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Acute Pancreatitis: Management Update

Acute Pancreatitis: Management Update. Jamie S. Barkin, M.D., MACP, MACG, AGAF, FASGE Professor of Medicine University of Miami, Miller School of Medicine Chief, Division of Gastroenterology Mount Sinai Medical Center. Overview of Acute Pancreatitis.

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Acute Pancreatitis: Management Update

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  1. Acute Pancreatitis: Management Update Jamie S. Barkin, M.D., MACP, MACG, AGAF, FASGE Professor of Medicine University of Miami, Miller School of Medicine Chief, Division of Gastroenterology Mount Sinai Medical Center

  2. Overview of Acute Pancreatitis • 85% of patients have interstitial pancreatitis; 15 (range 4 – 47%) have necrotizing pancreatitis • Among patients with necrotizing pancreatitis, 33% (range 16-47%) have infected necrosis • Approximately 10% of patients with interstitial pancreatitis experience organ failure, but in the majority it is transient • Mortality in acute pancreatitis overall, is approximately 5%: 3% in interstitial pancreatitis, 17% in necrotizing pancreatitis • In necrotizing pancreatitis, mortality 3-fold infected vs. sterile necrosis • Mortality increases with development of organ failure ~ 3% (0-8%) and with multi-system organ failure 47% (range 28-69) ACG Practice Guidelines in Acute Pancreatitis Am J Gastroenterol 2006;101:2379-2400

  3. Acute Pancreatitis:Concepts 2009 1) Volume replacement is the foundation of therapy 2) Establish severity • Utilize initial laboratory data • standardized modalities i.e. Ranson criteria require 48 hrs • CT abnormalities correlate with severity • No need for early CT to establish severity 3) Establish etiology • Importance is to prevent recurrence 4) Biliary Pancreatitis • Utilize laboratory markers for diagnosis of retained CBD • ERCP is only for treating patients with cholangitis

  4. Acute Pancreatitis: Concepts 2009 5)Do not use prophylactic antibiotics 6) CT guided aspiration is the diagnostic test for pancreatic infection & allows directed antibiotic therapy

  5. Acute Pancreatitis:Concepts 2009 (Cont) 7) Surgical intervention in patients with infected pancreatic necrosis but rarely in sterile necrosis 8) Early enteral feeding is safe, prevents leaky gut and is associated with less complications than TPN

  6. Definition of Severe Acute Pancreatitis (SAP) • SAP is acute pancreatitis with local and/or systemic complications • Local complications are: • necrotizing pancreatitis • Infected necrosis • Pancreatic abscess • Peripancreatic fluid collection and pseudocystic lesions • Systemic complications are: • Pulmonary and renal failure • Shock • Cardio-circulatory dysfunctions • systemic sepsis • coagulation disorder Bradley EL, III. Arch Surg 1993;128:585-590

  7. Acute Pancreatitis: Mechanisms of Intra and-Extrapancreatic Inflammation • Mediated by cytokines and other inflammatory mediators: • Activation of inflammatory cells • Chemo-attraction of activated inflammatory cells to the microcirculation • Activation of adhesion molecules allowing the binding of inflammatory cells to the endothelium • Migration of activated inflammatory cells into areas of inflammation ACG Practice Guidelines in Acute Pancreatitis. Am J Gastroenterol 2006;101:2379-2400

  8. Acute Pancreatitis Mechanism of organ dysfunction Volume depletion Visceral hypofusion  Capillary permeability  bowel permeability (  TNF, IL6, angioprotin adipokines) Bacterial translocation SIRS David Whitcomb, M.D.

  9. Causes of mortality DEATH Late (> one week) • Multiorgan failure • Pancreatic infections/sepsis Early (< one week) • Systemic inflammatory response syndrome (SIRS) • Multiorgan failure Acute Pancreatitis

  10. Systemic Inflammatory Response Syndrome (SIRS) ACG Practice Guidelines in Acute Pancreatitis Am J Gastroenterol 2006;101:2379-2400

  11. Prognosis in Acute Pancreatitis Prognosis • Bedside Assessment Underestimates severe disease • Scoring Systems Ranson, Glasgow, Apache, Rabenek • Serum Markers Trypsinogen activation peptide (TAP) C-reactive protein (CRP) Cytokines • Imaging criteria Fluid collections, necrosis Acute Pancreatitis

  12. Early Diagnostic Indicators in Acute Pancreatitis • Tachycardia, hypotension • Tachypnea, hypoxemia • Hemoconcentration • Oliguria • Encephalopathy Acute Pancreatitis Early Indicators of Severity

  13. Organ Dysfunction Affects Prognosis in Acute Pancreatitis 100 100 No organ dysfunction No deteriorating dysfunction Organ dysfunction 75 75 % Survival rate 50 50 Deteriorating dysfunction 25 25 0 10 20 30 40 50 60 70 80 90 Time (days) Time (days) 0 10 20 30 40 50 60 70 80 90 Acute Pancreatitis Organ Dysfunction Affects Prognosis A Buter et al., Brit. J. Surgery 2002; 89:298

  14. Obesity Worsens the Prognosis in Acute Pancreatitis Autoimmune Pancreatitis Obesity Worsens Prognosis 60 Effect may be greatest with a high waist / hip fat ratio Possible Mechanisms • ­ Free fatty acids • ­ Cytokines (TNFaIL-6) • ¯ Reduced diaphragmatic excursion Severe Pancreatitis Systemic complications 40 % Patients 20 0 <25 25-29 >29 Body Mass Index (kg/m2) J Martinez et al., Pancreas 1999; 19:15

  15. Diagnostic Guideline I: Look for Risk Factors of Severity at Admission • Older age (>55 yrs) • Obesity – BMI > 30 • Organ failure at admission • Pleural effusion and/or infiltrates • When organ failure is corrected within 48 hours, mortality is close to 0 • When organ failure persists for more than 48 h, mortality is 36% Level of Evidence III ACG Practice Guidelines in Acute Pancreatitis Am J Gastroenterol 2006;101:2379-2400

  16. APACHE II score = (acute physiology score) • Rectal temperature (C) • Mean arterial pressure (mmHg) • Heart rate (bpm) • Respiratory rate (bpm) • Oxygen delivery (mL/min) • PO2 mmHg) • Arterial pH • Serum sodium (mmol/L • Serum potassium (mmol/L) • Serum creatinine (mg/dL) • Hematocrit (%) • White cell count (103 /mL) • History of severe organ insufficiency ACG Practice Guidelines in Acute Pancreatitis. Am J Gastroenterol 2006;101:2379-2400

  17. Diagnostic Guideline II: Determination of severity by Laboratory Tests at Admission or < 48 Hours Level of Evidence III • Hematocrit ≥ 44 at admission and failure of admission hematocrit to decrease at 24 h are the best predictors of necrotizing pancreatitis – Absence of hemoconcentration at admission or during the first 24 h is strongly suggestive of a benign clinical course • C-reactive protein greater than 150 mg/L within the first 72 h of disease correlate with the presence of necrosis with a sensitivity and specificity that are both >80% –The peak of c-reactive protein is generally 36 – 72 h after admission, therefore this test is not helpful at admission in assessing severity ACG Practice Guidelines in Acute Pancreatitis Am J Gastroenterol 2006;101:2379-2400

  18. Hematocrit and Severity of Acute Pancreatitis Criteria Incidence of Necrosis Admission hematocrit >44% 50% OR fails to fall over first 24 hours Neither present 4% Acute Pancreatitis Hematocrit and Severity Brown J, et al., Pancreas 2000; 20:367

  19. Indications for Computed Tomography (CT) in Acute Pancreatitis Computed Tomography: Indications • Diagnosis • Prognosis • Detect complications Acute Pancreatitis

  20. Modified CT Severity Index Ref: Mortele K, et al. AJR 2004;183:1261-1265 Summary: Significant correlation with severity and organ failure

  21. Computed Tomography and Magnetic Resonance Imaging in the Assessment of Acute Pancreatitis Aim: To compare the accuracy of magnetic resonance imaging with computed tomography in assessing acute pancreatitis Method: MRI was performed with intravenous secretin and contrast medium Results • 39 patients were studied • Acute pancreatitis was assessed clinically as severe in 7 patients • Considering the Ranson score, MRI detected severe AP with 83% (58-96, 95% CI); sensitivity, 91% (68-98) specificity vs. 78% (52-93) and 86% (63-96) for CT • Magnetic resonance showed pancreatic duct leakage in 3 patients (8%) Arvanitakis M, et al. Gastroenterology 2004;126(3):715-23

  22. MRI Provides Prognostic Information in Acute Pancreatitis Acute Pancreatits MRI Provides Prognostic Information in Acute Pancreatitis CT vs MRI Score 10 8 6 CT-SI 4 2 0 2 4 6 8 10 0 MR-SI Arvanitakis, Gastro 2004,126

  23. Diagnostic Guideline IIIDetermination of Severity During Hospitalization Contrast-Enhanced CT Scan Not on admission if diagnosis is determined - • A few days after admission to distinguish interstitial from necrotizing pancreatitis when there is clinical evidence of increased severity. Level of Evidence III • To guide aspiration in patients with fluid collection to determine if infected ACG Practice Guidelines in Acute Pancreatitis Am J Gastroenterol 2006;101:2379-2400

  24. Etiologies of acute pancreatitis Acute Pancreatitis Etiologies

  25. Acute Idiopathic Pancreatitis: does it really exist or is it a myth? Background: • Gallstones and alcohol abuse are the most frequent causes (75% of patients) of acute pancreatitis • Consider hyperlipidemia, hypercalcemia and drugs • In 10% to 40%, no cause is identified • Identifying a cause in these patients is important, since the recurrence rate is high • Van Brummelen SE, et al. Scand J Gastroenterol (Suppl) 2003;(239):117-22

  26. Microlithiasis is the Most Common Cause Acute Idiopathic Pancreatitis Results: • Microlithiasis or biliary sludge is an important cause of acute ‘idiopathic’ pancreatitis in up to 80% of patients • Microlithiasis can be detected by trans-abdominal/endoscopic ultrasonography or polarizing light microscopy of bile • Acute pancreatitis can be prevented by performing cholecystectomy and opening the sphincter of Oddi • Adapted from: Van Brummelen SE, et al. Scand J Gastroenterol (Suppl) 2003;(239):117-22

  27. Microlithiasis: Effect of Treatment 100 80 % with recurrent pancreatitis 60 Ros 91 Lee 92 40 20 0 Untreated Treated Microlithiasis: Effect of Treatment E Ros, Gastroenterology 1991; 101:1701 SP Lee, N Engl J Med 1992, 326:589

  28. Etiologies of acute pancreatitis expanded Acute Pancreatitis Etiologies

  29. Drug-Induced Pancreatitis • 1.4% to 2.0% of patients • Mechanism – hypersensitivity - early vs. toxic metabolite (usually <12 weeks)

  30. Drug induced pancreatitis sorted by incidence Acute Pancreatitis

  31. Isoniazid Pegylated interferon alfa-2b Clarithromycin Metronidazole Trimethoprim - sulfamethoxazole Atorvastatin, Rosuvastatin, Simvastatin Estrogen/Tamoxifen Propofol Drug Induced Acute Pancreatitis 2009 Jawaid Q, et al. Dig Dis Sci 2002;47(3):614-17 Tosun E, et al. Acta Cardiol 2004;59(5):571-572 Chow KM, et al. Van Zuiden Communications 2004;62(1) Cecchi E, et al. Emergency Medicine Australasia 2004;16:473-475 Schouwenberg BJJW, Deinum J. van Zuiden Communication 2003;61(7) Singh S, et al. JOP J Pancreas 2004;5(6):502-504 Perego E, et al. JOP J Pancreas 2004;5(5):353-356 Nigwekar SU, Casey KJ. JOP J Pancreas 2004;5(6):516-519 Neth J med 2005;63:275

  32. Infections and pancreatitis Acute Pancreatitis

  33. Infectious Causes of Acute Pancreatitis:2003-2009 • Measles • Herpes Simplex • Hepatitis • A • B, C • E • HIV Takebayashi K, et al. Trop Gastroenterol 2003 Khanna S, Viji JC. Trop Gastroenterol 2003;24(1):25-6 Makharia GK, et al Trop Gastroenterol 2003;24(4):200-01 Tyner R, Turett G. South Med J 2004;97(4):393-94 Shintaku M, et al. Arch Pathol Lab Med 2003;127:231-234

  34. Other Causes of Acute Pancreatitis • Inflammatory bowel disease – Crohn’s (not 5 ASA) – 4-fold Ulcerative colitis 1.5 fold • Ischemia – • systemic lupus • sickle cell crisis • Preeclampsia-eclampsia • Toxins – carbofuran insecticides • Organophosphates Fan HC, et al. J Microbial Immunol Infect 2003;36(3):212-4 Ahmed S,et al. Am J Hematol 2003 73(3):190-3 Parmar MS. JOP 2004;5(2):101-4 Rizos E, et al. JOP 2004;5(1):44-7 Munk AM J Gastro 2004

  35. TG • Rare cause of acute pancreatitis • Serum triglycerides usually >1000 mg/dL • May cause chronic disease • Can be drug-induced: • Alcohol, estrogens, • isotretinoin, HIV-protease inhibitors TG lipase Free fatty acids Cell damage Acute Pancreatitis Hypertriglyceridemia

  36. Tumors as Causes of Acute Pancreatitis: • Primary • Pancreatic adenocarcinoma • IDPMT • Ampullary tumors • Lymphoma • Adult T-cell leukemia/lymphoma • Metastases • Lung Salva R, et al. Ann Surg 2004;239(5):678-85 Adv Thr 2005;22:225 Mori A, 2003 DDS

  37. Acute Biliary Pancreatitis Goals are to identify: • patients whose stones have not passed • patients with complications of stones – cholangitis • ERCP is done only if there is biliary obstruction with cholangitis

  38. Biliary Pancreatitis: What happens to CBD stones? • Stone or concretion is found in CBD • within 48 hours after admission in 62% – 75% • After 48 hours post admission CBD stones are found in 3% – 33% • The natural history of CBD stones is passage

  39. The Value of Magnetic Resonance Cholangio-pancreatography in Predicting CBD Stones in Patients with Gallstone Disease Results: • CBD stones were demonstrated in 43 (12%) of 366 patients • MRCP had – • an observed sensitivity of 95% • specificity of 100% • positive predictive value of 100% and • negativepredictive value of 98% Topal B, et al. Br J Surg 2003;90:42-47

  40. Treatment Guideline VIIIRole of ERCP and Biliary Sphincterotomy in Gallstone Pancreatitis • Indicated for clearance of bile duct stones in patients with severe pancreatitis, in those with cholangitis • ERCP should be performed primarily in patients with high suspicion of bile duct stones when therapy is indicated • EUS or MRCP can be used to identify common bile duct stones Level of Evidence: I ACG Practice Guidelines in Acute Pancreatitis. Am J Gastroenterol 2006;101:2379-2400

  41. Acute Biliary Pancreatitis: First 24 to 48 hours Jaundice with Bilirubin > 1.35 @ 24 hrs MRCP ERCP CBD stones Pos Neg Neg Pos Stone removal Elective surgical cholecystectomy

  42. Role of Surgery in Patients with Severe Acute Pancreatitis

  43. Early versus Late Necrosectomy in Severe Necrotizing Pancreatitis Patients were randomly allocated to two treatment arms as follows: • Group A included early necrosectomy (within 48 to 72 hours of onset) • Group B included late necrosectomy (at least 12 days after onset) Results: • Difference in the mortality rate (58% vs. 27%) was not statistically significant, the odds ratio for mortality was much higher in the early operation group • Early surgery in severe acute pancreatitis is only required in cases with proven early infection of the pancreatic necrosis (and not stable) Mier J, et al. Am J Surg 1997;173:71-7 Buchler MW, et al Dig Dis 1992;10:354-62 Mai G, et al Berlin, Blackwell Science 1999;475-85

  44. ROLE OF PROPHYLACTIC ANTIBIOTICS IN PATIENTS WITH SEVERE ACUTE PANCREATITIS

  45. The incidence of pancreatic infections increases with time Timing of Pancreatic Infections 100 80 60 % Cases 40 20 0 < 7 days 14-21 days 7-14 days > 21 days Acute Pancreatitis Adapted from H. Beger et al., Gastroenterology 1986; 91:433

  46. Local and Systemic Infections in Acute Pancreatitis • After week 1, the prognosis . is mainly determined by bacterial infection of pancreatic and peripancreatic necrosis • Mortality increases from 5% - 25% in patients with sterile necrosis to 15% - 28% in patients with infected necrosis Rau B, et al. J Am Coll Surg 1995;181:279-288 Rau B, et al. World j Surg 1997;21:155-161 Isenmann R, et al.Br J Surg 1999;86:1020-1024 Wilson PG, et al. J Antimicrob Chemother 1998;41(suppl A):51-63 Tenner S, et al. Gastroenterology 1997;113:899-903 Buchler MW, et al. Ann Surg 2000;232:619-626

  47. Preoperative morbidity in patients with infected and sterile necrosis Ref: Beger, et al. Pancreatology 2005;5:10-19 Cardiovascular complications (systemic Pa <80 mm Hg for > min 14 31.0 5 7.3 0.001* Pulmonary insufficiency (Pa02<60mm Hg) 18 40.0 10 14.3 0.01 Renal insufficiency (creatinine >120 M) 19 42.2 15 21.7 0.02 Sepsis (rectal temperature >38.5°C; leukocytes <4,000 or >12,000/mm3; platelets <150,000/mm3: base excess >-4 16 35.6 6 8.7 0.001* Gastrointestinal bleeding 8 17.8 4 5.8 0.05 *P=0.05 by Holm’s rejective multiple test procedure

  48. Antibiotic Therapy for Prophylaxis Against Infection of Pancreatic Necrosis in Acute Pancreatitis Aim: to determine the effectiveness and safety of prophylactic antibiotic therapy in patients with severe acute pancreatitis who have developed pancreatic necrosis Results • A survival advantage for antibiotic therapy (Odds ratio 0.32, p=0.02) was demonstrated • Pancreatic sepsis showed an advantage for therapy (Odds ratio 0.51, p=0.04) • Extra-pancreatic infection could be evaluated in three studies, but showed no significant advantage for therapy (Odds ratio 0.47, p=0.05) Cochrane Database Syst Rev 2003;(4):CD002941

  49. Antibiotic Therapy for Prophylaxis Against Infection of Pancreatic Necrosis in Acute Pancreatitis (Cont) • Surgery rates were not significantly reduced (Odds ratio 0.55, p=0.08) • Fungal infections showed no strongly increased preponderance with therapy (Odds ratio o.83, p=0.7) Reviewers’ Conclusion • Strong evidence that intravenous antibiotic prophylactic therapy for 10 to 14 days decreased the risk of super-infection of necrotic tissue and mortality in patients with severe acute pancreatitis with proven pancreatic necrosis at CT Cochrane Database Syst Rev 2003;(4):CD002941

  50. Prophylactic Antibiotic Treatment in Patients with Predicted Severe Acute Pancreatitis: A placebo-controlled, double-blind trial Method • 114 patients with acute pancreatitis in combination with a serum C-reactive protein exceeding 150 mg/L and/or necrosis on contrast-enhanced CT scan, were enrolled • Patients received either intravenous CIP (2 x 400 mg/day) + MET (2 x 500 mg/day) or PLA • Study medication was discontinued and switched to open antibiotic treatment when infectious complications, multiple organ failure sepsis or systemic inflammatory response syndrome (SIRS) occurred

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