Trial of Omega-3 Fatty Acid, Gamma-linolenic

Acid and Anti-oxidant Supplementation in the

Management of Acute Lung Injury (OMEGA)

B. Taylor Thompson M.D.

Medical Director, ARDSnet CCC

Boston, MA

NIH NHLBI

Metabolism of Dietary Fatty Acids

•Series 4 LT •Series 2 PG & TX •Series 3 PG & TX •Series 5 LT

•Arachidonic acid (AA) •Eicosapentaenoic acid )EPA)

•Docosahexaenoic acid (DHA)

•Membrane phospholipids

•Omega-6 •Omega-3

•cyclooxygenase

•lipoxygenase •free radical peroxidation

•cyclooxygenase

•lipoxygenase •free radical peroxidation

•F2-iP

•Pro-inflammatory, increase permeability,

platelets aggregation, cell adhesion & chemotaxis,

bronchoconstriction, vasoconstriction

•Anti-inflammatory, anti-aggregatory &

anti-adhesive, non-immunosuppressive,

vasodilation

•F3-iP

Background:N-3 Fatty Acids in ALI

• Three previous human studies using

continuous n-3 enteral feeds, each of ~ 100

patients showing:

– Improved PaO2 / FiO2 ratio 1,2,3

– Less time on ventilator 1,2,3

– Less time in ICU 1,3

– Fewer organ failures 1,3

– Lower mortality 3

1. Gadek JE, et al. CCM. 1999;27:1409-1420.

2. Singer P, et al. CCM. 2006;34:1033-1038.

3. Pontes-Arruda A, et al. CCM 2006;34:2325-33.

OMEGA: Hypothesis

Omega-3 fatty acid and anti-oxidant

supplementation, as compared to placebo,

will improve clinical outcomes in patients

with ALI or ARDS by attenuating systemic

inflammation.

NIH NHLBI

EDEN-OMEGA: Factorial Trial Design

Timing of Feeding

S U P P L E M E N T

“Early Full”

(n = 500)

“Early Trophic”

(n = 500)

N-3 +

Antioxidants

(n = 500)

Control

(n = 500)

n = 250 n = 250

n = 250 n = 250

OMEGA: Enteral Feeding Timeline

Day …28 0

Vent ALI Enteral Feeding

-2 -3

Enteral Feeding started

Initial dose of study Supplement

6 hrs

21

Supplement q12h

d 21 Extubation

NIH NHLBI

N-3 / A-O Supplement vs. Control

Daily Nutrients Nutrient

Energy, cal

Protein, g

Carbohydrate, g

Fat, g

EPA, g

DHA, g

GLA, g

Vitamin C, mg

All-natural Vitamin E, IU

B-carotene, mg

Zinc, mg

Selenium, ug

L-carnitine, mg

Taurine, mg

N-3/A-O Suppl (240mL)

480

3.8

4.2

44.6

6.84

3.40

5.92

1000

440

4.8

24.2

85.2

180

350

Control (240mL)

474

20

51.8

22

0

0

0

76

12

0

5.6

18

38

138

OMEGA: Inclusion Criteria

1. Presence of ALI / ARDS

a. P/F ratio ≤ 300

b. Bilateral infiltrates c / w pulmonary edema

c. Requirement for positive pressure ventilation via

ETT

d. No clinical evidence of left-sided cardiac failure

2. Presence of, or physician intent to place,

enteral feeding tube and begin enteral feeding

OMEGA: Endpoints

Primary

• Ventilator-free days to day 28

Secondary

• Mortality prior to hospital discharge to day 60

• ICU-free days to day 28

• Organ-failure free days to day 28

• Changes in serum / urine inflammatory biomarkers

Interim Monitoring

• Five interim analyses with asymmetric efficacy

and futility boundaries (Ware and Demets)

• 90.2 % Power to see a +2.25 VFD benefit with

OMEGA

OMEGA: Standardized Care

• 6 ml / kg PBW tidal volume strategy

• Conservative fluid management strategy

• Glucose control < 150 mg / dL

• GI Intolerances

NIH NHLBI

RESULTS

NHLBI ARDS Network. JAMA. Online, Oct 5, 2011.

OMEGA Stopped Early @ n=279

• VFDs in OMEGA crossed a futility boundary

(-0.90 VFDs)

OMEGA: Baseline Demographics

CHARACTERISTIC OMEGA

(N=143)

CONTROL

(N=129) P-Value

Age 56 + 17 53 + 17 0.21

Female (%) 52 50 0.67

Primary lung injury (%)

Pneumonia

Severe sepsis

Aspiration

Trauma

Other

52

23

12

5

6

53

21

18

2

5

0.66

Medical ICU (%) 85 86 0.55

OMEGA: Baseline Severity of Illness

CHARACTERISTIC OMEGA

(N=143)

CONTROL

(N=129)

P-

Value

APACHE III 94 + 25 92 + 29 0.65

Vasopressors 55% 48% 0.67

MAP (mmHg) 75 + 13 77 + 15 0.32

Pre-Study Fluid Intake (L/24h) 5.1 + 3.5 4.4 + 3.1 0.10

Creatinine (mg / dL) 2.0 + 1.9 1.8 + 1.5 0.41

Glucose (mg / dL) 134 + 55 125 + 47 0.17

Albumin (g / dL) 2.3 + 0.7 2.2 + 0.7 0.59

Percent of Total Plasma FAs

*P<0.05

Arachadonic

Acid

Eicosapentaenoic

Acid

•* •* •*

OMEGA: Percent of Patient-Days

with Gastrointestinal Intolerances

0

10

20

30

40

Abd

Dist/C

ram

p

Asp

irat

ion

Con

stip

atio

n

Dia

rrhea

Ele

vate

d GRV

Reg

urg

Vom

iting

Pe

rcen

t

Omega

Control

P<0.001

P=0.05

OMEGA: On Study PaO2 / FiO2

NHLBI ARDS Network. JAMA. Online, Oct 5, 2011.

OMEGA: Summary - Main Outcomes

Outcome Omega Control P-value

VFD to day 28 14.0 + 11.1 17.2 + 10.2 0.02

Death at 60 days (%) 26.6 16.3 0.054

ICU free days to day 28 14.0 + 10.5 16.7 + 9.5 0.04

NHLBI ARDS Network. JAMA. Online, Oct 5, 2011.

OMEGA: Organ Failure Free

Days to Day 28

0 4 8 12 16 20 24 28

CV

CNS

Coagulation

Hepatic

Renal

DaysOmega Control

P=0.02

P=0.02

P=0.17

P=0.11

P=0.12

OMEGA: Conclusion

Omega-3 fatty acid and anti-oxidant

supplementation twice daily to

enteral feeds does not improve

outcomes in patients with ALI and

may be harmful

NHLBI ARDS Network. JAMA. Online, Oct 5, 2011.

OMEGA Interim Monitoring

• Assymetric (futility) stopping rule. Not

designed to prove the OMEGA module =

harmful.

• VFDs in OMEGA were 3.2 days less and

crossed a futility boundary (-0.90 VFDs)

• 97.5% confident OMEGA has less than a

+0.2 VFD effect (expected benefit was +2.25

VFD)

OMEGA CI on VFDs includes the Null

Previous Studies vs. ARDSNet OMEGA

Previous Studies OMEGA

Analysis Evaluable Patients Intention to Treat

Design Full feeds Trophic / Full

Feeds

Control High Fat

(N-6, N-9)

High

Carbohydrate

N-3 Delivery Continuous

Infusion

BID Bolus

Dosing

Tidal Volume Uncontrolled 6 ml / kg PBW

Fluid Therapy Uncontrolled Conservative

Thank you on behalf of the ARDS

Network Investigators and Research

Coordinators

With special thanks to our OMEGA

patients and their families

OMEGA: 60-Day Mortality

P=0.054

26.6% 16.3%

0

5

10

15

20

25

30

OMEGA

Observed

OMEGA

Adjusted

Control

Observed

Control

Adjusted

FACTT

Conservative

%

OMEGA: 60-Day Mortality

P=0.054

26.6% 16.3%

0

5

10

15

20

25

30

OMEGA

Observed

OMEGA

Adjusted

Control

Observed

Control

Adjusted

FACTT

Conservative

%

26.6% 25.1% 16.3% 17.6%

0

5

10

15

20

25

30

OMEGA

Observed

OMEGA

Adjusted

Control

Observed

Control

Adjusted

FACTT

Conservative

%

P=0.11

OMEGA: 60-Day Mortality

P=0.054

P=0.11

NHLBI ARDS Network. JAMA. Online, Oct 5, 2011.

OMEGA: Glucose Levels and Insulin Use

40

60

80

100

120

140

160

0 1 2 3 4 5 6 7

Day

Glu

co

se m

g/d

L

0

1

2

3

4

5

Insu

lin

U/h

r

Omega glucoseControl glucoseOmega insulinControl insulin

OMEGA: Ventilator- and ICU-Free

Days to Day 28

P=0.04

P=0.02

OMEGA: Definition of Refractory Shock

VASOPRESSOR Infusion Rate Greater

than:

Dopamine 15 mcg / kg / min

Dobutamine 15 mcg / kg / min

Norepinephrine 30 mcg / min

Epinephrine 30 mcg / min

Neosynephrine 50 mcg / min

Vasopressin 0.04 units / min

Intra-Aortic Balloon Pump Any

OMEGA: Summary - Main Outcomes

Outcome Omega Control P-value

Death at 60 days (%) 26.6 16.3 0.054

VFD to day 28 14.0 + 11.1 17.2 + 10.2 0.02

ICU free days to day 28 14.0 + 10.5 16.7 + 9.5 0.04

NHLBI ARDS Network. JAMA. Online, Oct 5, 2011.