Navigating the Stormy Sea of Infected Necrotizing Pancreatitis: Are We There Yet? Well Almost!

See “Endoscopic versus surgical step-up approach for infected necrotizing pancreatitis (ExTENSION): long-term follow-up of a randomized trial,” by Onnekink MA, Boxhoorn L, Timmerhuis HC, et al, on page 712. See “Endoscopic versus surgical step-up approach for infected necrotizing pancreatitis (ExTENSION): long-term follow-up of a randomized trial,” by Onnekink MA, Boxhoorn L, Timmerhuis HC, et al, on page 712. Acute pancreatitis (AP) is associated with significant morbidity and mortality.1Garg P.K. Singh V.P. Organ failure due to systemic injury in acute pancreatitis.Gastroenterology. 2019; 156: 2008-2023Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar The short-term outcomes in AP are determined both by systemic and local complications. Persistent organ failure, which defines the severity of AP, leads to a high mortality of up to 30%–40%.1Garg P.K. Singh V.P. Organ failure due to systemic injury in acute pancreatitis.Gastroenterology. 2019; 156: 2008-2023Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 2Schepers N.J. Bakker O.J. Besselink M.G. et al.Impact of characteristics of organ failure and infected necrosis on mortality in necrotising pancreatitis.Gut. 2019; 68: 1044-1051Crossref PubMed Scopus (139) Google Scholar, 3Padhan R.K. Jain S. Agarwal S. et al.Primary and secondary organ failures cause mortality differentially in acute pancreatitis and should be distinguished.Pancreas. 2018; 47: 302-307Crossref PubMed Scopus (25) Google Scholar Among the local complications of AP, infected necrotizing pancreatitis (INP) is the most sinister. The treatment of INP has undergone a sea change over the past 2 decades moving away from the dogma of “open” surgical necrosectomy to “a conservative-first” step-up approach starting with antibiotics, drainage, and scaling up to minimally invasive necrosectomy, which can be achieved either through endoscopic, laparoscopic or video-assisted retroperitoneal debridement technique.4Garg P.K. Zyromski N.J. Freeman M.L. Infected necrotizing pancreatitis: evolving interventional strategies from minimally invasive surgery to endoscopic therapy-evidence mounts, but one size does not fit all.Gastroenterology. 2019; 156: 867-871Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Two randomized trials—TENSION and MISER—have shown that both endoscopic and minimally invasive surgical approaches were similar in terms of mortality in patients with INP. but with a higher rate of pancreatocutaneous fistula after minimally invasive surgery.5Brunschot S van Grinsven J van Santvoort HC van et al.Endoscopic or surgical step-up approach for infected necrotising pancreatitis: a multicentre randomised trial.Lancet. 2018; 391: 51-58Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar,6Bang J.Y. Arnoletti J.P. Holt B.A. et al.An endoscopic transluminal approach, compared with minimally invasive surgery, reduces complications and costs for patients with necrotizing pancreatitis.Gastroenterology. 2019; 156: 1027-1040.e3Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar In this issue of Gastroenterology, the Dutch Pancreatitis Study Group has reported on the long-term outcomes of patients with INP treated either by an endoscopic step-up or minimally invasive surgical approach as the extension of their TENSION trial.7Onnekink M.A. Boxhoorn L. Timmerhuis H.C. et al.Endoscopic versus surgical step-up approach for infected necrotizing pancreatitis (ExTENSION): long-term follow-up of a randomized trial.Gastroenterology. 2022; 163: 712-722Abstract Full Text Full Text PDF Scopus (8) Google Scholar Significant medium- and long-term outcomes after recovery from AP include a propensity to develop recurrent acute and even chronic pancreatitis, recurrence of peripancreatic fluid collections, pancreatic fistula, and functional consequences with endocrine and exocrine insufficiency. Conceptually, such outcomes may be determined by 3 factors:(i)Intrinsic susceptibility for recurrent pancreatitis, for example, alcohol abuse, gallstones and genetic susceptibility.(ii)Morphological consequences of the initial pancreatic insult leading to pancreatic glandular necrosis which may also involve the main pancreatic duct.(iii)The initial modality of treatment for infected necrosis. With regard to the intrinsic predisposition to recurrent AP (RAP), patients with gallstone have a 14%–60% risk of recurrence if timely cholecystectomy is not done.8Mustafa A. Begaj I. Deakin M. et al.Long-term effectiveness of cholecystectomy and endoscopic sphincterotomy in the management of gallstone pancreatitis.Surg Endosc. 2014; 28: 127-133Crossref PubMed Scopus (22) Google Scholar,9Frei G.J. Frei V.T. Thirlby R.C. et al.Biliary pancreatitis: clinical presentation and surgical management.Am J Surg. 1986; 151: 170-175Abstract Full Text PDF PubMed Scopus (71) Google Scholar Patients with alcohol-induced AP are also at a 33% risk of recurrence and even chronic pancreatitis particularly if they do not abstain from alcohol and smoking.10Lankisch P.G. Breuer N. Bruns A. et al.Natural history of acute pancreatitis: a long-term population-based study.Am J Gastroenterol. 2009; 104 (quiz 2806): 2797-2805Crossref PubMed Scopus (204) Google Scholar Patients with genetic polymorphisms/mutations in any of the pancreatitis associated genes such as PRSS1, SPINK1, and CFTR are at risk of RAP and often chronic pancreatitis.11Jalaly N.Y. Moran R.A. Fargahi F. et al.An evaluation of factors associated with pathogenic PRSS1, SPINK1, CTFR, and/or CTRC genetic variants in patients with idiopathic pancreatitis.Am J Gastroenterol. 2017; 112: 1320-1329Crossref PubMed Scopus (46) Google Scholar In the Dutch study,7Onnekink M.A. Boxhoorn L. Timmerhuis H.C. et al.Endoscopic versus surgical step-up approach for infected necrotizing pancreatitis (ExTENSION): long-term follow-up of a randomized trial.Gastroenterology. 2022; 163: 712-722Abstract Full Text Full Text PDF Scopus (8) Google Scholar 23 patients (28%) developed RAP owing to alcohol (n = 2), gallstones (n = 8), idiopathic (n = 10), endoscopic retrograde cholangiopancreatography (n = 1), pancreatic injury (n = 1), and unknown (n = 1) cause. The idiopathic etiology of AP, seen in ≤43% of patients with RAP, needs further study, but it is quite likely that such patients might have an underlying genetic polymorphism/mutation. It is, therefore, instructive to emphasize that etiology plays a significant role in the recurrence of pancreatitis and the role of the other variables such as initial modality of interventional treatment might not be important. Morphological changes that affect long-term outcomes are primarily related to the extent and distribution of pancreatic necrosis. If the necrotic process involves the main pancreatic duct (Figure 1), it can lead to ductal disruption, loss of a small segment of the main pancreatic duct and later ductal stricture, commonly referred to as disconnected pancreatic duct syndrome (DPDS). DPDS remains mostly asymptomatic but may lead to 3 problems: (i) persistence or recurrence of fluid collection owing to internal leakage of the pancreatic secretions, (ii) recurrence of pancreatitis in the part of the pancreas upstream of the ductal disruption and stricture, and (iii) asymptomatic, progressive atrophy of the proximal pancreas secondary to obstruction. The frequency of development of DPDS after acute necrotizing pancreatitis has been variably reported from 16% to 74%.12Lawrence C. Howell D.A. Stefan A.M. et al.Disconnected pancreatic tail syndrome: potential for endoscopic therapy and results of long-term follow-up.Gastrointest Endosc. 2008; 67: 673-679Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar, 13Bang J.Y. Wilcox C.M. Navaneethan U. et al.Impact of disconnected pancreatic duct syndrome on the endoscopic management of pancreatic fluid collections.Ann Surg. 2018; 267: 561-568Crossref PubMed Scopus (63) Google Scholar, 14Basha J. Lakhtakia S. Nabi Z. et al.Impact of disconnected pancreatic duct on recurrence of fluid collections and new-onset diabetes: do we finally have an answer?.Gut. 2021; 70: 447-449Crossref PubMed Scopus (19) Google Scholar In a study of 256 patients with walled off necrosis, 189 patients (73.8%) developed DPDS, but only approximately 13% of patients had recurrent events, either AP or fluid collections requiring intervention.14Basha J. Lakhtakia S. Nabi Z. et al.Impact of disconnected pancreatic duct on recurrence of fluid collections and new-onset diabetes: do we finally have an answer?.Gut. 2021; 70: 447-449Crossref PubMed Scopus (19) Google Scholar One is not sure though if the recurrent events were primarily owing to DPDS or the intrinsic predisposition. In the Dutch study, DPDS occurred in 22 patients (27%) with no difference between the endoscopic and surgical groups. Among the 23 patients with RAP, 12 had DPDS with an odds ratio of 1.8 compared with those without DPDS, suggesting it could be playing a role in recurrence of AP. Whether the third variable, namely, the type of initial intervention for INP affects the outcomes, is the focus of the current study.7Onnekink M.A. Boxhoorn L. Timmerhuis H.C. et al.Endoscopic versus surgical step-up approach for infected necrotizing pancreatitis (ExTENSION): long-term follow-up of a randomized trial.Gastroenterology. 2022; 163: 712-722Abstract Full Text Full Text PDF Scopus (8) Google Scholar The TENSION trial had shown that both the modalities were similar in terms of primary outcomes till 6 months of follow-up, except for a higher proportion of pancreatic fistula in 25.5% of patients treated with a percutaneous minimally invasive surgical approach. The authors have now followed these patients for a median of 7 years and shown that both the modalities were similar for the primary composite outcome, except for fewer percutaneous pancreatic fistula in the endoscopy group (8% vs 34%; relative risk, 0.23; 95% confidence interval, 0.08–0.83) requiring fewer reinterventions in the endoscopy arm (7% vs 24%; relative risk, 0.29; 95% confidence interval, 0.09–0.99). DPDS, large-bore percutaneous drains, and gravity providing an easy outflow are the likely reasons for the pancreatic fistula in the surgical arm. These results may not be applicable to other minimally invasive techniques, such as laparoscopic internal drainage and necrosectomy. Two randomized trials have shown that endoscopic and laparoscopic internal drainage provide similar success and complications rates in patients with walled-off necrosis.15Garg P.K. Meena D. Babu D. et al.Endoscopic versus laparoscopic drainage of pseudocyst and walled-off necrosis following acute pancreatitis: a randomized trial.Surg Endosc. 2020; 34: 1157-1166Crossref PubMed Scopus (24) Google Scholar,16Angadi S. Mahapatra S.J. Sethia R. et al.Endoscopic transmural drainage tailored to quantity of necrotic debris versus laparoscopic transmural internal drainage for walled-off necrosis in acute pancreatitis: a randomized controlled trial.Pancreatology. 2021; 21: 1291-1298Crossref PubMed Scopus (4) Google Scholar Video-assisted retroperitoneal debridement by design requires a 5-cm surgical incision for debridement and is not necessarily a minimally invasive procedure. A conceptually similar but minimally invasive technique is percutaneous endoscopic necrosectomy for laterally placed necrotic collections.17Dhingra R. Srivastava S. Behra S. et al.Single or multiport percutaneous endoscopic necrosectomy performed with the patient under conscious sedation is a safe and effective treatment for infected pancreatic necrosis (with video).Gastrointest Endosc. 2015; 81: 351-359Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar It is a bit surprising, however, that the authors kept the same composite primary outcome of organ failure, major complications, mortality, and local complications including perforation and bleeding for the current long-term study as well. Such a composite outcome is not as relevant for the long-term study primarily because one would not expect organ failure and death owing to pancreatitis per se after 6 months. Indeed, subsequent deaths occurred after ≥30 months and were all owing to unrelated causes. Notwithstanding the issue of primary outcome, the authors have provided excellent data about the local complications and functional consequences, which should guide caregivers to periodically follow-up with these patients. With regard to the endocrine and exocrine insufficiency, 42% of patients developed diabetes and 43% of patients pancreatic exocrine insufficiency (PEI) with no difference between the 2 groups.7Onnekink M.A. Boxhoorn L. Timmerhuis H.C. et al.Endoscopic versus surgical step-up approach for infected necrotizing pancreatitis (ExTENSION): long-term follow-up of a randomized trial.Gastroenterology. 2022; 163: 712-722Abstract Full Text Full Text PDF Scopus (8) Google Scholar Meta-analyses have shown that 23% of patients develop diabetes and 35% PEI after recovery from AP. Severe pancreatitis, pancreatic necrosis, age, and alcohol etiology are independent risk factors for functional insufficiencies.18Huang W. Iglesia-García D de la Baston-Rey I. et al.Exocrine pancreatic insufficiency following acute pancreatitis: systematic review and meta-analysis.Dig Dis Sci. 2019; 64: 1985-2005Crossref PubMed Scopus (35) Google Scholar,19Zhi M. Zhu X. Lugea A. et al.Incidence of new onset diabetes mellitus secondary to acute pancreatitis: a systematic review and meta-analysis.Front Physiol. 2019; 10: 637Crossref PubMed Scopus (34) Google Scholar The clinical implication of PEI, diagnosed by a fecal elastase of <200 μg/g stool, needs to be studied further for subclinical maldigestion of fat and micronutrients; therefore, the need for pancreatic enzymes supplementation. The regeneration of pancreas after acute necrotizing pancreatitis was the likely reason for improvement in PEI from 63% at 6 months to 43% later. Pancreatic regeneration has been demonstrated after distal pancreatectomy for pancreatic trauma.20Colney L. Tandon N. Garg P.K. et al.Exocrine and endocrine functions and pancreatic volume in patients with pancreatic trauma.Eur J Trauma Emerg Surg. 2022; 48: 97-105Crossref PubMed Scopus (3) Google Scholar On balance, endoscopic treatment with internal drainage, lavage, and endoscopic necrosectomy, if required, seems to be better than surgical treatment, albeit in a select group of patients suitable for endoscopic therapy, such as those with a well-organized necrotic collection predominantly in the lesser sac abutting the gastroduodenal wall. Immature collections and those away from the gastroduodenal wall are not suitable for per-oral endoscopic drainage. These should be treated with antibiotics first, followed by percutaneous drainage and percutaneous endoscopic necrosectomy later if required.17Dhingra R. Srivastava S. Behra S. et al.Single or multiport percutaneous endoscopic necrosectomy performed with the patient under conscious sedation is a safe and effective treatment for infected pancreatic necrosis (with video).Gastrointest Endosc. 2015; 81: 351-359Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar The POINTER trial, which compared early with delayed drainage for INP, by the same Dutch group has shown that 34.7% of patients could be treated with antibiotics alone in the delayed drainage group and ≤62.5% of patients with additional percutaneous drainage without necrosectomy in both the groups combined.21Boxhoorn L. Dijk SM van Grinsven J van et al.Immediate versus postponed intervention for infected necrotizing pancreatitis.N Engl J Med. 2021; 385: 1372-1381Crossref PubMed Scopus (38) Google Scholar A previous comparative study had shown that a “conservative-first” approach for infected necrosis with antibiotics and percutaneous drainage provided greater success than surgery.22Garg P.K. Sharma M. Madan K. et al.Primary conservative treatment results in mortality comparable to surgery in patients with infected pancreatic necrosis.Clin Gastroenterol Hepatol. 2010; 8: 1089-1094.e2Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar A meta-analysis also showed 60% success rate and 12% mortality with the conservative approach.23Mouli V.P. Sreenivas V. Garg P.K. Efficacy of conservative treatment, without necrosectomy, for infected pancreatic necrosis: a systematic review and meta-analysis.Gastroenterology. 2013; 144: 333-340.e2Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar The treatment for infected necrotizing pancreatitis has evolved over decades from an aggressive surgical approach to conservative to a more balanced step-up approach. In 1972, Geokas et al wrote, “A 10 minute surgical discussion of acute pancreatitis should probably include 9 minutes of silence.”24Geokas M.C. Van Lancker J.L. Kadell B.M. et al.Acute pancreatitis.Ann Intern Med. 1972; 76: 105-117Crossref PubMed Scopus (40) Google Scholar We obviously need to be more balanced; surgery is still required in a substantial number of patients either for infected necrosis or other complications.25Roch A.M. Maatman T. Carr R.A. et al.Evolving treatment of necrotizing pancreatitis.Am J Surg. 2018; 215: 526-529Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar We must individualize the choice of treatment, taking into consideration the following important variables: the timing of the infection, the location and maturity of the necrotic collection, expertise available, and the patient’s general condition. For example, in patients who are very sick and in intensive care, undertaking either surgical or endoscopic treatment under general anesthesia may not be a feasible option, but a percutaneous step-up approach, which can be done under conscious sedation, will be a more favorable strategy.26Jain S. Padhan R. Bopanna S. et al.Percutaneous endoscopic step-up therapy is an effective minimally invasive approach for infected necrotizing pancreatitis.Dig Dis Sci. 2020; 65: 615-622Crossref PubMed Scopus (15) Google Scholar Although there are many choices, a broad consensus seems to be emerging for infected necrosis: drainage of the infected fluid preferably by internal route, and defer or delay invasive intervention with minimal violation of the body’s integrity to prevent collateral damage. Our hope to further decrease the mortality from infected necrotizing pancreatitis in diverse settings outside of clinical trials and specialized units may be realized in the near future with a better understanding of this complex disease and better tools. Endoscopic Versus Surgical Step-Up Approach for Infected Necrotizing Pancreatitis (ExTENSION): Long-term Follow-up of a Randomized TrialGastroenterologyVol. 163Issue 3PreviewWhile the primary end point of mortality and major complications did not differ between groups, the endoscopic step-up approach resulted in overall fewer pancreaticocutaneous fistulas and fewer reinterventions during long-term follow-up. Full-Text PDF Open Access