Best Practice & Research Clinical Gastroenterology 27 (2013) 727743

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Gastroenterology

Early management of acute pancreatitis

Nicolien J. Schepers, MD, PhD Candidate a, d, *,
Marc G.H. Besselink, MD, PhD, Surgeon b,
Hjalmar C. van Santvoort, MD, PhD, Surgical Resident c,
Olaf J. Bakker, MD, PhD Candidate, Surgical Resident c,
Marco J. Bruno, MD, PhD, Professor, Gastroenterologist d,
for the Dutch Pancreatitis Study Group
a

Department of Operation Rooms, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
c
Department of Surgery, University Medical Center, Utrecht, The Netherlands
d
Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
b

a b s t r a c t
Keywords:
Pancreatitis
Pancreas
Diagnosis
Treatment
Review

Acute pancreatitis is the most common gastro-intestinal indication

for acute hospitalization and its incidence continues to rise.
In severe pancreatitis, morbidity and mortality remains high and is
mainly driven by organ failure and infectious complications. Early
management strategies should aim to prevent or treat organ failure and to reduce infectious complications. This review addresses
the management of acute pancreatitis in the rst hours to days
after onset of symptoms, including uid therapy, nutrition and
endoscopic retrograde cholangiography. This review also discusses
the recently revised Atlanta classication which provides new
uniform terminology, thereby facilitating communication
regarding severity and complications of pancreatitis.
2013 Elsevier Ltd. All rights reserved.

Abbreviations: ACS, abdominal compartment syndrome; CARS, compensatory anti-inammatory response syndrome; CBD,
common bile duct; CECT, contrast-enhanced computed tomography; ERC, endoscopic retrograde cholangiography; ERCP, endoscopic
retrograde cholangiopancreatography; EUS, endoscopic ultrasound; HES, hydroxyethyl starch; ICU, intensive care unit; IDUS, intraductal ultrasound; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; SIRS, systemic inammatory response syndrome.

* Corresponding author. Dutch Pancreatitis Study Group, HP 690, Radboud University Nijmegen Medical Center, PO Box 9101,
6500HB Nijmegen, The Netherlands. Tel.: 31 614411960; fax: 31 243613834.
E-mail address: [email protected] (N.J. Schepers).
1521-6918/$ see front matter 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bpg.2013.08.007

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Introduction
Acute pancreatitis is the most common gastro-intestinal reason for acute hospitalization in the
United States with annually more than 270,000 admissions and estimated costs of 2.6 billion dollars
[1]. The incidence of acute pancreatitis continues to rise and the burden on patients and society is
expected to increase even more [13].
Acute pancreatitis is an inammatory process that is initiated by intra-acinar activation of proteolytic pancreatic enzymes, which ultimately leads to autodigestive injury of the pancreatic gland.
Modulated by cytokines and other inammatory mediators, intrapancreatic and extrapancreatic
inammation is generally accompanied by a systemic inammatory response syndrome (SIRS).
Acute pancreatitis is associated with an overall mortality rate of up to 5% [1,4]. Approximately 15% of
patients with pancreatitis develop pancreatic or extrapancreatic necrosis, which is associated with
hospitalizations that can often last for several months [4]. These patients have a high risk of complications such as organ failure or infected necrosis with mortality rates of 35% and 20%, respectively [5].
Early management strategies (i.e. arbitrarily dened as within the rst ve days) in patients with
acute pancreatitis are aimed at preventing or treating complications such as infections, organ failure
and ultimately mortality.
Immediately after clinical presentation a comprehensive clinical work-up is mandatory and
important decisions regarding management, including supportive care, need to be taken (Table 1). This
review addresses the possibilities for management and early invasive interventions which might
ameliorate the disease course and improve outcome in patients with acute pancreatitis.
Methods
A PubMed search was performed using the terms (pancreatitis (MeSH Terms)) AND (pancreatitis
(Title/Abstract)) NOT (chronic (Title/Abstract) OR carcinoma (Title/Abstract) OR autoimmune (Title/
Abstract)). A restriction in the search to articles in English, studies in human adults and a publishing
date between May 2010 and May 2013, resulted in 672 hits. The titles were scanned manually and
articles of interest regarding early management were reviewed. In addition, the evidence based
guideline on the treatment of acute pancreatitis, established during the International Association of
Pancreatology/American Pancreatic Association annual meeting in 2012, was reviewed. Relevant
literature was extracted from the reference lists of the selected articles.
Diagnosis
The diagnosis of acute pancreatitis is made by fullling two of the three following criteria: (1)
abdominal pain, (2) an elevated serum lipase or amylase (>3 times the upper limit of normal), (3)
Table 1
Key points early management in acute pancreatitis.
Diagnosis

 Acute pancreatitis; two out of three:

Abdominal pain
Elevated amylase/lipase >3 times upper limit of normal
B Characteristic ndings on CT, MRI or ultrasound
Establish aetiology
Monitor and predict severity (limited accuracy)
Abdominal ultrasound
CT not routinely advised at admission, only after 45 days in case of lack of clinical improvement
Balanced upon clinical response
510 mg/kg/h (no specic recommendation for uid type)
Cholangitis: emergency ERC
Predicted mild biliary pancreatitis: no ERC
Predicted severe biliary pancreatitis: no consensus about value ERC
Predicted mild pancreatitis: on patients demand, early start
Predicted severe pancreatitis: no consensus on timing of nutrition
B
B

Imaging
Fluid therapy
Bile duct
management
Nutrition













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characteristic ndings of acute pancreatitis on imaging, usually contrast-enhanced computed

tomography (CECT) [6]. In most cases, acute pancreatitis is diagnosed by abdominal pain and an
elevated serum lipase or amylase. In certain circumstances, for instance longer duration of complaints where serum amylase and lipase levels may have normalized, sedated patients or in case of
suspected early complications, additional imaging is required. Characteristic ndings of acute
pancreatitis on CECT or magnetic resonance imaging (MRI), conrm the diagnosis [79]. As a CECT
early in the disease course may underestimate the extent of pancreatic or extrapancreatic necrosis,
and often does not result in a change in management, it should not be performed routinely at
admission [7,10,11].

Key points diagnosis

Acute pancreatitis, two out of three; (1) abdominal pain, (2) >3 times elevated serum lipase
or amylase (3) characteristic ndings of acute pancreatitis on imaging.
CECT is not routinely advised at admission.

Clinical course
The initial phase of acute pancreatitis is characterized by pancreatic inammation that usually
presents as SIRS [12,13]. Approximately 30% of patients develop SIRS within 48 h after admission
[13]. Persistent organ failure is the key determinant of mortality in acute pancreatitis and is associated with a mortality of 2535% [5,1315]. In theory, SIRS is followed by a compensatory antiinammatory response syndrome (CARS), a state of immune suppression, making patients more
susceptible for infections including infection of pancreatic necrosis [16]. The mortality in the second
phase of acute pancreatitis is mostly caused by infected necrotizing pancreatitis [15].
About 85% of patients with acute pancreatitis develop interstitial oedematous pancreatitis [4].
The inammatory oedema of the pancreas usually resolves within one week [17]. Necrosis occurs in the
approximately other 15% of patients, which can involve the pancreatic parenchyma, extrapancreatic
tissues or both [6,18]. Extrapancreatic necrosis alone is associated with fewer complications as
compared to solely parenchymal necrosis. However, once infection of extrapancreatic necrosis occurs,
mortality rate is similar as for infected pancreatic parenchymal necrosis [19]. The recent revision of the
Atlanta classication describes pancreatic and extrapancreatic collections in order to provide a
consistent, worldwide classication in terminology. This description differentiates acute extrapancreatic uid collection, pancreatic pseudocyst, acute necrotic collection and walled-off necrosis [6].
Table 2 provides denitions, according to the revisited Atlanta, of the morphological features in acute
pancreatitis.

Key points clinical course

Persistent organ failure is dened as >48 h, transient as 48 h.
Persistent organ failure is the key determinant of mortality.
Pancreatic necrosis can involve the pancreatic parenchyma, extrapancreatic tissues or both.

Predicting severity
Prognostic scoring systems have been developed to identify patients with a high risk of severe
pancreatitis for three reasons. First, they may determine which patients need intensive monitoring

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Table 2
Denitions in acute pancreatitis [6,116].
Interstitial oedematous pancreatitis Inammation of pancreatic parenchyma and extrapancreatic tissue,
without necrosis
Necrotizing pancreatitis
Parenchymal and/or extrapancreatic necrosis
Severity
Mild
No organ failure or local/systemic complications
Moderate
Transient organ failure or local/systemic complications
Severe
Persistent organ failure (>48 h)
Intra-abdominal hypertension
>12 mmHg, technique described in guideline [116]
Abdominal compartment syndrome >20 mmHg and new organ failure
Collections
Acute extrapancreatic uid
Extrapancreatic uid associated with interstitial oedematous pancreatitis
collection
Pancreatic pseudocyst
Encapsulated collection of uid without necrosis, after interstitial oedematous
pancreatitis
Acute necrotic collection
Collection containing uid and necrosis associated with necrotizing
pancreatitis
Walled-off necrosis
Encapsulated collection in necrotizing pancreatitis

on high dependency units because of a high risk of organ failure. Second, the subgroup of patients
can be selected in whom early, aggressive intervention is indicated. Third, they may be used to
stratify patients in clinical trials with different (predicted) severities of acute pancreatitis [20].
The accuracy of the scoring systems, however, remains disappointing. In clinical practice their
use is further limited by the complexity of many scoring systems. There are several scoring systems
that are based on a combination of clinical and biochemical parameters (Acute Physiology and
Chronic Health Evaluation (APACHE)-II, the Ranson score, Modied Glasgow or Imrie score, Creactive protein, Bedside Index of Severity in Acute Pancreatitis (BISAP), Harmless Acute Pancreatitis Score (HAPS) and blood urea nitrogen (BUN)). A systematic review demonstrated that most
prognostic variables and scoring systems have high negative predictive values, but low positive
predictive values regarding positive predictive power [21]. In addition, CECT scoring systems can
assess the extent of the morphological abnormalities. As they do not outperform clinical scoring
systems with regard to prognosis, a CECT at admission solely for severity assessment is not recommended [11]. Recently a head-to-head comparison was performed on the accuracy of the scoring
systems in predicting persistent organ failure [22]. Receiver operating characteristic analysis at
admission showed modest results (0.620.84 in the training cohort and 0.570.74 in the validation
cohort). Although the modied Glasgow score served as best predictor, the conclusion was drawn
that the presently available scoring systems have reached their maximal performance and that
combining clinical scoring systems does not further improve predictive value. To improve early
management in patients with acute pancreatitis, there still remains a need for accurate markers to
predict the disease course.
Simple laboratory values such as BUN and creatinin and more complex laboratory scoring
systems have shown to have similar accuracies [22,23]. In line with their simplicity for clinical use, the
upcoming IAP/APA guidelines recommend persistent SIRS (>48 h) as a marker to predict severity
because of its easy utility and worldwide recognition, while awaiting more accurate scoring systems
[13,24,25]. The fact that persistent organ failure is the key determinant of mortality in pancreatitis
plays an important role in this recommendation.
The revised Atlanta classication has three groups of clinical severity: mild, moderate and severe
pancreatitis. Mild pancreatitis is characterized by no organ failure or extrapancreatic collections.
Moderate pancreatitis, has transient organ failure (48 h) or extrapancreatic collections. Severe
pancreatitis involves persistent organ failure (>48 h). Prospective studies are needed to identify the
validity and clinical use of the classication and the rst validation study has recently been published
[26]. Some authors have suggested to divide clinical severity into four groups [27].

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Key points predicting severity

None of the available scoring systems for predicting severity is clearly superior, and new
markers are needed.
The revisited Atlanta classication denes mild, moderate and severe pancreatitis.

Aetiology
Although several factors are known to potentially cause acute pancreatitis, the exact pathogenesis
remains unclear [28]. There is a large variation in aetiology of acute pancreatitis between countries.
Most cases of acute pancreatitis are caused by biliary stones or sludge, followed by alcohol abuse
[29,30]. The rise in incidence of acute pancreatitis has been attributed to either the increase of
abdominal obesity a risk factor for gallstones ageing or an increase of alcohol consumption [2,30
32]. Less frequent causes of pancreatitis are hypercalcaemia, hypertriglyceridemia, endoscopic retrograde cholangiopancreatography (ERCP), medication and trauma.
The aetiology of pancreatitis should be determined on admission as this tailors management
strategies. Medical history (gallstone disease, alcohol abuse, medication, metabolic syndromes),
physical examination and biochemical tests (liver tests, calcium, triglycerides) help to differentiate
between biliary and metabolic causes [33].
Diagnosing biliary pancreatitis in the early course of the disease may be difcult. The rst challenge
is to reliably ascertain whether common bile duct (CBD) stones are present. Unfortunately, clinical
predictors of biliary obstruction (i.e. cholestatic liver enzymes) and radiologic ndings have shown to
be unreliable in predicting the presence of CBD stones in the early stages of biliary pancreatitis [34].
Elevations of biochemical markers, such as bilirubin, alkaline phosphatase, gammaglutamyltransferase, alanine aminotranferase (ALAT) and aspartate aminotransferase suggest a
biliary cause. However, about 1520% of the patients with biliary pancreatitis manifest with normal
liver function tests [35]. ALAT is thought to be the most useful biochemical marker in predicting a
biliary origin in acute pancreatitis. An ALAT level of >150 IU/L (2.55 mkat/L, an approximately three-fold
elevation) has been shown to have a positive predictive value of 88100% in determining a biliary
origin [3638]. Within 48 h of hospital admission, an ALAT level of >80 IU/L (1.00 mkat/L, an
approximately two-fold elevation) is also associated with a high probability (positive predictive value
79100%) of biliary pancreatitis [33,39].
Abdominal ultrasound should be performed at admission to detect gallstones or sludge. The choice
for this non-invasive imaging modality is often made because of its availability and low costs.
Abdominal ultrasound has a high sensitivity for cholecystolithiasis, but has a low sensitivity (20%) for
stones in the CBD in acute pancreatitis and can be troublesome in obese patients [34,40]. CECT is also
not attractive as a test for CBD stones as sensitivity is 40% [40]. Finally, of the non-invasive imaging
modalities, the result of a head-to-head comparison study of the ability of magnetic resonance cholangiopancreatography (MRCP) to detect choledocholithiasis in biliary pancreatitis was high, approximately 90% [40,41]. However, small gallstones (<5 mm) in the common bile duct can be easily missed
on MRCP [42]. This is particularly relevant as especially small stones are known to cause biliary
pancreatitis [43].
Of all imaging modalities, endoscopic ultrasound (EUS) is clearly superior in detecting choledocholithiasis, with a high sensitivity and specicity of 8996% [36,44,45]. However, EUS has
practical limitations because of its limited availability. The sensitivity of endoscopic retrograde
cholangiography (ERC) is 90% [40]. In contrast to EUS, ERC has a 47% risk of developing complications, which can even be higher in patients with pancreatitis [46,47]. Based on these considerations it
is clear that EUS and MRCP could play an important role in selecting patients for ERC. One study
already showed that 71% of ERCs may be avoided using EUS as guidance [45]. Finally, intraductal
ultrasonography (IDUS) has shown to be the best predictor for detecting choledocholithiasis with a
sensitivity of 95% but obviously requires bile duct cannulation [40].

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In about 1015% of the cases the aetiology of pancreatitis remains unclear, although thorough
investigation with IDUS, EUS or MRCP eventually reveals a biliary origin in a signicant amount of
presumed idiopathic cases [48].

Key points aetiology

Biliary stones or sludge are the most common cause of pancreatitis in most countries.
An ALAT >150 IU/L (>2.55 mkat/L) is highly suggestive for a biliary cause.
EUS or MRCP are modalities of choice to detect CBD stones.
Pain management
The predominant symptom of acute pancreatitis is abdominal pain. In addition to increasing patient
comfort, alleviating pain moderates the physiological response to pain and immunological mechanisms. Intravenous opiates are usually necessary to control pain, though no evidence supports the use
of a specic opiate [4,49]. Oxygen saturation should be monitored, as a side-effect of opiates is respiratory suppression.
Fluid therapy
In order to prevent intravascular volume depletion, hypoperfusion and organ failure, adequate uid
resuscitation is critical in the early management of acute pancreatitis to reduce complications and
mortality [50,51]. In clinical practice, extensive uid resuscitation is used as this is thought to maintain
the microcirculation of the pancreas [52]. Recently, two randomized trials showed that too aggressive
uid therapy may result in higher mortality. The rst trial compared infusion rates of 1015 mg/kg/h
with 510 mg/kg/h [53]. The second trial compared slow to rapid haemodilution aiming at a turning
point of a haematocrit of 35% within 48 h [54]. Based on the available literature, it can be concluded
that an infusion rate of 510 ml/kg/h seems appropriate, balanced upon clinical response (urine output
and heart rate) [25]. Few studies have investigated the type of uid that should be administered
[55,56]. Recent data suggests that Ringers lactate solution is superior to saline solution in preventing a
SIRS [56]. Others suggest that a combination of normal saline, hydroxyethyl starch (HES) and glutamine
is more efcient in resuscitation of severe pancreatitis by reducing SIRS [57]. In contrast, in a multicenter, blinded, randomized trial, patients with severe sepsis who were resuscitated with HES, had an
increased risk of death and were more likely to require renal-replacement therapy, compared to those
receiving Ringers acetate [58]. A recent systematic review concluded that there is a lack of quality
evidence on uid therapy in acute pancreatitis [59]. In conclusion, uid resuscitation is a cornerstone in
the treatment of pancreatitis and should be balanced upon clinical response.
Key points uid therapy and pain management
An infusion rate of 510 ml/kg/h with response monitoring is appropriate for most patients.
There is no clear superior type of uid, more studies are needed.

Bile duct management

Especially small gallstones and sludge are associated with an increased risk of biliary pancreatitis
[43]. The exact pathogenesis of biliary pancreatitis remains unknown [60]. Once biliary obstruction is
thought to be present, decompression is thought to improve the disease course.
Since the introduction of ERC in the seventies as a diagnostic and therapeutic tool, it has become the
standard treatment modality for patients with choledocholithiasis in biliary pancreatitis [61]. In order

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to improve the outcome in biliary pancreatitis by decompression of the ampullary orice and the bile
duct, the effects of ERC have been investigated in experimental and clinical studies [6265]. These
studies suggest that a temporary biliary obstruction does not only initiate an attack of biliary
pancreatitis, but also aggravates the disease course. Furthermore, post-mortem studies identied
stones in the CBD of patients that died of necrotizing pancreatitis [66,67]. In the view of these ndings,
biliary decompression might be a potential life-saving intervention.
On the other hand, ERC plus endoscopic sphincterotomy is an invasive procedure associated with a
complication rate of 810% and mortality rate of approximately 1% [68,69]. It is well known that in
many patients CBD stones pass spontaneously in which case an ERC would be redundant [70,71].
In the past decades several randomized trials investigated the role of ERC in biliary pancreatitis.
There is an undisputed indication for an urgent ERC in case of cholangitis [72,73]. Endoscopic biliary
decompression and drainage reduces complications and mortality of patients with cholangitis due to
choledocholithiasis [74]. However, it remains challenging to diagnose cholangitis in a patient with SIRS
due to acute pancreatitis and its denition differs among randomized trials in pancreatitis; from
Charcots triad [75] to leaving the decision to an Expertpanel [66], or not reporting the denition of
cholangitis [65,76]. Diagnostic criteria for cholangitis are not based on patients with acute (biliary)
pancreatitis. Initially Charcots triad of jaundice, abdominal pain and fever was used, later the Tokyo
Guidelines (TG07) were presented to increase accuracy [77]. Recently the Tokyo Guidelines (TG13)
where updated in which an inammatory response is dened as a temperature >38  C or a CRP 1 mg/
dL [73]. Randomized trials of ERC in biliary pancreatitis consistently used higher cut-off values
implicating that the diagnosis of cholangitis in the setting of pancreatitis is a separate entity. If the TG13
are applied, it is likely that patients with acute biliary pancreatitis are misclassied with cholangitis
and therefore might undergo a redundant ERC. Future research should focus on the appropriate
diagnostic criteria for cholangitis in the setting of acute biliary pancreatitis.
Persistent biliary obstruction is considered as an indication for ERC [4,49,78,79], although there is
no ofcial denition for biliary obstruction. Previously we mentioned the limitations of the
biochemical and imaging modalities in detecting choledocholithiasis in the early setting of acute biliary
pancreatitis [34]. Early ERC may be benecial in patients with cholestasis. However, this suggestion is
based on randomized trials with varying diagnostic criteria for cholestasis and enrolment of patients
with or without cholestasis. A prospective observational cohort study demonstrated ERC reduced
complications in patients with predicted severe pancreatitis and cholestasis [80].
There is consensus in international guidelines that ERC is not benecial in predicted mild biliary
pancreatitis [4,49,79].
International guidelines and meta-analyses are conicting on the subject of ERC in predicted severe
biliary pancreatitis [4,49,79,81]. The UK guidelines state that an urgent ERC is indicated in predicted
severe biliary pancreatitis. The American Gastroenterological Association, the American College of
Gastroenterology and the Italian association state that early ERC in predicted severe biliary pancreatitis
without signs of cholangitis is controversial [4,49,78]. These guidelines are based on different selection,
analysis and interpretation of available studies, which is explained by several limitations in the individual study designs [65,66,75,76,82]. First, different scoring systems to predict the severity of the
disease and improper selection criteria were used. This increases the risk for misclassication by
including patients with a predicted mild disease course and with cholangitis. In addition, no criteria
were set to guarantee that the ERC was performed by an experienced endoscopist to avoid a high failure
cannulation and complication rate [76,82]. The criteria for a biliary aetiology were suboptimal, so that for
example in the study of Fan et al only 65% of the patients had true biliary pancreatitis. In the randomized
trials the denition for early ERC varied from within 24 h to 72 h after admission or onset of pain. Studies
suggest that the duration of duct obstruction is correlated to the severity of the pancreatitis [62,83].
According to this, ERC should be performed as early as possible. In the studies of Neoptolemos and Fan a
sphincterotomy was only performed in case CBD stones were identied at ERC [66,82]. A meta-analysis
revealed that only 53% of the patients received a sphincterotomy [84], although a prospective observational study found that sphincterotomy was associated with a reduction of overall complication rate
implying that sphincterotomy should be an integral part of ERC treatment [80].
A recent Cochrane meta-analysis studying the role of early ERC in gallstone pancreatitis, found no
signicant improvement in mortality, and local and systemic, complications, regardless of the

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predicted severity [72]. Besides the limitations in study design of the included trials, the pooled sample
size of patients with predicted severe biliary pancreatitis is small and thus statistically underpowered
to draw denite conclusions.
The potential benecial effect of ERC in the subgroups of predicted severe biliary pancreatitis,
should be evaluated in future research with a sufcient number of patients, and statistical power, to
detect differences in outcome. A randomized controlled trial in patients with predicted severe biliary
pancreatitis without cholangitis is currently ongoing (ISRCTN97372133).

Key points bile duct management

Urgent ERC is indicated in case of cholangitis.

ERC is not indicated in predicted mild pancreatitis, regardless of persistent cholestasis.
ERC is possibly indicated in patients with cholestasis.
ERC is possibly indicated in patients with predicted severe pancreatitis.

Prevention of infection
Infection prophylaxis would seem a useful strategy since infectious complications have a signicant
impact on mortality [85]. Bacteraemia in acute pancreatitis is an independent predictor for mortality
and increases the risk of infected necrosis [85].
For decades the prophylactic role of antibiotics has been subject of discussion. Randomized trials on
antibiotic prophylaxis in acute pancreatitis showed conicting results [8689]. This is most likely
caused by limitations in the study design, such as different inclusion criteria and the type of antibiotics
that were used. Based on the most recent meta-analyses, guidelines advise that antibiotics should not
be prescribed routinely as prophylaxis [90,91].
Selective decontamination of the intestinal tract reduces mortality in general (non-pancreatitis)
intensive care unit (ICU) patients [92]. In line with these results, benecial effects of selective
decontamination in severe acute pancreatitis have been observed [93]. Although in this study, selective
decontamination reduced infection of pancreatic necrosis, the study design has been criticized. The
study was not placebo-controlled, nor was it blinded and no statistically signicant reduction in
mortality was observed. In addition, the benecial effect might be due to the simultaneous administration of intravenous antibiotics for (suspected) non-pancreatic infections such as pneumonia.
Furthermore, the potentially benecial results should be weighed against an increase in antibiotic
resistance, gram-positive overgrowth or fungi colonization [94].
Probiotic prophylaxis was hypothesized to reduce infectious complications in acute pancreatitis.
A large randomized-placebo controlled trial (PROPATRIA) in patients with predicted severe
pancreatitis found no effect on infectious complications but an increased rate of bowel ischaemia
and mortality in patients who received probiotics [95]. Therefore, use of probiotics (at least the
mixture of probiotics used in the PROPATRIA study) is strongly discouraged in patients with predicted severe pancreatitis, although the exact pathophysiological mechanism of this adverse effect
remains unknown [96].
Many prophylactic strategies focus on reducing bacterial translocation in relation to the intestinal
permeability [97]. Several studies have been performed to study the role of early nutrition in this
respect.

Key points prevention of infection

Intravenous antibiotics should not be used as prophylaxis.
Enteral probiotics should not be prescribed in patient with pancreatitis.

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Nutrition
Nutrition in acute pancreatitis has evolved greatly over the past decades. Initially, it was thought
that feeding would stimulate pancreatic enzyme secretion and that enteral nutrition should be avoided. Over time, the key role of maintaining the integrity of the intestine became evident. Feeding
became a supportive measure by which the intestinal mucosal integrity could be preserved and bacterial translocation is thought to be reduced [98,99].
Enteral nutrition has proven to be superior to parenteral nutrition regarding the occurrence of
systemic infections, multi-organ failure and mortality [100]. Only in case enteral feeding is not tolerated, parenteral nutrition should be initiated to preserve adequate intake [101].
Patients with predicted mild pancreatitis can restart oral feeding on their own request. Immediate
feeding has shown to be safe and leads to shorter hospital stay in patients with predicted mild
pancreatitis [102]. Restrictions with regard to food consistency are not needed, i.e. a full solid diet
resulted in shorter hospital stay in patients with mild pancreatitis [103].
Patients with predicted severe pancreatitis should receive nasoenteral tube feeding only if they
cannot tolerate oral intake. In order to preserve the intestinal function and prevent bacterial translocation, it is recommended to initiate enteral nutrition early in the disease course [4,101]. A systematic
review demonstrated that the benecial effect of nutritional support might be associated with timing
of the start of nutrition [104]. In line, a retrospective analysis of 197 cases demonstrated that early
enteral nutrition (<48 h) was superior to delayed enteral nutrition (>48 h) for the prevention of
infected necrosis and mortality in predicted severe acute pancreatitis [105]. A meta-analysis of early
enteral feeding (<36 h of admission or within 36 h of surgery) in critically care patients showed a
reduction in infectious complications and hospital stay [106]. A randomized trial in 60 patients with
severe acute pancreatitis demonstrated that enteral nutrition within 48 h after admission can moderate the immune response and improve outcome compared to start of enteral nutrition after seven
days [107]. A multicenter randomized trial investigating the timing of enteral nutrition in patients with
predicted severe pancreatitis has recently been completed and awaits nal analysis (ISRCTN18170985).

Key points nutrition

In predicted mild pancreatitis oral intake can immediately be restarted after admission
without restrictions.
In predicted severe pancreatitis it is unclear whether early enteral nutrition improves
outcome.

Recurrent biliary events

After biliary pancreatitis, cholecystectomy or endoscopic sphincterotomy should be performed in
order to prevent recurrent biliary pancreatitis, biliary colics and cholecystitis [4,79]. Endoscopic
sphincterotomy has shown to reduce the risk of recurrent biliary pancreatitis, but not of other biliary
events, such as cholecystitis or biliary colics [108]. Therefore, one should strive to always perform a
cholecystectomy early following an attack of biliary pancreatitis unless this is not safe or feasible, e.g. in
older or unt candidates or in patients with extrapancreatic collections. In these cases endoscopic
sphincterotomy is acceptable [109]. Although sphincterotomy clearly will not prevent recurrent biliary
colics it will virtually eliminate the risk of recurrent biliary pancreatitis [108,110].
The timing of cholecystectomy after mild biliary pancreatitis still is subject to debate. As recurrent
events occur particularly in the rst months after recovery from pancreatitis, one should aim for quick
denitive management, provided that cholecystectomy can be performed safely [108,110]. Delay of
cholecystectomy increases the risk of a recurrent biliary event. A randomized trial investigating the
timing of cholecystectomy was prematurely stopped because a benecial effect in favour of cholecystectomy within 48 h after admission was observed [111]. These results should be interpreted with
some caution as the study was not adequately powered to study safety. A recent systematic review

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found a readmission rate prior to cholecystectomy in 95 of 515 patients (18%) because of recurrent
biliary pancreatitis, acute cholecystitis, and biliary colics after mild biliary pancreatitis. This study
further showed that early cholecystectomy is probably safe after mild biliary pancreatitis although
selection bias could not be fully excluded [110]. Currently a randomized trial is investigating the efcacy and safety of index cholecystectomy after biliary pancreatitis (ISRCTN72764151) [112].
In severe pancreatitis, with local and systemic complications, cholecystectomy is delayed until
resolution of symptoms or when extraperancreatic collections are resolved, which is usually after six
weeks [79,113]. Little is known about the recurrent events after severe pancreatitis prior to cholecystectomy and of the role of endoscopic sphincterotomy. In two retrospective studies no recurrent
events were reported [113,114].

Key points recurrent biliary events

Cholecystectomy should be performed after biliary pancreatitis to reduce the risk of
recurrent biliary events.
In mild pancreatitis current evidence is that cholecystectomy should be performed as soon
as possible after recovery. A randomized trial is needed.
In severe pancreatitis cholecystectomy should be delayed until resolution of symptoms or
when extraperancreatic collections are resolved.

Intensive care
The intensity of clinical monitoring in acute pancreatitis is best based on the presumed risk of
deterioration and therefore the predicted severity of acute pancreatitis. Clinical parameters,
described by the Society of Critical Care Medicine, can be used to triage for ICU admission [115]. The
crux in the management with acute pancreatitis is adequate uid resuscitation (see section uid
therapy) and to be aware of the occurrence of early complications that require intervention. Rapid
deterioration might be due to an abdominal compartment syndrome (ACS). A 2013 international
conference of experts dened ACS as an intra-adominal pressure of >20 mmHg and new organ
failure [116]. Sometimes a period of intra-abdominal hypertension (IAH), dened as 12 mmHg, is
observed prior to the new onset of organ failure. ACS and IAH have shown to contribute in gut
barrier failure [117]. Reported incidence rates of IAH are high between 59 and 78% in acute
pancreatitis and a portion of 27% developed ACS [118,119]. An extremely high mortality rate of ACS
up to 83% has been described [120].
The initial step in the treatment of ACS is to immediately lower abdominal pressure using nasogastric decompression, laxantia and muscle relaxants [116]. If clinical improvement is not achieved,
percutaneous drainage of intra-peritoneal uid should be attempted. If this does not sufce, surgical
decompressive laparotomy is probably indicated. Animal studies suggest that there is a narrow time
window for surgical intervention [121123]. A randomized trial comparing decompressive laparotomy
with percutaneus puncture with placement of abdominal catheter in patients with severe pancreatitis
and ACS, is currently ongoing (NCT00793715) [124].

Key point intensive care

Abdominal compartment syndrome is associated with high mortality and requires prompt
intervention.
Optimal treatment of abdominal compartment syndrome is currently unclear.
There is a 2013 international consensus guideline on the management of abdominal
compartment syndrome [116].

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737

Fig. 1. Flow-chart early management of acute pancreatitis.

Necrotizing pancreatitis
Sterile necrosis can be treated without invasive intervention in the vast majority of patients [18].
Around 30% of patients will develop infected necrosis [5,6]. Infected necrosis increases the death rate to
approximately 30% [15,18]. Infection is considered proven if gas is present in the extrapancreatic
collection or when ne-needle aspiration is positive for bacteria or fungi on gram stain and culture
[6,125]. There is no need for routine ne-needle aspiration in patients with clear clinical or imaging signs
of infected necrotizing pancreatitis as there is a small (1025%) risk of false negative results [126,127]. It is
generally accepted to administer intravenous antibiotics in case of suspected infected necrosis to mitigate
additional infectious complications [128]. Intervention to drain infected uid or remove infected necrosis
is justied in patients with progressive clinical deterioration despite maximal supportive therapy [18].
Currently it is common practice that intervention should be delayed until approximately four weeks in
order to minimize the risks of complications during intervention, in particular necrosectomy [18].
Infected necrosis should be treated by a step-up approach [18,129], consisting of catheter drainage,
either percutaneously or endoscopic transluminal, if necessary followed by surgical or endoscopic

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necrosectomy. A pilot randomized trial found endoscopic transgastric necrosectomy to be superior to

surgical necrosectomy in terms of new organ failure and overall complications [130]. An adequately
powered randomized trial, comparing the surgical step-up approach versus the endoscopic step-up
approach in patients with infected pancreatic necrosis, is currently ongoing (ISRCTN09186711).

Key points necrotizing pancreatitis

Infected necrosis is nearly always an indication for intervention.
Interventions should ideally be postponed until the collection has become walled-off
(typically >4 weeks) as this reduces complications.
Infected necrosis should be treated by a step-up approach, which starts with catheter
drainage, if needed followed by (minimally invasive) necrosectomy.
Summary
Acute pancreatitis is a common disease with a rising incidence. Recently, the revised Atlanta
classication presented new denitions on clinical severity and new terminology for extrapancreatic
collections (Table 1). Diagnosing acute pancreatitis also involves predicting the severity and establishing the aetiology to tailor management strategies in the early phase of acute pancreatitis. Recent
guidelines recommend SIRS as marker to predict severity because of its ease of use and its ability to
perform as good as complex models. An elevated ALAT (>150 IU/L) indicates a high probability of a
biliary origin. MRCP or EUS should be performed to detect the presence or absence of CBD stones.
Early management strategies in pancreatitis are based on preventing or treating organ failure and
preventing infectious complications (Fig. 1). Fluid resuscitation at an infusion rate of 510 ml/kg/h is
regarded as a cornerstone in the treatment of pancreatitis, although high quality studies supporting its
use are eagerly awaited. The approach to nutrition and feeding in acute pancreatitis has radically
changed over time. A pro-active approach with early enteral feeding is advocated in order to maintain
gut integrity. In mild pancreatitis oral intake can usually be resumed quickly after hospital admission.
In severe pancreatitis it is unclear whether early enteral nutrition improves outcome. Antibiotics
should not be administered prophylactic. In case of biliary pancreatitis, urgent ERC should be performed only in case of cholangitis and possibly in patients with cholestasis. ERC is not indicated in
predicted mild pancreatitis. In predicted severe biliary pancreatitis, the role of early ERC still needs to
be determined. Cholecystectomy should be performed early to reduce readmissions for biliary events.
In cases with severe pancreatitis it is appropriate to delay cholecystectomy to six weeks after the onset
of acute pancreatitis. In patients with severe acute pancreatitis, rapid deterioration may be due to
abdominal compartment syndrome or infected pancreatic necrosis which are conditions that are
associated with a high mortality rate and require intervention.
Practice points
 Acute pancreatitis is the most common gastro-intestinal reason for acute hospitalization and
the incidence is rising.
 An elevated ALAT >150 IU/L (2.55 mkat/L) is a good predictor for a biliary origin.
 Initial treatment should consist of:
Effective pain control
Infusion rate 510 ml/kg/h, adjusted upon clinical response
Imaging: abdominal ultrasound at admission. EUS or MRCP to detect CBD stones.
 ERC does not improve outcome in predicted mild biliary pancreatitis.
 Urgent ERC with sphincterotomy is indicated in case of cholangitis.
 Extrapancreatic uid collections are classied as acute extrapancreatic uid collection,
pancreatic pseudocyst, acute necrotic collection and walled-off necrosis.
B
B
B

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739

Research agenda








Accurate markers to predict severity of the disease course.

Validation of the proposed classications for severity of pancreatitis.
Fluid therapy in acute pancreatitis.
Diagnostic criteria for cholangitis in the setting of acute biliary pancreatitis.
Role of early ERC in predicted severe biliary pancreatitis.
Timing of enteral nutrition in predicted severe pancreatitis.
Timing of initial intervention in infected necrotizing pancreatitis.

Funding
N.J. Schepers is sponsored by The Netherlands Organization for Health Research and Development
(ZonMw, grant number 837002008) and the Foundation for Health Care Subsidies (Fonds NutsOhra,
grant number 1203-052) to perform clinical studies on acute pancreatitis. The sponsor had no
involvement in any stage of the manuscript.
Conict of interest
None.
Acknowledgements
N.J. Schepers drafted the manuscript. All authors edited the manuscript. All authors approved the
nal manuscript.
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