Pancreatic Pangs

Educational Objectives

The goal of this program is to improve the management of pancreatitis and pancreatic cancer. After hearing and as­similating this program, the clinician will be better able to:

1.   Review the patient and procedural risk factors for pancreatitis after endoscopic retrograde cholangiopancrea­tography.

2.   Discuss general management principles for treating pancreatitis.

3.   Compare enteral nutrition with total parenteral nutrition in the treatment of pancreatitis.

4.   Describe the role of probiotics in severe acute pancreatitis.

5.   Review the therapeutic options for pancreatic cancer.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. McClave is a consultant and is on the Speakers’ Bureaus for Nestle, Abbott Laboratories, and Kimberly-Clark. Dr. Goff is a consul­tant for OSI, Yakult, Daiichi, Amgen, and Abbott and has received research grants from OSI, Bristol-Myers Squibb, Im­Clone, sanofi-aventis, and ImmunoGen. Dr. Cohen and the planning committee reported nothing to disclose.

Acknowledgements

Dr. Cohen was recorded at the 32nd Annual New York Course, held December 17-20, 2008, in New York, NY, and sponsored by the Albert Einstein College of Medicine and the New York Society for Gastrointestinal Endoscopy. Dr. McClave was re­corded at the 14th Annual Medical and Surgical Approaches to GI Disorders Symposium, held July 20-24, 2009, in Kiawah Is­land, SC, and sponsored by the Medical College of Georgia. Dr. Goff was recorded at Gastroenterology and Hepatology Update 2009, held September 11-12, 2009, in Nashville, TN, and sponsored by the Vanderbilt Digestive Disease Research Center. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this pro­gram.

Post-ERCP Pancreatitis

Seth A. Cohen, MD, Attending Physician, Beth Israel Medical Center, New York, NY

Etiology: post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis  —  due to excessive manipula­tion that leads to edema, spasm of sphincter of Oddi, and obstruction of pancreatic duct, with activation of enzymes in pancreas; patient risk factors  —  female sex; younger age; suspected sphincter of Oddi dysfunction; previous ERCP pancreatitis; absence of chronic pancreatitis; patient selection important; stay within guidelines that recom­mend noninvasive work-up; diagnostic ERCP not in guidelines; procedural risk factors  —  associated with manipu­lation; extent of pancreatic duct injection; difficult cannulation; manipulation of papilla; precut sphincterotomy; balloon dilation; pancreatic sphincterotomy; ampullectomy

Study data: guidewire cannulation (GWC)  —  no dye injected; study compared GWC to standard cannulation; no pancreatitis found with GWC (4% with standard); cutting pancreatic sphincter  —  choice of sequence, ie, cut sphincter then place stent, or place stent then use needle knife to cut over it; study showed pancreatitis in 29% (mostly mild) with traction sphincterotome vs 0% with needle knife

Pancreatic ductal stenting: watershed study  —  80 patients with documented pancreatic sphincter dysfunction after biliary sphincterotomy randomized to stent or no stent; showed pancreatitis in 2.4% with stent, 26% without stent; other studies support placing stent after ERCP in high-risk patients; consensus to stent in ampullectomy; Japanese study  —  pancreatitis in 3% with stenting after ERCP vs 13% with no stent; difficulty with stent is obtaining deep cannulation of wire in pancreatic duct; avoid damaging pancreatic duct; survey of experts  —  no consensus on 1) which stent to use (3F or 5F) 2), length of time before checking x-ray (50% waited 1 wk, 3) how long to leave stent in place (most agreed on 5-14 days); disadvantages of stenting  —  increases length difficulty, risk, and cost of proce­dure; requires follow-up to ensure that stent removed and patient has x-ray; second procedure sometimes necessary if stent not removed; stenting arguably standard of care in high-risk cases; potential risks  —  inability to place stent leads to more manipulation; proximal tip jamming onto pancreatic duct; leaving stent in too long (³14 days) causes pancreatitis and results in chronic changes or migration of stent; endoscopic removal or surgery then required; fail­ure to stent increases risk for procedures

Medical Management of Pancreatitis

Stephen A. McClave, MD, Professor of Medicine, University of Louisville School of Medicine, Louisville, KY

Introduction: nutritional management  —  main form of primary therapy; acute pancreatitis  —  85% of cases mild to moderate and self-limited; 12% to 15% catastrophic, with severe complications, and mortality rate of 25% to 35%; initial management  —  supportive, regardless of severity; intravenous (IV) fluid volume resuscitation important (re­ducing hematocrit by 10% and maintaining urine output of 0.5 mL/kg per minute); analgesia important; correct electrolytes; determine disease severity; important to determine which patients to feed (only those with severe pan­creatitis); organ failure and necrosis within gland drive disease severity; indicators of severity  —Ranson’s criteria (RC) score £3; Acute Physiology and Chronic Health Evaluation (APACHE) II score £8; C-reactive protein (CRP) >150 mg/L; Balthazar computed tomography (CT) score >5; Atlanta classification with evidence of organ failure or pancreatic complications, plus abnormal prognostic signs based on Ranson score and APACHE score

Evaluating disease severity: worst score for Balthazar not >4 (must have £30% necrosis plus Balthazar’s original scoring to be in range of diagnosing severe pancreatitis); Atlanta classification  —looks at evidence of organ failure and/or local complications within gland; organ failure includes shock, pulmonary insufficiency, renal failure, and gastrointestinal (GI) bleeding; local complications include necrosis, abscess, and pseudocyst; either of 2 categories combined with unfavorable prognostic signs (RC score £3 or APACHE II score £8)

General management: antibiotic prophylaxis  —  controversial; largest study with best design showed no effect; if considering use of antibiotics, best choices include imipenem, meropenem, ciprofloxacin, and metronidazole (pen­etrate bed of pancreas); should not consider unless necrosis >30%; evidence of infection required, ie, shift to left (not just increased white blood cell [WBC] count) before starting antibiotics; no proven effect  —  nasogastric (NG) aspiration; pharmacologic agents (eg, somatostatin, protease inhibitors) and agents that reduce inflammation; peri­toneal lavage; surgical debridement in absence of infection controversial; look for etiology and rule out gallstone in common bile duct (CBD); urgent ERCP (within 12-24 hr) if evidence of cholangitis present (obstruction, increased liver enzymes, dilated CBD, fever, and increased WBC count with left shift); despite dilated CBD and increased liver enzymes, if no evidence of infection, 48 to 72 hr to perform ERCP; findings suggestive of gallstone pancreatitis  —  no history of alcohol intake; female sex; age >60 yr; alanine aminotransferase >3 times normal; his­tory of gallstones; dilated CBD; monitor and manage complications of shock, organ failure, sepsis, pseudocyst, and ascites; primary therapy  —  after adequately resuscitating patient early in admission (12-48 hr), initiating enteral feeding changes hospital course

Enteral nutrition (EN): benefit profound; maintains gut integrity; consequences of inadvertent pancreatic stimula­tion minimal; any signs of symptom exacerbation or inflammation in response to EN ameliorated by subtle adjust­ments in feeding strategy; start if anticipated that patient without oral intake for £7 days; preventing increases in permeability prevents bacteria from challenging immune system and upregulating inflammation (reduces chance for endotoxemia); sets tone for immune response (gut largest immune organ in body); affects innate system by  —  decreasing activation of macrophages and neutrophils and affecting line of lymphocytes emerging from gut (from T_H1 [inflammatory] to T_H2 [anti-inflammatory]); downregulating inflammation, which attenuates stress response and reduces disease severity; outcome benefits  —  compared to total parenteral nutrition (TPN), EN decreases infec­tion by ³50%, hospital length of stay (LOS) by 4 days, organ failure by 50%, need for surgical intervention by ³60%, and mortality by 60%; compared to no nutrition  —  2 European studies suggest that mortality reduced by ³75% with EN; consequences of providing EN  —  3 potentially adverse scenarios  —  1) silent stimulation of pan­creas and production of enzymes; occurred in 100% of patients in O’Keefe study, unless tip of tube >40 cm below ligament of Treitz; 2) uncomplicated exacerbation of symptoms; study showed that in first 6 days of jejunal feed­ing, amylase and lipase levels normalized and pain relieved, but after advancing to clear liquid diet, pain recurred and amylase levels increased; in large case series, uncomplicated exacerbation of symptoms seen in 20% of pa­tients; 3) exacerbation of disease process; clinically similar to exacerbation of systemic inflammatory response syn­drome (SIRS)

Pancreatic rest: not necessary to reduce enzymes to basal unstimulated level; subclinical level adequate for inflam­mation to resolve; compatible with feeding; catheter at ampulla to measure output not necessary (use symptoms for clinical guidance)

Who requires nutritional therapy: only 12% to 15% with severe pancreatitis; study showed that in mild pancreati­tis, permeability levels (markers) no different from controls; in severe uncomplicated pancreatitis, 4-fold increase in permeability; in severe pancreatitis with organ failure, further 4-fold increase above original 4-fold increase in permeability; when gut permeable, it becomes pro-inflammatory and responsible for subsequent secondary compli­cations; severe pancreatitis  —  high mortality (20%-25%) and complication rate; close to 0% chance of oral diet within 1 wk; requires and benefits from EN; lower APACHE II and Ranson scores signify low complication rate and close to 0% mortality, with chance of oral diet >80%; necrosis indication for EN; pseudocyst, ascites, and need for surgery part of natural disease process; surgery good opportunity to obtain definitive enteral access; intolerance only exclusion

Formula selection: choice immaterial; if tube below ligament of Treitz, any formula acceptable; the closer tube is to stomach, the more content of formula becomes issue because of stimulation of gland; pharmaconutrition  —  study looking at small peptide and medium-chain triglyceride formula showed hospital LOS shortened by 1 wk (due to better absorption); further benefit with fish oil formula (reduced hospital LOS, duration of EN, and complications); with arginine and fish oil formula, reduction of hospital and intensive care unit LOS; factors affecting tolerance  —  level of infusion within GI tract; content of formula; duration of ileus; institutional experience; individual varia­tion; change in content  —study showed that when formula changed from fat-free Vivonex or Criticare to Osmolite, significant change in lipase output seen; content at same level of feeding has big effect on stimulation of pancreas; tolerance  —the longer ileus sets up, the more problems with tolerance; study showed 0% tolerance if duration of il­eus £6 days; within 5 days, 50% tolerance; within 48 hr, 92% tolerance

Gastric feeding: should be aggressive and started early; narrow window of opportunity before ileus sets up and per­meability increased; timing critical; tolerated by majority of patients with severe pancreatitis if started early enough; Dobhoff NG tube  —simplest and most expedient strategy; quickens time to initiation of feeding; requires minimal expertise; facilitates early delivery of EN; gastric vs jejunal feeding  —  timing only benefit; time to initiate EN significantly less (16 hr) for gastric feeding; eventually, postpyloric feeding catches up; early-onset feeding (within 48 hr) maintains gut function, improves tolerance, and results in fewer problems with ileus and gastric sta­sis; track record  —  in Glasgow study, 70% of patients attained >75% of goal calories within 48 hr; no change in rate of infusion necessary; no change in CRP, APACHE scores, or analgesia

Role of probiotics: Pseudomonas worst organism for gut sepsis; when patient in shock, bacteria in gut determine de­gree of inflammatory response; normal bacteria induce release of tumor necrosis factor (TNF) and interleukin (IL)-6 from gut; pathogenic bacteria exaggerate response; feeding potentially prevents colonization of Pseudomonas and restores normal bacteria; Hungarian study  —  probiotic formula with live Lactobacillus found significant reduc­tion in necrosis, abscess, and hospital LOS (by 1 wk) vs formula with heat-killed Lactobacillus; Dutch multicenter trial  — in group that received probiotics, incidence of organ failure, need for surgical intervention, and ICU LOS twice that of controls; 9 patients developed thalassemia; death rate 2.5 times greater; higher CRP levels and lower rate of alcoholic etiology; Hungarian study predominantly alcoholic pancreatitis (less severe); in Dutch study, sub­jects 15 yr older and therapy too aggressive; speaker curtailing use of probiotics

Management algorithm: place Dobhoff tube in emergency department; once resuscitation complete, start feeding; if disease mild to moderate, advance to oral diet; if disease severe, continue feeding if tolerated; if not tolerated, shift formula or place tube lower; if still ineffective, switch to TPN

Therapeutic Options for Pancreatic Cancer

Laura W. Goff, MD, Assistant Professor of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, TN

Resectable disease: surgery only chance for cure; resectability subjective; exclusions for resectability  —  metastatic disease, involvement of superior mesenteric artery (SMA), inferior vena cava, aorta, or celiac axis; extensive supe­rior mesenteric vein (SMV) involvement; surgical mortality rate related to number of procedures performed by sur­geon or hospital; at high-volume centers (>16 pancreatic resections annually), mortality 3.8%; only 10% to 20% of tumors resectable at presentation; of those resected, recurrence rate 80% to 85% after surgery alone; recurrence rate higher if resection incomplete or if lymph nodes involved

Adjuvant therapy: GI Tumor Study Group (GITSG)  — looked at combination of radiation therapy (RT) and chemo­therapy after surgery to improve survival; primary end point survival; suggestion of improved survival in combina­tion treatment arm; one-third of patients received “inappropriate” RT, and compliance with chemotherapy incomplete; European Organization for Research and Treatment of Cancer (EORTC) trial  —  looked at same com­bination therapy as in GITSG trial, without additional chemotherapy; found no statistically significant improve­ment in median survival; suggestion of benefit in pancreatic cancer, but not in periampullary cancer; another European study  —  suggested inferior survival for treatment with chemoradiotherapy and statistically significant improvement with chemotherapy vs no chemotherapy (magnitude of benefit »10%); concluded that chemotherapy with fluorouracil (5-FU) improves outcome for patients with resected pancreatic cancer; on basis of trial, chemo­therapy alone standard adjuvant therapy for resected pancreatic cancer in Europe; study  —  found statistically signif­icant improvement in disease-free survival and median overall survival with gemcitabine; adjuvant gemcitabine beneficial in reducing chances for recurrence after resection; no difference found between gemcitabine-based che­motherapy vs 5-FU-based chemotherapy; conclusions  —adjuvant therapy improves survival over surgery alone; gemcitabine alone standard option

Locally advanced disease: question of whether neoadjuvant chemoradiation converts unresectable cancer into re­sectable potentially curable cancer; selection of patients matters; borderline resectable disease  —  study found 16% resection rate in patients deemed unresectable and treated with neoadjuvant chemoradiotherapy with 5-FU; case se­ries showed only 3 of 87 patients treated with chemoradiotherapy warranted reexploration; addition of RT to chemotherapy  —  possible benefit suggested; chemoradiotherapy more toxic than chemotherapy alone; for combina­tion arm, 18% survival at 18 mo (0% in chemotherapy alone)

Metastatic disease: gemcitabine  —  mainstay for >10 yr; compared to 5-FU, 23.8% improvement in clinical benefit response and slight improvement in median and 1-yr survival seen; palliative measure; multiple negative trials; more adverse effects using combination, compared to placebo; gemcitabine with erlotinib is option, but also gem­citabine alone, especially if focus on maximizing quality of life and minimizing side effects from chemotherapy

Suggested Reading

Andersson RG: Probiotics in acute pancreatitis. Br J Sur.95:941, 2008; Eckerwall GE et al: Early nasogastric feeding in pre­dicted severe acute pancreatitis: A clinical, randomized study. Ann Surg 244:959, 2006; Elmunzer BJ et al: A meta-analysis of rectal NSAIDs in the prevention of post-ERCP pancreatitis. Gut 57:1262, 2008; Fujita T: Survival for patients with pancreatic cancer after addition of gemcitabine to Fluorouracil chemoradiation. JAMA 299:2852, 2008; Jeejeebhoy KN: Total parenteral nu­trition: potion or poison? Am J Clin Nutr 74:160, 2001; Nagar AB et al: Prevention of post-ERCP pancreatitis: a little antacid might go a long way. Gut 57:1492, 2008; O'Keefe GE et al and the Inflammation and the Host Response to Injury Collabor­ative Research Program: Inflammation and the host response to injury, a large-scale collaborative project: patient-oriented re­search core--standard operating procedures for clinical care VIII--Nutritional support of the trauma patient. J Trauma 65:1520, 2008; Erratum in J Trauma 66:965, 2009; O'Keefe SJ et al: Feeding the injured pancreas. Gastroenterology 129:1129, 2005; Pa­pachristou GI et al: Complication of therapeutic endoscopic retrograde cholangiopancreatography. Gut 56:854, 2007; Sanabria A: Randomized controlled trial of the effect of early enteral nutrition on markers of the inflammatory response in predicted severe acute pancreatitis. Br J Surg 88:728, 2001; Shivnani AT: Adjuvant chemotherapy with gemcitabine for patients with resectable pancreatic cancer. JAMA 297:2581, 2007; Testoni PA: Simple measures to prevent post-ERCP pancreatitis? Gut 57:1197, 2008; Weale R et al: Letter 1: Randomized clinical trial of specific lactobacillus and fibre supplement to early enteral nutrition in pa­tients with acute pancreatitis (Br J Surg 2002; 89: 1103-1107) Br J Surg 90:122, 2003.