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Myriam DelhayeDépartement de Gastro-entérologieHôpital Erasme, Bruxelles
DES en Médecine Interne, 15/02/2014
Prise en charge des pancréatites aiguës
2
Acute pancreatitis
Diagnosis
Severity stratification
Predicted Predicted
mild disease severe disease
Etiological Early management
assessment
Hydratation Antibioprophylaxy Nutrition EBS
FIRST
WEEK
FROM
ONSET
3
Acute pancreatitis
Definition Acute inflammatory process of the pancreas Variable involvement of regional tissues
of remote organ systems
Diagnosis Abdominal pain characteristic of AP Serum lipase 3 N (lipase better than amylase)
CE-CT scan / MRI characteristic of AP 2/3
4
1997 2003
Europe 12.4 15.9/100,000/y (+30%)
Mean mortality 1.9% 1.4% p<0.001
Median LOS 6.4 d 5.8 d p=0.002
Acute pancreatitis
5
1st clinically based classification Atlanta 1992Mild AP vs. Severe AP(80-90%) (10-20%)
Bradley, Arch Surg 1993; 128: 586‐590
Acute pancreatitis
6
1st clinically based classification Atlanta 1992Mild AP vs. Severe AP(80-90%) (10-20%)
Local complications (necrosis > 30%, abscess, pseudocyst)
and/or Organ failure: shock syst BP < 90 mmHg pulmonary insufficiency PaO2 60 mmHg renal failure creat > 2 mg/dl after rehydratation GI bleeding > 500 ml/24h
or Ranson score 3 (at 48h)
or APACHE II score 8 (at any time)
Bradley, Arch Surg 1993; 128: 586‐590
Acute pancreatitis
7
Ranson scoreAt admission At 48 h
Age > 55 y Hct > 10%
WBC > 16000/mm3 BUN > 5 mg/dl
Glucose > 200 mg/dl Calcium < 8 mg/dl
LDH > 1,5 N PO2 < 60 mmHg
AST > 6 N Base deficit > 4 mEq/l
Fluid sequestration > 6 l
Ranson score Mortality0 – 2 0 – 3%3 – 5 11 – 15% 6 40%
moderately accurate to predict SAPrequires 48hmissing data
8
A. Variables +4 +3 +2 +1 0 +1 +2 +3 +4
Temperature (°C) ≥41 39/40,9 38,5/38,9 36/38,4 34/35,9 32/33,9 30/31,9 <30
MAP (mmHg) ≥160 130/159 110/129 70/109 50/69 <50
HR (bpm) ≥180 140/179 110/139 70/109 55/69 40/54 <40
RR (cpm) ≥50 35/49 25/34 12/24 11/10 6/9 <6
PO2 (mmHg)
If FiO2 : (A-a) DO2* ≥500 350/499 200/349 <200
If FiO2 < 0,5: PaO >70 61/70 55/60 <55
pH ≥7,7 7,6/7,69 7,5/7,59 7,33/7,49 7,25/7,32 7,15/7,24 <7,15
Na+ (mmol/l) ≥180 161/179 156/160 151/155 130/150 120/129 110/119 <110
K+ (mmol/l) ≥7,0 6/6,9 5,5/5,9 3,5/5,4 3/3,4 2,5/2,9 <2,5
Creatinine (µmol/l) ≥318 180/317 136/179 54/135 <0,6 <54
Hct (%) ≥60 50/59,9 46/49,9 30/45,9 20/29,9 <20
WBC (x1000/mm3) ≥40 20/39,9 15/19,9 3/14,9 1/2,9 <1
GCS Points = 15 – Actual GCS
Apache II score
9
B. Age 44 y 0
45 - 54 2
55 – 64 3
65 – 74 5
75 6
C. Comorbidity: add 2 points (elective surgery) or add 5 points (emergency surgery) for each associated disease:
Cardiac failure
Cirrhosis Child C
Severe BPCO
Dialysis
Immunosuppression
APACHE II score: points for A + points for B + points for C
Apache II score
Severe AP if score 8originally designed to predict ICU survivallarge number of parameters
10
Acute pancreatitis Need for revised classification
Heterogeneity in SAP pancreatic necrosis pseudocyst or abscess no OF SOF MOF transient OF persistent OF
Scoring system for organ failure added
GI bleeding deleted
Organized necrosis
Banks, Am JGE 2006; 101: 2379‐2400
11
Marshall Scoring System
Score
Organ system 0 1 2 3 4
Respiratory (PO2 /FiO2 ) > 400 301 - 400 201 - 300 101 - 200 101
Renal (serum creatinine, mg/dl)
1.5 > 1.5 - 1.9 > 1.9 - 3.5 > 3.5 - 5.0 > 5.0
Cardiovascular (systolic blood pressure, mmHg)
> 90 < 90Fluid
responsive
< 90Not fluid
responsive
< 90pH < 7.3
< 90pH < 7.2
OF = score 2 for each organ systemMOF = 2 OF the same dayPersistent OF = OF > 48 h
12
Acute pancreatitis Severity stratification Sequential Organ Failure Assessment score (SOFA score)
Vincent et al, Int Care Med 1996; 22: 707‐710
severity / number of OF transient vs. persistent OF
most significant predictor of death
13
Acute pancreatitis Transient OF vs. persistent OF
NOF Transient OF Persistent OFn = 116 n = 60
at entry
n = 11
new (7 d)
n = 88
at entry
n = 15
new (7 d)
Mortality 2.6% 1.4% 35%
duration of OF: marker of subsequent poor outcome in AP
persistent early OF high risk of local complications (77%)of death (35%)
aggressive supportive therapy
NOF / transient OF low risk of local complications (17%)of death (2%)Johnson et al, Gut 2004; 53: 1340-1344
14
Acute pancreatitis Factors associated with development of OF
OR
extent of necrosis < 30% vs. 30 – 50% 5.8 p=0.03
< 30% vs. > 50% 18.9 p=0.0004
infected necrosis vs. sterile necrosis(later)
3.3 p=0.02
Garg et al, Clin GE Hepatol 2005; 3: 159-166
15
Acute pancreatitis Predicted severity Multifactor scoring systems
Ranson score 3 (1974) Apache II score 8 (1985) Apache – 0 score = Apache II score + 1 pt BMI 26 – 30
+ 2 pts BMI > 30 SIRS / persistent SIRS
CRP > 15 mg/dl (at 48h after onset)
Serum hematocrit 44 – 47%
Creat > 2 mg/dl + glu > 250 mg/dl
at admissionat 24hat 48h
16
Acute pancreatitis Severity stratification
SIRS when 2 of the following
T° > 38° or < 36° HR > 90 b/min RR > 20 b/min or PaCO2 < 32 mmHg WBC > 12000 or < 4000/mm3
17
Acute pancreatitis: Severity stratification
Number of SIRS criteria within 24h of admission
Singh et al, Clin GE Hepatol 2009; 7: 1247‐1251
n = 252 patients with AP SIRS n = 155 (62%) on Day 1
18
Acute pancreatitis Severity stratification: Duration of SIRS
0
5
10
15
20
25
30
35
No SIRS Transient SIRS Persistent SIRS
Persistent OFPancreatic necrosisNeed for ICUDeath
Singh et al, Clin GE Hepatol 2009; 7: 1247‐1251
%
n=65 n=116 n=71
19
HAPs = Harmless AP score on admission (2009) No rebound tenderness and/or guarding Hematocrit 43% (♂) 39.6% (♀) Serum creat < 2 mg/dlHarmless course no necrosis
no need for dialysis or artificial ventilation
no death identification of patients with mild AP with PPV = 98%
Lankisch et al, Clin GE Hepatol 2009; 7: 702‐705
Acute pancreatitis
20
Management of acute pancreatitis
CT scan at admission? yes, in all cases IF unclear diagnosis yes, to assess severity if 48h after onset no :
• if clear diagnosis• if clinically mild AP• if < 48h after onset
21
Acute pancreatitis Severity stratification – Radiological criteria
Balthazar, Radiology 1985; 156: 767‐772 Balthazar, Radiology 1990; 174: 331‐336
CT severity index points
Morbidity (%)
Mortality (%)
Grade A Normal 0 0 B Pancreatic enlargement 1 0 C Peripancreatic changes 2 7 D Single fluid collection 3 42 E 2 or more fluid collections 4 60 Necrosis None 0 12 Mild (0-30%) 2 40 Moderate (30-50%) 4 75 Extensive (> 50%) 6 100 Total CT 0-3 8 3 severity index points 4-6
7-10 35 92
6 17
Interobserver agreement 0.48 – 0.70no reflection of SIRS
Mild Moderate Severe
CE-CT scan CTSI (1994) 0 – 3 4 – 6 7 – 10
22
CT CE - CT
23
Acute pancreatitis Severity stratification – CTSI vs. MRSI
Arvanitakis et al, Gastroenterology 2004; 126: 715-723; Stimac et al, Am JGE 2007; 102: 997-1004
CE-CT
MRI
4h 48h
72h 72h
T1 -w T2 -w
24
Acute pancreatitis: New classification
Mild AP Moderate AP Severe AP
Structural changes
Interstitial edema Interstitial edema + local complications (necrosis and/or FC)
Interstitial edema + local complications (necrosis and/or FC)
Functional changes
No OF Transient OF – persistent OFMarshall score 2> 48h
No MOF No MOF – MOF (transient or persistent)
Morbidity Low High High
Mortality No Low High
Talukdar et al, Clin GE Hepatol 2009; 7: S3‐S9; Vege et al, Am JGE 2009; 104: 710‐715; de Madaria et al, Pancreatology 2010; 10: 613‐619
25
Mild AP(n=91)
Moderate AP (n=42)
Severe AP (n=11)
LOS 10 d 20 d* 27 d*
ICU 0 2.4% 54.5%*
Nutritional support 2.2% 33.3%* 63.6%*
Invasive treatment 0 2.4% 45.5%*
Mortality 0 0 45.5%*
de Madaria et al, Pancreatology 2010; 10: 613-619
Acute pancreatitis: New classification
26
Acute pancreatitis: How to early stage?
Mild AP Moderate AP Severe AP Harmless AP score Apache II 6 Apache II 8
Ranson score 3
CTSI < 3 CTSI 3 CTSI 3
No OF Transient OF Persistent OF
No MOF No MOF MOF
No SIRS Transient SIRS Persistent SIRS
CRP 15 mg/dl CRP 15 mg/dl CRP > 15 mg/dl
at admissionat 24hat 48h
27
Acute pancreatitis
Diagnosis
Severity stratification
Predicted Predictedmild disease severe disease
Etiological Early managementassessment
Hydratation Antibioprophylaxy Nutrition EBS
FIRST
WEEK
FROM
ONSET
Predictedmoderate disease
28
Acute pancreatitis Etiology Clinical history:
alcohol intake u/w, previous gallstones, family history, viral illness, drugs intake, trauma,…
Laboratory data: liver function tests, TG, Ca++ (viral studies, autoimmune markers,
genetic testing,…)
Radiological findings: US early and repeated (CE-CT scan, MRI)
29
Acute pancreatitis
Early identification of patients with acute biliary pancreatitis ALT 3 N PPV 95% gallstones and/or sludge on US CBD dilated on US / CT ( 75 y: > 8 mm; > 75 y: > 10 mm) stones in the CBD (EUS / MRCP)
Sens (%) Spec (%) ACC (%)Liver function tests 85 69 76US 72 98 86US + LFT 95 100 98EUS 87 100 97MRCP 83 97 94
30
Acute pancreatitis
Diagnosis
Severity stratification
Predicted Predictedmild disease severe disease
Etiological Early managementassessment
Hydratation Antibioprophylaxy Nutrition EBS
FIRST
WEEK
FROM
ONSET
Predictedmoderate disease
31
AP: Rationale for aggressive hydratation in SAP
SAP
acute renal failure
intravascular volume
pancreatic infection
intestinal permeabilityto bacteria
intestinal ischemia perfusion in microcirculation of pancreasimpaired pancreatic microcirculation
pancreatic ischemia
NECROSIS
vascular permeability of capillaries
arterial vasospasmvasoactive mediators
NECROSIS
pancreatic ischemia
Microthrombi
Hypercoagulability
extravasation of intravascular fluid into 3d space
ischemia / reperfusioninjury
free radicals
32
Severe acute pancreatitis Early management
Fluid resuscitation recommendations
Gardner et al, Clin GE Hepatol 2008; 6: 1070‐1076
– Crystalloids preferred in most instance– Packed RBC when Hct < 25%– Albumin when serum alb < 2 g/dl
33
Acute pancreatitis
Diagnosis
Severity stratification
Predicted Predictedmild disease severe disease
Etiological Early managementassessment
Hydratation Antibioprophylaxy Nutrition EBS
FIRST
WEEK
FROM
ONSET
Predictedmoderate disease
34
Severe acute pancreatitis Prophylactic antibiotics
Cochrane review of 7 RCT: 404 patients
Antibiotic s
Placebo p RR
Mortality (n=7) 8.4% 14.4% 0.07 0.60
Infected pancreatic necrosis (n=7)
19.7% 24.4% 0.42 0.85
Non-pancreatic infection (n=5) 23.7% 36% 0.08 0.62
Overall infections (n=5) 37.5% 51.9% 0.12 0.69
Surgery (n=6) 22.6% 24% 0.58 0.90
Fungal infections (n=7) 3.9% 5% 0.91 1.06
Villatoro E, Cochrane Database of Systematic Reviews 2010; 5: 1‐49
No major problems with antibiotic resistance
vs
35
Infected pancreatic necrosis
Antibiotics versus placebo
Imipenem versus placebo
36
Severe acute pancreatitis Antibiotic prophylaxis
7 – 10 d imipenem in patients with pancreatic necrosis + OFin septic-appearing patients
Stop AB if blood culture, FNA culture,… ⊝
Talukdar and Vege, Clin GE Hepatol 2009; 7: S3‐S9
prophylactic antibiotics NOT recommended for patients with necrotizing pancreatitis
AB for patients – with evidence of sepsis– with proven pancreatic / extrapancreatic
infection
37
Acute pancreatitis
Diagnosis
Severity stratification
Predicted Predictedmild disease severe disease
Etiological Early managementassessment
Hydratation Antibioprophylaxy Nutrition EBS
FIRST
WEEK
FROM
ONSET
Predictedmoderate disease
38
Severe acute pancreatitis Early nutritional support
Lack of enteral feeding atrophy of the GI mucosa bacterial overgrowth intestinal permeability
bacterial translocation
39
Severe acute pancreatitis Early nutritional support
Metaanalysis of 5 RCT: TEN vs. TPN in predicted SAP (202 patients)
Infectious complications Mortality
TEN infectious complications in patients with predicted SAP mortality Petrov et al, Arch Surg 2008; 143: 1111‐1117
RR = 0.47 (p<0.001) RR = 0.32 (p<0.03)
40
Enteral nutrition which route?
41
Severe acute pancreatitis Early nutritional support
2 RCT on NG feeding vs NJ feeding comparable safety, morbidity, mortality
Eatcock, Am JGE 2005; 100: 432‐439
49 patients with SAP (Glasgow 3 or APACHE II 6 or CRP > 15 mg/dl)27 NG / 22 NJ
42
Acute pancreatitis Early management of nutrition Mild AP
refeeding within 24 – 72h of onset low fat solid diet > clear liquid diet
Severe AP enteral nutrition jejunal route if gastric feeding not tolerated start with standard formulae peptide-based formulae if standard formulae not tolerated
Espen guidelines, Meier et al, Clin Nutr 2006; 25: 275‐284
43
Acute pancreatitis
Diagnosis
Severity stratification
Predicted Predictedmild disease severe disease
Etiological Early managementassessment
Hydratation Antibioprophylaxy Nutrition EBS
FIRST
WEEK
FROM
ONSET
Predictedmoderate disease
44
Biliary APMild
Severe
ImprovementNo cholangitisNo jaundiceNo CBD stone
Cholecystectomy+OC
If stone in CBD
Early EBS
EBS
CholangitisJaundice
Biliary symptomssuggestive of CBD stone
Elective EBS
No improvementafter 48 h
cholecystectomy CIor prior cholecystectomy
Delayed cholecystectomy
45
Acute biliary pancreatitis
3rd metaanalysis: 702 patients early ERCP vs. conservative management(1st 1999: 3 RCT + 1 abstract 2nd 2004: 3 RCT 3rd 2008: 5 RCT)
Author (year) Patients % SAP Timing ERCP
MorbidityERCP / contr
MortalityERCP / contr
Neoptolemos (1988) 121 44 72h adm 17 34 2 8
Fan (1993) 195 42 24h adm 18 30 5 9
Folsch (1997) 238 19 72h onset 46 51 11 6
Zhou (2002) 45 31 24h adm 5 20 0 0
Oria (2007) 103 37 72h adm 22 17 6 2
Total 702 33 27 36 6 6
Moretti et al, Dig Liv Dis 2008; 40: 379‐385
46
Acute biliary pancreatitis
Complications Mortality Complications
Moretti et al, Dig Liv Dis 2008; 40: 379‐385
p=0.01NNT = 12
p=0.6
p=0. 9
p<0.0001NNT = 3
47
Acute biliary pancreatitis
Meta-analysis of early ES in acute biliary pancreatitis
cholangitis excluded
Talukdar and Vege, Clin GE Hepatol 2009; 7: S3‐S9
48
Management of acute pancreatitis: 1st week
Conclusions
Aggressive hydratation (cristalloids) aim: Hct of 10% if initial value 47% minimum : 3l / 24h no complaint of thirst!
Painkillers : Morphine IV (titration)
No systematic antibioprophylaxyNB : * infection of necrosis after 2 – 3 w from onset
* T° and CRP < SIRS at onset of AP* if antibioprophylaxy (immunocompromised, MOF,…) : Meronem
ICU admission if suspected severe AP for monitored hyperhydratation
49
Oedémateuse (75%) Nécrosante (25%)
Histoire naturellePancréatite aiguë
Collection liquidienne aiguë Collection post-nécrotique
Résolution Pseudokyste
Stérile Infecté
Nécrose organisée
Stérile Infectée
< 4 sem :
> 4 sem :
5050
Acute pancreatitis complications
Pancreatic fluid collectionsRevised Atlanta Classification
Early PFC ( 4 w of onset) Late PFC (> 4 w of onset)
– acute fluid collection Acute Pseudocyst (10-25% of AP)
> 50% of AP
most resolve spontaneously
– acute necrotic collection WON (80% of NP)
> 90% of NP
Banks PA et al, Gut 2013; 62: 102-111Resolution
5151
Acute fluid collection
Early ( 4 w), no wall, retroperitoneal space
Most resolve spontaneously within a few weeks
Banks PA et al, Gut 2013; 62: 102-111
5252
Acute necrotic collectionEarly ( 4 w), necrosis of pancreatic and/or peripancreatic tissues
Banks PA et al, Gut 2013; 62: 102-111
5353
Acute pseudocyst
Late (> 4 w), well-defined wall, liquid content
Banks PA et al, Gut 2013; 62: 102-111
5454
Walled-off necrosis (WON)
Late (> 4 w), liquefied necrosis, encapsulated in a wall variable amount of solid debris
54
5555
Acute pancreatitis complications
Imaging techniques: CT or MRI? Both show PFC localisation and extension Contrast injection can determine the presence of
pseudoaneurysms Solid material better demonstrated by MRI or EUS than CT
CTCT
Morgan, Radiology 1997; 203: 773-778; Morgan, Clin GE Hepatol 2008; 6: 1077-1085
MRIMRI
5656
Acute pancreatitis complications: WON
Indications for endoscopic intervention: for who?
Common indications: Suspected or confirmed infected necrosis clinical deterioration
In absence of infection: Ongoing OF (> 4 w) Ongoing gastric outlet, intestinal or biliary obstruction (> 4-8 w) Persistent symptoms (pain, unwellness > 8 w)
5757
Acute pancreatitis complications: WON
Optimal timing of intervention for suspected or confirmed infected WON: when?
conservative treatment n = 397N = 639 patients & NP(21 Dutch hospitals) intervention n = 242 (38%)
Time from admission to intervention
0 – 14 d(n = 45)
14 – 29 d(n = 98)
> 29 d(n = 99)
Mortality 56% 26% 15% P<0.001
The longer the time between admission and intervention the lower the risk of mortality
Van Santvoort HC et al, GE 2011; 141: 1254-1263
5858
Acute pancreatitis complications: WON Conservative treatment?
Conservative treatment vs Intervention
Van Santvoort HC et al, GE 2011; 141: 1254-1263
n = 397(62%)
n = 242(38%)
CTSI 4 (4 – 6) 8 (6 – 10) p<0.001Pancreatic necrosis 35% 76% p<0.001Peripancreatic necrosis alone 65% 24% p<0.001Extent of necrosis
30%30 – 50%> 50%
83% 6%11%
49%24%27%
p<0.001
51%
5959
Acute pancreatitis complications: WON Conservative treatment?
Primary conservative treatment for IPNSystematic review 8 studies (n = 324 patients)
Mouli et al, GE 2013; 144: 333-340
Success 64% (51 – 78)
Need for percutaneous drainage, necrosectomy or surgery
26% (15 – 37)
Mortality 12% (6 – 18)
Conservative management without necrosectomy is a successful approach for 64% of patients with IPN
6060
Acute pancreatitis complications: WON
Endoscopic intervention: How?
Step-up approach1st step:EUS-guided transmural drainage (ETD)
– initial access to the necrotic cavity– catheter/stents drainage of the collection
with infected fluid & necrosis– trans-gastric access >> transduodenal access
Baron TH, Clin GE Hepatol 2012; 10: 1202-1207
6161
Acute pancreatitis complications: WON
Endoscopic intervention: How?
Step-up approach2nd step: endoscopic transmural necrosectomy (ETN)
when no improvement or deterioration after ETD to remove infected necrotic debris
Baron TH, Clin GE Hepatol 2012 Seewald et al, GIE 2005
6262
A 25 y.o. man with acute alcoholic NP
1st step: ETD1 DP stent + NGC catheter
Infected WON
6363
2nd step: ETN2 DP stents + 1 UF SEMS + NGC catheter
6464
Acute pancreatitis complications: WON
Step-up approach (PANTER trial)Primary open necrosectomy vs Step-up-approach
n = 45 n = 43
1) percutaneous or endoscopic drainage
2) no clinical improvement after 72h VARD
3) failure open necrosectomy
Van Santvoort HC et al, NEJM 2010; 362: 1491-1502
Bakker OJ et al, JAMA 2012
6565
Acute pancreatitis complications: WON
Step-up approach (PANTER trial)Primary open necrosectomy vs Step-up-approach
n = 45 n = 43
Van Santvoort HC et al, NEJM 2010; 362: 1491-1502
outcomes significantly better in the step-up group compared to the open surgery group
Time since onset 29 d 30 d NS
New onset MOF or systemic complications
42% 12% p=0.001
Major complications or death 69% 40% p=0.006
Death 16% 19% NS
6666
Acute pancreatitis complications: WON
Results of endoscopic necrosectomyRetrospective series > 20 patients
N Median delay to drainage (d)
Success (%)
Complications (%)
Overall mortality
(%)
Gardner (2011)* 104 63 91 14 5.8
Seifert (2009) 93 41 68 26 19
Coelho (2008) 56 35 87 20 3.5
Lopes (2007) 26 – 94 8 0
Voermans (2007) 25 84 95 40 0
Papachristou (2007) 53 49 77 49 6
Baron (2002) 43 – 72 37 –
TOTAL 400 35 – 84 81.5% 26% 6.7%
Median procedures / patient: 3.2 *BMI > 32 = risk factor for failed ETN
6767
Acute pancreatitis complications: WON
Endoscopicnecrosectomy
New onset OF 0% 50% p=0.03
Pancreatic fistula 10% 70% p=0.002
Major compl. or death 20% 80% p=0.03
Mortality 10% 40% NS
suggests superiority of endoscopic necrosectomy over surgical necrosectomy for infected necrosis
Bakker OJ et al, JAMA 2012; 307: 1053-1061
vs VARD or opensurgical necrosectomy
n = 10 n = 10
6868
Acute pancreatitis complications: WON
Multigate way approach
Baron HT et al, Clin GE Hepatol 2012; 10: 1202-1207
Combined TM and percutaneous drainage
6969
What’s new for both pancreatic pseudocysts and WON?
Forward-view scope Can be used for “difficult” localizations…
Combination access devices One-step drainage
Stents Fully covered SEMS with wide flanges
69Yamamoto N et al, GIE 2013; 77: 809-814
7070
New stents
7171From M. Giovannini
7272
Treatment algorithm for SAP
van Brunschot S et al, Clin GE Hepatol 2012
7373
Treatment algorithm for SAP
van Brunschot S et al, Clin GE Hepatol 2012
74