1. RE-ENERGIZE Training Edmonton
A RandomizEd Trial of ENtERal Glutamine to MinimIZE Thermal Injury:
A multicenter Pragmatic RCT (definitive study)
Study Sponsor
Dr. Daren Heyland
Clinical Evaluation Research Unit
Project Leader: Maureen Dansereau
September 20th 2011

4. A RandomizEd trial of ENtERal Glutamine to minimIZE thermal injury
Double blind treatment
EN glutamine
2700 patients with TBSA
≥ 20% if yrs age
≥ 15% if yrs age
with inhalation injury
≥ 10% if ≥ 60 yrs age R
6 month mortality
Concealed
Stratified by site
Maltodextran
placebo

5. Total Sites: 59 sites worldwide!
Sweden: 1
Germany: 1
Canada: 8
France: 1
Serbia: 1
Spain: 3
United States: 38
Greece: 2
Italy: 1
Israel: 1
Australia: 2
Total Sites: 59 sites worldwide!

6. Why are we doing this trial?

7. RE-ENERGIZE Training Edmonton
Potential Beneficial Effects of Glutamine
Enhanced Heat
Shock Protein
Enhanced
insulin
sensitivity
Decreased Free
Radical availability
(Anti-inflammatory action)
Inflammatory Cytokine
Attenuation
NF-kB ?
Glutamine
Therapy
Glutathione
Synthesis
Reduced
Translocation
Enteric Bacteria
or Endotoxins
Reduction of
Infectious complications
Maintenance of
Intestinal
Mucosal Barrier
Lymphocyte
Function
Fuel for
Enterocytes
Lymphocytes
Nuclotide
Synthesis
GLN
pool
Critical Illness
GLN
Pool
Preservation
of TCA Function
Anti-catabolic
effect
Preservation of
Muscle mass
Preserved
Cellular
Energetics-
ATP content
September 20th 2011

8. Glutamine: Important Questions
Is glutamine ‘conditionally essential’?
Is glutamine safe?
Mechanism of harm?
Negative interactions between glutamine and antioxidants
What is the evidence for benefit in Burn patients?

9. Glutamine: A conditionally essential amino acid?
Glutamine levels drop:
- following extreme physical exercice
- after major surgery
- during critical illness
Low glutamine levels are associated with:
immune dysfunction
higer mortality in critically ill patients
Novak F, Heyland DK, A Avenell et al., Crit Care Med 2002
Oudemans-van Straaten HM, Bosman RJ, Treskes Met al., Intensive Car Med 2001

10. The “Oudemans-van Straaten-Study”
“high”
“low”
=> Low plasma glutamine at ACU admission is related to mortality.

11. Plasma Levels of Glutamine in Subset of Patients
Baseline median plasma glutamine and selenium levels were within normal limits in all patients (Supplementary Figure 2 and Table S5). Glutamine supplementation led to a statistically significant increase in plasma glutamine at both day 4 and day 7 of ACU stay (P < 0.001) whereas antioxidant supplementation led to a significant increase in plasma selenium at day 4 and 7 of ACU stay (P < 0.001).
Heyland N Engl J Med 2013;368:

12. Glutamine and glutathione at ACU admission in relation to outcome
Rodas Clinical Science (2012) 122, 591–597

13. P<0.001
P=NS

14. Future Trials Require Bedside Testing?

15. Plasma Glutamine Levels in Burn-injured Patients
24 Health Patients (control)
Parry-Billings Lancet 1990

16. GLN Levels in RE-ENERGIZE Burn Pts
N=18, unpublished observations

17. RCTs of IV Glutamine in ACU Patients (n=29)
RE-ENERGIZE Training Edmonton
RCTs of IV Glutamine in ACU Patients (n=29)
A trend towards a reduction in mortality
RR, 0.87, 95 % CI 0.75,1.01, p = 0.07, 27 trials,
A significant reduction in hospital mortality
RR 0.70, 95% CI 0.53, 0.92, p= 0.01, 15 trials,
A trend towards a reduction in infectious complications
RR, 0.89, 95 % CI 0.77,1.03, p = 0.12, 13 trials,
A significant reduction in hospital length of stay
weighted mean difference in days -2.56, 95% CI -4.71, -0.42, p=0.02, 11 trials
September 20th 2011

18. RCTs of EN Glutamine in ACU Patients (n=10)
RE-ENERGIZE Training Edmonton
RCTs of EN Glutamine in ACU Patients (n=10)
No significant difference on mortality
RR, 0.94, 95 % CI 0.65,1.36, p = 0.74
No impact on in infectious complications
RR, 0.93, 95 % CI 0.79,1.10, p = 0.39, 4 trials
A significant reduction in hospital length of stay
weighted mean difference in days -4.73, 95% CI -8.56,-0.90, p=0.02, 7 trials.
September 20th 2011

19. On behalf of the REDOXS Study Investigators
A RANDOMIZED TRIAL OF HIGH-DOSE GLUTAMINE AND ANTIOXIDANTS IN CRITICALLY ILL PATIENTS WITH MULTIORGAN FAILURE   The REDOXS study
On behalf of the REDOXS Study Investigators
N Engl J Med 2013;368:

20. R R R The REDOXS study antioxidants glutamine 1200 ACU patients
Factorial 2x2 design
Double blind treatment
glutamine R
1200 ACU patients R
Concealed
Stratified by site
Evidence of
placebo
Multi-organ failure
antioxidants
placebo R
placebo

21. The Research Protocol Inclusion Criteria Adults (>18)
With 2 or more organ failures related to their acute illness :
Requiring mechanically ventilation (P/F<300)
Clinical evidence of hypoperfusion defined by need for vasopressor agents for more than 2 hour
Renal dysfunction : Cr>171 (>1.93 mg/dL) or <500ml/24 hrs
platelet < 50

22. High dose associated with
Optimizing the Dose of Glutamine Dipeptides and Antioxidants In Critically Ill Patients: A Phase I dose finding study
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

23. Mortality Outcomes Note: all P values pertain to GLN vs No GLN;
no significant differences between AOX vs. No AOX

24. Other Clinical Outcomes
No differences between groups
SOFA
Need for dialysis
Duration of mechanical ventilation
PODS
infections
ACU and Hospital LOS

25. Selected Subgroup Analyses
OR (95% CI) compared to placebo
P-values*
Subgroup
Deaths/n (%)
GLN alone
AOX alone
GLN+AOX
Overall
363/1218 (30%)
1.40 ( )
1.20 ( )
1.42 ( )
Study Setting
Region
0.37
Canada
303/1044 (29%)
1.41 ( )
1.14 ( )
1.29 ( )
USA
44/131 (34%)
1.56 ( )
1.43 ( )
3.43 ( )
Europe
16/43 (37%)
0.86 ( )
2.40 ( )
0.89 ( )
Baseline Patient Characteristics
Admission category
0.52
Surgical
59/255 (23%)
2.16 ( )
1.94 ( )
1.58 ( )
Medical
304/963 (32%)
1.28 ( )
1.08 ( )
1.43 ( )
Cancer patients
0.74 No
297/1048 (28%)
1.48 ( )
1.15 ( )
1.42 ( )
Yes
66/170 (39%)
1.05 ( )
1.43 ( )
1.38 ( )
Etiology of Shock
0.71
Cardiogenic
74/240 (31%)
1.24 ( )
1.62 ( )
2.19 ( )
Septic
256/826 (31%)
1.43 ( )
1.06 ( )
1.21 ( )
Other/Unkown/None
33/152 (22%)
1.45 ( )
1.45 ( )
1.83 ( )
Vasopressors
<15 mcg/min
162/595 (27%)
1.58 ( )
1.66 ( )
1.50 ( )
>=15 mcg/min
201/623 (32%)
1.32 ( )
0.92 ( )
1.39 ( )
Renal dysfunction
0.035
216/776 (28%)
0.93 ( )
0.90 ( )
1.14 ( )
147/442 (33%)
2.75 ( )
2.16 ( )
2.15 ( )
OR-odds ratio; CI-confidence interval; GLN-Glutamine; AOX-antioxidants

26. Conclusions
Glutamine and antioxidants at doses studied in this study do not improve clinical outcomes in critically ill patients with multi-organ failure
Glutamine may be harmful
For both glutamine and antioxidants, the greatest signal of harm was in patients with multi-organ failure that included renal dysfunction upon study enrollment.

27. Metaplus Study
14 ACUs in the Netherlands, Germany, France, and Belgium.
301 adult patients who were expected to be ventilated and to require EN for more than 72 hours
Randomized to intervention feed
High-protein EN enriched with 21 grams of glutamine, extra antioxidants including an additional 275 mcg of selenium and an additional 7.5 grams of fish oils, n = 152)
or control (standard high-protein EN, n = 149).
Intention-to-treat analysis for total population as well as predefined medical, surgical, and trauma subpopulations.
Van Zanten JAMA 2014;312:514

28. Metaplus Study No differences in infection (primary end point)
53% in the enriched group vs 52% in the control group (P = .96).
No differences in any secondary end points including mortality, Sequential Organ Failure Assessment (SOFA) scores, mechanical ventilation duration, ACU and hospital lengths of stay, and subtypes of infections according to CDC definitions.
hazard ratio of 1.57 (95%CI, ; P = .04) for 6-month mortality adjusted for age and Acute Physiology and Chronic Health Evaluation II score
A higher 6-month mortality rate in the medical subgroup: 54% (95%CI, 40%-67%) in the enriched group vs 35% (95%CI, 22%-49%) in the control group (P = .04).
No signal of harm in renal failure
Van Zanten JAMA 2014;312:514

29. 2015 Canadian Nutrition CPGs: IV Glutamine
Recommendation:
When parenteral nutrition is prescribed to critically ill patients, we recommend parenteral supplementation with glutamine NOT be used*.
There are insufficient data to generate recommendations for intravenous glutamine in critically ill patients receiving enteral nutrition, but given the safety concerns we also recommend intravenous glutamine NOT be used in enterally fed critically ill patients.
*downgraded from ‘should be considered’

30. 2015 Canadian Nutrition CPGs: Combined IV+ EN Glutamine
Recommendation:
Based on one level 1 study (REDOXS) and 1 level 2 study, we strongly recommend that high dose combined parenteral and enteral glutamine supplementation NOT be used in critically ill patients

31. Key Question
If we conclude that glutamine has potential for harm, what impact does this have on our clinical recommendations for burn patients?

32. RE-ENERGIZE Training Edmonton
RCTs of Glutamine in Burn Injury Patients Total of 6 studies involving 225 patients
Effect on Mortality (n=4)
Margot, please update
The analysis of the 6 trials in 225 burn patients shows a significant effect on mortality (RR, 0.22, 95% CI 0.07, 0.62, p = 0.005, 4 trials), no effect on infections (RR, 0.78, 95 % CI 0.46, 1.31, p = 0.34, 3 trials) but a significant reduction in hospital length of stay (WMD: 6.06, 95% CI -9.91, -2.20, p= 0.002, 5 trials).15
RR, 0.22, 95% CI 0.07, 0.62, p = 0.005
September 20th 2011

33. RCTs of Glutamine in Burn Injury
RE-ENERGIZE Training Edmonton
RCTs of Glutamine in Burn Injury
Effect on Infection (n=3)
RR, 0.78, 95 % CI 0.46, 1.31, p = 0.34
September 20th 2011

34. RCTs of Glutamine in Burn Injury
RE-ENERGIZE Training Edmonton
RCTs of Glutamine in Burn Injury
Effect on Hospital Length of Stay (n=5)
WMD: 6.06, 95% CI -9.91, -2.20, p= 0.002
September 20th 2011

35. RE-ENERGIZE Training Edmonton
International observational study of nutritional support in mechanically ventilated patients following major burn injury (90 patients from 15 Countries)
Energy and Protein deficits in relation to mortality
(Relationship persisted despite adjustment for severity of illness)
Protein Deficit (g)
Energy Deficit (Kcal)
Energy deficit
Protein deficit
Survived
Died
48% of patients receiving glutamine
Glutamine administration was associated with survival when adjusted for APACHE II ( p = 0.007).
Czapran Burns 2014
September 20th 2011

36. RE-ENERGIZE and REDOXs
Differences Between
RE-ENERGIZE and REDOXs

37. Compelling Need to Answer the Study Question
Primary research question: In patients with severe, life-threatening burn injury, what is the effect of enteral glutamine on 6 month mortality? Secondary Research question: In patients with severe, life-threatening burn injury, what is the effect of enteral glutamine on -time to discharge alive from hospital, -hospital-acquired blood infections, -hospital mortality, -duration of stay in ACU and hospital, -health-related quality of life -and health care resources?

38. A RandomizEd trial of ENtERal Glutamine to minimIZE thermal injury
Double blind treatment
EN glutamine
2700 patients with TBSA
≥ 20% if yrs age
≥ 15% if yrs age
with inhalation injury
≥ 10% if ≥ 60 yrs age R
6 month mortality
Concealed
Stratified by site
Maltodextran
placebo

39. < 72 h (ACU admission to time of consent)
Study Overview
6 month
< 74 hours
Mortality assessment
< 72 h (ACU admission to time of consent)
2 h
ACU Admission
Consent Obtained
First Dose of IP
Randomization
3 mos.
Dosing until 7 days after last graft up to 3 mos.
Maintain regular contact
6 month
Data collection from ACU admission to 10 days after last graft up to 3 mos.
SF-36 Quality of Life Assessment
Activities of Daily Living
Instrumental Activities of Daily Living
Employment Status Assessment

40. Definitive Study: Inclusion Criteria
Deep 2nd and/or 3rd degree burns requiring skin grafting*.
For patients age 18 – 59 years we require a burn of ≥ 20% TBSA (Total Body Surface Area) or a minimum of 15 % TBSA when concomitant inhalation injury is present.
For patients aged 60 years or older we require a burn of ≥10% TBSA.
Smoke inhalation injury is defined as: restricted to injury below the glottis caused by
products of combustion.
Diagnosis of inhalation injury requires both of the following:
       1) history of exposure to products of combustion
       2) bronchoscopy revealing one of the following below the glottis
                      evidence of carbonaceous material
                      signs of edema or ulceration
*Note: there is no minimum area that requires grafting. As long as the total burn size meets the inclusion criteria and a graft is required, the patient is eligible.

41. Definitive Study: Exclusion Criteria
>72 hrs from admission to ACU (Acute Care Unit) to time of consent
Patients younger than 18 years of age (age of maturity for an eligible patient to obtain consent is 18 years in Canada and in the US)
In patients without known renal disease, renal dysfunction defined as a
serum creatinine >171 μmol/L or >1.93 mg/dL or
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).
In patients with acute on chronic renal failure (pre-dialysis), an absolute increase of >80 μmol/L or >0.9 mg/dL from baseline or pre-admission creatinine or a urine output of <500 ml/last 24 hours (or 80 ml/last 4 hours) will be required.
Patients with chronic renal failure on dialysis will be excluded.
Changed to REDOXS criteria to address reviewer’s concerns

42. Definitive Study: Exclusion Criteria
4. Liver cirrhosis -Child’s class C liver disease
5. Pregnancy (urine/blood tests for pregnancy will be done on all women of childbearing age by each site as part of standard ACU practice)
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 kg/m2
10. Enrolment in another industry sponsored ACU intervention study (co-enrollment in academic studies will be considered on a case by case basis)
11. Received glutamine supplement for > 24 hrs prior to randomization
12. Known allergy to maltodextrin, corn starch, corn, corn products or glutamine

43. Study Intervention OR MALTRIN® Maltodextrin
Enteral glutamine (0.5 gm/kg/day) or maltodextrin will be given through
the feeding tube, q4h until 7 days post last successful graft

44. Study Intervention
The study intervention is to be mixed in 50 mL of water per 5g packet and given as a bolus every 4 hours via the enteral route.  
Administer the study intervention immediately after mixing with water to avoid thickening of the mixture.
If the mixture becomes too thick to administer as a bolus, add water.
Have not observed increase in tube blockages
When the patient is tolerating oral feeds, the boluses may be switched to TID or QID via the oral route according to the patient’s preference, as long as the patient receives the daily prescribed number of packets.

45. Study Intervention
Avoid mixing the IP in water when given orally. Patients who participated in the pilot study reported it did not taste good when mixed with water.
There should be little to no difference in taste of the glutamine and maltodextrin.
Do NOT mix the study intervention with:
soda or
highly acidic juices, such as:
grapefruit juice
orange juice
lemonade.  
Why?
The study intervention becomes unstable in an acidic medium.

46. Duration of Study Intervention
ACU admission
7 days post last
successful graft
(max 3 months or ACU d/c, whichever first)
Study Intervention
Randomization

47. Co-interventions: Standardization of Nutrition
Prescribed calorie ranges
Prescribed protein ranges
Vitamin/mineral prescription
Optimization of the Delivery of Enteral Nutrition
Glycemic control
Arginine enriched formulas (> 6 gms arginine/L) i.e.
Pivot, Perative
Glutamine supplements or formulas containing higher than
standard amounts of glutamine i.e. Juven

49. Enteral Feeding Protocol
STOP enteral nutrition if the patient develops :
-bowel obstruction
-bowel perforation
-paralytic ileus
Start Enteral Nutrition as soon as possible after burn injury, preferably within 24 hrs of burn injury, if possible
WATER FLUSHES:
Flush tube with at least 10 mls of sterile water:
-q4hrs during feedings
-after aspiration for GRVs
-before and after meds
BLOCKED TUBE:
Pancrealipase, 8000 units, with crushed Na Bicarb 500mg in 5ml warm water via feeding tube as needed.
Elevate HOB to 45 degrees, if possible
If gastric feeding, check GRVs q 4 hrs.
1) Refeed gastric residual
2) Continue with Enteral Nutrition
Is the GRV
> 250 mls? NO
YES
Is this the 1st
GRV > 250 ml*?
YES NO
1) Refeed GRV to 250ml max and discard the rest
2) Start Maxeran 10mg IV q 6 hrs
3) Continue with Enteral Nutrition
This is a rechecked residual >250 mls:
1) Discard the residual
2) Continue with Motility agents
3) Switch to SMALL BOWEL FEEDING
4) Restart Enteral Nutrition
5) Monitor enteral nutrition tolerance, but do not monitor GRVs if small bowel feeding
* Gastric residual volume (GRV) of 250 mls is the minimum threshold volume. Volumes higher than 250 mls are acceptable if allowed at the individual site.

50. Outcomes Primary Outcome: 6 month mortality
Secondary Outcome: Time to discharge alive
Teritiary Outcomes:
Health-related quality of life 6 months)
Incidence of acquired bacteremias due to Gram negative organisms
Hospital Mortality
Duration of mechanical ventilation
ACU stay and hospital stay 50

51. Results of Pilot Study 203 patients enrolled in 8 sites
Approx 1 patient/site/month
>90% of prescribed doses of study medication were delivered.
Only 2% of patients have been lost to follow-up at 6 months.
Good compliance with study procedures and filling out the case report form
Plan to roll the data from the pilot trial into this current proposal so we have not analyzed the trial by group.

52. Results of Pilot Study: Patient Characteristics
RE-ENERGIZE Training Edmonton
Results of Pilot Study: Patient Characteristics
Characteristics n
Male/Female %
79/21
168
Age , yrs (mean, SD)
47.7 ± 18.3
179
% TBSA (mean, SD)
32.3 ± 15.3
Age + % TBSA (mean, SD)
80.0 ± 19.6
age + %TBSA <60
16.8%
age + %TBSA
52.0%
age + % TBSA >90
31.3%
% Mechanically Ventilated
64/149 (43%)
149
ACU LOS days (mean, SD)
32.6 ± 26.8
159
Hospital LOS days (mean, SD)
34.9 ± 29.5
153
ACU mortality
8/142 (6%)
150
6 month mortality
15%
106
September 20th 2011

53. Current Status and Timelines
Definitive Trial Funded by CIHR
Site start-up in progress
Pilot sites resume by Dec 1, 2015
Rest of Canadian sites initiate by end of 2015
New sites on board by end of second quarter 2016
Continue to develop network of interested burn units
4 years of enrolling patients

54. Questions and Discussion Points?
Patients?
Study Products
Feeding protocol
6 month follow up
Adequate research infrastructure
Competing studies
Financials and Timelines

55. Conclusions RE-ENERGIZE trial Thank you for your interest and support
Will ask a clinically important question
Has the potential to save lives and reduce morbidity whether positive or negative
Largest burn trial ever!
Thank you for your interest and support

56. RE-ENERGIZE Training Edmonton
Questions?
September 20th 2011