Slide 1. Slide 2. Slide 3. Acute Pancreatitis: An Evidence-Based Clinical Approach in Case. Important Clinical Questions

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1 Slide 1 Acute Pancreatitis: An Evidence-Based Clinical Approach in 2014 David G. Forcione, MD Associate Director Interventional Endoscopy Slide 2 Case A 68 yo M p/w acute onset of sharp epigastric pain, which has been unrelenting for 6 hours. +nausea/vomiting PMHx: HTN, CAD, GERD, remote PUD Initial VS: HR 114, BP 140/90 mm Hg, RR 24, T 37.6 C, O2 Sat 92% (RA) Labs: Amylase 1270 U/L (ULN 100), Lipase 3430 U/L (ULN 60) HCT 47%, WBC 18K, Ca mg/dl, ALT 295, AST 221, AP 217, TB 0.9 mg/dl, Glucose 240 mg/dl, BUN 47, Cr 1.3 Slide 3 Important Clinical Questions Is this acute pancreatitis? What is the cause? What imaging studies are important at this time? Does this patient need an ICU? How should I manage this patient? Fluids? Antibiotics? Nutrition? ERCP? Surgery?

2 Slide Updated guidelines on classification and management Am J Gastro 2013 Gut 2012 Slide 5 Epidemiology of Acute Pancreatitis One of the most common GI tract disorders $2.6 billion (2009) Ann Epidem 2007 Slide 6 Diagnostic Criteria >2 criteria should be met: Characteristic abdominal pain Amylase and/or lipase >3x upper limit normal Characteristic cross sectional imaging findings

3 Slide 7 What is pancreatitis type pain? Characteristic Findings NOT Location Epigastric/LUQ Crampy Onset Acute Colicky Quality Deep,penetrating/ Periumbilical knife-like, burning, Lower gas pocket abdominal sensation Caveats Immunosuppressed Acuity Severe, constant Altered MS Radiation Band-like upper abdomen Chronic pain Chronic pancreatitis Mid/Upper back Associated Features Anorexia, Nausea, Vomiting Slide 8 Serologic Testing Onset Levels Duration Source Caveats Amylase (<100 U/L) <4 hrs Height of elevation does not correlate with severity/prognosis Daily tracking: limited value 3-5 days Pancreatic Salivary 1) May be WNL in AP due to EtOH or hypertrig 2) Non-pancreatic conditions 3) Renal failure Lipase (<60 U/L) <3 hrs Height of elevation does not correlate with severity/prognosis Daily tracking: limited value 7-10 days Panc, Intestinal Salivary, Hepatic 1) Diabetics: higher baseline 2) Non-pancreatic conditions 3) Renal failure Slide 9 Approach to Serologic Testing Lipase is more specific than amylase >3x ULN: 98% specificity for AP Amylase/lipase levels.<3xuln WITH abdominal sxs WITHOUT abdominal sxs Pancreatitis Pancreatitis Gastroenteritis Renal failure Peptic ulcer disease Salivary (fractionation) Cholecystitis HIV SBO Metabolic acidosis (DKA) Mesenteric ischemia Macroamylase/lipase Appendicitis Drugs Celiac disease IBD Gynecologic

4 Slide 10 Role of Early Imaging TUS for all piotential cases of biliary pancreatitis Cross sectional imaging may be clinically indicated Diagnostic uncertainty Dx AP with clinical deterioration hrs after presentation Routine use of CT in ED for diagnosis of AP is unwarranted Dx is made by Hx/PE/Serologies Most pts have uncomplicated courses CT and MR appear comparable Necrosis may not be evident for 2-3 days >90% sensitivity/specificity Pros CT : availability, faster, cheaper Pros MR: CBD stones, non-contrast (renal failure/allergy) Challenging scenarios Pancreatic neoplasms Slide 11 Case 68 yo M p/w acute onset of sharp epigastric pain, which has been unrelenting for 6 hours. +nausea/vomiting PMHx: HTN, CAD, GERD, TUS: remote PUD Gallstones w/o cholecystitis Initial VS: HR 114, BP 140/90 CBD 6 mm (otherwise nl) mm Hg, RR 24, T 37.6 C, O2 Sat 92% (RA) CT: pancreatitis without necrosis Labs: Amylase 1270 U/L (ULN 100), Lipase 3430 U/L (ULN 60) HCT 47%, WBC 18K, ALT 295, AST 221, AP 217, TB 0.9 mg/dl Slide 12 Establish an etiology Important! Can be established in most cases Diagnosis-specific treatments Target reversible causes Prevention of future attacks Overusage of idiopathic and chronic pancreatitis labels

5 Slide 13 Etiology of Acute Pancreatitis: 2014 Other Alcohol Biliary Alcohol Biliary Slide 14 Most common etiologies: Biliary Biliary (50%) Pathogenesis Mechanical obstruction Reflux of bile into pancreas duct Spectrum Gallstones Sludge (TPN) Microlithiasis 3-7% pts with gallstones- >AP Men: greatest risk of bil AP (size<5 mm) Women: highest incidence (higher prevalence of stones) Slide 15

6 Slide 16 Biliary Pancreatitis - Findings Subacute/acute onset of pain 4-6 hrs post prandial (fatty meal) ALT elevation >150 U/L (3x ULN) PPV of 95% for the diagnosis of gallstone pancreatitis (sens 45%) TUS in all pts with AP Natural Hx: Most often resolves on its own (stone passes) Subset pts benefit from ERCP (cholangitis/obstruction) CCY recommended in all candidates (to prevent recurrent attacks) Slide 17 Most common etiologies: Alcohol Alcohol (30%) Pathogenesis Direct oxidative stress on pancreas Increases pancreatic enzyme synthesis Disrupts intracellular membranes- >autodigestion Activates stellate cells of the pancreas->fibrosis <5% heavy drinkers >5 yrs of heavy use (>50 gm/day ~ 3-4/drinks/day) Isolated alcoholic binges rarely, if ever, cause pancreatitis) Other sensitizers: Genetics, Tobacco, Anatomy Slide 18 Most important causes?: the other 20%: Structural Pancreas divisum Choledochocele Sphincter of Oddi dysfunction Neoplasm (5-14%) Ampullary mass Cystic neoplasms (IPMN) Ductal AdenoCA Mets to pancreas Inflammatory Celiac disease Autoimmune Pancreatitis Vascular Vasculitis (PAN, SLE) Atheroembolism Cholesterol embolism Intra-op shock (CABG) Traumatic Post-ERCP Trauma (blunt) Metabolic Hypertriglyceridemia: >1000 mg/dl Hypercalcemia Exogenous Drugs: uncommon (6-MP, DDI, pentamadine, diuretics, flagyl, ACEI, tamoxifen) Infection: mumps, HIV, Legionella, Ascaris Smoking Genetic (CFTR/SPINK/PRSS1) <25 yo, recurrent AP, FHx

7 Slide 19 How to diagnose the other 20% High degree of clinical suspicion don t assume! All pts Lipids, Ca++ Careful family history Medication review (uncommon!) Travel history Imaging if >1 attack (<40 yrs old): pancreas divisum Evaluation for neoplasm with imaging (CT/MRI/EUS) Pts >40 yrs old first episode of AP Additional sxs: wt loss, new DM, FHx Smoldering or relapsing course Do not assume cysts seen with acute pancreatitis are pseudocysts; THINK CYSTIC NEOPLASM Controversial Sphincter of Oddi dysfunction Post cholecystectomy microlithiasis Slide 20 Spectrum of Acute Pancreatitis Frequency 80% Subtypes Cross sectional Imaging Course Interstitial None Infected Homogenous Sterile enhnacement Necrosis (nonenhancement, >30%) Edema/stranding Collections Resolves within 1 week Necrotizing 20% Location Peripancreatic + Pancreatic Peripancreatic Pancreatic (rare) Morphology Variable Slide 21 Initial Assessment and Risk Stratification Most patients do well (80%) Development of systemic inflammatory response syndrome (SIRS) and organ failure (OF) are associated with morbidity and mortality SIRS presence within first 24 hrs predicts organ failure SIRS 1) Temperature <36 C or >38 C >2 = SIRS 2) Respirations >20/min or PaCO2 <32 mmhg 3) Heart rate >90/min 4) WBC <4,000/mm(3) or WBC >12,000/mm(3)

8 Slide 22 Defining Organ Failure in 2014: Marshall Scoring System (PaO2/FiO2) (Cr) >2 = organ failure Slide 23 Classification of AP Atlanta Classification (1992) Revised Classification (2012) Slide 24 Patterns of Diseases Based on SIRS and OF 80% PTS AP Resolution 15% PTS AP SIRS OF Stabilization AP SIRS OF Stabilization Death

9 Slide 25 Mortality Rates of AP All comers: 2-3% Mild AP (interstitial): 1% Necrotizing pancreatitis: 17% Sterile: 12% Infected: 30% Multi-organ failure: 47% Experience counts <10% mortality for necrotizing pancreatitis in expert centers Slide 26 Case 68 yo M p/w acute onset of TUS: sharp epigastric pain, which Gallstones w/o cholecystitis has been unrelenting for 6 CBD 6 mm (otherwise nl) hours. +nausea/vomiting PMHx: HTN, CAD, GERD, CT: pancreatitis without necrosis remote PUD Initial VS: HR 114, BP 140/90 SIRS: YES mm Hg, RR 24, T 37.6 C, Organ Failure: NO O2 Sat 92% (RA) Labs: Amylase 1270 U/L (ULN 100), Lipase 3430 U/L (ULN 60) HCT 47%, WBC 18K, ALT 295, AST 221, AP 217, TB 0.9 mg/dl Slide 27 Can we predict severity? 2014: remain unable to accurately predict which pts with AP will develop severe disease Many scoring systems developed/available.few are practical and can be used early Clinical Scoring Systems Ranson (1976) APACHE II (14 inputs) BISAP Serologic CRP, HCT, BUN Radiologic Balthazar CT score

10 Slide 28 Can we predict severity? 2014: remain unable to accurately predict which pts with AP will develop severe disease Many scoring systems developed/available.few are practical and can be used early Clinical Scoring Systems Ranson (1976) APACHE II (14 inputs) BISAP Serologic CRP, HCT, BUN Radiologic Balthazar CT score Slide 29 Clinical Scoring system: BISAP (2008) BUN>25 mg/dl Impaired mental status (GCS <15) SIRS 1) Temperature <36 C or >38 C 2) Respirations >20/min or PaCO2 <32 mmhg 3) Heart rate >90/min 4) WBC <4,000/mm(3) or WBC >12,000/mm(3) or more than 10% bands found on blood smear. Age >60 Pleural effusion Slide 30 Case 68 yo M p/w acute onset of TUS: sharp epigastric pain, which Gallstones w/o cholecystitis has been unrelenting for 6 CBD 6 mm (otherwise nl) hours. +nausea/vomiting PMHx: HTN, CAD, GERD, CT: pancreatitis without necrosis remote PUD Initial VS: HR 114, BP 140/90 SIRS: YES mm Hg, RR 24, T 37.6 C, Organ Failure: NO O2 Sat 92% (RA) Labs: Amylase 1270 U/L (ULN 100), Lipase 3430 U/L (ULN BISAP= 3 (age, SIRS, BUN>25) 60) 5% mortality HCT 47%, WBC 18K, ALT 295, AST 221, AP 217, TB 0.9 mg/dl

11 Slide 31 Serologic tests as predictors of severity: CRP CRP The most widely studied inflammatory marker in AP >150 mg/l at 48 hrs PPV 67%, NPV 86% for severe pancreatitis Slide 32 Serologic tests as predictors of severity: BUN BUN Elevation at presentation (>22 mg/dl) Failure to decline in 24 hrs Marker of volume status/third spacing Slide 33 Serologic tests as predictors of severity: HCT Hematocrit Hemoconcentration (HCT>44%) at admission Reflects degree of third spacing Failure to reverse hemoconcentration is a/w worse outcomes Pts with HCT <44% and with decline in first 24hrs a/w benign clinical course

12 Slide 34 Need to look at the whole picture The Doctor Luke Fildes, 1891 Slide 35 Cross Sectional Imaging: Early Use Has Limited Value Necrosis takes time to develop 3 studies on early imaging Pts with a clinical dx of AP 50% CT scan, 15% MRI No alternative dx found Low frequency of necrosis (<5%) 2.5x CT/MRI over no change in severity of AP Use: dx uncertainty, pts not improving by day 4, or suspected local complication (lumenal obstruction, pseudoaneurysm) Slide 36 Defining Pancreatitis by Imaging: Sharing A Common Terminology

13 Slide 37 Acute Pancreatitis- Interstitial Edematous Acute Peripancreatic Fluid Collections Pseudocysts Slide 38 Acute Necrotizing Pancreatitis Acute Necrotic Collection Walled Off Pancreatic Necrosis WOPN Slide 39 Management Update 2014 Initial Treatment Strategies Role of ERCP Role/Timing of CCY Nutritional Considerations Management of Necrosis Antibiotics? Debridement Indications? Timing? Methods?

14 Slide 40 Multidisciplinary Approach is Essential GI Nursing Radiology Pancreatitis Internist Nutritionist Intensivist Surgery Slide 41 Initial Treatment Strategies (0-36 hrs): The Critical Window No medication has been shown to be effective for AP Early Aggressive Hydration (EAH) is essential! Offsets the cascade Inflammation Cell death Microvascular Permeability Hypovolemia Vomiting Reduce PO Tachypnea Diaphoresis Third spacing Slide 42 How to employ EAH? Needs to be individualized.based on age/comorbidities (Cr, EF%)

15 Slide 43 Employing an EAH plan Bolus: 20 ml/kg (1-2L) Infusion: 3 ml/kg/hr ( ml/hr) Lactated Ringers vs NS LR associated with lower CRP levels LR associated with less SIRS WHY?? Better electrolyte balance More ph balanced NS-> Non gap met acidosis->trypsinogen activation Guide fluid at 12 and 24 hrs based on BUN, HCT, clinical status (resp status, UO) Slide 44 Beware of over-hydration! After 24 hrs, need to be mindful of volume status Volume overload/pulmonary edema Abdominal compartment syndrome Sepsis?Lower survival Slide 45 Initial Treatment Strategies Part II Best Supportive Measures DVT prophylaxis Incenctive spirometry PPI prophylaxis Electrolyte stabilization Nutrition Control/Prevention of extrapancreatic infection

16 Slide 46 Role of early ERCP 1) Acute biliary pancreatitis: Most times ->stone passes Spontaneously-> no role for ERCP Clinical trials (6 meta-anlalysis) reduced M+M when ERCP impemented within 24h: Clinical or radiologic evidence of biliary obstruction (Tb>5, dilated ducts) and/or Ascending cholangitis Use MRCP/EUS to guide grey cases 2) Acute traumatic pancreatitis Stenting of ductal disruption (pancreatic duct) Slide 47 Slide 48 Update on Post-ERCP pancreatitis (PEP) Remains the most common complication decreasing frequency Frequency (5-40%) Most mild Severe: 1/500 Mechanisms: early enzyme activation Thermal Hydrostatic pressure

17 Slide 49 Prophylactic Measures Against PEP #1: Do not do the ERCP! #2: Guidewire cannulation #3: Periprocedural IVF #4: Pancreatic duct stenting #5: Rectal NSAIDs PEP reduced by 60% with rectal indomethacin Slide 50 Role of Cholecystectomy Lap CCY vs Wait and See (Lancet 2002): 120 pts randomized High rate of recurrent events (18% within 90 days) Mild biliary AP: CCY during index hospitalization Severe biliary AP: wait until pancreatitis resolves due to higher risk of infection Pts too frail for CCY? Consider ERCP/biliary sphincterotomy->eliminate risk of biliary AP Empric CCY for recurrent idiopathic AP,? Microlithiasis. Not indicated >50% recurrence of AP Slide 51 Nutritional Considerations Rethinking NPO Historically: NPO -> clears over days 1 st 24 hrs: NPO Multiple studies demonstrate providing oral feeding early in AP (pts without ileus) a/w: Reduced LOS Reduced infectious complications Reduced M+M Low residue, low fat soft diet = clear liquids

18 Slide 52 Nutritional Support: Intolerant of PO Avoid TPN = complications (infection/thrombosis), expensive Enteral feeding options a/w better outcomes, less expensive, safer Nasogastric: easier Nasojejunal: more physiologic NIH sponsored study NG vs NJT Slide 53 Case 68 yo M acute biliary pancreatitis (ALT, U/S) and evidence of SIRS (HR/RR/WBC) on admission without organ failure BISAP 3 HCT 44%, BUN 47 mg/dl GI Consulted NPO on admission EAH instituted (LR) Anti-emetics, PCA, PPI, no antibiotics HCT 44%->36% at 24 hrs BUN 47 mg/dl->39 mg d/l at 24 hrs Improving LFTs, no cholangitis: ERCP not recommended No evidence of OF Started on clears in 24 hrs then ADAT Lap CCY on HD 4 D/C home HD 5 Slide 54 Management of Necrosis Antibiotics? Debridement Indications? Timing? Method?

19 Slide 55 Role of Antibiotics in AP Infectious complications = major source of M+M Extrapancreatic (pneumonia, line, UTI, CDiff, cholangitis) Pancreatic (infected necrosis) A/w higher mortality rate (30%) than sterile necrosis Since 1993, 11 abx trials (quinolone, carbapenems) No advantage of empiric abx for necrotizing pancreatitis NNT = 1429 One trial (1995) suggest selective gut decontamination with oral antifungal/antibacterial -> reduced M+M Probiotics = increased M+M Slide 56 When should antibiotics be used? Extrapancreatic infections Suspected infected pancreatic necrosis Cinical deterioration No improvement after 7-10 days Persistent fever without source Gas on CT Options CT guided FNA (issues!) Empiric treatment: carbapenems, quinolones No evidence to support routine addition of antifungals Slide 57 Managing Necrosis.Debride or Not? Historically ANY Necrosis = early debridement Outcomes: High M+M 2014: Infected necrosis + unstable = urgent open surgical debridement 2014: Delay debridement for >30 days if stable Allows for necrosis to become organized May be able to avoid entirely asx necrosis does not require treatment

20 Slide 58 Methods of debridement Stable pts with symptomatic mature (>30 days) or walled off pancreatic necrosis/wopn Surgical debridement Open Laparoscopic VARDs Percutaneous (IR): limited Endoscopic Interventional Endoscopist Step up approach Factors: Size Location Vasculature Pancreatic Necrosis Local expertise/experience Surgery Interventional Radiology Slide 59 Endoscopic Necrosectomy Optimal for pts with WOPN in close apposition to stomach or duodenum Optimally done in tertiary care centers with expertise and back-up Assess contents with MRI (how much fluid vs solid) EUS guidance Create a tract (15-18mm) between stomach/duodenum and WOPN Enter space with scope and debride Leave stents from stomach into cyst space 24 hr lavage with saline/abx Repeat manuel debridement every 2-7 days depending upon amount/purulence Slide 60

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25 Slide 73 Slide 74 Slide 75 Data for Endoscopic Management of WOPN 2011 (GI Endoscopy) 104 pts/6 centers Mean time to procedure: 63 days Successful resolution: 91% LOS: 12 days Complications: 14% Bleeding Death (6%) 2012 (JAMA) 22 pts/4 centers RCT Endoscopic vs VARDS Better outcomes with endoscopic

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27 Slide Slide Slide 81 Take Home Messages 1. AP is a clinical diagnosis 2. Establish a specific etiology for AP 3. BUN/HCT are useful markers of severity. 4. Early aggressive hydration is essential Avoid hemoconcentration! 5. No role for empiric antibiotics. Use selectively 6. Urgent ERCP for obstruction/cholangitis 7. Post ERCP pancreatitis prophylaxis = standard of care 8. Earlier impementation of enteral nutrition; avoid TPN 9. Necrosectomy is best done in >4 weeks in stable, sxs pts 10. Minimally invasive approaches are effective for WOPN

28 Slide 82 THANK YOU!!