1. Pre-admission Information, Education, and Counseling

The goal of pre-operative counseling is to set expectations about surgical and anesthetic procedures, as well as provide information regarding a care plan in the post-operative period. Pre-operative education and psychological preparation can reduce anxiety and increase patient satisfaction, which may improve fatigue and facilitate early discharge.7–9 Pre-operative education is also effective in reducing pain and nausea, and improving well-being when added to an existing ERAS protocol.10 11 Written information was determined to be superior to verbal in one randomized clinical trial in gynecologic oncology surgery.12 Ideally, patients should receive information in both written and oral form. The patient and a relative or care provider should meet with all members of the team including the surgeon, anesthetist, dietician, and nurse. Studies have shown that patients with gynecologic cancer prefer to be well informed, and support from a nurse at the time of diagnosis can reduce stress levels for up to 6 months.13 14

2. Prehabilitation

Cancer prehabilitation has been defined as “a process on the continuum of care that occurs between the time of cancer diagnosis and the beginning of acute treatment, includes physical and psychological assessments that establish a baseline functional level, identifies impairments, and provides targeted interventions that improve a patient’s health to reduce the incidence and the severity of current and future impairments”.15 Prehabilitation aims to optimize patients’ physical and mental well-being in anticipation of an upcoming stressor rather than a reactive process in which care is provided to restore wellness (ie, rehabilitation).16 There is currently no consensus-based definition, but a multimodal approach that encompasses the following principles is gaining popularity: (1) aerobic and resistance exercises to improve physical function, body composition, and cardiorespiratory fitness; (2) targeted functional exercises to minimize/prevent impairments; (3) dietary interventions to support exercise-induced anabolism as well as mitigate disease and/or treatment-related malnutrition; (4) psychological interventions to reduce stress, support behavior change, and encourage overall well-being.17

Recognizing the heterogeneity among prehabilitation interventions, timing, endpoints, and study populations,16 including the absence of direct evidence that a prehabilitation intervention successfully improves the outcomes of gynecologic oncology patients under ERAS care, a recommendation endorsing the integration of a prehabilitation program is premature. Few gynecologic prehabilitation studies have been conducted, and available studies have focused exclusively on pre- and post-operative functional exercises with conflicting results.18 Studies for multimodal prehabilitation before surgery in other abdominal cancers have shown a positive impact on patient outcomes. A meta-analysis in colorectal surgery found that nutrition prehabilitation with and without exercise shortened length of hospital stay by 2 days in a largely traditional (ie, non-ERAS) surgical care setting.19 A meta-analysis of prehabilitation interventions consisting of inspiratory muscle training, aerobic exercise, and/or resistance training found that prehabilitation decreased post-operative complications after intra-abdominal operations in a traditional surgical care setting (OR 0.59, 95% CI 0.38 to 0.91; p=0.03).20 Small prospective trials suggest that trimodal prehabilitation (exercise, nutrition, and anxiety-reduction elements) facilitates an earlier return to functional walking capacity after surgery for colorectal surgery in excess of what is achieved when ERAS is implemented alone.21 It is likely that patients with impaired pre-operative function will attain the greatest clinical benefit. A patient-led qualitative study suggested that patients perceived an enhanced recovery program should not be limited to the perioperative period, but should rather encompass the cancer care journey beginning at diagnosis.22 The addition of prehabilitation to the ERAS pathway, might, therefore, confer complementary patient-oriented and functional benefits.

3. Pre-operative Bowel Preparation

Pre-operative bowel preparation has traditionally been used under the assumption that the reduction in the stool burden may decrease post-operative infectious morbidity including anastomotic leak following bowel surgery. Although this theoretical benefit has yet to be unequivocally substantiated, in addition to patient dissatisfaction, its use has been associated with adverse outcomes due to pre-operative dehydration and electrolyte abnormalities that can hinder post-operative recovery.

Data from randomized controlled trials on the use of bowel preparation in gynecologic surgery are limited to patients undergoing minimally invasive gynecologic surgery. These studies have conclusively shown that its use is not associated with improved intraoperative visualization, ease of bowel handling or procedure performance.23–27

Given the lack of data investigating the use of bowel preparation before laparotomy for gynecologic surgery, data are extrapolated from the colorectal literature. Four meta-analyses showed that the use of mechanical bowel preparation was not associated with a decrease in overall mortality, surgical site infection rate, anastomotic leak rate, or reoperation compared with no mechanical bowel preparation.28–31 The interest in pre-operative bowel preparation was renewed in light of retrospective data suggesting that pre-operative use of oral antibiotics as bowel preparation may reduce hospital length of stay and readmissions after colorectal surgery.32 A meta-analysis of randomized controlled trials showed that a combination of oral antibiotics with mechanical bowel preparation was associated with a lower rate of surgical site infection overall (7.2% vs 16%, p<0.001) and incisional surgical site infections (4.6% vs 12.1%, p<0.001) with comparable organ space surgical site infections (4% vs 4.8%, p=0.56).33 Although no randomized controlled trials have compared oral antibiotics alone to no bowel preparation, retrospective studies have shown that oral antibiotics alone compared with no bowel preparation significantly reduced post-operative infectious morbidity including anastomotic leaks as well as major morbidity. The combination of oral antibiotics with mechanical bowel preparation did not offer any additional benefit in reducing post-operative infectious morbidity compared with oral antibiotics alone.34–36 These data suggest that oral antibiotics may have value as pre-operative bowel preparation and bring into question the significance of adding mechanical bowel preparation in this setting.

Recently there has been a trend in the colorectal surgery practice towards reintroducing pre-operative bowel preparation in the form of combined oral antibiotics with mechanical bowel preparation before colonic resections. In contrast, well-established ERAS pathways in gynecologic surgery without pre-operative bowel preparations (including cases with scheduled bowel resection) have been proven safe with very low rates of anastomotic leak.37 38 Furthermore, incorporation within established ERAS pathways of surgical site infection reduction bundles which similarly forgo bowel preparation have resulted in a significant decrease in the surgical site infection rate as low as 2.4% among ovarian cancer patients undergoing cytoreductive surgery with colonic resection, which represents the highest risk group for post-operative infectious morbidity.39 40 Notably, this compares favorably to surgical site infection bundles which incorporate combined oral antibiotics with mechanical bowel preparation, in which infection rates decreased to 7% in a comparable high-risk ovarian cancer population.41

4. Pre-operative Fasting and Carbohydrate Treatment

Surgical stress following major surgery induces a marked and well-defined post-operative metabolic response. The use of pre-operative oral carbohydrates and avoiding pre-operative fasting attenuate these post-operative responses.

Several randomized controlled trials have reported that clear fluids can be safely given up to 2 hours, and a light meal up to 6 hours, before elective procedures requiring general anesthesia, in children and adults.3 42

Pre-operative administration of oral carbohydrates 2–3 hours before induction of anesthesia has been shown to attenuate the catabolic response induced by overnight fasting and surgery.43 Since most investigations of oral carbohydrates used a pre-operative beverage containing 50 g carbohydrates, administration of beverages with less caloric content may not provide the anticipated clinical and metabolic benefits. Furthermore, beverages with high osmolality or fat content may slow gastric emptying.

Oral carbohydrates in randomized controlled trials have been shown to improve pre-operative well-being, reduce post-operative insulin resistance, decrease protein breakdown, better maintain lean body mass and muscle strength, and provide beneficial cardiac effects.43 Randomized trials on oral carbohydrates have been performed in major and minor upper gastrointestinal and colorectal surgery, and orthopedic, thoracic, cardiac, neurologic, and urologic surgery. In one randomized placebo-controlled trial, less post-operative nausea and vomiting, metoclopramide consumption, and improved patient satisfaction was noted 24 hours after abdominal myomectomy.44

A Cochrane review of abdominal, orthopedic, and cardiac surgery studies reported that preoperative carbohydrate treatment was associated with reduced post-operative insulin resistance, enhanced return of bowel function, and shorter hospital stay with no effect on post-operative complication rates.45 Large cohort studies in patients undergoing major colorectal surgery have shown that oral carbohydrates as part of an ERAS protocol significantly improved clinical outcome.46 47

Oral fluids including oral carbohydrates may not be administered safely in patients with documented delayed gastric emptying or gastrointestinal motility disorders as well as in patients undergoing emergency surgery. Although obese48 and diabetic49 patients have been included in recent studies of oral carbohydrates and no issues with regard to safety have been reported, studies are insufficient to allow a general recommendation.

5. Venous Thromboembolism Prophylaxis

Venous thromboembolism (VTE) is a major risk in gynecologic oncology patients with rates up to 3–4% in cervical cancer, 4–9% in endometrial cancer, and 17–38% in ovarian cancer.50–55 Approximately 3% of women with a new ovarian cancer diagnosis will have a concomitant VTE diagnosed before they start cancer treatment52; the risk of VTE approaches 12% during neoadjuvant chemotherapy55 and extends through at least the full course of primary therapy.56 The extended risk of VTE was also demonstrated in an analysis from the Million Women Study that showed the risk of VTE at 12 weeks post-operatively was 1/85 for cancer surgery and 1/365 for gynecologic surgery.57 The presence of malignancy, higher body mass index, age, pelvic surgery, extra-pelvic disease, histology, pre-operative corticosteroids, receipt of chemotherapy, immobility, and a hypercoagulable state have all been identified as independent risk factors for VTE and are common among women undergoing gynecologic surgery, especially for cancer.58 59 All gynecologic oncology patients who undergo major surgery lasting longer than 30 min should receive dual VTE mechanical prophylaxis and chemoprophylaxis with either low molecular weight heparin or unfractionated heparin and dual prophylaxis should continue throughout the hospital stay.59–61

Perioperative prophylaxis should include dual modality prophylaxis61 and should begin before the induction of anesthesia. A retrospective study comparing pre-operative versus post-operative initiation of prophylactic anticoagulation in patients undergoing surgery for gynecologic cancer showed a decreased rate of deep venous thrombosis (1.9% vs 8%; p=0.04) and a decreased rate of deep venous thrombosis-associated deaths (0 vs 2; p<0.001) among those who received pre-operative prophylaxis.62 Similarly, in a large retrospective surgical oncology study of 2058 patients who underwent surgery for cancer and received pre-operative heparin compared with 4960 historical controls, the rate of deep venous thrombosis and pulmonary embolism among those who received pre-operative prophylaxis was significantly lower.63 Importantly, prophylactic anticoagulation has not been shown to increase the risk of intraoperative bleeding, thrombocytopenia, and epidural hematoma.64 65 Therefore, epidural catheter placement and removal should be timed according to the last dose of heparin.64 65 The use of mechanical prophylaxis, specifically pneumatic compression devices, has been shown to decrease the rate of VTE when compared with no prophylaxis within the first 5 post-operative days. The efficacy of mechanical prophylaxis is equivalent to heparin alone, and leads to the greatest VTE risk reduction when combined with heparin in gynecologic oncology patients.66–68 Graduated compression stockings, when fitted properly, also appear to decrease the rate of deep venous thrombosis in hospitalized patients, especially when combined with another method of VTE prophylaxis.69

The risk of VTE extends beyond the post-operative hospital stay in patients undergoing cancer surgery.56 70 71 The randomized controlled trial ENOXACAN II demonstrated a 60% reduction in the VTE rate in patients undergoing surgery for cancer who received 28 days of low molecular weight heparin compared with those who received only 10 days of low molecular weight heparin.72 Additionally, a Cochrane review, a systematic review, and meta-analysis showed that extended prophylaxis for 28 days decreased overall VTE, deep venous thrombosis, and symptomatic VTE.73–75 Women undergoing gynecologic cancer surgery meet high-risk American College of Chest Physicians (ACCP) criteria and the ACCP, American Society of Clinical Oncology, and National Comprehensive Cancer Network guidelines59 61 76 recommend extended, 28-day chemoprophylaxis. While the role of extended prophylaxis in minimally invasive gynecologic surgery remains debated, VTE rates are in the range of 0.5% or less and do not appear to be modulated based on whether or not prophylaxis was given.77–80 Additionally, although direct-acting oral anticoagulants are a recommended therapy for VTE when diagnosed in patients with active cancer,81–83 the role for direct-acting oral anticoagulants for post-operative prophylaxis is currently limited to orthopedic surgery literature and requires further study in gynecologic surgery.84

Gynecologic cancer patients often start adjuvant chemotherapy within 3–5 weeks of surgery and prophylaxis during ambulatory chemotherapy remains understudied. The risk of VTE extends beyond the traditional 30 day post-operative complication window in these patients56 71 and is inherently present among those undergoing neoadjuvant chemotherapy for ovarian cancer.55 Extended low molecular weight heparin has been shown in two randomized, placebo controlled trials in solid tumors to reduce VTE during chemotherapy by 50%.85 86 The recently published randomized, placebo-controlled AVERT trial of prophylactic apixaban during solid tumor chemotherapy demonstrated a 60% reduction in VTE in those randomized to apixaban.87 However, VTE guidelines specific to gynecologic cancer are lacking.

6. Surgical Site Infection Reduction Bundles

Surgical site infections are defined as infections of the surgical incision or organ space that develop within 30 days of surgery.88 Surgical site infections are associated with increased patient morbidity, mortality, and healthcare expenditures and occur in up to 20–30% of gynecologic oncology patients undergoing a laparotomy.89–93 Surgical site infection reduction bundles have been demonstrated to decrease the risk of developing a surgical site infection in an additive fashion.39 41 91 94–98 Surgical site infection bundle elements include antimicrobial prophylaxis, skin preparation, avoiding hypothermia, avoiding surgical drains, and reducing perioperative hyperglycemia.

6.1 Antimicrobial Prophylaxis

Appropriate antibiotic prophylaxis includes administration of a first generation cephalosporin to cover skin flora.99 100 Cephalosporins have relatively broad coverage, are low cost, have a low allergenic potential, and are the recommended prophylaxis for simple hysterectomy.100 Additional anaerobic coverage is recommended if the bowel is entered during pelvic surgery for cancer.100 101 Dosage may need to be adjusted based on patient weight.99 100 Most antibiotics should be administered within 1 hour of incision in order to obtain the highest drug serum levels at incision.99 100 Antibiotic redosing should be monitored for compliance based on operative time and blood loss.99 100 Several surgical site infection reduction bundles include an emphasis on antibiotic dosing and timing of administration. Appropriate antimicrobial prophylaxis is a category 1B recommendation by the Centers for Disease Control and Prevention (CDC).39 41 91 97 102

6.2 Skin Preparation

Skin preparation is intended to decrease the amount of bacterial flora present on the skin before incision. This can be accomplished through pre-operative bathing at home as well as use of a skin preparation in the operating room before incision.99 There is level I evidence demonstrating a 40% lower surgical site infection rate associated with chlorhexidine-alcohol skin preparation compared with povidone-iodine103 and the CDC has endorsed alcohol-based skin preparation as a category 1A recommendation.102 Most surgical site infection reduction bundles have incorporated pre-operative bathing with a chlorhexidine-based antimicrobial soap and chlorohexidine-alcohol skin preparation before surgery.39 41 91 97

6.3 Prevention of Hypothermia

Intra-operative hypothermia has been linked to an increased risk of surgical site infections and cardiac events.104 Various methods to avoid intraoperative hypothermia have been evaluated including forced air blanket devices, underbody warming mattresses, and warmed intravenous fluid administration.104 In a randomized clinical trial comparing intraoperative warming only (control group) versus additional warming 2 hours before and after surgery (warming group) among patients undergoing major abdominal surgery, the rate of surgical site infections was decreased by half among those who were normothermic.104 The CDC endorses perioperative normothermia as a category 1A recommendation.102

6.4 Avoidance of Drains/Tubes

High quality evidence is lacking to address the role of subcutaneous or peritoneal drains in decreasing surgical site infections and evidence exists that drain biofilm colonization can be detected as early as 2 hours after placement.105 One surgical site infection reduction bundle implemented among gynecologic oncology patients included use of subcutaneous drains in obese patients. However, this surgical site infection reduction bundle also included other interventions with stronger surgical site infection reduction evidence.94 At this point, there is insufficient evidence to recommend inclusion of a subcutaneous drain or peritoneal drain as part of a surgical site infection reduction bundle and there may be harm by introducing a foreign body conduit for bacteria to travel into a surgical wound. Nasogastric intubation increases the risk of post-operative pneumonia after elective abdominal surgery and does not reduce the risk of wound dehiscence or intestinal leaks.106 107 As such, the use of drains should be tailored according to the surgical procedure and rationale for individualized drain placement.

6.5 Control of Perioperative Hyperglycemia

The prevalence of diabetes is 22% among the US population older than 65 years.108–110 The high prevalence suggests the need not only to implement interventions to obtain perioperative glycemic control but also to improve pre-operative screening. Perioperative hyperglycemia has been associated with increased risk of developing surgical site infections, in both diabetic and non-diabetic patients undergoing surgery,93 111–113 and the CDC recommends (category 1A) blood glucose levels be maintained at <200 mg/dL regardless of whether a patient is diabetic or not.102 A recent study among gynecologic oncology patients found that implementing an intensive post-operative glycemic control initiative using a continuous insulin infusion resulted in a 35% reduction in the rate of surgical site infections among patients with diabetes.114 Similarly, authors of another study decreased the surgical site infection rate by 55% through implementation of an initiative standardizing post-operative management of diabetic and pre-diabetic patients using a multidisciplinary team.109 Importantly, glucose management must avoid hypoglycemia as well as hyperglycemia as both extremes have been associated with higher mortality risk.115 116 It should be noted that other interventions that decrease insulin resistance are part of the ERAS protocol, including oral carbohydrate loading, minimally invasive surgery, early feeding, and thoracic epidural analgesia.3

7. Standard Anesthetic Protocol

The goals for the anesthesiologist are multiple: to provide hypnosis, analgesia, and optimal surgical conditions, and to optimize circulation, mean arterial pressure, and oxygen delivery, all with minimal residual anesthetic effects with rapid neurocognitive recovery and minimal nausea and vomiting. Propofol has become the standard medication for induction of general anesthesia because of its rapid onset, favorable antiemetic profile, and rapid recovery. General anesthesia can be maintained with inhalation anesthesia or total intravenous anesthesia. Short-acting inhalation agents such as sevoflurane or desflurane should be used. Continuous target controlled infusions of propofol have an additional benefit in reducing the incidence of post-operative nausea and vomiting.117 118 Several intravenous anesthetic agents may be used in combination with propofol to provide an effective total intravenous anesthesia regimen—dexmedetomidine, ketamine, and lidocaine. In addition to its direct sedative-analgesic properties, dexmedetomidine also reduces opioid requirements and minimum alveolar concentration levels for inhalational anesthetics.119–122

There is potential for ketamine to have benefits in reducing chronic post-operative pain, but the optimum treatment duration and dose for different operations has yet to be identified.123 124 Intravenous lidocaine infusion in the perioperative period decreases intraoperative anesthetic requirements, lowers pain scores, reduces post-operative analgesic requirements, and improves return of bowel function with decreased length of hospital stay.125 There is also evidence that ketamine, lidocaine, propofol, and avoidance of inhalational anesthetic agents may lead to a reduction in cancer recurrence. However, recognizing that multiple factors influence recurrence and survival, further research is needed to define the true impact of total intravenous anesthesia in gynecological malignancies and no recommendations can be currently made.126 127

High dose or long-acting opioids should be avoided to reduce post-operative opioid-related side effects. Short-acting opioid analgesics such as remifentanil may allow a consistently rapid recovery, but there is concern it may induce hyperalgesia. Nitrous oxide as well as being minimum alveolar concentration additive has analgesic properties but is associated with an increased rate of post-operative nausea and vomiting in a patient population with a high baseline risk.128 Both laparoscopic procedures and gynecological surgery are independent predictors of post-operative nausea and vomiting; therefore, it is reasonable to omit nitrous oxide during laparoscopic gynecologic surgery to prevent post-operative nausea and vomiting, and prophylaxis with a combination of at least two anti-emetics should be standard.129

Neuromuscular blocking agents provide muscle relaxation to facilitate surgical exposure in open surgery. In laparoscopic surgery they maintain muscle paralysis through the procedure and improve operating space and allow surgery at lower intra-abdominal insufflation pressures.130 Peripheral nerve stimulators should be used to monitor block and ensure correct reversal of neuromuscular block to reduce risks of residual muscle weakness that is a major risk for post-operative respiratory complications.131

Use of a bispectral index to guide anesthetic depth may allow reduction of anesthetic dose and hence facilitate rapid awakening.132 In the elderly, there is increased focus on using this tool to reduce the dose of inhalational anesthetic to avoid the risk of post-operative cognitive dysfunction and delirium133; a recent randomized controlled trial, however, has called this into question.134

Regional anesthetic techniques are a major component of a bundle of perioperative interventions of ERAS to reduce the stress response, as well as anesthetic and opioid use. Regional analgesic techniques include neuraxial (eg, epidural, spinal), peripheral nerve blocks, and wound infiltration.135 Multimodal non-opioid analgesia use decreases post-operative nausea and vomiting and allows more rapid recovery.136 137

Recent studies have shown a reduction in pulmonary complications in patients undergoing open abdominal surgery when a lung protective ventilation strategy is utilized (tidal volume 6–8 ml/kg with positive end expiratory pressure 6–8 cm H₂O).138 Randomized controlled trials have suggested that low tidal volumes, high positive end expiratory pressure, and recruitment maneuvers may be protective intraoperatively.139

8. Minimally Invasive Surgery

A key tenet of enhanced recovery is the focus on decreasing the stress response and modifying the metabolic response to surgical insult.1 Laparoscopic surgery has been associated with a decrease in both the inflammatory and immunomodulatory response to surgery compared with open procedures.140 141 While some studies suggest that classic endocrine metabolic responses are less influenced by minimally invasive surgery, others have suggested that minimally invasive surgery decreases the cortisol stress response compared with moderate and highly invasive surgeries.142

While most reports of the gynecologic ERAS programs have focused on open surgery, there is mounting evidence that the ERAS programs are also safe and feasible for patients undergoing minimally invasive surgery, including bowel procedures.143–145 The adoption of minimally invasive laparoscopy and robotic surgery in gynecology has led to substantial improvements in patient outcomes by decreasing intraoperative blood loss, length of stay, analgesic requirements, return of bowel function, length of hospitalization, and return to normal daily activities.146 147

With currently available data, it is not clear to what degree ERAS implementation has impacted outcomes for women undergoing minimally invasive surgery for gynecologic indications compared with minimally invasive surgery gynecologic procedures outside an ERAS program. Length of stay is a commonly reported metric for assessing the impact of ERAS programs. However, same day discharge is achievable for many patients undergoing gynecologic minimally invasive surgery procedures, regardless of whether or not the procedures were performed on a formal ERAS pathway.148 Retrospective comparative studies suggest that ERAS implementation in minimally invasive surgery demonstrated an association with improvements in length of stay and cost.149 Another series described an association of ERAS implementation with decreased intraoperative and post-operative morphine equivalents, decreased cost, and with increased patient satisfaction.144 Similar benefits have been identified in patients undergoing vaginal hysterectomy and urogynecologic procedures including shorter length of stay, decreased opioid intake, and higher patient satisfaction scores.37 150 151 From a patient’s perspective, undergoing minimally invasive surgery leads to faster recovery compared with open gynecologic surgery on an ERAS pathway. Patients undergoing minimally invasive surgery reported less pain, interference with walking, and fatigue compared with women undergoing open surgery on an ERAS pathway.152

The perioperative benefits of a minimally invasive surgery approach may be reduced by a number of elements, including uncontrolled pain, nausea and vomiting, fluid overload, limited ambulation, fatigue, and deconditioning. Age, blood loss, perioperative blood transfusion, and post-operative complications have been associated with prolonged length of stay after laparoscopic surgery.153 Urinary retention and inadequate pain control were the two top reasons why patients undergoing gynecologic minimally invasive surgery on an ERAS pathway were not discharged on the day of surgery, with 30% of delayed discharges attributed to each.143

Oncologic outcomes have been found to be equivalent in women undergoing minimally invasive surgery and open procedures for endometrial cancer,154 but not for early stage cervical cancer.155

Given the improvements in surgical recovery in patients undergoing minimally invasive surgery procedures compared with open surgery,146 147 152 minimally invasive surgery remains an important tenet of ERAS and is recommended for appropriate patients when long-term oncologic outcomes are similar, and where expertise and resources are available.

9. Perioperative Fluid Management/Goal-Directed Fluid Therapy

Intravenous fluid excess has been associated with a delayed return of bowel function, post-operative ileus, post-operative nausea and vomiting, and increased length of stay.156–158 Conversely, hypovolemia, if undetected, may lead to post-operative complications, including acute kidney injury, surgical site infections, sepsis, and delirium, as well as prolonged hospital stay.159–161 In order for the anesthesiologist to make decisions regarding fluid management, clinical parameters such as blood pressure are used, while the routine use of specific clinical goal-directed fluid therapy guidelines or algorithms using physiological measurements of blood flow, fluid responsiveness, and organ perfusion have not been universally adopted into clinical practice.162–164 This has led to wide variations in fluid volume administration across surgical practices and procedures.165

For high-risk surgical patients, goal-directed fluid therapy—a technique used to manage hemodynamics with the use of fluids and inotropes to improve tissue perfusion and oxygenation—has been associated with improvements in short- and long-term outcomes.166 167 One of the most important components of an ERAS program is the use of goal-directed fluid therapy; this may be facilitated by the use of minimally invasive hemodynamic monitoring to detect flow-related parameters and/or dynamic parameters of fluid responsiveness. This is done in order to titrate therapeutic interventions (intravenous fluids and/or inotropic therapy administration) to optimize end organ tissue perfusion.168 169

Goal-directed fluid therapy in ERAS pathways is simpler to implement as compared with patients on traditional surgical pathways. This is because patients on an ERAS pathway are not exposed to prolonged periods of fasting, or mechanical bowel preparations, and, in addition, are given carbohydrate loading solutions the night before and the morning of surgery, allowing for better hydration and a normal intravascular volume status.

A population-based study170 investigated intraoperative fluid administration practices across three surgical subspecialties and its association with post-operative recovery (64 hospitals including 8404 intestinal resections, 22 854 hysterectomies, and 1471 abdominopelvic endovascular procedures). There was a wide variation in fluid balance between hospitals (p<0.001, all procedures). The highest fluid balance hospitals had significantly longer adjusted post-operative length of stay than the lowest fluid balance hospitals for intestinal resections and hysterectomies. The authors concluded that high fluid balance hospitals have 12–14% longer risk-adjusted length of stay for visceral abdominal procedures, independent of complications and case complexity.

A recent multicenter randomized trial171 compared patients on a restrictive fluid regimen with a liberal fluid strategy. The liberal fluid group had a lower rate of acute kidney injury and surgical site infection, but otherwise there were no significant differences in outcomes. However, there is insufficient evidence to determine if the liberal fluid cohort was overhydrated, and there is evidence that the restrictive cohort was underhydrated. Furthermore, differences in fluid administration between groups were small, with <1.5 L difference intraoperatively. This study, however, has provided important information emphasizing the need to achieve euvolemia, not hypo- or hypervolemia.

A study of ERAS protocol implementation in women undergoing major gynecologic surgery compared surgical outcomes before and after implementation144; 136 ERAS protocol patients were compared with 211 historical controls. Goal-directed fluid therapy was guided by a fluid algorithm using the Masimo pleth variability index (measure of the dynamic changes in the perfusion index that occur during one or more complete respiratory cycles). The authors concluded that implementation of ERAS protocols in gynecologic surgery was associated with a substantial decrease in intravenous fluids (917.5 mL compared with 1410 mL; p<0.01). National Surgical Quality Improvement Program (NSQIP) outcomes including acute renal failure were not statistically different between groups.

10. Opioid Sparing Multimodal Post-operative Analgesia

Post-operative pain after gynecologic surgery plays a major role in patient quality of life and it may also be associated with higher rates of complications, longer hospital stays, increased readmission rates, and higher cost.172 173 When patients rely on opioid alone for post-operative analgesia, this may cause nausea, sedation, and fatigue while increasing the risk of addiction, thus leading to associated financial and social costs.174–176 Avoiding opioid use within a multimodal post-operative analgesia pathway, with greater emphasis on non-opioid medications, preserves or improves patient experience and functional recovery after surgery.37 177 Non-opioid alternatives include non-steroidal anti-inflammatory drugs, acetaminophen, gabapentin, and dexamethasone. Pre-operative education should stress the use of non-opioid alternatives as first-line therapy, and set expectations for post-operative pain control.

When used together, analgesics with different mechanisms of action may be synergistic, a concept which lays the foundation for post-operative pain management within ERAS protocols.178 We recommend routine pre-operative administration of oral acetaminophen, celecoxib, and gabapentin to reduce pain and opioid requirements.179 Intravenous acetaminophen should not be used routinely, recognizing its equivalent efficacy to the oral preparation at much higher expense. In general, oral administration of all post-operative medications in patients who can tolerate a diet is preferable to the intravenous route. While intravenous medications may be required for breakthrough pain, patient-controlled analgesia should be required in <5% of patients undergoing laparotomy. Incisional infiltration with either bupivacaine or liposomal bupivacaine has no systemic side effects when used appropriately, and should be incorporated into all ERAS protocols as a component of multimodal analgesia.37 180

The use of thoracic epidural analgesia and transversus abdominis plane blocks, both alternatives to local analgesia, has been frequently debated in patients undergoing major abdominal surgery. Thoracic epidural analgesia has been shown to effectively reduce post-operative pain and stress,181 182 but with some untoward effects such as a 30% risk of failure,183 hypotension requiring vasopressors,184 and hindrance of early mobilization.185 Transversus abdominis plane blocks are performed by injecting local anesthetic between the muscle layers of the trunk using ultrasound guidance, and has also been shown to reduce pain and opiate requirements after surgery.186 However, direct comparisons of thoracic epidural analgesia, transversus abdominis plane blocks, and incisional injection have not been performed and current literature has failed to show improvements over local injection. One trial showed lower pain scores and less opioid use in patients randomized to local injection of liposomal bupivacaine compared with transversus abdominis plane blocks following total abdominal hysterectomy.187 Other investigations in laparoscopic surgery have also failed to show improvements with transversus abdominis plane blocks.188–191 A randomized trial of conventional epidural versus transversus abdominis plane block demonstrated a 0.5 day decreased length of stay with transversus abdominis plane blocks, likely due to a slower transition to oral analgesics with thoracic epidural analgesia.192 The weight of current data supports the use of incisional injection over transversus abdominis plane blocks or thoracic epidural analgesia.

Patients using buprenorphine before surgery require special consideration. Buprenorphine is a mixed opioid agonist-antagonist at the mu (μ) and kappa (κ) receptors used for the treatment of opioid abuse. These pharmacodynamics prevent other opioids from binding to the κ receptor, therefore reducing the efficacy of all opioids after surgery. Management options include continuing buprenorphine through the perioperative period or discontinuation before surgery.193 The best option for patients undergoing minor procedures with the expectation of minimal post-operative pain is to continue buprenorphine, recognizing that high doses of opioid may be required for treatment of more severe pain. While discontinuation may be the best option if significant pain is expected, it must occur at least 3–7 days pre-operatively given its long half-life, and is associated with a higher risk of relapse for patients treated for dependence. Recognizing these challenges, all patients using buprenorphine should be evaluated by a pain specialist for optimal management.

It has been recognized that there are great discrepancies in patients’ responses to medications including opioids, with a contribution of inherited differences.194 Pharmacogenomics is an emerging field in individualized medicine, generally focusing on genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and drug targets that may explain inter-individual variation in drug efficacy and toxicity.195 This information has emerging importance in post-surgical opioid administration, with one study showing a 50% reduction in opioid use as well as excellent analgesia using pharmacogenetic-guided input.196

In recent years there has been an increased focus on the reduction of outpatient opioid prescribing, especially in post-surgical patients. A number of investigations have demonstrated that surgeons overprescribe opioids at discharge, with wide variations in prescribing practices among providers.197 It is generally accepted that 6% of opioid-naive patients will become chronic opioid users after surgery, while the rate is as high as 21% for those who require chemotherapy after surgery.198 199 Improving opioid stewardship among surgeons and their teams is an important facet of opioid use reduction, and can be successfully implemented using standardized guidelines. A large, prospective initiative evaluated patient opioid use after surgery and found that a large proportion of patients used little or no opioids after surgery.200

11. Perioperative Nutrition

Several randomized studies on early feeding have been performed in gynecologic oncology and ovarian cancer.201–206 Maintenance of appropriate nutritional status post-operatively has led to improvements in return of bowel activity, reduced length of hospital stay, and equivalent complication rates as measured by wound healing, anastomotic leaks, or pulmonary complications.203 204 207 In colorectal patients, delivery of post-operative nutrition on day 1 is an independent prognostic factor of 5-year survival and mortality.207–209

Perioperative nutritional supplementation, or immune nutrition, is another field of research, examining the roles of polyunsaturated fatty acids, arginine, glutamine, antioxidants, and nucleotides on the effects of inflammation and post-operative healing.207 210 211 Arginine supplemented diets, which may improve vasodilation and tissue oxygenation, have been examined in a large systematic review, and showed a reduction in overall infection (RR 0.59) and length of hospital stay with no difference in mortality compared with a heterogeneous control group of nutrition regimens.212 Although most of the included trials were from gastric/colon surgery, one study in gynecologic oncology supported these results.213 Several large randomized trials in colorectal patients compared an immune nutrition/high protein diet to a high calorie supplement and found a lower rate of infection and length of stay in the immune nutrition group.214 Higher post-operative protein intake is also associated with earlier discharge.215 Currently there are no definitive guidelines for surgical patients as it pertains to protein needs; however, in the acute care setting guidelines have recommended up to 2.0 g of protein/kg/day and 25–30 kcal/kg/day.207 216 It appears that a high protein diet post-operatively may reduce complications and the role of immune nutrition and arginine supplementation continues to evolve.

12. Prevention of Post-operative Ileus

Return of bowel function is often the last milestone met before post-operative hospital discharge after laparotomy. Rates of post-operative ileus as high as 30% have been reported among women undergoing open gynecologic cancer surgery,217 218 and nearly 40% among women undergoing ovarian cancer debulking requiring a bowel resection.218 Factors that influence the return of bowel function include, but are not limited to, exposure to opioids, fluid balance, extent of peritoneal disease and complexity of surgery, receipt of transfusion, and post-operative abdomino-pelvic complications.218

Several interventions have been shown to decrease the risk of post-operative ileus either through direct or indirect effects. The implementation of minimally invasive surgery reduces the rate of post-operative ileus147; however, not all patients are candidates for minimally invasive surgery. Among patients requiring laparotomy, interventions that stimulate the enteric nervous system and reduce opioid use have been shown to enhance bowel recovery time and reduce the rate of post-operative ileus. Simple interventions of early feeding, coffee consumption, and gum chewing have been shown to be effective in decreasing the time to bowel function return.180 217 219–223 ERAS programs that include early feeding, as well as euvolemia, early ambulation, and multi-modal analgesia, have been shown to decrease the rate of post-operative ileus by two- to five-fold with current rates ranging from 3–10% in studies of women undergoing high complexity open gynecologic cancer surgery.180 221 Post-operative coffee consumption has been shown to reduce the rate of post-operative ileus in women undergoing gynecologic cancer surgery from 30% to 10%.217 While the use of chewing gum is safe and inexpensive, a large well-conducted randomized trial recently showed no benefit.224

Blocking or reducing the effect of opioids on the gastrointestinal tract has also been shown to reduce the time to bowel recovery and reduce the rate of post-operative ileus. Alvimopan is an oral selective μ-antagonist with very low bioavailability that works directly within the gastrointestinal tract to block the negative effects of opioids on gut motility. Randomized controlled trials in colorectal surgery, bladder resection and reconstruction, and ovarian cancer surgery have all demonstrated a reduction in time to bowel recovery and post-operative ileus in the setting of alvimopan use.225–227 Alvimopan has been approved by the US Food and Drug Administration (FDA) for perioperative, in-hospital use for patients undergoing planned bowel resection and the first dose is given pre-operatively, before opioid exposure. Reduction in opioid consumption through implementation of ERAS pathways that leverage multimodal analgesia and/or liposomal bupivacaine have also led to reduced post-operative ileus rates.180 221 In fact, the utilization of liposomal bupivacaine instead of bupivacaine-HCl as a single intervention change in an established ERAS protocol37 reduced total opioid consumption and also reduced post-operative ileus by 50%.180

13. Patient Reported Outcomes, Including Functional Recovery

ERAS programs aim to accelerate and support patients' return to full functional recovery. Post-operative recovery follows a specific pattern that starts with a rapid deterioration from baseline function in the immediate post-operative period and then gradually rehabilitates back to or surpasses the pre-operative baseline.228 The recovery process is complex and encompasses the multiple dimensions of physical, emotional, economic, and social health.229

Surgical recovery can be conceptualized to occur in three phases: early, intermediate, and late.230 Patients spend the majority of the recovery period outside acute hospital settings, and thus it can be challenging to monitor and evaluate surgical recovery with standard metrics. Patient reported outcomes are uniquely positioned to track and study surgical recovery in a patient-centered fashion across multiple domains and longitudinally over time across all phases of recovery. Patient reported outcome instruments measure any aspect of a patient’s health status with information derived directly from the patient.231

To date, there is a paucity of patient reported outcome studies focusing on gynecologic patients within ERAS programs. In one study comparing women undergoing open gynecologic surgery on and off an ERAS pathway, the ERAS cohort reported significantly lower symptom burden from fatigue, as well as lower total interference composite scores (symptom interference with work, activity, walking, enjoyment of life, mood, and relations with others).177

Time to recovery will vary depending on the dimension or symptom being measured. For example, economic recovery and return to work may lag behind emotional or physical dimensions of recovery. In one study, patients on an ERAS pathway reported return to mild or no fatigue in 10 days compared with 30 days for the pre-ERAS cohort, while returning to mild or no interference with walking after laparotomy was reported at a median of 5 days for ERAS patients compared with 13 days in the pre-ERAS group.177 Patients undergoing minimally invasive surgery on an ERAS pathway reported a return to mild or no interference with walking at a median of 2 days.152

Consistent collection and documentation of patient reported outcomes within ERAS programs can help institutions monitor, understand, and compare patterns of recovery. Patient reported outcomes, including symptom burden assessment, can also be tracked to guide individual post-operative care. The RECOvER checklist, which outlines best practices for reporting on ERAS studies, recommends including references to validation of study instruments when reporting patient reported outcomes.232 Careful consideration of instrument selection should go beyond whether the instrument was validated in a gynecologic surgical population, but should include thoughtful evaluation of the specific content and purpose of the instrument, responsivity in the gynecologic surgical population, designed recall period, minimally important difference, and mode of administration. Timing of measures should include a pre-operative baseline assessment, with the remainder of measurements designed thoughtfully based on an a priori hypothesis to balance patient burden with expected fluctuations in the patient reported outcome responses. Wearable technologies that track functions such as steps, distance walked, sleep, and other physiologic processes can also contribute to the documentation and understanding of functional recovery and post-operative mobilization.

14. Role of ERAS in Pelvic Exenteration and Hyperthermic Intra-Peritoneal Chemotherapy

In this section of the guidelines, we focus on two procedures where the risk of perioperative complications and poor outcomes is high and thus aim to provide support for the consideration of implementation of the principles of the ERAS guidelines, highlighting a number of items considered most critical in the perioperative recovery of the patient.

Total pelvic exenteration remains one of the most extensive procedures performed in gynecologic oncology where post-operative morbidity is a major concern, with complication rates as high as 60–95%.233 234 The post-operative 30-day mortality is 0.7% and the 90-day mortality is 2.2%.235 The most common complications include urinary tract complications, wound dehiscence, infections, and organ system failure. Surgical complexity, hemoglobin levels, and the presence of three or more comorbidities are independently associated with severe complications.235 A second procedure associated with high levels of perioperative morbidity is hyperthermic intra-peritoneal chemotherapy (HIPEC). Although it is considered an experimental procedure in the setting of gynecologic cancer in most centers, HIPEC is gaining increasing popularity in certain scenarios. Recent data from a prospective randomized trial evaluating the role of HIPEC in the setting of neoadjuvant chemotherapy showed that patients who underwent interval surgery plus HIPEC had an overall survival advantage over those who underwent surgery alone (45.7 months vs 33.9 months).236 Complication rates are consistently high, with grade 3–4 morbidity in up to a third of patients.237

In the setting of such high complexity procedures, it is essential to implement strategies that will minimize complication rates and ideally return the patient as quickly as possible to normal daily activities. In these patients, elements such as pre-operative optimization, nutritional counseling and early post-operative feeding, perioperative fluid management, thromboembolism prophylaxis, balanced post-operative fluid therapy, perioperative glucose control, and early mobilization should ultimately translate into improved outcomes. Pre-operative counseling is a key element in compliance and thus all patients should be provided detailed information regarding the aims of the program. In patients undergoing pelvic exenteration or HIPEC therapy, insulin resistance may accentuate the already high risk of perioperative complications. Therefore, carbohydrate loading should be considered, as it may attenuate the increased insulin resistance related to such prolonged and extensive surgery. Perioperative fluid management is also of paramount importance in major surgery and in high-risk patients. Anesthesiologists should therefore focus on the use of advanced hemodynamic monitoring to individualize fluid therapy and optimize oxygen delivery. Reduction in surgical site infection is key in patients undergoing pelvic exenteration or HIPEC therapy. Recent studies have shown that implementation of a comprehensive glycemic control initiative can lead to a decrease in surgical site infection from 14.6% to 5.7%.109 In addition, early mobilization intuitively will promote a faster and safer recovery by reducing the risk of thromboembolic events, as well as the risk of pulmonary complications. In addition, emphasis on early ambulation will reduce muscle atrophy and will also prepare patients for a faster return to functional activity.

15. Discharge Pathways

Patients managed under an ERAS pathway are discharged in an intermediate phase of recovery, with the recovery process expected to extend into the home setting. Hospital discharge is a key transition phase for patients and caregivers. Assessing patients’ readiness for discharge is an essential component of the discharge planning process.238 Detailed education should be provided to the patient and caregiver. Important aspects of discharge education include the information content, the frequency of education, timing, and delivery method.

A decreased length of stay reduces the time available to provide discharge teaching, so it is recommended to initiate discharge education and expectations during the pre-operative visit. It is also crucial to provide tailored information to meet the needs of the individual patient. In a post-discharge follow-up study, the need to implement reliable protocols that identify patients who are at risk for poor understanding and execution of hospital discharge instructions was emphasized.239

A study published recently on an ERAS program for colorectal surgery showed that 93% of the patients were satisfied with the discharge information, and 90% felt they were ready for discharge.240 Ensuring that patients’ informational needs have been met before hospital discharge sets the stage for successful self-management of recovery at home.241 With improved post-operative education and closer follow-up, it is estimated that 50% of hospital readmissions may be preventable.242

16. ERAS Audit and Reporting

Implementation of ERAS requires coordination by a multidisciplinary team spanning the entire continuum of care from pre-operative counseling to return to normal function. Assessing adherence to specific ERAS elements is an essential component of an ERAS program. Observational studies from colorectal surgery including more than 10 000 patients have described a strong correlation between increasing compliance with ERAS guidelines and decreased rates of complications and shorter lengths of stay.47 243 While there are no randomized studies in gynecologic oncology comparing auditing of compliance with ERAS elements to no auditing, a non-randomized Canadian prospective study of more than 500 gynecologic oncology patients using an ERAS compliance audit tool found that an increase in ERAS compliance from 56% to 77% was associated with a 31.4% reduction in adjusted length of stay and net cost savings of $952 per patient.220 Active auditing appears to be more effective at achieving compliance than passive implementation alone.244 245

ERAS reporting should include enough information on compliance to define the impact of individual ERAS elements on outcomes. Insufficient reporting of compliance may lead to incorrect conclusions.246 To improve the quality of ERAS reporting, ERAS USA and the ERAS Society have published the Reporting on ERAS Compliance, Outcomes, and Elements Research (RECOvER) Checklist. This tool delineates best practices for reporting clinical pathways and describing compliance.232 Clinicians are encouraged to use ERAS auditing tools. Two examples include the ERAS Interactive Audit System (EIAS) (http://erassociety.org/interactive-audit/) and the Agency for Healthcare Research and Quality (AHRQ) safety program for improving surgical care and recovery (https://www.ahrq.gov/professionals/quality-patient-safety/hais/tools/enhanced-recovery/index.html).