WORKUP	Section 5 of 11
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Lab Studies:

• 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 defining an etiology and looking for complications.

• 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. Elevations can occur in anyone 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 reference ranges within a few days.

• Lipase has a slightly longer half-life and 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 amylase levels.

• 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 prognosis.

• Liver-associated enzymes

• Determine alkaline phosphatase, total bilirubin, aspartate aminotransferase, and alanine aminotransferase levels to search for evidence of gallstone pancreatitis.

• An alanine aminotransferase level greater than 150 U/L suggests gallstone pancreatitis and a more fulminant disease course.

• Calcium, cholesterol, and triglycerides: Determine these levels to search for an etiology of pancreatitis (hypercalcemia or hyperlipidemia) or complications of pancreatitis (hypocalcemia resulting from saponification of fats in the retroperitoneum). However, be wary of the fact that baseline serum triglyceride levels can be falsely lowered during an episode of acute pancreatitis.

• Serum electrolytes, BUN, creatinine, and glucose: Measure these to look for electrolyte imbalances, renal insufficiency, and pancreatic endocrine dysfunction.

• CBC count

• 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.

• Leukocytosis may represent inflammation or infection.

• 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.

• Arterial blood gases

• Measure ABGs if a patient is dyspneic.

• Whether tachypnea is due to acute respiratory distress syndrome or diaphragmatic irritation must be determined.

• Trypsin and its precursor trypsinogen-2 in both the urine and the peritoneal fluid have been evaluated as possible markers for acute 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 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.

Imaging Studies:

• Although unnecessary in most cases of pancreatitis, 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.

• Abdominal radiography

• This modality has a limited role in acute pancreatitis.

• These radiographs are primarily used 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 the pancreas may indicate chronic pancreatitis.

• Abdominal ultrasonography

• This 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.

• Ultrasonography cannot measure the severity of disease.

• Abdominal CT scanning

• This is generally not indicated for patients with mild pancreatitis unless a pancreatic tumor is suspected (usually in elderly patients).

• CT scanning 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.

• Abdominal CT scans also provide prognostic information based on the following grading scale developed by Balthazar:
  • A - Normal

  • B - Enlargement

  • C - Peripancreatic inflammation

  • D - Single fluid collection

  • E - Multiple fluid collections

• 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.

In mild cases, the gland exhibits interstitial edema and an inflammatory infiltrate without hemorrhage or necrosis, usually with minimal or no organ dysfunction. In severe cases, 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, while the gland is usually less affected; hence, overestimation of the extent of pancreatic necrosis is not uncommon. 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, while 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. Each has advantages and disadvantages, and none is currently recognized as a criterion standard.

Patients are diagnosed with severe acute pancreatitis if they show evidence of organ failure (ie, systolic blood pressure <90 mm Hg, PaO₂ <60 mm Hg, serum creatinine >2 mg/dL, >500 mL/24 h GI bleeding), local complications (eg, necrosis, abscess, pseudocyst), or a Ranson score of more than 3 or an APACHE score of more than 8, as described below.

• The Ranson criteria are perhaps best known; however, 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% to predict morality.

• Acute physiology and chronic health evaluation

• The acute physiology and chronic health evaluation (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, APACHE II, simplified acute physiology score, IMRIE score), but it still remains cumbersome.

• The sensitivity is 77%, and the specificity is 84%.

	TREATMENT	Section 6 of 11
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Medical Care: The medical management of mild acute pancreatitis is relatively straightforward. The patient is kept NPO (non per os, ie, nothing by mouth), and intravenous 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.

In contrast, patients with severe acute pancreatitis require intensive care. Within hours to days, a number of complications (eg, shock, pulmonary failure, renal failure, gastrointestinal bleeding, multiorgan system failure) may develop. The goals of medical management are to provide aggressive supportive care, decrease inflammation, limit infection or superinfection, and identify and treat complications as appropriate.

• Fluids: Patients are kept NPO and require intravenous hydration. Especially in the early phase of the illness, aggressive fluid resuscitation is critically important. This cannot be overemphasized. There is no universal consensus showing a definitive advantage of one type of fluid over another type. Resuscitation should be enough to maintain hemodynamic stability, which is usually an initial several liter fluid bolus followed by 250-500 cc/h continuous infusion. Careful attention should be paid to signs of overhydration, such as pulmonary edema causing hypoxia.

• Antibiotics
  • Antibiotics, usually drugs of the imipenem class, should be used in any case of pancreatitis complicated by infected pancreatic necrosis. They should not be given routinely for fevers, especially early in the disease course, as this symptom is almost universally secondary to the inflammatory response and not an infectious process.

  • Several controlled trials have evaluated the role of empiric antibiotics in patients with severe acute necrotizing pancreatitis for infectious prophylaxis. Antibiotics should not be used as prophylaxis in patients with mild pancreatitis.

  • 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. This showed some benefit in preventing infectious complications. Unfortunately, fungal superinfection tends to develop later in the clinical course, although this risk is probably overinflated.

  • A randomized trial failed to show any benefit of ciprofloxacin and metronidazole in preventing infectious complications, and thus this drug combination is not routinely used for prophylaxis in this disease.

  • The bottom line is that antibiotic prophylaxis in severe pancreatitis is controversial. If one does decide to use antibiotic prophylaxis in patients admitted with severe acute pancreatitis, they should be placed on drugs of the imipenem class.

• ERCP: 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 ERCP with sphincterotomy and stone extraction is indicated.

• Nutrition
  • Early initiation of enteral nutritional supplementation and maintenance of a positive nitrogen balance is important in patients with severe pancreatitis.

  • Theoretical considerations regarding the ability of the enterocyte to maintain a barrier against bacterial translocation favor nasojejunal feedings. Thus, in all patients admitted to the ICU, nasojejunal feedings should be attempted beginning at admission. For patients with mild acute pancreatitis, nasojejunal feedings can be avoided unless patients are unable to tolerate oral intake for over 1 week.

  • Depending on the situation, TPN, which has been shown to reduce mortality rates, may be necessary. However, TPN should generally be reserved as a second-line therapy behind enteral feeding.

• Emerging treatments
  • Although the role cytokines play in systemic inflammatory response syndrome appears important, a recent 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.

• Clinical vigilance
  • In the following weeks (to months) after 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.

  • The clinician cannot rely on clinical grounds alone to differentiate infected and sterile pancreatic necrosis. When clinical signs of infection or a systemic inflammatory response is present in the setting of necrotizing pancreatitis, CT-guided needle aspiration is indicated.

Surgical Care: Surgical intervention, whether by minimally invasive or conventional open techniques, is indicated when an anatomical complication amenable to a mechanical solution is present. Depending on the situation and local expertise, this may require the talents of an interventional radiologist, interventional endoscopist, and/or surgeon (alone or in combination).

• Pancreatic duct disruption: Damage to the pancreatic ductal system may allow pancreatic juice to leak from the gland. The sudden development of hypocalcemia or a rapid increase in retroperitoneal fluid on CT scan is suggestive of this condition.

• When imaging studies contain corroborating data, the condition is initially managed by percutaneous placement of a drainage tube into the fluid collection under the guidance of ultrasonography or CT scanning. Fluid amylase or lipase levels in the ten thousands strongly suggest the presence of a ductal disruption.

• In the appropriate clinical setting, endoscopic retrograde pancreatography confirms the diagnosis and provides a treatment option. Transpapillary stent placement or, preferably, placement of a 6F 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 techniques.

• Refractory cases may require surgery. If the 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: By definition, peripancreatic fluid collections persisting for more than 4 weeks are termed acute pseudocysts. Pseudocysts lack an epithelial layer and, thus, are not considered true cysts. In addition, the term cyst is also a misnomer, as most of these collections are filled with necrotic debris and not fluid. A more descriptive term for these collections may be organized necrosis. Most of these can be followed clinically. When pseudocysts 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. The following therapeutic approaches may be implemented, depending on anatomical relationships and the duration of the natural history of the complication.

• Percutaneous aspiration: 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 percutaneous drainage.

• Endoscopic techniques: Pseudocysts may be managed endoscopically by 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 is placed into the cyst cavity, and the stent should be smaller than the diameter of the pancreatic duct. The technical success rate is 83%, with a complication rate of 12%. Generally, however, pancreatic stents are difficult to monitor, prone to obstruction, and associated with 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%, with a complication rate of 17%. The transduodenal approach is associated with fewer complications and recurrences than the transgastric approach.

• Surgical cyst-enterostomy: Based on prospective data from the 1970s, surgery is 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 rate of 3-5%. Recently, this dogma has been challenged by 2 retrospective studies in which patients with smaller asymptomatic pseudocysts (ie, <5 cm) rarely developed complications (<10%).

• Infected pancreatic necrosis: Surgery is recommended when large areas of the pancreas are necrotic and percutaneous CT-guided aspiration demonstrates infection based on a positive Gram stain result. Antibiotic therapy alone is not sufficient to achieve a cure. Aggressive surgical debridement and drainage is necessary to remove dead tissue and to clear the infection.

• Pancreatic abscesses: 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.

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, treatment of the patient must address 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 with all patients admitted with alcoholic pancreatitis.

• Patients with hypertriglyceridemic- or hypercalcemic-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.

• It is optimal for patients admitted with gallstone pancreatitis to have a cholecystectomy prior to discharge and not, for example, 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.

• 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 maximize their therapeutic regimen.

Diet: 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 intravenous 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. The success of nasogastric tube feedings has also recently been compared to nasojejunal feedings in one randomized study. The study showed equivalent outcomes for patients with severe pancreatitis fed with nasogastric feedings compared with nasojejunal feedings.

• However, TPN may be required in patients who are unable to maintain their caloric needs with enteral nutrition or because adequate jejunal access cannot be maintained. TPN 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. A recent prospective, randomized study showed that initiating 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 stay.

	MEDICATION	Section 7 of 11
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Currently, no medications are used to treat acute pancreatitis specifically. Therapy is primarily supportive and involves intravenous fluid hydration, analgesics, antibiotics (in severe pancreatitis), and treatment of metabolic complications (eg, hyperglycemia, hypocalcemia).

	MISCELLANEOUS	Section 9 of 11
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Medical/Legal Pitfalls:

• Serum amylase and lipase levels can be elevated in patients with brain injury (eg, cerebrovascular accident, brain trauma).

• These patients are generally cared for in an intensive care unit and require mechanical ventilation.

• Pancreatic enzyme elevations may rise and fall dangerously over many days to weeks. The elevation is believed to result from the hyperstimulation of the pancreas from a central mechanism, but no evidence of acute pancreatitis is present on imaging studies.

• Failure to identify disease severity can be an area of medical/legal hazard. Recognizing patients with severe acute pancreatitis as soon as possible is critical to achieving optimal outcomes.

Special Concerns:

• Recurrent acute pancreatitis 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.

• Abdominal 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 MRCP. If this 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 by EUS is indicated. This has a better sensitivity for detecting biliary sludge and microlithiasis, which are probably the most common causes of recurrent idiopathic pancreatitis. EUS may also help detect periampullary lesions missed by abdominal CT scanning or MRCP.

• If prior studies showed evidence of microlithiasis or biliary sludge, a cholecystectomy is indicated. If the patient has already had a 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 are indicated.

• The role of genetic testing is emerging, and whether testing for cationic trypsinogen mutations or atypical 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 is placed last in the evaluation because patients with suspected SOD (especially resulting from sphincter of Oddi dyskinesia) have a very high rate of post-ERCP pancreatitis, and creating more iatrogenic complications than cures of recurrent pancreatitis is a concern.

	PICTURES	Section 10 of 11
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Caption: Picture 1. Suspected acute pancreatitis. Etiologic factors and forms of acute pancreatitis. Ranson criteria.
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Caption: Picture 2. Mild pancreatitis. Favorable prognostic signs for acute pancreatitis. Medical management and studies used for acute pancreatitis.
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Caption: Picture 3. Prognostic indicators for severe pancreatitis and ICU management.
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Caption: Picture 4. Diagnosis and treatment of necrotizing pancreatitis.
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Caption: Picture 5. Treatment of and studies used for pancreatic pseudocysts.
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Caption: Picture 6. Idiopathic recurrent pancreatitis. Etiologies for acute pancreatitis.
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Caption: Picture 7. Pancreatic abscess. Definition of an abscess.
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Caption: Picture 8. This patient with acute gallstone pancreatitis underwent endoscopic retrograde cholangiopancreatography. The cholangiogram shows no stones in the common bile duct and multiple small stones in the gallbladder. The pancreatogram shows narrowing of the pancreatic duct in the area of the genu, the result of extrinsic compression of the ductal system by inflammatory changes in the pancreas.