Early Oral Protein-Containing Diets Following Elective Lower Gastrointestinal Tract Surgery in Adults: A Meta-Analysis of Randomized Clinical Trials.

doi:10.21203/rs.3.rs-29449/v1

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Early Oral Protein-Containing Diets Following Elective Lower Gastrointestinal Tract Surgery in Adults: A Meta-Analysis of Randomized Clinical Trials.

https://doi.org/10.21203/rs.3.rs-29449/v1

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published 23 Mar, 2021

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Background: Although current guidelines make consensus recommendations for the early resumption of oral intake after surgery, a recent comprehensive meta-analysis failed to identify any patient-centred benefits. We hypothesized this finding was attributable to pooling studies providing effective protein-containing diets with ineffective non-protein liquid diets. Therefore, the aim of this paper was to investigate the safety and efficacy of early oral protein-containing diets versus later (traditional) feeding after elective lower gastrointestinal tract surgery in adults.

Methods: PubMed, Embase and the China National Knowledge Infrastructure databases were searched from inception until 1 August 2019. Reference lists of retrieved studies were hand searched to identify randomized clinical trials reporting mortality. No language restrictions were applied. Study selection, risk of bias appraisal and data abstraction were undertaken independently by two authors. Disagreements were settled by obtaining an opinion of a third author. Majority decisions prevailed. After assessment of underlying assumptions, a fixed-effects method was used for analysis. The primary outcome was mortality. Secondary outcomes included surgical site infections, postoperative nausea and vomiting, serious postoperative complications and other key measures of safety and efficacy .

Results: Eight randomized clinical trials recruiting 657 patients were included. Compared with later (traditional) feeding, commencing an early oral protein-containing diet resulted in a statistically significant reduction in mortality (Odds Ratio [OR] 0.31, P =0.02, I 2 =0%). An early oral protein-containing diet also significantly reduced surgical site infections (OR 0.39, P =0.002, I 2 =32%), postoperative nausea and vomiting (OR 0.62, P =0.04, I 2 =37%), serious postoperative complications (OR 0.60, P =0.01, I 2 =25%) and significantly improved other major outcomes. No harms attributable to an early oral protein-containing diet were identified.

Conclusions: The results of this systematic review can be used to upgrade current guideline statements to a Grade A recommendation supporting an oral protein-containing diet commenced before the end of postoperative day 1 after elective lower gastrointestinal surgery in adults.

Surgery

postoperative nutrition

protein

elective surgery

meta-analysis

mortality

Early oral intake after elective surgery is considered to be “safe and vital for optimizing postoperative outcomes.”¹ Meta-analyses have shown that, compared to later (traditional) feeding, early oral intake after elective colorectal surgery may significantly reduce postoperative infections,² serious postoperative complications,³ anastomotic leaks,⁴ and mortality.⁵ However, the most comprehensive systematic review and meta-analysis conducted by leading experts on the topic, updated in 2019, failed to confirm any of these previously reported important clinical benefits.⁶ All of these previous meta-analyses based their conclusions on a pooled assessment of protein-containing diets with non-protein liquid diets.

Early initiation of a protein-containing diet has been shown to significantly reduce mortality after urgent or emergency surgery for major trauma ⁷ and major burn injury.⁸ Furthermore, pneumonia, sepsis, gastrointestinal hemorrhage and duration of hospital stay are also significantly reduced in these surgical populations.⁷^,⁸ We were unable to find any meta-analyses that explicitly focused on the benefits of an early oral protein-containing diet after elective surgery.

The purpose of this systematic review was to identify, appraise and synthesize evidence from randomized clinical trials (RCTs) evaluating the impact of an early oral protein-containing diet, compared to later (traditional feeding), on outcomes after elective lower gastrointestinal tract surgery in adults. The primary outcome for meta-analysis was mortality.

This study was conducted and reported in compliance with established methodological guidelines.⁹ Detailed study methods were published on-line in advance of search close-out.¹⁰

Study selection, risk of bias appraisal and data abstraction were undertaken by two authors. Disagreements were settled by obtaining an opinion of a third independent author. Majority decisions prevailed.

Literature search

Medline (www.PubMed.org), Embase (www.EMBASE.com) and the China National Knowledge Infrastructure (www.CNKI.com.cn) were searched from inception until 1 August 2019. Appropriate database specific statements and terms⁷^,⁸ are reported in the Online-only Supplement. Reference lists of retrieved papers were hand searched.

Study selection

All RCTs comparing early oral or enteral nutrition to later (traditional) feeding published in any language were retrieved in full and screened for inclusion. The intervention of interest was defined as oral or enteral intake initiated within 24 hours of surgery using a drink, food or solution that contained calories and protein. The comparison group was accepted to include any form of nutrition commenced later than 24 h after surgery. When needed, end of Postoperative Day [POD] 1 was used to define the outer limit for this 24 h period.

RCTs reporting mortality conducted in adult patients who had received surgery to the lower gastrointestinal tract (distal to the ligament of Treitz) were eligible for inclusion and were reviewed in detail.

Risk of bias

Included trials were appraised on the reporting of three key methodological criteria: 1) maintenance of allocation concealment; 2) use of blinding and; 3) completeness of follow-up. Major flaws leading to a recognized high risk of bias were defined a priori as clear failure to maintain allocation concealment ¹¹ and excessive (>10%) loss to follow-up.¹²

Outcomes

The primary outcome was mortality, assessed at the longest reported follow-up interval. Secondary outcomes included physical function, quality of life, duration of hospital stay, requirement for intensive care unit (ICU) admission, surgical site infections, anastomotic leak/dehiscence, postoperative nausea and vomiting, pneumonia and need for re-operation. Number of patients with intra-abdominal abscess/peritonitis, severe postoperative complications and postoperative infections were also assessed.

Statistical analysis

The Mantel-Haenszel method was used to calculate the odds ratio (OR) metric unless data was sparse, in which case the Peto method was used.^{11, 13} The underlying assumption behind the fixed effects model was assessed with a formal chi-square test of heterogeneity ¹⁴ and quantified using the I² metric.¹⁵ Important heterogeneity was defined as a P-value for the test of heterogeneity (P_{heterogeneity}) less than 0.10 or I² greater than 50%.¹⁶ Publication bias was assessed using a Funnel plot of the primary outcome.

Analysis was conducted using RevMan Version 5.3.5 for Windows (The Cochrane CollaborationÒ, Oxford, England, 2014). A two-tailed P-value less than 0.05 was accepted to indicate statistical significance.

Sensitivity analysis

Focused on the primary outcome, the sensitivity analysis considered trials with less certainty regarding protein content of the intervention group’s early nutrition.

Heterogeneity and stratified analysis

If important heterogeneity was detected, the following a priori identified potential sources of heterogeneity were investigated via stratified analysis: 1) methodological quality; 2) intervention timing and dose; 3) co-interventions and comparison intervention received; and 4) measurement and timing of outcomes.¹⁷

Literature search and Study selection

The primary literature search identified 2,947 abstracts of potentially eligible studies. Review of retrieved abstracts and hand searching of reference lists of published guidelines and systematic reviews resulted in 196 articles identified for retrieval. Of these 196 articles, 53 RCTs appeared to address key aspects of the primary study question. Eight of these 53 RCTs were deemed eligible for inclusion. Figure 1 reports the study selection flow. The Online-only Supplement provides additional details regarding RCTs deemed not eligible (eTable 1).

The eight included RCTs enrolled 657 participants.¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵ Primary information regarding each of these eight RCTs was abstracted directly from the publications cited above. Additional information on three RCTs ²²^,²³^,²⁵ were available from the systematic review by Herbert et al.⁶ Herbert et al. obtained these additional details by direct correspondence with the authors of these three RCTs.

Two included RCTs established early oral intake by using a protein drink,^{18, 24} two RCTs provided enteral nutrition via a feeding tube,^{19, 22} and four RCTs commenced a solid diet containing protein on POD 1.^{20, 21, 23, 25} Details of the study populations and study interventions are reported in Table 1.

Study	Patient population	Protocol for Early Nutrition Intervention	Control
Beier-Holgersen 1996	60 patients with gastrointestinal disease undergoing abdominal surgery (87% underwent colorectal surgery).	Start within 4 h of surgery (POD 0): 60 mls of protein drink (Nutricia Nutridrink, Orange) every hour, for total of 600 ml. POD 1: 1000 ml of protein drink; POD 2: 1400 ml protein drink; POD 3 & 4: 1800 ml protein drink.	Placebo (water with orange flavor) following same protocol as early protein drink group.
Carr 1996	28 patients undergoing intestinal resection distal to the ligament of Treitz.	Start within 2 to 3 h of surgery (POD 0): 25 ml/h EN (Fresubin, Fresenius) via N-J tube. Rate increased by 25 ml every 4 h until target of 35 ml/kg/day achieved.	NPO until passage of flatus.
Lau 2014	111 elective colorectal surgery patients.	Start POD 1: Solid diet that left minimal residue in the lower intestinal tract after digestion and absorption.	Start POD 1: Clear liquids, specifically omitting all solids (Ex. milk, and fruit juice with pulp). POD 2: Advanced to solid diet.
Minig 2009	51 gynecologic oncology patients. (Over 70% also had rectosigmoid resection in addition to hysterectomy.)	Start POD 0: Clear fluids and other liquids (tea, apple juice etc). If fluids tolerated, progress to regular diet by end of POD 1.	NPO until resolution of ileus.
Mulrooney 2004	73 patients undergoing colonic resection	Start within 24 h of surgery: 25 ml/h EN (Nutrison Standard, Nutricia) via N-J tube; POD 2: 50 ml/h EN; POD 3: 75 ml/h: POD 4: EN increased to calculated nutritional targets.	NPO until passage of flatus.
Ortiz 1996	190 patients undergoing elective colon and rectal surgery.	Early removal of NG tube with clear liquids on POD 0 followed by regular diet on POD 1.	NPO until resolution of ileus.
Shen 2013	82 patients with colorectal cancer undergoing surgery.	Start POD 1: 200 mls 0.9% Saline and 200 ml EN; POD 2: 500 to 1000 mls EN; POD 3: 1500 to 2000mls of EN; POD 4: 2000 mls EN continued until POD 7.	Start standard PN POD 2: standard PN continued until POD 7.
Stewart 1998	88 patients undergoing elective colorectal resection with anastomosis, without stoma formation.	Start within 4 h of surgery (POD 0): free fluids; POD 1: Solid diet.	NPO until passage of flatus or bowel movement.
POD: postoperative day; EN: enteral nutrition solution containing protein, NPO: nil per os, PN: parenteral nutrition solution containing glucose, amino acids and protein, N-J: naso-jejunal tube.

Table 1

Characteristics of included studies

Risk of Bias

Three RCTs explicitly reported the process used to maintain allocation concealment,^{19, 20}^,²¹ whilst the remaining five were unclear. One study achieved blinding using a placebo intervention.¹⁸ Three studies documented failure to follow-up all randomized patients, with one reporting loss of 6.3% (7/111)²⁰ of randomized patients, a second reporting 9.1% (8/88) loss ²⁵ and the third documenting loss of 21.5% (11/51) of randomized patients.²¹ Based on a priori defined criteria,^{11, 12} only one study was found to have a major methodological flaw resulting in a high risk of bias.²¹ The funnel plot of the primary outcome did not reveal publication bias (eFigure 1).

Mortality

Eight RCTs enrolling 657 patients were included in the analysis of mortality. Two studies reported mortality at study day 30,^{18, 20} one reported mortality at study day 60,²² with the remaining five studies reporting mortality at time of hospital discharge. Mortality data for the trial by Mulrooney et al ²² was abstracted from the systematic review by Herbert et al.⁶ Herbert et al. reported corresponding with Mulrooney et al to obtain this mortality information.

Compared with later (traditional) feeding, commencing an early oral protein-containing diet resulted in a statistically significant reduction in mortality (OR 0.31, 95% Confidence Interval [CI] 0.12 to 0.80, P=0.02, Figure 2), with no heterogeneity (P_{heterogeneity}=0.95, I²=0%).

Physical function

Three studies reported measures of physical function. Carr et al. reported change in handgrip strength,¹⁹ Stewart et al. documented time to mobilization after surgery²⁵ and Minig et al. assessed physical function at study day 30 using the European Organization for Research and Treatment of Cancer (EORTC) C-30.²¹

Carr et al. reported a mean 9.6 (Standard Deviation [SD] 2.1) kg loss in handgrip strength in control patients, and a 6.7 (3.2) kg loss in handgrip strength in patients who received an early diet containing protein.¹⁹ Assessed using a standard t-test for differences between groups, patients who received an early diet containing protein experienced significantly less handgrip strength loss (2.9 kg less, 95% CI 0.9 to 4.9kg, P=0.01).

Minig et al. failed to find a significant difference between groups with regards to physical function assessed at study day 30 using EORTC C-30 (76.1±14.3 early vs. 62.1±25.3 traditional, P=0.146).²¹

Stewart et al. also failed to find a significant difference between groups with regards to time to mobilization after surgery.²⁵ Stewart et al. did not report the actual times to mobilization for each group.

Because of the differences in outcome metrics reported, these measures of physical function could not be pooled.

Quality of life

One RCT reported formal measures of quality of life.²¹ Minig et al. failed to find a significant difference in EORTC OV-28 assessed at study day 30.

Duration of hospital stay

All eight included RCTs reported duration of hospital stay. One trial reported differences in median hospital stay,¹⁸ with the remaining seven reporting mean (SD). Mean (SD) hospital stay data for the trials by Minig et al., Mulrooney et al., and Stewart et al. was abstracted from the systematic review by Herbert et al.⁶ Herbert et al. reported corresponding with these authors to obtain this additional mean (SD) information regarding hospital stay.

Using a non-parametric test, the individual RCT conducted by Beier-Holgersen et al. reported a trend towards a reduction in median hospital stay for patients who received an early diet containing protein: median 8 vs. 11.5 days (P=0.08).¹⁸

Meta-analysis of the mean (SD) length of stay data reported by seven RCTs recruiting 598 patients demonstrated a significantly shorter hospital stay for patients randomized to receive an early oral protein-containing diet (-2.12 days, 95% CI -2.74 to -1.49 days, P<0.00001, eFigure 2), however, important heterogeneity was detected (P_{heterogeneity}=0.00006, I²=75%). Sources of this heterogeneity are investigated further with stratified analysis (see later in Results).

Intensive Care Unit admission

Three studies explicitly reported Intensive Care Unit (ICU) admission rates after surgery.¹⁸^,²¹^,²³ Meta-analysis did not reveal any significant difference between groups (OR 0.61, 95% CI 0.24 to 1.53, P=0.29, eFigure 3), with no heterogeneity (P_{heterogeneity}=0.55, I²=0%).

Surgical site infections

All eight RCTs documented surgical site infection rates,¹⁸^,¹⁹^,²⁰^,²¹^,²²^,²³^,²⁴^,²⁵ however one combined reporting of surgical site infections with urinary tract infections and therefore could not be included in this pooled analysis.¹⁹ Surgical site infection data for the trial by Mulrooney et al. was abstracted from the systematic review by Herbert et al.⁶ Herbert et al. reported corresponding with Mulrooney et al. to obtain this additional information.

The seven RCTs that explicitly reported surgical site infections enrolled 625 patients. Patients who received an early oral protein-containing diet were significantly less likely to experience a surgical site infection (OR 0.39, 95% CI 0.21 to 0.71, P=0.002, Figure 3), with no important heterogeneity (P_{heterogeneity}=0.19, I²=32%).

Anastomotic leak/dehiscence

Five RCTs enrolling 439 patients reported anastomotic leak,¹⁸^,²¹ anastomotic leak/dehiscence,²²^,²⁵ or anastomotic breakdown.²³ None of these trials reported using explicit and objective criteria to diagnose a leak/dehiscence/breakdown. Anastomotic leak/dehiscence data for the trial by Mulrooney et al. was abstracted from the systematic review by Herbert et al.⁶ Herbert et al. reported corresponding with Mulrooney et al. to obtain this additional information.

Meta-analysis did not find any significant difference between groups (OR 0.74, 95% CI 0.30 to 1.87, P=0.53, eFigure 4) and no important heterogeneity was detected (P_{heterogeneity}=0.10, I²=49%).

Postoperative nausea and vomiting

Three studies reported nausea.¹⁸^,²⁰^,²⁵ Using a Likert scale, Lau et al. reported a significantly lower nausea score in the early diet containing protein group compared to the traditional group (2.5 early vs. 4.7, P=0.01).²⁰ However, Stewart et al. failed to find a significant difference between groups using a visual-analogue nausea scale (29 early vs. 31, reported as Not Significant[NS]),²⁵ and Beier-Holgersen et al. also failed to find a significant difference between groups in the incidence of nausea (19/30 early vs. 22/30, NS).¹⁸ Due to the different measures used to assess nausea, pooled analysis could not be undertaken.

Three RCTs reported the number of patients who vomited,¹⁸^,²⁰^,²⁵ two RCTs reported the number of patients with ‘nausea and vomiting’ combined,¹⁹^,²¹ and one study provided a graphical representation of vomiting on each study day but did not explicitly report rates.²³

Pooled analysis of the five RCTs enrolling 312 patients that explicitly reported rates demonstrated a significant reduction in postoperative nausea and vomiting attributable to the provision of an early oral protein-containing diet (OR 0.62, 95% CI 0.38 to 0.99, P=0.04, eFigure 5), with no important heterogeneity (P_{heterogeneity}=0.17, I²=37%).

Pneumonia

Six RCTs enrolling 585 patients reported pneumonia.¹⁸^,²⁰^,²²^,²³^,²⁴^,²⁵ Pneumonia data for the trials by Mulrooney et al. and Stewart et al. was abstracted from the systematic review by Herbert et al.⁶ Herbert et al. reported corresponding with Mulrooney et al. and Stewart et al. to obtain this additional information.

Pooled analysis failed to demonstrate a significant difference between groups (OR 0.73, 95% CI 0.32 to 1.66, P=0.45, eFigure 6), with no heterogeneity (P_{heterogeneity}=0.60, I²=0%).

Need for re-operation

Three RCTs enrolling 204 patients explicitly reported need for reoperation.¹⁸^,²⁰^,²¹ Pooled analysis failed to demonstrate a significant difference between groups (OR 0.49, 95% CI 0.16 to 1.51, P=0.22, eFigure 7), with no heterogeneity (P_{heterogeneity}=0.84, I²=0%).

Intra-abdominal abscess/peritonitis

Six RCTs reported intra-abdominal abscess/peritonitis.¹⁸^,²⁰^,²¹^,²²^,²³^,²⁴ Data for the trial by Mulrooney et al. was abstracted from the systematic review by Herbert et al.⁶ Herbert et al. reported corresponding with Mulrooney et al. to obtain this additional information.

Pooled analysis of these six RCTs enrolling 545 patients demonstrated a significant reduction in the onset of intra-abdominal abscess/peritonitis in patients who received an early oral protein-containing diet (OR 0.20, 95% CI 0.06 to 0.66, P=0.008, eFigure 8), with no heterogeneity (P_{heterogeneity}=0.98, I²=0%).

Number of patients with serious postoperative complications

Six RCTs enrolling 552 patients explicitly reported the total number of patients in each study group who had at least one serious postoperative complication.¹⁸^,²⁰^,²¹^,²³^,²⁴^,²⁵ Serious postoperative complications included acute myocardial infarction, anastomotic leak/dehiscence, unexpected return to surgery, hospital readmission within 30 days of discharge, surgical site infection, peritonitis, intestinal obstruction, and other postoperative infections. Because mortality served as the primary outcome for this study, it was not included in this analysis of serious postoperative complications.

Pooled analysis of these six RCTs revealed that the provision of an early oral protein-containing diet resulted in significantly fewer patients developing a serious postoperative complication (OR 0.60, 95% CI 0.40 to 0.89, P=0.01, eFigure 9). Despite reporting of a different subset of serious postoperative complications by each study, there was no important heterogeneity (P_{heterogeneity}=0.25, I²=25%).

Number of patients with a postoperative infection

Four RCTs enrolling 210 patients reported the number of patients who had at least one postoperative infection.¹⁸^,¹⁹^,²¹^,²⁴ Based on pooled analysis of these four RCTs, the provision of an early oral protein-containing diet resulted in a significant reduction in the number of patients who experienced a postoperative infection (OR 0.17, 95% CI 0.08 to 0.37, P<0.0001, eFigure 10), with no heterogeneity (P_{heterogeneity}=0.83, I²=0%).

Sensitivity analysis

Focused on the primary outcome, the sensitivity analysis considered trials with less certainty regarding protein content of the intervention group’s early nutrition. Thirteen clinical trials enrolling 1,216 patients were identified for inclusion in the sensitivity analysis.

These RCTs described their early nutrition intervention as “water”,²⁶ “5% glucose”,²⁷^,²⁸ “clear liquid”,²⁹^,³⁰ “allowed to drink”,³¹ “oral liquids”,³² an “oral liquid diet”,³³ a “fluid diet”,³⁴ “fluids”,³⁵ a “liquid diet”,³⁶ a “semi-fluid diet”,³⁷ or “filtrate liquids”.³⁸

Inclusion of these 13 RCTs in a sensitivity analysis failed to find an impact of early non-protein liquid diets on mortality (OR 1.01, 95% CI 0.29 to 3.51, P=0.99). Furthermore, there was important heterogeneity between RCTs that evaluated a protein-containing diet and RCTs that evaluated non-protein liquid diets, suggesting these different interventions have different effects on mortality (P_{heterogeneity}=0.14, I²=54.7%, Figure 4).

Heterogeneity and stratified analysis

The only statistically significant result demonstrating important heterogeneity was the analysis of duration of hospital stay (I²=75%, eFigure 2). Stratified analysis based on study intervention (enteral nutrition/solid diet/protein drink supplement) meaningfully reduced heterogeneity within each strata (eFigure 11). Interpretation of results within each strata revealed that early enteral nutrition did not have any effect on duration of hospital stay (1.05 days, 95% CI -0.077 to 2.87 days, P=0.26, I²=0%), whilst both an early solid protein-containing diet (-1.86 days, 95% CI -2.73 to -1.00, P<0.000001, I²=35%) and early use of protein drink supplements (-3.54 days, 95% CI -4.59 to -2.49, P<0.000001, I²=0%) significantly reduced duration of hospital stay.

This systematic review identified eight RCTs that evaluated the impact of an early oral protein-containing diet on outcomes after elective lower gastrointestinal tract surgery in adults. Compared to later (traditional) feeding, resumption of an oral protein-containing diet before the end of POD 1 significantly reduced mortality, surgical site infection rate, postoperative nausea and vomiting, serious postoperative complications and other key measures of recovery after surgery. Furthermore, sensitivity analysis evaluating the early resumption of a non-protein liquid diet failed to find any effect on mortality.

Mitochondrial biogenesis and recovery from abdominal surgery

Surgery to the lower gastrointestinal tract results in local tissue injury at the site of the external incision and also compromises gut barrier function, even with only mild intestinal handling.³⁹^,⁴⁰ As a result of increased gut permeability, bacterial translocation occurs and initiates a systemic inflammatory response.⁴¹^,⁴²^,⁴³^,⁴⁴ Systemic inflammation arising from low-grade endotoxemia is known to impair mitochondrial function leading to a measurable reduction in energy production capacity.⁴⁵ Mitochondrial dysfunction can depress protein synthesis ⁴⁶ and impair immune response.⁴⁷

Mitochondrial biogenesis is the process of growth and replication undertaken by mitochondria in response to an increased need for energy production during metabolic stress.⁴⁸ Serial muscle biopsies obtained from critically ill patients suggest that mitochondrial biogenesis may confer a survival advantage from critical illness by compensating for mitochondrial dysfunction and allowing increased energy demands to be met.⁴⁹

Amino acids are accepted to stimulate mitochondrial biogenesis by activating the mammalian target of rapamycin (mTOR) pathway.⁴⁶^,⁵⁰^,⁵¹ The direct effect of early protein intake on the active up-regulation of mitochondrial biogenesis provides a plausible mechanism of action to explain the survival advantage, and other important outcome benefits, demonstrated in this meta-analysis.⁴⁹

Anastomotic leak

Anastomotic leak is one of the most serious adverse events after colorectal surgery.⁵²^,⁵³ Animal models demonstrate that initiating a protein-containing diet immediately after abdominal surgery significantly increases the strength of an ileal or colorectal anastomosis.⁵⁴ Although our meta-analysis failed to find a significant reduction in the number of patients experiencing an anastomotic leak (eFigure 4), we did identify a significant reduction in the number of patients experiencing intra-abdominal abscess/peritonitis (eFigure 8). Based on the severity grading scheme proposed by Rahbari et al.,⁵² a reduction in intra-abdominal abscess/peritonitis suggests that an early oral diet containing protein may have reduced the severity (Grade B or C) of anastomotic leaks. We strongly recommend that future trials in this field use pre-defined explicit criteria to objectively diagnose and grade the severity of anastomotic leaks.

Duration of hospital stay

Due to the presence of substantial and important heterogeneity in the assessment of duration of hospital stay, pooled analysis of this outcome may be misleading.¹⁷ Heterogeneity between trials can arise for a number of reasons, including real differences in the study intervention, patient populations and/or the severity/stage of disease studied by each trial. The purpose of stratified (grouped) analyses is to investigate these potential sources of important heterogeneity.¹⁷

When studies were stratified (grouped) based on intervention (enteral feeding tube vs. solid diet vs. protein drink supplement), we found that duration of hospital stay was significantly reduced by receiving an early solid diet or protein drink supplement, with no heterogeneity within each strata (eFigure 11). However, since a number of stratified analyses were undertaken, these results should be viewed as hypothesis generating. We strongly recommend that future meta-analyses conduct assessments of duration of hospital stay stratified by intervention and interpret their results within each strata.

The role of early nutrition in enhanced recovery after surgery programs

Early nutrition is considered to be an essential component of enhanced recovery after surgery (ERAS) programs.⁵⁵ Striking recent data from a 911 patient observational study demonstrates that after undergoing colorectal cancer surgery in an ERAS program, delivery of nutrition on the day of operation was a strong independent predictor of 5-year postoperative survival.⁵⁶ This study does report that a significant number of patients received ‘nutritional supplements’ on the day of surgery, but it does not record whether these supplements contained protein thus, unfortunately, early protein intake was not completely assessed. Based on the results of our sensitivity analysis (Figure 4), we found a mortality benefit of early protein intake, not early calories alone. Small observational studies have demonstrated that higher early protein intake by ERAS patients undergoing elective colorectal surgery is associated with a shorter duration of hospital stay.⁵⁷ Future studies in this field need to ensure that the effects of early protein intake are assessed more thoroughly.

Which patients benefit the most?

It is intuitively appealing to attempt to identify individual patients who are most likely to benefit from an early oral protein-containing diet after elective lower gastrointestinal tract surgery. For example, if we could prove that patients who receive open operative procedures for malignant disease benefit most, we could focus our efforts on these patients. Unfortunately, the included clinical trials do not report outcomes by identifiable patient subgroups such as nutritional status, type of procedure or specific underlying disease. However, because the analysis of our primary outcome (mortality) does not demonstrate any heterogeneity (P_{heterogeneity}=0.95, I²=0%) it supports the conclusion that there is no one subgroup of patients who benefit more than any other and that all patients included in this meta-analysis are likely to benefit in a similar fashion. Likewise, even though each clinical trial enrolled a different patient population who received different surgical procedures for different inciting causes, a lack of statistical heterogeneity supports the conclusion that the overall benefit from early oral protein diets are similar across all of these studies.

Strengths and limitations

The literature search supporting this systematic review was extensive and was not restricted by language of publication.⁶ With the inclusion of eight RCTs recruiting 657 patients, the results of our meta-analysis are robust: significant benefits were demonstrated across multiple meaningful outcomes with no analysis suggesting any harm.

Whilst only one included RCT was identified as having a major methodological flaw leading to a potential high risk of bias,²⁵ all clinical trials in this field would benefit from improved reporting. Authors of RCTs should always report sufficient details regarding randomization such that the reader is assured that allocation concealment was maintained. Furthermore, outcomes should be reported on all patients randomized into an RCT and, finally, although blinding of a study intervention is not always feasible, blinded outcome assessment and adjudication is always possible. The most recent CONSORT Statement serves as an excellent guide with regards to the minimum standards for reporting an RCT.⁵⁸

We did not assess time to first flatus, duration of ileus or time to first stool movement as we are unaware of any studies validating their use as surrogate measures for clinically meaningful outcomes.⁵⁹ Furthermore, we are unaware of any evidence-based statements from authoritative bodies or societies that make recommendations for their continued use to guide decisions to withhold nutrition from surgical patients.¹

Finally, it is important to note that the clinical trials included in this meta-analysis did not set out to determine the amount of protein that should be targeted over the first few postoperative days to achieve maximum benefit. Each of the included trials was pragmatic, and attempted to achieve any protein intake during the first 24 h post-op. As in the real world, patients may refuse oral intake during the first 24 hours. Due to the pragmatic nature of these trials, patients who refused oral intake were still included in the intention to treat analysis. Thus, the benefits established by these clinical trials are very likely to be achieved in the real world. Additional research is required to determine whether higher targets may benefit patients more.

This first systematic review focused exclusively on the effects of an early oral protein-containing diet versus later (traditional) feeding following elective lower gastrointestinal tract surgery found eight RCTs that addressed this clinical question. Meta-analysis of these eight RCTs demonstrated a significant reduction in mortality, and improvements in other key important outcomes, arising from an early oral protein-containing diet, with no indications of any harms. Furthermore, none of our analyses found any benefits in favor of later (traditional) feeding. Our results support a Grade A recommendation for an oral protein-containing diet to be initiated before the end of POD 1 after lower gastrointestinal surgery. If it is felt a clear liquid is clinically indicated, it is important to understand that protein-containing clear liquid supplements are widely available.

CNKI, China National Knowledge Infrastructure; EORTC, European Organization for Research and Treatment of Cancer.

Ethics and approval

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

All data generated or analyzed during this study are included in this published article, its supplementary information files and the primary randomized controlled trials cited for inclusion.

Competing interests

Drs Pu, Heighes, Simpson, Wang, Hugh and Ms Liang reported no funding conflicts. Dr Doig reported receiving academic research grants related to nutrition in critical illness from the Australian National Health and Medical Research Council, Fresenius Kabi Deutschland GmbH and Baxter Healthcare Pty Ltd and speakers honoraria from Fresenius Kabi Deutschland GmbH, Baxter Healthcare Australia, Pty Ltd, Nestle Healthcare, Vevy, Switzerland and Nutricia Pharmaceutical (Wuxi) Co., Ltd. China. Dr Wischmeyer reported receiving grant funding related to Improving Nutrition Delivery in Acute Illness from the National Institute of Health National Heart, Lung, and Blood Institute R34 HL109369, Canadian Institutes of Health Research, Baxter, Fresenius, Lyric Pharmaceuticals, Isomark, Inc, and Medtronics. He served as a consultant on Improving Nutrition Care in Intensive Care Unit (ICU) and Perioperative Medicine to Nestle, Abbott, Fresenius, Baxter, Medtronics, Nutricia, and Lyric Pharmaceuticals, and Takeda for research related to this work. He received honoraria or travel expenses for lectures on improving nutrition care in illness from Abbott, Fresenius, and Medtronics.

Funding

The conduct of this study was not funded by any source.

Authors’ Contributions

GSD conceived and designed the study, managed the project, conducted the statistical analysis, interpreted the results and helped draft the manuscript. GSD had full access to all of the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. HP and PTH contributed to study design, managed the project, participated in the critical appraisal of the literature, interpreted the results and helped draft the manuscript. FS, YW, ZL and PW participated in the study design and critical appraisal of the literature, interpreted the results, and contributed significantly towards critical revisions of the manuscript. TJH interpreted the results and contributed significantly towards critical revisions of the manuscript.

Gordon S Doig PhD (Epidemiology and Biostatistics) was responsible for and conducted all analyses. He had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Acknowledgements

Not applicable.

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Early Oral Protein-Containing Diets Following Elective Lower Gastrointestinal Tract Surgery in Adults: A Meta-Analysis of Randomized Clinical Trials.

Status:

Journal Publication

Version 1

Abstract

Figures

Background

Materials And Methods

Literature search

Study selection

Risk of bias

Outcomes

Statistical analysis

Sensitivity analysis

Heterogeneity and stratified analysis

Results

Literature search and Study selection

Risk of Bias

Mortality

Physical function

Quality of life

Duration of hospital stay

Intensive Care Unit admission

Surgical site infections

Anastomotic leak/dehiscence

Postoperative nausea and vomiting

Pneumonia

Need for re-operation

Intra-abdominal abscess/peritonitis

Number of patients with serious postoperative complications

Number of patients with a postoperative infection

Sensitivity analysis

Heterogeneity and stratified analysis

Discussion

Mitochondrial biogenesis and recovery from abdominal surgery

Anastomotic leak

Duration of hospital stay

The role of early nutrition in enhanced recovery after surgery programs

Which patients benefit the most?

Strengths and limitations

Conclusions

List Of Abbreviations

Declarations

Ethics and approval

Consent for publication

Availability of data and material

Competing interests

Funding

Authors’ Contributions

Acknowledgements

Reference

Supplementary Files

Status:

Journal Publication

Version 1