Acute Pancreatitis Rajeev Jain M D December 15

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

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

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

Enzyme Secretion acinus pancreatic duct microscopic view of pancreatic acini duodenum

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

Digestive Enzymes in the Pancreatic Acinar Cell PROTEOLYTIC ENZYMES Trypsinogen Chymotrypsinogen Proelastase Procarboxypeptidase A Procarboxypeptidase B AMYOLYTIC ENZYMES Amylase LIPOLYTIC ENZYMES Lipase Prophospholipase A 2 Carboxylesterase lipase NUCLEASES Deoxyribonuclease (DNAse) Ribonuclease (RNAse) OTHERS Procolipase Trypsin inhibitor

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

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

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

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

Acute Pancreatitis Etiology

Acute Pancreatitis Associated Conditions • 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 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

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

Pancreas divisum

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 (R 122 H) • Other genetic defects - CFTR - SPINK 1

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

Acute Pancreatitis Pathogenesis premature enzyme activation autodigestion of pancreatic tissue local vascular insufficiency local complications activation of white blood cells release of enzymes into the circulation distant organ failure

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

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

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

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

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

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

Acute Pancreatitis Clinical Manifestations PANCREATIC PERIPANCREATIC 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 SYSTEMIC Cardiovascular: hypotension Pulmonary: pleural effusions, ARDS Renal: acute tubular necrosis Hematologic: disseminated intravascular coag. Metabolic: hypocalcemia, hyperglycemia

Acute Pancreatitis Time Course ER presentation cytokine release organ failure

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?

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

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

Glasgow Criteria Non-alcoholic Pancreatitis 1. 2. 3. 4. 5. 6. 7. 8. WBC > 15, 000 Glucose > 180 BUN > 16 Arterial PO 2 < 60 mm Hg Ca < 8 Albumin < 3. 2 LDH > 600 U/L AST or ALT > 200 U/L

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.

Severe Acute Pancreatitis • Scoring systems - 3 Ranson criteria - 8 APACHE II points - 5 CT points • Organ failure - shock (SBP < 90 mm. Hg) - pulmonary edema / ARDS (Pa. O 2 < 60 mm. Hg) - renal failure (Cr > 2. 0 mg/dl) • Local complications - fluid collections pseudocysts - necrosis (mortality 15% if sterile, 30 -35% if infected) - abscess

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

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

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)

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

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

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

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

Factors Differentiating Mild from Severe Pancreatitis Mild Severe Pancreatitis Admissions 80% 20% Pancreatic necrosis No Yes Oral diet within 5 days 80% 0% Morbidity 8% 38% Mortality 3% 27% Parameter

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

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

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 4 x 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

Summary of Prospective RCTs Enteral vs Parenteral Nutrition for Acute Pancreatitis Mc. Clave et al. Kalfarenztos et al. Windsor et al. 1997 1998 No of patients 32 38 34 Etiology Et. OH 19/32 -- Biliary 23/34 19% 100% 38% Semi-elemental Polymeric Cost 5 x less 3 x less -- Outcome No difference Fewer comp Less SIRS Severe pancreatitis Enteral formula

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

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.