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Severe Acute Pancreatitis: Since the Classical
81
enzymes, which causes auto-digestion of the pancreatic parenchyma [1]. In all
cases of AP, the triggered cause in 60-80% in developed countries is attributed
to biliary illnesses or alcohol abuse. The incidence of idiopathic pancreatitis
emerges as an etiology more and more frequently, seemingly due to the
increase in rates of morbid obesity [1, 2], Although the incidence of AP
continues to increase, the mortality rate remains the same [3]. Males and
females are similarly affected despite alcohol abuse being more common in
men and biliary illnesses more common in women [4].
The Atlanta classification describes AP as mild, moderate, and severe [5].
Mild presentation (Interstitial edematous pancreatitis) is 80-90% more
frequent, is self-limited, and resolves without serious complications in
about one week [3]. It is characterized by the absence of pancreatic or
peripancreatic necrosis and mortality is rare [6].
In moderate AP, there are local complications (collection of
peripancreatic fluid, peripancreatic necrosis) or systemic
complications (exacerbation of the pre-existing illness), and organ
failure is transient <48 h. The morbidity and mortality is higher than
in mild AP, and the event lasts about 2-3 weeks [3].
Severe AP (SAP) is characterized by persistent organ failure >48 h,
with presence of local and systemic complications; accumulation of
peripancreatic fluid, pancreatic and peripancreatic necrosis (sterile or
infected); and pseudocysts and necrosis (sterile or infected) can
appear. SAP has a mortality rate from 5-35% [7]. Early diagnosis and
classification of its severity should be managed aggressively in order
to prevent lethal multiple organ failure (MOF) [8]. The development
of infected necrosis indicates severity and is considered the primary
cause of death [9].
Acute pancreatitis has a biphasic clinical course. The first 1-2 weeks after
the onset of symptoms are characterized by the appearance of the systemic
inflammatory response syndrome (SIRS). The SIRS is a direct result of serious
systemic inflammation, seemingly unrelated to the infection. Among
complications, infections with bacteremia are frequently associated with the
use of mechanical ventilators [10]. Early organ failure presents approximately
2 days after hospitalization and affects all the organs, but can be present from
the outset. Fatal cases of AP are related to MOF and if infected necrosis occurs
about 43% of patients die. After 1-2 weeks evolution, SAP presents with the
Alejandra Guillermina Miranda-Díaz et al.
82
compensatory anti-inflammatory response syndrome (CARS), which is related
to infection and infected necrosis [11].
The patient’s response to management can vary depending on the
seriousness of the AP; and there can improvement with treatment measures or
they can present with early onset MOF with deterioration about 3-4 weeks
after its onset, due to infected necrosis. With early organ failure that does not
improve after 2-3 weeks of intensive therapy, or with the appearance of gas
bubbles, it is recommended to confirm or discard infection in order to
determine the need for antibiotic therapy or some type of interventional
procedure [12].
COMPLICATIONS OF SAP
Infected Necrotic Pancreatitis
Infection in pancreatic and peripancreatic necrosis is unusual during the
first week after the episode of necrotizing pancreatitis demonstrating a greater
increase in peripancreatic fat. It is speculated that the infection occurs when
there are focal air bubbles in the pancreas and/or peripancreatic tissues [13].
Infection of the pancreatic necrosis occurs early (<3 weeks) and is associated
with higher mortality rate than in infections that present later on [14].
Infections are frequently polymicrobial and involve aerobic and anaerobic
bacteria. The most common causal microorganisms originate from the
gastrointestinal tract and include: Escherichia coli, Klebsiella spp,
Enterobacter spp, Proteus spp, Pseudomona aeruginosa, Bacteroides spp,
Clostridium spp and Enterococci [15]. Consequently, in infected SAP,
prophylactic broad-spectrum antimicrobials are often administered with the
aim to reduce the incidence of pancreatic and peripancreatic infections and
mortality [16].
Compartmental Syndrome
The global incidence of intra-abdominal hypertension in SAP is about 50-
75% and abdominal compartmental syndrome is about 10-25% [17]. The
increase in intra-abdominal pressure provokes upward displacement of the
hemi diaphragms and causes atelectasis and hypercapnia. Also, if bilateral
pleural effusion occurs, it can lead to severe hypoxia. The development of
Severe Acute Pancreatitis: Since the Classical
83
intra-abdominal hypertension and the compartmental syndrome greatly
impacts morbidity and mortality. The combined effect of the inflammatory
process itself and the aggressive fluids administration could be damaging.
According to the International Consensus of 2007, the abdominal
compartmental syndrome is defined by an increase in intra-abdominal pressure
>20 mmHg with signs of MOF. While the optimal treatment strategy for
abdominal compartmental syndrome is still not well-defined, percutaneous
drainage could be useful as an initial step in the presence of free intra-
abdominal fluid. If this does not lead to immediate clinical improvement or if
liquid is not present on the left side, the next recommended step is the
performance of decompressive laparotomy. The majority of authors advise
against exploring the pancreas during decompression of the compartmental
syndrome, because it is too early to remove the necrosis safely, and there is the
risk of infecting the developing, yet likely still sterile at that stage, necrosis.
An interesting alternative after decompressive laparotomy, could be the
application of the vacuum-assisted closure system (VAC) with exchanges
every 48-72 h [18]. Figure 1A
Figure 1. Severe Acute Pancreatitis. 1A) Vacuum-assisted closure system (VAC)
applied to a patient with SAP with compartmental syndrome. 1B) and 1C) Observation
of removal of necrotic pancreatic tissue. Previously, the purulent necrotic
peripancreatic material was drained. 1D) and 1E) Show the application of the VAC
system; and 1F) Time lapse in the management with the VAC system.
Alejandra Guillermina Miranda-Díaz et al.
84
Walled-Off Pancreatic Necrosis (WOPN)
Severe acute pancreatitis can complicate with WOPN in its late phase
(minimum of 4 weeks after onset of the illness) [19]. Because the
morphological changes occur late in the course of necrotizing AP, WOPN
consists of a circumscribed area that contains the remains of parts of the
pancreas and necrotic fluid, stemming from some necrotic area. The
translation of the term originally proposed in the English language can cause
initial controversy; however, the radiological concept includes defined, well-
demonstrated changes that are described by the term ‘muralled-off pancreatic
necrosis’ that stems from the expression ‘In wall-off,’ which means building a
mural around a determined space; in this case in pancreas [20].
Pancreatic Pseudocysts
Defined as a round collection or ovoid form, circumscribed and
homogenous, with liquid rich in amylase, which develops late in the course of
AP (About 4 weeks after the initial event), and does not contain any sign of
necrosis or solid material within it. They are surrounded by a capsule of non-
epithelialized granular tissue, and are found in intra or extra-pancreatic spaces
[36]. Pseudocysts consist of the natural development of collections of
peripancreatic fluid, which persist for >4 weeks and occur in 10-20% of
patients. The term ‘pseudocyst’ is used for the majority of cases of collections
of extra-pancreatic fluids. Visualization of the walls of the pseudocyst
(Capsule) in images is possible depending on the wall’s thickness, and the
observation of a circumscribed accumulation of fluid should always be seen.
Pseudocysts can disappear spontaneously or develop complications such as
bleeding and infection. ‘Pancreatic abscess’ is the term adopted by the Atlanta
classification that is actually no longer in use and should be replaced by
‘infected pseudocyst’ [21].
METHODS
Initial clinical manifestations of AP are based on intense abdominal pain,
serum amylase or lipase ≥3 times higher than normal and after 72-96 h of
evolution, and findings of AP on computed tomography (CT) with the
presence of relevant morphological changes. It is recommended that the group
Severe Acute Pancreatitis: Since the Classical
85
of patients with a high risk of suffering SAP benefit from aggressive fluid
replacement, broad vigilance for the timely detection of organ failure, timely
adequate administration of antibiotics, and specific therapeutic procedures
such as endoscopic sphincterotomy and interventional radiology [22].
Clinical Evaluation
There are diverse methods to evaluate for AP. Individual parameters such
as age, presence of pleural effusion, obesity; levels of blood urea nitrogen,
creatinine, hematocrit; C-reactive protein and procalcitonin, have been
described [23]. There are also multiple parameters that evaluate severity of the
pancreatic and systemic damage, among which are found: the Ranson’s
criteria, the SIRS, the Glasgow scale, and the Acute Physiology and Chronic
Health Evaluation II (APACHE II). Liver enzymes can be elevated; in
particular the alanine aminotransferase (ALT), where levels >150 IU/L tend to
be a substitute marker for pancreatitis due to gallstones, with a positive
predictive value of 95%. Findings of AST >100 U/L also seem to be useful
[24].
The Bedside Index of Severity in Acute Pancreatitis (BISAP score) is the
newest predictive scoring system and is a reliable tool to identify AP patients
who have a high risk of unfavorable outcomes, in comparison with the
classical Ranson’s criteria and the APACHE II classification system. The
BISAP index was proposed as a simple, precise method to early identify
patients with high risk of hospital mortality [25, 26]. It primarily evaluates
levels of blood urea nitrogen >25 mg/dL, impairment of mental state, the
development of SIRS, age >60 years, and the presence of pleural effusion. The
BISAP score is 95% specific but 51% sensitive in predicting mortality due to
SAP [27, 28]. The prognostic utility of the different clinical and radiological
scoring systems in AP is compatible with the BISAP score because it has the
highest accuracy to predict premature MOF and mortality [29, 30].
Ranson’s Criteria
In the ‘Seventies’ of the past century Ranson’s criteria was designed. This
classification system, upon hospitalization, evaluates: age >55 years, white
blood cell count >16,000/mm
3
, blood glucose >200 mg/100 mL; serum lactic
dehydrogenase >350 IU/L, and AST >250 IU/100 mL; and, after the first 48 h:
Alejandra Guillermina Miranda-Díaz et al.
86
hematocrit <10%, increase in blood urea nitrogen >5 mg/100 mL, serum
calcium <8 mg/100 mL, arterial p0
2
< 60 mmHg, base deficit >4 mq/dL, and
~>6000 mL of fluid requirements [31]. Recently, a retrospective analysis was
published on 21 patients with SAP, where the Ranson’s score had a global
sensitivity of 75%, a specificity of 77%, a positive predictive value (PPV) of
49%, and a negative predictive value (NPV) of 91%; outstanding in the high
rate of false positives that SAP doesn’t have [32]. For the APACHE II
classification, an 81% sensitivity, 65.7% specificity, PPV of 26.2%, and NPV
of 95.8% were reported [22].
It must be emphasized that a definitive consensus does not exist on which
scoring system should be used. Recent norms suggest that existing scoring
systems have limited value because they all have a good NPV but a low PPV.
Nonetheless, it is recommended to complete the evaluation on all patients with
pancreatitis and to stratify or categorize them as high or low risk, since the
majority of scoring systems require 48 h for the exact score, and the systems
based in CT are also inaccurate in the early phase of the illness because the
necrosis becomes evident 48 h after the onset of the symptomatology [33].
Table 1 shows the sensitivity, specificity, and the positive and negative
predictive values of some evaluation systems.
Table 1. Evaluation Methods in Severe Acute Pancreatitis. Shows the
sensitivity, specificity, positive predictive value, and negative predictive
value in SAP. The data were obtained from various bibliographic
references, the majority of which are found in the primary text
Sensitivity
Specificity
Predictive
value (+)
Predictive
value (-)
Ranson
75%
77%
49%
91% [25]
ALT
95% Gallstones
[17]
CT
87%
100% [34]
MR
83%
91% [50]
BISAP
51%
91% [20, 21]
40.48%
96.23%
APACHE II
81%
65.7%
26.2%
95.8%
[26]
CTSI
100% Pancreatic
necrosis
100% Pancreatic
necrosis
CRP
86%
87%
75%
93%
ALT: alanine-aminotransferase; CT: Computed Tomography; MR: Magnetic Resonance;
BISAP: Bedside index for severity in acute pancreatitis; APACHE-II, Acute
physiology and chronic health evaluation-II, CTSI: Computed tomography severity
index; CRP: C-reactive protein, measured after 24 h.
Severe Acute Pancreatitis: Since the Classical
87
Ultrasound
Ultrasound is the imaging method that is most relevant at the affliction’s
onset to detect sediment or gallstones in the gallbladder or common bile duct.
The diagnosis of biliary pancreatitis is based in the formation of images, but
can also be made in absence of them when the common bile duct is >10 mm in
patients >75 years of age. When the cause of AP cannot be determined,
ultrasound or endoscopic echography is recommended as a first-line to
evaluate occult microlithiasis in 57% of cases, neoplasia, or chronic
pancreatitis [34].
Endoscopic Retrograde Cholangeo-Pancreatography (ERCP)
with Sphincterotomy
Is the endoscopic procedure recommended in the case of lithiasic illness,
which can reveal sediment or gallstones in the gallbladder or the common bile
duct. Patients with biliary pancreatitis who present with cholangitis or stones
in the bile duct should be subjected to ERCP within the first 24 h from the
onset of pancreatitis. However, the evidence reported in a recent meta-analysis
did not demonstrate any benefit from ERCP in the evolution of SAP [35].
Radiological Classification Systems
The diagnosis and classification of AP is aided by CT or magnetic
resonance (MR), ideally performed 72 h after the appearance of symptoms,
with the objective of achieving the most accurate classification of the
pancreatic necrosis. Extension of the necrosis correlates well with the
incidence of infected necrosis, MOF, need for debridement, morbidity, and
mortality. Characteristics of the CT images in AP include diffuse or focal
amplification of the pancreas, the peripancreatic fat, thickening of the
peripancreatic fascia, and the presence of fluids [36]. Normal assessment of
the pancreas by CT is classified because it is surrounded by fat in the
transverse section. It has a homogeneous attenuation and is identified by its
relationship to the superior mesenteric artery and the duodenum [37]. Normal
pancreatic parenchyma have ~50-80 Hounsfield Units (HU) [38]. Computed
tomography has an 87% sensitivity and 100% specificity in the detection of
pancreatic necrosis [39]. The role that CT plays in predicting SAP has been
Alejandra Guillermina Miranda-Díaz et al.
88
evaluated by different methods such as the Balthazar score categorized by
grades: a) Grade A, normal; Grade B, enlargement of the pancreas; Grade C,
peripancreatic inflammation; Grade D, accumulation of fluid; and Grade E, ≥2
fluid collections with or without gas bubbles [40]. This assessment system is
based on size, shape, and density of the pancreatic anomalies and of the
peripancreatic tissue, to predict severity of the AP [41]. In 1990, Balthazar
validated the severity of AP with the Computed Tomography Severity Index
(CTSI). This system combines the initial classification system (1985) with the
presence and extension of pancreatic necrosis. This severity index has more
prognostic accuracy than the previous scoring method, but it has some
limitations since the score does not incorporate organ failure, additional
complications of the pancreatic parenchyma or vascular/peripancreatic
vascular complications, and correlation with the final outcome. CT alone
should be used for the initial assessment if doubts exist regarding the clinical
diagnosis or normal level of lipase/amylase. Doubt in the clinical diagnosis
can be due to the pain not being typical, or if some alternative diagnosis
(suspected intestinal perforation or ischemia) should be excluded [42, 43, 44].
The Modified Computed Tomography Severity Index (MCTSI) developed by
Mortele, et al., [45] is a system that is easy to calculate and reproduce, and
correlates more widely with the appearance of infection, MOF, the necessity
for percutaneous surgical intervention, duration of hospital stay, and mortality,
than the CTSI [46]. The MCTSI, apart from being more accurate than the
CTSI, has a stronger statistical correlation than the clinical outcome [47]. The
Contrast Enhanced Computed Tomography index (CECT) is considered the
gold standard in imaging modality for evaluating patients with AP [48]. The
role in the formation of images is not only for diagnosing AP, but
demonstrates the presence and extension of pancreatic necrosis and
complications. The ideal time to obtain the CECT is 48-72 h after the
appearance of the acute attack, since the possibilities of finding necrotizing
pancreatitis increases [49]. The ideal moment to repeat CT imaging is
indicated when the clinical picture changes significantly, which can occur with
the appearance of fever, decrease in hematocrit, or signs of sepsis. The CT is
an indispensible complement to guide the needle and place a catheter in the
bed of the pancreas, as well as monitoring the success of treatment in patients
who have been subjected to percutaneous intervention, endoscopy, or surgery
[50]. On the other hand, the usefulness of the Extra-pancreatic Inflammation
on Computed Tomography (EPIC) index and the Renal Rim Sign is unclear
because these scoring systems have not been compared to the conventional
radiological scoring systems such as the CTSI, CECT, and the MCTSI [51].
Severe Acute Pancreatitis: Since the Classical
89
Magnetic Resonance
Magnetic resonance (MR) is often reserved for the detection of
choledocholithiasis not seen on CT, and to outline the anatomy of the
pancreatic duct. Although CT continues to be ideal for pancreatic necrosis in
the majority of institutions, some groups prefer MR [52]. The advantages of
MR are that it doesn’t produce ionizing radiation and it has a grand capacity to
show the bile ducts in high resolution, which makes it ideal for pregnant
patients. MR is recommended in patients with poor renal function who should
not receive contrast mediums (typically with GFR <35 mL/min) [50].
Magnetic resonance offers better defined resolution than the improved CT
without contrast. Using Ranson’s criteria as a gold standard, Arvanitakis, et.
al., compared CT and MR in the detection of areas of hypo perfusion
compatible with pancreatic necrosis and found that MR offers higher
sensitivity (83% vs. 78%) and specificity (91% vs. 86%). However, MR
produces more motion artifacts [53]. Magnetic resonance is recommended to
be used as a second line investigation [54]. The MR by Diffusion Weighted
Imaging (DWI) emerges as a promising technique in the early diagnosis of AP
[55]. The DWI explores the random movement of water molecules in the
body. The grade of restriction to the diffusion of water correlates inversely
with the cellularity of the tissue and the integrity of cellular membranes. The
DWI is considered a powerful tool in AP evaluation, because the inflammatory
processes correlate with restricted water diffusion [56]. The main advantage of
DWI is that it does not require any contrast medium, since intravenous
contrast medium is contraindicated in AP patients with renal failure.
According to the literature, measured values of the apparent diffusion
coefficient (ADC) of the head are 1.02 X 10
3
and 1.94 x 10
-3
mm
2
/s. The head
and the body have ADC values that are slightly higher compared to the tail
[57].
MANAGEMENT ALTERNATIVES IN ACUTE PANCREATITIS
The majority of studies published in the literature are retrospective: very
few studies report comparative, prospective techniques. However, it is
recommended that SAP patients traditional be treated with intestinal repose,
pain control, intravenous fluids, correction of electrolyte and metabolic
alterations, early enteral nutrition, and close monitoring to maintain adequate
organ perfusion. All patients with MOF or SAP, according to the definition of
Alejandra Guillermina Miranda-Díaz et al.
90
the revised version of the Atlanta classification, should be managed in the
Intensive Care Unit (ICU) [58].
Artificial Nutrition
Because enteral nutrition can stimulate pancreatic and intestinal secretion,
the concept of pancreas rest is a dogma in the management of SAP. However,
intestinal repose is associated with intestinal atrophy, the overgrowth of
bacteria, and is responsible for endotoxemia and an increase in serum levels of
inflammatory cytokines, of bacterial translocation, and the induction of SIRS.
Prolonged fasting is also associated with a higher risk of infected pancreatic
necrosis [59]. On the other hand, the use of early enteral nutrition (Within the
first 48 h after hospitalization) has been demonstrated as beneficial in patients
with AP, since it improves clinical outcomes through the reduction of
infections, particularly pancreatic infections. Patients with AP should be
managed without oral ingestion until abdominal pain, nausea and vomiting are
resolved [60]. In mild AP, enteral nutrition can be implemented from the first
or second day after hospital admission [61]. Early enteral nutrition by naso-
jejunal (NJ) tube improves AP if the patient does not resume a normal diet
within 3 days. Early enteral nutrition by NJ tube moderates the excessive
immune response during the early phase of SAP without causing
immunosuppression. Despite early enteral nutrition improving clinical
outcomes it has not been demonstrated to decrease hospital mortality in
patients with SAP [62]. Total parenteral nutrition should be avoided if at all
possible [63].
Pharmacological Treatment
There are few existing studies that report the different pharmacological
options available for the treatment of AP in experimental and clinical trials.
Evidence based in the pharmacological treatment of AP is limited. To follow,
some treatment alternatives are mentioned.