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

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 2700 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 2,700 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).

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.