The REDOXS © Study REducing Deaths from OXidative Stress Dietitian and Pharmacy Training March 2009 Study Chair Dr. Daren Heyland, MD, FRCPC Project Leaders Rupinder 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 +AOXGlutamine + AOX Dipeptiven + Selenium AOXAOX onlyPlacebo + Selenium GLNGlutamine onlyDipeptiven + Placebo Placebo Placebo + Placebo Study Groups SC blindedPharmacist 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 Orders Study 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 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 31 st 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 in 2% 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

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 Log Pharm Manual p 14

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 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 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 Logs One 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 error REDOXS 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 >REDOXS