Acute PancreatitisAcute Pancreatitis

Rajeev Jain, M.D.Rajeev Jain, M.D.

December 15, 2003December 15, 2003

Normal Anatomy & PhysiologyNormal Anatomy & Physiology

• neutralize neutralize chymechyme

• digestive digestive enzymesenzymes

• hormoneshormones

Exocrine FunctionExocrine Function

pancreatic duct

common bileduct

ampulla

pancreatic enzymes

TAILTAIL

BODYBODY

HEADHEAD

UNCINATEUNCINATE

Enzyme SecretionEnzyme Secretion

pancreatic duct

duodenum

acinus

microscopic viewof pancreatic acini

Enzyme SecretionEnzyme Secretion

HormonalCCKgastrin

Neuralacetylcholine

VIPGRP

Secretin (hormonal)

H2Obicarbonate

Digestive Enzymes in the Digestive Enzymes in the Pancreatic Acinar CellPancreatic Acinar Cell

PROTEOLYTICPROTEOLYTIC LIPOLYTIC ENZYMESLIPOLYTIC ENZYMES ENZYMESENZYMES LipaseLipaseTrypsinogenTrypsinogen Prophospholipase A2Prophospholipase A2ChymotrypsinogenChymotrypsinogen Carboxylesterase lipaseCarboxylesterase lipaseProelastaseProelastaseProcarboxypeptidase AProcarboxypeptidase A NUCLEASESNUCLEASESProcarboxypeptidase BProcarboxypeptidase B Deoxyribonuclease (DNAse)Deoxyribonuclease (DNAse)

Ribonuclease (RNAse)Ribonuclease (RNAse)AMYOLYTIC ENZYMESAMYOLYTIC ENZYMESAmylaseAmylase OTHERSOTHERS

ProcolipaseProcolipaseTrypsin inhibitorTrypsin inhibitor

Normal Enzyme ActivationNormal Enzyme Activation

trypsinogen trypsin

chymotrypsinelastase

phospholipasecarboxypeptidase

enterokinase

chymotrypsinogenproelastase

prophospholipaseprocarboxypeptidase

duodenal lumen

Exocrine StimulationExocrine Stimulation

• The moreThe more proximal the nutrient infusion…the greater the proximal the nutrient infusion…the greater the pancreatic stimulation pancreatic stimulation (dog studies)(dog studies)- stomachstomach – maximal stimulation – maximal stimulation- duodenumduodenum – intermediate stimulation – intermediate stimulation- jejunumjejunum – minimal / negligible stimulation – minimal / negligible stimulation

• Elemental formulas tend to cause less stimulation than Elemental formulas tend to cause less stimulation than standard intact formulasstandard intact formulas- intact proteinintact protein > > oligopeptidesoligopeptides > > free amino acidsfree amino acids

• Intravenous nutrients (even lipids) do not appear to Intravenous nutrients (even lipids) do not appear to stimulate the pancreasstimulate the pancreas

Protective MeasuresProtective Measures

• COMPARTMENTALIZATIONCOMPARTMENTALIZATION - digestive enzymes are - digestive enzymes are contained within contained within zymogen granuleszymogen granules in acinar cells in acinar cells

• REMOTE ACTIVATIONREMOTE ACTIVATION - digestive enzymes are secreted as - digestive enzymes are secreted as inactive proenzymesinactive proenzymes within the pancreas within the pancreas

• PROTEASE INHIBITORSPROTEASE INHIBITORS – – trypsin inhibitortrypsin inhibitor is secreted is secreted along with the proenzymes to along with the proenzymes to suppresssuppress any premature any premature enzyme activationenzyme activation

• AUTO “SHUT-OFF”AUTO “SHUT-OFF” – trypsin – trypsin destroysdestroys trypsin in high trypsin in high concentrationsconcentrations

Acute PancreatitisAcute PancreatitisDefinitionDefinition

• Acute inflammatory process involving the Acute inflammatory process involving the pancreaspancreas

• Usually painful and self-limitedUsually painful and self-limited

• Isolated event or a recurring illnessIsolated event or a recurring illness

• Pancreatic Pancreatic functionfunction and and morphologymorphology return return to normal after (or between) attacksto normal after (or between) attacks

EtOH35%

Idiopathic10%

Other10% Gallstones

45%

Acute PancreatitisAcute PancreatitisEtiologyEtiology

• CholelithiasisCholelithiasis

• Ethanol abuseEthanol abuse

• IdiopathicIdiopathic

• MedicationsMedications

• HyperlipidemiaHyperlipidemia

• ERCPERCP

• TraumaTrauma

• Pancreas divisumPancreas divisum

• HereditaryHereditary

• HypercalcemiaHypercalcemia

• Viral infectionsViral infections- MumpsMumps- CoxsackievirusCoxsackievirus

• End-stage renal failureEnd-stage renal failure

• Penetrating peptic ulcerPenetrating peptic ulcer

Acute PancreatitisAcute PancreatitisAssociated ConditionsAssociated Conditions

Acute PancreatitisAcute PancreatitisCausative DrugsCausative Drugs

• AIDS therapy:AIDS therapy: didanosine, pentamidine didanosine, pentamidine

• Anti-inflammatory:Anti-inflammatory: sulindac, salicylates sulindac, salicylates

• Antimicrobials:Antimicrobials: metronidazole, sulfonamides, tetracycline, metronidazole, sulfonamides, tetracycline, nitrofurantoinnitrofurantoin

• Diuretics:Diuretics: furosemide, thiazides furosemide, thiazides

• IBD:IBD: sulfasalazine, mesalamine sulfasalazine, mesalamine

• Immunosuppressives:Immunosuppressives: azathioprine, 6-mercaptopurine azathioprine, 6-mercaptopurine

• Neuropsychiatric:Neuropsychiatric: valproic acid valproic acid

• Other:Other: calcium, estrogen, tamoxifen, ACE-I calcium, estrogen, tamoxifen, ACE-I

Adjusted ORs for PancreatitisAdjusted ORs for Pancreatitis

2.54.8

12.4

42.1

0

5

10

15

20

25

30

35

40

45

Pan

crea

titi

s, O

Rs

Female Nl TBili SOD Difficultcannulation

Freeman et al. Gastrointest Endosc. ‘97.

Pancreas divisumPancreas divisum

Hereditary PancreatitisHereditary Pancreatitis

• Autosomal dominant with 80% phenotypic Autosomal dominant with 80% phenotypic penetrancepenetrance

• Recurrent acute pancreatitis, chronic pancreatitis, Recurrent acute pancreatitis, chronic pancreatitis, and 50-fold increased risk of pancreatic cancerand 50-fold increased risk of pancreatic cancer

• Mutation in cationic trypsinogen gene (R122H)Mutation in cationic trypsinogen gene (R122H)

• Other genetic defectsOther genetic defects- CFTRCFTR- SPINK1SPINK1

failed protectivemechanisms

acinar cellinjury

prematureenzyme activation

Acute PancreatitisAcute PancreatitisPathogenesisPathogenesis

autodigestion of pancreatic tissue

release ofenzymes intothe circulation

activationof white

blood cells

localcomplications

localvascular

insufficiency

premature enzyme activation

distantorgan failure

Acute PancreatitisAcute PancreatitisPathogenesisPathogenesis

• STAGE 1: Pancreatic InjurySTAGE 1: Pancreatic Injury- EdemaEdema- InflammationInflammation

• STAGE 2: Local EffectsSTAGE 2: Local Effects- Retroperitoneal edemaRetroperitoneal edema- IleusIleus

• STAGE 3: Systemic ComplicationsSTAGE 3: Systemic Complications- Hypotension/shockHypotension/shock- Metabolic disturbancesMetabolic disturbances- Sepsis/organ failureSepsis/organ failure

SEVERITYSEVERITYMildMild

SevereSevere

Acute PancreatitisAcute PancreatitisPathogenesisPathogenesis

• Abdominal painAbdominal pain- EpigastricEpigastric- Radiates to the backRadiates to the back- Worse in supine positionWorse in supine position

• Nausea and vomitingNausea and vomiting

• FeverFever

Acute PancreatitisAcute PancreatitisClinical PresentationClinical Presentation

Acute PancreatitisAcute PancreatitisDifferential DiagnosisDifferential Diagnosis

• CholedocholithiasisCholedocholithiasis

• Perforated ulcerPerforated ulcer

• Mesenteric ischemiaMesenteric ischemia

• Intestinal obstructionIntestinal obstruction

• Ectopic pregnancyEctopic pregnancy

• SymptomsSymptoms- Abdominal painAbdominal pain

• LaboratoryLaboratory- Elevated amylase or lipase Elevated amylase or lipase

• > 3x upper limits of normal> 3x upper limits of normal

• RadiologyRadiology- Abnormal sonogram or CTAbnormal sonogram or CT

Acute PancreatitisAcute PancreatitisDiagnosisDiagnosis

Causes of IncreasedCauses of IncreasedPancreatic EnzymesPancreatic Enzymes

AmylaseAmylase LipaseLipase

PancreatitisPancreatitis ↑↑ ↑↑

ParotitisParotitis ↑↑ NormalNormal

Biliary stoneBiliary stone ↑↑ ↑↑

Intestinal injuryIntestinal injury ↑↑ ↑↑Tubo-ovarian Tubo-ovarian

diseasedisease ↑↑ NormalNormal

Renal failureRenal failure ↑↑ ↑↑

MacroamylasemiaMacroamylasemia ↑↑ NormalNormal

Acute PancreatitisAcute PancreatitisDiagnosisDiagnosis

• EtOH: historyEtOH: history

• Gallstones: abnormal LFTs & sonographic Gallstones: abnormal LFTs & sonographic evidence of cholelithiasisevidence of cholelithiasis

• Hyperlipidemia: lipemic serum, Tri>1,000Hyperlipidemia: lipemic serum, Tri>1,000

• Hypercalcemia: elevated CaHypercalcemia: elevated Ca

• Trauma: historyTrauma: history

• Medications: history, temporal associationMedications: history, temporal association

Acute PancreatitisAcute PancreatitisClinical ManifestationsClinical Manifestations

PANCREATICPANCREATIC

PERIPANCREATICPERIPANCREATIC

SYSTEMICSYSTEMIC

Mild:Mild: edema, inflammation, fat necrosis edema, inflammation, fat necrosisSevere:Severe: phlegmon, necrosis, hemorrhage, phlegmon, necrosis, hemorrhage, infection, abscess, fluid collectionsinfection, abscess, fluid collections

Retroperitoneum, perirenal spaces, mesocolon, Retroperitoneum, perirenal spaces, mesocolon, omentum, and mediastinumomentum, and mediastinum

Adjacent viscera:Adjacent viscera: ileus, obstruction, perforation ileus, obstruction, perforation

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

Acute PancreatitisAcute PancreatitisTime CourseTime Course

0 12 24 36 48 60 72 84 96

hours from pain onset

ER presentation cytokine release organ failure

Predictors of SeverityPredictors of Severity

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

therapytherapy

• When are they needed?When are they needed?- optimally, within first 24 hours (damage control optimally, within first 24 hours (damage control

must begin must begin earlyearly))

• Which is best?Which is best?

Severity Scoring SystemsSeverity Scoring Systems

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

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

hourshours

• Computed Tomography Severity IndexComputed Tomography Severity Index- much better diagnostic and predictive toolmuch better diagnostic and predictive tool- optimally useful at 48-96 hours after symptom onsetoptimally useful at 48-96 hours after symptom onset

Ranson CriteriaRanson CriteriaAlcoholic PancreatitisAlcoholic Pancreatitis

AT ADMISSIONAT ADMISSION

1.1. Age > 55 yearsAge > 55 years

2.2. WBC > 16,000WBC > 16,000

3.3. Glucose > 200Glucose > 200

4.4. LDH > 350 IU/LLDH > 350 IU/L

5.5. AST > 250 IU/LAST > 250 IU/L

WITHIN 48 HOURSWITHIN 48 HOURS

1.1. HCT drop > 10HCT drop > 10

2.2. BUN > 5BUN > 5

3.3. Arterial PO2 < 60 mm HgArterial PO2 < 60 mm Hg

4.4. Base deficit > 4 mEq/LBase deficit > 4 mEq/L

5.5. Serum Ca < 8Serum Ca < 8

6.6. Fluid sequestration > 6LFluid sequestration > 6L

NumberNumberMortalityMortality

<2<21%1%

3-43-416%16%

5-65-640%40%

7-87-8100%100%

Glasgow CriteriaGlasgow CriteriaNon-alcoholic PancreatitisNon-alcoholic Pancreatitis

1.1. WBC > 15,000WBC > 15,000

2.2. Glucose > 180Glucose > 180

3.3. BUN > 16BUN > 16

4.4. Arterial PO2 < 60 mm HgArterial PO2 < 60 mm Hg

5.5. Ca < 8Ca < 8

6.6. Albumin < 3.2Albumin < 3.2

7.7. LDH > 600 U/LLDH > 600 U/L

8.8. AST or ALT > 200 U/LAST or ALT > 200 U/L

CT Severity IndexCT Severity Index

appearanceappearance normalnormal enlargedenlarged inflamedinflamed 1 fluid 1 fluid collectioncollection

2 or more 2 or more collectionscollections

gradegrade AA BB CC DD EE

scorescore 00 11 22 33 44

necrosisnecrosis nonenone < 33%< 33% 33-50%33-50% > 50%> 50%

scorescore 00 22 44 66

scorescore morbiditymorbidity mortalitymortality

1-21-2 4%4% 0%0%

7-107-10 92%92% 17%17%

Balthazar et al. Radiology 1990.Balthazar et al. Radiology 1990.

Severe Acute PancreatitisSevere Acute Pancreatitis

• Scoring systemsScoring systems 3 Ranson criteria3 Ranson criteria 8 APACHE II points8 APACHE II points 5 CT points5 CT points

• Organ failureOrgan failure- shock (SBP < 90 mmHg)shock (SBP < 90 mmHg)- pulmonary edema / ARDS (PaOpulmonary edema / ARDS (PaO22 < 60 mmHg) < 60 mmHg)- renal failure (Cr > 2.0 mg/dl)renal failure (Cr > 2.0 mg/dl)

• Local complicationsLocal complications- fluid collections fluid collections pseudocysts pseudocysts- necrosis (mortality 15% if sterile, 30-35% if necrosis (mortality 15% if sterile, 30-35% if

infected)infected)- abscessabscess

Goals of TreatmentGoals of Treatment• Limit systemic injuryLimit systemic injury

- support and resuscitation – support and resuscitation – effectiveeffective- decrease pancreatic secretion – decrease pancreatic secretion – ineffective / ineffective /

harmful?harmful?- inhibit inflammatory mediators – inhibit inflammatory mediators – ineffectiveineffective- inhibit circulating trypsin – inhibit circulating trypsin – ineffective (too late)ineffective (too late)- removing gallstones – removing gallstones – mostly ineffectivemostly ineffective

• Prevent necrosisPrevent necrosis – – how?how?

• Prevent infectionPrevent infection- antibiotics (imipenem and ciprofloxacin) – antibiotics (imipenem and ciprofloxacin) –

probablyprobably effective in necrotic pancreatitiseffective in necrotic pancreatitis- prevent colonic bacterial translocationprevent colonic bacterial translocation- removing gallstones – removing gallstones – variably effectivevariably effective

Treatment of Treatment of MildMild PancreatitisPancreatitis

• Pancreatic restPancreatic rest

• Supportive careSupportive care- fluid resuscitation – watch BP and urine fluid resuscitation – watch BP and urine

outputoutput- pain controlpain control- NG tubes and HNG tubes and H22 blockers or PPIs are usually blockers or PPIs are usually

not helpfulnot helpful

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

Treatment of Treatment of SevereSevere PancreatitisPancreatitis

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

• Rule-out necrosisRule-out necrosis- contrasted CT scan at 48-72 hourscontrasted CT scan at 48-72 hours- prophylactic antibiotics if presentprophylactic antibiotics if present- surgical debridement if infectedsurgical debridement if infected

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

Role of ERCPRole of ERCP

• Gallstone pancreatitisGallstone pancreatitis- CholangitisCholangitis- Obstructive jaundiceObstructive jaundice

• Recurrent acute pancreatitisRecurrent acute pancreatitis- Structural abnormalitiesStructural abnormalities- NeoplasmNeoplasm- Bile sampling for microlithiasisBile sampling for microlithiasis

• Sphincterotomy in patients not suitable for Sphincterotomy in patients not suitable for cholecystectomycholecystectomy

Nutrition in Acute Nutrition in Acute PancreatitisPancreatitis

• Metabolic stressMetabolic stress- catabolism & hypermetabolism seen in 2/3 of catabolism & hypermetabolism seen in 2/3 of

patientspatients- similar to septic state similar to septic state (volume depletion may (volume depletion may

be a major early factor in the above be a major early factor in the above derangements)derangements)

• Altered substrate metabolismAltered substrate metabolism- increased cortisol & catecholaminesincreased cortisol & catecholamines- increased glucagon to insulin ratioincreased glucagon to insulin ratio- insulin resistanceinsulin resistance

• Micronutrient alterationsMicronutrient alterations- calcium, magnesium, potassium, etccalcium, magnesium, potassium, etc

Systemic Changes in Acute Systemic Changes in Acute PancreatitisPancreatitis

• HyperdynamicHyperdynamic- Increased cardiac outputIncreased cardiac output- Decreased systemic vascular resistanceDecreased systemic vascular resistance- Increased oxygen consumptionIncreased oxygen consumption

• HypermetabolismHypermetabolism- Increased resting energy expenditureIncreased resting energy expenditure

• CatabolismCatabolism- Increased proteolysis of skeletal muscleIncreased proteolysis of skeletal muscle

Reduced Oral Intake in Reduced Oral Intake in Acute PancreatitisAcute Pancreatitis

• Abdominal pain with food aversionAbdominal pain with food aversion

• Nausea and vomitingNausea and vomiting

• Gastric atonyGastric atony

• IleusIleus

• Partial duodenal obstructionPartial duodenal obstruction

Factors Differentiating Mild from Factors Differentiating Mild from Severe PancreatitisSevere Pancreatitis

ParameterParameterMildMild

PancreatitisPancreatitis

SevereSevere

PancreatitisPancreatitis

AdmissionsAdmissions 80%80% 20%20%

Pancreatic Pancreatic necrosisnecrosis NoNo YesYes

Oral diet within 5 Oral diet within 5 daysdays 80%80% 0%0%

MorbidityMorbidity 8%8% 38%38%

MortalityMortality 3%3% 27%27%

TPN in Acute PancreatitisTPN in Acute Pancreatitis

• delay until volume repleted & electrolytes correcteddelay until volume repleted & electrolytes corrected

• check triglycerides first – goal <400check triglycerides first – goal <400

• lipids are OK to use lipids are OK to use (possible exception of sepsis)(possible exception of sepsis)

• monitor glucose levels carefullymonitor glucose levels carefully- can see insulin insufficiency can see insulin insufficiency andand resistance resistance- may need to limit calories at firstmay need to limit calories at first- separate insulin drip may be neededseparate insulin drip may be needed

TPN in Acute PancreatitisTPN in Acute Pancreatitis

• Benefit or harm?Benefit or harm?- early uncontrolled studies suggested benefitearly uncontrolled studies suggested benefit- two retrospective studies (70’s & 80’s) two retrospective studies (70’s & 80’s)

showed showed no benefitno benefit with TPN in pancreatitis with TPN in pancreatitis- 1987 – randomized study of early TPN vs. IVF 1987 – randomized study of early TPN vs. IVF

alone showed more sepsis, longer stays, & no alone showed more sepsis, longer stays, & no fewer complications with TPNfewer complications with TPN

• When to use TPN?When to use TPN?- jejunal access is unavailablejejunal access is unavailable- ileus prevents enteral feedingileus prevents enteral feeding- patients in whom TEN clearly exacerbates patients in whom TEN clearly exacerbates

pancreatitispancreatitis

Enteral Nutrition in Acute Enteral Nutrition in Acute PancreatitisPancreatitis

• studiesstudies- late 80’slate 80’s – patients who received jejunal feeding tubes – patients who received jejunal feeding tubes

at the time of surgery, did well with earlyat the time of surgery, did well with earlypost-op enteral supportpost-op enteral support

- 19911991 – randomized study of early TPN vs. early TEN – randomized study of early TPN vs. early TEN post-op showed no short-term differencepost-op showed no short-term difference

- 19971997 – early TPN vs. early TEN (Peptamen) via – early TPN vs. early TEN (Peptamen) via nasojejunal tube in 32 patients showed no difference nasojejunal tube in 32 patients showed no difference except 4x less cost & less hyperglycemiaexcept 4x less cost & less hyperglycemia

- 19971997 – similar study showed fewer complications and – similar study showed fewer complications and lower cost without change in length of staylower cost without change in length of stay

- 19981998 – similar study showed more sepsis and organ – similar study showed more sepsis and organ failure in the TPN groupfailure in the TPN group

McClave et al. McClave et al.

19971997

Kalfarenztos et al.Kalfarenztos et al.

19971997

Windsor et al.Windsor et al.

19981998

No of patientsNo of patients 3232 3838 3434

EtiologyEtiology EtOH 19/32EtOH 19/32 - -- - Biliary 23/3Biliary 23/344

Severe Severe pancreatitispancreatitis 19%19% 100%100% 38%38%

Enteral Enteral formulaformula Semi-elementalSemi-elemental Semi-elementalSemi-elemental PolymericPolymeric

CostCost 5x less5x less 3x less3x less - -- -

OutcomeOutcome No differenceNo difference Fewer compFewer comp Less SIRSLess SIRS

Summary of Prospective RCTsSummary of Prospective RCTsEnteral vs Parenteral Nutrition for Acute Enteral vs Parenteral Nutrition for Acute

PancreatitisPancreatitis

Total Enteral Nutrition in Total Enteral Nutrition in Severe PancreatitisSevere Pancreatitis

• may start as early as possiblemay start as early as possible- when emesis has resolvedwhen emesis has resolved- ileus is not presentileus is not present

• nasojejunal route preferred over nasojejunal route preferred over nasoduodenalnasoduodenal

• likely decreases risk of infectious likely decreases risk of infectious complications by reducing complications by reducing transmigration of colonic bacteriatransmigration of colonic bacteria

ConclusionsConclusions

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

• Gallstones and alcohol are the leading causes of Gallstones and alcohol are the leading causes of acute pancreatitis.acute pancreatitis.

• In mild pancreatitis, nutritional support is usually In mild pancreatitis, nutritional support is usually not required not required

• In severe pancreatitis, nutritional support will In severe pancreatitis, nutritional support will likely be required with the enteral route preferred likely be required with the enteral route preferred over TPN because of both safety and cost.over TPN because of both safety and cost.