Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1649_Библиотеки_им_академика_М_И_Перельмана.pdf
Management of Acute Biliary Pancreatitis
111
The disease is characterized by different degree of severity from a mild
edematous – interstitial inflammation, as a self – limiting disease, to a severe
type with local necrotizing inflammation and systemic complications as
systemic inflammatory response syndrome (SIRS) and organ failure.
AP is one of the most common gastrointestinal diseases. Annual incidence
worldwide is 4, 9 – 73 cases per 100.000 people/year with an increase in the
annual incidence in many countries [1].
The data from England, Denmark, US report the incidence of AP from 4,
8 to 24, 2 cases per population of 100.000 [2].
There is certainly an increase due to better clinical and diagnostic
knowledge of the disease, at the same time with real increase of pancreatitis.
The incidence of Acute biliary pancreatitis (ABP) per year has been
reported by different communications between 4, 9 to 80 cases per 100.000
people and also has been increasing over the past two decades [3].
PATHOPHYSIOLOGY
AP is an inflammatory disease characterized by various degrees of
pancreatic and peripancreatic tissues damage varying from edema,
inflammation, parenchymal cells injury, necrosis.
AP develops from autodigestion processes of the gland accomplished by
enzymes that have been inappropriately activated in the gland. Trypsin first
and the activation of other pancreatic proenymes follows (proelastase,
chemotrypinogen, ecc…). The enzymes activation in the pancreatic
parenchyma, that is the pancreatic acini, is the basic and initial process of
pancreatitis of all etiology. The first consideration is about the sequence of cell
events.
Normally digestive pancreatic enzymes are secreted by acinar cells as
inactive proenzymes into pancreatic ductal system and subsequently into
duodenum where the activation [4] takes place of trypsinogen to active trypsin
by enterokinase and low duodenal pH.
Many theories has been proposed for explanation of pathophysiology of
AP. The most likely sequence of events indicates the alteration of exocytosis
(the discarge of pancreatic enzymes in the acinar lumen), the block of
secrection of newly synthetized enzymes, the formation of condensing
vacuolis (fusion of newly synthetized zymogens and lysosome with
hydrolases). Finally the contact between lisosomal hydrolases and pancreatic
Vincenzo Neri
112
enzymes allows the intracellular activation of trypsin and other pancreatic
proenzymes [5].
ETIOLOGY
Etiologic factors of AP are various and with different frequence and
geographic distribution.
Most frequent causes are biliary obstruction and alcohol consumption that
are confirmed in almost 80% of patients; the remaining 20% comprises
pancreatitis with various etiologies. In summary the etiologies of AP can be
subdivided:
genetic causes hereditary pancreatitis;
obstructive causes:
biliary pancreatitis: gallstones/papillary stenosis;
tumours;
pancreas divisum;
metabolic causes:
alcohol;
hypercalcemia;
hyperlipidemia;
drugs.
In this presentation our attention should be focused on biliary causes.
The pathologic sequences of acute biliary pancreatitis (ABP) can be
hypotized: the gallstones passage through the duodenal papilla or subsequent
papillary edema causes obstruction at the ampulla also temporary, damaging
the biliary flow with the bile reflux into the pancreatic duct leading the start of
the pancreatitis [6, 7, 8, 9].
The hypothesis has been proposed in the past [10] and so far always
shown but there are some details not well classified: the confluence in a
common duct in the ampulla of biliary and pancreatic ducts is frequently but
not always present (70 – 85%) [11]; moreover the stones impacted at the
ampulla have been reported in less than 5% of the patients with AP [12].
Probably the papillary obstruction should be in most cases temporary due
to the passage of biliary sludge, small stones (<5 mm), microlithiasis wich can
cause a transient papillary obstacle but enough to cause bile reflux into
Management of Acute Biliary Pancreatitis
113
Wirsung duct and start pancreatitis. Moreover we must also consider the
edema and papillary stenosis, injury so stable, that can persist the obstacle. In
the obstructive hypothesis of the pathophysiology of ABP we have to clarify
which formality allows the onset of pancreatitis.
The papillary obstruction causes the bile – pancreatic duct blokage with
two crucial consequences: the bile reflux in pancreatic ductal system and
hypertension of bile and pancreatic juice based on the increase of the serum
level of cholecystokinin and also on obstruction of ampulla. Cholecystokinin
stimulates the acinar pancreatic cells and hepatocytes to promote the
secrection of bile and of pancreatic juice with pancreatic digestive enzymes.
The consequent intraductal hypertension (biliary and pancreatic) and the
papillary obstruction allow the bile reflux in the pancreatic duct system [13,
14].
The role of genetic factor should be evaluated in the onset and evolution
of AP. The mutation of gene SPINK1 (serine protease inhibitor Kazal type 1)
can predispose to pancreatitis because this gene has function as a critical
feedback inhibitor of trypsin.
DIAGNOSTIC ASSESSMENT OF BILIARY ETIOLOGY OF AP
The etiological assessment can be a guide in the therapeutic programmes.
The clinical appareance of ABP should be defined on the basis of detailed
history and careful physical examination. Prior hystory of biliary colic, should
be an appropiate data. Clinical picture consists of nausea, vomiting,
tachycardia, tachypnea, hypertermia and abdominal pain in mesogastrium
radiating through the back with abdominal wall tenderness superficial or
depth, and muscolar rigidity of varying degrees. Pleural effusion, particulary
on left side, can be present. Auscultation shows bowel sounds decreased or
absent. In the diagnostic criteria there are also characteristic laboratory data
such as serum amylase and lipase >3 x upper limit of normal.
Serum amylase increases at the onset of the disease and decreases in a few
days (3-5 days); on the contrary the lipase tends to remain elevated for longer.
The increase level of serum amylase has not correlation with severity of
pancreatitis.
Several laboratory tests contribute to define biliary etiology of
pancreatitis: first of all the liver function tests (AST, ALT, ALP, yGT,
bilirubin), fasting serum calcium and lipid profile.
Vincenzo Neri
114
In particular among liver function tests ALT had a positive predictive
value of 95% in diagnosis of acute gallstone pancreatitis [15]. The imaging
exams play the central role in the etiological assessment of pancreatitis. At the
first level abdominal US may demostrate gallbladder lithiasis and/or
gallstones, sludge, microlithiasis, etc. in the common bile duct (CBD) or also a
dilatation of the CBD (>8mm) and impacted CBD stone. Nevertheless van
Santvoort [16] and our privious report [17] demonstrated that CBD dilation
>8mm had poor sensitivity, specificity, PPV, NPV.
On the contrary the association of increased liver function tests and
gallbladder stone on US reach a sensitivity of 97% and specificity of 100% in
the diagnosis of ABP.
At the second level of imaging exams there are contrast enhanced CT and
MRI. Both these instrumental exams have double diagnostic role: the
assessment of pancreatic parenchima damage, involvement of pancreatic
tissue, presence of fluid-necrotic collections and on the other hand the
detection of bile stones, CBD dilatation, that is to recognize biliary origin of
pancreatitis.
EVOLUTION OF ABP
AP in the majority of patients (70-80%) occurs as a mild-moderate
disease; on the contrary 20-30% shows a severe course. Moreover within the
severe forms, approximately in 20% of the cases, development of persistent
organ failure and/or of infected pancreatic collections necessitates the
definition of the most severe forms, identified as critical, early severe acute
pancreatitis [18, 19].
The clinical appearance of the critical forms shows a very severe disease
with early hypoxaemia, progressive multiple organ dysfunction, compromised
computed tomography severity index (CTSI), increased incidences of necrosis,
infection, and sometime abdominal compartment syndrome (ACS). In
summary the critical forms of pancreatitis are characterized by a short course
and very high mortality rate, to 40% [20, 21].
Severe acute pancreatitis can be seen as a biphasic disease, with the first
phase –first two weeks- characterized by early toxic–enzymatic injury, SIRS
and a late phase –third and fourth week- characterized by septic complications
of necrotic tissue and of pancripancreatic fluid necrotic collections.
Management of Acute Biliary Pancreatitis
115
The first phase of pancreatitis can develop in most cases with disease
quickly responsive to intensive care based on aggressive rehydratation.
On the contrary several cases can quickly evolve into SIRS and multi
organ dysfunction syndrome (MODS).
The most relevant clinical feature of AP is the progress and worsen from
local disease to general involvement. The key of this evolution is the tissue
response of the pancreas acinars cell necrosis. Locally the phlogosis directs the
actviation of macrophages and attraction of activated polymorphonuclear cells.
SIRS can develops from the passage of inflammatory mediators (pro-anti
inflammatory mediators released from the splanchnic area) to systemic
compartments by lymphatic system, portal vein, and general circulation.
Vascular alterations cause gut barrier failure with bacterial translocation and
endotoxin diffusion. The final results are distant MODS and generally later
infection of fluid-necrotic pancreatic-peripancreatic gatherings [22, 23, 24, 25,
26, 27, 28, 29, 30].
Revised Atlanta Criteria [19] indicate that peripancreatic necrosis can be a
risk factor for worsening of severe acute pancreatitis and some data from the
literature suggest that it may occurs also with minimal pancreatic necrosis
[31].
Visceral fat lypolisis in peripancreatic necrosis, as peripancreatic fluid-
necrotic collections causes lipotoxicity of unsatured fatty acids (UFAs) that are
elevated in biliary severe acute pancreatitis with high level of unsatured
triglicerides (UTGs). The increased UFAs cause organ failure including acute
lung injury, renal tubular toxicity, renal failure and hypocalcaemia [32, 33,
34]. Peripancreatic necrotic gatherings with “production” of UFAs cause
MODS and consiquently increased mortality, converting mild/moderate acute
pancreatitis in severe or early severe pancreatitis indipendent of pancreatic
necrosis, underlining that the mild onset of the disease can develops in the
severe form [35].
EARLY ASSESSMENT OF ABP
The severity of ABP at the onset varies from mild forms, with no systemic
or local complication, moderate forms with morphologic, local evidence of
disease and systemic complications such organ failure but with quick
resolution (within 48 hours) and finally severe forms with persistent organ
Vincenzo Neri
116
failure [19]. Mild panreatitis has generally favorable evolution without
mortality risk; in the moderate forms there is minimal risk of mortality. Finally
in the severe forms the risk of mortality increase to 15-40% with the general
involvement as SIRS and MODS [36]. The severity of pancreatitis has been
assessed by several scoring system [20].
Table 1.
Unifactorial markers of severity most recurrent in the literature
Sensibility
Specificity
VPP
VPN
Accuracy
References
CRP
(> 150mg/L at
24 and 48h)
57-94.1%
60-90%
36-90%
75-95.7%
76-80%
[37, 38, 39-
48]
TAP
Urinary
Trypsinogen
Activation
Peptide
(increased at
admission and
after 12h)
58-100%
73-89.7%
39-
78.6%
85-96.3%
---
[37, 46-52]
Procalcitonin
(> 160
fmol/mL at
admission)
infected
pancreatic
necrosis
marker
altered
permeability
of gut barrier
marker
67-100%
20-89%
55-
64.7%
82.6-93%
85%
[40, 53-60]
Hct
(at admission
and after 24h)
cut off: 43% M
– 39% F
61-74%
38-45%
24-37%
61-97%
---
[61-64]
Hyperglycemia
(>125mg/dL)
pancreatic
necrosis
index
complication
index
83-100%
49%
28%
92-100%
---
[63, 65-67]
Management of Acute Biliary Pancreatitis
117
Table 2.
Multifactorial bioclinic scores
Sensibility
Specificity
VPP
VPN
Accuracy
References
Ranson
33-83%
79-98%
45-83%
86-95%
78-89%
[68, 69 ,
70, 71-82]
Glasgow
33-83%
79-98%
45-83%
86-95%
78-89%
BALI (after
48h)
BUN >
25mg/dL
Age > 65y
LDH >
300U/L
IL6 >
300pg/dL
18%
98%
---
---
---
APACHE II
> 7
52-62%
77-86%
46-57%
84-88%
---
APACHE II
> 9
50-75%
69-72.4%
20-52.9%
87.5-
89%
---
Simplified
prognostic
tests
Lypasemia
Calcemia
Glycemia
WBC
71.4%
75.5%
---
---
---
MOSS/OF
Correlation with outcome / indirect index of severity
Simplified acute physiology score
Predictive model for the final result
Age
High creatinine in 72h
mechanical ventilation
chronic impairment
Renal and respiratory failure
Predictive factors of severity, except clinical evaluation, may be divided
into direct and indirect. The direct factors are morphologic based on
anatomical compromission of the pancreas and assessed by imaging exams
(US, CT, MRI). The indirect methods can be subdivided in monofactorial and
multifactorial. The first (monofactorial) can make the prognostic assessment
by means of single laboratory marker. These consist of several hematic,
urinary biochemical data that can be early detector of systemic inflammatory
response and multiorgan failure. In the Table 1 we report the monofactorial
Vincenzo Neri
118
markers more reported in the literature. Into these markers are reliabe and very
early CRP, TAP (urniary trypsinogen activation peptide), procalcitonin.
The multifactorial prognostic scoring systems consist of Ranson and
Glasgow scores, specific for the pancreatitis and APACHE II score which is
not specific. In the Table 2 had shown the multifactorial severity scoring
system most employed in the practice.
Should be useful the distinction between the single factors or the
multifactorial scores that are reliable only at the onset of pancreatitis attack or
on the contrary active and effective late after 24-48 hours from the onset when
the general impairment has already made.
The new scoring systems meet the need to assess severity of disease
within the first 24h. The Harmless Acute pancreatitis score [83], aims to
identify the mild/moderate pancreatitis. On the other hand there is the Bedside
index of Severity in Acute pancreatitis (BISAP) [84] based on the evaluation
of 5 criteria: blood urea nitrogen (BUN) > 25mg/dL, age >60 years, impaired
mental status, SIRS and pleural effusion. For BISAP a score of > 2 is
associated with a 10 fold increase in mortality risk. Beside mono –
multifactorial scores there is the morphological/pathological evaluation of the
pancreas and peripancreatic tissues by imaging exams: US, TC, MRI. The
imaging exams are very important for the pathological definition of
pancreatitis, and prognostic – therapeutic evaluation, but are not useful for
early assessment of severity because the complete evolution of the pancreatic
and peripancreatic damage generally can develop within 24-48 hours [85, 86,
87]. The US provides guidance informations, nevertehless the CT represents a
valuable method to identify the degree of pancreatic impairment.
CT images obtained within 72 h of onset allow the use of CTSI and
modified CT severity index (MCTSI) with Balthazar scoring for grading of
acute pancreatitis and points for necrosis. The classification is based on
morphological and functional feature: local or diffuse enlargement of the
pancreas, pancreatic gland abnormalities, peripancreatic inflammation with
pancreatic and peripancreatic fluid collections and areas of non-enhanced
parenchyma (that is necrotic). The imaging evaluation should be integrated
and completed always within 24-72h by CT assessment of pancreatic size
index (PSI), extra pancreatic inflammation on CT index score (EPIC) and
extra-pancreatic score (EP) [88]. There are valuable differences between
clinical and laboratory prognostic scoring systems and radiologic prognostic
scoring systems. The first should detect early the severe evolution of the
disease providing the prognostic evaluation. On the other hand imaging exams
as CT or MRI have certainly a diagnostic role and provide a prognostic
Management of Acute Biliary Pancreatitis
119
evaluation but also are very useful for detecting degree of pancreatic and
peripancreatic damage and complications and finally they guide the
indications for surgery and interventional procedures. Bollen and coll [89].
compared CTSI, MCTSI with APACHE II index. They showed any significant
differences between MCTSI and CTSI in evaluating the severity of AP.
Clinical scoring systems correlate with organ failure and mortality whereas
radiologic scoring systems diagnose carefully the severity of pancreatitis and
better define the need for surgical procedure.
In summary the evaluation of severity of AP should employ several
detector following the onset and development of acute attack. At the admission
can be useful BUN, hematocrit, procalcitonin, chest x ray; at 24 – 48h, BISAP,
Ranson, Glasgow score, APACHE II; after the 48h MCTSI and CTSI. MRI
provides images and pathological data overlappable to CT.
THERAPEUTIC APPROACH OF ABP
The therapeutic program of ABP should follow the evolution of the
disease.
The first approach, usually based on medical treatment, is overlappable for
pancreatitis of any etiology.
The various differences in the early therapeutic approach are conditioned
by the clinical feature of the pancreatic attack.
Acute pancreatitis can develop with a wide range of disease, ranging from
mild form to a severe or early severe, rapidly progressive illness.
Mild acute pancreatitis usually is a self limiting form developing only
pancreatic and/or peripancreatic oedema without change of the enhancement
of pancreatic parenchyma on contrast enhanced CT (CECT). The medical
treatment includes as main measure the intravenous fluid replacement; in
summary it is usually conservative.
The aims of the treatment of mild moderate ABP are the following:
control of pain, fluid electrolyte replacement, nutrition, removal of the
persistent papillary obstacle. In the first phase at the onset the severe and early
severe forms of ABP can show a clinical picture with local and/or systemic
complications. The clinical severity corresponds to degree of pancreas
impairment assessed with Balthazar score. Usually this score ranges between 5
to 8. The major morbidity is linked to simple organ dysfunction or worse, to
MODS, with hypoxaemia. It can also manifest pancreatic sepsis and ACS; the
latter require urgent surgical intervention. These formes require management
Vincenzo Neri
120
in intensive care. In early severe formes there is a great compromission of
general conditions by early toxic – enzymatic injury and high rate of early
mortality (more than 10%). The later phase of the disease (third and fourth
week) is characterized by septic complications of pancreatic or peripancreatic
fluid – necrotic collections. In the severe forms the therapeutic approach is
more complex with early fluide resuscitation for the correction of hypovolemia
[90]. Hypovolemia is due, over the all, to third space extravasation, secondly
to vomiting, respiratory losses, and diaphoresis. The specific purpose of the
correction of hypovolemia is to avoid the decrease of macro/microcirculation
and sequently the cascade of events leading to pancreatic necrosis [91].
The early fluid administration is the first line therapeutic approach and
should be adequate in the severe forms of the disease to reach the beneficial
effects. The fluid resuscitation with lactated Ringer’s solution showed more
resolutive effects on development of severe acute pancreatitis based on major
balancement of pH with reduction in the SIRS evolution and levels of CRP.
Attentif care should be raccomended on early fluid administration: we
should be carefully consider the need of aggressive fluid therapy at the onset
because it can be detrimental in the patients without fluid depletion or with
chronic cardiovascular comorbidities.
The pain control can be accomplished, following the severity of the pain,
by administration of non-steroidal, antinflammatory drugs (NSAIDs) as a first
line, and then opioids. The pharmacological control of the pain should be
considered a very important object in the treatment of AP.
In the therapeutic program of AP the bowel rest is the most debatable
mesaure. This therapeutic choice is still present in the clinical practice, (but
not with defined diffusion) and also reported in the literature [92].
The pathophisiology of severe acute pancreatitis proves that risk of
pancreatic and peripancreatic fluid necrotic collections contamination comes
from bacterial translocation. The bacterial translocation is due to failure of
integrity of gut barrier based on morphological changes in the gut associated
with fasting, bacterial overgrowth, motility changes, immunosoppression.
Several studies show that enteral nutrition in the severe acute pancreatitis
(such as parenteral nutrition), should be used with the improvement of severity
evolution and clinical outcome of the disease [93].
The great variety of acute pancreatitis in severit grade, type of
complications and patients comorbidities makes difficult the choice between
enteral or parenteral nutrition. In summary Italian guidelines recommend using
enteral nutrition rather than parenteral nutrition in severe acute pancreatitis or