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clinica e terapia
emergency care journal - organizzazione, clinica, ricerca • Anno VII numero 2 • Giugno 2011 • www.ecj.it
Materiale protetto da copyright. Non fotocopiare o distribuire elettronicamente senza l’autorizzazione scritta dell’editore.
5
emergency
care
journal
Acute Pancreatitis: Pathophysiology, Clinical Aspects,
Diagnosis e Treatment
Raffaele Pezzilli, Bahjat Barakat*, Dario Fabbri, Andrea Imbrogno*, Mario Cavazza**
Pancreas Unit, Department of Digestive Diseases and Internal Medicine, *Emergency Department Sant’Orsola-Malpighi Hospital, Bologna
Acute pancreatitis is an acute inflammation of the pancreas. The
clinical classification of the disease recognizes the mild acute
pancreatitis, characterized by the absence of local and/or systemic
complications, and the severe disease, characterized by the presence
of local complications such as necrosis, abscess or pseudocysts and/
or distant organ failure. Gallstones constitute the predominant
etiological factor. The severity assessment is essential for proper
initial treatment of the disease. Primary objectives to achieve in
the treatment of acute pancreatitis essentially are: pain control,
electrolyte support and energy intake, removal of the causal agent,
attenuation of the inflammation, and prevention and eventual
treatment of local and systemic complications of necrotizing forms.
Keywords: Acute pancreatitis; Disease management; Severity
assessment; Therapy.
ABSTRACT
Introduction
Acute pancreatitis is an acute inflammation of the pancreas with
variable involvement of peripancreatic tissues and/or distant or-
gans. The inflammatory process may be limited to the pancreatic
gland with edema or necrosis, or it may involve the surrounding
tissues and/or distant organs, so the clinical manifestations ran-
ge from mild abdominal pain to very serious presentations with
high mortality rate [1]. Episodes of acute pancreatitis in patients
who will subsequently develop anatomical, clinical and functio-
nal features compatible with chronic pancreatitis are classified
as the former until the final diagnosis is established. The now
widely accepted classification of the disease and its complica-
tions is a clinical classification prominently known as the Atlan-
ta classification [2] and is shown below.
Mild acute pancreatitis is characterized by a favorable clinical
course in the absence of local and/or systemic complications.
The predominant pathological expression is interstitial edema
more or less associated with peripancreatic steatonecrosis (Fi-
gure 1).
Severe acute pancreatitis is characterized by the presence of lo-
cal complications such as necrosis, abscess or pseudocysts and
/ or organ failure. In most cases it is the clinical expression of
the presence of pancreatic necrosis; in fact, patients with acu-
te edematous-interstitial pancreatitis rarely present a clinically
severe form of the disease. The organ failure was defined as
shock (systolic blood pressure < 90 mmHg), pulmonary insuf-
ficiency (PaO2 < 60 mmHg), renal failure (serum creatinine >
2 mg/dl after rehydration) or gastrointestinal bleeding (> 500
cc/24h).
Pancreatic necrosis is a focal or diffuse area of non-viable paren-
chyma, which typically is associated with peripancreatic steato-
necrosis. Computed tomography with intravenous contrast bo-
lus is currently the best diagnostic method (accuracy 80-90%).
Pancreatic necrosis rarely involves the entire gland in its entire
thickness; usually it remains confined to the periphery and spa-
res the glandular core. Haemorrhagic foci are present in varying
degrees. The necrosis may become infected (10-30% of cases)
and the distinction between sterile and infected pancreatic ne-
crosis is important because the therapeutic approach (mainly
medical therapy in sterile pancreatic necrosis, surgical in the
infected type) and prognosis (mortality rate about three times
higher in infected pancreatic necrosis) differ considerably. The
diagnostic gold-standard for suspected infection of pancreatic
necrosis is represented by microbial cultures of material from
percutaneous needle aspiration (Figure 2).
Acute fluid collection is a localized effusion in or near the pancre-
as, without granulation fibrous wall. It tends to appear early and
regresses spontaneously in most cases. It is not considered a sign
of disease severity unless it becomes infected.
Pseudocysts is a collection of pancreatic juice enclosed by a wall
lacking epithelialization and appearing as a result of acute pan-
creatitis, chronic pancreatitis or pancreatic trauma. The matu-
ration of a pseudocyst after acute pancreatitis requires at least
4 weeks after the onset of the disease. A post-acute pancreatitis
pseudocyst is therefore an acute fluid collection persisting more
than 4 weeks surrounded by a well-defined wall (Figure 3).
Walled-off pancreatic necrosis is an intra-abdominal collection
of pus (usually near the pancreas), appearing after an attack of
acute pancreatitis or after pancreatic trauma. Pus predominates
and there is only small amount of necrotic tissue, distinguishing
it from non-infected pancreatic necrosis. A pseudocyst presen-
ting pus within its walls is also correctly defined as a walled-off
pancreatic necrosis [3].
Fig. 1 - Multidetector computer tomography: edematous pancreatitis.
clinica e terapia
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6
clinica e terapia
Pathophysiology
There are many recognized causes of acute pancreatitis, but su-
rely gallstones constitute the predominant etiological factor in
our geographical area [4]. Less frequently, acute pancreatitis is
related to chronic use or abuse of alcohol and even more rarely
is secondary to abdominal surgery, diagnostic and/or interven-
tional endoscopical procedures on the papilla of Vater, abdomi-
nal trauma, dyslipidemia or the use of drugs with pancreatic
toxicity [5-7]. The mechanisms by which the various etiological
factors trigger pancreatic inflammation have not yet been ful-
ly identified but it seems proved with sufficient certainty that,
whatever the initial pathogenic noxious stimuli, the earliest pa-
thogenetic events are triggered inside the acinar cells [8] . Under
normal conditions these cells produce digestive enzymes and
lysosomal enzymes, the former segregated in lysosomal vacuo-
les, the latter in the vacuoles of zymogen. In acute pancreatitis
this strict compartmentalization can be overridden by alteration
of a complex biological process, calcium-dependent, defined as
“stimulus-secretion coupling”. A colocalization of lysosomes
and zymogen granules in a unique vacuole is thus determined:
the lysosomal enzyme cathepsin B can activate trypsinogen at
this point with consequent cascade activation of other protea-
ses and phospholipases. It follows the rupture of vacuoles, cell
damage, necrosis and release of cellular activated enzymes in
the interstitium. Local processes of vasoconstriction-dilatation
determine infiltration of inflammatory cells and increased ne-
crosis. In the most severe forms of acute pancreatitis it is present
a complex biochemical cellular and humoral response not sub-
stantially different from what happens in other serious diseases
such as septic shock, the poly-trauma and extensive burns. The
magnitude and the continuation of such events, assignable to
the so-called SIRS (systemic inflammatory response syndrome),
affect the extent and severity of local damage and progression
to systemic complications [9]. Implicated mediators are various
cytokines such as interleukin-1 (IL-1), IL-6, IL-8, TNF (tumor
necrosis factor), PAF (platelet activating factor) [9,10]. All these
mediators are markedly elevated in the first 24 hours of illness,
whereas the anti-inflammatory cytokines to (IL-2, IL-10) are re-
duced. The result is the activation of neutrophils, monocytes,
lymphocytes, platelets and endothelial cells. The increased ex-
pression of cell adhesion molecules and integrins on neutrophils
results in increased adhesion to the endothelium, diapedesis and
invasion of distant organs (first of all the lungs) where hyperac-
tive neutrophils call forth other polymorphonuclear leukocytes
and result in extensive tissue destruction [11]. The presence of
trypsin, chymotrypsin and elastase in the pancreatic intersti-
tium, in serum and peritoneal fluid is responsible for activation
Fig. 2 - Multidetector computer tomography: Necrotizing pancre-
atitis.
Fig. 3 - Ultrasonography:
pancreatitis pseudocyst (Ps)
The main pancreatic duct is
dilated (W).
clinica e terapia
emergency care journal - organizzazione, clinica, ricerca • Anno VII numero 2 • Giugno 2011 • www.ecj.it
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7
of the coagulation-fibrinolysis systems, endothelial cells, PMN
leukocytes and monocytes-macrophages with synthesis and re-
lease of cytokines, superoxide ions and PAF [8]. The latter is
a key mediator capable of stimulating the release of other pro-
inflammatory cytokines, increase vascular permeability, induce
a negative inotropic effect, leukocyte chemotaxis, tissue edema
and cellular damage. It is possible to clearly appreciate the pos-
sibility of a serious involvement of distant organs up to the deve-
lopment of the “fearsome” multi-organ failure syndrome.
Evaluation and stratification of
severity of acute pancreatitis
Severity assessment is essential for proper initial treatment in
the management of acute pancreatitis and this constitutes a
recommendation of grade A in the Italian guidelines on acute
pancreatitis [12]. These guidelines also suggest that assessment
of severity should be done by a scoring system such as Acute
Physiology and Chronic Health Evaluation (APACHE) II [12]:
an APACHE-II score greater than 8 is important for determi-
ning treatment policy and identifying the need for transfer to
a referral unit. Serum C-reactive protein values grater than 150
mg/dL are useful for severity assessment, but they may not re-
flect severity within the first 48 h after onset. In addition con-
trast-enhanced CT scanning and contrast- enhanced MRI play
an important role in severity assessment. The CT severity in-
dex, as proposed by Balthazar et al. [13], should be used. In
fact, the gold-standard for the presence of pancreatic necrosis
is the computed tomography (CT) with intravenous contrast
medium, which should be done after 72 hours from pain onset
and after rehydration of the patient; it may be possibly repeated
according to the clinical situation. Management in, or referral
to, high-volume units is necessary for patients with extensive
necrotizing pancreatitis or other complications who may require
care in the intensive therapy unit or interventional radiological,
endoscopic or surgical procedures and this constitutes a recom-
mendation of grade B [12].
Therapy
Background
One of the recurring features of acute pancreatitis is the frequent
presence of a variably long period of time, sometimes days,
between the onset of symptoms and hospitalization. This is a
factor that affects the very effectiveness of therapeutic measures
and ensures that treatment is more often aimed at controlling
the progression of the disease rather than at interfering with
initial pathogenetic phenomena. The delay in hospital makes it
difficult to interpret results of therapeutic trials and impossible
a homogeneous analysis of aggregate data from multiple studies,
as the timing of treatment is often not specified, or the onset
of symptoms is considered at the time of hospitalization. The
time frame in which there is a reasonable chance of specifically
antagonize the inflammatory mediators and activated pancreatic
enzymes to mitigate or prevent the development of a partial or
total impairment of distant organs is about 2-3 days after the
onset of pain and this period is also called interventional win-
dow [14]. All this should lead to a “specific” treatment as early
as possible and at the same time confirms that it is absolutely
unnecessary and wasteful to use these same drugs in patients
who come late to the observation, often in the second week of
illness, at a stage where there are already signs of impairment
of distant organs. In this clinical scenario, treatment should be
more rationally targeted toward measures useful in supporting
cardiovascular, respiratory and renal systems and preventing
septic complications. It is possible to affirm that for every four
patients with acute pancreatitis, three will respond favorably to
conservative medical treatment, while the fourth will present
complications with a one in three chance of suffering a fatal
outcome [15]. From these simple evaluations are derived three
important corollaries:
a) the majority of patients benefits from a conservative therapy,
not surgery,
b) the early identification of those patients at increased risk of
developing complications is crucial for prognosis and the-
rapy;
c) surgical therapy is to be reserved for those patients who
develop specific complications, primarily the infection of
pancreatic necrosis and / or peripancreatic fluid collections.
Essentially, the severity of an acute attack leads to the develop-
ment of a necrotizing form of the disease and pancreatic necrosis
is not only responsible for the clinical severity, but also the onset
of complications and, ultimately, mortality. At the present state
of knowledge a severe form of acute pancreatitis can not adequa-
tely be dealt without the support of a CT scan available full-time
and other multi-specialistic skills/human resources and equip-
ment. The guidelines of the British Society of Gastroenterology
[16] and the Italian of the Italian Association for the Study of
the Pancreas [12] suggest that a specialized center for the tre-
atment of severe acute pancreatitis should have the following
characteristics:
1. allocation in a general hospital where the major medical and
surgical specialties are present;
2. multidisciplinary team with specialists in Internal Medicine,
Surgery, Endoscopy, Critical Care and Intensive Care and
Pathology,
3. day and night availability of CT and ultrasound with staff
expert in percutaneous treatments, the availability of ma-
gnetic resonance and angiography may be useful but not
essential,
4. the presence of daytime endoscopists experienced in endo-
scopic retrograde cholangiopancreatography (ERCP) and
related interventional procedures.
Objectives and methods of conservative treatment
Primary objectives to achieve in the treatment of acute pancre-
atitis essentially are:
1. pain control,
2. electrolyte support and energy intake,
3. removal of the causal agent, when possible,
4. attenuation of inflammatory and autolytic processes at the
glandular level (“specific” therapy),
5. prevention and eventual treatment of local and systemic
complications of necrotizing forms.
For mild forms of disease, in most cases the first three steps are
sufficient for clinical resolution. In severe forms, the therapeutic
engagement is more complex and patients may, with reasonable
frequency, require periods of hospitalization in intensive care
units. The therapeutic approach to severe acute pancreatitis is
reported in Figure 4.
The control of pain must be swift and effective: for this purpose,
meperidine is the drug of choice [15].
Supportive therapy is a measure of fundamental importance that
counterbalances the seizure of the fluids and hypercatabolism par-
ticularly important in severe forms. The maintenance of cardiova-
scular parameters, renal and respiratory can in many cases prevent
the onset of multisystem complications. The pancreatic hypoper-
fusion, secondary to inadequate maintenance of plasma volume is
indeed able to trigger and increase the phenomena of pancreatic
necrosis. Patients with mild forms, for which it is expected an oral
refeeding within 4-6 days of hospitalization, do not need an ag-
gressive nutritional approach [15]. In contrast, in severe forms to-
tal parenteral nutrition (TPN) must be used, which must take into
account in its formulation of any metabolic imbalances (such as
acidosis or alkalosis, hyperglycemia, hypocalcemia, and hypoka-
lemia ipomagenesiemia) and cardiovascular complications [15].
Recently, enteral nutrition through naso-jejunal probe has been
used with good results in patients with severe acute pancreatitis
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emergency care journal - organizzazione, clinica, ricerca • Anno VII numero 2 • Giugno 2011 • www.ecj.it
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instead of the NPT. The pathophysiological assumption is that the
NPT does not provide all essential nutrients (eg glutamine) and
does not fuction as intestinal barrier which can increase intestinal
permeability to toxins and bacterial translocation.
The early removal of the causative agent makes it paramount to
achieve a sufficiently precise etiologic diagnosis and early inter-
vention. In clinical practice, this translates, at least in our popu-
lation, in the identification of a mechanism for biliary obstruc-
tion, transient or persistent, complete or partial, in about 2/3
of cases. The removal of biliary obstruction using endoscopic
techniques has now entered into the routine treatment of these
patients.[12, 16]. The “specific” therapy of acute pancreatitis re-
lies on antisecretory and antiprotease drugs.
The use of somatostatin and its synthetic analogue octreotide is
much debated. The results of published studies, many uncon-
trolled and with small case series or not stratified by severity
of illness, are controversial, although a metanalytical evaluation
shows, in general, a therapeutic advantage. From the theoreti-
cal point of view, the negative effects of vasoconstriction of the
splanchnic circulation and contraction of the sphincter of Oddi
outstripped the hypothetical beneficial effects related to inhibi-
tion of exocrine pancreatic secretion.
Among antiprotease drugs the gabexate mesylate showed a po-
sitive effect in patients with severe acute pancreatitis, with si-
gnificant reduction of systemic complications and the need for
surgery but not mortality compared with placebo. The dosage
used in early studies was 3 g/day by continuous intravenous in-
fusion, but subsequently it was found that a dose of 1.5 g/day in
the same manner for a period of treatment of 7-8 days is also a
viable option [17]. The best results are obtained when the admi-
nistration starts earlier than the onset of symptoms.
The use of systemic antibiotics for the prevention of pancreatic
infections is one of the cornerstones of conservative treatment
of severe forms of acute pancreatitis. Several studies have shown
a significant reduction in the incidence of pancreatic and extra-
pancreatic infections but not mortality in patients treated with
imipenem-cilastatin [18]. Quinolones, due to their pharmacoki-
netic characteristics and their range of action, should ensure an
effective prophylactic action as well. However, in a recent ran-
domized prospective trial, patients treated with pefloxacin sho-
wed an incidence of infected necrosis significantly higher than
patients treated with imipenem (34% vs 10%) [19]. At present,
therefore, it is recommended for all patients with acute necroti-
zing pancreatitis an early administration of imipenem-cilastatin
at a dose of 1.5-2 g/day, lasting for at least two weeks.
Objectives and indications of surgical treatment
The infection of pancreatic necrosis in the course of acute pan-
creatitis is a very serious medical condition and its presence is
associated with a marked increase in risk of death; it developes
in percentages varying from 15 to 70% of all patients with acute
necrotizing pancreatitis and accounts for more than 80% of
deaths from acute pancreatitis. The risk of infection increases
with the extent of necrosis and the days after initiation of acute
pancreatitis, reaching a peak incidence (70%) after three weeks
[20]. In most cases the infection is caused by Gram-negative
bacteria of enteric origin, and about two thirds of infections are
caused by a single microbiological agent. Therefore, E. coli is the
most frequent causative agent (26%), followed by Pseudomo-
nas, Klebsiella and Proteus species. Frequently Gram positive
infections are also detected, such as Staph.aureus (15%), Strep-
tococcus faecalis and Enterococcus or other anaerobic bacteria,
and in some cases by fungi. In clinical terms acute pancreatitis
with sterile necrosis can be difficult to distinguish from a form
with infected necrosis, because both can give fever, leukocyto-
sis and abdominal pain. But this distinction is very important,
since the mortality in patients with infected necrosis that did not
underwent early surgery is high. TC or ultrasound-guided per-
cutaneous suction of the necrotic material and/or peripancre-
atic fluid collections, with a fresh microscopic examination and
bacterial culture, is safe and accurate (sensitivity and specific-
ity exceeding 95%) and must be used, even repetitively, usually
from the second week of illness, in patients whose clinical con-
dition worsens or does not tend to improve, despite the removal
of any causative agent and the implementation of a vigorous
supportive treatment. Debridement is the surgical treatment of
choice of infected necrosis and the only therapeutic doubt con-
cerns the type of intervention to perform (classic necrosectomy
with drainage-washing or open packing technique). Recently
other treatment options, such as percutaneous, endoscopic or
minimally invasive surgery have been proposed [21-23]. These
methods require highly experienced operators, are not risk-free
and should be for the moment limited to patients unfit for sur-
gery because of a high anesthetic risk.
8
Fig. 4 - Therapeutic approach
to severe acute p ancreatitis.
clinica e terapia
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9
clinica e terapia
The treatment of patients with sterile pancreatic necrosis re-
mains controversial. Surgical treatment offers no demonstrable
survival benefits compared with supportive treatment; in ad-
dition, because the surgery may cause postoperative infection
of necrotic tissue in 25-50% of cases with a very high second-
ary mortality, a surgical indication in any case sterile necrosis
should be considered with prudence and care. Even when the
necrotic process determines rupture of the main pancreatic duct
and necrosis remains sterile, there are good prospects for a reso-
lution of the disease with conservative therapy. The precise role
of surgery in the treatment of sterile necrosis is therefore limited
and should be reserved for selected cases, such as those patients
in whom repeated attempts at oral re-feeding after 5-6 weeks of
therapy are associated with abdominal pain, nausea, vomiting or
recurring pancreatitis. At this stage of the disease, however, gen-
erally necrosis is more demarcated and the surgical act is easier.
In other cases, supportive care associated with prophylactic an-
tibiotic treatment should be the primary treatment [24-28]. It is
therefore very important to perform in due time (possibly dur-
ing the same hospitalization for mild forms, usually at a distance
of three to four weeks for severe) a cholecystectomy in case of
gallstones in order to prevent recurrence of acute episodes [12].
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