Acute Pancreatitis

Rajeev Jain, M.D.

December 15, 2003

Normal Anatomy & Physiology
neutralize
chyme
digestive
enzymes
hormones

Exocrine Function
pancreatic duct
common bile
duct
ampulla
pancreatic enzymes
TAIL
BODY
HEAD
UNCINATE

Enzyme Secretion
pancreatic duct
duodenum
acinus
microscopic view
of pancreatic acini

Enzyme Secretion
Hormonal
CCK
gastrin
Neural
acetylcholine
VIP
GRP
Secretin (hormonal)
H
2
O
bicarbonate

Digestive Enzymes in the
Pancreatic Acinar Cell
PROTEOLYTIC LIPOLYTIC ENZYMES
ENZYMES Lipase
Trypsinogen Prophospholipase A2
Chymotrypsinogen Carboxylesterase lipase
Proelastase
Procarboxypeptidase A NUCLEASES
Procarboxypeptidase B Deoxyribonuclease (DNAse)
Ribonuclease (RNAse)
AMYOLYTIC ENZYMES
Amylase OTHERS
Procolipase
Trypsin inhibitor

Normal Enzyme Activation
trypsinogen trypsin
chymotrypsin
elastase
phospholipase
carboxypeptidase
enterokinase
chymotrypsinogen
proelastase
prophospholipase
procarboxypeptidase
duodenal lumen

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


EtOH
35%
Idiopathic
10%
Other
10%
Gallstones
45%
Acute Pancreatitis
Etiology

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
Associated Conditions

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
2.5
4.8
12.4
42.1
0
5
10
15
20
25
30
35
40
45
P
a
n
c
r
e
a
t
i
t
i
s
,

O
R
s
Female Nl TBili SOD Difficult
cannulation
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


failed protective
mechanisms
acinar cell
injury
premature
enzyme activation
Acute Pancreatitis
Pathogenesis

autodigestion of pancreatic tissue
release of
enzymes into
the circulation
activation
of white
blood cells
local
complications
local
vascular
insufficiency
premature enzyme activation
distant
organ failure
Acute Pancreatitis
Pathogenesis

STAGE 1: Pancreatic Injury
- Edema
- Inflammation
STAGE 2: Local Effects
- Retroperitoneal edema
- Ileus
STAGE 3: Systemic Complications
- Hypotension/shock
- Metabolic disturbances
- Sepsis/organ failure
SEVERITY
Mild









Severe
Acute Pancreatitis
Pathogenesis

Abdominal pain
- Epigastric
- Radiates to the back
- Worse in supine position
Nausea and vomiting
Fever


Acute Pancreatitis
Clinical Presentation

Acute Pancreatitis
Differential Diagnosis
Choledocholithiasis
Perforated ulcer
Mesenteric ischemia
Intestinal obstruction
Ectopic pregnancy

Symptoms
- Abdominal pain
Laboratory
- Elevated amylase or lipase
> 3x upper limits of normal
Radiology
- Abnormal sonogram or CT


Acute Pancreatitis
Diagnosis

Causes of Increased
Pancreatic Enzymes
Amylase Lipase
Pancreatitis

Parotitis

Normal
Biliary stone

Intestinal injury

Tubo-ovarian
disease

Normal
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



PERIPANCREATIC




SYSTEMIC
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

Cardiovascular: hypotension
Pulmonary: pleural effusions, ARDS
Renal: acute tubular necrosis
Hematologic: disseminated intravascular coag.
Metabolic: hypocalcemia, hyperglycemia

Acute Pancreatitis
Time Course
0 12 24 36 48 60 72 84 96
hours from pain onset
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
1. Age > 55 years
2. WBC > 16,000
3. Glucose > 200
4. LDH > 350 IU/L
5. AST > 250 IU/L

WITHIN 48 HOURS
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
Number
Mortality
<2
1%
3-4
16%
5-6
40%
7-8
100%

Glasgow Criteria
Non-alcoholic Pancreatitis
1. WBC > 15,000
2. Glucose > 180
3. BUN > 16
4. Arterial PO2 < 60 mm Hg
5. Ca < 8
6. Albumin < 3.2
7. LDH > 600 U/L
8. AST or ALT > 200 U/L

CT Severity Index
appearance normal enlarged inflamed
1 fluid
collection
2 or more
collections
grade A B C D E
score 0 1 2 3 4
necrosis none < 33% 33-50% > 50%
score 0 2 4 6
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 (PaO
2
< 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 H
2
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
Mild
Pancreatitis
Severe
Pancreatitis
Admissions 80% 20%
Pancreatic
necrosis
No Yes
Oral diet within 5
days
80% 0%
Morbidity 8% 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

McClave et al.
1997
Kalfarenztos et al.
1997
Windsor et al.
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
Summary of Prospective RCTs
Enteral vs Parenteral Nutrition for Acute
Pancreatitis

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.