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

Normal Anatomy & Physiology neutralize chyme neutralize chyme digestive enzymes digestive enzymes hormones hormones

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

Enzyme Secretion pancreatic duct duodenum acinus microscopic view of pancreatic acini

Enzyme Secretion Hormonal CCK gastrin Neural acetylcholine VIP GRP Secretin (hormonal) H 2 O bicarbonate

Digestive Enzymes in the Pancreatic Acinar Cell PROTEOLYTICLIPOLYTIC ENZYMES ENZYMESLipase ENZYMESLipase TrypsinogenProphospholipase A2 ChymotrypsinogenCarboxylesterase lipase Proelastase Procarboxypeptidase ANUCLEASES Procarboxypeptidase BDeoxyribonuclease (DNAse) Ribonuclease (RNAse) AMYOLYTIC ENZYMES AmylaseOTHERS Procolipase Trypsin inhibitor

Normal Enzyme Activation trypsinogentrypsin chymotrypsin elastase phospholipase carboxypeptidase enterokinase chymotrypsinogen proelastase prophospholipase procarboxypeptidase duodenal lumen

Exocrine Stimulation The more proximal the nutrient infusion…the greater the pancreatic stimulation (dog studies) 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 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 Intravenous nutrients (even lipids) do not appear to stimulate the pancreas

Protective Measures COMPARTMENTALIZATION - digestive enzymes are contained within zymogen granules in acinar cells COMPARTMENTALIZATION - digestive enzymes are contained within zymogen granules in acinar cells REMOTE ACTIVATION - digestive enzymes are secreted as inactive proenzymes within the pancreas 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 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 AUTO “SHUT-OFF” – trypsin destroys trypsin in high concentrations

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

Acute Pancreatitis Etiology

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

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

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

Pancreas divisum

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

failed protective mechanisms acinar cell injury premature enzyme activation Acute Pancreatitis Pathogenesis

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

STAGE 1: Pancreatic Injury STAGE 1: Pancreatic Injury - Edema - Inflammation STAGE 2: Local Effects STAGE 2: Local Effects - Retroperitoneal edema - Ileus STAGE 3: Systemic Complications STAGE 3: Systemic Complications - Hypotension/shock - Metabolic disturbances - Sepsis/organ failure SEVERITYMildSevere Acute Pancreatitis Pathogenesis

Abdominal pain Abdominal pain - Epigastric - Radiates to the back - Worse in supine position Nausea and vomiting Nausea and vomiting Fever Fever Acute Pancreatitis Clinical Presentation

Acute Pancreatitis Differential Diagnosis Choledocholithiasis Choledocholithiasis Perforated ulcer Perforated ulcer Mesenteric ischemia Mesenteric ischemia Intestinal obstruction Intestinal obstruction Ectopic pregnancy Ectopic pregnancy

Symptoms Symptoms - Abdominal pain Laboratory Laboratory - Elevated amylase or lipase > 3x upper limits of normal > 3x upper limits of normal Radiology Radiology - Abnormal sonogram or CT Acute Pancreatitis Diagnosis

Causes of Increased Pancreatic Enzymes AmylaseLipase Pancreatitis↑↑ Parotitis↑Normal Biliary stone ↑↑ Intestinal injury ↑↑ Tubo-ovarian disease ↑Normal Renal failure ↑↑ Macroamylasemia↑Normal

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

Acute Pancreatitis Clinical Manifestations PANCREATICPERIPANCREATICSYSTEMIC 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

Acute Pancreatitis Time Course ER presentationcytokine releaseorgan failure

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

Severity Scoring Systems Ranson and Glasgow Criteria (1974) Ranson and Glasgow Criteria (1974) - based on clinical & laboratory parameters - scored in first hours of admission - poor positive predictors (better negative predictors) APACHE Scoring System 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 Computed Tomography Severity Index - much better diagnostic and predictive tool - optimally useful at hours after symptom onset

Ranson Criteria Alcoholic Pancreatitis AT ADMISSION 1. Age > 55 years 2. WBC > 16, Glucose > LDH > 350 IU/L 5. AST > 250 IU/L WITHIN 48 HOURS 1. HCT drop > BUN > 5 3. Arterial PO2 < 60 mm Hg 4. Base deficit > 4 mEq/L 5. Serum Ca < 8 6. Fluid sequestration > 6L Number Mortality <21% 3-416%5-640%7-8100%

Glasgow Criteria Non-alcoholic Pancreatitis 1. WBC > 15, Glucose > BUN > Arterial PO2 < 60 mm Hg 5. Ca < 8 6. Albumin < LDH > 600 U/L 8. AST or ALT > 200 U/L

CT Severity Index appearancenormalenlargedinflamed 1 fluid collection 2 or more collections gradeABCDE score01234 necrosisnone < 33% 33-50% > 50% score0246 scoremorbiditymortality1-24%0% %17% Balthazar et al. Radiology 1990.

Severe Acute Pancreatitis Scoring systems Scoring systems -  3 Ranson criteria -  8 APACHE II points -  5 CT points Organ failure Organ failure - shock (SBP < 90 mmHg) - pulmonary edema / ARDS (PaO 2 < 60 mmHg) - renal failure (Cr > 2.0 mg/dl) Local complications Local complications - fluid collections  pseudocysts - necrosis (mortality 15% if sterile, 30-35% if infected) - abscess

Goals of Treatment Limit systemic injury 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 necrosis – how? Prevent infection Prevent infection - antibiotics (imipenem and ciprofloxacin) – probably effective in necrotic pancreatitis - prevent colonic bacterial translocation - removing gallstones – variably effective

Treatment of Mild Pancreatitis Pancreatic rest Pancreatic rest Supportive care Supportive care - fluid resuscitation – watch BP and urine output - pain control - NG tubes and H 2 blockers or PPIs are usually not helpful Refeeding (usually 3 to 7 days) Refeeding (usually 3 to 7 days) - bowel sounds present - patient is hungry - nearly pain-free (off IV narcotics) - amylase & lipase not very useful here

Treatment of Severe Pancreatitis Pancreatic rest & supportive care 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 Rule-out necrosis - contrasted CT scan at hours - prophylactic antibiotics if present - surgical debridement if infected Nutritional support Nutritional support - may be NPO for weeks - TPN vs. enteral support (TEN)

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

Nutrition in Acute Pancreatitis Metabolic stress 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 Altered substrate metabolism - increased cortisol & catecholamines - increased glucagon to insulin ratio - insulin resistance Micronutrient alterations Micronutrient alterations - calcium, magnesium, potassium, etc

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

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

Factors Differentiating Mild from Severe Pancreatitis ParameterMildPancreatitisSeverePancreatitis Admissions80%20% Pancreatic necrosis NoYes Oral diet within 5 days 80%0% Morbidity8%38% Mortality3%27%

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

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

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

McClave et al Kalfarenztos et al Windsor et al No of patients Etiology EtOH 19/ Biliary 23/34 Severe pancreatitis 19%100%38% Enteral formula Semi-elementalSemi-elementalPolymeric Cost 5x less 3x less - - Outcome No difference Fewer comp Less SIRS Summary of Prospective RCTs Enteral vs Parenteral Nutrition for Acute Pancreatitis

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

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