Acute Pancreatitis

Resident Conference

October 5, 2004

Rachel Dunagin, MD

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

Pathophysiology

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

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

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

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

Etiology: Medications

• Uncommon cause

• Azathioprine, 6-mercaptopurine and ddI have 5-10% risk of acute pancreatitis

• >100 meds implicated

Definitely Cause Pancreatitis

• Azathioprine• Asacol• Cytosine arabinoside• Estrogens• Norethindrone/mestr-

anol• Isoniazid

• 6-mercaptopurine• Metronidazole• Pentamidine• Tetracycline• Trimethoprim/

sulfamethoxazole (TMP/SMX)

• Valproic Acid

Implicated Agents

• Industrial chemicals (Parathion)• Scorpion venom

Viral Infections

• Mumps – most common in adults

• Coxsackie-B

• Epstein-Barr

• Rubella

• Influenza A

• Varicella

• Hepatitis A, B, C, E

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

Rare Etiologies

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

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

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.

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.

DiagnosisClinical 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

Diagnosis

Signs:Mild Pancreatitis – mild abdominal tenderness, no guardingSevere 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

Cullen’s Sign

Grey-Turner’s Sign

Diagnosis

• Due to third-space fluid loss and systemic toxicity– Pulse 100-150– BP hypertensive in beginning, then

hypotensive due to 3rd spacing and hypovolemia

– Temp: initially normal, then increase to 101-103 within 1-3d

– Tachypnea and shallow respirations

Nonspecific Lab Findings

• Leukocytosis

• Hyperglycemia

• Hypocalcemia

• LFTs: AST, ALT, AlkPhos, Bilirubin

• Hypertriglyceridemia

• Hypoxemia

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)

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

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

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

Radiology

• Sonography

• Computer Tomography (CT)

• Magnetic resonance imaging (MRI)

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.

A

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).

B

Computer Tomography (CT)

• Imaging modality of choice for diagnosis, determining severity, and identifying complications

• Sensitivity: 90% for diagnosis of acute pancreatitis• Specificity: 98-100%• 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

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%

Indications for CT

• Severe acute pancreatitis (Ranson score ≥3 or APACHE II score ≥8)

• Mild pancreatitis with no response to conservative management after 48-72 hours (confirm dx, re-assess severity, identify complications)

• May repeat q7-10 day if no improvement or if deterioration.

Severity:Open Drainage due to Pancreatic Necrosis

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

Trypsinogen Activation Pathway

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.

Severity

• Ranson Criteria ≥ 3

• APACHE II score ≥ 8

• Hematocrit ≥ 44

• CT severity index ≥ 6

• 1992 Atlanta Symposium: evidence of organ failure or local complications

Ranson Criteria

**Can not be applied fully for 48 hours **Poor predictor later in the disease **Single snapshot in time

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

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

CT Severity Index

A: Normal pancreasB: Enlargement of pancreas, heterogeneous

enhancement without peripancreatic disease

C: Pancreatic abnormalities with peripancreatic disease

D: Small or single fluid collectionE: 2 or > fluid collection or pancreatic

abscess

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.

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

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

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

Treatment

• Fluids– IV hydration, aggressive (300-500ml.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

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

TreatmentIntensive monitoring All patients

Aggressive hydration All patients

Adequate analgesics All patients

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

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)

Pancreatic Necrosis

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

Pancreatic Necrosis

Pancreatic Necrosis

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

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.

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

Investigation of Pseudocysts

• Ultrasound – assess change in size of cyst

• Endoscopic Ultrasound – used increasingly

• CT – define relationship to adjacent organs

• ERCP – define duct anatomy

Treatment of Pseudocyst

1. 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

Treatment of Pseudocysts

2. Endoscopic drainage and insertion of pigtail catheter

- transpapillary

- transmural

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%)