Jeddah Gut Club monthly meeting

1
Jeddah Gut Club monthly meeting
Management of Acute Pancreatitis
21/11/2005

• Yousef A. Qari
• Consultant Gastroenterologist
• King A.aziz University Hospital

2
Acute Pancreatitis

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

3
Mortality of acute pancreatitis

• The overall mortality remains approximately 5 to
  10
• Rises to gt40 if sterile necrosis becomes
  superinfected

4
Etiology of Acute pancreatitis

• Gallstones
• 
  80 of cases.
• Alcohol
• Endoscopic retrograde cholangiopancreatography
  (ERCP) (overall 5 -20)
• Medications
• Trauma
• Neoplasms 10 of
  patients.
• Anatomic variants
• Metabolic problems
• Hypercalcemia
• Hypertriglyceridemta

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Etiology of Acute pancreatitis

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

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Classification of Acute pancreatitis

• Mild
• ( interstitial pancreatitis)
• Majority of cases
• Minimal organ failure
• Uneventful recovery
• Responds well to supportive therapy

• Severe
• (necrotizing pancreatitis)
• Approximately 20 of patients
• Associated with
• Organ failure
• local complications
• Necrosis
• Infection
• Pseudocyst formation
• Requires intensive monitoring and specific
  therapies and has a more guarded prognosis.

7
Clinical and radiologic scoring systems

• Since 1974
• 1985
• 1994
• New mellinium

• Ranson's criteria 1
• (APACHE II) system 2
• CT severity index 3,4
• Modified CT index
• Multidetector-row computed tomography (MDCT)
• MRI severity index
• MRI with gadolinium (MRCPs)
• Contrast enhanced EUS

1. Ranson JHC et al. Surg Gynecol Obstet 1974
   13969-81
2. Knaus WA et al. Crit Care Med 1985 13818-829
3. Balthazar EJ et al Radiology1990 174331-336
4. Balthazar EJ et al , Radiology 1994 193297-306

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The role of imaging in acute pancreatitis

• Confirm the diagnosis
• Identify necrosis
• Determine the presence of complications
• Fluid collections
• Vascular abnormalities
• Assessment of severity

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Multidetector-row computed tomography (MDCT)

• The imaging study of choice for Acute
  pancreatitis
• Faster image acquisition
• Improved resolution
• Can be converted into three-dimensional
  reconstructions

10
CT severity index, by Balthazar in 1994

• Focuses on the presence and degree of
• Pancreatic inflammation (fluid collections)
• Necrosis.
• Successfully used to predict overall morbidity
  and mortality
• Limitations
• Does not correlate significantly with
• Development of organ failure
• Extrapancreatic parenchymal complications
• Peripancreatic vascular complications
• The interobserver agreement is approximating 75.

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CT severity index, by Balthazar in 1994
I - Pancreatic inflammation 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
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CT severity index, by Balthazar in 1994
II - Pancreatic Necrosis II - Pancreatic Necrosis
Prognostic Indicator Points
 None 0
lt/ 30 2
 gt 30-50 4
gt 50 6
Mild (score, 0-3 points), moderate (4-6 points),
or severe (7-10 points).
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Modified CT Severity Index by Koenraad in 2004
I- Pancreatic inflammation 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
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Modified CT Severity Index by Koenraad in 2004
II- Pancreatic necrosis II- Pancreatic necrosis
Prognostic Indicator Points
 None 0
 lt/ 30 2
 gt 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).
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Correlation of Scoring Indexes With Patient
Outcome
Variables Statistically significant correlation Statistically significant correlation
Variables CT severity index (Balthazer)1994 Modified index (Koenraad)2004
The length of the hospital Only with mild severity groups With all severity groups
The need for surgical or percutaneous interventions Yes Yes
The presence of infection Yes Yes
Development of organ failure No Yes
Koenraad J et al, Am J Roentgenol
183(5)1261-1265, 2004
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Comparison between currently accepted and
modified CT severity indexes

• 74-year-old man with acute pancreatitis. Axial
  contrast-enhanced CT scan shows
• One fluid collection in anterior pararenal space
• Minimal necrosis (lt 30).
• On currently accepted CT severity index score was
  5 (moderate pancreatitis)
• On modified CT severity index score was 8 (severe
  pancreatitis)

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MRCP-severity index

• Based on the existing Balthazar CTSI
• 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
126715723.
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MRCP-severity index

• Correlated with
• Serum level of C-reactive protein at 48 hours
• Duration of hospitalization
• Ranson score
• Morbidity from local and systemic complications.

Arvanitakis M, et al.. Gastroenterology 2004
126715723.
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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.
2004126(suppl 2)A-29.
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Acute Pancreatitis -- Prediction of Severity
using early hematocrit values

• Retrospective evaluation of 230 patients
• They found that
• 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.
200499S48.
21
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
• PaO2 of less than 60 mm Hg
• Ventilatory support.
• Cardiovascular system failure
• Systolic BP of lt 90 mm Hg
• signs of peripheral hypoperfusion
• need for vasopressor or inotropic agents
• Renal failure
• serum creatinine level gt 300 µmol/L
• urine output lt 500 mL/24 hr or lt 180 mL/8 hr
• need for hemo- or peritoneal dialysis.

Fagon JY et al .Intensive Care Med 1993
19137-144
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Characterization of ICU patients using a model
based on the presence or absence of organ
dysfunctions and/or infection

• Evidence of organ failure
• Central nervous system failure
• Glasgow Coma Scale score greater than 6 in the
  absence of sedation
• Sudden onset of confusion or psychosis.
• Hepatic failure
• Serum bilirubin levels greater than 100 µmol/L
• Alkaline phosphatase levels gt3 the normal range.
• Hematologic system failure
• Hematocrit level lt 20,
• WBC lt 2,000/mm3,
• Platelet count of lt 40,000/mm3.

Fagon JY et al .Intensive Care Med 1993
19137-144
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Principles for managing patients with acute
pancreatitis

• Assessing the severity remains the key element
  in the initial assessment of patients.

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Principles for managing patients with acute
pancreatitis

• Supportive care with close attention to volume
  status and electrolyte balance
• Fasting of the patient
• Pain management using narcotic agents.
• 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)CD002941
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Principles for managing patients with acute
pancreatitis (Contd)

• Early detection of complications
• Prophylactic broad-spectrum antibiotics for
  patients with predicted severe pancreatitis
• Identification of patients who may benefit from
  ERCP (when severe pancreatitis is
  complicated by progressive jaundice or
  cholangitis)
• Adequate nutritional support

Bassi C, Cochrane Database of Systematic Reviews.
2003(4)CD002941
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Increased risk of post ERCP Pancreatitis

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

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Increased risk of post ERCP Pancreatitis

• (1 10)
• 1-2 after ERCP
• 1-4 after biliary endoscopic sphincterotomy
  (ES)
• 4-8 after pancreatic ES
• 13-35 after minor papilla ES

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Prevention of post-ERCP pancreatitis

• Not useful
• Corticosteroids
• Antibiotics
• Anticholinergics
• Interleukin-10
• Lexipafant
• Lidocaine sprayed on the ampulla of Vater
• Volume expansion with 10 Dextran-40

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Prevention of post-ERCP pancreatitis

• Potentially useful Require further studies
• Somatostatin
• Nitroglycerine
• Diclofenac
• intravenous secretin
• High-dose allopurinol
• Gabexate

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Prevention of post-ERCP pancreatitis

• Most useful
• Proper technique and patient selection
• Pancreatic duct stenting in high risk patients

31
Prevention of post-ERCP pancreatitis

• Somatostatin
• Inhibition of exocrine secretion of the pancreas,
  which plays an important role in the pathogenesis
  of acute pancreatitis.
• Direct anti-inflammatory and cytoprotective
  effects.

Uhl W, Buchler MW, Malfertheiner P et al. Gut.
19994597-104.
Cavallini G et al, Dig Liver Dis.
200133192-201.
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Prevention of post-ERCP pancreatitis

• Diclofenac
• Diclofenac is a potent inhibitor of phospholipase
  A2, which regulates inflammatory mediators,
  including prostaglandins, leukotrienes, and
  platelet activating factor.
• 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,
1241786-1791.
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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, 571-7.
34
Pancreatic stenting in patients "at-risk of
post-ERCP pancreatitis

• Problems
• Inability to place a pancreatic duct stent
• Ampullary trauma
• Pancreatic duct changes
• Need to repeat endoscopy to retrieve stents

Fazel A et al. Gastrointest Endosc 2003,
57291-294.
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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

36
Advantages and disadvantages of performing ERCP
to seal and stent a pancreatic duct disruption in
patients with acute pancreatitis.

• Pros
• Pancreatic ductal disruption or leak is a common
  event in severe pancreatitis(37)
• Predicts a prolonged hospital stay.
• 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.

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Advantages and disadvantages of performing ERCP
to seal and stent a pancreatic duct disruption in
patients with acute pancreatitis.

• Pros
• Pancreatic ductal disruption or leak is a common
  event in severe pancreatitis(37)
• Predicts a prolonged hospital stay.
• 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.

• Against
• Lack of controlled data
• A subgroup of patients,
• Pancreatic ascites
• Peripancreatic fluid collections
• 
  
• May benefit from an ERCP usually after the
  first 2 weeks

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Antibiotic therapy for prophylaxis against
infection of pancreatic necrosis in acute
pancreatitis

• The mortality risk rises to gt40 if sterile
  necrosis becomes superinfected
• Window of opportunity of 1 2 weeks
• Strong evidence that intravenous antibiotic for
  10 to 14 days decreased the risk of
  superinfection of necrotic tissue and mortality

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Indications for surgical intervention

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

40
The timing of pancreatic debridement

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

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Idiopathic Recurrent Acute Pancreatitis

• 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

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Idiopathic Recurrent Acute Pancreatitis

• 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

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Idiopathic Recurrent Acute Pancreatitis

• 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.

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Management of Idiopathic Recurrent Acute
Pancreatitis

• 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

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Comparison between currently accepted and
modified CT severity indexes

• 266 patients acute pancreatitis during a 1-year
  period
• 66 underwent contrast-enhanced MDCT within 1 week
  of the onset of symptoms.
• Parameters
• The length of the hospital stay (in days)
• The need for surgical intervention
• The need for percutaneous intervention
  (aspiration and drainage)
• Evidence of infection in any organ system
  (positive results on a Gram stain or culture or
  the combination of a fever gt100F and an elevated
  WBC gt 15,000/mm3)
• Evidence of organ failure

Koenraad J et al, Am J Roentgenol
183(5)1261-1265, 2004
47

• 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-?B also
  occurs early in experimental pancreatitis..
• expression of interleukin-6, tumor necrosis
  factor-a, 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.

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Conclusion

• 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 Ca2
  mobilization, pH changes, and early transcription
  factors such as NF-?B.
• 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

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Balthazar Computed Tomography Severity Index
(CTSI)

• Graded the severity of pancreatitis on the basis
  of
• Degree of pancreatic inflammation
• Degree of pancreatic necrosis.
• Correlated with
• Morbidity
• Mortality
• Not correlated with
• organ failure
• peripancreatic complications

Balthazar EJ .et al Radiology 1990 174331336.