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

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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: