Trial of Omega-3 Fatty Acid, Gamma-linolenic Acid and Anti …€¦ · CV CNS Coagulation Hepatic...
Transcript of Trial of Omega-3 Fatty Acid, Gamma-linolenic Acid and Anti …€¦ · CV CNS Coagulation Hepatic...
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.