Acute Pancreatitis

Practice Essentials

Recognizing patients with severe acute pancreatitis as soon as possible is critical for achieving optimal outcomes. Management depends largely on severity. Medical treatment of mild acute pancreatitis is relatively straightforward. Treatment of severe acute pancreatitis involves intensive care. Surgical intervention (open or minimally invasive) is indicated in selected cases. Signs and symptoms Symptoms of acute pancreatitis include the following:

• Abdominal pain (cardinal symptom): Characteristically dull, boring, and steady; usually sudden in onset and gradually becoming more severe until reaching a constant ache; most often located in the upper abdomen and may radiate directly through to the back

• Nausea and vomiting, sometimes with anorexia

• Diarrhea

Patients may have a history of the following:

• Recent operative or other invasive procedures

• Family history of hypertriglyceridemia

• Previous biliary colic and binge alcohol consumption (major causes of acute pancreatitis)

The following physical findings may be noted, varying with the severity of the disease:

• Fever (76%) and tachycardia (65%); hypotension

• Abdominal tenderness, muscular guarding (68%), and distention (65%); diminished or absent bowel sounds

• Jaundice (28%)

• Dyspnea (10%); tachypnea; basilar rales, especially in the left lung

• In severe cases, hemodynamic instability (10%) and hematemesis or melena (5%); pale, diaphoretic, and listless appearance

• Occasionally, extremity muscular spasms secondary to hypocalcemia

The following uncommon physical findings are associated with severe necrotizing pancreatitis:

• Cullen sign (bluish discoloration around the umbilicus resulting from hemoperitoneum)

• Grey-Turner sign (reddish-brown discoloration along the flanks resulting from retroperitoneal blood dissecting along tissue planes); more commonly, patients may have a ruddy erythema in the flanks secondary to extravasated pancreatic exudate

• Erythematous skin nodules, usually no larger than 1 cm and typically located on extensor skin surfaces; polyarthritis

Diagnosis

Once a working diagnosis of acute pancreatitis is reached, laboratory tests are obtained to support the clinical impression, such as the following:

• Serum amylase and lipase

• Liver-associated enzymes

• Blood urea nitrogen (BUN), creatinine, and electrolytes

• Blood glucose

• Serum cholesterol and triglyceride

• Complete blood count (CBC) and hematocrit; NLR

• C-reactive protein (CRP)

• Arterial blood gas values

• Serum lactic dehydrogenase (LDH) and bicarbonate

• Immunoglobulin G4 (IgG4): elevated in autoimmune pancreatitis

Diagnostic imaging is unnecessary in most cases but may be obtained when the diagnosis is in doubt, when pancreatitis is severe, or when a given study might provide specific information required. Modalities employed include the following:

• Abdominal radiography (limited role): Kidneys-ureters-bladder (KUB) radiography with the patient upright is primarily performed to detect free air in the abdomen

• Abdominal ultrasonography (most useful initial test in determining the etiology, and is the technique of choice for detecting gallstones)

• Endoscopic ultrasonography (EUS) (used mainly for detection of microlithiasis and periampullary lesions not easily revealed by other methods)

• Abdominal computed tomography (CT) scanning (generally not indicated for patients with mild pancreatitis but always indicated for those with severe acute pancreatitis)

• Endoscopic retrograde cholangiopancreatography (ERCP); to be used with extreme caution in this disease and never as a first-line diagnostic tool [1]

• Magnetic resonance cholangiopancreatography (MRCP) (not as sensitive as ERCP but safer and noninvasive)

Other diagnostic modalities include the following:

• CT-guided or EUS-guided aspiration and drainage

• Genetic testing

Acute pancreatitis is broadly classified as either mild or severe. According to the Atlanta classification, severe acute pancreatitis is signaled by the following [2] :

• Evidence of organ failure (eg, systolic blood pressure below 90 mm Hg, arterial partial pressure of oxygen [Pa O2] 60 mm Hg or lower, serum creatinine level 2 mg/dL or higher, GI bleeding amounting to 500 mL or more in 24 hours)

• Local complications (eg, necrosis, abscess, pseudocyst)

• Ranson score of 3 or higher or APACHE score of 8 or higher

Management Medical management of mild acute pancreatitis is relatively straightforward; however, patients with severe acute pancreatitis require intensive care. Initial supportive care includes the following:

• Fluid resuscitation [3]

• Nutritional support

Antibiotic therapy is employed as follows:

• Antibiotics (usually of the imipenem class) should be used in any case of pancreatitis complicated by infected pancreatic necrosis but should not be given routinely for fever, especially early in the presentation

• Antibiotic prophylaxis in severe pancreatitis is controversial; routine use of antibiotics as prophylaxis against infection in severe acute pancreatitis is not currently recommended

Surgical intervention (open or minimally invasive) is indicated when an anatomic complication amenable to a mechanical solution is present. Procedures appropriate for specific conditions involving pancreatitis include the following:

• Gallstone pancreatitis: Cholecystectomy

• Pancreatic duct disruption: Image-guided percutaneous placement of a drainage tube into the fluid collection [4] ; stent or tube placement via ERCP; in refractory cases, distal pancreatectomy or a Whipple procedure

• Pseudocysts: None necessary in most cases; for large or symptomatic pseudocysts, percutaneous aspiration, endoscopic transpapillary or transmural techniques, or surgical management

• Infected pancreatic necrosis: Image-guided aspiration; necrosectomy

• Pancreatic abscess: Percutaneous catheter drainage and antibiotics; if no response, surgical debridement and drainage

Background

This article focuses on the recognition and management of acute pancreatitis. Pancreatitis is an inflammatory process in which pancreatic enzymes autodigest the gland. The gland sometimes heals without any impairment of function or any morphologic changes; this process is known as acute pancreatitis. Pancreatitis can also recur intermittently, contributing to the functional and morphologic loss of the gland; recurrent attacks are referred to as chronic pancreatitis. Both forms of pancreatitis may present in the emergency department (ED) with acute clinical findings. Recognizing patients with severe acute pancreatitis as soon as possible is critical for achieving optimal outcomes Once a working diagnosis of acute pancreatitis is reached, laboratory tests are obtained to support the clinical impression, to help define the etiology, and to look for complications. Diagnostic imaging is unnecessary in most cases but may be obtained when the diagnosis is in doubt, when severe pancreatitis is present, or when an imaging study might provide specific information needed to answer a clinical question. Image-guided aspiration may be useful. Genetic testing may be considered. Management depends largely on severity. Medical treatment of mild acute pancreatitis is relatively straightforward. Treatment of severe acute pancreatitis involves intensive care; the goals of medical management are to provide aggressive supportive care, to decrease inflammation, to limit infection or superinfection, and to identify and treat complications as appropriate. Surgical intervention (open or minimally invasive) is indicated in selected cases

Pathophysiology

Normal pancreatic function The pancreas is a gland located in the upper posterior abdomen. It is responsible for insulin production (endocrine pancreas) and the manufacture and secretion of digestive enzymes (exocrine pancreas) leading to carbohydrate, fat, and protein metabolism. Approximately 80% of the gross weight of the pancreas supports exocrine function, and the remaining 20% is involved with endocrine function. The focus of this article is on the exocrine function of the pancreas. The pancreas accounts for only 0.1% of total body weight but has 13 times the protein-producing capacity of the liver and the reticuloendothelial system combined, which together make up 4% of total body weight. Digestive enzymes are produced within the pancreatic acinar cells, packaged into storage vesicles called zymogens, and then released via the pancreatic ductal cells into the pancreatic duct, where they are secreted into the small intestine to begin the metabolic process. In normal pancreatic function, up to 15 different types of digestive enzymes are manufactured in the rough endoplasmic reticulum, targeted in the Golgi apparatus and packaged into zymogens as proenzymes. When a meal is ingested, the vagal nerves, vasoactive intestinal polypeptide (VIP), gastrin-releasing peptide (GRP), secretin, cholecystokinin (CCK), and encephalins stimulate the release of these proenzymes into the pancreatic duct. The proenzymes travel to the brush border of the duodenum, where trypsinogen, the proenzyme for trypsin, is activated via hydrolysis of an N-terminal hexapeptide fragment by the brush border enzyme enterokinase. Trypsin then facilitates the conversion of the other proenzymes into their active forms. A feedback mechanism exists to limit pancreatic enzyme activation after appropriate metabolism has occurred. It is hypothesized that elevated levels of trypsin, having become unbound from digesting food, lead to decreased CCK and secretin levels, thus limiting further pancreatic secretion. Because premature activation of pancreatic enzymes within the pancreas leads to organ injury and pancreatitis, several mechanisms exist to limit this occurrence. First, proteins are translated into the inactive proenzymes. Later, posttranslational modification of the Golgi cells allows their segregation into the unique subcellular zymogen compartments. The proenzymes are packaged in a paracrystalline arrangement with protease inhibitors. Zymogen granules have an acidic pH and a low calcium concentration, which are factors that guard against premature activation until after secretion has occurred and extracellular factors have triggered the activation cascade. Under various conditions, disruption of these protective mechanisms may occur, resulting in intracellular enzyme activation and pancreatic autodigestion leading to acute pancreatitis. Pathogenesis of acute pancreatitis Acute pancreatitis may occur when factors involved in maintaining cellular homeostasis are out of balance. The initiating event may be anything that injures the acinar cell and impairs the secretion of zymogen granules; examples include alcohol use, gallstones, and certain drugs. At present, it is unclear exactly what pathophysiologic event triggers the onset of acute pancreatitis. It is believed, however, that both extracellular factors (eg, neural and vascular response) and intracellular factors (eg, intracellular digestive enzyme activation, increased calcium signaling, and heat shock protein activation) play a role. In addition, acute pancreatitis can develop when ductal cell injury leads to delayed or absent enzymatic secretion, as seen in patients with the CFTR gene mutation. Once a cellular injury pattern has been initiated, cellular membrane trafficking becomes chaotic, with the following deleterious effects:

• Lysosomal and zymogen granule compartments fuse, enabling activation of trypsinogen to trypsin

• Intracellular trypsin triggers the entire zymogen activation cascade

• Secretory vesicles are extruded across the basolateral membrane into the interstitium, where molecular fragments act as chemoattractants for inflammatory cells

Activated neutrophils then exacerbate the problem by releasing superoxide (the respiratory burst) or proteolytic enzymes (cathepsins B, D, and G; collagenase; and elastase). Finally, macrophages release cytokines that further mediate local (and, in severe cases, systemic) inflammatory responses. The early mediators defined to date are tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-8. These mediators of inflammation cause an increased pancreatic vascular permeability, leading to hemorrhage, edema, and eventually pancreatic necrosis. As the mediators are excreted into the circulation, systemic complications can arise, such as bacteremia due to gut flora translocation, acute respiratory distress syndrome (ARDS), pleural effusions, gastrointestinal (GI) hemorrhage, and renal failure. The systemic inflammatory response syndrome (SIRS) can also develop, leading to the development of systemic shock. Eventually, the mediators of inflammation can become so overwhelming that hemodynamic instability and death ensue. In acute pancreatitis, parenchymal edema and peripancreatic fat necrosis occur first; this is known as acute edematous pancreatitis. When necrosis involves the parenchyma, accompanied by hemorrhage and dysfunction of the gland, the inflammation evolves into hemorrhagic or necrotizing pancreatitis. Pseudocysts and pancreatic abscesses can result from necrotizing pancreatitis because enzymes can be walled off by granulation tissue (pseudocyst formation) or via bacterial seeding of the pancreatic or peripancreatic tissue (pancreatic abscess formation). Li et al compared two sets of patients with severe acute pancreatitis—one with acute renal failure and the other without it—and determined that a history of renal disease, hypoxemia, and abdominal compartment syndrome were significant risk factors for acute renal failure in patients with severe acute pancreatitis. [5] In addition, patients with acute renal failure were found to have a significantly greater average length of stay in the hospital and in the intensive care unit (ICU), as well as higher rates of pancreatic infection and mortality.

Etiology

Long-standing alcohol consumption and biliary stone disease cause most cases of acute pancreatitis, but numerous other etiologies are known. In 10%-30% of cases, the cause is unknown, though studies have suggested that as many as 70% of cases of idiopathic pancreatitis are secondary to biliary microlithiasis. Biliary tract disease One of the most common causes of acute pancreatitis in most developed countries (accounting for approximately 40% of cases) is gallstones passing into the bile duct and temporarily lodging at the sphincter of Oddi. The risk of a stone causing pancreatitis is inversely proportional to its size. It is thought that acinar cell injury occurs secondary to increasing pancreatic duct pressures caused by obstructive biliary stones at the ampulla of Vater, although this has not been definitively proven in humans. Occult microlithiasis is probably responsible for most cases of idiopathic acute pancreatitis. Alcohol Alcohol use is a major cause of acute pancreatitis (accounting for at least 35% of cases [6] ). At the cellular level, ethanol leads to intracellular accumulation of digestive enzymes and their premature activation and release. At the ductal level, it increases the permeability of ductules, allowing enzymes to reach the parenchyma and cause pancreatic damage. Ethanol increases the protein content of pancreatic juice and decreases bicarbonate levels and trypsin inhibitor concentrations. This leads to the formation of protein plugs that block pancreatic outflow. Most commonly, the disease develops in patients whose alcohol ingestion is habitual over 5-15 years. Alcoholics are usually admitted with an acute exacerbation of chronic pancreatitis. Occasionally, however, pancreatitis can develop in a patient with a weekend binging habit, and several case reports have described a sole large alcohol load precipitating a first attack. Nevertheless, the alcoholic who imbibes routinely remains the rule rather than the exception for the development of pancreatitis. Currently, there is no universally accepted explanation for why certain alcoholics are more predisposed to developing acute pancreatitis than other alcoholics who ingest similar quantities. Endoscopic retrograde cholangiopancreatography Pancreatitis occurring after endoscopic retrograde cholangiopancreatography (ERCP) is probably the third most common type (accounting for approximately 4% of cases). Whereas retrospective surveys indicate that the risk is only 1%, prospective studies have shown the risk to be at least 5%. The risk of post-ERCP acute pancreatitis is increased if the endoscopist is inexperienced, if the patient is thought to have sphincter of Oddi dysfunction, or if manometry is performed on the sphincter of Oddi. Aggressive preintervention intravenous (IV) hydration has been durably shown to prevent post-ERCP pancreatitis in randomized studies. More recently, rectal indomethacin has been employed; it has been shown to reduce the incidence of post-ERCP pancreatitis and is now widely accepted at most institutions. The literature continues to debate the role of rectal indomethacin. [7] Trauma Abdominal trauma (approximately 1.5%) causes an elevation of amylase and lipase levels in 17% of cases and clinical pancreatitis in 5% of cases. Pancreatic injury occurs more often in penetrating injuries (eg, from knives, bullets) than in blunt abdominal trauma (eg, from steering wheels, horses, bicycles). Blunt injury to the abdomen or back may crush the gland across the spine, leading to a ductal injury. Drugs Considering the small number of patients who develop pancreatitis compared to the relatively large number who receive potentially toxic drugs, drug-induced pancreatitis is a relatively rare occurrence (accounting for approximately 2% of cases) that is probably related to an unknown predisposition. Fortunately, drug-induced pancreatitis is usually mild. Drugs definitely associated with acute pancreatitis include the following:

• Azathioprine

• Sulfonamides

• Sulindac

• Tetracycline

• Valproic acid,

• Didanosine

• Methyldopa

• Estrogens

• Furosemide

• 6-Mercaptopurine

• Pentamidine

• 5-aminosalicylic acid compounds

• Corticosteroids

• Octreotide

Drugs probably associated with acute pancreatitis include the following:

• Chlorothiazide and hydrochlorothiazide

• Methandrostenolone (methandienone)

• Metronidazole

• Nitrofurantoin

• Phenformin

• Piroxicam

• Procainamide

• Colaspase

• Chlorthalidone

• Combination cancer chemotherapy drugs (especially asparaginase)

• Cimetidine

• Cisplatin

• Cytosine arabinoside

• Diphenoxylate

• Ethacrynic acid

In addition, there are many drugs that have been reported to cause acute pancreatitis in isolated or sporadic cases. Less common causes The following causes each account for less than 1% of cases of pancreatitis. Infection Several infectious diseases may cause pancreatitis, especially in children. These cases of acute pancreatitis tend to be milder than cases of acute biliary or alcohol-induced pancreatitis. Viral causes include mumps virus, coxsackievirus, cytomegalovirus (CMV), hepatitis virus, Epstein-Barr virus (EBV), echovirus, varicella-zoster virus (VZV), measles virus, and rubella virus. Bacterial causes include Mycoplasma pneumoniae, Salmonella, Campylobacter, and Mycobacterium tuberculosis. Worldwide, Ascaris is a recognized cause of pancreatitis resulting from the migration of worms in and out of the duodenal papillae. Pancreatitis has been associated with AIDS; however, this may be the result of opportunistic infections, neoplasms, lipodystrophy, or drug therapies. Hereditary pancreatitis Hereditary pancreatitis is an autosomal dominant gain-of-function disorder related to mutations of the cationic trypsinogen gene (PRSS1), which has an 80% penetrance. Mutations in this gene cause premature activation of trypsinogen to trypsin. In addition, the CFTR mutation plays a role in predisposing patients to acute pancreatitis by causing abnormalities of ductal secretion. At present, however, the phenotypic variability of patients with the CFTR mutation is not well understood. Certainly, patients homozygous for the CFTR mutation are at risk for pancreatic disease, but it is not yet clear which of the more than 800 mutations carries the most significant risk. In addition, the role of CFTR heterozygotes in pancreatic disease is unknown. Mutations in the SPINK1 protein, which blocks the active binding site of trypsin, rendering it inactive, also probably play a role in causing a predisposition to acute pancreatitis. This probably explains the predisposition, rather than the cause, of acute pancreatitis in these patients. If enough mutant enzymes become activated intracellularly, they can overwhelm the first line of defense (ie, pancreatic secretory trypsin inhibitor) and resist backup defenses (ie, proteolytic degradation by mesotrypsin, enzyme Y, and trypsin itself). Activated mutant cationic trypsin can then trigger the entire zymogen activation cascade. Hypercalcemia Hypercalcemia from any cause can lead to acute pancreatitis. Causes include hyperparathyroidism, excessive doses of vitamin D, familial hypocalciuric hypercalcemia, and total parenteral nutrition (TPN). Routine use of automated serum chemistries has allowed earlier detection and reduced the frequency of hypercalcemia manifesting as pancreatitis. Developmental abnormalities of pancreas The pancreas develops from two buds stemming from the alimentary tract of the developing embryo. There are two developmental abnormalities commonly associated with pancreatitis: pancreas divisum and annular pancreas. Pancreas divisum is a failure of the dorsal and ventral pancreatic ducts to fuse during embryogenesis. Probably a variant of normal anatomy, it occurs in approximately 5% of the population (see the images below); in most cases, it may actually protect against gallstone pancreatitis. It appears that the presence of a stenotic minor papillae and an atretic duct of Santorini are additional risk factors that together contribute to the development of acute pancreatitis through an obstructive mechanism (although this is controversial).

Acute pancreatitis. This image was obtained from a patient with pancreas divisum associated with minor papilla stenosis causing recurrent pancreatitis. Because pancreas divisum is relatively common in the general population, it is best regarded as a variant of normal anatomy and not necessarily as a cause of pancreatitis. In this case, note the bulbous contour of the duct adjacent to the cannula. This appearance has been termed Santorinicele. Dorsal duct outflow obstruction is a probable cause of pancreatitis when Santorinicele is present, and it is associated with a minor papilla that accommodates only a guide wire

Acute pancreatitis. Recurrent pancreatitis was associated with pancreas divisum in an elderly man. The pancreatogram of the dorsal duct shows distal stenosis with upstream chronic pancreatitis. After the stenosis was dilated and stented, his pain resolved and the patient improved clinically during 1 year of quarterly stent exchanges. Follow-up computed tomography (CT) scans showed resolution of the inflammatory mass. Although ductal biopsies and cytology were repeatedly negative, the patient's pain and pancreatitis returned when the stents were removed. He developed duodenal outflow obstruction and was sent to surgery; during the Whipple procedure, periampullary adenocarcinoma (of minor papilla) was revealed. Annular pancreas is an uncommon congenital anomaly in which a band of pancreatic tissue surrounds the second part of the duodenum. Usually, it does not cause symptoms until later in life. This condition is a rare cause of acute pancreatitis, probably through an obstructive mechanism. Sphincter of Oddi dysfunction can lead to acute pancreatitis by causing increased pancreatic ductal pressures. However, the mechanism of pancreatitis induced by such dysfunction in patients without elevated sphincter pressures on manometry remains controversial. Hypertriglyceridemia Clinically significant pancreatitis usually does not occur until a person’s serum triglyceride level reaches 1000 mg/dL. It is associated with type I and type V hyperlipidemia. Although this view is somewhat controversial, most authorities believe that the association is caused by the underlying derangement in lipid metabolism rather than by pancreatitis causing hyperlipidemia. This type of pancreatitis tends to be more severe than alcohol- or gallstone-induced disease. Tumors Obstruction of the pancreatic ductal system by a pancreatic ductal carcinoma, ampullary carcinoma, islet cell tumor, solid pseudotumor of the pancreas, sarcoma, lymphoma, cholangiocarcinoma, or metastatic tumor can cause acute pancreatitis. The chances of pancreatitis occurring when a tumor is present are approximately 14%. Pancreatic cystic neoplasms, such as intraductal papillary-mucinous neoplasm (IPMN), mucinous cystadenoma, or serous cystadenoma, can also cause pancreatitis. Toxins Exposure to organophosphate insecticide can cause acute pancreatitis. Scorpion and snake bites may also be causative; in Trinidad, the sting of the scorpion Tityus trinitatis is the most common cause of acute pancreatitis. Hyperstimulation of pancreas exocrine secretion appears to be the mechanism of action in both instances. Surgical procedures Acute pancreatitis may occur in the postoperative period of various surgical procedures (eg, abdominal or cardiopulmonary bypass surgery, which may damage the gland by causing ischemia). Postoperative acute pancreatitis is often a difficult diagnosis to confirm, and it has a higher complication rate than pancreatitis associated with other etiologies. The mechanism is unclear. Vascular abnormalities Vascular factors, such as ischemia or vasculitis, can play a role in causing acute pancreatitis. Vasculitis can predispose patients to pancreatic ischemia, especially in those with polyarteritis nodosa and systemic lupus erythematosus. Autoimmune pancreatitis Autoimmune pancreatitis, a relatively newly described entity, is an extremely rare cause of acute pancreatitis (prevalence, 0.82 per 100,000 individuals). When it does cause acute pancreatitis, it is usually in young people (approximately age 40 years) who may also suffer from other autoimmune diseases. The pathogenesis is unclear, but it is potentially related to immunoglobulin (Ig) G4 autoimmune disease. [8]

Epidemiology

Worldwide, the incidence of acute pancreatitis ranges between 5 and 80 per 100,000 population, with the highest incidence recorded in the United States and Finland. [14] In Luneburg, Germany, the incidence is 17.5 cases per 100,000 people. In Finland, the incidence is 73.4 cases per 100,000 people. Similar incidence rates have been reported in Australia. The incidence of disease outside North America, Europe, and Australia is less well known. In Europe and other developed nations, such as Hong Kong, more patients tend to have gallstone pancreatitis, whereas in the United States, alcoholic pancreatitis is most common. Age-related demographics The median age at onset depends on the etiology. [15] The following are median ages of onset for various etiologies:

• Alcohol-related - 39 years

• Biliary tract–related - 69 years

• Trauma-related - 66 years

• Drug-induced etiology - 42 years

• ERCP-related - 58 years

• AIDS-related - 31 years

• Vasculitis-related - 36 years

Hospitalization rates increase with age. For people aged 35-75 years, the rate doubles for males and quadruples for females. Sex-related demographics Generally, acute pancreatitis affects males more often than females. In males, the etiology is more often related to alcohol; in females, it is more often related to biliary tract disease. Idiopathic pancreatitis has no clear predilection for either sex. Race-related demographics The hospitalization rates of patients with acute pancreatitis per 100,000 population are 3 times higher for blacks than whites. These racial differences are more pronounced for males than females. The risk for African Americans aged 35-64 years is 10 times higher than for any other group. African Americans are at a higher risk than whites in that same age group. The annual incidence of acute pancreatitis in Native Americans is 4 per 100,000 population; in whites, 5.7 per 100,000 population; and in blacks, 20.7 per 100,000 population. [16]

Prognosis

The overall mortality in patients with acute pancreatitis is 10%-15%. Patients with biliary pancreatitis tend to have a higher mortality than patients with alcoholic pancreatitis. This rate has been falling over the last 2 decades as improvements in supportive care have been initiated. Type 2 diabetes mellitus has also been associated with higher severity and mortality in the setting of acute pancreatitis. [17] In patients with severe disease (organ failure), who account for about 20% of presentations, mortality is approximately 30%. [18] This figure has not decreased in the past 10 years. In patients with pancreatic necrosis without organ failure, the mortality approaches zero. In the first week of illness, most deaths result from multiorgan system failure. In subsequent weeks, infection plays a more significant role, but organ failure still constitutes a major cause of mortality. Acute respiratory distress syndrome (ARDS), acute renal failure, cardiac depression, hemorrhage, and hypotensive shock all may be systemic manifestations of acute pancreatitis in its most severe form. Identifying patients in the greatest need of aggressive medical treatment by differentiating their disease severity as mild or severe is recommended. In mild disease, the pancreas exhibits interstitial edema, an inflammatory infiltrate without hemorrhage or necrosis, and, usually, minimal or no organ dysfunction. In severe disease, the inflammatory infiltrate is severe, associated with necrosis of the parenchyma, often accompanied by evidence of severe gland dysfunction, and it may be associated with multiorgan system failure. Different strategies have been used to assess the severity of acute pancreatitis and predict outcome (see Workup and Staging). Several clinical scoring systems (eg, Ranson criteria, Glasgow, Imrie) are available. The APACHE II scoring system, though cumbersome, appears to be the best validated (see the APACHE II Scoring System calculator). Biological markers have also been used for this purpose. Genetic markers are being studied and have not yet come into clinical use. Peritoneal lavage has a high specificity (93%); however, it has a low sensitivity (54%). Dynamic CT scanning of the abdomen is widely available and useful in predicting the outcome of acute pancreatitis. When the Balthazar criteria (see Workup and Computed Tomography Scanning) are used, sensitivity is 87% and specificity is 88%. Suppiah et al examined the prognostic value of the neutrophil-lymphocyte ratio (NLR) in 146 consecutive patients with acute pancreatitis. [19] They found that elevation of the NLR during the first 48 hours of hospital admission was significantly associated with severe acute pancreatitis and was an independent negative prognostic indicator. The NLR is calculated from the white cell differential and provides an indication of inflammation. Khan et al examined the prognostic value of Modified Early Warning Score (MEWS) in identifying severe acute pancreatitis in 200 patients admitted to a single institution. [20] The investigators tracked the highest and mean daily scores. They found that patients with a high MEWS value > 2 on day one or mean value > 1.2 on day two was most accurate in predicting severe acute pancreatitis. The investigators concluded that MEWS is a reliable, safe, and inexpensive score that can be used easily at all levels of health care for prognosticating patients with acute pancreatitis. In a retrospective study of data from 822 patients hospitalized with acute pancreatitis, Mikolasevic et al found that patients who had nonalcoholic fatty liver at admission (n = 198; 24.1%) had a statistically higher incidence of moderately severe (35.4% vs 14.6%) and severe acute pancreatitis (20.7% vs 9.6%) than those without nonalcoholic fatty liver. [21] Moreover, these patients had higher (1) C-reactive protein levels not only on the day of admission but also at day 3, (2) APACHE II scores at admission, (3) CT scan severity index, and (4) occurrence of organ failure and local complications. Although mortality was also higher in the nonalcoholic fatty liver group compared to the group without this disease, the difference was not statistically significant. [21] Complications Acute fluid collections may occur, typically early in the course of acute pancreatitis. These are primarily detected by imaging studies rather than by physical examination. Because they lack a defined wall and usually regress spontaneously, most acute fluid collections require no specific therapy. An acute pseudocyst is a collection of pancreatic fluid that is walled off by granulation tissue after an episode of acute pancreatitis; it requires 4 or more weeks to develop. Although pseudocysts are sometimes palpable on physical examination, they are usually detected with abdominal ultrasonography or computed tomography (CT). Intra-abdominal infection is common. Within the first 1-3 weeks, fluid collections or pancreatic necrosis can become infected and jeopardize clinical outcome. From 3 to 6 weeks, pseudocysts may become infected or a pancreatic abscess may develop. A pancreatic abscess is a circumscribed intra-abdominal collection of pus, within or in proximity to the pancreas. It is believed to arise from localized necrosis, with subsequent liquefaction that becomes infected. The intestinal flora is the predominant source of bacteria causing the infection. The usual suspects are Escherichia coli (26%), Pseudomonas species (16%), Staphylococcus species (15%), Klebsiella species (10%), Proteus species (10%), Streptococcus species (4%), Enterobacter species (3%), and anaerobic organisms (16%). Fungal superinfections may occur weeks or months into the course of severe necrotizing pancreatitis. Pancreatic necrosis is a nonviable area of pancreatic parenchyma that is often associated with peripancreatic fat necrosis and is principally diagnosed with the aid of dynamic spiral CT scans. Distinguishing between infected and sterile pancreatic necrosis is an ongoing clinical challenge. Sterile pancreatic necrosis is usually treated with aggressive medical management, whereas almost all patients with infected pancreatic necrosis require surgical debridement or percutaneous drainage if they are to survive. Hemorrhage into the gastrointestinal (GI) tract, retroperitoneum, or the peritoneal cavity is possible because of erosion of large vessels. Intestinal obstruction or necrosis may occur. Common bile duct obstruction may be caused by a pancreatic abscess, pseudocyst, or biliary stone that caused the pancreatitis. An internal pancreatic fistula from pancreatic duct disruption or a leaking pancreatic pseudocyst may occur. In the weeks (to months) following presentation, the physician’s attention shifts to developing signs of intra-abdominal infection, pancreatic pseudocyst, intra-abdominal hemorrhage, colon perforation, obstruction or fistulization, and multiorgan system failure.

Clinical Presentation

History The cardinal symptom of acute pancreatitis is abdominal pain, which is characteristically dull, boring, and steady. Usually, the pain is sudden in onset and gradually intensifies in severity until reaching a constant ache. Most often, it is located in the upper abdomen, usually in the epigastric region, but it may be perceived more on the left or right side, depending on which portion of the pancreas is involved. The pain radiates directly through the abdomen to the back in approximately one half of cases. Nausea and vomiting are often present, along with accompanying anorexia. Diarrhea can also occur. Positioning can be important, because the discomfort frequently improves with the patient sitting up and bending forward. However, this improvement is usually temporary. The duration of pain varies but typically lasts more than a day. It is the intensity and persistence of the pain that usually causes patients to seek medical attention. Ask the patient about recent operative or other invasive procedures (eg, endoscopic retrograde cholangiopancreatography [ERCP]) or family history of hypertriglyceridemia. Patients frequently have a history of previous biliary colic and binge alcohol consumption, the major causes of acute pancreatitis.

Physical Examination The following physical examination findings may be noted, varying with the severity of the disease:

• Fever (76%) and tachycardia (65%) are common abnormal vital signs; hypotension may be noted

• Abdominal tenderness, muscular guarding (68%), and distention (65%) are observed in most patients; bowel sounds are often diminished or absent because of gastric and transverse colonic ileus; guarding tends to be more pronounced in the upper abdomen

• A minority of patients exhibit jaundice (28%)

• Some patients experience dyspnea (10%), which may be caused by irritation of the diaphragm (resulting from inflammation), pleural effusion, or a more serious condition, such as acute respiratory distress syndrome (ARDS); tachypnea may occur; lung auscultation may reveal basilar rales, especially in the left lung

• In severe cases, hemodynamic instability is evident (10%) and hematemesis or melena sometimes develops (5%); in addition, patients with severe acute pancreatitis are often pale, diaphoretic, and listless

• Occasionally, in the extremities, muscular spasm may be noted secondary to hypocalcemia

A few uncommon physical findings are associated with severe necrotizing pancreatitis:

• The Cullen sign is a bluish discoloration around the umbilicus resulting from hemoperitoneum

• The Grey-Turner sign is a reddish-brown discoloration along the flanks resulting from retroperitoneal blood dissecting along tissue planes; more commonly, patients may have a ruddy erythema in the flanks secondary to extravasated pancreatic exudate

• Erythematous skin nodules may result from focal subcutaneous fat necrosis; these are usually not more than 1 cm in size and are typically located on extensor skin surfaces; in addition, polyarthritis is occasionally seen

Rarely, abnormalities on funduscopic examination may be seen in severe pancreatitis. Termed Purtscher retinopathy, this ischemic injury to the retina appears to be caused by activation of complement and agglutination of blood cells within the retinal vessels. It may cause temporary or permanent blindness.

Differential Diagnoses

Diagnostic Considerations

Recognizing patients with severe acute pancreatitis as soon as possible is critical for achieving optimal outcomes.

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

• Acute peritonitis

• Macroamylasemia

• Macrolipasemia

• Malabsorption syndromes/processes

• Perforated viscus

Differential Diagnoses

• Acute Mesenteric Ischemia

• Acute Respiratory Distress Syndrome (ARDS)

• Bacterial Pneumonia

• Cholangitis

• Cholecystitis

• Chronic Pancreatitis

• Colon Cancer

• Community-Acquired Pneumonia (CAP)

• Emergent Treatment of Gastroenteritis

• Gallstones (Cholelithiasis)

• Gastric Cancer

• Irritable Bowel Syndrome (IBS)

• Large-Bowel Obstruction

• Myocardial Infarction

• Pancreatic Cancer

• Pancreatic Pseudocysts

• Peptic Ulcer Disease

• Viral Hepatitis

Workup

Approach Considerations Once a working diagnosis of acute pancreatitis is reached, laboratory tests are obtained to support the clinical impression. In addition to confirming the diagnosis, laboratory tests are helpful in determining the etiology and looking for complications. Although diagnostic imaging is unnecessary in most cases of pancreatitis, [22] visualization of inflammatory changes within the pancreas provides morphologic confirmation of the diagnosis. Obtain imaging tests when the diagnosis is in doubt, when severe pancreatitis is present, or when a given imaging study might provide specific information needed to answer a clinical question. Image-guided aspiration may be useful for differentiating infected from sterile necrosis and for draining fluid collections. Genetic testing for mutations associated with acute pancreatitis may be considered, even if effective treatments for these genetic conditions are lacking.

Laboratory Studies Amylase and lipase Serum amylase and lipase levels are typically elevated in persons with acute pancreatitis. However, these elevations may only indicate pancreastasis. In research studies, amylase or lipase levels at least 3 times above the reference range are generally considered diagnostic of acute pancreatitis. Serum amylase determinations are routinely available, but they are not specific for pancreatitis. Preferably, the amylase P level should be measured, which is somewhat more specific to pancreatic pathology. Elevations can occur in patients with small intestinal obstruction, mesenteric ischemia, tubo-ovarian disease, renal insufficiency, or macroamylasemia. Rarely, elevations may reflect parotitis. The serum half-life of amylase is short, and elevations generally return to the reference ranges within a few days. Lipase has a slightly longer half-life and its abnormalities may support the diagnosis if a delay occurs between the pain episode and the time the patient seeks medical attention. Elevated lipase levels are more specific to the pancreas than elevated amylase levels. Lipase levels remain high for 12 days. In patients with chronic pancreatitis (usually caused by alcohol abuse), lipase levels may be elevated in the presence of a normal serum amylase level. The level of serum amylase or lipase does not indicate whether the disease is mild, moderate, or severe, and monitoring levels serially during the course of hospitalization does not offer insight into the prognosis. Liver-associated enzymes Determine alkaline phosphatase, total bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels to search for evidence of gallstone pancreatitis. An ALT level higher than 150 U/L suggests gallstone pancreatitis and a more fulminant disease course. Serum electrolytes, BUN, creatinine, glucose, cholesterol, and triglycerides Obtain measurements for blood urea nitrogen (BUN), creatinine, and electrolytes; a great disturbance in the electrolyte balance is usually found, secondary to third spacing of fluids. Measure blood glucose level because it may be elevated from B-cell injury in the pancreas. Measure calcium, cholesterol, and triglyceride levels to search for an etiology of pancreatitis (eg, hypercalcemia or hyperlipidemia) or complications of pancreatitis (eg, hypocalcemia resulting from saponification of fats in the retroperitoneum). However, be aware that baseline serum triglyceride levels can be falsely lowered during an episode of acute pancreatitis. Complete blood count and hematocrit A complete blood count (CBC) demonstrates leukocytosis (white blood cell [WBC] count higher than 12,000/µL) with the differential being shifted toward the segmented polymorphonuclear (PMN) cells. Leukocytosis may represent inflammation or infection. Hemoconcentration at admission (an admission hematocrit value greater than 47%) has been proposed as a sensitive measure of more severe disease. However, this has subsequently been shown to have value only as a negative predictor—that is, a lack of hemoconcentration effectively rules out severe disease. If blood transfusion is necessary, as in cases of hemorrhagic pancreatitis, obtain type and cross-match. C-reactive protein A C-reactive protein (CRP) value can be obtained 24-48 hours after presentation to provide some indication of prognosis. Higher levels have been shown to correlate with a propensity toward organ failure. A CRP value in double figures (ie, ≥ 10 mg/dL) strongly indicates severe pancreatitis. CRP is an acute-phase reactant that is not specific for pancreatitis. Other tests Evaluate arterial blood gases if a patient is dyspneic. Whether tachypnea is due to acute respiratory distress syndrome (ARDS) or diaphragmatic irritation must be determined. Lactic dehydrogenase (LDH), BUN, and bicarbonate levels should be measured both at admission and at 48 hours in order to help determine the Ranson criteria for survival. Immunoglobulin G4 (IgG4) levels can be checked to evaluate for autoimmune pancreatitis, especially in recurrent acute pancreatitis that is not explained by an obvious etiology. However, this test is not specific, because IgG4 levels can be elevated in as many as 10% of patients with acute pancreatitis who do not have autoimmune pancreatitis. Trypsin and its precursor trypsinogen-2 in both the urine and the peritoneal fluid have been evaluated as possible markers for acute pancreatitis (especially post-ERCP pancreatitis) but are not widely used. Trypsinogen activation peptide (TAP) is formed when trypsinogen is cleaved to form trypsin and can be measured commercially in the urine to diagnose acute pancreatitis and to help determine the severity. Although not currently in use clinically, polymorphisms in the chemokine monocyte chemotactic protein 1 (MCP-1) gene may also predict severity. This is the first gene identified that plays a role strictly in predicting the severity of disease.

Abdominal Radiography Abdominal radiographs have a limited role in acute pancreatitis. Kidneys-ureters-bladder (KUB) radiography with the patient in the upright position is primarily performed to detect free air in the abdomen, indicating a perforated viscus, as would be the case in a penetrating, perforated duodenal ulcer. In some cases, the inflammatory process may damage peripancreatic structures, resulting in a colon cut-off sign, a sentinel loop, or an ileus. The presence of calcifications within or around the pancreas may indicate chronic pancreatitis.

Ultrasonography Abdominal ultrasonography Ultrasonography of the abdomen is the most useful initial test in determining the etiology of pancreatitis and is the technique of choice for detecting gallstones. In the setting of acute pancreatitis, sensitivity is reduced to 70%-80%. In addition, the ability to identify choledocholithiasis is limited. Although ultrasonography can be used as a screening test, it may not be specific if overlying gas shadows secondary to bowel distention are present. Ultrasonography cannot measure the severity of disease. Endoscopic ultrasonography Endoscopic ultrasonography (EUS) is an endoscopic procedure that allows a high-frequency ultrasound transducer to be inserted into the gastrointestinal (GI) tract to visualize the pancreas and the biliary tract. This study allows a more detailed image to be obtained than with transcutaneous ultrasonography because the high-frequency transducer can be introduced directly adjacent to the pancreas. Its principal role in the evaluation of acute pancreatitis is the detection of microlithiasis and periampullary lesions not easily revealed by other methods. This modality should not be used to help identify chronic pancreatitis until several months after the episode of acute pancreatitis. In specialized centers with highly trained medical staff, a secretin-stimulated EUS study may reveal resistance to ductal outflow at the level of the papilla, as evidenced by dilatation of the pancreatic duct to a greater extent and longer duration than in a healthy population. This can be helpful in evaluating patients with recurrent idiopathic pancreatitis.

Computed Tomography Scanning Abdominal computed tomography (CT) scanning is generally not indicated for patients with mild pancreatitis unless a pancreatic tumor is suspected (usually in elderly patients). It is always indicated in patients with severe acute pancreatitis and is the imaging study of choice for assessing complications. Scans are seldom needed within the first 72 hours after symptom onset unless the diagnosis is uncertain, because inflammatory changes are often not radiographically present until this time. [23] Abdominal CT scans also provide prognostic information based on the following grading scale developed by Balthazar and colleagues [24, 25, 26] :

• Grade A - Normal pancreas

• Grade B - Focal or diffuse gland enlargement

• Grade C - Intrinsic gland abnormality recognized by haziness on the scan

• Grade D - Single ill-defined collection or phlegmon

• Grade E - Two or more ill-defined collections or the presence of gas in or near the pancreas

The chances of infection and death are virtually nil in grades A and B but steadily increase in grades C through E. Patients with grade E pancreatitis have a 50% chance of developing an infection and a 15% chance of dying. Dynamic spiral CT scanning is used to determine the presence and extent of pancreatic necrosis. After the administration of an oral agent to define bowel structures, a study of the upper abdomen is performed twice, before and after administration of an intravenous (IV) bolus of iodine contrast agent. For a healthy pancreas, density numbers are in the range of 30-40 Hounsfield units on an unenhanced study, increasing to 100-150 Hounsfield units on an enhanced study. When pancreatic necrosis is present, focal or diffuse areas of unenhanced parenchyma on the second study suggest pancreatic necrosis. Pancreatic necrosis for research purposes is defined as loss of enhancement in at least 30% of the pancreatic parenchyma.

Magnetic Resonance Cholangiopancreatography Magnetic resonance cholangiopancreatography (MRCP) has an emerging role in the diagnosis of suspected biliary and pancreatic duct obstruction in the setting of pancreatitis. Heavily T2–weighted images provide a noninvasive image of the biliary and pancreatic ducts. [1] Although MRCP is not as sensitive as endoscopic retrograde cholangiopancreatography (ERCP), it is safer, noninvasive, and fast, as well as provides images useful in guiding clinical care decisions. MRCP should be used if choledocholithiasis is suspected but there is concern that pancreatitis might worsen if ERCP is performed.

Endoscopic Retrograde Cholangiopancreatography Endoscopic retrograde cholangiopancreatography (ERCP) is an endoscopic procedure used to evaluate the biliary and pancreatic ductal systems and is indicated in a subset of patients with acute pancreatitis (see the image below). However, ERCP should be used with extreme caution in patients with acute pancreatitis and should never be used as a first-line diagnostic tool in this disease. [1] This procedure should be performed only in the following situations:

• The patient has severe acute pancreatitis that is believed, and is seen on other radiographic studies, to be secondary to choledocholithiasis

• The patient has biliary pancreatitis and is experiencing worsening jaundice and clinical deterioration despite maximal supportive therapy

When combined with sphincterotomy and stone extraction, ERCP may reduce the length of hospital stay, the complication rate, and, possibly, mortality. In the case of biliary pancreatitis where a dilated obstructed common bile duct is diagnosed on the basis of the findings of computed tomography (CT) scanning or any other imaging modality and an elevated plasma bilirubin level (>5 mg/dL), ERCP with sphincterotomy is warranted within the first 72 hours. Biliary pancreatitis should always be treated eventually with a cholecystectomy after the process has subsided. Occasionally, ERCP with sphincter of Oddi manometry reveals sphincter of Oddi dysfunction (SOD) as the cause of recurrent idiopathic pancreatitis. Known risk factors for post-ERCP pancreatitis are summarized in table 1, below. [27, 28] In suspected SOD, especially SOD type 3, the risk of procedure-induced pancreatitis can exceed 30%. It is generally thought that the experience of the operator is a risk factor for post-ERCP pancreatitis. Although no difference was found between case volume of the endoscopist or center, high-volume centers treated a larger number of patients at high risk of pancreatitis and performed a significantly greater number of procedures. [28]

Image-Guided Aspiration and Drainage Computed tomography (CT)-guided needle aspiration is used to differentiate infected necrosis from sterile necrosis in patients with severe necrotizing pancreatitis. The needle is placed into an area of low attenuation in or around the pancreas of a patient with fever and tachycardia or other signs of a systemic inflammatory response syndrome, generally following the first week of severe pancreatitis. The procedure may be repeated weekly if clinically indicated. The specimen should be delivered to the laboratory within an hour and interpreted promptly. The specimen should always be evaluated for Gram stain, culture, and sensitivity. If the Gram stain shows bacteria or fungi, surgical debridement of the infected necrosis is generally indicated. An exception would be if the patient cannot tolerate surgery; in that case, CT-guided catheter drainage may be more effective. Endoscopic ultrasonography (EUS)-guided needle aspiration can often be used to differentiate infected necrosis from sterile necrosis in the same manner as CT-guided needle aspiration. EUS can also be used to guide drainage of pancreatic and peripancreatic fluid collections that have complicated an episode of acute pancreatitis. [29] These procedures should only be carried out once the pseudocyst has had the opportunity to mature. A complete description of these procedures is beyond the scope of this article.

Genetic Testing With the advent of molecular medicine, various genetic abnormalities have been identified with pancreatitis. Although effective treatments for these conditions have yet to be discovered, it is sometimes reasonable to begin testing for these mutations in patients with otherwise idiopathic pancreatitis, rather than subjecting the entire group to the risks of endoscopic sphincterotomy or stent placement for presumptive diagnosis of sphincter of Oddi dysfunction. As more is learned about molecular mechanisms and therapy, logical novel treatments may eventually be offered to these patients as part of clinical trials. Of course, as with any type of genetic testing, expert genetic counseling that addresses social, familial, insurance, and financial issues is essential for all persons before testing. In fact, it is the author’s policy not to perform any genetic testing unless patients are first counseled by a qualified genetic counselor. Hereditary pancreatitis has been associated with a mutation of cationic trypsinogen (PRSS1). At least 4 mutations have thus far been identified. These mutations appear to render the protein resistant to second-line proteolytic defense mechanisms. Patients with PRSS1 mutations typically develop their first episode of pancreatitis by the time they are in their mid teens. Most often, there is a strong family history of pancreatic disease (eg, acute or chronic pancreatitis, pancreatic malignancy). It should be noted that PRSS1 -related pancreatitis is very rare. Some patients with idiopathic pancreatitis have atypical mutations in the CFTR gene, which follows an autosomal recessive pattern of inheritance. This is a fascinating advance in understanding the spectrum of cystic fibrosis, in which phenotypic expression depends on the degree to which the mutation affects the activity of the CFTR enzyme’s function. Relatively minor mutations that do not affect pulmonary function may influence chloride transport in the pancreas enough to predispose individuals to recurrent idiopathic pancreatitis. Mutations in the SPINK1 gene can predispose patients to acute pancreatitis. The SPINK1 protein blocks the active binding site of trypsin, rendering it inactive. However, approximately 1 in 100 persons in the United States are at least heterozygotes for SPINK1. It is an autosomal recessive gene pattern of inheritance. Therefore, although mutations of the SPINK1 gene are not usually enough to cause pancreatitis, they are likely to be a cofactor responsible for pancreatitis in some individuals.

Histologic Findings For practical purposes, the infinite spectrum of pancreatitis severity is usually subdivided into mild and severe categories as follows:

• Mild pancreatitis - The gland exhibits interstitial edema and an inflammatory infiltrate without hemorrhage or necrosis, usually with minimal or no organ dysfunction

• Severe pancreatitis - Extensive inflammation and necrosis of the pancreatic parenchyma are present, often associated with severe gland dysfunction and multiorgan system failure

At surgery, peripancreatic fatty tissue is predominantly involved by necrosis, whereas the gland is usually less affected; hence, the extent of pancreatic necrosis is commonly overestimated. In very severe cases, arterial thrombosis may lead to panlobular infarction, in which the gland becomes a hemorrhagic, necrotic, gangrenous mass. The natural history of fat necrosis depends on its location and extent; small areas (< 1 cm) may resolve entirely, whereas large areas (>5 cm) may liquefy within a fibrotic capsule.

Staging Various strategies have been used to predict the severity and outcome of acute pancreatitis, including the Ranson, Acute Physiology and Chronic Health Evaluation (APACHE) II, Glasgow, and Imrie scoring systems. Each has advantages and disadvantages, and none is currently recognized as a criterion standard. For research purposes, the Atlanta classification of acute pancreatitis has been used to differentiate between severe and mild cases of acute pancreatitis. [2] According to this classification, patients are diagnosed with severe acute pancreatitis if they show the following:

• Evidence of organ failure (eg, systolic blood pressure below 90 mm Hg, arterial partial pressure of oxygen [Pa O2] 60 mm Hg or lower, serum creatinine level 2 mg/dL or higher, GI bleeding amounting to 500 mL or more in 24 hours)

• Local complications (eg, necrosis, abscess, pseudocyst)

• Ranson score of 3 or higher or APACHE score of 8 or higher

Ranson criteria Ranson used a series of different criteria for the severity of acute pancreatitis to formulate a scoring system that is still widely used. [30] Criteria present on admission include the following:

• Patient older than 55 years

• WBC count higher than 16,000/µL

• Blood glucose level higher than 200 mg/dL

• Serum LDH level higher than 350 IU/L

• AST level higher than 250 IU/L

Criteria developing during the first 48 hours include the following:

• Hematocrit fall of more than 10%

• BUN level increase by more than 8 mg/dL

• Serum calcium level lower than 8 mg/dL

• Pa O2 less than 60 mm Hg

• Base deficit higher than 4 mEq/L

• Estimated fluid sequestration higher than 6 L

Each of the above criteria counts for 1 point toward the score. A Ranson score of 0-2 has a minimal mortality, and the patient is admitted to the regular ward for medical therapy and support. A Ranson score of 3-5 has a 10%-%20% mortality rate, and the patient should be admitted to the intensive care unit (ICU). A Ranson score higher than 5 after 48 hours has a mortality of more than 50% and is associated with more systemic complications. Although the Ranson criteria are perhaps the best known scoring system, they have several drawbacks. First, 11 criteria are used, some of which are evaluated on day 1 and others on day 2. The Ranson score is valid only at 48 hours after onset and not at any other time during the disease. Second, the threshold for an abnormal value depends on whether the pancreatitis is caused by alcohol or gallstones. Finally, the sensitivity is only 73% and the specificity is 77% for predicting mortality. BUN An elevated BUN level at admission has been associated with an increase in severe acute pancreatitis and/or death. This corresponds well with the APACHE II score. The rise in BUN is thought to be due to hemoconcentration, which is a surrogate marker for intravascular depletion. Intravascular depletion is thought to be a key mediator of the inflammatory response in acute pancreatitis. APACHE II The APACHE score has the advantage of being able to assess the patient at any point during the illness; however, it is very cumbersome for routine clinical use. Attempts have been made to make this evaluation user friendly (eg, with APACHE II, the Simplified Acute Physiology Score [SAPS], and the Imrie score), but it remains cumbersome. The sensitivity is 77%, and the specificity is 84%. See the APACHE II Scoring System calculator. Biological markers The most widely available biological marker for staging acute pancreatitis is the hematocrit value. Admission hemoconcentration to a hematocrit value greater than 47% had been reported as a sensitive predictor of pancreatic necrosis at admission. However, a subsequent study has revealed admission hematocrit to be useful only as a negative predictor for necrosis in patients without hemoconcentration. CRP, a nonspecific acute-phase reactant produced by the liver in response to interleukin (IL)–6, is a useful marker at 36-48 hours. A CRP level greater than 6 at 24 hours or greater than 7 at 48 hours is consistent with severe acute pancreatitis. The sensitivity of this test is 73%, and the specificity is 71%. IL-6 levels begin to rise in the first several hours of pancreatitis, stimulating the release of CRP. Early studies of IL-6 as a biological marker appear promising, indicating that this may be a reliable indicator of pancreatitis severity. However, this conclusion is not yet validated, and IL-6 is not yet commercially available for clinical use in this setting. Several other blood tests show promise in predicting the severity of acute pancreatitis. These include trypsinogen activation peptide (TAP), polymorphonuclear elastase, and phospholipase A2. Like IL-6, they are generally not used in clinical practice and are more expensive than typically used tests. Some are only slightly better than using CRP. Genetic markers Polymorphisms in the chemokine monocyte chemotactic protein 1 (MCP-1) gene may play a role in predisposing patients to severe acute pancreatitis, although this marker is still under investigation and is not used clinically.

Treatment & Management

Approach Considerations

Medical management of mild acute pancreatitis is relatively straightforward. The patient is kept NPO (nil per os—that is, nothing by mouth), and intravenous (IV) fluid hydration is provided. Analgesics are administered for pain relief. Antibiotics are generally not indicated. If ultrasonograms show evidence of gallstones and if the cause of pancreatitis is believed to be biliary, a cholecystectomy should be performed during the same hospital admission. Feeding should be introduced enterally as the patient’s anorexia and pain resolves. Patients can be initiated on a low-fat diet initially and need not invariably start their dietary advancement using a clear liquid diet. Systematic reviews and meta-analyses have shown that administration of enteral nutrition may reduce mortality and infectious complications compared with parenteral nutrition. [31] Although the ideal timing to initiate enteral feeding remains undetermined, administration within 48 hours appears to be safe and tolerated. [31] Serum amylase and lipase levels can be elevated in patients with brain injury (eg, cerebrovascular accident or brain trauma). These patients are generally cared for in an intensive care unit (ICU) and require mechanical ventilation. Pancreatic enzyme elevations may rise and fall considerably over many days to weeks. The elevation is believed to result from hyperstimulation of the pancreas via a central mechanism, but no evidence of acute pancreatitis is present on imaging studies. Patients with severe acute pancreatitis require intensive care. Within hours to days, a number of complications (eg, shock, pulmonary failure, renal failure, gastrointestinal [GI] bleeding, or multiorgan system failure) may develop. The goals of medical management are to provide aggressive supportive care, to decrease inflammation, to limit infection or superinfection, and to identify and treat complications as appropriate. Autoimmune pancreatitis is a rare condition. Corticosteroids should not be used to treat this condition in the short term in patients who are suspected of having autoimmune pancreatitis and who present with acute pancreatitis. No evidence-based guidelines specify when a patient should be transferred to a more experienced or skilled medical center. However, if severe acute pancreatitis is suggested either by the Atlanta criteria [2] or by a C-reactive protein (CRP) level above 10 mg/dL, Ranson score of 4 or higher, or Acute Physiology and Chronic Health Evaluation (APACHE) II score of 9 or higher, consider transfer to an institution where an intensivist staffs the critical care unit and an interested subspecialist experienced in the diagnosis and treatment of pancreatitis is available. Further inpatient care depends on whether any of the complications of severe pancreatitis develop and how well patients respond to treatment. This ranges from a few days to several months of intensive care. Patients can be discharged when their pain is well controlled with oral analgesia, they are able to tolerate an oral diet that maintains their caloric needs, and all complications have been addressed adequately.

Initial Supportive Care

Fluid resuscitation Patients with acute pancreatitis lose a large amount of fluids to third spacing into the retroperitoneum and intra-abdominal areas. Accordingly, they require prompt intravenous (IV) hydration within the first 24 hours. Especially in the early phase of the illness, aggressive fluid resuscitation is critically important. This cannot be overemphasized. There is no universal consensus definitively favoring one type of fluid over another type; both crystalloids and colloids are used. Resuscitation should be sufficient to maintain hemodynamic stability. This usually involves administration of several liters of fluid as a bolus, followed by continuous infusion at a rate of 250-500 mL/h. Central venous pressure, pulmonary artery wedge pressure, and urine output (>0.5 mL/kg/h) can be followed up as markers of adequate hydration. Careful attention should be paid to signs of overhydration, such as pulmonary edema causing hypoxia. Nutritional support General guidelines for nutritional support of patients with acute pancreatitis include the following:

• In patients with mild uncomplicated pancreatitis, no benefit is observed from nutritional support, and the energy (caloric) intake received with IV dextrose 5% in water (D5W) suffices; oral feedings should be initiated once the patient’s pain and anorexia resolve

• In patients with moderate-to-severe pancreatitis, begin nutritional support early in the course of management, as soon as stabilization of fluid and hemodynamic parameters permits; optimally, nasojejunal feedings with a low-fat formulation should be initiated at admission

• Total parenteral nutrition (TPN) may be required when patients cannot meet their caloric needs with enteral nutrition or when adequate jejunal access cannot be maintained; the TPN solution should include fat emulsions in amounts sufficient to prevent essential fatty acid deficiency

• If surgery is required for diagnosis or complications of the disease, place a feeding jejunostomy at the time of the operation; use a low-fat formula

• Begin oral feedings once abdominal pain has resolved and the patient regains appetite; the diet should be low in fat and protein

Theoretical considerations regarding the ability of the enterocyte to maintain a barrier against bacterial translocation favor nasojejunal feedings—hence the recommendation to attempt initiating nasojejunal feedings at admission in all patients admitted to the intensive care unit (ICU). For patients with mild acute pancreatitis, nasojejunal feedings can be avoided unless patients are unable to tolerate oral intake for over 1 week. Research has not established whether nasojejunal tubes have an advantage over nasogastric tubes for enteral feeding. Although TPN, which has been shown to reduce mortality, may be necessary in certain situations, it should generally be reserved for use as a second-line therapy, behind enteral feeding. A prospective, randomized study showed that initiating oral feeding with a low-fat solid diet was as well tolerated as initiating feeding with a clear liquid diet, but it did not result in a shorter length of hospital stay. [32] In a 2014 randomized, multicenter study of 208 patients with acute pancreatitis, early nasoenteric tube feeding was not superior to an oral diet initiated 72 hours after presentation. [33] Tube feeding was provided if the oral diet was not tolerated. During 6 months of follow-up, major infection or death occurred in 30 of 101 patients (30%) in the early nasoenteric tube feeding group and in 28 of 104 patients (27%) in the oral diet group (risk ratio, 1.07; 95% confidence interval, 0.79 to 1.44; P = 0.76). [33] Of the 104 patients in the oral diet group, 72 (69%) did not require tube feeding.

Antibiotic Therapy

Antibiotics, usually drugs of the imipenem class, should be used in any case of pancreatitis complicated by infected pancreatic necrosis. However, they should not be given routinely for fever, especially early in the disease course, because this symptom is almost universally secondary to the inflammatory response and typically does not reflect an infectious process. Several controlled trials have evaluated the role of empiric antibiotics in patients with severe acute necrotizing pancreatitis for infectious prophylaxis. One such trial evaluated the role of imipenem-cilastatin initiated at admission to prevent infected pancreatic necrosis. This drug combination penetrates the pancreatic parenchyma and reduces the risk of intra-abdominal infection. It appeared to offer some benefit in preventing infectious complications. Unfortunately, fungal superinfection tends to develop later in the clinical course, although this risk is probably overemphasized. [34] A randomized trial failed to show any benefit from giving ciprofloxacin and metronidazole to prevent infectious complications. Accordingly, this drug combination is not routinely used for prophylaxis in the setting of acute pancreatitis. [35] The bottom line is that antibiotic prophylaxis in severe pancreatitis is controversial. At this time, the routine use of antibiotics as prophylaxis against infection in severe acute pancreatitis is not recommended.

Emerging Pharmacologic Treatments

Although the role that cytokines play in the systemic inflammatory response syndrome (SIRS) appears to be important, a large clinical trial of lexipafant, a platelet-activating factor antagonist, has shown no benefit in patients with severe acute pancreatitis. Because multiple pathways are involved in the inflammatory response, further research is needed in order to define which cytokine or combination of cytokines should be targeted to ameliorate the complications of acute pancreatitis. [36] Therapy directed against tumor necrosis factor-alpha (TNF-α) has been targeted as a potential treatment of acute pancreatitis; however, clinical trials have not yet determined its value in this setting.

Surgical Interventions

Surgical intervention, whether by minimally invasive or conventional open techniques, is indicated when an anatomic complication amenable to a mechanical solution is present (eg, acute necrotizing pancreatitis in which the necrotic phlegmon is excised to limit a potential site of sepsis, or hemorrhagic pancreatitis in which surgical control of bleeding is warranted). Depending on the situation and local expertise, this may require the talents of an interventional radiologist, an interventional endoscopist, or surgeon (individually or in combination). The images below provide examples of the treatment of severe acute pancreatitis by means of minimally invasive techniques.

Acute pancreatitis. Endoscopic retrograde cholangiopancreatography excluded suppurative cholangitis and established the presence of anular pancreas divisum. The dorsal pancreatogram showed extravasation into the retroperitoneum, and sphincterotomy was performed on the minor papilla. A pigtail nasopancreatic tube was then inserted into the dorsal duct and out into the retroperitoneal fluid collection. The other end of the tube was attached to bulb suction and monitored every shift.

Acute pancreatitis. Although percutaneous drains remove loculated fluid collections elsewhere in the abdomen, a nasopancreatic tube drains the retroperitoneal fluid collection. One week later, the retroperitoneal fluid collection was much smaller (the image is reversed in a horizontal direction). By this time, the patient was off pressors and was ready to be extubated

Gallstone pancreatitis

It is optimal for patients admitted with gallstone pancreatitis to undergo cholecystectomy before discharge, rather than being scheduled for a later date as an outpatient. Patients discharged with gallstone pancreatitis without a cholecystectomy are at high risk for recurrent bouts of pancreatitis. Aboulian et al found that in patients with mild gallstone pancreatitis, performing laparoscopic cholecystectomy within 48 hours of admission—regardless of whether abdominal pain or laboratory abnormalities had resolved—resulted in a shorter hospital stay and had no apparent impact on the technical difficulty of the procedure or the perioperative complication rate. [37] In a retrospective study of data from 316 Italian patients admitted for nonsevere acute gallstone pancreatitis over 14 years, investigators found that less than one third (31%) underwent early laparoscopic cholecystectomy (≤72 hours). [38] The most common factors related to surgical delay were the need to (1) stablilize comorbid conditions and (2) preoperatively investigate the common bile duct; other factors were significantly advanced age and an increased incidence of clinical signs indicating the presence of common bile duct stones. Although early laparoscopic cholecystectomy appeared to shorten overall hospitalization, the clinical outcomes were similar between those who underwent early surgery and those who underwent delayed laparoscopic cholecystectomy. [38] If the imaging and laboratory study findings are consistent with severe acute gallstone pancreatitis that is not responding to supportive therapy or with ascending cholangitis with worsening signs and symptoms of obstruction, early endoscopic retrograde cholangiopancreatography (ERCP) with sphincterotomy and stone extraction is indicated. Pancreatic duct disruption Damage to the pancreatic ductal system may allow the pancreatic juice to leak from the gland. The sudden development of hypocalcemia or a rapid increase in retroperitoneal fluid on computed tomography (CT) is suggestive of this condition. When imaging studies provide corroborating evidence, the condition is initially managed by percutaneous placement of a drainage tube into the fluid collection under the guidance of ultrasonography or CT scanning. [4] Fluid amylase or lipase levels in the 10,000s strongly suggest the presence of a ductal disruption. In the appropriate clinical setting, ERCP confirms the diagnosis and provides a treatment option. Transpapillary stent placement or, preferably, placement of a 6 French nasopancreatic tube attached to an external bulb suction device can successfully treat leaks by removing the sphincter tone and changing the dynamics of fluid flow in favor of ductal healing. Occasionally, leaks are associated with downstream stenoses that are also amenable to endoscopic treatment. Refractory cases may warrant surgery. If a persistent leak is present in the tail of the gland, a distal pancreatectomy is preferred. If the leak is in the head of the gland, a Whipple procedure is the operation of choice. Pseudocysts Peripancreatic fluid collections persisting for more than 4 weeks are referred to as acute pseudocysts. Pseudocysts lack an epithelial layer and thus are not considered true cysts. They also differ from true cysts in that they are usually filled with necrotic debris rather than fluid. Accordingly, pseudocysts may be better described by the term organized necrosis. Most pseudocysts can be followed clinically. However, when they are symptomatic (ie, associated with pain, bleeding, or infection) or are larger than 7 cm and are rapidly expanding in an acutely ill patient, intervention is indicated. Several different therapeutic approaches may be implemented, depending on the anatomic relations and on the duration of the natural history of the complication. In selected patients with very large fluid collections, percutaneous aspiration of pancreatic pseudocysts is a reasonable approach. Even though treatment failures are common when the pseudocyst communicates with the pancreatic ductal system, percutaneous drainage serves as a temporizing measure that may later lead to successful endoscopic or surgical intervention. Often, an infected pseudocyst (which by definition is regarded as a pancreatic abscess) can be successfully managed by means of percutaneous drainage. Pseudocysts may also be managed endoscopically with transpapillary or transmural techniques. Transpapillary drainage requires the main pancreatic duct to communicate with the pseudocyst cavity, ideally in the head or body of the gland. The proximal end of the stent (which should be smaller than the diameter of the pancreatic duct) is placed into the cavity. The technical success rate is 83%, the complication rate 12%. Generally, however, pancreatic stents are difficult to monitor, are prone to obstruction, and carry an increased risk of infection and ductal injury. Some noncommunicating pseudocysts may be amenable to transmural enterocystostomy. Technical success requires a mature cyst that bulges into the foregut, and the distance from the lumen to the cyst cavity should be less than 1 cm. The success rate is 85%, the complication rate 17%. The transduodenal approach is associated with fewer complications and recurrences than the transgastric approach. On the basis of prospective studies in the 1970s, surgery was recommended for persistent large (> 7 cm) pancreatic pseudocysts because complications developed in 41% of patients, 13% of whom died. Internal pseudocyst-enteric anastomosis became the standard of care, with an operative mortality of 3-5%. This dogma was subsequently challenged by 2 retrospective studies in which patients with smaller (ie, < 5 cm) asymptomatic pseudocysts rarely (< 10%) developed complications. Infected pancreatic necrosis

The clinician cannot rely on clinical findings alone to differentiate infected and sterile pancreatic necrosis. When clinical signs of infection or SIRS are present in the setting of necrotizing pancreatitis, CT-guided needle aspiration is indicated. Surgery is recommended when large areas of the pancreas are necrotic and percutaneous CT-guided aspiration demonstrates infection on the basis of a positive Gram stain. Antibiotic therapy alone is not sufficient to achieve a cure. Aggressive surgical debridement and drainage are necessary to remove dead tissue and to clear the infection. A study of patients with necrotizing pancreatitis and infected necrotic tissue determined that a step-up approach to treatment (consisting of percutaneous drainage followed, if necessary, by minimally invasive retroperitoneal necrosectomy) yielded better results than standard care with open necrosectomy. [39] Patients who received step-up treatment had a lower rate of major complications (new-onset multiorgan failure, multiple systemic complications, perforation of a visceral organ, enterocutaneous fistula, or bleeding) and death. Pancreatic abscess Pancreatic abscesses generally occur late in the course of pancreatitis. Many of these respond to percutaneous catheter drainage and antibiotics. Those that do not respond require surgical debridement and drainage.

Prevention

When the cause of pancreatitis can be determined, prevention depends on stopping the etiologic agent from causing subsequent episodes. In patients with documented gallstone pancreatitis—and probably in those with idiopathic recurrent pancreatitis as well—cholecystectomy is required. In patients who abuse alcohol, a dedicated person (eg, physician, psychologist, addiction counselor) who can help the patient overcome the addiction to alcohol is required. When an uncommon cause of pancreatitis is identified, the path of prevention is specific to the etiology.

Consultations

The most effective and soundly based treatment plan for any disorder is one aimed at the mechanism responsible for the development of the disorder. With that axiom in mind, consultations must be obtained with an eye to addressing the underlying cause of pancreatitis. Treatment of patients with alcohol-induced pancreatitis should go beyond the physical manifestations of this disease and address the underlying psychological addiction to alcohol. Simply telling patients they must stop drinking alcohol is not satisfactory. Successful treatment often requires the involvement and expertise of a chemical dependency counselor. The author favors in-hospital consultation for all patients admitted with alcoholic pancreatitis. Patients with hypertriglyceridemia- or hypercalcemia-induced pancreatitis require consultation with an endocrinologist. Rarely, such patients require surgical intervention for treatment of hyperparathyroidism or control of hyperlipidemia refractory to medical therapy. Patients with gallstones or microlithiasis revealed on imaging studies should have a surgical consultation for gallbladder removal. Because microlithiasis is the most common cause of idiopathic pancreatitis, a patient with recurrent idiopathic pancreatitis should undergo cholecystectomy before procedures associated with a higher risk of complications (eg, ERCP) are performed. Patients with medication-induced acute pancreatitis may benefit from clinical pharmacology consultation during their hospitalization to optimize their therapeutic regimen.

Long-Term Monitoring

Once the patient is stable enough to be discharged from the hospital, routine clinical follow-up care (typically including physical examination and amylase and lipase assays) is needed to monitor for potential complications of pancreatitis, especially pseudocysts. No evidence-based guidelines have been established for outpatient follow-up care. Generally, a reasonable time to see the patient is within 7-10 days from the date of hospital discharge to evaluate how he or she is doing and to check for signs or symptoms of complications. If the pancreatitis was moderate to severe and was associated with peripancreatic fluid collections, subsequent imaging studies are indicated to determine if a pseudocyst has developed.

Recurrent acute pancreatitis

Recurrent acute pancreatitis (see the image below) can be a challenging clinical problem. First, seek to determine the etiology using modalities that subject the patient to the least risk while simultaneously assessing for treatable causes.

Acute pancreatitis. A normal-appearing ventral pancreas is seen in a patient with recurrent acute pancreatitis. Dorsal pancreas (not pictured) showed evidence of chronic pancreatitis

Abdominal computed tomography (CT) scanning is a reasonable first approach. If neoplasia or chronic pancreatitis is found, it must be addressed and treated accordingly. If the CT scan is not diagnostic, order a magnetic resonance cholangiopancreatography (MRCP). If MRCP shows developmental abnormalities, strictures, or evidence of chronic pancreatitis, remember that endoscopic or surgical treatment may be of benefit in a subset of patients. If the MRCP findings are normal, further evaluation with endoscopic ultrasonography (EUS) is indicated. EUS has better sensitivity for detecting biliary sludge and microlithiasis, which are probably the most common causes of recurrent idiopathic pancreatitis. It may also help detect periampullary lesions missed by abdominal CT scanning or MRCP. If previous studies showed evidence of microlithiasis or biliary sludge, cholecystectomy is indicated. If the patient has already undergone cholecystectomy or if pancreatitis recurs, further evaluation by ERCP is indicated. This may reveal papillary stenosis, in which case a pancreatic and, possibly, biliary sphincterotomy is indicated. The role of genetic testing is emerging, and whether testing for cationic trypsinogen mutations, SPINK1 mutations, or CFTR mutations should be performed remains unclear, because no effective treatment currently exists for these diseases. If recurrent pancreatitis continues, ERCP with sphincter of Oddi manometry is indicated. This procedure is placed last in the evaluation because patients with suspected sphincter of Oddi dysfunction (especially that resulting from dyskinesia of the sphincter) have a very high rate of post-ERCP pancreatitis, and the possibility that ERCP may create iatrogenic complications rather than cure the recurrent pancreatitis is a concern.

Medication

Medication Summary The goal of pharmacotherapy is to relieve pain and minimize complications. Currently, no medications are used to treat acute pancreatitis specifically. Therapy is primarily supportive and involves intravenous (IV) fluid hydration, analgesics, antibiotics (in severe pancreatitis), and treatment of metabolic complications (eg, hyperglycemia and hypocalcemia).

Analgesics, Other Class Summary Pain control is essential for quality patient care. It ensures patient comfort, promotes pulmonary toilet, and has sedating properties, which are beneficial for patients who have sustained trauma or have painful lesions. Propoxyphene products were withdrawn from the US market on November 19, 2010. The withdrawal was based on new data showing QT prolongation at therapeutic doses. For more information, see the FDA MedWatch safety information. Acetaminophen (Tylenol, Feverall, Aspirin Free Anacin)

Acetaminophen is a peripherally acting drug of choice for mild to moderate pain and elevation of body temperature. Tramadol (Ultram, Ryzolt, Rybix)

Tramadol is a centrally acting analgesic for moderately severe pain. It inhibits the ascending pain pathways, altering perception of and response to pain. It also inhibits reuptake of norepinephrine and serotonin. Meperidine (Demerol)

Meperidine is a synthetic opioid narcotic analgesic for the relief of severe pain. It has multiple actions similar to those of morphine. It may produce less constipation, smooth muscle spasm, and depression of cough reflex than similar analgesic doses of morphine.

Antibiotics, Other Class Summary Antibiotics are used to cover the microorganisms that may grow in biliary pancreatitis and acute necrotizing pancreatitis. The empiric antibiotic regimen is usually based on the premise that enteric anaerobic and aerobic gram-bacilli microorganisms are often the cause of pancreatic infections. Once culture sensitivities are obtained, the antibiotic regimen can be adjusted accordingly. Imipenem and cilastatin (Primaxin) Imipenem is a thienamycin derivative with greater potency and broader antimicrobial spectrum than other beta-lactam antibiotics. Cilastatin inhibits dehydropeptidase activity and reduces cilastatin metabolism. Imipenem-cilastatin is used for the treatment of multiple-organism infections in which other agents either do not provide wide-spectrum coverage or are contraindicated because of potential toxicity. The 2 agents are generally administered in a 1:1 ratio. Ampicillin Ampicillin has bactericidal activity against susceptible organisms. It is an alternative to amoxicillin when the patient is unable to take medication orally. Ceftriaxone (Rocephin)

Ceftriaxone is a third-generation cephalosporin with broad-spectrum gram-negative activity; it has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. Ceftriaxone arrests bacterial growth by binding to 1 or more penicillin-binding proteins.

References

1. Telem DA, Bowman K, Hwang J, Chin EH, Nguyen SQ, Divino CM. Selective management of patients with acute biliary pancreatitis. J Gastrointest Surg. 2009 Dec. 13(12):2183-8. [Medline].

2. Banks PA, Bollen TL, Dervenis C, et al, for the Acute Pancreatitis Classification Working Group. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2013 Jan. 62(1):102-11. [Medline].

3. Haydock MD, Mittal A, van den Heever M, et al, for the Pancreas Network of New Zealand. National survey of fluid therapy in acute pancreatitis: current practice lacks a sound evidence base. World J Surg. 2013 Oct. 37(10):2428-35. [Medline].

4. Ai X, Qian X, Pan W, et al. Ultrasound-guided percutaneous drainage may decrease the mortality of severe acute pancreatitis. J Gastroenterol. 2010. 45(1):77-85. [Medline].

5. Li H, Qian Z, Liu Z, Liu X, Han X, Kang H. Risk factors and outcome of acute renal failure in patients with severe acute pancreatitis. J Crit Care. 2010 Jun. 25(2):225-9. [Medline].

6. Whitcomb DC, Yadav D, Adam S, et al, for the North American Pancreatic Study Group. Multicenter approach to recurrent acute and chronic pancreatitis in the United States: the North American Pancreatitis Study 2 (NAPS2). Pancreatology. 2008. 8(4-5):520-31. [Medline]. [Full Text].

7. Elmunzer BJ, Scheiman JM, Lehman GA, et al, for the U.S. Cooperative for Outcomes Research in Endoscopy (USCORE). A randomized trial of rectal indomethacin to prevent post-ERCP pancreatitis. N Engl J Med. 2012 Apr 12. 366(15):1414-22. [Medline].

8. Kamisawa T, Funata N, Hayashi Y, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003. 38(10):982-4. [Medline].

9. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013 Jun. 144(6):1252-61. [Medline]. [Full Text].

10. Peery AF, Dellon ES, Lund J, et al. Burden of gastrointestinal disease in the United States: 2012 update. Gastroenterology. 2012 Nov. 143(5):1179-1187.e3. [Medline]. [Full Text].

11. Singla A, Csikesz NG, Simons JP, et al. National hospital volume in acute pancreatitis: analysis of the Nationwide Inpatient Sample 1998-2006. HPB (Oxford). 2009 Aug. 11(5):391-7. [Medline]. [Full Text].

12. Krishna SG, Kamboj AK, Hart PA, Hinton A, Conwell DL. The changing epidemiology of acute pancreatitis hospitalizations: a decade of trends and the impact of chronic pancreatitis. Pancreas. 2017 Apr. 46(4):482-8. [Medline]. [Full Text].

13. Peery AF, Crockett SD, Murphy CC, et al. Burden and cost of gastrointestinal, liver, and pancreatic diseases in the United States: update 2018. Gastroenterology. 2019 Jan. 156(1):254-72.e11. [Medline]. [Full Text].

14. Banks PA. Epidemiology, natural history, and predictors of disease outcome in acute and chronic pancreatitis. Gastrointest Endosc. 2002 Dec. 56(6 suppl):S226-30. [Medline].

15. Morinville VD, Barmada MM, Lowe ME. Increasing incidence of acute pancreatitis at an American pediatric tertiary care center: is greater awareness among physicians responsible?. Pancreas. 2010 Jan. 39(1):5-8. [Medline].

16. Akhtar AJ, Shaheen M. Extrapancreatic manifestations of acute pancreatitis in African-American and Hispanic patients. Pancreas. 2004 Nov. 29(4):291-7. [Medline].

17. Huh JH, Jeon H, Park SM, et al. Diabetes mellitus is associated with mortality in acute pancreatitis. J Clin Gastroenterol. 2018 Feb. 52(2):178-83. [Medline].

18. Whitcomb DC. Clinical practice. Acute pancreatitis. N Engl J Med. 2006 May 18. 354(20):2142-50. [Medline].

19. Suppiah A, Malde D, Arab T, et al. The prognostic value of the neutrophil-lymphocyte ratio (NLR) in acute pancreatitis: identification of an optimal NLR. J Gastrointest Surg. 2013 Apr. 17(4):675-81. [Medline].

20. Khan A, Sarma D, Gowda C, Rodrigues G. The role of Modified Early Warning Score (MEWS) in the prognosis of acute pancreatitis. Oman Med J. 2021 May. 36(3):e272. [Medline]. [Full Text].

21. Mikolasevic I, Orlic L, Poropat G, et al. Nonalcoholic fatty liver and the severity of acute pancreatitis. Eur J Intern Med. 2017 Mar. 38:73-8. [Medline].

22. Kothari S, Kalinowski M, Kobeszko M, Almouradi T. Computed tomography scan imaging in diagnosing acute uncomplicated pancreatitis: Usefulness vs cost. World J Gastroenterol. 2019 Mar 7. 25(9):1080-7. [Medline]. [Full Text].

23. Imamura Y, Hirota M, Ida S, et al. Significance of renal rim grade on computed tomography in severity evaluation of acute pancreatitis. Pancreas. 2010 Jan. 39(1):41-6. [Medline].

24. Balthazar EJ, Ranson JH, Naidich DP, Megibow AJ, Caccavale R, Cooper MM. Acute pancreatitis: prognostic value of CT. Radiology. 1985 Sep. 156(3):767-72. [Medline].

25. Balthazar EJ, Robinson DL, Megibow AJ, Ranson JH. Acute pancreatitis: value of CT in establishing prognosis. Radiology. 1990 Feb. 174(2):331-6. [Medline].

26. Balthazar EJ. Staging of acute pancreatitis. Radiol Clin North Am. 2002 Dec. 40(6):1199-209. [Medline].

27. Badalov N, Tenner S, Baillie J. The prevention, recognition and treatment of post-ERCP pancreatitis. JOP. 2009 Mar 9. 10(2):88-97. [Medline].

28. Testoni PA, Mariani A, Giussani A, et al, for the SEIFRED Group. Risk factors for post-ERCP pancreatitis in high- and low-volume centers and among expert and non-expert operators: a prospective multicenter study. Am J Gastroenterol. 2010 Aug. 105(8):1753-61. [Medline].

29. Parihar V, Ridgway PF, Conlon KC, Huggett M, Ryan BM. The role of endoscopic intervention in the management of inflammatory pancreatic fluid collections. Eur J Gastroenterol Hepatol. 2017 Apr. 29(4):371-9. [Medline].

30. Imrie CW. Prognostic indicators in acute pancreatitis. Can J Gastroenterol. 2003 May. 17(5):325-8. [Medline].

31. Krishnan K. Nutritional management of acute pancreatitis. Curr Opin Gastroenterol. 2017 Mar. 33(2):102-6. [Medline].

32. Jacobson BC, Vander Vliet MB, Hughes MD, Maurer R, McManus K, Banks PA. A prospective, randomized trial of clear liquids versus low-fat solid diet as the initial meal in mild acute pancreatitis. Clin Gastroenterol Hepatol. 2007 Aug. 5(8):946-51; quiz 886. [Medline]. [Full Text].

33. Bakker OJ, van Brunschot S, van Santvoort HC, et al, for the Dutch Pancreatitis Study Group. Early versus on-demand nasoenteric tube feeding in acute pancreatitis. N Engl J Med. 2014 Nov 20. 371(21):1983-93. [Medline].

34. Maravi-Poma E, Gener J, Alvarez-Lerma F, et al, for the Spanish Group for the Study of Septic Complications in Severe Acute Pancreatitis. Early antibiotic treatment (prophylaxis) of septic complications in severe acute necrotizing pancreatitis: a prospective, randomized, multicenter study comparing two regimens with imipenem-cilastatin. Intensive Care Med. 2003 Nov. 29(11):1974-80. [Medline].

35. Isenmann R, Runzi M, Kron M, et al, for the German Antibiotics in Severe Acute Pancreatitis Study Group. Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial. Gastroenterology. 2004 Apr. 126(4):997-1004. [Medline].

36. Johnson CD, Kingsnorth AN, Imrie CW, et al. Double blind, randomised, placebo controlled study of a platelet activating factor antagonist, lexipafant, in the treatment and prevention of organ failure in predicted severe acute pancreatitis. Gut. 2001 Jan. 48(1):62-9. [Medline]. [Full Text].

37. Aboulian A, Chan T, Yaghoubian A, et al. Early cholecystectomy safely decreases hospital stay in patients with mild gallstone pancreatitis: a randomized prospective study. Ann Surg. 2010 Apr. 251(4):615-9. [Medline].

38. Guadagni S, Cengeli I, Palmeri M, et al. Early cholecystectomy for non-severe acute gallstone pancreatitis: easier said than done. Minerva Chir. 2017 Apr. 72(2):91-7. [Medline].

39. van Santvoort HC, Besselink MG, Bakker OJ, et al, for the Dutch Pancreatitis Study Group. A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med. 2010 Apr 22. 362(16):1491-502. [Medline].

40. [Guideline] Tenner S, Baillie J, DeWitt J, Vege SS, and the American College of Gastroenterology. American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol. 2013 Sep. 108(9):1400-15; 1416. [Medline].

41. [Guideline] Crockett SD, Wani S, Gardner TB, Falck-Ytter Y, Barkun AN, American Gastroenterological Association Institute Clinical Guidelines Committee. American Gastroenterological Association Institute Guideline on Initial Management of Acute Pancreatitis. Gastroenterology. 2018 Mar. 154(4):1096-101. [Medline].

42. [Guideline] Vege SS, Ziring B, Jain R, Moayyedi P, and the Clinical Guidelines Committee, American Gastroenterology Association. American Gastroenterological Association institute guideline on the diagnosis and management of asymptomatic neoplastic pancreatic cysts. Gastroenterology. 2015 Apr. 148(4):819-22; quiz 12-3. [Medline].

43. [Guideline] Leppaniemi A, Tolonen M, Tarasconi A, et al. 2019 WSES guidelines for the management of severe acute pancreatitis. World J Emerg Surg. 2019. 14:27. [Medline]. [Full Text].

44. Granger J, Remick D. Acute pancreatitis: models, markers, and mediators. Shock. 2005 Dec. 24 suppl 1:45-51. [Medline].

45. Wu BU, Hwang JQ, Gardner TH, et al. Lactated Ringer's solution reduces systemic inflammation compared with saline in patients with acute pancreatitis. Clin Gastroenterol Hepatol. 2011 Aug. 9(8):710-7.e1. [Medline].

46. Kim SB, Kim TN, Chung HH, Kim KH. Small gallstone size and delayed cholecystectomy increase the risk of recurrent pancreatobiliary complications after resolved acute biliary pancreatitis. Dig Dis Sci. 2017 Mar. 62(3):777-83. [Medline].

47. Petrov MS, Yadav D. Global epidemiology and holistic prevention of pancreatitis. Nat Rev Gastroenterol Hepatol. 2019 Mar. 16(3):175-84. [Medline]. [Full Text].

48. Machicado JD, Yadav D. Epidemiology of recurrent acute and chronic pancreatitis: similarities and differences. Dig Dis Sci. 2017 Jul. 62(7):1683-91. [Medline]. [Full Text].

49. [Guideline] Vege SS, DiMagno MJ, Forsmark CE, Martel M, Barkun AN. Initial medical treatment of acute pancreatitis: American Gastroenterological Association Institute Technical Review. Gastroenterology. 2018 Mar. 154(4):1103-39. [Medline].

50. Jeon CY, Papachristou GI, Pisegna JR, et al. A Case-CrossovEr study deSign to inform tailored interventions to prevent disease progression in Acute Pancreatitis (ACCESS-AP) - study design and population. Pancreatology. 2021 Jun 24. [Medline].

51. Duzenci D, Yalnız M, Ispiroglu M. Comparison between prognostic indicators in organ insufficiency with acute pancreatitis. Ulus Travma Acil Cerrahi Derg. 2021 Jul. 27(4):410-20. [Medline].