The clinical and economical impact of postoperative ileus in patients undergoing colorectal surgery.

BACKGROUND: Colorectal surgery is associated with postoperative ileus (POI). Despite its widespread manifestation, the influence of POI on recovery, quality of life (QoL), and costs is largely unknown. The aim of this study was to assess whether the inflammatory processes found in experimental studies are also evident in patients undergoing colorectal surgery. In addition, the impact of POI on short and long-term QoL and costs was investigated. METHODS: We analyzed the outcomes of the SANICS-II trial, including prospective evaluation of inflammatory parameters in blood samples, costs from a societal perspective and QoL, using validated questionnaires. Outcomes were compared between patients with and without POI, and in particular patients with POI as unique complication. KEY RESULTS: A total of 265 patients (POI, n = 66 vs non-POI, n = 199) were included and 38/66 had POI as only complication. CRP levels were significantly increased on postoperative day (POD) 1, 2, 3, and 4 in patients with POI. Furthermore, plasma levels of cytokines IL-6, Il-8 and IL-10 were significantly increased the first 2 days after resection. Patients with POI had a higher overall complication rate and a reduced QoL 3 months postoperatively, even in the only POI group. Moreover, mean societal cost per patient with POI was 38%-47% higher at 3 months postoperatively. CONCLUSIONS & INFERENCES: Supporting findings from experimental studies, inflammatory parameters were increased in patients with only POI and comparable with all patients with POI. These results demonstrate the impact and large contribution of POI in postoperative inflammation, costs and QoL in patients undergoing colorectal surgery.

An economic evaluation of perioperative enteral nutrition in patients undergoing colorectal surgery (SANICS II study).

AIMS: The objective of this (trial based) economic evaluation was to assess, from a societal perspective, the cost-effectiveness of perioperative enteral nutrition compared with standard care in patients undergoing colorectal surgery. MATERIALS AND METHODS: Alongside the SANICS II randomized controlled trial, global quality-of-life, utilities (measured by EQ-5D-5L), healthcare costs, production losses, and patient and family costs were assessed at baseline, 3 months, and 6 months. Incremental cost-effectiveness ratios (ICERs) (i.e. cost per increased global quality-of-life score or quality-adjusted life year [QALY] gained) and cost effectiveness acceptability curves were visualized. RESULTS: In total, 265 patients were included in the original trial (n = 132 in the perioperative enteral nutrition group and n = 133 in the standard care group). At 6 months, global quality-of-life (83 vs 83, p = .357) did not differ significantly between the groups. The mean total societal costs for the intervention and standard care groups were €14,673 and €11,974, respectively, but did not reach statistical significance (p = .109). The intervention resulted in an ICER of -€6,276 per point increase in the global quality of life score. The gain in QALY was marginal (0.003), with an additional cost of €2,941, and the ICUR (Incremental cost utility ratio) was estimated at €980,333. LIMITATIONS: The cost elements for all the participating centers reflect the reference prices from the Netherlands. Patient-reported questionnaires may have resulted in recall bias. Sample size was limited by exclusion of patients who did not complete questionnaires for at least at two time points. A power analysis based on costs and health-related quality-of-life (HRQoL) was not performed. The economic impact could not be analyzed at 1 month post-operatively where the effects could potentially be higher. CONCLUSIONS: This study suggests that perioperative nutrition is not beneficial for the patients in terms of quality-of-life and is not cost-effective.

Nutritional interventions to improve recovery from postoperative ileus.

PURPOSE OF REVIEW: Postoperative ileus (POI) is an important contributor to postoperative morbidity. However, postoperative outcomes have improved by enhanced recovery after surgery (ERAS) programs. Enteral nutrition is an essential part of ERAS and many studies suggest a therapeutic effect of nutrition on POI. RECENT FINDINGS: Early postoperative enteral nutrition has been shown to reduce various complications, including POI, although studies are heterogeneous. Experimental studies suggest that composition and timing of the enteral feed is important for the potential beneficial effects: lipid-enriched nutrition given just before, during, and directly after surgery was most effective in reducing POI in an experimental setting. In a clinical study in patients undergoing advanced rectal cancer surgery, direct start of enteral tube feeding reduced POI. Conversely, perioperative lipid-enriched enteral nutrition did not reduce POI in patients undergoing colorectal surgery with an ERAS protocol. SUMMARY: POI is common and remains an important determinant of postoperative recovery following colorectal surgery. Nutrition is a potential therapeutic means to reduce POI. Timing and composition of the enteral feed have been shown to be essential for the beneficial effects of enteral nutrition in an experimental setup. However perioperative lipid-enriched nutrition does not reduce POI in patients undergoing colorectal surgery with an ERAS protocol.

The Effect of Myopenia on the Inflammatory Response Early after Colorectal Surgery.

BACKGROUND: Myopenia (low skeletal muscle mass) is associated with an increased risk of complications following colorectal surgery, however, the underlying mechanism is poorly understood. This study investigates the effect of myopenia on the early postoperative systemic inflammatory response. MATERIALS AND METHODS: In 78 patients undergoing colorectal surgery, the presence of myopenia was preoperatively assessed using computed tomography images of the third lumbar vertebra. Interleukin-8 (IL-8) and soluble tumor necrosis factor receptor-1 (TNFRSF1A) were measured in plasma before and 4 h after start of surgery as part of a randomized controlled trial investigating the effect of perioperative gum chewing on the inflammatory response. Multivariable linear regression analysis was performed to assess the effect of myopenia on inflammatory markers while correcting for possible confounders. RESULTS: Four hours after start of surgery, IL-8 was higher in patients with myopenia than in patients without myopenia (352 ± 268 vs. 239 ± 211 pg/ml, P = 0.048), while TNFRSF1A was similar between groups. After adjusting for sex and the intervention with perioperative gum chewing, myopenia remained associated with higher postoperative IL-8 concentrations (P = 0.047). CONCLUSION: Myopenia may affect IL-8 early after colorectal surgery. However, more studies are needed to validate these findings.

Perioperative lipid-enriched enteral nutrition versus standard care in patients undergoing elective colorectal surgery (SANICS II): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Postoperative ileus and anastomotic leakage severely impair recovery after colorectal resection. We investigated the effect of perioperative lipid-enriched enteral nutrition versus standard care on the risk of postoperative ileus, anastomotic leakage, and other clinical outcomes. METHODS: We did an international, multicentre, double-blind, randomised, controlled trial of patients (≥18 years) undergoing elective colorectal surgery with primary anastomosis at six clinical centres in the Netherlands and Denmark. Patients were randomly assigned (1:1), stratified by location (colonic and rectal) and type of surgery (laparoscopic and open), via online randomisation software, with block sizes of six, to receive either continuous lipid-enriched enteral tube feeding from 3 h before until 6 h after surgery (intervention) or no perioperative nutrition (control). Surgeons, patients, and researchers were masked to treatment allocation for the entire study period. The primary outcome was postoperative ileus. Secondary outcomes included anastomotic leakage, pneumonia, preoperative gastric volumes, time to functional recovery, length of hospital stay, the need for additional interventions, intensive care unit admission, postoperative inflammatory response, and surgical complications. Analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02175979, and trialregister.nl, number NTR4670. FINDINGS: Between July 28, 2014, and February 20, 2017, 280 patients were randomly assigned, 15 of whom were excluded after random allocation because they fulfilled one or more exclusion criteria. 265 patients received perioperative nutrition (n=132) or standard care (n=133) and were included in the analyses. A postoperative ileus occurred in 37 (28%) patients in the intervention group versus 29 (22%) in the control group (risk ratio [RR] 1·09, 95% CI 0·95-1·25; p=0·24). Anastomotic leakage occurred in 12 (9%) patients in the intervention group versus 11 (8%) in the control group (RR 1·01, 95% CI 0·94-1·09; p=0·81). Pneumonia occurred in ten (8%) patients in the intervention group versus three (2%) in the control group (RR 1·06, 95% CI 1·00-1·12; p=0·051). All other secondary outcomes were similar between groups (all p>0·05). INTERPRETATION: Perioperative lipid-enriched enteral nutrition in patients undergoing elective colorectal surgery has no advantage over standard care in terms of postoperative complications. FUNDING: Netherlands Organisation for Health Research and Development (ZonMW), Fonds NutsOhra, and Danone Research.

Health-related quality of life and cost-effectiveness analysis of gum chewing in patients undergoing colorectal surgery: results of a randomized controlled trial.

BACKGROUND: Postoperative ileus (POI) and anastomotic leakage (AL) following colorectal surgery severely increase healthcare costs and decrease quality of life. This study evaluates the effects of reducing POI and AL via perioperative gum chewing compared to placebo (control) on in-hospital costs, health-related quality of life (HRQoL), and assesses cost-effectiveness. METHODS: In patients undergoing elective, open colorectal surgery, changes in HRQoL were assessed using EORTC-QLQ-C30 questionnaires and costs were estimated from a hospital perspective. Incremental cost-effectiveness ratios were estimated. RESULTS: In 112 patients, mean costs for ward stay were significantly lower in the gum chewing group when compared to control (€3522 (95% CI €3034-€4010) versus €4893 (95% CI €3843-€5942), respectively, p = .020). No differences were observed in mean overall in-hospital costs, or in mean change in any of the HRQoL scores or utilities. Gum chewing was dominant (less costly and more effective) compared to the control in more than 50% of the simulations for both POI and AL. CONCLUSION: Reducing POI and AL via gum chewing reduced costs for ward stay, but did not affect overall in-hospital costs, HRQoL, or mapped utilities. More studies with adequate sample sizes using validated questionnaires at standardized time points are needed.

Effect of Early vs Late Start of Oral Intake on Anastomotic Leakage Following Elective Lower Intestinal Surgery: A Systematic Review.

BACKGROUND: Experimental and clinical studies have demonstrated a beneficial effect of early enteral nutrition (EN) on anastomotic leakage following colorectal surgery. Early oral intake is a common form of early EN with various clinical benefits, but the effect on anastomotic leakage is unclear. This systematic review investigates the effect of early vs late start of oral intake on anastomotic leakage following lower intestinal surgery. METHODS: A systematic literature search was performed using the PubMed, Embase, Medline, and Cochrane databases. Randomized controlled trials were included that compared early (within 24 hours) vs late start of oral intake following elective surgery of the small bowel, colon, or rectum. Meta-analysis was performed for anastomotic leakage, overall complications, length of stay, and mortality. Sensitivity analysis was performed in which studies of inferior methodological quality were excluded. RESULTS: Nine studies including 879 patients met eligibility criteria. Early start of oral intake significantly reduced overall complications (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.46-0.93; P = .02), length of stay (mean difference, -0.89; 95% CI, -1.22 to -0.57; P < .001), and anastomotic leakage (OR, 0.40; 95% CI, 0.17-0.95; P = .04) compared with late start of oral intake. However, in the sensitivity analysis only the overall reduction of length of stay remained significant. CONCLUSION: The effect of early oral intake on anastomotic leakage is unclear as existing studies are heterogeneous and at risk of bias. High-quality studies are needed to study the potential benefit of EN on anastomotic healing.

Beneficial Effects of Early Enteral Nutrition After Major Rectal Surgery: A Possible Role for Conditionally Essential Amino Acids? Results of a Randomized Clinical Trial.

OBJECTIVES: To investigate direct postoperative outcome and plasma amino acid concentrations in a study comparing early enteral nutrition versus early parenteral nutrition after major rectal surgery. Previously, it was shown that a low plasma glutamine concentration represents poor prognosis in ICU patients. DESIGN: A preplanned substudy of a previous prospective, randomized, open-label, single-centre study, comparing early enteral nutrition versus early parenteral nutrition in patients at high risk of postoperative ileus after surgery for locally advanced or locally recurrent rectal cancer. Early enteral nutrition reduced postoperative ileus, anastomotic leakage, and hospital stay. SETTING: Tertiary referral centre for locally advanced and recurrent rectal cancer. PATIENTS: A total of 123 patients with locally advanced or recurrent rectal carcinoma requiring major rectal surgery. INTERVENTIONS: Patients were randomized (ALEA web-based external randomization) preoperatively into two groups: early enteral nutrition (early enteral nutrition, intervention) by nasojejunal tube (n = 61) or early parenteral nutrition (early parenteral nutrition, control) by jugular vein catheter (n = 62). Eight hours after the surgical procedure artificial nutrition was started in hemodynamically stable patients, stimulating oral intake in both groups. Blood samples were collected to measure plasma glutamine, citrulline, and arginine concentrations using a validated ultra performance liquid chromatography-tandem mass spectrometric method. MEASUREMENTS AND MAIN RESULTS: Baseline concentrations were comparable for both groups. Directly after rectal surgery, a decrease in plasma amino acids was observed. Plasma glutamine concentrations were higher in the parenteral group than in the enteral group on postoperative day 1 (p = 0.027) and day 5 (p = 0.008). Arginine concentrations were also significantly increased in the parenteral group at day 1 (p < 0.001) and day 5 (p = 0.001). CONCLUSIONS: Lower plasma glutamine and arginine concentrations were measured in the enteral group, whereas a better clinical outcome was observed. We conclude that plasma amino acids do not provide a causal explanation for the observed beneficial effects of early enteral feeding after major rectal surgery.

Diagnostic value of drain amylase for detecting intrathoracic leakage after esophagectomy.

AIM: To investigate the value of elevated drain amylase concentrations for detecting anastomotic leakage (AL) after minimally invasive Ivor-Lewis esophagectomy (MI-ILE). METHODS: This was a retrospective analysis of prospectively collected data in two hospitals in the Netherlands. Consecutive patients undergoing MI-ILE were included. A Jackson-Pratt drain next to the dorsal side of the anastomosis and bilateral chest drains were placed at the end of the thoracoscopic procedure. Amylase levels in drain fluid were determined in all patients during at least the first four postoperative days. Contrast computed tomography scans and/or endoscopic imaging were performed in cases of a clinically suspected AL. Anastomotic leakage was defined as any sign of leakage of the esophago-gastric anastomosis on endoscopy, re-operation, radiographic investigations, post mortal examination or when gastro-intestinal contents were found in drain fluid. Receiver operator characteristic curves were used to determine the cut-off values. Sensitivity, specificity, positive predictive value, negative predictive value, risk ratio and overall test accuracy were calculated for elevated drain amylase concentrations. RESULTS: A total of 89 patients were included between March 2013 and August 2014. No differences in group characteristics were observed between patients with and without AL, except for age. Patients with AL were older than were patients without AL (P = 0.01). One patient (1.1%) without AL died within 30 d after surgery due to pneumonia and acute respiratory distress syndrome. Anastomotic leakage that required any intervention occurred in 15 patients (16.9%). Patients with proven anastomotic leakage had higher drain amylase levels than patients without anastomotic leakage [median 384 IU/L (IQR 34-6263) vs median 37 IU/L (IQR 26-66), P = 0.003]. Optimal cut-off values on postoperative days 1, 2, and 3 were 350 IU/L, 200 IU/L and 160 IU/L, respectively. An elevated amylase level was found in 9 of the 15 patients with AL. Five of these 9 patients had early elevations of their amylase levels, with a median of 2 d (IQR 2-5) before signs and symptoms occurred. CONCLUSION: Measurement of drain amylase levels is an inexpensive and easy tool that may be used to screen for anastomotic leakage soon after MI-ILE. However, clinical validation of this marker is necessary.

The effects of stimulation of the autonomic nervous system via perioperative nutrition on postoperative ileus and anastomotic leakage following colorectal surgery (SANICS II trial): a study protocol for a double-blind randomized controlled trial.

BACKGROUND: Postoperative ileus and anastomotic leakage are important complications following colorectal surgery associated with short-term morbidity and mortality. Previous experimental and preclinical studies have shown that a short intervention with enriched enteral nutrition dampens inflammation via stimulation of the autonomic nervous system and thereby reduces postoperative ileus. Furthermore, early administration of enteral nutrition reduced anastomotic leakage. This study will investigate the effect of nutritional stimulation of the autonomic nervous system just before, during and early after colorectal surgery on inflammation, postoperative ileus and anastomotic leakage. METHODS/DESIGN: This multicenter, prospective, double-blind, randomized controlled trial will include 280 patients undergoing colorectal surgery. All patients will receive a selfmigrating nasojejunal tube that will be connected to a specially designed blinded tubing system. Patients will be allocated either to the intervention group, receiving perioperative nutrition, or to the control group, receiving no nutrition. The primary endpoint is postoperative ileus. Secondary endpoints include anastomotic leakage, local and systemic inflammation, (aspiration) pneumonia, surgical complications classified according to Clavien-Dindo, quality of life, gut barrier integrity and time until functional recovery. Furthermore, a cost-effectiveness analysis will be performed. DISCUSSION: Activation of the autonomic nervous system via perioperative enteral feeding is expected to dampen the local and systemic inflammatory response. Consequently, postoperative ileus will be reduced as well as anastomotic leakage. The present study is the first to investigate the effects of enriched nutrition given shortly before, during and after surgery in a clinical setting. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02175979 - date of registration: 25 June 2014. Dutch Trial Registry: NTR4670 - date of registration: 1 August 2014.