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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: • • • • • • • • 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 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… 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 • • • • • • • • • • 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) • Enteral Nutrition to start as per usual practice (patient stabilized, 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 and increase every 4 hrs as tolerated until goal rate • 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 – – – – – – 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 Enteral and parenteral solutions provided continuously over 24 h Rate of PN depends upon rate of EN Adjust PN hourly so that EN + PN = target rate as determined by dietitian/MD Initiate PN study solution at 25 ml/hr (or faster) and advance by 25 ml q 4 hrs to target rate as tolerated Monitor blood sugars and electrolytes every 4 hrs as needed 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? • • • • • 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