Current evidence of nutritional therapy in pancreatoduodenectomy: Systematic review of randomized controlled trials

Abstract Aim Evidence of nutritional therapies in pancreatoduodenectomy (PD) has been shown. However, few studies focus on the association between different nutritional therapies and outcomes. The aim of this review was to summarize the current evidence of nutritional therapies such as enteral nutrition (EN), immunonutrition, and synbiotics on postoperative outcomes after PD. Methods A systematic literature search of Embase, Medline Ovid, and Cochrane CENTRAL was done to summarize the available evidence, including randomized controlled trials, meta‐analyses and reviews, regarding nutritional therapy in PD. Results A total of 20 randomized controlled trials were included in this review. Safety and tolerability of EN in PD was shown. Giving postoperative EN can shorten length of stay compared to parenteral nutrition; however, the effect of EN on postoperative complications remains controversial. Postoperative EN should be given only on selective indications rather than routinely used, and preoperative EN is indicated only in patients with severe malnutrition. Giving preoperative immunonutrition is considered to reduce the incidence of infectious complications; however, evidence level is moderate and recommendation grade is weak. The beneficial effect of perioperative synbiotics on postoperative infectious complications is limited. Furthermore, the effectiveness of other nutritional supplements remains unclear. Conclusion Recently, evidence of enhanced recovery after surgery (ERAS) in PD has been increasing. Early oral intake with systematic nutritional support is an important aspect of the ERAS concept. Future well‐designed studies should investigate the impact of systematic nutritional therapies on outcomes following PD.


| INTRODUC TI ON
Pancreatoduodenectomy (PD) is a highly invasive procedure in abdominal surgery. Outcomes following PD have improved due to the development of the operative technique, surgical instruments, and perioperative management; however, complication and mortality rates are still high. [1][2][3] To improve clinical outcomes in gastrointestinal surgery, perioperative nutritional therapy is considered to be important.
A previous review regarding perioperative nutritional support in patients undergoing PD was published in 2006 and suggested that enteral nutrition (EN) is associated with lower incidence of postoperative infections. 4 However, this review evaluated only four studies focused on patients who underwent PD, including two randomized controlled trials (RCT), and further studies on this issue have been reported since 2006. Furthermore, the concept of enhanced recovery after surgery (ERAS), a multimodal strategy aimed to accelerate postoperative recovery, has recently been rapidly spreading in the field of PD. 5,6 The aim of the present review was to overview the current evidence of nutritional therapies such as EN, immunonutrition (IM), synbiotics and other nutritional supplements as a nutritional aspect of the ERAS concept, and to evaluate the association between nutritional therapies and postoperative outcomes in patients undergoing PD.

| MATERIAL S AND ME THODS
A systematic literature search of Embase, Medline Ovid, and Cochrane CENTRAL was carried out on January 11, 2019 using the following key words: diet therapy, enteral nutrition, synbiotics, supplements, enhanced recovery after surgery, and pancreatoduodenectomy (Table S1). The search was limited to RCT, meta-analyses, and reviews in English. The present study included articles reporting outcomes of nutritional therapies in patients following PD. After removing duplicate records, abstracts were screened independently by two investigators to determine eligible studies for further analysis. Full-text articles of the remaining records were subsequently retrieved and screened independently by two investigators. The present study is reported according to the Preferred Reporting Items for Systematic Reviewers and Meta-Analyses (PRISMA) guidelines. 7   In summary, the safety and tolerability of EN in PD has been shown according to several meta-analyses and a review. [30][31][32][33] Giving postoperative EN can shorten LOS compared to TPN; however, the effect of EN on postoperative complications following PD remains controversial. The concept of selective indication for artificial nutrition rather than routine use should be discussed. 5,6,15,34 Furthermore, preoperative EN should be indicated only in patients with severe malnutrition. 5,6,34

| Immunonutrition
Effect of IM has been examined over many years, and several systematic reviews have shown beneficial outcomes of IM in patients following gastrointestinal surgery. [35][36][37] The earliest RCT (Di Carlo et al 14  compare outcomes between the control group (standard nutrition, n = 9) and the treatment group (preoperative eicosapentaenoic acid-enriched nutrition, n = 11) after PD. There were no significant differences in perioperative interleukin-6 levels between the two groups (P = .68). Furthermore, no significant differences were found in the incidence of infectious complications (55% vs 78%, P = . 37) and overall complications (91% vs 78%, P = .57). No data on LOS were reported.
Giving preoperative IM is considered to reduce the incidence of infectious complications after PD; however, the evidence level of IM is moderate and the recommendation grade is weak according to the guidelines for perioperative care for PD by the ERAS Society. 5,6 Further well-designed studies with a large number of patients are required to address the current evidence.

| Synbiotics
Synbiotics consists of probiotics and prebiotics. Probiotics, live beneficial bacteria, can influence pathogenic mechanisms of bacterial translocation by increasing intestinal motility, stabilizing the intestinal barrier, and enhancing the innate immune system. 21 Prebiotics, such as fiber, is a non-digestible dietary ingredient that serves as a nutritional source for probiotics. Giving synbiotics may be helpful in preventing bacterial translocation especially following highly invasive surgery. Beneficial outcomes have been shown in a recent systematic review of 11 RCT in patients following highly invasive abdominal surgery. 38 It was concluded that improving the intestinal microenvironment and intestinal barrier function before surgery is crucial to prevent postoperative infections following highly invasive surgery.
Use of preoperative synbiotics could be helpful to improve intestinal microflora, and prevent bacterial translocation and the incidence of infectious complications.
Another systematic review of 28 RCT including 2511 patients following gastrointestinal surgery showed that giving perioperative synbiotics may prevent postoperative infections; however, the results need to be interpreted with caution as a result of the risk of bias and the potential publication bias. 39 Although recent reviews has shown the effectiveness of synbiotics in preventing postoperative infections in gastrointestinal surgery, 38,39 different outcomes were shown in two RCT after PD. 21,22 Sample sizes of these trials were small, and postoperative infectious complications after PD were mainly associated with the incidence of POPF. Therefore, the effect of synbiotics may be limited especially in patients following PD.

| Other nutritional supplements
To assess the effect of glutamine supplementation in patients un- No significant beneficial effects of glutamine supplementation and pONS were shown in double-blinded RCT. 23,24 In contrast, the beneficial effect of PUFA was shown in a RCT. 25 However, this trial was not double-blinded and the number of included patients was small. Therefore, further studies, including a large multicenter trial, are warranted for determining the effects of these nutritional supplements in patients undergoing PD.

| Enhanced recovery after surgery
Guidelines for perioperative care for PD have been published in 2012 by the ERAS Society in which available evidence was summarized and recommended for 27 care items. 5,6 However, the evidence of ERAS pathways for PD is limited because no RCT has been conducted to examine the effect of ERAS protocols in patients with PD.
In 2013, Coolsen et al 40   Accordingly, the evidence of ERAS in PD has been shown by recent meta-analyses and RCT. 26,27,[40][41][42] Systematic nutritional support is an important element of the ERAS concept; however, not all studies have investigated the effect of nutritional therapy within ERAS pathways.
In addition, which nutritional therapy should be used as perioperative systematic nutritional support in patients following PD? Future welldesigned studies should introduce nutritional therapies within ERAS protocols and investigate the impact of them on outcomes after PD.