Acute Pancreatitis

Rajeev Jain, M.D. December 15, 2003

Normal Anatomy & Physiology

neutralize chyme digestive enzymes hormones

Exocrine Function
common bile duct
HEAD BODY

TAIL

ampulla
UNCINATE

pancreatic duct

pancreatic enzymes

Enzyme Secretion
acinus

pancreatic duct microscopic view of pancreatic acini duodenum

Enzyme Secretion
Neural
acetylcholine VIP GRP

Hormonal
CCK gastrin

Secretin (hormonal)
H2O bicarbonate

Digestive Enzymes in the Pancreatic Acinar Cell

PROTEOLYTIC ENZYMES Trypsinogen Chymotrypsinogen Proelastase Procarboxypeptidase A Procarboxypeptidase B AMYOLYTIC ENZYMES Amylase LIPOLYTIC ENZYMES Lipase Prophospholipase A2 Carboxylesterase lipase

NUCLEASES Deoxyribonuclease (DNAse) Ribonuclease (RNAse) OTHERS Procolipase Trypsin inhibitor

Normal Enzyme Activation

enterokinase

duodenal lumen

trypsinogen
chymotrypsinogen proelastase prophospholipase procarboxypeptidase

trypsin
chymotrypsin elastase phospholipase carboxypeptidase

Exocrine Stimulation

The more proximal the nutrient infusionthe greater the pancreatic stimulation (dog studies) - stomach maximal stimulation - duodenum intermediate stimulation - jejunum minimal / negligible stimulation Elemental formulas tend to cause less stimulation than standard intact formulas - intact protein > oligopeptides > free amino acids Intravenous nutrients (even lipids) do not appear to stimulate the pancreas

Protective Measures

COMPARTMENTALIZATION - digestive enzymes are contained within zymogen granules in acinar cells REMOTE ACTIVATION - digestive enzymes are secreted as inactive proenzymes within the pancreas PROTEASE INHIBITORS trypsin inhibitor is secreted along with the proenzymes to suppress any premature enzyme activation

AUTO SHUT-OFF trypsin destroys trypsin in high concentrations

Acute Pancreatitis
Definition

Acute inflammatory process involving the

pancreas

Usually painful and self-limited Isolated event or a recurring illness Pancreatic function and morphology return
to normal after (or between) attacks

Acute Pancreatitis
Etiology
Other 10%

Idiopathic 10%

Gallstones 45%

EtOH 35%

Acute Pancreatitis
Associated Conditions
Cholelithiasis Ethanol abuse Idiopathic Medications Hyperlipidemia ERCP Trauma
Pancreas divisum Hereditary Hypercalcemia Viral infections - Mumps - Coxsackievirus

End-stage renal failure

Penetrating peptic ulcer

Acute Pancreatitis
Causative Drugs

AIDS therapy: didanosine, pentamidine Anti-inflammatory: sulindac, salicylates Antimicrobials: metronidazole, sulfonamides, tetracycline, nitrofurantoin Diuretics: furosemide, thiazides IBD: sulfasalazine, mesalamine Immunosuppressives: azathioprine, 6-mercaptopurine Neuropsychiatric: valproic acid Other: calcium, estrogen, tamoxifen, ACE-I

Adjusted ORs for Pancreatitis

45 40 42.1

Pancreatitis, ORs

35 30 25 20 15 10 5 0 Female Nl TBili SOD Difficult cannulation 2.5 4.8 12.4

Freeman et al. Gastrointest Endosc. 97.

Pancreas divisum

Hereditary Pancreatitis
Autosomal dominant with 80% phenotypic
penetrance

Recurrent acute pancreatitis, chronic pancreatitis,

and 50-fold increased risk of pancreatic cancer

Mutation in cationic trypsinogen gene (R122H) Other genetic defects

- CFTR - SPINK1

Acute Pancreatitis
Pathogenesis
acinar cell injury

premature enzyme activation

failed protective mechanisms

Acute Pancreatitis
Pathogenesis
premature enzyme activation

autodigestion of pancreatic tissue

local vascular insufficiency

local complications

activation of white blood cells

release of enzymes into the circulation

distant organ failure

Acute Pancreatitis
Pathogenesis
SEVERITY Mild

STAGE 1: Pancreatic Injury

- Edema - Inflammation

STAGE 2: Local Effects

- Retroperitoneal edema - Ileus

STAGE 3: Systemic Complications

Severe

- Hypotension/shock - Metabolic disturbances - Sepsis/organ failure

Acute Pancreatitis
Clinical Presentation

Abdominal pain
- Epigastric - Radiates to the back - Worse in supine position

Nausea and vomiting Fever

Acute Pancreatitis
Differential Diagnosis

Choledocholithiasis Perforated ulcer Mesenteric ischemia Intestinal obstruction Ectopic pregnancy

Acute Pancreatitis
Diagnosis

Symptoms
- Abdominal pain

Laboratory
- Elevated amylase or lipase > 3x upper limits of normal

Radiology
- Abnormal sonogram or CT

Causes of Increased Pancreatic Enzymes

Amylase
Pancreatitis
Parotitis Biliary stone Intestinal injury

Lipase

Normal

Normal

Tubo-ovarian disease
Renal failure Macroamylasemia

Normal

Acute Pancreatitis
Diagnosis

EtOH: history Gallstones: abnormal LFTs & sonographic

evidence of cholelithiasis

Hyperlipidemia: lipemic serum, Tri>1,000 Hypercalcemia: elevated Ca Trauma: history Medications: history, temporal association

Acute Pancreatitis
Clinical Manifestations
PANCREATIC Mild: edema, inflammation, fat necrosis Severe: phlegmon, necrosis, hemorrhage, infection, abscess, fluid collections Retroperitoneum, perirenal spaces, mesocolon, omentum, and mediastinum Adjacent viscera: ileus, obstruction, perforation SYSTEMIC Cardiovascular: hypotension Pulmonary: pleural effusions, ARDS Renal: acute tubular necrosis Hematologic: disseminated intravascular coag. Metabolic: hypocalcemia, hyperglycemia

PERIPANCREATIC

Acute Pancreatitis
Time Course
ER presentation cytokine release organ failure

12

24

36

48

60

72

84

96

hours from pain onset

Predictors of Severity
Why are they needed?
- appropriate patient triage & therapy - compare results of studies of the impact of
therapy

When are they needed?

- optimally, within first 24 hours (damage control
must begin early)

Which is best?

Severity Scoring Systems

Ranson and Glasgow Criteria (1974)
- based on clinical & laboratory parameters - scored in first 24-48 hours of admission - poor positive predictors (better negative predictors)

APACHE Scoring System

- can yield a score in first 24 hours - APACHE II suffers from poor positive predictive value - APACHE III is better at mortality prediction at > 24
hours

Computed Tomography Severity Index

- much better diagnostic and predictive tool - optimally useful at 48-96 hours after symptom onset

Ranson Criteria
Alcoholic Pancreatitis
AT ADMISSION WITHIN 48 HOURS

1. Age > 55 years 2. WBC > 16,000 3. Glucose > 200 4. LDH > 350 IU/L 5. AST > 250 IU/L

1. HCT drop > 10 2. BUN > 5 3. Arterial PO2 < 60 mm Hg 4. Base deficit > 4 mEq/L 5. Serum Ca < 8 6. Fluid sequestration > 6L
7-8 100%

Number Mortality

<2 3-4 1% 16%

5-6 40%

Glasgow Criteria
Non-alcoholic Pancreatitis

1. 2. 3. 4. 5. 6. 7. 8.

WBC > 15,000 Glucose > 180

BUN > 16
Arterial PO2 < 60 mm Hg Ca < 8

Albumin < 3.2

LDH > 600 U/L AST or ALT > 200 U/L

CT Severity Index
appearance
grade score normal A 0 enlarged B 1 inflamed C 2 1 fluid collection D 3 2 or more collections E 4

necrosis
score score 1-2

none 0

< 33% 2 morbidity 4%

33-50% 4 mortality 0%

> 50% 6

7-10

92%

17%
Balthazar et al. Radiology 1990.

Severe Acute Pancreatitis

Scoring systems - 3 Ranson criteria - 8 APACHE II points - 5 CT points Organ failure - shock (SBP < 90 mmHg) - pulmonary edema / ARDS (PaO2 < 60 mmHg) - renal failure (Cr > 2.0 mg/dl) Local complications - fluid collections pseudocysts - necrosis (mortality 15% if sterile, 30-35% if infected) - abscess

Goals of Treatment

Limit systemic injury - support and resuscitation effective - decrease pancreatic secretion ineffective / harmful? - inhibit inflammatory mediators ineffective - inhibit circulating trypsin ineffective (too late) - removing gallstones mostly ineffective Prevent necrosis how? Prevent infection - antibiotics (imipenem and ciprofloxacin) probably effective in necrotic pancreatitis - prevent colonic bacterial translocation - removing gallstones variably effective

Treatment of Mild Pancreatitis

Pancreatic rest Supportive care
- fluid resuscitation watch BP and urine
output - pain control - NG tubes and H2 blockers or PPIs are usually not helpful

Refeeding (usually 3 to 7 days) - bowel sounds present - patient is hungry - nearly pain-free (off IV narcotics) - amylase & lipase not very useful here

Treatment of Severe Pancreatitis

Pancreatic rest & supportive care
fluid resuscitation* may require 5-10 liters/day careful pulmonary & renal monitoring ICU maintain hematocrit of 26-30% pain control PCA pump correct electrolyte derangements (K+, Ca++, Mg++)

Rule-out necrosis
- contrasted CT scan at 48-72 hours - prophylactic antibiotics if present - surgical debridement if infected

Nutritional support
- may be NPO for weeks - TPN vs. enteral support (TEN)

Role of ERCP
Gallstone pancreatitis
- Cholangitis - Obstructive jaundice

Recurrent acute pancreatitis

- Structural abnormalities - Neoplasm - Bile sampling for microlithiasis

Sphincterotomy in patients not suitable for

cholecystectomy

Nutrition in Acute Pancreatitis

Metabolic stress - catabolism & hypermetabolism seen in 2/3 of patients - similar to septic state (volume depletion may be a major early factor in the above derangements) Altered substrate metabolism - increased cortisol & catecholamines - increased glucagon to insulin ratio - insulin resistance Micronutrient alterations - calcium, magnesium, potassium, etc

Systemic Changes in Acute Pancreatitis

Hyperdynamic
- Increased cardiac output - Decreased systemic vascular resistance - Increased oxygen consumption

Hypermetabolism
- Increased resting energy expenditure

Catabolism
- Increased proteolysis of skeletal muscle

Reduced Oral Intake in Acute Pancreatitis

Abdominal pain with food aversion Nausea and vomiting Gastric atony Ileus Partial duodenal obstruction

Factors Differentiating Mild from Severe Pancreatitis

Parameter Admissions Pancreatic necrosis Oral diet within 5 days Morbidity Mild Pancreatitis 80% No 80% 8% Severe Pancreatitis 20% Yes 0% 38%

Mortality

3%

27%

TPN in Acute Pancreatitis

delay until volume repleted & electrolytes corrected check triglycerides first goal <400 lipids are OK to use (possible exception of sepsis) monitor glucose levels carefully - can see insulin insufficiency and resistance - may need to limit calories at first - separate insulin drip may be needed

TPN in Acute Pancreatitis

Benefit or harm? - early uncontrolled studies suggested benefit - two retrospective studies (70s & 80s) showed no benefit with TPN in pancreatitis - 1987 randomized study of early TPN vs. IVF alone showed more sepsis, longer stays, & no fewer complications with TPN When to use TPN? - jejunal access is unavailable - ileus prevents enteral feeding - patients in whom TEN clearly exacerbates pancreatitis

Enteral Nutrition in Acute Pancreatitis

studies - late 80s patients who received jejunal feeding tubes at the time of surgery, did well with early post-op enteral support - 1991 randomized study of early TPN vs. early TEN post-op showed no short-term difference - 1997 early TPN vs. early TEN (Peptamen) via nasojejunal tube in 32 patients showed no difference except 4x less cost & less hyperglycemia - 1997 similar study showed fewer complications and lower cost without change in length of stay - 1998 similar study showed more sepsis and organ failure in the TPN group

Summary of Prospective RCTs

Enteral vs Parenteral Nutrition for Acute Pancreatitis
McClave et al. 1997 Kalfarenztos et al. Windsor et al. 1997 38 -100% Semi-elemental 3x less 1998 34 Biliary 23/34 38% Polymeric --

No of patients Etiology

32 EtOH 19/32 19% Semi-elemental 5x less

Severe pancreatitis Enteral formula Cost Outcome

No difference

Fewer comp

Less SIRS

Total Enteral Nutrition in Severe Pancreatitis

may start as early as possible
- when emesis has resolved - ileus is not present

nasojejunal route preferred over

nasoduodenal

likely decreases risk of infectious

complications by reducing transmigration of colonic bacteria

Conclusions
Acute pancreatitis is a self-limited disease in
which most cases are mild.

Gallstones and alcohol are the leading causes of

acute pancreatitis.

In mild pancreatitis, nutritional support is usually

not required

In severe pancreatitis, nutritional support will

likely be required with the enteral route preferred over TPN because of both safety and cost.