Felicia A. Ivascu
George D. Garcia
Danny Sleeman
Overview
Acute pancreatitis has an annual incidence of 5 to 40 per 100,000 (1,2) with an overall mortality of 1.5 per 100,000 (1). The clinical course of acute pancreatitis is often self-limited and results in little, if any, structural alteration of the gland and requires no intervention. Approximately one third of patients, however, develop pancreatic necrosis, which has an associated mortality rate that can be as high as 30% (1,3). All complications of this disease are potentially lethal and may require aggressive intervention to control or abort the process, and support the patient until the condition is resolved. Because of this, acute pancreatitis can be among the most difficult of clinical entities to treat. Very few, if any, other conditions present with such a myriad of origins, diagnostic difficulties, clinical manifestations, risk of multisystem involvement, and indeterminate prognosis for such a prolonged period. Severe acute pancreatitis often demands an extended stay in the intensive care unit and hours on hours of multidisciplinary care. Numerous causative factors of acute pancreatitis have been recognized. The most important risk factors for pancreatitis in adults are gallstones and excessive alcohol use, although clinically detectable pancreatitis never develops in most persons with these risk factors. The incidence of gallstone pancreatitis is increased among white women older than the age of 60 years (4,5) and is highest in patients with gallstones <5 mm in diameter (5,6). Other causes include metabolic derangements such as hypertriglyceridemia, duct obstruction (for example, related to tumor or pancreas divisum), medications (i.e., azathioprine, thiazides, and estrogens), and trauma. About 20% of cases remain idiopathic, although this classification is expected to become less common as factors of genetic predisposition and environmental susceptibility are elucidated (7).
Trypsin is the key enzyme in the activation of pancreatic zymogens. Underlying the pathophysiology of acute pancreatitis is the inappropriate conversion of trypsinogen to trypsin and a lack of prompt elimination of active trypsin inside the pancreas (7). Activation of other pancreatic enzymes causes injury to the gland and results in an inflammatory process that seems to be out of proportion to the response of other organs to a similar insult, possibly due to disturbances in the microcirculation of the pancreas and the exquisite sensitivity of the pancreas to ischemia (8). In addition to further significant tissue damage as a direct result, the inflammatory process may extend beyond the pancreas and result in the systemic inflammatory response syndrome, multiorgan failure, and ultimately, death.
Diagnosis of The Disease Process
At times, diagnosing acute pancreatitis may be as difficult as predicting the course or defining the treatment. Even with history, physical examination, laboratory values, radiographic studies, and special procedures, a conclusive diagnosis of acute pancreatitis and its complications is often elusive. The best approach may be to elucidate the history of a similar attack or hospitalization and identify associated etiologic factors, most commonly alcohol abuse or biliary tract disease.
The recurrence rate of acute pancreatitis has been reported to be as high as 33% (9) and can be even higher in the alcoholic population (10). Disease isolated to the head or tail of the pancreas may result in pain localized to the right or left upper quadrant with diaphragmatic irritation and referred pain to the subcapsular areas. The classic presentation of epigastric pain that radiates through to the back may be present in only 50% of patients presenting with acute pancreatitis. After the patient develops peritoneal signs, pancreatitis can mimic all other acute abdominal crises, especially those necessitating emergent surgery.
Laboratory Testing
Of the biochemical diagnostic criteria, the most commonly used is the serum amylase level (11). Serum amylase levels that are more than three times the upper limit of normal are almost always caused by acute pancreatitis given the appropriate clinical presentation (12). Although the serum amylase concentration begins to rise shortly after onset of the disease, it may return to normal levels in 2 to 4 days. However, a normal serum amylase level does not exclude the disease. In one series, up to 19% of patients with an attack of acute pancreatitis had a normal serum amylase level and an abnormal computerized tomography scan (13). Acute pancreatitis with normal serum amylase levels is often characterized by a high prevalence of patients with an alcoholic etiology and a longer duration of symptoms before admission (14). Other factors that may contribute to the absence of elevated serum amylase levels include return to normal levels prior to presentation or the inability of an inflamed or chronically diseased pancreas to produce a significant quantity of amylase. Pancreatitis secondary to biliary tract disease will often present with some of the highest serum amylase levels. In addition, an elevated alanine aminotransferase level in a patient without alcoholism who has pancreatitis is the single best predictor of biliary pancreatitis with a level more than three times the upper limit of normal having a positive predictive value of 95% for gallstone pancreatitis (15). The clinician must remain aware that an elevated serum amylase is not necessarily diagnostic of acute pancreatitis. The differential diagnosis of hyperamylasemia includes perforated or penetrating gastric ulcer, ruptured ectopic pregnancy, and intestinal obstruction or infarction. Measuring urinary amylase, amylase-to-creatinine ratios (16), and amylase isoenzymes (17) have shown little clinical advantage, with the exception of ruling out macroamylasemias.
An elevated concentration of serum lipase, however, is quite sensitive for diagnosis of acute pancreatitis secondary to alcohol abuse (18). Lipase levels tend to remain elevated longer than amylase concentrations. Therefore, an elevated lipase level can be useful information for patients who present later in the course of disease and who may have a normal amylase concentration. Serum lipase levels, although thought to be more specific for pancreatic destruction, have little, if any, role in predicting severity of disease.
Although elevated serum amylase and lipase levels are most widely used for the diagnosis of acute pancreatitis, as stated, they have little, if any, value in predicting the severity of disease. In an attempt at early prediction of severity of pancreatitis, the four most reliable serum markers are polymorphonuclear (PMN) elastase, albumin, C-reactive protein, and pancreatic amylase (14). An acute phase reactant, C-reactive protein, is most widely used. While elevated levels of C-reactive protein have been associated with pancreatic necrosis (19,20), a 24- to 48-hour latency for C-reactive protein to reach optimal predictability is well recognized (21,22,23,24), perhaps limiting its use as an early predictor of disease severity. Measuring levels of trypsinogen activation peptide (25) and trypsinogen-2 (26) are more specific for acute pancreatitis but are not widely available. Of the many cytokines that have been evaluated in an attempt to predict severity, interleukin (IL)-6 appears to hold the most promise, although further studies are needed (27) regarding its potential use as a clinically relevant predictor of disease severity.
Except for differentiation of other bacterial sources of peritonitis or diagnosis of complications of pancreatitis that would necessitate surgery, diagnostic peritoneal lavage has had little or no role in our institution in making the definitive diagnosis or assessing the prognosis of a given episode of pancreatitis.
Radiologic and Diagnostic Studies
Numerous radiologic findings are suggestive of, but not specific for, pancreatitis. These include dilatation of the first portion of the duodenum (duodenal ileus), dilatation of the first loop of the jejunum (jejunal ileus or sentinel loop), dilatation of the transverse colon or colon cutoff sign (secondary to a transverse colonic ileus), and elevated hemidiaphragm and pleural effusion, especially on the left side (secondary to diaphragmatic irritation and sympathetic pleural effusions).
Transabdominal pancreatic ultrasonography is not sensitive in the diagnosis of acute pancreatitis, often because of gas in the bowel. Ultrasonography frequently provides an incomplete view of the pancreas and the peripancreatic area, especially in patients who are obese with severe disease and excessive bowel gas secondary to ileus. In addition, if imaging of the tail of the pancreas in necessary, an incomplete view may occur because of poor sonic window. It can, however, be helpful in detection of early complications of pancreatitis and identification of associated biliary tract disease (28). Transabdominal ultrasound is more sensitive than either computerized tomography or magnetic resonance imaging for identifying cholelithiasis and sludge and for detecting dilatation of the biliary ducts, but is insensitive for the detection of distal biliary duct stones (4,5). Endoscopic ultrasonography may be the most accurate test for diagnosing or ruling out biliary causes of acute pancreatitis and may guide the use of endoscopic retrograde cholangiopancreatography (ERCP) (29).
Persistent biliary obstruction worsens the outcome and increases the severity of acute pancreatitis and predisposes the patient to progression to bacterial cholangitis. ERCP is used with endoscopic sphincterotomy to extract impacted gallstones and to drain infected bile in severe acute pancreatitis (30,31,32,33). Although ERCP has recognized risk, including bleeding and either causing or exacerbating pancreatitis, complications are uncommon when performed by experienced endoscopists. Three randomized trials involving a total of 511 patients with gallstone pancreatitis compared conservative management with ERCP and endoscopic sphincterotomy within 24 to 72 hours after admission. The studies showed a significantly lower risk of pancreatitis-associated complications in the ERCP group (31). Based on this evidence, it is recommended that patients with severe acute gallstone pancreatitis undergo early ERCP and, if indicated, endoscopic sphincterotomy (30). ERCP can also demonstrate ductal disruptions in traumatic pancreatitis and may also allow identification of pancreas divisum, thought to be a rare cause of acute pancreatitis.
In patients with abdominal pain of unclear cause, computerized tomography can confirm the diagnosis of acute pancreatitis and either rule out or confirm other causes of abdominal pain. When the use of intravenous radiocontrast material is contraindicated, the diagnosis of acute pancreatitis can be inferred from homogenous glandular enlargement and the presence of peripancreatic fluid collections (34). In the absence of contraindication, computerized tomography with radiocontrast is preferred, as contrast-enhanced computed tomography (CT) remains the gold standard in the diagnosis of pancreatic necrosis (35). Determination of the extent of pancreatic necrosis correlates with prognosis as mortality increases markedly in patients with necrosis involving more than 30% of the gland (36,37,38,39). Radiocontrast allows the identification of pancreatic necrosis, which appears as focal or diffuse zones of nonenhanced parenchyma. Areas of necrosis may not be present, however, for 48 to 72 hours after presentation. In the clinically stable patient with a contraindication to intravenous contrast, magnetic resonance imaging (MRI) is an alternative method to diagnose and evaluate the extent of pancreatic necrosis. MRI may also identify early duct disruption that is not visible on CT scan (40). Although contrast-enhanced CT allows the identification of pancreatic necrosis, there are no imaging techniques that allow precise and reliable identification of infected pancreatic necrosis. The appearance of air in the pancreatic parenchyma, caused by gas-producing bacteria, is not common in patients with infected pancreatic necrosis; however, when present it usually indicates infection. Fine-needle aspiration, under CT or ultrasound guidance, with Gram staining and culture of the aspirate is the gold standard for the diagnosis of infected pancreatic necrosis (41,42,43,44). Most series report sensitivity for the prediction of infected necrosis that ranges from 90% to 100% and specificity between 96% and 100% (41,45,46).
Although angiography does not have a role among the usual diagnostic techniques for pancreatitis, it has become useful for localizing hemorrhagic complications of the disease and extremely useful for nonoperative or preoperative control of bleeding vessels.
Classification
The Marseilles classification recognized four types of pancreatitis: (i) acute pancreatitis, (ii) recurrent acute pancreatitis, (iii) relapsing chronic pancreatitis, and (iv) chronic pancreatitis (47). This classification system has been useful to characterize the pathology of the gland and clinical episodes. The result of a 1992 International Symposium, the classification by Bradley (48) identified seven clinical entities: (i) acute pancreatitis, (ii) severe acute pancreatitis, (iii) mild acute pancreatitis, (iv) acute fluid collection, (v) pancreatic necrosis, (vi) pseudocysts, and (vii) pancreatic abscess.
The most relevant classification to the intensivist determines the degree of severity and progress of an individual episode of pancreatitis. Ranson et al. (49,50) established 11 clinical criteria, 5 of which were assessed on admission and 6 within 48 hours. They are well correlated with morbidity, number of days' stay in the ICU, and eventual mortality. The admission criteria are as follows: age older than 55 years, blood glucose level greater than 200 mg/dL, leukocyte count greater than 16,000/mm3, serum lactate dehydrogenase (LDH) level greater than 350 IU/L, and serum glutamic-oxaloacetic transaminase (SGOT) greater than 250 Sigma Frankel units. The criteria to be determined within 48 hours are as follows: serum calcium level less than 8 mg/dL, PaO2 less than 60 mm Hg, base deficit greater than 4 mEq/L, increase in blood urea nitrogen (BUN) of more than 5 mg/dL, decrease in hematocrit of more than 10 percentage points and more than 6 L fluid sequestration. The presence of fewer than 3 of these 11 criteria within 48 hours of admission usually correlates with a more benign form and course of disease, with an eventual mortality rate of 3%. The presence of three or more of these parameters on admission or within 48 hours usually implies a more severe form of pancreatitis and is associated with high risk of death and major complication.
The list of 11 numeric parameters proposed by Ranson et al. has suffered little discussion. With a single exception, the patients' age, these time-honored criteria are the result of the statistical analysis of 43 parameters. These parameters were gathered retrospectively from three overlapping series totaling 450 patients with acute pancreatitis (49,51,52). Of these 450 patients, however, only 94 (21%) had acute pancreatitis definitively confirmed by surgery or postmortem exam. Furthermore, the 13 parameters retained in the essentially statistical study of 1977 (51) were available in only 113 (38%) of the 300 patients studied, possibly representing a selection bias. Nevertheless, the Ranson scale has been used since the 1980s in virtually all studies relating to acute pancreatitis.
Treatment of Acute Pancreatitis
An overall approach to the therapy for acute pancreatitis should include placing the pancreas “at rest,” supporting the patient's nutritional and metabolic needs, correcting the acute causes of morality (i.e., cardiovascular collapse, respiratory insufficiency, and renal failure), detecting those complications of disease that require surgical intervention, and preventing and treating delayed causes of mortality (i.e., septic complications).
Gland Suppression
Suppression of the secretory function of the pancreas has been attempted by elimination of oral fluids (53,54), suppression of acid secretion with various H2 blockers (55,56) and antacids, and use of anticholinergics (47,57) and proteolytic enzyme inhibitors (58). Calcitonin (59) and somatostatin (60), which are potent inhibitors of pancreatic enzyme secretion, have also been subjected to clinical trials. Although there may be a good physiologic rationale, controlled randomized studies have not shown significant improvement.
Historically, it was felt that early feeding may increase the severity of the disease and re-exacerbate the inflammatory process. It was felt that most patients admitted to the ICU had pancreatitis of sufficient severity and associated ileus to prohibit enteral intake. Gut rest, with or without parenteral nutrition, had become regarded as the standard of care. However, it is now known that acute pancreatitis results in a hypermetabolic, hyperdynamic systemic inflammatory response syndrome that results in a catabolic state (61). Recent evidence suggests that enteral nutrition is not only feasible but may be desirable in such patients. The most severe complication of acute pancreatitis is pancreatic infection. The finding that the micro-organisms causing pancreatic infection are common enteric pathogens implies that bacterial translocation from the intestinal tract to the pancreas may have a role in the pathogenesis of infected pancreatic necrosis (62,63,64,65,66,67,68). Lack of enteral feeding results in atrophy of the gastrointestinal mucosa, bacterial overgrowth, increased gut permeability, and translocation of bacteria or bacterial products into the circulation. Total parenteral nutrition may, therefore, promote bacterial translocation in patients with pancreatitis.
Animal studies have shown that the site in the gastrointestinal tract to which feedings are delivered determines to what extent the pancreas is stimulated. Jejunal feedings have been shown to result in negligible increases in enzyme, bicarbonate, and volume output from the pancreas (69,70). This observation has been confirmed in humans (71). It has been suggested that enteral feeding stimulates lysosomal movement to the cell surface, minimizing the intracellular release of pancreatic enzymes and may, in fact, be therapeutic in acute pancreatitis (61). In addition, enteral nutrition reduces production of proinflammatory mediators that may also have therapeutic potential in such patients.
Several studies have now shown jejunal feeding to be not only less expensive than total parenteral nutrition but associated with fewer septic complications, possible modulation of the acute phase response (72,73,74,75,76,77,78), and shorter length of stay (61). Few studies, however, have addressed the potential problems associated with placement of nasojejunal tubes and the resulting delay in initiation of feeding. From studies of enteral feeding in burn patients, it seems that initiating enteral feeding within 48 hours of admission helps to maintain gut function, allowing improved tolerance and fewer problems with ileus and gastric stasis compared with feeding delayed by 4 or 5 days (79,80). In a small case series without controls, Eatock et al. (81) found that nasogastric feeding was well tolerated and did not appear to exacerbate pancreatitis. To confirm this, in the largest study to date of enteral feeding in patients with objectively graded acute pancreatitis, Eatock et al. compared the nasogastric route with the use of the nasojejunal route (82). He found that there was no evidence of exacerbation of disease with the nasogastric route, supporting the use of enteral feeding and challenging the commonly held belief that enteral feedings must be delivered distal to the ligament of Treitz.
Hypocalcemia in acute pancreatitis has many possible causes, including hypoalbuminemia (83) with decreased protein binding, formation of calcium soaps in the presence of fat necrosis (84), stimulation of calcitonin secretion (85) by increased serum glucagons (86), and decreased parathormone secretion by various mechanisms (87), but rarely is there a clinically significant decrease in ionized calcium. If deficits are found, however, calcium and magnesium are easily replaced.
Cardiovascular Collapse, Renal Failure, and Respiratory Insufficiency
One of the most important determinants of poor outcome in severe acute pancreatitis is the early development and persistence of organ dysfunction. Although various scoring systems, biomarkers, and radiologic findings can help identify patients at risk of organ dysfunction, these do not substitute for frequent clinical assessment and monitoring. Several clinical findings including thirst, poor urine output, progressive tachycardia, tachypnea, hypoxemia, agitation, confusion, a rising hematocrit level, and a lack of improvement within the first 48 hours are warning signs of impending severe disease (12). The cornerstone of management in early pancreatitis is fluid resuscitation and close monitoring for early manifestations of organ dysfunction. In addition to the frequent assessment of vital signs, the intravascular volume status should be monitored by means of physical exam and urinary output. Early identification of hypoxemia via either pulse oximetry or arterial blood gas measurement is also paramount.
Hypovolemia is easy to explain as a result of the chemical peritonitis that develops in these patients; the associated increased capillary permeability, relative lymphatic obstruction, and partial splanchnic venous obstruction can account for sequestration of up to 40% of the patient's circulatory plasma volume in just a few hours. Renal insufficiency may be a result of this massive fluid loss. If it is present, the association of renal failure in acute pancreatitis markedly increases the mortality in these patients (88).
Whether or not there is a myocardial depressant factor associated with severe pancreatitis (89), inotropic agents may be required to improve cardiac function if cardiac output remains low despite adequate filling pressures.
The respiratory insufficiency associated with severe pancreatitis is much more complex and is probably a combination of a decrease in functional residual capacity and shunting, which may be related to elevated paralyzed hemidiaphragms, basilar atelectasis, pleural effusion, empyema, pneumonia, micropulmonary emboli, or alveolar collapse secondary to the decrease in pulmonary surfactant, which is degraded by circulating pancreatic enzymes. Respiratory assistance with positive end-expiratory pressure (PEEP) is required until the process resolves and the patient can maintain adequate minute ventilation and oxygenation.
Patients with severe acute pancreatitis who meet conventional criteria should be admitted to the intensive care unit, as well as those patients who are at high risk of rapid deterioration such as the elderly (90), patients requiring ongoing volume resuscitation, those with renal failure, respiratory compromise, and evidence of substantial pancreatic necrosis (greater than 30%) (30). In addition, it has been recognized that morbidly obese patients are at increased risk for developing the severe form of acute pancreatitis. When compared to normal-weight patients, patients with a body mass index (BMI) of greater than or equal to 25 kg/m2 and less than 30 kg/m2 (overweight) or greater than 30 kg/m2 (obese), the number and type of complications increased as the body mass index increased (91) in a study of 250 patients with biliary pancreatitis.
It is not known if the outcome of severe acute pancreatitis is affected by the model of critical care delivery, as there are currently no studies examining this relationship. However, a review of 26 observational studies showed that a heterogenous group of critically ill patients, when cared for by an intensivist or using an intensivist consultant in a closed ICU, had a shorter length of stay and a lower mortality rate than similar patients cared for in units without such staffing patterns (92). It is not clear whether admission of all patients with severe acute pancreatitis to the ICU will result in better outcomes, as this has not been studied. The remaining challenge is the development of a more accurate predictor of organ failure so that patients who truly need intensive care can be admitted to the ICU without delay.
Therapeutic Peritoneal Lavage
Short-term (48–96 hour) therapeutic peritoneal lavage has clearly been demonstrated by Ranson and Spencer (52) to improve the early clinical condition of patients with acute pancreatitis. In their randomized, prospective studies, the mortality rate during the first 10 days decreased from 45% in control subjects to 0% in patients treated with peritoneal lavage. Cardiovascular instability and respiratory insufficiency improved and did not result in early mortality. The overall survival rate, however, was not significantly improved; the cause of death only shifted from cardiovascular and respiratory insufficiency to late infection of devitalized pancreatic and peripancreatic tissue. When compared to short-term lavage, long-term (7-day) peritoneal lavage in severe acute pancreatitis showed a reduction in both the incidence of pancreatic sepsis and its associated mortality rate (93). This therapy, however, is a major undertaking as it involves hourly lavage for at least 7 days with an antibiotic-containing isotonic balanced electrolyte solution.
More recently a meta-analysis of peritoneal lavage for acute pancreatitis was undertaken (94). This study identified eight randomized, prospective clinical trials evaluating the use of continuous lavage in patients with pancreatitis. The duration of lavage ranged from 1 to 12 days. In contrast to the studies referred to above and several uncontrolled prospective and retrospective reviews that almost universally supported its use based on comparisons with historical controls (95,96,97,98,99,100,101,102,103), the results of this study indicate that continuous peritoneal lavage with crystalloid solutions in patients with acute pancreatitis has not been associated with any significant improvement in morbidity or mortality. Despite the inherent limitations, the meta-analysis supported the findings of the individual studies, as none of these found a significant difference in either morbidity or mortality between treatment or control groups.
There are several reasons to explain why continuous lavage may not be of benefit in patients with acute pancreatitis. The presence of large volumes of fluid within the peritoneal cavity may degrade the peritoneal defense mechanisms due to the inability to localize the source of contamination through local fibrinous adhesions between omentum, loops of bowel, and the abdominal wall. The lavage may, in addition, enhance the absorption of inflammatory mediators into the systemic circulation via diaphragmatic stomata (104). The lavage may also potentially remove important local inflammatory mediators and thereby impair peritoneal defense mechanisms (105,106). Last, the peritoneal mesothelial cells are usually lost in association with peritonitis, and their regeneration may be important in the resolution of the inflammation (94). Lavage, with either crystalloid or peritoneal dialysis solutions, has been found to inhibit the rate of mesothelial healing (107).
To improve the efficacy of lavage in pancreatitis, studies have focused on the benefit of adding protease inhibitors to the lavage solution, and in experimental work on animal models of pancreatitis this has been found to improve prognosis (108). Based on the apparent success of this technique, there have been two randomized clinical trials of patients with acute fulminant pancreatitis (109,110). Patients were randomized to receive either lavage containing aprotinin (a protease inhibitor) or standard lavage solution. There was no significant difference in morbidity or mortality in either trial. Aprotinin is currently not available until further safety studies are done.
Despite several early, initially enthusiastic reports, the use of continuous lavage in patients with acute pancreatitis is not supported by the currently available evidence.
Antibiotics
Bacterial infection plays an important role in the course and the management of acute pancreatitis. In the mild, self-limited form of the disease, mortality rates are less than 1% and septic complications are rare. The past decade has seen a considerable increase in our understanding and management of necrotizing pancreatitis. The natural course of severe acute pancreatitis progresses in two phases (111). The first 14 days are characterized by the systemic inflammatory response syndrome as a result of the release of multiple inflammatory mediators. The second phase, beginning roughly 2 weeks after the onset of disease, is dominated by sepsis-related complications resulting from infection of pancreatic necrosis (112,113). In the natural course of the disease, infection of pancreatic necrosis occurs in up to 70% of patients and has become the most important risk factor for death from necrotizing pancreatitis (114,115,116). Several factors have been associated with the infection rate of pancreatic necrosis. It has been demonstrated that the frequency of infected necrosis correlates with the duration of disease. In patients with necrotizing pancreatitis, the proportion of patients with proven infected necrosis at the time of surgery increased from 22% to 24% after the first week to 36% to 55% after the second week and up to 72% after the third week (112,114). The extent of pancreatic necrosis may also be a risk factor for infection. Beger et al. (112) reported the highest infection rates in patients with more than 50% necrosis of the pancreas. This finding is supported by the data of other investigators (117). It appears, therefore, that the presence of a significant amount of necrosis (over 50% on CT scan) may be predictive of severe disease and help identify those patients at risk of developing septic complications.
Among patients with sterile necrotizing pancreatitis, mortality rates of 10% to 15% are reported (118), whereas infected pancreatic necrosis carries with it a mortality rate of up to 50% (62,112,119). Supporting the concept that infection is the major determinant of outcome, it has been demonstrated that in patients with sterile necrosis, the extent of necrosis correlated with the frequency of organ failure, whereas infected necrosis was associated with organ failure regardless of the extent of necrosis (120).
Interest has focused on the prophylactic use of antibiotics to prevent infectious complications and reduce the associated morbidity and mortality. Initial uncontrolled studies using prophylactic antibiotics in acute pancreatitis failed to demonstrate any effect on morbidity or mortality (121,122,123). However, ampicillin, the most commonly used drug in those trials, failed to reach its effective minimum inhibitory concentration (MIC) in normal or necrotic pancreatic tissue (124,125). Further animal and human studies have shown that third-generation cephalosporins, piperacillin, mezlocillin, 4-quinolone, metronidazole, and imipenem can achieve their MIC in pancreatic tissue, whereas, the aminopenicillins, first-generation cephalosporins, and aminoglycosides cannot (126). The choice of antibiotic agent is critical as the agent must have a spectrum of activity against the most commonly encountered organisms found in infected necrosis and must penetrate the pancreas adequately. Buchler et al. (127,128) and Bassi et al. (129) have identified imipenem as the antibiotic agent of first choice because it reached higher pancreatic tissue levels and provided higher bactericidal activity against most of the bacteria present in pancreatic infection compared with other types of antibiotics. In a comparison between meropenem and imipenem, there were no significant differences in septic complications, indication for surgery, or mortality (130), indicating that meropenem is equally effective. The combination of quinolones and metronidazole is not an effective antibiotic prophylaxis (131). Maravi-Poma et al., in a prospective, randomized, multicenter trial (132), compared two imipenem regimens for the prevention of septic complications in patients with severe acute necrotizing pancreatitis. Patients were randomized to receive antibiotic prophylaxis either for 14 days or at least 14 days and as long as major systemic complications of the disease persisted. They found that compared to a 14-day course, longer antibiotic administration in patients with acute necrotizing pancreatitis is not associated with a reduction in the incidence of septic complications of the disease. However, prolonged imipenem administration in patients with persisting systemic complications tends to reduce mortality in acute necrotizing pancreatitis compared to a 14-day regimen.
The issue of prophylactic antibiotics was revisited in a multicenter trial (133) of 74 patients with acute necrotizing pancreatitis diagnosed by computerized tomography. Patients were randomized to intravenous imipenem or no antibiotic prophylaxis. Pancreatic infection was diagnosed either by CT-guided aspiration or culture obtained at laparotomy. Among those receiving prophylactic antibiotics, there was a numeric reduction in local pancreatic infection and in mortality. In addition, there were significantly fewer episodes of sepsis among the prophylactic antibiotic group. In a study randomizing 60 patients with acute necrotizing pancreatitis to either prophylactic cefuroxime or no antibiotic prophylaxis, there was no reduction in local pancreatic infection or sepsis (134). However, there was a significant reduction in mortality in the prophylactic group.
More recently, a prospective single-center trial by Buchler et al. (111) evaluated the role of nonsurgical management, which included the use of early antibiotics, of necrotizing pancreatitis. This study confirmed that the conservative treatment of sterile necrosis using early antibiotics (imipenem–cilastatin) is safe and effective. Of 56 patients with sterile necrosis managed without surgery, only 1 died of acute respiratory distress syndrome not responsive to treatment. This trial also demonstrated an infection rate of 34% in necrotizing pancreatitis treated with early antibiotics, which is lower than prevalence data of up to 70% observed in patients who were not treated with prophylactic antibiotics (112,135,136). Nordback et al. (137) conducted a randomized study to compare the use of early versus delayed imipenem–cilastatin in the treatment of necrotizing pancreatitis. Ninety patients with acute necrotizing pancreatitis were randomized within 48 hours to either early imipenem–cilastatin or control. The primary end point was indication for necrosectomy due to infection. In the control group, imipenem–cilastatin was started when the operative indication was fulfilled. Early imipenem–cilastatin therapy significantly reduced the need for surgery and the overall number of major organ complications in acute necrotizing pancreatitis. Furthermore, the mortality rate was reduced by half. Likewise, a meta-analysis of prophylactic antibiotic administration in acute necrotizing pancreatitis (138) revealed a significant improvement in sepsis and mortality in patients with acute necrotizing pancreatitis receiving antibiotic prophylaxis and a trend toward a reduction in local pancreatic infection.
The bacterial spectrum of infection in acute necrotizing pancreatitis has been described as primarily Gram negative and, in part, anaerobic with the predominant pathogens including Escherichia coli, Pseudomonas species, Enterobacter, Bacteroides, and Proteus (139). Bacterial translocation from the gut has been demonstrated to be the main cause of infection in necrotizing pancreatitis (140,141,142,143). In addition to the safety and efficacy of early antibiotic treatment in necrotizing pancreatitis, a second major finding of Buchler et al. (111) was that early antibiotic treatment of necrotizing pancreatitis changes the spectrum of bacteria in those patients who develop infection. After the administration of antibiotics with primary efficacy against Gram-negative and anaerobic bacteria, more than half of patients who developed pancreatic infection were found to have Gram-positive infection.
Similarly, Howard and Temple (144) compared operative cultures from 61 consecutive patients with pancreatic necrosis treated during routine prophylactic antibiotic use to 34 consecutive patients with necrosis prior to the use of prophylactic antibiotics. They demonstrated a dramatic shift in bacteriology between the two time periods with 56% of isolates being Gram-negative organisms in the control group to only 26% in the antibiotic treatment group. Enterobacter, Pseudomonas, and Proteus made up 38% of the isolates in the control group, but Klebsiella was the predominant Gram-negative isolate in the control group. Enterococcus was found in similar percentages in both groups. But in the antibiotic group, other Gram-positive cocci, including S. epidermidis, S. aureus, and Corynebacterium species, made up 31% of all bacterial isolates. It is likely that these infections do not originate in the gut, but rather, are nosocomial infections acquired via venous catheters, urinary catheters, or endotracheal tubes. The argument that these infections are hospital acquired is supported by the fact that these infections tend to occur much later (typically after 20 days) whereas infections with Gram-negative organisms are seen much sooner, usually within 2 weeks of admission (111).
In addition to a shift from predominantly Gram-negative to Gram-positive organisms, the question arises as to whether antibiotic prophylaxis predisposes patients to fungal infection. De Waele et al. (145) reviewed data from an 8-year period for 46 patients with severe acute pancreatitis and infected pancreatic necrosis to determine the incidence of fungal infection and to identify risk factors for the development of fungal infection. They found an overall incidence for Candida infection of 37% and, excluding patients who received early antifungal prophylaxis, the incidence of Candida infection was as high as 50%, the highest figure ever described (145). Despite the fact that the total duration of antibiotic prophylaxis was very long and multiple types of antibiotics were administered to individual patients, both described as risk factors for the development of Candida infection (146), they failed to identify any risk factor for fungal infection among their patients.
Buchler et al. (111) found an incidence of fungal infection of 29% among patients receiving early antibiotic treatment for necrotizing pancreatitis. However, up to 25% of patients with necrotizing pancreatitis who do not receive antibiotics also develop fungal infection (147,148). Four of the randomized trials on antibiotic prophylaxis included the incidence of fungal superinfection (133,134,149,150). The incidence of fungal infection was below seven percent in three trials (133,134,150), whereas it exceeded 20% in one small study (149). These trials were recently meta-analyzed (131). The fungal infection rate was not different between patients receiving prophylactic antibiotics (4.9%) and those in the control group (6.7%). The conclusion of this meta-analysis was that antibiotic prophylaxis does not result in increased incidence of fungal infections.
Surgical Management
Most episodes of acute pancreatitis are mild and self-limiting, resolving spontaneously within 3 to 5 days. The mortality rate in these patients is less than 1%, and these patients do not routinely require intensive care or surgical management. However, there are several absolute indications for operative intervention in patients with severe acute pancreatitis, including prevention of recurrence and treatment of complications. As the conservative management of infected pancreatic necrosis associated with multiple organ failure has a mortality rate of up to 100% (151), proven infected pancreatic necrosis, as well as septic complications directly resulting from pancreatic infection, are indications for surgical intervention (132).
Treatment of Biliary Pancreatitis
Biliary pancreatitis is most often associated with the passage of a small common bile duct stone. Typically, the highest serum amylase levels may be present initially, but they return to normal, as do the patient's clinical signs and symptoms. Occasionally, a stone may become impacted at the ampulla of Vater. In this case, rapid progressive deterioration of the patient's clinical course may soon follow. For patients with severe acute gallstone pancreatitis, urgent biliary drainage and clearance of the common bile duct must be considered. There is general agreement that open cholecystectomy with supraduodenal bile duct exploration and insertion of a T tube is an unacceptable emergency procedure in patients with severe gallstone pancreatitis, as both higher morbidity and mortality rates have been shown following early surgery (132). There is general consensus that patients with signs and symptoms consistent with cholangitis and patients with severe acute gallstone pancreatitis and obstructive jaundice should undergo urgent endoscopic retrograde cholangiopancreatography (ERCP), and, if choledocholithiasis is confirmed, endoscopic sphincterotomy should be performed (30).
In patients with severe acute pancreatitis due to suspected or proven cholelithiasis but without obstructive jaundice, the role of ERCP and endoscopic sphincterotomy is less well defined. Three trials have examined the role of emergency ERCP and endoscopic sphincterotomy (defined as within 24 hours of admission or 72 hours of onset of symptoms) as compared to conservative management (152) or planned interval ERCP (152,153) in patients with biliary pancreatitis. In all three trials, endoscopic sphincterotomy and stone extraction were performed only if common bile duct stones were identified on ERCP.
Neoptolemos et al. (153) demonstrated significantly lower morbidity rates following emergency ERCP. There was an equal distribution of patients with cholangitis in both treatment groups, and the complication rate was significantly lower after emergency ERCP, even after exclusion of these patients. Patients with biliary obstruction were excluded in the Fölsch et al. (152) trial, and median bilirubin levels were equal in both groups in the Fan et al. (154) trial. These two trials failed to demonstrate significant effects on morbidity and mortality rates.
Both Neoptolemos et al. (153) and Fan et al. (154) evaluated the outcome for severe disease separately. Neither found a significant difference in complication and mortality rates in patients with mild biliary pancreatitis. In contrast, both trials demonstrated a significantly lower complication rate in patients with severe acute pancreatitis, but the difference in mortality rates did not reach statistical significance. Fan et al. (154) also found a decrease in the incidence of biliary sepsis in patients with severe biliary pancreatitis. A recent meta-analysis (30) of the trials of Fan et al. (154), Neoptolemos et al. (153) and Fölsch et al. (152) found that emergency ERCP and endoscopic sphincterotomy significantly reduced the overall complication rate without a significant effect on the mortality rate. Subgroup analyses of patients with mild biliary pancreatitis revealed no differences in overall complications or mortality. In contrast, ERCP significantly reduced both the overall complication and mortality rates in patients with severe biliary pancreatitis. In a meta-analysis of four randomized trials (48,152,153,154) by Sharma and Howden (155), they found a significantly lower morbidity and mortality rate following early ERCP when compared with interval ERCP. However, in this meta-analysis, patients with severe pancreatitis were not examined separately.
ERCP and endoscopic sphincterotomy have no influence on the outcome of mild biliary pancreatitis. Based on lower morbidity and reduced mortality rates, emergency ERCP and endoscopic sphincterotomy should be strongly considered in patients with severe biliary pancreatitis as well as in patients with standard indications for ERCP and endoscopic sphincterotomy such as obstructive jaundice and cholangitis.
Recurrence of acute pancreatitis in patients with cholelithiasis has been reported in 29% to 63% of cases if the patient is discharged from the hospital without additional treatment. The rationale for cholecystectomy and clearance of the common bile duct in these patients is to prevent recurrent biliary pancreatitis. The timing of cholecystectomy, however, depends on the clinical circumstances. In mild gallstone pancreatitis, cholecystectomy should be performed as soon as the patient has recovered from the attack and, preferably, during the same hospital stay. In severe gallstone pancreatitis, cholecystectomy should be performed once the inflammatory process has subsided and with sufficient clinical recovery to make the procedure technically easier and safer for the patient. Although the optimal timing for cholecystectomy is still under debate, if endoscopic sphincterotomy was performed, cholecystectomy should be performed within 6 weeks (156). Cholecystectomy can be performed safely after an episode of gallstone pancreatitis via the laparoscopic approach with a reported conversion to open rate of 0 to 16% (157,158,159).
Vascular Complications
Vascular complications of pancreatitis may be divided into systemic and local. The systemic vascular effects of acute pancreatitis are probably related to the release of pancreatic proteases, such as trypsin, which locally and distally may activate complement C5a and precipitate the coagulation cascade (160). This causes microscopic and physiologic changes in granulocytes that induce a cell-to-cell interaction and clumping. The clumps may then embolize and set the stage for further fibrin deposition and thrombosis. This phenomenon explains the leukoembolic damage of the posterior fundus of the eye in the syndrome of sudden blindness associated with sever trauma and pancreatitis (Purtscher retinopathy) (161). Other systemic effects of C5a may be granulocyte aggregation and leukoembolization of other vital tissues, such as the lung, kidney, and splanchnic and systemic vascular beds, which may explain some of the respiratory distress syndromes, renal insufficiency, splanchnic venous thrombosis, and incidence of pulmonary emboli in these patients (160).
There are both arterial and venous local vascular effects and complications of pancreatitis. Bleeding from pancreatic pseudocysts and ruptured pseudoaneurysms is the most often fatal complication of pancreatitis, carrying a mortality rate of 25% to 40% (162,163,164). Bleeding may present as melena from erosion into the proximal gastrointestinal tract or as hypovolemia and abdominal pain if there is rupture into the peritoneal cavity. Diagnosis is usually made late in the patient's clinical course or only at postmortem examination. Most patients with gastrointestinal tract bleeding secondary to acute or chronic pancreatitis are alcoholics, and the cause of the bleeding is usually missed because of more common causes of serious bleeding in this patient population (i.e., peptic ulcer disease, gastritis, varices, Mallory-Weiss tears). The development of aneurysms is probably related to the severe inflammation and enzymatic autodigestion of the pancreatic and peripancreatic arteries with eventual formation of a pseudoaneurysm. With growth and expansion, the pseudoaneurysms may rupture into pseudocysts, adjacent viscera, the peritoneal cavity, or the pancreatic duct.
The most common vessel involved in splanchnic pseudoaneurysms related to pancreatitis is the splenic artery, followed by the gastroduodenal and the inferior pancreaticoduodenal, but such involvement may occur with any of the adjacent splanchnic vessels (165). Patients with chronic pancreatitis may have as high as a 10% incidence of pseudoaneurysms demonstrated on angiographic studies, but bleeding from these rarely occurs unless they are associated with pseudocysts (166). The treatment of ruptured pseudoaneurysms requires that the diagnosis be recognized; therefore, the clinician must know of it, must have a high index of suspicion, and must have a well-defined diagnostic and therapeutic plan, including emergency upper endoscopy, selective visceral angiography, ultrasonography, and CT scanning. Control can be rendered by either selective arterial infusion of vasopressin (166) or angioembolization with Gelfoam (167), detachable intravascular balloons (168), Gianturco coils (169), or polymerizing adhesives (169). Surgical control is indicated only for immediate life-threatening bleeding or failure of interventional control of bleeding.
Hemoductal pancreatitis or hemosuccus pancreatitis is the complication of pseudoaneurysm rupture into the pancreatic duct and usually encompasses the triad of gastrointestinal bleeding, pancreatitis with epigastric pain, and partial common bile duct obstruction (170). The diagnosis can be confirmed by selective visceral angiography or ERCP. The treatment of this rare complication requires ligation of the pseudoaneurysm and possible pancreatic resection.
Venous complications of acute pancreatitis, although not as dramatic, may be just as lethal as their arterial counterparts. Venous thrombosis of the portal vein is a potential complication of acute or chronic pancreatitis. The patient's course is complicated by acute decompensation, hypotension with sequestration in the vascular bed, acidosis, hepatic enzyme elevation, alteration in clotting studies, and venous infarction of the bowel. Patients who survive this insult all develop portal hypertension, and some present months to years later with bleeding esophageal varices. Selective splenic venous thrombosis occurs more frequently, and patients usually present with an increased spleen size, unexplained blood loss, pain in the left upper quadrant and subscapular area, and possibly, hypotension and cardiovascular collapse because the subscapular hematoma ruptured into the free peritoneal cavity. The treatment is splenectomy with preoperative vascular control by angiographic techniques and balloons.
During drainage procedures for pancreatic pseudocysts in the presence of associated splenic venous thrombosis, the transgastric approach should be avoided to decrease postoperative bleeding from the rich submucosal plexus of high-pressure veins. In the absence of bleeding gastric varices, one may elect to leave the spleen in situ even with splenic vein thrombosis, because not all patients develop bleeding from gastric varices.
Pancreatic Pseudocyst
Peripancreatic fluid collections can occur as a result of acute pancreatitis, chronic pancreatitis, surgery (either pancreatic or other abdominal surgery), trauma, or neoplasia. With the exception of a cystic neoplasm, peripancreatic fluid collections form either as a result of a disruption in the pancreatic ductal system with subsequent fluid leakage or the maturation of peripancreatic necrosis. The terminology for acute pancreatitis and its complications has historically been confusing and often conflicting. The result is a difficulty interpreting literature dealing with treatment of pancreatic pseudocyst as often the term “pseudocyst” was applied when perhaps “acute fluid collection” would have been more appropriate, or vice versa. In response to this confusion, and in an attempt to dispel it, an International Symposium on Acute Pancreatitis was convened in 1992. The result is a standardized classification system (49) of acute pancreatitis and its complications.
According to these published definitions, an acute fluid collection is located in or near the pancreas, occurs early in the course of acute pancreatitis, and always lacks a wall of granulation or fibrous tissue (49). Acute fluid collections are common in patients with severe acute pancreatitis, occurring in up to 50% of cases (171,172). However, more than half of these lesions regress spontaneously (171,172). Rarely on the demonstrable on physical exam and are usually found with imaging techniques. The precise composition of these collections is not known. The critical clinical distinction between an acute fluid collection and a pseudocyst (or pancreatic abscess) is the lack of a defined wall.
Pseudocyst formation is a frequent complication of pancreatitis with a reported incidence of 10% to 20% in acute pancreatitis and 20% to 40% in chronic pancreatitis (173). Formation of an acute pseudocyst requires four or more weeks from the onset of acute pancreatitis. In contrast, chronic pseudocysts have a well-defined wall but arise in patients with chronic pancreatitis without a preceding episode of acute pancreatitis. It is defined as a collection of pancreatic juice that arises as a consequence of acute or chronic pancreatitis or pancreatic trauma that is enclosed by a nonepithelialized wall composed of either fibrous or granulation tissue. Pseudocysts in patients with acute pancreatitis are usually diagnosed with imaging studies, either CT scan or ultrasound, although they are occasionally palpable. The contents are usually rich in pancreatic enzymes and are most often sterile. Bacteria may be present in pseudocysts but often are of no clinical significance since they represent contamination and not clinical infection. When pus is present, the lesion is more correctly termed a pancreatic abscess. The distinction between pancreatic abscess and infected necrosis is critical for two reasons: the mortality risk for infected necrosis is double that for pancreatic abscess (174), and specific therapy for each condition may be markedly different.
The traditional management of pancreatic pseudocyst has been based for decades on a sentinel report by Bradley et al. (175), who studied 93 patients using ultrasound. They found spontaneous resolution of the pseudocyst in 24 of 54 patients studied, but all resolution took place before 6 weeks and was almost exclusively seen in collections less than 6 cm in size. They also found the incidence of complications increased after 6 weeks of follow-up. Thus, standard therapy became treatment if the pseudocyst persisted beyond 6 weeks and/or was larger than 6 cm. With improved imaging techniques, the criteria for intervention eventually were modified to include imaging confirming cyst wall “maturity.” Operative intervention was the mainstay, and the procedure performed was internal drainage via a cyst-enteric anastomosis, primarily cystgastrostomy or cystojejunostomy, depending on the location of the pseudocyst. The morbidity rate ranges from 7% to 37%, and mortality rates vary from 0 to 6% (176,177). The recurrence rate with the operative technique is approximately 10% (178). However, the traditional method of surgical drainage has been challenged by the introduction of less invasive techniques.
Percutaneous drainage was first introduced in the 1970s. Unfortunately, simple aspiration of the cyst has been associated with a recurrence rate of more than 70% and can, therefore, not be regarded as a definitive treatment (179,180). Continuous catheter drainage has shown better short-term results, with an 84% success rate and an average 7% recurrence rate (179,181,182). However, the prolonged presence of an indwelling catheter for several weeks and frequent fistula formation remain disadvantages of this technique.
Endoscopic drainage has been increasingly used during the last 10 years, either via a transpapillary route or through the gastrointestinal wall. The short-term results appear to be encouraging. Analyses of collective data indicate that resolution of cysts can be achieved in nearly 90% of patients, with morbidity rates of 9% to 25% and mortality rates of 0 to 1% (176,183). Data regarding long-term results to this point, however, remain scarce.
The question, then, arises as to which method to use. Nealon and Walser (184) have shown that the anatomy of the main pancreatic duct can be used to guide the choice of modality for treating pancreatic pseudocyst. In patients scheduled for either elective operation or percutaneous drainage of the pseudocyst, they performed endoscopic retrograde cholangiopancreatography 1 day prior to the procedure. They categorized the main pancreatic duct as either normal, normal with stricture, or normal with complete cutoff at some portion of the duct (184). A “normal” duct was meant to represent a duct without evidence of chronic pancreatitis. Patients were segregated for analysis into either normal, stricture with communication to the pseudocyst, stricture without communication, or complete cutoff. They found that pancreatic ductal anatomy correlated well with outcomes in patients treated with percutaneous drainage. Among failures of percutaneous drainage, all patients either had complete cutoff of the pancreatic duct or stricture with communication to the cyst. In either case, percutaneous catheter drainage would have a poor likelihood of success as no amount of long-term drainage could be expected to re-establish normal ductal drainage.
Likewise, determination of ductal anatomy has been used to determine the best route of endoscopic drainage. In a review (173) of 92 consecutive patients who underwent endoscopic drainage of pancreatic pseudocyst, the method was based on visualization of the pancreatic duct. If a connection between the pseudocyst and the pancreatic duct was confirmed, the transpapillary route was preferred and a single stent with multiple side holes was placed in the pancreatic duct, with the distal end of the stent positioned just proximal to the cyst. In all other cases, the transgastric or transduodenal route was chosen, depending on the position of the cyst and its relationship to the gut lumen. The technical success rate of the drainage procedure was 97%, and the mortality rate was 1% (173). Overall, endoscopic drainage was successful in treating the pseudocyst in 71% of patients (173).
It appears, then, that either percutaneous or endoscopic drainage techniques are comparable to the outcome of surgical drainage techniques in the appropriately selected patients. At our institution, patients are routinely treated with either percutaneous or endoscopic drainage, depending on the ductal anatomy, and surgical drainage is reserved for failure or complication of these methods.
Biliary Obstruction Due to Pancreatic Inflammation
Biliary obstruction may be found in as many as 25% of cases presenting with acute pancreatitis (185), and this obstruction, caused by pancreatic swelling, can be confused with a stone lodged at the ampulla. The intrapancreatic portion of the common bile duct becomes involved in the inflammatory process, but this usually resolves over the course of the disease (186). If the biliary obstruction does not resolve, a workup including ultrasonography, ERCP, or transhepatic cholangiography may be necessary to define the problem and the anatomy so that an appropriate decompressive procedure can be performed. If the patient develops cholangitis and becomes septic from infected bile in the obstructed duct, transhepatic cholangiography and drainage may be life-saving to provide decompression without subjecting the patient in septic shock to an emergency operation.
Pancreatic Necrosis, Infected Pancreatic Necrosis, and Abscess
Little is known of what triggers the release of activated pancreatic enzymes that autodigest the gland and surrounding retroperitoneal tissue and convert acute interstitial or edematous pancreatitis to pancreatic necrosis. If venous thrombosis and erosion to the small peripancreatic vessels occur, the combination is hemorrhagic necrotizing pancreatitis. Enteric bacterial contamination results in combined abscess and infected necrosis, which carries the highest mortality rate. The timing of this sequence of presentations in important. It is rare to see septic complications within the first week of presentation but not unusual after the second week, and they are almost universally present if the patient's course requires therapy for more than 3 weeks. Clinical signs of abdominal pain, fever, leukocytosis, associated severe systemic manifestations of hypotension, cardiovascular collapse, pulmonary insufficiency, renal failure, and mental status changes all strongly suggest the onset of this complication. The problem is rarely that of making the diagnosis of sepsis, but rather, of differentiating pancreatic necrosis and abscess formation from other sources of systemic sepsis such as pneumonia, urinary tract infection, and intravascular catheter-related infection.
Sequential contrast-enhanced computerized tomography is the best tool available for diagnosing and following this disease process. The study is diagnostic of abscess formation if air is seen in the phlegmon. Percutaneous fine-needle aspiration of the intrapancreatic or peripancreatic fluid collections can be used to confirm bacterial contamination in the absence of air. If necrosis is demonstrated on CT scan, aspirates are sterile, and the patient is not toxic, a conservative approach may be attempted. At present there is general agreement that surgery for severe pancreatitis should be deferred as long as the patient continues to respond favorably to conservative management. Early operation directed toward debridement of devitalized tissue to prevent septic complications has only led to increased morbidity and incidence of sepsis. Optimal surgical timing should occur, at the minimum, 2 to 3 weeks after the onset of pancreatitis to allow a sequestrum to form. The rationale for delaying surgical therapy is to permit proper demarcation of pancreatic and peripancreatic necrosis to occur, limiting the extent of surgery that is needed to facilitate debridement. This approach decreases the risk of bleeding and minimizes the surgery-related loss of vital tissue that predisposes to endocrine and exocrine pancreatic insufficiency.
In most studies published over the last decade, indication for surgery was defined by necrosis formation on CT scan and positive fine-needle aspiration. In the unstable patient, CT-guided percutaneous aspiration and drainage of pancreatic abscesses used as a temporizing measure before surgery may improve the patient's overall condition. Surgical techniques are still necessary for debridement and drainage if percutaneous drainage does not improve the septic course. The goal of surgery in patients with necrotizing pancreatitis is to remove all areas of necrotic tissue including necrotic pancreatic tissue and any infected necrotic tissue. In so doing, the risk of further complications may be minimized by reducing the progress of spreading necrosis and/or infection and the release of proinflammatory mediators. Resective procedures, such as partial or total pancreatectomy that also remove vital pancreatic tissue and healthy organs, are associated with high mortality rates.
The surgical techniques for the treatment of pancreatic necrosis are varied, and the ideal method is still debated. Generally agreed-on principles of surgical management include an organ-preserving approach that involves debridement or necrosectomy, minimization of intraoperative hemorrhage, and maximization of postoperative removal of retroperitoneal debris and exudate (132). Traditionally, three techniques have been used with comparable results; these include the following: (1) open necrosectomy with closed continuous lavage of the retroperitoneum, (ii) open necrosectomy that may or may not be staged with planned relaparotomies followed by delayed primary closure and drainage or with multiple drainage and relaparotomy as required, and (iii) open necrosectomy, often with marsupialization, with open packing and planned relaparotomies. It is reported that these approaches are associated with a postoperative mortality of less than 15%, but there has never been a trial that has prospectively compared these techniques (132). However, with the improvement in intensive care and success of conservative management, open surgery for infected pancreatic necrosis is becoming less frequent, and many young surgeons have likely never performed these procedures.
Minimal-access surgical approaches have been described in an attempt at reducing the mortality and substantial morbidity of open surgery for infected necrotizing pancreatitis (187). These approaches have used either an endoscopic or a videoscopic retroperitoneal approach for draining infected fluid. Because in most cases, the sequestrum is limited to the lesser sac, minimal-access retroperitoneal techniques have significant limitations for primary debridement. The use of a transperitoneal approach similar to that used for open debridement of necrotic pancreatic and peripancreatic necrosis has been largely anecdotal.
Recently, however, Parekh (187) reported the largest series of laparoscopic debridement for pancreatic necrosis. A hand-assisted laparoscopic (HAL) technique was used for the debridement of necrotizing pancreatitis. Hand-assisted laparoscopic surgery is useful for complex abdominal procedures since the benefits of traditional laparoscopic surgery are retained. In this series, 19 patients underwent laparoscopic evacuation of pancreatic necrosis, and in 18 patients, the procedure was completed. Four patients required reoperations, two using HALs and two open. There were no postoperative complications related to the HAL procedure itself, such as major wound infections, intestinal fistulae, or postoperative hemorrhage. Postoperative computed tomography confirmed adequacy of debridement. Although currently largely limited to a few specialized centers, HALs may provide a new option for the surgical treatment of selected patients with severe necrotizing pancreatitis.
We have become increasingly aggressive in our use of percutaneous debridement of infected pancreatic tissue. Early reports on the use of percutaneous drainage of infected pancreatic tissue were not encouraging. Lee et al. (188) reported a 33% mortality and a failure rate of over 50% with drainage alone. Kam et al. (189) reported three cases where catheter drainage was found to be inadequate and inappropriate. Szentkereszty et al. (190) reported a success rate of only 25% in 12 patients. The poor success rate likely reflects the inability to drain infected tissue and debris with relatively small drains. Van Sonnenberg et al. (191) reported a success rate of 86% when dealing with an abscess and not infected tissue.
In contrast to drainage alone where no debridement is undertaken, we use active debridement and removal of infected tissue at multiple settings. Shonnard et al. (192) reported the use of Nitrol snares for active debridement and removal of pancreatic tissue. Gouzi et al. (193), using lavage techniques, reported a 15% mortality rate and a success rate of 70%. Freeny et al. (194) reported a series of 34 patients. Their success rate was 47% with debridement alone and a mortality rate of 12%. Our group (195) reported an initial experience with 20 patients. We had a 0% mortality and a success rate of 100%. We have recently reviewed our experience, which includes 34 patients divided into two groups: critically ill patients who are intubated in the intensive care unit and stable patients who are on the surgical floor.
The overall mortality was 2.9%, and the success rate was 63%. The success rate was markedly different between the two groups. The critically ill group had a 100% failure rate, and the stable group had a success rate of 83%. Our conclusion was that debridement and lavage is an ineffective form of therapy in the critically ill patient. These results were comparable to those of Freeny et al. (194), who also found that the critically ill patients responded poorly. The technique of debridement varies; however, they generally include the placement of one to five catheters into the pancreatic and peripancreatic areas and the paracolic gutters. These catheters are gradually increased in size up to 16 French. An aggressive irrigation is then performed, and active removal of infected pancreatic tissue is undertaken two to three times per week. The catheters are removed once the drainage becomes minimal and the cavity becomes small. This approach is a slow process and requires an intensive time-consuming approach. This may be one of the reasons of its failure in the critically ill patient. However, when successful, this approach may avoid a major operative debridement.
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