Enhanced recovery after surgery review and urology applications in 2020

Abstract Purpose: To explore enhanced recovery after surgery (ERAS) components and their current application to major urologic surgeries, barriers to implementation and maintenance of the associated quality improvement. Data Identification: An English language literature search was done using PubMed. Study Selection: After independent review, 55 of the original 214 articles were selected to specifically address the stated purpose. Data Extraction: Clinical trials were included, randomized trials were prioritized, but robust observational studies were also included. Results of Data Synthesis: Many ERAS components have good data to support usage in radical cystectomy (RC) patients. Most ERAS programs include multidisciplinary teams carrying out multimodal pathways to hasten recovery after a major operation. ERAS components generally include preoperative counseling and medical optimization, venous thromboembolism prophylaxis, ileus prevention, avoidance of fluid overload, normothermia maintenance, early mobilization, pain control and early feeding, all leading to early discharge without increased complications or readmissions. Although there may not be specific data pertaining to other major urologic operations, the principles remain similar and ERAS is easily applicable. Conclusion: The benefits of ERAS programs are well established for RC and principles are easily applicable to other major urology operations. Barriers to implantation and maintenance of ERAS must be recognized to continue to maintain the benefits of these programs.

from the applications of ERAS leading to improved perioperative care. 1,2 However, the application of ERAS principles are applicable to most major urologic surgeries. Important ERAS components include preoperative counseling, medical optimization, avoidance of fasting, avoidance of bowel preparation, venous thromboembolism (VTE) prophylaxis, avoidance of salt and water overload, maintenance of normothermia, appropriate antibiotic use, ileus prevention, postoperative nausea and vomiting (PONV) prevention, pain control, early mobilization and early oral nutrition with avoidance of nasogastric tubes (NG). In this review, we aim to present ERAS applications in major urologic surgeries, a detailed narrative of each component and useful guidance for implementation. ERAS is often divided into three phases: preoperative, intraoperative and postoperative. All contacts who influence the patients' care throughout the health system are generally included in development and implementation in their respective segment.

| ME THODOLOGY AND LITER ATURE S E ARCH PRI ORITIZ ATI ON
A schematic diagram of ERAS is seen in Figure 1. 2 After primary review and initial screening of 214 abstracts, 120 articles with full texts were identified. After the secondary review and assessment of full texts, 55 articles regarding major urological and abdominal surgeries were selected. Two additional manuscripts were added after reference list review. Therefore, a total of 55 articles were included to specifically address the stated purpose. Table 1 lists an overview of the major studies included in this review and the key findings.

| Patient counseling
Preoperative counseling of patients can help to target expectations from the surgical and anesthesia teams. It may reduce fear, anxiety, fatigue, and pain and can contribute to accelerated postoperative recovery and early discharge. 3

| Stoma education and marking
Urostomy care requires manual skills and emotional adaptation.
Patients receiving a preoperative and postoperative detailed stoma education with a stoma specialist in an ERAS program have shorter LOS (6 vs 9 days) without any difference in readmission rate or early stoma complications. 4

| Preoperative optimization of medical condition
Optimization of cardiac, pulmonary and kidney disease, hypertension, diabetes, anemia, nutrition, cessation of excessive alcohol use and smoking all improve perioperative outcomes. 5 The pulmonary effects of smoking can be improved by quitting 4 weeks before surgery. 6

| Prehabilitation and exercise
Prehabilitation programs optimize a patient's preoperative condition to improve postoperative outcomes by promoting physical and psychological health and can be applicable to all patients undergoing major urologic operations. Although patients have a relatively short time to achieve optimization prior to surgery, a recent RCT in patients undergoing RC demonstrated home-based multimodal prehabilitation (exercise, nutrition program and psychosocial support) provided faster recovery after RC. 8

| Mechanical bowel preparation
Omitting both mechanical and antibiotic bowel preparation in RC with small bowel urinary diversions has demonstrated no difference in terms of gastrointestinal (GI) complications and wound infections. 9 Based on colorectal literature, it is recommended that patients undergo mechanical and chemical bowel preparations for diversions using the colon. 10

| Preoperative fasting and carbohydrate loading
Numerous studies have demonstrated that cessation of solid food and liquid intake, starting at midnight is associated with a number of metabolic derangements, including insulin resistance. 3 Shortening this period improves patients' comfort and reduces the surgical stress response. 11 Current guidelines by the ERAS society allows the intake of clear fluids up to 2 hours and solid foods up to 8 hours prior to surgery. 3 In the Cochrane Database, a review including 27 trials, demonstrated that preoperative carbohydrate loading was associated with a slightly decreased hospital LOS without affecting postoperative complication rates when compared with fasting and placebo. 12

TA B L E 1 (Continued)
postoperative ileus-related morbidity and reduced cost with a similar safety profile when compared to placebo. 13

| Pre-anesthetic medications
Long-acting anxiolytic premedication should not be routinely administered to patients as it may delay early postoperative recovery, mobilization and may cause cognitive impairment, particularly in elderly patients. 14

| Venous thromboembolism prophylaxis
VTE is the most common cause of the death within 30 days of urological cancer surgery. 15

| Antimicrobial prophylaxis
Patients benefit from prophylactic antibiotics, although the optimal regimen is unclear and likely depends on local antibiotic-resistance profiles. Antimicrobial coverage should include aerobic and anaerobic bacteria for patients undergoing bowel resection. A second or third generation cephalosporin or, alternatively, use of an aminoglycoside in combination with metronidazole or clindamycin is recommended to be administered within 1 h prior to skin incision. 3,10 In prolonged surgeries and in surgeries with increased blood loss,

| Skin preparation
Skin preparation prior to surgery using a chlorhexidine-alcohol scrub is suggested in ERAS guidelines to prevent surgical site infections (SSIs). However, in a Cochrane review, including >10 000 patients, authors reported no benefit for preoperative showering or bathing with chlorhexidine over other antiseptics in order to reduce SSIs. 20

| Anesthetic protocols
Collaboration with the anesthetic team is critical. The anesthesia team is responsible for influencing the outcome of surgery in multiple ways including: stress response to surgery, fluids and analgesia. ERAS anesthetic protocols include the use of thoracic (T9-11) epidural anesthesia (usually only needed for open surgery), minimal use of opioids, use of fentanyl-based short-acting opioids such as remifentanil when opioids are needed, along with strategies for prevention of hypothermia, hypoxemia and hypovolemia. 21 In a recent study, authors investigated the effect of including anesthesia ERAS components to an existing surgical ERAS program for RC.
They found a decrease in intraoperative transfusions and PONV. 22 Implementing non-opioid pain medications with regional anesthesia can decrease LOS, time to regular diet and decrease narcotic use. 23

| Perioperative fluid management
The aim of the fluid management is maintaining intravascular volume, cardiac output and tissue perfusion while avoiding overload.
Maintaining a net even fluid balance significantly decreases blood loss, LOS and overall complication rates. 28 Fluid management in patients undergoing major urologic surgery can be challenging, as urine output is often not measurable intraoperatively. Goaldirected fluid therapy (GDFT) can be used as an alternative by using a transesophageal doppler to monitor and optimize stroke volume. In a RCT of patients undergoing RC the incidence of ileus and PONV at 24 and 48 hours was significantly reduced with GDFT. 29 In addition, perioperative restrictive hydration employed in conjunction with a norepinephrine infusion in the context of ERAS program did not influence postoperative renal functions when compared with liberal hydration and did improve complication incidence. 30

| Nasogastric tube placement
Avoidance of a NG is recommended for ERAS patients. A Cochrane meta-analysis indicated increased postoperative complications without occurrence of any advantage if prophylactic NG tube was placed after major abdominal surgery. 31 In another meta-analysis, including 780 patients who underwent RC, while there were no differences in respiratory complications, the time of GI functional recovery and LOS were shorter in patients without a NG tube after surgery. 32 EAU ERUS working committee reached 85% consensus that the NG tube can be removed at extubation. 24 Therefore, NG decompression may be reserved to cases of prolonged postoperative ileus.

| Prevention of intraoperative hypothermia
Intraoperative normothermia is critical as hypothermic patients have higher wound infection incidence, more cardiac events and more bleeding. Maintaining normothermia intraoperatively is likely to reduce the infectious complications and shorten LOS. 33 Therefore, maintaining intraoperative normothermia with external heaters (forced air warming blankets) are strongly recommended and intravenous fluids given should be warmed.

| Urinary catheter
There is currently no study evaluating the optimal timing of removal of ureteric stents after RC or the transurethral catheter following RC with orthotopic neobladder. For other major urologic operations it is important to keep in mind that early removal of a transurethral urinary catheter following reduces the incidence of urinary tract infections and shortens the LOS. 34

| Pelvic drainage
Prophylactic abdominal or retroperitoneal drain placement after major urologic surgeries has been the traditional standard of care.
A recent meta-analysis on prophylactic drain placement in major uro-oncologic surgeries, including 3664 patients; showed that, for prostatectomy, postoperative complications were fewer in patients without drainage while there were no differences in incidences of re-intervention, lymphocele, hematoma or urinary retention.
Findings concluded for prostatectomy and partial nephrectomy, the placement of a drain can be omitted unless there is a deviation from the standard care. However, for RC, the evidence was insufficient to suggest drain omission. 35

| Nausea and vomiting
PONV is experienced by 25%-35% of surgical patients. This is the major cause of mobilization difficulty, delayed oral food intake, de-

| Early mobilization
Postoperative prolonged immobilization is associated with an increased risk of pneumonia, insulin resistance and muscle breakdown.
Encouraging early postoperative mobilization is also important for avoiding pain and ileus. 5 A recent prospective study evaluated the association between daily ambulation measured by wearable activity monitors and LOS among patients undergoing major surgery (including RC). They found that higher step count (up to 1000 steps) on postoperative day 1 was associated with a lower probability of a prolonged LOS. 37

| Postoperative analgesia
Ideal analgesia regimens after major surgery should relieve pain, assist in early mobilization, aid in the return of GI function, allow for oral nutrition and not increase complications (postoperative ileus, PONV, etc.). Multimodal opioid-sparing analgesia with regional or local anesthesia is recommended to provide effective pain management while minimizing the side effects of opioids. 40 In a doubleblinded RCT, patients undergoing RARP were assigned to receive either intravenous 1gram acetaminophen or placebo within 15 minutes after induction of anesthesia and repeat doses of acetaminophen or placebo was administered every 6hours for four doses.
In patients who received acetaminophen, hospital LOS was significantly shorter (by 32%) when compared to placebo and there were no differences in pain scores or opioid use. 41 As part of an ERAS multimodal analgesia plan, ultrasound transversus abdominal plane block provided lower usage of opioids, improvement in time to flatus, and a shorter hospital LOS compared to conventional post-RC pain management without observing any differences in complications or readmission rates. 42 Local wound infiltration with long acting liposomal bupivacaine is used in some institutions, however RCT data in major urologic operations is lacking.

| Early feeding
Postoperative early feeding is one of the most important components for postoperative well-being and early discharge. Traditionally, it has been thought that starting early enteral nutrition could increase GI complications, however, a Cochrane review of 13 RCTs revealed that earlier feeding might reduce the risk of postsurgical complications. 43 Additionally, early enteral nutrition (within 24 hours) has positive effects on insulin resistance, muscle function, and wound healing without increased morbidity. 44 The effect of specialized perioperative nutritional interventions (immune-enhancing nutrition, amino acids, multivitamin and mineral supplement, etc.) in patients undergoing RC has been evaluated, but small patient numbers limit the quality of evidence, however, there are promising ongoing RCTs in this area. 45

| Discharge
ERAS protocols allow for decreased LOS and earlier discharge.
Discharge parameters that usually need to be met include pain control with oral medications, tolerating full diet with at least 1-L oral intake per 24 hours, adequate mobilization and return of GI function. 1,3

| Follow-up
The aim of ERAS protocols is to provide rapid recovery and return to the baseline preoperative status. Although readmissions remain high in this area, ongoing work into decreasing readmissions is broadly being studied. 46

| Barriers of implementation of an ERAS program
Healthcare's increasing complexity and expenditures continue to challenge providers and administrators. Identifying modifiable perioperative processes such as ERAS has the potential to maximize efficiency in delivery of care and improve patient outcomes at the same time. Even with increasing evidence demonstrating better outcomes, there are still several barriers to full adoption and implementation. The first layer of difficulty comes from urologists with well-established systems who are ultimately required to change practice patterns at their respective institutions. On a recent survey among urologic oncologists, 64% always classified themselves as ERAS adopters but half of them omitted two or more of the core principles and only 20% endorsed using all them. 47 Reasons for low actual application of core principles vary and range from concerns regarding lack of enough evidence in the literature, the idea that ERAS do not work, to lack of institutional support. 47 Ideally, comprehensive assessment of baseline outcome data should be obtained before application of any protocol. This will provide data to be compared to once the benefits of the employed ERAS after surgery were also found to drive not only adherence, but satisfaction rates as well. Consistency of information provided to patients may ultimately give them confidence to take care of themselves at home and make them feel better prepared for discharge from the hospital.

| Implementation strategies
Given the complexity and high numbers of variables, ERAS guidelines require a designed execution strategy for successful implementation.
Multiple guidelines have been published, but two framework strategies became very popular: breakthrough and knowledge-to-action (KTA) implementation strategies. 50,51 The breakthrough strategy entails having an external agent who would make site visits, the creation of multidisciplinary groups with scheduled meetings to discuss all innovations and then multiple learning sessions. This group works continuously using an act-plan-study-do framework, supervised by external agents who support the whole process for about a year. 50 Similarly, the KTA process is a collaborative method that involves both the creation and application of knowledge. Briefly, it involves identifying potential problems, adapting existing knowledge to local context, assessing barriers to knowledge use, and selecting tailored interventions with subsequent monitoring and evaluation of outcomes. 51 Finally, since 2010 the ERAS society has stablished itself as a leader in the field and has issued multiple reviews and updates to facilitate the implementation of programs, including a guideline for perioperative care after RC for bladder cancer. 3 Ideally, this should serve more so as a starting point and summary of evidence so that modifications can be made in order to adapt processes to local practices.

| Evaluation of ERAS success
Implementation and maintenance of ERAS protocols depend on continued data collection, assessment of performance, and provision of feedback. 52  After an initial period of rapid increase in compliance, most authors have shown a decrease in adherence in the following years after implementation. 53 Interestingly, this well-described decrease in conformity does not seem to be related to worse clinical outcomes, functional recovery or complication rates. 53 Similarly, the impact on LOS despite a decrease in compliance with the protocol in the following 3-5 years after implementation appears to be minimal. 50 Since some providers demonstrate concerns regarding ERAS sustainability, it is very important to highlight that these observed trends in decreasing compliance over the years did not seem to negatively influence short-term treatment outcomes. 50

| Continuous quality improvement with ERAS
As described above, a concern after implementation of ERAS protocols is sustaining it on day-to-day practice. Maintaining an implemented ERAS protocol and its benefits in the setting of a quality improvement collaborative (QIC) demands several planned activities and focused interventions for programmatic maintenance and longevity. A recent pooled analysis of post-implementation data at multiple hospitals from the Netherlands identified potential strategies that could aid at sustaining ERAS outcomes. 54 Even though there were large variations within the group of hospitals included in the analysis, the data showed that most were still maintaining LOS below the national average, only slightly increased compared to 3-5 years earlier. 54 In general, strategies should target both professionals and the organization. Methodologies that were found to impact the staff were continued internal audit and feedback on outcomes, small-scale educational boosters, and constant reminders. On the other hand, the approaches that seemed to be helpful in sustaining benefits at an organizational level were the change in multiple care processes, delegation of responsibility and having multiple coordinators at different levels of care. 54 Despite growing evidence of ERAS success, examining the correlation between individual interventions and adherence rates is very important, as part of quality improvement measures. 2 One recent study proposed the creation of an importance-performance matrix in order to prioritize areas for improvement. 55 Quality evidence based protocols are key components of the ERAS. Performance is characterized by the adherence rate (number of patients that received an intervention/patient for whom the intervention was indicated). Remarkably, by combining these data on importance and performance, the authors were able to identify potential areas for improvement and that adherence does improve outcomes. 2,55 Another important aspect of ERAS is that constant change in practice eventually affects outcomes, like transformation in surgical techniques, development of newer non-opioid strategies to treat post-operative pain, etc. Therefore, compliance measures must change in order to account for changes brought in by the continuous evaluation of evidence and guideline modifications.

| LI M ITATI O N S
While ERAS principles can be applied to almost any urologic surgeries, there are currently no high or moderate level of evidence for other very common surgeries for a comprehensive ERAS pathway.

| CON CLUS ION
ERAS requires multidisciplinary and multimodal approaches to surgical recovery. Although much of the focus has been in patients undergoing RC, the principles are widely applicable to almost all major urologic oncology surgeries. It is unknown which components have the greatest influence on hastening recovery and they may very based on local and organizational cultures. Implementation is possible in almost every setting, although diligence is required to continue to maintain and improve an ERAS program.