- Email: [email protected]
Natural course of low output external pancreatic fistula in patients with disconnected pancreatic duct syndrome following acute necrotising pancreatitis
Journal Pre-proof Natural course of low output external pancreatic fistula in patients with disconnected pancreatic duct syndrome following acute necrotising pancreatitis Surinder Singh Rana, Ravi Sharma, Mandeep Kang, Rajesh Gupta PII:
S1424-3903(19)30808-7
DOI:
https://doi.org/10.1016/j.pan.2019.12.011
Reference:
PAN 1137
To appear in:
Pancreatology
Received Date: 12 September 2019 Revised Date:
16 October 2019
Accepted Date: 14 December 2019
Please cite this article as: Rana SS, Sharma R, Kang M, Gupta R, Natural course of low output external pancreatic fistula in patients with disconnected pancreatic duct syndrome following acute necrotising pancreatitis, Pancreatology (2020), doi: https://doi.org/10.1016/j.pan.2019.12.011. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V. on behalf of IAP and EPC.
Natural Course of Low Output External Pancreatic Fistula in Patients with Disconnected Pancreatic Duct Syndrome Following Acute Necrotising Pancreatitis
Surinder Singh Rana, MD, D.M Ravi Sharma, MSc Mandeep Kang, MD* Rajesh Gupta, MCh** Departments of Gastroenterology, Radiodiagnosis* and Surgery**, Post Graduate Institute of Medical Education and Research (PGIMER), Sector 12, Chandigarh – 160012, India There are no conflicts of interest and no financial disclosures to be made by any of the authors Presented at Digestive Disease Week 2019 at San Diego, USA Declarations of interest: None Author Contributions: 1. Surinder Singh Rana: Design, Collection and interpretation of data, drafting of manuscript 2. Ravi Sharma: Collection and interpretation of data 3. Mandeep Kang: Collection and interpretation of data 4. Rajesh Gupta: Collection and interpretation of data Conflicts of Interest: 1. Surinder Singh Rana: None 2. Ravi Sharma: None 3. Mandeep Kang: None 4. Rajesh Gupta: None Corresponding Author: 1
Dr Surinder Singh Rana Professor, Department of Gastroenterology PGIMER, Chandigarh – 160 012, India Tel: +91-172-2971605 Fax: +91-172-2744401 E-mail: [email protected]
2
Abstract Background: External pancreatic fistulae (EPF) associated with complete pancreatic duct (PD) disruption leading on to disconnected pancreatic duct syndrome (DPDS) is a therapeutic nightmare usually requiring surgery. However, spontaneous closure also has been reported. There is paucity of data on the natural history of EPF associated with DPDS. Objective: To retrospectively study outcome of conservative treatment in patients with low output (<200ml/day) EPF with DPDS following percutaneous or surgical intervention in acute necrotising pancreatitis (ANP). Methods: The data of patients of low output EPF with DPDS treated conservatively in our unit over last 5 years was retrospectively analysed. Their clinical course, complications as well as time taken for fistula closure was retrieved. Results: 33 patients (27 males; mean age: 40.5 ±9.3 years) of low output EPF and DPDS were studied. 31 patients developed EPF following percutaneous drainage (PCD) and 2 patients developed fistula following surgery. The drain fluid amylase ranged from 1600 to 32,000 IU/l and site of disruption was neck, proximal body and distal body in 4, 16 and 13 patients respectively. EPF closed spontaneously in all patients within 88.2 ± 63.46 days. PCD slipped out in 2 patients and led to formation of pseudocyst in 1 patient that was treated endoscopically. There has been no recurrence in any patient over follow up of 32.5 ± 21.9 months. Conclusion: Low output EPF developing post PCD or surgery in patients with DPDS following ANP closely spontaneously in majority of patients within 3 months with good long term outcome. Key words: acute pancreatitis; disconnected pancreatic duct syndrome; stent; fistula; Endosonography; magnetic resonance cholangiopancreatography
3
Introduction External pancreatic fistula (EPF) is characterised by leakage of pancreatic juice externally through the cutaneous site. This seepage of pancreatic juice occurs due to the disruption of pancreatic duct (PD).1 EPF can cause significant morbidity due to malnutrition consequent to external leakage of protein rich pancreatic juice as well as increased risk of skin excoriation and infection. The EPF have been traditionally classified as low output (<200 ml/day) and high output (>200 ml/day) EPF.2 The traditional management of EPF has been conservative treatment including nutritional support with attempts to reduce pancreatic secretions by either total parenteral nutrition or octreotide. Non-responders were usually treated with surgery.1,3,4 Recently, endoscopic transpapillary drainage has been developed as an effective and minimally invasive therapeutic alternative to surgery for management of EPF.1,4,5 It leads to closure of EPF in majority of patients if there is a partial disruption of the PD that can be bridged by endoprosthesis. However, endoscopic transpapillary drainage is usually not effective in patients with complete PD disruption.6 Complete PD disruption with presence of functional pancreas upstream to disruption leads on to disconnected pancreatic duct syndrome (DPDS).1,6 EPF with DPDS are difficult to manage because the disconnected pancreas continue to pour pancreatic juice through low resistance EPF and usually necessitates surgery.1,6 Sepsis, infection, electrolyte disturbances, malnutrition and infections are usually seen in patients with high output EPF with DPDS and therefore interventional treatment is recommended for managing these patients.3,4,7 However, these complications are less frequently reported in patients with low output EPF even with associated DPDS.1,8 Moreover, spontaneous closure of low output EPF in setting of
4
DPDS has also been occasionally reported.9 However, there is scanty data on the natural clinical course of low output EPF with DPDS. In this retrospective study, we have evaluated the natural clinical course of low output EPF developing post percutaneous or surgical intervention in acute necrotising pancreatitis (ANP) and associated with DPDS by studying the outcome and complications of conservative non-interventional treatment in them.
5
Patients and Methods The prospectively maintained database of patients with ANP seen over last five years at a pancreatology unit in a tertiary care hospital in north India was retrospectively searched to retrieve data of patients with low output EPF (<200 ml/day) and DPDS. The EPF was defined as external drainage of >50 ml/day of amylase rich fluid (more than three times the serum value) for more than 7 days.8 The
diagnosis
of
DPDS
cholangiopancreatography
was
confirmed
(MRCP)
or
on
magnetic
endoscopic
resonance retrograde
cholangiopancreatography (ERCP). On ERCP, DPDS was defined as either a cut off or blowout of main PD with inability to demonstrate upstream PD on pancreatogram.1,5,10 On MRCP, DPDS was defined as dilated upstream PD with a disconnected segment of pancreas downstream to dilated PD. During the last five years, the patients with low output EPF with co-existent DPDS and without co-existent pancreatic fluid collection that could be drained endoscopically were given an option of interventional treatment including surgery or complex
endoscopic
interventional
procedures
or
conservative
expectant
management. The data base of patient opting for conservative treatment was retrieved and analysed. Follow up protocol of Patients with low output EPF These patients were initially followed in the outpatient department every two weekly for first eight weeks. Thereafter, they were followed every four weekly till resolution or complication necessitating intervention. These patients were instructed to record the daily fistula output and report in the clinic if output ceases or any complication
6
arises. During the outpatient visit, patient’s body weight was recorded and serum albumin was measured every 4 weeks. None of the patients were given octreotide or total parenteral nutrition. The patients were taught catheter care and advised regular dressing at home. They were advised normal oral diet with protease rich pancreatic enzyme supplements. No other pharmacotherapy except antibiotics in patients with purulent output were given. Outcome definitions: Successful Closure of EPF: Defined as closure of EPF with removal of percutaneous drainage (PCD) and complete cessation of drainage of pancreatic juice from cutaneous site without resorting to surgery. Major complication: Any complication requiring surgery or interventional treatment for management of EPF.
7
Results Over a period of 5 years, 46 patients with low output EPF with associated DPDS were seen in our unit. Thirteen of these 46 patients were excluded as 4 patients underwent surgical closure of EPF, 6 patients underwent EUS guided internalisation of EPF, and 3 patients were lost to follow up. The endoscopic or surgical intervention was done after 6 to 8 weeks of per-cutaneous intervention. Finally, 33 patients (27 males; mean age: 40.5 ±9.3 years) of low output EPF with associated DPDS were studied (Table 1). All these patients had underlying ANP with 15 (45%) patients having >50% parenchymal necrosis. Of 33 patients, only 4 patients had concurrent DPDS (patients who presented with severe acute necrotizing pancreatitis that resulted in complete disruption of the pancreatic duct such that the head of the gland was not in continuity with a viable pancreatic body or tail) and 29 patients had delayed DPDS ( treated for an index episode of ANP in which pancreatic duct disruption was not recognized or apparent at imaging done during first admission). The etiology of ANP was alcohol in 17, gall stones in 10, post ERCP in 1, drug induced in 1 and idiopathic in 4 patients respectively. 31 patients developed EPF following percutaneous drainage PCD (single PCD in 26 patients and multiple PCD in 5 patients). Surgical necrosectomy led on to development of EPF in 2 patients. The drain fluid amylase ranged from 1600 to 32,000 IU/l. DPDS was confirmed on MRCP in 24 patients and ERCP in 9 patients. The site of disconnection was neck, proximal body and distal body in 4, 16 and 13 patients respectively (Fig 1). The daily fistula output ranged from 60 ml to 190 ml per day. The fistula output was clear in 25 patients and purulent in 8 patients. The patients with purulent output received antibiotics as per the sensitivity pattern. No endoscopic intervention was done in any patient. 8
The EPF closed spontaneously in all patients within 88.2 ± 63.46 days (range 29-292 days). No infective complication because of prolonged external drainage was observed in any patient. The PCD slipped out in 2 patients, 6 weeks and 22 weeks respectively, after the formation of EPF. The dislodgement of PCD at 6 weeks led on to formation of symptomatic pseudocyst that was treated endoscopically. No immediate or delayed symptoms of slippage were observed in the other patient with dislodgement at 22 weeks. There was no infective complication in any patient during the follow up. Twenty nine patients gained weight from the time period of first contact to closure of EPF. Four patients lost weight during the follow up (3,5,2,and 6Kg respectively) and all of them had developed diabetes and were on insulin. The median serum albumin level increased from 2.9 g/dl to 3.8 g/dl from the time period of first contact to closure of EPF. There has been no recurrence of EPF or fluid collection in any patient over follow up of 32.5 ± 21.9 months. Two patients had abdominal pain 4 months and 11 months after removal of PCD. The pain responded to oral analgesics, did not require hospitalisation, was not accompanied with elevation of pancreatic enzymes and did not require intervention. Long term follow up of patients who underwent intervention versus patients treated conservatively Ten patients (7 males) were treated at the outset with endoscopic or surgical intervention whereas 33 patients (27 males) were treated with conservative expectant management. None of the patients in either group had recurrence of EPF or any fluid collection. Three of 10 (30%) patients in intervention group whereas 9
9
/33 (27%) patients treated conservatively developed diabetes (p>0.05). None of the patients in either group developed steatorrhea.
10
Discussion EPF is an important consequence of percutaneous drainage of pancreatic fluid collections in ANP. They are usually formed due to DPDS with disconnected segment of pancreas continuing to secrete protein rich pancreatic juice. These difficult to treat EPF are not amenable to endoscopic transpapillary drainage because of inability to bridge the complete PD disruption by endoprosthesis. Therefore, EPF in the setting of DPDS is usually treated by surgery that has associated significant morbidity and occasional mortality. Recently, there have been reports of successful closure of complex EPF by use of complex endoscopic ultrasound (EUS) procedures including EUS guided transmural placement of stent in the PCD tract or PD in the disconnected pancreatic segment in order to internalise the pancreatic drainage.10–12 However, these are complex procedures available in selected tertiary care centres, are costly, have potential of serious complications and the long term consequences of transmural stents are not clear. Studies have shown that up to 75% of EPS close spontaneously without any intervention.2,8,13–15 However, the natural course of EPF in the setting of DPDS has not been adequately studied and there is paucity of data on the role of conservative treatment in management of EPF with DPDS. Limited data have suggested that EPF in the setting of DPDS does not close spontaneously and usually require endoscopic or surgical intervention for closure. In the current study we have shown that low output EPF in the setting of DPDS closes spontaneously without intervention in majority of patients within 3 months. Sikora et al studied 43 patients with EPF that developed following radiological or surgical interventions of infective complications of ANP.8 They reported that 88% of these patients had spontaneous closure of EPF within 109 ± 26 days. They also
11
attempted to identify the factors that could determine delayed closure of EPF but found that none of the factors including etiology of pancreatitis, extent of pancreatic necrosis, interval between onset and intervention, nature of intervention, presence of enteric fistula, amount of fistula output and use of octreotide, were significantly different in patients with either early or delayed closure of fistulae. However, they did not evaluate the pancreatic duct anatomy in their study. Howard et al studied 38 patients with EPF that developed after percutaneous or surgical intervention in acute or chronic pancreatitis or after pancreatectomy.2 They classified the EPF into three categories depending upon the underlying pancreatic disease as well as the PD anatomy: operative side fistulae following surgery, inflammatory side fistulae following acute or chronic pancreatitis and end fistulae having disconnected pancreatic duct. They reported that EPF closed spontaneously in 86% and 53% patients in operative side fistulae and inflammatory side fistulae respectively within mean time period of 11 and 22 weeks respectively. However, none of the EPF in end fistulae group closed spontaneously. Spontaneous closure in partial PD disruptions occur because of resolution of necrosis, fibrosis and healing of duct disruption.8,16 In setting of DPDS, the spontaneous closure of EPF occurs, possibly because of cessation of significant pancreatic juice secretion of disconnected pancreatic segment consequent to gradual acinar cell atrophy.6,17 This acinar cell atrophy is variable and will not happen in all patients with DPDS. It seems that patient with low output EPF had already significant pre-existent necrosis of the disconnected segment of pancreas due to ANP. Therefore, the EPF closed spontaneously in these patients due to atrophy of small amount of left over residual acinar cell volume in the disconnected segment of pancreas over next 3-6 months.
12
The appropriate time of intervention in EPF, especially following ANP, is debatable. The safety and efficacy of minimally invasive endoscopic transpapillary drainage in EPF has led on to advocacy of early endoscopic intervention in these patients.
1,4,5
Minimal invasiveness and excellent results of endoscopic transpapillary drainage coupled with risk of malnutrition and infection along with poor quality of life with prolonged external catheter drainage has led on to experts recommending early endoscopic intervention in patients with EPF.1,12 However, EPF with DPDS are a difficult management dilemma as endoscopic transpapillary drainage is ineffective. This condition requires complex endoscopic ultrasound interventions that are not widely available and are associated with significant complications. Therefore, alternative treatment options need to be explored for this difficult to treat condition. Our observation that majority of these low output EPF in DPDS close spontaneously within 3 months in majority of patients suggest that conservative expectant treatment of prolonged external drainage is a safe and effective management option. The low output EPF are not associated with metabolic, nutritional or electrolyte disturbances and similar was our observation also.8,13,14 Therefore, there is no risk of significant complication of prolonged expectant treatment till there is an unimpeded drainage of the fistula. Another presumed advantage of early intervention is prevention of endocrine or exocrine insufficiency by preserving the pancreatic function of the disconnected segment of pancreas. However, in our study there was no difference in the endocrine or exocrine insufficiency in patients who underwent early endoscopic or surgical intervention versus patients who were treated conservatively. An important question in such patients is to continue conservative treatment for how long? Expectant conservative treatment of prolonged external drainage up to 1 year, especially in patients with daily fistula output of <500 ml/day has been
13
suggested.2,13,14 Sikora et also reported that two third patients with EPF had low output fistulae and did not have any nutritional or skin problems and could be easily managed by patients at home.8 We feel that the timing of intervention should be decided upon various factors including the availability of experienced therapeutic endoscopic team, output of fistula, anatomy of pancreatic duct and risk of infective/nutritional complication of prolonged external drainage of pancreatic juice. Our results suggests that patients with low output EPF and DPDS should be managed conservatively initially for a period of 3 months as majority of them would close by then. Also, patients having a decreasing trend of EPF output can also be managed conservatively beyond three months as all out patients had their EPF closure within 292 days. Intervention is needed if the fistula continues to pour same or increased amount of pancreatic juice beyond three months, when there are associated infective or hemorrhagic complications or management of external drains become difficult due to high output, skin problems or poor quality of life. Our study has few important limitations. It was a single centre retrospective study with a sample size of 33 patients. Moreover, we did not assess the quality of life in these patients with prolonged catheter drainage. In conclusion, low output EPF developing post PCD or surgery in patients with DPDS following ANP closely spontaneously in majority of patients within 3 months with good long term outcome.
14
References:
1. Varadarajulu S, Rana SS, Bhasin DK. Endoscopic therapy for pancreatic duct leaks and disruptions. Gastrointest Endosc Clin N Am 2013;23:863-892. 2. Howard TJ, Stonerock CE, Sarkar J, et al. Contemporary treatment strategies for external pancreatic fistulas. Surgery 1998;124:627-632; discussion 632-633. 3. Kozarek RA, Traverso LW. Pancreatic fistulas: etiology, consequences, and treatment. Gastroenterologist 1996;4:238-244. 4. Larsen M, Kozarek R. Management of pancreatic ductal leaks and fistulae. J Gastroenterol Hepatol 2014;29:1360-1370. 5. Rana SS, Bhasin DK, Nanda M, et al. Endoscopic transpapillary drainage for external fistulas developing after surgical or radiological pancreatic interventions. J Gastroenterol Hepatol 2010;25:1087-1092. 6. Larsen M, Kozarek RA. Management of Disconnected Pancreatic Duct Syndrome. Curr Treat Options Gastroenterol 2016;14:348-359. 7. Smits FJ, van Santvoort HC, Besselink MG, et al. Management of Severe Pancreatic Fistula After Pancreatoduodenectomy. JAMA Surg 2017;152:540548. 8. Sikora SS, Khare R, Srikanth G, et al. External pancreatic fistula as a sequel to management of acute severe necrotizing pancreatitis. Dig Surg 2005;22:446451; discussion 452. 9. Saadia R. Fistulas of the Pancreas. Zuckschwerdt, 2001. https://www.ncbi.nlm.nih.gov/books/NBK7003/. Accessed August 31, 2019. 10.
Rana SS, Sharma R, Gupta R. Endoscopic treatment of refractory external pancreatic fistulae with disconnected pancreatic duct syndrome. Pancreatology 2019;19:608-613.
11.
Irani S, Gluck M, Ross A, et al. Resolving external pancreatic fistulas in patients with disconnected pancreatic duct syndrome: using rendezvous techniques to avoid surgery (with video). Gastrointest Endosc 2012;76:586593.e1-3.
12.
Baron TH, Kozarek RA. Nonoperative Management of Pancreatic Fistula: Why Not an Endoscopic Approach? JAMA Surg 2018;153:94.
13.
Ho HS, Frey CF. Gastrointestinal and pancreatic complications associated with severe pancreatitis. Arch Surg 1995;130:817-822; discussion 822-823.
15
14.
Tsiotos GG, Smith CD, Sarr MG. Incidence and management of pancreatic and enteric fistulas after surgical management of severe necrotizing pancreatitis. Arch Surg 1995;130:48-52.
15.
Fielding GA, McLatchie GR, Wilson C, et al. Acute pancreatitis and pancreatic fistula formation. Br J Surg 1989;76:1126-1128.
16.
Bassi C, Vesentini S, Pederzoli P, eds. Pancreatic Fistulas. Berlin Heidelberg: Springer-Verlag, 1992. https://www.springer.com/gp/book/9783540553380. Accessed September 1, 2019.
17.
Sandrasegaran K, Tann M, Jennings SG, et al. Disconnection of the pancreatic duct: an important but overlooked complication of severe acute pancreatitis. Radiographics 2007;27:1389-1400.
16
Legends for the figures: Fig 1a: Computed tomography done at day 5 of onset of pain: Patient with acute emphysematous pancreatitis having necrosis and air in the body of pancreas Fig 1b: Computed tomography post drainage of acute necrotic collection. Percutaneous drainage catheter is seen. Fig 1c: Magnetic resonance imaging (MRI) done at 6 weeks showing a mature EPF tract (arrow). Fig 1d: MRI at 3 months showing disconnected segment of pancreas (arrow) with dilated main pancreatic duct. Fig 1e: MRCP shows disconnection in body of pancreas (arrows) with dilated upstream pancreatic duct. Fig 1f: MRI after closure of EPF (at 10 months) shows dilated main pancreatic duct in disconnected segment. On comparing with MRI at 6 weeks (Fig 1c) and 3 months (Fig 1d) there is considerably atrophy of pancreatic parenchyma in the disconnected segment.
17
Table 1: Clinical and demographic profile of 33 patients with low output external pancreatic fistula (EPF) and disconnected pancreatic duct syndrome (DPDS)
Ag e* 38 45 31 60 38 29 43 38 59 32 41 38 56 42 38 29 49 33 19 48 37 39 43 39 46 33 53
S ex M M F M M M M F M M M F M M M M M M M M M F M M M F M
33 28 42 39 53 46
M M F M M M
Etiology Alcohol Alcohol Gall Stone Gall Stone Alcohol Idiopathic Alcohol Gall Stone Gall Stone Alcohol post ERCP Gall Stone Gall Stone Alcohol Alcohol Idiopathic Alcohol Gall Stone Idiopathic Alcohol Alcohol Gall Stone Alcohol Alcohol Alcohol Gall Stone Idiopathic Drug induced Alcohol Gall Stone Alcohol Alcohol Alcohol
Extent of pancreatic Necrosis (%) 30-50 30-50 >50 >50 >50 30-50 >50 30-50 30-50 >50 30-50 30-50 30-50 >50 30-50 30-50 >50 >50 30-50 >50 >50 30-50 >50 30-50 30-50 >50 >50
EPF Post Surgery No No No No No No No No No No No No No No No No No No No No Yes No No No Yes No No
EPF post PCD Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes Yes
Number of PCD Single Single Single Single Single Single Multiple Single Single Multiple Single Single Multiple Single Single Single Single Multiple Single Single NA Single Single Single NA Multiple Single
Site of Disconnecti on Distal Body Distal Body Distal Body Prox. Body Prox. Body Distal Body Prox. Body Prox. Body Distal Body Prox. Body Distal Body Prox. Body Distal Body Neck Distal Body Prox. Body Distal Body Prox. Body Prox. Body Prox. Body Prox. Body Distal Body Prox. Body Distal Body Prox. Body Prox. Body Distal Body
Days for EPF closure 68 41 31 272 78 56 46 81 57 43 38 132 43 69 39 59 142 89 67 85 93 29 56 48 59 68 49
Follow up (months) 72 69 67 2 62 61 58 56 52 50 49 46 43 41 38 36 34 31 29 25 23 20 17 15 12 10 8
30-50 30-50 30-50 >50 30-50 >50
No No No No No No
Yes Yes Yes Yes Yes Yes
Single Single Single Single Single Single
Neck Distal Body Prox. Body Prox. Body Neck Neck
156 65 132 182 292 146
5 3 2 9 13 17
*Age in years; M: Male; F: Female; yrs: Years; PCD: percutaneous drainage; NA: Not applicable; Prox: Proximal Body;
18
S1424-3903(19)30808-7
DOI:
https://doi.org/10.1016/j.pan.2019.12.011
Reference:
PAN 1137
To appear in:
Pancreatology
Received Date: 12 September 2019 Revised Date:
16 October 2019
Accepted Date: 14 December 2019
Please cite this article as: Rana SS, Sharma R, Kang M, Gupta R, Natural course of low output external pancreatic fistula in patients with disconnected pancreatic duct syndrome following acute necrotising pancreatitis, Pancreatology (2020), doi: https://doi.org/10.1016/j.pan.2019.12.011. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier B.V. on behalf of IAP and EPC.
Natural Course of Low Output External Pancreatic Fistula in Patients with Disconnected Pancreatic Duct Syndrome Following Acute Necrotising Pancreatitis
Surinder Singh Rana, MD, D.M Ravi Sharma, MSc Mandeep Kang, MD* Rajesh Gupta, MCh** Departments of Gastroenterology, Radiodiagnosis* and Surgery**, Post Graduate Institute of Medical Education and Research (PGIMER), Sector 12, Chandigarh – 160012, India There are no conflicts of interest and no financial disclosures to be made by any of the authors Presented at Digestive Disease Week 2019 at San Diego, USA Declarations of interest: None Author Contributions: 1. Surinder Singh Rana: Design, Collection and interpretation of data, drafting of manuscript 2. Ravi Sharma: Collection and interpretation of data 3. Mandeep Kang: Collection and interpretation of data 4. Rajesh Gupta: Collection and interpretation of data Conflicts of Interest: 1. Surinder Singh Rana: None 2. Ravi Sharma: None 3. Mandeep Kang: None 4. Rajesh Gupta: None Corresponding Author: 1
Dr Surinder Singh Rana Professor, Department of Gastroenterology PGIMER, Chandigarh – 160 012, India Tel: +91-172-2971605 Fax: +91-172-2744401 E-mail: [email protected]
2
Abstract Background: External pancreatic fistulae (EPF) associated with complete pancreatic duct (PD) disruption leading on to disconnected pancreatic duct syndrome (DPDS) is a therapeutic nightmare usually requiring surgery. However, spontaneous closure also has been reported. There is paucity of data on the natural history of EPF associated with DPDS. Objective: To retrospectively study outcome of conservative treatment in patients with low output (<200ml/day) EPF with DPDS following percutaneous or surgical intervention in acute necrotising pancreatitis (ANP). Methods: The data of patients of low output EPF with DPDS treated conservatively in our unit over last 5 years was retrospectively analysed. Their clinical course, complications as well as time taken for fistula closure was retrieved. Results: 33 patients (27 males; mean age: 40.5 ±9.3 years) of low output EPF and DPDS were studied. 31 patients developed EPF following percutaneous drainage (PCD) and 2 patients developed fistula following surgery. The drain fluid amylase ranged from 1600 to 32,000 IU/l and site of disruption was neck, proximal body and distal body in 4, 16 and 13 patients respectively. EPF closed spontaneously in all patients within 88.2 ± 63.46 days. PCD slipped out in 2 patients and led to formation of pseudocyst in 1 patient that was treated endoscopically. There has been no recurrence in any patient over follow up of 32.5 ± 21.9 months. Conclusion: Low output EPF developing post PCD or surgery in patients with DPDS following ANP closely spontaneously in majority of patients within 3 months with good long term outcome. Key words: acute pancreatitis; disconnected pancreatic duct syndrome; stent; fistula; Endosonography; magnetic resonance cholangiopancreatography
3
Introduction External pancreatic fistula (EPF) is characterised by leakage of pancreatic juice externally through the cutaneous site. This seepage of pancreatic juice occurs due to the disruption of pancreatic duct (PD).1 EPF can cause significant morbidity due to malnutrition consequent to external leakage of protein rich pancreatic juice as well as increased risk of skin excoriation and infection. The EPF have been traditionally classified as low output (<200 ml/day) and high output (>200 ml/day) EPF.2 The traditional management of EPF has been conservative treatment including nutritional support with attempts to reduce pancreatic secretions by either total parenteral nutrition or octreotide. Non-responders were usually treated with surgery.1,3,4 Recently, endoscopic transpapillary drainage has been developed as an effective and minimally invasive therapeutic alternative to surgery for management of EPF.1,4,5 It leads to closure of EPF in majority of patients if there is a partial disruption of the PD that can be bridged by endoprosthesis. However, endoscopic transpapillary drainage is usually not effective in patients with complete PD disruption.6 Complete PD disruption with presence of functional pancreas upstream to disruption leads on to disconnected pancreatic duct syndrome (DPDS).1,6 EPF with DPDS are difficult to manage because the disconnected pancreas continue to pour pancreatic juice through low resistance EPF and usually necessitates surgery.1,6 Sepsis, infection, electrolyte disturbances, malnutrition and infections are usually seen in patients with high output EPF with DPDS and therefore interventional treatment is recommended for managing these patients.3,4,7 However, these complications are less frequently reported in patients with low output EPF even with associated DPDS.1,8 Moreover, spontaneous closure of low output EPF in setting of
4
DPDS has also been occasionally reported.9 However, there is scanty data on the natural clinical course of low output EPF with DPDS. In this retrospective study, we have evaluated the natural clinical course of low output EPF developing post percutaneous or surgical intervention in acute necrotising pancreatitis (ANP) and associated with DPDS by studying the outcome and complications of conservative non-interventional treatment in them.
5
Patients and Methods The prospectively maintained database of patients with ANP seen over last five years at a pancreatology unit in a tertiary care hospital in north India was retrospectively searched to retrieve data of patients with low output EPF (<200 ml/day) and DPDS. The EPF was defined as external drainage of >50 ml/day of amylase rich fluid (more than three times the serum value) for more than 7 days.8 The
diagnosis
of
DPDS
cholangiopancreatography
was
confirmed
(MRCP)
or
on
magnetic
endoscopic
resonance retrograde
cholangiopancreatography (ERCP). On ERCP, DPDS was defined as either a cut off or blowout of main PD with inability to demonstrate upstream PD on pancreatogram.1,5,10 On MRCP, DPDS was defined as dilated upstream PD with a disconnected segment of pancreas downstream to dilated PD. During the last five years, the patients with low output EPF with co-existent DPDS and without co-existent pancreatic fluid collection that could be drained endoscopically were given an option of interventional treatment including surgery or complex
endoscopic
interventional
procedures
or
conservative
expectant
management. The data base of patient opting for conservative treatment was retrieved and analysed. Follow up protocol of Patients with low output EPF These patients were initially followed in the outpatient department every two weekly for first eight weeks. Thereafter, they were followed every four weekly till resolution or complication necessitating intervention. These patients were instructed to record the daily fistula output and report in the clinic if output ceases or any complication
6
arises. During the outpatient visit, patient’s body weight was recorded and serum albumin was measured every 4 weeks. None of the patients were given octreotide or total parenteral nutrition. The patients were taught catheter care and advised regular dressing at home. They were advised normal oral diet with protease rich pancreatic enzyme supplements. No other pharmacotherapy except antibiotics in patients with purulent output were given. Outcome definitions: Successful Closure of EPF: Defined as closure of EPF with removal of percutaneous drainage (PCD) and complete cessation of drainage of pancreatic juice from cutaneous site without resorting to surgery. Major complication: Any complication requiring surgery or interventional treatment for management of EPF.
7
Results Over a period of 5 years, 46 patients with low output EPF with associated DPDS were seen in our unit. Thirteen of these 46 patients were excluded as 4 patients underwent surgical closure of EPF, 6 patients underwent EUS guided internalisation of EPF, and 3 patients were lost to follow up. The endoscopic or surgical intervention was done after 6 to 8 weeks of per-cutaneous intervention. Finally, 33 patients (27 males; mean age: 40.5 ±9.3 years) of low output EPF with associated DPDS were studied (Table 1). All these patients had underlying ANP with 15 (45%) patients having >50% parenchymal necrosis. Of 33 patients, only 4 patients had concurrent DPDS (patients who presented with severe acute necrotizing pancreatitis that resulted in complete disruption of the pancreatic duct such that the head of the gland was not in continuity with a viable pancreatic body or tail) and 29 patients had delayed DPDS ( treated for an index episode of ANP in which pancreatic duct disruption was not recognized or apparent at imaging done during first admission). The etiology of ANP was alcohol in 17, gall stones in 10, post ERCP in 1, drug induced in 1 and idiopathic in 4 patients respectively. 31 patients developed EPF following percutaneous drainage PCD (single PCD in 26 patients and multiple PCD in 5 patients). Surgical necrosectomy led on to development of EPF in 2 patients. The drain fluid amylase ranged from 1600 to 32,000 IU/l. DPDS was confirmed on MRCP in 24 patients and ERCP in 9 patients. The site of disconnection was neck, proximal body and distal body in 4, 16 and 13 patients respectively (Fig 1). The daily fistula output ranged from 60 ml to 190 ml per day. The fistula output was clear in 25 patients and purulent in 8 patients. The patients with purulent output received antibiotics as per the sensitivity pattern. No endoscopic intervention was done in any patient. 8
The EPF closed spontaneously in all patients within 88.2 ± 63.46 days (range 29-292 days). No infective complication because of prolonged external drainage was observed in any patient. The PCD slipped out in 2 patients, 6 weeks and 22 weeks respectively, after the formation of EPF. The dislodgement of PCD at 6 weeks led on to formation of symptomatic pseudocyst that was treated endoscopically. No immediate or delayed symptoms of slippage were observed in the other patient with dislodgement at 22 weeks. There was no infective complication in any patient during the follow up. Twenty nine patients gained weight from the time period of first contact to closure of EPF. Four patients lost weight during the follow up (3,5,2,and 6Kg respectively) and all of them had developed diabetes and were on insulin. The median serum albumin level increased from 2.9 g/dl to 3.8 g/dl from the time period of first contact to closure of EPF. There has been no recurrence of EPF or fluid collection in any patient over follow up of 32.5 ± 21.9 months. Two patients had abdominal pain 4 months and 11 months after removal of PCD. The pain responded to oral analgesics, did not require hospitalisation, was not accompanied with elevation of pancreatic enzymes and did not require intervention. Long term follow up of patients who underwent intervention versus patients treated conservatively Ten patients (7 males) were treated at the outset with endoscopic or surgical intervention whereas 33 patients (27 males) were treated with conservative expectant management. None of the patients in either group had recurrence of EPF or any fluid collection. Three of 10 (30%) patients in intervention group whereas 9
9
/33 (27%) patients treated conservatively developed diabetes (p>0.05). None of the patients in either group developed steatorrhea.
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Discussion EPF is an important consequence of percutaneous drainage of pancreatic fluid collections in ANP. They are usually formed due to DPDS with disconnected segment of pancreas continuing to secrete protein rich pancreatic juice. These difficult to treat EPF are not amenable to endoscopic transpapillary drainage because of inability to bridge the complete PD disruption by endoprosthesis. Therefore, EPF in the setting of DPDS is usually treated by surgery that has associated significant morbidity and occasional mortality. Recently, there have been reports of successful closure of complex EPF by use of complex endoscopic ultrasound (EUS) procedures including EUS guided transmural placement of stent in the PCD tract or PD in the disconnected pancreatic segment in order to internalise the pancreatic drainage.10–12 However, these are complex procedures available in selected tertiary care centres, are costly, have potential of serious complications and the long term consequences of transmural stents are not clear. Studies have shown that up to 75% of EPS close spontaneously without any intervention.2,8,13–15 However, the natural course of EPF in the setting of DPDS has not been adequately studied and there is paucity of data on the role of conservative treatment in management of EPF with DPDS. Limited data have suggested that EPF in the setting of DPDS does not close spontaneously and usually require endoscopic or surgical intervention for closure. In the current study we have shown that low output EPF in the setting of DPDS closes spontaneously without intervention in majority of patients within 3 months. Sikora et al studied 43 patients with EPF that developed following radiological or surgical interventions of infective complications of ANP.8 They reported that 88% of these patients had spontaneous closure of EPF within 109 ± 26 days. They also
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attempted to identify the factors that could determine delayed closure of EPF but found that none of the factors including etiology of pancreatitis, extent of pancreatic necrosis, interval between onset and intervention, nature of intervention, presence of enteric fistula, amount of fistula output and use of octreotide, were significantly different in patients with either early or delayed closure of fistulae. However, they did not evaluate the pancreatic duct anatomy in their study. Howard et al studied 38 patients with EPF that developed after percutaneous or surgical intervention in acute or chronic pancreatitis or after pancreatectomy.2 They classified the EPF into three categories depending upon the underlying pancreatic disease as well as the PD anatomy: operative side fistulae following surgery, inflammatory side fistulae following acute or chronic pancreatitis and end fistulae having disconnected pancreatic duct. They reported that EPF closed spontaneously in 86% and 53% patients in operative side fistulae and inflammatory side fistulae respectively within mean time period of 11 and 22 weeks respectively. However, none of the EPF in end fistulae group closed spontaneously. Spontaneous closure in partial PD disruptions occur because of resolution of necrosis, fibrosis and healing of duct disruption.8,16 In setting of DPDS, the spontaneous closure of EPF occurs, possibly because of cessation of significant pancreatic juice secretion of disconnected pancreatic segment consequent to gradual acinar cell atrophy.6,17 This acinar cell atrophy is variable and will not happen in all patients with DPDS. It seems that patient with low output EPF had already significant pre-existent necrosis of the disconnected segment of pancreas due to ANP. Therefore, the EPF closed spontaneously in these patients due to atrophy of small amount of left over residual acinar cell volume in the disconnected segment of pancreas over next 3-6 months.
12
The appropriate time of intervention in EPF, especially following ANP, is debatable. The safety and efficacy of minimally invasive endoscopic transpapillary drainage in EPF has led on to advocacy of early endoscopic intervention in these patients.
1,4,5
Minimal invasiveness and excellent results of endoscopic transpapillary drainage coupled with risk of malnutrition and infection along with poor quality of life with prolonged external catheter drainage has led on to experts recommending early endoscopic intervention in patients with EPF.1,12 However, EPF with DPDS are a difficult management dilemma as endoscopic transpapillary drainage is ineffective. This condition requires complex endoscopic ultrasound interventions that are not widely available and are associated with significant complications. Therefore, alternative treatment options need to be explored for this difficult to treat condition. Our observation that majority of these low output EPF in DPDS close spontaneously within 3 months in majority of patients suggest that conservative expectant treatment of prolonged external drainage is a safe and effective management option. The low output EPF are not associated with metabolic, nutritional or electrolyte disturbances and similar was our observation also.8,13,14 Therefore, there is no risk of significant complication of prolonged expectant treatment till there is an unimpeded drainage of the fistula. Another presumed advantage of early intervention is prevention of endocrine or exocrine insufficiency by preserving the pancreatic function of the disconnected segment of pancreas. However, in our study there was no difference in the endocrine or exocrine insufficiency in patients who underwent early endoscopic or surgical intervention versus patients who were treated conservatively. An important question in such patients is to continue conservative treatment for how long? Expectant conservative treatment of prolonged external drainage up to 1 year, especially in patients with daily fistula output of <500 ml/day has been
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suggested.2,13,14 Sikora et also reported that two third patients with EPF had low output fistulae and did not have any nutritional or skin problems and could be easily managed by patients at home.8 We feel that the timing of intervention should be decided upon various factors including the availability of experienced therapeutic endoscopic team, output of fistula, anatomy of pancreatic duct and risk of infective/nutritional complication of prolonged external drainage of pancreatic juice. Our results suggests that patients with low output EPF and DPDS should be managed conservatively initially for a period of 3 months as majority of them would close by then. Also, patients having a decreasing trend of EPF output can also be managed conservatively beyond three months as all out patients had their EPF closure within 292 days. Intervention is needed if the fistula continues to pour same or increased amount of pancreatic juice beyond three months, when there are associated infective or hemorrhagic complications or management of external drains become difficult due to high output, skin problems or poor quality of life. Our study has few important limitations. It was a single centre retrospective study with a sample size of 33 patients. Moreover, we did not assess the quality of life in these patients with prolonged catheter drainage. In conclusion, low output EPF developing post PCD or surgery in patients with DPDS following ANP closely spontaneously in majority of patients within 3 months with good long term outcome.
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References:
1. Varadarajulu S, Rana SS, Bhasin DK. Endoscopic therapy for pancreatic duct leaks and disruptions. Gastrointest Endosc Clin N Am 2013;23:863-892. 2. Howard TJ, Stonerock CE, Sarkar J, et al. Contemporary treatment strategies for external pancreatic fistulas. Surgery 1998;124:627-632; discussion 632-633. 3. Kozarek RA, Traverso LW. Pancreatic fistulas: etiology, consequences, and treatment. Gastroenterologist 1996;4:238-244. 4. Larsen M, Kozarek R. Management of pancreatic ductal leaks and fistulae. J Gastroenterol Hepatol 2014;29:1360-1370. 5. Rana SS, Bhasin DK, Nanda M, et al. Endoscopic transpapillary drainage for external fistulas developing after surgical or radiological pancreatic interventions. J Gastroenterol Hepatol 2010;25:1087-1092. 6. Larsen M, Kozarek RA. Management of Disconnected Pancreatic Duct Syndrome. Curr Treat Options Gastroenterol 2016;14:348-359. 7. Smits FJ, van Santvoort HC, Besselink MG, et al. Management of Severe Pancreatic Fistula After Pancreatoduodenectomy. JAMA Surg 2017;152:540548. 8. Sikora SS, Khare R, Srikanth G, et al. External pancreatic fistula as a sequel to management of acute severe necrotizing pancreatitis. Dig Surg 2005;22:446451; discussion 452. 9. Saadia R. Fistulas of the Pancreas. Zuckschwerdt, 2001. https://www.ncbi.nlm.nih.gov/books/NBK7003/. Accessed August 31, 2019. 10.
Rana SS, Sharma R, Gupta R. Endoscopic treatment of refractory external pancreatic fistulae with disconnected pancreatic duct syndrome. Pancreatology 2019;19:608-613.
11.
Irani S, Gluck M, Ross A, et al. Resolving external pancreatic fistulas in patients with disconnected pancreatic duct syndrome: using rendezvous techniques to avoid surgery (with video). Gastrointest Endosc 2012;76:586593.e1-3.
12.
Baron TH, Kozarek RA. Nonoperative Management of Pancreatic Fistula: Why Not an Endoscopic Approach? JAMA Surg 2018;153:94.
13.
Ho HS, Frey CF. Gastrointestinal and pancreatic complications associated with severe pancreatitis. Arch Surg 1995;130:817-822; discussion 822-823.
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14.
Tsiotos GG, Smith CD, Sarr MG. Incidence and management of pancreatic and enteric fistulas after surgical management of severe necrotizing pancreatitis. Arch Surg 1995;130:48-52.
15.
Fielding GA, McLatchie GR, Wilson C, et al. Acute pancreatitis and pancreatic fistula formation. Br J Surg 1989;76:1126-1128.
16.
Bassi C, Vesentini S, Pederzoli P, eds. Pancreatic Fistulas. Berlin Heidelberg: Springer-Verlag, 1992. https://www.springer.com/gp/book/9783540553380. Accessed September 1, 2019.
17.
Sandrasegaran K, Tann M, Jennings SG, et al. Disconnection of the pancreatic duct: an important but overlooked complication of severe acute pancreatitis. Radiographics 2007;27:1389-1400.
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Legends for the figures: Fig 1a: Computed tomography done at day 5 of onset of pain: Patient with acute emphysematous pancreatitis having necrosis and air in the body of pancreas Fig 1b: Computed tomography post drainage of acute necrotic collection. Percutaneous drainage catheter is seen. Fig 1c: Magnetic resonance imaging (MRI) done at 6 weeks showing a mature EPF tract (arrow). Fig 1d: MRI at 3 months showing disconnected segment of pancreas (arrow) with dilated main pancreatic duct. Fig 1e: MRCP shows disconnection in body of pancreas (arrows) with dilated upstream pancreatic duct. Fig 1f: MRI after closure of EPF (at 10 months) shows dilated main pancreatic duct in disconnected segment. On comparing with MRI at 6 weeks (Fig 1c) and 3 months (Fig 1d) there is considerably atrophy of pancreatic parenchyma in the disconnected segment.
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Table 1: Clinical and demographic profile of 33 patients with low output external pancreatic fistula (EPF) and disconnected pancreatic duct syndrome (DPDS)
Ag e* 38 45 31 60 38 29 43 38 59 32 41 38 56 42 38 29 49 33 19 48 37 39 43 39 46 33 53
S ex M M F M M M M F M M M F M M M M M M M M M F M M M F M
33 28 42 39 53 46
M M F M M M
Etiology Alcohol Alcohol Gall Stone Gall Stone Alcohol Idiopathic Alcohol Gall Stone Gall Stone Alcohol post ERCP Gall Stone Gall Stone Alcohol Alcohol Idiopathic Alcohol Gall Stone Idiopathic Alcohol Alcohol Gall Stone Alcohol Alcohol Alcohol Gall Stone Idiopathic Drug induced Alcohol Gall Stone Alcohol Alcohol Alcohol
Extent of pancreatic Necrosis (%) 30-50 30-50 >50 >50 >50 30-50 >50 30-50 30-50 >50 30-50 30-50 30-50 >50 30-50 30-50 >50 >50 30-50 >50 >50 30-50 >50 30-50 30-50 >50 >50
EPF Post Surgery No No No No No No No No No No No No No No No No No No No No Yes No No No Yes No No
EPF post PCD Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes No Yes Yes
Number of PCD Single Single Single Single Single Single Multiple Single Single Multiple Single Single Multiple Single Single Single Single Multiple Single Single NA Single Single Single NA Multiple Single
Site of Disconnecti on Distal Body Distal Body Distal Body Prox. Body Prox. Body Distal Body Prox. Body Prox. Body Distal Body Prox. Body Distal Body Prox. Body Distal Body Neck Distal Body Prox. Body Distal Body Prox. Body Prox. Body Prox. Body Prox. Body Distal Body Prox. Body Distal Body Prox. Body Prox. Body Distal Body
Days for EPF closure 68 41 31 272 78 56 46 81 57 43 38 132 43 69 39 59 142 89 67 85 93 29 56 48 59 68 49
Follow up (months) 72 69 67 2 62 61 58 56 52 50 49 46 43 41 38 36 34 31 29 25 23 20 17 15 12 10 8
30-50 30-50 30-50 >50 30-50 >50
No No No No No No
Yes Yes Yes Yes Yes Yes
Single Single Single Single Single Single
Neck Distal Body Prox. Body Prox. Body Neck Neck
156 65 132 182 292 146
5 3 2 9 13 17
*Age in years; M: Male; F: Female; yrs: Years; PCD: percutaneous drainage; NA: Not applicable; Prox: Proximal Body;
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