REducing Deaths due to OXidative Stress: The REDOXS© Study: Can we provide adequate enteral nutrition to patients with Shock? Rupinder Dhaliwal John Drover John Muscedere Xuran Jiang Daren Heyland Critical Care Nutrition, Kingston ON, Canada 1

Background Delivery of adequate EN in critically ill patients with shock is problematic due to interruptions: high illness acuity other treatment priorities hesitancy to feed unstable patients requiring vasopressors Paucity of data from RCTs on feeding practices in this acutely ill population from multicentre trials Cresci NCP, McClave NCP 2003, Berger Am J Clin Nutr 2005 1

Purpose To report on the delivery of enteral nutrition in patients with shock in The REDOXS© study, a multicentre, randomized controlled trial of pharmaconutrition *high dose glutamine and antioxidants are dissociated from enteral/parenteral nutrition. Given via enteral and parenteral route 1

R R R REDOXS© Study Design antioxidants glutamine 1200 ICU patients Factorial 2x2 design glutamine R 1200 ICU patients R Evidence of placebo organ failure antioxidants placebo R placebo

Study Groups Enteral Supplement Parenteral Supplement GLN +AOX Glutamine + AOX Dipeptiven + Selenium AOX AOX only Placebo + Selenium GLN Glutamine only Dipeptiven + Placebo Placebo Placebo + Placebo Duration of intervention: 28 days (min 5 days) 1

Enteral Nutrition (EN) ENTERAL REDOXS formula PARENTERAL REDOXS formula EN and ENTERAL REDOXS being “Y”-ed in

Dosing Study High dose appears safe High dose associated with Parenterally Enterally Glutamine/day 0.35 gms/kg 30 gms Antioxidants per day 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

Inclusion Criteria mechanically ventilated adults, in ICU two or more of following organ failures related to acute illness P/F ratio ≤ 300 Renal dysfunction Platelet count < 50 mm3 Hypoperfusion requiring vasopressors for  2 hours Any dose norepinephrine, epinephrine, vasopressin OR  5 ug/kg/minute of dopamine OR > 50 ug/min phenylephrine OR Randomized to one of 4 groups within 24 hrs admission to ICU “Shock” defined as: Hypoperfusion requiring vasopressors for  2 hours Any dose norepinephrine, epinephrine, vasopressin or  5 ug/kg/minute of dopamine or > 50 ug/min phenylephrine 1

Exclusion Criteria 1

Methods Daily data collected from ICU admission to a minimum of 5 days and a maximum of 30 days timing of EN and volumes received incidence of high GRVs, GRV in mls use and timing of motility and small bowel feeding 1

Methods Sites were instructed to monitor the volumes of study supplements received daily and to make up for interruptions by infusing at double the hourly infusion rate Enteral and parenteral nutrition was initiated and maintained independently as per the Canadian Clinical Practice Guidelines Dietitians and Research Coordinators were asked to monitor delivery of enteral nutrition daily The use of motility agents and small bowel feeding was also encouraged for patients with gastrointestinal intolerance (feeding protocol) 1

Results: Patients May 2007 to July 2008 across 20 ICUs (Canada, Europe) 205 patients with shock were randomized N = 205 Cohort: 159 patients locked data 1

Results: Route of Nutrition Reasons for None: Extubation (11), Death (5), Withdrawal of life sustaining therapies (1), GI contraindication (5), Aspiration (n=1) 1

Results: Delivery of EN Start of Enteral Nutrition from ICU admit 20.2 hours (median, range 0-204.8) Duration of EN 9.2 days (median 6.8, range 0.1-30 days) Mean Volume of EN received 67% (range 2.5-199%) of prescribed (mean 1800 Kcals) Patients received < 80% prescribed mean volumes EN 97/135 (73%) Patients received <80% prescribed EN ≥ 1 day 133/135 (98.5%) 1

Results: Incidence of high GRVs N = 133 (< 80% on at least 1 day) N = 73/133 (55%) For 45% patients, reasons are based on reasons for witholding enteral study supplement 1

Results: motility agents Of those that had high GRV 57/73 (78%) got motility agents N = 57 % mean prescribed volume received 24 hr pre motility agents = 35.1% vs. 24 hr post motility agents = 55.9% (p=0.009) N= 57 motility agents Timing of Motility agents 12/57 (21%) started motility agents before high GRV 23/57 (40%) on the same day 22/57 (39%) started motility agents 1.6  0.9 days (mean, SD) after the first GRV> 250 mls 1

Results: small bowel feeding Of those that had high GRV 30/73 (41%) got Small bowel feeds N = 30 % mean prescribed volume received 24 hr pre small bowel = 54.2% vs. 24 hr post small bowel = 67.3% (p=0.36) N= 30 small bowel feeds Timing of small bowel feeds 6/30 (20%) started before high GRV 4/30 (14%) on the same day 20/30 (67%) started 4.7  3.5 days (mean, SD) after the first GRV> 250 mls 1

Conclusions In critically ill patients with shock, EN can be provided in the early phases of acute illness to majority of patients In some, delivery of EN is interrupted/compromised by non physiologic factors The delivery of EN in this population can be maximized by better adoption and earlier initiation of motility agents and small bowel feeding. close monitoring of the delivered volumes of EN 1

Acknowledgements J. Drover J. Muscedere D. K. Heyland J. Drover J. Muscedere A. Day X. Jiang D. Cook G. Pagliarello M. Albert for the REDOXS© Steering Committee and the Canadian Critical Care Trials Group Kingston General Hospital, St. Joseph’s Hospital, Hamilton, The Ottawa Hospital, Hopital du Sacre-Coeur, Montreal, Canada 1