Nutrition 28 (2012) Contents lists available at ScienceDirect. Nutrition. journal homepage:

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1 Nutrition 28 (2012) Contents lists available at ScienceDirect Nutrition journal homepage: Applied nutritional investigation Superiority of a fish oil enriched emulsion to medium-chain triacylglycerols/long-chain triacylglycerols in gastrointestinal surgery patients: A randomized clinical trial Jin Wang M.D., Jian-Chun Yu M.D. *, Wei-Ming Kang M.D., Zhi-Qiang Ma M.D. Department of General Surgery, eking Union Medical College Hospital, Chinese Academy of Medical Sciences and eking Union Medical College, Beijing, China article info abstract Article history: Received 27 May 2011 Accepted 15 August 2011 Keywords: Medium-chain triacylglycerols/long-chain triacylglycerols Liver function Inflammation Cytokines Objective: Compared with soybean oil, a fish oil enriched emulsion can improve the clinical outcomes of patients requiring parenteral nutrition. However, the superiority of fish oil emulsion to medium-chain triacylglycerols/long-chain triacylglycerols for short-term administration has seldom been discussed. Methods: Sixty-four adult patients with gastrointestinal diseases were randomly assigned to receive isocaloric and isonitrogenous total parenteral nutrition with an u-3 fatty acid enriched emulsion (Lipoplus; study group, n ¼ 32) or medium-chain triacylglycerols/long-chain triacylglycerols (Lipofundin; control group, n ¼ 32) for 5 d after surgery. Safety and efficacy parameters were assessed on postoperative days 1, 3, and 6. Results: Clinical outcomes including infectious complications and systemic inflammatory response syndrome were comparable between the two groups. Total bilirubin decreased over time in the study group versus an increase in the control group ( ¼ 0.017). Activated partial thromboplastin time in the study group was prolonged significantly compared with the control group from days 1 to 3 ( ¼ 0.002), although the prolongation stopped at the study termination. There were no differences in changes of C-reactive protein, interleukin (IL)-1, IL-8, IL-10, vascular endothelial growth factor (VEGF), and the distribution of the T-cell subpopulation between the two groups. However, fish oil consumption led to an increase in leukotriene B5/ leukotriene B4 and significant decreases in IL-6, tumor necrosis factor-a, and nuclear factor-kb. Furthermore, the overall changes in tumor necrosis factor-a and nuclear factor-kb were positively associated (R 2 ¼ 0.295, < 0.001). Conclusions: Gastrointestinal surgery patients benefited from a fish oil enriched emulsion rather than medium-chain triacylglycerols/long-chain triacylglycerols in the amelioration of liver function and immune status. The positive association of tumor necrosis factor-a and nuclear factor-kb might be involved in the potential anti-inflammation mechanism of fish oil. Ó 2012 Elsevier Inc. All rights reserved. Introduction Gastrointestinal surgery not only exacerbates the postoperative release of multiple inflammatory cytokines, which can lead to organ damage and severe complications [1], but also requires parenteral nutrition (N), which has long been known to cause devastating liver injury presenting as cholestasis [2]. Hence, it is critical to provide surgery patients with an appropriate N regimen that can decrease the excessive inflammatory responses and simultaneously protect liver function. * Corresponding author. Tel.: þ ; fax: þ address: yujch_pumch@163.com (J.-C. Yu)., as a third-generation lipid emulsion, is a rich source of the bioactive long-chain u-3 polyunsaturated fatty acids (UFAs) including eicosapentaenoic acid, docosapentaenoic acid (DA), and docosahexaenoic acid. Compared with u-6 UFAs in soybean oil, u-3 UFAs provide leukotriene (LT) B5, which has less biological activity to compete with the proinflammatory LTB4 against the conversion of linoleic acid to arachidonic acid [3]. Furthermore, u-3 UFAs decrease the release of proinflammatory cytokines, including tumor necrosis factor-a (TNFa), interleukin- (IL) 1 and IL-6, by inhibiting the activation of transcription factors such as nuclear factor-kb (NF-kB) [4]. Several experimental and clinical trials have further demonstrated that a fish oil enriched N regimen can ameliorate infections and reverse N-related cholestasis [5]. Conversely, /$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi: /j.nut

2 624 J. Wang et al. / Nutrition 28 (2012) some other studies have reported the opposite views on the efficacy of u-3 UFAs, with conflicting data [6 8]. Medium-chain triacylglycerol (MCT) is another recently developed emulsion compared with soybean oil and is based on saturated fatty acids with 8- and 10-carbon atoms. Compared with soybean oil, MCT is eliminated faster from the bloodstream by the lipoprotein lipase and less susceptible to lipid peroxidation. Moreover, MCTs have not been found to accumulate in liver or to affect cholesterol [9]. Thus far, the use of fish oil supplementation versus MCT/ long-chain triacylglycerol (LCT) in surgical patients has seldom been discussed. Thus, the safety and efficacy of parenteral emulsions of fish oil and after gastrointestinal surgery were evaluated in this prospective, double-blinded, randomized clinical trial. To understand the possible mechanism of fish oil in modulating inflammatory mediators, the levels of multiple cytokines and NF-kB in monocytes were measured in this study. Materials and methods atients Sixty-four patients with gastrointestinal diseases were recruited consecutively from June 2010 to February 2011 in eking Union Medical College Hospital. Qualified participants were randomly assigned to receive total N (TN) with a fish oil enriched emulsion (Lipoplus; study group, n ¼ 32) or (Lipofundin; control group, n ¼ 32) for 5 d after surgery. Randomization was conducted using a computer-generated randomization scheme. Codes were kept by an independent party. The participants and investigators were blinded to the randomization until all study data had been collected and verified. Included patients were 18 to 85 y old with a perceived need for postoperative nutrition after surgery for at least 5 d. atients with hyperlipemia, diabetes mellitus, pregnancy, hyperthyroidism, hepatic dysfunction, a body mass index lower than 18.5 kg/m 2 or higher than 28 kg/m 2, immunologic deficiency, coagulation disorders, or severe heart or renal disease were excluded from the study at enrollment. Other exclusion criteria were known alcohol or drug abuse, emergency surgery, and additional N or chemotherapy during the 2 wk before the trial. After the intervention, the patients were observed until hospital discharge. The study was in accordance with the principles of the Declaration of Helsinki. Voluntary informed written consents were obtained from all patients. The protocol was approved by the ethics committee of eking Union Medical College Hospital. All the parameters were assessed on postoperative days 1, 3, and 6. Nutritional regimen Lipoplus 20% (Braun Medical, Melsungen, Germany), an emulsion consisting of a mixture of 10% fish oil, 50% MCTs, and 40% soybean oil, was given to the study group; Lipofundin 20% (Braun Medical), a mixture of MCTs and soybean oil (50%:50%), was given to the control group. The emulsions contained similar amounts of phospholipids and other components but differed by a larger docosahexaenoic acid and eicosapentaenoic acid content in the fish oil product (2.3% and 2.6%, respectively). TN was started on the first day after surgery and ended on the morning of the sixth day. Both regimens were isonitrogenous and isocaloric, delivering 0.2 g of nitrogen, 3.0 g of glucose, and 0.8 g of lipid per kilogram of body weight as a daily dose from postoperative days 2 to 5; half the dose was given on the first day. Vitamins and electrolytes were added as required. All TN components were produced in 3-L bags under sterile conditions. Laboratory examination All patients had routine biochemistry and hematology determinations. Vital signs and adverse events were recorded every 4 h during the study period. N was allowed up to 6 h before the phlebotomy. Biochemical data collected included plasma levels of alanine and aspartate aminotransferases, g-glutamyl transferase, total bilirubin (TBIL), direct bilirubin, total triacylglycerols, total cholesterol, low-density lipoprotein, and high-density lipoprotein. Because the inhibition of coagulation is an established possible side effect of fish oil, the platelet count, activated partial thromboplastin time (ATT), prothrombin time, and bleeding events were recorded. Flow cytometry (Beckman-Coulter, Miami, FL, USA) was used to determine the proportions of CD4 þ cells, CD8 þ cells, and the CD4/CD8 ratio in peripheral blood. Measurements of inflammatory parameters Venous blood samples mixed with the anticoagulant ethylenediaminetetraacetic acid were collected for plasma inflammatory biomarker analysis. lasma was isolated by centrifugation at 1500 g for 15 min and then stored at 80 C before analysis. Immunoturbidimetry (IMMAGE 800, Beckman-Coulter) was used to measure the concentration of C-reactive protein. The amounts of LTB4 and LTB5 were measured using enzyme-linked immunosorbent assay kits (Cayman Chemical, Ann Arbor, MI, USA); Multiple plasma inflammatory cytokines, including IL-1b, IL-4, IL-6, IL-8, IL-10, TNF-a, interferon-g, and vascular endothelial growth factor (VEGF), were analyzed by a Bio-lex 200 System (Bio-Rad, Hercules, CA, USA) using the Fluorokine MA human inflammation multiplex kit (R&D, Minneapolis, MN, USA). Monocytes in peripheral blood were prepared as described previously [10]. The active form of NF-kB in monocytes was measured using an NF-kB p65 enzyme-linked immunosorbent assay kit (Invitrogen, Carlsbad, CA, USA). Standard curves were constructed for each analyte. Statistical analysis All statistical analyses and graphics were performed with SSS 13.0 (SSS, Inc., Chicago, IL, USA). For continuous variables, the data were expressed as mean standard deviation. The independent-samples t test was used to compare the means of these variables, and the chi-square test was used for categorical variables between two categories. Stepwise linear regression analysis was applied to investigate the relations between the changes of multiple inflammatory cytokines and NF-kB. < 0.05 was accepted as statistically significant. Results Clinical outcomes of the patients At baseline, defined as the day before surgery, the two groups were comparable in demographics, laboratory values, and immune status (Table 1). One patient with hepatitis C in the control group was excluded from the study owing to severe liver dysfunction after surgery. The remaining 63 patients completed the trial. There were 22 patients with gastric cancer (11 in control group, 11 in study group), 29 patients with colonic cancer (16 in control group, 13 in study group), and 13 patients with other Table 1 Characteristics of patients at baseline Characteristics Demographics Age (y) Male:female 21:11 18: BMI (kg/m 2 ) Laboratory values ALT (U/L) AST (U/L) GGT (U/L) TBIL (mmol/l) DBIL (mmol/l) TG (mmol/l) TC (mmol/l) LDL (mmol/l) HDL (mmol/l) Glucose (mmol/l) T (s) ATT (s) LT (10 9 /L) Immune status CD4 (%) CD8 (%) CD4/CD ALT, alanine aminotransferase; ATT, activated partial thromboplastin time; AST, aspartate aminotransferase; BMI, body mass index; DBIL, direct bilirubin; GGT, g-glutamyl transferase; HDL, high-density lipoprotein; LCT, long-chain triacylglycerols; LDL, low-density lipoprotein; MCT, medium-chain triacylglycerols; LT, platelet count; T, prothrombin time; TBIL, total bilirubin; TC, total cholesterol; TG, total triacylglycerols

3 J. Wang et al. / Nutrition 28 (2012) Table 2 Changes of laboratory variables from days 1 to 3 and days 1 to 6 in patients receiving different emulsions Variables Days 1 3 Days 1 6 Biochemistry ALT (U/L) AST (U/L) GGT (U/L) TBIL (mmol/l) DBIL (mmol/l) TG (mmol/l) TC (mmol/l) LDL (mmol/l) HDL (mmol/l) Coagulation T (s) ATT (s) LT (10 9 /L) Immune status CD4 (%) CD8 (%) CD4/CD ALT, alanine aminotransferase; ATT, activated partial thromboplastin time; AST, aspartate aminotransferase; DBIL, direct bilirubin; GGT, g-glutamyl transferase; HDL, high-density lipoprotein; LCT, long-chain triacylglycerols; LDL, low-density lipoprotein; MCT, medium-chain triacylglycerols; LT, platelet count; T, prothrombin time; TBIL, total bilirubin; TC, total cholesterol; TG, total triacylglycerols digestive diseases (5 in control group, 8 in study group). There was no difference between the groups in the distribution of diseases ( ¼ 0.606). No bleeding event was observed in either group during the intervention period. Infectious complications (two wound infections, three urologic infections, one respiratory tract infection, one intestinal infection) were observed in four patients in the control group and three patients in the study group, without significant differences ( ¼ 0.641). TN supplemented with fish oil decreased the incidence of systemic inflammatory response syndrome (1 of 32) compared with the control group (4 of 31), but no significance was observed ( ¼ 0.162). There were no serious adverse events in either group. Laboratory parameters of the patients Table 2 presents the changes of laboratory parameters in the two groups from days 1 to 3 and days 1 to 6. There was no difference in the change of TBIL between the two groups at days 1to3( ¼ 0.967). In contrast, TBIL in the study group decreased ( mmol/l) significantly at study termination, in contrast to an increase ( mmol/l) in the control group ( ¼ 0.017), as shown in Figure 1A. The ATT in the study group was significantly prolonged at days 1 to 3 compared with the control group ( versus s, ¼ 0.002). However, the prolongation reversed during the subsequent 3 d, and the changes of ATT were similar between the two groups at study termination ( versus s, ¼ 0.163), implicating a potential anticoagulant effect of fish oil during the earlier postoperative period (Fig. 1B). After 5 d of TN treatment, the distribution of CD4 cells increased slightly in the two groups with a simultaneous decrease in the CD8 percentage, which led to relative increases in the CD4/CD8 ratio. However, there was no difference in the changes of the CD4/CD8 ratio between the control and study groups ( versus , ¼ 0.299) at study Fig. 1. Significant changes of laboratory parameters at days 1 to 3 and days 1 to 6. (A) decreased TBIL significantly compared with the control group at study termination ( * ¼ 0.017). No difference in its changes was observed from days 1 to 3. (B) prolonged AT significantly compared with the control group ( * ¼ 0.002) from days 1 to 3, but the prolongation was similar at study termination ( * ¼ 0.163). Dashed lines, control group; solid lines, intervention group; whiskers designate standard deviation. ATT, activated partial thromboplastin time; d, change; TBIL, total bilirubin.

4 626 J. Wang et al. / Nutrition 28 (2012) termination. There was no significant difference observed in the other laboratory variables. Inflammatory biomarkers of the patients The values of IL-4 and INF-g were below the display range of the multiple cytokine kit. The trends over time of inflammatory biomarkers during the 5 d are depicted in Figure 2. LTB5/LTB4 in the study group increased over time and decreased in the control group (Fig. 2A). C-reactive protein and TNF-a increased with time, reaching plateaus on day 3 in both groups, and then decreased during the next 3 d (Fig. 2B,C). In addition, the concentration of TNF-a (nanograms per liter) in the study group was higher than that in the control group ( versus , ¼ 0.026) on day 1. IL-1, IL-6, IL-10, and VEGF decreased continuously in both groups from days 1 to 6 (Fig. 2D G). In contrast, the values of VEGF (nanograms per liter) in the study group were lower than those in the control group on day 1 ( versus , ¼ 0.029) and day 3 ( versus , ¼ 0.049). IL-8 decreased slightly in the study group but increased in the control group from days 1 to 6 (Fig. 2H). No significant differences were found in the other inflammatory markers between the two groups on days 1, 3, and 6. Fig. 2. Trends over time of inflammatory biomarkers during the 5 d study. (A) LTB5/LTB4 in the study group increased over time but decreased in the control group. (B, C) CR and TNF-a increased with time, reaching plateaus on day 3 in both groups, and then reversed during the next 3 d. The concentration of TNF-a in the study group was higher than that in the control group on day 1 (* ¼ 0.026). (D G) IL-1, IL-6, IL-10, and VEGF decreased continuously in both groups from days 1 to 6. Values of VEGF (nanograms per liter) in the study group were lower than those in the control group on day 1 ( * ¼ 0.029) and day 3 ( * ¼ 0.049). (H) IL-8 in the study group decreased slightly but increased in the control group. Dashed lines, control group; solid lines, intervention group; whiskers designate standard deviation. CR, C-reactive protein; IL, interleukin; LT, leukotriene; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor.

5 J. Wang et al. / Nutrition 28 (2012) Table 3 Changes of inflammatory parameters from days 1 to 3 and from days 1 to 6 in patients receiving different emulsions Variables Days 1 3 Days 1 6 CR (mg/l) LTB5/LTB IL-1b (ng/l) IL-6 (ng/l) IL-8 (ng/l) IL-10 (ng/l) TNF-a (ng/l) VEGF (ng/l) NF-kB (ng/l) CR, C-reactive protein; IL, interleukin; LCT, long-chain triacylglycerols; MCT, medium-chain triacylglycerols; NF, nuclear factor; TNF, tumor necrosis factor; VEGF, vascular endothelial growth factor The changes in inflammatory parameters in the two groups from days 1 to 3 and days 1 to 6 are presented in Table 3. From days 1 to 3, IL-6 in the study group decreased more than that in the control group ( ¼ 0.005); the increase of NF-kB in the study group was less than that in the control group ( ¼ 0.003). At study termination, fish oil consumption decreased IL-6 and significantly attenuated the increases in LTB5/LTB4, TNF-a, and NF-kB. There was no significant difference in the changes of the other biomarkers between the two groups. Figure 3 shows the changes of biomarkers, with significance between the two groups. Moreover, the overall changes in TNF-a ( ng/l) and NF-kB ( ng/l) were positively associated (R 2 ¼ 0.295, < 0.001), as shown in Figure 4. No correlation was found between NF-kB and the other inflammatory cytokines. Fig. 3. Significant changes in inflammatory parameters at days 1 to 3 and days 1 to 6. (A) LTB5/LTB4 in the study group was higher than in the control group at days 1 to 6 ( * ¼ 0.047). (B) The decreases of IL-6 in the fish oil group were greater than those in in the control group at days 1 to 3 ( * ¼ 0.005) and days 1 to 6 ( * ¼ 0.034). (C) The increase of TNF-a in the fish oil group was less than that in the control group ( * ¼ 0.017) at days 1 to 6. (D) The increase of NF-kB in the fish oil group was lower than that in the control group ( * ¼ 0.022) at study termination. Dashed lines, control group; solid lines, intervention group; whiskers designate standard deviation. d, change; IL, interleukin; LT, leukotriene; NF, nuclear factor; TNF, tumor necrosis factor.

6 628 J. Wang et al. / Nutrition 28 (2012) Fig. 4. The regression line of the changes (d) of TNF-a and NF-kB at study termination. The overall change of TNF-a (ng/l) was associated with that of NF-kB (ng/l) significantly (n ¼ 63, R square ¼ 0.295, < 0.001). d, change; NF, nuclear factor; TNF, tumor necrosis factor. Discussion Credible clinical and experimental data have supported the benefits from fish oil in the treatment and prevention of Nassociated cholestasis for long-term administration [11,12]. However, to our knowledge, there are few trials reporting the superiority of fish oil over the used for short-term administration in protecting liver function. In the present study, fish oil significantly decreased TBIL, whereas TBIL increased in the control group. Although the difference in the changes of direct bilirubin, an important indicator of cholestasis. between the two groups showed only borderline statistical significance ( ¼ 0.082), its decrease in the fish oil group ( mmol/l) was still greater in the control group ( mmol/l). Interestingly, fish oil prolonged the ATT significantly during the first 2 d, although the prolongation reversed during the subsequent 3 d without any bleeding events in either group. This phenomenon was consistent with the research by Heller et al. [13] who found that the coagulation activity in patients receiving TN with fish oil (Omegaven Fresenius Kabi, Bad Homburg, Germany) decreased significantly after major abdominal surgery but returned to physiologic levels after 6 d. In light of these findings, it is advisable to be prudent when infusing a fish oil enriched parenteral emulsion in patients with coagulation disorders, especially during the earlier postoperative period. revious studies have shown significant decreases in T- lymphocyte and CD4 numbers during stressed conditions [14]. Chiu et al. [15] also indicated that sepsis resulted in a lower CD4 percentage and that fish oil supplementation helped maintain the systemic T-helper cell percentage and the CD4/CD8 ratio. Similarly, Jiang et al. [16] reported that the infusion of fish oil significantly increased the CD4/CD8 ratio during the postoperative period compared with soybean oil. In our study, after 5 d of TN treatment, the distribution of CD4 cells increased slightly with the simultaneous decrease in the CD8 percentage, which led to relative increases in the CD4/CD8 ratio in both groups. However, no differences in the changes of the percentages of CD4 and CD8 and the CD4/CD8 ratio were observed between the two groups, indicating that fish oil and emulsions may be equally effective in modulating the T-cell subpopulation distribution for short-term application. Compared with soybean oil, mixed has been confirmed to improve immunologic function and decrease postoperative complications [17]. Thus, the expected superiority of fish oil in modifying the T-cell subpopulation may not have been detected because the itself had fewer immunologic side effects. atients undergoing major abdominal surgery often develop metabolic stress. The production of proinflammatory cytokines, such as IL-1, TNF-a [14], and other reactive compounds including LTB4, may greatly increase [5]. Wichmann et al. [18] found that the anti-inflammatory cytokine LTB5 was elevated in patients receiving a fish oil containing lipid emulsion, in addition to an increased LTB5/LTB4 ratio. The generation of TNF-a and IL-6 has been identified to be decreased during fish oil infusion in septic patients [19] or even in healthy volunteers [20]. Because the suspension array system has allowed highthroughput analysis, our series is the largest documented analysis of inflammatory biomarkers in surgical patients receiving different regimens of lipid emulsions. As a result, we observed no difference in the changes of C-reactive protein, IL-1, IL-8, IL-10, and VEGF between the two groups. However, fish oil decreased IL-6 significantly over time. In addition, fish oil consumption led to an increase of LTB5/LTB4, which is a critical anti-inflammatory indicator. Although TNF-a and NF-kB in the two groups increased continuously over time from days 1 to 6, the increases were attenuated significantly by the supplementation of the fish oil emulsion. Furthermore, the overall changes in TNF-a and NF-kB were related positively by an analysis of stepwise liner regression. Therefore, it is reasonable to speculate that fish oil might inhibit the release of inflammatory mediators by sustaining the activity of NF-kB, which has been not documented, to our knowledge, in previous clinical trials. The NF-kB system is a prominent mechanism responding to different external and internal cellular danger signals, such as oxidative stress and immune activation [21]. Various proinflammatory cytokines, including TNF-a, have been reported to cause the phosphorylation of p65 and subsequently induce NFkB activation [22]. Conversely, more recent studies have shown that the release of various proinflammatory cytokines is regulated by NF-kB [23]. However, these two hypotheses could explain the positive association of TNF-a and NF-kB in our study. There are some limitations in our study that merit consideration. A relatively small sample decreased the accuracy of the study, which directly affected the evaluation of the efficacy of the fish oil supplementation. In addition, the duration of the intervention may have been too short to modulate the T-cell subpopulation and reverse cholestasis. However, because the incorporation of u-3-ufas into the leukocyte membranes can be detected within 2 d of infusion [24], the anti-inflammatory effect of the fish oil could be expected during the 5 d. In conclusion, the use of a N emulsion containing 10% fish oil after gastrointestinal surgery was safe and well tolerated. The

7 J. Wang et al. / Nutrition 28 (2012) efficacy of fish oil in restoring liver function was observed even during the short-term administration. In light of the transient prolongation of ATT in the study group, it is advisable to be prudent when supplementing fish oil to patients with coagulation disorders, especially during the earlier postoperative period. Compared with the emulsion, the fish oil enriched emulsion was superior in modulating the excessive inflammatory response by inhibiting the release of multiple proinflammatory biomarkers. In addition, the mechanisms underlying the immune benefits from the u-3 fatty acid are likely caused by the suppressed activation of NF-kB in monocytes. However, given the limited understanding on the divergent mechanisms of anti-inflammation by fish oil, an explanation for the phenomenon is, at best, speculative. References [1] uiggros C, Chacon, Armadans LI, Clapes J, lanas M. 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