Enhanced Recovery after Surgery (ERAS) Protocol Is a Safe and Effective Approach in Patients with Gastrointestinal Fistulas Undergoing Reconstruction: Results from a Prospective Study

Background and Aims: An enterocutaneous fistula (ECF) poses a major surgical problem. The definitive surgical repair of persistent fistulas remains a surgical challenge with a high rate of re-fistulation and mortality, and the reasons for that is not the surgical technique alone. Enhanced Recovery after Surgery (ERAS®) is an evidence-based multimodal perioperative protocol proven to reduce postoperative complications. The aim of the study was to assess the clinical value of the ERAS protocol in surgical patients with ECF. Methods: ERAS protocol was used in all patients scheduled for surgery for ECF at the Stanley Dudrick’s Memorial Hospital in Skawina between 2011 and 2020. A multidisciplinary team (MDT) was in charge of the program and performed annual audits. A consecutive series of 100 ECF patients (44 females, 56 males, mean age 54.1 years) were evaluated. Postoperative complications rate, readmission rate, length of hospital stay, prevalence of postoperative nausea and vomiting were assessed. Registered under ClinicalTrials.gov Identifier no. NCT04771832. Results: ERAS protocol was successfully introduced for ECF surgeries; however, eight modifications to the ERAS program was performed in 2015. They led to improvement of surgical outcomes: reduction of postoperative nausea and vomiting (15 vs. 17% patients, p = 0.025), overall complication rate (11 vs. 10, p = 0.021), median length of hospital stay (overall and after surgery, p = 0.022 and 0.002, respectively). Conclusions: ERAS protocol can be successfully used for ECF patients. Prescheduled audits can contribute to the improvement of care.


Introduction
An enterocutaneous fistula (ECF) is an abnormal connection (fistula) between the intestine and the skin. It can develop spontaneously, as a complication of the inflammatory bowel disease or radiotherapy, but most often develops postoperatively as a result of iatrogenic intestinal lesions or leaking anastomosis [1]. The incidence of ECF has been estimated to be below 0.5 patients per 100,000 inhabitants and thought to complicate 0.8% to 2% of abdominal operations; it is one of the orphan diseases [2,3].
The treatment of patients with an ECF can be challenging and unsatisfactory, as the mortality rate can reach up to 10% [4,5]. It is mainly the consequence of sepsis, malnutrition, and electrolyte imbalances [4,6]. Surgery comes as the last step of the treatment, when the spontaneous closure is impossible. Generally speaking, 60% to 80% of patients will usually require a restorative procedure which is successful in 85% to 90% of these cases [7,8].
The definitive surgical repair of persistent fistulas remains a surgical challenge with a high rate of re-fistulation and mortality, and the reasons for that is not the surgical technique alone [5]. Another important issue is the optimal perioperative care. Introduced over a decade ago, Enhanced Recovery after Surgery (ERAS ® ) is an evidence-based multimodal perioperative protocol focused on stress reduction and the promotion of a return to function [9]. Evidence from both observational and RCTs supports reduced morbidity with the implementation of ERAS, including reduction in specific postoperative complications like surgical site and urinary tract infections. Surprisingly, a study on the implementation of ERAS in surgery for ECF has never been published.
The aim of the study was to assess the clinical value of ERAS protocol in surgical patients with ECF.

Methods
The study was performed at the General and Cancer Surgery Unit with the Intestinal Failure Center of the Stanley Dudrick's Memorial Hospital in Skawina, Poland. Starting January 2011, ERAS protocol was used in all patients scheduled for surgery for ECF.
The following components of ERAS protocol were implemented: (a) Preoperative: pre-admission education (health education, exercise advice, dietary guidance), organ function evaluation, minimized preoperative fasting (Fasting from solid food for 6 h and drinking ad libidum for 2 h before operation), carbohydrate loading, no or selective bowel preparation, venous thromboembolism prophylaxis and intravenous antibiotic prophylaxis. All aspects were presented in Table 1. Pain management Acetaminophen, NSAIDs, TEA *** * NSAIDs-non steroid anti-inflammatory drug. ** POD-postoperative day. *** Thoracic epidural anesthesia.
The multidisciplinary team (MDT), composed of two surgeons, two anesthetists, two surgical and one anesthesia nurse, physiotherapist, dietitian and psychologist, was established in January 2011 and made responsible for supervising the ERAS protocol.
MDT decided to implement all components of ERAS from the very beginning of the center's activity and re-evaluate the policy every 12 months. Modifications of the policy were allowed if the majority of MDT (>50%) voted for the change.
The consecutive series of a hundred patients was selected as the target group eligible for evaluation of the effectiveness and safety of the protocol.
Modifications of the protocol were supposed to reduce complications and/or compliance. Any aspect of each ERAS component could be verified and modified in any terms, including drug type, dose, procedure or intervention.
To evaluate the treatment efficacy following aspects were measured and compared at the beginning (January 2011) and the end (December 2020) of the observation period: To achieve this, patients were divided into two major groups: group 1 was formed of patients operated on between 2011 and 2015, and group 2 was formed of patients undergoing surgery between 2016 and 2020.

Statistics
All data were analyzed with Statsoft STATISTICA v.13 (StatSoft Inc., Tulsa, OK, USA). A descriptive study of the sample was carried out. Numerical variables are presented as mean ± standard deviation (SD) or median with interquartile range (IQR) if the distributions were nonparametric. The Pearson chi-square test of independence was used to examine the relationship between each variable and outcome. Fisher's exact test was used when the conditions for the chi 2 test were not met. The Shapiro-Wilk test was used to check for normal distribution of data and the T-student test was used for normally distributed quantitative data. For non-normally distributed quantitative variables, the Mann-Whitney U test was used. A p-value < 0.05 was considered statistically significant.
All procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Informed consent for proposed surgical treatment was obtained from all patients before surgery. This study was approved by the institutional research ethics board of National Cancer Institute in Krakow (KBET 27/10/2020) and was registered in the ClinicalTrials.gov.

Results
One hundred patients (44 females, 56 males, mean age 54.1 years) were operated on for gastrointestinal fistula and the restoration of the GI tract continuity was achieved. Patient profile was presented in Table 2.   Modifications of the protocol in 2015 led to improvement of surgical outcomes: reduction of postoperative nausea and vomiting (15 vs. 17 patients, p = 0.025), overall complication rate (11 vs. 10, p = 0.021), median length of hospital stay (overall and after surgery, p = 0.022 and 0.002, respectively). Complications other than those mentioned above that were evaluated included: surgical site infection, cardiopulmonary complications, urinary tract infections, anastomosis leak, abdominal wall dehiscence, intrabdominal fluid or abscess, collection, intra-abdominal bleeding, and postoperative paralytic ileus. Table 4 presents detailed characteristics of treatment outcomes.

Discussion
Surgery for ECF can be successful, yet demanding. In the Dutch center study, overall closure was achieved in 118 patients (87.4%) and restorative operations were successful in 97/107 patients (90.7%) [4]. Unfortunately, ECF surgical patients quite frequently develop complications. In Visschers' study, mortality rate reached 9.6% [4] and Klucinski et al. showed that severe complications (Clavien-Dindo grade III-V) made up 28.0% of all complications [5]. The fistula complexity determines the risk of severe postoperative complications or fistula recurrence after definitive surgical repair [4,5]. The high prevalence of postoperative complications if EFC patients should not be surprising, even in elective colorectal surgery the incidence of postoperative nausea and vomiting reaches (25-40%) [10].
Hence, the need for an improvement, and ERAS protocol seems to be a perfect solution to the problem. In colorectal surgery, ERAS protocol is already well established as the best care [11], because it has been proven to lower both recovery time and postoperative complication rates while being cost-effective at the same time [12] ERAS guidelines are now available for almost every type of major surgery, including colorectal, gastric, liver, pancreatic, esophageal, cytoreductive, cardiac, bariatric, lung, breast, and total hip/knee replacement.
In 2011, immediately after opening the surgical center in Skawina, ERAS protocol was introduced at our center for all types of major gastrointestinal procedures. Unlike for cancer surgeries, the necessity for modifications of initial recommendations was expected. Therefore, an internal auditing system was established. Annual meetings led to significant modifications of components of perioperative care, and the latter to the improvement of outcomes.
As expected, postoperative nausea and vomiting (PONV) was one of the most common issues. The use of the chewing gum and morning coffee, introduced from the early beginning, and early oral feeding led to the PONV prevalence of 46.9%. A change in the protocol, which was the allowance of liquids POD 1 instead of solid meals, helped to reduce PONV to 24.6%. No coffee or chewing gum was used.
Another revision, which was using single draining tube in case of large space in the abdominal cavity, helped to reduce the surgical complication rate from 34.4% to 14.5%. All protocol modifications from the 2015 MDT meeting also led to shortening of the length of hospital stay (overall and after surgery, p = 0.022 and 0.002, respectively).

Conclusions
To our knowledge, this is the first study on the implementation of ERAS in surgery for ECF. It showed that enhanced recovery program can be successfully used even for major, potentially risky surgery. It also demonstrated that audits are inevitable part of modern perioperative care, as constant modifications can contribute to the improvement of care.  Data Availability Statement: Data described in the manuscript, code book, and analytic code will be made available upon request pending application and approval at the Corresponding Author e-mail address.