Jeddah Gut Club monthly meeting 21112005 Yousef A

Jeddah Gut Club monthly meeting 21/11/2005 Yousef A. Qari Consultant Gastroenterologist King A. aziz University Hospital

Acute Pancreatitis n 100, 000 hospitalizations annually in the United States n 2000 (2%) directly related deaths from complications n 10% to 15% of deaths occur almost exclusively as a result of acute necrotizing pancreatitis

Mortality of acute pancreatitis n The overall mortality remains approximately 5% to 10% n Rises to >40% if sterile necrosis becomes superinfected

Etiology of Acute pancreatitis n Gallstones 80% of cases. n Alcohol n Endoscopic retrograde cholangiopancreatography (ERCP) (overall 5% -20%) n Medications Trauma Neoplasms Anatomic variants Metabolic problems n n – Hypercalcemia – Hypertriglyceridemta 10% of patients.

Etiology of Acute pancreatitis Rare causes of acute pancreatitis – Annular pancreas – Autoimmune Pancreatitis – Hereditary Pancreatitis – Familial adenomatous polyposis – Pseudopapillary tumor of the pancreas

Classification of Acute pancreatitis Mild Severe ( interstitial pancreatitis) (necrotizing pancreatitis) n Majority of cases n Minimal organ failure n Uneventful recovery n Responds well to supportive therapy n Approximately 20% of patients n Associated with – Organ failure – local complications n Necrosis n Infection n Pseudocyst formation n Requires intensive monitoring and specific therapies and has a more guarded prognosis.

Clinical and radiologic scoring systems n Since 1974 n Ranson's criteria [1] n 1985 n (APACHE II) system [2] n 1994 n CT severity index [3, 4] n New mellinium n Modified CT index – Multidetector-row computed tomography (MDCT) n MRI severity index – MRI with gadolinium (MRCPs) n 1. 2. 3. 4. Ranson JHC et al. Surg Gynecol Obstet 1974; 139: 69 -81 Knaus WA et al. Crit Care Med 1985; 13: 818 -829 Balthazar EJ et al Radiology 1990; 174: 331 -336 Balthazar EJ et al , Radiology 1994; 193: 297 -306 Contrast enhanced EUS

The role of imaging in acute pancreatitis n Confirm the diagnosis n Identify necrosis n Determine the presence of complications – Fluid collections – Vascular abnormalities n Assessment of severity

Multidetector-row computed tomography (MDCT) n The imaging study of choice for Acute pancreatitis n Faster image acquisition n Improved resolution n Can be converted into threedimensional reconstructions

CT severity index, by Balthazar in 1994 n Focuses on the presence and degree of: – Pancreatic inflammation (fluid collections) – Necrosis. n Successfully used to predict overall morbidity and mortality n Limitations – Does not correlate significantly with n n n Development of organ failure Extrapancreatic parenchymal complications Peripancreatic vascular complications – The interobserver agreement is approximating 75%.

CT severity index, by Balthazar in 1994 I - Pancreatic inflammation Prognostic Indicator Points Normal pancreas 0 Focal or diffuse enlargement of the pancreas 1 Intrinsic pancreatic abnormalities with inflammatory changes in peripancreatic fat 2 Single, ill-defined fluid collection or phlegmon 3 Two or more poorly defined collections or presence of gas in or adjacent to the pancreas 4

CT severity index, by Balthazar in 1994 II - Pancreatic Necrosis Prognostic Indicator Points None 0 </= 30% 2 > 30 -50% 4 > 50% 6 Mild (score, 0 -3 points), moderate (4 -6 points), or severe (7 -10 points).

Modified CT Severity Index by Koenraad in 2004 I- Pancreatic inflammation Prognostic Indicator Points Normal pancreas 0 Intrinsic pancreatic abnormalities with or without inflammatory changes in peripancreatic fat 2 Pancreatic or peripancreatic fluid collection or peripancreatic fat necrosis 4 Koenraad J et al, Am J Roentgenol 183(5): 1261 -1265, 2004

Modified CT Severity Index by Koenraad in 2004 II- Pancreatic necrosis Prognostic Indicator Points None 0 </= 30% 2 > 30% 4 Extrapancreatic complications (one or more of pleural effusion, ascites, vascular complications, parenchymal complications, or gastrointestinal tract involvement) 2 Mild (0 -2 points), moderate (4 -6 points), or severe (8 -10 points).

Correlation of Scoring Indexes With Patient Outcome Variables The length of the hospital Statistically significant correlation CT severity index (Balthazer)1994 Only with mild severity groups Modified index (Koenraad)2004 With all severity groups The need for surgical or percutaneous interventions Yes The presence of infection Yes No Yes Development of organ failure Koenraad J et al, Am J Roentgenol 183(5): 1261 -1265, 2004

Comparison between currently accepted and modified CT severity indexes n 74 -year-old man with acute pancreatitis. Axial contrastenhanced CT scan shows: – One fluid collection in anterior pararenal space – Minimal necrosis (< 30%). n On currently accepted CT severity index score was 5 (moderate pancreatitis) n On modified CT severity index score was 8 (severe pancreatitis)

MRCP-severity index n Based on the existing Balthazar CTSI n Advantage: – Non-nephrotoxic contrast agent gadolinium – Ability to generate cholangiopancreatography image – Detection of pancreatic duct disruption with the use of secretin Arvanitakis M, et al. . Gastroenterology 2004; 126: 715— 723.

MRCP-severity index Correlated with n Serum level of C-reactive protein at 48 hours n Duration of hospitalization n Ranson score n Morbidity from local and systemic complications. Arvanitakis M, et al. . Gastroenterology 2004; 126: 715— 723.

Acute Pancreatitis -- Prediction of Severity using serum proteomic patterns Patterns of low-molecular-mass biomarkers Reveal an underlying, organ-specific pathology. Sensitive and specific way to determine which patients are likely to develop multisystem failure Papachristou GI et al. Gastroenterology. 2004; 126(suppl 2): A-29.

Acute Pancreatitis -- Prediction of Severity using early hematocrit values Retrospective evaluation of 230 patients They found that n n Absence of hemoconcentration at admission (defined as a hematocrit value of 43 or less) Drop in 24 -hour hematocrit level had a negative predictive value of 94. 7% for the subsequent development of necrosis. Gardner TB et al. Am J Gastroenterol. 2004; 99: S 48.

Characterization of ICU patients using a model based on the presence or absence of organ dysfunctions and/or infection Evidence of organ failure Respiratory failure n – – Pa. O 2 of less than 60 mm Hg Ventilatory support. Cardiovascular system failure n – – – Systolic BP of < 90 mm Hg signs of peripheral hypoperfusion need for vasopressor or inotropic agents Renal failure n – – – serum creatinine level > 300 µmol/L urine output < 500 m. L/24 hr or < 180 m. L/8 hr need for hemo- or peritoneal dialysis. Fagon JY et al. Intensive Care Med 1993; 19: 137 -144

Characterization of ICU patients using a model based on the presence or absence of organ dysfunctions and/or infection Evidence of organ failure n Central nervous system failure – Glasgow Coma Scale score greater than 6 in the absence of sedation – Sudden onset of confusion or psychosis. n Hepatic failure – Serum bilirubin levels greater than 100 µmol/L – Alkaline phosphatase levels >3× the normal range. n Hematologic system failure – Hematocrit level < 20%, – WBC < 2, 000/mm 3, – Platelet count of < 40, 000/mm 3. Fagon JY et al. Intensive Care Med 1993; 19: 137 -144

Principles for managing patients with acute pancreatitis Assessing the severity remains the key element in the initial assessment of patients.

Principles for managing patients with acute pancreatitis n Supportive care with close attention to volume status and electrolyte balance n Fasting of the patient n Pain management using narcotic agents. n Predicting the severity of an attack and triaging of patients to intensive care units or a regular floor Bassi C, Cochrane Database of Systematic Reviews. 2003; (4): CD 002941

Principles for managing patients with acute pancreatitis (Cont‘d) n Early detection of complications n Prophylactic broad-spectrum antibiotics for patients with predicted severe pancreatitis n Identification of patients who may benefit from ERCP (when severe pancreatitis is complicated by progressive jaundice or cholangitis) n Adequate nutritional support Bassi C, Cochrane Database of Systematic Reviews. 2003; (4): CD 002941

Increased risk of post ERCP Pancreatitis Patient factors n n Sphincter of Oddi dysfunction Younger age Female sex History of prior post-ERCP pancreatitis Procedure factors n n n n Low endoscopist experience Small common bile duct diameter Pancreatic sphincterotomy Difficult biliary cannulation Precut sphincterotomy Multiple cannulations Sphincter of Oddi manometry

Increased risk of post ERCP Pancreatitis (1 – 10%) n n 1 -2% after ERCP 1 -4% after biliary endoscopic sphincterotomy (ES) 4 -8% after pancreatic ES 13 -35% after minor papilla ES

Prevention of post-ERCP pancreatitis Not useful n n n n Corticosteroids Antibiotics Anticholinergics Interleukin-10 Lexipafant Lidocaine sprayed on the ampulla of Vater Volume expansion with 10% Dextran-40

Prevention of post-ERCP pancreatitis Potentially useful: Require further studies n n n Somatostatin Nitroglycerine Diclofenac intravenous secretin High-dose allopurinol Gabexate

Prevention of post-ERCP pancreatitis Most useful n Proper technique and patient selection n Pancreatic duct stenting in high risk patients

Prevention of post-ERCP pancreatitis Somatostatin n Inhibition of exocrine secretion of the pancreas, which plays an important role in the pathogenesis of acute pancreatitis. n Direct anti-inflammatory and cytoprotective effects. Uhl W, Buchler MW, Malfertheiner P et al. Gut. 1999; 45: 97 -104. Cavallini G et al, Dig Liver Dis. 2001; 33: 192 -201.

Prevention of post-ERCP pancreatitis Diclofenac n Diclofenac is a potent inhibitor of phospholipase A 2, which regulates inflammatory mediators, including prostaglandins, leukotrienes, and platelet activating factor. n 100 mg rectal diclofenac given immediately after ERCP reduces the incidence of acute pancreatitis in patients at higher risk for post-ERCP pancreatitis Murray B, et al. Gastroenterology 2003, 124: 1786 -1791.

Prevention of post-ERCP pancreatitis Nitroglycerine Transdermal glyceryl trinitrate patch placed a half hour before the procedure and continued for 24 hours led to a reduction in post-ERCP pancreatitis Moretó M, Zaballa M, Casado I, et al. : Gastrointest Endosc 2003, 57: 1 -7.

Pancreatic stenting in patients "at-risk“ of post-ERCP pancreatitis Problems n Inability to place a pancreatic duct stent n Ampullary trauma n Pancreatic duct changes n Need to repeat endoscopy to retrieve stents Fazel A et al. Gastrointest Endosc 2003, 57: 291 -294.

Pancreatic stenting in patients "at-risk“ of post-ERCP pancreatitis Effective ? ? 5 randomized controlled trials Great reduction in the risk of post-ERCP pancreatitis Three-Fr gauge soft, unflanged, single pigtail pancreatic stents

Advantages and disadvantages of performing ERCP to seal and stent a pancreatic duct disruption in patients with acute pancreatitis. Pros n Pancreatic ductal disruption or leak is a common event in severe pancreatitis(37%) n Predicts a prolonged hospital stay. n Treatment with a combination of – Endoscopic stenting of the pancreatic duct – Percutaneous drains – Surgery as necessary Safe, will promote healing of the leak, and will improve patient outcome.

Advantages and disadvantages of performing ERCP to seal and stent a pancreatic duct disruption in patients with acute pancreatitis. Pros n Pancreatic ductal disruption or leak is a common event in severe pancreatitis(37%) n Predicts a prolonged hospital stay. n Treatment with a combination of Against n Lack of controlled data n A subgroup of patients, – Pancreatic ascites – Peripancreatic fluid collections – Endoscopic stenting of the pancreatic duct – Percutaneous drains – Surgery as necessary Safe, will promote healing of the leak, and will improve patient outcome. May benefit from an ERCP usually after the first 2 weeks

Antibiotic therapy for prophylaxis against infection of pancreatic necrosis in acute pancreatitis n The mortality risk rises to >40% if sterile necrosis becomes superinfected n Window of opportunity of 1 – 2 weeks n Strong evidence that intravenous antibiotic for 10 to 14 days decreased the risk of superinfection of necrotic tissue and mortality

Indications for surgical intervention n No universally valid answer n Persistence of organ failure and/or systemic inflammatory signs after 72 h of maximal supporting intensive care therapy is an indication for operative treatment.

The timing of pancreatic debridement n Controversial issue n Demarcation of pancreatic necrosis (2 -3 w) is a precondition for sufficient debridement n Necrosectomy, performed later than three weeks after the onset of disease higher rate of successful debridement of pancreatic necrosis

Idiopathic Recurrent Acute Pancreatitis n n n Laboratory analysis CFTR gene analysis sweat chloride test trypsin gene studies duodenal aspiration for microcrystals measurement of CA 19 -9 and CEA ERCP reveals a diagnosis in about 70% of patients with IRAP after a negative initial evaluation the procedure is not justified after the first episode of pancreatitis, [ bile is aspirated for microcrystals SOM is performed when SOD is suspected, minor papilla is cannulated when pancreas divisum is suspected. [75]

Idiopathic Recurrent Acute Pancreatitis n n n EUS is increasingly used to evaluate patients with IRAP EUS has equal or superior sensitivity to other commonly used tests in the diagnosis of microlithiasis and sludge. [ SOD is detected using secretin-stimulated EUS by demonstrating persistent dilatation of the pancreatic duct following secretin administration EUS has reasonable sensitivity and specificity in detecting structural lesions such as pancreas divisum] and an anomalous pancreatobiliary junction. [ Occult ampullary and pancreatic tumors may also be discovered. [ Finally, EUS can detect the presence of chronic pancreatitis in patients initially presenting with IRAP. [57, 58]

Idiopathic Recurrent Acute Pancreatitis n n n The primary value of MRCP for IRAP is in identifying anatomic abnormalities such as pancreas divisum, a choledochocele, anomalous pancreatobiliary junction, or annular pancreas MRCP may also detect neoplasia chronic pancreatitis microlithiasis its value for diagnosing these disorders has been minimally evaluated.

Management of Idiopathic Recurrent Acute Pancreatitis n n n n Therapeutic options are limited A number of "nonvalidated" therapies therefore exist for TIRAP Smooth muscle relaxers calcium-channel blockers nitrates, have been of limited utility in patients with SOD Pancreatic enzymes inhibitors antioxidants, such as beta carotene, methionine, vitamin C, and vitamin E, may be beneficial by inhibiting the release of oxygen-derived free radicals. [87] pancreatic duct stents or endoscopic sphincterotomy (biliary or pancreatic) in patients with TIRAP. [40, 88] There is only 1 prospective, randomized trial to have evaluated the use of pancreatic duct stents for this indication. [89] Patients randomized to stent placement suffered fewer episodes of pancreatitis during the nearly 3 -year follow-up. However, such therapy cannot be widely supported outside of a research protocol until more data are available. empiric laparoscopic cholecystectomy Empiric administration of ursodeoxycholic acid and a low-fat diet

Comparison between currently accepted and modified CT severity indexes n n 266 patients acute pancreatitis during a 1 -year period 66 underwent contrast-enhanced MDCT within 1 week of the onset of symptoms. Parameters n The length of the hospital stay (in days) n The need for surgical intervention n The need for percutaneous intervention (aspiration and drainage) n Evidence of infection in any organ system (positive results on a Gram stain or culture or the combination of a fever >100°F and an elevated WBC > 15, 000/mm 3) n Evidence of organ failure Koenraad J et al, Am J Roentgenol 183(5): 1261 -1265, 2004

n n n The calcium-dependent intra-acinar cell activation of pancreatic digestive zymogens, particularly proteases, is an early event in the initiation of acute pancreatitis. Activation of transcription factor NF-κB also occurs early in experimental pancreatitis. . expression of interleukin-6, tumor necrosis factor-α, and inducible nitric oxide synthase neurally mediated inflammation has an important role in acute pancreatitis. Neurogenic inflammation is mediated by peripheral release of chemical transmitters, including substance P inhibiting cyclo-oxygenase-2 by either pharmacologic inhibition or gene deletion reduced pancreatitis severity and lung injury Leukotrienes play a role in inflammation, ischemia, and reperfusion. Use of a peptide leukotriene receptor antagonist to improve experimental acute pancreatitis has been described. Translation of this research into prevention of ERCP-induced pancreatitis is noted in this review.

Conclusion n n n increased understanding of early cellular events and the regulation of early and late inflammatory mediators. The importance of neuronal mediators has been demonstrated and deserves further study. Arachidonic acid metabolites are important mediators of local inflammation and lung injury in experimental models. This has been translated into the use of diclofenac in prevention of post-ERCP pancreatitis. Local delivery of inflammatory inhibitors via the pancreatic duct should be explored for the prevention of ERCP-induced pancreatitis, as should combination therapy that blocks Ca 2+ mobilization, p. H changes, and early transcription factors such as NF-κB. Although progress continues in understanding of experimental pancreatitis and successfully attenuating the disease in the laboratory, there has been difficulty in translating this research into therapy for clinical acute pancreatitis. Better understanding of inflammatory cytokines, chemokines, and neurogenic mediators in experimental pancreatitis promises therapies to reduce pancreatic necrosis and lung injury in clinical pancreatitis

Balthazar Computed Tomography Severity Index (CTSI) n Graded the severity of pancreatitis on the basis of n Correlated with n Not correlated with – Degree of pancreatic inflammation – Degree of pancreatic necrosis. – Morbidity – Mortality – organ failure – peripancreatic complications Balthazar EJ. et al Radiology 1990; 174: 331— 336. •