Recent guidelines on acute pancreatitis

2.  Definition
 New and old classifications
 Investigations
 Prognosis
 New advances

3. Acute pancreatitis is defined as an acute
inflammatory process of the pancreas with
variable involvement of other regional tissues
or remote organ systems
( 1992 Atlanta Symposium )
Local inflammatory process involving premature
intracellular activation of digestive enzymes
within acinar cells leading to autodigestion of
the pancreatic tissue that can progress to
involve distant organs.

4. Limitations
 Definitions of severity and local complications
 Definition of organ failure
 The definition of necrotizing pancreatitis
 Did not include exact radiologic criteria for local
complications

5.  Acute pancreatitis (regardless of presence or
absence of chronic pancreatitis) is clinically defined
by at least the first 2 of 3 features :
 (a) abdominal pain suggestive of pancreatitis
(epigastric pain often radiating to the back)
 (b) serum amylase and lipase levels three or more
times normal
 (c) characteristic findings on CT,MRI, or USG
studies.

6.  Gallstones ( 30-60 %)
 Alcohol ( 15-30%)
 Following ERCP (5-20%)
 Hypertriglyceridemia (1.3- 3.8 %)
 Drug related ( 2-5 %)

7. ◦ Definite Cause
 5-Aminosalicylate
 6-Mercaptopurine
 Azathioprine
 Cytosine arabinoside
 Didanosine
 Diuretics
 Estrogens
 Furosemide
 Pentamidine
 Tetracycline
 Thiazides
 Trimethoprim-
sulfamethoxazole
 Valproic acid
◦ Probable Cause
 Acetaminophen
 α-Methyl-DOPA
 Isoniazid
 l-Asparaginase
 Phenformin
 Procainamide
 Sulindac

8. Recent studies:
Exenatide (GLP-1 analogue)
Sitagliptin (Dipeptidyl peptidase 4 inhibitor)
 Study in USA from 2005-2008- increase in
hospitalisation for patients treated with these
agents
 3 other studies- no significant difference

9. A follow-up study was conducted of 84,667
Swedish women and men, aged 46-84,
during 12 years
Early smoking cessation should be
recommended as a part of the clinical
management of patients with acute
pancreatitis.

10.  Cationic Trypsinogen mutations (PRSS1m,
R122Hm, N291)
 Pancreatic Secretory Trypsin Inhibitor
(SPINK1)
 CFTR
 Monocyte Chemotactic Protein (MCP1)

11.  USG -Must
 In the absence of gallstones and alcohol use, TG should be done and
considered the etiology if > 1,000 mg/dl.
 In pts > 40 years old, a pancreatic tumor should be considered
 Endoscopic investigation should be limited, as the risks and benefits
are unclear
 Patients with idiopathic AP (IAP) should be referred to higher centres
 Genetic testing -in young patients ( < 30 years old) if no cause is
evident and with family history of pancreatic disease

13.  SYMPTOMS
Abdominal Pain
BORING in character
Epigstrium and umbilical
region
Radiates to the back
Increases in supine position
Hiccups
Nausea
Vomiting

14. Physical findings-
 Low grade fever
 Tachycardia
 Hypotension
 Erythematous skin nodules
 Pulmonary findings- basilar rales,atelectasis,
pleural effusion
 Abdominal tenderness and guarding
 Epigastric mass
 Diminished bowel sounds
 Cullens sign
 Turners sign
 Fox sign

15.  AMYLASE (60-180 U/L)
≥ 3 fold
2 – 12 hrs. to 3-6 days
level not an indicator of severity
D/D OF HYPERAMYLASEMIA
PANCREATITIS WITH NORMAL AMYLASE

16.  LIPASE
0- 160 U/L
More specific
3 Fold increase usually diagnostic of acute
pancreatitis
Elevated for upto 7-14 days
level not an indicator of severity
OTHERS ENZYMES LEVEL
TRYPSIN
ELASTASE

17.  Leukocytosis ( 15,000- 20,000 per uL)
 Hemoconcentration (Hematocrit > 44%)
 Azotemia ( BUN > 22mg/dL)
 Hyperglycemia
 Hypocalcemia
 Hyperbilirubinemia ( >4 mg/dL)
 Hypertriglyceridemia
 Hypoxemia

18. IMAGING STUDIES
USG ABDOMEN
- Limited value
*Pancreatic edema
*Gall stone
*AC.cholecystitis
*D

19.  CT scan
◦ gold standard
◦ Helpful in diagnosis & management
◦ can confirm clinical impression of
acute pancreatitis in face of normal
amylase levels

20. Pancreatic edema
Peripancreatic fluid collection
Mesenteric fat stranding
Biliary tract stones
Pancreatic necrosis
Absence of enhancement(>3
cm or >30% gland)
1st 72 hrs CT underestimates
extent of necrosis

21.  CT can not differentiate btw fluid & debris
 Imaging can not differentiate btw sterile &
infected collection
 Might underestimate extent of tissue injury
in first few days

22. EARLY –within 1 week
 Characterised by SIRS and/or organ failure
LATE - > 1week
Characterised by local complications

23. Interstitial edematous pancreatitis
 (80%–90%)
 milder form
 diffuse enlargement of the pancreas
 peripancreatic fluid
 usually resolves quickly within a week
Necrotizing pancreatitis
 Tissue necrosis, either of parenchyma or the
peripancreatic tissues
 more aggressive form
 Usually involves both parenchyma and peripancreatic
tissue
 Pancreatic parenchyma necrosis – more severe

24. CECT diagnosis
 Pancreatic parenchyma –within 1st week
 Peripancreatic region-several days to a
week later.
 The eventual diagnosistic necrosis - is a
heterogenous collection of both solid and
liquid components.

25. Interstitial edematous pancreatitis:
CECT criteria
– pancreatic parenchyma enhances with the contrast
agent
– lack of peripancreatic necrosis
Necrotizing pancreatitis:
CECT criteria
– pancreatic parenchymal areas without enhancement
by intravenous contrast agent and/or
– peripancreatic necrosis

26. Severity of an attack appears to be determined
by events that occur within first 24 to 48 hrs
 Ranson’s criteria
 APACHE – II
 MODS

27. 4 degrees of severity:
1. Mild
2. Moderately severe
3. Severe acute pancreatitis
4. Critical acute pancreatitis
Based on the presence or absence of persistent
organ failure and local and systemic
complications

28. Mild AP –lack of organ failure and (peri)pancreatic
necrosis.
 Usually resolves within several days to a week.
Moderately severe AP - sterile (peri)pancreatic necrosis
and/or transient organ failure
-Resolves more slowly, may require interventions
Severe AP -persistent single or multiple organ failure
(>48 hours) OR infected (peri)pancreatic necrosis
-longer hospital stay, usually some form of
intervention
Critical AP - infected (peri) pancreatic necrosis AND
persistent organ failure

29. Risk factors for severity:
 Age more than 60yrs
 Obesity BMI more than 30
 Comorbid disease
Markers of severity within 24 hours
 SIRS ( temperature >38 degree or< 36 degree cent,pulse>
90, tachypnea >24,raised WBC >12000)
 Hemoconcentration(hct > 44%)
 BISAP
B: blood urea nitrogen (BUN )> 22mg%
I: impaired mental status
S: SIRS:2/4 present
A: age more than 60yrs
P: pleural effusion
Organ failure :Cardiovascular : systolic BP <90 mmhg ,heart
rate : more than 130
Pulmonary: pao2 <60mmhg
Renal : serum creatinine more than 2 mg%

30. Now Defined using the Modified Marshall
scoring system
 The most reliable marker for disease
severity in AP is persistent organ failure for
longer than 48 hours

31.  a )score of ≥2 in any one organ system defines “organ failure”
 b )scoring patients with pre-existent chronic renal failure
depends on the extent of deterioration over baseline renal
function

32.  Persistent organ failure -score of 2 or more
for longer than 48 hours of 1 (or more) of
the 3 organ systems
 Transient organ failure- score of 2 or more
for 1 (or more) of the 3 organ systems but
is present for less than 48 hours

33. The new classification stresses distinction between
collections consisting of fluid alone
VS
collections that arise from necrosis of pancreatic
parenchyma and/or peripancreatic tissues
The latter contains heterogenous collections that are
not solely “fluid”

34. Acute peripancreatic fluid collection:
-in interstitial edematous pancreatitis
-within the first 4 weeks
CECT criteria
– homogeneous fluid adjacent to pancreas confined by
peripancreatic fascial planes
– no recognizable wall
Pancreatic pseudocyst:
Encapsulated, well-defined collection but no or minimal
solid components
->4 weeks after onset
CECT criteria
– well-circumscribed, homogeneous fluid collection
– no solid component
– well-defined wall
– occurs only in interstitial edematous pancreatitis

35. Acute necrotic collection:
-Both fluid and solid components (necrosis)
- during necrotizing pancreatitis.
CECT criteria
– heterogeneous, varying of non-liquid density
– no encapsulating wall
– intrapancreatic and/or extrapancreatic
Walled-off necrosis:
Mature, encapsulated acute necrotic collection
Well-defined inflammatory wall
>4 weeks after onset of necrotizing pancreatitis.
CECT criteria
– heterogenous
– well-defined wall
– intrapancreatic and/or extrapancreatic

36. - SUPPORTIVE THERAPY
- TREAT SPECIFIC COMPLICATION

37.  MANAGEMENT OF PAIN
- Severe & difficult to control
- Narcotic medications
MEPERIDINE & its analogue preferable to MORPHINE

39. Ringer’s lactate -recommended initial fluid resuscitation
Goal directed IV fluid therapy with 5–10 ml/kg/h
GOALS:
1) heart rate < 120/min, mean arterial pressure between
65-85 mmHg (8.7–11.3 kPa), and urinary output > 0.5–
1ml/kg/h
2) biochemical targets of hematocrit 35-44%.
In most patients, 2500-4000 ml within the first 24 hours
wil be enough to achieve the goals

40. Preventing infectious complications
IV antibiotic prophylaxis – TO GIVE OR NOT TO ???
Selective gut decontamination has shown some
benefits, but further studies are needed.
Probiotic prophylaxis –NOT recommended

41. Oral feeding
 In mild pancreatitis –based on clinical improvement
 Enteral tube feeding -primary therapy in patients with
predicted severe acute pancreatitis .
 Either elemental or polymeric enteral nutrition
formulations
 ROUTE- nasojejunal or nasogastric
 Parenteral nutrition- second-line therapy

42. INTENSIVE CARE UNIT
WHOM TO ADMIT ?
1)Patients with severe acute and critical pancreatitis
2) Who may need interventional radiologic, endoscopic, or
surgical intervention.

44. CRAI (Continous Regional Arterial Perfusion)-
-protease inhibitor and antibiotic
-was not effective in reducing in-hospital
mortality rate in patients with acute
pancreatitis, but was associated with longer
hospital stay and higher costs

45.  Anti-secretory agents
 Protease inhibitors
 Anti-inflammatory agents and immunomodulators
 Anti-oxidants
 Potential future agents

46. Glucagon-
 SMA blood flow
 Dog and pig models- no benefit
Somatostatin (Octreotide)
 Preclinical studies- showed benefit
 Study with 50 patients with severe AP-
reduction in sepsis (76-24%) , hospital stay
( 33.1-20.66 d) and mortality ( 8-2 )

47. APROTININ
 Reduction in complement activation
 No overall effect on mortality
GABEXATE MESILATE
 Earlier studies – beneficial
 Large RCT – no clinical benefit
 NAFOMOSTAT
 New synthetic PI
 100 times more potent than Gabexate
 Clinical studies with CRAI- promising

48.  Hypothesis
 Rat models- showed gluthathione and
oxidized glutathione
1ST STUDY- N-ACETYLCYSTEINE,METHIONINE,BETA
CAROTENE,SELENIUM,ASCORBIC ACID
2nd STUDY – VIT A, C & E
3rd study – GLUTAMINE

49. FFP
 Hypothesis- inhibitory effect on proteolytic
activity
 Large RCT – no improved outcome
 Complement blocking – under study
 HEPARIN- ???
 CALCIUM BLOCKADE- a new breakthrough?

50.  Theory: AP has 3 immunological stages:
SIRS
CARS
MARS

51.  SIRS (Sytemic Inflammatory response syndrome)
HIGH PANCREATIC CALCIUM TRANSCRIPTION
DUCT PRESSURE INFLUX FACTOR ACTIVATION
(NF-ƘB)
INFLAMMATORY FACTORS
(TNF-α, IL-6, MCP-1 )
BLOOD
ENDOTHELIAL DYSFUNCTION , TISSUE HYPOXIA
ORGAN DYSFUNCTION

52. CARS(Compensatory Anti-inflammatory Syndrome)
 Increased Anti-inflammatory response
 Anergy in lymphocytes
 Depletion of T-lymphocytes
 Monocyte dysfunction(Decrease in HLA-DR)
 Impaired intestinal immune function
MARS (Med Anti-inflammatory Response Syndrome)
 Transient phase

53. NF-Ƙ B Inhibitors
 AMOBARBITAL
 PYRROLIDINE DITHIOCARBAMATE
- Both reduced pancreatic injury in animal models
TNF –α Blockade
 INFLIXIMAB (monoclocal antibody) –effective in animal
studies
INTERLEUKINS
 IL-10 – anti inflammatory
 Animals- exogenous supplementation with effective
fragment (IT9302),IL-10 gene transfer- more RCTS
required to assess efficacy

54. PAF inhibitors
LEXIPAFANT
 Reduced intestinal & lung inflammation
 Dose : iv infusion @ 100mg/d for 7 days within
72h after AP onset
 Phase III trial- no effect on death rates or organ
failure
Endothelin receptor antagonists
 ET1,ET2,ET3- associated with pancrearic necrosis
 Only animal studies
 No relevant information

55.  Immune cells and related factors
 MACROPHAGES-
 in vitro study- IL-4 & IL-13 converted M1
macrophages to M2
 In vivo- no effect
New direction?
Chemokines
 Cause migration of leukocytes to inflammation site
 CXC and CC subgroups
 Animal studies- antibodies ( anti-CC receptor 5
ligand antibodies) – reduced inflammation
 Not been confirmed by clinical trials

56. Immunostimulatory therapies
 Thymosin alpha 1 – restored CD4 T cell levels and
CD4/CD8 ratio
 Under trial
Agents improving monocyte function
 GM-CSF-
-improves balance between Th1 and Th2
-RCT-showed sc injection of 4mg/kg/day for 8d
restored monocyte immuncompetence
- good potential

57. Restoring intesitinal immune function
 Oral arginine, glutamine and probiotics-
increased SIgA and CD4 lympocytes in intestine
 Early enteral nutrition (within 48h) – increases
serum IgG levels and HLA-DR expression in T
lymphocytes
 More RCTS needed

58. Window period :
ANTI-INFLAMMATORY THERAPY- <24h
IMMUNE STIMULATION THERAPY- 3rd to 14th day
Lymphocytes all declined
CD4 count within 24-72h
CD4/CD8 after SAP attack
Th1/Th2
HLA-DR function on monocytes
IL8,IL6,IL2,IL12,TNF-α

59.  Urinary trypsin inhibitor – glycoprotein
 Derived from urine or synthetically produced
 Effective in acute pancreatitis, toxic shock and
Steven Johnsons syndrome
 Brand used in Japan- Miraclid
 India- marketed by Bharat Serums
Brand name- U-Tryp
Each vial- 50,000/1 lakh IU
Half life -40 mins
Phase IV trial -in sepsis by Lupin in India
Dose in pancreatitis- 2 lakh IU iv BD for 5 days

60.  ANTIBIOTIC
- INFECTED NECTROTIZING PANCREATITIS
- PROPHYLACTIC(SEVERE AP)
- BENEFIT OBSERVED
IMIPENEM
IMIPENEM + CILASTATATIN
CEFUROXIME
CIPROFLOXACIN +METRONIDAZOLE
- SELECTIVE GUT DECONTAMINATION
NORFLOXACIN
COLISTIN
AMPHOTERICIN
(EMERGENCE OF RESISTANT ORGANISMS)

62.  NECROTIZING PANCREATITIS
Indications for intervention in necrotizing infected
pancreatitis
1) Clinical suspicion of, or documented infected necrotizing
pancreatitis with clinical deterioration
2) Ongoing organ failure for several weeks after the onset
3) Routine percutaneous aspiration of peripancreatic
collections to detect bacteria is not indicated

63. Indications for intervention in sterile necrotizing
pancreatitis :
1) Ongoing gastric outlet, intestinal, or biliary obstruction
2) 2) Persistent symptoms like pain in patients with walled-
off necrosis without signs of infection
3) 3) Disconnected duct syndrome with persisting
symptomatic collection with necrosis without signs of
infections

64. Biliary tract management
 ERCP is not indicated in :
1) mild/severe biliary pancreatitis without cholangitis
 ERCP is indicated in
1) biliary pancreatitis with common bile duct obstruction
2) biliary pancreatitis and cholangitis
 Urgent ERCP (<24 hrs) is required in patients with acute
cholangitis.

65. Optimal interventional strategy in infected necrotizing
pancreatitis :
Initial image-guided percutaneous (retroperitoneal)
catheter drainage or endoscopic transluminal drainage
if necessary
endoscopic or surgical necrosectomy

66. Timing of cholecystectomy (or endoscopic sphincterotomy)
 Mild biliary pancreatitis – at admission
 Interval cholecystectomy after mild biliary pancreatitis-
risk of recurrent biliary pancreatitis.
 Patients with peripancreatic collections –delayed until the
collections either resolve or if they persist beyond 6
weeks
 Patients with biliary pancreatitis who have undergone
sphincterotomy and ERCP, cholecystectomy is advised –
WHY?

67. THANK YOU