YGYNO-975665; No. of pages: 9; 4C: Gynecologic Oncology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

Enhanced recovery pathways in gynecologic oncology

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Gregg Nelson a, Eleftheria Kalogera b, Sean C. Dowdy b,⁎

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Division of Gynecologic Oncology, Tom Baker Cancer Centre, Calgary, Alberta, Canada Division of Gynecologic Surgery, Mayo Clinic College of Medicine, Rochester, MN, USA

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Keywords: Enhanced recovery after surgery Gynecologic oncology Fast track surgery

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Objective. Many commonplace perioperative practices are lacking in scientific evidence and may interfere with the goal of optimizing patient recovery. Individual components of perioperative care have therefore been scrutinized, resulting in the creation of so-called “enhanced recovery” pathways (ERP), with the goal of hastening surgical recovery through attenuation of the stress response. In this review we examine the evidence for ERP in gynecologic oncology using data from our specialty and general surgery. Methods. We performed a systematic literature search on ERP in gynecologic oncology in June 2014 using PubMed/MEDLINE, EMBASE, and The Cochrane Library. All study types were included. References were hand reviewed to ensure completeness. The Enhanced Recovery After Surgery (ERAS) Society was contacted to identify any unpublished protocols. Results. Seven investigations were identified that examined the role of ERP in gynecologic oncology. Common interventions included allowing oral intake of fluids up to 2 hours before induction of anesthesia, solids up to 6 hours before anesthesia, carbohydrate supplementation, intra- and postoperative euvolemia, aggressive nausea/vomiting prophylaxis, and oral nutrition and ambulation the day of surgery. In addition, bowel preparations, the NPO after midnight rule, nasogastric tubes, and intravenous opioids were discontinued. While no randomized data are available in gynecologic oncology, significant improvements in patient satisfaction, length of stay (up to 4 days), and cost (up to $7600 in savings per patient) were observed in ERP cohorts compared to historical controls. Morbidity, mortality, and readmission rates were no different between groups. Conclusion. Enhanced recovery is a safe perioperative management strategy for patients undergoing surgery for gynecologic malignancies, reduces length of stay and cost, and is considered standard of care at a growing number of institutions. Our specialty would benefit from a formalized ERP such as ERAS which audits compliance to protocol care elements to optimize patient outcomes and value. © 2014 Published by Elsevier Inc.

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Article history: Received 18 August 2014 Accepted 5 October 2014 Available online xxxx

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• Enhanced Recovery Pathways (ERP) are safe for patients undergoing complex gynecologic oncology operations, including colonic resection. • Incorporation of a comprehensive ERP is associated with reduced length of stay, excellent patient satisfaction, and lower costs. • Successful implementation of ERP requires standardization and cooperation within the care team.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Enhanced recovery pathways in gynecologic oncology . . . . . . Challenging traditional elements of perioperative care . . . . . . Preoperative bowel preparation . . . . . . . . . . . . . . Overnight fasting rule and preoperative carbohydrate loading. Intraoperative fluid management. . . . . . . . . . . . . . Postoperative pain control . . . . . . . . . . . . . . . . .

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⁎ Corresponding author at: Eis LO-71, 200 First St. SW, Rochester, MN, 55905. E-mail address: [email protected] (S.C. Dowdy).

http://dx.doi.org/10.1016/j.ygyno.2014.10.006 0090-8258/© 2014 Published by Elsevier Inc.

Please cite this article as: Nelson G, et al, Enhanced recovery pathways in gynecologic oncology, Gynecol Oncol (2014), http://dx.doi.org/10.1016/ j.ygyno.2014.10.006

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G. Nelson et al. / Gynecologic Oncology xxx (2014) xxx–xxx

Prophylactic drainage . . . Nasogastric drainage . . . Early postoperative feeding Laxative use . . . . . . . Conclusions . . . . . . . . . Conflict of interest statement . . Acknowledgements . . . . . . References . . . . . . . . . .

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We performed a systematic literature search in June 2014 using PubMed/MEDLINE, EMBASE, and The Cochrane Library. Search terms included “enhanced recovery surgery”, “enhanced recovery programs”, “fast track surgery”, “ERAS”, and “gynecologic oncology.” No restrictions were placed on the search and all study types were included. The reference lists of all studies were hand reviewed to ensure completeness. In addition, the ERAS society was contacted to determine if there were any unpublished protocols and their website (http://www.erassociety.org/) was reviewed. This search identified seven studies that examined the

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Individual components of perioperative care have increasingly been evaluated from an evidence-based perspective, resulting in the creation of so-called “enhanced recovery” pathways (ERP) [1,2]. This approach was founded over a decade ago by European surgeons who challenged traditional surgical paradigms such as preoperative bowel preparation, the overnight fasting rule, and delayed postoperative feeding. These researchers soon learned that many commonplace perioperative practices were not only lacking in scientific evidence, but in fact interfered with efforts to most effectively prepare patients for surgery and hasten convalescence. These findings led to the adoption of practices thought to attenuate the stress response associated with surgery, including omission of bowel preparation, euvolemia, early postoperative feeding, and avoidance of intravenous opioids. Formalized evidence-based Enhanced Recovery After Surgery (ERAS) protocols are now available in areas such as colorectal, pancreatic and urological surgery [3–5] with a corresponding audit system (ERAS Interactive Audit System, EIAS) to ensure compliance [6]. Measuring compliance has proven to be a key factor required for success and sustainability of ERAS protocols [7]. There has been widespread uptake of these protocols internationally, particularly in colorectal surgery. Meta-analyses have shown an average reduction in length of stay of 2.5 days [8,9] and a decrease in complications by as much as 50%. The weight of this evidence is demonstrated by the fact that the National Surgical Quality Improvement Program (NSQIP) recently developed enhanced recovery fields for patients undergoing colorectal surgery. From a health economics perspective, ERP have resulted in a mean savings of 1651€ ($2245 USD) per patient [10].Thus, adoption of ERP across diverse surgical disciplines has the potential to improve outcomes, reduce complications, reduce costs, and thereby increase the value of health care. To date there has been little in the way of formal perioperative protocol development in the discipline of gynecologic oncology. Recognizing the need to continually improve the quality of care in the face of progressive economic constraints, all aspects of our surgical practice are likely to benefit from optimization and standardization. The goals of this review are: i) to determine the current extent of literature describing ERP in gynecologic oncology, ii) to examine the evidence within established protocols in surgical disciplines outside gynecologic oncology (eg: ERAS colorectal surgery) that may have implications for our practice, and iii) to set the stage for a comprehensive, standardized perioperative protocol in our specialty (ERAS Guideline).

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role of enhanced recovery in the setting of gynecologic oncology surgery. The results are described as follows and summarized in Tables 1–3. Marx et al. [11] were the first to evaluate accelerated recovery in our discipline. They compared 72 consecutive patients undergoing ovarian cancer surgery via laparotomy with conventional care (group 1) versus 69 consecutive patients undergoing similar surgery but receiving what they called “multimodal rehabilitation” (group 2). There was an equivalent, but low, number of patients requiring colonic resection in each group (n = 5). The multimodal rehabilitation program for this investigation and those below is described in Table 2. The median postoperative stay was reduced from 6 days in group 1 (mean 7.3) to 5 days in group 2 (mean 5.4) (p b 0.05). There was no difference in the overall complication rate, although severe medical complications were reduced in group 2 (14% versus 2%; p b 0.01). The readmission rate was higher in the conventional group compared with the multimodal group (10% versus 3%, respectively; p b 0.05). Eberhart et al. [12] evaluated 86 patients undergoing major abdominal surgery for ovarian cancer among which 40 patients were treated by a traditional algorithm (8 required bowel resection) compared to 46 patients treated by a multimodal “fast-track” algorithm (10 required bowel resection). Indicators of postoperative recovery were documented using a validated quality-of-life tool (PPP33 questionnaire). The main study findings were that patients in the fast-track program reported improvement in “autonomy,” “physical complaints,” and “postoperative pain;” they also reported their recovery to be faster compared to patients in the traditional group. There was no difference in postoperative complications between groups. Chase et al. [13] retrospectively reviewed 880 surgical admissions at an institution using a prescribed clinical pathway with no comparison cohort (Table 2). A preoperative diagnosis of cancer was present in 31%. All patients underwent laparotomy with 40% of surgeries being categorized as radical and/or staging procedures. The median length of hospital stay was 2 days. Fifty-nine patients (7%) were reported to have significant complications (most commonly postoperative ileus); only 5% required readmission. In the aforementioned studies, only a small fraction of patients required bowel resection. Gerardi et al. [14] studied only those patients who required recto-sigmoid colectomy as part of cytoreductive surgery for advanced ovarian and primary peritoneal cancers. Nineteen patients had their postoperative management prescribed by a standardized clinical pathway (Group A) whereas the comparison group of 45 patients (Group B) had care directed by individual surgeon preference (conventional). Total parenteral nutrition was used for patients with a preoperative serum albumin level ≤2.0 g/dl and/or if resumption of oral intake was anticipated to be ≥7 days postoperatively. While the median time to flatus was equivalent between groups (6 days, p = 0.95), median time to tolerance of diet was significantly shorter in the clinical pathway group compared to the conventional group (3 versus 6 days, respectively; p = 0.013). Group A had a shorter median length of hospital stay (7 days versus 10 days, p = 0.014) and there was a median reduction in hospital cost of $5410 per patient with implementation of the clinical pathway. There was no difference in the 30-day readmission rate (Group A 21% versus Group B 33%, p = 0.379). Carter [15] reported on his single-surgeon experience involving 389 patients who underwent fast track surgery via laparotomy for suspected

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G. Nelson et al. / Gynecologic Oncology xxx (2014) xxx–xxx t1:1 t1:2

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Table 1 Characteristics of included studies.

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Study

Patient population

Type of surgery

Enhanced recovery group (N)

Control group (N)

Main outcomes

t1:4 t1:5

Marx et al. (2006)

Ovarian cancer

Cytoreductive surgery

“Multimodal rehabilitation” (n = 69)

“Conventional care” (n = 72)

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Eberhart Ovarian cancer et al. (2008)

Cytoreductive surgery

Multimodal "Fast Track" (n = 46)

Traditional algorithm (n = 40)

t1:8 t1:9

Chase et al. (2008)

“Postoperative clinical pathway” (n = 880)

-

Length of stay, recovery of gastrointestinal function, postoperative complications, reoperations, readmissions, mortality quality of life measures (PPP33-questionnaire), postoperative complications Length of stay, postoperative complications, readmissions, mortality

t1:10 t1:11

Time to oral intake, time to flatus, length of “Postoperative management “Postoperative management directed by individual surgeon ICU stay, postoperative morbidity, length of dictated by a prescribed stay, 30-day readmissions, total hospital clinical pathway” (n = 19) preference” (n = 45) costs Carter et al. Gynecologic Cytoreductive surgery “Fast-track surgery Ability to tolerate early oral feeding, length (2012) malignancies and surgical staging program” (n = 389) of stay, readmissions, postoperative complications “Non-standardized care” Postoperative hypotension, time to oral “Multimodal enhanced Cytoreductive surgery, Kalogera Gynecologic (n = 235) intake, time to flatus, length of stay, recovery pathway” surgical staging and et al. (2013) malignancies, pelvic 30-day complications, 30-day readmissions, (n = 241) pelvic organ prolapse organ prolapse 30-day mortality surgery “Non-standardized care” Length of stay, postoperative complications, Wijk et al. Benign and malignant Abdominal hysterectomy “Enhanced recovery after readmissions (2014) gynecologic conditions with or without salpingo- surgery protocol” (n = 85) (n = 120) oophorectomy

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Benign and malignant Abdominal or vaginal gynecologic conditions hysterectomy; staging procedures Gerardi Ovarian cancer Primary cytoreductive et al. (2008) surgery

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Challenging traditional elements of perioperative care

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Common themes that run through all the studies described thus far include strategies to better prepare patients for surgery, attenuate the stress response of surgery and ultimately, to hasten recovery. Many of the individual care elements described (Table 2) are also contained within established ERAS protocols for colonic resection, rectal resection and urological surgery [3,5,19]. As these surgery types are frequently utilized by gynecologic oncologists, it is sensible to more formally adopt portions of these protocols into our own practice. Some clinicians are uncomfortable subjecting patients to a battery of care process changes without proving which interventions are effective. In this section we review the individual components of ERP to explore potential mechanisms and provide more specific data on their effectiveness. But much like “bundles” of interventions adopted to reduce surgical site infections, the many components of ERP are all critical to hasten recovery and achieve optimal patient satisfaction.

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Preoperative bowel preparation

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Sir William Halsted was the first to introduce the concept of mechanical bowel preparation in 1887 – a practice that was purported to result in a decrease in anastomotic leak and infection [20]. Many proponents also describe easier handling of the bowel, making bowel resections less cumbersome to perform. However, this practice often results in patient distress, may cause dehydration, and evidence of patient benefit is lacking [21]. Recently, a number of large retrospective studies have suggested that oral antibiotic bowel preparation may be associated with decreased infection rates [22–24]. However, this has not been verified in randomized trials. In fact, a systematic review of 18 randomized clinical trials (5805 patients) found no statistically significant evidence that patients benefit from either bowel preparation or rectal enemas [25]; specifically, the infection and anastomic leak rates in patients with a bowel preparation was 9.6% and 4.4%, respectively, compared to 8.5% and 4.5% for those without. They concluded that in colonic surgery, bowel cleansing may be safely omitted. The slow adoption of evidence-based practice was shown in a 2010 survey of 110 members of the Society of Gynecologic Oncology of Canada regarding their use, rationale, and understanding of the literature pertaining to bowel preparation for gynecologic oncology surgeries [26]. They found that nearly

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or confirmed gynecological cancer (final pathology confirmed cancer in 227 cases: 51% ovarian, 39% uterine, 9% cervical); there was no comparison group. The median length of stay was 3 days (range 2–27); 110 patients (28%) were discharged on POD2 and the readmission rate was 4%. Kalogera et al. [16] reported on 241 patients who underwent surgery (81 complex cytoreductive, 84 staging only, and 76 vaginal surgery cases) according to an ERP compared to 235 historic controls from one year earlier matched by procedure type. The ERP was among the most comprehensive of those reviewed. Wound infiltration with bupivacaine was utilized, but epidural analgesia was not used for patients with cancer due to concerns for hypotension necessitating vigorous fluid resuscitation. The ERP achieved the greatest benefit in the complex cytoreductive group, of which 57% underwent colonic or small bowel resection. PCA use decreased from 98.7% to 33.3% with an accompanying 80% reduction in total opioid use in the first 48 hours with no change in pain scores. The ERP resulted in a 4-day reduction in length of stay with no difference in readmission or complication rates. Furthermore, 30-day cost savings of more than $7600 per patient (18.8% reduction) was achieved. Ninety five percent of patients rated satisfaction with perioperative care as excellent or very good. Wijk et al. [17] reported on a modified ERAS protocol for abdominal hysterectomy patients. The ERAS Colonic Surgery Protocol [3] was modified to suit simple gynecology cases (while omentectomy was allowed, extensive pelvic surgery including lymphadenectomy and further procedures were excluded). They compared 120 historical patients undergoing hysterectomy (27% for cancer) with 85 patients undergoing hysterectomy (36% for cancer) following introduction of the protocol. The proportion of patients discharged at 2 days increased significantly from 56% pre-ERP to 73% post-ERP (p = 0.012). There were no differences in complication rates (5% versus 3.5% in primary stay, 12% versus 15% within 30 days of discharge). A Cochrane Review of perioperative ERP for gynecological cancer patients in 2012 did not identify any randomized clinical trials [18]. While they concluded that there was no evidence to support or refute the use of such programs, they did discuss the benefits shown in the non-randomized studies summarized above. Even in the absence of type I data confirming significant benefits on length of stay and cost, it is worth noting that the most important elements of enhanced recovery may be implemented at low or no cost, and universally improve patient comfort and satisfaction.

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Intraoperative fluid management

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Maintenance of euvolemia is one of the most important principles in ERP. Traditional dogma has favored purposeful administration of excess fluids over inadvertent fluid restriction to avoid potential oliguria and renal injury. However, it should be recognized and accepted that oliguria secondary to anti-diuretic hormone secretion is a normal stress response following surgery rather than a pathologic state. There is no

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Postoperative pain control

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In urologic, vascular, colorectal, and thoracic surgery there appears to be little controversy with respect to the efficacy of epidural analgesia for postoperative pain control. Epidural analgesia has been shown in a number of meta-analyses to be superior to intravenous opioid PCA in patients undergoing laparotomy or thoracotomy in terms of overall pain, pain at rest, and pain with activity [50,51]. Given differences in patient characteristics, it is unclear if these findings can be extrapolated to patients with gynecologic cancer as a number of studies show conflicting outcomes. In a nonrandomized study, de Leon-Casasola et al. investigated if the use of continuous epidural bupivacaine-morphine in the perioperative period was associated with a significant decrease in the recovery time of postoperative ileus when compared with parenteral morphine administration in 68 women who underwent uncomplicated radical hysterectomies [52]. Compared to the PCA group (n = 36), the epidural

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The “overnight fasting rule” or “NPO at midnight” is a surgical paradigm that has been ingrained in many surgeons since medical school, yet is largely unsupported by evidence or contemporary recommendations. It was introduced in the 1900’s after the first anesthesia death following aspiration of gastric contents was reported in an effort to minimize the risk of pulmonary aspiration of gastric contents during surgery. Intuitively, encouragement of dehydration and caloric restriction prior to a major physical insult is counter to the goal of expedited healing. Prolonged fasting leads not only to preoperative thirst and hunger, which are among the most important causes of preoperative patient discomfort, but also untoward metabolic changes which may adversely impact clinical outcomes. A Cochrane review of 22 randomized clinical trials found no evidence to suggest that a shortened fluid fast results in increased aspiration risk, regurgitation or related morbidity compared with the standard “NPO at midnight” fasting policy [27]. Administration of clear fluids up until 2 to 3 hours before surgery is safe with some investigators reporting safety with administration of clear fluids up to 90 minutes before surgery [1,28]. In fact, the standard fasting guidelines supported by most national societies, including the American Society of Anesthesiology, recommend clear fluids until two hours before the induction of anesthesia and a six-hour fast for solid food [29]. A 12-hour fasting period is adequate to cause a shift from the metabolic state of fasting to starvation, leading to rapid depletion of liver glycogen stores. The absence of an immediately available energy source at a time of increased energy demands has been shown to adversely affect perioperative outcomes [30]. Animal studies have shown that the ability to respond to injury and particularly to hemorrhagic stress is improved in the fed compared to the fasting state [31]. Moreover, surgical stress, fasting, pain, and immobilization all result in hyperglycemia and insulin resistance [32,33] which has been associated with complications following major abdominal surgery, cardiac surgery, and in the ICU setting [34,35]. Preoperative intravenous infusion of 10–20% glucose solution with insulin and potassium has been shown to successfully avoid the fasting metabolic state and prevent insulin resistance [36,37]. However, the need for concomitant insulin infusion, close monitoring of blood glucose and the need for access to large veins to avoid peripheral vein irritation make this practice inconvenient. Alternatively, a nearly iso-osmolar carbohydrate drink that is completely emptied from the stomach within 90 minutes from administration has been shown to be safe in preoperative patients [28,38] and effective in preventing insulin resistance [28, 39]. Other benefits include improvements in thirst, hunger, anxiety, nausea and vomiting, [38,40,41] and postoperative discomfort [42]. Yuill et al. suggested that preoperative carbohydrate administration may attenuate muscle mass depletion after surgery [43]. In a systematic review and meta-analysis, preoperative carbohydrate loading was associated with a reduction in hospital length of stay by 20% [28,43,44]; these findings were corroborated in a small randomized trial [45].

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doubt that aggressive fluid resuscitation is lifesaving in certain circumstances, such as septicemia. However, the adverse consequences may be significant. For example, in one study of patients with septicemia, the average extracellular overload in the first 48 hours was 12 liters, which may require three weeks to excrete [46]. In the average surgical patient, over-vigorous administration of fluids may result in subtler, but nevertheless significant side effects including electrolyte imbalances (eg hyponatremia) and expansion of the lung interstitium with pulmonary congestion and edema. Although clinically apparent in the lower extremities, edema of the small bowel may result in protracted recovery of bowel function and may contribute to adynamic ileus. Unfortunately, limiting administration of fluids is one of the most difficult hurdles to navigate since it is managed by multiple care providers, including the most junior members of the team, in both the intra- and postoperative period. Mindlessly opening an IV for 20–30 minutes may undo hours of careful fluid management. Cooperation between attending surgeons and anesthesiologists, house staff, and nurses is therefore necessary in order to achieve a goal of zero fluid balance. While limited data is available in the field of gynecology, euvolemia is a component of most ERP studies. For example, in one investigation, patients undergoing laparotomy for gynecologic cancer managed under ERP received on average over one liter less fluid compared with historical controls not managed under ERP [16]. In the colorectal literature, results from multiple studies, including randomized trials, have shown that fluid restriction with the goal of achieving euvolemia is associated with reduced hospital stay, cost, cardiopulmonary complications, and faster bowel recovery with no accompanying impairment in healing. Conversely, the use of liberal fluid administration is associated with longer length of hospital stay. Patients undergoing colorectal resections randomized to a fluid regimen designed to achieve zero balance had fewer cardiopulmonary complications (7% versus 24%; p b 0.001) compared to a group randomized to standard perioperative fluid management causing a 3− 7 kg increase in body weight [47]. In another investigation, patients receiving restricted intraoperative fluids had shorter time to flatus, fewer complications, and shorter length of stay compared to patients randomized to liberal intraoperative fluids. Importantly, this effect was present despite the fact that both groups received similar volumes of fluids postoperatively [48]. Thus, even modest degrees of fluid and salt overload in the operating room may lead to compromised outcomes. A meta-analysis of 9 randomized trials from nearly 1000 patients demonstrated reduced morbidity (OR 0.41; p = 0.005) in favor of restrictive fluid therapy [49]. It was necessary to treat only 6 patients with fluid restriction in order to avoid a single complication. Highlighting the need to coordinate care with anesthesiologists, these improvements in morbidity were not observed if fluid restriction was initiated only in the postoperative period.

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half of respondents (48%) routinely ordered bowel preparation despite acknowledgment in 77% that there was no good evidence to support its use. The most common reason for ordering bowel preparation was the belief that it decreased the risk of anastomotic leak and improved visualization. Seventy one percent felt that formal recommendations specific to the field of gynecologic oncology would be helpful.

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G. Nelson et al. / Gynecologic Oncology xxx (2014) xxx–xxx Table 2 Description of enhanced recovery pathways of included studies. Gerardi et al. (2008)

Carter et al. (2012)

Kalogera et al. (2013)

Wijk et al. (2014)

n/a n/a n/a +

+ n/a + -

+ n/a n/a n/a

n/a n/a n/a n/a

+ + + +

+ + + +

+ + + +

+ + n/a + +

+ + + + -

n/a n/a + n/a n/a

n/a n/a n/a n/a n/a

+ + + +

+ + + + +

+ + + + +

+ + + n/a + +

+ n/a + + + -

+ + + + + n/a

n/a + + n/a n/a

+ + + + + +

+ + + + + +

+ + + + + n/a

n/a: information not available.

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group (n = 32) required fewer days of nasogastric therapy (4 +/− 3 versus 8 +/− 2 days, p = 0.0001), tolerated solid foods sooner (6 +/− 2 versus 11 +/− 3 days, p b 0.0001), and had a shorter hospitalization time (10 +/− 3 versus 14 +/− 4 days, p = 0.0001). In a recent retrospective study, Rivard et al. studied postoperative pain control in 112 women who underwent laparotomy for suspected gynecologic malignancy [53]. Patients were divided into one of three groups: 1) PCA (n = 44); 2) PCA + TAP block (n = 30); and 3) patient-controlled epidural analgesia (PCEA, n = 38). Mean narcotic use and patient reported pain scores were compared. Patients in the TAP group used the least amount of narcotic on POD 0 and those in the PCEA group used less on POD 1 and 2. The PCEA group also reported lower pain scores on POD 1 and 2.

t3:1 t3:2

Table 3 Main outcomes of included studies.

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Outcomes⁎, 1, 2, 3

Marx et al. (2006)

Eberhart et al. (2008)

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Time to oral intake4

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-

t3:5

Time to flatus

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-

t3:6

Length of stay

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Postoperative complications5 Mortality

t3:10

Readmissions6

t3:11

Reoperations

t3:12 t3:13

Total hospital cost

ER: 5 (2–35) C: 6 (2–35)⁎ ER: 24.69% C: 31.9% ER: 0% C: 2.8% ER: 2.9% C: 9.7% ER: 4.3% C: 12.5% -

t3:14 t3:15

Quality of life measures

-

t3:16 t3:17 t3:18 t3:19 t3:20 t3:21 t3:22 t3:23 t3:24

R

t3:3

U

385 386

C

381 382

E

380

Gerardi et al. (2008)

Carter et al. (2012)

Kalogera et al. (2013)7

Wijk et al. (2014)

-

ER: 3 (1–20) C: 6 (1–14)⁎ ER: 6 (4–20) C: 6 (2–15) ER: 7 (3–27) C: 10 (5–30)⁎ ER: 57.9% C: 62.2% ER: 0% C: 2.2% ER: 21.1% C: 33.3% ER: 5.3% C: 4.4% ER: 23,912 (11,010–84,170) C: 30,205 (11,980–78,150) -

-

ER: 0 (0–1) C: 5 (3–7)⁎ ER: 3 (2–3) C: 4 (3–5)⁎

ER: 1 (0–2) C:1 (0–4) ER:1 (0–3) C: 1 (1–3) ER:2.4 (+/−1.2) C: 2.6 (+/−1.1)⁎ ER: 15.3% C: 12.5% ER: − C: − ER: 3.5% C: 4.2% ER: 1.2% C:1.7% -

-

-

-

ER: improved autonomy, physical complaints, postoperative pain

-

N C O -

ER: 2 (0–52) C: − ER: 7% C: − ER: 0.2% C: − ER: 5% C: − -

No difference -

-

In contrast, a number of studies have shown less dramatic results, particularly when considering other aspects of recovery. In a randomized controlled trial of 135 patients undergoing major open gynecologic cancer surgery, Ferguson et al. [4] compared PCEA to PCA. The primary endpoint was postoperative pain at rest and when coughing [54]. The PCEA group had significantly less pain on POD 1 and during the first 3 postoperative days when coughing compared to the PCA group (p b 0.05). The mean pain score at rest on POD 1 was 3.3 for the PCEA group compared to 4.3 for the PCA group (p = 0.01), but the median length of stay was equivalent (5 days, p = 0.93). Chen et al., in a prospective cohort study of 205 patients undergoing laparotomy for gynecologic oncology surgery, compared PCEA (n = 107) to PCA (n = 98) [55]. PCEA was associated with longer anesthesia time preoperatively

Chase et al. (2008)

R

378 379

T

t2:22

F

Chase et al. (2008)

O

Preoperative Education/counselling Same-day admission Minimization of fasting period Avoidance of bowel preparation Intraoperative Pre-emptive analgesia before OR entry Pre-emptive postoperative nausea and vomiting prophylaxis Attention to fluid balance Multimodal analgesia Avoidance of drains Postoperative Early mobilization Early removal of drains, lines, and urinary catheters Early oral intake Attention to fluid balance Balanced multimodal opioid-restrictive analgesia Routine use of laxatives

Eberhart et al. (2008)

R O

t2:4 t2:5 t2:6 t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13 t2:14 t2:15 t2:16 t2:17 t2:18 t2:19 t2:20 t2:21

Marx et al. (2006)

P

Enhanced recovery elements

D

t2:3

E

t2:1 t2:2

5

ER: 3 (2–27) C: − ER: (not directly reported) C: − ER: 0% C: − ER: 4% C: − ER: 0.5% C: − -

ER: 5 (4–7) C: 8 (6–11)⁎ ER: 21% C: 20.5% ER: 1.2% C: 1.3% ER: 25.9% C: 17.9% -

ER: improved overall quality of life (nos)

ER: Excellent/very good satisfaction in 95.2% for pain, in 87.2% for nausea

ER: 27,129 (22,950–39,188) C: 33,763 (26,846–42,258)⁎

-

⁎ P b 0.05. 1 Data are reported as percentages (%), mean (+/−SD), or median (range) except for Kalogera et al. where median (interquartile range) is reported. 2 Enhanced recovery group (ER); control group (C). 3 Time in days. 4 Kalogera et al.: time to general diet. 5 Marx et al.: 30-day postoperative complications; Chase et al.: “significant” inpatient complications; Gerardi et al.: 30-day postoperative complications GOG grade 2–4; Kalogera et al.: 30-day postoperative complications Accordion grade 3–4. 6 Marx et al., Gerardi et al., Kalogera et al., Wijk et al.: 30-day readmissions;Chase et al.: overall readmissions. 7 Outcomes reported for the patients with gynecologic malignancies undergoing complex cytoreductive surgery (ER, n = 81; controls: n = 78).

Please cite this article as: Nelson G, et al, Enhanced recovery pathways in gynecologic oncology, Gynecol Oncol (2014), http://dx.doi.org/10.1016/ j.ygyno.2014.10.006

389 390 391 392 393 394 395 396 397 398 399 400 401

425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467

Nasogastric drainage

506

Many surgeons have taken a conservative approach to postoperative feeding, employing routine use of nasogastric tubes and withholding oral feeding until bowel activity resumes, heralded by flatus. This practice was thought to be particularly important for patients who underwent bowel resections, under the belief that early feeding would increase the risk of anastomotic leak. But routine nasogastric tube use is responsible for a great deal of patient dissatisfaction and discomfort. Despite best intentions, recent literature has provided good evidence that this practice in fact slows recovery with no benefit to patients, supporting Hippocrates’ observation in Aphorisms, “A diet brought to the extreme point of attenuation is dangerous; and repletion, when in the extreme, is also dangerous.” The importance of adequate, not excessive, caloric intake on healing and well-being was apparent even in 400 BC. A meta-analysis of a total of 5230 patients randomized to selective or no nasogastric tube after major abdominal surgery showed that those without routine nasogastric tubes use had a highly significant decrease in time to resumption of bowel function, a reduction in pulmonary complications, and shorter hospital stay [81]. There were no differences in anastomotic leak rates between groups. Routine use of nasogastric tubes was associated with less vomiting, but increased patient discomfort. In patients with gynecologic cancer, those managed without nasogastric tubes had an equivalent rate of replacement compared to patients in whom it was used routinely (ie replacement after discontinuation) [16]. While many groups advocate for “selective” nasogastric

507

O

F

469 470

R O

423 424

Routine use of prophylactic drains following abdominopelvic surgery was first proposed by Billroth in 1881 and later by Sims in 1884 [65]. The rationale was to reduce early perioperative fluid collections that may serve as a nidus of infection. Furthermore, drains were believed to aid in the early detection of postoperative complications such as bleeding or anastomotic disruption. However, drains may have detrimental effects including an increase in the risk of infection, impairment of anastomotic healing, bleeding, pain or intra-abdominal retention [66–69]. Furthermore, while early detection and management of anastomotic leak has been thought to be associated with improved outcomes [70,71], a number of investigations have demonstrated that drains have low sensitivity in detecting leak (and bleeding) [72,73]. Thus, the presence of normal appearing drain output may even provide false reassurance leading to a delayed diagnosis despite the presence of suspicious clinical symptoms. Prophylactic drainage of non-pelvic anastomoses appears to be ineffective and has thus been abandoned in colorectal surgery [66,68,69,74]. Although the use of prophylactic drainage for pelvic anastomoses is more controversial given these procedures are associated with a higher anastomotic leak rate [67,75], the majority of the data suggests that routine prophylactic drainage provides no benefit after uncomplicated rectal surgeries [69,76–78]. The single exception is for very low anterior resections (defined as anastomosis within 6 cm from the anal verge) in which case a potential benefit cannot be definitively excluded [69,75,79, 80]. Data on the use of prophylactic drainage following pelvic surgery for gynecologic cancer are limited. We performed a retrospective study investigating the impact of prophylactic drainage on patients with ovarian cancer who underwent cytoreductive surgery including large bowel resection. Patients with drains had a slightly shorter time to diagnosis of anastomotic leaks, but this did not favorably impact the need for reoperation, morbidity, mortality or time to initiate chemotherapy [72]. We concluded that prophylactic drainage should be considered on a case-by-case basis and not used routinely. When utilized, drains should be removed within the first few postoperative days with the intent of reducing early contaminants and fluid collections that may play a role in abscess formation following low pelvic anastomoses.

P

421 422

468

D

419 420

Prophylactic drainage

T

417 418

C

415 416

E

413 414

R

411 412

R

409 410

O

408

C

406 407

N

404 405

(60 versus 44 min, p b 0.0001), longer time to first ambulation (49 versus 36 hours postoperatively, p = 0.03), and a higher rate of pressor use during surgery (78% versus 57%, p = 0.002). Pain control based on a visual analog scale was found to be equivalent on POD 1, but there tended to be more supplemental pain medications required in the PCEA group. There was no difference between the two groups in terms of time to tolerating regular diet or readiness for discharge. In considering the use of intrathecal anesthesia, it is important to distinguish a potential benefit in pain control from a potential benefit in overall postoperative recovery. In expert hands it would not be surprising to learn that epidural analgesia offers superior pain control compared to intravenous PCA. However, disadvantages include increased anesthesia preparation time, longer time to first ambulation, and more importantly, hypotension. The need for acute fluid resuscitation may potentially thwart efforts at attaining zero fluid balance, in particular for patients with ovarian cancer in whom large volumes of ascites are removed early in the operation. This concern was debated vigorously at the time our own ERP was planned. Prioritizing euvolemia, we ultimately made the decision to omit epidural anesthesia for patients with ovarian cancer. Despite this decision, we nevertheless observed a 4-day reduction in hospital stay, stable to improved pain scores, and an 80% reduction in the use of opioids in the first 48 hours compared to historic controls [16]. Furthermore, most patients will have excellent pain control with a combination of NSAIDS and oral opioids in small to moderate doses without an epidural; only about one-third of our patients were transitioned from oral narcotics to a PCA. Our experience is supported by results from a recent randomized trial in patients undergoing colorectal surgery [56]. Spinal anesthesia was associated with improved analgesia and consumption of less opioids compared to PCA. However, no benefit was observed in postoperative recovery as measured by other outcomes including length of stay. The ultimate goal of a multimodal analgesic approach is to achieve adequate pain control while avoiding opiate-induced side-effects such as somnolence, hypotension, depressed respiratory drive, urinary retention, nausea/vomiting and constipation/ileus. The use of adjunct drugs such as NSAIDS has been shown to be effective in reducing opiate use. Maund et al. performed a systematic literature review of sixty randomized controlled trials examining the effect of paracetamol (acetaminophen) and NSAIDS/COX-2 inhibitors on morphine consumption after major surgery [57]. They found that 24-hour morphine consumption was decreased with all non-opiate drugs and there was a significant reduction in nausea with NSAIDS compared to placebo. Despite these benefits, recent evidence has raised concern regarding a potential link between postoperative NSAID use and operative complications, most notably anastomotic leak [58–61]. A recent investigation by the STARSurg Collaborative group in Britain showed that postoperative NSAID administration was associated with a 28% reduction in overall complications, indicating a potentially beneficial anti-inflammatory effect [62]. Importantly, they did not find an association between NSAIDs and anastomotic leak. An increase in bleeding is another concern for NSAID use, particularly with respect to ketorolac [63]. Gobbel et al. performed a meta-analysis of twenty-seven randomized controlled trials comprising 2314 patients undergoing surgery (including major abdominal, gynecologic, and urologic procedures) in which ketorolac was used as part of a multimodal analgesic approach [64]. Pain control with ketorolac was superior to controls and equivalent to opioids with no significant increase in postoperative bleeding; adverse effects were not statistically different between the groups. Evidence for the use of intrathecal anesthesia is conflicting in gynecologic oncology, and may compromise other goals such as euvolemia and early ambulation. In colorectal surgery, there is some evidence that spinal anesthesia does not accelerate recovery compared to the use of PCA. More research is necessary to understand the advantages and disadvantages of epidurals on pain control, cost, and postoperative recovery in our patient population. However, it does not appear to be a critical component in the pathway.

U

402 403

G. Nelson et al. / Gynecologic Oncology xxx (2014) xxx–xxx

E

6

Please cite this article as: Nelson G, et al, Enhanced recovery pathways in gynecologic oncology, Gynecol Oncol (2014), http://dx.doi.org/10.1016/ j.ygyno.2014.10.006

471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505

508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530

G. Nelson et al. / Gynecologic Oncology xxx (2014) xxx–xxx

Laxative use

572 573

Laxatives are commonly employed to hasten the return of bowel function. Literature on this subject is scant in gynecologic oncology, although one prospective nonrandomized trial of 20 patients undergoing open radical hysterectomy demonstrated that milk of magnesia and biscolic suppositories were well-tolerated and associated with a reduction in hospital stay compared with historical controls [88]. A randomized trial of 68 patients undergoing hepatic resection via laparotomy showed a median one-day reduction in time to passage of stool with the use of magnesium hydroxide [89]. Although laxatives are commonly included in enhanced recovery protocols, available data points to a modest benefit. Effects have been rarely studied in isolation, but continued use seems reasonable given little if any adverse side effects. In contrast, in a meta-analysis of randomized trials, there is little evidence to support the use of prokinetics including erythromycin, the cholecystokinin-like drugs, cisapride, dopamine-antagonists, propranolol, vasopressin, or intravenous lidocaine or neostigmine [90]. Randomized trials have shown improved recovery for patients undergoing hysterectomy and colonic resection when Alvimopan, a peripheral mu antagonist, was used [21].Trials in gynecologic oncology are ongoing and this drug should be considered investigational as cost-effectiveness is explored.

550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568

574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592

C

548 549

E

546 547

R

544 545

R

542 543

N C O

540 541

U

538 539

Conflict of interest statement

641

The authors have no conflicts of interest for this manuscript.

642

Acknowledgements

643

F

571

536 537

O

569 570

Early feeding is perhaps the most visible deviation from traditional management protocols. Because it is the most simple to implement, it is often considered to be synonymous with enhanced recovery, to the neglect of other components. A number of randomized trials have been performed in gynecologic oncology on the subject of early feeding, dating back to 1998 [82–87]. Common findings include quicker resumption of bowel activity and reduced length of stay. No increase in major complications including wound healing, anastomotic leaks, or pulmonary complications were observed. One randomized study in patients with ovarian cancer demonstrated a significantly lower rate of complications for patients receiving early feeding, although complication rates were no different between groups when the analysis was limited to a smaller cohort of patients undergoing intestinal resections [84,85]. It is important to acknowledge that a higher rate of nausea has been consistently associated with early feeding, in both the gynecologic and colorectal literature. Despite this finding, no differences have been observed with respect to vomiting, abdominal distension, or nasogastric tube use. In our experience, this short-term nausea often passes with aggressive use of antiemetics, and oral feeding need not be prohibited. Patient satisfaction with control of nausea/vomiting was over 90% in one series despite a higher rate of nausea in the enhanced recovery group [16]. In reviewing the available literature, early feeding has been variously and vaguely defined, and often described as administration of clear liquids, “advanced as tolerated.” Under our algorithm, all patients, including those who undergo enteric resections, may resume a general diet the evening of surgery if they wish. The amount and type of food consumed is determined by the patient, not the provider. Oral intake is neither forced nor withheld, but simply encouraged. It is important to note that the dietary guidelines discussed in this section apply only to asymptomatic patients without a suspected complication. While isolated nausea or even vomiting may be observed with no alteration in diet, patients with abdominal distension and a clinical diagnosis of adynamic ileus should be managed with nasogastric decompression, intravenous hydration, and cessation of oral feeding. Feeding a patient with obvious abdominal distension will at best increase patient discomfort and prolong the course of ileus, and at worst lead to aspiration, wound complications, or enteric leak.

594 595

R O

534 535

In this review we outline elements of the enhanced recovery pathway. In addition to overwhelming type I evidence available in the colorectal literature supporting enhanced recovery, studies in gynecologic oncology demonstrate important improvements in postoperative recovery, patient satisfaction, and substantial cost reductions without additional risk to the patient. In light of these impressive benefits, the many elements of ERP are considered standard of care, not investigational, at an increasing number of institutions. Multiple critical elements are contained within the ERP bundle. Proactive interventions include allowing oral intake of fluids up to 2 hours before induction of anesthesia, solids up to 6 hours before anesthesia, carbohydrate supplementation, euvolemia, aggressive PONV prophylaxis, and oral nutrition and ambulation the day of surgery. Equally critical are reduction or complete discontinuation of practices that interfere with recovery such as the use of bowel preparations, the fasting after midnight rule, nasogastric tubes, and intravenous opioids. These components should be incorporated into clinical practice with as much vigor and enthusiasm as new therapies for cancer. After all, would you prescribe a medication that improved patient satisfaction, reduced length of stay by four days and reduced costs by over $7500 per patient? In contrast to novel therapeutics, ERP is available immediately at virtually no cost, and no unique resources are required. The disadvantage of ERP is that implementation requires compromise and standardization, teamwork within and between disciplines, and continuous collection of metrics with honest discussions in the event of noncompliance. Early feeding is the most commonly discussed component of ERP because it is the simplest practice to adopt. In contrast, concepts such as euvolemia require respectful communication between surgeons, anesthesiologists, nursing, and house staff before, during, and after surgery. It is worth repeating that two randomized trials have demonstrated that the benefits of fluid restriction are only apparent if initiated during surgery; postoperative fluid restriction alone was ineffective. Additional research is needed to definitively determine if prophylactic drainage is beneficial for patients with low rectal resections, if intrathecal analgesia offers advantages in both recovery and pain control compared to an optimized pain protocol, and if the use of laxatives hastens recovery. While many of the protocol elements in the studies reviewed were similar and all showed benefit, dissimilarities demonstrate the exigent need to develop a formalized, evidence-based guideline for patients undergoing surgery for gynecologic cancer. Such a guideline would be developed by international experts in our field and supported by the ERAS Society. Linking this guideline with ERAS is crucial in order to allow for audit of compliance which has proven to be a key factor required for the success and sustainability of such protocols [7]. Patients undergoing benign gynecologic surgery will also obtain benefit from an ERAS guideline.

P

Early postoperative feeding

593

D

533

Conclusions

E

tube use, we currently utilize nasogastric tubes only for the rare patient undergoing partial gastric resection.

T

531 532

7

596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640

Financial Support: Mayo Clinic Comprehensive Cancer Center P30 644 CA015083 and Mayo Clinic SPORE in ovarian cancer P50 CA136393 645 References [1] Kehlet H. Multimodal approach to control postoperative pathophysiology and rehabilitation. Br J Anaesth 1997;78:606–17. [2] Kehlet H, Wilmore DW. Multimodal strategies to improve surgical outcome. Am J Surg 2002;183:630–41. [3] Gustafsson UO, Scott MJ, Schwenk W, Demartines N, Roulin D, Francis N, et al. Guidelines for perioperative care in elective colonic surgery: Enhanced Recovery After Surgery (ERAS((R))) Society recommendations. World J Surg 2013;37:259–84.

Please cite this article as: Nelson G, et al, Enhanced recovery pathways in gynecologic oncology, Gynecol Oncol (2014), http://dx.doi.org/10.1016/ j.ygyno.2014.10.006

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[35] Sato H, Carvalho G, Sato T, Lattermann R, Matsukawa T, Schricker T. The association of preoperative glycemic control, intraoperative insulin sensitivity, and outcomes after cardiac surgery. J Clin Endocrinol Metab 2010;95:4338–44. [36] Lazar HL, Philippides G, Fitzgerald C, Lancaster D, Shemin RJ, Apstein C. Glucose-insulinpotassium solutions enhance recovery after urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg 1997;113:354–60 [discussion 360–2]. [37] Quinones-Galvan A, Ferrannini E. Metabolic effects of glucose-insulin infusions: myocardium and whole body. Curr Opin Clin Nutr Metab Care 2001;4:157–63. [38] Hausel J, Nygren J, Lagerkranser M, Hellstrom PM, Hammarqvist F, Almstrom C, et al. A carbohydrate-rich drink reduces preoperative discomfort in elective surgery patients. Anesth Analg 2001;93:1344–50. [39] Nygren J, Soop M, Thorell A, Efendic S, Nair KS, Ljungqvist O. Preoperative oral carbohydrate administration reduces postoperative insulin resistance. 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Perioperative outcomes comparing patient controlled epidural versus intravenous analgesia in gynecologic oncology surgery. Gynecol Oncol 2009;115:357–61. [56] Wongyingsinn M, Baldini G, Stein B, Charlebois P, Liberman S, Carli F. Spinal analgesia for laparoscopic colonic resection using an enhanced recovery after surgery programme: better analgesia, but no benefits on postoperative recovery: a randomized controlled trial. Br J Anaesth 2012;108:850–6. [57] Maund E, McDaid C, Rice S, Wright K, Jenkins B, Woolacott N. Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review. Br J Anaesth 2011;106:292–7. [58] Bhangu A, Singh P, Fitzgerald JE, Slesser A, Tekkis P. Postoperative nonsteroidal anti-inflammatory drugs and risk of anastomotic leak: meta-analysis of clinical and experimental studies. World J Surg 2014;38:2247–57. [59] Gorissen KJ, Benning D, Berghmans T, Snoeijs MG, Sosef MN, Hulsewe KW, et al. Risk of anastomotic leakage with non-steroidal anti-inflammatory drugs in colorectal surgery. Br J Surg 2012;99:721–7. [60] Holte K, Andersen J, Jakobsen DH, Kehlet H. Cyclo-oxygenase 2 inhibitors and the risk of anastomotic leakage after fast-track colonic surgery. Br J Surg 2009;96:650–4. [61] Klein M, Gogenur I, Rosenberg J. Postoperative use of non-steroidal antiinflammatory drugs in patients with anastomotic leakage requiring reoperation after colorectal resection: cohort study based on prospective data. BMJ 2012;345: e6166.

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[4] Lassen K, Coolsen MM, Slim K, Carli F, de Aguilar-Nascimento JE, Schafer M, et al. Guidelines for perioperative care for pancreaticoduodenectomy: Enhanced Recovery After Surgery (ERAS(R)) Society recommendations. World J Surg 2013;37:240–58. [5] Nygren J, Thacker J, Carli F, Fearon KC, Norderval S, Lobo DN, et al. Guidelines for perioperative care in elective rectal/pelvic surgery: Enhanced Recovery After Surgery (ERAS((R))) Society recommendations. World J Surg 2013;37:285–305. [6] ERAS Interactive Audit System (EIAS). In. [7] Gustafsson UO, Hausel J, Thorell A, Ljungqvist O, Soop M, Nygren J. Adherence to the enhanced recovery after surgery protocol and outcomes after colorectal cancer surgery. Arch Surg 2011;146:571–7. [8] Chambers D, Paton F, Wilson P, Eastwood A, Craig D, Fox D, et al. An overview and methodological assessment of systematic reviews and meta-analyses of enhanced recovery programmes in colorectal surgery. BMJ Open 2014;4:e005014. 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[13] Chase DM, Lopez S, Nguyen C, Pugmire GA, Monk BJ. A clinical pathway for postoperative management and early patient discharge: does it work in gynecologic oncology? Am J Obstet Gynecol 2008;199:541.e1–7. [14] Gerardi MA, Santillan A, Meisner B, Zahurak ML, Diaz Montes TP, Giuntoli II RL, et al. A clinical pathway for patients undergoing primary cytoreductive surgery with rectosigmoid colectomy for advanced ovarian and primary peritoneal cancers. Gynecol Oncol 2008;108:282–6. [15] Carter J. Fast-track surgery in gynaecology and gynaecologic oncology: a review of a rolling clinical audit. ISRN Surg 2012;2012:368014. [16] Kalogera E, Bakkum-Gamez JN, Jankowski CJ, Trabuco E, Lovely JK, Dhanorker S, et al. Enhanced recovery in gynecologic surgery. Obstet Gynecol 2013;122:319–28. [17] Wijk L, Franzen K, Ljungqvist O, Nilsson K. Implementing a structured Enhanced Recovery After Surgery (ERAS) protocol reduces length of stay after abdominal hysterectomy. 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