Which Factors Are Associated with Distal Pancreatectomy Outcomes' Optimization with the Application of an Enhanced Recovery After Surgery Program?

Abstract

Background:

Distal pancreatectomy (DP) represents the best therapeutic option for patients with body-tail pancreatic neoplasms (PNs). The enhanced recovery after surgery protocol is widely used for treating patients with PN to speed up postoperative recovery. This study aims to describe our institute's experience in the application of fast recovery protocol in a cohort of patients treated with DP, identifying predictors facilitating a decrease in the length of hospital stay.

Patient and Methods:

Were retrospectively enrolled 60 consecutive cases of DP performed from January 2016 to June 2022 in patients treated with enhanced recovery protocol, 25% of them were treated with spleen preserving procedure. Single-variable logistic regression models were used to evaluate the potential association between patient characteristics and the probability of postoperative complications. Standard linear regression models were used for length of stay, number of postoperative days (PODs) from surgery to full bowel function recovery, and PODs to the interruption of intravenous analgesia administration.

Results:

Thirty-four (57%) patients underwent open surgery and 26 (43%) laparoscopic surgery. Patients who underwent laparoscopic surgery and spleen-preserving procedures experienced a lower complication rate (P = .037), shorter length of stay, and time of analgesic requirements. With single-variable logistic regression models patients treated with laparoscopic surgery had statistically significant higher recovery times in terms of nasogastric tube removal (P = .004) and early enteral nutrition (P = .001).

Conclusion:

Continual refinement with enhanced recovery protocol for treating PN patients based on perioperative counseling and surgical decision-making is crucial to reduce patient morbidity and time for recovery.

Introduction

Left-sided pancreatic neoplasms (PNs) are one of the most common forms of pancreatic oncologic disease, and the incidence of ductal adenocarcinoma of the body and tail of the pancreas has also been increasing, remaining one of the deadliest cancers with a 2-year survival rate reported as 10% in unresectable pancreatic cancer with a median overall survival of 9.8 months. For this oncologic disease the prognosis totally depends on both undergoing surgery and staging (i.e., presence of positive nodes) with a 5-year survival rate after distal pancreatectomy (DP) with multimodal treatments of 29% with a median overall survival of 35 months.¹

The evolving approaches of minimally invasive DP for left-sided PNs have been implemented because it is associated with a 1% postoperative mortality rate in otherwise elderly patients with or without multiple comorbidities. In addition, it has become the therapy of choice even when vascular manipulation is required, entailing the risk of potentially lethal bleeding, or a rapid recovery to normal life is necessary, being also crucial for guaranteeing correct timing for the increasing efficacy of chemo/chemoradiotherapy.²

In recent decades, efforts have been made to improve postoperative patient recovery with the implementation of the Enhanced Recovery After Surgery (ERAS) protocol, enabling more aggressive open and laparoscopic surgical procedures.^3,4

Based on a two-decade liver transplant experience in the multidisciplinary approach to a careful patients' selection and care, a program of major pancreatic surgery has been progressively developed with the achievement of a standard of care comparable to that of other international reference centers.⁵ Precisely, it allowed to perform pancreatic cancer surgeries without further stressing hospital resources, meanwhile minimizing collateral damage to patients, and obtaining a 30-postoperative mortality (failure-to-rescue) of 2.4% in a period of time between January 1, 2019 and November 30, 2022 (Agenzia Nazionale per i Servizi Sanitari Regionali [AGENAS]. Programma Nazionale Esiti 2018. https://pne.agenas.it/index.php [accessed January 27, 2023]).

Although ERAS protocol has been widely introduced for treating patients with PN, there are still no clear indications for improving upon it in both open and laparoscopic surgery in terms of complication rates and, moreover, making the surgery faster and safer, reducing length of hospital stay (LOS), and controlling pain.^6,7

The introduction of very complex procedures that may take surgeons a while to learn to perform with acceptable results has further reinforced the DP indication for this type of surgery to be concentrated in implementation of the ERAS protocol.⁸

The transplant center is widespread focused on multidisciplinary reference centers involving anesthesiologists, surgeons, skilled nurses, and physical and respiratory therapists. Our experience with ERAS is described elsewhere.^9–12

The aim of this study is to describe our institute's experience in the application of the ERAS protocol in a cohort of left-sided PN patients, who underwent DP, to promote the rapid recovery of performance status and identify predictors facilitating decrease in LOS, and to explore possible factors that could have an impact on postoperative outcomes.

Materials and Methods

Study population

All consecutively recruited patients with a radiological and/or cytological diagnosis of benign, premalignant, or malignant left-sided pancreatic tumors who were admitted to our institution from January 1, 2016 to June 30, 2022 and treated with ERAS protocol for undergoing radical DP were included in this single-center retrospective study. Institutional research review board approval was granted by IRCCS ISMETT, and good clinical and research practices were adopted. Disease staging and clinical pictures were evaluated with the following variables: dosage of carbohydrate antigen 19–9 and carcinoembryonic antigen levels, complete serum laboratories, and physical examination, as well as radiological and endoscopic diagnosis. Particularly, endoscopic ultrasound fine-needle aspiration for solid lesions, fluid tumor markers and cytology in distinguishing benign from (pre)malignant pancreatic cystic lesions, total body multidetector computed tomography, and abdominal magnetic resonance with endovenous administration of contrast dye scans were done within 1 month before surgery. Oncologic staging and surgical decision-making were specifically tailored by a weekly multidisciplinary board for excluding any potential vascular involvement and/or, and exact locations, to exclude concomitant new lesions. Demographics, operative factors, and postoperative complications of patients were reviewed. Our approach, which emphasizes spleen-sparing-based laparoscopy, has been developed with the following exclusion criteria for minimally invasive approach: tumor size >8 cm, multivisceral resection beyond the pancreas and spleen, neoadjuvant radiotherapy, and chronic pancreatitis.^12,13

ERAS protocol pathways

As previously described for the treatment of hepatobiliary malignancy,¹² preoperative counseling was conducted starting from the first outpatient surgical visit, and patients received information on the ERAS protocol and offered specific rehabilitation and dietary assessments. A preoperative maltodextrin nutritional supplement was administered on the day of surgery, and a solid diet was maintained until 6 hours before surgery. During the intraoperative period, and after specific consent, the patients underwent careful fluid restriction, preoperative ultra-short antibiotic prophylaxis, epidural catheter placement, and administration of epidural analgesic drugs (bupivacaine 2%) during surgery (Fig. 1). Patients exited the operating room without a nasogastric tube and then began sipping water, following physical and respiratory consultations to achieve rapid mobilization for 2 hours on the day of surgery. Intravenous (IV) fluids were administered only 24–36 hours after surgery. After measurements of prothrombin time, activated partial thromboplastin time, and international normalized ratio, patients were treated with subcutaneous administration of low-molecular-weight heparin anticoagulants on the first postoperative day (POD) to prevent deep vein thrombosis. As discharge criteria, no temperature, stable hemodynamics, active bowel sounds or at least one bowel movement, and independent walking and feeding were entered in the medical records to allow patients to be discharged.

FIG. 1.

Positioning of laparoscopic trocars and skeletonization of venous splenomesenteric axis.

Statistical analysis

Continuous variables are described in terms of median and interquartile range (IQR), while categorical ones are described in terms of frequencies and percentages. Differences between groups were tested by means of the Mann–Whitney U test for continuous variables and Pearson's chi-square or Fisher's exact test, as appropriate, for categorical ones. To evaluate the potential association between patient characteristics and the probability of postoperative complications, single-variable logistic regression models were used, while standard linear regression models were used for LOS, number of PODs from surgery to full bowel function recovery, and number of PODs to the interruption of IV analgesia administration. All analyses were done with the R Statistical computing environment, version 3.6.3.

Results

Since the introduction of the ERAS protocol for pancreatic surgery patients at our institute (January 1, 2016) to December 31, 2022, 67 patients with a diagnosis of left-sided PN were identified as eligible for DP surgical option (Table 1). Of the recruited patients, 26 were men and 41 were women. The average age of the patients was of 60 years (median 63, IQR: 52–73); individuals undergoing laparotomic surgery are 4 years older in median than those who underwent a laparoscopic treatment, although this difference was not statistically significant. Body mass index (BMI) did not differ substantially between the two groups. Having undergone previous abdominal surgery did not seem to significantly influence the surgical option; in fact, 64% of patients undergoing open surgery and 62% of patients undergoing minimally invasive surgery had a history of abdominal surgery.

Table 1.

Preoperative and Intraoperative Characteristics of 67 Patients Who Underwent Distal Pancreatic Resection

	Overall	Open surgery	Mini-invasive surgery	P
N	67	39	28
Age, years	60 (52–73)	59 (53–72)	63 (51–75)	.554
Male sex	26 (39)	14 (36)	12 (43)	.747
BMI, kg/m²	25.4 (23.7–28.8)	25.2 (23.7–29.6)	25.6 (23.7–27.7)	.756
Previous abdominal surgery	42 (63)	24 (62)	18 (64)	1.000
Diagnosis				.163
Pancreatic ductal adenocarcinoma	22 (33)	15 (38)	7 (25)
Neuroendocrine tumor	18 (27)	10 (26)	8 (29)
Intraductal papillary mucinous neoplasm	12 (18)	4 (10)	8 (29)
Other cystic neoplasm	10 (15)	5 (13)	5 (18)
Chronic pancreatitis	4 (6)	4 (10)	0 (0)
Gastrointestinal stromal tumor	1 (2)	1 (3)	0 (0)
ASA physical status classification				.434
1	1 (2)	0 (0)	1 (4)
2	18 (27)	9 (23)	9 (32)
3	40 (60)	25 (64)	15 (54)
4	6 (9)	3 (8)	3 (11)
E	2 (3)	2 (5)	0 (0)
Length of surgery, minutes	260 (205–305)	265 (216–330)	233 (190–296)	.186
Intraoperative transfusion	3 (5)	3 (8)	0 (0)	.356
Conversion to open surgery	––	9 (23)	––	––
Hand assisted surgery	––	––	6 (21)	––
Spleen preservation	17 (25)	12 (31)	5 (18)	.361

Numerical variables are presented as median (IQR), categorical variables as number (percentage, %).

ASA, American Society of Anesthesiologists; BMI, body mass index; IQR, interquartile range.

Patients with both malignant and benign lesions were included. Overall, the most frequently encountered lesion was pancreatic ductal adenocarcinoma (33% of the total); other indications to surgery were pancreatic neuroendocrine tumor (27%), intraductal papillary mucinous neoplasm (18%), and other cystic tumors (15% including mucinous cystic tumors, serous cystic tumors, and pseudopapillary solid neoplasms), four cases (7%) of chronic pancreatitis, and one gastrointestinal stromal tumor (2%). Patients treated with open surgery showed a relatively higher prevalence of pancreatic adenocarcinoma (18 patients, 38%, versus 7, 25%, respectively), although this difference was not statistically significant.

All patients underwent a preoperative anesthesia evaluation. American Society of Anesthesiologists (ASA) classifications of physical status were quite similar for patients treated with open and mini-invasive surgery, with the vast majority of patients in class 3 (60%) and class 2 (27%); 2 patients were operated on with the open technique in an emergency setting. The median duration of surgery was 265 minutes (IQR: 216–330) for the open method and 233 (IQR: 190–296) for the laparoscopic technique.

Three patients among those operated with the open technique required transfusions. Spleen was preserved in 17 patients overall (25%), relatively more frequently in patients treated with open surgery (15, 31%) than in those with laparoscopic treatment (5, 18%). Overall, there were relatively little differences (and none statistically significant) between laparoscopic and open surgery among variables described in Table 1.

Postoperative clinical course

The most common complication reported by patients is pancreatic fistula (25% of the total population) of which the majority did not require medical or surgical treatment being a grade A fistula according to the classification of the International Study Group of Pancreatic Fistula (ISGPF).¹⁴

Only 1 patient treated with the laparotomy technique developed a Grade C fistula and therefore underwent reoperation. This repertoire is not statistically significant. Delayed postoperative gastric emptying was seen in 1 patient undergoing laparotomic DP and in no patient undergoing laparoscopy. A similar result was observed in patients who experienced intra-abdominal hemorrhage after surgery. In fact, 3 patients (5% of the total) treated with the laparotomy technique developed this complication, while the patients operated with the laparoscopic technique did not develop intra-abdominal hemorrhage.

Infectious risk was assessed by the possibility of developing intra-abdominal infections and surgical site infections. The first complication was observed in 12% of patients operated on with the laparotomic technique and in 4% of patients operated on laparoscopically. However, the comparison between the infectious complications is not statistically significant.

What derives from our case series is the significance of the development of other complications. Thirty-eight percentage of patients treated with the open technique developed complications such as bilateral pleural effusion, pneumonia, and chylous ascites. Three of these patients (5% of the total) were hospitalized again less than 30 days after surgery. Two of these presented with anemic abdominal collection and underwent percutaneous drainage and endoscopic necrosectomy, while one developed thrombosis of the subrenal aorta and was treated with antiplatelet agents.

Another data that according to the database provided is statistically significant are the severity of complications, which were assessed with the Clavien-Dindo classification. It was found that patients who were treated with the open technique developed complications with a higher degree of Clavien-Dindo (III or IV) compared to patients treated minimally. The possibility of adhering to the ERAS protocol for a patient represents one of the characteristics to be evaluated to understand the effectiveness of one treatment compared to another. Satisfactory and statistically significant data were reported from the analysis of compliance with the ERAS protocol of patients who underwent DP with a minimally invasive technique. About early nutrition, only 26% of patients operated on with the laparotomy technique resumed enteral nutrition early. On the contrary, 73% of patients treated with the minimally invasive technique benefited from early enteral nutrition with consequent early weaning of parenteral nutrition. Another fact taken into consideration is early mobilization. All of the patients treated minimally were mobilized from the first POD.

For patients treated with the open technique, 79% benefited from early mobilization. The timing of nasogastric tube removal and drainage also provided significant results in favor of the laparoscopic technique. Patients undergoing open surgery had the nasogastric tube removed on average on the second POD and the drains on the eleventh POD.

Patients treated laparoscopically benefited early from the removal of the nasogastric tube (on the first POD on average) and the drains (on the seventh POD on average). The analysis of the number of hospitalization days also provided data in favor of the minimally invasive technique. The average LOS is 5 days for the laparoscopic technique and seven for the laparotomy one. Regarding the number of patients who were placed on the epidural catheter, the analysis did not provide a significant difference (Table 2).

Table 2.

Postoperative Clinical Outcomes of Characteristics of 67 Patients Who Underwent Distal Pancreatic Resection

	Overall	Open surgery	Mini-invasive surgery	P
N	67	39	28
Length of stay, days	6.0 [5.0, 7.0]	7.0 [5.0, 8.0]	5.0 [4.0, 6.0]	<.001
Analgesic control by epidural catheter	52 (77.6)	32 (82.1)	20 (71.4)	.378
Nasogastric tube removal, days after surgery	1.0 [1.0, 2.0]	2.0 [1.0, 2.0]	1.0 [0.0, 2.0]	.001
Early nutrition	34 (50.7)	13 (33.3)	21 (75.0)	.001
Early mobilization	60 (89.6)	32 (82.1)	28 (100.0)	.036
Drain removal, days after surgery	9.0 [6.0, 13.5]	11.0 [6.0, 20.0]	7.0 [5.0, 9.2]	.071
Any complications	36 (53.7)	25 (64)	11 (39)	.052
Pancreatic fistula	19 (28.4)	11 (33)	8 (29)	.785
Pancreatic fistula severity (%)				.824
No fistula	48 (71.6)	22 (67)	20 (71)
A	14 (20.9)	7 (21)	7 (25)
B	4 (6.0)	3 (9)	1 (4)
C	1 (1.5)	1 (3)	0 (0)
Delayed gastric emptying = Y (%)	2 (3.0)	2 (5)	0 (0)	.506
SurgicalSiteInfection = Y (%)	5 (7.5)	3 (8)	2 (7)	1.000
IntraAbdominalInfection = Y (%)	7 (10.4)	6 (15)	1 (4)	.225
IntraAbdominalHemorrhage = Y (%)	3 (4.5)	3 (8)	0 (0)	.259
AnyOtherCompl = Y (%)	16 (23.9)	13 (33)	3 (11)	.043
MaxClavienDindo (%)				.088
0	28 (41.8)	11 (28)	17 (61)
I	16 (23.9)	11 (28)	5 (18)
II	17 (25.4)	12 (31)	5 (18)
III_a	5 (7.5)	4 (10)	1 (4)
IV_a	1 (1.5)	1 (3)	0 (0)
MaxClavien34 (%)				.022
0	28 (41.8)	11 (28)	17 (61)
I/II	33 (49.3)	23 (59)	10 (36)
III/IV	6 (9.0)	5 (13)	1 (4)
Readmission within 30 days	4 (6.0)	3 (8)	1 (4)	.635
Reoperation within 30 days	1 (1.5)	1 (3)	0 (0)	1.000

With single-variable logistic regression models patients treated with minimally invasive surgical approach had statistically significant higher recovery times in terms of nasogastric tube removal (Beta = −1.18, 95% confidence interval [CI]: −1.97 to −0.39, P = .004) and early enteral nutrition (Beta = 1.79, 95% CI: 0.75 to 2.93, P = .001). As could also be expected, the need for a more complex surgery in patients with previous abdominal surgery or spleen-preservation PN appeared to be not associated with a worse clinical course. Elderly patients had a similar probability of developing a longer hospital stay and need for an endovenous analgesic treatment for longer time. Functionally, recovery with an early mobilization was significantly affected by BMI of the patient (Beta = 0.11, 95% CI: −0.14 to 0.53, P = .051) and the possibility to obtain an analgesic control by epidural catheter (Beta = 2.53, 95% CI: 0.85 to 4.57, P = .005) (Table 3).

Table 3.

Univariate Statistical Models for Length of Hospital Stay, Time to Bowel Function Recovery, Time to Nasogastric Tube Removal, Early Oral Nutrition, and Early Postoperative Mobilization

	LOS			NG tube removal, POD			Early oral nutrition			Early mobilization
	Beta	95% CI	P	Beta	95% CI	P	OR	95% CI	P	OR	95% CI	P
Spleen preservation, Y	3.36	−2.19 to 8.9	.230	−0.33	−1.29 to 0.64	.500	1.12	−0.02 to 2.38	.064	−0.18	−1.83 to 1.83	.837
Minimally invasive approach, Y	−4.25	−9.04 to 0.54	.081	−1.18	−1.97 to −0.39	.004	1.79	0.75 to 2.93	.001	18.05	−170.37 to NA	.993
Age	0.07	−0.1 to 0.25	.386	−0.01	−0.04 to 0.02	.420	0	−0.03 to 0.03	.988	−0.05	−0.14 to 0.01	.143
Gender, Male	−2.92	−7.89 to 2.05	.245	−0.26	−1.13 to 0.61	.551	−0.81	−1.85 to 0.18	.112	−0.19	−1.78 to 1.51	.816
BMI	−0.09	−0.58 to 0.41	.730	−0.02	−0.1 to 0.07	.708	−0.01	−0.11 to 0.09	.867	0.11	−0.14 to 0.53	.051
Previous abdominal surgery, Y	−2.25	−7.21 to 2.71	.368	−0.17	−1.03 to 0.69	.699	−0.34	−1.35 to 0.66	.508	−1.39	−4.36 to 0.46	.212
Analgesic.control.by.epidural.catheter. Y	1.05	−5.38 to 7.47	.746	0.53	−0.57 to 1.63	.340	−0.13	−1.31 to 1.02	.082	2.53	0.85 to 4.57	.005

BMI, body mass index; CI, confidence interval; LOS, length of hospital stay; NG, nasogastric; POD, postoperative day.

Discussion

Among the most debated topics in the scientific literature of recent years is the comparison between new surgical techniques that have developed with progress and experimentation with new instruments. Considering the preoperative characteristics and the complexity of patient status in terms of BMI and previous abdominal surgery, the effectiveness of the technique and safety for the patient are the main objectives that surgeons set themselves to achieve increasingly satisfactory results.¹⁵

Pancreas surgery presents various difficulties related to the anatomical position of the gland, the relationships that malignant and benign lesions often contract with vital structures, the late diagnosis that frequently characterizes neoplastic diseases in this site, and the presence of anatomical congenital anomalies that often distinguish the population.^13,16

The complexity of pancreatic surgery, even if without spleen-preservation option, therefore, affects the evaluation and choice of the best surgical techniques in terms of postoperative outcome and healing effectiveness of the surgical operation.¹⁷

The chance to perform a minimally invasive approach with a related benefit from early enteral nutrition with consequent early weaning of parenteral nutrition reinforces that the strength of the experience of the surgeons and their team plays a fundamental role in this field.¹⁸

Neoplastic disease of the pancreas still has a low 5-year survival today, although mortality has decreased in recent decades. The importance of surgery is dictated by its healing potential.¹⁹

Being subjected to pancreatic resection surgery for the neoplastic disease is an opportunity for the patient to treat a disease that until a few decades ago would have led irremediably to death. For many years now, video-assisted surgery has replaced the laparotomy approach. This allowed for a better postoperative outcome in terms of hospitalization and complications.^20,21

From this point of view, it is easy to understand how essential it is to continue to investigate and evaluate the best surgical techniques to be able to treat the greatest number of patients definitively and grant them a dignified survival. In addition to the ultra-specialized technical knowledge necessary for the success of the operation, it is important to know how to make the most of the tools available and to adapt the procedure to individual patients and to overcome hospital volume helping the patients' selection and pancreatic surgery accreditation programs.²²

Although minimally invasive distal pancreatectomies offer some short-term benefits over open DP, safety remains a concern with minimally invasive pancreatoduodenectomy. Strict adherence to principles and judicious utilization of surgery within a multimodality framework is the way forward.²³

The greater adherence to the ERAS protocol is also confirmed for patients treated with a minimally invasive technique in terms of nutrition and early mobilization, LOS, and early removal of the nasogastric tube and peri-anastomotic drainages. This focus might be crucial to help patients for toughing to understand the fundamentals of pre- and postoperative care and does better in the postoperative rehabilitation process. Our experience suggests that, in this light, laparoscopic surgery may reduce the impact of surgery on the patient and allows extension of the indications for patients with a reduced performance status.^24–26

Footnotes

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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