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Enteral omega-3 fatty acid, gamma-linolenic acid, and antioxidant supplementation in acute lung injury.
Rice TW, Wheeler AP, Thompson BT, deBoisblanc BP, Steingrub J, Rock P, NIH NHLBI Acute Respiratory Distress Syndrome Network of Investigators, NHLBI ARDS Clinical Trials Network
(2011) JAMA 306: 1574-81
MeSH Terms: Acute Lung Injury, Adult, Aged, Antioxidants, Biomarkers, Dietary Supplements, Docosahexaenoic Acids, Double-Blind Method, Drug Therapy, Combination, Eicosapentaenoic Acid, Enteral Nutrition, Female, Humans, Inflammation, Intensive Care Units, Male, Middle Aged, Pneumonia, Sepsis, Survival Analysis, Treatment Outcome, Ventilator Weaning, gamma-Linolenic Acid
Show Abstract · Added March 5, 2014
CONTEXT - The omega-3 (n-3) fatty acids docosahexaenoic acid and eicosapentaenoic acid, along with γ-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 enteral 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, γ-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 enrolled in the n-3 and control groups. Despite an 8-fold increase in plasma eicosapentaenoic 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 unit-free days (14.0 vs 16.7; P = .04). Patients in the n-3 group also had fewer nonpulmonary organ failure-free days (12.3 vs 15.5; P = .02). Sixty-day hospital mortality was 26.6% in the n-3 group vs 16.3% in the control group (P = .054), and adjusted 60-day mortality was 25.1% and 17.6% in the n-3 and control groups, respectively (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, γ-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.
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23 MeSH Terms
2,3-Dinor-5,6-dihydro-15-F(2t)-isoprostane: a bioactive prostanoid metabolite.
Hou X, Roberts LJ, Taber DF, Morrow JD, Kanai K, Gobeil F, Beauchamp MH, Bernier SG, Lepage G, Varma DR, Chemtob S
(2001) Am J Physiol Regul Integr Comp Physiol 281: R391-400
MeSH Terms: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid, Animals, Brain, Calcium, Calcium Channel Blockers, Carbazoles, Dinoprost, Endothelium, Vascular, Enzyme Inhibitors, F2-Isoprostanes, Humans, In Vitro Techniques, Microcirculation, Prostaglandin Antagonists, Pyridines, Retinal Vessels, Swine, Thromboxane A2, Vasoconstriction, Vasoconstrictor Agents, gamma-Linolenic Acid
Show Abstract · Added December 10, 2013
15-F(2t)-isoprostane (15-F(2t)-IsoP), also termed 8-isoprostaglandin F(2alpha), is one of a series of prostanoids formed by free radical-mediated peroxidation of arachidonic acid and exerts potent biological actions such as vasoconstriction. We recently demonstrated that 15-F(2t)-IsoP is metabolized in humans to a major metabolite, 2,3-dinor-5,6-dihydro-15-F(2t)-IsoP (15-F(2t)-IsoP-M). 15-F(2t)-IsoP-M can also potentially be formed as a product of free radical-induced oxidation of the low abundance fatty acid gamma-linolenic acid. We confirmed that 15-F(2t)-IsoP-M is generated during oxidation of gamma-linolenic acid and explored whether it may exhibit biological activity. 15-F(2t)-IsoP-M caused marked constriction of porcine surface retinal and intraparenchymal brain microvessels, comparable to that observed with 15-F(2t)-IsoP. These effects were associated with increased thromboxane A(2) (TXA(2)) formation and were virtually abolished by TXA(2)-synthase and -receptor inhibitors (CGS-12970 and L-670596). Vasoconstriction induced by either 15-F(2t)-IsoP or 15-F(2t)-IsoP-M on perfused ocular choroid was also abrogated by TXA(2)-synthase inhibition as well as by removal of endothelium. Similar to 15-F(2t)-IsoP, 15-F(2t)-IsoP-M evoked vasoconstriction and TXA(2) generation by activating Ca(2+) influx from nonvoltage-gated channels (SK&F96365 sensitive) in the retina and from both nonvoltage- and N-type voltage-gated Ca(2+) channels (omega-conotoxin MVIIA sensitive), respectively, in brain endothelial and astroglial cells; smooth muscle cells were unresponsive to both agents. Cross-desensitization experiments further suggest that 15-F(2t)-IsoP and 15-F(2t)-IsoP-M act on the same receptor mechanism. Findings reveal a novel concept by which a beta-oxidation metabolite of 15-F(2t)-IsoP that can also be formed by nonenzymatic oxidation of gamma-linolenic acid is equivalently bioactive to 15-F(2t)-IsoP and may prolong the vascular actions of F(2)-IsoPs.
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21 MeSH Terms