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Published ahead of print on February 25, 2003, doi:10.1164/rccm.200207-674OC
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American Journal of Respiratory and Critical Care Medicine Vol 167. pp. 1321-1328, (2003)
© 2003 American Thoracic Society

Parenteral Nutrition with Fish Oil Modulates Cytokine Response in Patients with Sepsis

Konstantin Mayer, Stephanie Gokorsch, Christine Fegbeutel, Katja Hattar, Simone Rosseau, Dieter Walmrath, Werner Seeger and Friedrich Grimminger

Medizinische Klinik II, Justus Liebig University, Giessen; and Medizinische Klinik mit Schwerpunkt Infektiologie, Charité, Humboldt University, Berlin, Germany

Correspondence and requests for reprints should be addressed to Dr. Konstantin Mayer, Department of Internal Medicine, Justus-Liebig-University Giessen, Klinikstr. 36, D-35392 Giessen, Germany. E-mail: Konstantin.Mayer{at}innere.med.uni-giessen.de


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Infusion of fish oil-based (n-3) lipids may influence leukocyte function and plasma lipids in critical care patients. Twenty-one patients with sepsis requiring parenteral nutrition were randomized to receive an n-3 lipid emulsion rich in eicosapentaenoic acid and docosahexaenoic acid or a conventional (n-6) lipid emulsion (index fatty acid: arachidonic acid) for 5 days. The impact on plasma-free fatty acids, mononuclear leukocyte cytokine generation, and membrane fatty acid composition was examined. Cytokine synthesis by isolated mononuclear leukocyte was elicited by endotoxin. Before the onset of lipid infusion therapy, plasma-free fatty acid concentrations were greatly increased in septic patients, with arachidonic acid by far surpassing eicosapentaenoic acid and docosahexaenoic acid, a feature maintained during conventional lipid infusion. Within 2 days of fish oil infusion, free n-3 fatty acids increased, and the n-3/n-6 ratio was reversed, with rapid incorporation of n-3 fatty acids into mononuclear leukocyte membranes. Generation of proinflammatory cytokines by mononuclear leukocytes was markedly amplified during n-6 and was suppressed during n-3 lipid application. After termination of lipid administration, free n-3 fatty acid concentrations and mononuclear leukocyte cytokine synthesis returned to preinfusion values. Use of lipid infusions might allow us to combine intravenous alimentation with differential impact on inflammatory events and immunologic functions in patients with sepsis.

Key Words: monocyte • eicosapentaenoic acid • arachidonic acid • mononuclear leukocyte

Sepsis and septic shock continue to represent the major cause of death in intensive care medicine worldwide, with mortality rates ranging between 30% and 60% (1–3). Proinflammatory and potentially autotoxic mediators have been noted to contribute to the sequelae of events in experimental models of sepsis, and excessive generation of these mediators has been observed (4–6). The fact that this systemic inflammatory reaction is not only triggered by microbial invasion but is also encountered in response to severe tissue injury is reflected in the term systemic inflammatory response syndrome. Monocytes have been suggested to be intimately involved in controlling inflammatory cascades (7–9), based on their capacity to release both proinflammatory and antiinflammatory cytokines to direct activation and recruitment of further leukocyte populations.

Eicosanoids have long been implicated in both proinflammatory and antiinflammatory events occurring in sepsis (6, 10). The n-6 fatty acids, including arachidonic acid, represent the predominant polyunsaturated fatty acids in common western diets and current nutritional regimes. Eicosapentaenoic acid and docosahexaenoic acid are the most important members of the n-3 family of fatty acids in which the last double bond is located between the third and fourth carbon atom from the methyl end. Major sources of n-3 fatty acids are cold-water fish and seal meat, and n-3 fatty acids may serve as alternative lipid precursors for both cyclooxygenase and lipoxygenase pathways (11). Interestingly, many n-3 fatty acid–derived metabolites, including 5-series cysteinyl-leukotrienes, leukotriene B5, and thromboxane A3, possess markedly reduced inflammatory and vasomotor potencies compared with arachidonic acid–derived lipid mediators and may even exert antagonistic functions. Moreover, by incorporation into various membrane (phospho)-lipid pools, n-3 fatty acids may affect lipid-signaling events in different cell types (12, 13).

Diets with specific fat composition may influence inflammatory and immunologic events (immunonutrition). However, weeks of dietary supplementation with fish oil are required to effectively alter fatty acid composition of membrane lipids and related metabolic pathways in humans (14, 15). Nevertheless, a significant reduction of infectious complications and septic events was recently attributed to an enteral diet containing n-3 fatty acids in traumatized and surgical patients (16–18). Moreover, enteral or parenteral usage of n-3 lipids in experimental sepsis models resulted in enhanced survival and reduced lung failure (19–21). When administering a fish oil–based lipid emulsion via intravenous route in patients with inflammatory bowel and skin disease, we demonstrated rapid changes in cell membrane fatty acid composition and lipid mediator generation (22, 23).

In this study, the impact of an n-3 fatty acid-rich lipid emulsion (fish oil–based) on fatty profiles and monocyte cytokine generation was compared with that of a conventional (n-6 fatty acid–rich) lipid emulsion in a randomized fashion in septic patients requiring parenteral nutrition. The fish oil–based preparation shifted the n-3/n-6 ratio of plasma-free fatty acids from an n-6 to an n-3 predominance and reduced endotoxin-elicited monocyte proinflammatory cytokine generation. In contrast, endotoxin-induced monocyte cytokine generation was markedly amplified by the n-6 lipid infusion. Differential employment of n-3 versus n-6 lipid infusions might via intravenous alimentation impact inflammatory and immunologic events in patients with sepsis.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Design
Twenty-one patients fulfilling the criteria of sepsis and intolerant of enteral nutrition were recruited in the intensive care unit of the Department of Internal Medicine, Justus-Liebig University, Giessen (demographic data in Table E1). The study was conducted according to the Declaration of Helsinki and was approved by the university ethics committee. Written informed consent was obtained from each patient, next-of-kin, or legal guardian. The study was conducted as an open-label and randomized trial. Patients were randomly assigned to receive total parenteral nutrition employing either the standard n-6 lipid-infusion (Lipoven) or alternatively the n-3 lipid-infusion (fish oil–based; Omegaven); both emulsions were supplied by Fresenius Kabi (Bad Homburg, Germany). The fatty acid composition of these different lipid emulsions is given in Table E2. Via central venous catheter, 350 ml of a 10% n-6 or n-3-lipid emulsion was infused daily for 5 days. Infusion was divided into three portions (150, 100, and 100 ml), each over a 6-hour infusion period with a 2-hour break between portions. None of the patients had received lipid emulsions before entry into the study. The Acute Physiology and Chronic Health Evaluation II score was calculated from data obtained at baseline (24).

Patient Selection and Exclusion Criteria
Patients enrolled satisfied the clinical suspicion of infection and systemic inflammatory response within the previous 24 hours (25). Patients less than 18 years of age or with known or suspected pregnancy were excluded. Other exclusion criteria were treatment with corticosteroids (equivalent of 1 mg or more of prednisone/kg) within the previous 48 hours, treatment with other major immunosuppressive drugs, infection with human immunodeficiency virus, neutropenia not attributable to sepsis, a plasma triglyceride concentration of more than 400 mg/dl (more than 4.6 mM), participation in an other ongoing investigational clinical trial, and the presence of irreversible underlying disease anticipated to be rapidly fatal.

Blood Sampling
Blood was collected from the central venous catheter at 8:00 A.M. on Day 1 before the first lipid preparation was infused and on Days 2, 4, 6, 11, and 18, after a 2-hour interval without lipid infusion.

Control Group
Six healthy adults (age 22 to 68 years; three males and three females) served as the control group. Medical history, physical examination, and routine laboratory investigation were completely normal in all subjects. They took no medications and had no febrile disease in the month before the study. After an overnight fast, blood was collected at 8 hours by antecubital venipuncture.

Experimental Procedures
Materials.
Ficoll-Paque was obtained from Pharmacia Fine Chemicals (Uppsala, Sweden) and NycoPrep 1.068 was from Nycomed Pharma AS (Oslo, Norway). ELISA kits for determination of tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin (IL)-1ß, IL-6, IL-8, and IL-10 were obtained from Coulter-Immunotech (Hamburg, Germany).

Isolation of human mononuclear leukocytes and human monocytes.
Human mononuclear leukocytes were isolated from ethylenediaminetetraacetic acid-anticoagulated blood (0.125% wt/vol) using Ficoll-Paque (26). Human monocytes were isolated as described by Bøyum (27) with NycoPrep 1.068 yielding a purity of more than 85%. Cell viability, as assessed by trypan blue exclusion and by propidium iodide staining with subsequent fluorescence-activated cell sorting analysis (FACScan Flowcytometer; Becton Dickinson, San José, CA) ranged consistently above 96%.

Culture and stimulation of the cells.
Mononuclear leukocytes (5 x 105 in a 96-well tissue culture plate) and monocytes (5 x 105 in a 24-well tissue culture plate) were cultivated in media containing 1% heat-inactivated autologous serum, penicillin, streptomycin, and glutamine. Cells were stimulated with 0 (vehicle control), 1, and 10 ng/ml endotoxin from Salmonella typhimurium (Sigma-Aldrich, Darmstadt, Germany) for 24 hours at 37°C, 5% CO2. Incubation was stopped by freezing in liquid nitrogen.

Analysis of free fatty acids.
Nonesterified plasma fatty acids were analyzed as described (23). Citrate plasma was spiked with heptadecanoic acid as an internal standard. Lipids were extracted according to the method of Bligh and Dyer (28), followed by methylation with ethereal diazomethane. Fatty acid methylesters were purified by high-performance thin-layer chromatography and subjected to gas-chromatographic analysis as described (23).

Statistics
The values are given as the mean ± SEM. All statistical analyses were done with the SigmaStat computing package. Repeated-measures analysis of variance was used (29, 30); p values of less than 0.05 were considered to indicate statistical significance.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Study Patients and Clinical Data
Eleven septic patients were included in the n-6 treat group, and ten in the n-3 lipid infusion group. Two patients in the n-6 group died during the first day of the study. Because no follow-up data were obtained in these patients, their baseline values were excluded from data analysis. Baseline demographic data and clinical features of the study patients are given in Table E1. All patients fulfilled the criteria of severe sepsis or septic shock. Infusion of glucose, amino acid, and electrolyte solutions did not differ between the two groups. Leukocyte counts were 18,000 ± 4,700 and 15,600 ± 2,200 per mm3 in the n-6 and n-3 lipid infusion groups, respectively. In the group receiving conventional lipid infusion, five patients required vasopressor support (septic shock), and eight were mechanically ventilated. In the fish oil infusion group, five patients required catecholamines (septic shock), and all were mechanically ventilated. C-reactive protein in the n-6 group was 132.3 ± 12.3 mg/L compared with 187.1 ± 23.3 mg/L in the n-3 group. Baseline Acute Physiology and Chronic Health Evaluation II scores were 15.2 ± 2.0 and 19.6 ± 1.5 in the n-6 and in the n-3 lipid infusion group, respectively. During the clinical observation period of 14 days, another three patients died in the n-6 group, and five patients died in the n-3 group. When vasopressor therapy was reassessed on the 14th study day, one patient of the n-6 group and none of the n-3 group were treated with catecholamines. At this time, one patient of the n-6 group was still ventilated, whereas three patients in the n-3 group required mechanical respiratory support. After completion of the investigative lipid infusion period, patients received standard lipid emulsion infusion (Lipoven 20%). Enteral tube feeding was initiated as soon as tolerated. On the 11th day of the study, all six patients of the n-6 group received parenteral lipid emulsions, with three being additionally tube fed. At this time, the five surviving patients of the n-3 group all received intravenous lipids, and four of them were additionally fed via tube.

Plasma-Free Fatty Acids
In comparison to the healthy control subjects, all plasma-free fatty acids were markedly increased in the patients with sepsis even before onset of lipid infusion therapy (Table 1) . The overall sum of plasma-free fatty acids at Day 1 exceeded that in control subjects four- to fivefold. Baseline levels of free arachidonic acid were approximately sixfold increased as compared with the healthy volunteers, both for the n-3 and the n-6 lipid infusion group (Figure 1A) . Overall quantities and fatty acid profile remained largely unchanged in the n-6 lipid infusion group. In contrast, a marked increase in n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid was noted in patients receiving the fish oil–based lipid emulsion (Figures 1B and 1C). Concentrations of both n-3 fatty acids reached a maximum after 3 days of fish oil-based lipid infusion and rapidly decreased after cessation of the n-3 infusion regimen. The baseline predominance of plasma-free n-6 over n-3 fatty acids was reversed during the fish oil-based lipid administration, with the sum of eicosapentaenoic acid and docosahexaenoic acid concentrations surpassing the arachidonic acid level two- to threefold (Figure 1D).


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  		TABLE 1. Baseline plasma-free fatty acids before onset of lipid infusion in septic patients and healthy control subjects

 


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  		Figure 1. Plasma-free fatty acid concentrations in patients with sepsis undergoing n-3 (closed triangle) versus n- 6 (closed circle) lipid infusion, as compared with healthy control subjects (closed square). Mean ± SEM are given for arachidonic acid (AA; A), eicosapentaenoic acid (EPA; B), docosahexaenoic acid (DHA; C), and for the calculated ratio of (EPA+DHA)/AA (D). Note the interruption of time scale between Days 6 and 11, as well as Days 11 and 18. Error bars are missing when falling into symbol. *p < 0.05 and **p < 0.01 for comparison between patients with n-3 and n-6 lipid infusion.

 
Mononuclear Leukocyte Membrane Fatty Acid Composition
When compared with healthy control subjects, arachidonic acid content of the mononuclear leukocyte membrane fatty acids was decreased to nearly 50% at baseline. During the infusion period with either n-6 or n-3 lipids, this percentage of arachidonic acid remained largely constant in both groups (Figure 2A) . Eicosapentaenoic acid levels in mononuclear leukocyte membranes of patients with sepsis were comparable to healthy control subjects before the infusion regimens. In patients receiving fish oil–derived lipids, eicosapentaenoic acid content promptly increased several fold, with decline to control levels within 5 days after cessation of the lipid infusion (Figure 2B). In the n-6 lipid infusion group, only minor amounts of eicosapentaenoic acid in mononuclear leukocyte phospholipids were detected throughout. At baseline, docosahexaenoic acid levels were lower in patients with sepsis compared with healthy control subjects. Infusion of n-3 lipids, but not n-6 lipids, increased docosahexaenoic acid membrane content more than threefold (Figure 2C). These alterations in mononuclear leukocytes membrane fatty acid composition resulted in a considerable change in the ratio of (eicosapentaenoic acid + docosahexaenoic acid)/arachidonic acid, rising from approximately 1:10 at baseline to nearly 1:2.5 after 3 days of fish oil–derived lipid infusion.



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  		Figure 2. Mononuclear leukocyte membrane fatty acid composition in patients with sepsis undergoing n-3 (closed triangle) versus n-6 (closed circle) lipid infusion compared with healthy control subjects (closed square). Arachidonic acid (AA, A), eicosapentaenoic acid (EPA, B), and docosahexaenoic acid (DHA, C) are given in percentage of all membrane fatty acids (mean ± SEM). Note the interruption of time scale between Days 6 and 11, as well as between Days 11 and 18. *p < 0.05; **p < 0.01; for comparison between patients with n-3 and n-6 lipid infusion.

 
Cytokine Secretion by Isolated Mononuclear Leukocytes and Monocytes
Secretion of TNF-{alpha}, IL-1ß, IL-6, and IL-8 was provoked by 10 ng/ml of endotoxin in mononuclear leukocytes. Endotoxin-elicited cytokine release showed no significant difference between the two study groups at baseline and was comparable to healthy control subjects (Figures 3A–3D) . During n-3 lipid infusion, release of these cytokines decreased by approximately 30%. In contrast, a significant increase in endotoxin-elicited cytokine-secretion occurred in response to the n-6 lipid infusion regimen, with approximately doubling of values during the first 4 days, as determined for TNF-{alpha}. Subsequently, endotoxin-induced cytokines declined to baseline values. After termination of the infusion period, some increase in release of TNF-{alpha}, IL-1ß, and IL-6 was noted in both study groups. Similar kinetics were detected in isolated monocytes challenged with 10 ng/ml of endotoxin (Table E3). Secretion of TNF-{alpha}, IL-1ß, and IL-6 by mononuclear leukocytes or monocytes in the absence of endotoxin-challenge was slightly lower in both study groups when compared with healthy control subjects but did not show any significant difference between the two lipid infusion regimens (Table E3).



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  		Figure 3. Ex vivo mononuclear leukocyte cytokine release on stimulation with endotoxin; impact of n-3 versus n-6 lipid infusion. Mononuclear leukocytes were separated from patients with sepsis before (Day 1), during, and after the different lipid infusion regimens, and stimulation with 10 ng/ml of endotoxin was undertaken (closed triangle, n-3 lipid infusion; closed circle, n-6 lipid infusion). Control cells originated from healthy volunteers (closed triangle). Sham challenge in the absence of endotoxin is indicated by open symbols (open triangle, n-3 lipid infusion; open square, n-6 lipid infusion; open circle, healthy volunteers). Mean ± SEMs are given for TNF-{alpha} (A), IL-1ß (B), IL-6 (C), IL-8 (D), and IL-10 (E). Note the interruption of time scale between Days 6 and 11 as well as Days 11 and 18. Error bars are missing when falling into symbol. *p < 0.05 and **p < 0.01 for comparison between patients with n-3 and n-6 lipid infusion.

 
Endotoxin-evoked IL-10 release from mononuclear leukocytes and monocytes was markedly lower at baseline in both study groups as compared with healthy control subjects (Figure 3E and Table E3). Some increase in this cytokine was noted during n-6, but not during n-3-lipid infusion. In the absence of endotoxin stimulation, no difference in IL-10 synthesis from mononuclear leukocytes and monocytes was noted between n-6– versus n-3–infused patients.

All experiments addressing ex vivo release of cytokines from mononuclear leukocytes and monocytes in the presence of endotoxin were additionally performed using a concentration of 1 ng/ml of endotoxin. Total quantities of TNF-{alpha}, IL-1ß, IL-6, IL-8, and IL-10 were lower under these conditions, yet the time course and in particular the response to n-3 versus n-6-lipid infusion regimen fully corresponded to studies with 10 ng/ml of endotoxin (data not shown).

Serum Cytokine Levels
In all patients with sepsis, the baseline serum levels of TNF-{alpha}, IL-6, IL-8, and IL-10 were higher as compared with control subjects, with large variation of data (Table E4). Some decrease in these variables was noted over the 18-day observation period, with no significant difference between patients undergoing parenteral nutrition with n-3 lipids compared with those given n-6 lipids.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Overall levels of plasma-free fatty acids were markedly elevated in all patients under investigation, even before onset of any lipid infusion therapy, as previously observed by other groups (31, 32). The severity of sepsis in this study is reflected by the magnitude of this metabolic response, with 3- to 10-fold increased levels for all single fatty acids analyzed. Several factors may underlie this change in fatty acid homeostasis: (1) plasma-free fatty acid elevation is part of the general metabolic response syndrome to stress (33); (2) lipolysis in adipocytes and hepatic de novo lipogenesis are increased in sepsis (34–37), and muscle fatty acid oxidation is reduced (38); (3) secretory phospholipase A2 is elevated in sepsis (39); (4) vasopressors such as epinephrine or norepinephrine, presently administered to nearly 50% of all patients at baseline, preferentially increase plasma levels of polyunsaturated free fatty acids by activating lipoprotein lipase and hormone-sensitive lipoprotein lipase of adipose tissue (40, 41); and (5) heparin, used in low doses in all patients, is also an activator of lipoprotein lipase (42). Overall, these metabolic changes resulted in marked appearance of free concentrations of the eicosanoid precursor arachidonic acid between 25 and 50 µM. In comparison, approximately 6.5 µM of free arachidonic acid was detected in healthy control subjects, and measurements of free extracellular arachidonic acid within an inflammatory focus suggested levels between 10 and 50 µM (43–45).

After fish oil–based lipid infusion, a rapid increase in free plasmic eicosapentaenoic acid and docosahexaenoic acid levels was noted, rising to an average of approximately 35 and 65 µM, respectively. This resulted in a switch in the predominance of n-6 over n-3 to an n-3 over n-6 predominance (the eicosapentaenoic acid + docosahexaenoic acid)/arachidonic acid ratio then approached 3:1). Rapid hydrolysis of eicosapentaenoic acid– and docosahexaenoic acid–containing triglycerides in patients with sepsis can be assumed. This is concordant with the notion that synthetic lipid aggregates activate endothelial lipoprotein lipases, including a translocation of this enzyme from its cellular binding sites into the vascular compartment. Activation of the enzyme results in an increase in plasma-free fatty acids due to escape from local cellular uptake mechanisms (46). The kinetics and extent of plasma n-3 lipid increase thus exceed corresponding alterations in response to conventional dietary fish oil uptake by orders of magnitude (47, 48).

Parallel to the increase in plasma-free n-3 fatty acids, incorporation into the membranes of mononuclear cells became detectable. This was obvious for docosahexaenoic acid, the membrane content of which was reduced below control values in all septic patients, and was most impressive for eicosapentaenoic acid, with a large increase in the percentage of this n-3 fatty acid in membrane lipids. No significant change in mononuclear cell membrane content of arachidonic acid was noted during n-3 or n-6 based lipid infusion in patients with sepsis. However, arachidonic acid content was markedly reduced in both study groups compared with healthy control subjects. This finding resembles the decrease of polyunsaturated fatty acids seen in the essential fatty acid deficiency syndrome and is comparable to in vitro data originating from endothelial cells undergoing TNF-{alpha} challenge (49).

The most impressive finding of this study was the differential impact of the n-3 versus n-6 lipid preparations on mononuclear cytokine generation provoked by ex vivo endotoxin challenge. During the conventional n-6 lipid infusion an increase in TNF-{alpha}, IL-1ß, IL-6, and IL-8 synthesis became consistently detectable, in the total mononuclear leukocytes cell fraction and in isolated monocytes and both for the higher (standard) and the lower endotoxin concentration. In contrast, intravenous administration of n-3 lipids resulted in reduced proinflammatory cytokine generation under all experimental conditions. This observation is consistent with previous findings demonstrating that dietary n-3 fatty acids may suppress TNF-{alpha} and IL-1 release from mononuclear cells (50, 51). However, several weeks of oral fish oil supplementation were necessary to achieve such a change, whereas a 2-day infusion period sufficed to bring about changes in cytokine synthesis in this study. A post hoc data analysis was performed to test the hypothesis that increase in cytokine release after termination of the experimental lipid infusion period was due to a higher level of cytokine secretion of the surviving patients compared with the nonsurviving. However, the two subgroups of each infusion treatment did not differ significantly.

The mechanisms underlying the differential impact of n-6 versus n-3 lipids on mononuclear cell cytokine synthesis are currently unknown. Enhanced generation of five-series leukotrienes and three-series prostanoids may be expected under conditions of n-3 lipid infusion. This may subsequently reduce autocrine and paracrine proinflammatory loops in leukocyte activation (52). In addition, n-3 versus n-6 fatty acid membrane incorporation may differentially influence intracellular lipid signaling pathways. The magnitude of the phosphatidylinositol response, generation of inositolphosphates, and related secondary events have been noted to be influenced by the fatty acid composition of this phospholipid (53). Furthermore, secretion of platelet-activating factor may be suppressed in leukocytes enriched in n-3 fatty acids but enhanced in the presence of large quantities of n-6 fatty acids, with impact on cell–cell interaction and autocrine functions of this lipid mediator (54–56). Finally, membrane translocation and activation of protein kinase C were found to be influenced by membrane (in particular phosphatidylserine) n-3 fatty acid content (57). Moreover, experimental data suggest an inhibitory impact of fish-oil based lipids on endotoxin-induced signal transduction resulting in inflammatory cytokine generation. After preincubation with eicosapentaenoic acid, reduced endotoxin-stimulated nuclear factor-{kappa}B activation and subsequent TNF-{alpha} gene transcription as well as TNF-{alpha} release form murine macrophage cell line could be detected (58). After feeding a fish oil–enriched diet to mice, endotoxin-induced pro–IL-1 mRNA transcription was reduced (59). Clearly, further studies are required to elucidate the differential impact of n-3 versus n-6 lipid infusions on monocyte cytokine synthesis in patients with sepsis on a molecular level.

In contrast to the proinflammatory cytokines TNF-{alpha}, IL-1ß, IL-6, and IL-8, endotoxin-elicited secretion of the antiinflammatory cytokine IL-10 from mononuclear leukocytes and isolated monocytes was markedly suppressed in septic patients. This is of interest as the balance between proinflammatory and antiinflammatory cytokines is assumed to be of major importance for the sequelae of events in this disease (61, 62). Some moderate increase in IL-10 synthesis was noted in n-6–infused patients, whereas some further reduction in IL-10 formation occurred in response to n-3 lipid infusion regimen. In contrast to the distinct responses of mononuclear cells exposed to the different lipid preparations, a large variation of plasma cytokine levels was noted in septic patients. No significant impact of n-3 or n-6 lipid infusion regimen was detectable. The dissociation of serum cytokines from those secreted by monocytes ex vivo (60) has already been described and is probably caused by multiple confounding effects affecting plasma cytokine levels.

This study with a limited number of patients is clearly insufficient to evaluate impact of the n-3 versus n-6 lipid infusions on the clinical course of sepsis, including the development of organ failure and death. In many experimental models of inflammation (63–65) and in patients with severe ulcerative colitis and acute, extended guttate psoriasis (10, 66), parenteral administration of n-3 lipids, but not n-6 lipids, resulted in impressive dampening of inflammatory events. Moreover, reduction of monocyte proinflammatory cytokine (TNF-{alpha}, IL-1ß, IL-6, IL-8) generation in patients with sepsis under n-3 lipid infusion, in contrast to enhanced synthesis during infusion of n-6 lipids, is compatible with such a notion. However, the role of monocyte function in sepsis is largely unsettled and may even be different in "hyperinflammatory" and "antiinflammatory" periods of this disease (67, 68). Therefore, no speculation as to the overall impact of n-3 lipids on morbidity and mortality of sepsis can be offered. Suppression of hyperinflammatory events is considered as a suitable target in patients with sepsis, an idea underscored by successful treatment in animal models. However, strategies, based on these experimental models using antibodies against TNF-{alpha}, did not improve mortality in large-scale phase III trials (2). The correct timing and dosing of immunosuppression are therefore an ongoing matter of debate.

Independent of any interpretation of the n-3 lipid effects, it is obvious that the conventional n-6–based lipid infusions may not be considered as indifferent energy carriers for parenteral nutrition. Instead, they do exert pharmacologic effects in patients with sepsis by enhancing proinflammatory cytokine synthesis in monocytes facing endotoxin.

In conclusion, dramatically elevated levels of plasma-free fatty acids were noted in septic patients even in the absence of any lipid infusion, with n-6 (arachidonic acid) over n-3 (eicosapentaenoic acid, docosahexaenoic acid) precursor fatty acid predominance. This n-6 predominance was maintained during conventional lipid infusion. It was reversed within 24 to 48 hours to an n-3 over n-6 predominance by intravenous administration of fish oil–based lipids, with rapid incorporation of both eicosapentaenoic acid and docosahexaenoic acid into mononuclear cell membranes being demonstrated. The lipid infusion regimens exerted differential impact on monocyte cytokine synthesis, as investigated by ex vivo endotoxin challenge. Marked enhancement of proinflammatory cytokine generation during n-6 lipid infusion, but suppression of these mediators on administration of the n-3 lipid preparation, was detected. These findings extend the concept of immunonutrition to rapidly effective intravenous lipids: The choice of either n-3 or n-6 lipid infusion may offer the possibility to combine parenteral nutrition to impact immunologic functions in patients with sepsis.


   Acknowledgments
 
The authors thank Dr. R. Snipes for thorough linguistic editing of the manuscript and A. Tschuschner and K. Fietzner for excellent technical assistance.


   FOOTNOTES
 
Supported by Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 547 "Kardiopulmonales Gefäßsystem," Projekt B4.

This article includes portions of the doctoral thesis of Stephanie Gokorsch. Konstantin Mayer is recipient of a Novartis Research Scholarship.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

Received in original form July 9, 2002; accepted in final form February 23, 2003


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
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