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Abstract
Objective Information on the benefits of enhanced recovery after surgery (ERAS) when applied to advanced ovarian cancer() is minimal. The study objectives were to prospectively evaluate whether the implementation of ERAS in AOC patients improves post-operative recovery, and reduces the length of hospital stay (LOHS), without increasing the readmission rate or surgery-related complications; and to investigate ERAS protocol compliance.
Methods This was a prospective interventional study carried out at a single university teaching hospital. Patients undergoing laparotomy for advanced ovarian cancer (stages IIb–IV) from March 2017 to February 2018 were managed using an ERAS protocol. The conventional management (CM) period extended from January 2016 to December 2016. The primary outcome was reduction in LOHS. Secondary outcomes were ERAS protocol compliance, incidence of post-operative complications, and readmission rate.
Results The CM and ERAS groups each comprised 45 patients. Both the groups were comparable in terms of clinicopathological and operative characteristic. Median LOHS of the full cohort, primary debulking cohort, interval debulking cohort, staging surgery cohort (all 6 vs 4 days; p<0.001), and complex cytoreductive surgery cohort (5 vs 4 days; p=0.019) were significantly reduced in the ERAS group. The overall compliance for the ERAS protocol was 90.6%. Occurrence of moderate or severe (17.8% vs 0%; p=0.003) and ≥grade 2 extended Clavein-Dindo complications (22.2% vs 0%; p=0.001); and hospital stay due to occurrence of complications (31.1% vs 2.2%; p<0.001) were also significantly reduced in the ERAS group. There was no difference in the 30-day readmission rates.
Conclusion The results from our investigation suggest that the ERAS program can be successfully implemented in advanced ovarian cancer patients even in low-resource settings provided the program is modified to meet local needs so as not to increase healthcare costs.
- advanced ovarian cancer
- ERAS
- length of hospital stay
- compliance
- complications
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Prospective interventional trial on implementation of the ERAS program in advanced ovarian cancer (stage IIB–IV) based on guidelines for pre- and intra-operative care in gynecology oncology surgery: Enhanced Recovery After Surgery (ERAS) Society Recommendations Part I and Part II.
First trial to successfully implement the ERAS program in a low-resource setting with modification of certain elements to meet local needs including development of carbohydrate-rich drinks from the local staple diet so as not to increase costs.
First trial in gynecology oncology assessing the compliance of individual elements of the ERAS protocol in addition to overall compliance.
Introduction
Conventional peri-operative care has been challenged recently by the development of 'enhanced recovery after surgery' pathways aiming at reducing morbidity, hastening recovery, and shortening the length of hospital stay (LOHS).1 These 'enhanced recovery after surgery' (ERAS) or 'fast-track' protocols are comprised of multimodal interventions to reduce stress associated with surgery thus facilitating early recovery. In the mid-1990s these standardized evidence-based protocols were first incorporated into elective colonic surgery1 and since then have been adopted by many surgical disciplines.2
Recently, the ERAS Society has published guidelines for the peri-operative care of gynecological oncology patients,3 4 but the evidence has been mainly derived from either observational studies or based on findings from other surgical disciplines. Studies on the ERAS program in gynecological oncology are limited by the heterogeneity in the design of individual studies; composition of specific interventions; study participants with inclusion of either all gynecological malignancy patients and/or patients with benign conditions; and surgical procedures ranging from minimally invasive procedures for benign conditions to cytoreductive surgery for advanced ovarian cancer.5
In this prospective study we aimed to investigate how implementation of the ERAS program (based on guidelines recommended by the ERAS Society) in patients undergoing surgery for advanced ovarian cancer affects the LOHS in comparison with conventional management (CM). We also aimed to evaluate compliance with the ERAS protocol, and compare post-operative complications within 30 days after surgery with the two levels of care.
Methods
This was a prospective interventional trial conducted in the department of gynecology oncology at Amrita Institute of Medical Sciences (AIMS), Kerala, India, for which ethical clearance was granted by the institutional ethics committee.
Study participants, design, and setting
Patients diagnosed with an ovarian/fallopian tube/peritoneal cancer of any histology (subsequently collectively referred to as ovarian cancer) in the department of gynecology oncology, with clinical or radiological suspicion of advanced disease (stage IIb, III, IV) or relapse and planned for elective surgery (primary cytoreductive surgery/interval debulking surgery) were included in the trial. Exclusion criteria were: minimally invasive surgery for ovarian cancer; emergency surgery; and bowel resection during staging surgery for ovarian cancer (because of the involvement of the gastrointestinal surgery team in peri-operative care, which was not the part of the ERAS multidisciplinary team).
The prospective data from consecutive adult patients undergoing surgery for ovarain cancer within the ERAS protocol were compared with the retrospective cohort of patients before introduction of the ERAS protocol. All patients who underwent open surgery for ovarian cancer during the study intervention period were included in the analysis (Figure 1).
Consort flow chart. CM, conventional management; ERAS, enhanced recovery after surgery; MIS, minimally invasive surgery.
ERAS management group
The ERAS protocol was implemented in March 2017 after staff training during the period January–February 2017. The ERAS group comprised advanced ovarian cancer patients operated on from March 2017 to February 2018.
The ERAS protocol was based on published guidelines.3 4 Key components of the AIMS protocol included pre-admission patient education and counseling; carbohydrate loading drink the day prior to surgery and 2 hours before surgery; fasting for only 2 hours prior to surgery; pre-emptive analgesia; local wound infiltration at the end of the procedure; conservative peri-operative fluid management; minimization of post-operative narcotic use; early resumption of oral intake; and early post-operative ambulation. Intra-operative fluid management was at the discretion of the anesthesia provider. A gynecologic oncologist coordinator managed the project.
Development and implementation of the protocol required multidisciplinary collaboration among gynecologic oncologists, anaesthesiologists, nursing staff, operating room staff, dieticians, clinic, and pre-admission services. The success of the program was dependent on clear and consistent messages about expectations from patients regarding activity, diet, and pain management before, during, and after their hospital stay. Post-operative goals were communicated each day to the patients by the multidisciplinary team, aiming for discharge by post-operative day (POD) 3 or 4, if deemed clinically safe. An audit was performed every 3 months to examine compliance with each component of the ERAS protocol and also to confirm that this practice change did not increase complication rates. Written consent was obtained from all patients enrolled in the ERAS program.
Conventional management (CM) group
The CM group comprised advanced ovarian cancer patients operated on from January 2016 to December 2016. Of note, no significant changes in technology, surgical techniques, surgical team, and anaesthesiologist team took place between the ERAS and CM study periods.
Before the introduction of the ERAS protocol, patients were given pre-anesthetic medications and anxiolytics the night prior to surgery and were fasted overnight prior to surgery. Post-operatively, intravenous fluids were given until a diet was tolerated, and opiate-based analgesics were prescribed. Oral intake of clear liquid was rarely promoted on POD 0 to 1. Active ambulation was discouraged on POD 1. A Foley catheter was retained until the patient started walking comfortably. Non-opioid adjuncts were rarely administered.
Interventions unchanged between groups
All patients in both the groups underwent risk assessment, pre-operative medical consultation, and optimization of medical condition. Interventions unchanged between the groups were: combined (general + epidural) anesthesia; thromboembolism prophylaxis 12 hours prior to surgery; antibiotic prophylaxis (cefazolin 2 g intravenously) 30 min before surgery incision; peri-operative incentive spirometer; mechanical bowel preparation only in cases where bowel resection was expected, otherwise all other patients received rectal enema; maintenance of intra-operative euvolemia, euglycemia, and normothermia; and removal of nasogastric tube at the time of extubation.
Discharge criteria remained unchanged in both the groups and were as follows: adequate pain control with oral analgesia, tolerance of a general diet with adequate fluid intake, ambulation without support, non-distended abdomen, either flatus or a bowel movement, and adequate home supervision.
Outcomes
The aim of our study was the prospective evaluation of an ERAS protocol that included the whole application of ERAS principles in patients undergoing staging surgery for advanced ovarian cancer. The primary endpoint was the reduction in LOHS with the implementation of an enhancedrecovery after surgery pathway. LOHS was defined as the number of days from the day of surgery to discharge or death.
Secondary endpoints were: ERAS protocol compliance, incidence of pre-defined post-operative complications within 30 days after surgery, and readmission rate. Overall ERAS protocol compliance was calculated in the ERAS group as the average of all pre-, intra-, and post-operative ERAS elements in the protocol.
Post-operative complications were defined according to the standard definition. The severity of paralytic ileus and subacute intestinal obstruction (SAIO), diarrhea, and urinary retention was graded according to the extended Clavein-Dindo classification.6 Surgical site infection was classified into superficial, deep, and organ/space. Dyselectrolemia was classified as mild, moderate, and severe.
Data collection
Data collection was performed by the one researcher who did not participate in the peri-operative management of patients. Data collected were: clinicopathologic characteristics: age, body mass index (BMI), physical status defined by American Society of Anaesthesiologists (ASA score), performance status (Eastern Cooperative Oncology Group (ECOG) score), co-morbidity, stage and type of ovarian cancer; surgical characteristics: timing of surgery (primary debulking surgery (PDS), interval debulking surgery (IDS)), surgical procedure (staging procedure and complex cytoreductive surgery where extensive tumor debulking was done), type of resection (no residual disease (R0), residual disease <1 cm (R1), residual disease >1 cm (R2)), operative time (defined as time from skin incision to skin closure), and estimated blood loss.
Tabulation of length of stay in the post-anesthesia care unit, time to Foley’s catheter removal, time to start of liquid diet, time to start of semi-solid diet, time to first flatus, time to first stool, time to first sitting, time to first walk, and LOHS in days was performed. Data on pain score in the immediate post-operative period, 4 hours post-operatively, and on POD 1 and 2 were collected. The efficacy of pain control was assessed using a numeric pain scale. Data on analgesic (opioids and non-opioids) and intravenous fluids (crystalloid and colloid) used were collected. Complication data: fluid imbalance (overload/hypotension); dyselectrolemia; excessive post-operative nausea and vomiting, and gastritis; paralytic ileus and subacute intestinal obstruction; diarrhea; urinary retention; urinary tract infection; febrile illness and septicaemia; surgical site infection; prolonged LOHS due to complication; and readmission were tabulated.
Statistical analysis
The Wilcoxon rank sum test was used to compare differences in the central tendencies for continuous variables. Categorical data or differences in proportions were compared with the Pearson χ2 test. Statistical significance was defined as a p value <0.05. All the analyses were performed using IBM SPSS for Windows (version 20.0).
Results
Of 113 advanced ovarian cancer patients assessed for eligibility, 90 patients were included in the analysis: 45 in the ERAS (prospective) group and 45 in the CM (retrospective) group. Twelve patients with bowel resection, eight patients operated on during the training period, and three patients who underwent minimally invasive surgery were excluded from the study (Figure 1).
Patients’ clinicopathological and surgical characteristics are listed in Table 1. Both the groups were statistically similar in age, BMI, physical status (ASA score), performance status (ECOG score), and co-morbidities (p values all >0.05). More than 65% of the patients in both groups had serous epithelial ovarian cancer. Approximately 80% of the patients in both groups presented with stage III ovarian cancer. No statistically significant differences were found in the surgical indications, procedures, operative time, and blood loss (p values all >0.05).
Patients' clinicopathological and operative characteristics
The overall compliance with the various elements of the ERAS protocol was 90.6% (Table 2). The lowest compliance elements were tolerance of liquid diet on POD 0 (44.4%), followed in order by tolerance of semi-solid diet on POD 3 (53.3%), and ambulation on POD 0 (62.2%).
Protocol compliance in the enhanced recovery after surgery (ERAS) group
Post-anesthesia care unit stay (19 vs 8 hours, p<0.001), time to Foley’s catheter removal (3.75 vs 1 day, p<0.001), time to start of liquid diet (2.13 vs 1.06 days, p<0.001), time to start of semi-solid diet (4.35 vs 2.88 days, p<0.001), time to passage of first flatus (4.05 vs 1.55 days, p<0.001), time to passage of first stool (5.75 vs 3.25 days, p<0.005), time to first sitting (1.66 vs 0.69 days, p<0.001), and time to first walk (3.13 vs 1.04 days, p<0.001) were all significantly reduced in the ERAS group. Statistically significant reduction in pain score after 4 hours of surgery (2.9 vs 1.4, p<0.001), on POD 1 (2.6 vs 1.2, p<0.001), and on POD 2 (2.5 vs 0.9, p<0.001) were found in the ERAS group (Table 3).
Comparison of outcomes in the enhanced recovery after surgery (ERAS) and conventional management (CM) groups
Median LHOS (6 vs 4 days, p<0.001) was markedly reduced in the ERAS group (Table 4). The median LOHS of patients undergoing primarydebulking surgery and intervaldebulking surgery was reduced to 4 days when following the ERAS protocol. The median LOHS of patients undergoing staging and complex cytoreductive surgery was reduced to 4 and 5 days, respectively, with enhancedrecovery after surgery pathway implementation (Table 3). In the first 3 months of enhancedrecovery after surgery pathway implementation the LOHS was reduced by 1 day, which was further reduced by 2 days thereafter. Following the ERAS protocol, 53.3% (25) patients were discharged by POD 3 or 4 and 93.3% (42) patients by POD 6.
Comparison of intravenous fluids, analgesic and anti-emetics in the enhanced recovery after surgery (ERAS) and conventional management (CM) groups
Post-operatively there was significantly less requirement for intravenous fluids (7.19 vs 2.38 L, p<0.001) and analgesics: acetaminophen (13.81 vs 7.05 g, p<0.001), buprenorphine (880 vs 452.3 μg, p<0.001) in the ERAS group. Significantly fewer patients required tramadol for pain score ≥4 (48.9% vs 13.3%, p<0.001), none of the patients required fentanyl for breakthrough pain (26.7% vs 0, p<0.001), and none of the patients required continuous analgesic infusion (11.1% vs 0, p<0.001). In the ERAS group only 8.9% and 11.1% patients required additional analgesic on POD 1 and intravenous analgesic on POD 2, respectively. No difference was observed in the requirement for intravenous fluids and analgesics in the intra-operative period (P value for all >0.05) (Table 4).
A total of 17 (37.8%) patients developed at least one complication in the CM group vs 11 (24.4%) patients in the ERAS group. More patients in the CM group developed ≥grade 2 complications (22.2% vs 0; p=0.001), and moderate or severe complications (17.8% vs 0; p=0.003). Hospital stay due to complications was significantly prolonged in the CM group (31.1% vs 2.2%; p<0.001). No significant difference was found in the readmission rates (11.1% vs 2.2%; p=0.091), and there was no mortality in both the groups. Paralytic ileus/subacuteintestinal obstruction was the most frequent complication in the CM group (17.8% vs 6.7%; p=0.085) followed by surgicalsite infection (17.6% vs 15.6%; p=0.332), and dyselectrolemia (11.1% vs 4.4%; p=0.238). None of the patients in the ERAS group developed: ≥grade 2 severity paralytic ileus/subacuteintestinal obstruction (CM group two grade II, one grade IIIb and one IVa), diarrhea, urinary retention; moderate or severe dyselectrolemia; and deep or organ/space surgicalsite infection. Rate of urinary tract infection and febrile illness was similar in both groups. There was no significant increase in the excessive post-operative nausea and vomiting and gastritis, hypotension, and urinary retention in the ERAS group (Table 5).
Summary of 30-day post-operative complications in the enhanced recovery after surgery (ERAS) and conventional management (CM) groups
Discussion
This study demonstrated that a gynecological oncology ERAS program can be successfully implemented in patients undergoing laparotomy for advanced ovarian cancer (stage IIb–IV). With the adoption of the ERAS protocol, we have decreased LOHS without increasing readmission rate, with continued patient safety.
With the implementation of the ERAS protocol the median hospital stay of advanced ovarian cancer patients was reduced to 4 days. In the staging cohort (mean operating time 204 min) the LOHS was reduced by 2 days, whereas in the complex cytoreductive cohort (mean operating time 265.2 min) the LOHS was reduced by 1 day. Kalogera et al reported a LOHS reduction of 3 days in their complex cytoreductive cohort (mean operating time 227 min); however, they found no difference in the staging cohort (mean operating time 151 min).7 Marx et al reported a LOHS reduction of 1 day with a multimodal rehabilitation program.8 Carter et al reported a median LOHS of 4 days for ovarian cancer patients managed with the ERAS protocol.9 However, the median operating time in both these studies was only 120 and 150 min, respectively.8 9
Various studies in the literature have reported readmission rates ranging from 3% to 25.9% with the ERAS protocol.7–10 Also these studies have reported no difference in the readmission rate with the two levels of care. Consistent with the literature, in the current study the readmission rate in the ERAS group was lower (2.2%) but the difference was not statistically significant.
Various series on ERAS in gynecology oncology have found no significant difference in the post-operative complication rate with the fast-track protocol.7 8 10 11 Post-operative ileus was the most common complication reported with the ERAS protocol.7 10 Marx et al reported significantly reduced medical complications with the multimodal rehabilitation program.8Consistent with the literature we found no significant difference in overall complications. The most common complication in the ERAS group was post-operative ileus. The rate of ≥grade 2 (extended Clavein-Dindo classification) complications and moderate or severe complications was significantly reduced in the ERAS group. We also demonstrated that significantly fewer patients required a prolonged stay in hospital due to the occurrence of complications.
In the current trial the time interval for various outcomes were significantly reduced in the ERAS group. There was a significant reduction in the pain score, despite the reduced usage of post-operative opioids in the ERAS group. There was no significant increase in post-operative hypotension, urinary catheter re-insertion rate, and post-operatie nausea and vomiting in the ERAS group. Our results are in agreement with those of Kalogera et al who have reported a significantly reduced time to return of bowel function and time to starting a general diet, maintained patient pain comfort goal despite the reduced usage of opioid analgesics in the post-operative period, and no significant increase in the post-operative hypotension rate, and urinary catheter re-catheterisation rate.7 Similarly, Eberhart et al reported an improvement in autonomy, physical complaints, and post-operative pain with the fast-track program.11
Kalogera et al in their study highlighted that all interventions in the ERAS program are critical to the program's success.7To the best of our knowledge the current study is the first to report in the literature the compliance rate with the specific ERAS program interventions and an overall compliance rate of 90%.
Multidisciplinary teamwork and patient compliance are the keys to the success of the ERAS protocol. Having a guideline is not sufficeint reason to implement an ERAS program.12 13 Adherence to guidelines and improved outcomes are proven to have a linear relationship.14 For a program to be successful it is essential to develop and modify the program to meet local and national needs. Also before the program is implemented it is essential to understand and identify any potential barriers so that they can be overcome.15
In the Indian scenario one of the biggest barriers is the mentality of patients regarding staying in hospital for longer time periods. Overcoming this barrier was a great challenge but with continuous and consistent counseling we were able to overcome this barrier successfully. India is a country with limited resources. Our clinical team does not have nurse practitioners, and limitaions to counseling were overcome by making video recordings of the general advice which were played to patients during the pre-operative planning period. This made it easier for us to convey any general instructions. Whatever instructions were specific to individual patients was then conveyed to the patients concerned by the surgical team. In the current study we developed the carbohydrate loading drinks from the local staple diet instead of introducing branded drinks as this would have had a significant cost burden. Similarly in our setting, reduction in infection and complication rate leading to a better outcome is associated with more cost saving than simply a reduction in the length of hospital stay. In India where resources are limited, implementation of the ERAS program would help in freeing up hospital beds early and lead to better utilization of health resources.
Our current trial has limitations. Fewer patients, a single institution, and exclusion of advanced ovarian cancer patients who underwent bowel resection are the limiting factors of this study. A multicentre trial involving different institutions in India will be able to demonstrate whether the results obtained can be translated across India.
In summary, the institution of an enhancedrecovery after surgery pathway in advanced ovarian cancer resulted in a significant improvement in post-operative outcomes including reduced stay in the post-anesthesia care unit, early recovery of gastrointestinal function, excellent pain management with significantly reduced requirement for opioid and non-opioid analgesics, decreased length of hospital stay, and decreased moderate or severe and ≥grade 2 post-operative complications without an increase in readmission rates. Based on our experience we can conclude that the ERAS program can be successfully implemented in advanced ovarian cancer patients even in low-resource settings. However it is imperative that the program be modified to meet local needs so as not to increase healthcare costs.
References
Footnotes
Ethics approval Obtained.
Provenance and peer review Not commissioned, externally peer reviewed.