Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015 Masamichi Yokoe · Tadahiro Takada · Toshihiko Mayumi ·… [602580]

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Japanese guidelines for the management of acute pancreatitis: Japanese Guidelines 2015 Masamichi Yokoe · Tadahiro Takada · Toshihiko Mayumi ·… [602580]

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ORIGINAL ARTICLE
Japanese guidelines for the management of acute pancreatitis: Japanese
Guidelines 2015
Masamichi Yokoe · Tadahiro Takada · Toshihiko Mayumi · Masahiro Yoshida · Shuji Isaji · Keita Wada · Takao Itoi ·
Naohiro Sata · Toshifumi Gabata · Hisato Igarashi · Keisho Kataoka · Masahiko Hirota · Masumi Kadoya ·
Nobuya Kitamura · Yasutoshi Kimura · Seiki Kiriyama · Kunihiro Shirai · Takayuki Hattori · Kazunori Takeda ·
Yoshifumi Takeyama · Morihisa Hirota · Miho Sekimoto · Satoru Shikata · Shinju Arata · Koichi Hirata
Published online: 13 May 2015
© 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery
The author ’sa fﬁliations are listed
in the Appendix.
Correspondence to:
Toshihiko Mayumi, Department
of Emergency Medicine, School
of Medicine, University of
Occupational and Environmental
Health, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu, Fukuoka
807-8555, Japan
e-mail: [anonimizat]
DOI: 10.1002/jhbp.259Abstract
Background Japanese (JPN) guidelines for the management of acute pancreatitis were pub-
lished in 2006. The severity assessment criteria fo r acute pancreatitis were later revised by the
Japanese Ministry of Health, Labour and Welfare (MHLW) in 2008, leading to their publica-
tion as the JPN Guidelines 2010. Following the 2012 revision of the Atlanta Classi ﬁcations of
Acute Pancreatitis, in which the classi ﬁcations of regional complications of pancreatitis were
revised, the development of a minimally invasi ve method for local complications of pancrea-
titis spread, and emerging evidence was gathered and revised into the JPN Guidelines.
Methods A comprehensive evaluation was carried out on the evidence for epidemiology,
diagnosis, severity, treatment, post-endoscopi c retrograde cholangiopancreatography (ERCP)
pancreatitis and clinical indicators, based o n the concepts of the GRADE system (Grading of
Recommendations Assessment, Development and Evaluation). With the graded recommenda-
tions, where the evidence was unclear, Meta-An alysis team for JPN Guidelines 2015 conducted
an additional new meta-analysis, the results of which were included in the guidelines.
Results Thirty-nine questions were prepared in 17 subject areas, for which 43 recommen-
dations were made. The 17 subject areas were: Diagnosis, Diagnostic imaging, Etiology,
Severity assessment, Transfer indication, Fluid therapy, Nasogastric tube, Pain control, An-tibiotics prophylaxis, Protease inhibitor, Nutritional support, Intensive care, management of
Biliary Pancreatitis, management of Abdominal Compartment Syndrome, Interventions for
the local complications, Post-ERCP pancreatitis and Clinical Indicator (Pancreatitis Bundles
2015). Meta-analysis was conducted in the following four subject areas based on randomized
controlled trials: (1) prophylactic antibiotics use; (2) prophylactic pancreatic stent placement
for the prevention of post-ERCP pancreatitis; (3) prophylactic non-steroidal anti-
inﬂammatory drugs (NSAIDs) for the prevention of post-ERCP pancreatitis; and (4) perito-
neal lavage. Using the results of the meta-analysis, recommendations were graded to create
useful information. In addition, a mobile application was developed, which made it possible
to diagnose, assess severity and check pancreatitis bundles.
Conclusions The JPN Guidelines 2015 were prepared using the most up-to-date methods,
and including the latest recommended medical treatments, and we are con ﬁdent that this will
make them easy for many clinicians to use, and will provide a useful tool in the decision-
making process for the treatment of patients, and optimal medical support. The free mobile
application and calculator for the JPN Guidelines 2015 is available via http://www.jshbps.jp/
en/guideline/jpn-guideline2015.html
Keywords Acute pancreatitis · Antibiotics · Bundles · Diagnosis · Guidelines · Intensive
care · Nutrition · Pancreas · Post-ERCP pancreatitis · Severity assessment · SurgeryJ Hepatobiliary Pancreat Sci (2015) 22:405 –432
DOI: 10.1002/jhbp.259

Introduction
The Japanese (JPN) Guidelines for the management of acute
pancreatitis were published in the Journal of Hepato-
Biliary-Pancreatic Surgery in 2006, as evidence-based guide-
lines consisting of nine original papers [1 –9]. They were then
revised in 2010, including pancreatitis bundles as clinical in-
dicators [10 –20].
In 2012 the classi ﬁcation of localized complications of pan-
creatitis was revised in the Atlanta Classi ﬁcations [21], and at
the same time, minimally invasive surgeries such as interven-
tional endoscopy (IVE), and interventional radiology (IVR)
were advanced. Further, the de ﬁnitions of treatment guidelines
were revised in 2011 and the GRADE system (Grading of Rec-
ommendations Assessment, Development and Evaluation) [22 –
43] was adopted in this revision, leading to the development of
guidelines, which are applied closer to the site of treatment and
which better consider the bene ﬁts and risks to patients.
Methods
Scope/purposeThe purpose of these guidelines remains the same as that of
the JPN Guidelines (2006) [1 –9], and the JPN Guidelines
2010 [10 –20], namely to provide practical medical guidelines
for clinicians treating acute pancreatitis, to assist general clini-
cians to quickly determine the severity of acute pancreatitis
and take effective and appropriate medical treatments for the
patients with acute pancreatitis.
Stakeholder involvement
Members of the Revision Committee of JPN Guidelines 2015
included gastroenterologists, surgeons, emergency physi-
cians, radiologists, and endoscopists etc., and the guidelines
were then evaluated by a wide range of external parties, in-
cluding the general public, attorneys, internal medicine physi-
cians and surgeons.
These guidelines are designed to be used by all physicians
who treat acute pancreatitis, ranging from general clinicians to
physicians that specialize in severe acute pancreatitis.
Guideline preparation method
CQ preparation and literature searchMembers of the Revision Committee of JPN Guidelines 2015
reviewed the Clinical Questions (CQ) used in the JPN Guide-
lines (2006) and JPN Guidelines 2010, based on the importantclinical issues listed under the Scope, and then prepared new
CQ where needed. Keywords were extracted from the CQ,
and academic papers were collected. The MEDLINE,
Cochrane Library databases and Japana Centra Revuo
Medicina Web were used for this. In addition to a systematic
search using the JPN Guidelines 2010, papers published from
September 2008 to April 2014 were searched, and papers pub-
lished outside of this period were treated as being outside of
the scope of the search period.
Method of systematic literature reviewEvidence assessment was performed following the procedures
described below (Table 1).
(1) Extraction of risk/bene ﬁt outcomes from the CQ
(2) Evaluation of each paper: Preparation of structured
abstracts
The information in each article was summarized, includ-
ing the study design, and the risk of bias in the random-
ized controlled trials (RCTs) and observational studies
was determined.
(3) Method of de ﬁning the quality of evidence supporting
recommendations
Table 1 Quality of evidence
Comprehensive assessment of stored multiple papers by outcomes and
design.
(1) Initial assessment: Assessment by each study design group
A: SR (systematic review), MA (meta-analysis), RCT (randomized
controlled trial)
C: OS (observational study)
D: CS (case series, case report)
(2) Assessment of the presence/absence of factors which decrease
evidence levels
Risk of bias in study quality
Inconsistent results (different conclusions by various papers)
Indirect evidence (inconsistency between content within a paper
and CQ, or content in a paper which is not directly applicable to
clinical use)
Inaccurate data (insuf ﬁcient number of cases)
High probability of publication bias (only favorable results reported)
(3) Assessment of the presence/absence of factors which increase
evidence levels
Profound effects with no confounders (profound effects expected for
all cases)
Dose-response gradient (more profound effects expected with
increased dosage)
Possible confounders which diminish actual effects
Comprehensive assessment: The ﬁnal quality of evidence was assessed
and graded as A, B, C, DJ Hepatobiliary Pancreat Sci (2015) 22:405 –432 406

A comprehensive evaluation of the evidence was carried
out using the GRADE system [22 –43] and each of the
papers evaluated in (2) were evaluated in relation to each
of the outcomes presented in (1) above.
Grading the strength of recommendations
The strength of recommendations was graded with reference
to (1) the quality of the evidence, (2) the preferences of the pa-
tient, (3) risks and bene ﬁts and (4) cost estimates, etc. In terms
of consensus-building, a vote was taken using the Delphi
method and nominal group technique (NGT) method, and is-
sues with a support rate of more than 70% were approved.
The grading of recommendations was divided into two
categories, “1: Strong Recommendations ”and “2: Weak
Recommendations ”which are described, respectively, as
“recommendations ”and “suggestions. ”
Meta-analysis
The Meta-Analysis team for JPN Guidelines 2015 conducted
a new meta-analysis of four subjects of study using the evi-
dence obtained in the preparation of the guidelines, and usedthe results for the grading of recommendations.
(1) prophylactic antibiotics use [44]
(2) prophylactic pancreatic stent placement for the prevention
of post-endoscopic retrograd e cholangiopancreatography
(ERCP) pancreatitis
(3) prophylactic non-steroidal anti-in ﬂammatory drugs
(NSAIDs) for the prevention of post-ERCP pancreatitis
(4) peritoneal lavage (PL)
Results
Thirty-nine questions were prepared in 17 subject areas, for
which 43 recommendations were made (Table 2).
Diagnosis
CQ1 Which pancreatic enzyme measurements are important
when diagnosing acute pancreatitis?
The measurement of serum lipase is recommended for the di-
agnosis of acute pancreatitis.
However, when the measurement of lipase is dif ﬁcult, se-
rum amylase (pancreatic amylase) should be measured.
(1B)
<Comment >The detection of elevated levels of blood
pancreatic enzymes is crucial in the diagnosis of acutepancreatitis [4, 13, 21, 45 –52]. When the diagnosis acute pan-
creatitis cannot be differentiated from other diseases, serum li-
pase is superior to any other pancreatic enzymes, including
serum amylase [53] (Table 3).
CQ2 Is a urinary trypsinogen-2 dipstick useful in diagnosing
acute pancreatitis?
Urinary trypsinogen-2 dipstick may be useful for minimally
invasive method and rapid diagnosis of acute pancreatitis.
However, this is not commercially available in Japan and
therefore it cannot be recommended at this time.
(ungraded B )
<Comment >The diagnosis of acute pancreatitis using a
urinary trypsinogen-2 dipstick is highly effective in medical
institutions where a blood test cannot be examined, not
requiring blood sample, given the short time (5 min) required
for the test, its diagnostic ability, and the fact that it is roughly
equivalent to serum pancreatic enzymes [54 –56].
Diagnostic imaging
CQ3 Is ultrasonography recommended for the diagnosis of
acute pancreatitis?
When acute pancreatitis is suspected, ultrasonography is
recommended.
(1C)
<Comment >Ultrasonography, which enables the visual-
ization of ﬁndings associated with acute pancreatitis such as
pancreatic enlargement and in ﬂammatory changes around
the pancreas, is useful in diagnosing acute pancreatitis
[57, 58]. It can also visualize causes and abnormal ﬁndings as-
sociated with the pathological conditions of acute pancreatitis
such as ascites, bile duct stones and bile duct dilatation
(Fig. 1). Color Doppler ultrasonography is useful in the diag-
nosis of pseudoaneurysm developing inside the pseudocyst [59].
CQ4 Is computed tomography (CT) recommended in the di-
agnosis of acute pancreatitis?
CT is recommended for the diagnosis of acute pancreatitis.
(1C)
<Comment >When a de ﬁnitive diagnosis of acute pan-
creatitis is not possible based on clinical ﬁndings,
blood/urine tests or ultrasonography, or where the etiology
of pancreatitis is uncertain, contrast-enhanced dynamic CT
should be actively used as long as no renal function problems
are observed. Particularly in acute pancreatitis caused by pan-
creatic ductal stenosis due to pancreas tumors such as cancer,
a simple CT alone is very likely to overlook the causative pan-
creatic cancer [60 –62].J Hepatobiliary Pancreat Sci (2015) 22:405 –432 407

Table 2 Summary of recommendation
A.Diagnosis
1The measurement of serum lipase is recommended for the diagnosis of acute pancreatitis. However, when the measurement of lipase is
difﬁcult, serum amylase (pancreatic amylase) should be measured. (1B)
2Urinary trypsinogen-2 dipstick may be useful for minimally invasive method and rapid diagnosis of acute pancreatitis. However, this is
not commercially available in Japan and therefore it cannot be recommended at this time. (ungraded B)
B.Diagnostic imaging
3When acute pancreatitis is suspected, ultrasonography is recommended. (1C)
4CT is recommended for the diagnosis of acute pancreatitis. (1C)
5MRI is more useful than CT in diagnosing bile duct stones causing pancreatitis and hemorrhagic necrotizing pancreatitis. (2C)
6Contrast-enhanced CT is useful for the diagnosis of active hemorrhage and thrombosis associated with pancreatitis. (1C)
C.Etiology
7During etiological diagnosis, the diagnosis of gallstone-induced acute pancreatitis should be determined as the most important and
urgent issue, as this greatly affects the treatment, such as whether endoscopic papillary treatment should be performed or not. (1A)
D.Severity assessment
8In principle, it is recommended that a severity assessment be made immediately after diagnosis and repeated over time (especially within
48 h of the diagnosis). (1C)
9It is recommended that a scoring system is used for severity assessments. (1B)
10Contrast-enhanced CT is recommended for identifying poorly contrasted areas of acute pancreatitis and is also useful in the diagnosis
of complications. However, the possibility of exacerbating pancreatitis and renal function and allergic reactions associated with the
contrast must be considered. (2B)
E.Transfer indication
11Severe cases should be treated immediately at a facility capable of providing treatment for severe acute pancreatitis. Where such treatment
is difﬁcult at the facility, it is strongly recommended that the consideration be given to the immediate transfer of the patient. Even where the
case is mild in the early stages, severity assessments should be carried out repeatedly over time, and when the criteria are met, transfer
should be considered. (1C)
F.Fluid therapy
12An extracellular solution (Ringer ’s Lactate solution, etc.) is recommended as the initial infusion solution for acute pancreatitis. (1C)
13For patients in shock or with dehydration in the early phases of acute pancreatitis, short-time rapid ﬂuid resuscitation (150 –600 mL/h:
depending on the presence of shock and the dehydration level) is recommended. However, this should be carried out with great care in order to
avoid excessive ﬂuid infusion. For patients without dehydration, they should be monitored closely with an appropriate amount of ﬂuid infusion
(130 –150 mL/h). Particularly for patients with comorbidities such as cardiac or renal failure, the circulating blood volume should be careful
evaluated to determine the rate of ﬂuid infusion. (1C)
14If a mean arterial pressure of 65 mmHg or more and a urine output of 0.5 mL/kg per h or more has been secured in patients with acute
pancreatitis, rapid ﬂuid infusion should be discontinued and a reduction of the rate of ﬂuid infusion is suggested. The volume of infusion should
be adjusted to maintain these levels. (2C)
G.Nasogastric tube
15No remedial effect of nasogastric tube insertion has been observed for mild acute pancreatitis. Therefore, the routine use of nasogastric suction
tubes is not required. (1A)
H.Pain control
16Pain associated with acute pancreatitis is severe and persistent, raising the need of suf ﬁcient pain control. (1A)
I.Antibiotics prophylaxis
17The prophylactic administration of antibiotics is not necessary in mild acute pancreatitis, since the incidence and mortality rates of infectious
complications from mild acute pancreatitis are low. (1A)
The prophylactic administration of antibiotics in severe acute pancreatitis and necrotizing pancreatitis may improve the prognosis, if carried ou t
in the early phases of pancreatitis (within 72 h of onset). (2B)
18No remedial effect of the prophylactic administration of antifungal agents for acute pancreatitis has been observed. Therefore, routine
administration is not recommended. (1C)
J.Protease inhibitor
19The effectiveness of intravenous administration of protease inhibitor (gabexate mesilate) for improving the life prognosis and the rate of
complications of acute pancreatitis has not been clearly proven. Further consideration of the ef ﬁcacy of continuous high-dose intravenous
administration for severe cases is required. (ungraded B)
K.Nutritional support
20Intravenous hyperalimentation is not recommended for mild cases. (1B)
Total parenteral nutrition (not performed with oral or enteral nutrition) should be avoided if possible. (1B)
(Continues )J Hepatobiliary Pancreat Sci (2015) 22:405 –432 408

4–1: Can acute interstitial edematous pancreatitis be differ-
entiated from acute necrotizing pancreatitis using imaging
diagnosis?
By referring to the non-contrast CT level and the imaging
ability of contrast-enhanced CT for pancreas andperipancreatic tissues, acute peripancreatic ﬂuid collection
(APFC) associated with edematous pancreatitis can be differ-
entiated from acute necrotic collection (ANC) associated with
necrotizing pancreatitis. This can be useful in determining a
treatment strategy (Fig. 2).
(C)21In severe cases, it is more signi ﬁcant as a measure to prevent infection rather than as a route of nutrition support. It can be applied and
implemented for severe cases which do not have accompanying intestinal complications. (1A)
22If initiated in the early phase, enteral nutrition can reduce the incidence of complications and can contribute to an increased rate of survival.
Therefore, it is desirable that it be started within at least 48 h of admission. (2A)
23In principle, it is recommended that enteral feeding tubes be inserted into the jejunum through the Treitz ligament. However, if a feeding
tube cannot be inserted into the jejunum, nutrients can be infused into the duodenum or stomach instead. (2B)
24The initiation of oral administration should be determined using indicators such as the subsidence of abdominal pain and the serum pancreatic
enzyme (especially serum lipase) level, etc. (2B)
L. Intensive care
25No life-saving effect has been observed from peritoneal lavage for acute pancreatitis, and therefore it is not recommended. (2B)
26For severe cases where circulation dynamics are not stable with anuria even after suf ﬁcient initial ﬂuid infusion or cases with abdominal
compartment syndrome (ACS), CHF/CHDF should be introduced. (1C)
The ef ﬁcacy of CHF/CHDF in cases of severe acute pancreatitis not mentioned above is uncertain. Therefore, routine use is not recommended. (2C)
27Continuous Regional Arterial Infusion therapy is reported to be effective in reducing pancreatic infection and mortality rates for severe
acute pancreatitis and acute necrotizing pancreatitis, but its ef ﬁcacy has not been con ﬁrmed. (ungraded B)
M.Management of biliary pancreatitis
28Early ERCP/ES should be performed in gallstone-induced acute pancreatitis when complications of cholangitis or prolonged passage disorder
of the biliary tract are suspected. (1A)
29To prevent the recurrence of gallstone-induced acute pancreatitis, cholecystectomy is recommended for cases where such surgery is possible. (1B)
30A cholecystectomy should be performed as soon as gallstone-induced acute pancreatitis has been resolved. (1B)
N.Management of abdominal compartment syndrome
31The sequential measurement of IAP is recommended for cases with excessive ﬂuid infusion, high severity, renal and respiratory complications,
andﬂuid accumulation in multiple areas as observed by CT, since the onset of ACS increases the mortality rate in such cases. (2C)
32When there is persistent or recurrent IAP ≧12 mmHg, conservative treatment (gastrointestinal decompression, intra-abdominal decompression,
improvement of abdominal wall compliance, appropriate ﬂuid infusion and circulation management) should be initiated. The goal should be to
manage for IAP ≦15 mmHg. Surgical decompression should be considered only when internal treatment is not effective for patients with
IAP>20 mmHg and where the additional complication of organ failure is of concern. (2D)
O.Interventions for the local complications
33In principle, conservative treatment should ﬁrst be performed for necrotizing pancreatitis. The best indication for intervention is applied to
cases of infected pancreatic necrosis with suspected or con ﬁrmed infection accompanying an aggravated general condition. (1C)
34Infected pancreatic necrosis should be suspected when clinical symptoms and blood test ﬁndings deteriorate. Routine use of FNA is not required
for diagnosis, and clinical signs and CT should be used for a comprehensive determination. If an aggravated general condition is observed,
percutaneous drainage or endoscopic drainage should be given for diagnosis and treatment. (1C)
35If possible, therapeutic intervention for infected pancreatic necrosis should be performed after 4 weeks of onset, when the necrosis has been
sufﬁciently walled off, or in other words, during WON period. (2C)
36During therapeutic intervention for infected pancreatic necrosis, percutaneous (retroperitoneal) drainage or endoscopic transluminal drainag e
should be ﬁrst given, and if no improvement is achieved, necrosectomy should then be performed. Necrosectomy by endoscopic or retroperitoneal
approach is recommended. (2B)
P.Post-ERCP pancreatitis
37Prophylactic temporary pancreatic stent placement is useful as an effective endoscopic procedure for the prevention of post-ERCP pancreatitis.
This should only be performed in the high-risk groups* for post-ERCP pancreatitis given the risks and cost. (2A)
The guidewire method is very likely to reduce the incidence of post-ERCP pancreatitis. (2A)
38For the prevention of post-ERCP pancreatitis, the intrarectal administration of NSAIDs should be carried out for all cases undergoing ERCP with
no contraindications. (2A)
(Other drugs should not be used as routine preventive measures, since their ef ﬁcacy has been refuted or is uncertain.)
Q.Clinical indicators (Pancreatitis Bundles 2015 )
39A high rate of implementation of the pancreatitis bundles may contribute to improving prognosis of patients with severe acute pancreatitis. (1C)Table 2 (Continued)J Hepatobiliary Pancreat Sci (2015) 22:405 –432 409

<Comment >The differentiation of acute necrotizing pan-
creatitis from acute edematous pancreatitis is important in de-
termining the treatment strategy. The evaluation of acute
edematous pancreatitis and acute necrotizing pancreatitis is
difﬁcult with the non-contrast CT, and thus an angiographic
evaluation of the pancreas using contrast-enhanced dynamic
CT is needed [21, 63]. In many cases of early-onset pancrea-
titis (less than 1 week), the differentiation of acute
peripancreatic ﬂuid collection (APFC) associated with edem-
atous pancreatitis from acute necrotic collection (ANC) can be
difﬁcult. In the early phases of acute pancreatitis, the poorly
deﬁned pancreas in the arterial phase of dynamic CT imaging
can be reversible ischemia, and cannot be conclusively identi-
ﬁed as necrosis of the pancreatic parenchyma. However, nec-
rotizing pancreatitis is strongly suspected if a poorlycontrasted area is observed by dynamic CT more than 2 weeks
after onset [64] (Fig. 3).
4–2: Can walled-off necrosis (WON) be differentiated from
pancreatic pseudocyst (PPC) using imaging diagnosis?
By referring to the shape, extent and internal characteristics
(CT contrast level and magnetic resonance imaging (MRI)
signal intensity), PPC and WON can be differentiated. This
can be useful in determining a treatment regime.
(C)
<Comment >About 4 weeks after the onset of ANC, a
capsule-like rim appears around the fatty necrotic focus,
forming a shape called WON (Fig. 4). It is important to differ-
entiate pseudocysts that form by encapsulating ﬂuid collection
due to edematous pancreatitis from WON that is formed by
encapsulating necrotic substances due to necrotizing pancrea-titis [63, 65]. WON has an irregular shape, and not only ex-
tends to peripancreatic tissues and mesocolon, but also to
the paracolic gutter [63, 65, 66]. Inside WON, there is a mix-
ture of ﬂuid, necrotic substances and fat tissues, making the
CT contrast level higher than water concentration and, in
many cases, inhomogeneous. By referring to the shape, extent
and internal characteristics (CT contrast level and MRI signal
intensity), PPC and WON can be differentiated in many cases.
CQ5 In which cases is MRI useful for the diagnosis of acute
pancreatitis?
MRI is more useful than CT in diagnosing bile duct stones
causing pancreatitis and hemorrhagic necrotizing pancreatitis.
(2C)
<Comment >Although it can be dif ﬁcult in some cases to
differentiate parapancreatic fatty necrosis from ﬂuid collec-
tion by CT, an MRI enables the clear differentiation of fatty
necrosis from ﬂuid based on the signal strength. Compared
with ﬂuid, fatty necrosis presents higher signals in T1-
enhanced imaging and mildly lower signals in T2-enhanced
imaging [67 –69], and GdDTPA dynamic MRI imaging can
depict the foci of necrotizing pancreatitis as a poorly
contrasted area [70, 71].
CQ6 Is contrast-enhanced CT useful for the diagnosis of
vascular complication associated with acute pancreatitis?
Contrast-enhanced CT is useful for the diagnosis of active
hemorrhage and thrombosis associated with pancreatitis.
(1C)
<Comment >In acute pancreatitis, bleeding can occur in
the areas from the peripancreatic tissues to the mesentery
and mesocolon. Contrast-enhanced CT is necessary whenthere is a need to evaluate the presence of persistent bleedingTable 3 JPN diagnostic criteria*
1. Acute abdominal pain and tenderness in the upper abdomen.
2. Elevated levels of pancreatic enzymes in the blood or urine.
3. Abnormal ﬁndings of acute pancreatitis detected by US, CT or MRI.
Patients who present with at least two of the above three manifestations
and in whom other pancreatic diseases and acute abdomen have been
ruled out are diagnosed as having acute pancreatitis. However, acute
aggravation in chronic pancreatitis should be included as the category of
acute pancreatitis.
Note: Measurement of pancreatic enzymes (such as pancreatic amylase
and lipase) with high speci ﬁcity for the pancreas is desirable.
* The diagnostic criteria of acute pancreatitis was established by
the Japanese Ministry of Health, Labour, and Welfare 2008
Cited from Ref. [13]
Fig. 1 Ultrasonography. Mild pancreatic enlargement and ﬂuid accumu-
lation in the anterior pararenal space, transverse mesocolon and bursaomentalis can be observedJ Hepatobiliary Pancreat Sci (2015) 22:405 –432 410

[72]. Also, a peripancreatic arterial rupture can occur in acute
pancreatitis, accompanied by acute peripancreatic ﬂuid collec-
tion, causing internal bleeding (known as pseudoaneurysm)
[73, 74] (Fig. 5). Contrast-enhanced CT and color Doppler ul-
trasonography is necessary to accurately diagnose venous
thrombus [75].
Etiology
CQ7 Which pathological conditions should be considered as
priority issues during etiological diagnosis?
During etiological diagnosis, the diagnosis of gallstone-
induced acute pancreatitis should be determined as the most
important and urgent issue, as this greatly affects the treat-
ment, such as endoscopic papillary treatment.
(1A)
<Comment >Bilirubin, alanine aminotransferase (ALT),
aspartate aminotransferase (AST), and alkaline phosphatase
(ALP) values and an ultrasonography should be examined in all
cases to diagnose the presence of gallstone-induced acute pancre-
atitis [76]. MRI/magnetic resonance cholangiopancreatography(MRCP) can visualize common bile duct stones, an anoma-
lous arrangement of pancreaticobiliary ducts, and pancreas
divisum, and is useful for the etiological diagnosis of acute
pancreatitis [77 –79]. Endoscpic ultrasonography (EUS) has
a better capacity for visualizing common bile duct stones
compared to ultrasonography [80 –82]. It can diagnose bile
duct stones, chronic pancreatitis, pancreatic cancer and
intraductal papillary mucinous tumor, and is useful for the
etiological diagnosis of acute pancreatitis [83, 84].
Severity assessment
CQ8 When should a severity assessment be performed?In principle, it is recommended that a severity assessment be
made immediately after diagnosis and repeated over time (es-
pecially within 48 h of the diagnosis).
(1C)
<Comment >Severity assessments for acute pancreatitis
are useful for the appropriate int roduction of initial treatment,
and, when necessary, transfer to f acilities where treatment for
severe acute pancreat itis can be provided [85 –87]. A severity
assessment at the time of the di agnosis of acute pancreatitis
can increase the possibility of accurate treatment for the patient
and an improved prognosis. Repeated severity assessments
may be small in cost. Members of the Revision Committee of
JPN Guidelines 2015 reached the consensus that sequentially
repeated severity assessments are highly bene ﬁcial for patients.
The revised edition of the Atlanta Classi ﬁcations (2012) [21]
also state that “the severity of acute pancreatitis can be
reassessed on a daily basis while the pancreatitis is still evolv-
ing, and in particular re-evaluations should be made 24 h,
48 h and 7 days after admission to the hospital. ”
CQ9 Is a scoring system useful for severity assessments?
It is recommended that a scoring system is used for severity
assessments.
(a) (b)Fig. 2 Acute necrotic collection
(ANC). In non-contrast computed
tomography (CT) ( a), inhomoge-
neous ﬂuid retention (indicated by
the arrow) can be observed from the
transverse mesocolon to the leftparacolic gutter, accompanied with
internal fat accumulation. Although
it is poorly contrasted by contrast-
enhanced CT ( b), middle colic ar-
tery (MCA) running inside can beobserved. This can be diagnosed as
acute necrotic collection (ANC) in
the transverse mesocolon
Fig. 3 Classi ﬁcation of pancreatic ﬂuid collection by the revised Atlanta
classi ﬁcation. AFPC acute peripancreatic ﬂuid collection, ANC acute ne-
crotic collection, PPC pancreatic pseudocyst, WON walled-off necrosisJ Hepatobiliary Pancreat Sci (2015) 22:405 –432 411

(1B)
<Comment >Various scoring systems have been pro-
posed and are used at clinical sites for severity assessments
of acute pancreatitis. The Ranson score [88] was reported in
1974, the Glasgow score [89] in 1984, the APACHE-II [87]
in 1989, and the systemic in ﬂammatory response syndrome
(SIRS) [90] in 2006, all of which are used as scoring systems.
In terms of new scoring systems, the Panc 3 score [91] and
POP score [92] were proposed in 2007, the BiSAP score
[93] in 2008, and the HAPS score [94] in 2009.
The JPN Severity Score (JSS) was revised in 2008 [14]
(Table 4), and it has been reported that the best predictors of
organ failure are the JSS and BiSAP scores [95]. Also,
according to a report by Mounzer et al., in comparison to the
Ranson, Glasgow, APACHE-II, SIRS, POP, BiSAP, JSS and
HAPS scoring systems, the JSS had the best scoring capacity
for AUC at 48 h after admission [96].CQ10 Is contrast-enhanced CT useful for severity assess-
ments of acute pancreatitis that is suspected to increase in
severity?
(At facilities where treatment for acute pancreatitis is pro-
vided,) Contrast-enhanced CT is recommended for identify-
ing poorly contrasted areas of acute pancreatitis and is also
useful in the diagnosis of complications. However, the pos-
sibility of exacerbating pancreatitis and renal function and
allergic reactions associated with the contrast must be
considered.
(2B)
<Comment >The presence of necrotizing pancreatitis
and the extension of in ﬂammatory changes are closely
related to various complications and prognosis [97 –99],
and accurate diagnosis is necessary. The evaluation of
an enlarged pancreas, in ﬂammatory extension to
Fig. 5 Bleeding in acute pancreatitis.
In the non-contrast computed tomog-
raphy (CT) ( a), hemorrhagic fat ne-
crosis can be observed in the pancreas,
peripancreatic tissues, lesser sac space
and transverse mesocolon. High den-sity areas (*) can be partly observed,
accompanied by a bleeding mass. In
the dynamic CT ( b), contrast agent
leakage (pseudoaneurysm, indicated
by the arrowheads) inside the bleeding
mass can be observed, indicating per-
sistent bleeding
(c) (d)(b) (a)Fig. 4 Acute necrotic collection
(ANC) and walled-off necrosis
(WON). In the non-contrast computed
tomography (CT) ( a) and contrast-en-
hanced CT ( b), a high level of ﬂuid
concentration (*) was observed aroundthe enlarged pancreatic parenchyma,
and acute necrotic collection (ANC)
was suspected. In a non-contrast CT
(c) and contrast-enhanced CT ( d)c a r –
ried out 4 weeks after onset, an en-larged necrosis was encapsulated
(indicated by arrowheads) with an ir-
regular shape. This was diagnosed as
walled-off necrosis (WON) and a
drainage operation was performedJ Hepatobiliary Pancreat Sci (2015) 22:405 –432 412

peripancreatic fat tissue, ﬂuid collection, pseudocyst, and
fat necrosis are generally possible with non-contrast CT.
However, the diagnosis and evaluation of necrotizing
pancreatitis and its scope needed for severity assessments
is not possible with non-contrast CT, and contrast-
enhanced CT is required for this [100] (Figs 6 –8). If
contrast-enhanced CT is taken within 4 to 10 days of onset,
the diagnosis of necrotizing pancreatitis can be made with
an accuracy of almost 100% [97, 98, 100, 101].
Transfer indication
CQ11 When should patients with acute pancreatitis be
transferred to specialized hospital?
Severe cases should be treated immediately at a facility capa-
ble of providing treatment for severe acute pancreatitis. Wheresuch treatment is dif ﬁcult at the facility, it is strongly recom-
mended that the consideration be given to the immediate
transfer of the patient. Even where the case is mild in the early
stages, severity assessments should be carried out repeatedly
over time, and when the criteria are met, transfer should be
considered.
(1C)
<Comment >It has been reported that hospitals with a
large number of cases of acute pancreatitis have good
clinical outcomes [102 –104]. According to a report by
Murata et al. using Japan ’s Diagnosis Procedure Combina-
tion (DPC)* data, good clinical outcomes were achieved in
hospitals receiving a large number of patients annually
[103].
For cases considered “severe ”according to the JSS,
patients should be transferred to a facility where ICU manage-
ment, IVR, continuous hemodia ﬁltration (CHDF), endo-
scopic treatment for cholelithiasis, surgical treatment, a
Table 4 JPN Severity Score (JSS)
The severity scoring system of acute pancreatitis of the Japanese Ministry of Health, Labour and Welfare (2008)
Prognostic factors (1 point for each factor)
1. Base excess ≦/C03 mEq/L or shock (systolic blood pressure <80 mmHg)
2. PaO 2≦60 mmHg (room air) or respiratory failure (respirator management is needed)
3. BUN ≧40 mg/dL (or Cr ≧2.0 mg/dL) or oliguria (daily urine output <400 mL even after IV ﬂuid resuscitation)
4. LDH ≧2 times of upper limit of normal
5. Platelet count ≦100,000/mm3
6. Serum Ca ≦7.5 mg/dL
7. CRP≧15 mg/dL
8. Number of positive measures in SIRS criteria ≧3
9. Age≧70 years
CT grade by CECT1. Extrapancreatic progression of in ﬂammation
Anterior pararenal space 0p o i n t
Root of mesocolon 1p o i n t
Beyond lower pole of kidney 2p o i n t s
2. Hypoenhanced lesion of the pancreas
The pancreas is conveniently divided into three segments (head, body, and tail).
Localized in each segment or only surrounding the pancreas 0 point
Covers 2 segments 1p o i n t
Occupies entire 2 segments or more 2p o i n t s
1+2=T o t a ls c o r e
Total score = 0 or 1 Grade 1
Total score = 2 Grade 2
Total score = 3 or more Grade 3
Assessment of severity
(1) If prognostic factors are scored as 3 points or more, or (2) If CT grade is judged as Grade 2 or more, the severity grading is evaluated to be as
“severe ”.
Measures in SIRS diagnostic criteria: (1) Temperature >38 °C or <36 °C, (2) Heart rate >90 beats/min, (3) Respiratory rate >20 breaths/min or
PaCO
2<32 torr, (4) WBC >12,000 cells/mm3,<4,000 cells/mm3,o r>10% immature (band) forms
Modi ﬁed from Ref. [14]J Hepatobiliary Pancreat Sci (2015) 22:405 –432 413

nutritional support team (NST) and other measures for severe
acute pancreatitis are available.
*The Diagnosis Procedure Combination (DPC) is a case-
mix system, which is similar to the diagnosis-related groups
(DRGs) used in Medicare in the United States.
Fluid therapy
CQ12 What should be used as initial infusion solution?An extracellular solution (Ringer ’s Lactate solution, etc.) is rec-
ommended as the initial infusion s olution for acute pancreatitis.
(1C)
<Comment >According to two RCTs, Ringer ’s Lactate
solution was found to be more effective in reducing in ﬂam-
mation than saline. At the same time, colloid solution HES
was found to have the same reductive effect on in ﬂammation
as Ringer ’s Lactate solution, with a mild increase in abdomi-
nal muscle pressure [105, 106]. In an observational study of
patients with severe acute pancreatitis admitted to an ICU,
the volume of extracellular solution infused into survivors
within 48 h of admission was reported to be signi ﬁcantly
higher than that for non-survivors [107]. Also, in a prospec-
tive study of patients with severe acute pancreatitis who ex-
hibited shock and oliguria at the time of admission,
signiﬁcantly higher values for the rates of mechanical ventila-
tion and incidences of ACS and lethal rates were obtained in
the rapid ﬂuid expansion group [108]. Although there is not
sufﬁcient reliable evidence regarding what should be used
as the initial infusion solution for acute pancreatitis [109,
110], the bene ﬁts to patients when using an extracellular solu-
tion, especially Ringer ’s lactate solution, are considered to
sufﬁciently outweigh the risks.
CQ13 What is the optimal initial infusion rate at the onset of
acute pancreatitis?
For patients in shock or with dehydration in the early
phases of acute pancreatitis, short-time rapid ﬂuid resuscita-
tion (150 –600 mL/h: depending on the presence of shock
and the dehydration level) is recommended. However, this
should be carried out with great care in order to avoid exces-
siveﬂuid infusion. For patients without dehydration, they
Fig. 6 Computed tomography (CT) Grade 1 (JSS). In the contrast-en-
hanced CT, the mild enlargement of the entire pancreas can be observed
with no noticeable poorly contrasted areas. Since ﬂuid collection (*) can
be observed in the left anterior pararenal space and the root of the trans-
verse mesocolon, this can be diagnosed as CT Grade 1 acute pancreatitis
Fig. 7 Computed tomography (CT) Grade 2 (JSS). In the contrast-en-
hanced CT, poorly contrasted fat necrosis can be observed in the lesser
sac, left anterior pararenal space and transverse mesocolon. This wasdiagnosed as CT Grade 2 according to the necrosis level of the pancreas
(1/3-1/2) and due to the fat necrosis observed in the root of the transverse
mesocolon
Fig. 8 Computed tomography (CT) Grade 3 (JSS). In the contrast-en-
hanced CT, a large amount of ascites (AS) was observed. The enlarge-ment of the pancreatic body and a poorly contrasted area (indicated by
the arrows) were observed. Signi ﬁcant fat necrosis (*) reaching the trans-
verse mesocolon and left posterior peritoneal cavity space was observed.
This was diagnosed as CT Grade 3 severe acute pancreatitisJ Hepatobiliary Pancreat Sci (2015) 22:405 –432 414

should be monitored closely with an appropriate amount of
ﬂuid infusion (130 –150 mL/h). Particularly for patients with
comorbidities such as cardiac or renal failure, the circulating
blood volume should be careful evaluated to determine the
rate of ﬂuid infusion.
(1C)
<Comment >The results of the studies regarding the ini-
tialﬂuid infusion rate vary according to dehydration levels.
Patients with unstable circulation dynamics should be recog-
nized as being in a severe condition with a high mortality rate,
and their circulation dynamics should be more carefully eval-
uated and monitored. For such patients, the introduction of
colloid solution infusion, catecholamine administration, andin some cases, blood puri ﬁcation therapy may be considered
[21, 49 –51, 105, 108, 109, 111 –116].
CQ14 What are the indications for the termination of initial
rapid ﬂuid infusion for acute pancreatitis?
If a mean arterial pressure of 65 mmHg or more and a urine
output of 0.5 mL/kg per hour or more has been secured in pa-
tients with acute pancreatitis, rapid ﬂuid infusion should be
discontinued and a reduction of the rate of ﬂuid infusion is
suggested. The volume of infusion should be adjusted to
maintain these levels.
(2C)
<Comment >There are few reports on the usefulness of
indicators for the termination of rapid ﬂuid infusion. De-
creases in BUN, hematocrit (Ht), and CVP have been studied,
but these did not serve as useful indicators [105, 107, 110,
117]. In the Pancreatitis B undles, one item states, “For
acute pancreatitis, a suf ﬁcient amount of ﬂuid replacement
and monitoring should be performed within 48 h of onset,
and mean arterial pressure (MAP) should be maintained at65 mmHg or more and urinary output at 0.5 ml/kg per hour
or more, respectively [20]. ”The results of a nationwide sur-
vey of patients who developed acute pancreatitis through-
out the year of 2011 in Japan showed a signi ﬁcantly low
mortality rate of 9.5% in patients in compliance with these
levels, while the mortality rate of those in non-compliance
was 19.4%. This showed that compliance with the Bundles
can improve the life prognosis of patients [118].
Nasogastric tube
CQ15 Is a nasogastric tube useful for the remedy of acute
pancreatitis?
No remedial effect of nasogastric tube insertion has been ob-
served for mild acute pancreatitis. Therefore, the routine use
of nasogastric suction tubes is not required.(1A)
<Comment >At least eight RCTs [119 –126] have
been performed on nasogastric suction tube for mild to
moderate pancreatitis. However, no bene ﬁcial effects
such as reduced pain or shortened periods of hospitaliza-
tion were reported. Rather, the duration of abdominal
pain and nausea was prolonged with use of nasogastrictube [122, 125].
Pain control
CQ16 Is pain relief necessary for acute pancreatitis?Pain associated with acute pancreatitis is severe and persis-
tent, raising the need of suf ﬁcient pain control.
(1A)
<Comment >The appropriate use of analgesics was found
to be effective in reducing pain. It was further found that this
does not inhibit diagnosis or treatment [127]. A consensus has
not yet been reached as to which analgesics are useful inreducing pain from acute pancreatitis [128 –131].
Antibiotics prophylaxis
CQ17 Is the prophylactic administration of antibiotics effec-
tive in improving acute pancreatitis?
The prophylactic administration of antibiotics is not necessary
in mild acute pancreatitis, since the incidence and mortality
rates of infectious complications from mild acute pancreatitis
are low.
(1A)
The prophylactic administration of antibiotics in severe
acute pancreatitis and necrotizing pancreatitis may improve
the prognosis, if carried out in the early phases of pancreatitis
(within 72 h of onset).
(2B)
<Comment >Although a number of meta-analyses have
been performed on the prophylactic administration of antibi-
otics used for acute pancreatitis, the results have not been con-
sistent [132 –160]. Many recent reports have shown that it is
ineffective. However, the Meta-Analysis team for JPN Guide-
lines focused on the timing for starting antibiotic administra-
tion and the patients who received such treatments, and
performed a meta-analysis [44] using six RCTs conducted
on patients with severe acute pancreatitis or necrotizing pan-
creatitis within 48 and 72 h of onset [132, 133, 136, 137,
139, 141]. As a result, mortality and infectious pancreatic
complication rates were signi ﬁcantly reduced. However, to
meet the conditions of the timing to start antibioticJ Hepatobiliary Pancreat Sci (2015) 22:405 –432 415

administration, the type of antibiotics and the selection of sub-
jects, a large scale RCT is considered necessary [49]. Al-
though no clear understanding has been obtained regarding
the period of prophylactic antibiotic administration, continu-
ous administration for more than 2 weeks should be avoided
in patients with no signs of infection [161]. A possible in-
crease in complications such as fungal infections due to the
use of broad-spectrum antibiotics has also been reported
[162].
CQ18 Is the prophylactic administration of antifungal agents
effective for acute pancreatitis?
No remedial effect of the prophylactic administration of anti-
fungal agents for acute pancreatitis has been observed. There-
fore, routine administration is not recommended.
(1C)
<Comment >Recently, no large scale RCTs have been
performed on the preventive effects of antifungal administra-
tion for acute pancreatitis, and it is uncertain if such adminis-
tration can reduce mortality rates or shorten the period of
hospitalization [163 –168].
Protease inhibitor
CQ19 Is the intravenous administration of protease inhibitor
effective for acute pancreatitis?
The effectiveness of intravenous administration of protease
inhibitor (gabexate mesilate) for improving the life prognosis
and the rate of complications of acute pancreatitis has not been
clearly proven. Further consideration of the ef ﬁcacy of contin-
uous high-dose intravenous administration for severe cases is
required.
(ungraded B )
<Comment >In 17 reports [89, 169 –185] on the meta-
analysis of RCTs [186] published in 2014 no signi ﬁcant re-
duction in mortality rates was achieved by the administration
of protease inhibitor.
Nutritional support
CQ20 Is intravenous hyperalimentation useful for acute
pancreatitis?
Intravenous hyperalimentation is not recommended for mild
cases.
(1B)
Total parenteral nutrition (not performed with oral or en-
teral nutrition) should be avoided if possible.(1B)
<Comment >In two RCTs, no ef ﬁcacy was observed
from intravenous high calorie infusion for mild acute pancre-
atitis [187, 188]. In RCT conducted for severe acute pancrea-
titis, the medical cost of enteral nutrition for each patient was
shown to be one-third of that for intravenous alimentation
[189]. Also, the SIRS positive rate, CRP value and APACHE
II scores were signi ﬁcantly lower in patients receiving enteral
nutrition 7 days after admission. However, it has been also re-
ported that these indicators did not decrease in patients receiv-
ing intravenous alimentation [190]. Furthermore, a signi ﬁcant
decrease, not only in the rate of incidence of infectious necro-
tizing pancreatitis, but also in the infection rate of multiple or-gan failure and mortality rates were reported with enteral
nutrition for severe acute pancreatitis, when compared with
total parenteral nutrition [191].
CQ21 What are the signi ﬁcance and indications of enteral
nutrition?
In severe cases, it is more signi ﬁcant as a measure to prevent
infection rather than as a route of nutrition support. It can be
applied and implemented for severe cases which do not have
accompanying intestinal complications.
(1A)
<Comment >A number of RCTs have been performed in
the past, in which comparisons were made between enteral
nutrition and intravenous alimentation as treatments for acute
pancreatitis [188 –196]. A systematic review [197, 198] of
these tests reported that enteral nutrition was associated with
as i g n i ﬁcantly lower incidence of infection, reduced surgical
intervention and a reduced length of hospital stay in compar-
ison with total parenteral nutrition (without enteral nutrition)[197]. Therefore, enteral nutrition for severe cases is signi ﬁ-
cant as an infection prevention measure, and is considered to
contribute to the improvement of life prognosis.
CQ22 When is the optimal timing to start enteral nutrition?
If initiated in the early phase, enteral nutrition can reduce the
incidence of complications and can contribute to an increased
rate of survival. Therefore, it is desirable that it be started
within at least 48 h of admission.
(2A)
<Comment >The ef ﬁcacy of enteral nutrition, and a de-
crease in mortality rates have been demonstrated [191, 199].
Enteral nutrition can be started in the early phases of severe
pancreatitis, with great care for severe ileus, intestinal ische-
mia and intestinal necrosis. For severe pancreatitis, enteral nu-
trition should be started early and at a low dose. If possible, it
should begin within 48 h of admission.J Hepatobiliary Pancreat Sci (2015) 22:405 –432 416

CQ23 Which administration method should be used for en-
teral nutrition?
In principle, it is recommended that enteral feeding tubes be
inserted into the jejunum through the Treitz ligament. How-
ever, if a feeding tube cannot be inserted into the jejunum,
nutrients can be infused into the duodenum or stomach
instead.
(2B)
<Comment >The low executing rate of early enteral
nutrition has been a major issue [200]. The dif ﬁculty of
inserting alimentation tubes into the jejunum may be one
cause. It has been reported that enteral nutrition with gastrictube is not inferior to that with jejunal nutrition in terms of
safety and complications [201 –203]. Therefore, intragastric
alimentation can be also used as an alternative means of
administration.
23–1: What should be used to provide enteral nutrition?
Enteral nutrition can be provided from among digestible nutri-
ents, semi-digestible nutrients and component nutrients, con-
sidering the viscosity and osmotic pressure.
(B)
<Comment >No characteristic trend has been found in
analysis of the ef ﬁcacy of the components of enteral nutrition,
and there is not believed to be any signi ﬁcant difference be-
tween components [204 –210].
CQ24 When should oral administration be started?
The initiation of oral administration should be determined
using indicators such as the subsidence of abdominal pain
and the serum pancreatic enzyme (especially serum lipase)
level, etc.
(2B)
<Comment >Although abdominal pain after oral admin-
istration has not been studied in detail, D in Balthazar ’sC T
score, duration of sustained pain, high serum lipase concentra-
tion [211] and high CRP value, high serum amylase concen-
tration, and high serum lipase concentration in mild
pancreatitis [212] are reported to be associated with the
relapse of abdominal pains. The use of serum pancreatic en-
zymes (especially serum lipase) as an indicator to determine
the timing of the start of oral administration after acute pancre-
atitis is considered appropriate. In mild pancreatitis, results
have been reported, which support active early oral adminis-
tration [213, 214].
Aﬂowchart for the management of acute pancreatitis is
shown in Figure 9.Intensive care
CQ25 Can peritoneal lavage (PL) for acute pancreatitis
improve prognosis?
No life-saving effect has been observed from peritoneal
lavage for acute pancreatitis, and therefore it is not
recommended.
(2B)
<Comment >Twelve RCTs [215 –226] and one meta-
analysis [227] of peritoneal lavage have been performed, but
the diagnostic methods, severity assessment and treatment
methods for acute pancreatitis are inconsistent, resulting indiffering evaluations.
In both existing meta-analysis [228] and the new
meta-analysis performed by the Meta-Analysis team for JPN
Guidelines 2015, no effect was observed in the survival rate,
incidence of complications or length of hospital stay,
and therefore it was concluded that PL is not recommended.
CQ26 When and for what types of pancreatitis should
CHF/CHDF be introduced?
For severe cases where circulation dynamics are not stable
with anuria even after suf ﬁcient initial ﬂuid infusion or cases
with abdominal compartment syndrome (ACS), continuous
hemo ﬁltration (CHF)/CHDF should be introduced.
(1C)
The ef ﬁcacy of CHF/CHDF in cases of severe acute pan-
creatitis not mentioned above is uncertain. Therefore, routine
use is not recommended.
(2C)
<Comment >In a report by Pupelis et al., it was con-
cluded that the early application of continuous venovenous
hemo ﬁltration (CVVH) facilitates the reduction of intra-
abdominal hypertension (IAH) [229]. Xu et al. also reported
that as a result of CVVH carried out for cases of severe acute
pancreatitis with complications ACS, intra-abdominal pres-
sure (IAP) and tumor necrosis factor- α(TNF- α)w e r es i g n i ﬁ-
cantly decreased 24 h after CVVH commenced [230].
CQ27 Is the continuous regional arterial infusion of protease
inhibitors and antibiotics effective for acute necrotizing
pancreatitis?
Continuous regional arterial infusion therapy is reported to be
effective in reducing pancreatic infection and mortality rates
for severe acute pancreatitis and acute necrotizing
pancreatitis, but its ef ﬁcacy has not been con ﬁrmed.
(ungraded B )
<Comment >A number of observational studies have
concluded that the continuous regional arterial infusion ofJ Hepatobiliary Pancreat Sci (2015) 22:405 –432 417

protease inhibitors and antibiotics is effective [231 –235]. In
one RCT, additional antibiotics, urgent surgical frequencies
and mortality rates were signi ﬁcantly lower in a group treated
with regional pancreatic-arterial infusion than in a group not
treated with such a method [236]. However, it was pointed
out that bias could not be ruled out in the case of this RCT
[237]. The results of propensity score matching analysis using
the Diagnosis Procedure Combination (DPC) database
showed no signi ﬁcant differences between these two groups
regarding the hospital mortality rate and infection rate of com-
plications [238].Management of biliary pancreatitis
CQ28 For what types of gallstone-induced acute pancreatitis
can early ERCP/ES be carried out?
Early ERCP/ES should be performed in gallstone-induced
acute pancreatitis when complications of cholangitis or
prolonged passage disorder of the biliary tract are suspected.
(1A)
<Comment >Four RCTs [239 –242] were performed on
early endoscopic retrograde cholangiopancreatography
Fig. 9 Flowchart for the
management of acute pan-
creatitis. ACS abdominal
compartment syndrome,
ANC acute necrotic collec-
tion, APFC acute
peripancreatic ﬂuid collection,
CHF/CHDF continuous hemo
(dia)ﬁltration, PPC pancreatic
pseudocyst, WON walled-off
necrosisJ Hepatobiliary Pancreat Sci (2015) 22:405 –432 418

(ERCP) with and without endoscopic sphincterotomy (ES) for
acute pancreatitis. A meta-analysis [243] conducted for these
tests concluded that both the incidence rate of complications
and the mortality rate were low in the group treated with
ERCP/ES. At present, early ERCP/ES should be performed
for acute pancreatitis, which is diagnosed or suspected as
gallstone-induced pancreatitis, in cases of: (1) complications
of cholangitis; or (2) suspected prolonged passage disorder
such as in the development and/or deterioration of jaundice
(Fig. 10).
CQ29 Is cholecystectomy recommended to prevent the re-
currence of gallstone-induced acute pancreatitis?
To prevent the recurrence of gallstone-induced acute pancrea-
titis, cholecystectomy is recommended for cases where such
surgery is possible.
(1B)
<Comment >Cholecystectomy is considered a ﬁrst
choice treatment for preventing the recurrence of gallstone-
induced acute pancreatitis. ES + cholecystectomy is very
likely to be the most effective method of preventing the recur-
rence of pancreatitis and biliary tract complications. The rateof recurrence of biliary tract complications was high in the
group treated solely with ERCP + ES, and where there is no
reason not to perform a cholecystectomy, ERCP + ES should
not be considered on its own. The rate of recurrence of pancre-
atitis was high in the group with no treatment, and some types
of radical treatment were required [244 –258].
CQ30 What is the appropriate timing to perform cholecys-
tectomy for gallstone-induced pancreatitis?
A cholecystectomy should be performed as soon as the
gallstone-induced acute pancreatitis has been resolved.
(1B)
<Comment >The rate of recurrence of pancreatitis during
the recovery period after discharge is reported to be 32 –61%.
This rate is said to be particularly high within 6 weeks after
discharge [259 –261]. In a systematic review of the timing of
cholecystectomy for mild biliary pancreatitis, it was reported
that there was no readmission when cholecystectomy was per-
formed on patients at the time of ﬁrst admission [262]. A
meta-analysis on the safety of cholecystectomy within 48 h
of admission has also been conducted [263].
Management of abdominal compartment syndrome
CQ31 For what types of acute pancreatitis patients is IAP
measurement necessary?
The sequential measurement of IAP is recommended for cases
with excessive ﬂuid infusion, high severity, renal and respira-
tory complications, and ﬂuid accumulation in multiple areas
as observed by CT, since the onset of ACS increases the mor-
tality rate in such cases.
The measurement of IAP repeated over time is recom-
mended for cases with excessive ﬂuid infusion, high severity,
complications of renal and respiratory disorders, and ﬂuid ac-
cumulation in multiple areas as observed by CT, given that the
onset of ACS increases the mortality rate of such cases.
(2C)
<Comment >In acute pancreatitis, complications can be
induced by increased IAP. The World Society of Abdominal
Compartment Syndrome (WSACS) de ﬁnes this as where
intra-abdominal hypertension (IAH) persists at levels of
IAP≧12 mmHg [264, 265]. Moreover, IAH with a series of
pathological conditions including organ failure caused by is-
chemia in intra-abdominal and retroperitoneal organs, and cir-
culatory failure associated with respiratory failure and
anomalous venous return caused by diaphragmatic
eventration and increased intrathoracic pressure and is re-ferred to as ACS. ACS is de ﬁned as cases with
Fig. 10 Flowchart for the management of biliary pancreatitis. ERCP/ES
endoscopic retrograde cholangiopancreatography with or without endo-
scopic sphincterotomyJ Hepatobiliary Pancreat Sci (2015) 22:405 –432 419

IAP>20 mmHg accompanied by new organ disorder/failure
[264, 265].
The mortality rate of acute pancreatitis with complication of
ACS varies depending on the report [266 –275], but a system-
atic review by van Brunschot et al. showed a high mortality rate
of 47.5% [276]. Also, a large numbe r of complications from or-
gan disorder/failure have been s hown. The mortality rate of re-
gional pancreatic infection com plicated with ACS is reported
to be 24.0 –66.7% [267, 268, 272, 275, 276]. Acute pancreatitis
with excessive ﬂuid infusion, high severity, renal disorders,
creatinine levels, complicatio ns of respiratory disorders,
tachypnea, and ﬂuid collection in multiple areas, as observed
by CT, is likely to develop IAH/ACS [108, 266, 277, 278],and the measurement of IAP over time is necessary.
CQ32 How should IAH/ACS be treated?
When there is persistent or recurrent IAP ≧12 mmHg, conser-
vative treatment (gastrointestinal decompression, intra-
abdominal decompression, improvement of abdominal
wall compliance, appropriate ﬂuid infusion and circulation
management) should be initiated. The goal should be to man-
age for IAP ≦15 mmHg. Surgical decompression should be
considered only when internal treatment is not effective for
patients with IAP >20 mmHg and where the additional com-
plication of organ failure is of concern.
(2D)
<Comment >In 2013, WSASC recommended that con-
servative treatment for IAH be carried out ﬁrst [279]. The pro-
posed procedure for treatment is the step-wise implementation
of gastrointestinal decompression, intra-abdominal decom-
pression, improvement of abdominal wall compliance, and
appropriate ﬂuid infusion and circulation management for
the entire body and local areas. Also, the implementation ofsurgical decompression is suggested when internal treatment
is not effective for patients with IAP >20 mmHg and when
new organ disorders appear. Chen et al. reported a success rate
of medical treatment of 75.0% [268]. Also, Boone et al. re-
ported the performance of surgical depression for all cases
with ACS complications [280].
Interventions for local complications
CQ33 What are the indications for therapeutic intervention in
local pancreatic complications?
In principle, conservative treatments should ﬁrst be performed
for necrotizing pancreatitis. The best indication for interven-
tion is applied to cases of infected necrotizing pancreatitis
with suspected or con ﬁrmed infection accompanying an ag-
gravated general condition.(1C)
<Comment >Given that the mortality rate from early oper-
ations (within 72 h of onset) is very high [281], conservative
treatment should be ﬁrst performed for necrotizing pancreatitis.
High mortality rates of 12 –26% are observed for ANC or
WON accompanying infections [282 –284], and intervention
treatment is recommended for infectious necrotizing pancreati-
tis with suspected or con ﬁ
rmed infection accompanying an
aggravated general condition [47, 285, 286]. However, conser-
vative treatments such as antibio tic administration can be prior-
itized for stable general conditions, even if a diagnosis of
infectious necrotizing pancreatitis has been made [284, 287].
Rare indications include closed gastric drainage due to PPC[288 –291], or a restricted or closed pancreatic duct or
intrapancreatic bile duct due to necrosis of pancreatic paren-
chyma, etc. [292, 293].
CQ34 How should infected pancreatic necrosis be diagnosed?
Infected pancreatic necrosis should be suspected when clini-
cal symptoms and blood test ﬁndings deteriorate. Routine
use of ﬁne needle-aspiration (FNA) is not required for diagno-
sis, and clinical signs and CT should be used for a comprehen-
sive determination. If an aggravated general condition is
observed, percutaneous drainage or endoscopic drainage
should be given for diagnosis and treatment.
(1C)
<Comment >Findings suggestive of infected pancreatic
necrosis are a deterioration of clinical symptoms and blood
test results, a positive bacterial blood culture test, a positive
endotoxin test and increased procalcitonin values [294, 295],
as well as CT-identi ﬁed gas in the pancreas or peripancreatic
tissues. As direct diagnostic methods for infectious necrotiz-
ing pancreatitis, CT or US guided FNA can be used for bacte-
riological examination [296, 297]. In the past, the routine use
of FNA was recommended when infectious necrotizing pan-
creatitis was suspected, but this indication has become more
limited recently [282, 298 –300].
CQ35 When should therapeutic intervention for infected
pancreatic necrosis be carried out?
If possible, therapeutic intervention for infected pancreatic ne-
crosis should be performed after 4 weeks of onset, when the
necrosis has been suf ﬁciently walled off, or in other words,
during the WON period.
(2C)
<Comment >The mortality rate of necrotizing pancreati-
tis is signi ﬁcantly high from necrosectomy in the early phases
[281, 301, 302] and thus it is recommended to perform
necrosectomy after at least 4 weeks after the onset of acute
pancreatitis when necrosis has been suf ﬁciently walled offJ Hepatobiliary Pancreat Sci (2015) 22:405 –432 420

[47, 287, 303]. When infectious necrotizing pancreatitis is
suspected, postponing intervention treatment is recommended
until 4 weeks after onset when ANC becomes WON.
CQ36 How should the therapeutic intervention for infected
pancreatic be selected?
During therapeutic intervention for infected pancreatic necro-
sis, percutaneous (retroperitoneal) drainage or endoscopic
transluminal drainage should be ﬁrst given, and if no improve-
ment is achieved, necrosectomy should then be performed.
Necrosectomy by endoscopic or retroperitoneal approach is
recommended.
(2B)
<Comment >As intervention treatment for infectious nec-
rotizing pancreatitis, a step-wise approach has been proposed
[304], and the selection of minimally invasive method such
as percutaneous (retroperitoneal) drainage or endoscopic trans-
luminal drainage has been recommended [47, 287, 304 –307].
Necrosectomy should be considered necessary in cases
where drainage is not effective. Regarding the methods of
necrosectomy, the ef ﬁcacy of video-assisted retroperitoneal de-
bridement (VARD) and endoscopic necrosectomy has been
shown [284, 305, 308]. Regarding approach methods, the ret-
roperitoneal approach has fewer complications than the laparot-
omy approach [309, 310].
Post-ERCP pancreatitis
CQ37 Which endoscopic procedure is effective for the pre-
vention of post-ERCP pancreatitis?
Prophylactic temporary pancreatic stent placement is useful as
an effective endoscopic procedure for the prevention of post-
ERCP pancreatitis. This should only be performed in the high-
risk groups* for post-ERCP pancreatitis given the risks and cost.
(2A)
The guidewire method is very likely to reduce the inci-
dence of post-ERCP pancreatitis.
(2A)
<Comment >A number of RCTs and meta-analyses have
been performed on prophylactic temporary pancreatic stent
placement for high-risk groups of post-ERCP pancreatitis. In
most studies stent placement is reported to be effective for
the prevention of pancreatitis [311 –329]. Meta-analysis was
conducted on cannulation methods using contrast agent infu-
sion and guidewires. As a result, a signi ﬁcant reduction of
post-ERCP pancreatitis was observed in the group treated
with the guidewire method. Therefore, the guidewire method
c a nb eu s e da sa ﬁrst choice therapy [330].*The high-risk group for post-ERCP pancreatitis refers
to patients with con ﬁrmed or suspected Sphincter of Oddi
dysfunction, patients for whom cannulation is dif ﬁcult,
patients for whom pre-cut sphincterotomy has been per-
formed, or patients for whom balloon dilatation has been
provided.
CQ38 Which drug therapy is effective for the prevention
of post-ERCP pancreatitis? What are the indications for
this?
For the prevention of post-ERCP pancreatitis, the intrarectal
administration of NSAIDs should be carried out for all cases
undergoing ERCP with no contraindications.
(2A)
Other drugs should not be used as routine preventive mea-
sures, since their ef ﬁcacy has been refuted or is uncertain.
<Comment >NSAIDs administration signi ﬁcantly
inhibited the onset of post-ERCP pancreatitis [331 –334]. Re-
garding modes of administration, intrarectal administration
signiﬁcantly inhibited the onset of post-ERCP pancreatitis
[335, 336].
Clinical indicators
CQ39 Can compliance with the guidelines and bundles im-
prove patient prognosis?
A high rate of implementation of the pancreatitis bundles may
contribute to improving prognosis of patients with severe
acute pancreatitis.
(1C)
<Comment >Patients who received treatment, report
greater satisfaction in more than eight items of the Pancreatitis
Bundles (2010) and showed signi ﬁcantly lower mortality
rates than patients who received treatments that satis ﬁed seven
items or less [118].
In a questionnaire conducted in Germany, it was reported
that although surgeons in Germany were aware of the guide-
lines for the management of acute pancreatitis, approximately
50% performed treatments that varied from the guidelines
[337]. It has been reported, however, that since the publica-
tion of the French guidelines, treatments that are more in line
with the guidelines have been carried out in France [338]. It
is also reported that in Britain, the introduction of Pathway
improved the performance rates of CT, severity assessments
and ICU admission [339]. From the above reports, compli-
ance with the guidelines and Bundles may lead to the im-
provement of prognosis, but further consideration is still
required (Table 5).J Hepatobiliary Pancreat Sci (2015) 22:405 –432 421

Conclusion
The latest evidence-based guidelines for the management of
acute pancreatitis have been prepared with a clearly describedscope and purpose using the GRADE system. For subject
areas where no results have been obtained, new meta-analysis
was conducted for the grading of recommendations. Also, the
Pancreatitis Bundles 2015 was established, which can en-
hance awareness for improvements in the quality of treatment.
Furthermore, the JPN Guidelines 2015 provide a mobile ap-
plication that can be used easily in a daily clinical situation.
Effort has been made to maintain transparency and neutrality
during the preparation of these guidelines. The most up-to-
date preparation methods and recommendations were used.
In this way, we are con ﬁdent that clinicians will be able to eas-
ily follow these guidelines and that these guidelines will con-
tribute to improve the treatment of acute pancreatitis. Above
all, it is hoped that the JPN Guidelines 2015 will be used to
determine treatments for patients and will contribute to opti-
mal support for them.
Acknowledgments The authors thank Machiko Inoue, Tomohiko Ukai,
Yoshinori Noguchi of the Meta-Anal ysis team for JPN Guidelines 2015.
All expenses incurred in the preparatio n and publication of these guidelines
were paid by the relevant academic societies and research teams.
Conﬂict of interest Y. Takeyama has received honoraria from
Ajinomoto Pharmaceuticals Co., Ltd., Tokyo, Japan.
Prior to the preparation of these medical guidelines, all members of
the Guidelines Revision Committee declared any con ﬂicts of interest(COI). Effort was made to avoid biases in the guidelines with regard to
economic issues. Effort was also made to create a cooperative system
with a number of relevant academic societies and research organizations,
in order to avoid academic con ﬂicts of interest among individual aca-
demic societies.
Appendix: author ’sa fﬁliations
Masamichi Yokoe, General Internal Medicine, Japanese Red
Cross Nagoya Daini Hospital, Nagoya, Japan; Tadahiro
Takada and Keita Wada, Department of Surgery, Teikyo Uni-
versity School of Medicine, Tokyo, Japan; Toshihiko
Mayumi, Department of Emergency Medicine, School of
Medicine, University of Occupational and Environmental
Health, Kitakyushu, Japan; Masahiro Yoshida, Department
of Hemodialysis and Surgery, Chemotherapy Research Insti-
tute, International University of Health and Welfare,
Ichikawa, Japan; Shuji Isaji, Hepatobiliary Pancreatic and
Transplant Surgery, Mie University Graduate School of Med-
icine, Mie, Japan; Takao Itoi, Department of Gastroenterol-
ogy and Hepatology, Tokyo Medical University, Tokyo,
Japan; Naohiro Sata, Department of Surgery, Jichi Medical
University, Shimotsuke, Tochigi, Japan; Toshifumi Gabata,
Department of Radiology, Kanazawa University, School of
Medical Science, Kanazawa, Japan; Hisato Igarashi, Clinical
Education Center, Kyushu University Hospital, Fukuoka,
Japan; Keisho Kataoka, Otsu Municipal Hospital Shiga and
Kyoto Prefectural University of Medicine, Kyoto, Japan;
Masahiko Hirota, Department of Surgery, Kumamoto Re-
gional Medical Center, Kumamoto, Japan; Masumi Kadoya,
Department of Radiology, Shinshu University School ofTable 5 Pancreatitis Bundles 2015
In principle, compliance with all of the items is recommended for acute pancreatitis, except under special circumstances. Whether or not compliance
with the items has been carried out should be detailed on the medical record.
1. When a diagnosis of acute pancreatitis is made, repeated severity assessments should be carried out at diagnosis, and within 24 h, and 24 –48 h after
diagnosis based on the JPN Severity Score (JSS).
2. For patients with severe acute pancreatitis, transfer to an appropriate medical facility should be considered within 3 h after diagnosis has
been made.
3. For patients with acute pancreatitis, causes of pancreatitis should be differentiated within 3 h after diagnosis, using medical records, hematol ogical
examination and imaging studies.
4. For gallstone-induced pancreatitis, early ERC + ES should be considered in patients with accompanying cholangitis and/or prolonged passage
disorder of the biliary tract including the occurrence or aggravation of jaundice.
5. At a medical facility where treatment for severe acute pancreatitis is performed, abdominal contrast-enhanced CT studies should be performed
within 3 h after initial treatment. A non-enhanced area and the extent of the disease should be examined, and severity should be assessed on the
basis of the CT grades of acute pancreatitis.
6. For acute pancreatitis, suf ﬁcient amounts of ﬂuid replacement and monitoring should be performed within 48 h of onset, and mean arterial
pressure (MAP): diastolic blood pressure + (systolic blood pressure-diastolic blood pressure)/3 should be maintained at 65 mmHg or more and
urinary output at 0.5 ml/kg per h or more, respectively.
7. Pain control should be provided for acute pancreatitis.
8. Prophylactic wide-spectrum antibiotics should be administered for severe acute pancreatitis within 72 h of onset.9. Even if intestinal peristalsis is not present, enteral nutrition should be started in small amounts (jejunal administration is desirable) within
48 h of diagnosis.
10. Cholecystectomy should be performed after the subsiding of symptoms of pancreatitis for gallstone-induced pancreatitis accompanied by
cholecystolithiasis.J Hepatobiliary Pancreat Sci (2015) 22:405 –432 422

Medicine, Matsumoto, Japan; Nobuya Kitamura, Department
of Emergency and Critical Care Medicine, Kimitsu Chuo
Hospital, Kisarazu, Chiba, Japan; Yasutoshi Kimura and
Koichi Hirata, Department of Surgery, Surgical Oncology
and Science, Sapporo Medical University, Sapporo, Japan;
Seiki Kiriyama, Department of Gastroenterology, Ogaki Mu-
nicipal Hospital, Ogaki, Japan; Kunihiro Shirai, Department
of Emergency and Critical Care Medicine, Ichinomiya
Municipal Hospital, Ichinomiya, Japan; Takayuki Hattori,
Department of Radiology, Tokyo Metropolitan Health and
Medical Treatment Corporation, Ohkubo Hospital, Tokyo,
Japan; Kazunori Takeda, Department of Surgery, National
Hospital Organization Sendai Medical Center, Sendai, Japan;Yoshifumi Takeyama, Department of Surgery, Kinki University
Faculty of Medicine, Osaka, Japan; Morihisa Hirota, Division
of Gastroenterology, Tohoku University Graduate School of
Medicine, Sendai, Japan; Miho Sekimoto, The University of
Tokyo Graduate School of Public Policy, Health Policy Unit,
Tokyo, Japan; Satoru Shikata, Department of Family Medicine,
Mie Prefectural Ichishi Hospita l, Mie, Japan; Shinju Arata, Gas-
troenterological Center, Yokohama City University Medical
Center, Yokohama, Japan.
The QR codes (for iPhone and Android) to download the
mobile application can be found at http://www.jshbps.jp/en/
guideline/jpn-guideline2015.html.
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