Scandinavian Journal of Surgery 94: 124129, 2005

ALGORITHM FOR THE DIAGNOSIS AND TREATMENT

OF ACUTE BILIARY PANCREATITIS

N. Alexakis, J. P. Neoptolemos
Division of Surgery and Oncology, University of Liverpool, Liverpool, UK

ABSTRACT

Gallstones are the commonest cause of acute pancreatitis in developed countries. There
is now a considerable evidence base consolidated by a series of systematic reviews, meta-
analyses and guidelines that has established a clear algorithm for diagnosis and man-
agement. In the majority of patients the combination of ultrasonography and serum
alanine transaminase > 60 iu/l < 48hours of symptoms will identify gallstones as the
cause. The simplest method of severity assessment is a high level of serum C-reactive
protein (> 150 mg/l up to 72 hours after symptoms). In mild disease, all fit patients must
undergo laparoscopic cholecystectomy with intraoperative cholangiography or if not fit
for surgery then endoscopic sphincterotomy during the same admission to prevent fur-
ther attacks. All patients with severe disease should undergo endoscopic sphincteroto-
my in less than 72 hours. Patients with > 30 % necrosis should undergo fine needle as-
piration for bacteriology. Necrosectomy is indicated for infected necrosis or sterile necro-
sis if there are persisting clinically significant symptoms. There is increasing evidence
for the use of minimally invasive pancreatic necrosectomy. Enteral nutrition should be
instituted whenever possible but antibiotics should be reserved for patients with proven
sepsis. The presence of fungal infection requires active anti-fungal therapy. Patients
with severe disease should undergo cholecystectomy at a later stage. Patients who have
undergone necrosectomy require long-term follow-up because of delayed complications.
Key words: Acute biliary pancreatitis; gallstones; diagnosis; management; endoscopic sphincterotomy

INTRODUCTION patients is important, since there are specific thera-

Acute pancreatitis is a disease with an overall mor-
tality of approximately 46 % (which increases to 17
39 % in severe disease) and substantive morbidity
(14). Gallstones are the commonest cause of acute
pancreatitis in developed countries representing
around 60 % of all cases (1, 2). Identification of these
Correspondence:
John P. Neoptolemos, M.D.
Division of Surgery and Oncology
Royal Liverpool University Hospital
5th Floor UCD The Duncan Building
Daulby Street, Liverpool K69 3GA, UK
Email: J.P.Neoptolemos@liverpool.ac.uk
peutic implications and clear management strategies
are now supported by a substantive evidence base
(Figs 1 and 2).
DIAGNOSIS OF ACUTE PANCREATITIS
The diagnosis is based on a typical clinical presenta-
tion plus a serum amylase at least three times the
upper normal limit. Serum amylase peaks at around
24 hours after the onset of the attack and then expo-
nentially declines over the next 57 days. Serum li-
pase and elastase are also diagnostic but are not su-
perior to the amylase test (5). An emergency contrast
enhanced computed tomography scan must be per-
formed if there is any diagnostic uncertainty.
 Algorithm for the diagnosis and treatment of acute biliary pancreatitis 125

Fig. 1. Algorithm for the management of mild gallstone acute pancreatitis.

Fig. 2. Algorithm for the management of severe gallstone acute pancreatitis.

126 N. Alexakis, J. P. Neoptolemos
INITIAL MANAGEMENT: RESUSCITATION AND
TREATMENT OF ANY ORGAN DYSFUNCTION
Patients with acute pancreatitis are usually hypovol-
aemic and need optimal fluid resuscitation and close
monitoring in an appropriate setting (6). It is impor-
tant to recognise and treat any associated organ dys-
function (7).
IDENTIFICATION OF PATIENTS WITH BILIARY
PANCREATITIS
The recommended initial examination is ultrasono-
graphy to identify the presence of stones in the gall-
bladder and/ or in the main bile duct (MBD). The
sensitivity of the US in the detection of gallstones is
> 95 % in uncomplicated cases; however in the set-
ting of acute pancreatitis, sensitivity for gallstone de-
tection is only 6778 % due to the ileus and bowel
distension (8). Furthermore, sensitivity in the detec-
tion of MBD stones is between 2590 %.
Liver biochemistry is helpful for the diagnosis
of biliary pancreatitis. A meta-analysis found that a
3-fold increase of serum alanine transaminase (> 60
iu/l < 48hours of symptoms) will identify gallstones
as the cause in patients with pancreatitis with a posi-
tive predictive value of 95 % (9) and this has been
confirmed by a recent study (10). It should be kept
in mind that around 1015 % of patients with biliary
pancreatitis present with normal serum liver enzyme
and bilirubin levels (11).
Magnetic resonance cholangiography (MRCP) has
a high sensitivity (8495 %), specificity (96100 %),
positive predictive value (91100 %) and negative
predictive value (9298 %) for the detection of
choledocholithiasis (1215) but its role in biliary pan-
creatitis has not been evaluated. In particular is the
performance of MCRP in severely ill patients in
whom the diagnosis of biliary pancreatitis relies on
ultrasonography and biochemical tests. The accura-
cy of endoluminal ultrasonography in diagnosing
choledocholithiasis is high and similar to that of
MRCP (16).
PREDICTION OF DISEASE SEVERITY
Most patients will have mild disease but 1020 % will
develop severe disease (17). It is important to deter-
mine as early as possible whether the attack is likely
to be mild or severe for purposes of management
strategy and optimum use of resources. Clinical
judgement alone can be difficult in determining this,
especially during the first 2448 hours when disease
severity may rapidly change. The Atlanta classifica-
tion defines that severe disease is associated with or-
gan failure and/or local complications (necrosis, ab-
scess, pseudocyst) and is characterised by > 3 Ran-
son criteria, or > 8 APACHE II score points (18). The
Ranson criteria have no validity > 48 hours of dis-
ease onset, while the Apache II system can be used
at any time, but suffers from complexity. The Balt-
hazar CT score is based on the extent of pancreatic
necrosis and the number of acute fluid collections
(19). The serum level of the acute phase C-reactive
protein at a cut-off level of > 150mg/l, at 4872 hours
following symptom onset has independent prognos-
tic value for severe disease and is as accurate as the
multiple scoring systems (20). In a large study, the
sensitivity, specificity, positive predictive value and
negative predictive value 48 hours after admission
of the APACHE II score were 56 %, 64 %, 30 %, and
85 %, of the Ranson score were 89 %, 64 %, 38 % and
96 % and of the C-reactive protein cut off were 86 %,
61 %, 37 %, 37 % and 94 %, respectively (21). Urinary
trypsinogen activation peptide accurately predicts
severity at 24 hours after symptom onset (21) (58 %,
73 %, 39 % and 86 %, respectively) whilst the serum
amyloid A level (another acute phase protein) had a
better prediction than C-reactive protein at 24 and
48 hours following admission and symptom onset
and maintained discrimination between mild and se-
vere disease beyond the initial phase (22).
MANAGEMENT OF PATIENTS WITH
PREDICTED SEVERE ACUTE PANCREATITIS
Patients with a severe attack and certain high risk
patients (elderly, with gross obesity, requiring ongo-
ing volume resuscitation) will need to be managed
on an intensive therapy or high dependency unit (6).
Early enteral nutrition by a naso-jejunal tube is safe
and well tolerated in severe acute pancreatitis (23)
but care must be taken to provide sufficient calories.
Parenteral nutrition is more expensive, carries the
risks of sepsis and metabolic complications (24). Re-
cent meta-analyses agree that enteral nutrition did
not reduce mortality and although it was associated
with a lower incidence of complications (25, 26), this
needs to be interpreted in the light of missing data
and heterogeneity (26).
Contrast enhanced computed tomography is the
best way to assess the extent of pancreatic necrosis
with an overall accuracy of 87 %, a sensitivity of
100 % in cases of extended necrosis and of 50 % in
minor necrosis and specificity of almost 100 % (19).
Contrast enhanced computed tomography must be
performed > 72 hrs from onset of symptoms to allow
delineation of the necrosis (19). Magnetic resonance
imaging is also a reliable staging method with simi-
lar sensitivity and specificity to that of contrast en-
hanced computed tomography (27).
ENDOSCOPIC SPHINCTEROTOMY IN PATIENTS
WITH SEVERE GALLSTONE PANCREATITIS
The first important study of the role of endoscopic
retrograde cholangiography (ERCP) in altering the
course of acute biliary pancreatitis was performed in
Leicester UK, in which 121 patients were prospective-
ly stratified for disease severity prior to randomisa-
tion (28). The mortality rate was one (2 %) in the
59 patients randomized to urgent ERCP +/ endo-
scopic sphincterotomy compared to five (8 %) in the
62 patients randomized to conservative treatment
 Algorithm for the diagnosis and treatment of acute biliary pancreatitis
and the complication rates were 10 (17 %) and 17
(61 %), respectively. The differences were significant
in patients with a predicted severe attack with mor-
tality and complications rates of one (4 %) and six
(24 %) respectively in the 25 patients predicted severe
and treated by endoscopic sphincterotomy compared
to five (18 %) and 17 (61 %, p < 0.01) respectively in
the 28 patients predicted severe in the conservative
group (28). Critics of the study state that the benefits
were due to the relief of concomitant cholangitis
(6 in the urgent endoscopic sphincterotomy group
and 5 in the conservative group) but if these patients
were excluded from the analysis, there is still benefit
in the endoscopic sphincterotomy group, which is
significant in the severe cases (complications 15 % vs
60 %, p = 0.003) (28). In addition, the hospital stay
was shorter in the predicted severe urgent endo-
scopic sphincterotomy group (28).
Fan et al from Hong Kong prospectively rand-
omized 195 patients with acute pancreatitis to either
endoscopic sphincterotomy within 24 hours of pres-
entation or conventional therapy (29). Overall there
was a reduction in biliary sepsis in the urgent endo-
scopic sphincterotomy group compared to the con-
servatively management group (0 % vs 12 %) with
apparently no significant difference in mortality or
complications (29). One of the study problems is that
the method of severity assessment (blood glucose
and serum urea at admission) had low sensitivity
(29). Furthermore, only 127 (65 %) of the patients had
gallstones (29). Analysis of patients with gallstones
reveals similar results as those from the UK trial: in
the 30 patients with severe pancreatitis treated en-
doscopically there was only one (3 %) death and four
(13 %) with morbidity compared with five (18 %,
p=0.09) deaths and 15 (54 %, p = 0.003) with compli-
cations in the 28 patients with severe pancreatitis
treated conservatively (29). Moreover ERCP/endo-
scopic sphincterotomy was performed in 18 patients
with a severe attack at a median of 60 hours (29).
Thus 64 % of the conservative group with severe pan-
creatitis also had ERCP/endoscopic sphincterotomy
and mostly within 72 hours (29).
A multi-centre trial from Germany randomised 238
patients with suspected biliary pancreatitis to ERCP
+/ endoscopic sphincterotomy within 72 hours or
conservative treatment and did not show any bene-
fit (30). There were, however, many problems with
this study. Patients with obstructive jaundice were
excluded and underwent emergency endoscopic
sphincterotomy (30). The severity was only deter-
mined retrospectively and was undefined in some
patients (30). Because endoscopic sphincterotomy
was performed within 72 hours, severity scoring
would have been completed after endoscopic sphinc-
terotomy in many cases and any apparent positive
influence of endoscopic sphincterotomy on the
course of severe disease might have been lost by
moving patients to the mild disease category before
completion of the severity scoring (30). There were
17 (13.5 %) patients from the 126 patients in the en-
doscopic sphincterotomy group who developed
cholangitis, compared to 13 (11.6 %) cases in the 112
patients that had conservative treatment, an obser-
127
vation that indicates an inadequate endoscopic
sphincterotomy technique (30). Moreover, there were
10 (38 %) related deaths in the 26 patients with se-
vere disease that had an endoscopic sphincterotomy
compared to four (20 %) deaths in 20 patients with
severe pancreatitis treated conservatively (30). The
high mortality of 38 % in the severe patients treated
by endoscopic sphincterotomy contrasts sharply with
mortalities of 4 % and 3 % in comparable patients in
the UK and Hong Kong studies respectively( 28, 29).
The study also had poor recruitment of approximate-
ly two patients per hospital per year (30). A further
study from Poland has been published only as an
abstract and detailed analysis cannot be performed
(31).
A meta-analysis (32) concluded that ERCP plus en-
doscopic sphincterotomy reduces morbidity and
mortality in acute biliary pancreatitis but it was
based on the pooled data from all previous four
studies in which the Polish study (31) had the largest
number of patients (n = 280). The 2002 NIH consen-
sus on ERCP states that in patients with severe bil-
iary pancreatitis, early intervention with ERCP re-
duces morbidity and mortality compared with de-
layed ERCP (33). The 2002 International Association
of Pancreatology guidelines did not provide any rec-
ommendations on this subject (34). The conclusion
of a Cochrane review in 2004 was that the odds of
having complications are reduced in predicted severe
disease by early endoscopic sphincterotomy (34).
Moreover these results are controlled for confound-
ing due to associated acute cholangitis and are ro-
bust for clinical and statistical heterogeneity (34). The
2004 consensus guidelines of the Critical Care Socie-
ties recommends that ERCP should be performed
within 72 hours in the setting of obstructive jaundice
and acute pancreatitis due to suspected or confirmed
gallstones or in severe acute pancreatitis (without
obstructive jaundice) (6).
It must be emphasised that endoscopic sphincter-
otomy should be performed in severe disease even
if no MBD stones are visualised in cases highly sug-
gestive of disease of biliary origin such as presence
of gallstones, dilated bile ducts, high bilirubin or an
elevated alanine transaminase.
CHOLECYSTECTOMY IN PATIENTS WITH
MILD GALLSTONE PANCREATITIS
TO PREVENT FURTHER ATTACKS
A laparoscopic cholecystectomy should be per-
formed in all patients with mild disease prior to hos-
pital discharge as they run a 3040 % risk of recur-
rent attacks even within weeks from the first episode
(34, 36, 37). Routine cholangiography during laparo-
scopic cholecystectomy followed by selective post-
operative endoscopic sphincterotomy has been found
to be more efficient than routine pre-operative endo-
scopic retrograde cholangiopancreatography (38).
Laparoscopic common bile duct exploration and
postoperative ERCP are both safe and reliable in
clearing common bile duct stones. If the patient is
unfit for surgery, successful endoscopic sphincterot-
128 N. Alexakis, J. P. Neoptolemos
omy is an acceptable alternative to prevent recurrent
attacks (39).
Surgically fit patients who had undergone endo-
scopic sphincterotomy stone extraction and have con-
comitant cholelithiasis should undergo cholecystec-
tomy. A trial from Amsterdam recruited 120 patients
who had undergone ES with stone extraction and
randomised them to laparoscopic cholecystectomy
within 6 weeks or a wait and see policy (40). After a
median follow-up of 30 months, 27 (47 %) of 59 had
biliary symptoms compared to one (2 %) of 49 who
had cholecystectomy. Twenty two of these 27 pa-
tients underwent cholecystectomy (40).
SURGERY IN PATIENTS WITH SEVERE
GALLSTONE ACUTE PANCREATITIS
Because the features of the systemic inflammatory
response syndrome are identical to those of sepsis,
clinical parameters will not identify pancreatic infec-
tion before it is too late. Thus from day 57 of a se-
vere attack all patients must undergo a contrast en-
hanced computed tomography (34). If there is > 30 %
necrosis there should be weekly computed tomogra-
phy-guided fine needle aspiration for bacteriology
and fungi (FNAB) which has a sensitivity of 96 % for
detecting pancreatic infection (41).
The indications for surgery in severe acute pancre-
atitis are now well defined: positive FNAB stain or
culture or extra-intestinal gas on a contrast enhanced
computed tomography scan are indications for necro-
sectomy (42). Other indications for surgery include
sterile necrosis with persisting systemic or local
symptoms despite 34 weeks of maximal conserva-
tive treatment (31). Necrosectomy must be delayed
for at least 23 weeks to allow demarcation of the
necrosis (34). In a recent study, necrosectomy was
performed after a median of 31 days from disease
onset (4).
Conservative management of patients with sterile
necrosis has a mortality rate of 1.8 % while mortality
in patients with infected necrosis who undergo sur-
gery is 24 %39 % (4, 42, 43). There are three main
techniques that can be used for necrosectomy: open
necrosectomy with closed lesser sac lavage (44), re-
peated laparotomies with zipper to close the perito-
neum after each intervention or left open as laparos-
tomy (45) and minimally invasive necrosectomy (46).
Surviving patients with severe disease should under-
go cholecystectomy at a later stage (>6 weeks) as
there is increased morbidity and longer hospital stay
if they have an early operation (34, 37, 47).
PROPHYLACTIC ANTIBIOTICS AND USE OF
SEVERITY MODIFIERS
The 2002 IAP guidelines state that the use of prophy-
lactic antibiotics reduces infection rates in necrotis-
ing pancreatitis but may not improve survival (34).
This was prior to the largest double blind rand-
omized trial by Isenmann et al in 2004 that found no
benefit for the use of prophylactic antibiotics (48).
The 2004 consensus statement of Critical Care Socie-
ties recommended against the routine use of prophy-
lactic antibiotics due to the lack of conclusive evi-
dence (6). There is the problem of the microbial shift
from Gram negative to Gram positive organisms and
the development of fungal infection associated with
a high mortality (49). Moreover, there is concern
about the emergence of resistant organisms leading
to prolonged treatment (50). Antibiotics should be
used once sepsis is established using accepted inter-
national criteria (51) in accordance with Critical Care
Societies guidelines (52). The presence of fungal in-
fection requires active anti-fungal therapy (49).
FOLLOW-UP
Following recovery from mild acute pancreatitis
there are no clinically significant long term sequelae.
In severe necrotizing pancreatitis, however, there are
significant late complications in up to 60 % of pa-
tients (4) including delayed collections, pancreatic
pseudocyst, biliary stricture, persistent pancreatic fis-
tula, gastro-intestinal fistula, incisional hernia, pan-
creatic exocrine insufficiency and diabetes mellitus.
Thus long-term follow-up is required to monitor the
development of these complications and manage
them accordingly.
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Received: April 6th, 2005