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The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation
The American Journal of Surgery xxx (xxxx) xxx
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The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation Rauf Shahbazov a, Bashoo Naziruddin b, *, Osmaan Salam c, Giovanna Saracino b, Marlon F. Levy d, Ernest Beecherl b, Nicholas Onaca b a
Department of Surgery, Division of Transplantation, Upstate Medical University, 750 E. Adams Street, Syracuse, NY, 13210, USA Baylor Annette C. and Harold C. Simmons Transplant Institute, 3410 Worth Street, Suite 950, Dallas, TX, 75246, USA Islet Cell Laboratory, Baylor Scott and White Research Institute, 3812 Elm Street, Dallas, TX, 75226, USA d Department of Surgery, Hume-Lee Transplant Center, VCU Health, 1250 East Marshall Street, Richmond, VA, 23298, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 January 2019 Received in revised form 4 April 2019 Accepted 8 April 2019
Total pancreatectomy with islet autotransplantation is a promising treatment for refractory chronic pancreatitis. We analyzed postoperative complications in 83 TPIAT patients and their impact on islet graft function. We examined patient demographics, preoperative risk factors, intraoperative variables, and 30- and 90-day postoperative morbidity and mortality. Daily insulin requirement, HbA1c, C-peptide levels, and narcotic requirements were analyzed before and after surgery. Adverse events were recorded, with postoperative complications graded according to the Clavien-Dindo classification. There was no mortality in this patient group. Postoperative complications occurred in 38 patients (45.7%). Patients with postoperative complications were readmitted significantly more often within 30 days (p ¼ 0.01) and 90 days posttransplant (p < 0.0003) and had a significantly longer hospital stay (p ¼ 0.004) and intensive care unit stay (p ¼ 0.001). Insulin dependence and graft function assessed by HbA1c, C-Peptide and insulin requirements did not differ significantly by these complications. Postoperative complications after TPIAT are associated with longer hospital and intensive care unit stay and with readmission; however, the surgical complications do not affect islet graft function. © 2019 Published by Elsevier Inc.
Keywords: Total pancreatectomy Islet autotransplantation Chronic pancreatitis Surgical complications
Introduction Chronic pancreatitis (CP) is associated with irreversible morphological and functional abnormalities due to longstanding or recurrent inflammation and fibrosis of the pancreatic parenchyma.1,2 In most patients with CP, severe abdominal pain prompts them to seek further treatment options.3 The utilization of analgesia,4 nerve blocks, endoscopic decompression,5,6 surgical decompression of the main pancreatic duct, and partial resection of the pancreas are effective methods for early stages of this disease. However, these treatment options are not effective in all patients.7 Consequently, some patients whose medical and surgical
* Corresponding author. E-mail addresses: [email protected] (R. Shahbazov), bashoo.naziruddin@ bswhealth.org (B. Naziruddin), [email protected] (O. Salam), giovanna. [email protected] (G. Saracino), [email protected] (M.F. Levy), [email protected] (E. Beecherl), [email protected] (N. Onaca).
treatments have failed to achieve the desired relief are referred for total pancreatectomy (TP). Usually, these patients have significant impairments of quality of life due to pain8 as well as their need for narcotics. Although TP effectively eliminates pain9, it leads to surgically induced diabetes, which can have serious health consequences such as disabling episodes of hyperglycemia or hypoglycemia,10 increased morbidity and mortality, and target organ damage.11,12 TP with islet autotransplantation (TPIAT) has been shown to overcome this obstacle13 and retain pancreatic endocrine function, with patients either achieving insulin independence or requiring small doses of exogenous insulin to maintain normoglycemia.14e16 Moreover, usage of TPIAT as an early treatment option in the minimal-change CP group can be a costeffective strategy.17 Previous studies have tried to determine factors that predict successful outcomes following TPIAT. Some studies described body mass index,18 etiology of CP,19 severity of disease, duration of disease, previous pancreatic surgical procedure,20 transplanted tissue volume,21 and number and quality of islets22 as important factors
https://doi.org/10.1016/j.amjsurg.2019.04.007 0002-9610/© 2019 Published by Elsevier Inc.
Please cite this article as: Shahbazov R et al., The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.04.007
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for better graft function after TPIAT. Apart from insulin independence, these factors may contribute to both short-term and longterm quality of life following TPIAT.23 During the last decade, due to implementation of minimally invasive technologies, enhanced surgical techniques,24 and progressive preoperative care,25 immense improvements have been achieved in perioperative morbidity and mortality in pancreatic surgery. Additionally, the establishment of high-volume pancreatic centers with a focus on management of complications has given surgeons more confidence in offering aggressive treatment for CP. Although the outcome of TP procedures has improved, surgical complications still occur in the postoperative period.26 TP is a major abdominal procedure with high morbidity, ranging from 15% to 65%27din some cases resulting in abortion of the procedure.28 As postoperative complications can lead to an increase in inflammation or bacterial infections, they may influence islet engraftment by changing the microenvironment in the liver and activating immune reactions. Furthermore, complications could negatively impact islet cell function in the short- and long-term in TPIAT patients. To our knowledge, no studies have analyzed the effects of postoperative surgical complications in TPIAT patients. Here we describe the surgical complications of a large cohort of patients with TPIAT and their impact on short- and long-term outcomes. Materials and methods Patient selection This study was approved by the institutional review board. A prospectively maintained research database was queried to identify 83 consecutive patients who underwent TPIAT and completed a 1year follow-up evaluation. All patients with previously diagnosed CP were evaluated by a multidisciplinary team that included a gastroenterologist, an endocrinologist, and a transplant surgeon. The diagnosis of CP was based on the patient's history, laboratory results, computed tomographic scans, endoscopic retrograde
pancreatography, endoscopic ultrasonography, magnetic resonance imaging, and pathologic diagnosis. The indications for surgery were intractable pain despite previous medical and surgical intervention. Data extracted from the database included demographic characteristics, preoperative risk factors, intraoperative variables, and 30day postoperative morbidity and mortality as well as clinical and pathologic variables.
Operative procedure and islet cell transplantation TP was performed in all patients, including splenectomy with removal of the duodenum and distal common bile duct. During the surgery, the body and tail of the pancreas were mobilized first, with pancreatic blood supply being preserved as long as possible to minimize islet cell ischemia. The pancreas with attached tissue was removed and dissected free from the spleen and duodenum on the back table. After flushing through the arteries with University of Wisconsin solution, the pancreas duct was cannulated and placed in cold preservation solution and then transferred to a good manufacturing practice facility for further processing. Islet isolation was performed following the method previously described.22 Liberase MTF (Roche, Indianapolis, IN) or Collagenase NB with neutral proteases (SERVA Electrophoresis GMbH, Heidelberg, Germany) was infused into the main pancreatic duct for pancreas digestion. Islets were isolated by the modified Ricordi method, and when the tissue volume exceeded 20 mL, islets were purified using a COBE 2991 cell processor (Caridian BCT, Inc., Lakewood, CO) using a density-adjusted iodixanol-based continuous density gradient. Endotoxin tests, Gram staining, and bacterial and fungal cultures were performed on the final products and used as indicators of sterility. Isolated islets were infused into the portal vein via the mesenteric vein with heparin (70 U/kg body weight) while the patient was under general anesthesia. Portal pressures were routinely monitored during the islet infusion.
Table 1 Characteristics of 83 patients, with and without postoperative complications, undergoing total pancreatectomy and islet autotransplantation.a Characteristic
No complications (N ¼ 45)
Complications (N ¼ 38)
P value
Age (years) Male, n (%) Body mass index (kg/m2) Preoperative comorbidities Active tobacco use Alcohol abuse Weight loss of >10 kg History of ERCP and stent Previous surgery Previous pancreas surgery Previous abdominal surgery Chronic pulmonary disease Hypertension Diabetes Coronary artery disease Perioperative characteristics ASA grade 3 Estimated blood loss (mL) Intraoperative fluids (mL) Blood transfusion Length of stay (days) ICU length of stay (days) Postoperative characteristics Narcotic requirement at 1 year 30-day hospital readmission 90-day hospital readmission
42 (31, 50) 13 (28.9%) 26.8 (22.3, 30.2)
38 (30, 48) 13 (34.2%) 26.5 (21.5, 29.8)
0.593 0.641 0.818
18 (40.0%) 9 (20.0%) 7 (15.6%) 18 (40.0%) 39 (86.7%) 7 (15.6%) 24 (53.3%) 2 (4.4%) 17 (37.8%) 26 (57.8%) 1 (2.2%)
11 (28.9%) 11 (28.9%) 5 (13.2%) 16 (42.1%) 36 (94.7%) 4 (10.5%) 23 (60.5%) 1 (2.6%) 13 (34.2%) 17 (44.7%) 2 (5.3%)
0.358 0.441 1.000 1.000 0.279 0.538 0.657 1.000 0.820 0.275 0.591
4 (91.1%) 500 (300, 700) 4500 (4000, 5600) 16 (35.6%) 11.0 (9.0, 13.0) 1.0 (1.0, 2.0)
2 (5.3%) 500 (350, 1000) 5000 (4000, 5500) 18 (47.4%) 12.0 (11.0, 19.0) 2.0 (1.0, 2.0)
0.198 0.278 0.220 0.371 0.004 0.001
15 (33.3%) 6 (13.3%) 16 (35.6%)
15 (39.5%) 15 (39.5%) 29 (76.3%)
0.649 0.010 0.0003
ASA indicates American Society of Anesthesiologists score; ERCP, endoscopic retrograde cholangiopancreatography; ICU, intensive care unit. a Data are presented as the median value (25th, 75th percentiles) or n (%) of patients.
Please cite this article as: Shahbazov R et al., The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.04.007
R. Shahbazov et al. / The American Journal of Surgery xxx (xxxx) xxx Table 2 Postoperative complications in 83 patients undergoing of total pancreatectomy and islet autotransplantation.a Complications
N (%)
Overall complications Islet transplanterelated complications Portal vein thrombosis High portal pressure (>25 mm H2O) Fatty liver (heavy) TP surgeryerelated complications Perioperative bleeding Delayed gastric emptying Deep SSI Organ space SSI Superficial SSI Postoperative sepsis Septic shock Wound disruption Deep vein thrombosis Urinary tract infection Postoperative pneumonia
51 (100%) 9 (17.6) 2 (3.9%) 4 (7.8%) 3 (5.9%) 42 (82.4) 3 (5.9%) 12 (23.5%) 2 (3.9%) 1 (2.0%) 6 (11.8%) 5 (9.8%) 1 (2.0%) 4 (7.8%) 4 (7.8%) 3 (5.9%) 1 (2.0%)
TP indicates total pancreatectomy; SSI, surgical site infection. a Thirty-eight patients had a total of 51 complications.
Postoperative care All patients were monitored and examined in the intensive care unit (ICU) after surgery for a short period of time with intensive insulin therapy as well as strict blood glucose control (serum levels <120 mg/dL). Patients were converted to a basal bolus insulin regimen starting on postoperative day 3. All patients were discharged home with an individualized insulin regimen. The patient's portal vein flow was assessed by Doppler sonogram before and after surgical intervention. Lack of detection of portal flow by Doppler sonogram was considered as portal vein thrombosis. Longterm postoperative care was provided by the transplant surgeon and endocrinologists, who assessed improvement of clinical symptoms. Outcomes The average daily insulin requirement, HbA1c level, and Cpeptide level were measured before surgery, at hospital discharge,
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and at each subsequent postoperative patient encounter. Postoperative C-peptide levels were measured after fasting at 3, 6, and 12 months. Patients with a detectable C-peptide value (>0.3 ng/mL) were considered C-peptide positive. Graft function was measured from date of infusion to complete graft failure (first occurrence of Cpeptide <0.3 ng/mL). First achievement of insulin independence was measured from islet infusion to last follow-up or graft loss. Narcotic requirements were reported as morphine-equivalent quantity per day (MEQ/d) calculated from narcotic conversion software (Narcotic Converter; GlobalRPh Inc). Complications We included all adverse effects following the Common Terminology Criteria for Adverse Effects in Trials of Adult Pancreatic Islet Transplantation (version 4.0, May 2007) and graded postoperative complications on a scale of 1e4. Overall, a postoperative complication was defined as one or more of the following: delayed gastric emptying, any surgical site infection, postoperative sepsis or septic shock, wound disruption, urinary tract infection, acute renal failure, progressive renal insufficiency, postoperative pneumonia, postoperative ventilator dependency, need for cardiopulmonary resuscitation, postoperative myocardial infarction, postoperative stroke or coma, pulmonary embolism, deep venous thrombosis, and reoperation within 30 days of admission.27 Postpancreatectomy complications were graded according to the Clavien-Dindo classification.29 Statistical analysis The Wilcoxon two-sample test was used to compare continuous variables. Categorical variables were compared using the two-sided Fisher's exact test and expressed as median with interquartile ranges. Categorical variables are expressed as counts with percentages, and continuous variables as medians with interquartile ranges or means and standard deviations, as appropriate. A p value of 0.05 was considered statistically significant. Each clinical outcome measured over time was analyzed using linear and mixed regression models. This method allows the analysis of longitudinal data with multiple measurements taken on each subject by
Fig. 1. Etiology of chronic pancreatitis among total pancreatectomy and islet autotransplantation patients with no complications group (NC) and complications group (C).
Please cite this article as: Shahbazov R et al., The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.04.007
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Table 3 Pancreatic islet and transplant characteristics of 83 patients, with and without postoperative complications, undergoing total pancreatectomy and islet autotransplantation.a Characteristic
No complications (N ¼ 45)
Complications (N ¼ 38)
p value
Duration of pancreatectomy (h) Operative time (hours) Pancreas weight (g) Islet yield Pellet volume Purity (%) Viability (%) Portal pressure change (mm Hg)
4.1 (3.5, 5.4) 10.6 (9.3, 11.4) 86.3 (78.7, 101.4) 4,951 (2541, 6179) 9.5 (5.0, 13.0) 50.0 (30.0, 60.0) 96.6 (95.4, 97.7) 5.0 (2.0,8.0)
4.4 (3.5, 5.0) 10.5 (9.9, 11.9) 78.1 (58.9, 99.4) 5,210 (3138, 6376) 10.0 (3.0, 15.0) 55.0 (30.0, 100.0) 96.4 (92.2, 99.0) 5.5 (3.0, 10.0)
0.540 0.473 0.0035 0.487 0.617 0.568 0.441 0.568
a
Data are presented as the median value (25th, 75th percentiles).
examining not only differences between subjects, but also changes within subjects across time. Time-to-event variables were analyzed using Kaplan-Meier curves and compared using the log-rank test. All analyses were performed using SAS 9.3 (SAS Institute, Cary, NC).
with increased rate of hospital readmission, and hospital and ICU length of stay. The most common reported complications due to islet infusion
Results As shown in Table 1, there were no significant differences in age, body mass index, CP etiology, preoperative comorbidities, estimated blood loss, intraoperative fluid, or blood transfusion between TPIAT patients who had and did not have complications. However, readmission rates for 30 days and 90 days were higher in patients with complications than in patients with no complications (p ¼ 0.010 and 0.0003, respectively). Similarly, length of hospital stay and ICU stay were longer in patients with complications (p ¼ 0.004 and 0.001, respectively). There were no 30-day or 90-day postoperative deaths. A total of 51 severe surgical complications occurred in 38 of 83 patients (45.7%) (Table 2). Islet transfusionerelated complications occurred in a relatively small percentage of patients, with portal vein thrombosis (3.9%), high portal pressure (7.8%) and fatty liver (5.9%) notable among the total number of complications. Delayed gastric emptying (23.5%) followed by surgical infections (17.7%) were the most common surgery related complication. Only 16 patients with complications required surgical treatment (see Fig. 1). The only significantly different islet graft or infusion characteristic between patients who did and did not have complications was a higher pancreas weight in patients with no complications (86.3 vs. 78.1 g, p ¼ 0.0035) (Table 3). Primary graft function was not significantly affected by postsurgical complications (Fig. 2). Patient insulin requirements were similar at 1, 3, 6, and 12 months in the complication and noncomplication groups. Kaplan-Meier curves, censored at 1-year follow-up, depicted the probability of graft survival and insulin independence (Fig. 3); log rank test results showed no difference in graft survival and insulin independence between patients in the complication and noncomplication groups. Interestingly, patients without complications had a slightly higher pain score than patients with complications (Fig. 4a). Those with complications did receive more narcotics than those without complications, but the difference was not statistically significant (Fig. 4b). Discussion It has been reported that the incidence of adverse events reaches 38% after islet transplantation.30,31,32 Postoperative complications after TP can be higher, varying from 15% to 65%.27 In our cohort, the overall major complication rate for TPIAT recipients was 45.7%, within the reported range. While our study did not show an association between postoperative complications in TPIAT patients and decreased islet graft function, complications were associated
Fig. 2. Posttransplant graft function of islets for the no complication group (NC; n ¼ 45) and complication group (C; n ¼ 38): (a) hemoglobin A1c level, (b) C-peptide level, and (c) insulin requirements.
Please cite this article as: Shahbazov R et al., The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.04.007
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Fig. 3. (a) Graft survival and (b) insulin independence among total pancreatectomy and islet autotransplantation patients with no complications (NC, red, n ¼ 45) and complications (C, blue, n ¼ 38). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
include a transient increase in liver enzymes and portal vein thrombosis, but complications related to TP are far more severe and diverse in terms of glycemic control.32 They include delayed gastric emptying, surgical site infection, postoperative sepsis or septic shock, wound disruption, urinary tract infection, and acute renal failure. Furthermore, progressive renal insufficiency, postoperative pneumonia, postoperative myocardial infarction, postoperative stroke or coma, pulmonary embolism, and deep venous thrombosis have also been reported. In our case series, portal vein thrombosis developed in 2 patients (4.3%). First patient had previous several attack of severe pancreatitis. Second patient had previous pancreas surgery. Therefore, their total pancreatectomy procedure was challenging. Isolated islets are infused along with heparin (70 U/kg body weight) into the portal vein via a branch of the superior mesenteric vein. Portal pressures are routinely monitored during the islet infusion at every 5 min. When the portal pressure exceeds 22 mmHg, the infusion is halted and rest of the islets infused intraperitoneally. All patients had their portal vein assessed by duplex imaging before and after the surgical intervention on day 1, 3 and 5. Portal vein thrombosis was detected in one patient on postoperative day 1 and second patient on day 3 during routine duplex scanning. Both the patients were managed conservatively. Heparin infusion was started to achieve therapeutic level. After 36 h of heparin, patients were transitioned to low molecular weight heparin (LMWH) for 14 days. Then the patients were converted to aspirin 81 mg daily indefinitely with normal outcome.
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Fig. 4. (a) Pain score and (b) narcotic requirements among total pancreatectomy and islet autotransplantation patients with no complications (NC, blue, n ¼ 45) and complications (C, green, n ¼ 38). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Delayed gastric emptying (DGE) developed in 12 (23.5%) patients. Etiologies of DGE are multifactorial. Type of surgical procedure, chronic use of opioids, and duration of surgical procedure could be contributing factors for DGE. Our previous study has shown that the incidence of DGE was nearly identical between the pylorus preservation (PP) and non-pylorus preservation NPP groups (21.1% and 18.8%, respectively; P ¼ 1.00).33 In addition, in TPIAT, the portal vein pressure increased due to the islet infusion. High portal vein pressure could slow down gastro-intestinal function. It is important to note that all of the patients underwent splenectomy, which should reduce the volume of the portal vein flow. It believed that altered portal vein system can to suppress the patient's gastrointestinal peristalsis. We believe further studies necessary to prove it. We managed all patients with DGE with conservative measures using prokinetic medications such as metoclopramide and low dose erythromycin. Postoperative complications increase the body's systemic inflammatory reaction, and bacterial translocation after postoperative complications could also lead to production of acute stress protein in the liver. This microenvironment variation could influence islet engraftment. As islet allotransplantation is associated with more severe nonspecific and specific immune reactions than autotransplantation, complications could have different effects. Caiazzo et al. reported that complications had a negative impact on islet function after allotransplantation for the treatment of type 1 diabetes mellitus,34 whereas we did not find a significant difference in graft function between groups with and without surgical complications. A further explanation is that in islet autotransplantation, there is less of an immune response in the liver
Please cite this article as: Shahbazov R et al., The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.04.007
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sinusoids. TPIAT has made considerable progress in recent years,35 with developments in pancreas procurement and processing, innovations in islet isolation technology, and improved postoperative patient care.36 Several transplant centers have reported successful clinical outcomes with a high rate of insulin independence after TPIAT, demonstrating the potential for the procedure to serve as a safe and effective therapy for patients with CP.37 Even without the complications affecting graft function, the safety of the procedure could be improved by decreasing the complication rate. Our study did not examine how surgical complications affected patients’ quality of life, and further studies are needed to understand the full effect of complications on TPIAT patients. It is imperative that stringent measures be implemented to prevent the occurrence of postoperative complications, including even more comprehensive patient follow-up. Conflicts of interest All the authors declare no conflict of interest with the contents presented in this manuscript. Acknowledgments The authors thank Ms. Sharon Bruer and Ms. Ana M. Rahman for technical support. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.amjsurg.2019.04.007. Disclosure The authors declare no conflicts of interest. References 1. Muniraj T, Aslanian HR, Farrell J, Jamidar PA. Chronic pancreatitis, a comprehensive review and update. Part I: epidemiology, etiology, risk factors, genetics, pathophysiology, and clinical features. Dis Mon. 2014;60(12):530e550. https:// doi.org/10.1016/j.disamonth.2014.11.002. 2. Kanak MA, Shahbazov R, Yoshimatsu G, Levy MF, Lawrence MC, Naziruddin B. A small molecule inhibitor of NFkB blocks ER stress and the NLRP3 inflammasome and prevents progression of pancreatitis. J Gastroenterol. 2017;52(3): 352e365. https://doi.org/10.1007/s00535-016-1238-5. 3. Bouwense SA, de Vries M, Schreuder LT, et al. Systematic mechanismorientated approach to chronic pancreatitis pain. World J Gastroenterol. 2015;21(1):47e59. https://doi.org/10.3748/wjg.v21.i1.47. 4. Chauhan S, Forsmark CE. Pain management in chronic pancreatitis: a treatment algorithm. Best Pract Res Clin Gastroenterol. 2010;24(3):323e335. https:// doi.org/10.1016/j.bpg.2010.03.007. €ki C, Kyla €npa €€ 5. Haapama a L, Udd M, et al. Randomized multicenter study of multiple plastic stents vs. covered self-expandable metallic stent in the treatment of biliary stricture in chronic pancreatitis. Endoscopy. 2015;47(7): 605e610. https://doi.org/10.1055/s-0034-1391331. 6. Seicean A, Vultur S. Endoscopic therapy in chronic pancreatitis: current perspectives. Clin Exp Gastroenterol. 2014;8:1e11. https://doi.org/10.2147/ CEG.S43096. 7. Hoffmeister A, Mayerle J, Beglinger C, et al. Chronic Pancreatitis German Society of Digestive and Metabolic Diseases (DGVS). S3-Consensus guidelines on definition, etiology, diagnosis and medical, endoscopic and surgical management of chronic pancreatitis. Z Gastroenterol. 2012;50(11):1176e1224. https:// doi.org/10.1055/s-0032-1325479. 8. Olesen SS, Juel J, Nielsen AK, Frøkjær JB, Wilder-Smith OH, Drewes AM. Pain severity reduces life quality in chronic pancreatitis: implications for design of future outcome trials. Pancreatology. 2014;14(6):497e502. https://doi.org/ 10.1016/j.pan.2014.09.009. 9. Murphy MM, Knaus II WJ, Ng SC, et al. Total pancreatectomy: a national study. HPB. 2009;11(6):476e482. https://doi.org/10.1111/j.1477-2574.2009.00076.x. 10. Burkhart RA, Gerber SM, Tholey RM, et al. Incidence and severity of pancreatogenic diabetes after pancreatic resection. J Gastrointest Surg. 2015;19(2): 217e225. https://doi.org/10.1007/s11605-014-2669-z.
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Total pancreatectomy and islet autotransplantation in children for chronic pancreatitis: indication, surgical techniques, postoperative management, and long-term outcomes. Ann Surg. 2014;260(1):56e64. https://doi.org/10.1097/SLA.0000000000000569. 24. Zureikat AH, Nguyen T, Boone BA, et al. Robotic total pancreatectomy with or without autologous islet cell transplantation: replication of an open technique through a minimal access approach. Surg Endosc. 2015;29(1):176e183. https:// doi.org/10.1007/s00464-014-3656-x. 25. Kneuertz PJ, Pitt HA, Bilimoria KY, et al. Risk of morbidity and mortality following hepato-pancreato-biliary surgery. J Gastrointest Surg. 2012;16(9): 1727e1735. https://doi.org/10.1007/s11605-012-1938-y. 26. Tamirisa NP, Parmar AD, Vargas GM, et al. Relative contributions of complications and failure to rescue on mortality in older patients undergoing pancreatectomy. Ann Surg. 2016;263(2):385e391. 27. Datta J, Lewis Jr RS, Strasberg SM, et al. Quantifying the burden of complications following total pancreatectomy using the postoperative morbidity index: a multi-institutional perspective. J Gastrointest Surg. 2015;19(3):506e515. https://doi.org/10.1007/s11605-014-2706-y. 28. Shahbazov R, Yoshimatsu G, Dabous A, et al. The characteristics of aborted procedures in total pancreatectomy with islet autotransplantation for chronic pancreatitis. Pancreas. 2017;46(9):e76ee78. https://doi.org/10.1097/ MPA.0000000000000908. 29. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240(2):205e213. https://doi.org/10.1097/ 01.sla.0000133083.54934 (ae). 30. Barton FB, Rickels MR, Alejandro R, et al. Improvement in outcomes of clinical islet transplantation: 1999-2010. Diabetes Care. 2012;35(7):1436e1445. https://doi.org/10.2337/dc12-0063. 31. Takita M, Matsumoto S, Noguchi H, et al. Adverse events in clinical islet transplantation: one institutional experience. Cell Transplant. 2012;21(2-3): 547e551. https://doi.org/10.3727/096368911X605466. 32. McEachron KR, Bellin MD. Total pancreatectomy and islet autotransplantion for chronic and recurrent acute pancreatitis. Curr Opin Gastroenterol. 2018 Sep;34(5):367e373. 33. Shahbazov R, Yoshimatsu G, Haque WZ, et al. Clinical effectiveness of a pylorus-preserving procedure on total pancreatectomy with islet autotransplantation. Am J Surg. 2017;213(6):1065e1071. https://doi.org/10.1016/ j.amjsurg.2016.09.051. 34. Caiazzo R, Vantyghem MC, Raverdi V, et al. Impact of procedure-related complications on long-term islet transplantation outcome. Transplantation. 2015;99(5):979e984.
Please cite this article as: Shahbazov R et al., The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.04.007
R. Shahbazov et al. / The American Journal of Surgery xxx (xxxx) xxx 35. Radomski M, Zureikat AH. Total pancreatectomy and islet cell autotransplantation: outcomes, controversies and new techniques. JOP. 2015;16(1): 1e10. https://doi.org/10.6092/1590-8577/2892. 36. Tai DS, Shen N, Szot GL, et al. Autologous islet transplantation with remote islet isolation after pancreas resection for chronic pancreatitis. JAMA Surg.
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2015;150(2):118e124. https://doi.org/10.1001/jamasurg.2014.932. 37. Kesseli SJ, Smith KA, Gardner TB. Total pancreatectomy with islet autologous transplantation: the cure for chronic pancreatitis? Clin Transl Gastroenterol. 2015;6(1):e73. https://doi.org/10.1038/ctg.2015.2.
Please cite this article as: Shahbazov R et al., The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.04.007
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The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation Rauf Shahbazov a, Bashoo Naziruddin b, *, Osmaan Salam c, Giovanna Saracino b, Marlon F. Levy d, Ernest Beecherl b, Nicholas Onaca b a
Department of Surgery, Division of Transplantation, Upstate Medical University, 750 E. Adams Street, Syracuse, NY, 13210, USA Baylor Annette C. and Harold C. Simmons Transplant Institute, 3410 Worth Street, Suite 950, Dallas, TX, 75246, USA Islet Cell Laboratory, Baylor Scott and White Research Institute, 3812 Elm Street, Dallas, TX, 75226, USA d Department of Surgery, Hume-Lee Transplant Center, VCU Health, 1250 East Marshall Street, Richmond, VA, 23298, USA b c
a r t i c l e i n f o
a b s t r a c t
Article history: Received 7 January 2019 Received in revised form 4 April 2019 Accepted 8 April 2019
Total pancreatectomy with islet autotransplantation is a promising treatment for refractory chronic pancreatitis. We analyzed postoperative complications in 83 TPIAT patients and their impact on islet graft function. We examined patient demographics, preoperative risk factors, intraoperative variables, and 30- and 90-day postoperative morbidity and mortality. Daily insulin requirement, HbA1c, C-peptide levels, and narcotic requirements were analyzed before and after surgery. Adverse events were recorded, with postoperative complications graded according to the Clavien-Dindo classification. There was no mortality in this patient group. Postoperative complications occurred in 38 patients (45.7%). Patients with postoperative complications were readmitted significantly more often within 30 days (p ¼ 0.01) and 90 days posttransplant (p < 0.0003) and had a significantly longer hospital stay (p ¼ 0.004) and intensive care unit stay (p ¼ 0.001). Insulin dependence and graft function assessed by HbA1c, C-Peptide and insulin requirements did not differ significantly by these complications. Postoperative complications after TPIAT are associated with longer hospital and intensive care unit stay and with readmission; however, the surgical complications do not affect islet graft function. © 2019 Published by Elsevier Inc.
Keywords: Total pancreatectomy Islet autotransplantation Chronic pancreatitis Surgical complications
Introduction Chronic pancreatitis (CP) is associated with irreversible morphological and functional abnormalities due to longstanding or recurrent inflammation and fibrosis of the pancreatic parenchyma.1,2 In most patients with CP, severe abdominal pain prompts them to seek further treatment options.3 The utilization of analgesia,4 nerve blocks, endoscopic decompression,5,6 surgical decompression of the main pancreatic duct, and partial resection of the pancreas are effective methods for early stages of this disease. However, these treatment options are not effective in all patients.7 Consequently, some patients whose medical and surgical
* Corresponding author. E-mail addresses: [email protected] (R. Shahbazov), bashoo.naziruddin@ bswhealth.org (B. Naziruddin), [email protected] (O. Salam), giovanna. [email protected] (G. Saracino), [email protected] (M.F. Levy), [email protected] (E. Beecherl), [email protected] (N. Onaca).
treatments have failed to achieve the desired relief are referred for total pancreatectomy (TP). Usually, these patients have significant impairments of quality of life due to pain8 as well as their need for narcotics. Although TP effectively eliminates pain9, it leads to surgically induced diabetes, which can have serious health consequences such as disabling episodes of hyperglycemia or hypoglycemia,10 increased morbidity and mortality, and target organ damage.11,12 TP with islet autotransplantation (TPIAT) has been shown to overcome this obstacle13 and retain pancreatic endocrine function, with patients either achieving insulin independence or requiring small doses of exogenous insulin to maintain normoglycemia.14e16 Moreover, usage of TPIAT as an early treatment option in the minimal-change CP group can be a costeffective strategy.17 Previous studies have tried to determine factors that predict successful outcomes following TPIAT. Some studies described body mass index,18 etiology of CP,19 severity of disease, duration of disease, previous pancreatic surgical procedure,20 transplanted tissue volume,21 and number and quality of islets22 as important factors
https://doi.org/10.1016/j.amjsurg.2019.04.007 0002-9610/© 2019 Published by Elsevier Inc.
Please cite this article as: Shahbazov R et al., The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.04.007
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for better graft function after TPIAT. Apart from insulin independence, these factors may contribute to both short-term and longterm quality of life following TPIAT.23 During the last decade, due to implementation of minimally invasive technologies, enhanced surgical techniques,24 and progressive preoperative care,25 immense improvements have been achieved in perioperative morbidity and mortality in pancreatic surgery. Additionally, the establishment of high-volume pancreatic centers with a focus on management of complications has given surgeons more confidence in offering aggressive treatment for CP. Although the outcome of TP procedures has improved, surgical complications still occur in the postoperative period.26 TP is a major abdominal procedure with high morbidity, ranging from 15% to 65%27din some cases resulting in abortion of the procedure.28 As postoperative complications can lead to an increase in inflammation or bacterial infections, they may influence islet engraftment by changing the microenvironment in the liver and activating immune reactions. Furthermore, complications could negatively impact islet cell function in the short- and long-term in TPIAT patients. To our knowledge, no studies have analyzed the effects of postoperative surgical complications in TPIAT patients. Here we describe the surgical complications of a large cohort of patients with TPIAT and their impact on short- and long-term outcomes. Materials and methods Patient selection This study was approved by the institutional review board. A prospectively maintained research database was queried to identify 83 consecutive patients who underwent TPIAT and completed a 1year follow-up evaluation. All patients with previously diagnosed CP were evaluated by a multidisciplinary team that included a gastroenterologist, an endocrinologist, and a transplant surgeon. The diagnosis of CP was based on the patient's history, laboratory results, computed tomographic scans, endoscopic retrograde
pancreatography, endoscopic ultrasonography, magnetic resonance imaging, and pathologic diagnosis. The indications for surgery were intractable pain despite previous medical and surgical intervention. Data extracted from the database included demographic characteristics, preoperative risk factors, intraoperative variables, and 30day postoperative morbidity and mortality as well as clinical and pathologic variables.
Operative procedure and islet cell transplantation TP was performed in all patients, including splenectomy with removal of the duodenum and distal common bile duct. During the surgery, the body and tail of the pancreas were mobilized first, with pancreatic blood supply being preserved as long as possible to minimize islet cell ischemia. The pancreas with attached tissue was removed and dissected free from the spleen and duodenum on the back table. After flushing through the arteries with University of Wisconsin solution, the pancreas duct was cannulated and placed in cold preservation solution and then transferred to a good manufacturing practice facility for further processing. Islet isolation was performed following the method previously described.22 Liberase MTF (Roche, Indianapolis, IN) or Collagenase NB with neutral proteases (SERVA Electrophoresis GMbH, Heidelberg, Germany) was infused into the main pancreatic duct for pancreas digestion. Islets were isolated by the modified Ricordi method, and when the tissue volume exceeded 20 mL, islets were purified using a COBE 2991 cell processor (Caridian BCT, Inc., Lakewood, CO) using a density-adjusted iodixanol-based continuous density gradient. Endotoxin tests, Gram staining, and bacterial and fungal cultures were performed on the final products and used as indicators of sterility. Isolated islets were infused into the portal vein via the mesenteric vein with heparin (70 U/kg body weight) while the patient was under general anesthesia. Portal pressures were routinely monitored during the islet infusion.
Table 1 Characteristics of 83 patients, with and without postoperative complications, undergoing total pancreatectomy and islet autotransplantation.a Characteristic
No complications (N ¼ 45)
Complications (N ¼ 38)
P value
Age (years) Male, n (%) Body mass index (kg/m2) Preoperative comorbidities Active tobacco use Alcohol abuse Weight loss of >10 kg History of ERCP and stent Previous surgery Previous pancreas surgery Previous abdominal surgery Chronic pulmonary disease Hypertension Diabetes Coronary artery disease Perioperative characteristics ASA grade 3 Estimated blood loss (mL) Intraoperative fluids (mL) Blood transfusion Length of stay (days) ICU length of stay (days) Postoperative characteristics Narcotic requirement at 1 year 30-day hospital readmission 90-day hospital readmission
42 (31, 50) 13 (28.9%) 26.8 (22.3, 30.2)
38 (30, 48) 13 (34.2%) 26.5 (21.5, 29.8)
0.593 0.641 0.818
18 (40.0%) 9 (20.0%) 7 (15.6%) 18 (40.0%) 39 (86.7%) 7 (15.6%) 24 (53.3%) 2 (4.4%) 17 (37.8%) 26 (57.8%) 1 (2.2%)
11 (28.9%) 11 (28.9%) 5 (13.2%) 16 (42.1%) 36 (94.7%) 4 (10.5%) 23 (60.5%) 1 (2.6%) 13 (34.2%) 17 (44.7%) 2 (5.3%)
0.358 0.441 1.000 1.000 0.279 0.538 0.657 1.000 0.820 0.275 0.591
4 (91.1%) 500 (300, 700) 4500 (4000, 5600) 16 (35.6%) 11.0 (9.0, 13.0) 1.0 (1.0, 2.0)
2 (5.3%) 500 (350, 1000) 5000 (4000, 5500) 18 (47.4%) 12.0 (11.0, 19.0) 2.0 (1.0, 2.0)
0.198 0.278 0.220 0.371 0.004 0.001
15 (33.3%) 6 (13.3%) 16 (35.6%)
15 (39.5%) 15 (39.5%) 29 (76.3%)
0.649 0.010 0.0003
ASA indicates American Society of Anesthesiologists score; ERCP, endoscopic retrograde cholangiopancreatography; ICU, intensive care unit. a Data are presented as the median value (25th, 75th percentiles) or n (%) of patients.
Please cite this article as: Shahbazov R et al., The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.04.007
R. Shahbazov et al. / The American Journal of Surgery xxx (xxxx) xxx Table 2 Postoperative complications in 83 patients undergoing of total pancreatectomy and islet autotransplantation.a Complications
N (%)
Overall complications Islet transplanterelated complications Portal vein thrombosis High portal pressure (>25 mm H2O) Fatty liver (heavy) TP surgeryerelated complications Perioperative bleeding Delayed gastric emptying Deep SSI Organ space SSI Superficial SSI Postoperative sepsis Septic shock Wound disruption Deep vein thrombosis Urinary tract infection Postoperative pneumonia
51 (100%) 9 (17.6) 2 (3.9%) 4 (7.8%) 3 (5.9%) 42 (82.4) 3 (5.9%) 12 (23.5%) 2 (3.9%) 1 (2.0%) 6 (11.8%) 5 (9.8%) 1 (2.0%) 4 (7.8%) 4 (7.8%) 3 (5.9%) 1 (2.0%)
TP indicates total pancreatectomy; SSI, surgical site infection. a Thirty-eight patients had a total of 51 complications.
Postoperative care All patients were monitored and examined in the intensive care unit (ICU) after surgery for a short period of time with intensive insulin therapy as well as strict blood glucose control (serum levels <120 mg/dL). Patients were converted to a basal bolus insulin regimen starting on postoperative day 3. All patients were discharged home with an individualized insulin regimen. The patient's portal vein flow was assessed by Doppler sonogram before and after surgical intervention. Lack of detection of portal flow by Doppler sonogram was considered as portal vein thrombosis. Longterm postoperative care was provided by the transplant surgeon and endocrinologists, who assessed improvement of clinical symptoms. Outcomes The average daily insulin requirement, HbA1c level, and Cpeptide level were measured before surgery, at hospital discharge,
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and at each subsequent postoperative patient encounter. Postoperative C-peptide levels were measured after fasting at 3, 6, and 12 months. Patients with a detectable C-peptide value (>0.3 ng/mL) were considered C-peptide positive. Graft function was measured from date of infusion to complete graft failure (first occurrence of Cpeptide <0.3 ng/mL). First achievement of insulin independence was measured from islet infusion to last follow-up or graft loss. Narcotic requirements were reported as morphine-equivalent quantity per day (MEQ/d) calculated from narcotic conversion software (Narcotic Converter; GlobalRPh Inc). Complications We included all adverse effects following the Common Terminology Criteria for Adverse Effects in Trials of Adult Pancreatic Islet Transplantation (version 4.0, May 2007) and graded postoperative complications on a scale of 1e4. Overall, a postoperative complication was defined as one or more of the following: delayed gastric emptying, any surgical site infection, postoperative sepsis or septic shock, wound disruption, urinary tract infection, acute renal failure, progressive renal insufficiency, postoperative pneumonia, postoperative ventilator dependency, need for cardiopulmonary resuscitation, postoperative myocardial infarction, postoperative stroke or coma, pulmonary embolism, deep venous thrombosis, and reoperation within 30 days of admission.27 Postpancreatectomy complications were graded according to the Clavien-Dindo classification.29 Statistical analysis The Wilcoxon two-sample test was used to compare continuous variables. Categorical variables were compared using the two-sided Fisher's exact test and expressed as median with interquartile ranges. Categorical variables are expressed as counts with percentages, and continuous variables as medians with interquartile ranges or means and standard deviations, as appropriate. A p value of 0.05 was considered statistically significant. Each clinical outcome measured over time was analyzed using linear and mixed regression models. This method allows the analysis of longitudinal data with multiple measurements taken on each subject by
Fig. 1. Etiology of chronic pancreatitis among total pancreatectomy and islet autotransplantation patients with no complications group (NC) and complications group (C).
Please cite this article as: Shahbazov R et al., The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.04.007
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Table 3 Pancreatic islet and transplant characteristics of 83 patients, with and without postoperative complications, undergoing total pancreatectomy and islet autotransplantation.a Characteristic
No complications (N ¼ 45)
Complications (N ¼ 38)
p value
Duration of pancreatectomy (h) Operative time (hours) Pancreas weight (g) Islet yield Pellet volume Purity (%) Viability (%) Portal pressure change (mm Hg)
4.1 (3.5, 5.4) 10.6 (9.3, 11.4) 86.3 (78.7, 101.4) 4,951 (2541, 6179) 9.5 (5.0, 13.0) 50.0 (30.0, 60.0) 96.6 (95.4, 97.7) 5.0 (2.0,8.0)
4.4 (3.5, 5.0) 10.5 (9.9, 11.9) 78.1 (58.9, 99.4) 5,210 (3138, 6376) 10.0 (3.0, 15.0) 55.0 (30.0, 100.0) 96.4 (92.2, 99.0) 5.5 (3.0, 10.0)
0.540 0.473 0.0035 0.487 0.617 0.568 0.441 0.568
a
Data are presented as the median value (25th, 75th percentiles).
examining not only differences between subjects, but also changes within subjects across time. Time-to-event variables were analyzed using Kaplan-Meier curves and compared using the log-rank test. All analyses were performed using SAS 9.3 (SAS Institute, Cary, NC).
with increased rate of hospital readmission, and hospital and ICU length of stay. The most common reported complications due to islet infusion
Results As shown in Table 1, there were no significant differences in age, body mass index, CP etiology, preoperative comorbidities, estimated blood loss, intraoperative fluid, or blood transfusion between TPIAT patients who had and did not have complications. However, readmission rates for 30 days and 90 days were higher in patients with complications than in patients with no complications (p ¼ 0.010 and 0.0003, respectively). Similarly, length of hospital stay and ICU stay were longer in patients with complications (p ¼ 0.004 and 0.001, respectively). There were no 30-day or 90-day postoperative deaths. A total of 51 severe surgical complications occurred in 38 of 83 patients (45.7%) (Table 2). Islet transfusionerelated complications occurred in a relatively small percentage of patients, with portal vein thrombosis (3.9%), high portal pressure (7.8%) and fatty liver (5.9%) notable among the total number of complications. Delayed gastric emptying (23.5%) followed by surgical infections (17.7%) were the most common surgery related complication. Only 16 patients with complications required surgical treatment (see Fig. 1). The only significantly different islet graft or infusion characteristic between patients who did and did not have complications was a higher pancreas weight in patients with no complications (86.3 vs. 78.1 g, p ¼ 0.0035) (Table 3). Primary graft function was not significantly affected by postsurgical complications (Fig. 2). Patient insulin requirements were similar at 1, 3, 6, and 12 months in the complication and noncomplication groups. Kaplan-Meier curves, censored at 1-year follow-up, depicted the probability of graft survival and insulin independence (Fig. 3); log rank test results showed no difference in graft survival and insulin independence between patients in the complication and noncomplication groups. Interestingly, patients without complications had a slightly higher pain score than patients with complications (Fig. 4a). Those with complications did receive more narcotics than those without complications, but the difference was not statistically significant (Fig. 4b). Discussion It has been reported that the incidence of adverse events reaches 38% after islet transplantation.30,31,32 Postoperative complications after TP can be higher, varying from 15% to 65%.27 In our cohort, the overall major complication rate for TPIAT recipients was 45.7%, within the reported range. While our study did not show an association between postoperative complications in TPIAT patients and decreased islet graft function, complications were associated
Fig. 2. Posttransplant graft function of islets for the no complication group (NC; n ¼ 45) and complication group (C; n ¼ 38): (a) hemoglobin A1c level, (b) C-peptide level, and (c) insulin requirements.
Please cite this article as: Shahbazov R et al., The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.04.007
R. Shahbazov et al. / The American Journal of Surgery xxx (xxxx) xxx
Fig. 3. (a) Graft survival and (b) insulin independence among total pancreatectomy and islet autotransplantation patients with no complications (NC, red, n ¼ 45) and complications (C, blue, n ¼ 38). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
include a transient increase in liver enzymes and portal vein thrombosis, but complications related to TP are far more severe and diverse in terms of glycemic control.32 They include delayed gastric emptying, surgical site infection, postoperative sepsis or septic shock, wound disruption, urinary tract infection, and acute renal failure. Furthermore, progressive renal insufficiency, postoperative pneumonia, postoperative myocardial infarction, postoperative stroke or coma, pulmonary embolism, and deep venous thrombosis have also been reported. In our case series, portal vein thrombosis developed in 2 patients (4.3%). First patient had previous several attack of severe pancreatitis. Second patient had previous pancreas surgery. Therefore, their total pancreatectomy procedure was challenging. Isolated islets are infused along with heparin (70 U/kg body weight) into the portal vein via a branch of the superior mesenteric vein. Portal pressures are routinely monitored during the islet infusion at every 5 min. When the portal pressure exceeds 22 mmHg, the infusion is halted and rest of the islets infused intraperitoneally. All patients had their portal vein assessed by duplex imaging before and after the surgical intervention on day 1, 3 and 5. Portal vein thrombosis was detected in one patient on postoperative day 1 and second patient on day 3 during routine duplex scanning. Both the patients were managed conservatively. Heparin infusion was started to achieve therapeutic level. After 36 h of heparin, patients were transitioned to low molecular weight heparin (LMWH) for 14 days. Then the patients were converted to aspirin 81 mg daily indefinitely with normal outcome.
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Fig. 4. (a) Pain score and (b) narcotic requirements among total pancreatectomy and islet autotransplantation patients with no complications (NC, blue, n ¼ 45) and complications (C, green, n ¼ 38). (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
Delayed gastric emptying (DGE) developed in 12 (23.5%) patients. Etiologies of DGE are multifactorial. Type of surgical procedure, chronic use of opioids, and duration of surgical procedure could be contributing factors for DGE. Our previous study has shown that the incidence of DGE was nearly identical between the pylorus preservation (PP) and non-pylorus preservation NPP groups (21.1% and 18.8%, respectively; P ¼ 1.00).33 In addition, in TPIAT, the portal vein pressure increased due to the islet infusion. High portal vein pressure could slow down gastro-intestinal function. It is important to note that all of the patients underwent splenectomy, which should reduce the volume of the portal vein flow. It believed that altered portal vein system can to suppress the patient's gastrointestinal peristalsis. We believe further studies necessary to prove it. We managed all patients with DGE with conservative measures using prokinetic medications such as metoclopramide and low dose erythromycin. Postoperative complications increase the body's systemic inflammatory reaction, and bacterial translocation after postoperative complications could also lead to production of acute stress protein in the liver. This microenvironment variation could influence islet engraftment. As islet allotransplantation is associated with more severe nonspecific and specific immune reactions than autotransplantation, complications could have different effects. Caiazzo et al. reported that complications had a negative impact on islet function after allotransplantation for the treatment of type 1 diabetes mellitus,34 whereas we did not find a significant difference in graft function between groups with and without surgical complications. A further explanation is that in islet autotransplantation, there is less of an immune response in the liver
Please cite this article as: Shahbazov R et al., The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.04.007
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sinusoids. TPIAT has made considerable progress in recent years,35 with developments in pancreas procurement and processing, innovations in islet isolation technology, and improved postoperative patient care.36 Several transplant centers have reported successful clinical outcomes with a high rate of insulin independence after TPIAT, demonstrating the potential for the procedure to serve as a safe and effective therapy for patients with CP.37 Even without the complications affecting graft function, the safety of the procedure could be improved by decreasing the complication rate. Our study did not examine how surgical complications affected patients’ quality of life, and further studies are needed to understand the full effect of complications on TPIAT patients. It is imperative that stringent measures be implemented to prevent the occurrence of postoperative complications, including even more comprehensive patient follow-up. Conflicts of interest All the authors declare no conflict of interest with the contents presented in this manuscript. Acknowledgments The authors thank Ms. Sharon Bruer and Ms. Ana M. Rahman for technical support. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.amjsurg.2019.04.007. Disclosure The authors declare no conflicts of interest. References 1. Muniraj T, Aslanian HR, Farrell J, Jamidar PA. Chronic pancreatitis, a comprehensive review and update. Part I: epidemiology, etiology, risk factors, genetics, pathophysiology, and clinical features. Dis Mon. 2014;60(12):530e550. https:// doi.org/10.1016/j.disamonth.2014.11.002. 2. Kanak MA, Shahbazov R, Yoshimatsu G, Levy MF, Lawrence MC, Naziruddin B. A small molecule inhibitor of NFkB blocks ER stress and the NLRP3 inflammasome and prevents progression of pancreatitis. J Gastroenterol. 2017;52(3): 352e365. https://doi.org/10.1007/s00535-016-1238-5. 3. Bouwense SA, de Vries M, Schreuder LT, et al. Systematic mechanismorientated approach to chronic pancreatitis pain. World J Gastroenterol. 2015;21(1):47e59. https://doi.org/10.3748/wjg.v21.i1.47. 4. Chauhan S, Forsmark CE. Pain management in chronic pancreatitis: a treatment algorithm. Best Pract Res Clin Gastroenterol. 2010;24(3):323e335. https:// doi.org/10.1016/j.bpg.2010.03.007. €ki C, Kyla €npa €€ 5. Haapama a L, Udd M, et al. Randomized multicenter study of multiple plastic stents vs. covered self-expandable metallic stent in the treatment of biliary stricture in chronic pancreatitis. Endoscopy. 2015;47(7): 605e610. https://doi.org/10.1055/s-0034-1391331. 6. Seicean A, Vultur S. Endoscopic therapy in chronic pancreatitis: current perspectives. Clin Exp Gastroenterol. 2014;8:1e11. https://doi.org/10.2147/ CEG.S43096. 7. Hoffmeister A, Mayerle J, Beglinger C, et al. Chronic Pancreatitis German Society of Digestive and Metabolic Diseases (DGVS). S3-Consensus guidelines on definition, etiology, diagnosis and medical, endoscopic and surgical management of chronic pancreatitis. Z Gastroenterol. 2012;50(11):1176e1224. https:// doi.org/10.1055/s-0032-1325479. 8. Olesen SS, Juel J, Nielsen AK, Frøkjær JB, Wilder-Smith OH, Drewes AM. Pain severity reduces life quality in chronic pancreatitis: implications for design of future outcome trials. Pancreatology. 2014;14(6):497e502. https://doi.org/ 10.1016/j.pan.2014.09.009. 9. Murphy MM, Knaus II WJ, Ng SC, et al. Total pancreatectomy: a national study. HPB. 2009;11(6):476e482. https://doi.org/10.1111/j.1477-2574.2009.00076.x. 10. Burkhart RA, Gerber SM, Tholey RM, et al. Incidence and severity of pancreatogenic diabetes after pancreatic resection. J Gastrointest Surg. 2015;19(2): 217e225. https://doi.org/10.1007/s11605-014-2669-z.
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Please cite this article as: Shahbazov R et al., The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation, The American Journal of Surgery, https://doi.org/10.1016/j.amjsurg.2019.04.007