REDOXS

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A RandomizEd Trial of ENtERal Glutamine to
MinimIZE Thermal Injury Study Sponsors Dr. Paul
Wischmeyer (US) Dr. Dominique Garrel
(Canada) Clinical Evaluation Research
Unit Director Dr. Daren Heyland Project Leader
Rupinder Dhaliwal Project Assistant Maureen
Dansereau
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Why are we doing this trial? Look at the
literature on glutamine in burn injury
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Potential Beneficial Effects of Glutamine
GLN pool
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META ANALYSIS Effect of glutamine on INFECTIONS
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META ANALYSIS Effect of glutamine on LOS
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META ANALYSIS Effect of glutamine on mortality
The effects of glutamine on infectious morbidity
and mortality in burn patients have not been
determined in a large study
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Hypotheses

• In adult subjects with severe thermal burn
  injuries enteral
• glutamine
• 1) decreases in-hospital mortality
• 2) decreases infectious morbidity and shortens
  length of care in
• adult subjects with severe thermal burn
  injuries
• 3) decreases the cost of care of adult subjects
  with severe
• thermal burn injuries

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Objectives (Pilot Study)

• Recruitment rate
• Compliance with experimental procedure
• 3. Compliance with data collection and transfer
  to the
• Coordinating Centre (CERU)

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Study Design
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Study Overview
Imp Manual p 8
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Inclusion Criteria
Imp Manual p 12 Study Tools/CRF
Inclusion criteria all criteria 1, 2 and 3 must
be met for patient to be eligible
Assessed by the burn surgeon (clinical judgment,
Lund Browder) soon before randomization
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Exclusion Criteria
Imp Manual p 13 Tools/CRFs
Exclusion criteria patient is ineligible if any
one of the following is met
product to be given soon after injury
urine tests as standard of care
NPO not an exclusion
96 hrs if resuscitation before ICU
admission (per Site Investigator) Consent 24 hrs
from admit
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Imp Manual p 13
To minimize any potential contamination, patients
that have received glutamine supplements for gt24
hrs before randomization, should NOT be included
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RE-ENERGIZE Teamwork
Site Investigator Regulatory Inclusion/exclusion
criteria Burn outcome assessment ICU infection
adjudication SAE reporting
Pharmacist Checking allocation Dispensing Logs
Nurse Administration and recording of product
Research Coordinator Regulatory Screening/Randomi
zation Pharmacy communication Data
collection Study intervention monitoring Collabora
tion with SI SAE reporting Protocol Violation
reporting
Dietitian Optimizing nutrition Monitoring
Adequacy
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Investigational Product
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Study Intervention
Imp Manual p 14
OR
MALTRIN Maltodextrin
Enteral glutamine (0.5 gm/kg/day) or maltodextrin
will be given through the feeding tube, qx4h
until 7 days post last successful graft
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Imp Manual p 15

• Intervention to start ASAP
• within 2 hrs of randomization
• within 48 hrs-50 hrs of admission to ICU
• To be administered by RN as a bolus infusion via
• NG/feeding tube q 4 hrs
• If po, give TID or QID (mixed in apple juice,
  oatmeal, pudding, etc)
• NOT to be mixed with orange juice, grapefruit
  juice or lemonade
• Product is to given regardless of whether the
  attending MD wants to start enteral nutrition

supplement vs. nutrition
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Delivery of Supplement
Imp Manual p 15

• Powder is to be mixed in 50 mls water q 4 hrs by
  RN (sterile/tap as per standard practice for
  enteral nutrition) and given as a bolus. Followed
  by flushes
• Avoid any interruptions to the daily dose. Do not
  hold for surgery/procedures.
• Missed doses can be made up by doubling the dose
  at the next scheduled interval.

EXCEPTION weight lt 54 kgm, upto q 8 hrs. See
Dosing Chart
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Imp Manual, Study Tools
Dosing Weight Chart
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Duration of Study Intervention
Imp Manual p 16
even if d/c to another unit in your facility
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Missed Doses
Imp Manual p 15
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Pharmacy Procedures
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Training and Delegation Log
Imp Manual, appendix E
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Ordering of Product
Imp Manual p 18

• Before trial starts, CERU will arrange
  for intial product to be delivered from Colorado
• For subsequent orders, complete Product
  Order/Shipment Form

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Central Randomization System
Imp Manual p 19

• After randomization, Research Coordinator
  will immediately notify the pharmacy and provide
  
• the 8 digit randomization (automatically
  generated )
• the patients pre-burn weight
• and other details required by
• the pharmacist i.e. patient medical
  record ID

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CRS Pharmacy Login
Imp Manual p 19
Pharmacist to access Central Randomization
System (CRS) at https//ceru.hpcvl.queensu.ca/ran
domize/ One password per pharmacy (shared
amongst other pharmacy staff) CERU to assign
access to Central Randomization System (CRS)
after web access log signed
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CRS Home Screen
Imp Manual p 19

• After you Login, this is what you will see

Click on RE-ENERGIZE
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CRS Your Site
Imp Manual p 20

• On the next screen , your site name will be
  displayed

your site name will be displayed here
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CRS Treatment Assignment
Imp Manual p 20

• Treatment assignment for the patient will be
  displayed as below

Will be displayed as Glutamine (Nutrestore) OR
Placebo (Maltrin)
Check the patient ID
? print off the treatment assignment ? must be
signed by 2 pharmacists/delegates ? file in the
Pharmacy Study files
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Dosing
Imp Manual, appendix F
0.5 gm/kg/day pre burn weight
Need to determine where the product will be
stored
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Imp Manual, Study Tools
Dosing Weight Chart
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Existing Labels Exterior of Case
Imp Manual p 17,18
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Pre-Labels Individual Packets
Packets will have a sticker placed on them to
blind the product name Nutrestore and
Maltodextrin will be differentiated by lot s
(bottom of the packet)
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Labelling Blinded
Imp Manual p 23

• Need to create a blinded label for every
  package
• Send up enough packs to last a week
• Repeat weekly

May need to alter times to avoid midnight
administration (next study day)
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Dispensing Log
Imp Manual, appendix G
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Accountability Logs
Imp Manual, appendix H, I
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Storage and Temperature Logs
Imp Manual p 17, 18

• cool, dry area, 25?C (77 ?F)
• excursions allowed 15-30 ?C (59-86?F)
• cool, dry area, below 32 ?C (90 ?F)

MALTRIN Maltodextrin
Will be asked to send logs/documentation to CERU
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Role of Dietitian

• Assessment of energy and protein needs
• Start and stop times of nutrition
• Standardization of nutrition
• Avoidance of glutamine supplements
• Monitoring of nutritional adequacy

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Standardization of Nutrition Dietitian
Imp Manual Appendix C

• Prescribed calorie ranges
• Prescribed protein ranges
• Vitamin/mineral prescription
• Optimization of the Delivery of Enteral Nutrition
  
• Glycemic control

• Arginine enriched formulas (gt 6 gms arginine/L)
  i.e.
• Pivot, Perative
• Glutamine supplements or formulas containing any
  
• additional glutamine

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Imp Manual p 13
To minimize any potential contamination, patients
that have received glutamine supplements for gt24
hrs before randomization, should NOT be included
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Imp Manual Appendix C
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Feeding Intolerance/high GRVs?
Imp Manual p 16
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Case Report Forms p 14-15
Energy and Protein Needs Timing of start and
stop of EN and PN
Give RD a copy
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Case Report Forms p 22-23
Give RD a copy

• RD to calculate daily
• Closer to real time preferred so that action can
  be taken
• Need to refer to appendix 3

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Case Report Forms appendix p 3
Give RD a copy R Coordinator to enter in CRFs
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Nursing Procedures
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MD orders
Imp Manual p 38, Appendix C
Research Coordinator to write
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Bedside Nursing Procedures
Imp Manual, page 25-26

• Determine packets per interval (see Dosing
  Chart)
• At each dose, open the packets needed and pour
  into a sterile specimen cup
• Using a 60 ml syringe, add 50 mls of sterile
  water/tap water for each 5 gm package (as per
  standard practice for EN) mix well. Transfer the
  mixture into a 60 cc syringe
• Infuse as a bolus q 4 hrs unless po, then mix in
  liquid and give TID with meals/snacks
• Record all dosages given on the Medication
  Administration Record as RE-ENERGIZE supplement
  as packets per interval.
• To keep all the unused packages in a bag with the
  patients ID on it and give to Research
  Coordinator
• Make up for missed doses by giving dose in
  addition to next scheduled dose at next interval.
  Inform Research Coordinator of interruptions

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Imp Manual, Study Tools
Dosing Weight Chart
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Patient enrolment
48 hrs from admission
Research Coordinator informs RN Patient started
on intervention
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Role of Site Investigator
Delegation of Authority Patient EligibilitySAE
identification/assessmentICU Infection
adjudicationInvestigator Confirmation
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Delegation of Authority Logs
Imp Manual p 10, appendix A

• 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

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Eligibility confirmation
Imp Manual p 13
Document in the medical chart or Sign worksheet
by MD and keep as source
Prompted at time of Pre randomization
Patient enrolled to the RE-ENERGIZE study at
time hrs on date. Patient met all the inclusion
criteria and none of the exclusion criteria as
confirmed with Dr. ____________________.
Consent obtained from _____________
(relationship to patient) on dd/mmm/yyyy at time
hrs. All questions concerns addressed with
patient/family member at this time. Copy of
consent was given to patient/family member.
Sample Progress note entry (Imp Manual p 36)
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SAE Identification
Imp Manual p 41-51

• A serious adverse event is any untoward medical
  occurrence that at any dose,
• Results in death
• Is life threatening
• Requires or prolongs in-patient hospitalization
  
• Results in persistent or significant
  disability/incapacity
• May require medical or surgical intervention to
  prevent one of the other
• outcomes to defining serious
• Is a congenital anomaly/birth defect

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
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SAE Reporting Events must be Serious Adverse
Events and unexpected

A serious adverse event
An unexpected adverse event
Examples of unexpected events Cardiac arrest in
a pt without a history of cardiac disease. New
seizure in the absence previous seizure
disorder. Worsening encephalopathy in the
absence of liver disease. Ischemic bowel in the
absence of massive fluid resuscitation or
increased abdominal pressure/abdominal
compartment syndrome
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Infection AdjudicationSite Investigator to make
determination of a newly acquired infection
based on antibiotic and microbiology data
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Imp Manual, p 55
Determination must be made by SI
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Infection Adjudication tools

• 1. Antibiotic, antifungal antiviral Form
• 2. Microbiology Form
• 3. CRF Appendix - Categories of Infection
• 4. CRF Appendix - Definition of No Newly Acquired
  Infection
• 5. Electronic Data Capture System

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CRFs p 32-33
From ICU admit to 10 days post last graft
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CRFs p 34-35
No routine surveillance swabs No contaminants
(except in blood) Do not record NO growths
From ICU admit to 10 days post last graft
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Infection Adjudication REDCAP
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CRFs, p 44-45
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Research Coordinator
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Obtaining Informed Consent
Imp Manual pages 35-37

• Tri-Council Policy Statement Ethical Conduct for
  Research Involving Humans
• Free and informed consent refers to the
  dialogue,
• information sharing and general process through
• which prospective subjects choose to participate
  in
• research involving themselves

REFER TO CONSENT TRAINING MODULE
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After consent obtained
Imp Manual pages 36
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Screening Log
Imp Manual p 27

• Enter all patients onto Central Randomization
  System that
• meet inclusion criteria
• Even if they meet an exclusion criteria
• Even if you did not get consent

Inclusion Criteria Present Exclusion Criteria Present Informed Consent Obtained Enter into CRS
? ? NA ?
? ? NA ?
? ? ? ?
? ? ? ?
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CRS Login/Screening Log
Imp Manual p 27,28
Research Coordinator to access CRS to enter
Screening data at ceru.hpcvl.queensu.ca/randomize
/ One password per Research Coordinator (DO NOT
SHARE!) CERU to assign access to Central
Randomization System (CRS) after web access log
signed
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CRS Home Screen
Imp Manual p 28

• Once you have logged in successfully, you will be
  brought to the Home screen.

Click on RE-ENERGIZE
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CRS Adding Patient
Imp Manual p 29

• To enter data for a new patient, select the Add
  patient link.

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CRS Inclusion Criteria
Imp Manual p 30

• Click the Inclusion Criteria
• .

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CRS Exclusion Criteria
Imp Manual p 31

• Complete the exclusion criteria fields as
  appropriate

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CRS Pre-Randomization
Imp Manual p 32

• If consent is NOT obtained

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CRS Pre-Randomization
Imp Manual p 33

• If consent IS obtained,

DD-MMM-YYYY format Times 24-hour (military)
clock, must use colon () to be saved
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CRS Randomization
Imp Manual p 33

• Contact Pharmacist and inform them of the
  following
• Patient enrollment number (8 digit number)
• Pre-burn weight (in Kg)
• Any other patient details requested by the
  pharmacist (patient medical ID)
• Print a copy of the Randomization Web Form

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Site Status Page
Imp Manual p 34

• Listing of all patients screened and randomized
  at your site Click on the pt to review data

screening assigned to all patients entered in
the CRS enrollment only patients that are
randomized
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Patient Status Page
Imp Manual p 35

• Indicates the status of each data entry form for
  the patient

Status Symbol Description
Completed All data has been completed and saved.
Not Completed Data has not yet been entered on the fm.
Locked The patient has been randomized and the data is no longer able to be edited by the site user.
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MD orders
Imp Manual p 38, Appendix C
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Mock Case Report Forms
CRFs August 17th 2011

• May choose to use Mock eCRFs
• Medical Chart is considered as source
• MUST review instructions in mock eCRFs !!
• Data Entry is to be done on REDCAP (may appear
  different)

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Rules Data Collection
CRFs, page 3
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CRFs p10-11
Definition page 10
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CRFs p 12, 13
Also to be done by the attending surgeon
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CRFs p 12, 13
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CRFs p 14,15
Obtain from dietitian
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CRFs p 16-17
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CRFs p18-19
While ventilated from ICU admit to 10 days last
graft day as Day 1-14 daily, day 15 onwards
weekly
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CRFs p 20-21
From ICU admit to 10 days post last graft
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CRFs p 22-23
Obtain from dietitian
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CRFs p 24-25
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CRFs p 26-27
From ICU admit to 10 days post last graft
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CRFs p 28-29
From ICU admit to 10 days post last graft
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CRFs p 30-31
From ICU admit to 10 days post last graft
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CRFs p 32-33
From ICU admit to 10 days post last graft
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CRFs p 34-35
No routine surveillance swabs No contaminants
(except in blood) Do not record NO growths
From ICU admit to 10 days post last graft
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CRFs p 36-37
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CRFs p 38,39
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CRFs p 38,39
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Protocol Violations
CRFs p 44-45

• When any of the following occur
• Investigational Product (IP) Daily dose delivered
  is lt 80 prescribed.
• Example if the daily dose is 5 packages and the
  daily dose delivered is less than 4 packets, this
  is a protocol violation.
• IP dispensing/dosing error
• Accidental unblinding of IP
• Enrolment of a patient that does not fulfill
  inclusion/exclusion criteria
• Unapproved procedures performed
• All unanticipated problems involving risk to
  subjects or others
• participating in the study MUST be reported to
  the Project Leader for
• reporting to the Department of Defense.

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Must be reported to the Project Leader within 24
hrs of becoming aware
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CRFs p 38-39
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CRFs p 40-41
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Lab ProceduresRefer to Lab Training Module
Lab Manual

• Blood draws on
• Day 4 ( ? 48 hrs)
• Day 7 ( ? 48 hrs)
• Day 14 ( ? 48 hrs)
• Day 21 ( ? 48 hrs)

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Resources online
www.criticalcarenutrition.com
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