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The Effects of Immediate Enteral Feeding With a Formula Containing High Levels of [Omega]-3 Fatty Acids in Patients After Surgery for Esophageal Cancer

Posted on: Saturday, 7 May 2005, 03:00 CDT

ABSTRACT. Background: We investigated whether supplementation of enteral nutrition (EN) with ω-3 polyunsaturated acids (PUFAs) affected platelet aggregation, coagulation activity, and inflammatory response in the early stages after esophageal cancer surgery. Methods: Twenty-eight patients with esophageal cancer who underwent the same surgical procedure were selected for this study. All patients received EN, which was started immediately after the operation and was increased to a maximum volume of 1500 ml/day by the third postoperative day (POD). Eleven patients received a conventional EN formula (Ensure Liquid), while the remaining 17 patients received a different formula rich in ω-3 PUFAs (Racol [RAC]). Several markers of coagulation and fibrinolysis were determined in POD 2, while the concentrations of interleukin (IL)- G, IL-8, 6-keto-PGF1α and thromboxane B2 were determined on PODs 1, 3, and 5. Results: A total of 27 patients completed the study, 11 in the Ensure Liquid group and 16 in the RAC group. Administration of RAC significantly inhibited the postoperative decrease in platelet count. The level of D-dimer was attenuated significantly in the RAC group. Plasma IL-8 levels were decreased significantly in the RAC group on PODs 1 and 3. The anti- inflammatory effects of ω-3 PUFAs were confirmed by the clinical findings of lower body temperature. The plasma concentration of 6-keto-PFG1α also tended to decrease in the RAC group with a significant difference on POD 5. Conclusions: Early EN with a large amount of ω-3 PUFAs in reduced platelet aggregation, coagulation activity, and cytokine production. All these effects would be expected to be beneficial in patients following esophageal cancer surgery. The clinical significance of the changes in eicosanoid production remains to be established. (Journal of Parenteral and Enteral Nutrition 29:141-147, 2005)

We have reported previously that immediate enteral nutrition (EN) improved immunologie competence and suppressed excessive inflammatory responses in patients after esophageal cancer surgery.1 According to these findings, we consider that patients who have had radical esophageal surgery and been subjected to severe surgical stress may gain the most benefit from early enteral feeding. After this initial randomized, controlled trial, immediate EN was selected as the standard method in our department for postoperative nutrition support in patients with esophageal cancer. In 2000, we introduced an advanced schedule of immediate EN in which administration of EN was started earlier and at a faster rate than before (Table I). Subsequently, we changed the enterai formula from one containing a majority of ω-6 fatty acids and small amounts of ω-3 fatty acids to a formula containing a considerably greater proportion of ω-3 fatty acids.

Several studies have shown dietary supplementation with ω-3 polyunsaturated fatty acids (PUFAs) alters the composition of cell membranes and subsequent production of eicosanoids and cytokines.2,3 Specifically, ω-3 PUFAs increase the production of prostaglandins (PGs) of the 3-series and leukotrienes of the 5- series, and decrease production of 2-series PGs (PGE2) and 4-series leukotrienes. These changes in eicosanoid synthesis are associated with improved immunocompetence and a reduced inflammatory response to injury.4 Supplementation with ω-3 PUFAs in normal subjects results in increased bleeding times and reduced collagen-induced platelet aggregation.5-7 It appears this decrease in platelet aggregation occurs as a consequence of arachidonic acid (AA) being substituted by eicosapentaenoic acid (EPA), a change that leads to a reduction in the synthesis of thromboxane (TX) A2 and increased production of the antiaggregatory substance TXA3.8 There is also evidence from several studies that dietary supplementation with ω-3 PUFAs appears to depress prostacyclin (PGI2) and thromboxane (TXA2) synthesis.9-11 However, little is known on the effects of ω-3 PUFAs on human eicosanoid biosynthesis during severe surgical stress.

The effects of ω-3 PUFAs on coagulation activity also remain controversial, with 1 intervention study reporting reduced factor VIII activity with ω-3 supplements, whereas other extensive investigations of the coagulation system after fish-oil ingestion were unable to demonstrate any significant changes.13,14 Similarly, there is no consensus on whether plasma fibrinogen levels are altered after provision of ω-3 supplements.15 We therefore carried out a retrospective investigation to determine whether supplementation of EN with ω-3 PUFAs in patients after radical surgery for esophageal cancer affected platelet aggregation, coagulation activities, the inflammatory response, and whole-body production of PGI2 and TXA2.

TABLE I

Advancement schedules of enteral feeding

MATERIALS AND METHODS

Sixty-seven patients with esophageal carcinoma underwent curative surgical intervention at the National Defense Medical College between July 2000 and June 2003. From these patients, those who underwent laparotomy, right thoracotomy, and an intrathoracic or cervical esophagogastrostomy were selected for the study in order to equalize the degree of surgical invasion. Patients treated with chemotherapy or radiotherapy before surgery or with a ligated or resected thoracic duct were excluded from the study. Other exclusion criteria included long-term fasting because of esophageal obstruction, the presence of insulin-dependent diabetes mellitus, severe renal or hepatic diseases, or the previous use of corticosteroid or immunosuppressive medications. Twenty-eight patients met the eligibility criteria for the study. Fully informed consent was obtained from the patients before the study, which was carried out in accordance with the ethical standards of the 1975 Helsinki Declaration.

All patients received enterai feeding after the same advancement schedule outlined in Table I. Briefly, EN was started at an infusion rate of 20 mL/h within 2 hours of the patient being transferred to the ICU, followed by progression to a maximum volume of 1500 mL/d by the third postoperative day (POD). Eleven patients received a conventional enterai feeding formula (EL [Ensure Liquid]; Abbot, Tokyo, Japan) that contained corn-oil lipid with a ω-6 to ω-3 ratio of 44 (Table II). From August 2001, a different enterai feeding formula (RAC [Racol] ; Otsuka Pharmaceutical, Tokyo, Japan), was administered to the remaining 17 patients, with this formulation containing perilla, soybean, palm and corn oils as the source of the lipids with a ω-6 to ω-3 ratio of 3 (Table II). All 28 patients received continuous infusion of a parenteral mixture (Aminotripa; Otsuka) through a central venous catheter from PODl.

Surgical Procedures

If an intrathoracic anastomosis was possible, a laparotomy for preparation of the stomach as a substitute organ and an abdominal lymphadenectomy was performed before a right posterolateral thoracotomy for esophagectomy, regional lymphadenectomy, and esophagogastrostomy. If an intrathoracic anastomosis was not indicated because of location of the tumor, a right thoracotomy was followed by laparotomy and a cervical anastomosis. Bilateral cervical lymphadenectomy was performed simultaneously with the abdominal procedure if indicated. To obtain enterai access, a jejunostomy tube, constructed using the Witzel technique, was placed intraoperatively in the proximal jejunum. After surgery, all patients were given mechanical respiratory support for several hours or overnight. Epidural catheters were placed for administration of postoperative analgesia. Routine antibiotic prophylaxis with a second-generation cephalosporin or penicillin was administered. Heparin was not used in any patients during and after surgery.

Laboratory Parameters

Laboratory investigations that included a complete blood count were performed preoperatively, and again daily from PODs 1-7. A comparison of mean platelet count between the 2 groups was carried out, with patients who had undergone splenectomy being excluded from this analysis. Serum iron was measured preoperatively and on PODs 1, 2, and 5. Coagulation activity was assessed on POD 2 by determining the plasma concentration of fibrinogen, fibrin/fibrinogen degradation products (FDP), D-dimer, thrombin-antithrombin III complex (TAT) and α2 plasmin inhibitor-plasmin complex (PIC). Additional plasma samples were taken on PODs 1, 3, and 5 and stored at -70C for later assay. The plasma concentrations of interleukin 6 (IL-6) and interleukin 8 (IL-8) were determined by ELISA immunoassay using Quantikine human IL-6 and IL-8 ELISA Kits (R&D Systems, MN). Plasma PGI2, detected as the stable metabolite 6-keto-PGF1α, and TXA2, detected as the stable metabolite TXB2, were also measured on the stored plasma samples by enzyme immunoassay (Amersham Biosciences Corp, NJ).

TABLE II

Composition of the diets (per 100 mL)

Statistical Analyses

The data are expressed as mean SEM. Comparisons were made using the unpaired and paired Student's t tests and the χ^sup 2^ test. Resu\lts were considered statistically significant at a p value < .05.

RESULTS

Twenty-seven patients completed at least 7 days of enterai feeding and therefore were entered into the study. Eleven patients were given Ensure liquid [EL group], and 16 patients were given Racol [RAC group]. One patient who received the Racol formula was withdrawn from the study because of abdominal distention on POD5.

There was no significant difference in the means of age, body surface area, operative duration, or blood loss between the EL and RAC groups (Table III). Serum levels of total protein, albumin, and total cholesterol, chosen as markers of preoperative nutritional status, were similar in the 2 groups (Table III). The frequency of 3- field lymph-node dissection and the pathologic stage of the esophageal cancer were also similar in the 2 groups (Table III). Although there was no difference in daily caloric intake between the groups, there was a significant difference in enterai caloric intake on POD 3 (Fig. 1).

As 2 patients in the EL group and 1 patient in the RAC group had a splenectomy, platelet counts were compared between the remaining 9 and 15 patients in these groups, respectively. Platelet counts decreased in the early PODs, especially in the EL group, with significant differences being found between the groups on PODs 2, 3, and 4 (Fig. 2). Among the coagulation parameters determined on POD2, the levels of FDP in the EL group, and fibrinogen, D-dimer, TAT, and PIC in both groups were above the normal limit. A significant intergroup difference was found in D-dimer levels (Table IV).

TABLE III

A comparison of the clinical and surgical characteristics and preoperative nutritional status of the 2 groups

FIG. 1. Comparison of daily caloric intake administered parenterally and enterally. Total calories are divided into parenteral (dark bars) and enterai feeding (light bars). The left- hand bar for each POD represents the EL group and the right-hand bar the RAC group. The error bars represent the SEM of the total caloric intake; * signifies p < .05.

Although plasma IL-6 levels were similar in both groups, the levels of IL-8 were significantly reduced in the RAC group on PODs 1 and 3 (Fig. 3). There was no significant difference in leukocyte counts until POD 7 in the 2 groups, whereas serum iron levels were significantly lower in the EL group on POD 1 (Fig. 4).

Body temperature was measured every 2 hours in the early postoperative periods. Maximum body temperature on each POD was higher in the EL group than in the RAC group, with this difference being significant on PODs 2 and 3 (Fig. 5). There was also a significant difference between the 2 groups on PODs 2 and 3 in the total number of hours that the patients had a fever >38C (Fig. 5).

FIG. 2. Mean values of platelet counts in the EL (open circles) and RAC (closed circles) groups. The error bars represent the SEM; * signifies p < .05 and ** signifies p < .005.

TABLE IV

Coagulation parameters on POD2

In the RAC group, the plasma concentration of 6keto-PGF1α tended to decrease from POD 3. The difference between the 2 groups, although not significant on POD 3 (p = .06), became highly significant by POD 5 (p = .005). In contrast, TXB2 levels showed no significant difference between the groups throughout the study period (Fig. 6).

DISCUSSION

Platelet counts decrease during major surgery partly because of a loss of blood and infusion of stored, packed erythrocytes or plasma products. In addition, the pulmonary entrapment of platelets16 and platelet consumption around traumatized tissue play major roles in the decrease in platelet numbers. It is also possible that platelet aggregability, known to be activated in the early postoperative period, may be a cause of the early decrease in platelet count. DeCaterina et al17 demonstrated that patients accepted for coronary bypass surgery and provided with supplements of EPA and docosahexaenoic acid during the 4-week preoperative period had a significant increase in bleeding time and a reduction in collagen- induced platelet aggregation. However, in a similar clinical study, Nilsen et al18 were unable to demonstrate any significant effect of ω-3 PUFAs on postoperative bleeding time or platelet aggregability. Another study on platelet aggregation in surgical patients with either cancer or coronary artery disease19 revealed that supplementation for 1 week with Impact (Novartis Nutrition, Minneapolis, MN), a formula containing arginine, nucleotides, and fish oil, also did not alter platelet function. This report emphasized that clinicians should be aware of the possibility that both dose- and time-related effects of fish oil may be important causes of the adverse effects that occur in platelet function after surgery. In contrast to the present study, none of these earlier investigations showed that ω-3 PUFAs had a significant effect on platelet count. Our study, therefore, is the first to demonstrate that ω-3 PUFAs inhibit the reduction in platelet count that occurs in the early postoperative period. A similar clinical study has been carried out with the aim of determining whether supplementation of parenteral nutrition with fish oil affects platelet count and function postoperatively in patients with carcinoma of the gastrointestinal tract or pancreas.20 In these clinical settings, platelet counts decreased during surgery but returned to baseline values by POD 4, with the fish oil appearing to affect neither platelet count nor function. In our study, it is possible that the source of ω-3 PUFAs, especially perilla oil, had a more potent inhibitory effect on platelet aggregation than fish oil, or alternatively that some other component in each of the EN formulations influenced the results. Notwithstanding these possibilities, it is important to note that we observed significant differences in platelet counts in our study that may relate to the excessive and invariable surgical stress associated with surgery for esophageal cancer.

FIG. 3. Mean values of IL-6 and IL-8 levels in the EL (open circles) and RAC (closed circles) groups. The error bars represent the SEM; * signifies p < .05.

FIG. 4. Mean values of leukocyte count (above) and serum iron levels (below) in the EL (open circles) and RAC (closed circles) groups. The error bars represent the SEM; * signifies p < .05.

FIG. 5. Mean values of maximum body temperature (above) and the period of time that the patients had a temperature >38C (below) in the EL (open circles) and RAC (closed circles) groups. The error bars represent the SEM; * signifies p < .05 and ** signifies p < .01.

Recent studies have shown that increased levels of D-dimer predict the occurrence of deep-vein thrombosis after elective hip surgery21 and also the recurrence of venous thromboembolism after discontinuation of oral anticoagulant therapy.22 These high D-dimer levels indicate increased turnover of cross-linked fibrin and signify a hypercoagulable state and are therefore a marker of a prothrombotic condition. In the postoperative period, inflammatory processes caused by surgery or underlying disease may lead to a marked increase in plasma D-dimer concentrations.23 Our study demonstrated that although administration of ω-3 PUFAs may have reduced the hypercoagulable state associated with postoperative inflammatory processes, other coagulation and fibrinolytic parameters, such as FDP, TAT, and PIC, were similar in the 2 groups. Moreover, it appeared likely that primary fibrinolysis occurred during the early postoperative stages, up to POD 3, as during this time there was a smaller increase in formation of D-dimers than during the later period when the secondary fibrinolysis occurred. In order to prove whether ω-3 PUFAs inhibit the postoperative hypercoagulable state, serial measurements of a range of coagulation and fibrinolytic parameters are therefore required.

We observed that the plasma concentration of 6keto-PGF1α appeared to be affected by the fatty acid compound in each enterai feeding formula, whereas the concentration of TXB2 varied widely and was not affected by the type of fatty acid. An experimental study in anesthetized sheep demonstrated that infusion of lipopolysaccharide caused a marked elevation in the arterial plasma levels of TXB2 but not 6-ketoPGF1α.24 From these findings, we assume that postoperative infection may have markedly affected plasma TXA2 levels in our patients. A recent clinical study in patients with acute respiratory distress syndrome (ARDS)25 reported that increased plasma levels of PGI2, derived from high intake of linoleic acid, worsened oxygnation while increasing pulmonary shunts. Vasodilators such as PGI2 may affect gas exchange by increasing pulmonary blood flow or by decreasing pulmonary vascular tone, both mechanisms resulting in increased perfusion of unventilated lung units. Endogenous synthesis of PGI2 is facilitated by infusion of standard fat emulsions, leading to unblocking of hypoxic pulmonary vasoconstriction that is critical to be maintained in ARDS patients. However, it remains to be established whether increased plasma concentrations of PGI2 cause deterioration in pulmonary oxygenation in patients after highly invasive surgery.

We observed that EN containing large amounts of ω-3 PUFAs caused a marked inhibition of IL-8 production in the early postoperative period. After traumatic injury or endotoxemia, the plasma levels of several proinflammatory cytokines, including IL-8, become significantly elevated.26,27 It is possible that this elevation in plasma IL-8 levels acts as a biologic timer for the recruitment of neutrophils to the inflammatory loci. A recent clinical trial in patients with sepsis28 reported some very interesting results on the different effects that ω-3 and ω-6 lipid preparations had on mononuclear cytokine generation provoked by an ex vivo endotoxin chall\enge. During ω-6 lipid infusion, an increase in tumor necrosis factor-α (TNF-α), IL-1β, IL-6, and IL-8 synthesis was detected consistently in the total mononuclear leukocyte cell fraction and also in isolated monocytes. In contrast, intravenous administration of ω-3 lipids resulted in reduced generation of these proinflammatory cytokines. This reduction reached a maximum 24 hours after infusion of the lipids, a finding consistent with the results of our study that showed a significant difference in plasma IL-8 levels between the 2 groups on PODs 1 and 3. In fact, the volume of each enterai formula administered until the morning of POD 1 was >300 mL in most cases. This volume was sufficient to cause a significant difference in plasma IL-8 levels but not platelet counts between the 2 groups.

FIG. 6. Mean values of plasma 6-keto-PGFla and TXB2 levels in the EL (open circles) and RAC (closed circles) groups. The error bars represent the SEM; * signifies p < .01.

The mechanisms underlying the differential effects of ω-6 and ω-3 lipids on cytokine synthesis are currently unknown. Until recently, the attenuated inflammatory response after ingestion of ω-3 PUFAs was attributed mainly to reduced production of the eicosanoids PGE2 and leukotriene B4 by leukocytes. Inflammatory agonists stimulate synthesis of eicosanoids by enhancing the release of AA from the intracellular phospholipid pool, a process that is mediated by activation of phospholipases.29 Several studies have demonstrated there is a close relationship between the release and metabolism of AA and the generation of platelet activating factor (PAF).30,31 PAF is known to have a wide range of pro-inflammatory properties including increased chemotaxis,32 adherence, and aggregation33,34 of human neutrophils, and monocytes. PAF also induces these cells and macrophages to produce cytokines such as TNF- α, IL-6, and IL-8.35-37

Recent experimental data suggest that fish-oil-based lipids have an inhibitory effect on endotoxin-induced signal transduction that results in generation of inflammatory cytokines.38 Preincubation of a murine macrophage cell line with EPA was shown to cause reductions in endotoxin-stimulated nuclear factor-κB activation, subsequent TNF-α gene transcription, and release of TNF-α release. There is also evidence that mice fed a fish-oil-enriched diet have a reduced rate of endotoxin-induced pro-IL-1 mRNA transcription.39

Levels of serum iron decrease as a part of the acute phase response,40,41 as the release of cytokines leads to iron uptake by activated macrophages.4 Cytokines (IL-1, IL-6) are also directly involved in increased ferritin synthesis, which is under translational control.43,44 An increase in the ferritin content of hepatocytes results in enhanced iron storage capacity and retention in the liver and therefore may afford a protective response during the acute phase response.45 Goldblum et al46 suggested another mechanism of hypoferremia: that the stress-induced elevation of IL- 1 causes release of the iron-binding protein, lactoferrin from granulocytes into the circulation. The lactoferrin molecule chelates iron from transferrin and serves as the carrier protein for removal of iron from the intravascular compartment. Although there was no significant difference in leukocyte counts between the 2 groups in this study, a significant inhibition of postoperative hypoferremia was seen in the RAC group on POD 1. This result provides further support for our finding of a significant difference in plasma IL-8 levels between the 2 groups in the early postoperative period. The antiinflammatory effects of EN containing large amounts of ω-3 PUFAs were also indicated by the clinical findings that there was a significant reduction in body temperature after surgery and also a decrease in the duration of fever in a number of the patients. Several endogenous pyrogens have been identified, including the proinflammatory cytokines IL-1α, IL-1β, TNF-α, and IL- 6.47 These proinflammatory cytokines induce cyclooxygenase-2,48 which metabolizes AA and provides PGE2. Regardless of the source of pyrogens, PGE2 is considered a key fever mediator in the brain, and the agent ultimately is responsible for the upward shift in thermoregulation.49 Several studies in humans50-52 have demonstrated that dietary supplementation with ω-3 PUFAs as fish oil is associated with decreases in PGE2 production. Although it is not proved in this study that the ingestion of ω-3 PUFAs resulted in decreases in PGE2 production, it is at least a significant finding that the antipyretic effect of ω-3 PUFAs was potent and persistent in the early period after the esophageal cancer surgery.

CONCLUSIONS

This study showed that early enteral feeding of patients undergoing esophageal cancer surgery with a formula containing large amounts of ω-3 PUFAs had an inhibitory effect on the postoperative decrease in circulating platelet numbers, hypercoagulability, and IL-8 production. The antiinflammatory effects of ω-3 PUFAs were confirmed by the clinical finding of a lower body temperature after surgery. It is anticipated that these effects would be beneficial in these patients. Furthermore, this enteral feeding appeared to attenuate the plasma levels of PGI2 but not TXA2. In order to elucidate the clinical significance of these postoperative changes in eicosanoid production, further studies incorporating evaluation of hemodynamic and respiratory effects are necessary.

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Satoshi Aiko, MD, PhD; Yutaka Yoshizumi, MD, PhD; Shinichi Tsuwano, MD; Masaoki Shimanouchi, MD; Yoshiaki Sugiura, MD, PhD; and Tadaaki Maehara, MD, PhD

From the Department of Surgery II, National Defense Medical College, Tokorozawa, Saitama, Japan

Received for publication October 20, 2004.

Accepted for publication January 26, 2005.

Correspondence: Satoshi Aiko, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan. Electronic mail may be sent to saikomax@me.ndmc.ac.jp.

Copyright American Society for Parenteral and Enteral Nutrition May/ Jun 2005

Source: JPEN, Journal of Parenteral and Enteral Nutrition

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