OBSTRUCTION

ALCOHOL, OTHER TOXINS, AND DRUGS

METABOLIC DISORDERS

INFECTIONS

Many infectious agents may cause acute pancreatitis,⁷⁶ but often published reports do not meet usual standards for the diagnosis of pancreatitis or the infection. Using modern criteria for diagnosis of pancreatitis, definite pancreatitis exists if there is surgical, autopsy, or radiologic evidence; probable pancreatitis exists if there is biochemical evidence (more than three times the elevation of serum lipase or amylase) plus characteristic symptoms; and possible pancreatitis exists if there is only asymptomatic biochemical evidence. The definite criterion for an infection causing pancreatitis is finding the organism in the pancreas or pancreatic duct by stain or culture. Probable criteria for infection are culture of the organism from pancreatic juice or blood or serologic evidence combined with a characteristic clinical or epidemiologic setting. The criterion for a possible infection is culture of the organism from other body sites or serologic evidence of infection.

Using these criteria, definite pancreatitis has been associated with viruses (mumps, coxsackievirus, hepatitis B, cytomegalovirus, varicella-zoster, herpes simplex, Epstein-Barr, hepatitis A, and hepatitis C); the vaccine that contains attenuated measles, mumps, and rubella (MMR); bacteria (Mycoplasma, Legionella, Leptospira, Salmonella, tuberculosis, and brucellosis); fungi (Aspergillus and Candida albicans); and parasites (Toxoplasma, Cryptosporidium, Ascaris, Clonorchis sinensis). C. sinensis and Ascaris cause pancreatitis by blocking the main pancreatic duct. In acquired immunodeficiency syndrome (AIDS), infectious agents causing acute pancreatitis include cytomegalovirus, Candida, Cryptococcus neoformans, Toxoplasma gondii, and possibly Mycobacterium avium complex.⁷⁶

An infectious agent should be suspected of causing acute pancreatitis if the characteristic syndrome caused by the infectious agent is present because this occurs 70% of the time.⁷⁶ Because an infectious agent may be found in the pancreas without pancreatitis, routine search for an infection in idiopathic pancreatitis is not recommended because false-positive test results may result. In addition, it is unknown whether treating an infectious agent reverses pancreatic pathology.

VASCULAR DISEASE

Rarely, pancreatic ischemia causes pancreatitis. In most cases it is mild, but fatal necrotizing pancreatitis may occur. Ischemia may result from vasculitis (systemic lupus erythematosus)⁹⁸ and polyarteritis nodosa,⁹⁹ atheromatous embolization of cholesterol plaques from the aorta to the pancreas after transabdominal angiography,¹⁰⁰ intraoperative hypotension,¹⁰¹ hemorrhagic shock,¹⁰² ergotamine overdose, and transcatheter arterial embolization for hepatocellular carcinoma. Also, ischemia is one possible explanation for pancreatitis after cardiopulmonary bypass. In pigs, cardiogenic shock induced by pericardial tamponade causes vasospasm and selective pancreatic ischemia due to activation of the renin-angiotensin system.¹⁰³ Acute pancreatitis has occurred in long-distance runners, which may be on an ischemic basis.¹⁰⁴

TRAUMA

Either penetrating trauma (gunshot or stab wounds) or blunt trauma can damage the pancreas.¹⁰⁵ In most cases there is also injury to adjacent viscera. Laparotomy is essential in all cases of penetrating trauma to assess and treat all intra-abdominal injuries, including those to the pancreas. Blunt trauma results from compression of the pancreas by the spine, such as in an automobile accident. In blunt trauma it is important to determine preoperatively whether there is injury to the pancreas because depending on the severity of pancreatic injury, it will be necessary to include the pancreas in the surgical plan. Secondly, even in the absence of serious injury to adjacent organs, surgery or endoscopic therapy may be necessary to treat a pancreatic ductal injury.

The diagnosis of traumatic pancreatitis is difficult and requires a high degree of suspicion. Trauma can range from a mild contusion to a severe crush injury or transection of the gland; the latter usually occurs at the point where the gland crosses over the spine. Transection injury can cause acute duct rupture and pancreatic ascites. Clinically, it is impossible to determine on the basis of the characteristics of the abdominal pain and tenderness whether the pancreas has been injured as opposed to other intra-abdominal structures. Serum amylase activity may be increased in abdominal trauma whether or not the pancreas has been injured.

Diagnosis is highly dependent on CT, MRI, or magnetic resonance cholangiopancreatography (MRCP), which may show enlargement of a portion of the gland caused by a contusion or subcapsular hematoma, pancreatic inflammatory changes, or fluid within the anterior pararenal space if there is ductal disruption. The CT may be normal during the first two days despite significant pancreatic trauma. If there is a strong clinical suspicion of pancreatic injury or if the CT or MRCP scan shows an abnormality, ERCP is required to define whether there is pancreatic duct injury. If the pancreatic duct is intact and there are no other significant intra-abdominal injuries, surgery is not required. However, if ERCP reveals duct transection with extravasation of pancreatic fluid and there are no other intra-abdominal injuries, stenting of the pancreatic duct may be successful.¹⁰⁶ Serious injuries to the pancreas can be treated with appropriate débridement. Associated injuries to the duodenum or bile duct can be treated by biliary diversion, gastrojejunostomy, and feeding jejunostomy. External pancreatic fistulas occur in approximately one third of patients after surgery for pancreatic trauma. Octreotide may be beneficial after pancreatic injury.¹⁰⁷

The prognosis in patients with pancreatic trauma is favorable if there is no serious injury to other structures (regional blood vessels, liver, spleen, kidney, duodenum, and colon). However, duct injuries can scar and cause a stricture of the main pancreatic duct resulting in obstructive chronic pancreatitis.

POST-ERCP

Acute pancreatitis is the most common and feared complication of ERCP, associated with substantial morbidity and occasional mortality. About 500,000 ERCPs are performed annually in the United States. Asymptomatic hyperamylasemia occurs after 35% to 70% of ERCPs.¹⁰⁸ Acute pancreatitis occurs in 5% of diagnostic ERCPs, 7% of therapeutic ERCPs, and up to 25% in those with suspected sphincter of Oddi dysfunction or in those with a history of post-ERCP pancreatitis.¹⁰⁹ About half the cases are moderate to severe in intensity.

The mechanisms that lead to post-ERCP pancreatitis are complex and not fully understood. Rather than a single pathogenesis, post-ERCP pancreatitis is believed to be multifactorial, involving a combination of chemical, hydrostatic, enzymatic, mechanical, and thermal factors. Although there is some uncertainty in predicting which patients will develop acute pancreatitis following ERCP, a number of risk factors acting independently or in concert have been proposed as predictors of post-ERCP pancreatitis (Table 58-5).^110–113 Identification of these risk factors for post-ERCP pancreatitis is essential to recognize cases in which ERCP should be avoided if possible, or in which protective endoscopic or pharmacologic interventions should be considered.

Table 58-5 Factors That Increase the Risk of Post-ERCP Pancreatitis

ERCP, endoscopic retrograde cholangiopancreatography.

In general, the more likely a patient is to have an abnormal bile duct or pancreatic duct, the less likely the patient will develop post-ERCP pancreatitis. Cheng created a 160 variable database that prospectively evaluated more than 1000 patients from 15 centers in the midwestern United States.¹¹² Their study emphasized the role of patient factors, including age, sphincter of Oddi dysfunction (SOD), prior history of post-ERCP pancreatitis, and technical factors, including number of pancreatic duct (PD) injections, minor papilla sphincterotomy, and operator experience. The patient most at risk of developing post-ERCP pancreatitis was a woman with suspected choledocholithiasis and normal bilirubin, who underwent a sphincterotomy and no stone was found. In this patient population, more than a quarter of patients (27%) developed post-ERCP pancreatitis. MRCP and endoscopic ultrasound, which do not cause pancreatitis, can provide useful information (perhaps as accurate as ERCP) in many of these cases and are preferred modalities in the initial evaluation of such patients.

Early recognition of post-ERCP pancreatitis may be possible by evaluating serum amylase or lipase after the procedure.^114,115 In a study that involved 231 patients, the two-hour serum amylase and lipase were more accurate than a clinical assessment in distinguishing nonpancreatitis abdominal pain from post-ERCP acute pancreatitis. Serum values greater than 276 IU/L for amylase and greater than 1000 IU/L for lipase obtained from serum two hours after the procedure had almost a 100% positive predictive value for post-ERCP pancreatitis.¹¹⁶ More recently, Ito and colleagues found that if the serum amylase was normal at three hours, only 1% of patients had post-ERCP pancreatitis compared with 39% if the amylase was greater than five times the upper limit of normal.¹¹⁷ A serum amylase or lipase alone should not guide a decision of whether a patient has post-ERCP pancreatitis. However, it appears that the tests may assist the clinician’s assessment of a patient with post-ERCP abdominal pain.

Although there has been an interest in developing medications that can prevent post-ERCP pancreatitis, studies have failed to identify a medication worthy of widespread use. In terms of attenuating the inflammatory response, the most promising results have been seen with nonsteroidal anti-inflammatory drugs (NSAIDs). Two clinical trials have been published evaluating the role of diclofenac in reducing the incidence of post-ERCP pancreatitis.^116,118 Both trials placed patients on 100 mg of diclofenac by rectal suppository and both showed a reduction in the incidence of acute pancreatitis. However, another trial failed to show any benefit to diclofenec in preventing post-ERCP pancreatitis.¹¹⁹

It has been suggested that relaxation of the sphincter of Oddi following ERCP will promote pancreatic drainage and prevent acute pancreatitis. Several agents have been used in the effort to relax the sphincter of Oddi with the purpose of preventing post-ERCP pancreatitis. There have been three placebo-controlled randomized studies evaluating the use of nitroglycerin during ERCP, with negative results.^120–122 Furthermore, trials of oral nifedipine,^123,124 sprayed lidocaine,¹²⁵ and injected botulinum toxin¹²⁶ failed to demonstrated any benefit in the reduction of severity or incidence of post-ERCP pancreatitis. There have been several studies evaluating the role of glucocorticoids using a variety of agents including oral prednisolone or intravenous hydrocortisone or methylprednisolone, with essentially no benefit in reduction of severity or incidence of post-ERCP pancreatitis.

Gabexate is a protease inhibitor with anti-inflammatory properties. The in vivo effect of gabexate on inhibiting circulating trypsin is greater than most other protease inhibitors. In 1995, Messori and colleagues¹²⁷ published a meta-analysis of five trials^128–132 showing a statistically significant reduction in the incidence of complications in patients receiving gabexate after the development of post-ERCP pancreatitis. However, the trials were small and had a limited number of patients. Several additional trials have been published with conflicting results.^133–137 Although data are conflicting, it appears that infusions of the drug would likely need to be started 1 to 2 hours pre-ERCP and continued for 12 hours following ERCP to show a beneficial effect of the drug. In patients with a low risk, the costs likely outweigh any benefit. Currently, gabexate is not available in the United States.

Theoretically, inhibition of exocrine pancreatic secretion could prevent post-ERCP pancreatitis by inducing “rest” to a damaged gland. Although an attractive concept, there is little scientific basis to support this approach. Somatostatin and its synthetic octapeptide analog, octreotide, are potent inhibitors of pancreatic secretion. Although several trials of somatostatin have demonstrated an efficacy in reducing the incidence of post-ERCP pancreatitis,^138–143 the majority of the studies do not support the routine use of this medication.^144–150 Octreotide, the analog of somatostatin,¹⁵¹ was only effective in reducing post-ERCP hyperamylasemia, and did not reduce the incidence of post-ERCP pancreatitis.

Pancreatic stent placement clearly decreases the risk of post-ERCP pancreatitis in high-risk patients.¹⁵² Placement of pancreatic duct stents has become a standard practice for patients who are thought to be at high risk for pancreatitis after the procedure (see Table 58-5).¹⁵³ Pancreatic duct stent placement is effective presumably by preventing cannulation-induced edema that can cause pancreatic duct obstruction. Pancreatic sphincter hypertension is believed to be an important causative factor in post-ERCP pancreatitis and may explain the high risk of pancreatitis in patients with SOD. There is prolonged alleviation of ductal obstruction when pancreatic stents are placed. Typically, 3- to 5-French unflanged pancreatic stents are used in the following settings: SOD, difficult cannulation, biliary orifice balloon dilation, and precut sphincterotomy. In general, pancreatic duct stents are not beneficial in patients who undergo routine biliary sphincterotomy. In all reported studies, which cumulatively include 1500 high-risk patients undergoing ERCP, only 1 patient developed severe pancreatitis after a pancreatic duct stent had been placed.¹⁵⁴ Aside from the obvious benefits in preventing post-ERCP pancreatitis regarding morbidity and mortality, prophylactic stent placement is a cost-effective strategy for the prevention of post-ERCP pancreatitis for high-risk patients.¹⁵⁵

Guidewire cannulation, whereby the biliary or pancreatic duct is initially cannulated by a guidewire inserted through the catheter or sphincterotome, has been shown to decrease the risk of pancreatitis (see Table 58-5).¹⁵⁶ In a study of 400 consecutive patients who underwent ERCP by a single endoscopist, randomized to initial cannulation with contrast versus initial cannulation by a guidewire under fluoroscopic control, pancreatitis rates were profoundly different. No cases of acute pancreatitis were seen in the guidewire group compared with eight cases in the standard contrast group (P < 0.001). Cannulation success rates between the standard contrast and guidewire techniques were comparable 98.5% versus 97.5%. A later study¹⁵⁷ confirmed a decrease in post-ERCP pancreatitis in 300 patients prospectively randomized to guidewire cannulation compared with conventional radiocontrast. However, the decrease in post-ERCP pancreatitis appears to be related to a decreased need for precut sphincterotomy in patients undergoing guidewire cannulation.

POSTOPERATIVE

Postoperative pancreatitis can occur after abdominal or thoracic surgery.¹⁵⁸ Pancreatitis occurs after 0.4% to 7.6% of cardiopulmonary bypass operations^113,159 and after 6% of liver transplantations.¹⁶⁰ Twenty-seven percent of patients undergoing cardiac surgery develop hyperamylasemia, and 1% develop necrotizing pancreatitis.¹¹³ Significant risks for pancreatitis after cardiopulmonary bypass are preoperative renal insufficiency, postoperative hypotension, and administration of calcium chloride perioperatively. Mortality from postoperative pancreatitis is said to be higher (up to 35%) than for other forms of pancreatitis. Contributors to morbidity and mortality from postoperative pancreatitis are delay in diagnosis, hypotension, medications (e.g., azathioprine/perioperative calcium chloride administration), and infections.

HEREDITARY AND GENETIC

Hereditary pancreatitis is an autosomal dominant disorder with variable penetrance.^161–169 It is discussed in Chapter 57.

CONTROVERSIAL CAUSES

MISCELLANEOUS

Pancreatitis has been rarely associated with Crohn’s disease.¹⁶⁴ A recent case control study from Denmark found a 4-fold increase in acute pancreatitis in patients with Crohn’s and a 1.5-fold increase in patients with ulcerative colitis. This has been attributed by some to the use of drugs such as aminosalicylates/sulfasalazine, azathioprine, or 6-mercaptopurine (see Table 58-4). Theories to support a relationship between idiopathic inflammatory bowel disease (IBD) and pancreatitis are that pancreatitis is an extraintestinal manifestation of IBD, that duodenal Crohn’s disease can cause obstruction to the flow of pancreatic juice, that granulomatous disease can involve the pancreas, or that there is an autoimmune process affecting the pancreas. Celiac disease¹⁶⁵ has also been described in association with pancreatitis, but the relationship remains uncertain. It has been suggested that abnormalities in the normal barrier of the small bowel seen in patients with celiac disease may allow excessive absorption of amylase from the intestinal lumen, leading to hyperamylasemia. In the setting of abdominal pain in a patient with celiac disease, it is not uncommon to find elevations in the serum amylase in the absence of acute pancreatitis.¹⁶⁶ Pancreatitis has been seen in patients after severe burns.¹⁶⁷ A relationship of smoking with acute pancreatitis has been suggested. A Swedish case control study showed that there is a fourfold increased rate of acute pancreatitis in heavy smokers compared with nonsmokers.¹⁶⁸

Autoimmune pancreatitis (discussed in the next chapter in more detail) typically presents as a mass or fullness in the pancreas. It is most commonly seen in older men, with biliary obstruction and an elevation of the serum immunoglobulin (IgG₄) level. Occasionally, patients will present with signs and symptoms of chronic pancreatitis, such as stricturing of the main pancreatic duct, diabetes, exocrine pancreatic insufficiency, or as acute pancreatitis. Investigators have more recently described patients with autoimmune recurrent pancreatitis, especially in younger women often without the classic elevation of serum IgG₄.¹⁶⁹

HISTORY

Abdominal pain is present at the onset of most attacks of acute pancreatitis, but the timing of abdominal pain is variable. Biliary colic may herald or progress to acute pancreatitis. Pain in pancreatitis usually involves the entire upper abdomen. However, it may be epigastric, in the right upper quadrant, or, infrequently, confined to the left side. Pain in the lower abdomen may arise from the rapid spread of pancreatic exudation to the left colon.

Onset of pain is rapid but not as abrupt as that of a perforated viscus. Usually it is at maximal intensity in 10 to 20 minutes. Occasionally, pain gradually increases and takes several hours to reach maximum intensity. Pain is steady and moderate to very severe. There is little pain relief with changing position. Frequently, pain is unbearable, steady, and boring. Band-like radiation of the pain to the back occurs in half of patients. Pain that lasts only a few hours and then disappears suggests a disease other than pancreatitis, such as biliary colic or peptic ulcer. Pain is absent in 5% to 10% of attacks, and a painless presentation may be a feature of serious fatal disease.⁴

Ninety percent of patients have nausea and vomiting. Vomiting may be severe, may last for hours, may be accompanied by retching, and may not alleviate pain. Vomiting may be related to severe pain or to inflammation involving the posterior gastric wall.

PHYSICAL EXAMINATION

Physical findings vary with the severity of an attack. Patients with mild pancreatitis may not appear acutely ill. Abdominal tenderness may be mild, and abdominal guarding is absent. In severe pancreatitis, patients look severely ill and often have abdominal distention, especially epigastric, which is due to gastric, small bowel, or colonic ileus. Almost all patients are tender in the upper abdomen, which may be elicited by gently shaking the abdomen or by gentle percussion. Guarding is more marked in the upper abdomen. Tenderness and guarding are less than expected, considering the intensity of discomfort. Abdominal rigidity, as occurs in diffuse peritonitis, is unusual but can be present, and differentiation from a perforated viscus may be impossible in these instances. Bowel sounds are reduced and may be absent.

Additional abdominal findings may include ecchymosis in one or both flanks (Grey Turner’s sign; Fig. 58-3) or about the periumbilical area (Cullen’s sign), owing to extravasation of hemorrhagic pancreatic exudate to these areas. These signs occur in less than 1% of cases and are associated with a poor prognosis. Rarely there is a brawny erythema of the flanks caused by extravasation of pancreatic exudate to the abdominal wall. A palpable epigastric mass may appear during the disease from a pseudocyst or a large inflammatory mass.

Figure 58-3. Grey Turner’s sign. Ecchymoses in the flanks in a 24-year-old man with a two-day history of upper abdominal pain secondary to mild acute alcoholic pancreatitis.

(Courtesy of Nadia Habal, MD, Dallas, Tex.)

The general physical examination, particularly in severe pancreatitis, may uncover markedly abnormal vital signs if there are third-space fluid losses and systemic toxicity. Commonly, the pulse is 100 to 150 beats/minute. Blood pressure can be initially higher than normal and then lower than normal with third-space losses and hypovolemia. Initially the temperature may be normal, but within one to three days it may increase to 101°F to 103°F owing to the severe retroperitoneal inflammatory process and the release of inflammatory mediators from the pancreas.¹⁷⁵

Tachypnea and shallow respirations may be present if the subdiaphragmatic inflammatory exudate causes painful breathing. Dyspnea may accompany pleural effusions, atelectasis, ARDS, or congestive heart failure. Chest examination may reveal limited diaphragmatic excursion if abdominal pain causes splinting of the diaphragm, or dullness to percussion and decreased breath sounds at the lung bases if there is a pleural effusion. There may be disorientation, hallucinations, agitation, or coma,¹⁷⁶ which may be due to alcohol withdrawal, hypotension, electrolyte imbalance such as hyponatremia, hypoxemia, fever, or toxic effects of pancreatic enzymes on the central nervous system. Conjunctival icterus may be present due to choledocholithiasis (gallstone pancreatitis) or bile duct obstruction from edema of the head of the pancreas, or from coexistent liver disease.

Uncommon findings include subcutaneous nodular fat necrosis,¹⁷⁷ thrombophlebitis in the legs, and polyarthritis. Subcutaneous fat necroses are 0.5- to 2-cm tender red nodules that usually appear over the distal extremities but may occur over the scalp, trunk, or buttocks. They occasionally precede abdominal pain or occur without abdominal pain, but usually they appear during a clinical episode and disappear with clinical improvement. If they occur over a joint, they may be confused with arthritis.

Some physical findings point to a specific cause of acute pancreatitis. Hepatomegaly, spider angiomas, and thickening of palmar sheaths favor alcoholic pancreatitis. Eruptive xanthomas and lipemia retinalis suggest hyperlipidemic pancreatitis. Parotid pain and swelling are features of mumps. Band keratopathy (an infiltration on the lateral margin of the cornea) occurs with hypercalcemia.

DIFFERENTIAL DIAGNOSIS

The abdominal pain of biliary colic may simulate acute pancreatitis. It is frequently severe and epigastric, but it lasts for several hours rather than several days (see Chapter 65). The pain of a perforated ulcer is sudden, becomes diffuse, and precipitates a rigid abdomen; movement aggravates pain. Nausea and vomiting occur but disappear soon after onset of pain (see Chapter 52). In mesenteric ischemia or infarction, the clinical setting often is an older person with cardiac dysrhythmia or arteriosclerotic disease who develops sudden pain out of proportion to physical findings, bloody diarrhea, nausea, and vomiting. Abdominal tenderness may be mild to moderate, and muscular rigidity may not be severe despite severe pain (see Chapter 114). In intestinal obstruction, pain is cyclical, abdominal distention is prominent, vomiting persists and may become feculent, and peristalsis is hyperactive and often audible (see Chapter 119). Other conditions that enter into the differential diagnosis of acute pancreatitis are listed in Table 58-6.

PANCREATIC ENZYMES

In general, the diagnosis of acute pancreatitis relies on at least a three-fold elevation of amylase or lipase in the blood.¹⁷⁸

OTHER BLOOD AND URINE TESTS

Many nonenzymatic proteins are overexpressed in acute pancreatitis. Pancreatitis-associated protein (PAP), a heat shock protein, is undetectable in the normal pancreas but markedly increases in acute pancreatitis, with PAP detectable in serum. The sensitivity of serum PAP or pancreatic-specific protein (PSP) is no better than that of conventional tests,¹⁸⁷ but PAP and PSP are as accurate as serum amylase for the detection of acute pancreatitis.

The methemalbumin level in the circulation increases in acute pancreatitis, but it also increases in serious intra-abdominal conditions such as intestinal infarction, limiting its usefulness.

STANDARD BLOOD TESTS

The white blood cell count frequently is elevated, often markedly so in severe pancreatitis. The blood glucose also may be high and associated with high levels of serum glucagon. Serum aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and bilirubin also may increase, particularly in gallstone pancreatitis. Presumably, calculi in the bile duct account for these abnormalities. However, pancreatic inflammation may partially obstruct the distal bile duct in acute pancreatitis of other causes and cause abnormalities in liver biochemical tests. Nevertheless, aminotransferases may help distinguish biliary from alcoholic pancreatitis (see later).¹⁸⁸ The erythrocyte mean corpuscular volume (MCV) has been also shown to help differentiate alcoholic from nonalcoholic acute pancreatitis.¹⁸⁹ Alcoholic patients tend to have a higher MCV due to the toxic effects of alcohol on erythrocyte formation in the bone marrow. Serum triglyceride levels increase in acute pancreatitis, but also with alcohol use, uncontrolled diabetes mellitus, or defective triglyceride metabolism.

ABDOMINAL PLAIN FILM

Findings on a plain radiograph range from no abnormalities in mild disease to localized ileus of a segment of small intestine (“sentinel loop”) or the colon cut-off sign in more severe disease. In addition, an abdominal plain film helps exclude other causes of abdominal pain, such as bowel obstruction and perforation. Images of the hollow GI tract on an abdominal plain radiograph depend on the spread and location of pancreatic exudate. Gastric abnormalities are caused by exudate in the lesser sac producing anterior displacement of the stomach, with separation of the contour of the stomach from the transverse colon. Small intestinal abnormalities are due to exudate in proximity to small bowel mesentery and include ileus of one or more loops of jejunum (the sentinel loop), of the distal ileum or cecum, or of the duodenum. Generalized ileus may occur in severe disease.

Besides ileus, other abnormalities of the hollow GI tract may be present. The descending duodenum may be displaced and stretched by an enlarged head of the pancreas. In addition, spread of exudate to specific areas of the colon may produce spasm of that part of the colon and either no air distal to the spasm (the colon cut-off sign) or dilated colon proximal to the spasm. Head-predominant pancreatitis predisposes to spread of exudate to the proximal transverse colon, producing colonic spasm and a dilated ascending colon. Uniform pancreatic inflammation predisposes spread of exudate to the inferior border of the transverse colon and an irregular haustral pattern. Exudate from the pancreatic tail to the phrenicocolic ligament adjacent to the descending colon may cause spasm of the descending colon and a dilated transverse colon.

Other findings on plain radiography of the abdomen may give clues to etiology or severity, including calcified gallstones (gallstone pancreatitis), pancreatic stones or calcification (chronic pancreatitis with a bout of acute inflammation), and ascites (severe pancreatitis). Gas in the retroperitoneum may suggest a pancreatic abscess.

CHEST RADIOGRAPHY

Abnormalities visible on the chest roentgenogram occur in 30% of patients with acute pancreatitis, including elevation of a hemidiaphragm, pleural effusion(s), basal or plate-like atelectasis secondary to limited respiratory excursion, and pulmonary infiltrates. Pleural effusions may be bilateral or confined to the left side; rarely they are only on the right side.¹⁹⁰ Patients with acute pancreatitis found to have a pleural effusion and/or infiltrate on admission are more likely to have severe disease.¹⁹¹ During the first 7 to 10 days, there also may be signs of congestive heart failure or acute respiratory distress syndrome. Pericardial effusion is rare.

ABDOMINAL ULTRASONOGRAPHY

Abdominal ultrasonography is used during the first 24 hours of hospitalization to search for gallstones, dilation of the bile duct due to choledocholithiasis, and ascites. If the pancreas is seen (bowel gas obscures the pancreas 25% to 35% of the time), it is usually diffusely enlarged and hypoechoic. Less frequently there are focal hypoechoic areas. There also may be ultrasonographic evidence of chronic pancreatitis, such as intraductal or parenchymal calcification and dilation of the pancreatic duct. Ultrasound is not a good imaging test to evaluate extrapancreatic spread of pancreatic inflammation or necrosis within the pancreas and consequently is not useful to ascertain severity of pancreatitis. During the course of acute pancreatitis, ultrasound can be used to evaluate progression of a pseudocyst (discussed later). Due to overlying gas, the diagnosis of cholelithiasis may be obscured during the acute attack but may be found after bowel gas has receded.

ENDOSCOPIC ULTRASONOGRAPHY

Usually endoscopic ultrasonography (EUS) is not helpful early in acute pancreatitis. Imaging of the pancreas during an attack of acute pancreatitis and weeks following an episode reveal signals that are not normal (typically hypoechoic) and indistinguishable from chronic pancreatitis and malignancy. However, after a month, especially in patients with idiopathic interstitial pancreatitis, EUS may help determine the presence of small tumors, pancreas divisum, and bile duct stones.¹⁹² EUS is equal to MRCP and ERCP but far more sensitive than either abdominal ultrasonography or CT in detecting common duct stones.¹⁹³ In a patient with biliary pancreatitis, whose serum bilirubin is rising in the setting of biliary sepsis, ERCP should not be delayed by first performing EUS (see later). Although there has been some concern that ERCP can worsen pancreatitis in such settings, ERCP appears to be safe in acute pancreatitis if needed. One caveat is that the contrast instillation into the pancreatic duct could introduce infection into necrotic areas of the pancreas. For this reason, EUS might be the best method of evaluating the bile duct in a patient with necrotizing pancreatitis.¹⁹⁴

COMPUTED TOMOGRAPHY

CT is the most important imaging test for the diagnosis of acute pancreatitis and its intra-abdominal complications.¹⁹⁵ The three main indications for a CT in acute pancreatitis are to exclude other serious intra-abdominal conditions, such as mesenteric infarction or a perforated ulcer; to stage the severity of acute pancreatitis; and to determine whether complications of pancreatitis are present, such as involvement of the GI tract or nearby blood vessels and organs, including liver, spleen, and kidney.¹⁹⁶ Helical CT is the most common technique. If possible, scanning should occur after the patient receives oral contrast, followed by intravenous contrast to identify any areas of pancreatic necrosis. If there is normal perfusion of the pancreas, interstitial pancreatitis is said to be present (see Fig. 58-1). Pancreatic necrosis manifested as perfusion defects after intravenous contrast may not appear until 48 to 72 hours after onset of acute pancreatitis (see Fig. 58-2).

Contraindications to using intravenous contrast are a patient’s history of severe allergy (respiratory distress or anaphylaxis) or significant renal impairment (serum creatinine greater than 2 mg/dL). If severe renal impairment requires dialysis, intravenous contrast medium may be used.¹⁹⁷ Hives or less severe allergic reactions with previous administration of iodinated contrast material are not absolute contraindications, but a nonionic contrast agent should be used, and 200 mg of hydrocortisone should be administered intravenously every six hours for four doses starting before the scan and 50 mg of diphenhydramine (Benadryl) should be given intramuscularly 30 minutes before the scan.¹⁹⁸

It has been suggested that intravenous contrast media early in the course of acute pancreatitis might increase pancreatic necrosis because iodinated contrast medium given at the onset of pancreatitis increases necrosis in experimental rat acute pancreatitis.¹⁹⁹ However, it did not do so in the opossum.²⁰⁰ Data in humans are conflicting. Two retrospective studies suggested that early contrast-enhanced CT worsened pancreatitis¹⁹⁹ but this was not corroborated by a third retrospective study.¹⁹⁸

The severity of acute pancreatitis has been classified into five grades (A to E) based on findings on unenhanced CT¹⁹⁹ (see following). Although the presence of gas in the pancreas suggests pancreatic infection with a gas-forming organism, this finding can also accompany sterile necrosis (Fig. 58-4) with microperforation of the gut or adjacent pseudocyst into the pancreas.²⁰¹ Moreover, the great majority of pancreatic infections occur in the absence of gas on CT scan.

Figure 58-4. Acute necrotizing pancreatitis. Contrast-enhanced computed tomography that shows the pancreas (P) is surrounded by peripancreatic inflammation that contains bubbles of air (arrows) due to sterile necrosis. The patient was not clinically ill, and therefore an abscess was not considered likely. G, gallbladder.

MAGNETIC RESONANCE IMAGING

MRI provides similar information regarding the severity of pancreatitis as does CT. MRI is as good as CT in detecting necrosis and fluid collections. MRI is better than CT, but equal to EUS and ERCP in detecting choledocholithiasis²⁰² The MRCP contrast agent gadolinium, previously thought to be safe in patients with renal failure,²⁰³ can cause nephrogenic systemic fibrosis (NSF), which has raised concern.²⁰⁴ MRI is less accessible and more expensive than CT. MRI also requires the patient to remain still during capture of images, which typically is longer than with spiral CT. The use of intravenous secretin prior to MRCP allows a better visualization of the pancreatic ducts. This has been shown to be particularly useful in the evaluation of patients with idiopathic pancreatitis and recurrent pancreatitis.²⁰⁵

SCORING SYSTEMS

ORGAN FAILURE

There is considerable interest among pancreatologists in using organ failure to predict severity. The Atlanta criteria defined which organ systems are of importance: pulmonary, renal, and cardiovascular. However, these criteria did not attempt to quantitate or prognosticate using organ failure. It has been appreciated that multiorgan failure or persistent single organ failure has a greater associated mortality than transient single organ failure. Multisystem organ failure is defined as two or more organs failing on the same day, rather than one organ failing on one day and another failing on the subsequent day. Patients with multisystem organ failure or persistent organ failure have a much higher mortality rate (approaching 50%) compared with patients with single and transient organ failure.²²² Persistent organ failure is defined as lasting greater than 24 hours regardless of intervention. Survival among patients with organ failure at admission has also been shown to correlate with the duration of organ failure. When organ failure is corrected within 48 hours, mortality is close to zero. When organ failure persists for more than 48 hours, mortality is 36%.²²³ The Marshall Scoring System²²⁴ for organ failure is commonly used by intensivists for patients admitted to an intensive car unit. Data have not yet been generated using this system to prognosticate mortality in acute pancreatitis. Studies are needed to determine if this scoring system improves on the Ranson and APACHE scoring systems.

PERITONEAL LAVAGE

Percutaneous recovery of any volume of peritoneal fluid with a dark color or recovery of at least 20 mL of free intraperitoneal fluid of dark color portends a significant mortality.²²⁵ The sensitivity of peritoneal lavage is 36% to 72%, and the specificity is greater than 80% to 100%.²²⁶ An advantage is that it can be used any time, but it has not gained wide acceptance because it is invasive.

LABORATORY MARKERS

Because the degree of elevation of serum amylase and lipase does not distinguish mild from severe pancreatitis,²¹⁹ other factors have been examined.

COMPUTED TOMOGRAPHY

The finding of extensive fluid collections or extensive necrosis on CT has been correlated with severe disease. Balthazar reported that 5 of 37 (13.5%) patients who had grade D or E findings on CT died, as opposed to none of 51 who had grades B or C findings (Table 58-7).¹¹⁹ Using the CT severity index (CTSI score) (see Table 58-7), among those with a score of 0 to 6, 3 of 77 (3.8%) died, as compared with 2 of 11 (18%) with scores of 7 to 10. The CT grading scores correlate better with local complications (pseudocysts and abscesses) than with mortality. Among the 37 patients with a grade D or E score, 54% developed a local complication, whereas only 2 of 51 (3.9%) with grades A through C developed this problem.²¹¹ Thus, the data do not confirm that the CTSI is any more predictive than the grades A through E score.

Table 58-7 Computed Tomography (CT) Grading System of Balthazar and CT Severity Index (CTSI)

* Highest attainable score = 10 (Balthazar grade E + necrosis >50%).

There is controversy in the literature as to whether the extent of necrosis on CT predicts organ failure. Two studies failed to show any correlation between these two events,^223,235 whereas a third study found a strong correlation.²³⁶

CHEST RADIOGRAPHY

A pleural effusion documented within 72 hours of admission^190,193 by chest radiography (or CT) correlates with severe disease.

GENERAL CONSIDERATIONS

Patients with acute pancreatitis require adequate intravenous hydration and adequate analgesia to eliminate or markedly reduce pain. The patient is usually on nothing per mouth until any nausea and vomiting have subsided. Abdominal pain can be treated with opiate analgesics, often by a patient-controlled anesthesia pump. Opiate dosing is monitored carefully and adjusted on a daily basis according to ongoing needs. Although morphine has been reported to increase sphincter of Oddi tone and increase serum amylase,²³⁷ its use to treat the pain of pancreatitis has not been shown to adversely effect outcome. Nasogastric intubation is not used routinely because it is not beneficial in mild pancreatitis. It is used only to treat gastric or intestinal ileus or intractable nausea and vomiting. Similarly, proton pump inhibitors or H₂-receptor blocking agents⁶⁹ are not beneficial and not used.

Figure 58-5. Algorithm for the management of acute pancreatitis at various stages in its course. CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; ETOH, ethyl alcohol; FNA, fine-needle aspiration; GS, gallstones; ICU, intensive care unit; IV, intravenous; NG, nasogastric; NJ, nasojejunal; NPO, nil per os (nothing by mouth); TGs, triglycerides.

The patient should be carefully monitored for any signs of early organ failure such as hypotension, pulmonary, or renal insufficiency by closely following vital signs and urinary output. Tachypnea should not be assumed to be due to abdominal pain; monitoring oxygen saturation and, if needed, blood gases is advised and oxygen supplementation is mandatory if there is hypoxemia. It cannot be overemphasized that any patient who exhibits signs of early organ dysfunction should be immediately transferred to intensive care monitoring as deterioration can be rapid and fatal.

FLUID RESUSCITATION

As the inflammatory process progresses early in the course of the disease, there is an extravasation of protein-rich intravascular fluid into the peritoneal cavity resulting in hemoconcentration. The decreased perfusion pressure into the pancreas leads to microcirculatory changes that lead to pancreatic necrosis. An admission hematocrit of more than 47% and a failure of the admission hematocrit to decrease at 24 hours have been shown to be predictors of necrotizing pancreatitis.²³⁸

The relationship of hematocrit to severity of pancreatitis implies that the opposite is also true. Early vigorous intravenous hydration for the purpose of intravascular resuscitation is of foremost importance. The goal is to decrease the hematocrit. Laboratory and clinical studies with intravenous dextran to promote hemodilution have suggested efficacy in preventing severe disease.²³⁹ Too often patients with acute pancreatitis are given suboptimal intravenous hydration. One of the markers of severity of pancreatitis defined by Ranson and colleagues is intravascular losses (“fluid sequestration”). Ranson and colleagues found that a sequestration of more than 6 L of fluids during the first 48 hours was an independent predictor of disease severity in non-gallstone pancreatitis.¹⁴ If this amount of fluid (6 L) is added to the minimal intravenous fluid requirements of a 70-kg person during the first 48 hours, intravenous hydration should be at least 250 to 300 mL/hour for 48 hours. The rate of volume replacement is likely to be more important during the first 24 hours, when a rising hematocrit has been shown to correlate closely with severe disease. A study from the Mayo Clinic showed that patients with severe acute pancreatitis who do not receive at least one third of their initial 72-hour cumulative intravenous fluid volume during the first 24 hours after emergency department presentation are at risk for greater mortality than those who are initially resuscitated more aggressively.²⁴⁰

Maintaining adequate intravascular volume in patients with severe disease may require 5 to 10 L of fluid such as isotonic saline daily for the first several days (200 to 400 mL/hour). Respiratory distress often suggests development of ARDS independent of intravascular volume status. However, in a patient with unclear cardiac output, a Swan-Ganz catheter can be useful to gauge fluid resuscitation and to avoid congestive heart failure.

RESPIRATORY CARE

Hypoxemia (oxygen saturation <90%) requires supplemental oxygen, ideally by nasal prongs or by face mask if needed. If nasal oxygen fails to correct hypoxemia or if there is fatigue and borderline respiratory reserve, endotracheal intubation and assisted ventilation are required early. It is important to use a Swan-Ganz catheter to determine whether hypoxemia is due to congestive heart failure (increased pulmonary artery wedge pressure) or to primary pulmonary damage (normal or low pulmonary artery wedge pressure). Due to the common and indolent nature of hypoxemia affecting patients with acute pancreatitis, current guidelines recommend the initial routine use of nasal cannula oxygen to all patients with acute pancreatitis.¹²

ARDS is the most serious respiratory complication of acute pancreatitis; it is associated with severe dyspnea, progressive hypoxemia, and increased mortality. It generally occurs between the second and seventh day of illness (but can be present on admission) and consists of increased alveolar capillary permeability causing interstitial edema. Chest radiography may show multilobar alveolar infiltrates. Treatment is endotracheal intubation with positive end-expiratory pressure ventilation, often with low tidal volumes to protect the lungs from volutrauma. No specific treatment will prevent or resolve ARDS. After recovery, pulmonary structure and function usually return to normal.

CARDIOVASCULAR CARE

Cardiac complications of severe acute pancreatitis include congestive heart failure, myocardial infarction, cardiac dysrhythmia, and cardiogenic shock. An increase in cardiac index and a decrease in total peripheral resistance may be present and respond to infusion of crystalloids. If hypotension persists even with appropriate fluid resuscitation, intravenous dopamine may help maintain the systemic blood pressure. Dopamine does not impair the microcirculation of the pancreas as do other vasoconstrictors.

METABOLIC COMPLICATIONS

Hyperglycemia may present during the first several days of severe pancreatitis but usually normalizes as the inflammatory process subsides. Blood sugars fluctuate, and insulin should be administered cautiously. Hypocalcemia due to low serum albumin causes no symptoms and requires no specific therapy. However, reduced serum ionized calcium may occur and cause neuromuscular irritability. If hypomagnesemia coexists, magnesium replacement should restore serum calcium to normal. Causes of magnesium depletion include vomiting, loss of magnesium in the urine, or deposition of magnesium in areas of fat necrosis. Once the serum magnesium is normal, signs or symptoms of neuromuscular irritability may require administering intravenous calcium gluconate as long as the serum potassium is normal and digitalis is not being given. Intravenous calcium increases calcium binding to myocardial receptors, which displaces potassium and may induce a serious dysrhythmia.

ANTIBIOTICS

Antibiotics are not indicated in mild pancreatitis. However, pancreatic sepsis (infected necrosis and, less often, abscess) and nonpancreatic sepsis (line sepsis, urosepsis, or pneumonia) are major sources of morbidity and mortality in severe acute pancreatitis. Thus, it would seem logical to consider antibiotic prophylaxis to improve the outcome.

The use of prophylactic antibiotics in acute pancreatitis to prevent complications is controversial. In the 1970s, controlled studies compared intravenous antibiotics to no therapy in the treatment of mild acute alcoholic pancreatitis,²⁴¹ with negative results. However, low-risk patients were studied (mild alcoholic disease with no mortality) and the wrong antibiotic (ampicillin) was used.²⁴² In the 1980s, the bacteriology of infected pancreatic tissue was elucidated by analyzing either surgical specimens²⁴³ or fine-needle aspirations of the pancreas.²⁴² The majority of organisms detected were gram-negative aerobic or anaerobic species (Escherichia coli, Enterobacter aerogenes, Pseudomonas aeruginosa, Proteus species, Klebsiella pneumoniae, Citrobacter freundii, and Bacteroides species), with occasional gram positives (Streptococcus faecalis, Staphylococcus aureus, Streptococcus viridans, Staphylococcus epidermidis) and rare fungi (Candida species). Studies in the early 1990s elucidated the appropriate antibiotics to use given these organisms and the level of penetration of antibiotics into necrotic pancreatic tissue.²⁴⁴ Imipenem, fluoroquinolones (ciprofloxacin, ofloxacin, pefloxacin), and metronidazole emerged as the drugs that achieved the highest inhibitory concentrations in pancreatic tissue, whereas aminoglycosides did not. Several randomized controlled (no placebo given), nonblinded clinical trials of prophylactic intravenous antibiotics in patients with severe pancreatitis were performed in Europe in the 1990s.^245–248 One study added oral nonabsorbable antibiotics to the intravenous antibiotic regimen.²⁴⁹ Meta-analyses of the intravenous antibiotic trials showed that mortality of necrotizing pancreatitis was significantly reduced by antibiotics.^250,251

Very little comparative information is known as to which antibiotic is the most effective. One study compared pefloxacin to imipenem in severe disease, showing imipenem to be significantly more effective in reducing pancreatic and extrapancreatic infection; however, mortality was unaffected.²⁵² Likewise, little information is available on the length of treatment. One investigation compared one week of ciprofloxacin to three weeks and showed that longer treatment reduced the rates of pancreatic and nonpancreatic infection.²⁵³

The aforementioned studies have been criticized because they were not placebo-controlled, double-blinded studies. Furthermore, the use of prophylactic antibiotics in all patients with severe pancreatitis raises the concern that some patients will become superinfected with resistant organisms or fungi, which might lead to greater mortality in the future. Two studies have used double-blind randomized protocols to study this question. The first randomized 114 patients with severe acute pancreatitis to prophylactic ciprofloxacin plus metronidazole or to placebo. Patients suspected of having an infection were allowed open-label antibiotics. There were no differences in rates of infected necrosis or mortality. The only difference noted was that the group randomized to receive placebo eventually received more open-label antibiotics than the group randomized to receive the original antibiotics (46% vs. 28%).²⁵⁴ Dellinger and colleagues²⁵⁵ performed a multicenter, double-blind placebo-controlled randomized study in 32 centers in North America and Europe. One hundred patients were equally randomized to two groups, meropenem (1 g intravenously every eight hours) or placebo within 5 days of the onset of symptoms. Meropenem was continued for 7 to 21 days. This study demonstrated no significant difference between the treatment groups for pancreatic or peripancreatic infection, mortality, or requirement for surgical intervention. Based on these last two placebo-controlled studies, routine use of antibiotics is questionable in the absence of biliary sepsis or obvious pancreatic or peripancreatic infection. Although practice guidelines published prior to this latest paper recommended the use of prophylactic antibiotics in patients with severe necrotizing pancreatitis,²⁵⁶ more recent guidelines¹² state that prophylactic antibiotics should not be used for the purpose of preventing infection in patients with necrotizing pancreatitis.

ENDOSCOPIC

The question of early removal of a possibly impacted gallstone in improving the outcome of gallstone pancreatitis remains a controversial issue. There have been three randomized fully published studies comparing urgent ERCP plus sphincterotomy (for any retained stones) versus conventional treatment in the management of gallstone pancreatitis.^257–259 The earliest study,²⁵⁷ a single-center investigation from England, found that urgent ERCP within 72 hours of admission improved the outcome (complications and mortality) of patients with severe, but not mild, acute gallstone-induced pancreatitis. The second,²⁵⁸ another single-center study from Hong Kong, found that the urgent intervention group had a reduction in biliary sepsis and a trend toward lower mortality compared with the control group. The third and largest study from Germany²⁵⁹ included 22 centers and came to an opposite conclusion, namely, that there was a higher complication rate and a trend toward higher mortality in the urgently treated ERCP group compared with standard nonurgent therapy. Differences in the designs of these studies do not allow direct comparisons. However, there is consensus that severe acute gallstone pancreatitis with ascending cholangitis (jaundice and fever) is an indication for urgent ERCP (see Chapter 61).

In a prospective study of biliary pancreatitis using ERCP, Uomo and colleagues⁵¹ noted a 30.5% incidence of main pancreatic duct leakage. It has been proposed that early endoscopic stenting of the main pancreatic duct in patients with this problem may shorten hospital stay and the need for subsequent necrosectomy. Lau and colleagues²⁶⁰ evaluated 144 patients with severe acute pancreatitis and found that the presence of a PD leak was significantly associated with the development of necrosis. Patients with a PD leak had a longer length of stay compared with the patients with acute pancreatitis with no PD leak. In this retrospective study, patients who underwent early ERCP and had a PD stent placed were less likely to have other more invasive interventions performed, such as placement of external drains. Although PD stents have been shown to be helpful in the management of late complications related to pancreatic duct disruption, such as fistulas and pseudocysts, it remains unclear that routine use of these stents will prevent late complications. Kozarek and associates found that PD stent placement was associated with polymicrobial contamination of the pancreas.²⁶¹ Although the contamination was largely asymptomatic, the benefit of placing a stent in the PD early in the course of acute pancreatitis to treat a duct disruption must be weighed against the possibility of seeding sterile necrosis with organisms that could lead to infected necrosis. Until randomized studies are performed, it is not clear whether potential advantages of early pancreatic duct stenting outweigh the risks.

NUTRITIONAL

In general, intravenous feedings are continued until patients are able to tolerate liquids or solids. The timing of early feedings is unclear. One report suggested that early refeeding improved outcome and allowed early discharge.²⁶² However, a meta-analysis of three studies showed that early refeeding prolonged hospitalization.²⁶³ The question of whether an elevated serum amylase or lipase should influence the clinician to prolong the time to refeeding has been addressed. One hundred sixteen patients with acute pancreatitis were fed at the clinician’s discretion; 21% developed pain on refeeding 250 kcal/day.²⁶⁴ If the serum lipase was more than three-fold elevated, refeeding increased the clinical relapse rate compared with the group in which the lipase was less than three-fold elevated (39% vs. 16%). However, the corollary of this finding is that most patients with three-fold elevated serum lipase levels do not have a recrudescence of their pain on refeeding. Once refeeding is begun, a low-fat diet appears to be comparable to a clear liquid diet as the initial meal.²⁶⁵

Formerly, total parenteral nutrition (TPN) was the standard of care for refeeding patients with severe acute pancreatitis. Sax and coworkers²⁶⁶ randomized 54 patients with mild pancreatitis to intravenous nutrition or to TPN. The TPN group had a greater number of septic complications and longer hospitalizations. McClave²⁶⁷ randomized 30 patients with mild to moderate pancreatitis to receive TPN or enteral feedings administered through a nasoenteric tube, beginning 48 hours after admission. The Ranson and APACHE scores and blood glucose levels normalized more quickly in the enteral group, and the length of hospitalization showed a trend toward a shorter stay in the enteral group. Windsor²⁶⁸ randomized 34 patients with either mild to moderate pancreatitis to either oral feedings or TPN or with severe pancreatitis to either enteral feedings via a nasoenteric tube or TPN. The group receiving oral or enteral feedings had shorter intensive care unit (ICU) stays and improved acute phase response markers and disease severity scores compared with the TPN group. Kalfarentzos²⁶⁹ randomized 38 patients with severe necrotizing pancreatitis to TPN versus nasoenteric feedings. The enteral group had fewer septic complications and fewer total complications, although hospital stay, ICU stay, and days until resumption of a regular diet were similar in the two groups. Thus, these studies demonstrate that enteral nutrition is cheaper and safer and is preferable in patients with severe acute pancreatitis. It is still unclear, however, when nutrition should be initiated and for how long it needs to be continued. Furthermore it is unclear if nasoenteric feedings are needed or if nasogastric or even oral feedings are similarly effective if the patient tolerates this modality. Along those lines, a UK group randomized 50 patients with severe pancreatitis to nasogastric versus nasoenteric tube feedings. No difference was seen in the ability to tolerate feedings, in markers of inflammation, or in morbidity or mortality between the groups.²⁷⁰ They also noted no differences in the length of hospital stay or complications in patients with severe acute pancreatitis.

SURGICAL THERAPY

Cholecystectomy is routinely performed in patients with gallstone pancreatitis, and a consensus conference suggested that in mild or severe gallstone pancreatitis, cholecystectomy should be performed as soon as the patient has recovered and the acute inflammatory process has subsided.²⁷¹ A second potential role for surgery in pancreatitis is to debride pancreatic necrosis (necrosectomy) or drain a pancreatic abscess. With regard to pancreatic necrosectomy, the data are more complicated and evolving. Studies in the 1980s suggested that early necrosectomy (within the first week of hospitalization for severe disease) reduced mortality. However, in the only randomized study comparing early (within 72 hours of admission) to late necrosectomy (12 days or more after admission), the mortality with early operation was greater than with later débridement (56% vs. 27%).²⁷² Some investigators have reported that it is important to differentiate sterile necrosis from infected necrosis by fine-needle aspiration of the pancreas. Sterile necrosis can be managed nonoperatively because the mortality of this condition without surgery is less than 5%.^273,274 Infected necrosis (as documented by fine-needle aspiration of the pancreas with Gram stain and cultures), on the other hand, has been historically regarded as an indication for surgical débridement because of the previous belief that infected necrosis treated medically has a nearly uniform fatal outcome.^275,276 This has led to the recommendation that patients who are not improving on maximal medical therapy or who develop organ failure should have a fine-needle aspiration of the pancreas (Fig. 58-6). The finding of infection should then lead to a consideration of surgical intervention.

Figure 58-6. Walled-off pancreatic necrosis. Non–contrast-enhanced computed tomography reveals a 5.4-cm pus-filled fluid collection (arrows) with the tip of an aspirating needle in its lumen. The abscess is anterior to the pancreas (P) and medial to the stomach (S). A right subhepatic fluid collection (F) is present.

However, surgical therapy of infected pancreatic necrosis carries a substantial mortality of 15% to 73%,^275–278 especially when it is carried out early within the first few weeks of the disease. Thus, it is unclear if the higher mortality rates that have been reported in patients with infected necrosis are the result of the underlying disease or the early surgical intervention. It has been shown that delaying surgical débridement beyond the fourth week in patients with pancreatic necrosis is associated with a lower mortality rate.²⁷⁷ The concept that infected pancreatic necrosis requires prompt surgical débridement has been challenged by several reports of patients who have been treated by antibiotic therapy alone.^278–280

A series of 28 patients with infected pancreatic necrosis was treated prospectively with antibiotics rather than urgent surgical débridement.²⁸¹ Among 12 patients who eventually required elective surgical intervention, there were two deaths. Among the other 16 patients who were treated with long-term antibiotic therapy, there were also two deaths. Thus, 14 of 28 patients with infected necrosis were successfully treated with no surgical, endoscopic, or radiologic drainage.

The types of necrosectomy operations that have been recommended include necrosectomy with closed continuous irrigation via indwelling catheters, necrosectomy with closed drainage without irrigation, or necrosectomy and open packing. There have been no randomized prospective trials comparing these various procedures. All are generally considered to provide equal benefit in skilled surgical centers.

Several additional procedures have been introduced that are less invasive than standard open surgical débridement of infected necrosis. These techniques have generally been reserved for patients with infected pancreatic necrosis who are too ill to undergo prompt surgical débridement (such as those with organ failure or serious comorbid disease) and include laparoscopic necrosectomy with placement of large-caliber drains under direct surgical inspection and percutaneous catheter drainage of infected necrosis (see Chapter 26). Other minimally invasive approaches, including endoscopic (see Chapter 61) or a combined endoscopic and laparoscopic approach may become more commonly used as skill and technology advance.

OTHER THERAPEUTIC AGENTS OF POSSIBLE OR QUESTIONABLE EFFICACY

Pancreatic protease inhibitors have been used to treat established severe acute pancreatitis and to prevent post-ERCP pancreatitis (see earlier section). Gabexate mesylate is the most widely studied pancreatic protease inhibitor. A meta-analysis of five clinical trials of gabexate mesylate in acute pancreatitis found no effect on the 90-day mortality rate, but a reduced incidence of complications.²⁸² This agent is not available in the United States. Multiple trials of the antisecretory hormone somatostatin or its synthetic analog octreotide have failed to show convincing evidence of efficacy in the treatment of acute pancreatitis.²⁸³ The use of anti-inflammatory cytokines has so far not shown efficacy. The largest experience has been with lexipafant, a PAF inhibitor. After initial promising reports,²⁸⁴ subsequent studies have not shown clear efficacy.²⁸⁵

Japanese investigators have suggested that pancreatic protease inhibitors and antibiotics can be better targeted to the affected regions in the pancreas with continuous regional arterial infusion (CRAI) into the celiac, splenic, inferior pancreaticoduodenal, and common hepatic arteries. Using CT, Anai and colleagues²⁸⁶ showed that with CRAI the contrast was distributed to the entire pancreas in six of nine patients with inflammation of the entire pancreas; in the remaining three patients, contrast material did not penetrate the entire area of pancreatic inflammation. Two later studies suggested that intra-arterial infusion of the protease inhibitor nafamostat mesylate plus imipenem reduces mortality when compared with intravenous infusion of the same agents.^287,288 These studies warrant further investigation. Many other measures have been shown to be ineffective in randomized trials, including anticholinergics, glucagon, fresh frozen plasma, and peritoneal lavage.^60,289 Infectious complications and associated mortality are major concerns in acute pancreatitis. Enteral administration of probiotics might prevent infectious complications, but convincing evidence is scarce. Although an early study suggested that probiotics might decrease infectious complications,²⁹⁰ other studies have suggested an increase in morbidity and mortality.²⁹¹ In this more recent study, infectious complications occurred in 46 patients in the probiotics group (30%) and in 41 of those in the placebo group (28%). Twenty four patients in the probiotics group died (16%), compared with 9 (6%) in the placebo group (relative risk of death, 2.53; 95% confidence interval, 1.22 to 5.25). Nine patients in the probiotics group developed bowel ischemia (8 with fatal outcome), compared with none in the placebo group (P = 0.004). At the present time, probiotic prophylaxis should therefore not be administered in this category of patients.²⁹²

PSEUDOCYST

A pseudocyst may occur secondary to acute pancreatitis, pancreatic trauma, or chronic pancreatitis. It usually contains a high concentration of pancreatic enzymes and variable amounts of tissue debris. Most are sterile. Regardless of size, an asymptomatic pseudocyst does not require treatment.^293,294 It is satisfactory to monitor the pseudocyst with abdominal ultrasonography. Pseudocysts can be complicated by infection, intracystic hemorrhage (Fig. 58-7), or rupture leading to pancreatic ascites. Further, pseudocysts can migrate into the chest or other unusual locations. In patients with known pseudocysts, new symptoms, such as abdominal pain, chills, or fever, should alert the clinician to the emergence of an infected pseudocyst or abscess. Treatment choices include surgical, radiologic, and endoscopic drainage. No randomized prospective trials have compared these methods.

Table 58-8 Complications of Acute Pancreatitis

ORGAN DYSFUNCTION

Organ dysfunction has been discussed extensively earlier in the chapter. Respiratory insufficiency is the most common systemic complication associated with pancreatitis. The causes are multifactorial and include pleural effusions, pneumonia, atelectasis, and ARDS. Oxygen supplementation, antibiotics, thoracentesis, and assisted ventilation may be necessary. Renal complications are due to hypovolemia causing prerenal azotemia or hypotension, leading to acute tubular necrosis. These are treated by increasing intravenous fluid administration in the former case or with hemofiltration or hemodialysis in the latter situation. Shock is usually caused by hypovolemia secondary to third-space losses, vomiting, and interstitial pancreatic edema. Other uncommon causes of hypotension include myocardial infarction and pericardial effusions. Fluid replacement in severe acute pancreatitis is best accomplished using central venous– or Swan-Ganz catheter–assisted monitoring. As mentioned, mortality is substantially increased with increasing organ dysfunction especially if shock is involved.²²⁶

METABOLIC DISTURBANCES

Hyperglycemia and hypocalcemia are common in severe disease. Hyperglycemia is usually transient and is due to insulin deficiency from presumed islet cell necrosis or hyperglucagonemia. It is uncommon for these complications to require aggressive treatment.

COAGULATION DISORDERS

Mild coagulation defects are common in acute pancreatitis as measured by elevated d-dimer levels in the blood.³⁰⁶ Full-blown disseminated intravascular coagulation (DIC) with a bleeding diathesis associated with a hypercoagulable state is very uncommon.

FAT NECROSIS

Fat necrosis occurs in subcutaneous tissue, bone, retroperitoneal tissue, peritoneum, mediastinum, pleura, and pericardium.¹⁹¹ Histologically fat cells are necrotic, associated with a diffuse inflammatory infiltration. The subcutaneous lesions are circumscribed tender red nodules that are adherent to the skin but are movable over deeper structures. Most commonly they are over the ankles, fingers, knees, and elbows. The lesions may drain through the skin. Rarely there is also necrosis of adjacent tendons or involvement of joints, particularly the metatarsal, interphalangeal, wrist, knee, and ankle joints. The lesions usually resolve after days to weeks.

MISCELLANEOUS

Pancreatic encephalopathy consists of a variety of central nervous system symptoms occurring in acute pancreatitis, including agitation, hallucinations, confusion, disorientation, and coma.¹⁹⁸ A similar syndrome may be due to alcohol withdrawal, and other causes are possible, such as electrolyte disturbances (e.g., hyponatremia) or hypoxia. Purtsher’s retinopathy (discrete flame-shaped hemorrhages with cotton wool spots) can cause sudden blindness.³⁰⁷ It is thought to be due to microembolization in the choroidal and retinal arteries.