The RE-ENERGIZE Study: RandomizEd Trial of ENtERal Glutamine to minimIZE Thermal Injury (RE-ENERGIZE)

Effects of Enteral Glutamine Supplementation on Mortality and Infectious Morbidity in Severely Burned Patients: a Multi-center Pilot Trial

The purpose of this study is to test the following hypotheses:

1. Enteral glutamine administration decreases in-hospital mortality in adult patients with severe thermal burn injuries.
2. Enteral glutamine administration decreases hospital-acquired blood stream infections from Gram negative organisms and length of stay in ICU and hospital for adult patients with severe thermal burn injuries.
3. Enteral glutamine administration will improve the physical function of surviving burn injured patients and reduce their cost of care.

The objectives of this trial are to determine the overall treatment effect and safety of glutamine in burn patients. Specifically, the investigators want to assess the following outcomes in a sample of 1200 patients in 80 sites:

1. In patients with severe, life-threatening burn injury, what is the effect of enteral glutamine on time to discharge alive from hospital
2. In patients with severe, life-threatening burn injury, what is the effect of enteral glutamine on 6 month mortality, hospital-acquired blood stream infections from Gram negative organisms, hospital mortality, duration of stay in ICU and hospital, health-related quality of life, and health care resources?

Study Overview

• Status: Active, not recruiting
• Conditions: Burns
• Intervention / Treatment: Dietary supplement: Enteral Glutamine; Dietary supplement: Placebo

Detailed Description

Burn injuries represent a public health problem worldwide, ranked fourth in all injuries and are among the leading cause of disability adjusted life years in low and middle-income countries. More than in any other injury, the inflammation and catabolism associated with severe burns can exacerbate nutrient deficiencies, thereby predisposing patients to impaired immune function and increased risk of developing infectious complications, organ dysfunction, and death. Consequently, over the last few decades numerous trials have evaluated the impact of different nutrition/nutrient strategies in severe burns patients. Glutamine is of particular interest in this regard as it appears vital for a number of key stress-response pathways in serious illness. The existing randomized trials of glutamine supplementation in burns patients have suggested a significant reduction in mortality, infection, and hospital length of stay. However, in other critically ill patient populations, there is a signal of increased mortality associated with glutamine administration. Given this conflicting evidence, burn practitioners are either harming or saving lives with glutamine use. We hypothesize that the inexpensive therapeutic strategy tested in this multicenter randomized controlled clinical trial of supplemental enteral glutamine in 1200 severe burn injury patients will lead to lower morbidity and mortality and reduced health care costs in an otherwise very devastating and disabling injury worldwide.

In our pilot study (Critical Care Medicine, 2003, 31:2444) we found a protective effect of glutamine against blood infection in severely burned adult patients. In addition, a significant decrease in mortality was observed with glutamine. These results should be tested with a multi-center trial because our study was small and did not have mortality as an end point.

The specific aims of the study are to determine the overall treatment effect and safety of glutamine in burn patients. Clinical outcomes will be: mortality, time to discharge alive, incidence of acquired bacteremia due to Gram negative organisms, hospital mortality, duration of mechanical ventilation, ICU stay and hospital stay. The cost-effectiveness of glutamine administration will also be measured if the results show a decrease in length of care or a reduced incidence of acquired bacteremia due to Gram negative organisms with glutamine.

The study will be a large, multicenter, double-blind, pragmatic, randomized controlled trial of 1200 patients with severe burns randomly allocated to receive enteral glutamine or placebo. Randomization will be concealed and stratified by site allocating patients 1:1 to either glutamine or matching placebo by the method of permuted blocks of random undisclosed size within strata. Patients will be adults, a minimum of 18 years old, with deep 2nd and/or 3rd degree burns requiring grafting, and for patients age 18 - 39 years a (Total Body Surface Area) TBSA burn ≥ 20% or in the presence of an inhalation injury a minimum of 15% TBSA burn is required; for patients age 40 - 59 years a TBSA burn ≥ 15% is required; for patients aged 60 years or older a TBSA burn ≥ 10% is required. The study will include approximately 80 burn centers in Canada, the US, Europe and Latin America. Patients will receive glutamine or a placebo through their feeding tube, every 4 hours or TID or QID if taking things by mouth, for a total of 0.5 g/kg/day for patients with a BMI <35. Patients with a BMI ≥35 will receive 0.5 g/kg/day based on an obesity-adjusted body weight. The study intervention will be administered until ≥7 days after the last successful grafting operation or until discharge from acute care unit or 3 months from admission, whichever comes first. Resuscitation, nutritional support, pain management, infection control and surgical care will be done according to standardized procedures.

The Data will be collected and managed by a professional and centralized organization for multi centres clinical research (Clinical Evaluation Research Unit, Kingston, Ontario, Canada).

• Study Type: Interventional
• Enrollment (Actual): 1201
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Styria
    • Graz, Styria, Austria
      • Medical University of Graz
• Belgium
  • Ghent, Belgium, 9000
    • Ghent University Hospital
  • Liège, Belgium, 4000
    • University Hospital of Liege
• Brazil
  • São Paulo, Brazil, 05403-000
    • The Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo
• Canada
  • Quebec, Canada
    • HEJ/Centre des Grands Brules
  • Alberta
    • Calgary, Alberta, Canada
      • Foothills Medical Centre
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • HHS/Hamilton Firefighters Burn Unit
    • Toronto, Ontario, Canada, M4N 3M5
      • Ross Tilley Burn Centre, Sunnybrook Health Sciences Centre
  • Quebec
    • Montreal, Quebec, Canada, H2X 0A9
      • CHUM/Centre des Grands Brules
• Dominican Republic
  • Santo Domingo, Dominican Republic, 10602
    • Instituto Tecnologico de Santo Domingo
• Germany
  • North Rhine-Westphalia
    • Aachen, North Rhine-Westphalia, Germany, 52062
      • RWTH Aachen University
  • Rhein
    • Ludwigshafen, Rhein, Germany
      • Berufsgenossenschaftliche Unfallklinik Ludwigshafen
• Italy
  • TO
    • Torino, TO, Italy, 10126
      • A.O.U. Città della Salute e della Scienza di Torino
• Paraguay
  • Asunción, Paraguay
    • Centro Nacional de Quemaduras y Cirugia Reconstructiva
• Singapore
  • Singapore, Singapore
    • Singapore General Hospital
• Spain
  • Valencia, Spain, 46026
    • Hospital Universitario La Fé
• Sweden
  • Uppsala, Sweden, 75124
    • Uppsala University Hospital
• Thailand
  • Mueang Nonthaburi, Thailand, 40002
    • Khon Kaen University
  • NOI
    • Bangkok, NOI, Thailand
      • Siriraj Hospital, Divison of Trauma Surgery, Mahidol University
  • Pathumwan
    • Bangkok, Pathumwan, Thailand, 1873
      • King Chulalongkorn Memorial Hospital Chulalongkorn University
• United Kingdom
  • Edgbaston
    • Birmingham, Edgbaston, United Kingdom, B15 2GW
      • University Hospitals Birmingham NHS Foundation Trust
  • England
    • Liverpool, England, United Kingdom
      • St Helens & Knowsley Teaching Hospitals
    • London, England, United Kingdom, SW10 9NH
      • Chelsea and Westminster Hospital
    • Newcastle Upon Tyne, England, United Kingdom, NE7 7DN
      • Newcastle upon Tyne Hospitals
  • London
    • Manchester, London, United Kingdom, M13 9WL
      • Manchester University NHSFT
  • West Yorkshire
    • London, West Yorkshire, United Kingdom
      • Pinderfields Hospital, Mid Yorkshire NHS Trust
• United States
  • Alabama
    • Mobile, Alabama, United States, 36609
      • University of South Alabama Medical Center
  • Arizona
    • Phoenix, Arizona, United States, 85008
      • Arizona Burn Center at Maricopa Medical Center
  • California
    • Los Angeles, California, United States, 90089-9235
      • Southern California Regional Burn Ctr at LAC & USC Med. Ctr.
    • Sacramento, California, United States, 95817
      • Shriners Hospitals For Children Northern California
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Department of Anesthesiology, University of Colorado
    • Greeley, Colorado, United States, 80631
      • North Colorado Medical Center - Banner Health
  • Connecticut
    • Bridgeport, Connecticut, United States, 06610
      • Connecticut Burn Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20782
      • The Burn Center at Washington Hospital Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • Shands Burn Center at the University of Florida
    • Tampa, Florida, United States, 33606
      • University of South Florida/Tampa Gen. Hosp. Reg. Burn Center, FL
  • Georgia
    • Augusta, Georgia, United States, 30909
      • Joseph M Still Burn Center
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Department of Surgery University of Iowa Hospitals & Clinics
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Mercy Hospital St. Louis
  • Nebraska
    • Lincoln, Nebraska, United States, 68150
      • CHI St.Elizabeth Regional Burn Center
    • Omaha, Nebraska, United States, 68198-7835
      • The Nebraska Medical Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Akron, Ohio, United States, 44308-1062
      • Akron's Children's Hospital, Paul & Carol David Foundation
    • Columbus, Ohio, United States, 43210
      • The Ohio State University Wexnar Medical Center
  • Oregon
    • Portland, Oregon, United States, 97232
      • Legacy Emmanuel Hospital & Health Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • The Western Pennsylvania Hospital Burn Center
  • Tennessee
    • Memphis, Tennessee, United States, 38102
      • Firefighters' Regional Burn Center TN, University of Tennesse Health & Sciences Center
  • Texas
    • Dallas, Texas, United States, 8563
      • University of Texas Southwestern
    • Fort Sam Houston, Texas, United States, 78234-7767
      • JBSA Fort Sam Houston
    • Galveston, Texas, United States, 77555
      • University of Texas Medical Branch
    • Houston, Texas, United States, 77030
      • Memorial Hermann/UTHSC
  • Washington
    • Seattle, Washington, United States, 98195-9796
      • Harbourview Medical Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53202
      • Columbia-St. Mary's, Milwaukee, Wi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Deep 2nd and/or 3rd degree burns requiring grafting

2. Patient meets one of the following 4 criteria:

   1. Patients 18 - 39 years of age with ≥ 20% TBSA* burn
   2. Patients 18 - 39 years of age with ≥ 15% TBSA* burn and with inhalation injury
   3. Patients 40 - 59 years of age with ≥ 15% TBSA* burn
   4. Patients ≥ 60 years of age ≥ 10% TBSA* *TBSA - Total Body Surface Area

Exclusion Criteria:

1. > 72 hrs from admission to ICU to time of consent.
2. Patients younger than 18 years of age.

3. a) Patients without known renal disease and renal dysfunction defined as a serum creatinine >171 µmol/L or a urine output of less than 500 mL/last 24 hours (or 80 mL/last 4 hours if a 24 hour period of observation is not available).

   b) Patients with acute on chronic renal failure (pre-dialysis) with an absolute increase of >80 µmol/L from baseline or pre-admission creatinine or a urine output of <500 mL/last 24 hours (or 80 mL/last 4 hours).

   c) Patients with chronic renal failure on dialysis will be excluded.

4. Liver cirrhosis - Child-Pugh class C liver disease
5. Pregnant or lactating females.
6. Contra-indication for EN: intestinal occlusion or perforation, intra-abdominal injury.
7. Patients with injuries from high voltage electrical contact.
8. Patients who are moribund (not expected to survive the next 72 hours).
9. Patients with extreme body sizes: BMI < 18 or > 50
10. Enrollment in another industry sponsored ICU intervention study.
11. Received glutamine supplement for > 24 hrs prior to randomization
12. Known allergy to maltodextrin, corn starch, corn, corn products or glutamine.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Enteral Glutamine; 0.5 g/kg/day mixed in water and given via nasogastric or feeding tube as boluses q 4 hrs or TID or QID if po	Dietary supplement: Enteral Glutamine; 0.5g/kg/day powdered glutamine to be mixed in with water and given via nasogastric or feeding tube q4 hrs or TID or QID if po.; Other Names: Glutamine
Placebo Comparator: Placebo; Mixed in with water and given via nasogastric or feeding tube as boluses q 4hrs or TID or QID if po	Dietary supplement: Placebo; Maltodextrin mixed with water given via NG or feeding tube Q 4 hours or TID or QID if po.; Other Names: Maltodextrin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to Discharge Alive	3 months

Secondary Outcome Measures

Outcome Measure	Time Frame
6 Month Mortality	6 Months

Other Outcome Measures

Outcome Measure	Time Frame
Health-Related Quality of Life - in particular the physical function domain of the SF-36, ADL, and IADL questionnaires.	6 Month
Incidence of acquired bacteremia due to Gram negative organisms	3 Months
Hospital Mortality	3 Months
Duration of Mechanical Ventilation	3 months
ICU Stay	3 Months
Hospital Stay	3 Months

Collaborators and Investigators

• Sponsor: Daren K. Heyland
• Collaborators: Canadian Institutes of Health Research (CIHR)
• Investigators: Principal Investigator: Daren Heyland, MD, Queen's University

Publications and helpful links

General Publications

• Garrel D, Patenaude J, Nedelec B, Samson L, Dorais J, Champoux J, D'Elia M, Bernier J. Decreased mortality and infectious morbidity in adult burn patients given enteral glutamine supplements: a prospective, controlled, randomized clinical trial. Crit Care Med. 2003 Oct;31(10):2444-9. doi: 10.1097/01.CCM.0000084848.63691.1E.
• Zhou YP, Jiang ZM, Sun YH, Wang XR, Ma EL, Wilmore D. The effect of supplemental enteral glutamine on plasma levels, gut function, and outcome in severe burns: a randomized, double-blind, controlled clinical trial. JPEN J Parenter Enteral Nutr. 2003 Jul-Aug;27(4):241-5. doi: 10.1177/0148607103027004241.
• Peng X, Yan H, You Z, Wang P, Wang S. Effects of enteral supplementation with glutamine granules on intestinal mucosal barrier function in severe burned patients. Burns. 2004 Mar;30(2):135-9. doi: 10.1016/j.burns.2003.09.032.
• Heyland DK, Wibbenmeyer L, Pollack JA, Friedman B, Turgeon AF, Eshraghi N, Jeschke MG, Belisle S, Grau D, Mandell S, Velamuri SR, Hundeshagen G, Moiemen N, Shokrollahi K, Foster K, Huss F, Collins D, Savetamal A, Gurney JM, Depetris N, Stoppe C, Ortiz-Reyes L, Garrel D, Day AG; RE-ENERGIZE Trial Team. A Randomized Trial of Enteral Glutamine for Treatment of Burn Injuries. N Engl J Med. 2022 Sep 15;387(11):1001-1010. doi: 10.1056/NEJMoa2203364. Epub 2022 Sep 9.
• Heyland DK, Wischmeyer P, Jeschke MG, Wibbenmeyer L, Turgeon AF, Stelfox HT, Day AG, Garrel D. A RandomizEd trial of ENtERal Glutamine to minimIZE thermal injury (The RE-ENERGIZE Trial): a clinical trial protocol. Scars Burn Heal. 2017 Dec 12;3:2059513117745241. doi: 10.1177/2059513117745241. eCollection 2017 Jan-Dec.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2010
• Primary Completion (Anticipated): December 1, 2021
• Study Completion (Anticipated): December 1, 2021

Study Registration Dates

• First Submitted: September 25, 2009
• First Submitted That Met QC Criteria: September 25, 2009
• First Posted (Estimate): September 28, 2009

Study Record Updates

• Last Update Posted (Actual): December 30, 2021
• Last Update Submitted That Met QC Criteria: December 9, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Nutrition; Glutamine; Critical Care; Randomized Clinical Trial; Themal Burn Injuries; Outcome Assessment; Total Body Surface Area
• Other Study ID Numbers: RE-ENERGIZE; CIHR # 190808 (Other Grant/Funding Number: CIHR)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No