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

Sponsor

Daren K. Heyland (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT00985205

Collaborator

Canadian Institutes of Health Research (CIHR) (Other)

1,201

Enrollment

Locations

Arms

132

Anticipated Duration (Months)

22.7

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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

Enteral glutamine administration decreases in-hospital mortality in adult patients with severe thermal burn injuries.
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.
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:

In patients with severe, life-threatening burn injury, what is the effect of enteral glutamine on time to discharge alive from hospital
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?

Condition or Disease	Intervention/Treatment	Phase
Burns	Dietary Supplement: Enteral Glutamine Dietary Supplement: Placebo	Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

1201 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Dec 1, 2010

Anticipated Primary Completion Date :

Dec 1, 2021

Anticipated Study Completion Date :

Dec 1, 2021

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Time to Discharge Alive [3 months]

Secondary Outcome Measures

6 Month Mortality [6 Months]

Other Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Deep 2nd and/or 3rd degree burns requiring grafting
Patient meets one of the following 4 criteria:
Patients 18 - 39 years of age with ≥ 20% TBSA* burn
Patients 18 - 39 years of age with ≥ 15% TBSA* burn and with inhalation injury
Patients 40 - 59 years of age with ≥ 15% TBSA* burn
Patients ≥ 60 years of age ≥ 10% TBSA* *TBSA - Total Body Surface Area

Exclusion Criteria:

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

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

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

Contacts and Locations

Locations

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