1. Resident Conference October 5, 2004 Rachel Dunagin, MD
Acute Pancreatitis
Resident Conference
October 5, 2004
Rachel Dunagin, MD

2. Background Acute Inflammatory process of pancreatic parenchyma
A stimulus leads to release of activated digestive enzymes from acinar cells into interstitium
Results in autodigestion of pancreas and adjacent tissue
Activated inflammatory mediators convert a localized inflammatory response into a systemic inflammatory process, resulting in increased tissue and vascular permeability
End result: hypovolemia, shock, ARDS, multisystem organ failure
Majority: mild self-limited course; 15-25% severe, complicated course; 5% mortality

3. Pathophysiology

4. Trypsin activates kallikrein – increased vasc permeability – edema and fluid shift from intravasc space to interstitium
Chymotrypsin – vasodilatation, Incr cap leakage – pooling of fluid in venous sys – shock and decr cardiac fxn
Elastase – destroy connective tissue in vasc wall – microemboli – DIC and bleeding
Phospholipase A – irritate panc tissue – tissue necrosis
Lipase – overflow into tissue and systemic circ – fat necrosis of panc and surrounding tissue

5. Etiology Gallstone (35%) Microlithiasis Alcoholism (30%) Medication
Trauma/Sphincter of Oddi Dysfunction
Infection
Duodenal Diverticula
Hypercalcemia
Vascular Abnormalities
Post-operative
Neoplasm
Pancreas Divisum
Autoimmune
Hereditary
Idiopathic (30%)
Hypertriglyceridemia
Cystic Fibrosis
Most common causes: Gallstone and Etoh; Gallstone #1, except in certain geographic areas – Etoh
Parasitic infections – ascariasis (#2 cause in Kashmir)
Hereditary AD c variable penetrance, suspect if > or = 2 fam members c pancr and episode of abd pain in childhood, incr’d risk pancreatic CA (40% by 70yo)
Idiopathic 10%
Kids – abdominal trauma, Mumps
Pregnancy is not a cause of pancreatitis; if occurs during preg likely underlying hyperlipiemia in pre-gestational state, mgmt is same, higher risk prematurity

6. Etiology: Gallstones ½ of all cases of acute pancreatitis
3-8% patients with symptomatic cholelithiasis develop pancreatitis
Older women
80% patients previously thought to have idiopathic etiology are due to microlithiasis, tiny gallstones, and biliary sludge
Mechanism unclear – pancreatic ductal obstruction does not full explain pathogenesis
More common in older women b/c they are more likely to have gallstones, however if GS found in man and woman, man more likely to develop pancr

7. Etiology: Alcohol
Interferes with normal process of pancreatic secretion
Excessive deposition of GP-2 (protein involved in maintaining normal pancreatic secretion) leads to ductal obstruction
Daily consumption 80g alcohol over 5-15 years before first attack of alcoholic pancreatitis occurs
Acute attacks 1-3 days after drinking
Men >40yo

8. Etiology: Hypertriglyceridemia
>1000mg/dL
50% with hyperTG have falsely normal amylase level due to interference of lipemic specimen with assay
Therefore, must dilute serum to get accurate serum amylase level

9. Etiology: Medications
Uncommon cause
Azathioprine, 6-mercaptopurine and ddI have 5-10% risk of acute pancreatitis
>100 meds implicated

10. Definitely Cause Pancreatitis
Azathioprine
Asacol
Cytosine arabinoside
Estrogens
Norethindrone/mestr-anol
Isoniazid
6-mercaptopurine
Metronidazole
Pentamidine
Tetracycline
Trimethoprim/sulfamethoxazole (TMP/SMX)
Valproic Acid

11. Implicated Agents Industrial chemicals (Parathion) Scorpion venom
Release acetylcholine from pancr nerves – prolonged hyperstimualtion of pancr acinar cells

12. Viral Infections Mumps – most common in adults Coxsackie-B
Epstein-Barr
Rubella
Influenza A
Varicella
Hepatitis A, B, C, E
If associated c acute fulminant viral hepatitis – pancreatitis is usually asymptomatic

13. AIDS and Pancreatitis 10% with AIDS develop acute pancreatitis
Asymptomatic pancreatic lesions in 30-50% of autopsy cases
Common infectious etiologies: CMV, MAC, Crypto, M. TB, Toxoplasma
Common medication etiologies: pentamidine, ddI, ddC and TMP/SMX

14. Rare Etiologies SLE Polyarteritis Nodosum Autoimmune pancreatitis
Fungal infections
Bacterial infections: Legionella, Brucellosis
Ampullary tumors
Metastatic tumors (breast, lung)
Pancreas Divisum

15. Pancreatic Divisum Debatable cause
Represents 5-7% of population per autopsy and ERCP studies
Normal Pancreatic Development:
Dorsal and ventral pancreatic buds fuse during 8th week gestation to form main pancreatic duct; drains through major papilla.
Small duct often persists between the main pancreatic duct and the minor papilla

16. Pancreatic Divisum
Embryonic dorsal and ventral ducts fail to migrate and fuse abnormally.
Two noncommunicating duct systems:
Inferior portion of head of pancreas drained by rudimentary ventral duct through the major papilla.
Remainder of pancreas drained by dorsal duct through the minor papilla.

17. Pancreatic Divisum: Hypothesis of pancreatitis etiology
First proposed in 1977
Increased resistance to flow through a small minor papilla.
If so, would reason that recurrent pancreatitis would stop after endoscopic minor papilla sphincterotomy, or insertion of endoscopic stent across the minor papilla.
Some disagree on basis that incidence of pancreas divisum is the same in patient with or without pancreatitis and 95% with pancreatic divisum do not develop pancreatitis
Other arguments against: pancreatitis develops in adulthood, not childhood in those with pancreatic divisum
Still remains controversial.

18. Diagnosis
Clinical signs and symptoms, confirmed with lab/radiologic studies
Symptoms:
Acute abdominal pain
Location: entire abdomen or localized in midepigastric, RUQ or left flank
Intensity: maximized within 10 – 20 min of acute attack
Quality: steady, moderate to severe, little relief with change of position, unbearable, refractory to narcotics
Radiation: band-like to the back
Anorexia, nausea, emesis
CNS manifestations: disorientation, hallucinations, agitation, or coma
Acute abdominal pain at onset of attack, biliary colic
Pain may be in lower abdomen 2/2 rapid spread of pancreatic exudation to the left colon, pain may be absent in 5-10% attacks
Emesis: severe lasting hours, 90% pts, retching, not alleviate pain
CNS: due to Etoh w/d, hypotension, electrolyte imbalance, hypoxemia, fever and toxic effects of pancreatic enzymes on CNS.

19. Diagnosis
Signs:
Mild Pancreatitis – mild abdominal tenderness, no guarding
Severe Pancreatitis - epigastric tenderness and guarding, rebound tenderness, abdominal distention (due to gastric ileus or dilatation of transverse colon)
Decreased or absent bowel sounds
May be mistaken for acute abdomen
If severe, extensive peripancreatic fat necrosis with hemorrhagic fluid within the peritoneum and/or retroperitoneum → Cullen’s sign, Grey-Turner’s sign
Palpable epigastric mass = pseudocyst or large inflammatory mass
Subcutaneous nodular fat necrosis, thrombophlebitis in legs, polyarthritis
All are tender in upper abdomen, elicited by gently shaking abdomen or by gentle percussion
Tenderness and guarding are less than expected considering the intensity of discomfort.
SQ nodular fat necrosis – 0.5-2cm tender red nodules over distal extremities or scalp, trunk or buttocks, precede abdominal pain or occur s abdominal pain

20. Cullen’s Sign
Cullen’s sign: periumbilical ecchymosis from peritoneal hemorrhage
Only seen in 1% of pts c severe disease

21. Grey-Turner’s Sign
Grey-Turner’s sign: flank ecchymosis from retroperitoneal hemorrhage
1% of severe cases

22. Diagnosis Due to third-space fluid loss and systemic toxicity
Pulse
BP hypertensive in beginning, then hypotensive due to 3rd spacing and hypovolemia
Temp: initially normal, then increase to within 1-3d
Tachypnea and shallow respirations
Temp due to severe retroperitoneal chemical burn and rls of inflam mediators of panc

23. Nonspecific Lab Findings
Leukocytosis
Hyperglycemia
Hypocalcemia
LFTs:  AST,  ALT,  AlkPhos,  Bilirubin
Hypertriglyceridemia
Hypoxemia
Low Ca – neuromuscular irritability, Make sure to check Mg level b4 replacing Ca (decr 2/2 emesis), also no give Ca gluc until check K and make sure if on dig b/c can cause serious arrhythmia by displacing K

24. Laboratory Testing Serum Amylase Most widely accepted
2-3x upper limit of normal
Does not correlate with severity of disease
30% of Alcoholics with acute pancreatitis have normal amylase levels
? of using elevated lipase to amylase level to predict alcoholic acute pancreatitis
ALT 3x upper limit of normal + elevated amylase is highly sensitive for gallstone pancreatitis (95% PPV)
Abnl 85-90% of cases
Elevates w/n 2-12hrs, remains elevated for 3-5d in uncomplicated attacks, if not at normal by 48-72hr = continuing pancr cell destruction
Elevated lipase to amylase of >2:0 is 91% sensitive and 76& specific for Etoh pancr

25. Laboratory Tests Caution!! -- Other causes of elevated amylase level
Can be of pancreatic or salivary origin
Any inflammatory process of abdomen:
Perforated peptic ulcer
Intestinal obstruction
Cholecystitis
Generalized peritonitis
Mesenteric ischemia
Ruptured AAA/ectopic pregnancy
Renal failure
Macroamylasemia: due to benign change in peptide processing in Golgi (amylase is bound to immunoglobulin or abnormal serum protein), forms a large complex which is difficult to clear through the kidneys

26. Laboratory Testing Serum Lipase
More sensitive and specific than amylase
Greater than 2-3x upper limit of normal
Does not correlate with severity of disease
Elevated on day 1, remains elevated longer than amylase
Increased (<2x) in severe renal insufficiency

27. Other Lab Tests
Pancreatitis associated protein (PAP), heat shock protein
Trypsinogen activation peptide (TAP), 5-amino acid peptide cleaved from trypsinogen to produce active trypsin
Non-specific Markers: CRP, neutrophil elastase, complement, TNF, IL6
Methemalbumin level
PAP elevated in acute pancreatitis, higher in severe than mild pancr in 1st 24hr of disease, help c prognosis
TAP – urine, serum, detect early acute pancr, if elevated in urine predict severe acute pancreatitis
Meth – incr in acute pancr and other intraabdomin conditions

28. Radiology Sonography Computer Tomography (CT)
Magnetic resonance imaging (MRI)

29. Ultrasound
Fails to completely to completely image the pancreas 2/2 overlying bowel gas
Superior to CT in visualizing gallbladder and biliary tree for gallstones
Negative US does not rule out gallstone as etiology because:
1. Not sensitive for common bile duct stones.
2. Only 50% of those with microlithiasis have + US.
3. View may be obstructed by ileus and underlying structures obscured by bowel gas.
Sensitivity 62-95%
Use to exclude gallstones, CBD stones, f/u pseudocysts or fluid collections

30. A B
Acute Pancreatitis.  A.  Transverse scan.  B.  Longitudinal scan.  The head of the pancreas (H) is enlarged as revealed by the red arrowheads and decreased in echogenicity because of edema.  The surrounding structures are superior mesenteric vein (v), superior mesenteric artery (a), abdominal aorta (A), and inferior vena cava (IVC).

31. Computer Tomography (CT)
Imaging modality of choice for diagnosis, determining severity, and identifying complications
Sensitivity: 90% for diagnosis of acute pancreatitis
Specificity: %
Not necessary for mild acute pancreatitis; however is useful to rule out other abdominal processes presenting with abdominal pain.
Mild disease: no abnormalities, diffuse enlargement of pancreas, loss of normally sharp border, homogenous attenuation, inflammatory stranding in peripancreatic fat and adjacent soft tissue, fluid collections, pseudocysts, pancreatic necrosis
Spiral CT c oral contrast and IV contrast to id area of pancreatic necrosis (may not appear for 48-72hr)

32. Computer Tomography (CT)
Necrotizing pancreatitis:
Non-enhancement of ≥ 1/3 of pancreas or >3cm of non-enhancement of the pancreas on dynamic, IV contrast-enhanced CT.
If > 30% gland involved, sensitivity approaches 100%

33. Indications for CT
Severe acute pancreatitis (Ranson score ≥3 or APACHE II score ≥8)
Mild pancreatitis with no response to conservative management after hours (confirm dx, re-assess severity, identify complications)
May repeat q7-10 day if no improvement or if deterioration.

34. MRI – good as CT to detect necrosis, better to detect choledocholithiasis and ductal abnormalities, may replace CT in future

36. Severity: Open Drainage due to Pancreatic Necrosis

37. Severity
Not predicted by degree of pain, etiology or serum amylase level.
CRP: > 120mg/L in pts with acute pancreatitis typically have necrotizing pancreatitis.
Phospholipase A2: elevated in severe disease, esp those who develop necrosis, ARDS, and shock
Urinary trypsinogen activation peptide: ≥ 10ng/mL has 100% PPV of severe pancreatitis
Peritoneal Lavage: any volume of peritoneal fluid with a dark color or recovery of at least 20mL of free intraperitoneal fluid = 33% mortality
Urinary TAP: able to predict severity at admission, may prove to be of great importance in future

38. Trypsinogen Activation Pathway

39. Severity
Hematocrit ≥ 47% at admission or failure of admission hematocrit to decrease at 24hrs is strong predictor of development of pancreatic necrosis.
Compromised microcirculation of pancreatic parenchyma precipitated by fluid sequestration with intravascular volume depletion and hemoconcentration leads to development of necrotizing pancreatitis.
Therefore, intense hydration is important.

40. Severity Ranson Criteria ≥ 3 APACHE II score ≥ 8 Hematocrit ≥ 44
CT severity index ≥ 6
1992 Atlanta Symposium: evidence of organ failure or local complications

41. Ranson Criteria **Can not be applied fully for 48 hours
Table 1:
Ranson Criteria
At Admission
During Initial 48 Hours
Age > 55 yrs
Hematocrit falls by > 10 mg/dl
WBC > 16,000/cc
BUN increases by > 5 mg/dl
Glucose > 200 mg/dl
Calcium < 8 mg/dl
LDH > 350 IU/L
PaO2 < 60 mmHg
AST > 250IU/L
Base deficit > 4 mg/dl
Fluid sequestration > 6 L
Mortality <5% if 0,1,2 Ranson’s signs
10% if 3,4, or 5
>60% if 6 or more signs
>6 signs = high incidence of systemic complications, necrosis and infected necrosis
**Can not be applied fully for 48 hours
**Poor predictor later in the disease
**Single snapshot in time

42. APACHE II Criteria Multivariate scoring system
12 measurable variables: temperature, heart rate, respiratory rate, mean arterial BP, oxygenation, arterial pH, serum potassium, sodium and creatinine, hematocrit, WBC, and Glasgow Coma Scale
Account for premorbid state and age
Can be used throughout course of illness, but is complex and cumbersome
Survive if score 9 or less during 1st 48hrs
13 or > high likelihood of dying

43. CT Severity Index A: Normal pancreas
B: Enlargement of pancreas, heterogeneous enhancement without peripancreatic disease
C: Pancreatic abnormalities with peripancreatic disease
D: Small or single fluid collection
E: 2 or > fluid collection or pancreatic abscess
E = most severe case

44. Atlanta Symposium Criteria
40 Internationally renowned experts on pancreatic disease met to define severity of pancreatitis
Defined based on outcome: organ failure and/or anatomic complications
Mild acute pancreatitis: minimal or no organ system dysfunction with complete and uneventful recovery; interstitial edema of parenchyma
Severe acute pancreatitis: evidence of life-threatening systemic complications or pancreatic collection.

45. Severe Acute Pancreatitis
Systemic Complications:
Shock: SBP <90mm Hg
Pulmonary Insufficiency: PaO2 ≤ 60mm Hg
Renal failure: Cr > 2mg/dL after rehydration
GI bleeding: > 500ml/24hr
DIC: platelets < 100,000/mm3, fibrinogen < 1g/L, fibrin degradation products > 80mug/mL
Hypocalcemia: < 7.5mg/dL

46. Severe Acute Pancreatitis
Pancreatic Collections
Pancreatic Necrosis: diffuse or focal areas of nonviable pancreatic parenchyma
Pancreatic Abscess: well-circumscribed collection of pus containing little or no necrotic tissue
Acute Pseudocyst: collection of enzyme-rich, pancreatic fluid enclosed by a wall of fibrous tissue

47. Treatment
Goals: halt progression of local disease and prevent remote organ failure
Nutritional Support:
Pancreatitis is catabolic state
Benefit of pancreatic “rest” by limiting oral intake is unproven, however is widely used
Evidence that early enteral nutrition is safe
Nasojejunal feeding limits pancreatic secretion
Preferable to oral or nasogastric feeding
General belief is NPO until pain resolves (off narcotics)

48. Treatment Fluids Analgesics ERCP
IV hydration, aggressive ( ml.hr) especially in the early phase of illness with goal hemodilution to Hct 30%
May need NG tube (if persistent nausea and vomiting or ileus), Foley catheter and central line or Swan-Ganz catheter to monitor hydration status
Analgesics
Adequate pain control is essential
50-100mg Meperidine (Demerol) IV q3-4hr
Hydromorphone (Dilaudid) PCA
Avoid Morphine b/c it increases sphincter of Oddi tone and increases serum amylase
ERCP
If severe acute gallstone pancreatitits or ascending cholangitis is indicated, then early ERCP with sphincterotomy and stone extraction is indicated.
Is not to be used in mild acute pancreatitis
ERCP: recent studies show only helpful if severe acute pancreatitis complicated by biliary sepsis

49. Pancreatic Infection: A Word on Antibiotics
Antibiotics – there is no role for routine use
Indicated if severe attack with necrosis of pancreas
Typical organisms: from gut = E coli, Pseudomonas, Klebsiella, Enterococcus
Treatment: selective decontamination of gut with oral nonabsorbable antibiotics, systemic antibiotics, and enteral feedings to avoid catheter-related infections.
Imipenem/cilastin penetrate pancreatic parenchyma and reduces incidence of intra-abdominal infection.
Unfortunately, there is a tendency for fungal superinfection to develop later in clinical course.
Other options: 3rd gen cephalosporin, piperacillin, mezlocillin, fluoroquinolones and metronidazole
75% monomicrobial

50. Treatment Intensive monitoring All patients Aggressive hydration
Adequate analgesics
H2 receptor antagonist/proton pump inhibitors
Unproven benefits
Antibiotic prophylaxis
Patients with sterile necrosis
ERCP
Early in patients with severe biliary pancreatitis/bilary sepsis;
Late in patients with acute gallstone pancreatitis when liver function test are persistently elevated prior to cholecystectomy
Surgery
If pancreatic abscess
If sterile necrosis and deteriorate or fail to improve after 4-6 wks of medical management
If infected necrosis
Cholecystectomy for acute gallstone pancreatitis and recurrent, idiopathic pancreatitis
TPN
Patients with necrotizing pancreatitis
Direct and indirect inhibitors of pancreatic secretions – little use incl glucagon, somatostatin, atropine
Octreotide may be useful in treating high-output pancreatic fisutlas but otw ineffective
PAF antagonist, lexipafant may reduce extrapancreatic complications if given w/n 48hr of onset of acute pancreatitis – theory is IL6, 8, PAF, and aTNF cause most of extrapancreatic complications

51. Complications of Acute Pancreatitis
EARLY COMPLICATIONS
Cardiovascular Collapse
Respiratory Failure
Renal Failure
GI bleeding
DIC
Visual Disturbance
Change in mental status
Metabolic disturbance
Acute fluid collections
Pancreatic Necrosis
LATE COMPLICATIONS
Pseudocysts
Pseudoaneurysms
Perforation
Obstruction
Fistulization
Infection (abscess, infected necrosis)

53. Pancreatic Necrosis

54. Pancreatic Necrosis: Sterile
Clinically mild, low mortality rate
Systemic antibiotics to prevent secondary pancreatic infection
Enteral nutrition with advancement to oral feedings once organ failure subsides.
If no improvement in 1st 7-10d, ? of severe sterile or infected necrosis, proceed to CT-guided percutaneous aspiration to r/o infection

55. Pancreatic Necrosis

56. Pancreatic Necrosis

57. Pancreatic Necrosis: Infective
Infected Necrosis:
Guided percutaneous aspiration to demonstrate pancreatic infection
Common bugs – Klebsiella, E coli, Staph aureus
Occasional bugs – Candida
Prompt debridement preceded by appropriate antibiotic based on Gram stain or culture
Surgical debridement – gentle blunt finger dissection followed by closure of abdomen with external Penrose or JP drain, closure of abdomen with large soft drain within retroperitoneum for intermittent or continuous saline lavage or open packing of abdomen for pancreatic debridement q2-3d

59. Complications: Pseudocysts
Fibrous walled peri-pancreatic fluid collection
Present for > 1 month
No epithelial lining
Fluid has high amylase content
35% of patients develop peri-pancreatic fluid collections
> 50% resolve spontaneously over 3 month period
Complication rate increases over 6 weeks
Diagnosis may be suggested by persistent elevation of serum amylase
Planned intervention at 6 weeks.
Acute fluid collections are not pseudocysts

60. Classification of Pseudocysts
Type 1 – normal duct anatomy; no fistula between duct and cyst.
Type 2 – abnormal duct anatomy; no fistula
Type 3 – abnormal duct anatomy and fistula

61. Investigation of Pseudocysts
Ultrasound – assess change in size of cyst
Endoscopic Ultrasound – used increasingly
CT – define relationship to adjacent organs
ERCP – define duct anatomy

62. Treatment of Pseudocyst
Percutaneous Drainage
- US or CT guided
- 80% successful in Type 1 cyst
- Less successful if fistula to duct is present
- Occasionally associated with pancreatic abscess or fistula

63. Treatment of Pseudocysts
2. Endoscopic drainage and insertion of pigtail catheter
- transpapillary
- transmural

64. Treatment of Pseudocysts
3. Surgical Drainage
- cystogastrotomy or Roux Loop Cystojejunostomy
- allows adequate internal drainage
- perform biopsy of cyst wall to exclude cystadenocarcinoma
- mortality (~5%) = percutanous drainage
- lower recurrence rate (5% vs 20%)