A systematic review of methodology in nutritional trials in patients undergoing pancreatoduodenectomy
Review Article

A systematic review of methodology in nutritional trials in patients undergoing pancreatoduodenectomy

James M. Halle-Smith1 ORCID logo, Keshav Krishnan2, Jasmin Kirupananthan2, Kayaththery Varathan2, Richard Laing3, Mary E. Phillips4 ORCID logo, Keith J. Roberts1, Andrew M. Smith5, Samir Pathak5

1Department of Hepatobiliary and Pancreatic Surgery, University of Birmingham and Queen Elizabeth Hospital Birmingham, Birmingham, UK; 2Department of Pancreatic Surgery, University of Leeds, Leeds, UK; 3Department of Upper GI Surgery, Royal Stoke University Hospital, Stoke-on-Trent, UK; 4Department of Nutrition and Dietetics, Royal Surrey University Hospitals, Guildford, UK; 5Department of Pancreatic Surgery, St James Hospital Leeds, Leeds, UK

Contributions: (I) Conception and design: JM Halle-Smith, S Pathak; (II) Administrative support: JM Halle-Smith, S Pathak; (III) Provision of study materials or patients: JM Halle-Smith, K Krishnan, J Kirupananthan, K Varathan; (IV) Collection and assembly of data: JM Halle-Smith, K Krishnan, J Kirupananthan, K Varathan; (V) Data analysis and interpretation: JM Halle-Smith, S Pathak; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: James M. Halle-Smith, MBChB MRCS. Department of Hepatobiliary and Pancreatic Surgery, University of Birmingham and Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Birmingham B15 2GW, UK. Email: james.hallesmith@doctors.org.uk.

Background: Malnutrition is highly prevalent amongst pancreatoduodenectomy (PD) patients and remains a major modifiable risk factor for postoperative morbidity and mortality. However, studying nutritional interventions is difficult due to multiple methodological issues. The aim of this review is to report and compare the administration of different nutritional therapies as well as reporting of nutritional outcomes in randomised controlled trials (RCTs) of PD patients.

Methods: A systematic review of RCTs reporting the effect of different nutritional interventions after PD was performed according to the PRISMA guidelines.

Results: In the 20 suitable studies identified, there was widespread variation in when oral diet was started, ranging between postoperative day (POD)1 and POD7. Regarding enteral tube feeding, multiple different feed types were used and feed administration was highly variable, for both rate and duration. In terms of outcome types, 17 (85%) studies reported biochemical outcomes with serum albumin being the most common (12 studies, 57%) and 12 (57%) reported anthropometric outcomes with body mass index (BMI) being the most common (7 studies, 33%).

Conclusions: Amongst the published RCTs investigating the effect of different nutritional routes after PD, widespread variation in the methodology was evident. This has implications for both interpretation of results and for design of future nutritional trials. Multiple biochemical and anthropometric outcomes were reported but quality of life measures, such as the SF-36 recommended by a recently published core outcome set (COS), were not used.

Keywords: Pancreatoduodenectomy (PD); systematic review; malnutrition

Submitted Sep 17, 2024. Accepted for publication Jan 29, 2025. Published online Aug 11, 2025.

doi: 10.21037/hbsn-24-524

Highlight box

Key findings

• There is widespread variation in the methodology used to investigate different nutritional routes after pancreatoduodenectomy (PD) which causes difficulty in interpretation of results. Many of these trials report biochemical or anthropometric nutritional outcomes rather than quality of life measures which are recommended by the recently published core outcome set (COS).

What is known and what is new?

• Patients undergoing PD are at high risk of malnutrition. There are multiple routes by which nutrition can be delivered postoperatively.

• This manuscript highlights the different methodologies used in the literature both in terms of interventions and outcome reporting.

What is the implication, and what should change now?

• This study highlights the methodological heterogeneity amongst trials of nutritional interventions after PD. In order to facilitate meaningful comparison and translation into clinical practice, future trials should clearly report details of interventions used and report outcomes according to the recently published COS.

Introduction

The mainstay of treatment for periampullary and pancreatic malignancy remains surgical resection, most often with pancreatoduodenectomy (PD), combined with systemic chemotherapy. PD is a complex intervention associated with persistently high rates of postoperative morbidity and mortality, with the most common contributor being the development of a postoperative pancreatic fistula (POPF) (1-5).

Malnutrition is prevalent amongst PD patients even before surgery (6,7) and increases drastically during inpatient stay, to greater than 75% (8). Importantly for PD patients, already a cohort at risk of postoperative morbidity, malnutrition has been shown to increase postoperative complications, reduce quality of life and survival after surgery (6,8,9). Furthermore, weight loss of greater than 10% postoperatively is associated with reduced uptake and completion of adjuvant chemotherapy after pancreatectomy (10). Malnutrition is complex to diagnose with significant variation in incidence dependent on the assessment tool used (7,11), and changes in body composition, often without weight loss also associated with poor surgical outcomes (12,13). As a result, there is a clear unmet clinical need for strategies to improve the perioperative nutritional status of PD patients.

Randomised controlled trials (RCTs) are considered to represent the optimal method for assessing the effectiveness of interventions. However, designing a clinical trial to robustly assess the efficacy of nutritional regimens in pancreatic cancer surgery patients has historically been fraught with difficulties including slow recruitment (14) and a lack of suitable outcomes.

Nutritional management after PD is complex, with multiple combinations of feed types and rates used in clinical practice. Therefore, to make meaningful comparisons of the nutritional effect of different feeding regimens after PD, it is important to understand the exact methodology used in clinical trials of nutritional interventions in PD patients; this will impact on nutritional outcomes of these patients which may go some way to explain the variation in results and inform the design of future research in this area.

Therefore, the primary aim of this review is to report and compare the administration of different nutritional therapies in RCTs evaluating these interventions in PD patients. The secondary aim is to look at inclusion criteria within these RCTs, the reporting of nutritional outcomes after PD, and compare this to the recently published core outcome set (COS) for nutritional and metabolic clinical effectiveness trials (15). We present this article in accordance with the PRISMA reporting checklist (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-524/rc).

Methods

Eligibility criteria

Studies suitable for inclusion in this study were RCTs that reported outcomes according to different feeding routes after PD (both pylorus-preserving PD and classical Whipple) with the full text available in English. Review articles, opinion papers, case reports, animal studies, and studies not reporting results of different nutritional routes separately were excluded. Studies that were more than 30 years old were excluded due to changes in clinical practice.

Search strategy

A systematic literature search of PubMed, MEDLINE, Embase, and the Cochrane Library for RCTs evaluating nutritional interventions in PD patients was first performed in May 2023. The search term was restricted to titles and abstracts, and results were merged and screened using Rayyan. The search term involved variations of ‘pancreatoduodenectomy’ and ‘nutrition’. The full search term is available in Appendix 1. Reference lists of included studies were cross-checked to identify additional relevant studies.

Selection process

Results were screened for eligibility by three reviewers (J.M.H.S., K.K., and J.K.). Any discrepancies were resolved through discussion with the senior author (S.P.). The PRISMA flow diagram of included studies is shown in Figure 1.

Figure 1 PRISMA flowchart.

Data collection process

Characteristics of the included studies, as well as the patients included, were collected. The following data points related to nutritional intake were also collected: nutritional routes, type of feed, rate of feed, and when feed was introduced. Following this, outcomes reported in each of the studies to assess different nutritional interventions were also collected. The inclusion criteria used by each study were also sought from each included study. Due to the nature of the data collected, no quantitative syntheses were performed.

Results

Twenty relevant studies were identified and included in the present study, with a total of 1,549 patients (16-35). Most studies reported nutritional management and outcomes for patients after PD, with some also including patients who underwent total pancreatectomy and distal pancreatectomy (16). Of note, some studies excluded patients with severe malnutrition preoperatively and others excluded patients who were receiving nutritional support preoperatively (27,30). One study excluded all patients who had a pancreatogastrostomy reconstruction (23).

The majority of the studies (18/20) reported the details of oral intake for included patients. Studies reporting other nutritional routes included 6/20 nasojejunal feeding, 7/20 feeding jejunostomy tube, and 7/20 parenteral nutrition (Table 1). The majority of studies were single centre and one study received industry funding from a company that provides nutritional products (Table 2) (32).

Table 1

Characteristics of included studies

Study Year Number of patients Pancreatic operations included Oral diet Nasojejunal tube Jejunostomy tube Parenteral nutrition
Ergenc et al. (16) 2021 38 PD, TP, DP √ X X X
Folwarski et al. (17) 2021 40 PD √ √ X X
Bergeat et al. (18) 2020 111 PD √ X X X
Wu et al. (19) 2019 114 PD √ X X X
Miyauchi et al. (20) 2019 71 PD √ X X X
Perinel et al. (21) 2016 204 PD X √ X √
Fujii et al. (22) 2015 30 DP √ X X √
Fujii et al. (23) 2015 59 PD √ X X √
Zhu et al. (24) 2014 68 PD √ √ √ X
Aida et al. (25) 2014 50 PD √ X X X
Zhu et al. (26) 2013 76 PD √ √ X X
Park et al. (27) 2012 38 PD √ √ X √
Liu et al. (28) 2011 60 PD √ X √ √
Tien et al. (29) 2009 247 PD √ X √ √
Grizas et al. (30) 2008 60 PD √ X √ X
Rayes et al. (31) 2007 80 PD √ √ X X
Mack et al. (32) 2004 36 PD √ X X X
Duerksen et al. (33) 2002 10 PD X X √ X
Di Carlo et al. (34) 1999 100 PD √ X √ √
van Berge Henegouwen et al. (35) 1997 57 PD √ X √ X

“√” means included in the study; “X” means not included in study. DP, distal pancreatectomy; PD, pancreatoduodenectomy; TP, total pancreatectomy.

Table 2

Additional characteristics of included studies

Study Year Country/region Single or multi centre Industry funding Nutritional exclusion criteria used
Ergenc et al. (16) 2021 Turkey Single None Severe malnutrition
Folwarski et al. (17) 2021 Poland Single None Contraindication for postoperative enteral feeding
Bergeat et al. (18) 2020 France Single None Previous gastric surgery
Wu et al. (19) 2019 Taiwan Multi None None
Miyauchi et al. (20) 2019 China Single None Gastrointestinal obstruction
Perinel et al. (21) 2016 France Multi None None
Fujii et al. (22) 2015 Japan Multi None None
Fujii et al. (23) 2015 Japan Multi None PG excluded
Zhu et al. (24) 2014 China Single None None
Aida et al. (25) 2014 Japan Single None Gastrointestinal obstruction
Zhu et al. (26) 2013 China Single None None
Park et al. (27) 2012 Korea Single None Preoperative nutritional support
Liu et al. (28) 2011 China Single None None
Tien et al. (29) 2009 China Single Not stated None
Grizas et al. (30) 2008 Lithuania Single Not stated Preoperative enteral nutrition
Rayes et al. (31) 2007 Germany Single Not stated Contraindication for postoperative enteral feeding
Mack et al. (32) 2004 USA Single Yes, Novartis Nutrition Preoperative nutritional support
Duerksen et al. (33) 2002 Canada Single None Severe malnutrition
Di Carlo et al. (34) 1999 Italy Single Not stated Not stated
van Berge Henegouwen et al. (35) 1997 Netherlands Single None Postoperative complication affecting enteral nutrition

PG, pancreaticogastrostomy.

Oral feeding

In terms of oral feeding, liquids were most commonly introduced on postoperative day (POD)1 (9/18 studies) but was reported up to POD7. The introduction of solid food was more variable, with some studies not giving a specific day, rather stating that it was at the discretion of the surgical team. The most common day for introduction of solid oral diet reported was POD7, in 4/18 studies. The majority of patients were fed by a concurrent feeding route (enteral or parenteral) in the postoperative period, with 13/18 studies feeding patients via the enteral route in addition to oral intake (Table 3).

Table 3

Oral feeding

Study POD liquids started POD solid food started Other feeding routes used at the same time
Ergenc et al. (16) POD1 POD1 No
Folwarski et al. (17) POD1 POD1 Yes, NJ
Bergeat et al. (18) POD1 “Gradually introduced according to patient tolerance” Yes, NG tube
Wu et al. (19) POD3 POD3 Yes, GJ
Miyauchi et al. (20) POD1 POD1 Yes, GJ
Fujii et al. (22) – POD6 Yes, TPN
Fujii et al. (23) – POD6 Yes, TPN
Zhu et al. (24) – POD7 Yes, NJ/JT
Aida et al. (25) – POD 5 Yes, GJT
Zhu et al. (26) – POD7 Yes, NJ
Park et al. (27) POD4 POD7 Yes, NJ/TPN
Liu et al. (28) POD7 POD 7 Yes, JT/TPN
Tien et al. (29) – – Yes, NG
Grizas et al. (30) POD1 POD4 No
Rayes et al. (31) POD1 POD2 Yes, NJ
Mack et al. (32) POD1 At the discretion of surgical team Yes, NG
Di Carlo et al. (34) POD1 POD1 No
van Berge Henegouwen et al. (35) POD1 POD1 (if patient responds well to liquid diet) NG tube

GJ, gastojejunostomy; GJT, gastojejunostomy tube; JT, jejunostomy; NG, nasogastric; NJ, nasojejunal; POD, postoperative day; TPN, total parenteral nutrition.

Enteral nutrition

Enteral nutrition was administered via nasojejunal or feeding jejunostomy routes; the rates and type of feed used in the included studies are summarised in Tables 4,5. Regarding nasojejunal feeding, widespread differences in the types of feed, rates of feed, and concurrent oral feeding were observed. Different feed types were used across the studies, with Nutrison Advanced Peptisorb (Nutricia Clinical Care) being the only feed type used in more than one study. Feed was administered in a continuous manner in three studies, and in a cyclical manner in two studies (Table 4). This was similar for those patients fed via feeding jejunostomy, where the type of feed used varied considerably as well as the rate of feed (Table 5).

Table 4

Enteral nutrition with nasojejunal tube

Study Type of feed Rate of feed Concomitant oral feeding permitted Timing of feed
Folwarski et al. (17) Enteral probiotic nutrition (polymeric) Started 4 h postoperatively at 20 mL/h. Then 30 mL/h in the next 12 h. Then 40 and 60 mL/h in POD4 Yes Cyclical (12 h/day)
Perinel et al. (21) Combination of non-specified enteral feed and normal saline 25 mL/h initially, increasing by 25 mL/h every 24 h No 20 h feed, 4 h saline
Zhu et al. (24) Peptisorb (hydrolysed) Gradual increase until 30 mL/kg on POD6 – Continuous
Zhu et al. (26) GNS (24 h), Peptisorb (POD3) (hydrolysed) Gradual increase until 30 mL/kg/d on POD6 No Continuous
Park et al. (27) Jevity RTH (polymeric and fibre-containing) 20 mL/h increased by 20 mL/h per day – Cyclical (18 h/day)
Rayes et al. (31) Enteral Stresson, Pfrimmer Nutricia (immunonutrition and polymeric) 25 mL/h from POD1, increased to 1 mL/kg from POD1 until POD8 Yes Continuous

GNS, glucose normal saline; POD, postoperative day.

Table 5

Enteral nutrition with feeding jejunostomy tube

Study Type of feed Rate of feed Concomitant feeding permitted Timing of feed
Zhu et al. (24) Peptisorb (partially hydrolysed) Gradual increase until 30 mL/kg on POD6 – Continuous
Liu et al. (28) Unspecified polymeric with added omega-3 oils and fibre 27 kcal/kg/day – –
Tien et al. (29) Commercially available enteral nutrition solution, with glucose-to-lipid ratio of 70:30 Progressively increased by 10 mL/day until the goal of full nutrition (25 kcal/kg) was reached Yes (oral) Continuous
Grizas et al. (30) Enteral Semper standard and Fresubin standard (polymeric) 20 mL/h on POD1 then increased in 20 mL/h steps until POD6 Yes (oral) Continuous
Duerksen et al. (33) EF Vital Abbott HN or PIEF Impact Novartis (concentrated, partially hydrolysed) 25 mL/h for 8 h, 50 mL/h for 8 h, and 75 mL/h for 8 h Yes (oral) Continuous
Di Carlo et al. (34) SEN (polymeric); IEN (Impact, Novartis Nutrition) (immunonutrition) Initially 10 mL/h on POD1 then 30 mL/h on POD2 until 25 kcal/kg Yes (oral) Continuous
van Berge Henegouwen et al. (35) Nutrison enteral compact (concentrated polymeric) Continuous enteral (0–24 h; 1,500 kcal/24 h) from POD4; cyclic enteral (6–24 h; 1,125 kcal/18 h) from POD4 Yes (oral) Both continuous or cyclical

POD, postoperative day.

Parenteral nutrition

Administration of parenteral nutrition was more standardised and is summarised in Table 6. Concomitant oral feeding was reported to be permitted in two studies (21,34), and where the rate was reported, feed was given continuously.

Table 6

Parenteral nutrition

Study Type of feed Rate of feed Concomitant feeding permitted Timing of feed
Perinel et al. (21) PN formula containing amino acids and carbohydrates. Lipid content not specified Rate of feed not specified, but target feed: 30 kcal/kg/day with 1.5 amino acids/kg/day with a ratio of carbohydrates/amino acids of 3:2. Continued until oral food intake reached 60% of nutritional requirements Oral Continuous
Fujii et al. (22) 1,600 kcal feed, all in one (contains lipid, amino acids, and carbohydrates) N/A N/A Continuous
Fujii et al. (23) 1,600 kcal feed, all in one (contains lipid, amino acids, and carbohydrates) N/A N/A Continuous
Park et al. (27) PN formula specified to contain: glucose, lipid, and vitamins Gradual increase until 800 kcal/day – N/A
Liu et al. (28) Main content of the TPN formulas were glucose, alanine, aspartic acid, phenylalanine, glutamic acid, glycine, histidine, isoleucine, lysine, methionine, praline, serine, threonine. Lipid content not specified 27 kcal/kg/day N/A N/A
Tien et al. (29) PN (readymade bags containing lipid, amino acid, and glucose) Commenced if no oral intake after 1 week, or <50% oral intake after 2 weeks. Discontinued when consuming 25 kcal/kg orally without vomiting – –
Di Carlo et al. (34) Unspecified PN formula N/A Oral Continuous

N/A, not available; PN, parenteral nutrition; TPN, total parenteral nutrition.

Nutritional outcomes

The outcomes used to evaluate nutritional outcomes in the included trials are summarised in Table 7. Outcomes were separated into biochemical, anthropometric, and nutritional intake. The most common biochemical outcome reported was serum albumin, with prealbumin and retinol binding protein also reported but less frequently. In terms of anthropometric measures, body mass index (BMI) was the most commonly used. Nutritional intake was most commonly measured by calories consumed, with specific macronutrient intake (such as protein and carbohydrate) also reported in some studies. Other relevant outcomes included scores such as the nutritional risk index, prognostic nutritional index, and the nutritional risk score 2002.

Table 7

Nutritional outcomes reported

Study Biochemical Anthropometric Nutritional values Other relevant nutritional outcomes
Ergenc et al. (16) X X X Passing flatus, bowel movement and fluid retention in NG tube and the day of its removal
Folwarski et al. (17) Albumin BMI Protein intake Nutritional risk score 2002, patient appetite (visual analogue scale), passing flatus, bowel movement, NG tube removal and fluid retention in NG tube and the day of its removal
Bergeat et al. (18) X X X NGT reinsertion rate (time and causes)
Wu et al. (19) Albumin BMI Time to reach calorie target X
Miyauchi et al. (20) Albumin, prealbumin, RBP, transferrin, EPA, Con A, PHA, plasma IL-6, PNI % body weight loss X Prognostic nutritional index
Perinel et al. (21) Albumin, prealbumin, NRI Body weight, BMI X Nutritional risk index
Fujii et al. (22) X X Calories consumed X
Fujii et al. (23) X X Calories consumed X
Zhu et al. (24) X X Calories, carbohydrates, fat, and protein consumed X
Aida et al. (25) X X Calories, carbohydrates, fat, and protein consumed X
Zhu et al. (26) Albumin, total protein X Calories consumed X
Park et al. (27) Protein, albumin BMI Calories consumed First day of bowel movement
Liu et al. (28) Total protein, albumin, retinol binding protein X Calories consumed X
Tien et al. (29) Albumin Body weight loss Calories consumed X
Grizas et al. (30) Albumin BMI Calories and protein consumed X
Rayes et al. (31) Prealbumin BMI Calories, protein, carbohydrates, and lipids consumed X
Mack et al. (32) X Body weight loss Calories consumed NGT reinsertion rate
Duerksen et al. (33) Albumin BMI Calories, protein, carbohydrates, and fat consumed Volume of pancreatic secretions (lipase, amylase, chymotrypsin, bicarbonate, and protein) with secretin
Di Carlo et al. (34) Albumin Weight loss, malnutrition Days until full nutritional goal of 25 kcal/kg X
van Berge Henegouwen et al. (35) Albumin X X Days until oral diet continued, CCK, PP, and SBTT on POD10

“X” means not included in study. BMI, body mass index; CCK, cholecystokinin; Con A, concanavalin A-stimulated lymphocyte proliferation; EPA, eicosapentaenoic acid; IL-6, interleukin-6; NG, nasogastric; NGT, nasogastric tube; NRI, nutritional risk index; PHA, phytohemoglutinin-stimulated lymphocyte proliferation; PNI, prognostic nutritional index; POD, postoperative day; PP, pancreatic polypeptide; RBP, retinol binding protein; SBTT, small bowel transit time.

The recently published COS for nutritional trials (the CONCISE guidelines) recommends the use of the physical component score of the SF-36 questionnaire at 30 and 90 days post-randomisation (15). A study reported more subjective measures, such as patient appetite via a visual analogue scale (16), but none of the trials included in this study measured patient-reported outcome measures (PROMs). Furthermore, the most common anthropometric outcome measure used in the included trials was BMI. Other measures recommended by the CONCISE guidelines (15), namely the global leadership on malnutrition (GLIM) scoring system (15,36), or functional tests such as the 6-minute walk test or sit-to-stand test were not used in any of the included studies.

Discussion

Malnutrition remains a significant challenge in PD patients. As such, there is great interest in interventions that may improve the nutritional status of these patients. However, appraising the existing evidence for these interventions is difficult, in part due to the methodological variation in the published literature.

This systematic review reports and compares the administration of different nutritional therapies in RCTs of PD patients. The greatest variation was observed in the enteral feeding groups, through both nasojejunal and feeding jejunostomy routes. Almost every included study used a different feed formulation and the administration routine varied considerably between trials, with half of the studies giving feed in a cyclical manner and the other half in a continuous manner. Rates of feed also varied between the included studies. This is an important observation, for when nutritional routes have been compared in the past, whether that be directly at an individual study level or as part of systematic reviews (37,38), enteral nutrition studies are often grouped together. However, the significant heterogeneity reported in this review makes this problematic as the type of feed or the manner in which it is administered (rate or routine) can have a significant difference. For example, one study compared both cyclical and continuous feeding administration through a feeding jejunostomy (35). In this study, it was observed that patients in the cyclical group were able to tolerate more feed and so had greater nutritional intake (measured in terms of calories). The importance of this is that even within one nutritional route (enteral), the rate in which feed was administered can make a difference in the nutritional intake of patients. This makes bulk comparisons between nutritional routes difficult.

In terms of oral diet, liquids were introduced at a similar time across the studies (POD1) but variation was observed in the timing of solid diet being introduced. This is important because early oral feeding (EOF), typically defined as the introduction of solid food by POD2, has been shown to improve the calorific and protein intake in PD patients as well as reduced length of stay (39,40). Of the 18 studies that reported oral intake details, six of these allowed solid intake by POD2. This is important because this heterogeneity is likely to influence patient outcomes and so bulk comparisons between oral and other nutritional routes are more challenging. It should also be acknowledged that over the past few years, there has been a push towards early oral intake as a part of enhanced recovery after surgery programmes (16,39,41).

A further source of heterogeneity was the type of enteral feed used in each study. For example, two formulations named in the included studies were the Peptisorb (Nutricia Clinical Care) and Jevity RTH (Abbott Nutrition) feeds. As is to be expected, the nutritional compositions of these feeds differ, with Peptisorb containing 4 g protein and 100 kcal per 100 mL of feed, is low in fat, fibre free feed with the protein component hydrolysed to peptides, whilst Jevity RTH contains 6.4 g protein and 154 kcal per 100 mL of feed, is a concentrated whole protein (polymeric) feed with additional fibre (42). When different rates are combined with different feed compositions, this leads to significant heterogeneity in the nutritional values received by each cohort. Given that calorific and protein intake are known to be linked to outcomes after pancreatic surgery (6,8,9,43), these variations are likely to have had a bearing on patient outcomes even though they are using the same nutritional route (enteral). Furthermore, polymeric feeds may well require pancreatic enzyme replacement therapy (PERT) for absorption, whereas partially hydrolysed feeds may be absorbed without PERT (44).

Some of the enteral feeds used contain probiotics, immunonutrition or were started at relatively fast rates—this introduces further variables when considering morbidity and infectious complications, and high-rate enteral feed is a risk factor for complications including ischaemic bowel (45). Other factors that should be considered when deciding on enteral nutrition feed type and rate in PD patients include inotrope rates, delayed gastric emptying, and management of complications such as chyle leak. Regarding parenteral nutrition, some studies did not include lipids in their feed composition which results in a high concentration of glucose administration, which can result in hepatic steatosis and have an adverse effect on both glycaemic control and respiratory function (46).

Trials of nutritional interventions are important; expert guidelines and quality improvement programs recognise that nutrition is the one key modifiable risk factor after major surgery (43,47-49). However, it is important that these trials are appropriately designed. It has previously been acknowledged that measuring the effect of different nutritional outcomes in studies is difficult, so a COS for clinical effectiveness trials of nutritional interventions has recently been put together with an international Delphi consensus process—the CONCISE guidelines (15). To ensure that future trials investigating nutritional interventions in pancreatic surgery are assessing clinically relevant outcomes, it is advisable that they are designed in accordance with this COS (15). For example, none of the trials included in this study measured PROMs. The CONCISE guidelines recommend the use of the physical component score of the SF-36 questionnaire at 30 and 90 days post-randomisation, so future trials should incorporate this into their design (15). Furthermore, the most common anthropometric outcome measure used in the included trials was BMI. Future trials should avoid this and instead use the GLIM scoring system (15,36), or functional tests such as the 6-minute walk test or sit-to-stand test (15).

A further methodological challenge and consideration for nutritional trials in surgical patients is how nutritional intake, in terms of calories and protein for example, is calculated. When administering nutrition solely through the parenteral or enteral route, this is more straightforward. However, this review demonstrates that most patients are permitted some oral intake along with enteral or parenteral nutrition. This makes quantifying nutritional intake accurately more challenging, since it relies on recall or paper food charts which are notoriously inaccurate (50,51). Future studies could therefore incorporate newer technology such as real-time monitoring using digital food charts (52).

Limitations in reporting nutritional management after PD are common across the included studies and thus also within this review. Nutritional management of PD patients is complex and decided on an individual patient basis according to risk profile. For example, some will manage patients at high risk of POPF differently to those at lower risk. Equally, some will change nutritional routes according to postoperative results, such as drain fluid amylase or inflammatory markers. Similarly, the use of an NG tube routinely may differ according to the type of PD performed; with some leading an NG tube for longer in those with a classical PD due to higher risk of bleed at the anastomosis. This means that bulk comparisons, reporting, and standardisation of nutritional practice after PD are challenging.

Conclusions

This review highlights significant heterogeneity amongst enteral and oral nutritional routes which make bulk comparisons challenging. This has multiple implications for the design of future nutritional trials in pancreatic surgery. Firstly, it is vital that any future studies in this area clearly report which nutritional products have been used as interventions as well as the rates used. It is also vital that studies report concomitant feeding permitted, at what point feeding is initiated after surgery as well as how the development of complications such as POPF affect feeding. In terms of outcome reporting, proper consideration should be given to the outcomes chosen in any future trials to assess the efficacy of nutritional interventions, namely by referring to recently published COS, the CONCISE guidelines. A high-quality prospective study which captures nutritional practice after PD, and factors that affect this, is required to properly understand current real-world practice. Following this, a consensus study may be required to ascertain research priorities and acceptable trial design for future studies.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-524/rc

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-524/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-24-524/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Halle-Smith JM, Krishnan K, Kirupananthan J, Varathan K, Laing R, Phillips ME, Roberts KJ, Smith AM, Pathak S. A systematic review of methodology in nutritional trials in patients undergoing pancreatoduodenectomy. Hepatobiliary Surg Nutr 2026;15(3):70. doi: 10.21037/hbsn-24-524

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