CARING FOR THE
CRITICALLY ILL PATIENT
ONLINE FIRST
Enteral Omega-3 Fatty Acid, -Linolenic Acid,
and Antioxidant Supplementation
in Acute Lung Injury
Todd W. Rice, MD, MSc
Arthur P. Wheeler, MD
B. Taylor Thompson, MD
Bennett P. deBoisblanc, MD
Jay Steingrub, MD
Peter Rock, MD, MBA
for the NIH NHLBI Acute
Respiratory Distress Syndrome
Network of Investigators
E
ARLY ACUTE LUNG INJURY (ALI) IS
characterizedbyneutrophiliclung
inflammation,permeability,1,2 and
intravascular and alveolar fibrin
deposition.3 The proinflammatory and
prothrombotic fatty acid eicosanoid de-
rivatives of cyclooxygenase (eg, throm-
boxaneA2)and5-lipoxygenase(eg,leuko-
triene B4) enzymes are mediators of these
processes.4-6 The type and inflamma-
tory activity of eicosanoids liberated
during inflammation depends on the
membrane phospholipid composi-
tion: omega 6 (n-6) fatty acid arachi-
donate yields highly reactive and in-
flammatory dienoic prostaglandins and
series 4 leukotrienes, whereas omega-3
(n-3) fatty acids such as docosahexae-
noic acid (DHA) and eicosapentae-
noic acid (EPA) favor production of less
active and potentially anti-inflamma-
tory trienoic prostaglandins and se-
ries 5 leukotrienes.7,8 Patients at risk of
developing ALI have n-3 levels approxi-
mately 25% of normal and those with
For editorial comment see p 1599.
1574 JAMA, October 12, 2011Vol 306, No. 14
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Context The omega-3 (n-3) fatty acids docosahexaenoic acid and eicosapentaenoic
acid, along with -linolenic acid and antioxidants, may modulate systemic inflammatory
response and improve oxygenation and outcomes in patients with acute lung injury.
Objective To determine if dietary supplementation of these substances to patients
with acute lung injury would increase ventilator-free days to study day 28.
Design, Setting, and Participants The OMEGA study, a randomized, double-
blind, placebo-controlled, multicenter trial conducted from January 2, 2008, through
February 21, 2009. Participants were 272 adults within 48 hours of developing acute
lung injury requiring mechanical ventilation whose physicians intended to start en-
teral nutrition at 44 hospitals in the National Heart, Lung, and Blood Institute ARDS
Clinical Trials Network. All participants had complete follow-up.
Interventions Twice-daily enteral supplementation of n-3 fatty acids, -linolenic acid,
and antioxidants compared with an isocaloric control. Enteral nutrition, directed by a
protocol, was delivered separately from the study supplement.
Main Outcome Measure Ventilator-free days to study day 28.
Results The study was stopped early for futility after 143 and 129 patients were en-
rolled in the n-3 and control groups. Despite an 8-fold increase in plasma eicosapen-
taenoic acid levels, patients receiving the n-3 supplement had fewer ventilator-free
days (14.0 vs 17.2; P=.02) (difference, 3.2 [95% CI, 5.8 to 0.7]) and intensive
care unitfree days (14.0 vs 16.7; P=.04). Patients in the n-3 group also had fewer
nonpulmonary organ failurefree days (12.3 vs 15.5; P=.02). Sixty-day hospital mor-
tality was 26.6% in the n-3 group vs 16.3% in the control group (P=.054), and ad-
justed 60-day mortality was 25.1% and 17.6% in the n-3 and control groups, respec-
tively (P=.11). Use of the n-3 supplement resulted in more days with diarrhea (29%
vs 21%; P=.001).
Conclusions Twice-daily enteral supplementation of n-3 fatty acids, -linolenic acid,
and antioxidants did not improve the primary end point of ventilator-free days or other
clinical outcomes in patients with acute lung injury and may be harmful.
Trial Registration clinicaltrials.gov Identifier: NCT00609180
JAMA. 2011;306(14):1574-1581
Published online October 5, 2011. doi:10.1001/jama.2011.1435 www.jama.com
Author Affiliations: Division of Allergy, Pulmonary, and Anesthesiology, University of Maryland School of
Critical Care Medicine, Vanderbilt University School Medicine, Baltimore (Dr Rock).
of Medicine, Nashville, Tennessee (Drs Rice and NHLBI ARDS Clinical Trial Network participants are
Wheeler); Pulmonary and Critical Care Unit, Depart- listed at the end of this article.
ment of Medicine, Massachusetts General Hospital, Corresponding Author: Todd W. Rice, MD, MSc,
Boston (Dr Thompson); Pulmonary and Critical Care T-1218 MCN, Vanderbilt Medical Center, Nashville,
Medicine, Louisiana State University Health Sciences TN 37232-2650 (todd.rice@vanderbilt.edu).
Center, New Orleans (Dr deBoisblanc); Critical Care Caring for the Critically Ill Patient Section Editor: Derek
Medicine, Baystate Medical Center, Springfield, Mas- C. Angus, MD, MPH, Contributing Editor, JAMA
sachusetts (Dr Steingrub); and Department of (angusdc@upmc.edu).
2011 American Medical Association. All rights reserved.
 DIETARY SUPPLEMENTATION IN ACUTE LUNG INJURY

established ALI have n-3 levels as low

Figure 1. Patient Screening, Enrollment, and Follow-up
as 6% of normal,9 suggesting a poten-
tial role for n-3 dietary supplementa-
2778 Patients screened
tion in patients with ALI. Preclinical
data indicate that the n-6 -linolenic 2506 Excluded a
acid (GLA), in conjunction with the n-3 500 Severe chronic lung disease
445 Time window (acute lung injury
fatty acid EPA, reduces neutrophil >48 h or intubated >72 h)
417 Inability to obtain consent
leukotriene synthesis and stimulates 306 Likely fatal underlying disease
production of the vasodilator prosta- 250 Recent intracranial hemorrhage
194 Severe liver disease
glandin E1, which also may be benefi- 167 Moribund
113 Refractory shock
cial in ALI.10,11 108 Coagulopathy
83 Refused consent
Three randomized controlled stud-
ies, conducted in patients with ALI or
272 Randomized
sepsis-induced respiratory failure,
demonstrated an association between
143 Randomized to receive n-3 supplement 129 Randomized to receive isocaloric control
the administration of an enteral for- 142 Received n-3 supplement as randomized 129 Received isocaloric control as randomized
mula enriched in n-3 fatty acids, GLA, 1 Received no n-3 doses

and antioxidants and improved oxy-

143 Completed trial and included in primary analysis 129 Completed trial and included in primary analysis
genation and respiratory physiology
compared with an unenriched, high-
All 272 enrolled patients had complete follow-up to the earlier of hospital discharge or day 60. The omega-3
fat formula.12-14 Improvements also (n-3) supplement comprised the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid, the omega-6
were observed among these trials in -linolenic acid, and antioxidants.
a Reasons for exclusion sum to more than 2506 because patients could be excluded for more than 1 reason.
length of intensive care unit (ICU)
stay, new organ failures,12,14 and mor-
tality. 14 However, interpretation of was obtained from every patient or sur-
Table 1. Daily Nutrients in Omega-3 (n-3)
these results is limited by the small rogate prior to any study procedure. De- vs Control Supplements
sample sizes and as-treated analyses of tails of the methods are available in the n-3 Control
only those patients who tolerated full eMethods. Nutrient (240 mL) (240 mL)
enteral nutrition (n=98, 95, and 103). Energy, kcal 480 474
Therefore, we sought to test the Patients Protein, g 3.8 20
effects of enteral supplementation of Patients with ALI requiring mechani- Carbohydrate, g 4.2 51.8
n-3 fatty acids, GLA, and antioxidants cal ventilation whose physicians in- Fat, g 44.6 22
on clinically important outcomes in tended to start enteral nutrition were EPA 6.84 0
patients with ALI in a phase 3 trial eligible for inclusion. Specifically, pa- DHA 3.40 0
using a novel approach of twice-daily tients had to be receiving mechanical GLA 5.92 0
bolus administration that would allow ventilation, have a ratio of partial pres- Vitamin C, mg 1000 76
an intention-to-treat analysis and sure of arterial oxygen (PaO2) to frac- All-natural vitamin E, IU 440 12
inclusion of patients unable to toler- tion of inspired oxygen (FIO2) of less Beta-carotene, mg 4.8 0
ate continuous full feeding. We than 300 (adjusted if altitude ex- Zinc, mg 24.2 5.6
hypothesized that supplementation ceeded 1000 m), and have bilateral pul- Selenium, g 85.2 18
with n-3 fatty acids, GLA, and anti- monary infiltrates consistent with LCarnitine, mg 180 38
oxidants would increase the ratio of edema on chest radiograph without Taurine, mg 350 138
n-3 to n-6 fatty acids, reduce inflam- clinical evidence of left atrial hyperten- Abbreviations: DHA, docosahexaenoic acid; EPA, eicos-
apentaenoic acid; GLA, -linolenic acid.
matory mediators, and improve the sion.15 The most frequent exclusion cri-
primary outcome of ventilator-free teria are shown in FIGURE 1 (full ex-
days and other clinical outcomes in clusion criteria are available in the
patients with ALI. eMethods, available at http://www.jama rich control (TABLE 1). Participants
.com). Patients were stratified by hos- were also simultaneously randomized
METHODS pital and the presence of shock at base- to a separate ongoing trial (the EDEN
The trial was approved by the institu- line and then randomized via a study) comparing low- vs full-calorie
tional review board at each of the 44 en- centralized Web-based system to re- enteral nutrition in a 22 factorial de-
rolling hospitals of the National Heart, ceive either twice-daily enteral supple- sign.16 Per National Institutes of Health
Lung, and Blood Institute ARDS Clini- mentation of n-3 fatty acids, GLA, and protocol, race and ethnicity were col-
cal Trials Network, listed at the end of antioxidants (n-3 supplement) or an lected from administrative data using
this article. Written informed consent isocaloric-isovolemic carbohydrate- census definitions.
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DIETARY SUPPLEMENTATION IN ACUTE LUNG INJURY

tal at day 60 were considered to have

Figure 2. Plasma Levels of Eicosapentaenoic Acid (EPA) and Plasma Ratio of EPA to
Arachidonic Acid (AA) survived. Selected plasma fatty acid lev-
els were measured at baseline and days
Plasma EPA levels
n-3 Supplement
Plasma EPA-AA ratio 3, 6, and 12 (eMethods).
55 Control 2.0
Group mean values
50
1.0 Statistical Analysis
45
With a maximum enrollment of 1000
40
patients and 4 planned interim analy-

EPA: AA Ratio
35
ses, the study had statistical power of
EPA, mg/L

30
25
90.7% to detect a 2.25-day increase in
0.1
20
VFDs, assuming a mean of 14 VFDs and
15
standard deviation of 10.5. The study
10
was monitored using a group sequen-
5
tial design with asymmetric stopping
0 0.01
boundaries for efficacy and futility de-
0 3 6 12 0 3 6 12 signed using alpha and beta spending
Study Day Study Day boundaries (eMethods).19 An indepen-
No. of patients
n-3 Supplement 24 24 17 8 24 24 17 8
dent data and safety monitoring board
Control 30 24 17 9 30 24 17 9 (DSMB) conducted an analysis of se-
rum n-3 levels after enrollment of the
The omega-3 (n-3) supplement comprised the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid,
the omega-6 -linolenic acid, and antioxidants. Plasma levels of EPA increased almost 8-fold in the n-3 group first 60 patients, a safety analysis after
while remaining unchanged in the control group; AA levels did not change in either group, resulting in a simi- enrollment of 100 patients, and an in-
lar increase in plasma EPA:AA ratio. Levels were measured in the first 60 patients. Because of unavailable samples,
actual measurements are from 24 n-3 and 30 control patients at baseline (24 in each group at day 3, 17 in terim analysis after enrollment of 272
each group on day 6, and 8 n-3 and 9 control patients on day 12). patients. Although VFDs was the pri-
mary end point, the DSMB was ad-
vised to consider mortality in their de-
Study Procedures 150 mg/dL (to convert to mmol/L, mul- cision to stop the trial for either efficacy
The n-3 or control supplement was ad- tiply by 0.0555), with tighter control al- or futility.
ministered enterally as twice-daily bo- lowed per local usual practice. Patients Means and standard deviations are
luses of 120 mL beginning within 6 were maintained in the semirecum- reported for baseline continuous vari-
hours of randomization. The isocaloric- bent position to decrease the risk of as- ables, and counts and percentages are
isovolemic control was identical in ap- piration and nosocomial pneumonia.18 reported for baseline categorical vari-
pearance and smell to the deodorized ables, with differences assessed using
n-3 supplement. Dosing continued un- Primary and Secondary End Points t tests and 2 tests, respectively. Plasma
til the earliest of 21 days, 48 hours of The primary end point of this study levels of IL-6, IL-8, leukotrienes, and
unassisted breathing, or extubation. The was ventilator-free days (VFDs), urinary isoprostanes were log trans-
energy provided by the boluses supple- defined as the number of days alive formed and compared using analysis of
mented that provided by each primary and breathing without assistance variance with baseline levels as covar-
physicians choice of standard continu- from randomization to day 28. VFDs iates. Categorical outcome variables are
ous nonn-3-enriched enteral for- were counted only for the final reported as percentages with 95% con-
mula. The rate of continuous enteral period of unassisted breathing in fidence intervals. The continuous out-
feeding was managed by a protocol with patients who required more than 1 come variables (VFDs, ICU-free days,
an algorithm for gastrointestinal intol- episode of assisted breathing through and organ failurefree days) are re-
erances (eMethods). The supplement day 28. Patients who died before day ported as means and standard devia-
was administered even if enteral nutri- 28 were assigned zero VFDs. tions, with differences assessed using
tion was interrupted, as long as the pa- Secondary end points included 60- analysis of variance controlling for base-
tient was tolerating enteral medications. day mortality before hospital dis- line shock and enrollment group of the
Patient care was managed accord- charge with unassisted breathing, num- EDEN study.
ing to simplified versions of the ber of ICU- and organ failurefree days, Logistic regression controlling for
lung protective ventilation and fluid- frequency of gastrointestinal intoler- baseline shock and randomization
conservative hemodynamic manage- ance, plasma levels of IL-6 and IL-8 group of the EDEN study was used to
ment protocols used in previous ARDS on days 3 and 6, urinary levels of analyze mortality. Adjusted mortality
Network trials (eMethods).6,17 Institu- series 4 and 5 leukotrienes on day 6 rates were calculated using 7 baseline
tion-specific insulin protocols were used (eMethods), and development of new mortality-predicting covariates de-
to target blood glucose ranges of 80 to infections. Patients alive in the hospi- rived from a previous study of similar
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 DIETARY SUPPLEMENTATION IN ACUTE LUNG INJURY

populations20: age, Acute Physiology increased plasma EPA levels 8-fold on n-3derived leukotriene E5 was unde-
and Chronic Health Evaluation III days 3, 6, and 12, whereas levels in con- tectable in plasma in both groups at
(APACHE III) score, plateau pres- trol patients remained unchanged baseline and on day 6. Urinary levels
sure, missing plateau pressure, num- (Figure 2). Plasma levels of the n-6 ara- of F2-isoprostane, the lipid peroxida-
ber of organ failures, and the alveolar- chidonic acid did not change in either tion stress marker derived from n-6 fatty
arterial difference in Pa O 2 value. group over the first 12 study days. The acids, were similar in both groups at
Proportion curves over time were resulting change in plasma fatty acid lev- baseline and did not change signifi-
plotted for survival and unassisted els (eFigure 1) did not alter plasma lev- cantly in either group on day 6. Uri-
breathing. els of IL-6 or IL-8, which decreased nary levels of F3-isoprostanes, derived
All analyses were performed using similarly in both groups on days 3 and from n-3 fatty acids, were also similar
SAS version 9.2 (SAS Institute Inc, Cary, 6 (eFigure 2A). Likewise, plasma leuko- at baseline but were significantly higher
North Carolina) on an intention-to- triene E4 levels did not change on study in the n-3 group on day 6 compared
treat basis, with 2-sided P .05 con- day 6 in either group (eFigure 2B). The with controls (eFigure 2C).
sidered significant. P values were not
corrected for multiple comparisons or
early stopping. Table 2. Baseline Characteristics of Patients
No. (%)
RESULTS n-3 Control
The study was stopped by the DSMB for Characteristic (n = 143) (n = 129)
futility at the first interim analysis af- Age, mean (SD), y 55.5 (17.0) 52.9 (16.5)
ter 143 patients had been randomized Women 68 (48) 65 (50)
to receive the n-3 supplement and 129 Race/ethnicity
White (not Hispanic) 102 (71) 94 (73)
to receive the isocaloric control. Se- Black (not Hispanic) 27 (19) 18 (14)
vere chronic lung disease, ALI present Hispanic 7 (5) 16 (12)
greater than 48 hours, mechanical ven- Other/NA 5 (5) 1 (1)
tilation for longer than 72 hours, and Diabetes 46 (32) 42 (33)
inability to obtain consent were the Medical ICU 122 (85) 111 (86)
most frequent exclusions (Figure 1). All APACHE III score, mean (SD) a 93.8 (24.9) 91.8 (29.3)
patients had complete follow-up to the Vasopressor use 78 (55) 62 (48)
earlier of hospital discharge or day 60. Propofol use 43 (30) 30 (23)
Baseline propofol infusion rate, median (IQR), mg/h 30.0 (11.0-80.0) 26.5 (8.0-107.0)
Study Supplement Pharmacokinetics
Nonpulmonary organ or system failures 1.3 (0.8) 1.3 (0.9)
and Pharmacodynamics (maximum of 4), mean (SD), No.
Daily calories provided by enteral nu- Arterial pressure, mean (SD), mm Hg 75.1 (13.2) 76.7 (15.3)
trition were similar for both groups on Central venous pressure, mean (SD), mm Hg 10.7 (4.9) 11.2 (4.1)
days 0 through 12 (eTable), and the P Prestudy fluid intake, mean (SD), mL/24 h 5085 (3543) 4387 (3063)
value for interaction with the EDEN Albumin, mean (SD), g/dL 2.3 (0.7) 2.2 (0.7)
study was .47. Patients in both groups Tidal volume, mean (SD), mL/kg 7.0 (1.6) 6.8 (1.3)
received an average of 85% of the Plateau airway pressure, mean (SD), cm H2O 23.3 (4.8) 22.8 (5.5)
planned twice-daily dosages of the study PEEP, mean (SD), cm H2O 8.6 (3.5) 8.7 (3.3)
supplement. Patients receiving the n-3 Minute ventilation, mean (SD), L/min b 11.4 (3.1) 10.6 (2.9)
supplement had more frequent in- Respiratory rate, mean (SD), breaths/min 25.7 (7.2) 24.7 (7.2)
stances of gastrointestinal intoler- PaO2:FIO2 ratio, mean (SD) 159.9 (75.6) 172.5 (84.6)
ance. Diarrhea occurred in 28.7% and Oxygenation index, mean (SD) 11.7 (7.4) 10.5 (7.3)
20.9% of ventilated days in the n-3 and Primary cause of lung injury
Pneumonia 74 (52) 69 (53)
control groups, respectively (P=.001).
Sepsis 33 (23) 27 (21)
Both groups experienced similar inci-
Aspiration 17 (12) 23 (18)
dences of gastric residual volumes
Trauma 7 (5) 2 (2)
greater than 400 mL (3.2% vs 4.0%;
Multiple transfusion 4 (3) 1 (1)
P=.30), abdominal distention (9.3% vs
Other 8 (6) 7 (5)
7.4%; P=.19), and vomiting (3.8% vs Abbreviations: APACHE III, Acute Physiology and Chronic Health Evaluation III; FIO2, fraction of inspired oxygen; ICU,
2.4%; P=.09). intensive care unit; IQR, interquartile range; NA, not available; n-3, omega-3; PaO2, partial pressure of arterial oxy-
gen; PEEP, positive end-expiratory pressure.
Baseline plasma levels of EPA a Higher scores indicate a higher severity of illness.
b The n-3 group had a higher minute ventilation and trend toward greater net fluid administration in the 24-hour preen-
were about 2 mg/L in both groups
rollment period than the control group.
(FIGURE 2). The n-3 study supplement
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DIETARY SUPPLEMENTATION IN ACUTE LUNG INJURY

Figure 3. PEEP, Plateau Pressure, and PaO2:FIO2 Ratio During Study

PEEP Plateau pressure PaO2: FIO2 ratio

10 28 260

Plateau Pressure, cm H20

240
8 26

PaO2: FIO2 Ratio

220
PEEP, cm H20

6 24 200

180
4 22
160
n-3 Supplement
2 20
Control 140

0 18 130
0 1 2 3 4 7 0 1 2 3 4 7 0 1 2 3 4 7
Study Day Study Day Study Day

No. of patients
n-3 Supplement 143 138 131 116 105 68 99 100 94 78 60 42 136 110 101 92 77 50
Control 129 125 101 91 80 49 93 95 76 62 57 35 126 101 75 68 61 34

The omega-3 (n-3) supplement comprised the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid, the omega-6 -linolenic acid, and antioxidants. Error
bars indicate 95% confidence intervals. Positive end-expiratory pressure (PEEP) was similar between groups during the study; plateau pressures were similar between
groups except day 2 during the first week (P=.04). Oxygenation (ratio of partial pressure of arterial oxygen [PaO2] to fraction of inspired oxygen [FIO2]) did not differ
between groups.

age of slightly more than 1 unit of in-

Figure 4. Minute Ventilation and PaCO2 During Study sulin per hour over the first 7 days
Minute ventilation PaCO2
(eFigure 3).
13 50
Numerically more patients in the n-3
group were receiving vasopressors at
Minute Ventilation, L/min

12 48
enrollment, a difference that persisted
PaCO2, mm Hg

46
11 through day 7 (eFigure 4). The n-3
44
10 group had a trend toward more net fluid
42
9
administration in the 24 hours prior to
40
n-3 Supplement enrollment (5085 [SD, 3543] mL vs
8 Control 38 4387 [SD, 3063] mL; P =.09). The n-3
7
0 1 2 3 4 7
36
0 1 2 3 4 7
group also had a trend toward greater
Study Day Study Day cumulative fluid balance over the first
No. of patients 7 study days (2082 [SD, 8088] mL vs
n-3 Supplement 133 138 129 113 100 67 137 110 101 92 77 50
Control 119 122 98 88 76 46 126 101 75 68 61 34 94 [SD, 7071] mL; P =.07). No differ-
ences in the development of new in-
The omega-3 (n-3) supplement comprised the n-3 fatty acids docosahexaenoic acid and eicosapentaenoic acid,
the omega-6 -linolenic acid, and antioxidants. Error bars indicate 95% confidence intervals. Minute ventila-
fections were found between groups
tion was similar between groups except day 3 (P=.01); Partial pressure of arterial carbon dioxide [PaCO2] val- (ventilator-associated pneumonia, 7%
ues were slightly higher in the control group at days 1 (P=.04), 2 (P=.08), and 4 (P=.07). [95% CI, 3%-11%] for the n-3 group vs
8% [95% CI, 3%-12%] for the control
Baseline Characteristics temperature. Values also were similar group [P=.81]; bacteremia, 11.2% [95%
and Study Variables for positive end-expiratory pressure, CI, 6%-16.4%] vs 10.9% [95% CI, 5.5%-
Baseline characteristics are shown in plateau pressure, and PaO2:FIO2 ratio 16.2%] [P=.91]; or Clostridium difficile
TABLE 2. Pneumonia (52%) and sepsis (FIGURE 3) and minute ventilation and associated diarrhea, 4.2% [95% CI,
(23%) were the most common etiolo- partial pressure of arterial carbon di- 1.6%-8.9%] vs 3.9% [95% CI, 1.3%-
gies of ALI. Although both groups had oxide FIGURE 4. 8.8%] [P =.98]).
similar APACHE III scores, the n-3 Serum albumin and protein levels did
group had higher minute ventilation not differ between groups at baseline Clinical Outcomes
(11.4 [SD, 3.1] L/min vs 10.6 [SD, 2.9] or during the study. Baseline serum glu- The n-3 supplement group had fewer
L/min; P=.04). Baseline creatinine, glu- cose values were similar in both groups VFDs to study day 28 compared with
cose, and albumin levels were similar (134 [SD, 55] mg/dL vs 125 [SD, 47] controls (14.0 [SD, 11.1] vs 17.2 [SD,
between groups. mg/dL; P=.17) and consistently aver- 10.2], P=.02) (difference, 3.2 [95% CI,
Over the first 7 days, both groups had aged less than 150 mg/dL in both 5.8 to 0.7]) and fewer ICU-free days
similar values for heart rate, systolic groups through day 7 (eFigure 3). Pa- (14.0 [SD, 10.5] vs 16.7 [SD, 9.5],
blood pressure, respiratory rate, and tients in both groups received an aver- P=.04) (TABLE 3). In the n-3 group, 38
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Table 3. Clinical Outcomes a
Outcome
Ventilator-free days from day 1 to day 28
Death before discharge home, % (95% CI)
Unadjusted
Adjusted for differences in baseline covariates
No. of days not spent in an intensive care unit
from day 1 to day 28
No. of days without failure of circulatory, coagulation,
hepatic, or renal organs from day 1 to day 28
a Patients discharged from the hospital alive before 60 days are considered alive for all-cause 60-day hospital mortality. Mortality was adjusted for age, Acute Physiology and Chronic
Health Evaluation III score, plateau pressure, missing plateau pressure, number of organ failures, and the alveolar-arterial difference in PaO2.
of the 143 patients (26.6% [95% CI,
19.3%-33.8%] died prior to day 60 or
hospital discharge compared with 21 of
the 129 (16.3% [95% CI, 9.9%-
22.7%]) in the control group (P=.054).
When adjusted for baseline variables
previously shown to be associated with
mortality in ALI, the n-3 group had
25.1% (95% CI, 9.2%-41.0%) 60-day
mortality vs 17.6% (95% CI, 3.3%-
31.9%) in the control group (P = .11).
Probabilities of survival and breathing
without assistance to day 60 for both
groups are shown in FIGURE 5.
COMMENT
12-14
In contrast to previous studies, in
this study enteral supplementation of
n-3 fatty acids, GLA, and antioxidants
did not improve lung physiology or
clinical outcomes in patients with ALI
compared with supplementation of an
isocaloric control. In addition, the n-3
supplement did not protect from noso-
comial infections or improve nonpul-
monary organ function.
Several noteworthy differences
between the current and previous
studies may explain the observed
differences. The 3 previous studies
used continuous enteral infusions to
deliver the supplements, whereas we
used bolus delivery. Previous studies
required patients to tolerate a spe-
cific goal feeding rate, either to enter
the trial or to be included in the
analysis, and many randomized
patients were unable to tolerate the
required infusion rates, introducing
potential bias. To increase the likeli-
hood that the treatment would be
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DIETARY SUPPLEMENTATION IN ACUTE LUNG INJURY
Mean (SD)
n-3
(n = 143)
14.0 (11.1) 17.2 (10.2)
26.6 (19.3-33.8) 16.3 (9.9-22.7)
25.1 (9.2-41.0) 17.6 (3.3-31.9)
14.0 (10.5) 16.7 (9.5)
12.3 (11.1) 15.5 (11.4)
tolerated, our study used a small-
volume supplement (120 mL) twice
daily to deliver similar doses of n-3
fatty acids, GLA, and antioxidants, as
were given in previous studies. We
used an intention-to-treat analysis,
which accounted for all randomized
patients. It is possible that bolus
administration of the high-fat supple-
ment may have caused the increased
incidence of diarrhea observed in the
n-3 group.
Another major difference between
this and previous studies is the com-
position of the control supplement. The
control in the previous studies12-14 was
a commercially available, high-fat for-
mulation containing predominately n-6
and omega-9 (n-9) fatty acids selected
to match the percentage of calories from
fat, protein, and carbohydrate in the n-3
formulation. In contrast, our study used
an isocaloric supplement containing
mostly carbohydrate calories instead of
lipids. Because n-6 and n-9 fatty acids
can be metabolized into inflammatory
prostaglandins and series-4 leukotri-
enes,7,8 it is possible that the control for-
mulations in previous studies may have
been proinflammatory, accounting for
the differences in outcomes between
groups. However, we found no im-
provement in clinical outcomes for n-3
fatty acid supplementation compared
with a largely carbohydrate control.
We hypothesized that the n-3 supple-
ment would improve clinical out-
comes compared with the control
supplement. We did not design our
study to determine if the control supple-
ment would yield better outcomes than
Control P
(n = 129) Difference (95% CI) Value
3.2 (5.8 to 0.7) .02
10.3 (0.7 to 19.9) .054
7.5 (3.1 to 18.1) .11
2.7 (5.1 to 0.3) .04
3.2 (5.9 to 0.5) .02
Figure 5. Proportion Curves of 60-Day
Hospital Survival and Unassisted Breathing
n-3 Supplement
Alive
Breathing without assistance
Control
Alive
Breathing without assistance
100
90
80
70
Patients, %
60
50
40
30
20
10
0 5 10 15 20 25 30 35 40 45 50 55 60
Days After Randomization
The omega-3 (n-3) supplement comprised the n-3 fatty
acids docosahexaenoic acid and eicosapentaenoic acid,
the omega-6 -linolenic acid, and antioxidants. Per-
centages were calculated daily; all patients com-
pleted follow-up and the denominators were the com-
plete cohorts (143 for the omega-3 [n-3] group and
129 for the control group). Solid lines are survival curves
and represent proportion of patients surviving at each
period; dashed lines represent the proportion of pa-
tients breathing without assistance at each period. The
areas above the solid lines represent the proportion
of patients who have died in each group at each pe-
riod; the areas below the dashed lines represent the
proportion of patients alive and free of mechanical ven-
tilation in each group at each period. Areas between
the solid and dashed lines indicate percentages alive
and still receiving mechanical ventilation in each group
at each period.
the n-3 supplement. Thus, the effi-
cacy and futility stopping boundaries
were not symmetric, with stopping for
futility being easier than for efficacy.
The DSMB recommended terminating
the study at the first interim analysis be-
cause the primary end point (VFDs) and
the major secondary end point (mor-
JAMA, October 12, 2011Vol 306, No. 14 1579
Corrected on October 18, 2011
DIETARY SUPPLEMENTATION IN ACUTE LUNG INJURY
tality) crossed the predefined futility
boundaries, making the probability of
a positive trial going forward very low.
Despite P values of .02 and .054 for VFD
and mortality, respectively, we cannot
confidently conclude there was harm
in the n-3 group, because this may have
been a chance observation.21 For ex-
ample, if our stopping boundaries for
efficacy and futility had been the same,
P.001 would have been required at
the first interim analysis to conclude
that the control supplement was supe-
rior. In addition, there was slight im-
balance of age, APACHE III score,
PaO2:FIO2 ratio, and minute ventila-
tion favoring the control group.
Nonetheless, it remains possible that
there is a hierarchy of energy sources
in patients with ALI. Carbohydrates and
protein (as in our control) may result
in better clinical outcomes than lip-
ids, and at the same time n-3 fatty ac-
ids may result in better clinical out-
comes than n-6 and n-9 fatty acids.
Historically, carbohydrates have been
avoided in ventilated patients because
of concerns regarding hyperglycemia
and increased production of carbon di-
oxide.22 The extra carbohydrates in the
control supplement of our study did not
appear to exacerbate either hypergly-
cemia or hypercapnea. However, our
study attempted to maintain blood glu-
cose levels less than 150 mg/dL,23 and
overall mean serum glucose and insu-
lin utilization were similar in the 2
groups.
Last, we controlled mechanical ven-
tilation and fluids, nonexperimental co-
variates that have been shown to affect
clinical outcomes in ALI.6,17 Interpre-
tation of results of the previous trials
may be limited by the diversity of these
important therapeutic interventions. Be-
yond reducing mortality and ventila-
tor time, lung-protective ventilation has
also been shown to decrease systemic
inflammation and organ dysfunc-
tion. 24 It is possible that the anti-
inflammatory effects of lung-protec-
tive ventilation obscured further
reductions associated with use of the
n-3 supplement. Similarly, the use
of a conservative fluid-management
1580 JAMA, October 12, 2011Vol 306, No. 14
Corrected on October 18, 2011
Downloaded from jama.ama-assn.org at HINARI on October 21, 2011
strategy has been shown to expedite lib-
eration from the ventilator,17 further re-
ducing opportunity for new interven-
tions to show benefit. Despite enrolling
a population with high severity of ill-
ness, overall mortality in this study was
only 21.7%, considerably lower than
that seen in the 3 previous studies of
n-3 fatty acids12-14 and in other studies
of patients with ALI.6,17,20
Despite significant increases in
plasma n-3 levels, we did not demon-
strate a reduction in levels of inflam-
matory biomarkers. The reason why
twice-daily supplementation failed to
alter plasma biological marker levels is
unclear. It is possible that more fre-
quent or near-continuous dosing is nec-
essary to see benefits. Although incor-
poration of n-3 fatty acids into cell
membranes was not directly mea-
sured, data suggest that plasma levels
correlate well with phospholipid mem-
brane content,25,26 suggesting that our
administration of n-3 fatty acids should
have had a biological effect. Although
the EPA and DHA dosages adminis-
tered in this study were similar to those
used in previous studies12-14 we did not
measure actual pharmacokinetics, so we
cannot directly compare with the se-
rum EPA levels reported by Gadek et
al.12
Reduced levels of IL-8 and leuko-
triene B4 in bronchoalveolar lavage fluid
have been observed in patients with ALI
treated with n-3 fatty acids and corre-
lated with improvements in pulmo-
nary physiology.27 Although we did not
perform bronchoalveolar lavage, we did
not find any improvement in respira-
tory physiology, specifically PaO2:FIO2
ratio, positive end-expiratory pres-
sure, and plateau pressure in patients
receiving the n-3 supplement. It is pos-
sible the relatively short duration of
acute illnesses like ALI, coupled with
current treatment modalities with lung-
protective ventilation and conserva-
tive fluid management, may not allow
enough time for enteral n-3 fatty acid
supplementation to have effect. How-
ever, fatty acid composition and cell re-
sponses to stimuli may be modified
within hours of treatment with EPA or
2011 American Medical Association. All rights reserved.
DHA, and modest doses alter plasma
and cellular content within 1 to 3 days.28
Even parenteral administration of n-3
fatty acids, which would presumably al-
ter plasma and cellular content more
quickly, has failed to alter the inflam-
matory response in critically ill pa-
tients.29,30
CONCLUSIONS
This study suggests that twice-daily
enteral supplementation of n-3 fatty
acids, GLA, and antioxidants change
plasma levels of n-3 fatty acids but
do not improve clinical outcomes or
biomarkers of systemic inflammation
in patients with ALI and in fact may
be harmful.
Published Online: October 5, 2011. doi:10.1001
/jama.2011.1435
Author Contributions: Dr Thompson had full access
to all of the data in the study and takes responsibility
for the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Rice, Wheeler, Thompson,
deBoisblanc, Steingrub, Rock.
Acquisition of data: Rice, Wheeler, Thompson,
deBoisblanc, Steingrub, Rock.
Analysis and interpretation of data: Rice, Wheeler,
Thompson, Steingrub, Rock.
Drafting of the manuscript: Rice, Wheeler, Thompson,
Steingrub, Rock.
Critical revision of the manuscript for important in-
tellectual content: Rice, Wheeler, Thompson,
deBoisblanc, Steingrub, Rock.
Statistical analysis: Thompson.
Obtained funding: deBoisblanc, Steingrub.
Administrative, technical, or material support: Rice,
Wheeler, Thompson, deBoisblanc, Steingrub, Rock.
Study supervision: Rice, Wheeler, Thompson,
deBoisblanc, Rock.
Conflict of Interest Disclosures: All authors have com-
pleted and submitted the ICMJE Form for Disclosure of
Potential Conflicts of Interest and none were reported.
Funding/Support: This study was supported by Na-
tional Heart, Lung, and Blood Institute (NHLBI) con-
tracts HHSN268200536165C, HHSN268200536176C,
and HHSN268200536179C. Abbott Nutrition, Co-
lumbus, Ohio, provided the omega-3 fatty acid, -lino-
lenic acid, antioxidant, and control supplements used
in the study.
Role of the Sponsor: Neither the NHLBI nor Abbott
Nutrition had any role in the design and conduct of
the study; the collection, analysis, and interpretation
of the data; or the preparation, review, or approval
of the manuscript.
NIH NHLBI Acute Respiratory Distress Syndrome Net-
work of Investigators: University of Washington, Har-
borview (*L. Hudson, C. Hough, M. Neff, K. Sims, T. Wat-
kins); Baystate Medical Center (*J. Steingrub, *M. Tid-
swell,L.DeSouza,C.Kardos,L.Kozikowski,K.Kozikowski);
Baylor College of Medicine (K. Guntupalli, V. Bandi, C.
Pope); Johns Hopkins Hospital (*R. Brower, H. Fessler,
D. Hager, P. Mendez-Tellez, K. Oakjones, D. Needham);
Johns Hopkins Bayview Medical Center ( J. Sevransky,
A. Workneh, S. Han, S. Murray); University of Maryland
(C. Shanholtz, G. Netzer, P. Rock, A. Sampaio, J. Titus);
Union Memorial Hospital (P. Sloane, T. Beck, H. High-
field); Washington Hospital Center (D. Herr, B. Lee,
N. Bolouri); Cleveland Clinic Foundation (*H.P. Wiede-

mann, R.W. Ashton, D.A. Culver, T. Frederick, J.J. Ko-
mara, J.A. Guzman, A.J. Reddy); University Hospitals
of Cleveland (R. Hejal, M. Andrews, D. Haney); Me-
troHealth Medical Center (A.F. Connors, S. Lasalvia,
J.D. Thornton, E.L. Warren); University of Colorado
Health Science Centers (*M. Moss, A. Benson, E. Burn-
ham, B. Clark, L. Gray, C. Higgins, B.J. Maloney, M.
Mealer); National Jewish Health (S. Frankel); St An-
thonys Hospital (T. Bost, P. Dennen, K. Hodgin); Den-
ver Health Medical Center (I. Douglas, K. Overdier,
K. Thompson, R. Wolken); Duke University (*N.
MacIntyre, L. Brown, C. Cox, M. Gentile, J. Govert,
N. Knudsen); University of North Carolina (S. Car-
son, L. Chang, J. Lanier); Vanderbilt University (*A.P.
Wheeler, G.R. Bernard, M. Hays, S. Mogan, T.W. Rice);
Wake Forest University (*R.D. Hite, P.E. Morris, A. Har-
vey, M. Ragusky, K. Bender); Moses Cone Memorial
Hospital (P. Wright, S. Gross, J. McLean, A. Over-
ton); University of Virginia ( J. Truwit, K. Enfield, M.
Marshall); LDS Hospital (T. Clemmer, R. Tanaka, L.
Weaver); Intermountain Medical Center (*A. Morris,
A. Ahmed, A. Austin, N. Dean, C. Grissom, A. Fitz-
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JAMA, October 12, 2011Vol 306, No. 14 1581
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