Acute Pancreatitis

1. Acute Pancreatitis Rajeev Jain, M.D. December 15, 2003

2. neutralize chyme digestive enzymes hormones Normal Anatomy & Physiology

3. Exocrine Function BODY common bile duct TAIL HEAD pancreatic duct ampulla UNCINATE pancreatic enzymes

4. Enzyme Secretion acinus pancreatic duct microscopic view of pancreatic acini duodenum

5. Enzyme Secretion Neural acetylcholine VIP GRP Hormonal CCK gastrin Secretin (hormonal) H2O bicarbonate

6. Digestive Enzymes in the Pancreatic Acinar Cell PROTEOLYTIC LIPOLYTIC ENZYMES ENZYMES Lipase Trypsinogen Prophospholipase A2 Chymotrypsinogen Carboxylesterase lipase Proelastase Procarboxypeptidase A NUCLEASES Procarboxypeptidase B Deoxyribonuclease (DNAse) Ribonuclease (RNAse) AMYOLYTIC ENZYMES Amylase OTHERS Procolipase Trypsin inhibitor

7. Normal Enzyme Activation enterokinase duodenal lumen trypsinogen trypsin chymotrypsinogen proelastase prophospholipase procarboxypeptidase chymotrypsin elastase phospholipase carboxypeptidase

8. Exocrine Stimulation • The moreproximal the nutrient infusion…the greater the pancreatic stimulation (dog studies) • stomach – maximal stimulation • duodenum – intermediate stimulation • jejunum – minimal / negligible stimulation • Elemental formulas tend to cause less stimulation than standard intact formulas • intact protein > oligopeptides > free amino acids • Intravenous nutrients (even lipids) do not appear to stimulate the pancreas

9. Protective Measures • COMPARTMENTALIZATION - digestive enzymes are contained within zymogen granules in acinar cells • REMOTE ACTIVATION - digestive enzymes are secreted as inactive proenzymes within the pancreas • PROTEASE INHIBITORS – trypsin inhibitor is secreted along with the proenzymes to suppress any premature enzyme activation • AUTO “SHUT-OFF” – trypsin destroys trypsin in high concentrations

10. Acute PancreatitisDefinition • Acute inflammatory process involving the pancreas • Usually painful and self-limited • Isolated event or a recurring illness • Pancreatic function and morphology return to normal after (or between) attacks

11. Acute PancreatitisEtiology

12. Cholelithiasis Ethanol abuse Idiopathic Medications Hyperlipidemia ERCP Trauma Pancreas divisum Hereditary Hypercalcemia Viral infections Mumps Coxsackievirus End-stage renal failure Penetrating peptic ulcer Acute PancreatitisAssociated Conditions

13. Acute PancreatitisCausative Drugs • AIDS therapy: didanosine, pentamidine • Anti-inflammatory: sulindac, salicylates • Antimicrobials: metronidazole, sulfonamides, tetracycline, nitrofurantoin • Diuretics: furosemide, thiazides • IBD: sulfasalazine, mesalamine • Immunosuppressives: azathioprine, 6-mercaptopurine • Neuropsychiatric: valproic acid • Other: calcium, estrogen, tamoxifen, ACE-I

14. Adjusted ORs for Pancreatitis Freeman et al. Gastrointest Endosc. ‘97.

15. Pancreas divisum

16. Hereditary Pancreatitis • Autosomal dominant with 80% phenotypic penetrance • Recurrent acute pancreatitis, chronic pancreatitis, and 50-fold increased risk of pancreatic cancer • Mutation in cationic trypsinogen gene (R122H) • Other genetic defects • CFTR • SPINK1

17. prematureenzyme activation Acute PancreatitisPathogenesis acinar cell injury failed protectivemechanisms

18. Acute PancreatitisPathogenesis premature enzyme activation autodigestion of pancreatic tissue local vascular insufficiency activation of white blood cells release ofenzymes into the circulation localcomplications distantorgan failure

19. Acute PancreatitisPathogenesis SEVERITY Mild Severe • STAGE 1: Pancreatic Injury • Edema • Inflammation • STAGE 2: Local Effects • Retroperitoneal edema • Ileus • STAGE 3: Systemic Complications • Hypotension/shock • Metabolic disturbances • Sepsis/organ failure

20. Acute PancreatitisClinical Presentation • Abdominal pain • Epigastric • Radiates to the back • Worse in supine position • Nausea and vomiting • Fever

21. Acute PancreatitisDifferential Diagnosis • Choledocholithiasis • Perforated ulcer • Mesenteric ischemia • Intestinal obstruction • Ectopic pregnancy

22. Acute PancreatitisDiagnosis • Symptoms • Abdominal pain • Laboratory • Elevated amylase or lipase • > 3x upper limits of normal • Radiology • Abnormal sonogram or CT

23. Causes of IncreasedPancreatic Enzymes

24. Acute PancreatitisDiagnosis • EtOH: history • Gallstones: abnormal LFTs & sonographic evidence of cholelithiasis • Hyperlipidemia: lipemic serum, Tri>1,000 • Hypercalcemia: elevated Ca • Trauma: history • Medications: history, temporal association

25. Acute PancreatitisClinical Manifestations PANCREATIC PERIPANCREATIC SYSTEMIC Mild: edema, inflammation, fat necrosis Severe: phlegmon, necrosis, hemorrhage, infection, abscess, fluid collections Retroperitoneum, perirenal spaces, mesocolon, omentum, and mediastinum Adjacent viscera: ileus, obstruction, perforation Cardiovascular: hypotension Pulmonary: pleural effusions, ARDS Renal: acute tubular necrosis Hematologic: disseminated intravascular coag. Metabolic: hypocalcemia, hyperglycemia

26. Acute PancreatitisTime Course ER presentation cytokine release organ failure

27. Predictors of Severity • Why are they needed? • appropriate patient triage & therapy • compare results of studies of the impact of therapy • When are they needed? • optimally, within first 24 hours (damage control must begin early) • Which is best?

28. Severity Scoring Systems • Ranson and Glasgow Criteria (1974) • based on clinical & laboratory parameters • scored in first 24-48 hours of admission • poor positive predictors (better negative predictors) • APACHE Scoring System • can yield a score in first 24 hours • APACHE II suffers from poor positive predictive value • APACHE III is better at mortality prediction at > 24 hours • Computed Tomography Severity Index • much better diagnostic and predictive tool • optimally useful at 48-96 hours after symptom onset

29. AT ADMISSION Age > 55 years WBC > 16,000 Glucose > 200 LDH > 350 IU/L AST > 250 IU/L WITHIN 48 HOURS HCT drop > 10 BUN > 5 Arterial PO2 < 60 mm Hg Base deficit > 4 mEq/L Serum Ca < 8 Fluid sequestration > 6L Ranson CriteriaAlcoholic Pancreatitis Number <2 1% 3-4 16% 5-6 40% 7-8 100% Mortality

30. Glasgow CriteriaNon-alcoholic Pancreatitis • WBC > 15,000 • Glucose > 180 • BUN > 16 • Arterial PO2 < 60 mm Hg • Ca < 8 • Albumin < 3.2 • LDH > 600 U/L • AST or ALT > 200 U/L

31. CT Severity Index Balthazar et al. Radiology 1990.

32. Severe Acute Pancreatitis • Scoring systems •  3 Ranson criteria •  8 APACHE II points •  5 CT points • Organ failure • shock (SBP < 90 mmHg) • pulmonary edema / ARDS (PaO2 < 60 mmHg) • renal failure (Cr > 2.0 mg/dl) • Local complications • fluid collections  pseudocysts • necrosis (mortality 15% if sterile, 30-35% if infected) • abscess

33. Goals of Treatment • Limit systemic injury • support and resuscitation – effective • decrease pancreatic secretion – ineffective / harmful? • inhibit inflammatory mediators – ineffective • inhibit circulating trypsin – ineffective (too late) • removing gallstones – mostly ineffective • Prevent necrosis– how? • Prevent infection • antibiotics (imipenem and ciprofloxacin) – probablyeffective in necrotic pancreatitis • prevent colonic bacterial translocation • removing gallstones – variably effective

34. Treatment of Mild Pancreatitis • Pancreatic rest • Supportive care • fluid resuscitation – watch BP and urine output • pain control • NG tubes and H2 blockers or PPIs are usually not helpful • Refeeding (usually 3 to 7 days) • bowel sounds present • patient is hungry • nearly pain-free (off IV narcotics) • amylase & lipase not very useful here

35. Treatment of Severe Pancreatitis • Pancreatic rest & supportive care • fluid resuscitation* – may require 5-10 liters/day • careful pulmonary & renal monitoring – ICU • maintain hematocrit of 26-30% • pain control – PCA pump • correct electrolyte derangements (K+, Ca++, Mg++) • Rule-out necrosis • contrasted CT scan at 48-72 hours • prophylactic antibiotics if present • surgical debridement if infected • Nutritional support • may be NPO for weeks • TPN vs. enteral support (TEN)

36. Role of ERCP • Gallstone pancreatitis • Cholangitis • Obstructive jaundice • Recurrent acute pancreatitis • Structural abnormalities • Neoplasm • Bile sampling for microlithiasis • Sphincterotomy in patients not suitable for cholecystectomy

37. Nutrition in Acute Pancreatitis • Metabolic stress • catabolism & hypermetabolism seen in 2/3 of patients • similar to septic state (volume depletion may be a major early factor in the above derangements) • Altered substrate metabolism • increased cortisol & catecholamines • increased glucagon to insulin ratio • insulin resistance • Micronutrient alterations • calcium, magnesium, potassium, etc

38. Systemic Changes in Acute Pancreatitis • Hyperdynamic • Increased cardiac output • Decreased systemic vascular resistance • Increased oxygen consumption • Hypermetabolism • Increased resting energy expenditure • Catabolism • Increased proteolysis of skeletal muscle

39. Reduced Oral Intake in Acute Pancreatitis • Abdominal pain with food aversion • Nausea and vomiting • Gastric atony • Ileus • Partial duodenal obstruction

40. Factors Differentiating Mild from Severe Pancreatitis

41. TPN in Acute Pancreatitis • delay until volume repleted & electrolytes corrected • check triglycerides first – goal <400 • lipids are OK to use (possible exception of sepsis) • monitor glucose levels carefully • can see insulin insufficiency and resistance • may need to limit calories at first • separate insulin drip may be needed

42. TPN in Acute Pancreatitis • Benefit or harm? • early uncontrolled studies suggested benefit • two retrospective studies (70’s & 80’s) showed no benefit with TPN in pancreatitis • 1987 – randomized study of early TPN vs. IVF alone showed more sepsis, longer stays, & no fewer complications with TPN • When to use TPN? • jejunal access is unavailable • ileus prevents enteral feeding • patients in whom TEN clearly exacerbates pancreatitis

43. Enteral Nutrition in Acute Pancreatitis • studies • late 80’s – patients who received jejunal feeding tubes at the time of surgery, did well with earlypost-op enteral support • 1991 – randomized study of early TPN vs. early TEN post-op showed no short-term difference • 1997 – early TPN vs. early TEN (Peptamen) via nasojejunal tube in 32 patients showed no difference except 4x less cost & less hyperglycemia • 1997 – similar study showed fewer complications and lower cost without change in length of stay • 1998 – similar study showed more sepsis and organ failure in the TPN group

44. Summary of Prospective RCTsEnteral vs Parenteral Nutrition for Acute Pancreatitis

45. Total Enteral Nutrition in Severe Pancreatitis • may start as early as possible • when emesis has resolved • ileus is not present • nasojejunal route preferred over nasoduodenal • likely decreases risk of infectious complications by reducing transmigration of colonic bacteria

46. Conclusions • Acute pancreatitis is a self-limited disease in which most cases are mild. • Gallstones and alcohol are the leading causes of acute pancreatitis. • In mild pancreatitis, nutritional support is usually not required • In severe pancreatitis, nutritional support will likely be required with the enteral route preferred over TPN because of both safety and cost.