Transcript REDOXS© Trial Pilot - Critical Care Nutrition

A Randomized Trial of Supplemental Parenteral Nutrition in
Under and Over Weight Critically Ill Patients:
©
The
REDOXS
Study
The TOP UP Trial
REducing Deaths due to OXidative Stress
October 17th 2011
Study Sponsor: Dr. Daren Heyland
Project Leader: Rupinder Dhaliwal
Project Assistant: Roger Leung
Clinical Evaluation Research Unit
Protocol: Version March 28th 2011
Background & Objectives
• Point prevalence survey of nutrition practices in
ICU’s around the world conducted Jan. 27, 2007
• Enrolled 2772 patients from 158 ICU’s over 5
continents
• Included ventilated adult patients who remained in
ICU >72 hours
What study patients actually received?
• Average Calories in all groups:
– 1034 kcals and 47 gm of protein
Result:
• Average caloric deficit in Lean Pts:
– 7500kcal/10days
• Average caloric deficit in Severely Obese:
– 12000kcal/10days
Relationship of Caloric Intake, 60 day Mortality and BMI
60
BMI
All Patients
< 20
20-25
25-30
30-35
35-40
>40
Mortality (%)
50
40
30
20
10
0
0
500
1000
Calories Delivered
1500
2000
ICU patients are not all created equal…should
we expect the impact of nutrition therapy to be
the same across all patients?
TOP UP Trial: Hypothesis
Increased early energy and protein
delivery with PN+EN to underweight
(BMI < 25) and obese (BMI ≥ 35) critically
ill patients will result in improved
survival at 60 day versus standard EN
alone
Objectives
• Perform an initial multi-center pilot study in
Canada,USA, France & Belgium in 160 patients to
demonstrate feasibility
• Assuming feasibility, large-scale 2000 patient multicenter, multinational trial will be undertaken
Study Design
Randomized Trial (unblinded)
EN only
Primary
Outcome
ICU patients
BMI <25
BMI >35
Fed enterally
R
Stratified by:
Site
BMI
Med vs Surg
On EN
60-day
mortality
EN plus supplemental PN for 7 days
Objectives: Pilot Study
Primary Aim:
• Difference in the calories and protein received between the control and
intervention groups
• Estimate recruitment rate
• Evaluate the safety, tolerance, and logistics around providing
supplemental PN in the study population, e.g.
• To ensure adequate glycemic control in both groups
• To ensure other metabolic consequences of the feeding strategies
are minimized
• To establish adequate compliance with study protocols and
completion of case report forms.
Secondary Aims:
• Explore the effect of differential intake of protein/energy on muscle mass
and muscle function.
Outcomes:Pilot study
Primary outcome: 60 day mortality
Secondary outcomes:
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ICU (28 day) mortality
Hospital mortality
Duration of mechanical ventilation
Duration of stay (ICU and hospital)
Development of ICU-acquired infections
Multiple organ dysfunction (SOFA and PODS)
Functional status, HR QOL at 3 & 6 months
Muscle Function Tests
Imp Manual p 9
Study Overview
Pilot Study: Participating Sites
Target: 160 patients from 9 institutions
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Royal Alexandra Hospital, Edmonton (Jim Kutsogiannis)
University of Alberta Hospital, Edmonton (Dean Karvellas)
University of Colorado, US (Paul Wischmeyer )
Erasme University Hospital, Brussels (Jean Charles Preiser)
Hôpitaux Universitaires, Strasbourg, France (Michael Hasselmann)
Grey Nun’s Hospital, Edmonton (Dan Stollery)
University of Wisconsin (Ken Kudsk)
University of Vermont (Renee Stapleton)
Oregon Health Sciences University (Robert Martindale)
TOP UP Teamwork
Site Investigator
Nurse
Regulatory
Adjust EN + PN hourly
Inclusion/exclusion criteria Product Reconstitution?
Pharmacist ICU infection adjudication
SAE reporting
Checking allocation
Dispensing
Logs
Dietitian
Study Coordinator
Regulatory
Screening/Randomization
Pharmacy communication
Data collection
Study intervention monitoring
Collaboration with SI
SAE reporting
Protocol Violation reporting
Dosing Calculation
Optimizing nutrition
Monitoring Adequacy
Role of Site Investigator
Delegation of Authority
Patient Eligibility
ICU Infection adjudication
SAE identification/assessment
Investigator Confirmation
Imp Manual p 11,12
Delegation of Authority Logs
“The Investigator should maintain a list of appropriately qualified persons
to whom the investigator has delegated significant trial-related duties
(ICH section 4.1.5)”
Completed Log to be sent to CERU before start of trial
Imp Manual p 13, CRFs
Inclusion Criteria
1) Mechanically ventilated adult patients (≥18 years old)
2) Expected to remain mechanically ventilated for more than 72 hours
3) On enteral nutrition or expected to initiate enteral nutrition within 48
hours from ICU admission
Interpret “48 hrs” as “7 days” due to exclusion criteria # 4
4) BMI < 25 or >35 based on pre-ICU actual or estimated dry weight
If using estimated weight/height, you may add a buffer of  1
for BMI after rounding
Imp Manual p 14, CRFs
Exclusion Criteria
1.
>48 hours from admission to ICU to time of consent (any ICU)
2.
Not expected to survive an additional 48 hours from screening
evaluation
3.
Lack of commitment to full, aggressive care (anticipated withholding or
withdrawing treatments in the first week but isolated DNR acceptable)
Imp Manual p 14, CRFs
Exclusion Criteria
4.
Patients with an absolute contraindication to EN deemed to require PN
for the first 7 days of ICU admission (e.g. GI obstruction or no GI tract access for
any reason)
Inclusion criteria #3 means this will never be captured
5.
Already at goal rate of Enteral Nutrition at screening evaluation (at ≥
60% target rate and no evidence of intolerance i.e. high GRVs)
What about patients that have not been challenged with EN?
To enrol the right type of patient
AS A GUIDELINE
if patient has not been challenged with EN…
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 is NOT at risk for EN intolerance  is at risk for EN intolerance
Refer to list of risk factors for GI intolerance
Imp Manual p 15
Risk Factors for EN Intolerance
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High APACHE Scores (>25)
On more than 1 pressor, or increasing doses of pressors
Receiving continuous infusion of narcotics
High NG/OG output (> 500 mls over 24 hrs)
Recent surgery involving esophagus, stomach or small bowel OR
peritoneal contamination with bowel contents
Pancreatitis
Multiple GI investigations
Recent history of diarrhea/ C.difficile
Surgical patients with future OR’s planned
Abdominal Aortic Aneurysm (emergency vascular surgery)
Imp Manual p 15
Imp Manual p 14, CRFs
Exclusion Criteria
6.
Patients already receiving PN on admission to ICU (does NOT refer to
those that received PN in hospital prior to this acute episode of
illness)
7.
Patients with diabetic ketoacidosis or non ketotic hyperosmolar coma
8.
Pregnant or lactating patients
9.
Patients with clinical fulminant hepatic failure (see definition)
10.
Dedicated port of central line not available
11.
Known allergy to study nutrients (soy, egg or olive products)
12.
Enrolment in another industry sponsored ICU intervention study
(co- enrollment in academic studies will be considered on a case by case basis)
Eligibility confirmation
Prompted at time of Pre randomization
Refer to Consent
Training Slides
Infection Adjudication
Site Investigator to make determination of a
newly acquired infection based on antibiotic
and microbiology data
Infection Adjudication
CRS/REDCAP manual p 21-27
CRFs p 40, 41
Suspicion of ICU Infection:
Antibiotics
• Is this antibiotic prescribed for prophylaxis?
• Is this a substitute for an antibiotic previously ordered for
an infection that occurred within 72 hrs of admission to
ICU?
NO to both
Clinical Suspicion of Infection
Need adjudication by
Site Investigator/MD Delegate
YES to either
No adjudication needed
CRFs p 42, 43
Suspicion of ICU Infection:
Microbiology
Is this organism a manifestation of an infection that
occurred within the first 72 hrs of admission?
NO
Clinical Suspicion of Infection
Need adjudication by
Site Investigator/MD Delegate
YES
Indicate if:
Relapse/Recurrent OR
Persistent infection
No adjudication needed
CRS/REDCAP Manual p 24
Infection Adjudication: REDCAP
This is a newly acquired infection
This is NOT a newly acquired infection
This is a previously adjudicated infection
Infection Adjudication
Site Investigator will need:
1. Access to view the Infection Adjudication table on
REDCAP (Research Coordinator to show this)
2. Appendix 9 Categories of Infection
3. Appendix 10 Definitions of No Newly Acquired Infection
4. Medical Chart
Refer to CRS/REDCAP Manual pages 21-27 for step by
step process
SAE Identification and Reporting
Imp Manual p 38-49
SAE Identification
A serious adverse event is any untoward medical occurrence that at any
dose,
 Results in death
 Is life threatening (the subject was at immediate risk of death from the event
 Results in persistent or significant disability/incapacity
 Requires in patient hospitalization possibly related to the use of the study
materials
 Prolongs of hospitalization.
 Is a congenital anomaly or birth defect
 Is an important medical event that may jeopardize the patient and may
require medical or surgical intervention to prevent one of the outcomes listed
above medically important condition
An unexpected adverse event is that event that is NOT expected due to
the progression of the underlying disease or co-morbid illnesses.
Adverse Event must be serious and unexpected to be reported
Imp Manual p 40
SAE Reporting (to CERU)
Must be done on
electronic data capture
system and faxed to
CERU
Imp Manual p 42-44
Imp Manual p 45-48
Imp Manual p 45-48
Imp Manual appendix J
SAE Reporting to Regulatory Bodies
If SAE is related,
CERU will report to
Regulatory bodies,
Sites and Baxter
within 7 days (fatal) or
15 days (non fatal)
CRS/REDCAP Manual p 30
Investigator Confirmation
Imp Manual p 17
Study Groups
Name of Group
Supplemental PN
EN only
Intervention
EN (enteral nutrition) plus
Olimel
EN
Dosing Procedures
(both groups)
Dosing of the intervention will depend upon the energy and
protein needs of the patient
To be determined by the dietitian/MD
Protocol, Imp Manual p 25
Protein and Calorie needs
Guidelines for Dosing of Protein and Energy Based on BMI
Upon enrolment, the dietitian/MD will:
1.
Calculate prescribed energy and protein intake as per standard practice
2.
Ensure that minimum energy and protein needs are met as follows
Minimum Energy
Minimum Protein
BMI<25
25 kcals/kg actual wt
1.2 g/kg actual wt
BMI ≥ 35
20 kcals/kg ABW*
1.2 g/kg ObesityABW*
*Obesity-adjusted Body weight= IBW + [actual weight – IBW] x 0.25,
where IBW is ideal body weight (BMI of 25)
Imp Manual p 25
Prescribed Volume
3. Determine the prescribed volume for EN (or study PN, or EN + study
PN) in mls/24 hrs to meet the prescribed energy and protein needs
MUST use enteral formula of 1.2  0.2 kcal/ml
Meet protein needs over energy needs
4. Determine the hourly rate of EN (or study PN, or EN + study PN)
(assume PN = 1 Kcal/ml)
Must be done
asap after
randomization
Study Tools
Minimum Energy and Protein calculator
Minimum energy
BMI < 25 25 kcals/kg actual weight
Minimum Protein
1.2 g/kg actual weight
BMI ≥ 35 20kcals/kg ABW*
1.2 g/kg Obesity– ABW*
*ABW=adjusted body weights. Weights in obese patients to be calculated
according to the following formula:
Obesity-adjusted body weight= IBW +[actual weight-IBW] X 0.25 where IBW
is ideal body weight based on BMI of 25
1) BMI Calculator
Height =
Weight =
BMI =
cm
kg
2) Minimum Energy and Protein Intake
If BMI < 25,
Minimum Energy =
kcal
Minimum Protein =
g
If BMI ≥ 35,
Minimum Energy =
Minimum Protein =
kcal
g
This calculator assumes the height and weight have been estimated and
automatically allows for a buffer of 1 BMI.
Other considerations…Propofol
Propofol calories to be factored into assessment of
caloric needs, only as per discretion of
dietitian/MD
Imp Manual p 17
Enteral Nutrition (both groups)
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Enteral Nutrition to start as per usual practice (patient stabilized, NG/Feeding
tube in place)
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Standard enteral nutrition formula 1.0 to 1.4 kcals/ml
» (hypercaloric formulas not allowed)
» NO protein supplements (for 7 days)
» NO probiotics (for 7 days)
» NO glutamine supplements (for 7 days)
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Start at 25 ml/hr and increase every 4 hrs as tolerated until goal rate
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Discontinue when the feeding tube comes out
Refer to Enteral Nutrition Algorithm & Paired Feeding
Algorithm appendices C & F
Imp Manual p 18
Trace Elements and Multivitamins
• DO NOT add to the PN solution
• If patient does not receive EN and is dependant on PN for >48 hrs,
IV supplementation is recommended
Suggested guidelines
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Standard doses of multivitamins
5 mg zinc
1 mg copper
0.5 mg manganese
10 mg chromium
60mcg selenium.
doses can be adjusted
at discretion of the
medical team
• use commercially available trace element solutions
Dietitian
Determine Energy/protein needs (prescribed Volume)
Follow Canadian Clinical Practice Guidelines
Assist with data collection
Baseline Nutrition Assessment
Daily EN monitoring
Daily PN monitoring (non study PN)
Baseline Nutrition
CRFs p 12-13
CRFs p 20-21,23
Daily EN Monitoring
CRFs p 22, 24
Daily PN Monitoring (non study PN)
CRFs p 3
Study Days and Data Collection
Data MUST be collected according to calendar day as described below
Do NOT collect data according to your flow sheet unless it runs from
07:00-07:00
Supplemental PN group
Imp Manual p 17,18
Olimel N9E (5.7%)
Amino acids
3-in-1 PN solution that contains
glucose, lipid emulsion and an amino
acids
Dextrose
Blend of desirable lipids: olive oil,
soybean oil (ratio 80/20)
Alpha-tocopherol/moderate PUFA,
better vitamin E status
less lipid peroxidation.
Protein and energy content of Olimel
N9E enables the maintenance of an
adequate nitrogen/energy balance
Lipid emulsion
Spike insertion site
1 Litre bags, provided by Baxter
Product monograph
Olimel N9E (with electrolytes)
Imp Manual p 18
Olimel N9E
Once reconstituted, will be a milky color
Unmixed product: store between 15 to 30 degrees C. Do not
Freeze. Once reconstituted, use immediately
If pre-activation occurs at time of delivery, do not use and
report to Baxter
Dedicated Central line needed,
piggybacking with other lines not
recommended unless standard practice
for PN at your site
Imp Manual p 19
When to start Olimel?
Start as soon as central line access
Preferably within 2 hrs of randomization
Imp Manual p 19-20
Paired Feeding
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Enteral and parenteral solutions provided continuously over 24 h
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Rate of PN depends upon rate of EN
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Adjust PN hourly so that EN + PN = target rate as determined by
dietitian/MD
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Initiate PN study solution at 25 ml/hr (or faster) and advance by 25 ml q
4 hrs to target rate as tolerated
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Monitor blood sugars and electrolytes every 4 hrs as needed
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Do not advance PN/EN if BS, K, Phosp, Mag becoming more
abnormal (ranges as per your local site)
To reach the target combined rate by
EN plus PN within 24 hrs from
randomization
Imp Manual appendix F
Imp Manual p 24
Sample MD orders
(Supplemental Group)
Imp Manual p 20
Duration of Study Intervention
ICU admission
Randomization
Consent to be obtained
within 48 hrs from
ICU admit
Study Intervention
7 days post randomization
Imp Manual p 19
Before or at 7 days: Supplemental Group
Duration of intervention = ICU admission to 7
days post randomization
ICU admit
If d/c from ICU to ward
prior to 7 days
Continue study PN until:
• 50 % goal rate until day 7 OR
• until patient tolerating adequate
po intake, whatever happens first
NO daily titration needed
7 days post randomization
If in ICU & PN indicated,
use Olimel
If out of ICU & PN indicated,
use standard PN
Imp Manual p 20
Use of Non Study Parenteral Nutrition
If parenteral nutrition is truly indicated
 In ICU: use Olimel until study day 28 maximum
 When on floor after ICU: use standard PN
Both groups:
If non study PN
received
before 7 days
PROTOCOL VIOLATION
Report to CERU asap
EN only group
Imp Manual p 17-18
Enteral Nutrition
•
Enteral Nutrition to start as per usual practice (patient stabilized and
NG/Feeding tube in place)
• Standard enteral nutrition formula
• 1.0 to 1.4 kcals/ml
» (hypercaloric formulas not allowed)
» NO protein supplements (for 7 days)
» NO probiotics (for 7 days)
» NO glutamine supplements (for 7 days)
• Start at 25 ml/hr (or and increased every 4 hrs as tolerated until goal
rate
• Discontinue when the feeding tube comes out
Refer to Enteral Nutrition Algorithm
Imp Manual appendix C
Imp Manual p 21
Before or at 7 days: EN only group
Duration of intervention = ICU admission to 7
days post randomization
ICU admit
If within 7 days, PN is clinically
indicated and still in ICU,
Use Olimel
If Olimel or any PN is received before 7
days, this is considered a Protocol
Violation and must be reported to CERU!
7 days post randomization
If after 7 days,
PN is clinically indicated and
still in ICU use Olimel
If out of ICU & PN indicated,
use standard PN
Both groups
EN only &
Supplemental PN group
Imp Manual p 18
Trace Elements and Multivitamins
• DO NOT add to the PN solution
• If patient does not receive EN and is dependant on PN for >48 hrs,
IV supplementation is recommended
Suggested guidelines
–
–
–
–
–
–
Standard doses of multivitamins
5 mg zinc
1 mg copper
0.5 mg manganese
10 mg chromium
60mcg selenium.
doses can be adjusted
at discretion of the
medical team
• use commercially available trace element solutions
Imp Manual p 18
Co-interventions
Follow Canadian Nutrition Guidelines
Glycemic Control Protocol
Daily sedation vacations
Sepsis management guidelines
Daily trials of weaning from mechanical ventilation
Investigational Product
Dispensing & Storage
Pharmacy
For most sites, the pharmacy may only be involved in the initial
receipt of the Olimel.
The Research Coordinator/delegate will therefore be responsible
for the following:
 storage of Olimel
 dispensing of Olimel (including addition of labels)
 completion of dispensing and accountability logs
 sending temp logs to CERU monthly
 maintenance of inventory and destruction of the
expired/unused product
CRS/REDCAP Manual p 12
Central Randomization System
Upon randomization, Research Coordinator will be notified of the study group
the patient has been randomized to
EN only or
EN + Supplemental PN
Imp Manual p 22-23
Supplemental PN
For day 1:
Research Coordinator to obtain hourly rate of infusion
from dietitian/MD
Prepare enough 1 litre bags of the
investigational product to last one day
Example: Dietitian/MD has determined that the hourly rate is 65
ml/hr:
the total volume needed for 1 day would be 65 X 24 = 1536 mls.
The pharmacist /delegate is to prepare 2 X 1 Litre bags of the
product.
In order to prevent running out of product before the bag
change time, you may need to send 2 X 1 litre bags on day 1
Supplemental PN
For Subsequent days:
The Research Coordinator to determine how much enteral
nutrition the patient is anticipated to tolerate and will prepare
enough Olimel accordingly.
Example:
1. Goal rate = 65 ml/hr
2. Patient tolerating 25 ml/hr well today (or expected to)
3. Prepare enough product for remaining volume = 40 ml/hr X 24
= 960 mls = 1 X 1 litre bag
Olimel in overpouch
After removing pouch, check the Oxygen indicator
Black
Light yellow
brown
Check non permanent seals
Confirm the integrity of the bag and of the nonpermanent seals.
Use only if the bag is
 not damaged, if the non-permanent seals are intact (i.e. no mixture of
the contents of the three compartments)
 if the amino acids solution and the glucose solution are clear, colourless
practically free of visible particles, and
 if the lipid emulsion is a homogeneous liquid with a milky appearance
1. Ensure that the product is at room temperature when breaking the non- permanent seals
2. After removing overpouch, manually roll bag from hanger side down
Continue rolling the bag until all non permanent seals are broken ½ way
Solution turns milky showing that the seals are broken (1/2 way)
Mix well by inverting the bag 3 times
Solution will turn to a milky color & is ready to hang
Imp Manual p 23
Labels
Study: The TOP-UP Study
ID #: NCT01206166
Olimel N9E
Unblinded labels
PARENTERAL USE ONLY
Appx 3” x 5” size
Canadian Sponsor: Dr. Daren Heyland
Clinical Evaluation Research Unit, Kingston
General Hospital,
76 Stuart St, Kingston, ON K7L 2V7
Generate and attach 1 label for
outside of reconstituted bag
Randomization #: _________
Patient ID: ________________
Patient Name: _____________
Directions: Run at maximum goal rate of
XX ml/hr and titrate down as enteral feeds
increase.
Storage: Room temperature
Expiration: 24 hrs
Labels must be placed on extra
bags needed for after hours
(expiration date and time must be
recorded…..by RN)
Imp Manual appendix D
Imp Manual appendix E
Imp Manual p 26
Nursing Procedures
Training Slides available on
Reconstitution of Olimel
www.criticalcare nutrition.com
Overview of steps and timelines
Screen patient
Eligible patient
(checked by MD)
Research Coordinator obtains consent
Randomizes patient on CRS
Dietitian determines dosing of calories and protein
Writes sample entry Note in chart
Facilitates Medical Orders in chart
Research Coordinator/Pharmacist
dispenses product for patient
Research Coordinator informs RN
Patient started on intervention
48 hrs + 2
hrs from
admission
Muscle Function
Tests
Imp Manual p 28-30, CRFs 32-33
Weekly U/Sounds
Why?
To assess Muscle Layer Thickness (MLT) of the M.
vastus intermedius and M. rectus femoris
When?
Weekly PLUS within 72 hrs of CT Scan
Whom?
• To be done by site investigator or designated
clinician (RN specialist, R Coordinator, RN, fellow)
How?
Refer to Ultrasound Procedure pages 28-39 Imp Manual
CRF p 34-35
Abdominal/Pelvic CT Scan
Why?
Assess muscle mass (at 3rd lumbar vertebrae) as a predictor of
lean tissue mass
When?
CT Scans done 1-2 days prior or after ICU admission and all
subsequent scans
Whom?
Research Coordinator to retrieve scans of previously done CTs and
obtain copies and send DE-IDENTIFIED to University of Waterloo
How?
• CT Images already performed for clinical reasons
• Not to be done for the study if not clinically indicated
Mourtzakis M et al Critical Care Canada Forum, 2009.
Imp Manual p 31
Hand Grip Strength
Why?
To assess the physical strength
When?
ICU discharge
Whom?
To be done by the Research Coordinator
How?
•
On a patient that is awake and attentive, upright with elbow at 90
degrees
•
Using a hand dynamometer (Jamar) on dominant hand, three
readings (sustained 5 sec, rest for 15 sec between)
•
REFER TO HAND GRIP STRENGTH TEST MODULE (SLIDES)
Imp Manual p 32-34
6 Minute Walk Test
Why?
One time measure of functional status of patients
When?
Prior to hospital discharge
Whom?
To be done by the Research Coordinator
How?
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Calculate the total distance walked by patient in 6 minutes.
On a patient that is able to walk, need a long corridor (30 metres)
Patients with recent unstable angina are excluded
Ensure that the patient is safe, chair nearby
Worksheets, specific instructions, script provided
CRF page 36,37
Rehab Practices
Need to get from physio, RN flowsheet or RN
(daily)
Imp Manual
Research Coordinator Procedures
Consent (Training Module)
Training of nurses
Data Collection
Protocol Violations
CRFs Oct 17th 2011
Case Report Forms
CRS/REDCAP Manual Oct 17th 201l
Resources online
www.criticalcarenutrition.com