Role of Pharmaconutrition in ICU in relation to reducing oxidative stress: The REDOXS study Daren K....

A RANDOMIZED TRIAL OF HIGH-DOSE GLUTAMINE AND

ANTIOXIDANTS IN CRITICALLY ILL PATIENTS WITH

MULTIORGAN FAILURE

The REDOXS study

Daren K. Heyland MD

Professor of MedicineQueen’s University, Kingston, ON Canada

On behalf of the REDOXS Study Investigators

Disclosures

• The investigator-initiated study was funded by the Canadian Institutes of Health Research.

• Fresenius Kabi provided intravenous glutamine and enteral supplements, and an unrestricted grant-in-aid.

• Biosyn provided the intravenous selenium to all participating European sites.

• None of these agencies had a decisional role in the conception, design, conduct, analysis, interpretation of results or decision to publish.

Mucosal Barrier Integrity

Inflammation

Cellular Immune Function

Oxidative StressMito

Function

In Search of the Magic Pharmaconutrient

Heyland DK, Cook DJ, Guyatt G. Does the Formulation of Enteral Feeding Products Influence Infectious Morbidity and Mortality in the Critically Ill Patient: A

Critical Review of the Evidence. Crit Care Med 1994;22:1192-1202.

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

Glutamine: A conditionally essential amino acid?

Potential Beneficial Effects of Glutamine

Fuel forFuel forEnterocytesEnterocytes

Fuel forFuel forLymphocytesLymphocytes

Nuclotide Nuclotide SynthesisSynthesis

Maintenance ofMaintenance ofIntestinalIntestinalMucosal BarrierMucosal Barrier

Maintenance ofMaintenance ofLymphocyteLymphocyteFunctionFunction

Preservation Preservation of TCA Functionof TCA Function

Decreased FreeRadical availability (Anti-inflammatory action)

GlutathioneGlutathioneSynthesisSynthesis

GLNGLNpoolpool

GlutamineTherapy

Enhanced HeatEnhanced Heat Shock ProteinShock Protein

Anti-cataboliceffect

Preservation of Muscle mass

Reduced Reduced TranslocationTranslocationEnteric BacteriaEnteric Bacteriaor Endotoxinsor Endotoxins

Reduction ofReduction ofInfectious Infectious complicationscomplications

Increased AutophagyIncreased Autophagy

Preserved CellularEnergetics- ATP content

GLNGLNPoolPool

Critical IllnessCritical Illness

Enhanced insulin sensitivity

0

1

2

3

4

5

6

Baseline 1 week

Study Date

Seru

m H

SP 7

0 (n

g/m

l)

GLN Patients Control Patients

*

IV Glutamine Enhances Serum HSP-70 in Critically Ill Patients with

Sepsis/SIRSALA-GLN treatment ALA-GLN treatment leads to significant leads to significant enhancement of enhancement of serum HSP-70 with serum HSP-70 with 7 days of treatment7 days of treatment

ALA-GLN ALA-GLN mediated mediated enhancement of enhancement of HSP-70 correlates HSP-70 correlates with decreased ICU with decreased ICU length of stay and length of stay and time on ventilatortime on ventilator

Ziegler Intensive Care Medicine, 31:1079-1086, 2005

Mechanism of Enteral Glutamine

• 3 RCTs of enteral glutamine

• Burns patients– Increased plasma glutamine

– Improved permeability

– Decreased endotoxin levels

– Reduced GNB infections

– Reduced hospital LOS

– Reduced mortality

Garrell CCM 2003;31:2444, Zhou JPEN 2003 27;241; Peng Burns 2004;30:135

Mortality CCM 2002

Current version posted on www.criticalcarenutrition.com

OFRCONSUMPTION

OFR

PRODUCTION

Depletion ofAntioxidant EnzymesOFR Scavengers Vitamins/Cofactors

InfectionInflammationIschemia

OFR production > OFR consumption =Impaired- organ function- immune function- mucosal barrier function

Complications and Death

OXIDATIVESTRESS

Rationale for Antioxidants

In Critical Illness, Low Levels of Se related to Severity of Illness

Manzanares ICM 2009;35:882

Healthy Controls

ICU Patients

ICU+SIRS

ICU +MODS

…and Correlate with GPx activity

Manzanares ICM 2009;35:882

Effect on Mortality

Current version posted on www.criticalcarenutrition.com

The Research Protocol

In critically ill patients with a clinical evidence of organ failure …– What is the effect of glutamine

supplementation compared to placebo– What is the effect of antioxidant

supplementation compared to placebo

…on 28 day mortality?

The Question(s)

N Engl J Med 2013;368:1489-97.

1200 ICU patientsEvidence of

Multi-organ failureR

glutamine

placebo

ConcealedStratified by site

R

R

antioxidants

placebo

Factorial 2x2 designDouble blind treatment

placebo

antioxidants

The REDOXS study


• 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 or <500ml/24 hrs– platelet < 50

Inclusion Criteria


• > 24 hrs from admission to ICU • Not expected to survive • Lack of commitment to full aggressive care • Absolute contraindication to EN• Severe acquired brain injury

– severe head trauma– post cardiac arrest with suspicion of anoxic injury – Grade 4 or 5 SAH– stroke resulting in coma or Intubation

• Routine cardiac surgery • Seizure disorder requiring treatment • Burns (>30% BSA)

Exclusion Criteria

Optimizing the Dose of Glutamine Dipeptides and Antioxidants In Critically Ill Patients:

A Phase I dose finding study

• 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

Parenterally Enterally

Glutamine/day 0.35 gms/kg 30 gms

Antioxidantsper day

500 mcg Selenium

Vit C 1500 mgVit E 500 mg

B carotene 10 mgZinc 20 mgSe 300 ug

Glutamine Dipeptides • Free L-glutamine has limited solubility and stability • Synthetic dipeptides (ala-gln, gly-gln) overcome

these difficulties• 8.5 gms of dipeptide=6 gms of glutamine

Vit C 1500 mg

Vit E 500 mg

B-carotene 10 mg

Zinc 20mg

Selenium 300ug

Glutamine 30 gms

Enteral Study Supplement EN REDOXS © Formula

Parenteral Study Supplements Dipeptiven and Selenium

+ Selenium

(Biosyn)

Study supplements started within 24 hrs of admissionContinued for 28 days or until death or discharge from ICU

Results

N Engl J Med 2013;368:1489-97.

Patient Flow

Patient Characteristics (1)

Patient Characteristics PLACEBO GLN AOX AOX+GLN P values

n 300 301 307 310 Age* 62.8±13.7

(18.0-89.0)62.5±15.0 (19.0-91.5)

63.6±14.3 (18.0-92.0)

64.3±14.0 (22.0-92.9)

0.40

Sex 0.45Female 122 (40.7%) 110 (36.5%) 130 (42.3%) 130 (41.9%)

Male 178 (59.3%) 191 (63.5%) 177 (57.7%) 180 (58.1%) APACHEII score* 26.0± 7.4(6.0-

49.0)26.6± 7.6(8.0-

48.0)25.9± 7.1(9.0-

51.0)26.8± 7.4

(10.0-49.0)0.39

Charlson Comorbidity Index* 1.7± 1.8(0.0- 8.0)

1.5± 1.6(0.0- 8.0)

1.8± 1.8(0.0-10.0)

1.8± 1.8(0.0-11.0)

0.24

Functional Comorbidity Index* 1.5± 1.4(0.0- 6.0)

1.4± 1.4(0.0- 7.0)

1.5± 1.4(0.0- 6.0)

1.5± 1.3(0.0- 7.0)

0.28

Admission 0.42

Medical 236 (78.7%) 238 (79.1%) 254 (82.7%) 235 (75.8%) Surgical: Elective 26 (8.7%) 27 (9.0%) 19 (6.2%) 35 (11.3%)

Surgical: Emergency 38 (12.7%) 36 (12.0%) 34 (11.1%) 40 (12.9%)

Primary ICU diagnosis 0.15Cardiovascular / vascular 70 (23.3%) 54 (17.9%) 53 (17.3%) 60 (19.4%)

Respiratory 97 (32.3%) 101 (33.6%) 94 (30.6%) 83 (26.8%) Gastrointestinal 17 (5.7%) 21 (7.0%) 32 (10.4%) 25 (8.1%)

Neurologic 2 (0.7%) 4 (1.3%) 5 (1.6%) 2 (0.6%) Sepsis 86 (28.7%) 88 (29.2%) 98 (31.9%) 106 (34.2%)

Trauma 10 (3.3%) 9 (3.0%) 5 (1.6%) 7 (2.3%) Metabolic 6 (2.0%) 8 (2.7%) 9 (2.9%) 5 (1.6%)

Hematologic 0 (0.0%) 2 (0.7%) 0 (0.0%) 4 (1.3%) Renal 0 (0.0%) 2 (0.7%) 0 (0.0%) 5 (1.6%)

Gynecologic 1 (0.3%) 0 (0.0%) 0 (0.0%) 0 (0.0%) Orthopedic 0 (0.0%) 1 (0.3%) 2 (0.7%) 3 (1.0%)

Other 11 (3.7%) 11 (3.7%) 9 (2.9%) 10 (3.2%)


Patient Characteristics PLACEBO GLN AOX AOX+GLNP values

n 300 301 307 310 Etiology of shock 0.79

Cardiogenic 72 (24.0%) 54 (17.9%) 57 (18.6%) 57 (18.4%) Septic 191 (63.7%) 206 (68.4%) 218 (71.0%) 211 (68.1%)

Neurogenic 2 (0.7%) 3 (1.0%) 3 (1.0%) 2 (0.6%) Anaphylactic 0 (0.0%) 1 (0.3%) 1 (0.3%) 0 (0.0%) Hemorrhagic 13 (4.3%) 10 (3.3%) 9 (2.9%) 16 (5.2%)

Uncertain Origin 11 (3.7%) 15 (5.0%) 13 (4.2%) 14 (4.5%) Not in shock 9 (3.0%) 9 (3.0%) 4 (1.3%) 5 (1.6%)

Other 2 (0.7%) 3 (1.0%) 2 (0.7%) 5 (1.6%) Ethnicity 0.15

White 274 (91.3%) 262 (87.0%) 274 (89.3%) 284 (91.6%) Black or African American 7 (2.3%) 15 (5.0%) 9 (2.9%) 3 (1.0%)

Hispanic 2 (0.7%) 5 (1.7%) 6 (2.0%) 6 (1.9%) Asian or Pacific Islander 9 (3.0%) 11 (3.7%) 8 (2.6%) 10 (3.2%)

Native 2 (0.7%) 5 (1.7%) 8 (2.6%) 6 (1.9%) Other 6 (2.0%) 3 (1.0%) 2 (0.7%) 1 (0.3%)

Inclusion criteria A PaO2/FiO2 ratio of ≤300 282 (94.0%) 285 (94.7%) 287 (93.5%) 285 (91.9%) 0.56

Clinical evidence of hypo-perfusion 277 (92.3%) 278 (92.4%) 286 (93.2%) 293 (94.5%) 0.68Renal dysfunction 104 (34.7%) 117 (38.9%) 99 (32.2%) 122 (39.4%) 0.20

A platelet count of ≤50 mm3 16 (5.3%) 21 (7.0%) 12 (3.9%) 18 (5.8%) 0.42


Patient Characteristics PLACEBO GLN AOX AOX+GLNP values

n 300 301 307 310 Hours in ICU prior to randomization†

17.9[13.4 to 21.5]

17.7[12.7 to 21.1]

18.4[12.3 to 21.5]

18.0[13.3 to 21.6]

0.85

Number of organ failures 0.101 1 (0.3%) 2 (0.7%) 1 (0.3%) 0 (0.0%) 2 221 (73.7%) 206 (68.4%) 236 (76.9%) 216 (69.7%) 3 76 (25.3%) 85 (28.2%) 69 (22.5%) 90 (29.0%) 4 2 (0.7%) 8 (2.7%) 1 (0.3%) 4 (1.3%)

First organ dysfunction to initiation of EN supplements(hours)†

23.0[17.0 to 27.3]

21.4[15.9 to 26.4]

21.5[16.8 to 26.0]

21.7[17.0 to 27.0]

0.52

First organ dysfunction to initiation of PN supplements(hours)†

22.3[16.5 to 26.5]

21.0[14.8 to 25.0]

21.1[16.0 to 25.5]

21.5[16.3 to 26.0]

0.21

*mean±SD(min,max)† Median [IQR](min,max)Counts and percentage for all categorical variables

Nutritional Outcomes

GlutamineNo

Glutaminep

valuesAntioxidants No Antioxidants

P values

*Adequacy of calories from total nutrition

Mean±SD(range) 47.8±29.0 (0.0-118.8)

48.4±29.5 (0.0-116.5)

0.8248.4±29.7 (0.0-118.8)

47.9±28.8 (0.0-116.5)

0.74

Adequacy of protein from total nutrition

Mean±SD(range) 43.4±27.7 (0.0-112.4)

43.2±27.9 (0.0-148.0)

0.8243.8±28.3 (0.0-148.0)

42.8±27.3 (0.0-106.1)

0.60

Adequacy of calories from EN Mean±SD(range) 45.0±29.4

(0.0-118.8)46.1±30.1 (0.0-116.5)

0.6645.4±29.9 (0.0-118.8)

45.7±29.5 (0.0-116.5)

0.84

Adequacy of protein from EN Mean±SD(range) 40.8±27.8

(0.0-112.4)41.1±28.2 (0.0-148.0)

1.0041.0±28.3 (0.0-148.0)

40.8±27.7 (0.0-106.1)

1.00

Type of Nutrition 0.50 0.48EN Only 459 (75.1%) 466 (76.8%) 462 (74.9%) 463 (77.0%)PN Only 8 (1.3%) 13 (2.1%) 14 (2.3%) 7 (1.2%)EN+PN 37 (6.1%) 30 (4.9%) 35 (5.7%) 32 (5.3%)

None 107 (17.5%) 98 (16.1%) 106 (17.2%) 99 (16.5%)Time of initiation of EN(hours)

Mean±SD(range) 28.8±40.6 (0.0-412.1)

26.2±25.7 (0.0-241.5)

0.7628.7±38.9 (0.0-412.1)

26.2±28.3 (0.0-304.9)

0.94

Compliance with Study Procedures

GlutamineNo

Glutaminep

valuesAntioxidants

No Antioxidants

P values

*% EN supplements received

Mean±SD (range) 71.0±26.4 (0.0-104.7)

70.9±27.2 (0.0-133.3)

0.8070.1±26.7 (0.0-

104.2)71.7±26.9 (0.0-

133.3)0.18

% PN supplements receivedMean±SD (range) 88.8±17.6

(0.0-147.2)89.5±17.8 (0.0-133.3)

0.4289.1±18.0 (0.0-

147.2)89.2±17.3 (0.0-

133.3)0.74

Duration of EN study supplement Median (Q1,Q3) 6.8

[3.2 to 13.6]6.8

[3.5 to 13.2]0.94

6.7[3.3 to 13.0]

6.9 [3.2 to 13.8]

0.61

Duration of PN study supplement Median (Q1,Q3) 7.9

[4.8 to 14.8]7.9

[5.0 to 14.0]0.58

7.8 [4.9 to 14.7]

7.9 [5.0 to 14.5]

0.63

Primary Outcome

Primary outcome of 28 day mortality using all 1218 evaluable patients (ITT)

Glu

tam

ine

(glu

t)

Antioxidants (AOX)

Yes No

AOX OR conditioned on

GlutOverall adjusted OR

of AOX

Yes 101/310 (32.6%) 97/301 (32.2%)1.02 (0.72, 1.43)

1.09 (0.86-1.40; p=0.48*)

No89/307 (29.0%) 76/309 (25.3%)

1.20 (0.84, 1.72)

Glut OR conditioned on AOX 1.18 (0.83-1.66) 1.40 (0.98-2.00)

Overall adjusted OR for glut 1.28 (1.00-1.64; p=0.049*)

AOX by glut interaction

p=0.49

OR=odds ratio. ORs are presented with 95% confidence intervals in parentheses. An OR>1 indicates increased mortality with treatment.

All odds ratios adjust for presence of shock at baseline. Overall ORs also adjust for other treatment factor.*To account for the two interim analyses, we pre-specified statistical significance of the final analysis at a two-sided p<0.044 in our protocol. Thus, our primary outcome did not reach statistical significance for either intervention.

Primary outcome of 28 day mortality using 1025 patients who received ≥5 days of supplements

Glu

tam

ine

(glu

t)

Antioxidants (AOX)

Yes No

AOX OR conditioned on

GlutOverall adjusted OR

of AOX

Yes 55/255 (21.6%) 60/246 (24.4%) 0.85 (0.56-1.30)0.98 (0.73-1.32;

p=0.90)No 55/263(20.9%) 49/261 (18.8%) 1.14 (0.74-1.76)

Glut OR conditioned on AOX 1.03 (0.68-1.57) 1.39 (0.91-2.13)

Overall adjusted OR for glut 1.20 (0.89-1.62; p=0.23)

AOX by glut interaction

p=0.33

OR=odds ratio. ORs are presented with 95% confidence intervals in parentheses. An OR>1 indicates increased mortality with treatment.

All odds ratios adjust for presence of shock at baseline. Overall ORs also adjust for other treatment factor.

Mortality Outcomes

P=0.07

P=0.049

P=0.02

P=0.02

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

Overall 6 Month SurvivalAll evaluable patients (ITT)

Glutamine vs. no-Glutamine (P=0.02)

Overall 6 Month SurvivalAll evaluable patients (ITT) Antioxidant vs. no- Antioxidant (P=0.87)

Pre-specified Sub-group AnalysisGlutamine vs. No Glutamine

Favours GLN OR Favours No GLN

0.5 0.7 0.9 1.5 2.0 3.0

Charlson co-morbidity index > 1

Charlson co-morbidity index 0-1

Age >=75

Age 65-74

Age 55-64

Age <55

Other admission diagnosis

Sepsis

APACHE II Score > median

APACHE II Score <= median

>2 organ failures on presentation

2 organ failures on presentation

All Patients p=0.049

p=0.47

p=0.05

p=0.10

p=0.31

p=0.11

p=0.33

p=0.07

p=0.55

p=0.05

p=0.57

p=0.10

p=0.22

p=0.48

p=0.82

p=0.3428 day mortality, OR with 95% CI)

Pre-Specified Sub-group AnalysisAntioxidant vs. No Antioxidants

Favours AOX OR Favours No AOX

0.5 0.7 0.9 1.5 2.0 3.0

Charlson co-morbidity index > 1

Charlson co-morbidity index 0-1

Age >=75

Age 65-74

Age 55-64

Age <55

Other admission diagnosis

Sepsis

APACHE II Score > median

APACHE II Score <= median

>2 organ failures on presentation

2 organ failures on presentation

All Patients

p=0.10

p=0.22

p=0.48

p=0.82

p=0.34

p=0.15

p=0.65

p=0.69

p=0.07

p=0.84

p=0.79

p=0.30

p=0.14

p=0.48

p=0.98

28 day mortality, OR with 95% CI

Other Clinical Outcomes

• No differences between groups– SOFA– Need for dialysis– Duration of mechanical ventilation– PODS– infections– ICU and Hospital LOS

Effect of Glutamine on HRQOL

Short Form-36 at 3 months

Effect of Glutamine on HRQOL

Short Form-36 at 6 months

Plasma Levels of Glutamine in Subset of Patients

P <0.001

Plasma Levels of Selenium in Subset of Patients

P <0.001

Adverse Events

ARM PLACEBO GLN AOX AOX+GLNn 301 301 307 309

Number of patients ever had an UREA>50

12(4.0%) 43(14.3%) 12(3.9%) 39(12.6%)

Number of patients ever had diarrhea >750 ml or >5/day 112 (37.2%) 105 (34.9%) 107 (34.9%) 120 (38.8%)

Proportion of study days with diarrhea >750 or >5/day

368/4032=9.1% 358/3866=9.3% 336/3933=8.5% 448/4109=10.9%

Signs of phlebitis or extravasations

7(2.2%) 10(3.3%) 10(3.3%) 18(5.8%)

Post-hoc Secondary Analyses

Kaplan-Meier Survival Curve by Treatment Arm

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 (0.98-2.00) 1.20 (0.84-1.72) 1.42 (1.00-2.03)Study Setting Region 0.37

Canada 303/1044 (29%) 1.41 (0.96-2.07) 1.14 (0.77-1.67) 1.29 (0.88-1.89)

USA 44/131 (34%) 1.56 (0.51-4.81) 1.43 (0.47-4.38) 3.43 (1.17-10.07)

Europe 16/43 (37%) 0.86 (0.12-5.9) 2.40 (0.39-14.88) 0.89 (0.14-5.48)Baseline Patient Characteristics Admission category 0.52

Surgical 59/255 (23%) 2.16 (0.91-5.15) 1.94 (0.78-4.82) 1.58 (0.67-3.76)

Medical 304/963 (32%) 1.28 (0.87-1.89) 1.08 (0.73-1.60) 1.43 (0.97-2.12)Cancer patients 0.74

No 297/1048 (28%) 1.48 (1.01-2.18) 1.15 (0.77-1.71) 1.42 (0.97-2.10)

Yes 66/170 (39%) 1.05 (0.41-2.73) 1.43 (0.60-3.40) 1.38 (0.58-3.27)Etiology of Shock 0.71

Cardiogenic 74/240 (31%) 1.24 (0.56-2.79) 1.62 (0.75-3.51) 2.19 (1.03-4.67)

Septic 256/826 (31%) 1.43 (0.93-2.19) 1.06 (0.69-1.63) 1.21 (0.79-1.86)

Other/Unkown/None 33/152 (22%) 1.45 (0.46-4.57) 1.45 (0.43-4.86) 1.83 (0.60-5.78)Vasopressors 0.37

<15 mcg/min 162/595 (27%) 1.58 (0.92-2.70) 1.66 (0.97-2.84) 1.50 (0.87-2.58)

>=15 mcg/min 201/623 (32%) 1.32 (0.82-2.13) 0.92 (0.57-1.51) 1.39 (0.87-2.22)Renal dysfunction 0.035

No 216/776 (28%) 0.93 (0.59-1.46) 0.90 (0.58-1.40) 1.14 (0.74-1.77)

Yes 147/442 (33%) 2.75 (1.50-5.03) 2.16 (1.15-4.07) 2.15 (1.17-3.94)OR-odds ratio; CI-confidence interval; GLN-Glutamine; AOX-antioxidants

Examination of Treatment Effect by Baseline Renal Dysfunction and Post-Baseline Dialysis

Multivariable Subgroup OR (95% CI) Compared To Placebo Arm

Renal Dysfunction

Ever On Dialysis deaths/n (%) GLN alone AOX alone GLN+AOX

No No 158/634 (25%)

1.1 (0.6-1.8) 1.1 (0.6-1.8) 1.3 (0.8-2.2)

No Yes 58/142 (41%) 0.4 (0.2-1.2) 0.5 (0.2-1.3) 0.6 (0.3-1.6)

Yes No 76/240 (32%) 3.9 (1.7-9.0) 3.3 (1.4-7.8) 1.6 (0.7-3.8)

Yes Yes 71/202 (35%) 1.8 (0.7-4.4) 1.4 (0.6-3.5) 3.1 (1.2-7.6)

OR-odds ratio; CI-confidence interval; GLN-glutamine; AOX-antioxidants

Cells in bold indicate treatment arm had significantly higher 28 day mortality than placebo at p<0.05.

Adjusted Analysis

• The 28-day mortality rates in the placebo, glutamine, antioxidant and combination groups were 25%, 32%, 29% and 33% respectively.

• Compared to placebo, the unadjusted OR (95% CI) of mortality was 1.4 (1.0-2.0, P =0.063), 1.2 (0.8-1.7, P =0.31) and 1.4 (1.0-2.0, P=0.049) in the glutamine, antioxidant and combined groups respectively.

• After adjusting for all statistically significant baseline characteristics, the corresponding adjusted ORs remained virtually unchanged at 1.4 (1.0-2.1, P =0.054) 1.2(0.8-1.8, P =0.34) and 1.4 (0.9-2.0, P =0.10)

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.

• Patients with multi-organ failure not uniformly associated with low plasma glutamine levels

• May have provided insufficient selenium

Where did we go wrong with Glutamine?

• Moved from RCTs of IV glutamine in PN patients (meta-analysis) to patient with multi-organ failure thinking they would be more glutamine deficient

• Dosing study was inadequate– No plasma glutamine levels– No kinetics/dynamics in renal failure

• Others?

• eExperimental Diet enriched with Glutamine, AOX, and Omega 3 FFAs

A van Zanten, unpublished data

Future Trials Require Bedside Testing?

Where does that leave Glutamine?

Updated Meta-analysis of IV Glutamine (n=28 RCTs)

OverallMortality

Note: Does not include EN GLN studies nor REDOXS study

RR=0.87(0.75,1.02)

P=0.08

Study or Subgroup2.3.1 Patients on PN

GriffithsPowell-TuckWischmeyerXian-LiFuentes-Orozco 2004DechelotteTianSahinEstivarizFuentes-Orozco 2008Yang 2008Perez-Barcena 2008CaiLuoDuskaPerez-Barcena 2010AndrewsCekmanGrauWernermanZieglerSubtotal (95% CI)

Total eventsHeterogeneity: Tau² = 0.00; Chi² = 19.55, df = 19 (P = 0.42); I² = 3%Test for overall effect: Z = 1.93 (P = 0.05)

2.3.2 Patients on EN

PalmeseOzgultekinErogluSubtotal (95% CI)


Total (95% CI)

Total eventsHeterogeneity: Tau² = 0.00; Chi² = 19.99, df = 22 (P = 0.58); I² = 0%Test for overall effect: Z = 1.76 (P = 0.08)Test for subgroup differences: Chi² = 0.21, df = 1 (P = 0.65), I² = 0%

Events

1814

2022221213

17024

88398

15

195

612

1

19

214

Total

42831520175820203222251555111023

2501559

20575

1072

42202082

1154

Events

2520

5332566530

20002

806

131119

234

812

1

21

255

Total

42851621165620203122251555

91020

2521568

20875

1081

42202082

1163

Weight

12.6%6.2%1.1%0.3%0.8%0.6%1.0%1.1%0.5%1.0%0.5%0.3%8.3%

0.3%0.9%

37.9%1.6%3.9%2.9%6.5%

88.2%

2.5%9.0%0.3%

11.8%

100.0%

M-H, Random, 95% CI

0.72 [0.47, 1.11]0.72 [0.39, 1.32]0.43 [0.10, 1.88]0.15 [0.01, 2.73]0.63 [0.12, 3.28]0.97 [0.14, 6.62]0.40 [0.09, 1.83]0.33 [0.08, 1.46]0.16 [0.02, 1.26]0.40 [0.09, 1.85]0.33 [0.04, 2.99]

7.00 [0.39, 124.83]0.85 [0.50, 1.44]

Not estimable5.00 [0.27, 92.62]

1.74 [0.36, 8.51]1.11 [0.87, 1.42]0.50 [0.15, 1.64]0.80 [0.37, 1.73]0.74 [0.30, 1.80]0.79 [0.43, 1.43]0.84 [0.71, 1.00]

0.75 [0.28, 1.97]1.00 [0.60, 1.66]

1.00 [0.07, 14.90]0.94 [0.61, 1.47]

0.87 [0.75, 1.02]

Year

199719992001200420042006200620072008200820082008200820082008201020112011201120112012

200620082009

PN GLN Control Risk Ratio Risk RatioM-H, Random, 95% CI

0.1 0.2 0.5 1 2 5 10Favours PN GLN Favours control


Hospital Mortality


RR=0.68 (0.51,0.89)P= 0.005

Study or Subgroup

GriffithsPowell-TuckWischmeyerXian-LiFuentes-Orozco 2004DechelotteSahinPerez-Barcena 2008EstivarizLuoYang 2008Perez-Barcena 2010Ziegler

Total (95% CI)


Events

1814

2022231010

15

60

Total

42831520175820153211252375

436

Events

2520

5332606031

19

93

Total

428516211656201531

9252075

431

Weight

41.0%20.1%

3.4%0.9%2.8%2.0%3.5%0.9%1.8%

1.6%0.8%

21.2%

100.0%

M-H, Random, 95% CI

0.72 [0.47, 1.11]0.72 [0.39, 1.32]0.43 [0.10, 1.88]0.15 [0.01, 2.73]0.63 [0.12, 3.28]0.97 [0.14, 6.62]0.33 [0.08, 1.46]

7.00 [0.39, 124.83]0.16 [0.02, 1.26]

Not estimable0.33 [0.04, 2.99]0.29 [0.01, 6.78]0.79 [0.43, 1.43]

0.68 [0.51, 0.89]

Year

1997199920012004200420062007200820082008200820102012

PN GLN Control Risk Ratio Risk RatioM-H, Random, 95% CI

0.1 0.2 0.5 1 2 5 10Favours PN GLN Favours control


Hospital Mortality Study or Subgroup

1.8.1 High Quality Studies (8+)

GriffithsPowell-TuckWischmeyerFuentes-Orozco 2004DechelotteSahinPerez-Barcena 2008EstivarizLuoZieglerSubtotal (95% CI)


1.8.2 Low Quality Studies (<8)

Xian-LiYang 2008Perez-Barcena 2010Subtotal (95% CI)


Total (95% CI)

Total eventsHeterogeneity: Tau² = 0.00; Chi² = 7.93, df = 11 (P = 0.72); I² = 0%Test for overall effect: Z = 2.79 (P = 0.005)Test for subgroup differences: Chi² = 1.57, df = 1 (P = 0.21), I² = 36.2%

Events

1814

2222310

15

59

010

1

60

Total

42831517582015321175

368

20252368

436

Events

2520

5326060

19

86

331

7

93

Total

4285161656201531

975

365

21252066

431

Weight

41.0%20.1%

3.4%2.8%2.0%3.5%0.9%1.8%

21.2%96.8%

0.9%1.6%0.8%3.2%

100.0%

M-H, Random, 95% CI

0.72 [0.47, 1.11]0.72 [0.39, 1.32]0.43 [0.10, 1.88]0.63 [0.12, 3.28]0.97 [0.14, 6.62]0.33 [0.08, 1.46]

7.00 [0.39, 124.83]0.16 [0.02, 1.26]

Not estimable0.79 [0.43, 1.43]0.70 [0.53, 0.92]

0.15 [0.01, 2.73]0.33 [0.04, 2.99]0.29 [0.01, 6.78]0.26 [0.06, 1.19]

0.68 [0.51, 0.89]

Year

1997199920012004200620072008200820082013

200420082010

PN Glutamine Control Risk Ratio Risk RatioM-H, Random, 95% CI

0.01 0.1 1 10 100Favours PN Glutamine Favours control

Influence of the methodological quality of the study


Infection


RR=0.86 (0.73,1.03)P=0.10


GriffithsWischmeyerZhou 2004Fuentes-Orozco 2004DechelotteFuentes-Orozco 2008Perez-Barcena 2008GrauAndrewsZieglerSubtotal (95% CI)



PalmeseErogluSubtotal (95% CI)


Total (95% CI)

Total eventsHeterogeneity: Tau² = 0.03; Chi² = 19.86, df = 11 (P = 0.05); I² = 45%Test for overall effect: Z = 1.67 (P = 0.10)Test for subgroup differences: Chi² = 1.24, df = 1 (P = 0.27), I² = 19.1%

Events

28734

239

1124

13433

276

138

21

297

Total

4212151758221559

25075

565

422062

627

Events

2694

1232161331

13123

297

2110

31

328

Total

4214151656221568

25275

575

422062

637

Weight

12.5%5.7%1.6%3.1%

10.3%6.5%

11.1%9.9%

18.2%9.4%

88.3%

6.9%4.8%

11.7%

100.0%

M-H, Random, 95% CI

1.08 [0.78, 1.48]0.91 [0.49, 1.68]0.75 [0.20, 2.79]0.31 [0.13, 0.77]0.69 [0.47, 1.03]0.56 [0.32, 0.99]0.85 [0.59, 1.22]0.89 [0.60, 1.34]1.03 [0.87, 1.22]1.43 [0.94, 2.20]0.89 [0.74, 1.07]

0.62 [0.36, 1.07]0.80 [0.40, 1.60]0.68 [0.45, 1.05]

0.86 [0.73, 1.03]

Year

1997200120042004200620082008201120112012

20062009

PN Glutamine Control Risk Ratio Risk RatioM-H, Random, 95% CI

0.1 0.2 0.5 1 2 5 10Favours PN glutamine Favours control


ICULength of Stay


WMD=-2.46 (-4.74, -0.18) P=0.03


Fuentes-Orozco 2004ZhangLuoPerez-Barcena 2008Fuentes-Orozco 2008EstivarizCaiCekmanSubtotal (95% CI)

Heterogeneity: Tau² = 22.29; Chi² = 101.60, df = 7 (P < 0.00001); I² = 93%Test for overall effect: Z = 1.42 (P = 0.16)


PalmeseOzgultekinErogluSubtotal (95% CI)

Heterogeneity: Tau² = 0.00; Chi² = 1.31, df = 2 (P = 0.52); I² = 0%Test for overall effect: Z = 2.11 (P = 0.03)

Total (95% CI)

Heterogeneity: Tau² = 10.25; Chi² = 103.50, df = 10 (P < 0.00001); I² = 90%Test for overall effect: Z = 2.11 (P = 0.03)Test for subgroup differences: Chi² = 0.68, df = 1 (P = 0.41), I² = 0%

Mean

7.211.73

7.622.9

1112

22.119.2

1211.8

14

SD

9.26.57

0.720.611.7

24.912

4.65.9

2

Total

1722111522325515

189

42202082

271

Mean

7.313.39

6.920.5

11.1423

23.827.4

1317.3

15

SD

4.55.08

0.916

7.416

5.112

3.416.4

2

Total

1622

91522315515

185

42202082

267

Weight

8.2%10.1%13.1%

2.4%7.2%

11.8%12.2%

4.6%69.6%

12.3%5.3%

12.7%30.4%

100.0%

IV, Random, 95% CI

-0.10 [-5.00, 4.80]-1.66 [-5.13, 1.81]0.70 [-0.02, 1.42]

2.40 [-10.80, 15.60]-0.14 [-5.93, 5.65]

-11.00 [-13.22, -8.78]-1.70 [-3.57, 0.17]

-8.20 [-16.79, 0.39]-2.70 [-6.43, 1.03]

-1.00 [-2.73, 0.73]-5.50 [-13.14, 2.14]

-1.00 [-2.24, 0.24]-1.08 [-2.08, -0.08]

-2.46 [-4.74, -0.18]

Year

20042007200820082008200820082011

200620082009

PN GLN Control Mean Difference Mean DifferenceIV, Random, 95% CI

-10 -5 0 5 10Favours PN GLN Favours control


HospitalLength of Stay


WMD=-2.42 (-4.60, -0.24) P=0.03

Study or Subgroup

Powell-TuckWischmeyerZhou 2004Fuentes-Orozco 2004Xian-LiSahinFuentes-Orozco 2008Perez-Barcena 2008Yang 2008EstivarizZiegler

Total (95% CI)

Heterogeneity: Tau² = 6.35; Chi² = 28.63, df = 10 (P = 0.001); I² = 65%Test for overall effect: Z = 2.18 (P = 0.03)

Mean

43.44042

16.525.314.2

30.1835.5

13.4820

25.1

SD

34.110

78.97.64.4

10.4233.61.42

225.6

Total

8312151720202215251575

319

Mean

48.94046

16.728.616.4

26.5942.9

15.1830

20.5

SD

38.49

6.67

6.93.9

13.328.81.14

615.5

Total

8514151621202215251275

320

Weight

3.3%6.0%9.9%8.8%

10.7%15.3%

6.4%0.9%

19.1%12.9%

6.8%

100.0%

IV, Random, 95% CI

-5.50 [-16.48, 5.48]0.00 [-7.36, 7.36]

-4.00 [-8.87, 0.87]-0.20 [-5.65, 5.25]-3.30 [-7.75, 1.15]-2.20 [-4.78, 0.38]3.59 [-3.47, 10.65]

-7.40 [-29.80, 15.00]-1.70 [-2.41, -0.99]

-10.00 [-13.54, -6.46]4.60 [-2.17, 11.37]

-2.42 [-4.60, -0.24]

Year

19992001200420042004200720082008200820082012

PN Glutamine Control Mean Difference Mean DifferenceIV, Random, 95% CI

-10 -5 0 5 10Favours PN Glutamine Favours control

Canadian Nutrition CPGs: IV Glutamine

Recommendation:• When parenteral nutrition is prescribed to critically

ill patients, parenteral supplementation with glutamine should be considered*.

• However, we strongly recommend that glutamine NOT be used in critically ill patients with multi-organ failure.

• here are insufficient data to generate recommendations for intravenous glutamine in critically ill patients receiving enteral nutrition.

*downgraded from ‘strongly recommend’

Canadian Nutrition CPGs: EN Glutamine• No new studies since 2009

• Conclusions are: – 1) Glutamine supplemented enteral nutrition may be associated

with a reduction in mortality in burn patients, but inconclusive in other critically ill patients.

– 2) Glutamine supplemented enteral nutrition may be associated with a reduction in infectious complications in burn and trauma patients.

– 3) Glutamine supplemented enteral nutrition is associated with a significant reduction in hospital length of stay in burn and trauma patients.

• Recommendation:

Enteral glutamine should be considered in burn and trauma patients. There are insufficient data to support the routine use of enteral glutamine in other critically ill patients.*

*warning against use in multi-organ failure

Canadian Nutrition CPGs: Combined IV+ EN Glutamine

Recommendation:• Based on one level 1 study (REDOXS), we strongly

recommend that high dose combined parenteral and enteral glutamine supplementation NOT be used in critically ill patients with multi-organ failure.

Is the patient in shock or have multi-organ failure, particularly renal failure?

Patient is PN dependent

Is the patient: Burns? Trauma?

Is EN possible?

Give EN Glutamine 0.35-0.5 gm/kg/day as long as they are on EN

Do not give any glutamine, neither

EN or PN

Give IV Glutamine 0.35 gm/kg/day as long as they are on PN

Yes

Yes

NoYes

Do not give glutamine

No

No

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