The REDOXS© Study REducing Deaths due to OXidative Stress

The REDOXS© StudyREducing Deaths from OXidative Stress

Dietitian and Pharmacy TrainingMarch 2009

Study ChairDr. Daren Heyland, MD, FRCPC

Project LeadersRupinder Dhaliwal, RD and Janet Overvelde

Administration of Study Supplements

Duration of study supplements

Maximum 28 days

Minimum 5 days: In patients with ICU LOS < 5 days and get discharged to ward

Enteral Supplement

Parenteral Supplement

GLN +AOX Glutamine + AOX Dipeptiven + Selenium

AOX AOX only Placebo + Selenium

GLN Glutamine only Dipeptiven + Placebo

Placebo PlaceboPlacebo + Placebo

Study Groups

SC blinded Pharmacist unblinded

Enteral Study Supplement EN REDOXS © Formula

Parenteral Study Supplements (Dipeptiven and Selenium)

+

US Product: selenium injection

EU: selenase (Biosyn)

Study Supplements

• Pharmacist is unblinded

• Supplements to start ASAP– within 24 hrs of admission to ICU– within 2 hrs of randomization

• Duration: 28 days or death or ICU discharge – min of 5 days IF transferred to ward, if not until ICU d/c– Continuous infusion X 24 hrs but can be doubled up (12 hrs

max)

SS Manual p 4-10

Infusion of Supplements

• 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– May piggyback with IV fluids, albumin, PN (no heparin/insulin)

• Enteral supplement– NG tube OK or feeding tube– 20 ml/hr, can be given via Y connector– start regardless of whether MDs want to start enteral nutrition

nutrients vs. nutrition

• Minimize interruptions, make up volume– Infuse at double rate for 12 hrs maximum on Day 1

• Intolerance to enteral feeding ( refer to feeding protocol)

• Other enteral formulas, vitamins, minerals• Renal Dysfunction

– Switch to lower protein formula– Restrict fluid– Refer to appendix (page 12)

If received volumes < Prescribed = Protocol Violation……….notify Methods Centre !!

SS Manual p 10-16

Template of Study OrdersStudy Supplement Manual Page 11

Imp. Manual: Tools

To optimize delivery of

supplements

Study day 1= ICU admission

until end of your flowsheet

ENTERAL REDOXS formula PARENTERAL

REDOXS formula (but will be in a normal saline type bag)

Enteral Nutrition (EN)

EN and ENTERAL REDOXS being “Y”-ed in

Role of the Dietitian

Optimizing Enteral Nutrition

Canadian CPGs

www.criticalcarenutrition.com

Feeding Protocol

Glycemic Protocol

Elevate the Head of the Bed

Motility Agents

Small Bowel Feeding

RD manual p 13

SS Manual p 16

Baseline Nutrition

Dietitian to collect:• Prescribed kcal and

protein (baseline)• Type of nutrition

support• Start and stop date and

times• Refer to Dietitian

Manual

RD Manual p 5,6

Imp Manual p 29,30

Daily Nutrition Data

Dietitian to collect

(for max 30 days):• Energy protein intake

• Add propofol

• Interruptions

• Type of enteral formula

• + location of feeding tube (daily data)

Collection in real time essential !

RD Manual p 7,11

Imp Manual p 37-39

Dietitian Checklist Imp Manual: Tools

RD Manual: 19,20

Checklist is a tool…refer to webpage for data to be entered in eCRF

July 31st 2008 version online

Propofol ≥ 6 hrs

Include in daily calories received as follows:– If on EN only, add to EN calories– If on PN only, add to PN calories– If on EN + PN, add to PN calories

Do not add if not receiving EN or PN

Study Supplement Compliance

• Volumes must be monitored DAILY in real time by Study Coordinator.

• If volumes < prescribed, need to report to CERU or provide explanation and take action to prevent recurrence.

Protocol Violation

Protocol Deviation

Imp Manual p 34

Study Coordinator

Study Coordinator to ensure compliance

Dietitian to help

• Maximize EN nutrient and nutrition delivery – use of feeding protocols– small bowel feeding

• Minimize interruptions, make up volume• Other enteral formulas with supplemental glutamine, vitamins,

minerals not allowed– No supplements with high amounts of Zinc (5 mg max)

• Renal Dysfunction– Switch to lower protein formula– Restrict fluid– Refer to appendix

If received volumes < Prescribed = Protocol Violation……….Study Coordinator to notify Methods Centre !!

Pilot study: Interruptions due to high urea only in2% patient days (9% patients)

RD Manual p 12-17

Case study: High GRVs

Mr. Smith who is 4 days post laporotomy (findings show bowel is not compromised) has had high gastric residual volumes > 500 mls for the last 48 hours. His enteral feeds have been interrupted several times and are now on hold. The MD in charge has also stopped the enteral study supplements to give the gut a rest and he now wishes to start parenteral nutrition.

What to do?

FAQs

• What if the prescribed calories and protein changes over the 28 days of the study duration?

• How do I get a prescribed calorie/protein level if the dietitian has not assessed this?

Daily Monitoring

Dietitian• Enteral Nutrition Adequacy

Study Coordinator• 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

Pharmacy

Supply of Supplements

• Fresenius Kabi: Dipeptiven, EN REDOXS

• Selenium: BIOSYN (EU), Baxter (Canada) or Pharmacy to purchase on own* (US)

• Before start: Supplies to be shipped to sites once Ethics approval received

• Need updated pharmacy contact and shipping address

*US sites: refer to Work Instruction for Selenium

Pharmacy Web Access To be completed by 2 of the most responsible pharmacists or technicians

Password can be shared by all pharmacy staff

Pharmacy Manual p 4

The REDOXS© Study REducing Deaths due to OXidative Stress

Pharmacy Web access Signature Log

INSTITUTION: SITE NUMBER: INVESTIGATOR: Please complete the Electronic Data Capture (EDC) System Access Signature Sheet for the most responsible Pharmacist/technician(s) at your site who will be checking the randomization or dispensing/checking study supplements. A signature and email address is required to create user accounts for the web based system for the REDOXS© Study.

NAME TITLE SIGNATURE EMAIL DATE

NOTE: By completing the information in the table above, the individual confirms they have been delegated the responsibility of checking the randomization and dispensing/verifying study supplements for the REDOXS© Study. The individual agrees to keep their password confidential to prevent unauthorized access to the data. Reference: ICH GCP 5.5.3

Pharmacy Log In Pharmacy Manual p 5

Pharmacy Treatment assignment

Note: this is not the randomization list that will be used for the study.

Pharmacy Manual p 6

Dispensing

• ICU pharmacist dispensing pharmacist

• Sign signature log

• Enteral supplements– no mixing needed

• Parenteral supplements– Mixing required: Dipeptiven (Glutamine) +

Selenium (AOX) + Normal Saline

If hypernatremia, can be mixed in with D5W instead of saline!

Pharm Manual p 12

Enteral Products

• Obtain appropriate enteral product • Infuse at 20 ml/hour for all patients• Generate pharmacy label (need 2 labels)

Pharm Manual p 12, 29

Remove company label and staple to Form B

Attach pharmacy label to bottle

(maintain blinding)

Pharm Manual p 12, 13

Enteral Dispensing LogPharm Manual p 14

Mixing of Parenteral SupplementsDipeptiven (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 vialEU sites: dose is 10 mls (500 micrograms) = 1 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

Pharm Manual p 15

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”)

Pharm Manual p 18, 32

Refer to Revised

Worksheets on web

Nov 2007

Appendix F: Height and Dose of

Dipeptiven

Pharm Manual p 36

Parenteral Worksheet: GLN

Use Revised

Worksheets (for >196 cms)

on web November 2007

Pharm Manual p 15, 31-41

Parenteral Worksheet: AOX

Use Revised

Worksheets (for >196 cms)

on web November 2007

Parenteral Worksheet: AOX+GLN

Use Revised

Worksheets (for >196 cms)

on web November 2007

Parenteral Worksheet: Placebo

Use Revised

Worksheets (for >196 cms)

on web November 2007

• Do NOT ignore overfill in Normal Saline bag

• Remove the volume of known overfill from normal saline bag

New change to Pharmacy Procedures: March 2009

Parenteral Label

Pharm Manual p 16, 42

Parenteral Study Supplement Log

Pharm Manual p 17

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

Pharm Manual p 10

Nutrient Accountability LogsOne log for each product except

for normal saline

Pharm Manual p 19-25

Monthly Site Inventory Log

Fax in to CERU monthly

Pharm Manual p 8,9

EU sites: From Biosyn

US sites: Pharmacy stock vs. Baxter

Temperature Log

Fax similar log to CERU monthly

Pharm Manual p 10, 11

Delegation of Authority Log

Main pharmacist to sign this Delegation of Authority Log

Pharmacy Delegation Log

All pharmacy staff involved to sign

Case Study: Dosing errorREDOXS Pharmacist away for weekend and returns on Monday and after reviewing logs realizes that Mr. J.S accidentally received the wrong supplements. Should have received GLN but received GLN+AOX instead for the last 18 hours.

What to do? 1. Stop the infusion immediately

2. Inform research coordinator ASAP, maintain blinding

3. Notify CERU immediately, Note to File (blinded to Methods centre, unblinded on site)

4. Steps to prevent recurrence

FAQs Pharmacy

• Keep vials of returned/destroyed products?

• One password for all Pharmacists/technicians?

• Pharmacist or technician that dispenses the supplements?

P. Manual page 16

REDOXS© Circular and Bulletin

Questions?? Imp Manual Tools

Resources available www.criticalcarenutrition.com >REDOXS