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Acute Pancreatitis

  1. Acute Pancreatitis Rajeev Jain, M.D. December 15, 2003
  2. Normal Anatomy & Physiology • neutralize chyme • digestive enzymes • hormones
  3. Exocrine Function pancreatic duct common bile duct ampulla pancreatic enzymes TAIL BODY HEAD UNCINATE
  4. Enzyme Secretion pancreatic duct duodenum acinus microscopic view of pancreatic acini
  5. Enzyme Secretion Hormonal CCK gastrin Neural acetylcholine VIP GRP 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 trypsinogen trypsin chymotrypsin elastase phospholipase carboxypeptidase enterokinase chymotrypsinogen proelastase prophospholipase procarboxypeptidase duodenal lumen
  8. Exocrine Stimulation • The more proximal 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 Pancreatitis Definition • 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. EtOH 35% Idiopathic 10% Other 10% Gallstones 45% Acute Pancreatitis Etiology
  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 Pancreatitis Associated Conditions
  13. Acute Pancreatitis Causative 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 2.5 4.8 12.4 42.1 0 5 10 15 20 25 30 35 40 45 Pancreatitis, ORs Female Nl TBili SOD Difficult cannulation 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. failed protective mechanisms acinar cell injury premature enzyme activation Acute Pancreatitis Pathogenesis
  18. autodigestion of pancreatic tissue release of enzymes into the circulation activation of white blood cells local complications local vascular insufficiency premature enzyme activation distant organ failure Acute Pancreatitis Pathogenesis
  19. • STAGE 1: Pancreatic Injury - Edema - Inflammation • STAGE 2: Local Effects - Retroperitoneal edema - Ileus • STAGE 3: Systemic Complications - Hypotension/shock - Metabolic disturbances - Sepsis/organ failure SEVERITY Mild Severe Acute Pancreatitis Pathogenesis
  20. • Abdominal pain - Epigastric - Radiates to the back - Worse in supine position • Nausea and vomiting • Fever Acute Pancreatitis Clinical Presentation
  21. Acute Pancreatitis Differential Diagnosis • Choledocholithiasis • Perforated ulcer • Mesenteric ischemia • Intestinal obstruction • Ectopic pregnancy
  22. • Symptoms - Abdominal pain • Laboratory - Elevated amylase or lipase • > 3x upper limits of normal • Radiology - Abnormal sonogram or CT Acute Pancreatitis Diagnosis
  23. Causes of Increased Pancreatic Enzymes Amylase Lipase Pancreatitis ↑ ↑ Parotitis ↑ Normal Biliary stone ↑ ↑ Intestinal injury ↑ ↑ Tubo-ovarian disease ↑ Normal Renal failure ↑ ↑ Macroamylasemia ↑ Normal
  24. Acute Pancreatitis Diagnosis • 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 Pancreatitis Clinical 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 Pancreatitis Time Course 0 12 24 36 48 60 72 84 96 hours from pain onset 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. Ranson Criteria Alcoholic Pancreatitis AT ADMISSION 1. Age > 55 years 2. WBC > 16,000 3. Glucose > 200 4. LDH > 350 IU/L 5. AST > 250 IU/L WITHIN 48 HOURS 1. HCT drop > 10 2. BUN > 5 3. Arterial PO2 < 60 mm Hg 4. Base deficit > 4 mEq/L 5. Serum Ca < 8 6. Fluid sequestration > 6L Number Mortality <2 1% 3-4 16% 5-6 40% 7-8 100%
  30. Glasgow Criteria Non-alcoholic Pancreatitis 1. WBC > 15,000 2. Glucose > 180 3. BUN > 16 4. Arterial PO2 < 60 mm Hg 5. Ca < 8 6. Albumin < 3.2 7. LDH > 600 U/L 8. AST or ALT > 200 U/L
  31. CT Severity Index appearance normal enlarged inflamed 1 fluid collection 2 or more collections grade A B C D E score 0 1 2 3 4 necrosis none < 33% 33-50% > 50% score 0 2 4 6 score morbidity mortality 1-2 4% 0% 7-10 92% 17% 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) – probably effective 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 Parameter Mild Pancreatitis Severe Pancreatitis Admissions 80% 20% Pancreatic necrosis No Yes Oral diet within 5 days 80% 0% Morbidity 8% 38% Mortality 3% 27%
  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 early post-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. McClave et al. 1997 Kalfarenztos et al. 1997 Windsor et al. 1998 No of patients 32 38 34 Etiology EtOH 19/32 - - Biliary 23/34 Severe pancreatitis 19% 100% 38% Enteral formula Semi-elemental Semi-elemental Polymeric Cost 5x less 3x less - - Outcome No difference Fewer comp Less SIRS Summary of Prospective RCTs Enteral 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.

Hinweis der Redaktion

  1. The pancreas lies in the retroperitoneum nestled in the C-loop of the duodenum and posterior to the stomach. Physiologic function of the pancreas. The human pancreas has three general functions: (1) neutralizing the acid chyme entering the duodenum from the stomach; (2) synthesis and secretion of digestive enzymes after a meal; and (3) systemic release of hormones that modulate metabolism of carbohydrates, proteins, and lipids.
  2. To understand pancreatitis, you need a basic understanding of pancreatic exocrine function
  3. The pancreatic acinar cells are specialized cells which synthesize, store, and secrete digestive enzymes These digestive enzymes are stored in zymogen granules (shown in blue) which serve as a compartment for inactive pro-enzymes thus preventing auto-activation.
  4. Enzyme secretion is stimulated by neural pathways or by hormones with 2 most potent stimulators being CCK and secretin. The pancreatic fluid is rich in bicarbonate which makes it alkaline and the total daily volume is approx. 2.5 L.
  5. There are several different classes of digestive enzymes secreted by the pancreatic acinar cells. Most of these enzymes are proenzymes which are inactive with the exceptions of amylase and lipase. Protein Starch and glycogen Fat Amino acids Other
  6. This slide shows the mechanism of proenzyme activation in the intestinal lumen. The duodenum is the most important sensory organ involved in pancreatic secretion, and is the site where the meal and pancreatic exocrine secretions meet. The duodenal mucosa contains endocrine cells, which release secretin in response to luminal acid, and cholecystokinin (CCK) in response to proteins or fats. The duodenum is also rich in sensory (afferent) vagal nerve fibers that respond to changes in pH, amino acids, lipids, and express receptors for CCK and secretin. Trypsin can catalyze the activation of other zymogens Once trypsin is present in an amount that exceeds the ability of trypsin inhibitor to inactivate it, trypsin can catalyze the activation of other zymogens (eg, chymotrypsinogen, proelastase, procarboxypeptidase A and B, prophospholipase A), as well as of trypsinogen itself, initiating the ;autodigestion; of the pancreas.
  7. Here are the details…
  8. ORs adjusted for their independent effect relative to a reference rate of pancreatitis of 1.1% for a typical low-risk patient (male, elevated bilirubin but no chronic pancreatitis and w/o any risk factors)
  9. talk about failure of compartmentalization, premature activation, and overwhelming or absence of inhibitors
  10. Three stages of pathophysiology of acute pancreatitis The pathophysiology of acute pancreatitis can be considered as involving three stages. The first stage is pancreatic injury with edema, inflammation, necrosis of pancreatic fat, and variable degrees of necrosis of pancreatic secretory cells. The second stage is spread of the inflammatory process to surrounding tissues, with development of retroperitoneal edema, peripancreatic fat necrosis, and an ileus, with ;third spacing; of fluid and electrolytes in the gastrointestinal tract resulting in hemoconcentration (increased hematocrit). The third stage involves systemic complications, such as hypotension/shock, multiorgan system failure (eg, respiratory, renal), metabolic disturbances, such as hypoalbuminemia and hypocalcemia, and sepsis.
  11. In the early stages of pancreatic injury and inflammation, proinflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-8, and tumor necrosis factor (TNF)-A, appear to be released from tissue macrophages within the pancreas. Neutrophil activation likely results from release of IL-8 from macrophages and endothelial cells and release of platelet-activating factor (PAF) from endothelial cells. Later in the process, release of cytokines from T-helper lymphocytes (eg, IL-2, interferon- C) may also participate in the inflammatory response [3]
  12. Resent data has curbed some of the excitement re: use of APACHE in early pancreatitis. In short, prediction of severity is sub optimal at the present time.
  13. So, even if we can’t identify severe cases sooner, the CT index appears to be the best way to judge severity.
  14. intestinal decontamination study – no improvement
  15. mild panc – support is all that’s needed hypotension probably predisposes to necrosis (poor microcirculation)
  16. *common serious error to underestimate volume needs may need SG catheter – lookout for ARF or ARDS we have impacted the early mortality by better support…late mortality still problem
  17. elevated TG cause acute panc and are present in EtOH panc.
  18. No evidence that early TPN does anything but increase infectious events.