will allow an efficient economic evaluation
study shortly after completion of the clinical study and is planned within the 4 year time frame
and of the study (Milestone M5 and deliverable D2).
In the unlikely event of premature interruption of the study, the health economic analysis will
be performed after the safety interim analysis on which the decision to stop was based.
Previous experience in detailed analyses of healthcare resource utilization in large
randomized clinical studies, as well as close collaboration with the Finance & Accounting
department and the pharmacies of both participating hospitals will guarantee successful and
timely accomplishment of this deliverable.
Work package 3
The mechanistic studies will be coordinated by and performed in the Leuven Laboratory of
Intensive Care Medicine and in the Erasmus MC. Part of the mechanistic analyses will be
systematically performed throughout the study. More specifically, leukocyte function tests
require the fresh isolation of leukocytes and hence will be performed in parallel with work
package 1. Thus, these analyses will be completed at the end of the clinical study (milestone
M6 and deliverable D3). The samples needed for the other mechanistic studies will be taken
throughout the clinical study and as deliverable 4 (D4) will be available together with M3 and
D1. The other mechanistic studies involving the investigation of autophagy, genetics and
cytokines in relation to the inflammatory response, as well as of the neuroendocrine axes will
be planned and started in the last phase after completion of the clinical study.
In (the unlikely) case the study would be terminated prematurely, the mechanistic studies will
be even more important, as the clinical community will ask for due explanations for harm
caused during the study. Therefore, in any case they will be started shortly after all clinical
data have been collected.
Version 3: 22-04-2012 15 of 51
Version 3: 22-04-2012 16 of 51
4. STUDY POPULATION
4.1 Population Base

The patient group of critically ill children ( 0 – 18 yrs), represents a significant proportion of
the ICU population. In 2010, the 10-bed Leuven PICU admitted 527 critically ill children, the
majority requiring artificial ventilation. 61% of the cases were admissions after cardiac
surgery. Individual critically ill children had a median ICU stay of 3 days (inter-quartile range
of 2-6 days) (mean 5.5 days). In the 35-bed PICU of the University of Rotterdam 1700
critically ill children were admitted in 2010 of which 600 (35.3%) were ventilated. Patients
stayed in the PICU for a median of 2 days (mean 7.8 days). We anticipate an inclusion rate
of 200-250 patients per centre per year.
4.2 Inclusion criteria

All critically ill children admitted to the participating PICUs are evaluated for nutritional risk
and eligibility for inclusion in this study. All critically ill children, with nutritional risk score
expected to stay in PICU for more than 24h are eligible for inclusion.
4.3 Exclusion criteria

Exclusion criteria are a “do not resuscitate” code at the time of PICU admission, expected
death within 12 hours, re-admission to the PICU after previously being participating in the
PEPaNIC trial (except when < 48 hours after the initial discharge and still in the intervention
window of the first 7 days), transfer from another PICU after a stay of more than seven days,
ketoacidotic or hyperosmolar coma on admission or inborn metabolic diseases requiring
specific diet, premature newborns (<37 weeks gestational age), patients on Total Parenteral
Nutrition for >7 days prior to inclusion, short bowel syndrome or other conditions which
required home-PN.
4.4 Sample size calculation

The sample size (N=1440, 720 per arm) is calculated in order to detect, with at least 80%
power (one-tailed; the two-tailed power is 70%) and 95% certainty, a reduction in PICU
infections from 20% to 15% and, with at least 90% power (two-tailed) and 95% certainty, a
reduction in mean duration of stay in PICU of 1 day. With this sample size, and for safety
reasons, also any substantial impact on mortality (increase or decrease with an absolute +/-
2%, although unexpected taken the adult data), can be excluded with a power of around 62-
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75% depending on the true mortality in the total population. We plan to calculate the true
power of the study for detection of any eventual smaller differences in these outcomes.
Version 3: 22-04-2012 18 of 51
5. TREATMENT OF SUBJECTS
5.1 Investigational treatment
The treatment, or intervention, in our study is best described as withholding PN in the early
course of disease to reach currently recommended energy and protein intakes, when enteral
delivery of these intakes is insufficient. In both allocation groups of the study, patients will be
evaluated on a day to day basis to see which amount of enteral intake can be provided. The
“early PN” group will receive current standard nutritional practice, which prescribes that PN
should be added to EN as soon as possible in the course of disease, to achieve energy and
protein goals. In the “late PN” group, we will wait to add PN, when EN is insufficient, until day
7.
“Late PN”, the so-called “intervention-group”.

Both in Leuven and Rotterdam, patients randomised to the “late PN” group will receive a
mixture of Glucose 5% and NaCl 0.9% at, respectively, 60% and 40% of the total flow rate
that is required to obtain standard optimal hydration taking into account the volume of EN
that is being delivered. If enteral feeding of at least 80% of the calculated calories is not
possible after 7 days in ICU, PN, as specified below, is initiated on day 8.
The infusions will be supplemented with micronutrients and vitamins as they would have
received when provided PN.
When the blood glucose levels fall spontaneously below 50 mg/dl, the standard glucose of
5% in the late PN group will be switched to 10% glucose until blood glucose level is above 80
mg/dl. At this point the infusion of glucose 10% will be stopped and switched again to
glucose 5%.
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Early PN”, this nutritional regime is the standard therapy in the participating centres and
therefore accounts as the "control-group".
Both centres will use their current pharmaceutical nutritional products for enteral as well as
parenteral nutrition. The differences between the products provided by the different
pharmaceutical companies are small clinically irrelevant differences in glucose, lipid and
protein intakes.
Despite the different pharmaceutical companies, nutritional regimes from both centres will be
aiming for the same energy and protein targets.
Fluid intake will be provided as follows; patients not requiring fluid restriction receive 100
ml/kg/day for the first 10 kg bodyweight, 50 ml/kg for the next 10 kg, and 20 ml/kg for the
bodyweight over 20 kg, patients who require fluid restriction, total fluid intake is 50% on day 1
and 2, and 75% on day 3.
Nutritional target calculations

Energy intake
• < 10 kg bodyweight : 100 kcal/kg/day
• 10-20 kg bodyweight : 1000 kcal/day + (50 kcal/kg/day for weight over 10 kg)
• > 20 kg bodyweight : 1500 kcal/day + (20 kcal/kg/day for weight over 20 kg)
Protein target
• 0-10 kg bodyweight : 1.5-3 g/kg/day
• 10-20 kg bodyweight : 1-3 g/kg/day
• > 20 kg bodyweight : 1-2 g/kg/day
Day 1:
In the PICUs from both centers, patients randomised to the “early PN” group upon admission
to PICU receive a glucose mixture [Leuven; Glucose15%/Vaminolact® (Fresenius),
Rotterdam; Glucose 10–20% (Baxter)] to achieve glucose intake approximately double of the
intake in the “late PN” group, with additional trace elements (Peditrace) and minerals
(Addamel, Novum, Fresenius) and vitamins (Cernevit, Soluvit, Vitintra; Baxter) to be
administered in both centers.
Day 2-3:
For all patients on intravenous (IV) nutrition, lipids [Leuven; (20g/100ml) SMOFlipid®
Fresenius, Sweden, Rotterdam; (20g/100ml) Intralipid® (Baxter), Oliclinomel® (Baxter)] are
added from day 2-3 onward, and increased depending on the age and within the fluid
limitation potentially required by the patient.
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Additionally, protein intake [Leuven; Vaminolact® or Vamin18® (Fresenius, Sweden),

Rotterdam; Primene® (Baxter), Oliclinomel® (Baxter)] will be increased to reach target goals.
On day 2-7, pharmacy-prepared PN preparations are prescribed to achieve protein and

energy goals, as described above, unless adequate enteral nutritional intake is expected.
Any enterally delivered energy is taken into account twice daily to reduce the energy
delivered by PN. When EN covers 80% of optimal calculated caloric needs, PN is stopped.
When the patient starts to take oral nutrition, the PN and/or EN is reduced and eventually
stopped. Whenever enteral or oral intake falls below 50% of calculated caloric needs, the PN
is restarted.
The volumes of PN and EN to be given according to the treatment group are calculated by
the patient data management system (PDMS). These calculations are based on the
nutritional intake during the previous day and the clinical evolution of the patient. The amount
of protein and glucose administered during the previous day, as well as the target, will be
displayed by the PDMS to further guide the prescription of macronutrients.
The additional trace elements (Peditrace) and minerals (Addamel Novum, Fresenius)
and vitamins (Cernevit, Soluvit, Vitintra; Baxter) will be administered in both centers
daily until until patients receive at least 80% of their caloric intake enterally.
Enteral nutrition and micronutrient administration

In all patients from both study arms, provided haemodynamically stable and without formal
contraindication, EN is initiated on the afternoon following the ICU admission with the
patients in semirecumbent position. Enteral feeding will start 6 hrs after admission in the
PICU and will be done according to protocol (cfr appendix 1). Trace elements (Peditrace)
and minerals (Addamel Novum, Fresenius) and vitamins (Cernevit, Soluvit, Vitintra;
Baxter) will be administered daily IV to all patients from day 2 at 4:00 pm. IV micronutrient
substitution will be stopped when patients receive at least 80% of their caloric needs via the
enteral route.
In infants, breast milk, the patient’s home milk formula or a protein-energy dense formula
(Nutrilon®, Infatrini®; Nutricia Netherlands) is used. Older children receive standard
commercially available enteral feeding (Nutrison®, Nutrini-formulas; Nutricia Netherlands)
unless contra-indicated.
Enteral feeding is administered through a gastric tube in a continuous way and is gradually
increased as dictated by tolerance. Switch to oral intake is made as soon as deemed safe.
Version 3: 22-04-2012 21 of 51
The increase of EN volume, the use of gastroprokinetics and duodenal feeding tubes are
described in standing-orders for EN. Procedures for slow parenteral administration will be
identical for all patients.
Blood glucose management

Blood glucose management will be performed as through standard practice in both
participating centers. (for both protocols see the appendices)
In Leuven, patients in both study groups receive continuous insulin infusion to target blood
glucose levels of 50-80 mg/dl when aged < 1y and 70-100 mg/dl when aged >= 1 year. Blood
glucose and potassium are monitored systematically every 1 – 4 hours on the blood gas
analyser (ABLRadiometer ®, Copenhagen, Denmark) using arterial blood samples.(14)
In Rotterdam, patients in all age groups receive continuous insulin infusion to target blood
glucose levels of 72-145 mg/dl, except for patients with traumatic brain injury (108-145
mg/dl), using a step-wise nurse driven glucose control protocol. Blood glucose and
potassium are monitored systematically every 1 – 3 hours on the blood gas analyser (ABL
625; Radiometer®, Copenhagen, Denmark) using arterial blood samples.(15)
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Nutritional protocol showing schematic decision tree
Version 3: 22-04-2012 23 of 51
Handling of re-admissions to ICU

Patients who are re-admitted to ICU after a participation in PEPaNIC are not eligible for re-
inclusion. Patients who are readmitted to the PICU within 48 hours of discharge and who are
still within the 7 days time window of the initial randomization receive the nutrition-schedule
they were assigned to during the initial ICU admission. Patients readmitted later will be fed at
the discretion of the attending physician.
5.2 Use of co-intervention (if applicable)

Not applicable
5.3 Escape medication (if applicable)

Not applicable
6. INVESTIGATIONAL MEDICINAL PRODUCT

Not applicable.
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7. METHODS
7.1 Study parameters/endpoints
7.1.1 Main study parameter/endpoint

The primary efficacy endpoints of for this RCT are included into Work Package 1 and are
the incidence of new infections and the time to discharge alive from ICU. Number of patients
with new infections and types of infection will be assessed by numbers and percentages, and
the duration of any antibiotics therapy initiated after randomization for those patients
requiring antibiotics will be analyzed by non-parametrical tests. As the time of ICU discharge
to the regular ward may be affected by the availability of beds on the regular wards, which
could induce bias, we a priori decided to analyze “time to discharge from ICU” as “time to
ready for discharge from ICU”. A patient is considered “ready for discharge” as soon as all
clinical conditions for ICU discharge have been fulfilled (no longer in need for vital organ
support). Time to discharge alive from ICU will be reported by Kaplan-Meier plots, with ICU
non-survivors censored beyond the longest ICU stay of survivors and censoring time of
both treatment groups. The impact of “late PN” versus “early PN” will be analyzed, with and
time window of the randomized intervention in ICU, also the proportion of patients staying
beyond 8 days in ICU will be reported.
7.1.2 Secondary study parameters/endpoints

Work Package 1
All analyses will be performed uncorrected as well as corrected for age, nutritional status and
risk categories and type and severity of illness. Time-to-event analysis will be analyzed
similarly as the primary endpoint. Proportion of patients requiring support of vital organ
functions and distribution of duration of support will be analyzed by non-parametric or
parametric testing depending on the normality of the distribution in the subgroup of patients
for which support was needed. Proportions will be compared using chi-square testing.
Results of repeated measurements will be analyzed using an appropriate model for
longitudinal data.
a. Time to final (alive) weaning from mechanical respiratory support: patients still on
mechanical respiratory support at closing of the data file (90 days after last patient
inclusion) will be censored at that time point. ICU non-survivors will be censored
beyond the longest duration of mechanical respiratory support of the survivors.
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b. Kidney failure: Proportion of patients in need for renal replacement therapy (RRT)
during ICU stay; distribution of duration of RRT (for those patients requiring RRT);
proportion of patients with a post-randomization diagnosis of new kidney injury/failure
(defined by modified Risk, Injury, Failure, Loss, and End-stage Kidney (RIFLE)
classification criteria as a plasma creatinine doubling or more during ICU stay) in both
treatment groups. In addition, the duration of a score RIFLE≥2 will be used as a marker
of time to recovery of kidney damage.
c. Need for pharmacological or mechanical haemodynamic support during ICU stay, and
duration of such need.
In addition, time to final (alive) weaning from all pharmacological or mechanical
haemodynamic support in ICU will be analyzed, with ICU non-survivors censored
beyond the longest duration of pharmacological or mechanical haemodynamic support
of the survivors and censoring time of patients still on such support at closing of the
data file (90 days after last patient inclusion) over both treatment groups.
d. Number of readmissions to the PICU.
e. Liver dysfunction: Proportion of patients during the time window of the intervention and
during the whole ICU stay presenting with cholestatic or cytolytic liver dysfunction will
be compared.
f. Inflammation: Effect of the intervention on inflammation will be analyzed by comparing
the distribution of the highest value reached during ICU stay and changes from baseline
to the highest value and by comparing time profiles of daily C-Reactive Protein values.
g. Child health questionnaire scores (WEEFIM, HUI, CHQ) at hospital discharge in both
treatment groups will be compared. And at follow-up at 3 and 12 months post-discharge.
Work Package 2: Health economy analysis

As PN is a major contributor to the healthcare costs of critically children and the clinical
outcome is not yet known, an extensive health economic analysis will be included in the
study planning. The economic analysis will be performed from a health care perspective and
will be estimated for the period during hospitalization OR one year after admission?. The
economic evaluation will be performed in accordance with the Dutch guidelines (27).
First, we will calculate and compare the direct medical costs of early versus late PN.
Real medical costs will be calculated by multiplying the volumes of health care use with the
corresponding unit prices. Based on the analysis of the patients’ detailed invoices, we will
allocate healthcare costs into 8 categories (per diem hospitalization costs, honoraria,
pharmacy costs, clinical chemistry costs, radiology costs, blood products, graft products,
miscellaneous), representing the different reimbursed services and products during ICU and
Version 3: 22-04-2012 26 of 51
hospital stay. These cost categories have been validated in the health economic analysis of
the adult EPaNIC study.
The drug costs will be analyzed using the first level of the World Health Organisation (9)
Anatomical Therapeutic Chemical (ATC) classification. We hypothesize that antimicrobials
(class J) are the determining driver for differences in pharmacy costs. This is based on the
idea that late PN will reduce the incidence of new infections in the ICU.
A model will be constructed to estimate the hypothetical cost difference between early PN
and late PN if all acquisition costs related to PN would have been chargeable. This modeling
is important to make the results interpretable for readers in different healthcare systems. PN
is in variable proportions charged to the patient directly, the hospital or the insurers.
Therefore, the data from Rotterdam and Leuven will be converged to one hypothetical
system of PN billing.
Costs for inpatient days in hospitals will be estimated as real, basic costs per day using
detailed hospital administrative information. For the calculation of other medical costs, we will
used charges as published in Dutch guidelines as a proxy of real costs (27).
All analyses will be performed on an intention-to-treat basis. The cost differences between
early and late PN will be analyzed using the Mann–Whitney U test. Since cost data per
patient (but not per day care) are typically highly skewed, we use nonparametric bootstrap
techniques to derive a 95% confidence interval for the differences in distributions of the direct
medical costs.
Furthermore, we will explore whether late PN is cost-effective compared to early PN. This will
be assessed by calculating the incremental cost-effectiveness ratio (ICER), defined as the
difference in costs of late versus early PN, divided by the average change in effectiveness.
The primary effect measure is number of patients with a prevented new infection in ICU.
Secondary outcome measure is quality of life as measured by validated questionnaires.
Overall utility scores for population-based quality of life will be obtained and expressed as
QALY’s. QALY’s will be calculated by multiplying the utility of a health state by the time spent
in this health state.
Cost-effectiveness of late PN as compared to early PN will be analyzed as the difference in

PN costs per patient with a prevented new infection in ICU. In the ideal scenario late PN will
result in an improvement of the clinical outcome as well as a reduction of the healthcare
costs. If late PN conveys a clinical improvement at a higher cost, this cost effectiveness in
Version 3: 22-04-2012 27 of 51
two health care systems will be important to guide the respective governmental health care
departments into the decisions of the reimbursement of PN.
For the health economic analysis we will collaborate with the finance & accounting and
pharmacy departments of the two participating hospitals. Template database structures will
be set-up in advance during the enrolment of the patients in the trial to allow an efficient
health economic analysis in the framework of the study.
Work Package 3: Mechanistic analyses in relation to short- and long-term outcome

Impact of early versus late PN on infection and the inflammatory response
The incidence of new, ICU-acquired, infections is a primary efficacy endpoint in the
presented study. Based on the results of the adult EPaNIC study (1), we anticipate a lower
infection rate with late PN as compared with early PN. We will investigate whether
differences in leukocyte function could explain in part such effect. Therefore, blood samples
will be taken at pre-set time points during ICU stay for the isolation of monocytes and
granulocytes to assess their chemotactic, phagocytosis and oxidative burst capacity (17, 18).
Antimicrobial defense depends on, amongst others, efficient clearance of intracellular
pathogens in the autophagic pathway (xenophagy) (10). Indeed, inactivation of autophagy in
macrophages and neutrophils has been shown to increase susceptibility to infection. It has
previously been demonstrated an autophagy-deficiency phenotype in liver and skeletal
muscle of fed prolonged critically ill patients (11). Importantly, a recent study in prolonged
critically ill rabbits demonstrated a role for early PN in suppression of the autophagic pathway
during critical illness (19). If autophagy would be similarly compromised in leukocytes by
early PN, such effect may contribute to a reduced incidence of infections with late PN. We
will address this question in a subset of well-matched patients. We will also measure the p62
protein levels of isolated white blood cells obtained upon admission and on day 3 and 7 in
ICU, which is known to accumulate when autophagy is deficient/insufficient, as well as the
LC3-II/LC3-I ratio as a marker of mature autophagosome formation (20-22). In addition, we
will isolate leukocyte DNA from all patients to investigate whether genetic predisposition by
single nucleotide polymorphisms (SNPs) in genes of the autophagic core machinery may
play a role in susceptibility to infections and whether any such SNP would interact with the
nutritional approaches of the study design. The autophagy pathway and/or proteins also
appear to play a crucial role in the control of inflammatory signaling and regulation of
inflammatory transcriptional responses (10). In this regard, it has been shown that increased
levels of p62 activate the pro-inflammatory transcription factor NF-kB. We will study the
impact of early versus late PN on pro- and anti-inflammatory cytokines (interleukin-1beta (IL-
1beta), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, tumor-necrosis-factor-alpha, interferon-gamma).
Version 3: 22-04-2012 28 of 51
Impact of early versus late PN on the neuroendocrine axes

Critical illness is hallmarked by striking alterations in the hypothalamic-pituitary-peripheral
hormone axes (neuroendocrine axes), according to a biphasic pattern (23). The peripheral
effector hormone levels are reduced in both phases of critical illness, although the etiology is
different with peripheral target organ resistance in the acute phase and relative
hypopituitarism in the prolonged (chronic) phase.
The hypothalamic-pituitary-adrenal axis shows a biphasic, but somewhat different response
as compared with the other axes, with cortisol as effector hormone being high in both
phases. The responses of the neuroendocrine axes during prolonged critical illness overall
have been linked to the development of a characteristic hypercatabolic state, resulting in
feeding-resistant muscle wasting, and the severity of the disturbances has been associated
with the high risk of morbidity and mortality of the patients. Not only excessive activation of
the hypothalamic-pituitary-adrenal axis, but also adrenal insufficiency contributes to morbidity
in critically ill children (24).
It was previously hypothesized that strict blood glucose control with intensive insulin therapy
would mildly reactivate the somatotropic and thyrotropic axes and anabolism in critically ill
children in view of a larger functional capacity of the hypothalamus and pituitary, and the
higher amount of nutrition they receive as compared with adult critically ill patients.
Unexpectedly and despite improved ICU outcome, however, this therapy further suppressed
the somatotropic axis and increased the urea/creatinine ratio as a marker of catabolism (25).
Also the low-T3 syndrome could not be reversed by this therapy (unpublished data).
Unpublished data obtained in a rabbit model of prolonged critical illness suggest that relative
fasting during critical illness reduces (peripheral) activation of the somatotropic and
thyrotropic axes with lower levels of insulin-like growth factor-I (IGF-I) and triiodothyronine
(T3) levels, but also attenuates the rise in the stress hormone cortisol as compared with
moderate dose intravenous feeding during critical illness. These findings urge a thorough
analysis of the impact of early versus late PN on these neuroendocrine axes in the critically ill
children included in our study. We hypothesize that late PN results in suppression of the
neuroendocrine axes, in concert with the intensive insulin therapy. Unlike conventional belief,
we also hypothesize that such suppressed neuroendocrine axes during prolonged critical
illness could be associated with a beneficial acute and long-term clinical outcome.
We will evaluate the activation of the somatotropic axis in the acute and chronic phase of
critical illness by measuring the levels of growth hormone (GH), acid-labile subunit (ALS),
IGF-I and its binding proteins (IGFBP-1 and IGFBP-3), the activation of the thyrotropic axis
by analysis of thyroxin (T4), T3, reverse T3 (rT3) and thyroid stimulating hormone (TSH), and
the adrenal axis by adrenocorticotropic hormone (ACTH) and cortisol. The metabolism of
cortisol will be studied further by the relative levels of its metabolites excreted in urine (26).
Version 3: 22-04-2012 29 of 51
The impact of early versus late PN on the neuroendocrine axes will be studied in relation to
markers of catabolism, muscle volume and strength, as well as clinical outcome. The clinical
outcome will be assessed during follow-up consultations that are held in the departments that
have referred their patients to the ICU in Leuven and Rotterdam.
The epigenetics of early versus late PN
It has been known since a long time that dietary exposures can have health consequences
years or decades later. E.g. the later health of babies who were in the womb during the
Dutch famine in the winter of 1944 was greatly affected by the caloric restriction of their
mothers. The children of pregnant women exposed to famine were shown to be more
susceptible to chronic adult diseases such as diabetes, obesity and cardiovascular disease.
Apparently, the short period of caloric restriction can be “remembered” by the body further on
in life. There is a growing body of evidence that epigenetic mechanisms mediate this
memory. Epigenetic mechanisms alter the gene expression without changing the primary
DNA sequence. Rather the epigenetic mechanisms work through DNA methylation, histone
modifications and non-coding microRNAs. During the clinical trial, biological material (spun-
down cells from whole blood samples) will be collected from the study patients to compare
these epigenetic changes between the early and late PN treatment groups. The mechanistic
findings will be correlated with the acute and the long-term outcome of the critically ill study
patients.
7.1.3 Other study parameters
Safety endpoints
Safety endpoints comprise vital status, hypoglycemia, SAEs and complications related to the
mode of nutrition. Survival up to 90 days after randomization in both treatment groups will be
compared by Kaplan Meier survival plots. The impact of “late PN” versus “early PN” will be
analyzed, with and without correction for risk factors, by Cox proportional hazard analysis. In
addition, we will record in-ICU and in-hospital mortality, and will analyze differences with Chi-
square testing. As the randomized study intervention only takes place during a time window
up to the 8th day in ICU, we also plan to analyze early lethality within this time window in the
intention-to-treat population as part of the safety analysis.
As patients not receiving early PN may be considered at increased risk for hypoglycemia, we
will report for both groups the number of patients experiencing hypoglycemia <40 mg/dl
during the time window of the randomized intervention. Hypoglycemia resistant to parenteral
glucose administration is considered as a SAE and the incidence during the time window of
the randomized intervention will be reported for both groups. In addition, overall blood
glucose control during the time window of the intervention will be compared using daily
morning blood glucose as well as daily maximal and minimal blood glucose.
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Safety issues also comprise the occurrence of feeding-mode-related complications during

the time window of the intervention. Therefore, occurrence of these complications (digestive
intolerance, complicated insertion of feeding tubes, pneumothorax, haemothorax and
subclavian or carotid artery puncture, occlusion or displacement of central venous catheters
or gastric feeding tubes) will be reported for both treatment groups.
7.2 Randomisation, blinding and treatment allocation

Randomization
The study will use a prospective, randomized, controlled, parallel-group design. On
admission patients will be randomly assigned to receive EN combined with early PN or only
EN. At ICU admission, consecutive patients will be randomly assigned to one of these two
treatment groups using a centralized computer randomisation. Randomisation will be done in
a 1:1 allocation ratio in permuted blocks of 10 (The block size remains unknown to bed-side
physicians and nurses, responsible for patient recruitment and therapy assignment) and
stratified according to primary diagnostic category on admission:
I Medical-ICU admissions (infectious or non-infectious): (a) respiratory (b) cardiac (c) renal
(d) haematological/oncological (e) gastro-intestinal/hepatic (f) neurological (g) other.
II Surgical-ICU admissions (elective or urgent) according to referral discipline (a) cardiac

surgery (b) solid organ transplants (c) pulmonary/oesophageal surgery (d) abdominal surgery
(e) neurosurgery (f) trauma/orthopaedic surgery (g) burns (more than 20% BSA is burned
and/or patient requires ventilation)
Blinding of treatment allocation

Treating physicians and patients cannot be blinded. All outcome assessors, which are
investigators not directly involved in the patients care (such as statisticians, laboratory
personnel, infectious disease specialists, pathologists and physiotherapists involved in the
strength measurement) as well as physicians and nurses in the conventional wards are
blinded to treatment allocation.
7.3 Study procedures

Data collection following recruitment
Baseline characteristics
At baseline, data on demographic and clinical characteristics of the patients are obtained.
Disease specific risk scores (such as the Risk-Adjustment in Congenital Heart Surgery or
RACHS score) are calculated, co-morbidities and known use of important medications prior
Version 3: 22-04-2012 31 of 51
to admission are noted: these comprise, among others, the presence of congenital disease
or syndrome, gestational age at birth, gender, ethnicity, paediatric risk scores, presence /
history of cancer, diabetes mellitus, kidney failure, liver failure, chronic heart failure and
sepsis upon admission. In addition, we record the need for and the number of days of
mechanical ventilatory support, of mechanical and pharmacological haemodynamic support,
of renal replacement therapies, days on antibiotics and days requiring a central line.
Outcome characteristics
All medications received by the patients during ICU stay are registered. Every day the
amount of kilocalories, lipids, proteins, carbohydrates delivered by either PN or EN are
calculated from the PDMS in an automated manner and entered into the case record form
(CRF). Interruptions of EN delivery and predefined digestive intolerance are registered daily.
Mechanical complications such as displacement or obstruction of the enteral feeding tube or
the central venous catheter, and clinical complications such as pneumothorax, hemothorax
and subclavian or carotid artery puncture are recorded daily. All medications received by the
patients during ICU stay are registered. Every day the amount of kilocalories, lipids, proteins,
carbohydrates delivered by either PN or EN are calculated from the PDMS in an automated
manner and entered into the case record form (CRF). Of the gastric residual volume
discarded, half of the volume will be considered to be EN and half gastric secretions. The
duration (in min) and cause of interruption of delivery of EN will be recorded. Digestive
intolerance will be registered as vomiting, tracheal aspiration of enteral feeding (defined 8),
diarrhea, and gastric residue above 5ml/kg (see appendix for definitions). Tube displacement
or obstruction will be labeled as mechanical complications. Occlusion and dislodging of
central venous catheters will be recorded as mechanical complications. Pneumothorax,
hemothorax and arterial puncture will be recorded as clinical complications. Number of ICU
days with a central line in situ will be noted. The characteristics will be monitored until
discharge from ICU, day 90 of hospital stay or death.
Blood samples
The maximum blood volume will be maximum 5 ml/kg for the entire study period. For a
detailed description of the blood samples and tests see figure below. Blood samples are
taken upon ICU admission and daily until discharge from ICU, or death. The blood samples
will be taken from lines placed for clinical purposes or in combination with pricks requested
for clinical purposes. A subset of the samples are immediately stored on ice for future
endocrine measurements. Processed serum and plasma as well as the spun-down blood
cells will be stored and frozen for mechanistic analyses.
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All whole blood glucose levels are measured on arterial blood using a blood gas analyser on
each ICU and are registered for later calculation of glucose metrics. Analyses on blood and
urine for the primary clinical analyses include routine chemistry, haematology, and markers
of inflammation. Further epigenetic, metabolic, endocrine and inflammatory measurements
on stored samples in the context of mechanistic analyses will be stored until final analysis.
Urine samples will be stored and frozen until final analysis.
Primary endpoint characteristics
All new infections of the lungs, the blood stream, the urinary tract and wounds are recorded
by an infectious disease specialist. Bacteraemia is further classified by responsible pathogen
and as catheter-related blood stream infection versus other bacteraemia.
Additional data collection
For mechanistic and exploratory studies, muscle strength testing (> 6 years of age) at
discharge and an ultrasound evaluation during admission of the skeletal muscle, liver, and
adipose tissue compartments will be performed.
Urine (nitrogen / bone metabolism / cortisol metabolites / biomarkers for renal failure; NGAL)
and stool samples (biomarkers gut function; citrulline / calprotectin) will be collected on daily
basis.
We will also perform standard anthropometric tests, upper-arm and lower-leg circumference,
in addition to standard weight and height for age. These analyses will be repeated at the
follow-up at 3 and 12 months post-discharge, on condition of obtaining adequate additional
funding.
Questionnaires and long term follow-up
Furthermore, as far as practically feasible, every patient is approached just prior to hospital
discharge, to complete a validated, semi-structured child health questionnaire (Functional
Independence Measure (WEEFIM), Health Utilities Index (HUI) and Child Health
Questionnaire (CHQ)).
We also will thoroughly assess long-term clinical outcome. This not only encompasses
survival rate 3 years after inclusion in the study. It will also involve a detailed functional and
neurocognitive examination, by means of questionnaires such as mentioned above. These
analyses will be repeated at the follow-up at 3 and 12 months post-discharge, on condition of
obtaining adequate additional funding. This will be organised in the framework of current
follow-up consultations of these critically ill children.
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Randomisation
Anthropometry
Ultra sound
Blood, Urine and

stool samples
Indirect Calorimetry
Day 0 1 2 3 4 5 6 7
Figure Samples.
Blood samples are taken upon ICU admission and daily at 06:00h until discharge from ICU,
death or end of study. Upon admission three blood samples will be taken; namely two yellow
“STOL”-tubes each containing a maximum of 3.5 milliliter blood and 1 purple “EDTA”-tube of
1.8 milliliter blood.
During the following days until the patient has left the PICU we will daily take a yellow
“STOL”-tube (containing max 3,5 milliliter blood) and a purple “EDTA”-tube (containing 1,8
milliliter blood) for further analyses.
A subset of the samples will be immediately stored on ice for future endocrine
measurements. Processed serum and plasma as well as the spun-down blood cells will be
frozen and stored.
Analyses on the morning sample will include routine clinical chemistry, hematology (Hgb,
WBC, TC), and markers of inflammation (CRP), liver function ALT, AST, ALP, GGT, bilirubin
total/direct. A number of metabolic, hormonal and inflammatory study analyses will be
performed on selected days.
The latter comprise, among others, coagulation & fibrinolysis tests, cytokines and markers of
oxidative stress.
Also on selected days stool (single sample) urine (5 tubes of 5 mL out of 24 hours’ urine
collection) will be stored for further evaluation.
each ICU and are registered for later calculation of glucose metrics.
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7.4 Withdrawal of individual subjects

Subjects can leave the study at any time for any reason if they wish to do so without any
consequences. The investigator can decide to withdraw a subject from the study for urgent
medical reasons.
7.4.1 Specific criteria for withdrawal (if applicable)

Not applicable
7.5 Replacement of individual subjects after withdrawal

Subjects that withdraw after randomization has been conducted will not be replaced, subjects
that have not been allocated and withdraw after signing the consent form but before the start
of randomization will be replaced.
7.6 Follow-up of subjects withdrawn from treatment

A register is kept of all patients evaluated for inclusion and of patients who withdraw from the
study. The latter are clinically followed up without their data being analyzed in the study,
according to intention-to-treat analysis.
7.7 Premature termination of the study

As the previous study in adults has shown that lethality was not different among the study
groups and that morbidity was prevented by withholding feeding, and since the participating
centers are currently providing early PN, repeated interim analyses for efficacy are not
required. However, one formal “safety” interim analysis will be planned after patient number
720 has left the ICU, during which the independent DSMB will have access to un-blinded
results on ICU mortality, hospital mortality and serious adverse events. The DSMB will then
judge on whether or not to prematurely stop the clinical trial for safety reasons, or to perform
more safety interim analyses. The DSMB will advise on eventual continuation of the study to
completion, under monitoring of the serious adverse event. Because the primary efficacy
endpoint will not be analyzed, no correction of the significance level at the final analysis will
be necessary. In (the unlikely) case the study would be terminated prematurely, the
mechanistic studies will be even more important, as the clinical community will ask for due
explanations for harm caused during the study. Therefore, in any case they will be started
shortly after all clinical data have been collected.
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8. SAFETY REPORTING
underfeeding. However, safety measures will be taken to further decrease these risks. Our
study may provide support for current practice, may give “neutral” results for which the cost-
effectiveness study will provide necessary information for guiding therapy, or may challenge
the presumed innocence of PN. Thus, there is no risk associated with the intrinsic value of
these results.
The burden is expected to be minimal as it will only entail additional blood draws, which will
be taken from clinical lines or in addition to pricks for clinical purpose. The long-term follow
up will be held as part of already organised follow-up outdoor clinics and which are
developed to help children and their parents to recover physically, emotionally and socially
after ICU admissions. For mechanistic and exploratory studies, muscle strength testing and
an ultrasound evaluation of the skeletal muscle and adipose tissue compartments will be
performed. Furthermore, as far as practically feasible, every patient is approached just prior
to hospital discharge, to complete a validated, semi-structured child health questionnaire
(Functional Independence Measure (WEEFIM), Health Utilities Index (HUI) and Child Health
In order to monitor the quality of the enteral and parenteral nutrition management during the
study we will register all known complications possibly related to them. These complications
should not be considered as adverse events since the study intervention is to withhold
parenteral feeding during one week. These known complications of parenteral feeding will
not be reported to the sponsor until the end of the trial.

Digestive intolerance: either vomiting, tracheal aspiration of enteral feeding (defined in 7),
diarrhea, or gastric residue above 5ml/kg, abdominal distention (see appendix for
definitions).

Clinical complications: pneumothorax, hemothorax and arterial puncture, central line
replacement due to suspicion of catheter-related blood stream infections
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Safety endpoints
Safety endpoints comprise vital status, hypoglycaemia, SAEs and complications related to
the mode of nutrition. Survival up to 90 days after randomisation in both treatment groups will
be compared by Kaplan Meier survival plots. The impact of “late PN” versus “early PN” will
be analysed, with and without correction for risk factors, by Cox proportional hazard analysis.
In addition, we will record in-ICU and in-hospital mortality, and will analyse differences with
Chi-square testing. As the randomised study intervention only takes place during a time
window up to the 8th day in ICU, we also plan to analyse early lethality within this time
window in the intention-to-treat population as part of the safety analysis.
As patients not receiving early PN may be considered at increased risk for hypoglycaemia,
we will report for both groups the number of patients experiencing hypoglycaemia <40 mg/dl
during the time window of the randomised intervention. Hypoglycaemia resistant to
parenteral glucose administration is considered as a SAE and the incidence during the time
window of the randomised intervention will be reported for both groups. In addition, overall
blood glucose control during the time window of the intervention will be compared using daily
or gastric feeding tubes) will be reported for both treatment groups
Interim analysis
centres are currently providing early PN, repeated interim analyses for efficacy are not
endpoint will not be analysed, no correction of the significance level at the final analysis will
be necessary.
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8.1 Section 10 WMO event

In accordance to section 10, subsection 1, of the WMO, the investigator will inform the
subjects and the reviewing accredited METC if anything occurs, on the basis of which it
appears that the disadvantages of participation may be significantly greater than was
foreseen in the research proposal. The study will be suspended pending further review by
the accredited METC, except insofar as suspension would jeopardise the subjects’ health.
The investigator will take care that all subjects are kept informed.
8.2 Adverse and serious adverse events

Adverse events are defined as any undesirable experience occurring to a subject during the
study, whether or not considered related to the experimental treatment. All adverse events
reported spontaneously by the subject or observed by the investigator or his staff will be
recorded.
A serious adverse event is any untoward medical occurrence or effect that at any dose:
- results in death;
- is life threatening (at the time of the event);
- requires hospitalisation or prolongation of existing inpatients’ hospitalisation;
- results in persistent or significant disability or incapacity;
- is a new event of the trial likely to affect the safety of the subjects, such as an
unexpected outcome of an adverse reaction, lack of efficacy of an IMP used for the
treatment of a life threatening disease, major safety finding from a newly completed
animal study, etc.
All SAEs will be reported through the web portal ToetsingOnline to the accredited METC that
approved the protocol, within 15 days after the sponsor has first knowledge of the serious
adverse reactions. SAEs that result in death or are life threatening should be reported
expedited. The expedited reporting will occur not later than 7 days after the responsible
investigator has first knowledge of the adverse reaction. This is for a preliminary report with
another 8 days for completion of the report.
Safety endpoints specifically for PEPaNIC

The clinical research team guarantees a daily follow-up of patient screening and inclusion,
availability of requested clinical data in the clinical patient files and protocol compliance.
Each non-compliance to the protocol and other questions or problems are reported to the
study monitor and discussed with the principal investigators. Serious Adverse Events (SAE)
are also reported to the study coordinating investigator/project leader (K.U.Leuven). The
Version 3: 22-04-2012 38 of 51
study monitor regularly provides the sponsor with reports on inclusions and SAE. Regular
meetings are organized with principal investigators and clinical research team to discuss the
daily progression of the research project.
glucose administration, or with clinical symptoms, is considered as a SAE and the incidence
during the time window of the randomized intervention will be reported for both groups. In
addition, overall blood glucose control during the time window of the intervention will be
compared using daily morning blood glucose as well as daily maximal and minimal blood
glucose.
Further safety endpoints comprise vital status, hypoglycemia, SAEs and complications
related to the mode of nutrition. Survival up to 90 days after randomization in both treatment
groups will be compared by Kaplan Meier survival plots. The impact of “late PN” versus
“early PN” will be analyzed, with and without correction for risk factors, by Cox proportional
hazard analysis. In addition, we will record in-ICU and in-hospital mortality, and will analyze
differences with Chi-square testing. As the randomized study intervention only takes place
during a time window up to the 8th day in ICU, we also plan to analyze early lethality within
this time window in the intention-to-treat population as part of the safety analysis.
Above mentioned SAE’s and safety endpoints will be handled and reported within the
standard timeframe as described above.
8.2.1 Suspected unexpected serious adverse reactions (SUSAR)
Not applicable
8.2.2 Annual safety report

Not applicable
Version 3: 22-04-2012 39 of 51
8.3 Follow-up of adverse events

All adverse events will be followed until they have abated, or until a stable situation has been
reached. Depending on the event, follow up may require additional tests or medical
procedures as indicated, and/or referral to the general physician or a medical specialist.
8.4 Data Safety Monitoring Board (DSMB)

The coordinating investigator/project leader (K.U.Leuven) provides direct access to the CRF,
the source data and the study master file for monitoring, Independent Ethics committee
review and regulatory inspection. The coordinating investigator/project leader (K.U.Leuven)
established an independent data safety monitoring board (DSMB) (Prof. dr. J Vranckx, Prof.
dr. em. R Bouillon, Prof. dr. em. P Lauwers, Prof.dr. M Bruynooghe (statisticus)), which holds
no conflicts of interest with the sponsor or coordinating investigator/project leader
(K.U.Leuven). The coordinating investigator/project leader (K.U.Leuven) appoints one
monitor. The monitor verifies that the trial is performed in accordance to the protocol as
described in the European Medicine Agency’s “Note for guidance on good clinical practice
CPMP/ICH/135/95” as well as the Declaration of Helsinki. Monitoring will be performed and
will be reported following the sponsor’s standing operating procedures. No fault insurance is
covered by Fortis Corporate Insurance NV (Leuven) and Akkermans Van Elten Assurantiën
BV (Rotterdam).
One formal “safety” interim analysis will be planned after patient number 720 has left the
ICU, during which the independent DSMB will have access to un-blinded results on ICU
mortality, hospital mortality and serious adverse events. The DSMB will then judge on
whether or not to prematurely stop the clinical trial for safety reasons, or to perform more
safety interim analyses. The DSMB will advise on eventual continuation of the study to
be necessary.
The advice(s) of the DSMB will be notified upon receipt by the sponsor to the METC that
approved the protocol. With this notification a statement will be included indicating whether
the advice will be followed.
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9. STATISTICAL ANALYSIS
9.1 Descriptive statistics

The current statistical analysis plan comprises the primary and secondary clinical endpoints
of this RCT (work package 1). These include the acute clinical effects of the intervention
during ICU stay and hospitalization, including survival up to 90 days after randomization.
power (one- tailed; the two-tailed power is 70%) and 95% certainty, a reduction in PICU
infections from 20% to 15% and, with at least 90% power (2-tailed) and 95% certainty, a
General rules of the statistical analysis

All analyses will be done on intention to treat basis. The analyses will be performed on the
whole set of patients and by subgroups of patients based on the primary diagnostic
categories used as prognostic factors for stratification and on septic/non-septic groups of
patients.
A consort diagram will be reported. The data file will be finalised 90 days after inclusion of
the last patient. To assess compliance with the study protocol, the amounts of PN and EN
actually given in the two study groups during the intervention window of 7 days will be
reported as absolute numbers and percentages of target calories. Discrete variables will be
summarised by frequencies and percentages and analysed by (exact) Chi- square test or
logistic regression analysis. Continuous variables will be summarised by use of either mean
or standard deviations (SD) or median and interquartile range as appropriate and compared
using Student’s t-test or Mann-Whitney-U test, as appropriate. Time to event analysis will be
performed by Cox proportional hazard analysis. All outcomes will be analysed in an
uncorrected manner as well as (jointly) corrected for risk factors (type and severity of illness,
age, on admission nutritional status and risk scores). A priori defined subgroup analyses will
be performed for patients admitted to ICU after cardiac surgery as compared with all other
patients; for patients with and without sepsis upon admission; for patients with contra-
indications for EN on admission or not. For all endpoints, differences will be considered
Version 3: 22-04-2012 41 of 51
statistically significant whenever the p-value is lower than 0.05 without correction for multiple
testing.
Safety endpoints
Safety endpoints comprise vital status, hypoglycaemia, serious adverse events and
complications related to the mode of nutrition. Survival up to 90 days after randomization in
both treatment groups will be compared by Kaplan Meier survival plots. The impact of “late
PN” versus “early PN” will be analyzed, with and without correction for risk factors, by Cox
proportional hazard analysis. In addition, we will record vital status at ICU and hospital
discharge, and will analyze differences with Chi-square testing. As the randomized study
intervention only takes place during a time window up to the 8th day in ICU, we also plan to
analyze early lethality within this time window in the intention to treat population as part of the
safety analysis.
9.2 Univariate analysis

Discrete variables will be summarized by frequencies and percentages and analyzed by
(exact) Chi-square test or logistic regression analysis. Continuous variables will be
summarized by use of either mean or standard deviations (SD) or median and interquartile
range as appropriate and compared using Student’s t-test or (exact) Mann-Whitney-U test,
as appropriate. Time to event analysis will be performed by Cox proportional hazard
analysis. Time to discharge alive from ICU will be reported by Kaplan-Meier plots, with ICU
9.3 Multivariate analysis

All outcomes will be analyzed in an uncorrected manner as well as (jointly) corrected for risk
factors (type and severity of illness, age, on admission nutritional status and risk scores).
Another a priori defined subgroup analysis will be performed for patients admitted to ICU
after cardiac surgery as compared with all other patients. Also an a priori subgroup analysis
is planned for patients with and without sepsis upon admission.
Version 3: 22-04-2012 42 of 51
longitudinal data.
c. Need for pharmacological or mechanical hemodynamic support during ICU stay, and
hemodynamic support in ICU will be analyzed, with ICU non-survivors censored
beyond the longest duration of pharmacological or mechanical hemodynamic support
be compared.
treatment groups will be compared.
Version 3: 22-04-2012 43 of 51
9.4 Interim analysis

be necessary.
The safety analyses will be done on the whole set of patients and by subgroups of patients
based on the primary diagnostic categories used as prognostic factors for stratification and
on septic/non-septic groups of patients.
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10. ETHICAL CONSIDERATIONS
10.1 Regulation statement

The study will be conducted in accordance to the protocol as described in the European
Medicine Agency’s “Note for guidance on good clinical practice CPMP/ICH/135/95” as well
as the Declaration of Helsinki (59th WMA General Assembly, Seoul, Korea, October 2008)
and in accordance with the Medical Research Involving Human Subjects Act (WMO).
10.2 Recruitment and consent

The study protocol and consent forms will be sent for approval by the Institutional Review
Board of the Katholieke Universiteit Leuven and the Erasmus MC (Lokale uitvoerbaarheid)
and by the competent Belgian and Dutch authorities (CCMO). Written informed consent is
obtained from the parents or the legal guardian by the investigator’s team or one of the
supervising doctors, who will inform the parents of the patients (and the patients themselves
if the age is > 12 years) and ask for their consent. The parents / legal guardians and (if
applicable) the patients will receive a patient information letter and an informed consent form.
Written informed consent will be obtained from the patient or the closest family member or
legal guardian. For planned PICU admissions after elective procedures, informed consent
will be asked beforehand, if possible.
For emergency PICU admissions, treatment allocation will be done after assessment of the
patient for eligibility by the attending physician within the time frame of two hours. If eligible,
the patient will be randomized into the study and the allocated glucose infusion (with
micronutrients) will be started. Informed consent will be asked within the time frame of 24
hours (deferred informed consent) as a nutritional regimen has to be initiated already on
admission. When consent is given, the allocated nutritional regimen will proceed (Early (with
additional lipids and protein targeting nutritional goals < day3) vs Late (no PN)). When NO
consent is given, the nutritional regimen and glucose infusion will be placed under
responsibility of the supervising clinical team of doctors.
The parents or legal guardians can withdraw the patient from the study at any time, without
penalty or impact on treatment.
10.3 Objection by minors or incapacitated subjects (if applicable)

The children can withdraw from the study at any time, without penalty or impact on treatment.
(art 4 lid 2 WMO) Neither will the child be forced to undergo the additional tests, such as
muscle strength testing, the ultrasound evaluation of the skeletal muscle and adipose tissue
compartments, or the questionnaires and follow-up evaluations. In this matter, also non-
Version 3: 22-04-2012 45 of 51
verbal resistance will be taken into account by the investigator’s team. The specific test will
then not be performed, without taking the subject out of the study as a whole.
10.4 Benefits and risks assessment, group relatedness

During the informed consent process, it will be made extremely clear that participation in this
study will provide no direct benefits to the patient and that refusal to participate will have zero
impact on the care received by any of the nursing medical staff. The risks will be kept to a
minimum. This study requires this specific study group of critically ill children of different age
groups. Although the study has been performed in adults, these results should not be
translated directly to children as both the metabolic as well as nutritional kinetics in children
of different age groups vary significantly form adults.
10.5 Compensation for injury

The sponsor/investigator has a liability insurance which is in accordance with article 7,
subsection 6 of the WMO.
No fault insurance is covered by Fortis Corporate Insurance NV (Leuven) and Akkermans
Van Elten Assurantiën BV (Rotterdam).
The sponsor has an insurance which is in accordance with the legal requirements in the
Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical
Research in Humans of 23th June 2003). This insurance provides cover for damage to
research subjects through injury or death caused by the study.
1. € 450.000,-- (i.e. four hundred and fifty thousand Euro) for death or injury for each
subject who participates in the Research;
2. € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or injury for
all subjects who participate in the Research;
3. € 5.000.000,-- (i.e. five million Euro) for the total damage incurred by the
organisation for all damage disclosed by scientific research for the Sponsor as
‘verrichter’ in the meaning of said Act in each year of insurance coverage.
The insurance applies to the damage that becomes apparent during the study or within 4
years after the end of the study.
10.6 Incentives
Not applicable
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11. ADMINISTRATIVE ASPECTS AND PUBLICATION
11.1 Handling and storage of data and documents

Data are collected electronically in a pseudonymized CRF, unambiguously linked to the
source file. The subject identification codes are safeguarded by the principle investigators.
Data are manually transferred (and checked for accuracy) into the CRF by the clinical
research assistance team on a daily basis from the ICU PDMS and the Leuven University
Hospitals Clinical Working Station (KWS). Extensive range and consistency checks are
performed by the study monitor. Vital status at 90 days will be recorded for all patients, by
the National Death Registries when this information is not available in the hospital
information system or the regional network of pediatricians.
The handling of personal data will comply with the Dutch Personal Data Protection Act (in
Dutch: De Wet Bescherming Persoonsgegevens, WBP).
11.2 Amendments
Amendments are changes made to the research after a favourable opinion by the accredited
METC has been given. All amendments will be notified to the METC that gave a favourable
opinion.
All substantial amendments will be notified to the METC and to the competent authority.
Non-substantial amendments will not be notified to the accredited METC and the competent
authority, but will be recorded and filed by the sponsor.
11.3 Annual progress report

The sponsor/investigator will submit a summary of the progress of the trial to the accredited
METC once a year. Information will be provided on the date of inclusion of the first subject,
numbers of subjects included and numbers of subjects that have completed the trial, serious
adverse events/ serious adverse reactions, other problems, and amendments.
11.4 End of study report

The investigator will notify the accredited METC of the end of the study within a period of 8
weeks. The end of the study is defined the time-point 90 days after the inclusion of the last
patient.
In case the study is ended prematurely, the investigator will notify the accredited METC,
including the reasons for the premature termination.
Within one year after the end of the study, the investigator/sponsor will submit a final study
Version 3: 22-04-2012 47 of 51
report with the results of the study, including any publications/abstracts of the study, to the
accredited METC.
11.5 Public disclosure and publication policy

This is an investigator initiated study. This study will be registered as a clinical trial in a public
trial registry.
The investigators aim to publish all results obtained from the study unreservedly.
Version 3: 22-04-2012 48 of 51
12. REFERENCES
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6. Verbruggen SC, Coss-Bu J, Wu M, Schierbeek H, Joosten KF, Dhar A, et al. Current
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7. Verbruggen SC, Schierbeek H, Coss-Bu J, Joosten KF, Castillo L, van Goudoever JB.
Albumin synthesis rates in post-surgical infants and septic adolescents; influence of amino
acids, energy, and insulin. Clin Nutr 2011;30(4):469-77.
8. Verbruggen S, Sy J, Arrivillaga A, Joosten K, van Goudoever J, Castillo L. Parenteral
Amino Acid Intakes in Critically Ill Children: A Matter of Convenience. JPEN J Parenter
Enteral Nutr 2010;34(3):329-40.
9. Derde S, Vanhorebeek I, Guiza F, Derese I, Gunst J, Fahrenkrog B, et al. Early Parenteral
Nutrition Evokes a Phenotype of Autophagy Deficiency in Liver and Skeletal Muscle of
Critically Ill Rabbits. Endocrinology 2012.
10. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature
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12. Vlasselaers D, Milants I, Desmet L, Wouters PJ, Vanhorebeek I, van den Heuvel I, et al.
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13. WHO ‘Prevention of hospital-acquired infections; a practical guide, 2nd edition’
www.who.int/csr/.../whocdscsreph200212.pdf
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14. Vlasselaers D, Mesotten D, Langouche L, Vanhorebeek I, van den Heuvel I, Milants I, et

al. Tight glycemic control protects the myocardium and reduces inflammation in neonatal
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17. Ellger B, Debaveye Y, Vanhorebeek I, Langouche L, Giulietti A, Van Etten E, et al.
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Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical
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19. Derde S, Vanhorebeek I, Ververs EJ, Vanhees I, Darras VM, Van Herck E, et al.
Increasing intravenous glucose load in the presence of normoglycemia: effect on outcome
and metabolism in critically ill rabbits. Crit Care Med 2012;38(2):602-11.
20. Bjorkoy G, Lamark T, Pankiv S, Overvatn A, Brech A, Johansen T. Monitoring autophagic
degradation of p62/SQSTM1. Methods Enzymol 2009;452:181-97.
21. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, et al. Impairment of
starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol
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22. Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, et al. Autophagy is
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24. Langer M, Modi BP, Agus M. Adrenal insufficiency in the critically ill neonate and child.
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25. Gielen M, Mesotten D, Brugts M, Coopmans W, Van Herck E, Vanhorebeek I, et al.
Effect of intensive insulin therapy on the somatotropic axis of critically ill children. J Clin
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26. Cuzzola A, Petri A, Mazzini F, Salvadori P. Application of hyphenated mass spectrometry
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5. Summary of all amendments to the protocol -
Changes in research protocol project NL-38772.000.12 (Pediatric Early versus late Parental Nutrition
In Critical illness (PEPaNIC)
Description:
1. The addition of the Stollery Children’s Hospital Edmonton as third center

2. The addition of the collection of buccal swabs to determine gastrointestinal intolerance and
inflammation
3. The addition of the collection of hair samples for long term cortisol levels
4. The addition of the specifics of blood sampling for epigenetics as described in the first version
of the protocol
5. Adjustments to the patient information forms for all of the above mentioned changes.
Specific changes of protocol:
- Ad Protocol Title and information: Stollery Children's Hospital Edmonton, Canada added as
third center with the following researchers: Dr. Joffe, dr. Guerra and dr. Larsen. Drs. D. Kerklaan
added as researcher in Erasmus MC Rotterdam
- Ad 1: introduction and rationale: rationale expanded with information on gastrointestinal

intolerance:
One of the goals of the PEPaNIC study is to look into the tolerance for enteral nutrition (EN).
In critically ill children EN is preferred because it is more physiological, presents fewer
complications, leads to a better outcome and is less expensive than PN. However, EN often
fails in this patient group due to impaired gastrointestinal (GI) motility, digestion and absorption
following ischemia, inflammation or starvation leading to intolerance to EN. To improve future
EN tolerance in critically ill children we have to gain insight in parameters of influence in this
complex process.
One of the paramaters is mucosal inflammation, which can be related to malabsorption, as
seen in patients with inflammatory bowel disease (IBD). Intestinal epithelial cells play a role
in initiating and regulating mucosal immune responses through the secretion of chemokines.
Studies in patients with IBD showed that epithelial cells derived from the intestine produce
significant amounts of pro and anti- inflammatory chemokines (CXCL-8, CXCL-9 and CXCL-
10). Chemokine expression can be measured in buccal epithelium which can be used as a
reflection of intestinal inflammation.
- Ad 2: objectives: objectives of research on feeding intolerance added

To study the underlying physiological mechanisms of enteral nutrition (EN) intolerance of
critically ill children and to identify markers of tolerance for EN to use in future intervention
studies clinical signs of intolerance (gastric residual volume, diarrhoea, vomiting, abdominal
swelling) will be recorded. Buccal swabs will be collected at several moments and will be
stored for analysis (epithelial cell expression of chemokines).
- Ad 5.1: treatment of subjects - investigational treatment: local practice in Edmonton added:

In Edmonton patients in all age groups receive continuous insulin infusion to target blood
glucose levels <180 mg/dl
Changes research protocol PEPaNIC Rotterdam 1

- Ad 7.1.2: methods – secondary study parameters/endpoints: the collection of hair samples for
long term cortisol levels and the collection of buccal swabs for inflammation and feeding
intolerance added:
Impact of early versus late PN on the neuroendocrine axes: The metabolism of cortisol will be
studied further by the relative levels of its metabolites excreted in urine (26) and by collecting hair
samples for the long term cortisol levels.
h. Enteral nutrition (EN) tolerance: proportion of patients with diarrhoea, high gastric residual
volumes, vomiting and/or abdominal swelling and relation with buccal epithelial cell expression
of chemokines (CXCL-8. CXCL-9 and CXCL-10)
- Ad 7.3: data collection following recruitment:

collection of hair samples, complementary blood samples and buccal swabs added. Figure
adjusted accordingly. Ultrasound deleted
Around 100 strands of hair from the posterior vertex of the scalp will be cut off as soon as possible
after admission and this will be repeated after 3 weeks- 2 months if possible.
Buccal swabs will be collected at day of admission (day 1), day 2, 4 and 6, and possibly on
day of discharge and will be immersed in RNA-later and stored at -80C. Buccal epithelial cell
expression of chemokines (CXCL-8. CXCL-9 and CXCL-10) will be measured in by Taqman
analysis.
In children > 10 kg 1,8 milliliter extra blood (EDTA and heparine) will be collected on 4 selected
days
- Ad 7.3: data collection following recruitment: collection of PAXtube for epigenetic purposes
specified.
On day 3,5 and 7 a ‘PAX-tube’ (containing 2 milliliter blood) will be collected.
Changes in patient information forms (in Dutch):
1. Ouders/verzorgers:
- Ad inleiding: Het onderzoek wordt gedaan op de afdeling Intensive Care van het Sophia
Kinderziekenhuis Erasmus MC. Het onderzoek wordt ook uitgevoerd in het Universitair
Ziekenhuis te Leuven, België en het Kinderziekenhuis in Edmonton, Canada.
- Ad 1. Doel: doel uitgebreid met onderzoek naar intolerantie:

Een ander doel van het onderzoek is om te kijken naar het verdragen van voeding via de
darmen, waarom dat bij het ene kind wel gaat en bij het andere niet. Dit doen we door naar
verschillende factoren te kijken die van invloed zijn op het verdragen van voeding door de
darm, namelijk darmhormonen, darmschade en ontsteking in de darm.
- Ad 3: Hoe wordt het onderzoek uitgevoerd? Toegevoegd:

De gegevens van uw kind zullen tijdens de hele opname op de Intensive Care verzameld
worden.

- Ad 4. Wat merk uw kind van het onderzoek? Toegevoegd:
We zullen een plukje haar (ongeveer 100 haren) van het achterhoofd afnemen om te kijken
naar het niveau van de stresshormonen. Dit stukje haar zal zo dicht mogelijk bij de hoofdhuid
afgeknipt worden. Het plukje haar dat weggeknipt wordt zal, waar mogelijk, op een zodanige
manier verwijderd worden dat de rest van het haar hier weer overheen valt, waardoor het
niet te zien is.
We zullen op een aantal dagen een kleine hoeveelheid wangslijmvlies afnemen bij uw kind
om te kijken naar cellen uit het afweersysteem. Het afnemen van het wangslijmvlies gaat
door met een borsteltje langs de binnenkant van de wangen te wrijven. Dit doet geen pijn.
Bij punt 3: Deze vragenlijst sturen wij 3 en 12 maanden na de opname op de Intensive Care
afdeling naar u op.
Verwijderd:
Er zal tijdens de opname met een echografie (dat zijn geluidsgolven) naar de spieren, lever
en vet van uw kind worden gekeken. Dit doet geen pijn.
- Ad 8. Mogelijke voor –en nadelen? Toegevoegd:

Er wordt een plukje haar (ongeveer 100 haren)van het achterhoofd van uw kind weggeknipt.
Het plukje haar dat weggeknipt wordt zal, waar mogelijk, op een zodanige manier verwijderd
worden dat de rest van het haar hier weer overheen valt, waardoor het niet te zien is. Er
zijn geen risico’s of bijwerkingen bekend van deze handeling.
We zullen wangslijmvlies afnemen door met een borsteltje langs de binnenkant van de
wangen te wrijven. Dit kan kortdurend een raar gevoel geven, maar doet geen pijn. Er zijn
geen risico’s of bijwerkingen bekend van deze handeling.
- Ad 14. Wat gebeurt er met de gegevens van uw kind? Toegevoegd

Lichaamsmateriaal, dit is bloed, urine, wangslijmvlies, haar en ontlasting, wordt gedurende het
onderzoek met een code bewaard en na afloop van het onderzoek vernietigd.
- Ad toestemmingsformulier: Toegevoegd
Ik geef wel/geen toestemming om hoofdhaar bij mijn kind af te knippen ten behoeve van
wetenschappelijk onderzoek.
2. Adolescent:
- Ad Korte samenvatting: Toegevoegd

…Wij zullen voor dit onderzoek extra bloed, urine, poep, haar en wangslijmvlies verzamelen,
en daarnaast….
- Ad inleiding (pagina 1): Het onderzoek wordt gedaan op de afdeling Intensive Care van het
Sophia Kinderziekenhuis -Erasmus MC. Het onderzoek wordt ook uitgevoerd in het
Universitair Ziekenhuis te Leuven, België en het Kinderziekenhuis in Edmonton, Canada.
- Ad 1. Doel: toegevoegd: Een ander doel van het onderzoek is om te kijken naar het
verdragen van voeding via de darmen, waarom lukt dat wel of niet. Dit doen we door naar
verschillende factoren te kijken die van invloed zijn op het verdragen van voeding door de
darm, namelijk darmhormonen, darmschade en ontsteking in de darm.
- Ad 3: Hoe wordt het onderzoek uitgevoerd? Toegevoegd:

Jouw gegevens zullen tijdens de hele opname op de Intensive Care verzameld worden.

- Ad 4. Wat merk je van het onderzoek? Toegevoegd
We zullen een plukje haar (ongeveer 100 haren) van je achterhoofd knippen om te kijken
naar het niveau van de stresshormonen. Dit stukje haar zal zo dicht mogelijk bij je hoofdhuid
afgeknipt worden. Het plukje haar dat weggeknipt wordt zal zo geknipt worden dat de rest van
je haar hier weer overheen valt, waardoor het niet te zien is.
We zullen op een aantal dagen een kleine hoeveelheid wangslijmvlies afnemen bij je
afnemen om te kijken naar cellen uit het afweersysteem. Het afnemen van het
wangslijmvlies gaat door met een borsteltje langs de binnenkant van je wangen te wrijven.
Dit doet geen pijn.
Bij punt 3: Deze vragenlijst sturen wij 3 en 12 maanden na jouw opname op de Intensive
Care afdeling naar jullie op.
Verwijderd:
Er zal tijdens de opname met een echografie (dat zijn geluidsgolven) naar je spieren, lever
en vet worden gekeken. Dit doet geen pijn.
- Ad 8. Mogelijke voor –en nadelen? Toegevoegd

Er wordt een plukje haar (ongeveer 100 haren)van je achterhoofd weggeknipt. Het plukje haar
dat weggeknipt wordt zal zo geknipt worden dat de rest van het haar hier weer overheen
valt, waardoor het niet te zien is. Er zijn geen risico’s of bijwerkingen bekend van deze
handeling.
We zullen wangslijmvlies afnemen door met een borsteltje langs de binnenkant van je
wangen te wrijven. Je kunt hierdoor kortdurend een raar gevoel hebben. Dit doet geen pijn
- Ad toestemmingsformulier: Toegevoegd
Ik geef wel/geen toestemming om mijn hoofdhaar af te knippen ten behoeve van
wetenschappelijk onderzoek.

6. Most recent protocol (incl. most recent statistical analysis plan) -
Paediatric Early versus late

Parenteral Nutrition In Critical illness
- PEPaNIC
(December 2013)
PROTOCOL TITLE ‘Paediatric Early versus late Parenteral Nutrition In Critical illness’
Protocol ID PEPaNIC - NL
Short title PEPaNIC
Version 5
Date 17-12-2013
Coordinating investigator/project Prof. Dr. G Van Den Berghe, Katholieke

leader Universiteit, Leuven, Belgium
Principal investigator(s) (in Erasmus MC – Sophia Children’s Hospital

Dutch:
Prof. Dr. D Tibboel
hoofdonderzoeker/uitvoerder)
Dr. SCAT Verbruggen
Multicenter research: per site
Dr. KFM Joosten
Drs. D. Kerklaan
Katholieke Universiteit, Leuven, Belgium
Prof. Dr. G Van Den Berghe
Prof. Dr. D. Mesotten
Prof. I Vanhorenbeek
Dr. L Desmet
Dr. T Fivez
Stollery Children's Hospital Edmonton, Canada
Dr. A. Joffe
Dr. G. G. Guerra
Dr. B. Larsen
Sponsor (in Dutch: Investigator Initiated

verrichter/opdrachtgever)
Independent physician(s) Prof. Dr. IKM Reiss, Neonatology, Erasmus MC –

Sophia Children’s Hospital
Laboratory sites <if applicable> Laboratory Paediatrics,

Erasmus MC –Sophia, Rotterdam
Laboratory Intensive Care Medicine, University

Hospital Leuven, Belgium
Pharmacy <if applicable> Erasmus MC – Sophia (Rotterdam site)
University Hospital Leuven (Leuven site)
Stollery Children's Hospital Edmonton
PROTOCOL SIGNATURE SHEET
Name Signature Date
For non-commercial research, Prof. Dr. D. Tibboel

Head of Department:
Head of department,
Pediatric ICU
Coordinating Investigator/Project Dr. KFM Joosten

leader
18-12-2013
Principal Investigator: Dr.

SCAT Verbruggen
TABLE OF CONTENTS
1. INTRODUCTION AND RATIONALE .............................................................................. 9

2. OBJECTIVES ................................................................................................................11
3. STUDY DESIGN ...........................................................................................................14
4. STUDY POPULATION ..................................................................................................17
4.1 Population Base .....................................................................................................17
4.2 Inclusion criteria .....................................................................................................17
4.3 Exclusion criteria ....................................................................................................17
4.4 Sample size calculation ..........................................................................................17
5. TREATMENT OF SUBJECTS .......................................................................................19
5.1 Investigational treatment ........................................................................................19
5.2 Use of co-intervention (if applicable) ......................................................................24
5.3 Escape medication (if applicable) ...........................................................................24
6. INVESTIGATIONAL MEDICINAL PRODUCT ................................................................24
7. METHODS ....................................................................................................................25
7.1 Study parameters/endpoints ...................................................................................25
7.1.1 Main study parameter/endpoint .......................................................................25
7.1.2 Secondary study parameters/endpoints ..........................................................25
7.1.3 Other study parameters ...................................................................................30
7.2 Randomisation, blinding and treatment allocation ..................................................31
7.3 Study procedures ...................................................................................................31
7.4 Withdrawal of individual subjects ............................................................................34
7.4.1 Specific criteria for withdrawal (if applicable) ...................................................34
7.5 Replacement of individual subjects after withdrawal ...............................................35
7.6 Follow-up of subjects withdrawn from treatment .....................................................35
7.7 Premature termination of the study.........................................................................35
8. SAFETY REPORTING ..................................................................................................36
8.1 Section 10 WMO event ..........................................................................................38
8.2 Adverse and serious adverse events ......................................................................38
8.2.1 Suspected unexpected serious adverse reactions (SUSAR) ...........................39
8.2.2 Annual safety report ........................................................................................39
8.3 Follow-up of adverse events...................................................................................40
8.4 Data Safety Monitoring Board (DSMB) ...................................................................40
9. STATISTICAL ANALYSIS .............................................................................................41
9.1 Descriptive statistics ...............................................................................................41
9.2 Univariate analysis .................................................................................................42
9.3 Multivariate analysis ...............................................................................................42

9.4 Interim analysis ......................................................................................................44
10. ETHICAL CONSIDERATIONS...................................................................................45
10.1 Regulation statement .............................................................................................45
10.2 Recruitment and consent........................................................................................45
10.3 Objection by minors or incapacitated subjects (if applicable) ..................................45
10.4 Benefits and risks assessment, group relatedness .................................................46
10.5 Compensation for injury .........................................................................................46
10.6 Incentives ...............................................................................................................46
11. ADMINISTRATIVE ASPECTS AND PUBLICATION ..................................................47
11.1 Handling and storage of data and documents ........................................................47
11.2 Amendments ..........................................................................................................47
11.3 Annual progress report ...........................................................................................47
11.4 End of study report .................................................................................................47
11.5 Public disclosure and publication policy..................................................................48
12. REFERENCES ..........................................................................................................49
LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS
ABR ABR form, General Assessment and Registration form, is the application
form that is required for submission to the accredited Ethics Committee (In
Dutch, ABR = Algemene Beoordeling en Registratie)
AE Adverse Event
AR Adverse Reaction
CA Competent Authority
CCMO Central Committee on Research Involving Human Subjects; in Dutch:
Centrale Commissie Mensgebonden Onderzoek
CV Curriculum Vitae
DSMB Data Safety Monitoring Board
EU European Union
EudraCT European drug regulatory affairs Clinical Trials
GCP Good Clinical Practice
IB Investigator’s Brochure
IC Informed Consent
IMP Investigational Medicinal Product
IMPD Investigational Medicinal Product Dossier
METC Medical research ethics committee (MREC); in Dutch: medisch ethische
toetsing commissie (METC)
(S)AE (Serious) Adverse Event
SPC Summary of Product Characteristics (in Dutch: officiële productinfomatie
IB1-tekst)
Sponsor The sponsor is the party that commissions the organisation or performance
of the research, for example a pharmaceutical
company, academic hospital, scientific organisation or investigator. A party
that provides funding for a study but does not commission it is not
regarded as the sponsor, but referred to as a subsidising party.
SUSAR Suspected Unexpected Serious Adverse Reaction
Wbp Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgevens)
WMO Medical Research Involving Human Subjects Act (in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen
Version 5: 17-12-2013 6 of 51
SUMMARY
Rationale: It has recently been shown in a large randomized study in adult ICU patients that
the early PN caused an increase of morbidity (infections and increased length of stay on the
ICU). Such a study is warranted also in critically ill children of different age groups, as PN
has been associated with increased incidence of complications, such as (line) infections,
hyperglycemia and hepatic steatosis. It has not been studied whether early PN, when enteral
feeding is insufficient, influences the outcome of critically ill children.
Objective: The ultimate aim of this project is to answer the question whether insufficient EN
should or should not be supplemented with PN early in the disease course of critical illness in
children. The scientific objectives of the study are the following: 1) Performing the first well-
designed and sufficiently powered, multicentre RCT to test the effects of early PN
supplementation on the health of critically ill children. 2) Performing an economic evaluation
study, investigating the costs and cost-effectiveness, during hospitalisation of early versus
late PN supplementation. 3) Starting to unravel potential mechanisms that underlie any
difference in acute and long term outcome with early or late PN supplementation by studying
metabolic, endocrine, inflammatory and (epi.)genetic markers.
Study design: This study is a large, three-centre, non-blinded, randomized, controlled study.
Study population: Critically ill children (0 – 18 yrs), with nutritional risk score
expected to stay in PICU for more than 24h are eligible for inclusion. Exclusion criteria are a
“do not resuscitate” code at the time of PICU admission, expected death within 12 hours, re-
admission to the PICU after previously being randomised to the PEPaNIC trial, transfer from
another PICU after a stay of more than seven days, ketoacidotic or hyperosmolar coma on
admission or inborn metabolic diseases requiring specific diet, premature newborns (<37
weeks gestational age), patients on Total Parenteral Nutrition for >7 days prior to inclusion,
short bowel syndrome or other conditions which required home-PN.
Intervention: The “early PN” strategy will be the nutritional management currently applied in
the participating centres, acting as “control”. The “late PN” strategy comprises initiation of this
strategy only after day 7 in PICU, patients will receive a mixture of Glucose 5% and NaCl
0.9% at, respectively, 60% and 40% of the total flow rate that is required to obtain standard
optimal hydration taking into account the volume of EN that is being delivered. If enteral
Version 5: 17-12-2013 7 of 51
feeding of at least 80% of the calculated calories is not possible after 7 days in ICU, PN, as
specified above, is initiated on day 8.
Main study parameters/endpoints: We will compare “early PN” with “late PN” in paediatric
ICU patients at risk of developing malnutrition in the ICU. The primary focus of the PEPaNIC
study is clinical outcome, more specifically the acquisition of new ICU infections, the
dependency on intensive medical care and convalescence from critical illness.
Nature and extent of the burden and risks associated with participation, benefit and
group relatedness: The burden is expected to be minimal as it will only entail additional
blood draws, which will be taken from clinical lines or in addition to pricks for clinical purpose.
The long-term follow up will be held as part of already organised follow-up outdoor clinics
and which are developed to help children and their parents to recover physically, emotionally
and socially after ICU admissions. For mechanistic and exploratory studies, muscle strength
testing and an ultrasound evaluation of the skeletal muscle and adipose tissue compartments
will be performed. Furthermore, as far as practically feasible, every patient is approached just
prior to hospital discharge, to complete a validated, semi-structured child health
questionnaire (Functional Independence Measure (WEEFIM), Health Utilities Index (HUI)
and Child Health Questionnaire (CHQ)).
underfeeding. However, safety measures will be taken to further decrease these risks.
GROUP relatedness: This study was already performed in adult ICU patients. However, the
results of this study should NOT be translated one-on-one to the pediatric patient, as critically
ill children of different age groups have different metabolic and nutritional issues. Therefore,
this study deserves to be repeated in our population of critically ill children.
Version 5: 17-12-2013 8 of 51
1. INTRODUCTION AND RATIONALE
It has recently been shown that withholding parenteral nutrition (PN.) during the first week of
critical illness (Late PN) is beneficial in comparison with the early supplementation of
insufficient enteral nutrition (EN) with PN (Early PN) in critically ill adults (1). The benefits of
Late PN mainly encompassed a decrease in the incidence of new infections in the ICU, a
shortening of the stay in the ICU and hospital, and a reduction in healthcare costs. These
findings put pressure on the current guidelines by the European Society of Parenteral &
Enteral Nutrition (ESPEN), which recommend the practice of Early PN in critically adults (2).
These current medical practice and expert panels advocate the early supplementation by
PN. This is based on the premise that PN is probably beneficial, and if not, harmless. This
contrasts strongly with the findings of the study in adult critically ill patients where it has been
shown that this early supplementation by PN is not providing benefit and is actually causing
harm to patients by increasing the morbidity and delaying recovery.
The detrimental impact of the practice of Early PN in critically ill adults has alerted the clinical
community that also the guidelines for nutritional strategy in paediatric critically ill patients are
merely based on expert opinion. Not only is Early PN current practice in most paediatric
ICUs, it is also often more aggressively promoted (3, 4). This is further evidenced by the
presence of national governmental healthcare programs that include the success rate for
reaching nutritional goals as a quality benchmark (5). Therefore critically ill children may be
exposed to risk by the aggressive feeding protocols, which were previously deemed innocent
or even beneficial. We and others have shown recently that current aggressive feeding
protocols with early high protein and lipid intakes, not only fail to achieve anabolism, but have
potential negative side effects, such as increased risk of developing hyperglycemia,
dyslipidemia and insulin resistance (6, 7). Furthermore, there is currently no evidence of
beneficence of early supplementation of parenteral nutrition, although this is practiced in
multiple PICU’s according current guidelines. PN has been associated with increased
incidence of complications, such as (line) infections, hyperglycemia and hepatic steatosis.
Furthermore, it is well recognized that the quality of current PN solutions lack sufficient
scientific basis and are potentially harmful (8). Therefore, it is unclear whether an early
supplementary intervention of parenteral nutrition to try and decrease catabolism in critically
ill children outweighs the potential harm of such therapy. Furthermore, recent studies have
suggested a negative role of early aggressive nutrition in the interference of autophagy of
cellular damage in critically ill patients, a process that may protect against infectious
diseases and hyperinflammation (9-11). Children are in the early phase of their life when the
fundaments of metabolism are developing. Therefore, it cannot be excluded that the
aggressive nutritional support given to critically ill children has repercussions on the long run,
Version 5: 17-12-2013 9 of 51
until later in their adult life. And thus, such a study deserves to be performed in a population
of critically ill children.
In our study we aim to evaluate whether the current practice of Early PN in critically ill
children really provides clinical benefits over a strategy of withholding PN during the first 7
days in the paediatric ICU. The evaluation will be done in a multicentre randomized
controlled trial performed in three large expert tertiary referral paediatric ICUs. The study will
be statistically sufficiently powered to detect differences in clinically relevant outcome
variables (the rate of new infections and the length of stay in the ICU). The trial will also be
able to detect a doubling or halving of the mortality rate with a respectable statistical power
(details on statistical power are given in the description further on). The results of this
randomized controlled trial will provide, for the first time, high quality evidence for practice
guidelines for nutrition in critically ill children. It will answer the question whether Early PN is
beneficial, harmful or neutral in comparison with the new therapy of withholding PN during
the first week of critical illness. In weighing this evidence for current nutritional practice, this
study will take into account 1) the short-term as well as the long-term health effects of the
feeding protocols, 2) costs, and cost-effectiveness and 3) some insights into the underlying
mechanisms of the observed clinical differences.
Also, one of the goals of the PEPaNIC study is to look into the tolerance for enteral nutrition
(EN). In critically ill children EN is preferred because it is more physiological, presents fewer
complications, leads to a better outcome and is less expensive than PN. However, EN often
fails in this patient group due to impaired gastrointestinal (GI) motility, digestion and
absorption following ischemia, inflammation or starvation leading to intolerance to EN. To
improve future EN tolerance in critically ill children we have to gain insight in parameters of
influence in this complex process.
One of the parameters is mucosal inflammation, which can be related to malabsorption, as
seen in patients with inflammatory bowel disease (IBD). Intestinal epithelial cells play a role
in initiating and regulating mucosal immune responses through the secretion of chemokines.
Studies in patients with IBD showed that epithelial cells derived from the intestine produce
significant amounts of pro and anti-inflammatory chemokines (CXCL-8, CXCL-9 and CXCL-
10). Chemokine expression can be measured in buccal epithelium which can be used as a
reflection of intestinal inflammation.
Version 5: 17-12-2013 10 of 51
2. OBJECTIVES
The ultimate aim of this project is to answer the question whether insufficient EN should or
should not be supplemented with PN early in the disease course of critical illness in children.
The scientific objectives of the study are divided into 3 main work-packages (WP 1-3) and
are the following:
- WP1: Performing and completing the first well-designed and sufficiently powered,
multicentre RCT to test the effects of early PN supplementation on the health of
critically ill children. The short-term outcome analysis, as well as a substantial part of
the long-term follow-up, will be completed within the time frame of the study.
- WP2: an economic evaluation, in which costs and cost-effectiveness will be
investigated of early versus late PN supplementation during hospitalization.
- WP3: Starting to unravel potential mechanisms that underlie any difference in acute
and long term outcome with early or late PN supplementation by studying metabolic,
endocrine, inflammatory and (epi.)genetic markers in the blood of critically ill children
included in the study.
Primary Objective:
The primary focus of the PEPaNIC study is clinical outcome, more specifically the acquisition
of new ICU infections, the dependency on intensive medical care and convalescence from
critical illness, this is part of WP1.
The primary efficacy endpoints for this RCT are the incidence of new infections and the time
to discharge alive from ICU. We expect to see a decrease in secondary infections from 20%
to 15%, which is based on a previous study in critically ill children in Leuven (12) and on
retrospective data in critically ill children who were admitted for at least four days in the
PICU, Rotterdam.
Number of patients with new infections and types of infection will be assessed by numbers
and percentages, and the duration of any antibiotics therapy initiated after randomisation for
those patients requiring antibiotics will be analysed by non-parametrical tests. As the time of
ICU discharge to the regular ward may be affected by the availability of beds on the regular
wards, which could induce bias, we a priori decided to analyse “time to discharge from ICU”
as “time to ready for discharge from ICU”. A patient is considered “ready for discharge” as
soon as all clinical conditions for ICU discharge have been fulfilled (no longer in need for vital
organ support). Time to discharge alive from ICU will be reported by Kaplan-Meier plots, with
ICU non-survivors censored beyond the longest ICU stay of survivors and censoring time of
both treatment groups. The impact of “late PN” versus “early PN” will be analysed, with and
Version 5: 17-12-2013 11 of 51
time window of the randomised intervention in ICU, also the proportion of patients staying
beyond 8 days in ICU will be reported. Analyses on blood and urine for the primary clinical
analyses include routine chemistry, haematology, and markers of inflammation. Further
epigenetic, metabolic, endocrine and inflammatory measurements on stored samples in the
context of mechanistic analyses will be planned. All new infections of the lungs, the blood
stream, the urinary tract and wounds are recorded by an infectious disease specialist. A
nosocomial infection is defined as a localized or systemic condition 1) that results from
adverse reaction to the presence of an infectious agent(s) or its toxin(s) and 2) that was not
present or incubating at the time of admission to the PICU. The information used to
determine the presence and classification of an infection should be a combination of clinical
findings and results of laboratory and other tests. Definitions various types of proven and
suspected infections will be used according to clinical, laboratory evidence and/or supportive
data. WHO definitions for nosocomial infections will be used (13).
WHO definitions for nosocomial infections (13).
Version 5: 17-12-2013 12 of 51
Clinical evidence is derived from direct observation of the infection site or review of other
pertinent sources of data, such as the patient’s chart. Laboratory evidence includes results of
cultures, antigen or antibody detection tests, or microscopic visualization. Supportive data
are derived from other diagnostic studies, such as x-ray, ultrasound, computed tomography
(CT) scan, magnetic resonance imaging (MRI), radiolabel scan, endoscopic procedure,
biopsy, or needle aspiration. It will be recorded during the entire ICU period until discharge,
death or until day 90 of admittance.
Bacteraemia is further classified by responsible pathogen and as catheter-related blood
To study the underlying physiological mechanisms of enteral nutrition (EN) intolerance of
critically ill children and to identify markers of tolerance for EN to use in future intervention
studies clinical signs of intolerance (gastric residual volume, diarrhoea, vomiting, abdominal
swelling) will be recorded. Buccal swabs will be collected at several moments and will be
stored for analysis (epithelial cell expression of chemokines).
Secondary Objectives:
WP2. Performing an economic evaluation study, investigating the effects of early versus late
PN supplementation during hospitalization.
WP3. Starting to unravel potential mechanisms that underlie any difference in acute and
long-term outcome with early or late PN supplementation by studying metabolic, endocrine,
inflammatory and (epi.)genetic markers in the blood of critically ill children included in the
study.
Version 5: 17-12-2013 13 of 51
3. STUDY DESIGN
This study is a large, three-centre, non-blinded, randomized, controlled study. The study
intervention will last for a maximum of 7 days per patient, and the entire study (final patient
completed study) is anticipated to last 4 years, excluding the long-term follow-up, the health-
economic analysis and the completion of the mechanistic studies. (See figure)
The “early PN” strategy will be the nutritional management currently applied in the
participating centres, acting as “control”.
The “late PN” strategy comprises initiation of this strategy only after day 7 in PICU.
Timeline of the entire study

The first milestone (M1) of the study will be the start of the large RCT in the centre of the
coordinating investigator/project leader in Leuven, closely followed by our center at Erasmus
MC-Sophia. The study will continue in parallel in all three centers until patient number 720
will have left the ICU. At that time point, a safety interim analysis will be performed (milestone
M2). Three possible scenarios are foreseen depending on the result of this analysis:
1. The interim analysis shows harm by “Late PN” and the clinical study will be prematurely
stopped (“no go” decision).
2. The data safety monitoring board requests a new safety interim analysis because of
reasonable doubt about the safety of “Late PN”. In that case, the study will continue in all
three centers under very strict monitoring, and planning of additional safety interim analyses
if necessary, until the end of the study (either when completed or when prematurely
stopped).
3. The study will be continued in all three centers as planned, without further interim
analyses, until all 1440 patients have been included.
In all three scenarios the end of the study will be milestone 3 (M3). Together with the
finalization and cross-check of the clinical database and the writing of the corresponding
manuscript of the short-term clinical outcome, this will constitute deliverable 1 (D1). Hence,
D1 is guaranteed irrespective of premature interruption of the study. In view of the outcome
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results of the adult EPaNIC study, such premature interruption will rather be unlikely. The
applicants have extensive experience in the management of large RCTs, including in
critically ill children, and handling and monitoring of the corresponding large clinical
databases. This invaluable experience will be key to successful accomplishment of this
ambitious study.

The fourth milestone (M4) will be targeted for before the end of the clinical study and consists
of the setup of appropriate template database structures for import of the data that will be
needed for the health economy analysis. This will allow an efficient economic evaluation
study shortly after completion of the clinical study and is planned within the 4 year time frame
and of the study (Milestone M5 and deliverable D2).
In the unlikely event of premature interruption of the study, the health economic analysis will
be performed after the safety interim analysis on which the decision to stop was based.
Previous experience in detailed analyses of healthcare resource utilization in large
randomized clinical studies, as well as close collaboration with the Finance & Accounting
department and the pharmacies of all participating hospitals will guarantee successful and
timely accomplishment of this deliverable.
Work package 3
The mechanistic studies will be coordinated by and performed in the Leuven Laboratory of
Intensive Care Medicine and in the Erasmus MC. Part of the mechanistic analyses will be
systematically performed throughout the study. More specifically, leukocyte function tests
require the fresh isolation of leukocytes and hence will be performed in parallel with work
package 1. Thus, these analyses will be completed at the end of the clinical study (milestone
M6 and deliverable D3). The samples needed for the other mechanistic studies will be taken
throughout the clinical study and as deliverable 4 (D4) will be available together with M3 and
D1. The other mechanistic studies involving the investigation of autophagy, genetics and
cytokines in relation to the inflammatory response, as well as of the neuroendocrine axes will
be planned and started in the last phase after completion of the clinical study.
In (the unlikely) case the study would be terminated prematurely, the mechanistic studies will
be even more important, as the clinical community will ask for due explanations for harm
caused during the study. Therefore, in any case they will be started shortly after all clinical
data have been collected.
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4. STUDY POPULATION
4.1 Population Base

The patient group of critically ill children ( 0 – 18 yrs), represents a significant proportion of
the ICU population. In 2010, the 10-bed Leuven PICU admitted 527 critically ill children, the
majority requiring artificial ventilation. 61% of the cases were admissions after cardiac
surgery. Individual critically ill children had a median ICU stay of 3 days (inter-quartile range
of 2-6 days) (mean 5.5 days). In the 35-bed PICU of the University of Rotterdam 1700
critically ill children were admitted in 2010 of which 600 (35.3%) were ventilated. Patients
stayed in the PICU for a median of 2 days (mean 7.8 days). We anticipate an inclusion rate
of 200-250 patients per centre per year.
4.2 Inclusion criteria

All critically ill children admitted to the participating PICUs are evaluated for nutritional risk
and eligibility for inclusion in this study. All critically ill children, with nutritional risk score
expected to stay in PICU for more than 24h are eligible for inclusion.
4.3 Exclusion criteria

Exclusion criteria are a “do not resuscitate” code at the time of PICU admission, expected
death within 12 hours, re-admission to the PICU after previously being participating in the
PEPaNIC trial (except when < 48 hours after the initial discharge and still in the intervention
window of the first 7 days), transfer from another PICU after a stay of more than seven days,
ketoacidotic or hyperosmolar coma on admission or inborn metabolic diseases requiring
specific diet, premature newborns (<37 weeks gestational age), patients on Total Parenteral
Nutrition for >7 days prior to inclusion, short bowel syndrome or other conditions which
required home-PN.
4.4 Sample size calculation

power (one-tailed; the two-tailed power is 70%) and 95% certainty, a reduction in PICU
infections from 20% to 15% and, with at least 90% power (two-tailed) and 95% certainty, a
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5. TREATMENT OF SUBJECTS
5.1 Investigational treatment
The treatment, or intervention, in our study is best described as withholding PN in the early
course of disease to reach currently recommended energy and protein intakes, when enteral
delivery of these intakes is insufficient. In both allocation groups of the study, patients will be
evaluated on a day to day basis to see which amount of enteral intake can be provided. The
“early PN” group will receive current standard nutritional practice, which prescribes that PN
should be added to EN as soon as possible in the course of disease, to achieve energy and
protein goals. In the “late PN” group, we will wait to add PN, when EN is insufficient, until day
7.
“Late PN”, the so-called “intervention-group”.

In Leuven, Rotterdam and Edmonton patients randomised to the “late PN” group will receive
a mixture of Glucose 5% and NaCl 0.9% at, respectively, 60% and 40% of the total flow rate
that is required to obtain standard optimal hydration taking into account the volume of EN
that is being delivered. If enteral feeding of at least 80% of the calculated calories is not
possible after 7 days in ICU, PN, as specified below, is initiated on day 8.
The infusions will be supplemented with micronutrients and vitamins as they would have
received when provided PN.
When the blood glucose levels fall spontaneously below 50 mg/dl, the standard glucose of
5% in the late PN group will be switched to 10% glucose until blood glucose level is above 80
mg/dl. At this point the infusion of glucose 10% will be stopped and switched again to
glucose 5%.
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Early PN”, this nutritional regime is the standard therapy in the participating centres and
therefore accounts as the "control-group".
All centres will use their current pharmaceutical nutritional products for enteral as well as
parenteral nutrition. The differences between the products provided by the different
pharmaceutical companies are small clinically irrelevant differences in glucose, lipid and
protein intakes.
Despite the different pharmaceutical companies, nutritional regimes from all participating
centres will be aiming for the same energy and protein targets.
Fluid intake will be provided as follows; patients not requiring fluid restriction receive 100
ml/kg/day for the first 10 kg bodyweight, 50 ml/kg for the next 10 kg, and 20 ml/kg for the
bodyweight over 20 kg, patients who require fluid restriction, total fluid intake is 50% on day 1
and 2, and 75% on day 3.
Nutritional target calculations

Energy intake
• < 10 kg bodyweight : 100 kcal/kg/day
• 10-20 kg bodyweight : 1000 kcal/day + (50 kcal/kg/day for weight over 10 kg)
• > 20 kg bodyweight : 1500 kcal/day + (20 kcal/kg/day for weight over 20 kg)
Protein target
• 0-10 kg bodyweight : 1.5-3 g/kg/day
• 10-20 kg bodyweight : 1-3 g/kg/day
• > 20 kg bodyweight : 1-2 g/kg/day
Day 1:
In the PICUs from all centers, patients randomised to the “early PN” group upon admission to
PICU receive a glucose mixture [Leuven; Glucose15%/Vaminolact® (Fresenius), Rotterdam;
Glucose 10–20% (Baxter)] to achieve glucose intake approximately double of the intake in
the “late PN” group, with additional trace elements (Peditrace) and minerals (Addamel,
Novum, Fresenius) and vitamins (Cernevit, Soluvit, Vitintra; Baxter) to be administered
in all centers.
Day 2-3:
For all patients on intravenous (IV) nutrition, lipids [Leuven; (20g/100ml) SMOFlipid®
Fresenius, Sweden, Rotterdam; (20g/100ml) Intralipid® (Baxter), Oliclinomel® (Baxter)] are
added from day 2-3 onward, and increased depending on the age and within the fluid
limitation potentially required by the patient.
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Additionally, protein intake [Leuven; Vaminolact® or Vamin18® (Fresenius, Sweden),

Rotterdam; Primene® (Baxter), Oliclinomel® (Baxter)] will be increased to reach target goals.
On day 2-7, pharmacy-prepared PN preparations are prescribed to achieve protein and

energy goals, as described above, unless adequate enteral nutritional intake is expected.
Any enterally delivered energy is taken into account twice daily to reduce the energy
delivered by PN. When EN covers 80% of optimal calculated caloric needs, PN is stopped.
When the patient starts to take oral nutrition, the PN and/or EN is reduced and eventually
stopped. Whenever enteral or oral intake falls below 50% of calculated caloric needs, the PN
is restarted.
The volumes of PN and EN to be given according to the treatment group are calculated by
the patient data management system (PDMS). These calculations are based on the
nutritional intake during the previous day and the clinical evolution of the patient. The amount
of protein and glucose administered during the previous day, as well as the target, will be
displayed by the PDMS to further guide the prescription of macronutrients.
The additional trace elements (Peditrace) and minerals (Addamel Novum, Fresenius)
and vitamins (Cernevit, Soluvit, Vitintra; Baxter) will be administered in all centers daily
until until patients receive at least 80% of their caloric intake enterally.
Enteral nutrition and micronutrient administration

In all patients from both study arms, provided haemodynamically stable and without formal
contraindication, EN is initiated on the afternoon following the ICU admission with the
patients in semirecumbent position. Enteral feeding will start 6 hrs after admission in the
PICU and will be done according to protocol (cfr appendix 1). Trace elements (Peditrace)
and minerals (Addamel Novum, Fresenius) and vitamins (Cernevit, Soluvit, Vitintra;
Baxter) will be administered daily IV to all patients from day 2 at 4:00 pm. IV micronutrient
substitution will be stopped when patients receive at least 80% of their caloric needs via the
enteral route.
In infants, breast milk, the patient’s home milk formula or a protein-energy dense formula
(Nutrilon®, Infatrini®; Nutricia Netherlands) is used. Older children receive standard
commercially available enteral feeding (Nutrison®, Nutrini-formulas; Nutricia Netherlands)
unless contra-indicated.
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Enteral feeding is administered through a gastric tube in a continuous way and is gradually
increased as dictated by tolerance. Switch to oral intake is made as soon as deemed safe.
The increase of EN volume, the use of gastroprokinetics and duodenal feeding tubes are
described in standing-orders for EN. Procedures for slow parenteral administration will be
identical for all patients.
Blood glucose management

Blood glucose management will be performed as through standard practice in all
participating centers. (for protocols see the appendices)
In Leuven, patients in both study groups receive continuous insulin infusion to target blood
glucose levels of 50-80 mg/dl when aged < 1y and 70-100 mg/dl when aged >= 1 year. Blood
glucose and potassium are monitored systematically every 1 – 4 hours on the blood gas
analyser (ABLRadiometer ®, Copenhagen, Denmark) using arterial blood samples.(14)
In Rotterdam, patients in all age groups receive continuous insulin infusion to target blood
glucose levels of 72-145 mg/dl, except for patients with traumatic brain injury (108-145
mg/dl), using a step-wise nurse driven glucose control protocol. Blood glucose and
potassium are monitored systematically every 1 – 3 hours on the blood gas analyser (ABL
625; Radiometer®, Copenhagen, Denmark) using arterial blood samples.(15)
In Edmonton patients in all age groups receive continuous insulin infusion to target blood
glucose levels <180 mg/dl
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Nutritional protocol showing schematic decision tree
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Handling of re-admissions to ICU

Patients who are re-admitted to ICU after a participation in PEPaNIC are not eligible for re-
inclusion. Patients who are readmitted to the PICU within 48 hours of discharge and who are
still within the 7 days time window of the initial randomization receive the nutrition-schedule
they were assigned to during the initial ICU admission. Patients readmitted later will be fed at
the discretion of the attending physician.
5.2 Use of co-intervention (if applicable)

Not applicable
5.3 Escape medication (if applicable)

Not applicable
6. INVESTIGATIONAL MEDICINAL PRODUCT

Not applicable.
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7. METHODS
7.1 Study parameters/endpoints
7.1.1 Main study parameter/endpoint

The primary efficacy endpoints of for this RCT are included into Work Package 1 and are
the incidence of new infections and the time to discharge alive from ICU. Number of patients
with new infections and types of infection will be assessed by numbers and percentages, and
the duration of any antibiotics therapy initiated after randomization for those patients
requiring antibiotics will be analyzed by non-parametrical tests. As the time of ICU discharge
to the regular ward may be affected by the availability of beds on the regular wards, which
could induce bias, we a priori decided to analyze “time to discharge from ICU” as “time to
ready for discharge from ICU”. A patient is considered “ready for discharge” as soon as all
clinical conditions for ICU discharge have been fulfilled (no longer in need for vital organ
support). Time to discharge alive from ICU will be reported by Kaplan-Meier plots, with ICU
7.1.2 Secondary study parameters/endpoints

Work Package 1
longitudinal data.
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c. Need for pharmacological or mechanical haemodynamic support during ICU stay, and
haemodynamic support in ICU will be analyzed, with ICU non-survivors censored
beyond the longest duration of pharmacological or mechanical haemodynamic support
be compared.
g. Child health questionnaire scores in both treatment groups will be compared at 3 and 12
months post-discharge.
h. Enteral nutrition (EN) tolerance: proportion of patients with diarrhoea, high gastric residual
volumes, vomiting and/or abdominal swelling and relation with buccal epithelial cell
expression of chemokines (CXCL-8. CXCL-9 and CXCL-10)
Work Package 2: Health economy analysis

As PN is a major contributor to the healthcare costs of critically children and the clinical
outcome is not yet known, an extensive health economic analysis will be included in the
study planning. The economic analysis will be performed from a health care perspective and
will be estimated for the period during hospitalization OR one year after admission?. The
economic evaluation will be performed in accordance with the Dutch guidelines (27).
First, we will calculate and compare the direct medical costs of early versus late PN.
Real medical costs will be calculated by multiplying the volumes of health care use with the
corresponding unit prices. Based on the analysis of the patients’ detailed invoices, we will
allocate healthcare costs into 8 categories (per diem hospitalization costs, honoraria,
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pharmacy costs, clinical chemistry costs, radiology costs, blood products, graft products,
miscellaneous), representing the different reimbursed services and products during ICU and
hospital stay. These cost categories have been validated in the health economic analysis of
the adult EPaNIC study.
The drug costs will be analyzed using the first level of the World Health Organisation (9)
Anatomical Therapeutic Chemical (ATC) classification. We hypothesize that antimicrobials
(class J) are the determining driver for differences in pharmacy costs. This is based on the
idea that late PN will reduce the incidence of new infections in the ICU.
A model will be constructed to estimate the hypothetical cost difference between early PN
and late PN if all acquisition costs related to PN would have been chargeable. This modeling
is important to make the results interpretable for readers in different healthcare systems. PN
is in variable proportions charged to the patient directly, the hospital or the insurers.
Therefore, the data from Rotterdam and Leuven will be converged to one hypothetical
system of PN billing.
Costs for inpatient days in hospitals will be estimated as real, basic costs per day using
detailed hospital administrative information. For the calculation of other medical costs, we will
used charges as published in Dutch guidelines as a proxy of real costs (27).
All analyses will be performed on an intention-to-treat basis. The cost differences between
early and late PN will be analyzed using the Mann–Whitney U test. Since cost data per
patient (but not per day care) are typically highly skewed, we use nonparametric bootstrap
techniques to derive a 95% confidence interval for the differences in distributions of the direct
medical costs.
Furthermore, we will explore whether late PN is cost-effective compared to early PN. This will
be assessed by calculating the incremental cost-effectiveness ratio (ICER), defined as the
difference in costs of late versus early PN, divided by the average change in effectiveness.
The primary effect measure is number of patients with a prevented new infection in ICU.
Secondary outcome measure is quality of life as measured by validated questionnaires.
Overall utility scores for population-based quality of life will be obtained and expressed as
QALY’s. QALY’s will be calculated by multiplying the utility of a health state by the time spent
in this health state.
Cost-effectiveness of late PN as compared to early PN will be analyzed as the difference in

PN costs per patient with a prevented new infection in ICU. In the ideal scenario late PN will
result in an improvement of the clinical outcome as well as a reduction of the healthcare
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costs. If late PN conveys a clinical improvement at a higher cost, this cost effectiveness in
three health care systems will be important to guide the respective governmental health care
departments into the decisions of the reimbursement of PN.
For the health economic analysis we will collaborate with the finance & accounting and
pharmacy departments of the three participating hospitals. Template database structures will
be set-up in advance during the enrolment of the patients in the trial to allow an efficient
health economic analysis in the framework of the study.
Work Package 3: Mechanistic analyses in relation to short- and long-term outcome

Impact of early versus late PN on infection and the inflammatory response
The incidence of new, ICU-acquired, infections is a primary efficacy endpoint in the
presented study. Based on the results of the adult EPaNIC study (1), we anticipate a lower
infection rate with late PN as compared with early PN. We will investigate whether
differences in leukocyte function could explain in part such effect. Therefore, blood samples
will be taken at pre-set time points during ICU stay for the isolation of monocytes and
granulocytes to assess their chemotactic, phagocytosis and oxidative burst capacity (17, 18).
Antimicrobial defense depends on, amongst others, efficient clearance of intracellular
pathogens in the autophagic pathway (xenophagy) (10). Indeed, inactivation of autophagy in
macrophages and neutrophils has been shown to increase susceptibility to infection. It has
previously been demonstrated an autophagy-deficiency phenotype in liver and skeletal
muscle of fed prolonged critically ill patients (11). Importantly, a recent study in prolonged
critically ill rabbits demonstrated a role for early PN in suppression of the autophagic pathway
during critical illness (19). If autophagy would be similarly compromised in leukocytes by
early PN, such effect may contribute to a reduced incidence of infections with late PN. We
will address this question in a subset of well-matched patients. We will also measure the p62
protein levels of isolated white blood cells obtained upon admission and on day 3 and 7 in
ICU, which is known to accumulate when autophagy is deficient/insufficient, as well as the
LC3-II/LC3-I ratio as a marker of mature autophagosome formation (20-22). In addition, we
will isolate leukocyte DNA from all patients to investigate whether genetic predisposition by
single nucleotide polymorphisms (SNPs) in genes of the autophagic core machinery may
play a role in susceptibility to infections and whether any such SNP would interact with the
nutritional approaches of the study design. The autophagy pathway and/or proteins also
appear to play a crucial role in the control of inflammatory signaling and regulation of
inflammatory transcriptional responses (10). In this regard, it has been shown that increased
levels of p62 activate the pro-inflammatory transcription factor NF-kB. We will study the
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impact of early versus late PN on pro- and anti-inflammatory cytokines (interleukin-1beta (IL-
1beta), IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, tumor-necrosis-factor-alpha, interferon-gamma).
Impact of early versus late PN on the neuroendocrine axes
Critical illness is hallmarked by striking alterations in the hypothalamic-pituitary-peripheral
hormone axes (neuroendocrine axes), according to a biphasic pattern (23). The peripheral
effector hormone levels are reduced in both phases of critical illness, although the etiology is
different with peripheral target organ resistance in the acute phase and relative
hypopituitarism in the prolonged (chronic) phase.
The hypothalamic-pituitary-adrenal axis shows a biphasic, but somewhat different response
as compared with the other axes, with cortisol as effector hormone being high in both
phases. The responses of the neuroendocrine axes during prolonged critical illness overall
have been linked to the development of a characteristic hypercatabolic state, resulting in
feeding-resistant muscle wasting, and the severity of the disturbances has been associated
with the high risk of morbidity and mortality of the patients. Not only excessive activation of
the hypothalamic-pituitary-adrenal axis, but also adrenal insufficiency contributes to morbidity
in critically ill children (24).
It was previously hypothesized that strict blood glucose control with intensive insulin therapy
would mildly reactivate the somatotropic and thyrotropic axes and anabolism in critically ill
children in view of a larger functional capacity of the hypothalamus and pituitary, and the
higher amount of nutrition they receive as compared with adult critically ill patients.
Unexpectedly and despite improved ICU outcome, however, this therapy further suppressed
the somatotropic axis and increased the urea/creatinine ratio as a marker of catabolism (25).
Also the low-T3 syndrome could not be reversed by this therapy (unpublished data).
Unpublished data obtained in a rabbit model of prolonged critical illness suggest that relative
fasting during critical illness reduces (peripheral) activation of the somatotropic and
thyrotropic axes with lower levels of insulin-like growth factor-I (IGF-I) and triiodothyronine
(T3) levels, but also attenuates the rise in the stress hormone cortisol as compared with
moderate dose intravenous feeding during critical illness. These findings urge a thorough
analysis of the impact of early versus late PN on these neuroendocrine axes in the critically ill
children included in our study. We hypothesize that late PN results in suppression of the
neuroendocrine axes, in concert with the intensive insulin therapy. Unlike conventional belief,
we also hypothesize that such suppressed neuroendocrine axes during prolonged critical
illness could be associated with a beneficial acute and long-term clinical outcome.
We will evaluate the activation of the somatotropic axis in the acute and chronic phase of
critical illness by measuring the levels of growth hormone (GH), acid-labile subunit (ALS),
IGF-I and its binding proteins (IGFBP-1 and IGFBP-3), the activation of the thyrotropic axis
by analysis of thyroxin (T4), T3, reverse T3 (rT3) and thyroid stimulating hormone (TSH), and
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the adrenal axis by adrenocorticotropic hormone (ACTH) and cortisol. The metabolism of
cortisol will be studied further by the relative levels of its metabolites excreted in urine (26)
and by collecting hair samples for the long term cortisol levels. The impact of early versus
late PN on the neuroendocrine axes will be studied in relation to markers of catabolism,
muscle volume and strength, as well as clinical outcome. The clinical outcome will be
assessed during follow-up consultations that are held in the departments that have referred
their patients to the ICU in Leuven and Rotterdam.
The epigenetics of early versus late PN
It has been known since a long time that dietary exposures can have health consequences
years or decades later. E.g. the later health of babies who were in the womb during the
Dutch famine in the winter of 1944 was greatly affected by the caloric restriction of their
mothers. The children of pregnant women exposed to famine were shown to be more
susceptible to chronic adult diseases such as diabetes, obesity and cardiovascular disease.
Apparently, the short period of caloric restriction can be “remembered” by the body further on
in life. There is a growing body of evidence that epigenetic mechanisms mediate this
memory. Epigenetic mechanisms alter the gene expression without changing the primary
DNA sequence. Rather the epigenetic mechanisms work through DNA methylation, histone
modifications and non-coding microRNAs. During the clinical trial, biological material (spun-
down cells from whole blood samples) will be collected from the study patients to compare
these epigenetic changes between the early and late PN treatment groups. The mechanistic
findings will be correlated with the acute and the long-term outcome of the critically ill study
patients.
7.1.3 Other study parameters

Safety endpoints
Safety endpoints comprise vital status, hypoglycemia, SAEs and complications related to the
mode of nutrition. Survival up to 90 days after randomization in both treatment groups will be
compared by Kaplan Meier survival plots. The impact of “late PN” versus “early PN” will be
analyzed, with and without correction for risk factors, by Cox proportional hazard analysis. In
addition, we will record in-ICU and in-hospital mortality, and will analyze differences with Chi-
square testing. As the randomized study intervention only takes place during a time window
up to the 8th day in ICU, we also plan to analyze early lethality within this time window in the
intention-to-treat population as part of the safety analysis.
glucose administration is considered as a SAE and the incidence during the time window of
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the randomized intervention will be reported for both groups. In addition, overall blood
glucose control during the time window of the intervention will be compared using daily
7.2 Randomisation, blinding and treatment allocation

Randomization
The study will use a prospective, randomized, controlled, parallel-group design. On
admission patients will be randomly assigned to receive EN combined with early PN or only
EN. At ICU admission, consecutive patients will be randomly assigned to one of these two
treatment groups using a centralized computer randomisation. Randomisation will be done in
a 1:1 allocation ratio in permuted blocks of 10 (The block size remains unknown to bed-side
physicians and nurses, responsible for patient recruitment and therapy assignment) and
stratified according to primary diagnostic category on admission:
I Medical-ICU admissions (infectious or non-infectious): (a) respiratory (b) cardiac (c) renal
(d) haematological/oncological (e) gastro-intestinal/hepatic (f) neurological (g) other.
II Surgical-ICU admissions (elective or urgent) according to referral discipline (a) cardiac

surgery (b) solid organ transplants (c) pulmonary/oesophageal surgery (d) abdominal surgery
(e) neurosurgery (f) trauma/orthopaedic surgery (g) burns (more than 20% BSA is burned
and/or patient requires ventilation)
Blinding of treatment allocation

Treating physicians and patients cannot be blinded. All outcome assessors, which are
investigators not directly involved in the patients care (such as statisticians, laboratory
personnel, infectious disease specialists, pathologists and physiotherapists involved in the
strength measurement) as well as physicians and nurses in the conventional wards are
blinded to treatment allocation.
7.3 Study procedures

Data collection following recruitment
Baseline characteristics
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At baseline, data on demographic and clinical characteristics of the patients are obtained.
Disease specific risk scores (such as the Risk-Adjustment in Congenital Heart Surgery or
RACHS score) are calculated, co-morbidities and known use of important medications prior
to admission are noted: these comprise, among others, the presence of congenital disease
or syndrome, gestational age at birth, gender, ethnicity, paediatric risk scores, presence /
history of cancer, diabetes mellitus, kidney failure, liver failure, chronic heart failure and
sepsis upon admission. In addition, we record the need for and the number of days of
mechanical ventilatory support, of mechanical and pharmacological haemodynamic support,
of renal replacement therapies, days on antibiotics and days requiring a central line.
Outcome characteristics
All medications received by the patients during ICU stay are registered. Every day the
amount of kilocalories, lipids, proteins, carbohydrates delivered by either PN or EN are
calculated from the PDMS in an automated manner and entered into the case record form
(CRF). Interruptions of EN delivery and predefined digestive intolerance are registered daily.
Mechanical complications such as displacement or obstruction of the enteral feeding tube or
the central venous catheter, and clinical complications such as pneumothorax, hemothorax
and subclavian or carotid artery puncture are recorded daily. All medications received by the
patients during ICU stay are registered. Every day the amount of kilocalories, lipids, proteins,
carbohydrates delivered by either PN or EN are calculated from the PDMS in an automated
manner and entered into the case record form (CRF). Of the gastric residual volume
discarded, half of the volume will be considered to be EN and half gastric secretions. The
duration (in min) and cause of interruption of delivery of EN will be recorded. Digestive
intolerance will be registered as vomiting, tracheal aspiration of enteral feeding (defined 8),
diarrhea, and gastric residue above 5ml/kg (see appendix for definitions). Tube displacement
or obstruction will be labeled as mechanical complications. Occlusion and dislodging of
central venous catheters will be recorded as mechanical complications. Pneumothorax,
hemothorax and arterial puncture will be recorded as clinical complications. Number of ICU
days with a central line in situ will be noted. The characteristics will be monitored until
discharge from ICU, day 90 of hospital stay or death.
Blood samples
The maximum blood volume will be maximum 5 ml/kg for the entire study period. For a
detailed description of the blood samples and tests see figure below. Blood samples are
taken upon ICU admission and daily until discharge from ICU, or death. The blood samples
will be taken from lines placed for clinical purposes or in combination with pricks requested
Version 5: 17-12-2013 32 of 51
for clinical purposes. A subset of the samples are immediately stored on ice for future
endocrine measurements. Processed serum and plasma as well as the spun-down blood
cells will be stored and frozen for mechanistic analyses.
each ICU and are registered for later calculation of glucose metrics. Analyses on blood and
urine for the primary clinical analyses include routine chemistry, haematology, and markers
of inflammation. Further epigenetic, metabolic, endocrine and inflammatory measurements
on stored samples in the context of mechanistic analyses will be stored until final analysis.
Urine samples will be stored and frozen until final analysis.
Primary endpoint characteristics
All new infections of the lungs, the blood stream, the urinary tract and wounds are recorded
by an infectious disease specialist. Bacteraemia is further classified by responsible pathogen
and as catheter-related blood stream infection versus other bacteraemia.
Additional data collection
For mechanistic and exploratory studies, muscle strength testing (> 6 years of age) at
several moment during admission will be performed.
Urine (nitrogen / bone metabolism / cortisol metabolites / biomarkers for renal failure; NGAL)
and stool samples (biomarkers gut function; citrulline / calprotectin) will be collected on daily
basis.
We will also perform standard anthropometric tests, upper-arm and lower-leg circumference,
in addition to standard weight and height for age. These analyses will be repeated at the
follow-up at 3 and 12 months post-discharge, on condition of obtaining adequate additional
funding.
Buccal swabs will be collected at day of admission (day 1), day 2, 4 and 6, and possibly on
day of discharge and will be immersed in RNA-later and stored at -80C. Buccal epithelial cell
expression of chemokines (CXCL-8. CXCL-9 and CXCL-10) will be measured in by Taqman
analysis.
Around 100 strands of hair from the posterior vertex of the scalp will be cut off as soon as
possible after admission and this will be repeated after 3 weeks- 2 months if possible.
Questionnaires and long term follow-up

Furthermore, as far as practically feasible, every patient is approached just prior to hospital
discharge, to complete a validated, semi-structured child health questionnaire (Functional
Independence Measure (WEEFIM), Health Utilities Index (HUI) and Child Health
We also will thoroughly assess long-term clinical outcome. This not only encompasses
survival rate 3 years after inclusion in the study. It will also involve a detailed functional and
Version 5: 17-12-2013 33 of 51
neurocognitive examination, by means of questionnaires such as mentioned above. These

analyses will be repeated at the follow-up at 3 and 12 months post-discharge, on condition of
obtaining adequate additional funding. This will be organised in the framework of current
follow-up consultations of these critically ill children.
Figure Samples.
Blood samples are taken upon ICU admission and daily at 06:00h until discharge from ICU,
death or end of study. Upon admission three blood samples will be taken; namely two yellow
“STOL”-tubes each containing a maximum of 3.5 milliliter blood and 1 purple “EDTA”-tube of
1.8 milliliter blood.
During the following days until the patient has left the PICU we will daily take a yellow
“STOL”-tube (containing max 3,5 milliliter blood) and a purple “EDTA”-tube (containing 1,8
milliliter blood) for further analyses. On day 3,5 and 7 a ‘PAX-tube’ (containing 2 milliliter
blood) will be collected. In children > 10 kg 1,8 milliliter extra blood (EDTA and heparine) will
be collected on 4 selected days.
A subset of the samples will be immediately stored on ice for future endocrine
measurements. Processed serum and plasma as well as the spun-down blood cells will be
frozen and stored.
Analyses on the morning sample will include routine clinical chemistry, hematology (Hgb,
WBC, TC), and markers of inflammation (CRP), liver function ALT, AST, ALP, GGT, bilirubin
total/direct. A number of metabolic, hormonal and inflammatory study analyses will be
performed on selected days.
The latter comprise, among others, coagulation & fibrinolysis tests, cytokines and markers of
oxidative stress.
Also on selected days stool (single sample,) urine (5 tubes of 5 mL out of 24 hours’ urine
collection), 100 strands of hair and buccal swabs will be stored for further evaluation.
each ICU and are registered for later calculation of glucose metrics.
7.4 Withdrawal of individual subjects

Subjects can leave the study at any time for any reason if they wish to do so without any
consequences. The investigator can decide to withdraw a subject from the study for urgent
medical reasons.
7.4.1 Specific criteria for withdrawal (if applicable)

Not applicable
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7.5 Replacement of individual subjects after withdrawal

Subjects that withdraw after randomization has been conducted will not be replaced, subjects
that have not been allocated and withdraw after signing the consent form but before the start
of randomization will be replaced.
7.6 Follow-up of subjects withdrawn from treatment

A register is kept of all patients evaluated for inclusion and of patients who withdraw from the
study. The latter are clinically followed up without their data being analyzed in the study,
according to intention-to-treat analysis.
7.7 Premature termination of the study

be necessary. In (the unlikely) case the study would be terminated prematurely, the
mechanistic studies will be even more important, as the clinical community will ask for due
explanations for harm caused during the study. Therefore, in any case they will be started
shortly after all clinical data have been collected.
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8. SAFETY REPORTING
underfeeding. However, safety measures will be taken to further decrease these risks. Our
study may provide support for current practice, may give “neutral” results for which the cost-
effectiveness study will provide necessary information for guiding therapy, or may challenge
the presumed innocence of PN. Thus, there is no risk associated with the intrinsic value of
these results.
The burden is expected to be minimal as it will only entail additional blood draws, which will
be taken from clinical lines or in addition to pricks for clinical purpose. The long-term follow
up will be held as part of already organised follow-up outdoor clinics and which are
developed to help children and their parents to recover physically, emotionally and socially
after ICU admissions. For mechanistic and exploratory studies, muscle strength testing and
an ultrasound evaluation of the skeletal muscle and adipose tissue compartments will be
performed. Furthermore, as far as practically feasible, every patient is approached just prior
to hospital discharge, to complete a validated, semi-structured child health questionnaire
(Functional Independence Measure (WEEFIM), Health Utilities Index (HUI) and Child Health
In order to monitor the quality of the enteral and parenteral nutrition management during the
study we will register all known complications possibly related to them. These complications
should not be considered as adverse events since the study intervention is to withhold
parenteral feeding during one week. These known complications of parenteral feeding will
not be reported to the sponsor until the end of the trial.

Digestive intolerance: either vomiting, tracheal aspiration of enteral feeding (defined in 7),
diarrhea, or gastric residue above 5ml/kg, abdominal distention (see appendix for
definitions).

Clinical complications: pneumothorax, hemothorax and arterial puncture, central line
replacement due to suspicion of catheter-related blood stream infections
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Safety endpoints
Safety endpoints comprise vital status, hypoglycaemia, SAEs and complications related to
the mode of nutrition. Survival up to 90 days after randomisation in both treatment groups will
be compared by Kaplan Meier survival plots. The impact of “late PN” versus “early PN” will
be analysed, with and without correction for risk factors, by Cox proportional hazard analysis.
In addition, we will record in-ICU and in-hospital mortality, and will analyse differences with
Chi-square testing. As the randomised study intervention only takes place during a time
window up to the 8th day in ICU, we also plan to analyse early lethality within this time
window in the intention-to-treat population as part of the safety analysis.
As patients not receiving early PN may be considered at increased risk for hypoglycaemia,
we will report for both groups the number of patients experiencing hypoglycaemia <40 mg/dl
during the time window of the randomised intervention. Hypoglycaemia resistant to
parenteral glucose administration is considered as a SAE and the incidence during the time
window of the randomised intervention will be reported for both groups. In addition, overall
blood glucose control during the time window of the intervention will be compared using daily
or gastric feeding tubes) will be reported for both treatment groups
Interim analysis
centres are currently providing early PN, repeated interim analyses for efficacy are not
endpoint will not be analysed, no correction of the significance level at the final analysis will
be necessary.
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8.1 Section 10 WMO event

In accordance to section 10, subsection 1, of the WMO, the investigator will inform the
subjects and the reviewing accredited METC if anything occurs, on the basis of which it
appears that the disadvantages of participation may be significantly greater than was
foreseen in the research proposal. The study will be suspended pending further review by
the accredited METC, except insofar as suspension would jeopardise the subjects’ health.
The investigator will take care that all subjects are kept informed.
8.2 Adverse and serious adverse events

Adverse events are defined as any undesirable experience occurring to a subject during the
study, whether or not considered related to the experimental treatment. All adverse events
reported spontaneously by the subject or observed by the investigator or his staff will be
recorded.
A serious adverse event is any untoward medical occurrence or effect that at any dose:
- results in death;
- is life threatening (at the time of the event);
- requires hospitalisation or prolongation of existing inpatients’ hospitalisation;
- results in persistent or significant disability or incapacity;
- is a new event of the trial likely to affect the safety of the subjects, such as an
unexpected outcome of an adverse reaction, lack of efficacy of an IMP used for the
treatment of a life threatening disease, major safety finding from a newly completed
animal study, etc.
All SAEs will be reported through the web portal ToetsingOnline to the accredited METC that
approved the protocol, within 15 days after the sponsor has first knowledge of the serious
adverse reactions. SAEs that result in death or are life threatening should be reported
expedited. The expedited reporting will occur not later than 7 days after the responsible
investigator has first knowledge of the adverse reaction. This is for a preliminary report with
another 8 days for completion of the report.
Safety endpoints specifically for PEPaNIC

The clinical research team guarantees a daily follow-up of patient screening and inclusion,
availability of requested clinical data in the clinical patient files and protocol compliance.
Each non-compliance to the protocol and other questions or problems are reported to the
study monitor and discussed with the principal investigators. Serious Adverse Events (SAE)
are also reported to the study coordinating investigator/project leader (K.U.Leuven). The
Version 5: 17-12-2013 38 of 51
study monitor regularly provides the sponsor with reports on inclusions and SAE. Regular
meetings are organized with principal investigators and clinical research team to discuss the
daily progression of the research project.
glucose administration, or with clinical symptoms, is considered as a SAE and the incidence
during the time window of the randomized intervention will be reported for both groups. In
addition, overall blood glucose control during the time window of the intervention will be
compared using daily morning blood glucose as well as daily maximal and minimal blood
glucose.
Further safety endpoints comprise vital status, hypoglycemia, SAEs and complications
related to the mode of nutrition. Survival up to 90 days after randomization in both treatment
groups will be compared by Kaplan Meier survival plots. The impact of “late PN” versus
“early PN” will be analyzed, with and without correction for risk factors, by Cox proportional
hazard analysis. In addition, we will record in-ICU and in-hospital mortality, and will analyze
differences with Chi-square testing. As the randomized study intervention only takes place
during a time window up to the 8th day in ICU, we also plan to analyze early lethality within
this time window in the intention-to-treat population as part of the safety analysis.
Above mentioned SAE’s and safety endpoints will be handled and reported within the
standard timeframe as described above.
8.2.1 Suspected unexpected serious adverse reactions (SUSAR)
Not applicable
8.2.2 Annual safety report

Not applicable
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8.3 Follow-up of adverse events

All adverse events will be followed until they have abated, or until a stable situation has been
reached. Depending on the event, follow up may require additional tests or medical
procedures as indicated, and/or referral to the general physician or a medical specialist.
8.4 Data Safety Monitoring Board (DSMB)

The coordinating investigator/project leader (K.U.Leuven) provides direct access to the CRF,
the source data and the study master file for monitoring, Independent Ethics committee
review and regulatory inspection. The coordinating investigator/project leader (K.U.Leuven)
established an independent data safety monitoring board (DSMB) (Prof. dr. J Vranckx, Prof.
dr. em. R Bouillon, Prof. dr. em. P Lauwers, Prof.dr. M Bruynooghe (statisticus)), which holds
no conflicts of interest with the sponsor or coordinating investigator/project leader
(K.U.Leuven). The coordinating investigator/project leader (K.U.Leuven) appoints one
monitor. The monitor verifies that the trial is performed in accordance to the protocol as
described in the European Medicine Agency’s “Note for guidance on good clinical practice
CPMP/ICH/135/95” as well as the Declaration of Helsinki. Monitoring will be performed and
will be reported following the sponsor’s standing operating procedures. No fault insurance is
covered by Fortis Corporate Insurance NV (Leuven) and Akkermans Van Elten Assurantiën
BV (Rotterdam).
One formal “safety” interim analysis will be planned after patient number 720 has left the
ICU, during which the independent DSMB will have access to un-blinded results on ICU
mortality, hospital mortality and serious adverse events. The DSMB will then judge on
whether or not to prematurely stop the clinical trial for safety reasons, or to perform more
safety interim analyses. The DSMB will advise on eventual continuation of the study to
be necessary.
The advice(s) of the DSMB will be notified upon receipt by the sponsor to the METC that
approved the protocol. With this notification a statement will be included indicating whether
the advice will be followed.
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9. STATISTICAL ANALYSIS
9.1 Descriptive statistics

The current statistical analysis plan comprises the primary and secondary clinical endpoints
of this RCT (work package 1). These include the acute clinical effects of the intervention
during ICU stay and hospitalization, including survival up to 90 days after randomization.
power (one- tailed; the two-tailed power is 70%) and 95% certainty, a reduction in PICU
infections from 20% to 15% and, with at least 90% power (2-tailed) and 95% certainty, a
General rules of the statistical analysis

All analyses will be done on intention to treat basis. The analyses will be performed on the
whole set of patients and by subgroups of patients based on the primary diagnostic
categories used as prognostic factors for stratification and on septic/non-septic groups of
patients.
A consort diagram will be reported. The data file will be finalised 90 days after inclusion of
the last patient. To assess compliance with the study protocol, the amounts of PN and EN
actually given in the two study groups during the intervention window of 7 days will be
reported as absolute numbers and percentages of target calories. Discrete variables will be
summarised by frequencies and percentages and analysed by (exact) Chi- square test or
logistic regression analysis. Continuous variables will be summarised by use of either mean
or standard deviations (SD) or median and interquartile range as appropriate and compared
using Student’s t-test or Mann-Whitney-U test, as appropriate. Time to event analysis will be
performed by Cox proportional hazard analysis. All outcomes will be analysed in an
uncorrected manner as well as (jointly) corrected for risk factors (type and severity of illness,
age, on admission nutritional status and risk scores). A priori defined subgroup analyses will
be performed for patients admitted to ICU after cardiac surgery as compared with all other
patients; for patients with and without sepsis upon admission; for patients with contra-
indications for EN on admission or not. For all endpoints, differences will be considered
Version 5: 17-12-2013 41 of 51
statistically significant whenever the p-value is lower than 0.05 without correction for multiple
testing.
Safety endpoints
Safety endpoints comprise vital status, hypoglycaemia, serious adverse events and
complications related to the mode of nutrition. Survival up to 90 days after randomization in
both treatment groups will be compared by Kaplan Meier survival plots. The impact of “late
PN” versus “early PN” will be analyzed, with and without correction for risk factors, by Cox
proportional hazard analysis. In addition, we will record vital status at ICU and hospital
discharge, and will analyze differences with Chi-square testing. As the randomized study
intervention only takes place during a time window up to the 8th day in ICU, we also plan to
analyze early lethality within this time window in the intention to treat population as part of the
safety analysis.
9.2 Univariate analysis

Discrete variables will be summarized by frequencies and percentages and analyzed by
(exact) Chi-square test or logistic regression analysis. Continuous variables will be
summarized by use of either mean or standard deviations (SD) or median and interquartile
range as appropriate and compared using Student’s t-test or (exact) Mann-Whitney-U test,
as appropriate. Time to event analysis will be performed by Cox proportional hazard
analysis. Time to discharge alive from ICU will be reported by Kaplan-Meier plots, with ICU
9.3 Multivariate analysis

All outcomes will be analyzed in an uncorrected manner as well as (jointly) corrected for risk
factors (type and severity of illness, age, on admission nutritional status and risk scores).
Another a priori defined subgroup analysis will be performed for patients admitted to ICU
after cardiac surgery as compared with all other patients. Also an a priori subgroup analysis
is planned for patients with and without sepsis upon admission.
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longitudinal data.
c. Need for pharmacological or mechanical hemodynamic support during ICU stay, and
hemodynamic support in ICU will be analyzed, with ICU non-survivors censored
beyond the longest duration of pharmacological or mechanical hemodynamic support
be compared.
treatment groups will be compared.
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9.4 Interim analysis

be necessary.
The safety analyses will be done on the whole set of patients and by subgroups of patients
based on the primary diagnostic categories used as prognostic factors for stratification and
on septic/non-septic groups of patients.
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10. ETHICAL CONSIDERATIONS
10.1 Regulation statement

The study will be conducted in accordance to the protocol as described in the European
Medicine Agency’s “Note for guidance on good clinical practice CPMP/ICH/135/95” as well
as the Declaration of Helsinki (59th WMA General Assembly, Seoul, Korea, October 2008)
and in accordance with the Medical Research Involving Human Subjects Act (WMO).
10.2 Recruitment and consent

The study protocol and consent forms will be sent for approval by the Institutional Review
Board of the Katholieke Universiteit Leuven and the Erasmus MC (Lokale uitvoerbaarheid)
and by the competent Belgian and Dutch authorities (CCMO). Written informed consent is
obtained from the parents or the legal guardian by the investigator’s team or one of the
supervising doctors, who will inform the parents of the patients (and the patients themselves
if the age is > 12 years) and ask for their consent. The parents / legal guardians and (if
applicable) the patients will receive a patient information letter and an informed consent form.
Written informed consent will be obtained from the patient or the closest family member or
legal guardian. For planned PICU admissions after elective procedures, informed consent
will be asked beforehand, if possible.
For emergency PICU admissions, treatment allocation will be done after assessment of the
patient for eligibility by the attending physician within the time frame of two hours. If eligible,
the patient will be randomized into the study and the allocated glucose infusion (with
micronutrients) will be started. Informed consent will be asked within the time frame of 24
hours (deferred informed consent) as a nutritional regimen has to be initiated already on
admission. When consent is given, the allocated nutritional regimen will proceed (Early (with
additional lipids and protein targeting nutritional goals < day3) vs Late (no PN)). When NO
consent is given, the nutritional regimen and glucose infusion will be placed under
responsibility of the supervising clinical team of doctors.
The parents or legal guardians can withdraw the patient from the study at any time, without
penalty or impact on treatment.
10.3 Objection by minors or incapacitated subjects (if applicable)

The children can withdraw from the study at any time, without penalty or impact on treatment.
(art 4 lid 2 WMO) Neither will the child be forced to undergo the additional tests, such as
muscle strength testing, the ultrasound evaluation of the skeletal muscle and adipose tissue
compartments, or the questionnaires and follow-up evaluations. In this matter, also non-
Version 5: 17-12-2013 45 of 51
verbal resistance will be taken into account by the investigator’s team. The specific test will
then not be performed, without taking the subject out of the study as a whole.
10.4 Benefits and risks assessment, group relatedness

During the informed consent process, it will be made extremely clear that participation in this
study will provide no direct benefits to the patient and that refusal to participate will have zero
impact on the care received by any of the nursing medical staff. The risks will be kept to a
minimum. This study requires this specific study group of critically ill children of different age
groups. Although the study has been performed in adults, these results should not be
translated directly to children as both the metabolic as well as nutritional kinetics in children
of different age groups vary significantly form adults.
10.5 Compensation for injury

The sponsor/investigator has a liability insurance which is in accordance with article 7,
subsection 6 of the WMO.
No fault insurance is covered by Fortis Corporate Insurance NV (Leuven) and Akkermans
Van Elten Assurantiën BV (Rotterdam).
The sponsor has an insurance which is in accordance with the legal requirements in the
Netherlands (Article 7 WMO and the Measure regarding Compulsory Insurance for Clinical
Research in Humans of 23th June 2003). This insurance provides cover for damage to
research subjects through injury or death caused by the study.
1. € 450.000,-- (i.e. four hundred and fifty thousand Euro) for death or injury for each
subject who participates in the Research;
2. € 3.500.000,-- (i.e. three million five hundred thousand Euro) for death or injury for
all subjects who participate in the Research;
3. € 5.000.000,-- (i.e. five million Euro) for the total damage incurred by the
organisation for all damage disclosed by scientific research for the Sponsor as
‘verrichter’ in the meaning of said Act in each year of insurance coverage.
The insurance applies to the damage that becomes apparent during the study or within 4
years after the end of the study.
10.6 Incentives
Not applicable
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11. ADMINISTRATIVE ASPECTS AND PUBLICATION
11.1 Handling and storage of data and documents

Data are collected electronically in a pseudonymized CRF, unambiguously linked to the
source file. The subject identification codes are safeguarded by the principle investigators.
Data are manually transferred (and checked for accuracy) into the CRF by the clinical
research assistance team on a daily basis from the ICU PDMS and the Leuven University
Hospitals Clinical Working Station (KWS). Extensive range and consistency checks are
performed by the study monitor. Vital status at 90 days will be recorded for all patients, by
the National Death Registries when this information is not available in the hospital
information system or the regional network of pediatricians.
The handling of personal data will comply with the Dutch Personal Data Protection Act (in
Dutch: De Wet Bescherming Persoonsgegevens, WBP).
11.2 Amendments
Amendments are changes made to the research after a favourable opinion by the accredited
METC has been given. All amendments will be notified to the METC that gave a favourable
opinion.
All substantial amendments will be notified to the METC and to the competent authority.
Non-substantial amendments will not be notified to the accredited METC and the competent
authority, but will be recorded and filed by the sponsor.
11.3 Annual progress report

The sponsor/investigator will submit a summary of the progress of the trial to the accredited
METC once a year. Information will be provided on the date of inclusion of the first subject,
numbers of subjects included and numbers of subjects that have completed the trial, serious
adverse events/ serious adverse reactions, other problems, and amendments.
11.4 End of study report

The investigator will notify the accredited METC of the end of the study within a period of 8
weeks. The end of the study is defined the time-point 90 days after the inclusion of the last
patient.
In case the study is ended prematurely, the investigator will notify the accredited METC,
including the reasons for the premature termination.
Within one year after the end of the study, the investigator/sponsor will submit a final study
Version 5: 17-12-2013 47 of 51
report with the results of the study, including any publications/abstracts of the study, to the
accredited METC.
11.5 Public disclosure and publication policy

This is an investigator initiated study. This study will be registered as a clinical trial in a public
trial registry.
The investigators aim to publish all results obtained from the study unreservedly.
Version 5: 17-12-2013 48 of 51
12. REFERENCES
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versus late parenteral nutrition in critically ill adults. N Engl J Med 2011;365(6):506-17.
2. Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, et al. ESPEN
Guidelines on Parenteral Nutrition: intensive care. Clin Nutr 2009;28(4):387-400.
3. Skillman HE, Wischmeyer PE. Nutrition therapy in critically ill infants and children. JPEN J
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Enteral Nutr 2011;35(4):523-9.
nutritional risk screening tool in hospitalized children. Clin Nutr 2010;29(1):106-11.
6. Verbruggen SC, Coss-Bu J, Wu M, Schierbeek H, Joosten KF, Dhar A, et al. Current
recommended parenteral protein intakes do not support protein synthesis in critically ill
septic, insulin-resistant adolescents with tight glucose control. Crit Care Med
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7. Verbruggen SC, Schierbeek H, Coss-Bu J, Joosten KF, Castillo L, van Goudoever JB.
Albumin synthesis rates in post-surgical infants and septic adolescents; influence of amino
acids, energy, and insulin. Clin Nutr 2011;30(4):469-77.
8. Verbruggen S, Sy J, Arrivillaga A, Joosten K, van Goudoever J, Castillo L. Parenteral
Amino Acid Intakes in Critically Ill Children: A Matter of Convenience. JPEN J Parenter
Enteral Nutr 2010;34(3):329-40.
9. Derde S, Vanhorebeek I, Guiza F, Derese I, Gunst J, Fahrenkrog B, et al. Early Parenteral
Nutrition Evokes a Phenotype of Autophagy Deficiency in Liver and Skeletal Muscle of
Critically Ill Rabbits. Endocrinology 2012.
10. Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature
2011;469(7330):323-35.
11. Vanhorebeek I, Gunst J, Derde S, Derese I, Boussemaere M, Guiza F, et al. Insufficient
activation of autophagy allows cellular damage to accumulate in critically ill patients. J Clin
Endocrinol Metab 2011;96(4):E633-45.
12. Vlasselaers D, Milants I, Desmet L, Wouters PJ, Vanhorebeek I, van den Heuvel I, et al.
Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised
controlled study. Lancet 2009;373(9663):547-56.
13. WHO ‘Prevention of hospital-acquired infections; a practical guide, 2nd edition’
www.who.int/csr/.../whocdscsreph200212.pdf
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14. Vlasselaers D, Mesotten D, Langouche L, Vanhorebeek I, van den Heuvel I, Milants I, et

al. Tight glycemic control protects the myocardium and reduces inflammation in neonatal
heart surgery. Ann Thorac Surg 2010;90(1):22-9.
15. Verhoeven JJ, Brand JB, van de Polder MM, Joosten KF. Management of hyperglycemia
in the pediatric intensive care unit; implementation of a glucose control protocol. Pediatr Crit
Care Med 2009;10(6):648-52.
16. WHO. Management of severe malnutrition: a manual for physicians and other senior
health workers. Geneva: World Health Organization 1999.
17. Ellger B, Debaveye Y, Vanhorebeek I, Langouche L, Giulietti A, Van Etten E, et al.
Survival benefits of intensive insulin therapy in critical illness: impact of maintaining
normoglycemia versus glycemia-independent actions of insulin. Diabetes 2006;55(4):1096-
105.
18. Henckaerts L, Nielsen KR, Steffensen R, Van Steen K, Mathieu C, Giulietti A, et al.
Polymorphisms in innate immunity genes predispose to bacteremia and death in the medical
intensive care unit. Crit Care Med 2009;37(1):192-201, e1-3.
19. Derde S, Vanhorebeek I, Ververs EJ, Vanhees I, Darras VM, Van Herck E, et al.
Increasing intravenous glucose load in the presence of normoglycemia: effect on outcome
and metabolism in critically ill rabbits. Crit Care Med 2012;38(2):602-11.
20. Bjorkoy G, Lamark T, Pankiv S, Overvatn A, Brech A, Johansen T. Monitoring autophagic
degradation of p62/SQSTM1. Methods Enzymol 2009;452:181-97.
21. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, et al. Impairment of
starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol
2005;169(3):425-34.
22. Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, et al. Autophagy is
required to maintain muscle mass. Cell Metab 2009;10(6):507-15.
23. Van den Berghe GH. Acute and prolonged critical illness are two distinct neuroendocrine
paradigms. Verh K Acad Geneeskd Belg 1998;60(6):487-518; discussion 518-20.
24. Langer M, Modi BP, Agus M. Adrenal insufficiency in the critically ill neonate and child.
Curr Opin Pediatr 2006;18(4):448-53.
25. Gielen M, Mesotten D, Brugts M, Coopmans W, Van Herck E, Vanhorebeek I, et al.
Effect of intensive insulin therapy on the somatotropic axis of critically ill children. J Clin
Endocrinol Metab 2011;96(8):2558-66.
26. Cuzzola A, Petri A, Mazzini F, Salvadori P. Application of hyphenated mass spectrometry
techniques for the analysis of urinary free glucocorticoids. Rapid Commun Mass Spectrom
2009;23(18):2975-82.
27. Hakkaart-van Roijen L et al. Handleiding voor kostenonderzoek, methoden en standaard
kostprijzen voor economische evaluaties in de gezondheidszorg. CVZ. 2010
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Stollery Children’s Hospital Edmonton
Version number 3
27-02-2013

STUDY PROTOCOL
TABLE OF CONTENTS

I. PROTOCOL SYNOPSIS ......................................................................................... 3
II. INTRODUCTION ................................................................................................. 6
III. KEY STUDY OBJECTIVES ................................................................................... 7
IV. STUDY POPULATION .......................................................................................... 7
VI. STUDY PROCEDURES ........................................................................................ 8
VII. INVESTIGATIONAL PRODUCTS ...................................................................... 12
VIII. OUTCOME MEASURES ................................................................................... 12
IX. ADVERSE EVENTS ............................................................................................ 13
XI. ADMINISTRATIVE AND LEGAL ASPECTS ...................................................... 15
XII.STUDY PERSONNEL ......................................................................................... 16
References……………………………….………………………………………………...31

2
Patients
Principal Investigators for the KULeuven:

Dr. Lars Desmet
Dr. Tom Fivez

Dr. Koen Joosten
Dr. SaschaVerbruggen
Principal Investigators for Stollery Children’s Hospital Edmonton:

Dr. Ari Joffe
Dr. Gonzalo Garcia Guerra
Dr. Bodil Larsen
Trial Centres: University Hospitals of the KU Leuven, Belgium; the University Hospital of the Erasmus
Universiteit Rotterdam, the Netherlands; Stollery Children’s Hospital, University of
Alberta, Edmonton, Canada.
Test Preparation: Parenteral nutrition complementing enteral nutrition versus enteral nutrition
Reference Drug: Smoflipid or Intralipid 20%
Method of Intravenous administration according to calculated caloric needs.
administration:
Patient Population: Children with critical illness and a STRONGkids score of 2 points or more (cfr
appendix2)
evaluation:
Duration of patient 3 to 3.5 years
recruitment:
study
post-randomization.
3
- Structural differences in muscle tissue during ICU stay up to 90 days post-randomization.
Criteria: All Patients admitted to the PICU with a STRONGkids score higher or equal to 2 upon
ICU admission.
Exclusion criteria:
- Neonates 6 weeks old or less with congenital heart disease planned for, or after,
surgery for the heart disease, at Stollery Children’s Hospital.
- Patients with a DNR order at the time of ICU admission.
hours after the initial PICU discharge)
- Patients already enrolled in another outcome interventional RCT.
- Patients transferred from another paediatric or neonatal intensive care after a stay of
more than 7 days
- Patients suffering from diabetic ketoacidosis or hyperosmolar coma on admission.
require home PN
- Patients with suspected or established inborn metabolic diseases requiring specific
diet
- Patients who do not have a central venous catheter or arterial line within the first
hours after PICU- admission
4
intention-to-treat basis. The data file will be finalized 90 days after inclusion
calories.
Discrete variables will be summarized by frequencies and percentages and
analyzed by (exact) Chi- square test or logistic regression analysis.
Continuous variables will be summarized by use of either mean or standard
analysis.
All outcomes will be analyzed in an uncorrected manner as well as
multiple testing.
Laboratory tests: Will be performed by LaboIntensieve Geneeskunde KU Leuven.

and at the central laboratory of the Erasmus MC in Rotterdam and at the
Hospital Laboratory at Stollery Children’s Hospital.
5
II. INTRODUCTION
A widely held assumption is that in children, nutrition not only serves the maintenance of body tissues, but
also allows them to grow, which is particularly important during infancy and adolescence, when the fast
growth makes healthy children vulnerable to caloric restriction [6, 7]. Therefore, in the current European and
American guidelines for nutrition in hospitalized children, PN is recommended to prevent/correct malnutrition
randomized studies of nutritional support in critically ill children during the first week of critical illness should
include a control arm in which no nutritional support is administered or goals for nutritional support are used.
Part of the rationale is that anabolism, and hence growth, cannot occur during the catabolic phase that
occurs early during critical illness.
a multi-centre RCT performed in three large, expert, tertiary, referral PICUs. The study will be sufficiently
6

- Patients with a DNR order at the time of ICU admission.
discharge from PICU)
- Patients who do not need a central venous catheter or arterial line within the first hours after PICU-
admission.
- Patients transferred from another paediatric or neonatal intensive care after a stay of more than 7 days
- Patients suffering from diabetic ketoacidosis or hyperosmolar coma on admission.
- Patients with suspected or established inborn metabolic diseases requiring specific diet
- neonates 6 weeks old or less with congenital heart disease planned for or after surgery for the heart
disease. This is an exclusion at Stollery Children’s Hospital, due to competing studies.
7
physician.
clinically followed up without his data being analyzed in the study. A separate patient log with minimal data
will register all patients withdrawn from the study.
allocation. In Canada, the usual practice of end-of-life decisions will be used.
V. STUDY TIMETABLE
The patient inclusion started on 18 June 2012 in Leuven and on 13 September 2012 in Rotterdam. A
four months after admission of the first patient.
Written informed consent will be obtained from the patient or the closest family member or legal guardian.
For planned PICU admissions after elective procedures, informed consent may be asked for beforehand. For
emergency PICU admissions, treatment allocation will be done after assessment of the patient for eligibility
by the attending physician within the time frame of two hours. If eligible, the patient will be randomized into
the study and informed consent will be asked within the time frame of 24 hours (deferred informed consent)
as a nutritional regimen has to be initiated on admission. A duplicate of the signed informed consent will be
given to the patient or the closest family member or legal guardian. The patient’s referring physician may
also be informed about the patient’s participation. The family member or the patient can withdraw from the
trial, at any time, without impact on his treatment or penalty.
Netherlands, and at the University of Alberta, in Edmonton, Canada.
6.2. Randomization
8
randomization. Randomization will be done in a 1:1 ratio in permuted blocks of 10 and stratified according to
I Medical-ICU admissions (≤1 year or >1 year): (a) neurologic, (b) other
II Surgical-ICU admissions (≤1 year or >1 year): (a) cardiac surgery, (b) other
Bedside nurses and doctors will not know the block size.
KULeuven protocol
PN preparation is available. Children weighing more than 40kg will receive adult parenteral nutrition.
Erasmus MC protocol
9
Stollery Children’s Hospital Protocol:
On admission to PICU a patient’s energy expenditure will be assessed by a registered dietitian. Metabolic
support is initiated as soon as possible, with the goal to match energy expenditure to the measured or
estimated resting energy expenditure of the child. The urgency of initiation of nutrition support is dependent
on nutritional risk prior to admission, disease state and age. If indirect calorimetry cannot be done, 65% of
basal metabolic rate is used (FAO-WHO) to determine caloric requirement. This number is adjusted daily by
the dietitian based on the acute phase response and clinical picture of the child. If nutrition needs cannot be
met enterally, PN is added to achieve caloric demand. On admission to PICU patients receive a glucose
infusion of approximately 3-4 mg/kg/minute dextrose within the total fluid intake prescribed by medical staff.
At that time either enteral feeds are initiated or if needed, PN is ordered (and adjusted daily if necessary) at
individually prescribed doses of protein, carbohydrate and fat.
Both in Leuven and Rotterdam, patients randomized to the “late PN” group will receive a mixture of Glucose
At Stollery Children’s Hospital the usual practice will be used, as described above. No PN will be added
during the first 7 days of critical illness in the PICU. Intravenous glucose will be given as D5W NS infused to
10
make the total fluid intake prescribed by the attending medical team. This is usually about 75% maintenance
fluid calculated. If the glucose level is below 50mg/dl, this maintenance fluid will be changed to D10W NS or
higher if required. .
will be given weekly. At Stollery Children’s Hospital, the trace elements and minerals and vitamins will be
dosed as follows:
* children under 12 months will receive 2 mls/kg/day of a pediatric multi vitamin solution (Pediatric Sandoz)
(to a maximum of 5 mls/day) and 0.3 mls/kg/day (to a maximum of 1 ml/day) of house neonatal trace
element solution (content: zinc sulfate 5mg/ml; copper 0.4mg/ml; chromium 4mcg/ml, selenium 40mcg/ml)
daily and extra selenium and carnitine if a deficiency is documented.
* Children over 12 months will receive 5 mls/day of a pediatric multi vitamin solution and 0.02 mls/kg/day (to
a maximum of 1 ml/day) of pediatric trace element solution with extra selenium and carnitine as required
volume will be considered to be EN and half gastric secretions. The duration and cause of interruption of
delivery of EN will be recorded. Problematic digestive intolerance will be registered as vomiting, tracheal
Blood samples are taken upon ICU admission and daily at 06:00h until discharge from ICU or death. If the
patient is staying in the PICU longer than 16 days, blood samples will be taken every four days and a final
sample at discharge. Upon admission three extra blood samples will be taken; namely two yellow SST-5
tubes (BD Vacutainer SST II Advance ref 367955) each containing 5 milliliter blood and 1 purple EDTA tube
(BD Vacutainer K2E 3,6mg ref 38841) of 2 milliliter blood. During the following days until the patient has left
11
the PICU we will daily take an extra yellow SST-5 tube (containing 5 milliliter blood) and an extra purple
EDTA(BD Vacutainer K2E 3,6mg ref 38841) (containing 2 milliliter blood) for further analyses. When the
child weighs less than 10 kg the SST-5 tube is replaced by an SST-3.5 tube(BD Vacutainer SST II Advance
ref 367957) (containing 3.5 milliliter blood). At Stollery Children’s Hospital, this has been modified to be:
admission day consisting of two serum tubes of 3.5ml, and 1 EDTA tube of 2 ml; and on day 1, day 3,
day 7, day 9, and discharge day, 1 EDTA tube of 2 ml and 1serum tube of 3.5ml.
A subset of the samples will be immediately stored on ice and processed in a cold chain for future endocrine
measurements. Processed serum and plasma as well as the spun-down blood cells will be frozen and
stored.
Analyses on the 06:00h (usually at 0400 at Stollery Children’s Hospital) sample will include routine tests,
often including clinical chemistry, hematology (Hgb, WBC, TC), and markers of inflammation (CRP), liver
function ALT, AST, ALP, GGT, bilirubin total/direct. A number of metabolic, hormonal and inflammatory study
analyses will be performed on selected days from the stored samples mentioned above. The latter include
coagulation & fibrinolysis tests, cytokines and markers of oxidative stress. Also on selected days urine (5
tubes of 5 mL out of 24 hours’ urine collection) will be stored for further evaluation (e.g. cortisol metabolites,
NGAL).
All whole blood glucose levels are measured on arterial blood using a blood gas analyzer on each ICU and
are registered for later calculation of glucose metrics (cfr appendix 7).
adaptations for the pediatric population. (cfr appendix 4).
All (suspected) new infections of the lungs, the blood stream, the urinary tract and wounds are recorded in
the patient data file by the bedside senior intensive care specialists. New infections or suspected new
Bacteraemia is further classified by responsible pathogen and as catheter-related blood stream infection
versus other bacteraemia.
adipose tissue will be performed. This will not be done at the Stollery Children’s Hospital site. Furthermore,
as far as practically feasible, every patient is approached just prior to hospital discharge, to complete a
validated, semi- structured child health questionnaire (either HUI, CHQ, PEDI-NL, SDQ).
PEPaNIC study (4 months, 2 year, 4 years). Long-term follow-up at 2 years will also include a clinical
paediatric examination and neurocognitive testing by a qualified paediatric psychologist if funding for this
portion is obtained. Follow-up at 4 years after inclusion will consist of the questionnaire, the clinical paediatric
examination and a full neurocognitive testing, if funding for this portion is obtained.
control group will receive standard therapy, i.e.PN with or without lipids or electrolytes within one week. In
12
discharge from ICU.
when they are no longer in need of vital organ system support, and the attending intensivist has asked for a
bed on the ward for transfer of the patient.

survivors.
randomization diagnosis of new kidney injury/failure (defined by modified Risk, Injury, Failure, Loss, and
will be analyzed, with ICU non-survivors censored beyond the longest duration of pharmacological or
- Inflammation: Effect of the intervention on inflammation will be analyzed by comparing the distribution of
comparing time profiles of C-Reactive Protein values.
-Child health questionnaire scores (HUI, CHQ, PEDI-NL, SDQ), reflecting the state of the child before
adipose tissue.
13


Clinical complications: pneumothorax, hemothorax and arterial puncture due to central line insertion, central
line replacement due to suspicion of catheter-related blood stream infections
IX. ADVERSE EVENTS
Hypoglycemia (< 40 mg/dL) resistant to iv glucose administration will be considered as a

serious adverse event. This adverse event will be reported to the sponsor.
10.1. Sample size
75% depending on the true mortality in the total population. We plan to re calculate the power of the study,
based on the incidence of new infections, in the control group after inclusion of patient number 480. We
anticipate that 3-3.5 years will be needed to take this study to completion, provided informed consent will be
at least 80%. If required, additional study sites will be included. To face worse recruitment, we anticipate
requiring 4 years to complete the clinical study (excluding long term follow up) and 1 more year to process
samples and data.
A consort diagram will be reported. The data file will be finalized 90 days after inclusion of the last patient. To
14
calories. Discrete variables will be summarized by frequencies and percentages and analyzed by (exact)
Chi- square test or logistic regression analysis. Continuous variables will be summarized by use of either
proportional hazard analysis. All outcomes will be analyzed in an uncorrected manner as well as (jointly)
patients.
i. ICU mortality (in 2 blinded study groups; when differences are significant, the board will call for unblinding).
ii. Proportion of patients requiring mechanical ventilation for more than 7 days (only aggregated data of both
groups) in comparison with those from the previous annual reports of the department.
iv. SAE: Therapy resistant hypoglycaemia (in 2 blinded study groups; when differences are significant, the
board will call for unblinding).
will be performed and will be reported following the sponsor’s SOPs. No fault insurance is covered by Fortis
Corporate Insurance NV. A copy of the insurance policy is included. Publication policy and financing will be
addressed in separate agreements.
The research database (eCRF) will be hosted on the University Hospitals Leuven servers. This closed
network is only accessible for employees and affiliated persons who have to use a personal login and
password to log into the system. Equipment can only have access to the network after
registration/installation by the central ICT service. The hospital network is protected by a firewall but
authorized research staff can access the network over the internet using a secure SSL-solution (juniper) with
15
one-time passwords (using a Vasco Digipass), creating a remote desktop.
The firewall and external access procedure has been audited and approved regularly by external
organizations.
The research database resides on the central servers with mirrored or RAID5 system disks and restricted
access. Backups are made hourly. The database is written in FilemakerPro 11 and is login/password
protected. The FilemakerPro application is required to open the database and is available on the server. The
internet browser is only used to create the secured connection to the server.
For reasons of data integrity and internal control during data input, name and hospital number are stored in a
separate table linked to the eCRF, but these data will be only accessible for the Edmonton Research staff
and the principal database manager on a login/password basis. All access to the database is logged. When
the database is finalized, the identity data will be detached from the eCRF and stored in Edmonton.
16
Statisticians
Microbiologists
Pathologists
….
17
Appendix 1
Kleine zuigeling:
Voedingen:

- Ileus
- Darmischemie

- Aspiratie risico
Maagresidu
Diarree
- Etiologie?
18
19
Adressogram
Informed consent formulier : PEPaNIC Versienummer 3

17-12-2012
Geachte Mevrouw,
Geachte Heer,
medische zorgen te geven aan de patiënten, maar ook constant de huidige
inzichten.
Na uitgebreide heelkundige ingrepen en tijdens ernstige kritieke ziekte zijn patiënten soms
opstarten van aanvullende veneuze voeding de overlevingskansen van deze patiënten
duidelijk verbeterde. Ook de risico’s op complicaties namen duidelijk af in vergelijking met de
patiënten waarbij de veneuze voeding vroegtijdig werd opgestart.
deelnemen.
zorgenafdeling ingedeeld worden in een groep waarbij de veneuze voeding laattijdig wordt
bepaald. Uw kind zal verder dezelfde maximale zorgen krijgen. Het deelnemen aan de studie
de spiermassa en het onderhuids vetweefsel. Het zou kunnen dat we over enkele jaren Uw
20
kind uitnodigenvoor een vrijblijvende opvolgconsultatie.Om een beter inzicht te krijgen in de
evolutie van uw kind na hospitalisatie op intensieve zorgen, zullen we op regelmatige
tijdstippen een vragenlijst opsturen.
De superioriteit van een van beide voedingsschema's is nog nooit aangetoond bij kinderen.
Een theoretisch risico zou kunnen zijn dat de bloedsuikerwaarde iets lager zou kunnen zijn
wanneer de voeding laattijdig wordt opgestart. Echter, deze bloedsuikerwaarde wordt continu
opgevolgd en onmiddellijk gecorrigeerd zo deze afwijkend is.
te allen tijde het recht om deelname aan de studie stop te zetten. De studie brengt geen
enkele bijkomende kosten met zich mee. Gegevens en resultaten van dit onderzoek kunnen
gebruikt worden voor publicatie in wetenschappelijke tijdschriften doch zonder dat
persoonlijke gegevens worden vermeld en met volledige waarborg van de anonimiteit.
Conform de Belgische wet inzake experimenten op de menselijke persoon van 7 mei 2004 is
de opdrachtgever van het onderzoek zelfs foutloos, aansprakelijk voor alle schade die de
deelnemer en/of zijn rechthebbenden oplopen en die rechtstreeks dan wel onrechtstreeks
verband houdt met de proef. De opdrachtgever heeft een verzekering afgesloten die deze
aansprakelijkheid dekt. Indien U schade zou oplopen ten gevolge van uw deelname aan
deze studie zal die schade bijgevolg worden vergoed conform de Belgische wet inzake
experimenten op de menselijke persoon van 7 mei 2004.
Deze studie werd goedgekeurd door de Commissie Medische Ethiek van UZ/KU Leuven.
Deze goedkeuring mag echter niet beschouwd worden als een aanzet tot deelname aan de
studie.
Prof DrDieterMesotten Prof Dr Greet Van den Berghe

Senior-assistent Prof Dr Dirk Vlasselaers
Dr Lars Desmet
21
“vroegtijdig versus laattijdig opstarten van aanvullende intraveneuze voeding” en stem ermee
in dat mijn kind hieraan deelneemt.
Naam patiënt:
………………………………………………………………………………………..
………………………………………………………………………………………..
Handtekening(en) : …………………………………………………………………………..
Leuven, ….. / ……./ 201…
Naam Arts:…………………………………………………………………………………
Handtekening:……………………………………………………………………………..
Datum:……………………………………………………………………………………...
Een duplicaat van het IC werd aan de patiënt of aan een van de ouders overhandigd.
22
Appendix 4
SIRS
presence of at least 2criteria, representing an acute change from baseline and in the absence of other
known causes for these changes
SEVERE SEPSIS
1. Glasgow coma scale <15 (in the absence of CNS disease)
SEPTIC SHOCK
2. Glasgow coma scale <15 (in the absence of CNS disease)
23
Appendix 6


(zie nomogram)
dag 1 : 40 x M x 24 = ………………… ml
dag 2 : 50 x M x 24 = ………………… ml
dag 3+ : 60 x M x 24 = ………………… ml
100 ml/kg/dag: 100 ml x G = ………………… ml (= T)


Konakion 2mg 1/week

Apotheek:
24

(zie nomogram)
dag 1 : 40 x M x 24 = ………………… ml
dag 2 : 50 x M x 24 = ………………… ml
dag 3 : 60 x M x 24 = ………………… ml
dag 4+ : 80 x M x 24 = ………………… ml
100 ml/kg/dag: 100 ml x G = ………………… ml (= T)

Cernevit®: 1 ml = …………….. (= N) ml

Apotheek:
25

(zie nomogram)
dag 1 : 40 x M x 24 = ………………… ml
dag 2 : 50 x M x 24 = ………………… ml
dag 3 : 60 x M x 24 = ………………… ml



Cernevit®:2.5 ml = …………....(= N) ml
Konakion 5mg 1/week

Apotheek:
26

(zie nomogram)

dag 1 : 40 x M x 24 = ………………… ml
dag 2 : 50 x M x 24 = ………………… ml
dag 3 : 60 x M x 24 = ………………… ml


Cernevit®: 2.5 ml = ………………(= N) ml

Apotheek:
27
Appendix 7
GLYCEMIEBELEID BIJ
KINDEREN OP ITE TE
GASTHUISBERG
bij kinderen aangetoond (Lancet 2009;373(9663):547-56). Daarom passen we ook bij

Figuur 1
zelf anticiperende beslissingen te nemen in het streven naarnormoglycemie.
toekomen.
28
(figuur 2).
overschrijdt.
insuline-infuus glyc> bovengrens glyc> 2x
Gewicht
0,9%)
Figuur 2
systeem.
 De controle van deglycemietot binnen de fysiologische grenzen is noodzakelijk.
nieuweglycemiecontrole uitvoeren ter preventie van hypoglycemie.
 Bij hypoglycemie wordt glucose IV (1 ml glucose 50%/ kg LG) (50% =
500mg/ml)toegediend (fig.3).
STOP insuline
geefgluc 50% (1 ml/kg)

Figuur 3
29
insuline-infuus.
glycemiecontrole.

o Stress
o Koorts
plaatsen).
30
31
References
17.
2011;27(2):133-137.
11. George Briassoulis, ShekharVenkataramanand Ann Thompson. Cytokines and Metabolic

expenditure be predicted in critically ill children?PediatrCrit Care Med 2003; 4:176 –180)
32
2002
PhD et al. Energy expenditure in critically ill children. PediatrCrit Care Med 2007; 8:264 –267
33
8. Ethical approval of the initial protocol -
KU Leuven
9. Ethical approval of the most recent protocol -
KU Leuven
11. Ethical approval of the most recent protocol -
Stollery Children’s Hospital Edmonton
Approval Form
Date:April 23, 2013

Principal Investigator:Ari Joffe
Study ID:Pro00038098
Study Title:
Impact of Early Parenteral Nutrition Completing Enteral Nutrition in
Paediatric Critically Ill Patients
Approval Expiry Date:April 22, 2014
Approved Consent Document:
Approval DateApproved Document
4/23/2013PEPaNIC Information and Consent Revised
Funding/Sponsor:IWT (Agency for Innovation by Science and

Technology) TBM project 110685
Thank you for responding to all matters arising from your presentation of
this study at the April 19, 2013 Health Research Ethics Board - Biomedical
Panel meeting. There are no outstanding issues, and the study is
approved. The Protocol (version number 3, 27-02-2013) and the consent
(undated link above) are both approved.
The Health Research Ethics Board assessed all matters required by section
50(1)(a) of the Health Information Act. Subject consent for access to
identifiable health information, will be obtained by someone involved in
the clinical care of the participant, and appropriate procedures for such
consent have been approved by the HREB - Biomedical Panel. In order to
comply with the Health Information Act, a copy of the approval form is
being sent to the Office of the Information and Privacy Commissioner.
A renewal report must be submitted next year prior to the expiry of this
approval if your study still requires ethics approval. If you do not renew
on or before the renewal expiry date (April 22, 2014), you will have to
re-submit an ethics application.
The membership of the Health Research Ethics Board - Biomedical Panel
complies with the membership requirements for research ethics boards as
defined in Division 5 of the Food and Drug Regulations and the Tri-Council
Policy Statement. The HREB - Biomedical Panel carries out its functions in
a manner consistent with Good Clinical Practices.
Approval by the Health Research Ethics Board does not encompass
authorization to access the patients, staff or resources of Alberta Health
Services or other local health care institutions for the purposes of the
research. Enquiries regarding Alberta Health Services administrative
approval, and operational approval for areas impacted by the research,
should be directed to the Alberta Health Services Research Administration
office, #1800 College Plaza, phone (780) 407-6041.
Sincerely,
S.K.M. Kimber, MD, FRCPC
Chair, HREB Biomedical
Note: This correspondence includes an electronic signature (validation and
PEPaNIC Ethics Approval Edmonton.txt[17-11-2015 15:24:33]

approval via an online system).
PEPaNIC Ethics Approval Edmonton.txt[17-11-2015 15:24:33]

13. Trials paper - Final published protocol and statistical analysis plan
Fivez et al. Trials (2015) 16:202
TRIALS
DOI 10.1186/s13063-015-0728-8
STUDY PROTOCOL Open Access
Impact of withholding early parenteral nutrition

completing enteral nutrition in pediatric critically
ill patients (PEPaNIC trial): study protocol for a
randomized controlled trial
Tom Fivez1†, Dorian Kerklaan2†, Sascha Verbruggen2, Ilse Vanhorebeek1, Sören Verstraete1, Dick Tibboel2,
Gonzalo Garcia Guerra3, Pieter J Wouters1, Ari Joffe3, Koen Joosten2, Dieter Mesotten1 and Greet Van den Berghe1*
Abstract
Background: The state-of-the-art nutrition used for critically ill children is based essentially on expert opinion and
extrapolations from adult studies or on studies in non-critically ill children. In critically ill adults, withholding parenteral
nutrition (PN) during the first week in ICU improved outcome, as compared with early supplementation of insufficient
enteral nutrition (EN) with PN. We hypothesized that withholding PN in children early during critical illness reduces the
incidence of new infections and accelerates recovery.
Methods/Design: The Pediatric Early versus Late Parenteral Nutrition in Intensive Care Unit (PEPaNIC) study is an
investigator-initiated, international, multicenter, randomized controlled trial (RCT) in three tertiary referral pediatric
intensive care units (PICUs) in three countries on two continents. This study compares early versus late initiation of PN
when EN fails to reach preset caloric targets in critically ill children. In the early-PN (control, standard of care) group, PN
comprising glucose, lipids and amino acids is administered within the first days to reach the caloric target. In the
late-PN (intervention) group, PN completing EN is only initiated beyond PICU-day 7, when EN fails. For both study
groups, an early EN protocol is applied and micronutrients are administered intravenously. The primary assessor-blinded
outcome measures are the incidence of new infections during PICU-stay and the duration of intensive care dependency.
The sample size (n = 1,440, 720 per arm) was determined in order to detect a 5% absolute reduction in PICU infections,
with at least 80% 1-tailed power (70% 2-tailed) and an alpha error rate of 5%. Based on the actual incidence of new
PICU infections in the control group, the required sample size was confirmed at the time of an a priori- planned
interim-analysis focusing on the incidence of new infections in the control group only.
Discussion: Clinical evidence in favor of early administration of PN in critically ill children is currently lacking, despite
potential benefit but also known side effects. This large international RCT will help physicians to gain more insight in
the clinical effects of omitting PN during the first week of critical illness in children.
Trial registration: ClinicalTrials.gov: NCT01536275 on 16 February 2012.
Keywords: Critical illness, Children, Nutrition, Sepsis, Lipid, Protein, Glucose, Infection
* Correspondence: greet.vandenberghe@med.kuleuven.be
†
Equal contributors
1
Clinical Department and Laboratory of Intensive Care Medicine, Academic
Division Cellular and Molecular Medicine, KU Leuven University and Hospital,
Herestraat 49, B-3000 Leuven, Belgium
Full list of author information is available at the end of the article
© 2015 Fivez et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Fivez et al. Trials (2015) 16:202 Page 2 of 9
Background EN supply is insufficient [10,17]. Most guidelines advise

Nutritional support for children in intensive care doing this early so that the recommended daily allowances
The state-of-the-art nutrition used for critically ill children for children are reached on day 2 or 3 after PICU admis-
is essentially based on expert opinion, small studies with sion. These recommendations are based on evidence from
surrogate endpoints and extrapolations from adult studies cohort studies without a control group, case series or ex-
or from studies in healthy children outside the ICU. It is pert opinion (Grade D level).
widely accepted that in healthy children, nutrition not only The ongoing controversy on optimal amount, compos-
serves to maintain body tissues but also allows growth, ition and timing of administration of PN in critically ill
which is considered of particular importance during in- children may in fact conceal the fact that there is no
fancy and adolescence [1,2]. In hospitalized children, espe- hard evidence for any use of PN in critically ill children.
cially in the young, the current European and American Supported by the results of a Cochrane systematic re-
guidelines for nutrition recommend early parenteral nutri- view, Joffe et al. concluded that randomized trials inves-
tion (PN) to prevent/correct malnutrition and to sustain tigating the role of intravenous nutritional support
appropriate growth when enteral nutrient (EN) supply is during the first week of critical illness in children should
insufficient [3,4]. Observational studies suggest that about be performed and should include a control arm in which
a quarter of children, most notably infants, admitted to no nutritional support is administered or hypocaloric
pediatric intensive care units (PICUs) develop a pro- goals (below basal metabolic rate) for nutritional support
nounced caloric deficit [1]. The stores of energy, fat and are used [18].
protein in children are limited, leaving children to rely on
muscle mass to provide necessary substrates for metabol- Rationale of the study and study hypothesis
ism. The energy deficit observed with acute critical illness A recent randomized controlled trial (RCT) in critically
in children has been associated with adverse outcome [5]. ill adults [19] showed that the early provision of PN
Based hereon, it is current practice in PICUs to start PN worsened rather than improved outcomes as compared
in the acute phase of critical illness to supplement insuffi- with withholding PN and thus tolerating a substantial
cient EN with the intention to avoid underfeeding [3,4]. caloric deficit up to 1 week in ICU. Also, other studies
However, overfeeding may also be harmful [6-9]. It is diffi- did not show clinical benefit of early PN in adult ICU
cult to administer the correct amount of nutrition, avoid- patients [20,21]. Hitherto, no well-designed RCT has
ing overfeeding as well as underfeeding. been performed in critically ill children. The aim of the
PEPaNIC trial (the acronym stands for Pediatric version
Varying nutritional guidelines and clinical practices of the effect of Early Parenteral Nutrition to complete
It is currently advised to assess energy expenditure con- insufficient enteral nutrition in ICU patients) is to inves-
sidered to reflect energy requirements, through the use tigate whether a strategy of withholding PN during the
of indirect calorimetry during the course of critical ill- first 7 days in the PICU (late PN) provides clinical bene-
ness and to use this technique for determining individu- fit over the current practice of early PN in critically ill
alized targets to guide nutritional therapy [10]. However, children. We hypothesize that withholding PN for 1
a European survey conducted in 2004 showed that only week in the PICU reduces new infections and shortens
17% of the PICUs use this technique [11] and the tech- the duration of PICU-stay.
nique itself has not been well standardized [12,13]. In This hypothesis is currently being tested in a multicenter
the most critically ill, major caveats are present, such as superiority RCT performed in three large, tertiary referral
respiratory support with more than 40% oxygen and the PICUs (University Hospitals Leuven, Leuven, Belgium;
use of uncuffed tubes resulting in unpredictable mea- Erasmus Medical Center, Sophia Children’s Hospital,
sures. The use of standard equations to predict energy Rotterdam, The Netherlands; Stollery Children’s Hospital,
expenditure and/or requirements also carries the risk of Edmonton, AB, Canada). The centers were invited to par-
overfeeding and underfeeding [14-16]. ticipate based on a self-declared routine use of early PN in
Experts worldwide agree that there are insufficient data the PICU. It was anticipated that this routine use of early
to make evidence-based recommendations for the optimal PN differs among centers. This was considered to be an
target of caloric intake in critically ill children and for the asset as it contributes to the external validity of the
optimal time after onset of critical illness by which this PEPaNIC trial.
target should be reached. The lack of widely accepted
caloric targets for critically ill children results in nutri- Methods/Design
tional strategies that vary substantially across centers. The Ethical approval
current European and American guidelines for nutrition The study protocol and (deferred) informed consent
in hospitalized children recommend PN to prevent or cor- forms were approved by the institutional ethical review
rect malnutrition and to sustain appropriate growth when boards in Leuven, Belgium (ML8052 Amend-ID0005),
Rotterdam, The Netherlands (NL38772.000.12) and patients, severity of illness scores are calculated such as
Edmonton, AB, Canada (Pro00038098). Informed consent the PEdiatric Logistic Organ Dysfunction PELOD score
is given in writing by the parents or the legal guardians, and, for cardiac surgery patients, the Risk-Adjustment in
confirmed by the child when older than 7 years, after pro- Congenital Heart Surgery or RACHS score. The Pediatric
viding all information orally in plain language and in writ- RISk of Mortality (PRISM) score cannot be used for this
ing. For planned admissions, informed consent is obtained study as the nutritional management is expected to affect
prior to surgery/procedure. For unplanned admissions, in- the highest blood glucose concentration during the first
formed consent is obtained within 24 hours after admis- 24 hours. In addition, co-morbidities prior to admission
sion on the PICU (deferred informed consent as the are noted. These comprise, among others, the presence of
nutritional therapy should be initiated from PICU admis- a genetic syndrome, gestational age at birth, presence/
sion onward). history of cancer, diabetes mellitus, kidney failure and
infection upon admission.
Patients’ eligibility - Inclusion criteria
Upon admission to the participating PICUs, all critically Randomized treatment allocation
ill children are screened for nutritional risk and eligibil- Randomization procedure
ity for inclusion in the PEPaNIC clinical study [22]. All Randomization to early PN or late PN in a 1:1 ratio, is
non-eligible patients, identified by the local investigators, performed centrally (KU Leuven, Belgium) by use of a
are logged. dedicated computerized system, accessible in all centers
Critically ill children, newborn to 17 years (inclusive around the clock, 7 days a week. The computer algorithm
or exclusive depending on the local definition of a allocates every consecutive, eligible patient per center to
pediatric patient) old, with a STRONGkids (Nutritional one of the two treatment arms in a blinded fashion by use
risk score) score of 2 points or more and who are likely of permuted blocks per diagnostic stratum to create paral-
to stay in the PICU for more than 24 hours, are eligible lel groups. The block size is unknown to bedside physi-
for inclusion [22]. cians, nurses and members of the research team. Patients
are stratified per study site according to age groups (<1
Exclusion criteria year and ≥ 1 year) and the following primary diagnostic
Patients fulfilling one or more of the following criteria categories on admission:
are excluded:
I. Medical-PICU admissions (infectious or non-
STRONGkids score lower than 2 on PICU infectious): (a) neurological (b) other.
admission [22] II. Surgical-PICU admissions (elective or emergency)
Not critically ill (for example, anticipated oral intake according to referral discipline (a) cardiac surgery
within 24 hours) (b) other.
Non-pediatric patients (aged 17 or older, compare
with above) Treatment allocation and blinding
Premature newborns (<37 weeks gestational age Concealed allocation to the randomized treatment was re-
upon admission in the PICU) alized by use of the computerized randomization system
‘Do not resuscitate’ code at the time of PICU described above. It was considered not feasible to blind
admission treating physicians and patients for the allocated treatment
Expected death within 12 hours during the time window of the randomized intervention.
Readmission to PICU after already having been After discharge to the normal ward, all treating physicians
randomized are unaware of the randomized treatment allocation. All
Enrollment in another intervention trial outcome assessors and investigators not directly involved
Transfer from another PICU or neonatal ICU after a in the patients care, such as statisticians, infectious disease
stay of more than 7 days specialists and laboratory personnel, are fully blinded to
Ketoacidotic or hyperosmolar coma treatment allocation.
Inborn metabolic diseases requiring specific diet
Short bowel syndrome or other conditions requiring Common strategy for early EN in both study arms
PN for more than 7 days prior to PICU admission The initiation and increase of EN, and the use of gastro-
prokinetics are prescribed in the standing orders for EN
Data collection at study entry in each center. Both groups receive micronutrients (trace
At baseline, data on demographic (age, gender, race/ elements, minerals and vitamins) intravenously from day
ethnicity, (pre-)admission bodyweight and height) and 2 onwards until the amount of EN given reaches 80% of
clinical characteristics of the patients are obtained. For all the caloric target.
Randomized interventions nitrogen) is added from day 2 onward at 25 ml/kg/day

Patients randomized to the early-PN strategy (standard (<10 kg) or 20 ml/kg/day (10 to 30 kg). From day 2
of care or control group) receive this type of nutrition onwards, Intralipid® (Baxter, Kobaltweg 49, 3542 CE
according to current management in each of the partici- Utrecht) is added initially at a dose of 10 ml/kg/day (<10
pating centers, which were recruited based on a routine kg) or 7.5 ml/kg/day (10 to 30 kg), increasing to 20 or
use of early PN. For patients randomized to the late-PN 15 ml/kg/day respectively. For patients who require fluid
group (intervention group), all PN is withheld during restriction, intake is adjusted accordingly. Children > 30
the first week in the PICU. The international setting of kg on IV nutrition receive from day 2 onwards Olimel
the trial brings some variation in the control group (see N5 (Baxter, 5.2 mg/ml nitrogen, 115 mg/ml glucose)
study rationale and hypothesis), while the intervention when central lines are in place or Olimel N4 (Baxter, 4.0
group is strictly standardized (‘no PN during the first mg/ml nitrogen, 75 mg/ml glucose) when only periph-
week in PICU’). eral lines are in place; the dose is 48 ml/kg/day. Any
enterally-delivered energy is assessed twice daily and the
Standard of care or control group: early-PN energy delivered by PN is reduced accordingly. Energy
In the Leuven (BE) PICU, patients randomized to the goals for enteral nutrition are based on the body weight-
early-PN group receive a mixture of glucose 30% and based Schofield equation [23] (first day of admission)
Vaminolact® (Fresenius, Uppsala, Sweden) in equal and on the Recommended Dietary Allowances (RDA,
amounts upon admission to PICU, comprising 150 mg/ml Dutch Health Council) for the subsequent length of stay
glucose and 4.7 mg/ml nitrogen. For patients who require (Dietary Reference Intake: energy, protein and digestible
fluid restriction, total fluid intake is 50 ml/m2/h on days 1 carbohydrates, 2001, Health Council of the Netherlands:
and 2 (the day after admission and further referred to as The Hague). Energy goals and composition of parenteral
day 2), and 60 ml/m2/h on day 3. Patients not requiring nutrition are based on the European Society of Pediatric
fluid restriction receive 100 ml/kg/day for the first 10 kg Gastroenterology, Hepatology and Nutrition (ESPGHAN)
bodyweight, 50 ml/kg for the next 10 kg, and 20 ml/kg for guidelines [4]. When EN covers 80% of calculated caloric
the bodyweight over 20 kg, to be reached within 3 days. needs, PN is stopped. When the patient starts with oral
For all patients on intravenous (IV) nutrition, and within nutrition, PN and/or EN is reduced and eventually
the fluid limitation described above, lipids (SMOFlipid® stopped. Whenever enteral or oral intake falls below 50%
(20 g/100 ml), Fresenius, Uppsala, Sweden) are added of calculated caloric needs, PN is restarted.
from the second morning after admission, initially at a In the Edmonton (CA) PICU, the patient’s energy ex-
dose of 1.5 g/kg/day, increasing to a maximum of 3 g/kg/ penditure is assessed upon admission by a registered
day, depending on the age. On the third morning after ad- dietitian when possible. Nutritional support is initiated as
mission, pharmacy-prepared PN preparations are pre- soon as possible, with the goal to match energy expend-
scribed, unless adequate enteral nutritional intake is iture (measured or estimated resting energy expenditure
expected. PN preparations contain a mixture of glucose of the child). The urgency of initiation of nutrition support
50% and SMOFlipid® covering respectively 60 to 70% and is dependent on nutritional risk prior to admission, disease
40 to 30% of calculated energy target and a 1.5 to 2.5 g/kg state and age. If indirect calorimetry cannot be done, 65%
protein intake, according to age, by Vaminolact®. If the of basal metabolic rate is used Food and Agriculture
body weight is above 5 kg, Vaminolact® is replaced by Organization-World Health Organization (FAO-WHO) to
Vamin 18® (Fresenius, Uppsala, Sweden). Any enterally- determine caloric requirement. This number is adjusted
delivered energy is taken into account twice daily to re- daily by the dietitian based on the acute phase response
duce the energy delivered by PN. When EN covers 80% of and clinical picture of the child. If nutritional require-
optimal calculated caloric needs, PN is stopped. When the ments cannot be met enterally, PN is added to achieve cal-
patient starts to take oral nutrition, the PN and/or EN is oric target. On admission to PICU, patients receive a
reduced and eventually stopped. Whenever enteral or oral glucose infusion of approximately 3 to 4 mg/kg/minute
intake falls below 50% of calculated caloric needs, the PN taking into account the total fluid prescribed by medical
is restarted. staff. At that time EN is initiated when possible. On the
In the Rotterdam (NL) PICU, patients randomized to morning of day 2, if the patient is not already on full en-
the ‘early-PN’ group receive a continuous glucose infu- teral feeding, 20% IV lipids are initiated at 0.5 g/kg/day.
sion upon admission to PICU (<30 kg; 4 to 6 mg/kg/ On the morning of day 3, if the patient is not already on
min, > 30 kg; 2 to 4 mg/kg/min). From day 2 onwards full enteral feeding, lipid infusion is increased to 1 g/kg/
the glucose intake is increased for all children on IV nu- day and a solution of amino acids and concentrated glu-
trition to 8.3 mg/kg/min (5 to 10 kg), 6.9 mg/kg/min (10 cose is added. The caloric goal is Basal Metabolic Rate
to 30 kg) or 4 mg/kg/min (>30 kg). Primene® (Baxter, when the patient is intubated and Total Energy Expend-
Kobaltweg 49, 3542 CE Utrecht) (5.5 to 5.7 mg/ml iture when the patient has been extubated.
Intervention group: late-PN (ABL 625; Radiometer, Copenhagen, Denmark) using ar-
In the 3 centers, patients randomized to the late-PN terial or capillary blood samples.
group receive a mixture of glucose 5% and NaCl 0.9% at, In Edmonton, patients in all age groups receive continu-
respectively, 60% and 40% of the total flow rate that is ous insulin infusion at the discretion of the attending
required to obtain optimal hydration, as prescribed by physician when blood glucose levels exceed 180 mg/dl.
the attending physician, taking into account the volume The attending physician sets the lower target range limit.
of EN that is being delivered. No other forms of PN
(lipid or protein infusions) are administered. When the Other procedures and guidelines
amount of EN that is administered still covers less than Other medical treatments are not described by the study
80% of the calculated targets after 1 week in the PICU, protocol. Patients are weaned from the ventilator and
supplemental PN is initiated on day 8 according to the from hemodynamic support according to standardized
current PN protocols in each center. guidelines used in each participating PICU. End-of-life
The medical and nursing staff of the PICU were all in- decisions, when further intensive care is considered to
formed and trained extensively during regular meetings be futile, are taken in consensus by senior PICU physi-
before the start of the trial and were familiarized with cians and the referring specialist.
the protocol. In order to optimize protocol compliance,
the protocol was programmed in the patient data man- Handling of re-admissions to the PICU
agement system (PDMS). The use of this program was Patients who are readmitted to the PICU after a partici-
explained to every nurse, trainee and resident on the pation in PEPaNIC are not eligible for reinclusion. Pa-
PICU and was always supervised by the senior staff. tients who are readmitted to the PICU within 48 hours
Adherence to the protocol in Leuven and Rotterdam of discharge and who are still within the 7 days’ time
was guaranteed by using a PDMS guided system and by window of the initial randomization receive the nutrition
careful follow-up by study nurses. In Edmonton, a paper strategy they were randomly assigned to during the ini-
protocol was used and adherence checked by an inde- tial PICU admission. Patients readmitted more than 48
pendent study nurse and physician. hours after PICU discharge will be fed at the discretion
of the attending physician (standard care).
Criteria for stopping the study intervention
When in the intervention arm (late-PN group), blood glu- Outcome measures
cose concentration falls spontaneously (without exogen- Primary endpoints
ous insulin) below 50 mg/dl, the standard infusion of The two primary endpoints of this RCT are: (i) the inci-
glucose 5% is switched to 10% glucose until blood glucose dence of new infections during PICU- stay and (ii) the
concentration is higher than 80 mg/dl and stable. There- duration of PICU dependency. The latter will be re-
after, the infusion of glucose 10% is stopped again and ported as the crude number of PICU-stay days and as
switched back to glucose 5%. the time to live discharge from PICU, to account for
mortality as a competing risk.
Blood glucose management Also, the proportion of patients from the intention-to-
In Leuven, patients in both study groups receive con- treat population who stayed 8 days or more in PICU will
tinuous insulin infusion to target blood glucose levels of be reported. This is not only reflecting the proportion of
50 to 80 mg/dl when aged < 1 year and 70 to 100 mg/dl prolonged critically ill patients but also examines effects
when aged ≥ 1 year. Blood glucose and potassium are of the randomized intervention beyond the time window
monitored systematically every 1 to 4 hours on the blood of the randomized intervention in PICU.
gas analyzer (ABL Radiometer, Copenhagen, Denmark) The incidence of new infections for all patients in the
using undiluted arterial blood samples drawn via a VAMP® three centers will be scored in consensus by the same two
system (Edwards Lifescience Pontbeekstraat 4 1702 Groot- assessors (infectious disease specialists), who are blinded
Bijgaarden), Edwards Lifescience Pontbeekstraat 4 1702 for treatment allocation. This assessment is based on an a
Groot-Bijgaarden [24] and insulin infusion is adjusted priori-drafted protocol [19], which makes use of pre-
when needed. scribed antibiotics and clinical infection and inflammation
In Rotterdam, patients in all age groups receive con- data.
tinuous insulin infusion using a step-wise nurse-driven As the timing of PICU discharge to a regular ward
glucose control protocol to target blood glucose levels of may be affected by the availability of beds on regular
72 to 145 mg/dl, except for patients with traumatic brain wards, which could induce bias, we a priori decided to
injury for whom the target is set at 108 to 145 mg/dl analyze ‘time to discharge from PICU’ as ‘time to ready
[25]. Blood glucose and potassium are monitored sys- for discharge from PICU’. A patient is considered ‘ready
tematically every 1 to 3 hours on the blood gas analyzer for discharge’ as soon as all clinical conditions for PICU
discharge have been fulfilled (no longer in need for, or at 9. Nutrition delivered during PICU-stay. The
risk of, vital organ support). macronutrients and calories administered during the
intervention window and thereafter during PICU-
Secondary safety endpoints stay will be compared between the treatment groups.
Secondary safety endpoints comprise: (i) death during Total amount of macronutrients, as well as the
PICU-stay and during the time window of the random- amounts administered parenterally and enterally, will
ized intervention (up to day 8), (ii) the proportion of pa- be reported.
tients with at least 1 episode of severe hypoglycemia 10. Structural and functional differences in muscle tissue
(<40 mg/dl), (iii) in-hospital mortality and (iv) 90-day during PICU-stay. By ultrasonography, skeletal
mortality. As a specific Serious Adverse Event (SAE), muscle thickness of the quadriceps, as a marker of
hypoglycemia resistant to bolus administration of glu- muscle wasting, will be reported in a subset of
cose during the time window of the randomized inter- patients. In addition, handgrip strength will be
vention will be reported for both groups. measured in a subset of patients older than 6 years.
11. Intolerance to enteral feeding during PICU-stay.
Secondary efficacy endpoints Markers of tolerance to enteral feeding will be
determined in a subset of patients. Markers in blood,
1. Time to (live) discharge from hospital and duration stool and buccal swab samples will be investigated.
of hospital stay, for both the index hospitalization
and total hospitalization including stay in the Further pre-planned studies (execution depending on
referred hospital. further funding), of which the detailed protocols and the
2. Time to final (live) weaning from mechanical methods for statistical analysis will be reported separ-
respiratory support and duration of mechanical ately, are here listed below:
ventilation.
3. Kidney failure. Proportion of patients in need for 1. Direct healthcare-related costs. Total, direct
renal replacement therapy (RRT) during PICU-stay healthcare costs during index PICU-stay will be
and the duration of RRT (for those patients requiring compared between the treatment groups [26].
RRT). Also, the further analysis of the maximum and 2. Mechanistic studies. Explanations of any observed
daily serum level of creatinine and urea during the effects of delayed administration of PN as compared
intervention window and during PICU-stay will be with standard of care will be assessed. These will
reported. Other plasma and urine markers of kidney comprise, among others, metabolic, endocrine,
function will be investigated. inflammation and (epi)genetic analyses, the
4. Need for pharmacological or mechanical investigation of the role of severity of illness, the use
hemodynamic support during PICU-stay and of indirect calorimetry, the type of blood glucose
duration of such need. In addition, time to final (live) management, and post-randomization factors such
weaning from all pharmacological or mechanical as type and dose of administered macronutrients,
hemodynamic support in PICU will be analyzed. and disease evolution [27].
5. Number of readmissions to the PICU. The 3. Long-term follow-up. This will include
proportion of patients readmitted within 48 hours developmental and neurocognitive assessments,
after discharge will be recorded. Also the proportion metabolic, endocrine, inflammation and (epi)genetic
of patients readmitted to the PICU beyond 48 hours studies, with a healthy matched control group
during their index hospital stay will be reported, as investigated over time in parallel.
these patients will have been excluded from
treatment allocation and will receive standard care. Data collection following recruitment
6. Liver dysfunction. Markers of liver function will be All systemically applied medications received by the pa-
measured and proportion of patients with abnormal tients during the stay in PICU are registered. Every day
tests will be compared. the quantities of kilocalories, carbohydrates, lipids and
7. Inflammation. Effect of the intervention on proteins delivered by either PN or EN are calculated and
inflammation will be analyzed by comparing markers entered into the electronic Case Record Form (eCRF).
of inflammation. Both peak values and time courses The need for and the number of days of mechanical ven-
will be analyzed. tilatory support, of mechanical and pharmacological
8. Duration of antibiotic treatment. The duration of hemodynamic support, of renal replacement therapies,
antibiotic treatment (whenever given) within the days on antibiotics and days requiring a central line are
intervention window and during the PICU-stay will recorded. Blood, urine, buccal mucosal swabs and hair
be compared between the groups. samples are taken upon PICU admission and during
PICU-stay. Such samples are appropriately handled (col- the clinical patient files and protocol compliance. Non-
lected on ice when required) and immediately stored (at compliance to the protocol and other questions or prob-
room temperature or at −20°C/−80°C as appropriate) for lems are reported to the study monitor and discussed
future measurements. Analyses on blood and urine for with the principal investigators and trial steering com-
the primary clinical analyses include routine chemistry, mittee. SAEs are reported to the study sponsor and, if
hematology, and markers of inflammation. Further meta- needed, to the local ethics committee. The study moni-
bolic, endocrine, inflammatory and (epi)genetic measure- tor regularly provides the sponsor and the DSMB with
ments on stored samples in the context of mechanistic reports on inclusions and SAEs. Regular meetings are
analyses are planned. For mechanistic and exploratory organized with principal investigators and clinical re-
studies, ultrasound evaluation of the skeletal muscle, in search teams to discuss the daily progression of the
combination with muscle strength measurements will be PEPaNIC trial.
performed in a subset of patients [28-30]. Quality of life The protocol has been instructed in each hospital to
on admission and after 4 to 6 months is recorded through all clinical medical and nursing staff through frequent
a validated, semi-structured questionnaire, filled out by teaching sessions and clinical feedback rounds. The
the parents, which is repeated at 2 and 4 years after enroll- protocol decision support is integrated into the PICU
ment in the PEPaNIC trial. PDMS in Leuven and Rotterdam, facilitating the pre-
scription of the exact amounts of PN and EN according
Data handling and record keeping to protocol and clinical evolution.
Data are collected electronically in an anonymized eCRF, In order to achieve adequate participant enrollment to
unambiguously linked to the source file. Data are manu- reach target sample size, regular meetings and site visits
ally transferred and checked for accuracy into the eCRF take place every 3 months together with the Rotterdam
by the clinical research assistants’ team on a daily basis. team and via teleconferences with the Edmonton team.
Extensive range and consistency checks are performed Regular data auditing is done by the administrative trial
by the study monitor. All original records, such as con- team, the DSMB and by the central independent audit
sent forms, eCRFs and relevant correspondence, will be procedure in place at the University Hospital of Leuven in
archived at the participating centers, according to the compliance with the European Trials Directives.
local regulations. Vital status at 90 days (and at later
follow-up times) will be recorded for all patients, by the Statistical analysis plan
National Death Registries. When this information is not One Consolidated Standards of Reporting Trials
available, vital status will be checked through the hos- (CONSORT) diagram will be reported.
pital information system or the regional network of pedi- Protocol compliance will be documented by comparing
atricians and general practitioners. the actual amounts of PN and EN during the interven-
All data are stored anonymously. Investigators in- tion window and this will be reported as absolute num-
volved in the trial do not have direct access to the data- bers of calories and weight units.
base. In addition, the study monitor has logged the use For the primary and secondary endpoints taking place
of the database. After the trial, the study monitor will during PICU-stay all data will be available. In case of re-
store all data in a secured file that is only accessible by quest for discontinuation of the study intervention by pa-
the study monitor himself. tients, parents or legal guardians, this will be respected,
but all data will be analyzed. In case of consent with-
Trial organization drawal, the parents will be asked whether the data can be
The sponsor (KU Leuven) provides direct access to the used for analysis. In case this would not be allowed, all
eCRF, the source data and the study master file for mon- data of that patient will be removed from the database,
itoring, for review by the independent ethics committee and this will be reported in the CONSORT diagram. At all
and regulatory inspection. The sponsor established an time, the intention-to-treat principle will be respected and
independent data safety monitoring board (DSMB). The reported. No data imputation will be undertaken for any
sponsor appointed one monitor. The monitor verifies of the primary or secondary outcomes.
that the trial is performed in accordance to the protocol Variables will be summarized as frequencies and per-
as described in the European Medicine Agency’s ‘Note centages, means and standard errors of the means, or
for guidance on good clinical practice CPMP/ICH/135/ medians and interquartile ranges, as appropriate.
95.’ as well as the Declaration of Helsinki. Monitoring Results will be analyzed with the use of chi-square test-
is performed and reported according to the sponsor’s ing, Student’s t-test or non-parametric testing (Wilcoxon
standard operating procedures. The clinical research rank-sum test, Van der Waerden test or Median test), as
team guarantees a daily follow-up of patient screening appropriate. Kaplan-Meier plots will be used to document
and inclusion, availability of requested clinical data in time-to-event effects, and the time-to-event effect size will
be estimated with the use of Cox proportional-hazard ana- assess any of the efficacy endpoints, no adjustments of the
lysis. All time-to-event analyses will also be performed on P-values are needed.
data censored at 90 days. As death is a competing risk for
duration of care outcomes, non-survivors will be censored Discussion
beyond the longest duration of such care required for sur- The clinical evidence for the administration of PN in crit-
vivors [19]. All outcomes will be analyzed both with and ically ill children is missing [18]. Thousands of children are
without adjustment for baseline risk factors, including the annually exposed to this non-evidence-based treatment,
diagnostic and age groups, severity of illness, severity of which is assumed to result in faster recovery (benefit). This
nutritional risk and center. The latter is considered neces- large international RCT will help PICU physicians to ob-
sary to account for the differences among centers in nutri- tain more insight into the possibility of the omission of PN
tion given to the control group and the variation in blood during the first week of critical illness. A significant differ-
glucose control targets. For these analyses, P-values will be ence in the safety and/or efficacy endpoints will provide
considered significant when at or below 0.05 without cor- important evidence for optimizing clinical patient care.
rection for multiple comparisons. To assess whether any Also a neutral result will provide important insight, as this
eventual impact of the intervention on the primary end- would mean that clinicians can safely withhold PN in all
points is affected by the baseline risk factor subgroups, comparable patients during the first week of ICU stay,
interaction P-values will be calculated (logistic regression which would have an impact on healthcare spending in the
or Cox proportional hazard analysis) with a threshold for PICU.
significance of interaction set at a P-value of < 0.1. All ana-
lyses will be conducted on an intention-to-treat basis. Trial status
The study was initiated as planned on 18 June 2012. At
Sample size calculation and interim analyses the time of the safety interim analyses (after 480 and 750
In the design phase of the PEPaNIC trial, and based on study patients discharged from PICU), the DSMB ad-
the previous adult EPaNIC trial results, the sample size vised the continuation of the trial and ratified the initial
(N = 1,440, 720 patients per arm) was determined in sample size of 1,440 patients as adequate to test the hy-
order to detect a reduction in the incidence of new in- pothesis. On 1 December 2014, 1,130 patients have been
fections during PICU-stay from 20 to 15% (Absolute included into the PEPaNIC trial. Recruitment of the last
Risk Reduction 5%), with at least 80% 1-tailed power patient is expected for October 2015.
and at least 70% 2-tailed power and at an alpha error of
5%. With this sample size, the trial can also detect a Abbreviations
CONSORT: Consolidated Standards of Reporting Trials; DSMB: data safety
major safety issue, such as a doubling of the PICU mor- monitoring board; eCRF: electronic case record form; EN: enteral nutrition;
tality rate from 4% (the baseline mortality in the Leuven ESPGHAN: European Society of Paediatric Gastroenterology, Hepatology and
center) to 8% with a statistical power of 89% in a 2-sided Nutrition; FAO-WHO: Food and Agriculture Organization-World Health
Organization; PDMS: patient data management system; PELOD: PEdiatric
test with an alpha error of 5%. This sample size will also Logistic Organ Dysfunction; PEPaNIC: impact of withholding early parenteral
allow to detect a reduction in mean duration of stay in nutrition completing enteral nutrition in pediatric critically ill patients -
PICU of 1 day with at least 90% power (2-tailed) and Pediatric Early versus Late Parenteral Nutrition in Intensive Care Unit;
PICU: pediatric intensive care units; PN: parenteral nutrition; PRISM: Pediatric
95% certainty. RISk of Mortality; RACHS score: Risk-Adjustment in Congenital Heart Surgery
Two interim analyses of the safety endpoints (except score; RCT: randomized controlled trial; RDA: Recommended Dietary
90-day mortality) only were planned (after inclusion of Allowances; RRT: renal replacement therapy; SAE: serious adverse event.
480 upon specific request of the DSMB, and after inclu- Competing interests
sion of 50% of the study population). It was a priori de- The authors declare that they have no competing interests.
cided to determine the actual incidence of new infections
during PICU-stay in the 3 centers, as this was not known Authors’ contributions
TF: participated in the design of the study and analysis plan, helped to draft
exactly for each of the participating centers prior to trial the manuscript. DK: participated in the design of the analysis plan, helped to
initiation. In order to allow statistical repowering and to draft the manuscript. SV: participated in the design of the study, revising the
judge the necessity of inclusion of more trial sites, the as- manuscript for important intellectual content. IV: participated in the design
of the study, revising the manuscript for important intellectual content. SV:
sessment of incidence of new infections during PICU-stay revising the manuscript for important intellectual content. DT: revising the
in the control group took place after inclusion of 750 pa- manuscript for important intellectual content. GGG: revising the manuscript
tients. Based on this actual incidence of new PICU infec- for important intellectual content. PJW: participated in the design of the
study, revising the manuscript for important intellectual content. AJ: revising
tions in the control group, the hypothesized absolute risk the manuscript for important intellectual content. KJ: participated in the
reduction of 5% and an alpha error rate of 5%, the sample design of the study, revising the manuscript for important intellectual
size of 1,440 patients (720 patients in each arm) was found content. DM: conceived the study, study design and analysis plan, helped to
draft the manuscript. GVdB: conceived the study, study design and analysis
sufficiently large to yield a statistical power of 77% 2-sided plan, helped to draft the manuscript. All authors read and approved the final
and of 85% 1-sided. As these interim analyses did not manuscript.
Acknowledgements 15. Hardy CM, Dwyer J, Snelling LK, Dallal GE, Adelson JW. Pitfalls in predicting
The study is funded by the Agency for Innovation by Science and Technology resting energy requirements in critically ill children: a comparison of
(IWT-TBM 110685), Fonds NutsOhra and the Erasmus - Trustfonds. predictive methods to indirect calorimetry. Nutr Clin Pract. 2002;17:182–9.
GVdB, through the University of Leuven, receives long-term structural 16. White MS, Shepherd RW, McEniery JA. Energy expenditure in 100 ventilated,
research financing via the Methusalem program, funded by the Flemish critically ill children: improving the accuracy of predictive equations.
government (METH/08/07 and METH/14/06) and holds a European Research Crit Care Med. 2000;28:2307–12.
Council Advanced Grant (AdvG-2012-321670) from the Ideas Program of the 17. Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, et al.
EU FP7. DM holds a Senior Clinical Investigator Fellowship of the Research ESPEN Guidelines on Parenteral Nutrition: intensive care. Clin Nutr.
Foundation FWO-Flanders. 2009;28:387–400.
18. Joffe A, Anton N, Lequier L, Vandermeer B, Tjosvold L, Larsen B, et al.
Nutritional support for critically ill children. Cochrane Database Syst Rev.
Study sponsor 2009;CD005144.
KU Leuven Research and Development, Waaistraat 6 bus 5105, B-3000 19. Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G,
Leuven, Belgium. et al. Early versus late parenteral nutrition in critically ill adults. N Engl J
Med. 2011;365:506–17.
Author details 20. Doig GS, Simpson F, Sweetman EA, Finfer SR, Cooper DJ, Heighes PT, et al.
1
Clinical Department and Laboratory of Intensive Care Medicine, Academic Early parenteral nutrition in critically ill patients with short-term relative
Division Cellular and Molecular Medicine, KU Leuven University and Hospital, contraindications to early enteral nutrition: a randomized controlled trial.
Herestraat 49, B-3000 Leuven, Belgium. 2Intensive Care Unit, Department of JAMA. 2013;309:2130–8.
Pediatrics and Pediatric Surgery, Erasmus Medical Center, Sophia Children’s 21. Heidegger CP, Berger MM, Graf S, Zingg W, Darmon P, Costanza MC, et al.
Hospital, Rotterdam, The Netherlands. 3Department of Pediatrics, Intensive Optimisation of energy provision with supplemental parenteral nutrition in
Care Unit, University Alberta, Stollery Children’s Hospital, Edmonton, AB, critically ill patients: a randomised controlled clinical trial. Lancet.
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22. Hulst JM, Zwart H, Hop WC, Joosten KF. Dutch national survey to test the
Received: 4 December 2014 Accepted: 22 April 2015 STRONGkids nutritional risk screening tool in hospitalized children. Clin Nutr.
2010;29:106–11.
23. Schofield WN. Predicting basal metabolic rate, new standards and review of
previous work. Hum Nutr Clin Nutr. 1985;39(Suppl):5–41.
24. Vlasselaers D, Milants I, Desmet L, Vanhorebeek I, van den Heuvel I, Mesotten D,
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www.biomedcentral.com/submit

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Protocol

1. Original protocol, final protocol, summary of changes.

For the Erasmus Universiteit Rotterdam:

For Stollery Children’s Hospital Edmonton:

For the Erasmus Universiteit Rotterdam:

For Stollery Children’s Hospital Edmonton:

Impact of Early Parenteral Nutrition Completing Enteral Nutrition

SYNOPSIS OF STUDY RATIONALE ......................................................................... 2

The PEPaNIC-study is an investigator-initiated, non-commercial, multi-centre randomized controlled, parallel

Principal Investigators for the KULeuven:

Prof. Dr. Dieter Mesotten

Principal Investigators for the Erasmus Universiteit, Rotterdam:

Secondary - Mortality up to 90 days post-randomization.

- Patients with a DNR code at the time of ICU admission.

Laboratory tests: Will be performed by Labo Intensieve Geneeskunde KU Leuven.

IV. STUDY POPULATION

4.1. Inclusion Criteria

4.2. Exclusion criteria

- Patients with a DNR code at the time of ICU admission.

4.4. Withdrawal of patients from the study

VI. STUDY PROCEDURES

6.1. Written informed consent

6.3. Feeding schedules

a.1. Early PN (control arm of the study)

a.2. Late PN (intervention arm of the study)

VII. INVESTIGATIONAL PRODUCTS

VIII. OUTCOME MEASURES

8.1. Primary outcome

8.2. Secondary outcome

- Death (ICU, hospital, 90-day mortality):

8.3. Complications possibly related to nutrition management

*Complications possibly related to enteral feeding

*Complications possibly related to parenteral feeding

IX. ADVERSE EVENTS

Hypoglycemia (< 40 mg/dL) resistant to iv glucose administration will be considered as a serious

10.1. Sample size

10.2. Efficacy variables and analysis

10.3. Safety variables and analysis

XI. ADMINISTRATIVE AND LEGAL ASPECTS

Protocol Enterale Voeding op de PICU

Absolute Contra indicaties:

Relatieve Contra indicatie:

Informed consent formulier : PEPaNIC

In de hoop op uw medewerking te kunnen rekenen, danken wij U bij voorbaat,

Prof Dr Dieter Mesotten Prof Dr Greet Van den Berghe

Ik, ondergetekende, heb de nodige inlichtingen gekregen betreffende het onderzoek

Naam en relatie tot de patiënt

Leuven, ….. / ……./ 201…

Een duplicaat van het IC werd aan de tegenpartij overhandigd

1. Temperature >38°C rectal or <36°C rectal

2. Heart rate > 90th percentile for age

3. Respiratory rate > 90th percentile for age or hyperventilation to PaCO2<32mmHg

4. Wbc count >12000cells/mm3 or <4000

SEPSIS = SIRS secondary to a systemic infection

Sepsis + any one of the following

1. Glasgow coma scale <15( in the absence of CNS disease)

1. Requirement for inotropic or vasopressor effect (excluding dopamine >6microgram/kg/min)

2. Glasgow coma scale <15( in the absence of CNS disease)

At admission: determine STRONGkids

Early PN completing EN EN only

! start EN within 6 hrs start EN within 6 hrs

If 7 days after admission EN

Oral nutrition < 50% caloric

Stop TPN as soon as 80% of