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Cytoreductive Surgery and HIPEC in an Enhanced Recovery After Surgery Program: A Feasibility Study
j o u r n a l o f s u r g i c a l r e s e a r c h - 2 0 1 9 ( - ) 1 e7
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Cytoreductive Surgery and HIPEC in an Enhanced Recovery After Surgery Program: A Feasibility Study Pamela W. Lu, MD,a,b,*,1 Adam C. Fields, MD,a,1 Galyna Shabat, MD, PhD,a Ronald Bleday, MD,a Joel E. Goldberg, MD, MPH,a Jennifer Irani, MD,a Matthias Stopfkuchen-Evans, MD,c and Nelya Melnitchouk, MD, MSca,b,* a
Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts Center for Surgery and Public Health, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts c Department of Anesthesia and Pain Management, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts b
article info
abstract
Article history:
Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy
Received 1 August 2019
(HIPEC) have historically been associated with high morbidity given the physiologic insult
Received in revised form
of an extensive operation. Enhanced Recovery after Surgery (ERAS) pathways have been
26 September 2019
successful in improving postoperative outcomes for many procedures but have not been
Accepted 20 October 2019
well studied in these cases. We examined the feasibility and effect of ERAS pathway
Available online xxx
implementation for patients undergoing CRS/HIPEC. Materials and methods: Patients with peritoneal carcinomatosis who underwent CRS/HIPEC
Keywords:
between October 2015 to September 2018 were identified. Patient characteristics, disease
Peritoneal neoplasms
pathology, and perioperative outcome data were obtained. Primary outcomes were hos-
Hyperthermic intraperitoneal
pital length of stay (LOS), 30-d readmissions, renal dysfunction, and complications.
chemotherapy
Results: Of the 31 patients who were included, 11 (35.5%) patients underwent CRS/HIPEC
HIPEC
prior to the implementation of the ERAS pathway, and 20 (64.5%) patients underwent CRS/
Cytoreductive surgery
HIPEC according to the ERAS guidelines. There were no significant differences in the
Enhanced recovery
baseline clinical or pathologic characteristics between groups. There was a significant decrease in LOS with ERAS pathway management from 9 d to 6 d (P ¼ 0.002). No patients from either cohort experienced acute kidney injury. There was no significant difference in 30-d readmission rates or complications. Conclusions: In this feasibility study, ERAS pathway utilization significantly decreased postoperative LOS for patients undergoing CRS/HIPEC, without evidence of increased complications or readmissions. ERAS programs should be considered for integration into future CRS/HIPEC protocols. ª 2019 Elsevier Inc. All rights reserved.
* Corresponding author. Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, 02115. Tel.: þ617 732-8460; fax: þ617 734-0336. E-mail addresses: [email protected] (P.W. Lu), [email protected] (N. Melnitchouk). 1 Co-first authors. 0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2019.10.042
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j o u r n a l o f s u r g i c a l r e s e a r c h - 2 0 1 9 ( - ) 1 e7
Introduction Intraperitoneal spread of malignancy can result from a variety of primary tumors, with a wide range of prognoses.1 In select patients where the tumor is limited to the intraperitoneal cavity with a resectable disease burden, cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer survival benefit where traditional surgery and systemic chemotherapy does not.2 However, the management of disseminated peritoneal disease with CRS and HIPEC has historically been associated with high morbidity and mortality due to the significant physiologic insult of the treatment.3 While recent studies showing improved safety profiles of CRS and HIPEC with comparable rates of morbidity and mortality compared to other high-risk oncologic surgeries,4,5 few specialized institutions offer this relatively resource-intensive procedure, and the perioperative practices vary widely amongst providers.2 Enhanced Recovery after Surgery (ERAS) practice guidelines have been used to formulate perioperative pathways, which utilize a multimodal approach to temper the physiologic response to surgical insults. The goal of these pathways is to improve postoperative recovery, reduce postoperative complication rates, and to shorten hospital length of stay.6 Initially developed for elective colorectal surgeries, these pathways have also shown to be successful in improving recovery after other types of surgeries as well, including orthopedic, gynecologic, and emergency surgeries.7-9 Despite the success of ERAS guidelines in improving postoperative outcomes, there have been some criticisms, especially with respect to the concern for increased readmission rates due to postoperative ileus, and potential for renal injury in the context of stringent fluid management implemented within ERAS pathways.10,11 While it has been shown that standardization of some perioperative practices, including intraoperative technique, use of epidural analgesia as part of multimodal pain control, and early postoperative mobilization have improved outcomes after CRS/HIPEC, utilization of a full ERAS evidencebased pathway has not been well examined.12-14 The goal of this feasibility study is to examine the utility and safety of utilizing a comprehensive, validated ERAS pathway for perioperative management of patients undergoing CRS and HIPEC at a single institution.
Materials and methods Patient population Patients with a diagnosis of peritoneal carcinomatosis who underwent abdominal CRS and HIPEC with mitomycin-C between October 2015 and September 2018 performed by a single surgeon were identified. Chart review was performed, and information regarding patient characteristics, perioperative management, intraoperative details, ERAS pathway component compliance, and postoperative outcomes were extracted based on documentation. This study was reviewed by the
Brigham and Women’s Hospital (BWH) Institutional Review Board and deemed exempt.
Enhanced recovery after surgery protocol Patients were separated into two groups. The patients who underwent surgery prior to the implementation of the ERAS protocol were designated as pre-ERAS, and those who were managed according to the ERAS protocol were designated as the ERAS group. The BWH ERAS protocol is a comprehensive pathway that was initially implemented in 2015 for patients undergoing elective colorectal surgery. At a patient’s preoperative outpatient appointment, education regarding components of the pathway and postoperative expectations are provided, along with bowel preparation and carbohydrate beverage supplies. On the day of surgery, oral carbohydrate loading occurs 2 to 3 h prior to the scheduled operative time. Upon arrival to the preoperative holding area, patients are given oral analgesic agents and neuraxial analgesia access is obtained if indicated. Intraoperatively, goal-directed fluid therapy (GDFT) or zero fluid balance is maintained based on the patient’s risk profile as described by Miller et al.15 Postoperatively, intravenous fluid (IVF) is discontinued after 6 h, avoidance of nasogastric tubes allows for early diet advancement, and early urinary catheter removal and patient mobilization is achieved. No promotility agents are used. A detailed schematic depicting the stages of the BWH ERAS pathway is shown in Figure 1.
HIPEC technique All HIPEC was performed with the same standardized protocol. Both CRS and intraperitoneal chemotherapy were performed via an open technique. The total duration of intraperitoneal chemotherapy perfusion was 90 min; 30 mg of mitomycin-C was administered over the first 60 min, then an additional 10 mg of mitomycin-C was administered over the last 30 min.
Study variables Patients who underwent intraabdominal CRS and HIPEC with mitomycin-C for peritoneal carcinomatosis were included. The primary outcomes of this study were hospital length of stay and postoperative complications. Postoperative complications included kidney injury, unplanned readmission within 30 d, and Clavien-Dindo Grade III/IV complications. Kidney injury was defined in two levels: acute kidney injury (AKI) was defined as peak creatinine of two times the baseline creatinine, and acute renal failure (ARF) was defined as peak creatinine of three times the baseline creatinine. Peak creatinine was identified as the highest measured serum creatinine level during the patient’s postoperative in-hospital stay. These distinctions are based on the Risk, Injury, Failure, Loss, and End-stage renal disease criteria set forth by the Acute Dialysis Quality Initiative.16 This criterion was chosen to avoid criteria that rely on urine output calculations, as ERAS management includes early removal of urinary catheters and would compromise accuracy.17 Secondary outcomes were
lu et al eras in hipec patients
3
Fig. 1 e Enhanced Recovery After Surgery Pathway Schematic Figure 1 Footnotes: aACE: Angiotensin-converting Enzyme b ARB: Angiotensin Receptor Blockers cNSAIDS: Nonsteroidal Antiinflammatory Drugs dDVT: Deep Vein Thrombosis eTAP: Transversus Abdominal Plane fIVF: Intravenous Fluids gPOD: Postoperative day. (Color version of the figure is available online.)
length of postoperative intensive care unit (ICU) stay, intraoperative, and postoperative fluid management trends.
Statistical analysis Fisher’s exact tests were carried out for categorical variables, and Wilcoxon Rank Sum tests were performed for continuous variables. Two-tailed P < 0.05 was considered significant for all tests. All statistical analysis was conducted using Stata statistical software, version 15.0 (StataCorp 2017, College Station, TX: StataCorp LLC).
refused epidural placement), and intraoperatively adherence to ERAS prescribed fluid management was 100%. Postoperatively, adherence to timed cessation of intravenous fluids was 100%, and the diet advancement adherence was 75%.
Length of stay Compared to the median hospital LOS seen in the preERAS group of 9 (Interquartile Range (IQR): 8, 12) days, the ERAS group had a significant decrease in LOS to 6 (IQR: 4.5, 7) days (P ¼ 0.002). Postoperative ICU LOS significantly decreased, from a median of two (IQR: 1, 3) days in the preERAS group to zero (IQR: 0, 0.5) days in the ERAS group (P < 0.001).
Results Postoperative complications Patient characteristics A total of 31 patients met the inclusion criteria. 11 (35.5%) patients underwent CRS/HIPEC prior to the implementation of the ERAS pathway, and 20 (64.5%) patients underwent CRS/ HIPEC following the ERAS pathway guidelines. The two patient groups had no significant differences in age, gender, baseline renal function, rates of preexisting central venous access, operative time, intraoperative blood loss, primary tumor site and histology, disease burden, or extent of surgical resection (P > 0.05 for all). Patients in the preERAS group had significantly more intraoperative central lines (P ¼ 0.013), and significantly more surgical drains placed (P ¼ 0.027) compared to the ERAS group (Table 1).
There were no incidents of AKI or ARF in either the preERAS or ERAS groups. There was a decrease in postoperative 30d readmission rates, with three (27.3%) readmissions preERAS and one (5%) readmission after ERAS was implemented, but this difference was not statistically significant (P ¼ 0.115) (Table 2). With respect to clinically significant, or Clavien-Dindo Grade III or IV complications, two instances were identified. One preERAS patient presented with an intraabdominal abscess, which required drainage by Interventional Radiology followed by related pleural effusion requiring thoracoscopic washout (Grade IIIa/IIIb, respectively). One ERAS patient presented with hyponatremia and intraabdominal abscess requiring drainage by Interventional Radiology (Grade IIIa). Both instances were associated with hospital readmission.
ERAS pathway guideline adherence Perioperative fluid management Compliance with the pre-operative education and bowel preparation/oral carbohydrate loading was 100%. The maximization of nonnarcotic and neuraxial analgesia was 95% (one patient
There was a significant decrease in total intraoperative IVF administration after implementation of ERAS guidelines, from
4
j o u r n a l o f s u r g i c a l r e s e a r c h - 2 0 1 9 ( - ) 1 e7
Table 1 e Patient characteristics and operative details. Variable Age
Pre-ERAS n ¼ 11
ERAS n ¼ 20
47 [43, 55]
50 [46, 58]
0.549
13 (65%)
1.0
Female Preoperative creatinine
7 (63.6%)
P-value
0.73 [0.69, 0.8]
0.74 [0.66, 0.84]
1.0
PCI* score
10 [8,15]
13.5 [10, 16.5]
0.25
CCy score
0 [0,0]
0 [0,0]
0.052
Histology
0.36
Adenocarcinoma
8 (72.7%)
11 (55.0%)
LAMNz
3 (27.3%)
6 (30%)
Mesothelioma
0
3 (15.0%)
Primary tumor site
0.32
Appendix
7 (63.6%)
Colorectal
4 (36.3%)
4 (20%)
0
4 (20%)
Otherx
12 (60%)
Central venous access placement
5 (45.5%)
1 (5.0%)
0.013
Preexisting central access
7 (63.6%)
11 (55.0%)
0.72
Operative time (min)
391 [351, 490]
347 [303.5, 412.5]
0.15
Estimated blood loss (mL)
400 [250, 750]
150 [100, 400]
Bowel resection
10 (90.9%)
0.081
16 (80%)
0.63
Bowel anastomoses
0.45
0
2 (18.2%)
6 (30.0%)
1
6 (54.5%)
12 (60.0%)
2 or more
3 (27.3%)
2 (10.0%)
Ostomy
6 (54.5%)
4 (20.0%)
0.11
Splenectomy
7 (63.6%)
10 (70.7%)
0.50
Pelvic peritonectomy
9 (81.8%)
18 (90%)
0.60
Partial gastrectomy
1 (9.1%)
1 (5.0%)
1.0
Subcapsular liver resection
9 (81.8%)
15 (75%)
1.0
Diaphragmatic resection
9 (81.8%)
14 (70%)
0.68
Surgical drain placement
0.027
0
5 (45.5%)
18 (90.0%)
1
3 (27.3%)
1 (5.0%)
2
3 (27.3%)
1 (5.0%)
*
PCI: Peritoneal Cancer Index. y CC: Completeness of Cytoreduction Score. z LAMN: Low-grade Appendiceal Mucinous Neoplasm. x Includes jejunum, peritoneum (mesothelioma), and ovary.
a median of 924 (IQR: 660, 1075) mL per hour in the preERAS group to 523 (IQR: 483, 617) mL per hour in the ERAS group (P ¼ 0.005). In comparing intraoperative crystalloid and colloid administered between the two groups, there was a significant decrease in intraoperative crystalloid administered after ERAS implementation: a median of 523 (IQR: 386, 788) mL per hour was given in the preERAS group and 342 (IQR: 277, 433) mL per hour in the ERAS group (P ¼ 0.009). There was no significant difference in intraoperative colloid administration (P ¼ 0.08). (Fig. 2). There was also a significant decrease in the median urine output during each operation, with 120 (IQR: 66, 226) mL per hour in the preERAS group compared to 67 (IQR: 38, 101) mL per hour in the ERAS group (P ¼ 0.009). There was a significant decrease in total IVF administration in the first 24 h postoperatively, from a median 3228 (IQR: 2050, 4313) mL in
Table 2 e Postoperative outcomes. Variable
Pre-ERAS n ¼ 11
ERAS n ¼ 20
Pvalue
Postoperative ICU* Admission
10 (91%)
5 (25%)
0.001
Postoperative ICU LOSy
2 [1,3]
0 [0, 0.5]
<0.001
Total hospital LOS
9 [8,12]
6 [4.5, 7]
0.002
30 d readmission
3 (27.2%)
1 (5%)
0.115
0
0
Renal injury Clavien-Dindo III/IV complication * y
ICU: Intensive Care Unit. LOS: Length of Stay.
1 (9.1%)
1 (5)
1.0
lu et al eras in hipec patients
5
Fig. 2 e Intraoperative fluid management. (Color version of the figure is available online.)
the preERAS group to 1517 (IQR: 626, 1785) mL in the ERAS group (P < 0.001).
Postoperative ileus Ileus was defined as obstipation in conjunction with intolerance of oral intake. Patients in the preERAS cohort had routine nasogastric tube (NGT) placement postoperatively, which was not removed until the return of bowel function. In the ERAS cohort, early postoperative diet advancement was followed. One (5%) ERAS patient had a clinical diagnosis of postoperative ileus requiring NGT placement. Four (20%) ERAS patients were unable to complete the prescribed diet pathway advancement due to nausea, vomiting or distension, though did not require NGT replacement.
Discussion In this retrospective feasibility study of 31 patients, we demonstrate that the implementation of perioperative ERAS guidelines for patients undergoing CRS/HIPEC was associated with a significant decrease in hospital LOS and postoperative ICU LOS, without increasing postoperative complications of kidney injury or unplanned 30-d readmission. The feasibility and implementation of enhanced recovery pathways are understudied in this patient population. CRS/HIPEC has been historically associated with significant morbidity and mortality due to the significant physiologic insult of a large debulking surgery, along with the resulting systemic effects of intraperitoneal chemotherapy. In a systematic review published in 2009, Chua et al. describe a wide range of reported morbidity in CRS/HIPEC studies from 12% to 52%, and mortality rates ranging from 0.9% to 5.8%.3 Of note, the lower end of morbidity and mortality were seen in high volume sites, where experience and resources likely contributed to improved patient outcomes.3 Our study, performed at a high volume site, demonstrated lower rates of morbidity and mortality in both the preERAS and ERAS groups. In a single institution, nonERAS study evaluating 29 patients who underwent CRS/HIPEC with mitomycin-C, Witkamp et al. reported a mean postoperative LOS of 23 d, compared to shorter durations of 9.8 d in the preERAS group and 6.6 d seen in the
ERAS group of our study.18 In contrast, a study evaluating the outcomes of 90 patients after CRS/HIPEC performed with minimally invasive technique reported mean LOS of 7.4 d, which is in range of our ERAS cohort despite our open technique. This may point to the efficacy of multimodal postoperative analgesia, which is a facilitator to the early mobilization emphasized by ERAS.6,19 The success of ERAS pathways in reducing LOS without increased morbidity and mortality has been well documented in many postsurgical patient populations, including those undergoing colorectal, orthopedic, gynecologic, hepatic, and gastric surgeries.20-23 One study has examined the use of ERAS specifically in the CRS/HIPEC population and showed a similar reduction in LOS from 11 d to 7 after implementationehowever, this study evaluated a population with a very low median PCI score of four which may limit generalizability.14 We demonstrated similar outcomes in our CRS/HIPEC patient cohort with respect to LOS reduction and decreased postoperative readmissions and observed that the majority of patients were able to advance as planned without clinical setbacks, such as ileus. As perceptions of CRS/HIPEC have changed, more surgeons have adopted the practice over the past 10 y.2 Efforts to standardize the practice have been made, with the American Society of Peritoneal Surface Malignancies releasing consensus guidelines on delivery of HIPEC for colorectal cancer patients in 2014.24 However, these guidelines did not address the perioperative management of CRS/HIPEC patients. In 2017, MacIver et al. reported the results of an international survey of high-volume CRS/HIPEC surgeons which demonstrated that although 74% of respondents incorporated some ERAS principles in their practice, 83% of respondents reported routine postoperative nasogastric tube placement, which is in contradiction to the early postoperative diet advancement recommended in ERAS guidelines.2 In our ERAS cohort, zero patients had postoperative nasogastric tubes, which allowed for rapid postoperative diet advancement. MacIver’s study also demonstrated that postoperative IVF management varied widely between surgeons. Judicious fluid management is utilized in the ERAS pathway due to the association of excess intravenous fluid administration with a delayed return of bowel function postoperatively.15,25 The adherence to ERAS IVF management was evidenced in our study by the significant decrease in intraoperative and
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postoperative IVF administered in the ERAS group compared to the preERAS group, and likely contributed to the decreased overall LOS. There are some limitations to our study that must be considered. Acute renal injury has recently been raised as a potential adverse effect of the implementation of ERAS pathway guidelines, although reported results are variable.10,11,17 With respect to renal injury, certain agents utilized for HIPEC may place certain patients at higher risk of renal injury. Our study examined only patients who underwent HIPEC with mitomycin-C, which results in low systemic absorption and despite renal clearance, is not associated with a high risk of renal injury when used intraperitoneally.26 Other agents, such as cisplatin, present a significant risk of renal injury when used as a HIPEC agent, and the fluid management prescribed by ERAS may increase this risk, which would not be reflected in our patient cohort. Additionally, our classification of AKI/ARF was based on RIFLE serum creatinine levels, as accurate urine output measurement is limited due to the early removal of urinary catheters as part of the ERAS pathway guidelines. The modified Acute Kidney Injury Network (AKIN) or Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines have been posited to have increased sensitivity and specificity of detecting kidney injury compared to the RIFLE creatinine criteria and may lend bias to our results.27 Finally, our study utilizes retrospective data with a small sample size at a single institution before and after implementation of ERAS, which can contribute to unadjusted bias. Despite these limitations, our study has several strengths. First, the patient characteristics of the pre-ERAS and ERAS cohorts were similar. Second, this study took place in an institution where ERAS pathways have been routinely used since 2015, ensuring familiarity with the protocol and improved ability to adhere to the guidelines across all involved disciplines. Finally, this is one of the few available studies that examine the outcomes after implementation of a comprehensive, evidence-based, perioperative ERAS protocol in CRS/HIPEC patients.
Conclusions With this feasibility study, we demonstrate that the ERAS pathway may be safely and effectively utilized in patients undergoing CRS/HIPEC. Additional studies should be performed to further investigate the efficacy of ERAS in this unique patient population across institutions, and incorporation of ERAS pathways should be considered in future iterations of CRS/HIPEC consensus guidelines.
Acknowledgment Author Contributions: Pamela Lu and Adam Fields contributed equally to the conceptualization, design, methodology, formal analysis, original draft writing, and critical revisions of the manuscript. Galyna Shabat contributed to data acquisition and curation and critical revisions of the work. Ronald Bleday,
Joel Goldberg, Jennifer Irani, and Matthias Stopfkuchen-Evans contributed to the conception of work and critical revisions. Nelya Melnitchouk contributed to the conception of work, data acquisition and curation, design, methodology, and critical revisions. All authors have made final approval of the manuscript, and agree to be accountable for all aspects of the work.
Disclosure No authors have any financial or conflicts of interest to disclose.
references
1. Coccolini F, Gheza F, Lotti M, et al. Peritoneal carcinomatosis. World J Gastroenterol. 2013;19:6979e6994. 2. Maciver AH, Al-Sukhni E, Esquivel J, Skitzki JJ, Kane JM, Francescutti VA. Current delivery of hyperthermic intraperitoneal chemotherapy with cytoreductive surgery (CS/HIPEC) and perioperative practices: an international survey of high-volume surgeons. Ann Surg Oncol. 2017;24:923e930. 3. Chua TC, Yan TD, Saxena A, Morris DL. Should the treatment of peritoneal carcinomatosis by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy still be regarded as a highly morbid procedure?: a systematic review of morbidity and mortality. Ann Surg. 2009;249:900e907. 4. Foster JM, Sleightholm R, Patel A, et al. Morbidity and mortality rates following cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy compared with other high-risk surgical Oncology procedures. JAMA Netw Open. 2019;2:e186847. 5. Jafari MD, Halabi WJ, Stamos MJ, et al. Surgical outcomes of hyperthermic intraperitoneal chemotherapy: analysis of the american college of surgeons national surgical quality improvement program. JAMA Surg. 2014;149:170e175. 6. Beverly A, Kaye AD, Ljungqvist O, Urman RD. Essential Elements of multimodal analgesia in enhanced recovery after surgery (ERAS) guidelines. Anesthesiol Clin. 2017;35:e115ee143. 7. Auyong DB, Allen CJ, Pahang JA, Clabeaux JJ, MacDonald KM, Hanson NA. Reduced length of Hospitalization in primary total Knee Arthroplasty patients using an Updated enhanced recovery after orthopedic surgery (ERAS) pathway. J Arthroplasty. 2015;30:1705e1709. 8. Practice CoG. ACOG Committee Opinion No. 750: perioperative pathways: enhanced recovery after surgery. Obstet Gynecol. 2018;132:e120ee130. 9. Paduraru M, Ponchietti L, Casas IM, Svenningsen P, Zago M. Enhanced recovery after emergency surgery: a systematic review. Bull Emerg Trauma. 2017;5:70e78. 10. Marcotte JH, Patel K, Desai R, et al. Acute kidney injury following implementation of an enhanced recovery after surgery (ERAS) protocol in colorectal surgery. Int J Colorectal Dis. 2018;33:1259e1267. 11. Medlock G, Berg A, Stevenson IM. Acute kidney injury following enhanced recovery for orthopaedic joint replacement surgery-role of preoperative kidney disease? Br J Anaesth. 2017;119:338e339. 12. Kuijpers AM, Aalbers AG, Nienhuijs SW, et al. Implementation of a standardized HIPEC protocol improves outcome for peritoneal malignancy. World J Surg. 2015;39:453e460.
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13. Osseis M, Weyrech J, Gayat E, et al. Epidural analgesia combined with a comprehensive physiotherapy program after Cytoreductive Surgery and HIPEC is associated with enhanced post-operative recovery and reduces intensive care unit stay: a retrospective study of 124 patients. Eur J Surg Oncol. 2016;42:1938e1943. 14. Siddharthan R, Dewey E, Billingsley K, Gilbert E, Tsikitis VL. Feasibility and benefits of an enhanced recovery after surgery protocol for patients undergoing cytoreductive surgery and heated intraperitoneal chemotharpy: a single institution experience. Am J Surg. 2019. [Epub ahead of print]. 15. Miller TE, Roche AM, Mythen M. Fluid management and goaldirected therapy as an adjunct to Enhanced Recovery after Surgery (ERAS). Can J Anaesth. 2015;62:158e168. 16. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, workgroup ADQI. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care. 2004;8:R204eR212. 17. Horres CR, Adam MA, Sun Z, et al. Enhanced recovery protocols for colorectal surgery and postoperative renal function: a retrospective review. Perioper Med (Lond). 2017;6:13. 18. Witkamp AJ, de Bree E, Kaag MM, et al. Extensive cytoreductive surgery followed by intra-operative hyperthermic intraperitoneal chemotherapy with mitomycin-C in patients with peritoneal carcinomatosis of colorectal origin. Eur J Cancer. 2001;37:979e984. 19. Nimmo SM, Foo ITH, Paterson HM. Enhanced recovery after surgery: pain management. J Surg Oncol. 2017;116:583e591.
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20. Ljungqvist O, Scott M, Fearon KC. Enhanced recovery after surgery: a review. JAMA Surg. 2017;152:292e298. 21. Varadhan KK, Neal KR, Dejong CH, Fearon KC, Ljungqvist O, Lobo DN. The enhanced recovery after surgery (ERAS) pathway for patients undergoing major elective open colorectal surgery: a meta-analysis of randomized controlled trials. Clin Nutr. 2010;29:434e440. 22. Lv L, Shao YF, Zhou YB. The enhanced recovery after surgery (ERAS) pathway for patients undergoing colorectal surgery: an update of meta-analysis of randomized controlled trials. Int J Colorectal Dis. 2012;27:1549e1554. 23. Brustia R, Slim K, Scatton O. Enhanced recovery after liver surgery. J Visc Surg. 2018;156:127e137. 24. Turaga K, Levine E, Barone R, et al. Consensus guidelines from the American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States. Ann Surg Oncol. 2014;21:1501e1505. 25. Lobo DN, Bostock KA, Neal KR, Perkins AC, Rowlands BJ, Allison SP. Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial. Lancet. 2002;359:1812e1818. 26. Goodman MD, McPartland S, Detelich D, Saif MW. Chemotherapy for intraperitoneal use: a review of hyperthermic intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy. J Gastrointest Oncol. 2016;7:45e57. 27. Lopes JA, Jorge S. The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review. Clin Kidney J. 2013;6:8e14.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Cytoreductive Surgery and HIPEC in an Enhanced Recovery After Surgery Program: A Feasibility Study Pamela W. Lu, MD,a,b,*,1 Adam C. Fields, MD,a,1 Galyna Shabat, MD, PhD,a Ronald Bleday, MD,a Joel E. Goldberg, MD, MPH,a Jennifer Irani, MD,a Matthias Stopfkuchen-Evans, MD,c and Nelya Melnitchouk, MD, MSca,b,* a
Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts Center for Surgery and Public Health, Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts c Department of Anesthesia and Pain Management, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts b
article info
abstract
Article history:
Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy
Received 1 August 2019
(HIPEC) have historically been associated with high morbidity given the physiologic insult
Received in revised form
of an extensive operation. Enhanced Recovery after Surgery (ERAS) pathways have been
26 September 2019
successful in improving postoperative outcomes for many procedures but have not been
Accepted 20 October 2019
well studied in these cases. We examined the feasibility and effect of ERAS pathway
Available online xxx
implementation for patients undergoing CRS/HIPEC. Materials and methods: Patients with peritoneal carcinomatosis who underwent CRS/HIPEC
Keywords:
between October 2015 to September 2018 were identified. Patient characteristics, disease
Peritoneal neoplasms
pathology, and perioperative outcome data were obtained. Primary outcomes were hos-
Hyperthermic intraperitoneal
pital length of stay (LOS), 30-d readmissions, renal dysfunction, and complications.
chemotherapy
Results: Of the 31 patients who were included, 11 (35.5%) patients underwent CRS/HIPEC
HIPEC
prior to the implementation of the ERAS pathway, and 20 (64.5%) patients underwent CRS/
Cytoreductive surgery
HIPEC according to the ERAS guidelines. There were no significant differences in the
Enhanced recovery
baseline clinical or pathologic characteristics between groups. There was a significant decrease in LOS with ERAS pathway management from 9 d to 6 d (P ¼ 0.002). No patients from either cohort experienced acute kidney injury. There was no significant difference in 30-d readmission rates or complications. Conclusions: In this feasibility study, ERAS pathway utilization significantly decreased postoperative LOS for patients undergoing CRS/HIPEC, without evidence of increased complications or readmissions. ERAS programs should be considered for integration into future CRS/HIPEC protocols. ª 2019 Elsevier Inc. All rights reserved.
* Corresponding author. Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, 02115. Tel.: þ617 732-8460; fax: þ617 734-0336. E-mail addresses: [email protected] (P.W. Lu), [email protected] (N. Melnitchouk). 1 Co-first authors. 0022-4804/$ e see front matter ª 2019 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2019.10.042
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Introduction Intraperitoneal spread of malignancy can result from a variety of primary tumors, with a wide range of prognoses.1 In select patients where the tumor is limited to the intraperitoneal cavity with a resectable disease burden, cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer survival benefit where traditional surgery and systemic chemotherapy does not.2 However, the management of disseminated peritoneal disease with CRS and HIPEC has historically been associated with high morbidity and mortality due to the significant physiologic insult of the treatment.3 While recent studies showing improved safety profiles of CRS and HIPEC with comparable rates of morbidity and mortality compared to other high-risk oncologic surgeries,4,5 few specialized institutions offer this relatively resource-intensive procedure, and the perioperative practices vary widely amongst providers.2 Enhanced Recovery after Surgery (ERAS) practice guidelines have been used to formulate perioperative pathways, which utilize a multimodal approach to temper the physiologic response to surgical insults. The goal of these pathways is to improve postoperative recovery, reduce postoperative complication rates, and to shorten hospital length of stay.6 Initially developed for elective colorectal surgeries, these pathways have also shown to be successful in improving recovery after other types of surgeries as well, including orthopedic, gynecologic, and emergency surgeries.7-9 Despite the success of ERAS guidelines in improving postoperative outcomes, there have been some criticisms, especially with respect to the concern for increased readmission rates due to postoperative ileus, and potential for renal injury in the context of stringent fluid management implemented within ERAS pathways.10,11 While it has been shown that standardization of some perioperative practices, including intraoperative technique, use of epidural analgesia as part of multimodal pain control, and early postoperative mobilization have improved outcomes after CRS/HIPEC, utilization of a full ERAS evidencebased pathway has not been well examined.12-14 The goal of this feasibility study is to examine the utility and safety of utilizing a comprehensive, validated ERAS pathway for perioperative management of patients undergoing CRS and HIPEC at a single institution.
Materials and methods Patient population Patients with a diagnosis of peritoneal carcinomatosis who underwent abdominal CRS and HIPEC with mitomycin-C between October 2015 and September 2018 performed by a single surgeon were identified. Chart review was performed, and information regarding patient characteristics, perioperative management, intraoperative details, ERAS pathway component compliance, and postoperative outcomes were extracted based on documentation. This study was reviewed by the
Brigham and Women’s Hospital (BWH) Institutional Review Board and deemed exempt.
Enhanced recovery after surgery protocol Patients were separated into two groups. The patients who underwent surgery prior to the implementation of the ERAS protocol were designated as pre-ERAS, and those who were managed according to the ERAS protocol were designated as the ERAS group. The BWH ERAS protocol is a comprehensive pathway that was initially implemented in 2015 for patients undergoing elective colorectal surgery. At a patient’s preoperative outpatient appointment, education regarding components of the pathway and postoperative expectations are provided, along with bowel preparation and carbohydrate beverage supplies. On the day of surgery, oral carbohydrate loading occurs 2 to 3 h prior to the scheduled operative time. Upon arrival to the preoperative holding area, patients are given oral analgesic agents and neuraxial analgesia access is obtained if indicated. Intraoperatively, goal-directed fluid therapy (GDFT) or zero fluid balance is maintained based on the patient’s risk profile as described by Miller et al.15 Postoperatively, intravenous fluid (IVF) is discontinued after 6 h, avoidance of nasogastric tubes allows for early diet advancement, and early urinary catheter removal and patient mobilization is achieved. No promotility agents are used. A detailed schematic depicting the stages of the BWH ERAS pathway is shown in Figure 1.
HIPEC technique All HIPEC was performed with the same standardized protocol. Both CRS and intraperitoneal chemotherapy were performed via an open technique. The total duration of intraperitoneal chemotherapy perfusion was 90 min; 30 mg of mitomycin-C was administered over the first 60 min, then an additional 10 mg of mitomycin-C was administered over the last 30 min.
Study variables Patients who underwent intraabdominal CRS and HIPEC with mitomycin-C for peritoneal carcinomatosis were included. The primary outcomes of this study were hospital length of stay and postoperative complications. Postoperative complications included kidney injury, unplanned readmission within 30 d, and Clavien-Dindo Grade III/IV complications. Kidney injury was defined in two levels: acute kidney injury (AKI) was defined as peak creatinine of two times the baseline creatinine, and acute renal failure (ARF) was defined as peak creatinine of three times the baseline creatinine. Peak creatinine was identified as the highest measured serum creatinine level during the patient’s postoperative in-hospital stay. These distinctions are based on the Risk, Injury, Failure, Loss, and End-stage renal disease criteria set forth by the Acute Dialysis Quality Initiative.16 This criterion was chosen to avoid criteria that rely on urine output calculations, as ERAS management includes early removal of urinary catheters and would compromise accuracy.17 Secondary outcomes were
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Fig. 1 e Enhanced Recovery After Surgery Pathway Schematic Figure 1 Footnotes: aACE: Angiotensin-converting Enzyme b ARB: Angiotensin Receptor Blockers cNSAIDS: Nonsteroidal Antiinflammatory Drugs dDVT: Deep Vein Thrombosis eTAP: Transversus Abdominal Plane fIVF: Intravenous Fluids gPOD: Postoperative day. (Color version of the figure is available online.)
length of postoperative intensive care unit (ICU) stay, intraoperative, and postoperative fluid management trends.
Statistical analysis Fisher’s exact tests were carried out for categorical variables, and Wilcoxon Rank Sum tests were performed for continuous variables. Two-tailed P < 0.05 was considered significant for all tests. All statistical analysis was conducted using Stata statistical software, version 15.0 (StataCorp 2017, College Station, TX: StataCorp LLC).
refused epidural placement), and intraoperatively adherence to ERAS prescribed fluid management was 100%. Postoperatively, adherence to timed cessation of intravenous fluids was 100%, and the diet advancement adherence was 75%.
Length of stay Compared to the median hospital LOS seen in the preERAS group of 9 (Interquartile Range (IQR): 8, 12) days, the ERAS group had a significant decrease in LOS to 6 (IQR: 4.5, 7) days (P ¼ 0.002). Postoperative ICU LOS significantly decreased, from a median of two (IQR: 1, 3) days in the preERAS group to zero (IQR: 0, 0.5) days in the ERAS group (P < 0.001).
Results Postoperative complications Patient characteristics A total of 31 patients met the inclusion criteria. 11 (35.5%) patients underwent CRS/HIPEC prior to the implementation of the ERAS pathway, and 20 (64.5%) patients underwent CRS/ HIPEC following the ERAS pathway guidelines. The two patient groups had no significant differences in age, gender, baseline renal function, rates of preexisting central venous access, operative time, intraoperative blood loss, primary tumor site and histology, disease burden, or extent of surgical resection (P > 0.05 for all). Patients in the preERAS group had significantly more intraoperative central lines (P ¼ 0.013), and significantly more surgical drains placed (P ¼ 0.027) compared to the ERAS group (Table 1).
There were no incidents of AKI or ARF in either the preERAS or ERAS groups. There was a decrease in postoperative 30d readmission rates, with three (27.3%) readmissions preERAS and one (5%) readmission after ERAS was implemented, but this difference was not statistically significant (P ¼ 0.115) (Table 2). With respect to clinically significant, or Clavien-Dindo Grade III or IV complications, two instances were identified. One preERAS patient presented with an intraabdominal abscess, which required drainage by Interventional Radiology followed by related pleural effusion requiring thoracoscopic washout (Grade IIIa/IIIb, respectively). One ERAS patient presented with hyponatremia and intraabdominal abscess requiring drainage by Interventional Radiology (Grade IIIa). Both instances were associated with hospital readmission.
ERAS pathway guideline adherence Perioperative fluid management Compliance with the pre-operative education and bowel preparation/oral carbohydrate loading was 100%. The maximization of nonnarcotic and neuraxial analgesia was 95% (one patient
There was a significant decrease in total intraoperative IVF administration after implementation of ERAS guidelines, from
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Table 1 e Patient characteristics and operative details. Variable Age
Pre-ERAS n ¼ 11
ERAS n ¼ 20
47 [43, 55]
50 [46, 58]
0.549
13 (65%)
1.0
Female Preoperative creatinine
7 (63.6%)
P-value
0.73 [0.69, 0.8]
0.74 [0.66, 0.84]
1.0
PCI* score
10 [8,15]
13.5 [10, 16.5]
0.25
CCy score
0 [0,0]
0 [0,0]
0.052
Histology
0.36
Adenocarcinoma
8 (72.7%)
11 (55.0%)
LAMNz
3 (27.3%)
6 (30%)
Mesothelioma
0
3 (15.0%)
Primary tumor site
0.32
Appendix
7 (63.6%)
Colorectal
4 (36.3%)
4 (20%)
0
4 (20%)
Otherx
12 (60%)
Central venous access placement
5 (45.5%)
1 (5.0%)
0.013
Preexisting central access
7 (63.6%)
11 (55.0%)
0.72
Operative time (min)
391 [351, 490]
347 [303.5, 412.5]
0.15
Estimated blood loss (mL)
400 [250, 750]
150 [100, 400]
Bowel resection
10 (90.9%)
0.081
16 (80%)
0.63
Bowel anastomoses
0.45
0
2 (18.2%)
6 (30.0%)
1
6 (54.5%)
12 (60.0%)
2 or more
3 (27.3%)
2 (10.0%)
Ostomy
6 (54.5%)
4 (20.0%)
0.11
Splenectomy
7 (63.6%)
10 (70.7%)
0.50
Pelvic peritonectomy
9 (81.8%)
18 (90%)
0.60
Partial gastrectomy
1 (9.1%)
1 (5.0%)
1.0
Subcapsular liver resection
9 (81.8%)
15 (75%)
1.0
Diaphragmatic resection
9 (81.8%)
14 (70%)
0.68
Surgical drain placement
0.027
0
5 (45.5%)
18 (90.0%)
1
3 (27.3%)
1 (5.0%)
2
3 (27.3%)
1 (5.0%)
*
PCI: Peritoneal Cancer Index. y CC: Completeness of Cytoreduction Score. z LAMN: Low-grade Appendiceal Mucinous Neoplasm. x Includes jejunum, peritoneum (mesothelioma), and ovary.
a median of 924 (IQR: 660, 1075) mL per hour in the preERAS group to 523 (IQR: 483, 617) mL per hour in the ERAS group (P ¼ 0.005). In comparing intraoperative crystalloid and colloid administered between the two groups, there was a significant decrease in intraoperative crystalloid administered after ERAS implementation: a median of 523 (IQR: 386, 788) mL per hour was given in the preERAS group and 342 (IQR: 277, 433) mL per hour in the ERAS group (P ¼ 0.009). There was no significant difference in intraoperative colloid administration (P ¼ 0.08). (Fig. 2). There was also a significant decrease in the median urine output during each operation, with 120 (IQR: 66, 226) mL per hour in the preERAS group compared to 67 (IQR: 38, 101) mL per hour in the ERAS group (P ¼ 0.009). There was a significant decrease in total IVF administration in the first 24 h postoperatively, from a median 3228 (IQR: 2050, 4313) mL in
Table 2 e Postoperative outcomes. Variable
Pre-ERAS n ¼ 11
ERAS n ¼ 20
Pvalue
Postoperative ICU* Admission
10 (91%)
5 (25%)
0.001
Postoperative ICU LOSy
2 [1,3]
0 [0, 0.5]
<0.001
Total hospital LOS
9 [8,12]
6 [4.5, 7]
0.002
30 d readmission
3 (27.2%)
1 (5%)
0.115
0
0
Renal injury Clavien-Dindo III/IV complication * y
ICU: Intensive Care Unit. LOS: Length of Stay.
1 (9.1%)
1 (5)
1.0
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Fig. 2 e Intraoperative fluid management. (Color version of the figure is available online.)
the preERAS group to 1517 (IQR: 626, 1785) mL in the ERAS group (P < 0.001).
Postoperative ileus Ileus was defined as obstipation in conjunction with intolerance of oral intake. Patients in the preERAS cohort had routine nasogastric tube (NGT) placement postoperatively, which was not removed until the return of bowel function. In the ERAS cohort, early postoperative diet advancement was followed. One (5%) ERAS patient had a clinical diagnosis of postoperative ileus requiring NGT placement. Four (20%) ERAS patients were unable to complete the prescribed diet pathway advancement due to nausea, vomiting or distension, though did not require NGT replacement.
Discussion In this retrospective feasibility study of 31 patients, we demonstrate that the implementation of perioperative ERAS guidelines for patients undergoing CRS/HIPEC was associated with a significant decrease in hospital LOS and postoperative ICU LOS, without increasing postoperative complications of kidney injury or unplanned 30-d readmission. The feasibility and implementation of enhanced recovery pathways are understudied in this patient population. CRS/HIPEC has been historically associated with significant morbidity and mortality due to the significant physiologic insult of a large debulking surgery, along with the resulting systemic effects of intraperitoneal chemotherapy. In a systematic review published in 2009, Chua et al. describe a wide range of reported morbidity in CRS/HIPEC studies from 12% to 52%, and mortality rates ranging from 0.9% to 5.8%.3 Of note, the lower end of morbidity and mortality were seen in high volume sites, where experience and resources likely contributed to improved patient outcomes.3 Our study, performed at a high volume site, demonstrated lower rates of morbidity and mortality in both the preERAS and ERAS groups. In a single institution, nonERAS study evaluating 29 patients who underwent CRS/HIPEC with mitomycin-C, Witkamp et al. reported a mean postoperative LOS of 23 d, compared to shorter durations of 9.8 d in the preERAS group and 6.6 d seen in the
ERAS group of our study.18 In contrast, a study evaluating the outcomes of 90 patients after CRS/HIPEC performed with minimally invasive technique reported mean LOS of 7.4 d, which is in range of our ERAS cohort despite our open technique. This may point to the efficacy of multimodal postoperative analgesia, which is a facilitator to the early mobilization emphasized by ERAS.6,19 The success of ERAS pathways in reducing LOS without increased morbidity and mortality has been well documented in many postsurgical patient populations, including those undergoing colorectal, orthopedic, gynecologic, hepatic, and gastric surgeries.20-23 One study has examined the use of ERAS specifically in the CRS/HIPEC population and showed a similar reduction in LOS from 11 d to 7 after implementationehowever, this study evaluated a population with a very low median PCI score of four which may limit generalizability.14 We demonstrated similar outcomes in our CRS/HIPEC patient cohort with respect to LOS reduction and decreased postoperative readmissions and observed that the majority of patients were able to advance as planned without clinical setbacks, such as ileus. As perceptions of CRS/HIPEC have changed, more surgeons have adopted the practice over the past 10 y.2 Efforts to standardize the practice have been made, with the American Society of Peritoneal Surface Malignancies releasing consensus guidelines on delivery of HIPEC for colorectal cancer patients in 2014.24 However, these guidelines did not address the perioperative management of CRS/HIPEC patients. In 2017, MacIver et al. reported the results of an international survey of high-volume CRS/HIPEC surgeons which demonstrated that although 74% of respondents incorporated some ERAS principles in their practice, 83% of respondents reported routine postoperative nasogastric tube placement, which is in contradiction to the early postoperative diet advancement recommended in ERAS guidelines.2 In our ERAS cohort, zero patients had postoperative nasogastric tubes, which allowed for rapid postoperative diet advancement. MacIver’s study also demonstrated that postoperative IVF management varied widely between surgeons. Judicious fluid management is utilized in the ERAS pathway due to the association of excess intravenous fluid administration with a delayed return of bowel function postoperatively.15,25 The adherence to ERAS IVF management was evidenced in our study by the significant decrease in intraoperative and
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postoperative IVF administered in the ERAS group compared to the preERAS group, and likely contributed to the decreased overall LOS. There are some limitations to our study that must be considered. Acute renal injury has recently been raised as a potential adverse effect of the implementation of ERAS pathway guidelines, although reported results are variable.10,11,17 With respect to renal injury, certain agents utilized for HIPEC may place certain patients at higher risk of renal injury. Our study examined only patients who underwent HIPEC with mitomycin-C, which results in low systemic absorption and despite renal clearance, is not associated with a high risk of renal injury when used intraperitoneally.26 Other agents, such as cisplatin, present a significant risk of renal injury when used as a HIPEC agent, and the fluid management prescribed by ERAS may increase this risk, which would not be reflected in our patient cohort. Additionally, our classification of AKI/ARF was based on RIFLE serum creatinine levels, as accurate urine output measurement is limited due to the early removal of urinary catheters as part of the ERAS pathway guidelines. The modified Acute Kidney Injury Network (AKIN) or Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines have been posited to have increased sensitivity and specificity of detecting kidney injury compared to the RIFLE creatinine criteria and may lend bias to our results.27 Finally, our study utilizes retrospective data with a small sample size at a single institution before and after implementation of ERAS, which can contribute to unadjusted bias. Despite these limitations, our study has several strengths. First, the patient characteristics of the pre-ERAS and ERAS cohorts were similar. Second, this study took place in an institution where ERAS pathways have been routinely used since 2015, ensuring familiarity with the protocol and improved ability to adhere to the guidelines across all involved disciplines. Finally, this is one of the few available studies that examine the outcomes after implementation of a comprehensive, evidence-based, perioperative ERAS protocol in CRS/HIPEC patients.
Conclusions With this feasibility study, we demonstrate that the ERAS pathway may be safely and effectively utilized in patients undergoing CRS/HIPEC. Additional studies should be performed to further investigate the efficacy of ERAS in this unique patient population across institutions, and incorporation of ERAS pathways should be considered in future iterations of CRS/HIPEC consensus guidelines.
Acknowledgment Author Contributions: Pamela Lu and Adam Fields contributed equally to the conceptualization, design, methodology, formal analysis, original draft writing, and critical revisions of the manuscript. Galyna Shabat contributed to data acquisition and curation and critical revisions of the work. Ronald Bleday,
Joel Goldberg, Jennifer Irani, and Matthias Stopfkuchen-Evans contributed to the conception of work and critical revisions. Nelya Melnitchouk contributed to the conception of work, data acquisition and curation, design, methodology, and critical revisions. All authors have made final approval of the manuscript, and agree to be accountable for all aspects of the work.
Disclosure No authors have any financial or conflicts of interest to disclose.
references
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