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Septic complications of acute pancreatitis

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296 Bratisl Lek Listy 2006; 107 (8): 296 – 313

TOPICAL REVIEW

Septic complications of acute pancreatitis

Mifkovic A, Pindak D, Daniel I, Pechan J

2nd Department of Surgery, Faculty of Medicine, Comenius University, Bratislava, Slovakia.

mifkovic@gmail.com

Abstract

Acute pancreatitis (AP) is a potentially lethal disease. There are numerous studies published on acute
pancreatitis. This article presents the results of research of many scientists in the field of acute pancre-
atitis. The main aim of this article is to present the possible septic complications of acute pancreatitis,
its diagnostic and treatment modalities.
Early morbidity and mortality are the result of activation of mediators with failure of circulation and
other organ systems. The overall mortality of patients with acute necrotising pancreatitis is in the range
of 10–15 %. Secondary pancreatic infection and sepsis develop in 40–70 % of patients with 80 %
mortality. Pancreatic infection is caused by bacterial contamination of pancreatic necrosis. Infection is
usually recorded in the second week of the disease in 24 % and in 71 % during the fourth week of the
disease. The incidence of secondary infection and sepsis correlates with the extent of pancreatic necro-
sis. The prevention of infection and sepsis by systemic administration of antibiotics is considered a
principal step in the therapy of acute pancreatitis (Ref. 62).
Key words: septic complications, acute pancreatitis, antibiotics, systemic administration.

Acute pancreatitis (AP) is an acute inflammatory disease of
the pancreatic gland with autodigestion of pancreatic tissue of-
ten incurring variable damage to adjacent organs. Therefore this
disease has frequently a very complicated and life-threatening
course. AP occurs in 2 –3 % of all cases of acute abdominal in-
flammation (Steinberg et al, 2001). The course of acute pan-
creatitis is very variable. It often heals by first intention (80 %).
It relatively rarely develops into chronic pancreatitis (CHP). The
incidence of AP is 1–5/100,000 per year (Vavreèka, 2001). Ac-
cording to autopsy statistics, AP is revealed in 0.26 –3.36 % of
examined bodies.
We distinguish two basic clinical forms of AP, namely mild
– edematous and severe haemorrhagic-necrotic forms. The course
of mild form is uncomplicated. The severe form of AP is accom-
panied by higher risk of complications, and its mortality is higher.
The mild form usually does not become severe. The severe form
is characterized by local complications (pancreatic necrosis,
pseudocysts and abscesses) or systemic complications (dysfunc-
tion of organ systems, shock, ARDS). As they are in mutual in-
teraction it is not possible to study them separately, thus they
must be comprehended as a complex.
The main pathophysiologic role in AP is played by autodi-
gestion of pancreatic tissue by its own enzymes. Inflammatory
mediators, active metabolites, hypoperfusion of pancreas and
higher vascular permeability are pathogenetic factors of AP.
Activated enzymes play a great role in their systemic effect which
is accompanied by infections caused by intestinal microorgan-
isms.
The most important etiologic factors are alcohol abuse or its
excessive intake and cholecystolithiasis. There are some other
very important etiologic factors as postoperative or postinstru-
mental AP (ERCP – endoscopic retrograde cholangiopancrea-
ticography), traumatic AP, hyperlipoproteinaemia, hyperpara-
thyreosis, infectious diseases, AP induced by drugs, AP based on
congenital anomalies and obstruction of pancreatic duct. In 10–
25 % of all AP cases the etiological factor is not revealed. These
cases are referred to as idiopathic AP. It has been recorded that
2/3–3/4 of idiopathic cases of AP are caused by microlithiasis.
During the course of severe AP we distinguish 2 phases of
the disease. The first phase begins directly after the onset of AP.
2nd Department of Surgery, Faculty of Medicine, Comenius University,
Bratislava, Slovakia
Address for correspondence: A. Mifkovic, MD, 2nd Dept of Surgery
LFUK, Antolska 11, SK-851 07 Bratislava 5, Slovakia.
Phone: +421.903182928
 Mifkovic A et al. Septic complications of acute pancreatitis… 297
It is characterised by the release of mediators and toxic substances
consequently leading to the progression of systemic inflamma-
tory response syndrome (SIRS). The second phase begins usu-
ally 14 days after the onset and is characterised by infection of
pancreatic necrosis with other septic complications.
Infectious complications of AP can be fatal. Septic compli-
cations occur in 5 % of all patients with AP and in 22 % of pa-
tients with severe form of AP (Karsenti, 2003). Necrosis devel-
ops in 15 –25 % of all patients with AP. Local infection is pre-
sented in 40 – 70 % of patients with necrotising pancreatitis
(Isenmann et al, 2002).
Approximately one half of patients with necrotising pancre-
atitis die due to complications of infected pancreatic necrosis
(Büchler et al, 2002).
When treating these complications we concentrate on the
treatment of sepsis, SIRS, septic shock, multiorgan dysfunction
syndrome (MODS) and the treatment of local septic complica-
tions. We use the broad spectrum of medical interventions. Very
important is the systemic treatment of SIRS and MODS. Often
we have to execute invasive endoscopic, percutaneous and sur-
gical procedures that sometimes can be a life-saving tool. The
course of this disease is frequently unpredictable. The optimal
treatment often fails despite the fact that all therapeutic modali-
ties have been used. This is the reason why it is necessary to
continue in studying the septic complications of AP. It would be
very beneficial to work out unified and universal therapeutic
guidelines for infectious complications of AP.
Definition and classification of acute pancreatitis
In September 1992 there was a meeting of 40 worldwide ac-
cepted experts at AP and its complications. Their goal was to
create a unified classification usable in clinical practice. These
experts from 15 countries were specialized in six clinical branches
and in 3 days they worked out and accepted the definitions and
classification of AP (Bradley, 1993).
Classification of AP (Bradley, 1993):
Mild form: without organ dysfunction or local complication.
Severe form: pancreatitis with signs of organ dysfunction
and/or local complication – necrosis, abscess, pseudocyst.
Acute pancreatitis – is an acute inflammatory process in the
pancreas with variable damage incurred to peripancreatic tissue
and remote organ systems. It usually begins suddenly and is ac-
companied by epigastric pain with variable clinical findings rang-
ing from mild tenderness to peritoneal irritation. Other symp-
toms include vomiting, higher body temperature, tachycardia,
leucocytosis and elevation of pancreatic enzymes in serum and/or
in urine. Pathological picture varies from microscopic interstitial
edema and fatty necrosis of peripancreatic tissue to macroscopic
areas of pancreatic and peripancreatic necrosis and bleeding.
Severe AP is associated with organ failure and/or local com-
plications as necrosis, abscess or pseudocyst. The development
of pancreatic necrosis manifests by the clinical picture of severe
pancreatitis. Uncommonly patients with intestinal pancreatitis
can have a severe form of AP. Usually the severe form manifests
as being severe right from its beginning. The transformation of a
mild form of AP to its severe form is rare.
Mild acute pancreatitis – is associated with minimum organ
dysfunction, heals by first intention and has no severe signs of
AP. The predominant finding in both macroscopic and histologi-
cal pictures of this form is the interstitial edema. Pancreatic ne-
crosis is rare. If it is found it is restricted to microscopic areas
only. Peripancreatic fatty necrosis can be present.
Acute fluid collections are formed in the early phase of AP in
or next to pancreas; they do not have their own wall of granulat-
ing and fibrotic tissue. The incidence is of 30 –50 %, and more
than a half of them resorb spontaneously. These collections can
be the early phase of the development of abscess or pseudocyst.
Most of them regress spontaneously; others can develop into a
pseudocyst or abscess. The exact content of collections is not
known. Sometimes bacteria can be found. When compared to
pseudocysts or abscesses, the most important distinctive factor
is the absence of the defined wall.
Pancreatic necrosis is a diffuse or demarcated area of dead
pancreatic tissue, which is typically associated with peripancreatic
fatty necrosis. The macroscopic picture contains focal or diffuse
areas of devitalised parenchyma and peripancreatic fat. Fatty ne-
crosis can be irregular, superficial or profound and fused. The
microscopic findings include great interstitial fatty necrosis with
damaged vessels, acinar cells, pancreatic isles and pancreatic
ductal systems.
Pancreatic abscess is a demarcated intra-abdominal collec-
tion of pus usually located adjacent to pancreas and containing
no or only a little amount of pancreatic necrosis. It usually de-
velops as a consequence of AP and abdominal (pancreatic)
trauma. The presence of pus with positive cultivation and mini-
mal or no pancreatic necrosis in the clinical picture differ the
pancreatic or peripancreatic abscess from infected necrosis.
Pathophysiology of pancreatic infection
Bacterial translocation. Pathological bacterial translocation
leading to the dissemination of infection can be accompanied by
many severe clinical conditions. Bacterial translocation is the
final consequence of the damage incurred to native defensive
mechanisms (paralytic ileus with dysmicrobia, damaged intesti-
nal barrier and failure of the immune system). In experiment we
can achieve this condition by traumatic contusion of the pan-
creas, intestinal obstruction, haemorrhagic shock, administration
of ATB, total parenteral nutrition or irradiation. The mechanism
responsible for the disorder of motility is considered non-spe-
cific. In the past the main cause of bacterial translocation was
thought to be the decrease in pancreatic or biliary secretion. To-
day it is apparent that the impact of pancreatitis on intestinal
motility is connected with neurohumoral regulation and the ef-
fects of inflammatory mediators (Špièák, 2005).
There are some published studies, where their authors prove
the decrease in gut propulsion during acute experimental pan-
298 Bratisl Lek Listy 2006; 107 (8): 296 – 313
creatitis. This is followed by disproportional increase in the
number of Gram-negative bacteria in the colon and their trans-
location.
The dependence of gut dysmicrobia on propulsion of small
intestine was proved in the outcomes of one trial where the de-
crease in myoelectrical activity was caused by the administra-
tion of morphine (Špièák, 2005). The decrease in the motility
alone can open the path for the translocation that is the conclu-
sive prolongation of the time of contact of the intestinal wall
with bacteria. The increase in intestinal permeability for bacteria
is also caused by the affected secretion of mucus, change in the
function of cellular membranes and intracellular junctions and
damaged lymphatic drainage (Foitzik, 2001). Normal permeabil-
ity of intestinal barrier cannot be achieved unless the vascular
circulation of the gut is intact. Shock and reperfusion lead to
ischaemia of intestinal wall and incur damage to the latter de-
fence mechanisms (Špièák, 2005).
Some published studies prove the increase in intestinal per-
meability of the cavity AP. One of the explanations of the in-
creasing permeability is the impaired intestinal barrier. It is still
unclear which of the sub-barriers (mucosa, cellular membrane,
tight junctions, epithelium, lymphatic tissue) are altered during
AP. The translocation can be performed in 2 ways, namely via
paracellular or transcellular paths. The physiological function of
intestinal wall barrier cannot be achieved unless the blood sup-
ply is intact. Shock and reperfusion lead to ischaemia of intes-
tinal mucosa and bring on bacterial translocation (Büchler et
al, 1999). Hotz et al (1996) report a case where the blood sup-
ply of colonic mucosa was greatly damaged just in the begin-
ning of AP. The reduction in blood circulation correlated with
the stage of AP.
Regarding the presented facts it is necessary to realize that
during the course of pancreatitis the drugs that are commonly
administered can create conditions favourable for bacterial trans-
location. Morphine is a substance decreasing the intestinal mo-
tility. H2 blockers and inhibitors of the proton pump increase
both the pH and bacterial colonisation within the gastric cavity.
Catecholamines decrease the congestion in the splanchnic area.
Contrast substances and somatostatin decrease the intestinal mi-
crocirculation. Total parenteral nutrition decreases the intestinal
motility, leads to mucosal atrophy as well as decreases the func-
tions of the immune system (Foitzik, 2001).
Immune system and cytokines. Alteration in the immune sys-
tem is one of many factors contributing to bacterial transloca-
tion. The numbers of circulating lymphocytes CD4 and CD9 sub-
types of T-lymphocytes are reduced, whereas the activity of granu-
locytes is increased. 10 % of all patients with AP have pancre-
atic infection. Infection of pancreatic necrosis develops in 40–
70 % (Foitzik, 2001).
In the past years the approach to pathophysiology and the
global management of AP have been radically changed. The key
role in pathophysiology of AP is ascribed to pathologic inflam-
matory reaction. The severe form of AP is presented by systemic
inflammatory reaction (SIRS) that can progress to multiorgan
failure (MOF).
The role of cytokines was examined during experimental
pancreatitis and in clinical practice in patients suffering from
AP. The damage of pancreas leads to a systemic response by
means of activated leukocytes and PAF-like substances (Platelet
Activating Factor) released into circulation from the impaired
pancreas. Activated leukocytes release other mediators into the
circulation, which consequently start producing the inflamma-
tory response proteins in the liver (Büchler et al, 1999).
The metabolically damaged pancreatic acinar cells release
free oxygen radicals consequently activating the neutrophils,
which in turn release chemotactic substances. This leads to the
local accumulation of neutrophils. The locally activated neutro-
phils release more free radicals as well as phospholipase A2.
The latter is able to catalyze the releasing of PAF from the mem-
brane phospholipids. PAF continues in activating the neutrophils
and increases the permeability of capillary endothelium. This
causes extravasation of fluid from the circulation and tissue edema
occurs (Büchler et al, 1999).
The systemic activation of neutrophils and monocytes is the
consequence of released activated enzymes, PAF and migrating
activated neutrophils from the pancreas. All of these processes
contribute to the development of SIRS. The generalized leak of
fluid through the endothelium of capillaries leads to hypovolemia
and hypotension. The interstitial fluid in the lungs deteriorates
the respiratory functions and thus leads to hypoxemia. The im-
pairment of perfusion and reduction of the transfer of oxygen to
vitally important organs lead to the reduction of renal functions
and intestinal ischaemia.
The ischemia of gastrointestinal mucosa damages the defence
barrier function of intestinal mucosa. The gut bacteria penetrate
into the interstitial space and their transportation into circulation
takes place by lymphatic vessels. This hypothesis of AP patho-
genesis is based on experimental evidence as well as on the com-
prehension of pathologic mechanisms participating in SIRS un-
der other conditions. The direct evidence of this thesis in human
AP is still missing, however model experiments show a rational
basis for the treatment of AP (Büchler et al, 1999).
Infection complications in acute pancreatitis
Five to nine percent of all patients with AP suffer from pan-
creatic infection. Local septic complications can occur in all types
of AP. In general, they correlate with the extent of pancreatic or
peripancreatic necrosis.
Infection develops in 40 –70 % of AP cases complicated by
necrosis. We should distinguish two basic factors in the devel-
opment of pancreatic infection. Firstly, it is the presence and
extent of pancreatic or extrapancreatic necrosis. The secondary
pancreatic infection is considered to be the most important de-
terminant of morbidity and mortality in patients with AP
(Mithöffer et al, 1997).
In most cases, the course of AP correlates with pathomor-
phological changes of pancreas. The morphologic picture of se-
vere pancreatitis resides in pancreatic necrosis. The risk of in-
fection of the necrosis correlates with the extent of the necrotic
 Mifkovic A et al. Septic complications of acute pancreatitis… 299
area. The pancreatic infection has a negative impact on the fol-
lowing course of the disease. It can lead to death and is an indi-
cation for surgical treatment of the pancreas. The incidence of
the development of severe complications and lethality in infected
necrosis is higher than that in sterile necrosis (Karsenti, 2003).
The severity of AP depends on the presence and extent of pan-
creatic necrosis as well as on the amount of released vasoactive
and toxic substances. The presence of bacterial contamination in
pancreatic necrosis plays an important role (Karsenti, 2003).
The frequency of infection complications correlates with the
severity of AP. The infection can be localised as an infected
pseudocyst or it can be multilocular and spreading diffusely in
the whole of retroperitoneum as the infected pancreatic necrosis.
The development of pancreatic infection complications occur in
severe AP, in patients with proven bacteriemia and in patients in
bad clinical state one week after the onset of the disease (Olejník
et al, 2002).
The most important factor predisposing to infection is the
necrosis of the pancreatic tissue. 89 % of cases of all infections
are accompanied by pancreatic necrosis, but only 32 –37 % of
cases with necroses are infected (Garg, 2001). The patients with
moderate extent of necrosis are infected in 25 % of cases, great
necroses are infected in more than 50 % of cases (Büchler et al,
2002). The unilocular peripancreatic fluid collection is accom-
panied by infection in 17 %; if the number of these collections is
higher than 2, the risk of infection is 61 %. If the necrosis is
infected, the mortality is 15 –50 % despite surgical intervention
(Vivek, 2000).
In 80 % of cases the course of AP is mild and without com-
plications, in 15 –20 % of cases it is a severe necrotising form
with possible septic complications (Büchler et al, 2002). The
morbidity and mortality of AP is related to the presence of pan-
creatic necrosis. The prognosis is influenced mainly by the de-
velopment of complications. The main role in complications is
played by infection of necrosis which is the most important fac-
tor of the prognosis (Büchler et al, 2002, Bìlohlávek et al, 2001).
The infection usually does not manifest in the first week of
the disease. In most cases the infection occurs after 14 –22 days
after the onset of AP (Isenmann et al, 2002). If the infection
appears in the first week, the administration of ATB does not
decrease the mortality. The recommended period of ATB admin-
istration is 10 –14 days or even longer according to the progress
of the disease.
The local septic complications of AP include acute fluid col-
lections that can be infected and represent the precursor of the
development of pseudocysts or abscesses. Other local septic com-
plications are acute pseudocysts, infected pancreatic necroses and
pancreatic abscesses.
Acute fluid collections
According to Atlanta consensus the acute fluid collection is
the fluid in the surrounding of pancreas that is not demarcated
by the organised tissue structure. It usually appears up to 4 weeks
after the onset of AP. Its incidence is 50 % of all patients with
AP and 85 % of cases with necrotising form of AP. The fluid
collections are the indicator of the severity of AP, Balthasar uses
them as one of criteria of CT classification of AP (Balthasar et
al, 1990). Most of these collections tend to regress spontane-
ously after 4 –6 weeks. They are more often visualised in the
head or cauda of the pancreas than in the corpus of the pancreas
by CT and USG imaging. The fluid collections can spread to
omental bursa, mesenterium, transverse mesocolon, subhepatic ,
perisplenic and perirenal space and to the minor pelvis. If they
do not regress they tend to change into pseudocysts in 4–10 weeks
(Maher, 2004).
According to some investigations the organising ability of
free peripancreatic fluid of is greater than that of fluid with fatty
or pancreatic necrotic tissue (Maher, 2004). Acute fluid collec-
tions cause that the pain increases, the course of pancreatitis
worsens, there is infection and the risk of rupture, haemorrhage
or obstruction of duodenum or common bile duct. The infection
of collections can be related to the infected pancreatic necrosis
(Uhl et al, 2002). Some authors have tried to classify these fluid
collections according to their content of fluid, presence of ne-
crosis and damage incurred to pancreatic ducts.
According to Uhl et al (2000) acute fluid collections (AFC)
occur in 40 –50 % of patients with AP. In 50 % of cases we can
see spontaneous resorption (Maher, 2004). If these collections
persist they can transform into pseudocysts. More often they are
located either within or outside the pancreas.
Acute fluid collections are often confused with pseudocysts;
however these two entities are basically different. Fluid collec-
tions do not have their own walls and they appear in the early
stage of the disease. AFCs addapt to their anatomical space where
they either persist or continuously regress. Often they are localised
in the anterior pararenal space and in the omental bursa. Collec-
tions can be seen also in atypical locations like mediastinum,
posterior pararenal space and the pelvis (Maher, 2004).
In 50 % of all cases we can see spontaneous regression of
AFCs without being diagnosed by needle aspiration or percuta-
neous drainage (Maher, 2004). The patients with AP complica-
tions including peripancreatic fluid collections and signs of sep-
sis need the diagnostic aspiration in order to exclude the infec-
tion. If the aspirated fluid after microbiological analysis is posi-
tive we can execute the percutaneous drainage.
Infected pancreatic necrosis
The infected pancreatic necrosis is a part of demarcated dead
tissue of pancreas that is infected with microbes. It is considered
to be a severe complication of AP having a negative influence
on its course. Theoretically the origin of infection can be any-
where in the human organism. The spread of infection can be
hematogenous, lymphogenous or per continuitatem.
The infected pancreatic necrosis is the most frequent type of
pancreatic infection. The bacterial infection of pancreatic necro-
sis was recorded in 1–10 % of all patients with AP and in 40 –
70 % of all patients with necrotizing pancreatitis (Büchler et al,
1999). Büchler et al compared infected and sterile pancreatic
300 Bratisl Lek Listy 2006; 107 (8): 296 – 313
necrosis and they concluded that patients with infected pancre-
atic necrosis have an increased risk of developing systemic life-
threatening complications. The clinical management in patients
with infected pancreatic necrosis is different from that in pa-
tients with sterile necrosis (Büchler et al, 1999).
In samples of pancreatic tissue taken during surgery for cul-
tivation showed an increased incidence of infected pancreatic
necrosis up to 21st day after the onset of AP. Twenty-five per-
cent of patients who were operated on during the first week after
the onset of the disease had a positive bacteriologic test. Positive
bacteriologic results were recorded in 36 % of patients who were
operated on during the second week. The bacteriologic findings
in patients who were operated on during the third week were
positive in 71 % of cases. The cultivations from patients oper-
ated on during the fourth week after the onset were positive in
47 % of cases. The cultivations done during the surgery after the
28th day were positive in 36 % of cases (Büchler et al, 1999).
It happens relatively often that the differentiation of infected
necrosis from sterile necrosis cannot be based on clinical, labo-
ratory or morphological information. The USG and CT-guided
fine needle aspiration of necrotic collections followed by micro-
scopic cultivation of the sample is often used in current clinical
practice. This procedure is relatively less invasive, precise, easy
to perform and safe (Baron et al, 1996, Uhl et al, 2002). If the
necrosis is voluminous there is no other possibility than to use
use ultrasound-guided needle aspiration, in other cases we use
CT-guided aspiration. The risk of infection of sterile necrosis by
the needle is minimal. We can take the sample from any part of
the lesion.
This procedure is not indicated in all cases but only in pa-
tients with necrotising AP with the development of sepsis (Uhl
et al, 2002). In such cases it is not recommended to waste time
by proving the presence of infection. If the CT picture shows the
source of sepsis (for example an abscess) we gain the material
during surgery. On the other hand we should not be afraid to
repeat the procedure if the course of the disease demands it. In
some published papers the sensitivity is 96 % and specificity
99.5 %. Today the indication for differentiation of sterile from
infected necrosis is generally accepted.
Once the pancreatic necrosis is proven to be infected and
there are septic complications caused by the pancreatic infec-
tion, surgical intervention becomes indicated. (Büchler et al,
2002). The mortality in patients with infected pancreatic infec-
tion is over 30 %. It is considered that 80 % of all deaths caused
by AP are related to septic complications (Gloor et al, 2001).
The conservative treatment of infected pancreatic necrosis ac-
companied by multiorgan failure is associated with mortality up
to 100 %.
Professor Beger, the head of the Surgical Department in Ulm
in Germany together with his colleagues created a conception of
pancreatic infection. There is also another group specialised in
the diseases of pancreas supervised by Professor Büchler in Bern.
Beger et al (2003) published a study performed on 1,442 pa-
tients with AP included. Pancreatic necrosis was proven by CT
in 300 patients (20.8 %). In 99 patients (33 %) the necrosis was
infected, in other cases it was sterile. Infected necrosis occurred
in 6.8 % of all patients with AP. Pancreatic abscess developed in
40 patients, i.e. in 13.3 % of all patients with necrotizing pan-
creatitis and in 2,8 % of all patients with AP. The risk of pancre-
atic infection increases with time (Beger et al, 2003). Out of pa-
tients treated surgically during the first week the infection was
proven only in 25 %. The ratio of infected pancreatic infection
increased up to 36 % or 71 % during the second and third weeks
respectively (Beger et al, 2003).
The risk of developing the pancreatic infection depends on
the extent of pancreatic necrosis. If the necrosis takes 30 % of
pancreas the infection is proven in 26.5 %; if the necrosis takes
more than 50 % of pancreas the risk of infection is 38.2 % (Beger
et al, 2003). Moon-Tong Cheung (2005) published a paper on
the treatment of pancreatic necrosis. He sees the extent of the
necrosis and the presence of infection as the most important fac-
tors influencing the effect of treatment and the prognosis of pa-
tients with pancreatic necrosis.
The thesis about ATB treatment should be created on the
base of good knowledge of pathogenesis and development of
infection during AP. The development of pancreatic necrosis is
always very fast, the risk of its infection is continuous. Most
often the infectious contamination of the necrosis occurs in the
second week of the disease (Büchler et al, 2002). It was proven
in many trials that the bacteria colonising the pancreatic necro-
sis are those from the intestinal lumen. Under the selective pres-
sure of ATB prophylaxis the Gram-positive cocci are in major-
ity. Continuously more often the fungal infection is recorded
(Bìlohlávek et al, 2001).
The microbial agents get into the necrotic focus within the
pancreas via blood, lymph, by transcending the biliary ducts,
through the portal system or through the wall. Their reservoir is
undoubtedly the colon. The infection spreads through the intesti-
nal wall. This phenomenon is referred to as bacterial translocation
(Büchler et al, 2002). During AP we can accept their spread from
biliary ducts, kidneys and intestines (Špièák, 2005). Some experi-
mental works have proved their spreading from biliary ducts and
kidneys. It has been absolutely proven that it is the colon serving
as the reservoir of microbial agents infecting the pancreas (Špièák,
2005). Bacterial translocation is one of the main aspects of patho-
genesis of severe pancreatitis. We should mention that bacterial
translocation occurs also under physiological conditions too, but
the amount of bacteria overcoming the intestinal barrier is small
and they are killed by immunological mechanisms of the body.
The spectrum of bacteria infecting the necrotic foci within
the pancreas can be seen in the samples taken during surgical
necrectomy or by aspiration biopsy. In most cases the bacterial
infection is monomicrobial and depends on the bacterial spec-
trum within the intestinal content. According to the trial done by
Ulm during the period from 1982 to 1993 the monomicrobial
infection of pancreatic necrosis was proven in 69 % whereas
polymicrobial infection in 31 % of all cases. The infection within
abscesses was proved to be monomicrobial in 46 % and polymi-
crobial in 54 % of all 106 patients. The most frequent microbial
agent was E. coli (Beger et al, 1999).
 Mifkovic A et al. Septic complications of acute pancreatitis… 301
Probably under the selective pressure of ATB the spectrum
of bacteria infecting the necrotic foci within the pancreas changed
significantly in a relatively short period of time. According to
the trial done by Bern in 1999 the infection in patients with acute
necrotising pancreatitis was caused by G+ bacteria in 84 %
whereas G- bacteria were present in 40 % of 37 infected pancre-
atic necroses (aspiration biopsy). The cultivation revealed that
in 4 % of cases the infection was caused by anaerobic microbial
agents and in 36 % it was caused by fungi (Candida species)
(Beger et al, 1999). Since the lethality was only 8 % a question is
to be posed as to how extensive the impact of the change in
bacterial spectrum is on the course of infected necrotising pan-
creatitis.
Pancreatic abscess
Pancreatic abscess is a well demarcated intraabdominal col-
lection of pus localised either within or adjacent to pancreas. It
occurs in later stages of AP, typically in 4 –6 weeks after its on-
set. Pancreatic abscesses occur as a consequence of AP, trauma
of the pancreas or surgical operation near the pancreas. Pancre-
atic abscesses are considered to be the later consequence of AP
(Büchler et al, 1999).
According to some trials, abscesses complicating the severe
pancreatitis occur in 2 –9 % of patients with AP. More often they
occur after the trauma of the pancreas than in patients with alco-
hol abuse. According to Beger et al (1998) 16–23 % of all ab-
scesses they develop in pancreas damaged by chronic pancreatitis.
When compared to infected pancreatic necrosis, pancreatic
abscess is characterized by milder clinical signs and by a signifi-
cantly decreased APACHE II and Ranson score. Systemic com-
plications as shock, respiratory and renal insufficiency occur less
commonly in patients with pancreatic abscesses. The mortality
is significantly decreased in patients with abscesses than in pa-
tients with pancreatic necrosis (Büchler et al, 1999). The bacte-
rial spectrum in patients with abscesses is similar to that of
bacteria in infected pancreatic necrosis. In more than 50 % of
abscesses we can record the presence of 2 or more bacterial
species.
Abscesses most often develop from subacute pancreatic ne-
crosis or from the fluid collection. According to information from
literature, the most of abscesses are multilocular, whereas unilocu-
lar abscesses are rare. Abscesses can be localised within the pan-
creas, adjacent to it or adjacent to intestinal loops. When com-
pared with pancreatic necrosis the spectrum of microorganisms
in abscesses is polymicrobial (Uhl et al, 2002). The bacterial
spectrum is the same as that in intestinal aerobic flora (Beger et
al, 1998). The pathway of the spreading of infection is subject to
current discussions.
The clinical picture of pancreatic abscess is different from
that of pancreatic necrosis. The patients with pancreatic abscesses
have undulating fever, leukocytosis and unspecific abdominal
pain. Organ failure and metabolic disturbances that are common
during severe pancreatitis are rare at the time when the pancre-
atic abscess is diagnosed.
The main diagnostic tools are USG and CT able to image the
demarcated collection. The diagnosis is confirmed by cultiva-
tion of the content aspired from the abscess. CT is mandatory in
order to know anatomical relations. MRI is a tool helping to
distinguish solid parts of the abscess from fluid (Toouli, 2002).
The treatment of abscess is multimodal. It can be treated by
surgical operation, percutaneous drainage or endoscopic inter-
vention. Non-surgical intervention can fail in case of multilocu-
lar abscess or due to its heterogeneous content. In such cases
long-term drainage is ineffective. The surgical treatment can be
executed in several modifications. Administration of effective
ATB able to penetrate the pancreatic tissue forms a part of the
treatment. The outcome of pure ATB treatment with no interven-
tion is doomed not to be successful. The lethality in patients
with abscess is below 10 %, thus very low when compared to
infected necrosis (Büchler et al, 1999).
It is the secondary infection of pancreatic or peripancreatic
necrosis that greatly participates in mortality due to AP. This
infection afflicts either the necrotic foci within the pancreas or
the already developed abscesses. Pancreatic abscesses are con-
sidered to be rare complications when compared with infected
pancreatic necrosis (Srikanth, 2002).
In his paper, Srikanth describes the treatment of patients with
pancreatic abscesses. In his trial he included 21 patients with
pancreatic abscesses. Twelve of them were treated by percutane-
ous catheter drainage (PCD), 9 patients were treated by conven-
tional surgical operation (in 2 patients PCD was executed before
operation). Two patients were treated conservatively. The total
mortality was 9.5 % (2/21). PCD could be done in 57 % of pa-
tients. It was successful in 83.3 %; the mortality after PCD was
8.3 %. Surgical intervention was necessary in 33 % and success-
ful in 85.7 % of patients, mortality was 14.2 %. Complications
were recorded in 4 of 9 patients who were treated with PCD and
in 8 of 9 treated surgically. Pancreatic abscess is a potentially
lethal complication in patients with severe AP. Early diagnosis
and prompt intervention are mandatory however the patients must
be selected precisely. Computer tomography serves as the base
indicating whether surgical treatment or PCD is to be performed.
In the treatment of pancreatic abscesses, the role of PCD and
that of surgical intervention are complementary. The success of
the management of pancreatic abscess greatly depends on good
cooperation of the surgeon with the interventional radiologist as
well as on correct timing of therapeutic modalities in its treat-
ment (Srikanth, 2002).
In the treatment of abscess Toouli recommends to proceed in
just the same way as in that of pseudocyst. Some authors prefer
external drainage to internal, i.e. endoscopic drainage (Toouli,
2002).
Infected pancreatic pseudocysts
Pancreatic pseudocysts are localised collections of pancre-
atic secretion of cystic structure without their own epithelial lin-
ing. Their walls consist of granular or fibrous tissue. They occur
in acute and chronic pancreatitis, as well as in patients with trau-
302 Bratisl Lek Listy 2006; 107 (8): 296 – 313
matic damage incurred to their pancreas. Acute pancreatitis is
complicated by pseudocysts in 5 %, while chronic pancreatitis is
complicated by pseudocysts in 20 –40 % of all cases (Byrne et
al, 2002). During the course of AP, pseudocysts develop by col-
liquation of the necrotic tissue within or adjacent to the pancreas
or by disruption of the pancreatic duct. They can be localised
within any part of the pancreas (intrapancreatic location) or ad-
jacent to it (peripancreatic location, most often within the omen-
tal bursa). Pseudocysts contain fluid with a high concentration
of pancreatic enzymes. The ionic content is similar to that of
blood plasma. In pseudocyst fluid tissue detritus and digested
blood can appear. The content can be limpid, whitish or dark. As
a result of acute inflammation the membranes of inflammatory
cells and granulating tissue demarcate the damaged or devitalised
tissue. The second option is ductal disruption leading to the leak
of pancreatic secretion into the interstitial space where it imme-
diately starts the inflammatory reaction. Pseudocyst complicat-
ing the course of AP can be diagnosed by USG, CT or ERCP if
they communicate with the main pancreatic duct.
Acute fluid collection differs from pseudocysts lacking the
newly created wall. The clinical manifestation of acute fluid col-
lection or pseudocyst starts after it reaches a particular size. Its
symptoms are non-specific caused by pressure on the surround-
ing organs or structures. Nausea and sickness appear if the pres-
sure on the duodenum occurs. Total or partial ileus can develop
if the obstruction of the transversal colon takes place. Icterus
occurs if the pressure on the terminal part of the common bile duct
is present. Postacute pseudocysts appear usually after 4–6 weeks
after the onset of AP and they can be localised within as well as
outside the pancreas. The formerly sterile content rich in pancre-
atic enzymes can be contaminated. The diameter of postacute
pseudocysts can reach several dozens of centimetres. Pseudocysts
in patients with chronic pancreatitis are usually smaller.
Laboratory examinations are non-specific; sometimes the
level of serum amylases can be elevated. The main diagnostic
tools are USG and CT. Computer tomography is the basic ex-
amination should we suspect that there may be a pseudocyst. It
helps also in planning the next treatment. Computer tomography
exactly shows the size, location and relation to surrounding tis-
sues. According to its density we can estimate the probable prop-
erties of the content. USG examination is non-invasive, avail-
able and relatively cheap. It is used to monitor the dynamics of
changes of the pseudocyst. EndoUSG examination in combina-
tion with aspiration is an imaging tool with high sensitivity
(Memis et al, 2002).
D’Egidio divides pseudocysts into 3 types (D’Egidio et al,
1992):
Type I pseudocysts are acute and appear as a consequence of
AP. In this type pancreatic ducts are normal and do not commu-
nicate with cysts.
Type II pseudocysts develop after AP however they can pos-
sibly communicate with pancreatic ducts.
Type III pseudocysts develop in patients with chronic pan-
creatitis with significant stenosis proximal to pseudocyst; as a
rule they communicate with the pancreatic duct.
Various studies report the incidence of postacute pancreatic
pseudocysts to be in the range of 2–15 %. In compliance with the
results gained at the Ulm Clinic (1,331 patients with AP) 56 out of
75 pseudocysts (75 %) caused difficulties; the rest of them were
asymptomatic. The most frequent sign is blunt abdominal pain.
Further signs include nausea, vomiting, weight loss, ileus and jaun-
dice. Large pseudocysts can be palpable. Since 1970‘s it has be-
come known that 50 % of pseudocysts regress spontaneously.
The authors from Mayo Clinic have proved that pseudocysts
can resorb spontaneously with no complications. The probabil-
ity of such resorption is indirectly proportional to the size of
pseudocysts. Ninety percent of cysts that are less than 4 cm large
resorb spontaneously, whereas the resorption takes place only in
20 % of cysts over 6 cm.
Most frequent complications of pancreatic pseudocysts in-
clude their infection, biliary and intestinal obstruction, haemor-
rhage, rupture and internal fistula. Infection of pseudocyst is
defined not only by the presence of bacteria, but also by clinical
signs of sepsis.
The therapy of pseudocyst or acute fluid collection after AP
depends on the dynamics of the pathological process. In the past,
the criterion indicating the necessity of surgical treatment was
based on the size of pseudocyst being over 6 cm. It has been
backed away from this criterion because the mortality of surgi-
cally treated patients was high, namely 5–12 % (Memis et al,
2002). Asymptomatic patients are nowadays treated conserva-
tively regardless of the size of pseudocysts. Spontaneous regres-
sion and resorption take place in ca 25 % of cases.
Surgical therapy is currently indicated only in the presence
of complications, namely in ca 50 % of cases. In the rest of pa-
tients total resorption does not have to necessarily take place,
however pseudocysts remain stable, i.e. they persist or partially
regress. The present-day therapy in patients with pancreatic
pseudocysts depends on the clinical course, the presence or ab-
sence of symptoms, as well as on time that has elapsed since the
onset of AP. It also depends on the location of pseudocysts and
appearance of complications.
In favourable cases pseudocysts develop already during the
fourth week or later. They are asymptomatic and no infection or
other obstructive complications appear. Patients should be fol-
lowed by gastroenterologist in monthly intervals. CT or USG
are performed in order to monitor the size of pseudocysts. Should
the cyst grow and clinical signs appear (pain, intestinal obstruc-
tion associated with vomiting and impossibility of oral food in-
take, septic symptoms) percutaneous drainage is indicated as well
as endoscopic intervention or surgical treatment.
Invasive methods include percutaneous drainage of pseudo-
cysts under USG or CT control.
Pseudocysts must be emptied and their content is subject to
cultivation and biochemical examinations.
Should infection be proved, it is possible to wash out the rest
of the cavity by crystalloid solutions with disinfectants. The drain-
age can be kept for several days or months.
Should the pancreatic secretion be long-term, it is possible
that the cysts communicate with the ductal system. In such cases
 Mifkovic A et al. Septic complications of acute pancreatitis… 303
fistulography is indicated or ERCP is to be done with the intro-
duction of stent into the pancreatic duct (bridging). Non-surgi-
cal methods also include the endoscopic drainage of cysts.
Gastrofiberscopic examination reveals the location of the vault-
ing of pseudocysts on the back wall of the stomach or within the
duodenum; the content of cysts is evacuated by aspiration.
The current opportunities as to the way of treating pancre-
atic cysts are wide. It is difficult to compare individual studies
since they do not use standard classification and terminology.
Very frequently the selection of therapeutic procedures is im-
plied by the character of the disease and anatomical circum-
stances. In general the primary success rate in all presented pro-
cedures is high, while the recurrence rate is 10 –20 %, complica-
tions occur in 10 % and lethality is 1– 3 %. Comparative studies
are required however their performance is difficult (Rau et al,
1998).
The surgical treatment resides in external or internal drain-
ing or resection. Prior to the decision to proceed to surgery some
factors have to be considered as the overall state, etiology, clas-
sification of pancreatitis, or the presence of complications as well
as the anatomy of the cyst and pancreatic duct. Prior to the surgi-
cal treatment ERCP should be performed in order to judge the
pancreatic ductal system, possible pressure upon the stomach or
the communication between cysts and duct (Špièák, 2005). The
preferable surgical treatment of pseudocyst is its internal drain-
age. Depending on the location of pseudocyst various surgical
approaches can be taken, namely transgastric pseudocysto-
gastrostomy (according to Jurasz), retrogastric pseudocysto-
gastrostomy (according to Jedlièka), pseudocystojejunostomy
with an isolated omega loop or according to Roux. It is also pos-
sible to perform transduodenal pseudocystoduodenostomy (ac-
cording to Kerschner).
There are some other surgical methods including the extir-
pation of pseudocysts together with the distal resection of pan-
creas. This is performed when the cyst is localized in the tail.
Should the proximal part of the pancreatic duct be obstructed
the isolated Roux-en-Y loop is sewn onto the resection surface
of pancreas. The external peroperative drainage of pancreatic
pseudocyst is done only in cases of immature pseudocysts or
abscesses when percutaneous drainage is not safe.
Percutaneous aspiration is indicated due to diagnostic rea-
sons in order to prove infection. It is not appropriate to perform
aspiration in order to attempt to evacuate the pseudocyst. Pseudo-
cysts reappear in 70 % of such cases. Repeated aspiration in-
creases the risk of complications (Špièák, 2005).
Percutaneous drainage (PCD) is a frequently used method.
Several approaches are possible, namely transperitoneal, retro-
peritoneal and transhepatic techniques. Their results are compa-
rable. Several studies describe their successful application in cases
of infected pseudocysts. Percutaneous drainage and aspiration
are absolutely inappropriate in pseudocysts communicating with
pancreatic ducts with their stenosis distal to the latter communi-
cation.
The outer drainage is indicated in cases of infected pseudo-
cysts and intracystic hemorrhage. Pancreatic fistula complicates
the postoperative course in 10 % of patients, especially after an
erroneous decision to operate while the Wirsung’s duct is stenotic
before the cystoductal communication (Bradley et al, 2002). In-
ternal drainage is performed in well demarcated and uncompli-
cated pseudocysts. The most frequent approaches include pseudo-
cystogastrostomy or pseudocystojejunostomy. Less frequent are
cystoduodenostomies. Drainage can be currently done in form
of laparoscopy. They are advantageous due to their low invasive-
ness. The duration of surgery is ca 2 hours; hospitalization takes
ca 4 days (Baron et al, 2002).
Endoscopic therapy can secure the drainage of pseudocyst
by introducing a stent in site of the pseudocyst pressing upon the
back wall of the stomach or duodenum; such case is referred to
as endoscopic pseudocystoduodenostomy or endoscopic pseudo-
cystogastrostomy. There are records of pancreatic abscesses suc-
cessfully healed in this way (Štancel, 2005).
ERCP is appropriate especially in patients with severe AP
incurred by cholelithiasis. It has been proved that the withdrawal
of main complications in cases of severe pancreatitis is statisti-
cally significant. It has been proved that early ERCP with EPS
and replacement of concrements done up to 72 hours in patients
with severe AP complicated by biliary sepsis significantly re-
duce the main complications (12 % vs. 61 %) (Shankar et al,
2004). ERCP can also reveal abnormalities in the ductal system
of pancreas as e.g. divided pancreas or pseudocysts communi-
cating with the pancreatic ductal system. The AP management
requires a good cooperation of surgeon, gastroenterologist trained
in endoscopy and interventional radiologist.
Percutaneous drainage is mainly indicated in cases of infec-
tion, fever, pain, growing pseudocysts, biliary or gastrointestinal
obstructions, and when the acute process turns into chronicity.
Transgastric insertion of double-J catheter with one of its ends
introduced into the pseudocyst and the other in the stomach can
be performed endoscopically or laparoscopically. This method
requires cooperation of an experienced endoscopist (Shankar et
al, 2004). Fine-needle aspiration is not used as a therapeutic pro-
cedure because when repeated, the collections tend to reoccur.
Draining catheter techniques are considered to be more efficient
(Shankar et al, 2004).
The signs of compression in adjacent organs require urgent
treatment. It seems that best therapy is the internal drainage
that can be performed endoscopically or surgically (Toouli,
2000). Endoscopic therapy resides in the introduction of stent
into the pseudocyst either via the papilla or through the stom-
ach or duodenal wall. Currently, it is the endoscopic perfor-
mance of transmural cystogastrostomy or cystoduodenostomy
that is preferred because this method brings on fewer compli-
cations (Toouli, 2002). Non-randomized studies comparing
endoscopic and surgical methods of therapy indicate that the
main factor determining the optimal method is rather a ques-
tion of local possibilities and experience. Several studies bring
evidence that internal drainage is much safer than external drain-
age due to low morbidity, mortality and recurrence of pseudo-
cysts (Toouli, 2002).
304 Bratisl Lek Listy 2006; 107 (8): 296 – 313
Sepsis and septic shock due to infectious complications in acute
pancreatitis
The clinical manifestation is not brought on only by microbes;
it is especially caused by the system of immunoinflammatory
reactions of the host (Krkoška, 2001). The current definitions are
based on the principal significance of the systemic response of the
host to the aggression and have been formulated at the Consensus
Conference in USA in 1992 as follows (Krkoška, 2001):
Systemic inflammatory response syndrome is a systemic re-
sponse to a range of both infectious and non-infectious insults
including trauma, pancreatitis, amniotic fluid embolism, etc. SIRS
is defined by the presence of two or more of the following clini-
cal signs: body temperature over 38 °C or below 36 °C, pulse
over 90/minute, breathing rate over 20/minute or a decrease in
paCO2 below 4.3 kPa.
Sepsis is a systemic inflammatory response brought on by
infection.
Severe sepsis is a state of getting into the stage of septic
shock. It is defined by the criteria of sepsis and at the same
time by the presence of at least one of the following signs of
organ hypoperfusion: disturbed consciousness, hypoxemia, in-
creased lactatemia, diuresis decreased below 30 ml/hour, or be-
low 0.5 ml/kg/hour.
Septic shock can be divided into the early and refractory
stages. The early stage of septic shock is defined as severe sepsis
with hypotension manageable by common treatment of shock
(intake of fluid or pharmacological intervention). The refractory
stage of septic shock is defined as a septic shock with refractory
hypotension lasting for over one hour despite adequate supple-
ment of volume by means of vasopressoric therapy.
Etiology of sepsis Under certain conditions sepsis can be
brought on by any of microbes (especially at the presence of
predisposition factors). The predisposition is considered to be
e.g. immunodeficiency or the presence of alien material. Most
frequent etiologic factors are bacteria and yeast fungi. The sys-
temic inflammatory response can be brought on also by other
microbes (ricketsia, viruses, fungi, parasites). The ability of mi-
crobes to bring on sepsis is given by the reactivity of their super-
ficial structures. According to large foreign studies it is espe-
cially Gram-positive bacteria that prevail in the etiology of noso-
comial sepsis. Out of Gram-negative bacteria it is mostly E.coli,
Enterobacter. spp., Pseudomonas aeruginosa, Proteus spp., Kleb-
siella spp. and Acinetobacter spp.. Anaerobes include especially
Bacteroides fragilis. The fact that the number of immunocom-
promised hosts increases contributes to the increase in the num-
ber of septic cases brought on by mycotic agents (especially
yeasts) as well as some of other rare pathogens.
Pathophysiology of sepsis Recent knowledge in the field of
pathogenesis of systemic inflammatory response brings evidence
that immunologic and biochemical procedures within the body
are uniform. In this way the body reacts to various types of ag-
gression (including infections).
The reaction of the acute phase is based on stereotypic cas-
cade activation of inflammatory mediators and protein molecules.
The difference between localised and systemic activation of in-
flammatory processes is in the fact that the local reaction is lim-
ited to a particular local region. The aim of this immunoinflam-
matory reaction is to eliminate local aggression (i.e. infection)
and to renew the physical integrity and physiological processes.
The maintenance of the defensive character of this reaction is
determined by the maintenance of its regulation and by the local
effect of inflammatory mediators. Should deregulation and de-
localisation take place, the original defensive actions become
self-destructive and inflict damage to the host. The whole patho-
genesis of sepsis can be summarised in four stages:
– Triggering stimulus,
– Systemic inflammatory response (SIRS and MODS),
– Multi-organ failure (MOF),
– Death due to septic shock.
Triggering stimulus of sepsis Infectious agents usually form
the primary focus within some of host tissue. This primary focus
is too difficult to be localised. Sepsis rarely develops by direct
inoculation of microbes into the circulation. In case of Gram-
negative etiology it is the endotoxin, in Gram-positive microbes
it is some other cellular wall component. Their toxicity and in-
flammatory effect reside in their ability to bring on immunoin-
flammatory response in the host.
Markers of pancreatic sepsis The severity of affliction of
pancreas, i.e. the extent of pancreatic necrosis with its possible
infection can be monitored by several various markers. When
evaluating the clinical contribution of markers it is necessary to
consider their physiologic and pathophysiologic features, the
method of assessment and a particular question which is to be
answered. The golden standard of assessment of pancreatic ne-
crosis is considered to be the C-reactive protein (CRP). It was
discovered already in 1930. According to various authors, the
limiting values range from 120 to 200 mg/L. The CRP level
achieves its maximum in four days after the onset of disease
(Špièák, 2005).
The laboratory recognition of infected, sterile and pancre-
atic necrosis is based on the detection of several inflammatory
mediators including synovial phospholipase PLA, interleukin IL-
8, procalcitonin, and TNF-alpha. The examination of procalci-
tonin (PCT) seems to be promising and available. Its level of
1.8 mg/ml indicates infected necrosis with 94 % sensitivity and
90 % specificity (Uhl et al, 1998).
The detection of pancreatic necrosis is based on CT with
contrast bolus. CT or USG-guided bioptic punctions of infected
pancreatic necrotic foci are of vital value when combined with
bacteriological examination of the aspired material (Uhl et al,
2002). These approaches were implemented into clinical prac-
tice at the end of 1980‘s and since the half of 1990‘s they have
become standard methods also under our conditions. Various
studies assess the sensitivity and specificity of CT to be in range
of 90–100 % (Uhl et al 2002).
In case of infection the whole extent of necrosis is most com-
monly homogenous and biopsy requires to be neither repeated
nor otherwise targeted. The examination is relatively safe. The
examination of CRP should be part of examination performed at
 Mifkovic A et al. Septic complications of acute pancreatitis… 305
the admission. In the coming years it can be replaced by other
biochemical markers. As soon as CRP exceeds its standard value,
the clinical picture deteriorates and signs of sepsis occur. CT
with contrast bolus should be performed up to 5–10 days from
the onset of disease. In case that pancreatic necrosis is found and
pancreatogenic sepsis is suspected bioptic punction should be
performed (Špièák, 2005).
Systemic inflammatory response After the release of e.g. en-
dotoxins into circulation, systemic activations of various in-
flammatory cells take place, especially those of macrophages,
monocytes and polymorphonuclear cells. Activated inflamma-
tory cells release a wide spectrum of mediators. In the begin-
ning, primary cytokines are released, namely tumour necrosis
factor (TNF) and interleukin-1 (IL-1). They activate other in-
flammatory cells to release secondary cytokines (IL-6, IL-8, in-
terferon gamma etc.). At the same time however their antago-
nists are produced. This results in formation of a so-called
cytokine net. Individual cytokines within the net either potenti-
ate or inhibit each other. The final effect depends on the interac-
tion of all participating cytokines. The triggering stimulus (e.g.
endotoxin) and pro-inflammatory cytokines activate the comple-
ment, coagulatory and kinin-calicrein protein systems.
Pathogenic actions on the endothelial level in the area of
capillary bed within individual tissues and organs determine the
further development of sepsis and its possible development into
multiorgan failure. Endothelium is the target of most septic me-
diators. The presented processes damage the capillary walls and
in this way bring on dysfunction or failure of tissues and organs.
Multiple-organ dysfunction syndrome SIRS brings on a state
referred to as a multi-organ dysfunction syndrome (MODS). The
changes are especially marked in so-called shock organs (lungs,
kidneys, liver, gut, heart). In these organs it is the endothelium
that becomes severely damaged. Regarding the progression of
shock the most significant damage is that of gastrointestinal
mucosa. The balance between coagulation and fybrinolysis be-
comes gradually disturbed resulting in the tendency of hyper-
coagulation and disseminated intravascular coagulation (DIC).
Should two or more organs fail the so-called multi-organ failure
syndrome takes place.
Acute respiratory distress syndrome (ARDS) is a pulmonary
manifestation of damaged microcirculation due to sepsis and its
pathomechanisms.
Renal failure is associated with centralisation of circulation
and microcirculatory changes. Functional failure takes place when
creatinine clearance decreases below 0.42 ml/s. When sepsis turns
into septic shock oliguria drops below 0.5 ml/kg/h.
Hepatic failure develops by combining several factors, espe-
cially due to damaged microcirculation and direct toxic effect of
sepsis. It manifests as increases in bilirubin and aminotrasferases,
as well as signs of disturbed proteosynthesis. Intestinal failure
takes place during sepsis due to damaged microcirculation and
subsequently disturbed barrier function of intestinal mucosa. This
results in translocation of intestinal microbes and toxins into
portal blood and splanchnic lymph. Should hepatic filtration or
detoxification functions not be able to localize the process within
the splanchnic region, sepsis is further accelerated and septic
shock appears.
DIC develops as a result of activated coagulatory system. It
is defined as high thrombin activity and plasmin regulation dis-
order resulting in the development of hypercoagulation, degra-
dation and consumption of coagulation factors, inhibitors and
platelets.
Heart failure is the terminal stage of sepsis and its develop-
ment into the refractory stage of septic shock.
Risk factors predisposing to organ failure in patients with
necrotising pancreatitis still remain unclear to a certain extent.
In their retrospective study, Isenmann et al (1999) investigated
the relation between the extent of pancreatic necrosis, infection
and organ failure incidence. Their investigated set consisted of
273 patients with necrotising pancreatitis. According to the ex-
tent of necrosis assessed by use of CT they were divided into 3
groups. The first group consisted of patients with necrosis below
30 % of pancreatic tissue, in the second group the extent of necro-
sis was in range of 30–50 % and in the third group the necrotic
affliction exceeded 50 % of pancreatic tissue. The authors found
out that organ failure was more frequent in patients with infected
pancreatic necrosis when compared with patients with sterile ne-
crosis (Isenmann, 1999). The incidence of organ failure depends
on bacterial infection and extent of necrosis. The latter plays an
important role also in patients with sterile necrosis. Infected pan-
creatic necrosis is associated with high incidence of organ dys-
function disregarding the extent of necrosis (Isenmann, 1999).
In their study, Gloor et al analysed mortality in patients with
severe AP. The mortality associated with acute necrotising pan-
creatitis most frequently results from MODS, most frequently
up to 14 days from the onset of the disease and is associated with
septic complications in severe AP. The subjective of the study
was to analyse the course of the disease in patients who died due
to severe AP. The prospective study included 263 patients with
AP. All of them were monitored at ICU. The overall mortality
fluctuated about the level of 4 %. No patient died up to 14 days
from the onset of the disease. The median of death was the 91st
day (interval 15 –209). Ranson score, APACHE II score during
the first week of the disease, pre-existing comorbidity, BMI, in-
fection and extent of pancreatic necrosis were significantly asso-
ciated with mortality (Gloor et al, 2001).
Early death due to severe acute pancreatitis is rare, espe-
cially as a result of modern intensive therapy at ICU. In 90 % of
cases the death took place in more than 3 weeks after the onset
of disease. The infection of pancreatic necrosis is considered to
be the main risk factor of death (Gloor et al, 2001).
The multi-organ dysfunction syndrome developing after the
systemic activation of leukocytes is the main cause of death in
AP attack. In their study, Shokuhi et al investigated the levels of
selected inflammatory mediators. Plasmatic levels of IL-8 in AP
are increased. The levels of other chemokines as growth-related
oncogene α (GRO α) and epithelial neutrophil-activating pro-
tein 78 (ENA 78), which are also potential neutrophilic chemo-
attractants and activators have never been evaluated in a clinical
study.
306 Bratisl Lek Listy 2006; 107 (8): 296 – 313
The study included 51 patients with AP, of whom 27 patients
suffered from severe form and 24 patients had a mild form of AP
(according to Atlanta classification). Plasmatic samples were
gained, and assessed were the levels of CRP, IL-8, GRO-α
and ENA 78. Plasmatic levels of IL-8, GRO-α and ENA 78 were
increased in patients suffering from severe form of AP when
compared with those with mild form of AP. GRO-α and ENA 7
have an important role in the process of inflammatory response
in AP (Shokuhi et al, 2002).
Septic shock
Septic shock develops as a result of bacteriemia, sepsis (sep-
ticemia), infection of tissue or inflammation. Toxic substances
produced by microbes especially endotoxins (lipopolysaccharide,
LPS) of Gram-negative bacteria release endogenic vasodilators
with cardiopressive effect. Circulatory abnormalities and multi-
organ dysfunctions appear.
American Society of Critical Care Medicine (SCCM) defines
the septic shock as a syndrome characterized by hypotension and
hypoperfusion despite sufficient intake of fluid (Krkoška, 2001).
After their release into the circulation, microbes and prod-
ucts of inflammatory processes can cause a state referred to as
sepsis (septicemia). Its clinical manifestation includes fever,
tremor, tachycardia, tachypnoe, vasodilation and disorders of
consciousness of various extents. Concomitant development of
hypotension and hyperperfusion of organs is referred to as septic
shock. Hypoperfusion is the cause of diffuse damage incurred to
cells and tissues. When extensive, signs of damage within mul-
tiple necrotic foci begin to appear organ failure develops. In such
cases, patients die despite best care. Septicemia can develop due
to any abrupt infection; septic shock develops most frequently
due to infections caused by Gram-negative bacteria. The mortal-
ity due to septic shock achieves 70 % (Hulin et al, 2002).
Clinical manifestation of septicemia and septic shock resides
in mutual interaction of invading microbes and immune mecha-
nisms of the body. A vicious circle develops on the level of mi-
crocirculation, namely between the decreasing tissue profusion
and progressive deterioration of capillary endothelium. This pro-
cess incurs damage to the tissues. Should the vicious circle be
not interrupted, the state has a lethal outcome (Hulín et al, 2002).
The last stage of any type of shock including septic shock is
a state referred to as multi-organ failure. The severe form of AP
is typical for the development of MODS appearing soon after
the onset of the basic disease and with local complications, namely
with pancreatic infection usually developing after the acute phase
of disease. Despite successful intensive treatment, optimal sur-
gical treatment and possibilities of percutaneous endoscopic and
surgical drainage of infected necrotic foci, this disease is charac-
terized by high morbidity and mortality (Olejník et al, 2002).
Organ dysfunction (MODS) occurs in one fourth of patients
with AP. Mortality is associated with the severe form of AP in
range of 10 –60 % depending on the presence of sterile or in-
fected pancreatic necroses. The final result is basically deter-
mined by the intensity of early MOF, the extent of (peri)pancreatic
necrosis and the presence of infection within pancreatic necro-
sis, the incidence of which depends on the volume of necrotic
sites. In addition to introductory intraacinar activation of pan-
creatic proenzymes and damage incurred to local microcircula-
tion, it is the excessive stimulation of effectory immune cells
that is considered to be the critical pathophysiologic mechanism.
Its intensity influences the extent of local inflammatory response
and the secondary damage of retroperitoneal tissues.
The local inflammatory and necrotic processes are activated
by the complex of proinflammatory mechanisms and mediators
bringing on the secondary excessive systemic inflammatory re-
sponse (SIRS). This is currently considered to be the main cause
of early disseminated organ damage (MODS) (Rau, 2006).
The current knowledge of pathophysiologic mechanisms
participating in both local and systemic damage incurred to tis-
sue has been significantly widened; the supportive and empiric
treatment of such patients has changed into being more targeted.
New therapeutic procedures include early endoscopic sphinc-
terotomy with extraction of concrements in biliary AP, antibiotic
prophylaxis and/or selective digestive decontamination aimed at
decreasing the incidence of pancreatic infection. Therapeutic
restriction of exocrine pancreatic secretion and antiprotease
therapy failed in improving mortality in clinical studies despite
encouraging results in experimental pancreatitis.
It still remains unclear as to how to intervene successfully
into direct manipulation with glandular microcirculation. The
modulation of inflammatory response during the initial phase of
acinar damage should theoretically reduce the damage of far or-
gans and the extent of local necrotizing process serving as culti-
vation medium for bacterial proliferation should decrease, thus
the survival should improve.
The development of retroperitoneal inflammation (or even
necrosis) triggers the cascade of non-specific mechanisms of in-
flammatory response (Montravers, 2001). Should these mecha-
nisms exceed the area of primary damage within the tissue, their
destructive and reparative features are dislocated from retro-
peritoneum into other organ systems. The dominant role within
inflammatory damage incurred to microcirculation is played by
vascular endothelium, being the common and universal organ.
Endothelium is entitled to be referred to as an organ due to its
weight of 1500 g and the size of its surface. Its enzymatic, recep-
tor-bearing and humoral facilities are the measures of its func-
tions, even in case of systemic diffuse inflammation (Montravers,
2001).
Local mechanisms trigger and demarcate the inflamed site;
the systemic inflammatory response transfers the inflammatory
activity via humoral way into sites distant to the primary dam-
age. The starting site of distant damage is the endothelium (Hack,
2001). Cascade-like changes take place on molecular level even-
tually resulting in a uniform process of unfavourable changes in
local perfusion, infiltrative and inflammatory anatomic damage
incurred to tissues followed by deterioration of functions in in-
dividual tissues and organs (Telek, 2001).
HMGB-1 and septic shock. It has been recently found out
that there is a correlation between the stage of septic shock and
 Mifkovic A et al. Septic complications of acute pancreatitis… 307
HMGB-1 (high-mobility group B-1). HMGB-1 is not produced
and released at the beginning of septic shock. Its increase is ob-
served as late as after several hours or days. HMGB-1 can be
released into extracellular space where it acts as a pro-inflamma-
tory cytokine. HMGB-1 is a member of the big family of inflam-
matory proteins formed by intracellular proteins. Within the ex-
tracellular space, they serve as markers of necrosis. It is to be
said however that they enter the extracellular space either from
necrotic cells or by active secretion from macrophages and neu-
trophils. The complete biologic background of these necrotic
markers is not known. Depending on its level, the presence of
HMGB-1 is either beneficial or very harmful. High levels acti-
vate an extensive inflammatory response. HMGB-1 is a chemo-
tactic signal; it activates the neutrophils, monocytes, macrophages
and endothelial cells; it increases the expression of adhesive
molecules as well as of tissue plasminogen activator. HMGB-1
alters significantly the permeability of enterocytes; it is the cause
of collapsed intestinal barrier as well as of the translocation and
subsequent dissemination of bacteria throughout the body.
HMGB-1 released from necrotic cells in a large amount enhances
the multi-organ failure. The production of TNF increases in
several minutes, however the increased level of HMGB-1 ap-
pears as late as several hours after the onset of shock. From
this viewpoint HMGB-1 is probably the very factor that
„changes the shock“. Its experimental active production from
macrophages and neutrophils is observed 20 hours after the
stimulation. The plateau is reached within the range of 20-71
hours. Many experimental and clinical workers maintain that
HMGB-1 is the very factor, that is a sufficient trigger of lethal
multi-organ failure in septic shock. The experimental inhibi-
tion of HMGB-1 suppresses the development of septic shock
symptoms and increases the survival in experimental sepsis
(Hulín, Ïuriš, 2006).
The nervous system, through the vagus nerve, controls in-
flammation by decreasing the release of tumor necrosis factor-α
from endotoxin stimulated macrophages. This anti-inflammatory
effect is mediated by an interaction of acetylcholine, the princi-
pal neurotransmitter of the vagus nerve, with macrophage cho-
linergic nicotinic receptors expressing the α7 subunit. Tracey et
al realised an experimental study. This study provides the first
evidence for a therapeutic potential of the vagus nerve and the
“nicotinic anti-inflammatory pathway” in attenuating inflamma-
tion and injury during experimental pancreatitis (Tracey, 2006).
In patients who died due to septic shock, HMGB-1 serum
concentration was 84 pg/ml and in surviving patients it was 25
pg/ml. Each procedure decreasing the plasmatic level of HMGB-
1 increases the chance of survival. HMGB-1 and other molecu-
lar mechanisms have a significant impact on the course of shock
and they often “decide” its fate (Hulin and Ïuriš, 2006).
Infectious agents and antibiotics in septic complications of
acute pancreatitis
Bacterial translocation via the intestinal wall can possibly be
paracellular or transcellular. There are local and non-specific
mechanisms inhibiting the onset of pancreatic infection. Local
effects include the bactericidal character of pancreatic secretion
and rich lymphatic drainage of pancreas. Non-specific mecha-
nisms include normal peristalsis, intestinal mucin, enzymes and
immunoglobulin A, intestinal lymphatic system and balanced
composition of intestinal flora with anaerobic bacteria inhibit-
ing the intestinal adhesion and overproduction of pathogenic
Gram-negative bacteria. Bacteria that overcome the barriers are
killed within lymphatic nodes or by mononuclear phagocytic
system of liver (Büchler et al, 1999).
In the past, discussions took place as to whether the further
spreading and inoculation of pancreatic infection takes place ei-
ther via blood and lymph or it is mainly spread per continuitatem.
Finally it is held that the infection mainly spreads via blood and
lymph. Špièák (2005) proved that bacterial colonization within
lymphatic nodes increases with time, and achieves 100 % in 24
hours after inducing experimental pancreatitis in rats by admin-
istration of taurocholate.
The most frequent agents within the infected pancreatic tis-
sue or fluid collection include E.coli, followed by Klebsiella
Pneumoniae, Enterococci, Staphylococcus and Pseudomonas.
Anaerobic strains achieve only 10 % of all pancreatic infections.
Gradually, Gram-positive bacteria begin to prevail (Gloor et al,
2001).
According to Vivek (2000) the most frequent pathogens in
pancreatic infection include E. coli (25 –35 %), Klebsiella pneu-
moniae (24 %), Enterococcus sp. (24 %), Pseudomonas sp. (11–
16 %), Staphylococcus aureus (14 –15 %), Proteus sp. (10 %),
Klebsiella sp. in 10 %, Streptococcus aerob. (4 –7 %), Entero-
bacter sp. (2 –7 %), Bacteroides (6 %), Anaerobic (10–15 %).
In the past period several antibiotic substances have been
investigated as to their pharmacological kinetics. In addition to
their effect on the assumed pathogens ATB must have the ability
to increase its concentration within the pancreas. The penetra-
tion of ATB into pancreas was investigated in human pancreatic
tissue and within pancreatic secretion (gained at ERCP) under
physiologic conditions as well as under the condition of AP. Low
concentration of antibiotics within the secretion does not neces-
sarily mean low concentration within the pancreatic tissue (Špièák
et al, 1999).
Büchler et al (1992) published his study dealing with con-
centrations of individual antibiotics within the pancreatic resected
tissue compared with their concentrations within serum. He di-
vided antibiotics into three groups as follows:
1. Their concentrations as well as therapeutic effects are ab-
solutely insufficient (metilmicin, tobramycin).
2. It is assumed that they affect only some bacterial species
(mezlocilin, ceforaxim, piperacilin, ceftizoxim).
3. Their concentrations within pancreas are sufficient to elimi-
nate a majority of assumed microbial strains (ciprofloxacin,
ofloxacin, imipenem).
The effect of antibiotics is defined by three factors (Büchler
et al, 1992):
– Type of bacteria infecting the pancreatic necrotic tissue,
– Concentration of antibiotics within tissue,
308 Bratisl Lek Listy 2006; 107 (8): 296 – 313
– Percentage of inhibited bacterial strains at minimum in-
hibiting concentration of antibiotics.
As obvious, the theory of pancreatic infection precisely for-
mulated during the past 15 years has brought on the requirement
of massive ATB prophylaxis. The weak spot of this approach is
the selection of multi-resistant bacteria and an increased frequency
of fungal infection. The original fungal contamination of pan-
creatic necrosis did not exceed 5 %. Gloor et al (2001) published
their results indicating that the incidence of fungal infection in-
creased up to 21 % (12 –41 %). Mortality associated with fungal
superinfections ranged from 25 % to 64 %, the fact of which
was statistically significant in three studies when compared to
pancreatic infection with no fungal colonization (Gloor et al,
2001).
The significance of fungal infection is still under discussion
(Beger et al, 1999). The infection of necrotic tissue of pancreas
has acquired an increasing trend. Out of the total of infections of
necrotic tissue of pancreas, mycotic infections participate in a
range of 12 –24 % of cases (Isenmann et al, 2002). Most fre-
quently the involved agent is Candida albicans. The increase in
colonization is associated also with the invasive approach to
patients (cannulae, operations) as well as with frequent use of
antibiotics due to AP. The survival of patients with mycotic in-
fection of necrotic tissue of pancreas is worse and the mortality
is reported to be about 43 % (Isenmann et al, 2002).
In general there is a rule that fungal superinfection increases
with the duration of antibiotic prophylaxis. Regarding the given
problem some questions remain still to be answered, namely as
to how long the ATB prophylaxis should take, whether it is ap-
propriate to change it after some time, as well as to whether indi-
vidual mono-component or combined antibiotics should be ad-
ministered. It is a question if it is appropriate to include also an
antifungal medicament into prophylaxis (Mai et al, 1999). Medich
et al, (1993) administered fluorescent bacteria per os and after
the induction of pancreatitis they regularly isolated them from
pancreas, rarely from lymphatic nodes, whereas never from liver,
spleen or other organs.
Widdinson et al (1994) proved the presence of marked bac-
teria within the pancreas after their peroral administration. The
translocation of bacteria was effectively inhibited by the isola-
tion of bowl by plastic wrapping.
Antibiotic prophylaxis of AP Prophylactic administration of
ATB is a long-term (14 or more days) application of antimicro-
bial substance in order to inhibit or decrease infectious compli-
cations of severe necrotizing AP and to decrease the mortality.
Antibiotic prophylaxis is indicated only in severe form of AP,
namely in selected patients (Adam, 2001). The patient must ful-
fill the following criteria: extent of pancreatic necrosis in range
of 15–50 %; CRP over 120 mg/L; presence of solitary peripancre-
atic fluid collection; Ranson score over 3 or APACHE II over 6
as well as the presence of organ dysfunction. APACHE II score
alone is not a sufficient marker in the diagnosis of severe pan-
creatitis (Adam, 2001).
Pancreatic infection is the main cause of death in severe AP.
Antibiotic prophylaxis in AP is still subject to discussion and
investigation. First clinical studies did not record any positive
effect of prophylactic use of ATB on the course of disease and
results of therapy. These studies however did not include pa-
tients with mild course of AP, in whom septic complications ap-
pear rarely and the mortality is below 1 %. In the past years the
research has been focused on the finding of an antibiotic able to
decrease morbidity as well as mortality in necrotizing pancreati-
tis. Based on pharmacokinetic data of the large number of broad-
spectrum antibiotics, only those with the ability to reduce the
incidence of pancreatic infection were selected. The latter anti-
biotics included imipenem and chinolones (Büchler et al, 1999).
Based on results of multicentric control study, Imipenem is
considered to an ATB significantly able to reduce the incidence
of pancreatic infection in case that it was administered in pro-
phylaxis in patients with pancreatic necrosis. In this study, the
administration of ATB did not affect the mortality (Büchler et al,
1999). In a further control study Cefuroxime was used as a pro-
phylactic ATB. The authors recorded a significant improvement
in survival of patients with pancreatic infection (Büchler et al,
1999).
Control randomized studies unambiguously indicate that pro-
phylactic use of ATB with high factor (EF) in AP according to
given criteria leads to a significant decrease in the percentage of
septic complications from the range of 76 –80 % to that of 21–
27 %. In addition to the latter also mortality is significantly de-
creased (Büchler et al, 2002).
It is necessary to regard the fact that sterile necroses occur in
as many as 66 % of all cases of necrosis. It is necessary also to
consider the timing and period of ATB administration. The indi-
cation of antimycotic substances should be carefully considered
(Garg, 2001). Long-term ATB prophylaxis requires optimal se-
lection of the antibiotic drug (Gloor et al, 2001).
Strategy in using antibiotics in AP Antibiotic prophylaxis is
indicated in patients in whom it has been proved by CT that pan-
creatic necrosis takes over 30 % of pancreas or in patients with
CRP level over 150 mg/L. This means that about 80 % of all
patients with AP do not need prophylactic use of ATB at all.
Prophylactic administration of ATB is to be given at the begin-
ning of the disease. Pancreatic necrosis can develop up to 72
hours after the beginning of the disease, therefore it is necessary
to administer the ATB as soon as possible. The antibiotic drug
has to cover the whole microbial spectrum of the infected pan-
creatic necrosis (E. coli, Pseudomonas, Staphylococcus aureus,
Klebsiella, Proteus, Streptococcus faecalis, Enterobacter etc.).
To achieve the optimal tissue concentration of ATB and maxi-
mum inhibition of growth of bacteria within pancreas it is inevi-
table for the EF of antibiotic to reach values approaching most
closely that of 1.00. Antibiotic therapy has to last for the mini-
mum of 14 days, however it is appropriate to prolong the ATB
therapy up to three or four weeks because majority of pancreatic
infections occur after the fourteenth day (Büchler et al, 1999).
The current golden standard is based on the assessment of
ATB concentration within the pancreatic tissue in order to find
out the effect of therapy. The penetration of ATB into healthy
tissue of pancreas does not automatically guarantee good pe-
 Mifkovic A et al. Septic complications of acute pancreatitis… 309
netration into pancreatic necroses (Laws et al, 2000). Based on a
study of penetration of ATB into necrotic tissue it was discov-
ered that perforxacin, metronidazol and imipenem penetrate well,
whereas aminoglycosides have a low ability of penetration.
However, the sole penetration of ATB into tissue as well as
into necroses is not sufficient for the sake of successful therapy.
(Laws et al, 2000). The efficacy factor (EF) of ATB is assessed.
This factor includes good penetration into tissue as well as its
good effect on microbes. The value of 1 is an optimal factor. EF
of Imipenem is 0,98, followed by ofloxacin, ciprofloxacin,
mezlocilin and piperacilin (Sharma et al, 2001). Cefizoxim
and cefotaxim had good penetration; however they did not have
an impact on all bacteria (Sharma et al, 2001).
Surgical management in patients with infectious complica-
tions of acute pancreatitis
Lethality in severe form of AP remains high and ranges be-
tween 20 and 50 percent. The therapy has changed for several
times since the beginning of the twentieth century (Bank, 2002).
The opinions on surgical therapy of severe AP have also
changed during the past years. In 1980’s it was an aggressive
surgical approach that prevailed; in 1990’s the “wait-and-see”
approach was taken. Aggressive debridement between the sec-
ond and third weeks is recommended by “activist” surgeons. Con-
servative therapy is going to be chosen by “nihilist” surgeons.
Reasonable surgeons will operate as long as infection is proven
by FNA or when sterile necrosis does not resorb in 4 –6 weeks
(Büchler, 1999).
The prognosis of severe form of AP is affected especially by
early and high-quality intensive anti-shock therapy determining
the extent of damage within the pancreatic area and thus the fre-
quency, severity and extent of complications. On the other hand
neither the tactics of surgical therapy nor its timing should be
underestimated. Most frequent surgical complications of severe
forms of AP include internal pancreatic fistulae and abscesses,
followed by intestinal and biliary obstructions and vascular com-
plications. The therapy of abscesses, infected pseudocysts and
pancreatic necroses resides in intensive administration of ATB
and drainage of infected foci. Should the foci be appropriately
localized and well demarcated, as it is common in abscesses and
infected pseudocysts, it is possible to try percutaneous drainage.
Insufficient drainage and infected necroses lead to indication of
surgical revision and drainage (Olejník et al, 2002). In 1980‘s
Beger and Bradley produced a new conception of “debridement”,
i.e. removal of necrotic tissue.
The course of severe AP is characterised by two phases ac-
companied by two peaks of lethality. The early phase is charac-
terised by toxic and hypovolemic states and the death takes place
due to shock. The second later phase of shock is characterised by
local as well as systemic manifestations of infected pancreatic ne-
crosis. The prognosis is influenced especially by three factors:
– Extent of pancreatic and peripancreatic necrosis,
– Infection of necrosis,
– Toxic metabolites of pancreatic ascites (Špièák, 2005).
The infection of pancreatic necrosis is brought on in 30 –70
percent of patients at probability being proportionate to the ex-
tent of necrosis with the risk increasing at the beginning of the
second week of the disease (Špièák, 2005).
The strategy of surgical therapy in case of infected necroses
is based on assumptions as follows (Špièák, 2005):
– Fatal consequences of pancreatitis can be positively influ-
enced by removing the inflamed focus within the pancreas. This
interrupts the production of inflammatory mediators, toxins and
activated enzymes.
– The task of intensive therapy is to overcome the initial
phase of the disease in order to proceed into the stage when there
is a hope that drainage and debridement of the infected and
devitalised tissue can be successful.
– Early death takes place in the first week during the toxic
and hypovolemic phase of severe AP due to MOF. In this period
the lethality cannot be influenced by surgical intervention as its
causes cannot be affected by any operation.
Indication and timing of surgical therapy Traditionally it is
presented that absolute indication of surgical therapy is the proved
infected pancreatic necrosis. Early operation during the first two
weeks is indicated only in fulminant course with multiple organ
failure defying the conservative therapy and when the complica-
tion is defined and reparable. As the results of operations indi-
cated in this way are spurious, intensive effort should be exerted
to move into the further period of disease, in which due to gradual
demarcation of necrosis the hope of successful therapy increases.
The question as to how to proceed in fulminant course without
the infection of pancreatic necrosis being proved remains still
open (Špièák, 2005).
It is generally accepted that absolute indication of radical
surgical therapy is based on the proof of infected pancreatic ne-
crosis. As far as therapy of sterile necrosis is concerned the opin-
ions differ. The current strategy is “wait-and-see”. The necrec-
tomic approach in cases of sterile necroses was questioned for
the first time by Smadja and Bismuth who have proved that sub-
sequent lethality is higher when compared with the control group
that has not been operated on.
When reviewing available literature, Widdinson et al discov-
ered that when there was no secondary infection of pancreas, the
lethality in 130 patients surgically treated due to sterile pancre-
atic necrosis was 7.1 %. However the lethality in 26 patients
(20 %) with secondary infection achieved 57 %. Six of 23 pa-
tients surgically treated for sterile necrotising pancreatitis devel-
oped secondary infection with lethality of 50 % (Uomo et al,
1996).
Regarding the successful therapy and the achievement of good
prognosis in patients with AP it is the performance of perfect
surgical management that determines successful therapy. The
emphasis has to be put on the strategy of treating the primary
inflammatory focus and the prophylaxis and therapy of multiple
organ failure.
In the past the main part of therapy of pancreatic necrosis
was represented by necrosectomy. Today early surgical interven-
tion in acute pancreatic necrosis is performed more frequently in
310 Bratisl Lek Listy 2006; 107 (8): 296 – 313
infected necrosis and/or if multiple organ failure develops. In
patients with infected necrosis mortality without surgical inter-
vention achieves 100 % and with operation it fluctuates in the
range of 19 –82 % ( Büchler, 1999).
The task and timing of surgical intervention remain open to
dispute. Some surgeons tend to perform early extensive pancre-
atic resections, others prefer active intensive conservative therapy
at an ICU while necrosectomy is performed when the infection
of necrosis is proved. The mortality in conservatively treated
patients with extensive pancreatic necrosis is fluctuating about
the level of 10 %. Surgical intervention does not reduce the mor-
tality (Büchler, 1999).
The possibilities of surgical methods of therapy of pancre-
atic necroses vary. The best method still remains open to dis-
pute. Conventional surgical drainage consists of open packing
with planned reoperations, i.e. open management is involved.
New techniques use debridement with local continuous high-
volume lavage therapy. In such cases closed management is in-
volved. Due to high mortality a majority of authors have backed
away from conventional surgical approach. Repeated operations
often remove all necrotic pancreatic tissue. Timing of surgical
performance is still open to dispute, however a majority of sur-
geons prefer to delay the intervention in order to have better
tissue demarcation during operation (Büchler et al, 1999).
Strategy of treatment of the primary focus Regarding the
universal mechanism of primary damage of organs in MODS,
the prevention of its development is principally based on the
localisation of peripancreatic inflammatory source. Correct in-
dication and timing of the surgical intervention are as a rule
the factors determining the survival of patients. Should dynami-
cally proceeding symptoms of organ failure be present, they
predetermine the time in which it is possible to surgically in-
tervene. After excluding other direct causes of the proceeding
extrapancreatic organ failure (hypovolemia, hypoxemia, acute
coronary attack, pulmonary embolism) it is necessary to con-
sider the primary inflammatory focus to be the source of dif-
fuse non-bacterial inflammatory reaction that manifests in other
organ systems. In this situation it is necessary to sensitively
consider the benefit of e.g. drainage and lavage of retrope-
ritoneum against the possible infection of the inflammatory
focus. There is no algorithm able to evaluate the complexity of
the state and to define unambiguously the surgical approach.
However it is certain that the conservative approach is not able
to stop the progression of MODS. At the same time the in-
creased risk of secondary infection of peritoneum and retro-
peritoneum with a significantly increased morbidity are accepted
(Olejník, 2002).
Prophylaxis and therapy of multiple organ failure Symptom-
atic maintenance of functions of threatened organ systems is
a significant factor of the final result of disease. Concomitant
failing/ failure of one organ is statistically expressed by an in-
crease in morbidity by 16 –22 % (Olejník, 2002). That is why
the monitoring and protection at least of the remnant functions
of particular organ is of vital value. The primary interest should
be focused on circulation and ventilation. They are mutually as-
sociated and dominant in the cascade of systemic transport of
oxygen to tissues. The decrease or depletion of their functional
reserve represents a high risk of another joined mechanism of
any organ damage – tissue hypoxia.
Diagnostic and indicative categorisation with multisystemic
prophylaxis and therapy are components of complex care of pa-
tients with severe form of AP. Patients with this diagnosis be-
long to the category of critically ill patients. The acceptance of
this statement gives reason for multidisciplinary coordination in
the diagnosis, deciding on therapy in patients with AP. The knowl-
edge of strategic diagnostic and therapeutic steps is crucial for
their correct timing and early performance.
Percutaneous necrosectomy Percutaneous necrosectomy is
considered to be a minimally invasive technique of removal of
residual debris from pancreas (Moon-Tong Cheung, 2005). Sev-
eral patients suffering from pancreatic necrosis have been sub-
ject to retrospective investigation. In these patients percutane-
ous pancreatic necrosectomy (PPN) was performed after PCD.
The necrotic cavity in these cases defied healing. After percuta-
neous necrosectomy the necrotic cavity healed up in majority of
patients, the rest of them required surgical revision. PPN is ad-
vantageous in patients whose necrosis is “organized” after the
attack of acute pancreatitis. Should symptoms and the cavity re-
main, the residual necrotic material is to be removed.
For the first time, PPN was introduced by Carter in 1993 in
order to remove residual necrotic material in patients after unsuc-
cessful PCD. This minimally invasive approach has an advantage
in the decrease in morbidity and mortality which is associated with
conventional surgical intervention (Moon-Tong Cheung, 2005).
IAP regulations of surgical management of AP In 2002 the
International Association of Pancreatology (IAP) developed evi-
dence-based regulations of surgical management of AP (Uhl et
al, 2002). These regulations contain 11 rules as follows:
1. Mild AP is not an indication for pancreatic surgery.
2. Prophylactic use of broad-spectrum ATB reduces the risk
of infection in CT-proved necrotizing pancreatitis, however does
not have to necessarily improve the survival.
3. Fine-needle-aspiration for bacteriologic examination has
to be performed in order to distinguish sterile or infected pan-
creatic necrosis in patients with signs of sepsis.
4. The presence of infected pancreatic necrosis in patients
with clinical symptoms of sepsis is an indication for surgical
intervention or radiologic drainage.
5. Patients with sterile pancreatic necrosis (with negative
result of fine-needle bacteriologic aspiration) have to be treated
conservatively and only selected cases have to be subject to in-
tervention.
6. Early surgical intervention up to 14 days from the onset of
the disease is not indicated in patients with necrotizing pancre-
atitis. It has to be done only in particular specific cases.
7. Surgical approach and other interventions have to pre-
serve pancreas including debridement or necrosectomy combined
with postoperational management, the fact of which maximizes
postoperative evacuation of retroperitoneal debris and exudate.
 Mifkovic A et al. Septic complications of acute pancreatitis… 311
8. Cholecystectomy has to be done for the purpose of avoid-
ing the development of biliary AP.
9. In case of mild biliary pancreatitis it is necessary to per-
form cholecystectomy as soon as possible after recovery, ideally
during one single hospitalization.
10. In severe biliary AP it is necessary to delay cholecystec-
tomy to the period after the fading of inflammatory response and
after clinical recovery of patient.
11. Endoscopic sphincterotomy is an approach alternative to
cholecystectomy in patients who are not able to be subject to
surgical intervention. In this way the risk of recurrent biliary
pancreatitis is reduced.
Japanese regulations of surgical management of AP Japa-
nese regulations of surgical management of AP (Isaji et al, 2006)
are summarized in the following rules:
1. By use of CT or USG-conducted FNA for bacteriologic
examination is to be performed in all patients suspicious of in-
fected pancreatic necrosis.
2. Infected pancreatic necrosis associated with the symptoms
of sepsis is an indication of surgical intervention.
3. In case of necrotizing pancreatitis it is necessary to per-
form early surgical intervention.
4. Patients with sterile pancreatic necrosis have to be treated
conservatively and surgical intervention has to be performed only
in selected cases, especially in sustaining organ complications
or in severe clinical state despite maximum intensive care.
5. In necrotizing pancreatitis it is necessary to perform early
surgical intervention.
6. In infected pancreatic necrosis it is necessary to perform
necrosectomy.
7. After the performance of surgical nerosectomy simple
drainage should be avoided; continuous enclosed lavage or open
drainage should be done.
8. In case of pancreatic abscess it is necessary to perform
surgical or percutaneous drainage.
9. When the clinical state after percutaneous drainage of pan-
creatic abscess is not improving it is necessary to perform surgi-
cal drainage.
10. Pancreatic symptomatic pseudocyst, pseudocyst with
concomitant complications and increasing diameter of pseudocyst
signal the need of percutaneous or endoscopic drainage.
11. Pancreatic pseudocyst having no tendency of healing af-
ter percutaneous drainage or endoscopic drainage has to be solved
surgically.
Conclusion
In majority of cases the course of AP is mild with minimum
complications associated with pancreatic edema. In severe cases
there is a high risk of pancreatic necrosis that subsequently can
succumb to infection. This state is usually the most frequent cause
of death after severe AP.
Early morbidity and mortality is the result of activated vaso-
active mediators with subsequent failure of circulation, respira-
tory and renal insufficiencies. Progress in the field of intensive
medicine reduces the early mortality due to AP; the overall mor-
tality in patients with acute necrotizing pancreatitis is in the range
of 10–15 %. Secondary pancreatic infection and sepsis develop
in 40 –70 % of patients with 80 % mortality. Pancreatic infec-
tion is caused by bacterial contamination of pancreatic necrosis.
In 24 % of cases the infection is usually recorded in the second
week of the disease and in 71 % during the fourth week of dis-
ease. The incidence of secondary infection correlates with the
extent of pancreatic necrosis. The prevention inflammation, in-
fection and sepsis by systemic administration of antibiotics is
considered the principal step in the therapy of AP.
Pancreatic infection is closely associated with the develop-
ment of pancreatic necrosis. Infection occurs very rarely in the
absence of necrotic tissue. Bacterial infection is in the most cases
caused by bacterial translocation from the bowls into pancreatic
necrosis. In this process the main role is played by three main
factors as follows: decreased intestinal motility together with
disturbed intestinal flora, impairment of the barrier function of
intestinal mucosa and the impaired function of immune system.
The causes of disturbed motility of small intestine in acute pan-
creatitis have not yet been unambiguously clarified. The alter-
ation of intestinal barrier can be the subsequence of impaired
microcirculation and ischemia. The significant role in the patho-
genesis of AP is played by oxygen radicals.
Should we succeed to understand better the effect of several
pathologic mechanisms which in the long run lead to bacterial
translocation, it will be possible in the future to develop thera-
peutic modalities that would prevent pancreatic infection.
The diagnosis and further monitoring of the course of AP is
mainly based on the measurement of CRP levels, serum amy-
lases and lipases. The imaging modalities in particular include
CT and USG.
The therapy of septic complications of acute pancreatitis can-
not do without conventional surgery; however there are several
indications when it is appropriate to use the possibilities of
interventional radiology and endoscopic therapy.
The complex therapy in patients with septic complications
of AP requires multidisciplinary cooperation of surgeons, gas-
troenterologists, radiologists, internists and anaesthesiologists.
Good mutual cooperation and correct timing of individual thera-
peutic interventions can bring recovery in this disease that is
very often unpredictable.
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Received June 5, 2006.
Accepted June 29, 2006.