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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1649_Библиотеки_им_академика_М_И_Перельмана.pdf
Acute Pancreatitis in Childhood
11
association between chronic renal failure in children and acute pancreatitis in
children deserves further study.
4.9. Special Considerations in Acute Recurrent Pancreatitis
As eluded above (4.7), the frequencies of the various aetiologies differ
depending on whether the individual has had recurrent episodes of pancreatitis
or a single event only. In the setting of acute recurrent pancreatitis, the two
most common aetiological factors were identified to be genetic (48%) and
anatomic anomalies (30%) (41 [accepted]). As such, investigations to evaluate
for these factors should be considered in children who present with more than
one episode of acute pancreatitis.
5. DEFINITIONS AND DIAGNOSIS
5.1. Definitions
With the primary aim of standardising the reporting of paediatric acute
pancreatitis, as well as to encourage communication with the different
specialists (namely: surgeons, radiologists and paediatricians) using the same
“language,” a shared definition of acute pancreatitis was required. However,
until 2012, no uniform terminology had been described in the literature to
define acute pancreatitis in children. For this reason, The International Study
Group of Paediatric Pancreatitis: In Search for a Cure (INSPPIRE) consortium
worked to establish recommendations for the diagnosis of acute pancreatitis,
acute recurrent pancreatitis and chronic pancreatitis. These definitions were
based on expert opinions gathered through the prism of adult studies due to the
sparse paediatric literature. The work was mainly based on the revision of the
Atlanta classification [41]. The results of the consortium proposed that
paediatric acute pancreatitis, acute recurrent pancreatitis and chronic
pancreatitis should be defined accordingly (Table 1).
5.2. Diagnosis
Having a standardised definition of acute pancreatitis is crucial not only to
provide specific criteria for the purposes of making a diagnosis but also to
Gilles Duvoisin and Chee Yee Ooi
12
enable future evaluation and research studies on the same condition using the
same criteria. However, the three main components of the definition/
diagnostic criteria are worthy of discussion.
Table 1. Definitions of acute, acute recurrent and chronic pancreatitis [17]
Acute Pancreatitis
At least 2 of the 3 items:
a) Abdominal pain suggestive of, or compatible with acute pancreatitis
b) Serum amylase and/or lipase activity at least ≥3 times upper limits of normal laboratory
range
c) Imaging findings characteristic of, or compatible with acute pancreatitis
Acute Recurrent Pancreatitis
At least 2 episodes of acute pancreatitis (as defined above), along with:
Complete resolution of pain (1 month pain-free interval the diagnoses of acute
pancreatitis)
OR
Complete normalization of serum pancreatic enzyme levels (amylase and lipase),
before the subsequent of acute pancreatitis is diagnosed, along with a complete
resolution of pain syndrome, irrespective of a specific time interval between episodes of
acute pancreatitis.
Chronic pancreatitis
At least one of the following 4:
a) Abdominal pain consistent with pancreatic origin and
imaging findings
1
suggestive of chronic pancreatic damage.
b) Evidence of exocrine pancreatic insufficiency
2
and and
imaging findings
1
suggestive of chronic pancreatitis damage
c) Evidence of endocrine pancreatic insufficiency
3
and
imaging findings
1
suggestive of chronic pancreatic damage
d) Surgical or pancreatic biopsy specimen with histologic findings consistent with chronic
pancreatitis
Note:
1
Imaging findings suggestive of chronic pancreatitis/pancreatic damages include: 1) Ductal
changes: irregular contour of the pancreatic ducts; intraductal filling defects; calculi;
stricture or dilatation; 2) Parenchymal changes: generalized or focal enlargement, irregular
contour, cavities, calcifications, heterogeneous echotexture. Imaging modalities may
include ultrasound (US), contrast-enhanced computerized tomography (CT), Magnetic
resonance imaging/Magnetic resonance cholangiopancreatography (MRI/MRCP),
endoscopic ultrasonography (EUS) and endoscopic retrograde cholangiopancreatography
(ERCP).
2
Exocrine pancreatic insufficiency (Not tested during an episode of acute pancreatitis). 1) Fecal-
elastase-1 monoclonal assay <100 mcg/g stool (2 separate samples done ≥1 month apart),
OR 2) Coefficient of dietary fat absorption <90% on a 72-hours fecal collection.
3
Endocrine pancreatic insufficiency (2006 WHO criteria for the diagnosis of diabetes mellitus):
1) Fasting glucose ≥7.0 mmol/l (126 mg/dl), OR 2) Plasma glucose ≥11.1 mmol/l (200
mg/dl) 2 hours after glucose load 1.75 g/kg children (to maximum 75 g glucose load).
Acute Pancreatitis in Childhood
13
5.2.1. Clinical Presentation
Abdominal pain is the most common and typical symptom in acute
pancreatitis (90%). However, it is not always present, especially in young
children. Epigastric tenderness is described in up to 85% of the patients.
Nausea and vomiting are found in 73% of cases [8].
Symptoms typical of acute pancreatitis are not always present in young
children. Firstly, abdominal pain associated with back pain is only described in
7% of the patient and radiation to the back affects a minority of patient in
comparison to the presentation in adults (6, 42). Secondly, children in the 0 to
2 years group present with less typical symptoms of abdominal pain (43%),
epigastric tenderness (57%), nausea and vomiting (29%) in comparison with
older children (Park 2010). Similarly, Kandula et al. documented that
abdominal pain or irritability were present in only 46% of patients under the
age of three with acute pancreatitis [21].
5.2.2. Elevations in Serum Pancreatic Enzymes
Serum amylase and lipase are the most common biochemical markers
used to diagnose acute pancreatitis. Amylase increase is first detected 2-12
hours after onset of symptoms; the level peaks at 12-72 hours and usually
normalizes within 2-5 days [43]. Its half-life was estimated to be
approximately 2 hours. 60% of serum amylase is salivary and the remaining is
pancreatic [1]. Lipase level rises within 4-8 hours after onset of symptoms,
peaks at 24 hours, and normalizes after 8-14 days [43]. Lipase has a half-life
lower than amylase between 6.9 and 13.7 hours.
Elevation in serum amylase and/or lipase need to be interpreted
appropriately based on the clinical context, as they can arise from organs other
than the pancreas. Take serum lipase, for example, it may be expressed in the
intestinal mucosa, stomach, adipose tissue and leukocytes [1]. Various
conditions (Table 2) may be associated with abnormally elevated levels [44].
In addition, measurements of serum amylase and lipase should be considered
in the context of the child’s age. It has been shown that the expression of
pancreatic enzymes such as amylase and lipase increase from birth and
continue during the first months of life. The rise of amylase is slower than the
rise of lipase [45]. For this reason, serum pancreatic enzyme, especially
amylase, should be used with caution to rule out acute pancreatitis if the
likelihood is high. In addition, toddlers and infants are more likely to be
diagnosed by serum lipase than amylase. Serum lipase level >3 times the
upper limit of normal was reported in 100% of children in the 0 to 2 years age
group versus 66% for amylase [8].
Gilles Duvoisin and Chee Yee Ooi
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Table 2. Conditions associated with a rise serum amylase or lipase
AMYLASE
LIPASE
Pancreas
Acute Pancreatitis
Acute Recurrent Pancreatitis
Chronic Pancreatitis (mild elevation or normal)
Pancreatic cancer (rare in children)
Abdominal causes mimicing Acute pancreatitis
Perforated or penetrating peptic ulcer
Perforated bowel
Obstructed bowel
Mesenteric infarction
Appendicitis
Cholecystitis
Liver disease
Severe gastroenteritis
Celiac disease
Other gastrointestinal
Oesophagitis
Renal
Renal insufficiency
Metabolic
Diabetic ketoacidosis
Macroamylasemia
Macrolipasemia
Salivary gland
Salivary trauma
Infection (Mumps)
Salivary duct obstruction
Thoracic
Pneumonia
Pulmonary embolism
Metastatic lung disease
Myocardial infarction
Extracorporeal circulation
Gynecology
Pregnancy
Ruptured ectopic pregnancy
Ovarian or Fallopian cysts
Pelvic inflammatory disease
Trauma
Cerebral Trauma
Burns
Other
HIV
Anorexia nervosa, bulimia
Acute Pancreatitis in Childhood
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Several authors described the varying sensitivities for serum pancreatic
enzymes levels in the diagnosis of paediatric acute pancreatitis. Regarding
serum amylase, Tiao et al. [26], Sanchez et al. [24] and Werlin et al. [6]
described sensitivities between 83% and 85.5%, while Park et al. [8] and
Coffey et al. [46] reported lower values of 50% and 54%, respectively.
Regarding serum lipase, the first two authors, Tiao et al. and Sanchez et al.
describe a sensitivity higher reaching 90% and 87,1% [24, 26]. Park et al.
showed a marked difference between the two tests with a sensitivity for lipase
of 77%, which is 27% more than amylase [8]. Finally, Coffey et al. describe a
sensitivity of 93% for serum lipase, the highest reported among the other
studies from: Tiao, Sanchez, Werlin and Park et al. [6, 8, 24, 26].
5.2.3. Radiological Presentation
Radiologic investigations are used to establish the diagnosis, investigate
the underlying aetiologies such as obstructive disorder, and to evaluate for
complications. According to various reports, imaging is performed in the
majority (84%) of cases of paediatric pancreatitis [34].
The morphologic features of acute pancreatitis were defined in the revised
Atlanta classification, based on CT imaging [41] pancreatitis can manifest as:
a) Interstitial oedematous pancreatitis (IOP): Acute inflammation of the
pancreatic parenchyma and peripancreatic tissues, but without
recognisable tissue necrosis.
b) Acute peripancreatic fluid collection (APFC): A peripancreatic fluid
associated with IOP with no peripancreatic necrosis.
c) Pancreatic pseudocyst (PPC): An encapsulated collection of fluid with
a well defined inflammatory wall usually outside the pancreas with
minimal or no necrosis. It usually occurs more than 4 weeks after
onset of IOP.
d) Necrotising pancreatitis (NP): Inflammation associated with
parenchymal necrosis and/or peripancreatic necrosis.
e) Acute necrotic collection (ANC): A collection containing variable
amounts of both fluid and necrosis associated with NP; the necrosis
can involve the pancreatic parenchyma and/or the peripancreatic
tissues.
f) Walled-off necrosis (WON): A mature, encapsulated collection of
pancreatic and/or peripancreatic necrosis that has developed a well
defined inflammatory wall. It occurs usually more than 4 weeks after
the onset of a NP.
Gilles Duvoisin and Chee Yee Ooi
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Table 3. Morphologic features of acute pancreatitis, Revised [41]
This classification can be summarised in Table 3.
The most commonly used imaging modalities include abdominal
ultrasound (US), contrast-enhanced computerized tomography (CT), magnetic
resonance imaging (MRI), magnetic resonance cholangiopancreatography
(MRCP), endoscopic ultrasonography (EUS) [6, 21, 22].
Ultrasound is the most commonly used imaging test in children, most
likely due to its easy access, and lack of radiation and requirement for general
anaesthesia. It was reportedly used in 50% to 79% of patients [6, 8, 21, 22]. It
allows assessment of two major findings of acute pancreatitis, which are an
increase pancreatic size and decreased pancreatic echogenicity, indicating
oedema. In addition, it can identify complication of acute pancreatitis and its
vascular component (venous thrombosis or pseudoaneurysm formation). US
may be helpful for evaluating the biliary tree/gallbladder [47, 48].
Furthermore, it can identify other causes of acute abdominal pain such as
appendicitis, intussusception or volvulus. Its overall sensitivity was reported
from 25% up to 67% [6, 8, 21, 46, 49]. However, US has its limitations as it is
operator dependant and its accuracy can be reduced by the overlying bowel
gas and overweight children.
Contrast-enhanced computer tomography (CT) is not recommended on
initial presentation, unless the diagnosis is uncertain [44]. Its sensitivity was
documented from 50 to 74%, which is superior to abdominal US to diagnose
acute pancreatitis [6, 8, 18, 21, 46]. The main role for CT imaging is to assess
the severity of acute pancreatitis and its complications, such as pancreatic
necrosis. Despite this, CT is less commonly performed (35 to 46% of cases)
compared to abdominal US [6, 8, 21, 22]. This is in part due to physicians,
especially paediatrician, being hesitant in exposing children to radiation [50].
With MRI and MRCP, it is possible to investigate the aetiology of acute
pancreatitis without exposing the child to any radiation or iodine contrast
agent. However, depending of the age and maturity of the child, it may have to
be performed under general anaesthesia. The efficacy of MRI is comparable to
Pancreatic
Necrosis
< 4weeks
>4weeks
Pancreatitis Fluidcollection
No
Interstitialoedematous
pancreatitis(IOP)
±
Acute
peripancreatic fluid
collection(APFC)
Pancreatic
pseudocyst (PPC)
Yes
Necrotisingpancreatitis
(NP)
±
Acutenecroticcollection
(ANC)
Walled
-offnecrosis(WON)
Acute Pancreatitis in Childhood
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CT, and on the other hand, MRCP showed good correlation with endoscopic
retrograde cholangiography or direct cholangiography for assessing the
pancreaticobiliary system, particularly for anatomic anomalies. However, CT
is more sensitive to diagnosis pancreatic pseudocyst (PPC) and is the modality
of choice for traumatic pancreatitis [51]. The other limitations of the MRCP
are related to the respiratory motion artefacts and low signal-to-noise ratio
leading to dark and grainy images. Small calibre pancreaticobiliary duct may
not be seen and nearby fluid-filled organs such the stomach or fluid collections
might overlap the pancreatic duct, affecting its visibility. In addition, secretin-
enhanced MRCP, based on the principle that secretin stimulates pancreatic
exocrine secretion, was postulated to increase the visualization of the
pancreatic duct. In contrast to the majority of adult studies showing a benefit
in using the secretin-enhanced MRCP, the only study in paediatric patients
[52] did not report any significant improvement in the image quality in
children.
Endoscopic ultrasonography (EUS) can be used for diagnosis and
therapeutic interventions and requires general anaesthesia. There is relatively
little literature regarding its use in paediatrics. Several case series have
described the procedure in children [53-55]. In 2009, Attila et al. [53] reported
40 interventions; ten of them were for pancreatitis. Recently, in 2015, Sheers
et al. [55] described 52 procedures, among them 20 had pancreatitis. Both of
the groups reported that the procedure was technically feasible and safe in
children above 3 years (more than 15 kg). EUS is suggested to have a better
capacity for visualizing common bile duct stones compared to US. However,
additional studies are needed to establish the role of EUS in the management
of acute pancreatitis.
5.2.5. Combination and Comparison of Serum Pancreatic Enzymes and
Imaging Tests
Using a retrospective cohort of children with acute pancreatitis, Coffey et
al. [46] evaluated the diagnostic yield of serum pancreatic enzymes (amylase,
lipase; >3 upper limit of normal) and imaging tests (US, CT). It was reported
that lipase (93%) and CT (67%) had the highest diagnostic yield followed by
amylase and US with 54% and 27% respectively. Furthermore, the diagnostic
yield of combination of tests of at least one serum pancreatic enzyme level and
one imaging test surpassed the use of any single test or the combination of
serum amylase and lipase. In approximately half (55%) of all cases of acute
pancreatitis associated with abnormal serum pancreatic enzyme levels
(amylase or lipase), imaging tests (US or CT) were normal. In contrary, only
Gilles Duvoisin and Chee Yee Ooi
18
5% of children with acute pancreatitis with abnormal imaging tests had normal
serum pancreatic enzyme levels.
In addition, there was poor agreement between the different tests. For
example, when serum lipase was performed in association with an US, the
tests agreed with each other (for a diagnosis of acute pancreatitis) in only 26%
of cases. These findings suggest that if a test is negative in the context of a
high probability of acute pancreatitis, clinician should not restrain to perform
additional tests with a superior diagnostic yield.
6. MANAGEMENT AND INVESTIGATION
The management of paediatric acute pancreatitis is complex and
complicated by the multiple possible aetiologies, no/limited specific
treatments and often unpredictable complications. Historically, the
management was mainly based on adult practices which aimed to provide
supportive care and limit pancreatic stimulation. There has recently been great
interest in the management of adult acute pancreatitis, which has led to several
modifications of treatment guidelines, with particular interests in early enteral
feeding and early fluid resuscitation [44, 56, 57]. However, this is lacking in
children and multicentre prospective studies are required to validate these
interventions in children.
6.1. Severity
The severity of acute pancreatitis varies and may range from a mild, self-
limited disease to a severe multisystem disorder that can lead to death. For this
reasons, it is crucial to establish, in the initial phase of the disease, the
likelihood of a severe episode. This may lead to allocate better resource such
as paediatric intensive care unit and to initiate appropriate treatment as early as
possible.
Before discussing predictive tools, a question should be considered:
“What features characterise severe acute pancreatitis?” In the adult literature,
the revised Atlanta classification in 2012 described the terminology and
classification of severity of adult pancreatitis [41]. The terminology is
important and includes transient organ failure (less than 48 hours), persistent
organ failure (more than 48 hours), and local and systemic complications. The
modified Marshall scoring system is used to describe organ dysfunction [58].
Acute Pancreatitis in Childhood
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Acute pancreatitis can be stratified into three categories: mild, moderately
severe and severe pancreatitis. Firstly, mild acute pancreatitis is characterised
by the absence of organ failure and local or systemic complication. Then,
moderately severe acute pancreatitis is defined by the presence of either
transient organ failure, local complication or systemic complications. Finally,
severe acute pancreatitis is characterized by persistent organ failure (single or
multiple) and usually have one or more local or systemic complications. It is
worth considering that acute pancreatitis is a dynamic evolving condition.
Consensus to establish classification of disease severity for children is
required.
The next question that has to be addressed: “Can the severity of the
disease be predicted?”. Prognosis systems have been proposed and validated in
adult acute pancreatitis: Ranson criteria [59, 60], Glasgow [61], modified
Glasgow [62] and the Acute Physiology and Chronic Health Evaluation II
Score (APACHEII) [63]. DeBanto et al. [20] developed a scoring system for
the severity of paediatric acute pancreatitis. Nevertheless, subsequent studies
suggested that the DeBanto scoring system may not be superior to the previous
adult-based system. Recently, Coffey et al. [27] proposed an early predictor of
severe paediatric acute pancreatitis. Children with serum lipase ≥7 times the
upper limit of normal, within the 24 hours of presentation, were significantly
more likely to develop a severe episode (OR 7.1, P < 0.001). A sensitivity of
85% and high negative predictive value of 89% were described, emphasising
its utility to rule out severe paediatric acute pancreatitis.
6.2. Early Aggressive Intravenous Fluid Resuscitation
In the management of adult acute pancreatitis, early fluid resuscitation has
become widely supported [56, 57, 64]. Patients with acute pancreatitis may
encounter hypovolaemia due to vomiting, reduced oral intake, third spacing of
fluids and increased respiratory losses. In addition, oedema and
microangiopathic effects can, in turn, decrease pancreatic blood flow and
increased the cellular damages and necrosis [65]. Early aggressive intravenous
hydration has been described to support micro- and macro-circulation, being
most beneficial during the first 24-48 h. This was associated with a reduction
in frequency of multi-organ failure [66] and mortality [67]. In 2013, The
International Association of Pancreatology (IAP) and the American Pancreatic
Association (APA) established recommendations [57] regarding the type of
fluid and the rate of infusion. Both recommended the use of Ringer’s lactate
Gilles Duvoisin and Chee Yee Ooi
20
for the initial fluid resuscitation [68]. The infusion rate should be between 5 to
10 ml/kg/h and should be used until resuscitation goals are reached, underlying
the importance of not over-resuscitating. The same year, the American College
of Gastroenterology published their recommendations [56]. Isotonic
crystalloid solutions have also been advised for the initial management of
acute pancreatitis, and Ringer’s lactate being the preferred solution. They
propose a perfusion rate of 250-500 ml/h which is slightly bellow the
recommendation of the IAP-APA previously described.
However, no such recommendations have been established for the
management of paediatric acute pancreatitis. Especially as children have a
different proportions of fluid compartments and often less comorbidities than
adults (e.g., congestive heart disease, chronic renal failure). Szabo et al. [69]
evaluated whether the recommendations for treatment of acute pancreatitis in
adults impact the outcome of paediatric acute pancreatitis. There was no
statistical difference in the length of stay if the children received 1.5 to 2 times
the maintenance IV fluid volume (Dextrose 5% Normal saline) in comparison
of normal rate of infusion with Dextrose 5% and ½ Normal saline. Further
studies are required to assess which IV fluid should be used in paediatric acute
pancreatitis, the rate of infusion and which are the best markers to assess the
hemodynamic state of children.
6.3. Gut Rest and Early Feeding
The traditional approach of treatment with fasting (or “gut rest”)
supported by intravenous fluids was based on the premise that this would
minimise the activity or stimulation of an already inflamed pancreas.
However, over the last decade, there is accumulating evidence that early
enteral feeding of patients with acute pancreatitis may be beneficial. In a
randomised controlled trial of fasting vs. immediate oral full diet in adult
patients with mild acute pancreatitis, there were no differences in pain, and
serum amylase and CRP levels but early feeding resulted in shorter hospital
stay (4 vs. 6 days) [70]. In addition, Moreas et al. demonstrated that adults can
start on a full solid diet without a need of a liquid or soft diet [71]. In a
separate study of adults with severe acute pancreatitis, enteral nutrition within
48 hours after admission was associated with decreased mortality, infections
and multi-organ failure [72]. Meta-analyses of adult acute pancreatitis studies
have demonstrated that enteral nutrition within 48 hours of admission results
in lower rates of multi-organ failure, less systemic infections and lower