Review Article
Necrotizing Pancreatitis: Advances in Management
Sarah A Moore1*, Ryan P. Dumas1 and Carrie A Sims2
1Department of Traumatology, Surgical Critical Care & Emergency Surgery, Perelman School of Medicine at the
University of Pennsylvania, Philadelphia, PA, USA
2Department of Surgery, Division of Traumatology, Surgical Critical Care & Emergency Surgery, Perelman School
of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
*Corresponding author: Sarah A Moore, Department of Traumatology, Surgical Critical Care & Emergency Surgery, Perelman School of Medicine at the University of Pennsylvania, 51 N. 39th Street, MOB Suite 120, Philadelphia, PA 19104, USA
Published: 26 Apr, 2017
Cite this article as: Moore SA, Dumas RP, Sims CA.
Necrotizing Pancreatitis: Advances in
Management. Clin Surg. 2017; 2: 1437.
Abstract
Acute pancreatitis is a common disease process that results in significant morbidity and mortality. While the disease course may be mild and self-limited, 15%-25% of patients develop necrotizing pancreatitis, which may become secondarily infected. The use of standardized scoring systems and clinical classification schemes has allowed multicenter trials to evaluate the management of necrotizing pancreatitis and have greatly improved outcomes. Supportive care with fluid resuscitation, nutrition, and appropriate use of antibiotics are the mainstays of early management. Once fluid collections have progressed to walled-off necrosis, catheter-based drainage is generally sufficient, with few patients requiring surgical intervention. Complications of necrotizing pancreatitis include mesenteric venous thrombosis, abdominal compartment syndrome, bowel perforation, and hemorrhage. Further understanding the appropriate timing of interventions may potentially lead to fewer complications, decreased length of hospitalization, and improved outcomes.
Introduction
Acute pancreatitis is a common disease process with greater than 275,000 hospital admissions
annually in the United States [1]. Moreover, the incidence of acute pancreatitis is on the rise, with
a 12% increase in emergency department visits and a 15% increase in hospital admissions annually
over the past decade [2]. With the incidence increasing, annual health care costs to treat acute
pancreatitis now exceed $2.6 billion annually [1]. Despite aggressive critical care, acute pancreatitis
remains deadly with over 8000 deaths per year in the United States and an overall mortality of
approximately 2% [2].
A wide range of etiologies can cause acute pancreatitis. The most common cause of acute
pancreatitis worldwide is gallstone disease, accounting for approximately 40% of cases. Alcoholinduced
pancreatitis, the second most common cause, accounts for 30% of cases. Hypertriglyceridemia,
drugs, genetic and autoimmune causes, endoscopic retrograde cholangiopancreatography (ERCP),
trauma, congenital malformations, infections, and surgical complications each account for a small
percentage of the remainder of cases. Diabetes, smoking, and obesity are common risk factors that
may be associated with idiopathic cases.
The majority of patients with acute pancreatitis have a self-limited disease course requiring a
short hospital admission for supportive care. However, 15-25% of patients with pancreatitis develop
pancreatic necrosis, which significantly increases both morbidity and mortality [3]. While sterile
pancreatic necrosis carries a 10% mortality risk, the mortality associated with infected necrosis may
be as high as 30%.
Clinical Diagnosis and Scoring
The International Association of Pancreatology (IAP) and American Pancreatic Association
(APA) suggest that a clinical diagnosis of acute pancreatitis requires 2 of 3 criteria: clinical signs
and symptoms (abdominal pain), laboratory abnormalities (serum amylase or lipase greater than
3 times upper limit of normal), and/or characteristic imaging findings (computed tomography
(CT) or magnetic resonance imaging (MRI)) [4]. The Atlanta classification, originally described
in 1992 and updated in 2012, remains the standard classification for acute pancreatitis and relies
on both clinical symptoms and radiographic imaging [5]. Acute pancreatitis is clinically classified
as mild, moderately severe, or severe. Mild pancreatitis has no organ failure or local or systemic
complications, and usually resolves in approximately a week. Moderately severe pancreatitis is
characterized by transient organ failure (less than 48 hours), local complications (such as necrosis or
fluid collections) or exacerbation of co-morbid disease. Severe acute pancreatitis is characterized by persistent single or multiple organ failure. The Atlanta classification further standardizes diagnosis using strict imaging criteria. Acute
pancreatitis is subdivided into two types: interstitial edematous
pancreatitis and necrotizing pancreatitis. Interstitial edematous
pancreatitis is characterized by enlargement of the pancreatic gland
due to inflammatory edema, with homogenous enhancement of
the gland on contrast-enhanced CT. The majority of interstitial
edematous pancreatitis resolves within a week. In contrast, necrotizing
pancreatitis demonstrates non-enhancement of pancreatic and/or
peri pancreatic tissues (Figure 1). Necrotizing pancreatitis develops
in 5-10% of patients and may evolve over the course of the first week
of clinical symptoms. As such, necrotizing pancreatitis may be missed
on early cross-sectional imaging. Pancreatic necrosis will further
evolve over time;it may remain solid or liquefy, become infected or
remain sterile, or it may persist or resolve. Importantly, there is no
correlation between the degree of necrosis and the likelihood for
development of infection [5].
In addition, the Atlanta classification includes standardization of
local complications, including acute peripancreatic fluid collection,
pancreatic pseudocyst, acute necrotic collection and walled-off
necrosis (Table 1). Acute peripancreatic fluid collections develop
early in the course of pancreatitis, usually in the setting of interstitial
edematous pancreatitis. Collections are homogenous and confined
to fascial planes adjacent to the pancreas without development of a
wall or capsule, and no necrosis is present. Pancreatic pseudocysts
develop later in the course of interstitial edematous pancreatitis and
have a well-formed wall or capsule. Pseudocysts form adjacent to
the pancreatic parenchyma and their maturation requires 4 or more
weeks. Acute necrotic collections develop exclusively in necrotizing
pancreatitis and present early in the course. These collections are
heterogeneous, with both solid and liquid components, and lack a
well-defined wall (Figure 2). Walled-off necrosis can develop later in
the course of necrotizing pancreatitis and is characterized by a welldeveloped
inflammatory wall with heterogeneous contents (Figure
3). Both acute necrotic collections and walled-off necrosis may be
within the pancreatic parenchyma or in the peripancreatic space.
Additionally, these collections may be infected or sterile.
A number of clinical classification schemes have been proposed
to help predict the morbidity and mortality of acute pancreatitis
including Ranson’s criteria and the Bedside Index of Severity in Acute
Pancreatitis (BISAP). Developed in the 1970’s, Ranson’s criteria
attempts to risk-stratify patients with acute pancreatitis using clinical
data from admission and then 48 hours later [6]. To calculate a score,
one point is assigned for each criteria met (Table 2). A score of 0-2
predicts a mortality of 1% or less, a score of 3-4 predicts a mortality
of 15%, a score of 5-6 predicts a mortality of 40%, and a score of 7 or
greater predicts a 100% mortality [6]. Unfortunately, Ranson’s criteria
cannot be calculated before 48 hours, thus limiting its usefulness in
real-time. Others have attempted to simplify risk-stratification using
fewer variables [7]. In particular, an admission hematocrit >44%
and/or a rise inserum BUN within24 hours are strongly predictive of
increased morbidity and mortality. If either criterion is fulfilled, rates
of persistent organ failure and pancreatic necrosis reached 53.6% and
60.3%, respectively [8]. In contrast, the BISAP is a mortality-based
prognostic scoring system that evaluates only 5 clinical variables
within the first 24 hours of admission [9] (Table 3). That being said,
although BISAP is certainly more simplistic, it does not appear to
outperform any other scoring schema in predicting the severity of
acute pancreatitis [10].
Figure 1
Figure 1
Acute necrotizing pancreatitis with non-enhancement of pancreatic
neck (arrow), and extensive peripancreatic inflammation without defined fluid
collections.
Figure 2
Figure 2
Acute necrotizing pancreatitis with acute necrotic collection
adjacent to pancreatic neck (white arrow) and non-occlusive portal vein
thrombus (black arrow).
Table 1
Table 2
Management
Management of acute pancreatitis is remains supportive with attention to pain control, hemodynamic status, endpoints of resuscitation, and nutrition. Patients with organ failure or evidence of systemic inflammatory response should be admitted to an intensive care unit.
Figure 3
Table 3
Fluid Management
Fluid resuscitation should be provided to all patients within
the first 12-24 hours. Although few studies have demonstrated a
significant difference in outcome based on the type of intravenous
fluid selected, one small randomized controlled trial showed a decrease
in the incidence of SIRS when Lactated Ringer’s was used compared
to normal saline [11]. Similarly, the volume expander, hydroxyethyl
starch, has been shown to increase risk of renal failure and mortality
in patients with sepsis, and thus is not currently recommended for
resuscitation [12].
While under-resuscitation can clearly be detrimental, overlyaggressive
fluid resuscitation can also be harmful. In a study
comparing5-10 ml/kg/hrto 10-15 ml/kg/hr of resuscitation, the
group receiving less fluid had lower rates of mechanical ventilation,
abdominal compartment syndrome, sepsis, and mortality [13]. The
benefit of judicious fluid administration was recently demonstrated
in a randomized trial investigating hemodilution as resuscitation
target. One hundred and fifteen patients were randomized to a
resuscitation target hematocrit of either >35% or < 35% at 48 hours.
Patients undergoing slower hemodilution, and thus decreased fluid
resuscitation, had lower rates of sepsis (58% vs 79%) and mortality
(66% vs 85%) [14].
Although endpoints of resuscitation in acute pancreatitis have
not been well studied, it seems prudent to follow standardized critical
care resuscitation guidelines within the first 24 hours. Specific goals
include targeting a central venous pressure of 8-12 mmHg, a mean
arterial pressure of ≥65 mmHg, a urine output of ≥0.5 ml/kg/hr, a
central venous oxygen saturation of 70%, and a normalization of
lactate levels [15].
Antibiotic Therapy
Despite their common use, there is noben efit in using prophylactic antibiotics for sterile necrotizing pancreatitis [16,17]. In two randomized, blinded, placebo-controlled trials, the use of antibioticsfailed to demonstrate a benefit to prophylactic antibiotics [18,19]. More recently, two large meta-analyses also failed to demonstrate a benefit with routine antibiotics, although the use of imipenem may be promising [20,21]. In fact, use of prophylactic antibiotics has been associated with increased infection with multidrug resistant organisms and Candida albicans [22]. Pending further study, both the Infectious Disease Society of America and the American College of Gastroenterology recommend against prophylactic antibiotics for necrotizing pancreatitis without evidence of infection [23]. Antibiotics are absolutely recommended for infected pancreatitis and should be targeted toward the specific organism.
Nutritional Support
Historically, enteral nutrition was thought to be contraindicated
in acute pancreatitis, and patients were supported completely with
total parenteral nutrition (TPN) and bowel rest. However, it is now
well-established that enteral nutrition is both safe and beneficial.
Significant evidence exists regarding the benefit early initiation of
feeds, with most studies suggesting reduced mortality, decreased
incidence of intra-abdominal hypertension, fewer infectious
complications, and less multi-organ failure when feeds are initiated
within the first 48 hours [24,25]. In mild acute pancreatitis, it is not
necessary restrict to a clear liquid diet and low fat oral nutrition
should be introduced promptly [26]. In more severe pancreatitis,
enteral feeds are preferable. In a recent Cochrane review comparing
TPN to enteral nutrition in patients with acute pancreatitis, enteral
nutrition absolutely provided superior support [27]. Enteral nutrition
was associated with reduced mortality (relative risk 0.50), reduced
multi-organ failure (relative risk 0.55), reduced systemic infection
(relative risk 0.39), decreased operative interventions (relative
risk 0.44), and decreased local complications (relative risk 0.74).
Although it is difficult to determine how enteral feeds are clinically
protective, proposed mechanisms include the prevention of gut
luminal atrophy and stasis the enhancement of intestinal barrier
function with decreased inflammatory activation, and the prevention
of gut bacterial and endotoxin translocation. Given these benefits,
the American College of Gastroenterology recommends avoiding
parenteral nutrition entirely unless an enteral route is not available,
not tolerated, or does not result in adequate calories [23].
While it is important to initiate enteral feeds early in severe
pancreatitis, the route by which nutrition is delivered does not appear
to be important. In fact, nasogastric, nasoduodenal, or nasojejeunal
feeds appear to be clinically equivalent with no difference in rates
of tracheal aspiration, worsening of abdominal pain, diarrhea, or
achieving caloric goals. Additionally, the route of enteral nutrition
did not impact mortality [28].
Diagnosis of Infected Necrosis
Although infected necrosis most commonly develops 2-4 weeks
after the onset of pancreatitis, it may occur at any time and the
transition from sterile to infected necrosis can be difficult to determine
[29]. Risk factors include: elevated intra-abdominal pressure, ileus,
hypotension, parenteral nutrition, and increased severity of illness as
measured by the Acute Physiology and Chronic Health Evaluation
(APACHE) II score [30-32]. Elevated D-dimer levels also appear predictive and likely are a proxy for disease severity.
The development of infected necrosis is confirmed by the
pathognomonic CT imaging findings of extra luminal gas within
pancreatic or peripancreatic tissues. However, this radiographic
finding may not always be present even with infection. Thus, the
diagnosis of infected necrosis must be suspected based on clinical
signs and symptoms, including fever, tachycardia, and leukocytosis.
In fact, in one retrospective analysis, only 12- 40% of patients with
infected necrosis had evidence of extra luminal gas on cross-sectional
imaging[29,33]. CT-guided aspiration has been suggested as a method
of confirming infection when imaging is inconclusive. CT guided
aspiration, however, has a reported 25% risk of false-negative results
[34]. Given the risk of under diagnosing infection, as well as the small
risk of introducing bacteria, there has not been universal adoption of
this technique. As such, the diagnosis of infected pancreatic necrosis
remains largely based on clinical suspicion.
When infected necrosis is suspected, antibiotics should be
initiated promptly. The majority of infections are monomicrobial
with gut-derived bacteria. The most common organisms include
Escherichia coli, Staphylococcus aureus, and Enterococcus faecalis, but
other pathogens are becoming more prevalent and increasingly more
drug resistant [22,35]. Additionally, patients treated with prophylactic
broad spectrum antibiotics have been found to have increased
incidence of infection from Candida albican [17]. If empiric therapy
is initiated, antimicrobials known to penetrate pancreatitis necrosis
(carbapenems, or quinolones,and metronidazole) should be chosen
initially. Antibiotic coverage may be expanded to include antifungals
or gram positives if the clinical picture fails to improve.
Drainage
Understanding the timing and indications for imaging-guided
drainage of necrotizing pancreatitis is critical. Acute peripancreatic
fluid collections rarely require any intervention, and largely resolve
on their own with supportive care. Similarly, pancreatic pseudocysts
(especially those less than 6 centimeters in size) tend to resolve with
supportive care. Pseudocysts that do not resolve are largely treated
successfully with endoscopic techniques and rarely require surgery
[36]. Non-infected pancreatic necrosis is also generally managed
with supportive care, allowing collections to evolve from acute
necrotic collections to organized walled-off necrosis. In the absence
of infection, the only indication for acute intervention is compressive
symptoms. Conversely, suspected or proven infected necrosis
generally requires percutaneous drainage, at a minimum.
Over the last few decades, interventions for pancreatitis have
changed greatly [37]. With increasing access to imaging-guided or
endoscopic drainage techniques, the role of open surgical drainage/
debridement has become increasingly limited andnecrosectomy
has largely been replaced by a well-described “Step-up” approach
encompassing imaging-guided catheter drainage, followed by
minimally invasive videoscopic or endoscopic necrosectomy in
a sequential fashion depending on clinical response to escalating
therapy. In 2010, the Dutch Pancreatitis Study group directly
compared the minimally invasive Step-Up approach to surgical
necrosectomy in 88 patients with acute necrotizing pancreatitis
(PANTER trial).The Step-up approach was associated with fewer
complications including multi-organ failure, incisional hernia and
new-onset diabetes [38]. Similarly, are sent Cochrane review found
that minimally invasive approaches resulted in fewer adverse events,
organ failure, and lower costs [37]. In fact, recent studies have shown
that over 60% of patients treated with percutaneous catheter drainage
had resolution of sepsis, with nearly half of these patients avoiding
surgery entirely [39]. Most guidelines suggest that any intervention
should be delayed until the necrosis can be walled off, which usually
takes at least 4 weeks [38,40].However, this recommendation is
largely based on the era of open necrosectomy. With the majority of
patients in the modern era being treated with a minimally invasive
approach, it is unclear if delaying intervention is still prudent.
In addition, certain conditions such as persistent SIRS, sepsis, or
abdominal compartment syndrome may force earlier catheter
drainage or surgical intervention. Moreover, increasing data suggest
that early intervention may be more beneficial than first appreciated.
In fact, early catheter drainage in the setting of suspected necrosis
may mitigated the need for further surgical necrosectomy [41].
The optimum timing of any percutaneous intervention, however,
remains unknown. Currently, The Dutch Pancreatitis Study Group is
conducting the POINTER trial, a randomized controlled trial, which
will determine if early or delayed catheter drainage leads to improved
outcomes [42].
Figure 4
Complications
Pseudoaneurysm and hemorrhage
Hemorrhage in the setting of necrotizing pancreatitis is a
relatively common complication. Hemorrhage is typically due
to the effect of inflammatory changes on nearby vasculature,
resulting in abnormalities in vascular wall and development of
pseudoaneurysms. Necrotic collections may also erode into vessels,
causing hemorrhage (Figure 4). In addition, mesenteric venous
thrombosis may result in sinastral portal hypertension, causing
gastric varices and upper gastrointestinal hemorrhage. Patients
classically present with a sentinel hemorrhage, followed by a larger,
often fatal hemorrhage. In one case series of over 1300 patients with
acute pancreatitis, 1% developed hemorrhagic complications, with a
34% mortality [43] Other case series have reported similar mortality
rates [44] Angiographic embolization is usually both diagnostic and
therapeutic, with a sensitivity rate of >95%, and rates of successful
hemostasis approaching 90%.[45,46].
Mesenteric venous thrombosis,br/>
Mesenteric venous thrombosis is a common complication of
acute pancreatitis, with a reported incidence of 14%. In patients with
necrotizing pancreatitis, however, the risk of thrombosis increases significantly with a reported incidence of 50% [47]. Interestingly, in
this case series, no patients developed complications from mesenteric
venous thrombosis, despite infrequent use of anticoagulation. In
another series, spontaneous recanalization was noted in up to one third
of patients [48]. The feared complication of upper gastrointestinal
bleed from gastric varices as a result of sinastral portal hypertension
is also quite rare, with an incidence of 4%-12% [49,50].
Intestinal complications
Local inflammation in necrotizing pancreatitis can affect not
only the regional vasculature, but also the intestines. The incidence of
intestinal complications ranges from 10 to 44%, with the transverse
colon being the most commonly affected [51,52]. Complications
include fistulization, stricture, or necrosis with perforation. These
complications may be a result of local inflammation, vascular
compromise, or drain placement. Surgical management remains the
mainstay of management, although some fistulas may be amenable to
non-operative treatment.
Abdominal compartment syndrome
Abdominal compartment syndrome (ACS) is diagnosed by a
combination of sustained intra-abdominal hypertension (IAH),
defined as a bladder pressure >12 mmHg, along with evidence of
end-organ failure. While the incidence of IAH in patients with
severe acute pancreatitis is 60-80%, thankfully the incidence of ACS
is only 27% [53]. Although randomized, controlled trials regarding
the management of ACS in pancreatitis are lacking, surgical
decompression should be viewed as a last resort. Other therapies
include decompression with nasogastric and rectal tubes, minimizing
fluid resuscitation if possible, and abdominal wall relaxation with
sedation and neuromuscular blockade. Percutaneous drainage of
intra-abdominal fluid is recommended if a large volume of ascites
is noted on imaging. As would be expected, mortality in patients
requiring decompressive laparotomy is high and exceeds 50% [53].
Conclusion
Acute pancreatitis is an increasingly common cause of morbidity and mortality worldwide. Significant advances in management have been made over the past two decades, with better understanding of the role of enteral nutrition and utilization of minimally invasive techniques for management of infected pancreatic necrosis. Although evidence-based management guidelines have been published, areas of uncertainty still exist regarding optimal use of antibiotic therapy, the diagnosis of infected necrosis, and timing for intervention in the setting of infected necrosis. The formation of large international consortium groups and multicenter trials will continue to advance the care of patients with acute pancreatitis and significantly improve our understanding of this physiologically complex disease.
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