Standard and immunomodulating enteral nutrition in patients after extended gastrointestinal surgery – A prospective, randomized, controlled clinical trial

Clinical Nutrition (2008) 27, 504e512

available at www.sciencedirect.com

http://intl.elsevierhealth.com/journals/clnu

ORIGINAL ARTICLE

Standard and immunomodulating enteral nutrition in patients after extended gastrointestinal surgery e A prospective, randomized, controlled clinical trial* Stanislaw Klek a,*, Jan Kulig a, Marek Sierzega a, Kinga Szczepanek a, ´ski a, Lucyna Scislo b, Elzbieta Walewska b, Aldona Kubisz a, Piotr Szybin Antoni M. Szczepanik a a

1st Department of Surgery, Jagiellonian University Medical College, Krakow, Poland Department of Clinical Nursing, Institute of Nursing and Midwifery, Faculty of Health Care, Jagiellonian University, Krakow, Poland

b

Received 21 January 2008; accepted 27 April 2008

KEYWORDS Enteral nutrition; Immunonutriton; Postoperative nutrition

Summary Background & aim: The immunomodulating enteral diets are intended to reduce the incidence of postoperative complications in surgical patients. The aim of the study was to assess the clinical effect of such nutrition. Materials and methods:: Between June 2004 and September 2007 196 well-nourished patients undergoing resection for pancreatic and gastric cancer were randomized in double-blind manner to receive postoperative enteral nutrition with immunostimulating diet (IMEN group) or standard oligopeptic diet (SEN group). Outcome measures were: number and type of complications, length of hospital stay, mortality, treatment tolerance, liver and kidney function. Results: One hundred and ninety six patients were initially enrolled, finally183 patients (91 SEN, 92 IMEN group; 69 F, 114 M, median age 61.2) were analyzed. Median postoperative hospital stay was 12.4 days (SD 5.9) in SEN and 12.9 days (SD 8.0) in IMEN group (p Z 0.42). Complications were observed in 21 patients (23.1%) in SEN and 23 (25.2%) in IMEN group (p > 0.05). Four (4.4%) patients in SEN group and 4 (4.4%) in IMEN had surgical complications (p > 0.05). There were no differences in liver and kidney function, visceral protein turnover and treatment tolerance.

*

Work presented at: 29th ESPEN Congress in Prague, 8e11 September 2007 (Outstanding Abstract Reward). * Corresponding author. 1st Department of Surgery, Jagiellonian University Medical College, 40 Kopernika Street, 31-501 Krakow, Poland. Tel./fax: þ48 12 424 8007. E-mail address: [email protected] (S. Klek). 0261-5614/$ - see front matter ª 2008 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved. doi:10.1016/j.clnu.2008.04.010

The clinical value of immnunomodulatory enteral nutrition in surgical patients

505

Conclusion: Results of our study showed no benefit of immunomodulating enteral nutrition over standard enteral nutrition in patients after major gastrointestinal surgery. The Trial was registered in Clinical Trials Database e number: NCT00576940. ª 2008 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Introduction

Materials and methods

Malnutrition is a common problem in patients requiring elective and emergency surgery for gastrointestinal neoplastic diseases. It exerts a detrimental influence on outcome of surgery, because it can suppress immune function, exaggerate stress response and cause organ system dysfunction. Hence, the elevated ratio of complicated wound healing or delayed recovery. Many authors had proven that preoperative nutrition improves postoperative outcome by helping to reduce postoperative morbidity and mortality, shorten hospital stay and decreasing postoperative complications.1e3 Torosian et al. also showed that only the severely malnourished patients benefit from preoperative parenteral nutrition, which reduce postoperative complications by 20%, therefore enteral nutrition should be chosen the method of choice.4 Still, there was a determination to improve the nutritional intervention, and, in late nineties, much consideration was paid to new formulas, supposed to modify the response of the immune system. Those, initially called immunostimulating, diets included arginine, glutamine, omega-3-fatty acids, vitamins C, E, and nucleotides. This type of nutrition became hot topic since some authors proved it to be more efficient than parenteral nutrition and standard enteral diet in improving the outcome of surgery.3,5,6 Diets changed name into more accurate ‘immunomodulating’, because it was observed that their effect is more complicated than only stimulating for the immune response e those nutrients stimulate pro- and antiinflammatory cytokines. After such an introduction, immunomodulating diets started to be used in surgical wards. Nowadays there is still some controversy over the real impact of immunomodulating formulas as a routine treatment of choice in all-surgical patients. The positive effects of immunonutrition observed in experimental models were often denied by clinical trials e in some studies comparing standard casein-based products as standard enteral nutrition (control group) versus immunostimulating formulas, showed similar outcome as far as postoperative complications were concerned.7e9 Lobo et al. demonstrated that immunostimulating diets showed no benefit over standard enteral nutrition when peptidebased diet was used.7 Those observations were also confirmed by others, not only as far as enteral, but also parenteral nutrition was concerned.8e10 Those results were however hard to compare because of the heterogeneity of study groups, sample numbers and differences in analytical approach. In order to address those ambiguities and to assess the real clinical value of enteral immunonutrition, a randomized, prospective clinical trial was conducted.

Study design and settings The study was a two-arm, randomized controlled clinical trial of nutritional therapy for postoperative complications in patients after gastric resection and pancreatoduodenectomy. The study was designed to explore rates and type of postoperative complications, the length of hospital stay, liver, kidney and immune function and treatment tolerance. The trial was set at 1st Department of General Surgery, Jagiellonian University in Cracow between June 2004 and September 2007. The study was designed to test the hypothesis that immunomodulating enteral nutrition would reduce the incidence of surgical and non-surgical complications following upper gastrointestinal surgery compared with standard, oligopeptic diet. The secondary objective of the study was to evaluate the effect of nutritional intervention on overall morbidity and mortality rates, and the length of hospital stay.

A/Inclusion and exclusion criteria Adults aged 18e80 years undergoing subtotal and total gastric resection with lymphadenectomy and pancreatoduodenectomy/total pancreatectomy with lymphadenectomy, in good general status (Karnofsky >80, Eastern Cooperative Oncology Group (ECOG) grade 0 or 1); with no confirmed neoplastic dissemination nor distant metastases; no severe concomitant disease (heart failure, chronic obstructive pulmonary disease (COPD), coronary aortic bypass graft (CABG), etc.), no history of known allergies or drug intolerance to analyzed substances were enrolled in the trial after giving written informed consent before operation. Patients with metastatic or unresectable disease, pregnant, in poor general status (Karnofsky <80, Eastern Cooperative Oncology Group (ECOG) >1), with recent history of severe heart, lung, kidney or liver failure, with history of allergies or drug intolerance were excluded.

Randomization and allocation of patients Following recruitment, all participants who met eligibility criteria were randomly assigned to either of the treatment groups: SEN group e standard enteral nutrition; IMEN group e immunostimulating enteral nutrition, using according to a computer generated randomization list managed by an external person not involved in the study. The CONSORT diagram shows the flow of participants through the study (Fig. 1).

506

S. Klek et al. Assessed for eligibility n=200

Excluded 4 (2 refused consent, 2 ineligible)

Randomised n = 196

Group SEN n = 98

Group IMEN n = 98

SEN: Excluded: 7 (3 refused consent, 3 unresectable disease, 1 protocol violation)

IMEN: Excluded: 6 (1 refused consent, 2 unresectable disease, 3 protocol violation)

SEN ANALYSED n = 91

IMEN ANALYSED n = 92

Figure 1 CONSORT diagram showing the flow of participants through each stage of the trial.

for the first 12 h, followed by infusion of Peptisorb (SEN group, Nutricia Ltd., Poland) or Reconvan (IMEN group, Fresenius Kabi, Poland) at the rate of: 20 ml/h on day 1, 50 ml/ h on day 2, 75 ml/h on day 3 and 100 ml/h thereafter until 7th day. Compositions of diets were shown in Table 2. Infusion pumps were used to administer the diet for 20e22 h with a 2e4 h rest period per 24 h. Oligopeptic, isocaloric diet was chosen as control diet because of the best tolerance of oligopeptic diets in small intestine. Infusion pumps guaranteed volume and speed control, doubtful in gravitational infusion systems.

Primary objective (primary end-point) The primary objective of this study was to evaluate the impact of immunomodulating enteral nutrition in general surgery patients on postoperative complications. The ratio of postoperative complications was selected as the primary outcome measure with the null hypothesis assuming that the routine use of immunostimulating enteral nutrition during postoperative period in patients after gastrointestinal surgery reduces the number of infectious and surgical complications. Definitions of complications were presented in Table 3.

Clinical management Secondary objectives (secondary end-point) All patients underwent resective procedures; enteral feeding tubes (Flocare Nutricia Ltd., 140 cm length) were inserted into the first jejunal loop 15e20 cm below the lowest intestinal anastomosis by a surgeon in cooperation with an anesthesiologist at the time of operation. The surgical team included three experienced general surgeons, and anesthesiology team included four persons. The characteristics of patients are presented in Table 1. Prior to operation body mass index (BMI), weight loss, full blood count with total lymphocyte count (TLC), albumin and prealbumin concentration, liver and kidney tests were assessed. After operation, on the 1st, 4th and 8th day, the following assessment were made: full blood count with total lymphocyte count (TLC), albumin and prealbumin concentration, liver and kidney tests, volume of diet administered and treatment tolerance assessment. The latter assessments were performed by physicians and nurses. Enteral feeding was commenced 6 h after operation using 5% glucose solutions at the rate of 20 ml per hour

Table 1

The secondary objectives included:     

length of hospital stay; function of immune system; assessment of liver and kidney function; assessment of visceral protein turnover; determination of the treatment tolerance.

Additionally, operating time, intraoperative blood loss, blood transfusions and the necessity for reoperation were recorded. Prior to the operation and on day 1, 4 and 8 afterwards the following parameters were determined in all patients: complete blood count with total lymphocyte count (TLC), albumin and prealbumin concentrations, as well as liver and kidney function tests. Postoperative mortality was defined as any death during the hospital stay after surgery. The length of the postoperative hospital stay was defined as the number of days from the day of operation until the date of discharge.

Demographic and disease profile

Age (mean [SE]) years Gender (M:F) Weight loss (insignificant [<10%]:significant [>10%]) over 3e6 months BMI (<19 kg/m2:>19 kg/m2) (n Z 183) Gastric resection subtotal 4/5: total (n Z 114) Pancreatoduodenectomy: total pancreatectomy (n Z 69) Albumin concentration on admission (g/l, [range]) (n Z 183) TLC on admission (no in mm3 [range]) (n Z 183)

SEN (n Z 91)

IMEN (n Z 92)

p value

62.1 (10.9) 35:13 73:18

62.3 (11.3) 34:14 76:16

p > 0.0.5 p > 0.05 p > 0.05

17:74 16:40 30:5 30.1 (22e42) 1680 (450e2350)

10:38 18:40 30:4 30.9 (21e43) 1686 (485e2155)

p > 0.05 p > 0.05 p > 0.05 p > 0.05 p > 0.05

The clinical value of immnunomodulatory enteral nutrition in surgical patients Table 2

Composition of enteral diets

Avera(g)e contents per 100 ml/100 kcal

Peptisorb

Reconvan

Energy (kcal) Protein (g) Carbohydrate (g) Polysaccharides (g) Sugars (g) Lactose (g) Total Fat (g) Saturates (g) Of which MCT (g) Dietary fiber (g)

100 4.0 17.6 14.6 1.7 0.1 1.7 1.0 0.8 0.0

100 5.5 18.0 13.3 0.7 0.15 4.1 3.3 1.9 0.0

507

power Z 0.80). Assuming a dropout rate of 15%, a total of 200 patients were required. The data were analyzed on an intention-to-treat basis with the SPSS v.14 (SPSS Inc., Chicago, IL) software package. The differences in proportions among groups were evaluated using the Chi-square test, and Yates correction was adopted if any of the expected frequencies were less than 5. Continuous data were analyzed using the ManneWhitney U-test. Potential risk factors for postoperative infectious complications were evaluated by univariate analysis using crosstabulation and multivariate logistic regression analysis. The differences at p < 0.05 were regarded as statistically significant.

Ethics and consent

Minerals Sodium mg (mmol) Potassium mg (mmol) Chloride mg (mmol) Calcium mg (mmol) Phosphorus (mg) Magnesium (mg) Iron (mg) Zinc (mg) Copper mc(g) Manganese (mg) Fluoride (mg) Molybdenum (mcg) Selenium (mcg) Chromium (mcg) Iodine (mcg)

100 (4.3) 150 (3.8) 125 (3.5) 80 (2.0) 72 23 1.6 1.2 180 0.33 0.10 10.0 5.7 6.7 13

138 207 141 80 (2.0) 60 25 1.33 1.2 133 0.63 0.27 10.0 6.7 6.7 13.3

Vitamins Vitamin A (mcg RE) Vitamin D (mcg) Vitamin E (mg a-TE) Vitamin K (mcg) Thiamine (mg) Riboflavin (mg) Niacin (mg NE) Pantothenic acid (mg) Vitamin B6 (mg) Folate (mcg) Vitamin B12 (mcg) Biotin (mcg) Vitamin C (mg)

82 0.70 1.3 5.3 0.15 0.16 1.8 0.53 0.17 27 0.21 4.0 10.0

70 0.88 1.0 6.7 0.2 0.16 1.6 0.47 0.16 27 0.27 5.0 6.7

Others Choline m(g) Taurine m(g) Osmolarity (mOsmol/l)

37 10 455

26.7 13 410

Sample size and statistical analysis Sample size was calculated using SamplePower (SPSS Inc., Chicago, IL). The overall rate of infectious complications following upper gastrointestinal surgery reported by previous studies was about 40%. To detect a 50% decrease caused by immunonutrition compared with standard nutrition, about 85 patients should be randomized to each of the two compared arms (alpha Z 0.05 two-sided,

The Ethics committee of Jagiellonian University approved the study (KBET/91/L/2004). Patients were personally approached and enrolled by one of two investigators (SK, KSM). Informed written consent was obtained from each participant before enrolment. The study was carried out following the international ethical recommendations stated in the Helsinki Declaration.

Role of sources of funding The study was conducted independently with no external sponsorship.

Results Two hundred patients was initially assessed for eligibility; 196 of them were randomized (four patients were excluded prior to randomization, two refused consent, two ineligible). During the trial phase further 13 of 196 patients were excluded, so 183 patients (69 F, 114 M, mean age 61.2) underwent final assessment. The excluded patients were included in intend-to-treat analysis (ITT). The CONSORT diagram shows the flow of participants through each stage the trial (Figure 1). Reasons for dropout were as follow: four withdrawals of consents (SEN-3, IMEN-1), five unresectable disease (SEN-3, IMEN-2), four protocol violations (SEN-1, IMEN-3). The final allocation was as follows: SEN group (n Z 91); IMEN group (n Z 92). The main demographic, clinical and biochemical baseline of 183 patients was summarized in Table 1 according to allocation group. Subjects of the study were well matched for age, gender, weight loss, BMI, type of surgery: gastric/pancreatic resection, total lymphocyte count (TLC) and albumin concentration as the indicator of nutritional status. The number of patients who were operated on for gastric and pancreatic carcinoma, as well as patients within both groups, was similar. Neither subtotal/total gastrectomy nor pancreatoduodenectomy/total pancreatectomy ratio differed among groups (Table 1).

508 Table 3

S. Klek et al. Definitions of complications

Complication

Definition

Wound infection Abdominal abscess Pneumonia

Purulent exudate in the wound with positive bacterial culture Collection of pus confirmed by percutaneous drainage or at reoperation Clinical signs of pneumonia and positive culture of tracheal aspirate, blood or brushing, and/or radiographic evidence Clinical symptoms and bacteria in urine (>100,000 colony-forming units/ml) Positive blood culture Local signs of inflammation, and/or the isolation of pathogen organisms in culture Fever >38  C or hypotension (<90 mmHg systolic BP) or oliguria (<20 ml/h) Any dehiscence of the fascia >3 cm Necessity of blood transfusion (2 U) Positive dye-swallow or contrast-swallow test Presence of dyspnoea and respiratory rate >35 breaths/min’ or PaO2 <70 mmHg Unstable blood pressure requiring use of extra fluids or cardiac stimulants Necessity of hemodialysis Increased serum bilirubin or hepatic enzyme level (50% above baseline) Drain output of any measurable volume of fluid on or after the 3rd postoperative day with an amylase content greater than three times the serum amylase activity Necessity for nasogastric suction for 8 days after surgery

Urinary tract infection Bacteremia Infection of venous catheter Sepsis Wound dehiscence Bleeding Anastomotic leak Respiratory tract failure Circulatory insufficiency Renal failure Hepatic dysfunction Pancreatic fistula Delayed gastric emptying

Postoperative follow-up

The length of hospital stay was similar in both groups: 12.4 days (SD 5.9) in SEN group and 12.9 days (SD 8.0) in IMEN group (p Z 0.42).

There were no significant differences between the two enteral groups as far as the volume of tube feeding delivered was considered, as shown in Table 3. For the purpose of this study, the observation period ended on the 8th postoperative day, after a full seven days of enteral feeding, but the mean duration of intervention in SEN and IMEN group was 8.4 (1.2 days) and 8.6 (1.4 days). Each group received similar amount of energy, proteins and nitrogen per day. Table 4 shows the intake in both groups.

Postoperative complications Table 5 shows the postoperative complications in two groups. Complications were observed in 21 (23.1%) in SEN and 23 (25.2%) in IMEN group. Infective complications were observed in 23 patients in SEN group and 21 in IMEN group. The analysis of prealbumin and albumin serum concentration was one of the secondary end-points, measured in order to assess visceral protein turnover with each type of nutrition. As demonstrated in Table 5, these differences were not significant (p > 0.05). There were no differences in liver and kidney function, analyzed by observation of clinical status and evaluation of laboratory tests. The mean concentrations of SGOT, SGTP, urea and creatinine are shown in Table 6 (p > 0.05). No fatal outcome related to liver or kidney dysfunction was observed. There was no difference in total lymphocyte count (TLC) between the groups nor in postoperative complications (Table 7).

Postoperative course Treatment tolerance was similar between groups, protocol violation caused by the lack of possibility of full planned dose delivery was the reason of premature treatment termination in four patients (SEN-2, IMEN-2), which was 2% of all evaluated patients. The borderline of planned delivery dose was 70% of initially prescribed dose. Blood transfusions were made in 12 patients in SEN and 11 in IMEN group; the median numbers of blood units were 2.5 in SEN, 2 in IMEN. IQRs (interquartile ranges) were: 1e 3.5 and 1e5, respectively. Albumin solutions were not used as standard treatment.

Table 4

Volume of feed per day in SEN and IMEN group

Days SEN (Peptisorb) IMEN (Reconvan)

Median volume (ml) IQR Median volume (ml) IQR

0

1

2

3

4

5

6

7

240

500

1000

1500

2000

2000

2000

2000

200e240 200

460e545 400

870e990 800

1420e1540 1200

1910e2100 1600

1850e2150 1600

1900e2050 1600

1830e2100 1600

180e240

370e450

690e840

1120e1270

1510e1660

1350e1850

1400e1680

1410e1620

The clinical value of immnunomodulatory enteral nutrition in surgical patients Table 5

509

Postoperative complications (n Z 183)

Type of complication

SEN (n Z 91)

IMEN (n Z 92)

p value

Infectious complications Pneumonia Urinary tract infection Surgical wound infection Abscess formation

15 (16.4%) 1 (1.1%) 5 (5.5%) 2 (2.2%)

13 (14.1%) 2 (2.1%) 4 (4.2%) 2 (2.1%)

p > 0.05 p > 0.05 p > 0.05 p > 0.05

Surgical complications Evisceration Pancreatic fistula Duodenal fistula Jejunal fistula Biliary fistula Surgical complications overall

0 1 1 2 0 4

1 0 1 1 1 4

(1.1%) (1.1%) (1.1%) (4.4%)

p > 0.05 p > 0.05 p > 0.05 p > 0.05 p > 0.05 p > 0.05

General complications Pulmonary thrombosis Myocardiac infarct Peripheral vein thrombosis Neurological complications Fatal outcome

0 0 0 0 1 (1.1%)

0 1 (1.1%) 0 0 1 (1.1%)

p > 0.05 p > 0.05 p > 0.05 p > 0.05 p > 0.05

Complications overall (patients)

21 (23.1%)

23 (25.2%)

p > 0.05

Uncomplicated postoperative period (patients)

70 (76.9%)

69 (75%)

p > 0.05

(1.1%) (1.1%) (2.2%) (4.4%)

Discussion The improvement of recovery after surgical procedures is the main point of interest since the surgical technique was mastered thanks to well-organized training, the use of special equipment, such as stapling devices or introduction of laparoscopic procedures, and the perioperative care was improved thanks to the standardized use of antibiotics and anticoagulants, improvement in infusion therapy and active physiotherapy. Deterioration of the nutritional status is a key factor affecting surgical result, as first described by Studley in 1936.11 Since then, enteral and parenteral nutrition have been used to overpower the detrimental effects of malnutrition. It has been proven that in moderately or severely malnourished patients undergoing major gastrointestinal surgery for 7e14 days will benefit from preoperative nutritional therapy even if the operation is postponed and that nutrition should be delivered to patients, who are unable

Table 6

Liver and kidney function SEN group

IMEN group

Hepatic function SGOT SGTP

36.6 (34.8) 44.6 (23.8)

38.6 (41.8) 42.7 (32.8)

Renal function Urea Creatinine

8.8 (4.2) 75.2 (33.2)

8.9 (5.2) 75.5 (43.2)

(1.1%)

to meet their nutrient needs orally for a period of 7e 10 days.12,13 This strategy helped to reduce postoperative complications in surgical patients; there is still, however, willingness to improve therapeutic outcome. This is why both, parenteral and enteral nutrition, have been modified over the years to prepare the most effective admixtures, helping to improve the therapeutic outcome. Over the last decade, attention has been directed toward a better understanding of the immunologic and inflammatory systems, with the ultimate goal of improving host defenses. Immunonutrition, defined as enteral or parenteral nutritional therapy based on variety of products, such as omega-3-fatty acids, glutamine, arginine, sulfur-containing amino acids, nucleotides and anti-oxidants, is supposed to have beneficial effects on postoperative recovery in surgical patients. Many studies on this type of nutrition showed its clinical effectiveness in terms of reduction of postoperative complications, shorter period of hospital stay and costs of hospitalization.3,6 As it was partially mentioned above, the ‘boom’ on immunonutrition started with studies of Braga et al. and Giannotti et al., confirmed later by ElMalt et al., Kelly et al. or Novak and Heyland et al., who showed the impact of diets containing arginine, glutamine, nucleotides and omega-3-fatty acids on postoperative complications.3,6,14e18 They observed shortening of hospitalization, reduction of complications and improved costeffectiveness. Therefore, the question occurred whether the immunonutrition should replace standard nutritional treatment in patients after extensive gastrointestinal surgery entirely. The question was, however, hard to answer, because after few years of initial admiration, some authors

510 Table 7

S. Klek et al. Serum albumin, prealbumin and TLC in all analyzed patients Before surgery

3rd day

8th day

SEN group Albumin (g/l) TLC (mm3) Prealbumin (mg/dl)

32.0 (SD: 4.4) 1580 (SD: 1010) 14.2 (SD: 7.7)

22.9 (SD: 4.3) 1410 (SD: 1060) 13.9 (SD: 8.0)

25.5 (SD: 3.4) 1350 (SD: 1005) 18.3 (SD: 7.9)

IMEN group Albumin TLC Prealbumin

32.2 (SD: 4.5) 1650 (SD: 350) 14.1 (SD: 5.9)

25.1 (SD: 4.0) 1510 (SD: 870) 11.8 (SD: 4.9)

25.9 (SD: 4.7) 1520 (SD: 1110) 17.6 (SD: 3.9)

began to question the factual clinical impact of immunostimulating formulas. Satinsky et al. or Heyland et al., as well as others, failed to prove benefits of immunonutrition, pointing out no reduction of complications of hospital stay.7,15,16,19 Some clinicists observed nothing but the reduction in the number of infectious complications without any cost-effectiveness benefit.8,10,20,22 Alivizatos et al. was even more controversial; he drew a conclusion that in malnourished cancer patients undergoing major gastrointestinal surgery, morbidity and mortality are not significantly influenced by the type of postoperative feeding.21 One of the major drawbacks acclaimed by the opponents of immunomodulating diets is their inability to improve mortality rates.22,23 Moreover, not all trials clearly confirmed that such formulas may reduce infectious complications, and some of them suggested even that immunonutrition can increase the risk of death.23,24 This was probably due to the fact that most patients undergoing upper gastrointestinal surgery, as in our case, are at low risk of dying after elective interventions. Many trials, in which nutritional intervention, even with immunomodulating diets, showed no clinical effect, were performed on well-nourished patients, while trials demonstrating reduction of complications included moderately or severely malnourished patients, as in Daly et al. and Heslin et al. studies.25,26 The same observations were made by Kudsk et al., who emphasized the heterogeneity of study groups in various clinical trials concerning immunonutrition.27e29 The same author as well as the group of authors who prepared ASPEN Guidelines pointed out that reasons of failure in credibility of clinical studies was caused by variability in the definitions of malnutrition and incidence of malnutrition and other co morbidities; the route of admission and duration of nutrition support; the amount and composition of the nutrition support; and the incidence of nutrition support-related complications.12,13,27e29 All the distrust and confusion about immunonutrition was well described by Bertolini et al., who wrote that the large body of evidence for positive effects of immunonutrition in experimental models and the contradictory results stemming from clinical trials makes the discussion on immunonutriton a typical example of communication difficulties between rationalism and empiricism.30 The present study was initiated to verify the hypothesis that immunonutrition can reduce the rate of infectious complications in patients without evidence of nutritional depletion. We selected a group of well-nourished patients

undergoing major upper gastrointestinal surgery in whom oral diet covering nutritional requirements would be delayed until about the 6th postoperative day.6 Both gastric and pancreatic caner patients cannot received oral diets covering at least 60% of their needs during first 6e7 postoperative days, hence nutritional support must be provided.18,19 It is also recommended to use enteral nutrition if only possible.18,19 Those were the reasons, gastric and pancreatic cancer patients were chosen to our study. The assumption was that the type of nutrition might influence the outcome in surgical patients, even in case of well-nourished or mildly malnourished patients. We used two diets similar in composition (except for immunomodulating ingredients and protein and calories contents), and the same tube feeding protocol. However, despite adequate patient compliance, postoperative immunomodulatory did not affect the primary outcome measure defined as the rate of infectious and surgical complications. As showed in Table 5, complications were observed in 21 patients (23.1%) in SEN and 23 (25.2%) in IMEN group (p > 0.05). Four (4.4%) patients in SEN group and 4 (4.4%) in IMEN had surgical complications (p > 0.05). The time of recovery was also similar; median postoperative hospital stay was 12.4 days (SD 5.9) in SEN group and 12.9 days (SD 8.0) in IMEN group (p Z 0.42). Because baseline clinical and demographic factors, including nutrition-related variables, were similar in patients receiving standard and immunomodulating diets, we believe that the study population was sufficiently homogenous to demonstrate potential advantages of immunomodulating formulas. At this point our observations are similar to other authors, cited above.7,21,26 There are several possible reasons responsible for the failure of the immunomodulating diets in our study and discrepancies with previous trials demonstrating beneficial effects of immunostimulating formulas. One of the most important issues is the study population. A recent metaanalysis of 13 randomized, controlled trials involving 1269 individuals demonstrated that perioperative immunonutrition in patients undergoing gastrointestinal surgery significantly reduced rates of postoperative infection (OR Z 0.41, 95% CI 0.30e0.54), shortened the length of hospital stay and improved various parameters of immune function.5 However, nearly all of these trials included patients with and without malnutrition, and the proportion of malnourished patients in some trials reached almost 60%.6e8,25,28

The clinical value of immnunomodulatory enteral nutrition in surgical patients Therefore, it is not clear whether the benefits reported in this meta-analysis could also be generalized to wellnourished patients. The lack of differences may be the result of the diet.7 Daly et al. performed the study using Impact, which differs in composition from Reconvan, though both diets contain immunonutrients. The amount of glutamine, arginine and omega-3-fatty acids is different in those diets, which may be crucial. Heyland et al. showed that diets with higher arginine concentration were more beneficial that others.15,16 The timing of nutritional intervention is another critical issue that remains to be determined; it is known that during postoperative period patients goes through opposite phases: systemic inflammatory response and antiinflammatory response, which differs this period from preoperative phase.7 Therefore, same substances given preoperatively may have beneficial effect because during this period’s inflammatory processes are different, moreover, it is easier to fulfill nutritional plan before than after operation.7 Our another point of interest was that he influence of immunomodulatory diet on liver and kidney function was the same as of the standard one. The same observation was made about the influence of this treatment on visceral proteins synthesis. There were no differences between groups. The study showed no clear benefit of immunomodulating enteral diets as far as postoperative complications, treatment tolerance; liver and kidney function and visceral protein synthesis are concerned. In our opinion it suggests that there is unquestionable need for enteral nutrition in surgical patients, but there is no need to administer more expensive immunomodulatory diets in all surgical patients.

Conflict of interest Authors certificate that no financial arrangements with an investigator have been made where study outcome could affect compensation; and that the investigator has no proprietary interest in the tested product; that the investigator does not have a significant equity interest in the sponsor of the covered study; and that the investigator has not received significant payments of other sorts.

References 1. Suchner U, Senftleben U, Eckart T, Scholz MR, Beck K, Murr R, et al. Enteral versus parenteral nutrition: effects on gastrointestinal function and metabolism. Nutrition 1996;12(1):13e22. 2. McClave SA, Snider HL, Spain DA. Preoperative issues in clinical nutrition. Chest 1999;115(Suppl. 5):64Se70S. 3. Braga M, Gianotti L, Radaelli G, Di Carlo V. Nutritional approach in malnourished surgical patients: a prospective randomized study. Arch Surg 2002;137(2):174e80. 4. Torosian MH. Perioperative nutrition support for patients undergoing gastrointestinal surgery: critical analysis and recommendations. World J Surg 1999;23(6):565e9. 5. Moore FA, Feliciano DV, Andrassy RJ. Early enteral feeding, compared with parenteral, reduces postoperative septic complications. Ann Surg 1992;216:172e83.

511

6. Gianotti L, Braga M, Gentilini O, Balzano G, Zerbi A, Di Carlo V. Artificial nutrition after pancreaticoduodenectomy. Pancreas 2000;21(4):344e51. 7. Lobo DN, Williams RN, Welch NT, Aloysius MM, Nunes QM, Padmanabhan J, et al. Early postoperative jejunostomy feeding with an immune modulating diet in patients undergoing resectional surgery for upper gastrointestinal cancer: a prospective, randomized, controlled, double-blind study. Clin Nutr 2006;25(5):716e26. 8. Senkal M, Mumme A, Eickhoff U, Geier B, Spath G, Wulfert D, et al. Early postoperative enteral immunonutrition: clinical outcome and cost-comparison analysis in surgical patients. Crit Care Med 1997;25(9):1489e96. 9. Chen DW, Wei Fei Z, Zhang YC, Ou JM, Xu J. Role of enteral immunonutrition in patients with gastric carcinoma undergoing major surgery. Asian J Surg 2005;28(2):121e4. 10. Klek S, Kulig J, Szczepanik AM, Jedrys J, Kolodziejczyk P. The clinical value of parenteral immunonutrition in surgical patients. Acta Chir Belg 2005;105(2):175e9. 11. Studley HO. Percentage of weight loss, a basic indicator of surgical risk in patients with chronic peptic ulcer. JAMA 1936;106:458e60. 12. ESPEN Guidelines on Enteral Nutrition. Clin Nutr 2006;4: 224e45. 13. Guidelines for the use of parenteral and enteral nutrition in adult and pediatric patients. J Parenter Enteral Nutr 2002; 1(Suppl.):1e150. 14. El-Malt M, Ceelen W, Boterberg T, Claeys G, De Hemptinne B, De Neve W, et al. Does the addition of glutamine to total parenteral nutrition have beneficial effect on the healing of colon anastomosis and bacterial translocation after preoperative radiotherapy? Am J Clin Oncol 2003;26(3):E54e9. 15. Heyland DK, Novak F, Drover JW, Jain M, Su X, Suchner U. Should immunonutrition become routine in critically ill patients? A systematic review of the evidence. JAMA 2001 22e9;286(8):944e53. 16. Heyland DK, Schroter-Noppe D, Drover JW, Jain M, Keefe L, Dhaliwal R, et al. Nutrition support in the critical care setting: current practice in Canadian ICUs e opportunities for improvement? J Parenter Enteral Nutr 2003;27(1):74e83. 17. Kelly D, Wischmeyer PE. Role of L-glutamine in critical illness: new insights. Curr Opin Clin Nutr Metab Care 2003; 6(2):217e22. 18. Novak F, Heyland DK, Avenell A, Drover JW, Su X. Glutamine supplementation in serious illness: a systematic review of the evidence. Crit Care Med 2002;30(9):2022e9. 19. Satinsky I, Mittak M, Foltys A, Kretek J, Dostalik J. Comparison various types of artificial nutrition on postoperative complications after major surgery. Rozhl Chir 2005;84(3):134e41. 20. Braunschweig CL, Levy P, Sheean PM, Wang X. Enteral compared with parenteral nutrition: a meta-analysis. Am J Clin Nutr 2001;74(4):534e42. 21. Alivizatos V, Athanasopoulos P, Makris N, Karageorgos N. Early postoperative glutamine-supplemented parenteral nutrition versus enteral immunonutrition in cancer patients undergoing major gastrointestinal surgery. J BUON 2005; 10(1):119e22. 22. Chen WJ, Yeh SL. Effects of fish oil in parenteral nutrition. Nutrition 2003;19(3):275e9. 23. Delmi M, Rapin CH, Bengoa JM. Dietary supplementation in elderly patients with fractured neck of the femur. Lancet 1990;335:1013e6. 24. Matarese LE, Steiger E, Seidner DL, Richmond B. Body composition changes in cachectic patients receiving home parenteral nutrition. J Parenter Enteral Nutr 2002;26(6):366e71. 25. Daly JM, Lieberman MD, Goldfine J, Shou J, Weintraub F, Rosato EF, et al. Enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids in patients after

512 operation: immunologic, metabolic, and clinical outcome. Surgery 1992 Jul;112(1):56e67. 26. Heslin MJ, Zatkany L, Leung D, Brooks AD, Hochwald SN. A prospective, randomised, trail of early enteral feeding after resection of upper gastrointestinal malignancy. Ann Surg 2003;27:567e77. 27. Kudsk KA, Tolley EA, DeWitt RC, Janu PG, Blackwell AP, Yeary S, et al. Preoperative albumin and surgical site identify surgical risk for major postoperative complications. J Parenter Enteral Nutr 2003;27(1):1e9.

S. Klek et al. 28. Kudsk KA. Dear miss milk toast. J Parenter Enteral Nutr 1998; 22(4):191e8. 29. Kudsk KA, Minard G, Wojtysiak SL, Croce M, Fabian T, Brown RO. Visceral protein response to enteral versus parenteral nutrition and sepsis in patients with trauma. Surgery 1994;116(3):516e23. 30. Bertolini G, Luciani D, Biolo G. Immunonutrition in septic patients: a philosophical view of the current situation. Clin Nutr 2007;26:25e9.