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Acute Pancreatitis

Rajeev Jain, M.D.


December 15, 2003

Normal Anatomy & Physiology


neutralize
chyme

digestive
enzymes

hormones

Exocrine Function
common bile
duct

BODY

TAIL
HEAD

pancreatic duct

ampulla
UNCINATE

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

trypsinogen
chymotrypsinogen
proelastase
prophospholipase
procarboxypeptidase

duodenal lumen

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

Acute Pancreatitis
Associated Conditions

Cholelithiasis
Ethanol abuse
Idiopathic
Medications

Pancreas divisum

End-stage renal failure

Hyperlipidemia
ERCP
Trauma

Hereditary
Hypercalcemia
Viral infections
- Mumps
- Coxsackievirus

Penetrating peptic ulcer

Acute Pancreatitis
Causative Drugs

AIDS therapy: didanosine, pentamidine

Diuretics: furosemide, thiazides

Anti-inflammatory: sulindac, salicylates


Antimicrobials: metronidazole, sulfonamides, tetracycline,
nitrofurantoin

IBD: sulfasalazine, mesalamine


Immunosuppressives: azathioprine, 6-mercaptopurine
Neuropsychiatric: valproic acid
Other: calcium, estrogen, tamoxifen, ACE-I

Adjusted ORs for Pancreatitis

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

Lipase

Intestinal injury

Tubo-ovarian
disease

Normal

Renal failure

Pancreatitis
Parotitis
Biliary stone

Macroamylasemia

Normal

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

PERIPANCREATIC

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

Acute Pancreatitis
Time Course

ER presentation

cytokine release

organ failure

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.
2.
3.
4.
5.

1.
2.
3.
4.
5.
6.

Age > 55 years


WBC > 16,000
Glucose > 200
LDH > 350 IU/L
AST > 250 IU/L

Number
Mortality

<2
3-4
1% 16%

5-6
40%

7-8
100%

HCT drop > 10


BUN > 5
Arterial PO2 < 60 mm Hg
Base deficit > 4 mEq/L
Serum Ca < 8
Fluid sequestration > 6L

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

normal

enlarged

inflamed

1 fluid
collection

2 or more
collections

grade

score

necrosis

none

< 33%

33-50%

> 50%

score

score

morbidity

mortality

1-2

4%

0%

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
Mild

Severe

Pancreatitis

Pancreatitis

Admissions

80%

20%

Pancreatic
necrosis

No

Yes

Oral diet within 5


days

80%

0%

Morbidity

8%

38%

Mortality

3%

27%

Parameter

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.

Kalfarenztos et al. Windsor et al.

1997

1997

1998

No of patients

32

38

34

Etiology

EtOH 19/32

--

Biliary 23/34

Severe
pancreatitis

19%

100%

38%

Enteral
formula

Semi-elemental

Semi-elemental

Polymeric

Cost

5x less

3x less

--

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.