Additional Details of Methods and Results

Additional Details of Methods and Results

SupplementaryText R21

Additional details of methods and results

Content

Search strategy…………………………………………………………………………..3

Eligibility criteria………………………………………………………………………..3

Data extraction…………………………………………………………………………..4

Assessment of methodological quality………………………………………………….5

Search results……………………………………………………………………………5

Study characteristics…………………………………………………………………….6

Risk of bias……………………………………………………………………………...6

References to studies included in the multiple-treatments meta-analysis………………7

WinBUGS codes for random effects model and fixed effects model for binary outcome data…………………………………………...... 19

WinBUGS codes for random effectsmeta-regressionmodel for binary outcome data………...... 22

RankogramandSUCRA……………………………………………………………….24

Inconsistency…………………………………………………………………………...26

Cross validation………………………………………………………………………...26

Between-study heterogeneity…………………………………………………………..27

Publication bias…………………………………………………………………………28

References……………………………………………………………………………...29

Search strategy

This multiple treatment meta-analysis followed the Preferred Reporting Items for Systematic Review and Meta analyses (PRISMA) statements (Supplementary PRISMA Checklist).1Using MEDLINE, the Web of Science, and the Cochrane Library, an English literature search was carried out for randomized controlled trials (RCTs) published from January 1990 to February 2013 that evaluated the clinical efficacy of SPN, SEN, IMPN, and IMEN in human adult patients undergoing elective gastrointestinal surgery. Also, bibliographic reviews and abstracts presented through 2013 were manually searched.The following text words and medical subject headings (MeSH) terms were used for searching: “Enteral Nutrition” AND/OR“Parenteral Nutrition” AND/OR “Immunomodulations” AND/OR“immunonutrition” AND/OR“immuno-enhancing” AND/OR “Omega-3 Fatty Acids” AND/OR “Omega-6 Fatty Acids” AND/OR “Arginine” AND/OR “Glutamine” AND/OR “Fish Oils” AND/OR “RNA” AND/OR “Nutritional Support” combined with “Randomized Controlled Trial” AND/OR “Gastrointestinal” AND/OR “Surgical Procedures” AND/OR “Perioperative Period” AND/OR “Postoperative Period” AND/OR “Preoperative Period”. The experimental designs taken into consideration were as follows: RCTs.

Eligibility criteria

SEN and IMEN were the perioperative delivery of any nutrient in solid or liquid form (including usual food intake) that passed through any part of the digestive tract, regardless of whether the patients received conventional oral diets with intravenous fluids (standard care) or tube feeds. SPN was defined as administration of nutritional liquids containing a minimum of glucose and amino acids that were perioperatively administered through the central or peripheral venous system. IMPN was also defined as administration of SPN with fish oil emulsions. If more than one version of the same study was retrieved, the most recent study was used.Exclusion criteria are as follows: (1) trials that investigated the efficacy of an oral nutritional supplement (sip feed); (2) trials that evaluated the impact of nutrition only on nutritional or physiologic outcomes (e.g., nitrogen balance or amino acid profile); (3) trials that treated patients receiving home parenteral nutrition; (4) trials that included cardiopulmonary, head injury, pediatric, gynecologic, urological, traumatic, emergency, transplantation surgery, chemotherapy, radiotherapy, or critically ill patients.

Data extraction

Data were extracted on study design, setting, patient population, pathology of diseases, site of surgery, the regimens, methods of nutritional support, and the outcome variables listed above. Outcomes assessed were the incidence of any infection, overall complication, mortality, wound infection, pneumonia, anastomotic leak, intra-abdominal abscess, sepsis, and urinary tract infectionfor binary outcome data. Data were extracted as the total number of patients affected by complications rather than the total number of incidences of complications.

Assessment of methodological quality

Study quality was assessed using the Cochrane risk of bias tool, an established tool based on the following domains: sequence generation for the randomization of subjects, allocation concealment of treatment, blinding of participants, personnel, and outcome assessors, incomplete outcome date, selective outcome reporting, and other sources of bias—study design, early stopping, baseline imbalance, and some other problems. For each study, the risk of bias was reported as “low risk”, “unclear risk”, or “high risk” in the domains.Bias assessment was performed using Review Manager Version 5.2.3 (Cochrane Collaboration, UK).2

Search results

Seventy-four studies totaling 7,572 participants met all of the inclusion criteria; SPN was compared with SEN in 29 studies; SPN was compared with IMPN in 18 studies; SPN was compared with IMEN in 12 studies; SEN was compared with IMPN in 2 studies; SEN was compared with IMEN in 29 studies, and IMPN was compared with IMEN in 2 studies(Supplementary Table 1 and Figure 2).

Study characteristics

Sixty studies stated the underlying pathology of the study participants, of which 48 studies (80%) were comprised of malignant status and the remaining 10 studies (20%) included both malignant and benign status (Supplementary Table 1). No study included only benign diseases. Twenty-two studies (30%) reported the number of patients with malnutrition (Supplementary Table 1). Patients were fed through either a catheter tube or orally with 21 kinds of EN (Supplementary Table 2); 5 kinds of IMEN and 15 kinds of SEN (Supplementary Tables 3 and 4). Seven kinds of parenteral lipid emulsions were administered; 3 kinds of IMPN, and 4 kinds of standard lipid emulsion (Supplementary Tables2 and 5). In fifty-seven studies, the nutrition was administered postoperatively; preoperatively in 13 studies, and perioperatively in 12 studies(Supplementary Table 2).

Risk of bias

The risk of bias was adequate for 37 studies (50%) in the randomized sequence, clear for 35 studies (47%) in the allocation concealment, adequate for 24 studies (32%) in the double blinding, complete for 13 studies (18%) in the blinding of the outcome assessment, low for 42 studies (57%) in the incomplete outcome data, low for 29 studies (39%)in the selective reporting, and free of other bias for 22 studies (30%) (Supplementary Figures 1A and 1B).

References to studies included in the multiple-treatments meta-analysis

  1. Hamaoui E, Lefkowitz R, Olender L, et al. Enteral nutrition in the early postoperative period: A new semi-elemental formula versus total parenteral nutrition. J Parenter Enteral Nutr. 1990;14:501–507.
  2. Schroeder D, Gillanders L, Mahr K, et al. Effects of immediate postoperative enteral nutrition on body composition, muscle function, and wound healing.J Parenter Enteral Nutr.1991;15:376–383.
  3. Von Meyenfeldt MF, Meijerink WJ, Rouflart MM, et al. Perioperative nutritional support: a randomised clinical trial. Clin Nutr. 1992;11:180–186.
  4. Reissman P, Teoh TA, Cohen SM, et al. Is early oral feeding safe after elective colorectal surgery? A prospective randomised trial. Ann Surg. 1995;222:73–77.
  5. Baigrie RJ, Devitt PG, Watkin DS. Enteral versus parenteral nutrition after oesophagogastric surgery: A prospective randomized comparison. Aust N Z J Surg. 1996;66:668–670.
  6. Beier-Holgersen R, Brandstrup B. Influence of early postoperative enteral nutrition versus placebo on cell-mediated immunity, as measured with the Multitest CMI. Scand J Gastroenterol. 1999;34:98–102.
  7. Carr CS, Ling KD, Boulos P, et al. Randomised trial of safety and efficacy of immediate postoperative enteral feeding in patients undergoing GI resection. BMJ. 1996;312:869–871.
  8. Ortiz H, Armendariz P, Yarnoz C. Is early postoperative feeding feasible in elective colon and rectal surgery? Int J Colorectal Dis.1996;11:119–121.
  9. Hartsell PA, Frazee RC, Harrison JB, et al. Early postoperative feeding after elective colorectal surgery. Arch Surg. 1997;132:518–521.
  10. Reynolds JV, Kanwar S, Welsh FKS, et al. Does the route of feeding modify gut barrier function and clinical outcome in patients after major upper GI surgery? J Parenter Enteral Nutr. 1997;21:196–201.
  11. Sand J, Luostarinen M, Matikainen M. Enteral or parenteral feeding after total gastrectomy: Prospective randomised pilot study. Eur J Surg. 1997;163:761–766.
  12. Shirabe K, Matsumata T, Shimada M, et al. A comparison of parenteral hyperalimentation and early enteral feeding regarding systemic immunity after major hepatic resection—the results of a randomized prospective study. Hepatogastroenterology. 1997;44:205–209.
  13. Stewart BT, Woods RJ, Collopy BT, et al. Early feeding after elective open colorectal resections: A prospective randomized trial. Aust N Z J Surg. 1998;68:125–128.
  14. Aiko S, Yoshizumi Y, Sugiura Y, et al. Beneficial effects of immediate enteral nutrition after esophageal cancer surgery. Surg Today. 2001;31:971–978.
  15. Bozzetti F, Braga M, Gianotti L, et al. Postoperative enteral versus parenteral nutrition in malnourished patients with GI cancer: A randomized multicentre trial. Lancet. 2001;358:1487–1492.
  16. Braga M, Gianotti L, Gentilini O, et al. Early postoperative enteral nutrition improves gut oxygenation and reduces costs compared with total parenteral nutrition. Crit Care Med. 2001;29:242–248.
  17. Pacelli F, Bossola M, Papa V, et al. EN-TPN Study Group. Enteral vs parenteral nutrition after major abdominal surgery: An even match. Arch Surg. 2001;136:933–936.
  18. Page RD, Ooa AY, Russell GN, et al. Intravenous hydration versus naso-jejunal enteral feeding after esophagectomy: A randomised study. Eur J Cardio-thorac Surg. 2002;22:666–672.
  19. Rayes N, Hansen S, Seehofer D, et al. Early enteral supply of fiber and Lactobacilli versus conventional nutrition: A controlled trial in patients with major abdominal surgery. Nutrition. 2002;18:609–615.
  20. Feo CV, Romanini B, Sortini D, et al. Early oral feeding after colorectal resection: A randomized controlled study. Aust NZ J Surg. 2004;74:298–301.
  21. Petkova PS. Improved clinical outcome in patients with early enteral nutrition after major abdominal surgery. Clin Nutr. 2004;23:1457–1458.
  22. Wu GH, Liu ZH, Wu ZH, et al. Perioperative artificial nutrition in malnourished gastrointestinal cancer patients. World J Gastroenterol. 2006;12:2441–2444.
  23. Wachtler P, König W, Senkal M, et al. Influence of a total parenteral nutrition enriched with omega-3 fatty acids on leukotriene synthesis of peripheral leukocytes and systemic cytokine levels in patients with major surgery. J Trauma. 1997;42:191–198.
  24. Kelbel I, Wagner F, Wiedeck-Suger H, et al. Effects of n-3 fatty acids on immune function: a double-blind, randomized trial of fish oil based infusion in post-operative patients. Clin Nutr. 2002;21:13–14.
  25. Weiss G, Meyer F, Matthies B, et al. Immunomodulation by perioperative administration of n-3 fatty acids. Br J Nutr. 2002;87:S89–S94.
  26. Heller AR, Rössel T, Gottschlich B, et al. Omega-3 fatty acids improve liver and pancreas function in postoperative cancer patients. Int J Cancer.2004;111:611–616.
  27. Kłek S, Kulig J, Szczepanik AM, et al. The clinical value of parenteral immunonutrition in surgical patients. Acta Chir Belg. 2005;105:175–179.
  28. Senkal M, Geier B, Hannemann M, et al. Supplementation of omega-3 fatty acids in parenteral nutrition beneficially alters phospholipid fatty acid pattern. J ParenterEnteral Nutr. 2007;31:12–17.
  29. Wichmann MW, Thul P, Czarnetzki HD, et al. Evaluation of clinical safety and beneficial effects of a fish oil containing lipid emulsion (Lipoplus, MLF541): data from a prospective, randomized, multicenter trial. Crit Care Med. 2007;35:700–706.
  30. Liang B, Wang S, Ye YJ, et al. Impact of postoperative omega-3 fatty acid-supplemented parenteral nutrition on clinical outcomes and immunomodulations in colorectal cancer patients. World J Gastroenterol. 2008;14:2434–2439.
  31. Badía-Tahull MB, Llop-Talaverón JM, Leiva-Badosa E, et al. A randomised study on the clinical progress of high-risk elective major gastrointestinal surgery patients treated with olive oil-based parenteral nutrition with or without a fish oil supplement. Br J Nutr. 2010;104:737–741.
  32. Jiang ZM, Wilmore DW, Wang XR, et al. Randomized clinical trial of intravenous soybean oil alone versus soybean oil plus fish oil emulsion after gastrointestinal cancer surgery. Br J Surg. 2010;97:804–809.
  33. Makay O, Kaya T, Firat O, et al. ω-3 Fatty acids have no impact on serum lactate levels after major gastric cancer surgery. J Parenter Enteral Nutr. 2011;35:488–492.
  34. Wang J, Yu JC, Kang WM, et al. Superiority of a fish oil–enriched emulsion to medium-chain triacylglycerols/long-chain triacylglycerols in gastrointestinal surgery patients: A randomized clinical trial. Nutrition. 2012;28:623–629.
  35. de Miranda Torrinhas RSM, Santana R, Garcia T, et al. Parenteral fish oil as a pharmacological agent to modulate postoperative immune response: A randomized, double-blind, and controlled clinical trial in patients with gastrointestinal cancer. Clin Nutr. 2012;doi:10.1016/j.clnu.2012.12.008.
  36. Han YY, Lain SL, Ko WJ, et al. Effects of fish oil on inflammatory modulation in surgical intensive care unit patients. Nutr Clin Pract. 2012;27:91–98.
  37. Ma CJ, Sun LC, Chen FM, et al. A double-blind randomized study comparing the efficacy and safety of a composite vs. a conventional Intravenous fat emulsion in postsurgical gastrointestinal tumor patients. Nutr Clin Pract. 2012;27:410–415.
  38. Zhu X, Wu Y, Qiu Y, et al. Effect of parenteral fish oil lipid emulsion in parenteral nutrition supplementation combined with enteral nutrition support in patients undergoing pancreaticoduodenectomy. J Parenter Enteral Nutr. 2013;37:236–242.
  39. Heslin MJ, Latkany L, Leung D, et al. A prospective, randomized trial of early enteral feeding after resection of upper GI malignancy. Ann Surg. 1997;226:567–580.
  40. Gianotti L, Braga M, Nespoli L, et al. Arandomized controlled trialofpreoperativeoralsupplementationwith aspecializeddietin patientswithgastrointestinal cancer.Gastroenterology. 2002;122:1763–1770.
  41. Helminen H, Raitanen M, Kellosalo J. Immunonutritioninelectivegastrointestinal surgerypatients. Scand J Surg. 2007;96:46–50.
  42. Suzuki D, Furukawa K, Kimura F, S et al. Effects of perioperative immunonutrition on cell-mediated immunity, T helper type 1 (Th1)/Th2 differentiation, and Th17 response after pancreaticoduodenectomy. Surgery. 2010;148:573–581.
  43. Liu C,Du Z,Lou C,et al. Enteral nutrition is superior to total parenteral nutrition for pancreatic cancer patients who underwent pancreaticoduodenectomy. Asia Pac J Clin Nutr. 2011;20:154–160.
  44. Daly JM, Lieberman MD, Goldfine J, et al. Enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids in patients after operation: immunologic, metabolic, and clinical outcome. Surgery. 1992;112:56–67.
  45. Daly JM, Weintraub FN, Shou J, et al. Enteral nutrition during multimodality therapy in upper gastrointestinal cancer patients. Ann Surg. 1995;221:327–338.
  46. Wachtler P, Hilger RA, König W, et al. Influence of a pre-operative enteral supplement on functional activities of peripheral leukocytes from patients with major surgery. Clin Nutr. 1995;14:275–282.
  47. Kenler AS, Swails WS, Driscoll DF, et al. Early enteral feeding in postsurgical cancer patients. Fish oil structured lipid-based polymeric formula versus a standard polymeric formula. Ann Surg. 1996;223:316–333.
  48. Senkal M, Mumme A, Eickhoff U, et al. Early postoperative enteral immunonutrition: clinical outcome and cost-comparison analysis in surgical patients. Crit Care Med. 1997;25:1489–1496.
  49. McCarter MD, Gentilini OD, Gomez ME, et al. Preoperative oral supplement with immunonutrients in cancerpatients. J Parenter Enteral Nutr. 1998;22:206–211.
  50. Braga M, Gianotti L, Radaelli G, et al. Perioperative immunonutrition in patients undergoing cancer surgery: results of a randomized double-blind phase 3 trial. Arch Surg. 1999;134:428–433.
  51. Senkal M, Zumtobel V, Bauer KH, et al. Outcome and cost-effectiveness of perioperative enteral immunonutrition in patients undergoing elective upper gastrointestinal tract surgery: a prospective randomized study. Arch Surg. 1999;134:1309–1316.
  52. Erdem NZ, Kulaçoĝlu İH, Temel NA, et al. Perioperative Oral Supplement with Immunonutrients in Gastrointestinal Cancer Patients. Turk J Med Sci. 2001;31:79–86.
  53. Braga M, Gianotti L, Nespoli L, et al. Nutritional approach in malnourished surgical patients: a prospective randomized study. Arch Surg. 2002;137:174–180.
  54. Jiang XH, Li N, Zhu WM, et al. Effects of postoperative immune-enhancing enteral nutrition on the immune system, inflammatory response, and clinical outcome. Chinese medical Journal. 2004;117:835–839.
  55. Farreras N, Artigas V, Cardona D, et al. Effect of early postoperative enteral immunonutrition on wound healing in patients undergoing surgery for gastric cancer. Clin Nutr. 2005;24:55–65.
  56. Guoxiang Y, Xinbo X, Xingpei L, et al. Effects of postoperative enteral immune-enhancing diet on plasma endotoxin level, plasma endotoxin inactivation capacity and clinical outcome. J Huazhong Univ Sci Technolog Med Sci. 2005;25:431–434.
  57. Lobo DN, Williams RN, Welch NT, 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;25:716–726.
  58. Xu J, Zhong Y, Jing D, et al. Preoperative enteral immunonutrition improves postoperative outcome in patients with gastrointestinal cancer. World J Surg.2006;30:1284–1289.
  59. Finco C, Magnanini P, Sarzo G, et al. Prospective randomized study onperioperativeenteralimmunonutritioninlaparoscopiccolorectalsurgery.Surg Endosc. 2007;21:1175–1179.
  60. Klek S, Kulig J, Sierzega M, et al. Standard and immunomodulating enteral nutrition in patients after extended gastrointestinal surgery--a prospective, randomized, controlled clinical trial. Clin Nutr. 2008;27:504–512.
  61. Gunerhan Y, Koksal N, Sahin UY, et al. Effect of preoperative immunonutrition and other nutrition models on cellular immune parameters. World J Gastroenterol. 2009 28;15:467–472.
  62. Okamoto Y, Okano K, Izuishi K, et al. Attenuation of the systemic inflammatory response and infectious complications after gastrectomy with preoperative oral arginine and omega-3 fatty acids supplemented immunonutrition. World J Surg. 2009;33:1815–1821.
  63. Sodergren MH, Jethwa P, Kumar S, et al. Immunonutrition in patients undergoing major upper gastrointestinal surgery: a prospective double-blind randomised controlled study. Scand J Surg. 2010;99:153–161.
  64. Fujitani K, Tsujinaka T, Fujita J, et al. Prospective randomized trial of preoperative enteral immunonutrition followed by elective total gastrectomy for gastric cancer. Br J Surg. 2012;99:621–629.
  65. Hübner M, Cerantola Y, Grass F, et al. Preoperative immunonutrition in patients at nutritional risk: results of a double-blinded randomized clinical trial. Eur J Clin Nutr. 2012;66:850–855.
  66. Sultan J, Griffin SM, Di Franco F, et al. Randomized clinical trial of omega-3 fatty acid-supplemented enteral nutrition versus standard enteral nutrition in patients undergoing oesophagogastric cancer surgery. Br J Surg. 2012;99:346–355.
  67. Giger-Pabst U, Lange J, Maurer C, et al. Short-term preoperative supplementation of an immunoenriched diet does not improve clinical outcome in well-nourished patients undergoing abdominal cancer surgery. Nutrition. 2013;29:724–729.
  68. Braga M, Vignali A, Gianotti L, et al. Immune and nutritional effects of early enteral nutrition after major abdominal operations. Eur J Surg. 1996;162:105–112.
  69. Schilling J, Vranjes N, Fierz W, et al. Clinical outcome and immunology of postoperative arginine, omega-3 fatty acids, and nucleotide-enriched enteral feeding: A randomized prospective comparison with standard enteral and low calorie/low fat i.v. solutions. Nutrition. 1996;12:423–429.
  70. Gianotti L, Braga M, Vignali A, et al. Effect of route of delivery and formulation of postoperative nutritional support in patients undergoing major operations for malignant neoplasms. Arch Surg. 1997;132:1222–1229.
  71. Di Carlo V, Gianotti L, Balzano G, et al. Complications of pancreatic surgery and the role of perioperative nutrition. Dig Surg. 1999;16:320–326.
  72. Braga M, Gianotti L, Vignali A, et al. Preoperative oral arginine and n-3 fatty acid supplementation improves the immunometabolic host response and outcome after colorectal resection for cancer. Surgery. 2002;132:805–814.
  73. Klek S, Kulig J, Sierzega M, et al. The impact of immunostimulating nutrition on infectious complications after upper gastrointestinal surgery: a prospective, randomized, clinical trial. Ann Surg. 2008;248:212–220.
  74. Klek S, Sierzega M, Szybinski P, et al. Perioperative nutrition in malnourished surgical cancer patients–a prospective, randomized, controlled clinical trial. Clin Nutr. 2011;30:708–713.

WinBUGS code for random effectsand fixed effects model for binary outcome data

A hierarchical model with random effectswas used to account for between-study variance, in which data was formatted in a binomial likelihood with a logit link function.3The probability of an event in arm reported in study is denoted by . The number of events in arm of study has the following binomial likelihood, where is the sample size. For the binomial likelihood, we model the probabilities on the logit scale, where is a random parameter for the baseline. Then, the random effects are distributed normally, where is a study-specific logarithm of the odds ratio and is the between study variance. The isexpressed by (treatment effects) and (reference treatment effect); that is, . Prior distribution needs to be set for , , and : , , and .4The estimated odds ratio (OR) of a treatment versus a treatment is derived as: , where for the treatment that has been denoted as the reference treatment. For a fixed effects model, the between study variance () is set to zero.WinBUGS codes were available at:

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