Fish Oil in Critical Illness: Mechanisms and Clinical Applications

SYNOPSIS

Fish oil is rich in omega-3 fatty acids which have been shown to be beneficial in multiple disease states that involve an inflammatory process. It is now hypothesized that omega-3 fatty acids may decrease the inflammatory response and be beneficial in critical illness. After a review of the mechanisms of omega-3 fatty acids in inflammation, research using enteral nutrition formulas and parenteral nutrition lipid emulsions fortified with fish oil are examined. The results of this research to date are inconclusive for both enteral and parenteral omega-3 fatty acid administration. More research is required before definitive recommendations can be made on fish oil supplementation in critical illness.

INTRODUCTION

The omega-3 fatty acids (FA) found in fish oil are essential and are thought to play a key role as a preventative and therapy for coronary artery disease, diabetes, hypertension, arthritis, cancer, and other inflammatory and autoimmune disorders.(1) In the last decade, omega-3 FA research has focused on their role in decreasing the production of inflammatory cytokines and eicosanoids and thus their potential benefit in critically ill patients. Sepsis is the leading cause of death in critically ill patients in the United States,(2) and sepsis causes the majority of case of acute lung injury (ALI), an inflammatory syndrome of hypoxemic respiratory failure and diffuse pulmonary infiltrates.(3) It is believed that the physical response to sepsis and to other forms of critical illness including ALI and trauma result from massive activation of the inflammatory cascade as well as immunosuppression, or immunoparalysis.(4–6) One feature of uncontrolled activation of the inflammation involves excessive production of proinflammatory cytokines and lipid-derived inflammatory mediators termed eicosanoids,(7) and a relatively new area of research has investigated the role of lipids provided during nutritional support of critically ill patients on both the stress response and clinical outcomes.

This review examines the role of omega-3 fatty acids in the inflammatory process and clinical research in which omega-3 FAs are administered both enterally and parenterally. Although research conducted in all critically ill patient populations is examined, more attention is focused on patients with sepsis or ALI due to their amplified inflammatory response.

OMEGA-3 FATTY ACIDS AND INFLAMMATION

The physiologic response to inflammation is complicated and includes increased blood flow and capillary permeability, thus allowing large molecules including antibodies and cytokines to reach damaged tissues. Although a normal response to infection or injury, inflammation can occur on a massive and uncontrolled scale, thus leading to excessive tissue damage and potential worsening of illness. This “overactivation” of the inflammatory response is characterized by high levels of cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, which, when present in excess, can be quite destructive and have been implicated in many of the pathologic responses that occur during severe sepsis and ALI.(5, 7)

The inflammatory response can be affected by phospholipids in the membranes of immune cells including macrophages, monocytes, and neutrophils. The fatty acid (FA) composition of cell membranes influences the fluidity of the membrane, which in turn can influence the activity of membrane-bound proteins such as enzymes, receptors, transporters, and lipid-based second messenger systems (“lipid signaling”).(8–10) Additionally, particular types of FAs affect the inflammatory response by providing the substrate for production of lipid inflammatory mediators including the eicosanoids. The primary unsaturated long-chain fatty acids in human cellular membranes include the omega-3 FAs eicosapentaenoic acid (EPA) and docosahexanoic acid (DHA), omega-6 FA arachidonic acid (AA), and omega-9 FA oleic acid.(11) Leukocyte membrane phospholipids are usually composed of approximately 30% polyunsaturated fatty acids (PUFAs).(11) Under a typical Western diet, the vast majority of PUFAs are omega-6 FAs (primarily AA), while only a small percentage are omega-3 FAs (12) AA is an omega-6 FA formed from linoleic acid which is present in high concentration in corn, sunflower, soybean and safflower oils. With activation of the inflammatory cascade, macrophages are able to mobilize up to 40% of its membrane lipid content by phospolipases to produce free AA.(11) Free AA is then further metabolized by cycloxygenase (COX) and 5-lipoxygenase (LOX) into pro-inflammatory eicosanoids, including the 2-series thromboxanes and prostaglandins and the 4-series leukotrienes(11) (Fig. 1). The affects of these eicosanoids in inflammation are well understood, especially thromboxane A₂ (TXA₂), prostaglandin E₂ (PGE₂), and leukotriene B₄ (LTB₄).(13) TXA₂ increases platelet aggregation, leukocyte adhesion, vascular permeability, pulmonary vasoconstriction, and bronchoconstriction,(14–15) and it has pro-thrombotic effects which may lead to tissue ischemia.(11) PGE₂ induces vasodilation, fever, vascular permeability during sepsis.(11, 13–14) LTB₄ activates leukocytes resulting in the generation of reactive oxygen species, release of proteases such as elastase, synthesis of lipid mediators, and neutrophil chemotaxis.(11) Of interest, platelet-activating factor (PAF) is tightly involved in the regulation of eicosanoid release through a two step activation process including phospholipase A2-dependent cleavage of membrane phospholipids, resulting simultaneously in the release of the active lipid mediator and free AA.(16)

Figure 1.

Eicosanoids Derived from Omega-6 and Omega-3 Fatty Acids. AA, arachidonic acid; COX, cycloxygenase; DHA, docosahexanoic acid; EPA, eicosapentaenoic acid; LOX, lipoxygenase; LT, leukotriene; PG, prostaglandin; TX, thromboxane.

The omega-3 FAs EPA and DHA are essential for normal growth and development and are highly enriched in the cell membranes of the brain and the eye. They have several known anti-inflammatory mechanisms of action and are effective in the secondary prevention of myocardial infarction and may have a role in the prevention and treatment of diabetes, hypertension, hypertriglyceridemia, and cancer as well as autoimmune disorders. The richest source of EPA and DHA is in fish oil, and increased dietary consumption increases incorporation into inflammatory cell membranes.(17) Omega-3 FAs replace AA in the phospholipid membrane; therefore, AA concentration is reduced and production of the highly inflammatory AA-derived eicosanoids is decreased due to substrate restriction. In addition to this replacement mechanism, EPA also inhibits the metabolism of AA into the inflammatory eicosanoids and is itself metabolized to a far less inflammatory series of eicosanoids (PGE₃ and LTB₅) than those derived from AA.(18–19) Fish oil has been shown in animal studies to decrease production of AA-derived eicosanoid inflammatory mediators by 40 to 70%.(20–21) In murine models of ALI, endogenous synthesis of omega-3 fatty acids in transgenic mice (22) or intravenous infusion of a fish oil-based lipid emulsion decreased edema formation, leukocyte infiltration, and sickness behavior (23–24). Exogenous delivery of fish oil reduced TNF-α while endogenous synthesis of omega-3 FA did not alter TNF-alpha generation but reduced generation of the pro-inflammatory nuclear factor (NF)-kappa B

An additional mechanism of action involving EPA and DHA has also recently been described. It is now known that resolution of inflammation is an active process, rather than simply absence of inflammatory signals.(25) Novel molecules called resolvins, protectins, and maresins (26–27); lipid mediators derived from EPA and DHA with potent pro-resolving, anti-inflammatory, and neuroprotective properties,(28–29) have been found to play an important role in the repair and resolution of inflammation.(30) Resolvin (Rv) E1 and Protectin D1 are quite well characterized resolving mediators effective in animal models of colitis and airway inflammation.(31–33) RvE1 has been found to activate cells by binding to an adopted orphan receptor called ChemR23, thereby decreasing the generation of the pro-inflammatory nuclear factor (NF)-kappa B.(34) In addition, it competes with binding of LTB4 to its receptor(35) leading to decreased activation of leukocytes. Administration of resolvin D2 has been shown to improve outcomes in a murine model of abdominal sepsis.(36)

In addition to mechanisms at the level of the cell membrane and involving resolvins and protectins, omega-3 FA may also have direct cardiac effects by interfering with ion-channels in cardiac myocytes. It has been suggested that omega -3 FA or derived metabolites may inhibit the delayed rectifier potassium channel or fast voltage-dependent sodium channels and L-type calcium channels, thereby reducing the arrhythmogenic potential in cardiac myocytes.(37) Of interest, one single center study in cardiac surgical patients suggested a reduced occurrence of post-operative atrial fibrillation after oral administration of n-3 FA.(38) These data are supported by another single center study in 102 cardiac surgical patients receiving either an intravenous fish oil-based lipid emulsion (Omegaven®, Fresenius Kabi, Bad Homburg, Germany) compared to a standard soybean-based lipid emulsion (Lipoven®, Fresenius Kabi, Bad Homburg, Germany). The authors reported reduced occurrence of post-operative atrial fibrillation and shorter length of stay in intensive care and hospital (39).

In addition, omega-3 FAs may affect the autonomic nerve system as well as the neuro-endocrine axis. Prior studies have demonstrated that dietary EPA and DHA reduces resting heart rate and improves heart rate variability.(40–41) EPA and DHA also reduced the generation of adrenocorticotropic hormone and norepinephrine in volunteers challenged with intravenous endotoxin,(42–43) and a fish oil-containing lipid emulsion in post-operative critically ill patients resulted in a trend to lower body temperature in a single center study. (44)

Although supplementation with omega-3 FAs is generally thought to reduce the unfavorable inflammatory effects of omega-6 FAs through the above mechanisms(45), there is also one omega-6 FA, gamma-linolenic acid (GLA), that may provide benefit in critical illness. GLA is found in evening primrose oil, black current seeds and borage oil and is rapidly converted to dihomo-GLA which is incorporated into immune cell phospholipids and which in principle should be further converted to AA.(46) However, GLA actually reduces the availability of AA and synthesis of AA-derived eicosanoids through unclear mechanisms. Dihomo-GLA is further metabolized to prostaglandin E₁ (PGE₁), a strong pulmonary and systemic vasodilator (Fig. 1).(47) In animal models of critical illness GLA with EPA and DHA have an additive effect to decrease inflammation and organ failure.(48) With this potential additive effect in mind, as discussed below, much of the omega-3 research in critically ill patients with sepsis and ALI has been conducted using a commercially available enteral feeding formula that contains EPA, DHA, GLA, and several antioxidant vitamins.(49–51)

ENTERAL OMEGA-3 FATTY ACIDS IN CRITICAL ILLNESS

Commercially available enteral nutrition formulas with added fish oil have been studied in mixed ICU populations; separately in surgical or medical ICU patients, and in critically ill patients with trauma or burns. Interpretation of data in this area is difficult due to differing amounts of EPA and DHA present in various enteral formulations (1.0–6.6 g/L) and the inclusion of other micronutrients in the formulas. (52) Furthermore, the degree of clinical response to fish oil containing formulas may vary between patients due to the type and severity of illnesses in the populations studied.

Due to the severe inflammatory response in patients with ALI and sepsis, many anti-inflammatory agents, including omega-3 FAs, have been investigated as potential therapies in these populations. Three randomized clinical trials (RCTs) using a commercial feeding formula (Oxepa®; Abbott Nutrition, Abbott Laboratories, Columbus, Ohio) which contains EPA, DHA, GLA, and several antioxidants in critically ill patients have been completed and published. Two of these RCTs included only patients with ALI (49–50) and the third studied patients with sepsis (51) (although nearly all of the patients in the third RCT had single-organ lung failure, i.e. ALI). All three of these trials randomized patients to receive either the enteral formula containing EPA, DHA, GLA, and antioxidants (Oxepa®) or an isonitrogenous, high-fat, low-carbohydrate enteral feeding formula that did not contain fish oil. One of the studies used a different control formula which was equal in fat content (55% fat) but differed in lipid composition from the control formulation used by the other two studies.(51) In Gadek et al. and Singer et al., the lipid content of the control formula was 97% corn oil, which is high in linoleic acid, an omega-6 FA.(49–50) The lipid in the control formula in Pontes-Arrudes et al. was 55.8% canola oil, 14% corn oil, 20%MCT, 7% high oleic safflower oil and 3.2% soy lecithin.(51)

In the first study, subjects in the treatment group received approximately of 7g EPA, 3g DHA, and 6g GLA per day.(49) Serial bronchoalveolar lavage (BAL) was done at study entry, day 4, and day 7. The treatment group had improved oxygenation at days 4 and 7 (p<0.0499); decreased duration of mechanical ventilation (p=0.027), reduced BAL fluid neutrophil (representing decreased lung inflammation) count at day 4 (p=0.008), decreased ICU length of stay (p=0.016), and new organ failures (p=0.018). Mortality was 16% in the treatment group and 25% in the control group (p=0.165).

In the second trial by Singer and co-workers, patients in the EPA/DHA/GLA/antioxidant group had a shorter, but statistically insignificant, duration of mechanical ventilation at day 14.(50) Hospital mortality in this study was very high (>75%) in both groups 3 months after the intervention.

The third trial in patients with sepsis (most of whom had ALI) found significant increases in ICU-free days (p<0.001), in ventilator-free days (p<0.001), and 28-day survival (52% vs. 33%, p=0.04) in the treatment group.(51) All patients tolerated near goal enteral feeding. Development of new organ dysfunctions was also reduced (p<0.001) in patients receiving the formula enriched with EPA, DHA and GLA.

In a meta-analysis of these three studies, the data from a total of 411 patients (296 who were considered evaluable) was analyzed.(47) The use of the treatment formula enriched with EPA, DHA, GLA and antioxidants was associated with a 60% reduction in the risk of 28-day all cause mortality (OR=0.40; 95% confidence interval [CI] = 0.24–0.68; p=0.001). Significant reductions were also found in the risk of developing new organ failures (OR = 0.17; 95% CI=0.08–0.34; p<0.0001), time on mechanical ventilation (standardized mean difference [SMD]=0.56; 95% CI=0.32–0.79; p<0.0001), and in length of stay in the ICU (SMD=0.51; 95% CI=0.27–0.74; p<0.0001) in patients who received the formula containing fish oil. A second meta-analysis by Marik & Zaloga confirmed the findings reporting improved mortality (OR 0.42, CI 0.26–0.68, p <0.001), secondary infections (OR 0.45, 95% CI 0.25–0.79, p<0.005), and length of stay (WMD −6.28 days, 95% CI −9.92 to −2.64) in patients who received enteral formulas that contained fish oil. (52) These studies have also been reviewed as part of the Canadian Clinical Practice Guidelines for enteral nutrition supplemented with fish oils, available at www.criticalcarenutrition.com; and are evaluated in the Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N) 2009 Critical Care Guidelines.(53–54)

Two additional publications from the randomized clinical trial by Gadek et al.(49) investigated mechanisms of action of EPA, DHA, GLA and antioxidants in patients with ALI. The first investigation reported on the antioxidant status of the participants with ALI and compared them to a group of healthy controls.(55) At enrollment, the patients with ALI had reduced levels of antioxidant vitamins and were found to be in a state of oxidative stress (as measured by total radical antioxidant potential and lipid peroxide levels) compared to healthy controls. After receiving the treatment formula, the levels of oxidative stress were not significantly reduced, but plasma levels of β-carotene and α-tocopherol were restored to normal while lipid peroxide levels did not increase; thus suggesting the antioxidants may have protected against further lipid peroxidation. The second ancillary study reported a significantly reduced level of interleukin-8 (a potent inflammatory cytokine and neutrophil chemoattractant) in bronchoalveolar lavage (BAL) fluid of patients in the treatment group (p=0.05), as well as a trend toward reduced levels of IL-6, LTB₄ and TNF-α.(56) Because the above trials investigated a single enteral formula (Oxepa®) containing multiple pharmaconutrients, the benefit attributed exclusively to omega-3 FAs is unknown.

Other enteral nutritional formulas enriched with omega-3 FAs have been studied in critically ill patients suffering from trauma, surgery, or burns. These formulas are usually supplemented with additional nutrients thought to affect immune function, such as the amino acids arginine or glutamine or antioxidant vitamins (57) The above mentioned meta-analysis by Marik & Zaloga analyzed data from enteral nutrition studies and separated the studies by the types of micronutrients included in the formula (fish oil, arginine or glutamine) and the population studied (surgical ICU, medical ICU, mixed ICU, burns, or trauma).(52) All studies in non-medical ICU patients included in this meta-analysis used a formula that also contained arginine. Mixed ICU patients with sepsis and ALI improved with the addition of fish oil to enteral feedings, but supplementation with fish oil and arginine (with or without glutamine) did not show benefit for patients in the surgical ICU or for those with trauma or burns.(52) Another meta-analysis has suggested that formulas containing arginine may benefit elective surgical patients but may be harmful to critically ill patients with sepsis.(58) Use of arginine containing formulas in critically ill patients showed a trend toward higher mortality, while there was no such effect in elective surgical patients.(58) Therefore, a negative effect or lack of benefit with use of these formulas that contain both arginine and fish oil in critically ill patients may be related to the arginine and not the omega-3 FAs, especially in critically ill medical ICU patients with sepsis.

When pharmaconutrients are combined with macronutrients in enteral feedings, it is difficult to generalize study results. Two recently completed, but not yet published, RCTs of omega-3 FAs in patients with ALI were designed to dissociate the pharmaconutrients from enteral feedings; the pharmaconutrients were administered enterally as medications while patients received standard enteral nutrition regimens per their treating physicians.(59–60) The preliminary results of these two recent RCTs were presented orally at the American Thoracic Society (ATS) International Conference held May 15–20, 2009 in San Diego, California. Both of these trials appear to challenge the positive results found in the previous RCTs using the enteral formula containing EPA, DHA, GLA, and antioxidants.(59–60) The first trial, the OMEGA study, is a large phase III RCT conducted by the National Institutes of Health, National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome Network (ARDSnet) to investigate whether an enteral supplement (delivered twice daily) containing EPA, DHA, GLA, and antioxidants would have benefit in patients with ALI.(60) This RCT was stopped due to lack of efficacy in March 2009 after accrual of 272 of the planned 1000 patients. The enteral supplement did not improve the outcomes of ventilator free days at day 28, ICU free days at day 28, or death at 60 days. The second study reported at the conference was a phase II randomized, double-blind, placebo-controlled trial of enteral fish oil (EPA and DHA) in 90 critically ill patients with ALI.(59) Fish oil or a saline placebo was given enterally as a medication, separate from enteral or parenteral nutrition in this trial. The primary endpoint was BAL fluid IL-8 and secondary endpoints included clinical outcomes as well as biomarkers of inflammation and injury, oxygenation, and lung compliance. None of the primary or secondary endpoints were significantly different between the treatment and control groups. Based on the preliminary results available from these two studies, the effect of enteral fish oil supplementation in patients with ALI and sepsis is currently unclear. Some limitations of the three earlier studies using the enteral formula enriched with EPA, DHA, GLA and antioxidants in patients with ALI include the small number of published studies to date, and the use of a control formula in two of the studies(49–50) that was high in linoleic acid, an omega-6 FA. It is currently unclear why the promising effect of the previous studies could not be reproduced in the two newer (unpublished) studies. There are differences between the designs of the different studies including the intervention, control formulas, and continuous administration vs. bolus administration of the agent.

Most studies investigating the effects of enteral fish oils included in an enteral feeding formula with other nutrients including arginine, glutamine, or antioxidants have been in non-medical ICU patents with trauma,(61–62) burns,(63–64) or surgery(65–66) and have found no benefits in mortality, length of hospital stay, or rates of new infections. However, many of these studies were small, with some intending only to detect differences in biochemical parameters or biomarkers. One large multi-center study in septic patients examined the effect of fish oil, arginine, and nucleotides and did demonstrate an improvement in mortality.(67) However, in subgroup analysis the overall effect was largely due to patients with a low Acute Physiologic and Health Evaluation Score (APACHE II), and mortality was actually worse in patients with a APACHE II score > 25. Therefore the effect of enteral fish oil in these populations is not clear. However, this conclusion is based on a small number of studies in each population.(52) Additional research is needed before any definitive recommendations can be made about enteral omega-3 FA supplementation in critically ill patients.

INCLUSION OF OMEGA-3 FATTY ACIDS IN PARENTERAL NUTRITION

Lipid emulsions are generally administered in parenteral nutrition (PN) regimens to provide a source of energy and essential fatty acids, and the specific type of fatty acids in the emulsions may impact the inflammatory response in critical illness. Soybean oil, consisting of roughly 54% linoleic acid (an omega-6 FA), is the lipid traditionally used in PN.(68) Concern has been raised over the potential pro-inflammatory, pro-coagulatory, and immunosuppressive properties of linoleic acid. However, clinical trials using these emulsions have provided conflicting evidence.(69) A meta-analysis of two studies(70–71) where standard lipids in PN were compared with no lipids suggested that PN with standard lipids may result in a higher infectious complication rate (p=0.02) than PN without lipids, although mortality was not different between the two groups.(72) The concern about lipid emulsions has led to new formulations which partially replace soybean oil with other oils including medium chain triglycerides (MCT), olive oil, or fish oil.(69)

Recent studies using parenteral fish oil emulsions have been conducted. In a study by Mayer et al.,(73) 21 who required PN due to intolerance of enteral nutrition were randomized in an open-label trial to receive an omega-3 FA lipid emulsion (Omegaven®; Fresenius Kabi, Bad Homburg, Germany) or a standard omega-6 lipid emulsion (Lipoven®; Fresenius Kabi) for 5 days. The omega-3 rich emulsion increased plasma concentrations of omega-3 free FAs and reversed the omega-3/omega-6 ratio toward favoring EPA and DHA over AA, reaching maximum effect in 3 days. In patients receiving the fish oil emulsion, EPA and DHA rapidly incorporated into mononuclear leukocyte cell membranes, increasing threefold in concentration. Ex vivo, these cells produced 30% less TNF-α, interleukin 1-β, IL-6, IL-8, and IL-10 when stimulated by endotoxin. However, serum cytokine levels between the patients receiving parenteral omega-3 FAs and the standard lipid emulsion were not different. In another study by the same authors, 10 patients with septic shock requiring PN randomly received fish oil fortified Omegaven® or the standard omega-6 rich Lipoven® for a total of 10 days.(74) C-reactive protein levels and leukocyte counts decreased in patients receiving the omega-3 emulsion and increased in patients receiving the omega-6 emulsion, with a trend toward significance (p=0.08 and p=0.09, respectively). Patients in the omega-6 group trended towards longer ventilation time (p=0.07). LTB₅ increased in the fish oil group, approaching an LTB₄/LTB₅ ratio of almost 20% by the end of the study infusion period. These results support the hypothesis that parenteral omega-3 FA in patients with septic shock modulates inflammatory mediator production and attenuates inflammation.

In a prospective, open label trial, infusion of omega-3 FAs during PN (Omegaven® ) improved diagnosis-related clinical outcomes in critically ill patients with major abdominal surgery (n=255), peritonitis and abdominal sepsis (n=276), non-abdominal sepsis (n=16), multi-trauma (n=59), severe head injury (n=18) or other diagnoses (n=37).(75) Both ICU and hospital lengths of stay were significantly reduced (both p<0.001) with doses of >0.05 gm fish oil/kg/day, and patients receiving >0.15 gm/kg/day needed less antibiotic treatment. Mortality was significantly decreased (p<0.05) in patients receiving >0.1 gm fish oil/kg/day. In an analysis of patients by diagnosis, according to mean fish oil dose received, patients with severe head injury (p<0.0001), multiple trauma (p<0.0001), and abdominal sepsis (p=0.0027), had significantly lower mortality. These results suggest benefit from parenteral omega-3, but this study was not controlled or blinded. Another recent trial randomized patients with severe acute pancreatitis to either a combination of 20% Omegaven® + 80% Lipoven® or Lipoven® alone.(76) There were no significant differences in white blood cell count, C-reactive protein, rates of organ dysfunction, infectious complications, or ICU length of stay. However, IL-6 decreased to a significantly greater degree between baseline and day 6 in patients in the fish oil group (p < 0.05). Additionally, oxygenation was significantly increased (p<0.05) and there was a significantly decreased need for renal replacement therapy (p<0.05) in the patients receiving fish oil.

In contrast to the positive results of the previous studies which were largely in surgically critically ill patients, a randomized, double-blind, controlled trial in critically ill medical patients found no clear medical benefit to parenteral omega-3 FAs.(77) In that study, 166 medical ICU patients were randomized to receive a mixture of medium- and long-chain triglycerides (Lipofundin MCT®; Braun Medical, Melsungen, Germany) or a combination of Omegaven® and Lipofundin MCT® for 7 days. Based on data from a prior study,(78) this RCT was designed to detect a biologic endpoint: more rapid reduction in IL-6 and greater monocyte expression of HLA-DR, a marker of immune competence, in the omega-3 group. The authors found no differences in IL-6 or HLA-DR between the treatment groups, nor did they detect differences in mortality, duration of mechanical ventilation, ICU length of stay, infectious complications, other inflammatory markers, or bleeding events.(77) One possible explanation for this lack of effect is that the start of the study occurred after the initial inflammatory process was already resolving. In addition, the study may have been underpowered. This study also used a control lipid emulsion that was lower in omega-6 FAs (due to the presence of MCT) than most standard lipid emulsions, and thus may have been less inflammatory.(77) Recently, another single center study in patients with the systemic inflammatory response syndrome was published where a parenteral lipid emulsion of MCT, soybean oil, and fish oil was compared to a lipid emulsion of MCT and soybean oil alone (Lipofundin-MCT®).(79) They reported a faster reduction in IL-6, improved ventilation parameters, and a trend toward reduced hospital length of stay (p<0.079).

No adverse effects have been reported with the administration of lipid emulsions fortified with fish oil, suggesting it is safe in critically ill patients.(69) Because available research to date provides conflicting data on the effects of parenteral omega-3 FAs in critically ill patients, its influence on inflammatory processes and clinical outcomes is remains unclear.

CONCLUSIONS

Although much is known about the mechanism of action of omega-3 FAs and their effect on cytokines and inflammatory mediators from research with animals humans, their effects on clinical outcomes in critically ill patients are not entirely clear, and further research is needed to determine any benefit. Trials of nutritional support and micronutrients, including omega-3 FAs, in critically ill patients are especially difficult to conduct and interpret for multiple reasons. First, patient enrollment can be difficult due to issues with surrogate consent as well as the short enrollment periods in most studies (e.g. most trial require enrollment within 24–48 hours after ICU admission in an effort to initiate the agents early in the course of critical illness). Second, critically ill patients are a very heterogeneous population and present with a wide variety of severe medical illnesses. This heterogeneity means that large numbers of patients are required to demonstrate an effect.(80) Third, the delivery of nutrition and micronutrients is frequently interrupted or poorly tolerated in ICU patients, thus resulting in decreased delivery of the agent being studied, especially if it is enteral. Fourth, in many studies of enteral and parenteral nutrients, many agents are frequently combined into one formula, and therefore the effect produced by a single agent cannot be determined. Fifth, choice of control group agent in many trials is also in issue. Finally, dosing data on both enteral and parenteral omega-3 fatty acids in critically ill are very sparse.

Prior research demonstrating positive effects of enteral omega-3 FAs in patients with sepsis and ALI involved the continuous administration of one enteral formula fortified with EPA, DHA, GLA and antioxidants.(49–51) These data are challenged by the use of bolus omega-3 FAs, either as a single enteral agent(59) or as part of an enteral immune-modulating cocktail.(60) The studies of parenteral omega-3 FAs that suggest a benefit have been conducted using a particular lipid emulsion (Omegaven®) and are not yet conclusive.(73–77) After understanding the limitations of all the previous studies and gaining insight into possible dosing-, timing-, and application-dependent effects, it is clear that additional randomized, double-blinded, controlled trials in which omega-3 FAs are administered separately from feedings (and the feeding formulas are devoid of other micronutrients) and the control agent is an inert placebo are needed to definitively inform patient care.

Table 1.

Published Randomized Controlled Trials Comparing a Commercial Enteral Feeding Formula Enriched with EPA, DHA, GLA, and Antioxidants to Another High-Fat Enteral Feeding Formula Without Fish Oils

	Gadek et al.49	Singer et al.50	Pontes-Arruda et al.51
Population Studied	ARDS	ALI	Severe Sepsis
	n=146	n=100	n=165
Study Design	R, C, DB	R, C	R, C, DB
Mean Fatty Acid Intake (g/day)
EPA	6.9	5.4	4.9
DHA	2.9	2.5	2.2
GLA	5.8	5.1	4.6
Significant Findingsa
Improved oxygenation	Yes	Yesb	Yes
Reduced ICU length of stay	Yes	No	Yes
Reduced ventilator time	Yes	Yesc	Yes
Reduced 28-day mortality	No	Yes	Yes
Fewer new organ failures	Yes	Not assessed	Yes

R, randomized; C, controlled; DB, double blind; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; GLA, gamma-linolenic acid; ALI, acute lung injury; ARDS, acute respiratory distress syndrome; FA, fatty acid.

^aStatistically significant (p<0.05);

^bDays 4, 7 only;

^cDay 7 only