Download REDOXS© Trial Pilot - Critical Care Nutrition

©
The REDOXS Study
REducing Deaths due to OXidative Stress
The REDOXS© Study
REducing Deaths from OXidative Stress
Study Chair
Dr. Daren Heyland, MD, FRCPC
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Project Leader
Rupinder Dhaliwal, BASc, RD
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Research Questions
In critically ill patients with severe organ
dysfunction, what is the effect of:
1) Glutamine supplementation compared to
placebo on 28-day mortality?
2) Antioxidant supplementation compared to
placebo on 28-day mortality?
Effect of Glutamine:
A Systematic Review of the Literature
Mortality
www.criticalcarenutrition.com
Effect of Glutamine:
A Systematic Review of the Literature
Infectious Complications
www.criticalcarenutrition.com
Effect of Combined Antioxidant
Strategies in the Critically Ill
Effect on Mortality
Inferences
Glutamine/day
Antioxidants
per day
Parenterally
Enterally
0.35 gms/kg
30 gms
500 mcg
Selenium
Vit C 1500 mg
Vit E 500 mg
B carotene 10 mg
Zinc 20 mg
Se 300 ug
• High dose appears safe
• High dose associated with
–
–
–
–
no worsening of SOFA Scores
greater resolution of oxidative stress
greater preservation of glutathione
Improved mitochondrial function
Heyland JPEN Mar 2007
Design
antioxidants
Factorial 2x2 design
1200 ICU patients
Evidence of
organ failure
glutamine
R
R
placebo
antioxidants
placebo
R
placebo
Study Groups
GLN +AOX
Enteral
Supplement
Parenteral
Supplement
Glutamine + AOX
Dipeptiven +
Selenium
Placebo +
Selenium
Dipeptiven +
Placebo
Placebo +
Placebo
AOX
AOX only
GLN
Glutamine only
Placebo
SC blinded
Placebo
Pharmacist unblinded
©
REDOXS
Teamwork
Site Investigator
Pharmacist
Regulatory
Inclusion/exclusion criteria
ICU infection adjudication
SAE reporting
Checking allocation
Dispensing
Logs
Dietitian
Study Coordinator
Regulatory
Screening/Randomization
Pharmacy communication
Data collection
Supplement monitoring
Collaboration with SI
SAE reporting
Protocol Violation reporting
Optimizing nutrition
Monitoring Adequacy
Optimizing Enteral Nutrition
Canadian CPGs
www.criticalcarenutrition.com
Feeding Protocol
Elevate the Head of the Bed
Motility Agents
Small Bowel Feeding
Baseline Nutrition
Dietitian to collect:
• Prescribed kcal and
protein (baseline)
• Type of nutrition
support
• Start and stop date and
times
• Refer to Dietitian
Manual
Dietitian Checklist
Study Supplement Compliance
• Volumes must be
monitored DAILY in
real time.
• If volumes <
prescribed, need to
report to CERU or
provide explanation and
take action to prevent
recurrence.
Protocol Violation
Protocol Deviation
Administration of Study
Supplements
Enteral Study Supplement
EN REDOXS © Formula
Parenteral Study Supplements
(Dipeptiven and Selenium)
+
Start of Supplements
• Start ASAP
– within 24 hrs of admission to ICU
– within 2 hrs of randomization
• Duration: 28 days or death or discharge
– min of 5 days
• Parenteral supplements
–
–
–
–
as soon as patient resuscitated
10 ml/hr dedicated central port (eg. one of a triple lumen)
can run peripherally if needed (watch for phlebitis)
Do NOT infuse with medications; IV fluids, albumin, nutrition OK
• Enteral supplement
– NG tube OK or feeding tube
– 20 ml/hr, can be given via Y connector
– start regardless of whether docs want to start enteral nutrition
• Maximize EN nutrient and nutrition delivery
– use of feeding protocols
– small bowel feeding
• Minimize interruptions, make up volume
• Other enteral formulas with supplmental glutamine, vitamins,
minerals not allowed
– No supplements with high amounts of Zinc
• Renal Dysfunction
– Switch to lower protein formula
– Restrict fluid
– Refer to appendix
Pilot study: Interruptions due to high urea only in
2% patient days (9% patients)
If received volumes < Prescribed = Protocol Violation……….notify
Methods Centre !!
Screening and Randomization
Web Login Page
Welcome Home Page
(Site Status Page)
Patient Status Page
Inclusion/exclusion criteria
Refer to inclusion/exclusion criteria
cards
Inclusion Criteria
Exclusion Criteria
CORRECTION: should be >24 hours from
ICU admission to time of consent
Randomization
Refer to Appendix 1
Randomization on Web
Screen New
Subject
“Only Subjects Who
Meet Inclusion
Criteria”
Screening Form
Inclusion/Exclusion
No Exclusion
Eligible for
Study
Pre Randomization
Form
Eligibility Must Be
Confirmed By MD
Do you obtain consent?
Yes
Consent Obtained
Subject’s Height in cm.
CLICK here to Randomize
Patient button
Subject is now Randomized
Enrollment Number Is____
Contact your Site Pharmacy and enter
date and time of contact.
Provide Height/Subject Initials/
DOB/Enrollment Number
Meets an
Exclusion
End
s
End
Pharmacist Receives call
from Study Coordinator
Explain why
No
Pharmacist Logs onto
Web
Pharmacist Receives
 Treatment Assignment
 Subject’s Initials
 Date of Birth
 Height
After Randomization
Study Coordinator Expected to Complete
Baseline Form & APACHE Score and
other Electronic CRFs
Pre-Randomization
 Consent
If Randomized
Print the page and notify the study pharmacist of:
• Patient randomization number
• Height in cms
• Patient initials and DOB
 Consent
Enter Screening Data for ALL
patients meeting inclusion criteria,
including those meeting an
exclusion criteria and those that
END
refuse consent!
Pharmacy
Pharmacy Log In
Pharmacy Treatment assignment
Note: this is not the
randomization list
that will be used for
the study.
Supply of Supplements
• Fresenius Kabi and Baxter (Calea)
• Before start: Supplies to be shipped to sites
• Need updated pharmacy contact and shipping
address
Dispensing
• ICU pharmacist  dispensing pharmacist
• Sign signature log
• Enteral supplements
– no mixing needed
• Parenteral supplements
– Mixing required: Dipeptiven (Glutamine) +
Selenium (AOX) + Normal Saline
Enteral Products
• Obtain appropriate enteral product
• Infuse at 20 ml/hour for all patients
• Generate pharmacy label (need 2 labels)
Remove company
label and staple to
Form B
Attach pharmacy
label to bottle
(maintain blinding)
Enteral Dispensing Log
Mixing of Parenteral Supplements
Dipeptiven (Glutamine) + Selenium (AOX) + Normal Saline
Final volume = 250 mls, hourly rate = 10 ml/hr.
1. Determine dose of Glutamine according to Normal weight
•
Normal Weight (kg) = height (cms) –100 cms
•
Dose of Dipeptiven = Normal wt. X 2.5 mls
(This equals to Normal wt. X 0.35 gms of Glutamine or Normal
weight X 0.5 gms of L-alanyl-L-Glutamine).
2. Dose of Selenium = 12.5 ml (500 micrograms) = 1.25 vial
3. Combine the Glutamine + Selenium and remove this volume from
250 ml of normal saline.
4. Replace normal saline with this mixture. Final volume =250 mls.
Parenteral Worksheet: AOX
Should be
10.8 ml/hr
Parenteral Worksheet: GLN
Should be
10.8 ml/hr
Parenteral Worksheet: AOX+GLN
Should be
10.8 ml/hr
Parenteral Worksheet: Placebo
Should be
10.8 ml/hr
Expiration of Supplements
• Selenium once opened: 24 hrs if refrigerated
• Dipeptiven once opened: mix immediately
• Once mixed, parenteral solutions have an
expiration of 96 hrs room temperature
– Can make in batches to last 3 days!!
Enteral Supplements once opened: 24 hrs
Parenteral Study Supplement Log
Parenteral Label
Dosages according to height (PN)
If > 6 feet 5 inches (>196 cms)
•Final volume of parenteral solution will be between 250-300 mls.
•Can still use 250 mls bag of saline
•If no normal saline to be used, use an empty sterile bag and add
supplements to the bag (instead of removing all normal saline)
•Final rate of solution will exceed 10 ml/hr
•Central line needed but peripheral may be used (72 hrs max)
Pilot Study: no one > 190 cms (6’3”)
Nutrient Accountability Logs
One log for each product except
for normal saline
Monthly Site Inventory Log
Fax in to CERU monthly
Temperature Log
Fax in to CERU monthly
Study Coordinator
General Rules for Data Collection
•
•
•
•
•
•
CERU to assign passwords, site #
Dates DD/MMM/YYYY, 00:00
Click on + to expand menu or taxonomy
Site Status Page: shows all patients
Patient Status Page : colour coding
Input warnings : help with query process
Site Status Page
Patient Status Page
Duration of Data Collection
For daily data
from Study Day 1 until Day 30 unless ICU discharge (actual)
or death occurs before day 30
EXCEPT the following:
– Study Supplement Compliance: maximum of 28 days.
– Microbiology: -7 days ICU admission to ICU discharge.
– Antibiotics: -7 days ICU admission and stop dates may
extend beyond ICU discharge.
– Patients with ICU stay < 5 days and transferred to ward:
collect all daily data from Study Day 1 and continue for 5
days in total (=120 hrs).
Study Day 1 is from ICU admission to end of flowsheet.
Study Day 2 and subsequent days are according to your 24 hr flowsheet
Baseline
 Hypotension
 Respiratory Failure
OK to wait
Must be completed
Logical sequence
APACHE II
May use existing APACHE
score if available
Lowest and highest values
Score automatically
generated
Study Supplement Timelines
Duration of supplements:
• Minimum 5 days (120 hrs)
• Maximum 28 days
Start and stop dates
and times
Baseline Nutrition
Dietitian to collect:
• Prescribed kcal and
protein (baseline)
• Type of nutrition
support
• Start and stop date and
times
• Refer to Dietitian
Manual
Daily Data
Study Day 1 is from
ICU admission to end of
your 24 hr flowsheet.
Study Day 2 and
subsequent days are
according to your 24 hr
flowsheet.
Dietitian may help by
collecting the location of
feeding tube
Daily Nutrition
• Dietitian to collect the
data and give to SC
• Close to real time to
ensure that patient is
being fed adequately.
• Use checklist (see
sample in Dietitian
Manual)
Dietitian Checklist
Study Supplement Compliance
• Volumes must be
monitored DAILY in
real time.
• If volumes <
prescribed, need to
report to CERU or
provide explanation and
take action to prevent
recurrence.
Protocol Violation
Protocol Deviation
Protocol Violation
Protocol Deviation
Volume of study supplement
actually received is less than the
prescribed volume in 24hrs
Volume of study supplement
actually received is less than the
prescribed volume in 24hrs
Enteral < 80% prescribed
Parenteral <90% prescribed
Enteral ≥ 80% < 100% prescribed
Parenteral ≥ 90% <100%
prescribed
Complete Violation Form
within 24 hours of
discovery
&
Fax to CERU
Attention: Project Leader
(613) 548-2428
Provide explanation on the
worksheet/web based data
entry (Study Supplement
Compliance)
Protocol
Violation
Form
Vasopressors/Inotropes
Highest hourly dose received
Concomitant Medications
Input Warnings
Microbiology
Collect all positive cultures
starting 7 days prior to ICU
admission.
If culture date> 72 hrs ICU
admission, 2 questions will
be asked to help determine
suspicion of ICU acquired
infection.
Suspicion of ICU Infection
• Is this culture a manifestation of a previously
diagnosed infection?
• Is this a routine surveillance swab?
NEED TO ASK SITE INVESTIGATOR
• If NO to both………………..flag for adjudication
(to be done after ICU outcomes).
Antibiotics
Period of data collection
starts 7 days prior to ICU
admission and may extend
beyond ICU discharge.
If abx started > 72 hr ICU
admission, 3 questions
will be asked to help
determine suspicion of
ICU acquired infection.
Suspicion of ICU Infection
• Is this antibiotic prescribed for prophylaxis?
• Is this a dose adjustment for an antibiotic ordered
for a previous infection?
• Is this a substitute for an antibiotic ordered for a
previous infection?
NEED TO ASK SITE INVESTIGATOR
• If NO to ALL………………..flag for adjudication
(to be done after ICU outcomes).
ICU Outcomes
All input warnings must be
addressed before you can
access this page. The input
warnings will appear at the top
of the Patient Status Page.
This page MUST be
completed before you can
proceed to the next web
pages
Infection Adjudication
All input warnings must be resolved
Automatic listing of relevant clinical data (microbiology.
antibiotics, daily data) that will enable the Site Investigator to
adjudicate newly acquired ICU infections.
Determination of ICU Infection
Was this culture or the prescription of this
antibiotic for a NEW ICU acquired infection?
(after 72 hours of admission from ICU
admission)?
Yes
Choose the appropriate
Categories of Infection (1-12)*
and if:
Definite Yes or
Probable Yes or
Possible Yes
No
NO, because it is
related to an
infection previously
diagnosed and
adjudicated.
NO, because it is
NOT an infection
Possible**
NO
*Categories of Infection: Appendix 8.2
**Definition of No: Appendix 8.3
END
Probable*
* NO
END
Hospital Outcomes
3 and 6 month f/up
SF-36 at 3 and 6 months
Investigator’s Confirmation
Only appears once the ICU and Hospital outcomes have been completed
and all input warnings have been resolved (Patient Status Page).
SAE Reporting
• Serious and Unexpected events
– regardless of relationships to supplements
• Initial report faxed within 48 hrs
• Final report at day 30, ICU d/c, death or 10
days from becoming aware of SAE
• Record the event, not the outcome (death)
SAE Initial Report
SAE Follow up Report
Daily Monitoring
• Enteral Study Supplement Volumes
< 80 % prescribed: Protocol Violation Form
>= 80 and < 100 %: Provide explanation
• Parenteral Study Supplement Volumes
< 90% prescribed: Protocol Violation Form
>=90 and < 100%: provide explanation
• SAEs: unexpected: report within 48 hrs, 10 days
• Start of antibiotics > 72 hrs ICU admit, ask SI
• Positive Cultures > 72 hrs ICU admit: ask SI
Threats to Success
•
•
•
•
Poor enrollment, competing studies.
Inadequate delivery of study supplements.
Inadequate delivery of enteral nutrition.
Additional training needs?
Questions?