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Authors: Brian Clyne, MD, Assistant Professor of Medicine, Division of Emergency Medicine, Brown University School of Medicine, Providence, RI; Brian Patel, MD, Department of Emergency Medicine, Rhode Island Hospital, Providence; and Jeremiah Schuur, MD, Department of Emergency Medicine, Rhode Island Hospital, Providence.
Peer Reviewers: Steven G. Rothrock, MD, FACEP, FAAP, Associate Professor of Emergency Medicine, Department of Emergency Medicine, University of Florida College of Medicine, Orlando Regional Medical Center, Orlando, FL; and Ralph Riviello, MD, FACEP, Assistant Professor, Department of Emergency Medicine, Thomas Jefferson University, Philadelphia, PA.
Pancreatitis is a heterogeneous inflammatory disease with a broad spectrum of clinical manifestations. Acute pancreatitis can present as a mild, self-limited illness with no sequelae or as fulminant multiple organ failure with circulatory collapse. Chronic pancreatitis may be clinically silent, marked by recurrent episodes of pain, or may cause endocrine and exocrine insufficiency. The outcome for an individual patient is difficult to predict at presentation. Despite improved diagnosis and treatment of complications, both acute and chronic pancreatitis carry significant morbidity and mortality.1 Knowledge of common etiologies, especially medications, can lead to the early and accurate diagnosis of pancreatitis in the emergency department (ED). Additionally, goal-directed therapy and recognition of potential complications can be life-saving. This review outlines the common causes of pancreatitis and provides a rational approach to diagnosis and management in the ED.—The Editor
The incidence of acute pancreatitis varies worldwide and between patient populations. In England and the Netherlands the incidence is 5-10 cases per 100,000 inhabitants; in Scotland and Denmark it is 25-35 per 100,000; and in the United States and Finland it is 70-80 per 100,000 inhabitants. The incidence appears to be increasing, but this may reflect better imaging and improved methods of diagnosis.2-4 The male to female ratio of acute pancreatitis is 1:0.6, and incidence increases with age.5 For unknown reasons, the incidence in black men is three times greater than in white men.6 The rate of chronic pancreatitis varies with the degree of alcohol abuse in the population studied, but in many parts of the world is in the range of 3-10 per 100,000 population.7 Biliary tract disease and alcohol account for the vast majority of acute pancreatitis cases in the United States. Gallstones, the most common etiology, are encountered more frequently in females, patients older than age 50, and in the community hospital setting.8 Alcohol abuse predominates in males, younger patients, and in the inner city. Alcohol abuse also is the most common cause of chronic pancreatitis.
Acute pancreatitis is more prevalent in certain patient groups, such as those with HIV, hypertriglyceridemia, or hypercalcemia.9,10 In children, abdominal trauma is the most common cause of acute pancreatitis, while cystic fibrosis is the most common cause of chronic pancreatitis.11,12
Although the majority of patients with acute pancreatitis have a mild, self-limited course, 15-25% will have a severe and complicated course, and there remains a 5% overall mortality.13
Acute Pancreatitis. There are a number of commonly identified precipitants of acute pancreatitis. Gallstones and alcohol abuse account for nearly 80% of cases. Despite a century of research, however, the pathogenesis of acute pancreatitis remains a matter of debate. Mechanical obstruction of the pancreatic duct or the ampulla of Vater by a biliary stone is thought to induce pancreatitis through ductal hypertension and subsequent bile reflux into the pancreatic duct.14,15 Similarly, edema at the ampulla of Vater due to a passed stone may produce pancreatic ductal hypertension. Alcohol is thought to be a direct cellular toxin, leading to intracellular accumulation of pancreatic enzymes and decreased bicarbonate and trypsin inhibitor concentrations. This enhances the formation of protein plugs and pancreatic outflow obstruction.
Regardless of the initiating force, premature activation of pancreatic enzymes is the central event in the pathogenesis of acute pancreatitis.16 The cellular mechanisms responsible for intrapancreatic activation of digestive enzymes, particularly trypsin, are unclear. Once activated, trypsin activates many other proteolytic and vasoactive enzymes, including elastase, phospholipase A2, and chymotrypsin.4 Release of these proteolytic enzymes from acinar cells leads to acute inflammation of the pancreatic parenchyma and surrounding tissues. This early phase, known as acute edematous pancreatitis, involves peripancreatic fat necrosis and interstitial edema. Trypsin also activates enzyme cascades such as coagulation, complement, kallikrien, and fibrinolysis.1 This may lead to further autodigestion of pancreatic tissue or to coagulation necrosis of the gland and the surrounding fatty tissue. In this more severe form of pancreatitis, known as acute hemorrhagic or necrotizing pancreatitis, there is parenchymal necrosis, hemorrhage, and impairment of endocrine and exocrine function.17
Local inflammation of the pancreas can lead to systemic circulation of pancreatic enzymes and inflammatory mediators such as platelet activating factor, tumor necrosis factor, and other cytokines. As a result, patients with severe acute pancreatitis may develop a systemic inflammatory response syndrome (SIRS) marked by renal failure, acute respiratory distress syndrome (ARDS), pleural effusions, and myocardial depression.1 Further complications from vasoactive substances include systemic vasodilation, increased vascular permeability, and disseminated intravascular coagulation.
Bacterial infection occurs in 30-70% of cases of acute necrotizing pancreatitis and likely is due to translocation of enteric bacteria through a compromised gastrointestinal barrier.18 Local and systemic infection is a major source of mortality in pancreatitis.19
Chronic Pancreatitis. Unlike acute pancreatitis, where the gland returns to normal histologic and biochemical function between attacks, chronic pancreatitis is characterized by irreversible morphological change and progressive loss of function. While alcohol is the most common and most widely studied etiology of chronic pancreatitis, approximately 30% of cases are idiopathic and numerous other rare causes exist. The reason that fewer than 10% of patients with alcoholism develop chronic pancreatitis is unknown.
Ingestion of alcohol in large quantities over a prolonged period causes increased protein secretion into pancreatic ducts and decreased fluid and bicarbonate production from ductal epithelial cells. Protein plugs and viscous fluid leads to progressive ductal obstruction, chronic inflammation, cellular atrophy, calcium deposition, and fibrosis.20 These progressive and irreversible changes cause a range of clinical findings, including abdominal pain, steatorrhea, malabsorption, and diabetes.2
Acute Pancreatitis. The hallmark of acute pancreatitis is severe, unremitting, deep abdominal pain. Pain is present at the onset and is the typical reason for seeking care. It usually is severe enough for patients to seek care directly at the ED. The pain classically is described as steady, located in the upper abdomen, and worse when supine. The exact location is variable, although it is epigastric more often than left-sided. Band-like radiation to the back is present in approximately half of cases.21 Patients with acute pancreatitis can present with peritonitis. There are rare reports of cases presenting without pain (5%) although this is not the authors’ experience.22
Alcoholic pancreatitis tends to begin six hours to three days after a binge or cessation of drinking. Gallstone pancreatitis can be preceded by biliary colic and should be suspected in patients who present with abdominal pain after a large or fatty meal. The pain usually lasts longer than the pain of biliary colic, which is limited to 6-8 hours.
Nausea and vomiting usually are present in patients with acute pancreatitis. These symptoms can continue for hours, and patients often are described as restless, agitated, and requiring large amounts of analgesia to control their symptoms. Dyspnea may occur as pulmonary complications (i.e., pleural effusion or ARDS) develop.
The physical examination in pancreatitis is variable, depending on the severity and time of presentation. The authors found no studies evaluating the utility of the physical exam in diagnosing acute or chronic pancreatitis. Fever and tachycardia can be present in moderate cases that do not have acute necrotizing pancreatitis or in severe cases with shock. Progression to shock, with hypotension, tachypnea, and respiratory failure, is a hallmark of severe necrotizing pancreatitis.
Abdominal tenderness often is epigastric and initially may be minimal, as the pancreas is a retroperitoneal organ. The retroperitoneal location may explain, in part, why patients often describe their pain as deep. In more advanced cases, peritoneal signs can be present even without infection, as the release of pancreatic enzymes directly irritates the peritoneum. Abdominal distension develops as fluid leaks into the retroperitoneum. The intra-abdominal irritation also frequently results in a small bowel ileus with diminished bowel sounds. Grey-Turner’s sign is ecchymosis in the flank; Cullen’s sign is periumbilical ecchymosis. These classic signs rarely are present (1% of cases), reflect intra-abdominal hemorrhage, and herald severe disease with poor prognosis.22
Respiratory signs and symptoms are common in acute pancreatitis. Patients may exhibit tachypnea and splinting due to diaphragmatic irritation even before pulmonary complications develop. If the patient is in true respiratory distress, it may represent ARDS, the most severe complication of pancreatitis. If the disease has progressed to acute necrotizing pancreatitis, shock or coma may occur. Examination may reveal signs of the systemic complications of acute necrotizing pancreatitis: sepsis, disseminated intravascular coagulation (DIC), and ARDS.
Other rare physical findings that may help to identify the etiology of pancreatitis include parotid swelling associated with mumps, hepatomegaly in alcoholic patients, and xanthomas in hyperlipidemic patients.
Later in the course of the disease, complications may become evident on physical examination. An abdominal mass representing a pseudocyst may become palpable. Panniculitis representing subcutaneous fat necrosis can occur. These are tender, erythematous nodules 1-2 cm in size, usually in the distal extremities. Thrombophlebitis in the legs can develop.
Chronic Pancreatitis. The major clinical features of chronic pancreatitis are abdominal pain and symptoms associated with pancreatic exocrine dysfunction. Abdominal pain is the usual reason for seeking care in the ED. The pain classically is described as severe, dull, and radiating to the back, but its history is variable.23 In one prospective cohort of 207 patients with chronic pancreatitis, two usual patterns emerged. One group had brief painful episodes (usually fewer than 10 days) separated by pain-free periods lasting from months to more than a year. The second group was characterized by long periods with daily pain necessitating repeated hospitalizations.24 Patients frequently avoid eating, as it may precipitate their pain. Nausea and vomiting frequently are associated with painful attacks.
Abdominal pain may be absent. In one retrospective study, 20% of patients with chronic pancreatitis initially presented to their doctors with symptoms of pancreatic dysfunction without pain.25 It is likely that the percentage of patients who seek care in the ED solely with symptoms of painless pancreatic dysfunction is substantially less.
Patients with pancreatic insufficiency present with steatorrhea, protein deficiency, or glucose intolerance. Symptoms associated with pancreatic insufficiency usually occur later in the disease, as more than 90% of pancreatic function must be lost before it becomes clinically apparent.26 Steatorrhea tends to occur prior to protein deficiency, as lipolysis usually is lost before proteolysis. Clinical complaints of steatorrhea are foul-smelling, loose, and greasy stools that are difficult to flush away. Glucose intolerance occurs frequently in the course of chronic pancreatitis, but true diabetes mellitus is a late complication. The destruction of pancreatic function leaves patients without insulin or its counteregulatory hormone glucagon. These patients require insulin, although ketoacidosis is rare. They are "brittle" diabetics who are at risk for hypoglycemia due to inability to produce glucagon. This combination especially is dangerous if patients continue to drink alcohol, with hypoglycemic coma a known cause of death.
The physical examination in chronic pancreatitis is nonspecific. Patients generally appear well-nourished, but in chronic alcoholic patients with advanced disease, weight loss and malnutrition may be apparent, or one may see signs of coexistent chronic alcoholic liver disease. Abdominal tenderness usually is upper abdominal and non-peritoneal, but no clear pattern exists. The findings of an abdominal mass, representing a pseudocyst, or a palpable spleen from splenic vein thrombosis are rare.
Acute Pancreatitis. Many causes of acute pancreatitis have been reported, but a few causes account for most cases. (See Table 1.) The two most frequent causes of acute pancreatitis in the United States are gallstones and alcohol abuse. Together these account for approximately 80% of all cases of acute pancreatitis.27 Exact percentages depend on the patient population. Gallstones clearly have been shown to cause acute pancreatitis, although the mechanism is debated. Approximately 35% of cases of acute pancreatitis are caused by gallstones, but only 3-7% of patients with gallstones ever develop acute pancreatitis.28,29 The cause and effect relationship has been proven, as cholecystectomy has been shown to prevent gallstone-induced pancreatitis.29
Alcoholic pancreatitis develops in drinkers with a history of prolonged, heavy alcohol consumption (at least 5-10 years), not after an occasional binge in a patient without a drinking history.27,30 About 10% of chronic alcoholics will develop attacks of acute pancreatitis that are clinically indistinguishable from other etiologies.
Many drugs have been reported to cause acute pancreatitis. Although there are numerous case reports showing association, causality is difficult to prove. Overall, the incidence of drug-induced pancreatitis is low, as illustrated by a comprehensive German report of pancreatitis cases from 45 centers. Only 22 of 1613 cases (1.4%) were related to medication use.31 Three recent review articles have evaluated the case reports.32-34 Although systems of classifying a medication’s association to pancreatitis have been developed (classifying a medication’s association to pancreatitis as definite, probable, or possible) the data behind the classifications are variable, leading reviewers to disagree about many drugs. Table 2 lists drugs strongly associated with pancreatitis in at least two of the three recent reviews of this subject. A recent analysis indicates that newer antipsychotic drugs may have a greater likelihood of causing pancreatitis than older agents.35 Textbooks, review articles, or on-line databases can be consulted for extensive lists of drugs with possible associations.
Pathogenesis of drug-induced pancreatitis is variable. In some cases it is due to a direct toxic effect (sulfonamides), in other cases it is due to an allergic reaction (6-mercaptopurine), while in the case of angiotensin-converting enzyme inhibitors, it is thought to be due to angioedema of the pancreas. Prognosis is excellent if the cause is identified and removed, with case series reporting lower than average rates of necrotizing pancreatitis and mortality.31
Traumatic pancreatitis can be divided into idiopathic and non-idiopathic cases. As the number of endoscopic retrograde cholangiopancreatography (ERCP) procedures has increased during the past 30 years, the percentage of pancreatitis cases related to ERCP has risen to 3-5%. The risk is higher when the procedure involves therapy (i.e., sphincterotomy or stents) and can occur in up to 25% of cases when sphincter of Oddi manometry is performed.36 Post-operative pancreatitis is seen most frequently after liver or renal transplantation and coronary artery bypass grafting. The prognosis in post-operative pancreatitis is worse than with other causes.37 Blunt and penetrating trauma both can cause pancreatitis, although it is a rare complication. A nine-year review of 16,188 trauma cases at a Level 1 trauma center showed a 0.4% incidence of pancreatic trauma, of which two-thirds were due to penetrating trauma, and almost all were diagnosed at laparotomy.38
Up to 30% of patients with pancreatitis will have no identifiable cause by history, laboratory tests, and ultrasound. Historically, 10% of acute pancreatitis cases were designated idiopathic after the workup. More recently, patients with idiopathic pancreatitis have undergone more extensive workups, including ERCP. These often reveal a treatable cause. One study showed that a presumed cause was found in 100 of 126 patients with idiopathic pancreatitis, and therapy was possible for a significant number of these patients.39 One frequently identified cause is biliary sludge, seen in 66-74% of these patients. Sludge is a viscous suspension in gallbladder bile that can contain small stones and usually is asymptomatic. Although no prospective studies have shown that treatment is curative, several retrospective studies suggest that cholecystectomy and papillotomy reduce future attacks.40,41 It is debated whether all patients with a first attack of pancreatitis and no identifiable cause should undergo extensive testing (including ERCP), as only a small percentage will develop another case of pancreatitis in the next three years.42
Both hypertriglyceridemia and hypercalcemia are uncommon but significant causes of pancreatitis. Infection frequently has been reported in association with pancreatitis, but, like drug-induced pancreatitis, the data for causality are weak with many of the reported organisms. Pregnancy is not a cause of pancreatitis, as shown in a 10-year case control study that failed to show an increased incidence in pregnant women compared to age-matched controls.43
While the etiology of pancreatitis is similar in children and adults, the overall incidence is lower in children. Blunt trauma and infection (such as mumps and other viral illnesses especially), congenital anomalies, and multi-system disease are the leading causes, with many cases ultimately classified as idiopathic.27
Chronic Pancreatitis. Compared to acute pancreatitis, there are fewer causes of chronic pancreatitis. The majority of cases are due to alcohol abuse (70-80%), with the risk related to duration and amount consumed.44 There are other important factors in the development of chronic pancreatitis in alcoholics, as only 5-10% of alcoholics will develop chronic pancreatitis.45 Ductal obstructions, hereditary pancreatitis, systemic diseases (e.g., systemic lupus erythematosus [SLE] or cystic fibrosis), and tropical pancreatitis are other major causes of chronic pancreatitis.
Pancreatitis must be differentiated from the large number of intra-abdominal, pulmonary, and cardiac processes that can present with acute abdominal pain, nausea, and vomiting. (See Table 3.) Historical features are most useful in prioritizing the differential diagnoses, as many patients will describe a history of heavy alcohol use or of gallstones, which together cause 80% of acute pancreatitis cases. The severity and length of the attack will help further differentiate these potential diagnoses. If the patient presents late in the course of pancreatitis, it may be easier to clinically exclude other processes, as acute pancreatitis can cause constant abdominal pain for days without relief or progression, unlike many other conditions.
Patients with a history of chronic pancreatitis may present with symptoms similar to previous flares and self-diagnose an exacerbation, but a thorough assessment usually is indicated.
The diagnosis of pancreatitis usually is made by history with confirmation by laboratory testing. Radiography is helpful for determining etiology and prognosis, but rarely is the sole means of diagnosis.
Laboratory. Many biochemical tests have been studied in their ability to diagnose and prognosticate pancreatitis. The tests that most frequently are used in the ED include amylase, lipase, transaminases, and non-specific markers of inflammation (i.e., C-reactive protein [CRP] and erythrocyte sedimentation rate [ESR]). As no perfect test to diagnose pancreatitis exists, emergency physicians must know the properties of each test and be able to apply the best available test.
Studies evaluating laboratory tests for pancreatitis have several weaknesses that have clouded debate regarding what is the ideal test. First, there is no clear gold standard for diagnosing pancreatitis. Early studies often used the laboratory test in question (usually amylase) as the sole marker or as one of the diagnostic criteria of pancreatitis.46-48 This artificially inflates the sensitivity of the test in question. Better constructed studies use a number of factors, including lab tests, computed tomography (CT) results, surgical findings, and discharge diagnoses, to define the population with pancreatitis. Second, the exact lab techniques used have varied between studies. Third, "normal limits" are difficult to define. They usually are defined in a sample of healthy young men that may be very different from the population at risk for pancreatitis. Fourth, sensitivity and specificity depend on the prevalence of pancreatitis in the study population and on the cut-off level chosen. This said, there are several well-conducted studies that can guide the emergency physician’s choice of diagnostic tests.
Lipases are enzymes secreted from pancreatic acinar cells that hydrolyze triglycerides into metabolic substrates. Normally, 99% is secreted into the pancreatic ductal system, while less than 1% makes its way into the serum through lymphatics and capillaries.49 This gives lipase the theoretical advantage of being more specific than amylase because it has less tissue distribution. Serum lipase increases within 4-8 hours of acute pancreatitis, peaks at around 24 hours, and decreases within 1-2 weeks.49 Traditionally, serum lipase was a difficult test to perform rapidly and accurately, was more costly, and was not widely available. This has been overcome with development of a radioimmunoassay for lipase and inclusion of co-lipase in commercially available kits.50,51 Lipase assays now are comparable to amylase in terms of cost, access, and speed.50 Sensitivity is quoted at between 85% and 100%, and specificity is reported at between 60% and 100%.52 The test characteristics depend on where the cut-off for a positive is set. At five times the upper limit of normal (ULN), the specificity of lipase was 100%, but sacrificed sensitivity to only 60%.53,54 Other conditions reported in association with elevated lipase include acute cholecystitis, bowel obstruction or infarction, duodenal ulcer, and diabetic ketoacidosis.52
Amylase is a small enzyme that cleaves starches into smaller carbohydrates. There are two major sources of amylase, the pancreas and salivary glands, and several minor sources. Although there are two different isoenzymes of amylase, they both are picked up by common techniques.55 Newer tests are being developed to test for amylase isoenzymes, but these are only in preliminary stages. There are many physiologic and pathologic causes of amylase elevations. (See Table 4.) The varied sources of hyperamylasemia give amylase a poor specificity, which is its major limitation. As a small protein, amylase is cleared renally and has a half-life of approximately two hours.55 In patients with acute pancreatitis, amylase rises within 6-24 hours, peaks at 48 hours, and normalizes in 5-7 days.46 Amylase levels normalize more rapidly than lipase levels. Many studies have shown that amylase can be normal in between 19% and 32% of patients with acute pancreatitis.52 This is most likely in alcoholic pancreatitis and acute flares of chronic pancreatitis.56,57 Reported sensitivities for amylase range between 60% and 98%, with specificities between 40% (ULN as cut-off) and 70-100% (five times ULN used as cut-off). By raising the cut-off value, specificity is gained at the expense of sensitivity.
The question for emergency physicians is which is the superior test to diagnose acute pancreatitis. Although there are theoretical limitations to each test, the studies that have compared amylase and lipase in patients with acute pancreatitis all conclude that lipase is better or equal. One study retrospectively looked at 352 cases that had laboratory tests in the ED and a CT-verified diagnosis of pancreatitis. They found that lipase was more sensitive: 19% had normal amylase levels, and of these two-thirds had elevated lipase.58 Another study compared a cut-off of three times the ULN in 306 adults with abdominal pain of whom 48 had pancreatitis. Amylase was 54% sensitive while lipase was 77% sensitive.59 A third study compared enzymes in two studies. In the first, they used a cut-off of three times ULN and found lipase to have a sensitivity of 100% and specificity of 99%, while amylase was 75% sensitive and 99% specific.60 In a second study comparing alcoholics with and without pancreatitis, amylase performed poorly, with a sensitivity of 45%, while lipase was 100% sensitive.56 Another study reported 57 episodes of acute pancreatitis and found amylase to have a sensitivity of 79% and lipase 96%, while both tests had similar specificities greater than 95%.57
Other investigators have looked into whether combinations of tests improve diagnostic accuracy. A few individual studies have recommended use of both amylase and lipase. Others have recommended use of a lipase-to-amylase ratio greater than 2 to suggest an alcoholic etiology to acute pancreatitis.61 Larger studies and meta-analyses conclude that neither of these strategies is more accurate than the use of lipase alone.52
A single prospective study evaluated a urinary screening dipstick for trypsinogen-2 in 447 ED patients with acute abdominal pain. The test showed a sensitivity of 94%, picking up 50 of 53 patients with acute pancreatitis, and all seven patients who had severe pancreatitis. It was 96% specific. It was more accurate than serum amylase, but serum lipase results were not reported.62 This test currently is not commercially available or in widespread use in the United States.
A recent meta-analysis has shown that an ALT (alanine aminotransferase) concentration greater than 150 IU/L is 96% specific for gallstone pancreatitis, but only 48% sensitive. Therefore, a value greater than 150 IU/L strongly suggests gallstones as the cause, but a lower value does not rule it out.63
Serum tests have been recommended as part of the workup for traumatic pancreatic injury in selected patients in the Advanced Trauma Life Support guidelines. Recent studies reveal that serum tests are neither sensitive nor specific for pancreatic injury in the setting of trauma.38,64,65
Therefore, when evaluating patients in whom there is a clinical suspicion for acute pancreatitis, lipase should be used as the initial serum test. If lipase is not available, amylase should be used. The use of serum tests for pancreatitis in abdominal trauma should be clinically directed, not routine. For a comprehensive review of amylase and lipase utilization, see the review by Vissers et al.52
Radiography is not highly sensitive for acute pancreatitis in the ED, so it should play an adjunctive role to clinical examination and laboratory testing.
X-rays often are ordered in patients with acute pancreatitis to evaluate for other potential diagnoses. Abdominal flat and upright and chest radiographs are most common. The abdominal series may show nothing, a focal ileus of a small intestine segment ("sentinel loop"), the colon cut-off sign, gallstones, or pancreatic calcifications of chronic pancreatitis. The chest film may show a pleural effusion, atelectasis, or signs of ARDS. Most plain films in patients with acute pancreatitis will have abnormalities, but the findings are nonspecific.66
Ultrasonography is only 67% sensitive for acute pancreatitis when gallstones are the cause, and is less sensitive for other causes.67 Ultrasound diagnosis of pancreatitis often is limited by operator technique and the inability to visualize the pancreas due to its retroperitoneal location and overlying intestinal gas. In addition, ultrasound availability may be limited. These factors limit the use of ultrasound in the ED. There is an important role for ultrasound in determining the etiology of acute pancreatitis, although this is not an emergent concern.
There are three indications for CT scan in acute pancreatitis: first, to exclude other serious intra-abdominal conditions, such as a posterior perforated ulcer, renal colic, or a dissecting aortic aneurysm; second, to stage the severity of acute pancreatitis; and third, to look for complications such as pancreatic pseudocyst, hemorrhage, or necrosis of other adjacent organs.68,69 Dynamic, spiral CT with oral and intravenous contrast is the test of choice, as this increases the sensitivity of prognostic pancreatic findings and does not damage the pancreas.70,71 Pancreatic necrosis may not appear until 48-72 hours after the onset of the disease, resulting in CT scan sensitivity as low as 70% for acute pancreatitis.69 The CT scoring system (see Table 5) developed by Balthazar is useful for prognosis, as grades A-C suffer low morbidity and mortality, while grades D and E have mortality up to 15%.72,73 Balthazar recommends waiting three days for the initial abdominal CT if the patient is not showing signs of serious pancreatitis (i.e., fever, peritonitis, or shock).69
Magnetic resonance cholangiopancreatography (MRCP) is better able to visualize intrahepatic and intraductal stones compared to all other diagnostic techniques and, thus, has a role in defining etiology in acute pancreatitis.74,75 Pancreas MRI now is being studied for prognosis. If available, this technique could determine prognosis, presence of gallstones, and complications from biliary tract disease. These techniques currently have a limited role in the ED.
ERCP is useful in determining the etiology of acute pancreatitis, pancreatic and biliary anatomy, and the presence of common bile duct stones. It also is useful therapeutically for removal of common bile duct stones and sphincter of Oddi papillotomy pancreatitis. It is beyond the scope of ED evaluation.
The authors recommend the following for the use of radiography in patients with acute pancreatitis: Plain abdominal films should be obtained as needed to evaluate for other potential causes of abdominal pain and vomiting (i.e., perforation or bowel obstruction); CT scan should be performed in the ED in cases of severe acute pancreatitis (e.g., peritonitis, shock, or ARDS) or when complications are suspected (i.e., necrotizing pancreatitis, abscess, or pseudocyst); other radiographic testing can be done as an inpatient; and notably, all patients with pancreatitis should receive an abdominal ultrasound within one day of admission to determine if they have gallstones.
Acute Pancreatitis. Despite numerous studies attempting to validate specific treatments, the key to the successful management of pancreatitis remains aggressive supportive therapy. In mild pancreatitis, this may involve only pain control and intravenous fluids, while in severe pancreatitis, patients may require intensive care unit (ICU) level of care, invasive monitoring, dialysis, and even mechanical ventilation.
All patients should receive adequate fluid resuscitation. Significant dehydration may occur as a result of third spacing of intravascular fluid due to the systemic inflammatory response and retroperitoneal sequestration of pancreatic secretions. Given the potential for significant fluid losses and shifts, a Foley catheter should be placed to monitor urine output in those patients requiring resuscitation. Urine output should be maintained at 0.5-1 cc/kg/hr. Patients should be resuscitated with normal saline or lactated Ringer’s as needed to maintain systolic blood pressure (SBP) greater than 100 mmHg and heart rate (HR) less than 100. Five to six liters of fluid may be required initially. With hydration, patients are likely to develop electrolyte imbalances. In particular, sodium, potassium, magnesium, and calcium levels should be monitored regularly and repleted as necessary.
Pain control is fundamental in treating pancreatitis. Historically, meperidine was cited as the narcotic of choice because it was believed to cause less sphincter of Oddi spasm.76 However, multiple literature reviews have failed to support this theory.77,78 One study found no evidence that meperidine is superior to morphine in relieving pain and concluded that all narcotics increase biliary pressure and interfere with peristalsis of the sphincter of Oddi.76 In fact, morphine may be of greater benefit because it provides longer pain relief with less risk of seizures.77,78 Thus, any narcotic can be used safely for analgesia and should be titrated to patient comfort.
Traditionally, nasogastric suction had been an integral part of treatment because it was felt that eliminating gastric secretions and decreasing the acidity of secretions delivered to the duodenum would prevent stimulation of the pancreas. However, recent studies have shown that nasogastric suctioning does not improve pain relief, shorten hospital stay, or shorten time to onset of feeding.79,80 It should be used only in patients with ileus or uncontrollable vomiting.
Initially, patients with mild pancreatitis should be kept on bowel rest or small amounts of clear liquids or ice chips, if tolerated, to decrease the stimulation of the pancreas during recovery. As the pain resolves, oral intake can be reinstituted slowly. However, patients with severe pancreatitis or those unable to take food orally for a prolonged period of time secondary to pain or vomiting will require supplemental nutrition. Multiple medical therapies have been studied for treatment of acute pancreatitis. H2 antagonists, specifically cimetidine, gained popularity through their ability to decrease gastric acidity, which theoretically could prevent stimulation of the pancreas. However, studies have not shown their use to be of any benefit.80,81 Other medications, including atropine, calcitonin, and somatostatin, also have failed to show a significant benefit in the treatment of pancreatitis.82-84 More recently, the protease inhibitors gabexate mesilate and aprotinin were studied; however, neither medication has been shown to improve clinical outcomes. Lexipafant, a platelet activating factor antagonist, recently has been proposed as a potential therapy to attenuate the development of multi-organ failure. Results have been conflicting. None of the above medications consistently have been shown to improve morbidity and mortality in pancreatitis and their routine use is not recommended.
Peritoneal lavage has been employed with the thought of removing toxic pancreatic exudates, but studies have failed to support this theory. No studies have found improved mortality; therefore, peritoneal lavage is not recommended.
Superinfection is a major cause of mortality in pancreatitis. It is thought to occur secondary to translocation of bacteria from the gastrointestinal tract. The use of antibiotic prophylaxis in mild pancreatitis does not appear to improve mortality based on early controlled trials, although these studies evaluated ampicillin, which does not adequately penetrate pancreatic tissue.85,86 Several meta-analyses have concluded that the early prophylactic use of antibiotics in acute severe necrotizing pancreatitis decreases the incidence of sepsis and mortality.87,88 Other studies have shown that imipenem-cilastatin reduces the incidence of infection in severe pancreatitis, but does not significantly affect overall mortality.89,90 Studies comparing various antibiotics have recommended the use of impenem over fluoroquinolones.91,92 Currently, it is recommended that patients with acute necrotizing pancreatitis receive imipenem-cilastatin for 2-4 weeks, although any broad-spectrum antibiotic covering both aerobic and anaerobic bacteria should be of benefit given the lack of direct antibiotic comparisons in controlled studies.87,92
The use of selective decontamination of the gut to prevent bacterial translocation also has been studied with mixed results. One study found that oral administration of colistin sulfate, amphotericin, and norfloxacin significantly improved morbidity and mortality in patients with severe necrotizing pancreatitis as compared to controls.93 Another study, however, found that giving oral polymyxin B, amikacin, and amphotericin B did not significantly improve survival.94 The routine use of selective decon-tamination is not advocated.
The use of ERCP in gallstone-induced pancreatitis also has been studied with encouraging results. Several studies have shown a decreased morbidity, including a reduction in the risk of biliary sepsis, in patients with both mild and severe gallstone pancreatitis who had gallstones removed urgently within 24-72 hours by ERCP with sphincterotomy.95,96 Recently, it has been suggested that ERCP be performed only in patients with clear evidence of obstruction by increased bilirubin or signs of cholangitis because there may be a risk of causing infection in otherwise sterile pancreatitis.92,97
The use of early biliary surgery as a potential treatment of gallstone pancreatitis also has had controversial results. Some have found no difference between early and delayed surgery.97 Others have found a higher mortality and morbidity in patients who had surgery within 48 hours vs. those who had surgery delayed after 48 hours, especially in patients with severe pancreatitis.98,99 The timing of biliary surgery currently is decided based on patient stability and surgeon preference.
Patients with infected necrotic pancreatitis as documented by CT-guided percutaneous aspiration should undergo surgical debridement with drainage.100-102,106 Patients with sterile necrotic pancreatitis initially should be managed medically, as studies have failed to show improvement in morbidity with surgical debridement, but debridement should be performed if symptoms persist after 4-6 weeks.102,103
Chronic Pancreatitis. The treatment of chronic pancreatitis includes pain control and avoidance of inciting factors such as alcohol. Patients with chronic pancreatitis often will need to be maintained on long-acting oral analgesics for a significant period of time and will have exacerbations that may require hospital admission for parenteral analgesia. Narcotic dependence often becomes an issue, and patients may benefit from participation in a pain clinic or other pain management program.
Patients with chronic pancreatitis and unremitting pain should be worked up for complications with a CT scan. ERCP is useful in some patients to assess for pancreatic strictures and obstructions. Dilation of strictures or stent placement can improve pain and reduce frequency of attacks. Surgical resection of the pancreas, such as the Whipple procedure, may be helpful in certain patients with uncontrollable pain by removing the damaged parenchyma and relieving duodenal and biliary obstruction. Drainage of pseudocysts can relieve pain, as well. Celiac plexus nerve block also has been attempted as a last resort, but side effects prevent the routine use of this therapy.104 Despite numerous efforts, no therapy consistently has shown a benefit in chronic pancreatitis.
Almost 25% of patients with pancreatitis develop complications, with an overall mortality of about 5-10%.4,102,105 Pancreatic infection accounts for 70-80% of deaths.4 Complications occur both locally in the pancreas and systemically.
In the first week of hospitalization, systemic effects may include multisystem organ failure involving the cardiovascular, pulmonary, and renal systems. Cardiovascular collapse can occur secondary to the SIRS and from bleeding and exudation of plasma into the retroperitoneum. Myocardial infarction can occur from hypotension and increased demand on the heart from the acute inflammatory process. Respiratory complications range from mild atelectasis to pleural effusions to severe ARDS requiring mechanical ventilation. Renal complications include acute renal failure secondary to hypotension and subsequent acute tubular necrosis that may require dialysis until renal function improves. Gastrointestinal complications include bleeding secondary to stress ulcerations, gastric varices from splenic vein thrombosis, or rupture of pancreatic pseudoaneurysms.4,111,116
Locally, necrosis of the pancreas can occur as early as the first week of illness. There is damage to the pancreatic capillary parenchymal network, acinar cells, islet cells, and the pancreatic ductal system. Between 10% and 20% of patients with acute pancreatitis develop pancreatic necrosis, with a mortality of 15-20%.2,104 Approximately 30-35% of patients with pancreatic necrosis develop infection, typically in the second or third week of illness.104 It is difficult to distinguish sterile from infected necrosis, as both can present with similar clinical and laboratory findings (i.e., fever or leukocytosis). If the question arises, a guided percutaneous aspiration should be performed for Gram stain and culture.
Pancreatic pseudocysts are walled-off collections of pancreatic secretions without an epithelial lining that develop in 1-8% of patients with acute pancreatitis. They are responsible for 5-10% of all deaths in chronic pancreatitis.4,104 Pseudocysts form after the third to fourth week of illness and last for more than four weeks. Up to 50% of pseudocysts resolve spontaneously, but when persistent, they can cause local effects such as pain, biliary or gastric obstruction, or they may erode into surrounding blood vessels, leading to hemorrhage. Pseudocysts also may rupture, leading to pancreatic ascites or the formation of pancreatic fistulas.102,104,105
Patients also can develop duodenal obstruction and biliary strictures. They will present with pain after eating, early satiety, nausea, vomiting, and abdominal distention.
Pancreatic fistulas to adjacent cavities, including bowel, skin, and biliary system, can develop if the pancreatic duct is disrupted. This complication should be suspected in patients who develop ascites, pleural effusions, or pericardial effusions. Diagnosis is confirmed by fistulograms for external fistulas or ERCP for internal fistulas. In most cases, surgery is required for definitive treatment.4,104
Abscesses also can develop near the pancreas when liquefied necrotic tissue is infected secondarily. They typically develop four or more weeks after the onset of symptoms and should be suspected in patients with persistent fevers, increasing white blood cell (WBC) count, and failure of improvement of symptoms. Diagnosis is made by CT scan with definitive treatment by percutaneous catheter drainage.106
Other rare complications include pancreatic encephalopathy, retinopathy, splenic rupture or hematoma, splenic vein thrombosis, pseudoaneurysms of adjacent arteries, and right kidney hydronephrosis and hydroureter.4,104
Various scoring systems integrating laboratory and clinical data have been developed to aid in predicting the severity of pancreatitis and subsequent risk of mortality. While many different scoring systems have been developed and studied, the three most utilized systems are the Ranson, Glasgow, and Acute Physiology and Chronic Health Evaluation (APACHE) scores.
Ranson et al developed a set of 11 risk factors based on a retrospective analysis of patients with pancreatitis.107 (See Table 6.) The five used on admission are: age older than 55 years, WBC count greater than 16,000/mm3, glucose greater than 200 mg/dL, LDH greater than 350 IU/L, AST greater than 250 IU/L. These reflect the severity of the acute inflammatory process. The other six criteria, which are determined at 48 hours, include hematocrit decrease greater than 10, blood urea nitrogen (BUN) increase greater than 5 mg/dL, calcium less than 8 mg/dL, PO2 less than 60 mmHg, base deficit greater than 4 mEq/L, and fluid sequestration greater than 6 L. These reflect the systemic effects of circulating enzymes on end organs.102 Applying these criteria retrospectively, Ranson found that mortality was increased in those patients with a greater number of risk factors. Patients with fewer than three signs had a very small risk of death or complications. The risk markedly increased with more than three signs, with a mortality of greater than 50% when six or more signs were present.30,102 However, one must take into consideration that these values were determined in an era prior to the aggressive resuscitation, antibiotics, and advanced critical care that is available presently. Thus, patients with greater than six Ranson criteria now routinely are surviving.108
The Glasgow or Imrie criteria were developed as a modification of the Ranson criteria by eliminating three of Ranson’s criteria (fluid sequestration, base deficit, and hematocrit change) and adding albumin less than 3.2 as one of the criteria.109 (See Table 6.) Imrie et al found that all patients in their study who died had three or more of the nine risk factors in the first 48 hours. A study in 1984 further modified the criteria to eight factors by eliminating AST, as the researchers found that it was not significant for predicting severe pancreatitis.13
The APACHE II criteria is a newer scoring system that is a simplified version of the APACHE criteria described by Knaus et al in 1981.110,111 The score is based on a weighted index of 12 physiologic criteria that represent the degree of acute illness as well as a pre-admission health evaluation, which indicates the health status of the patient prior to the onset of acute illness.102,110-112 The APACHE score has been shown to correlate with morbidity and mortality in patients with acute pancreatitis. One study found that no patients with a score greater than 20 survived.113
Contrast-enhanced CT also has been studied as a tool for establishing prognosis. Balthazar et al developed a CT severity index (see Table 5) based on a combination of peripancreatic inflammation, phlegmon, and degree of pancreatic necrosis (< 33%, 33-50%, > 50%). They found that patients with a high severity index (7-10 points) had a 92% morbidity and 17% mortality, while patients with a low CT severity index (0-2 points) had a 2% morbidity and 0% mortality.73,102 Others have found that CT scan is useful for the evaluation of local complications, but that it is not a good predictor of systemic complications.114
Various serum markers also have been suggested for use as indicators of prognosis including elastase, carboxypeptidase-N, C-reactive protein, alpha-1 antitrypsin, alpha-2 macroglobulin, complement C3, and other markers of systemic inflammation.115,116 While some of the serum markers appear promising, such as CRP and alpha-1 antitrypsin, further work needs to be done to confirm the reproducibility of previous findings. At this time, no single serum marker has been proven sufficient to predict prognosis.
Despite the many scoring systems and studies comparing these systems, the ideal system remains controversial. The APACHE II score, while more complicated to calculate, appears to be more useful because it can be calculated on admission to predict severity immediately and on a daily basis thereafter to monitor for improvement or further deterioration.110,111,113,117 In addition, some have found it to be more sensitive and specific for determining risk of morbidity and mortality than other scoring systems.113,114,117 Others, however, have not found it to be any more accurate.108,118,119
Critics of the Ranson criteria point out a lack of reproducibility in predicting severity in recent years. Its utility is questioned because of the biases present in the original study, including lack of confirmation of pancreatitis in all patients and absence of the final 11 criteria in all patients studied. A recent metaanalysis and comparison studies have supported these criticisms,115,120 but others have found that the Ranson criteria remains a valid predictor in critically ill patients.108,119
None of the criteria described have been clearly proven to be better than the others. Utilizing one of the scoring systems is important to aid in predicting which patients may develop complications and require ICU level of care, but should not be used alone in making an appropriate disposition. There is no set score in any scoring system above which a patient must be cared for in an ICU. Clinical judgment, aggressive treatment, and individual patient factors play an important role in determining outcome and disposition. These should be combined with the scoring system to determine disposition. Choosing the appropriate scale should be based on the physician’s level of comfort with the scoring system, availability of CT scanning and various serum markers, and the rapidity with which laboratory results are available to the physician.
Patients with acute pancreatitis secondary to a clear non-surgical etiology who can hydrate orally and have minimal pain may be discharged home. They should be given narcotic analgesics, recommendations for a clear liquid diet, and instructions for follow-up in 24-48 hours. This represents only a minority of patients. Most patients with acute pancreatitis require admission for fluid hydration, parenteral analgesia, bowel rest, and monitoring for the development of complications. Patients with severe pancreatitis, as evidenced by hemodynamic instability or end organ dysfunction, should be admitted to an ICU for critical care monitoring and supportive treatment. A surgeon should be consulted for patients with necrotizing pancreatitis, pancreatic abscess, or gallstone pancreatitis. These patients may be candidates for a variety of interventions, including surgical debridement, percutaneous drainage, ERCP, or cholecystectomy.
Patients presenting with exacerbations of chronic pancreatitis may be discharged home if their pain is controlled with oral analgesics and they can tolerate oral intake. Decisions on appropriate analgesics should be made in conjunction with the patient’s primary care physician. Outpatient follow-up should be arranged in 24-48 hours. Patients with severe pain, persistent vomiting, or evidence of dehydration should be admitted for intravenous analgesics and fluids.
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