GASTROENTEROLOGY

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OPTIMIZING OUTCOMES IN ACUTE PANCREATITIS

Murray Orbuch, MD

Acute pancreatitis continues to cause signicant morbidity and mortality despite dramatic advances in the understanding of its pathophysiology and its critical care management. The worldwide prevalence of this disease is variable, has been reported to be as high as 79 cases per 100,000, and is increasing for reasons that are not entirely clear [18]. Some studies suggest a high rate of undiagnosed pancreatitis, with approximately 40% of acute cases recognized only at autopsy [3]. Thus, it is imperative for primary and emergency care clinicians to identify those patients who are affected early in the course of pancreatitis to forestall the potential late adverse effects that are responsible for the high mortality rate. Herein lies the challenge. NOMENCLATURE The Atlanta International Symposium on Pancreatitis in 1992 set out to clarify denitions and criteria for acute pancreatitis [9]. Mild acute pancreatitis, accounting for almost 80% of all cases, is characterized by parenchymal interstitial edema of the pancreas, and no worse than minimal distal organ dysfunction. Recovery is usually rapid (measured in days) and any distal organs affected by the acute event quickly return to their baseline function. In severe acute pancreatitis, parenchymal and fat necrosis ensues, as well as profound multi-system organ failure, infection, and life-threatening hemodynamic instability. As with any paradigm for strict denitions in the clinical setting, many patients fall somewhere in between these categories.

From the Division of Gastroenterology, The Mount Sinai School of Medicine, New York, New York ....................................................................................................................................................

CLINICS IN FAMILY PRACTICE Volume 6 Number 3 September 2004

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PATHOPHYSIOLOGY Whatever the implicated cause of acute pancreatitis, the presumed trigger for the panoply of events seems to be an inappropriate activation of trypsin within the pancreatic acinar cells. Ultimate severity of the process is determined by whether endogenous proteolytic enzyme inhibitors can contain this event or if they are overcome and autodigestion of the pancreas ensues. In 80% of cases of acute pancreatitis, the inammation is localized, and little, if any, extrapancreatic involvement is seen. In the remaining 20% of cases, cytokines (including interleukin [IL]-1, IL-6, platelet activating factor, and tumor necrosis factor [TNF]) are released and the process of tissue destruction and inammation extends into the peripancreatic space. These cytokines also initiate distant events by stimulating the migration of macrophages into other abdominal organs, where immunocytes are recruited and the cycle of events is repeated and amplied [1012]. A full-blown systemic inammatory response often can follow these events. CAUSE The causes of acute pancreatitis are diverse and demonstrate changing trends over time and variation by geography (Box 1). Gallstones, biliary sludge and microlithiasis are recognized as the proximate cause in well over half of reported cases in several studies from around the world [8,1321]. Ethyl alcohol ingestion is the second most commonly reported cause of acute pancreatitisaccounting for approximately 30% of casesalthough it is unclear whether alcohol is a toxin or an exacerbating factor in individuals who have compromised pancreatic function [22]. Studies suggest a greater shift toward alcohol as the putative cause and irrespective of the exact pathophysiology, may reect increased alcohol consumption worldwide. Recent work suggests that alcohols effect may be related to the inducement of transient supraphysiologic levels of cholecystokinin that results in intrapancreatic zymogen activation [23,24]. The remaining causes of acute pancreatitis account for less than 15% of total cases by most accounts. Formerly, cases that were labeled as idiopathic pancreatitis numbered up to 10% of the total reported cases; however, recent studies suggest that half of these may be due to unrecognized microlithiasis [2527]. Therefore, it behooves the primary care clinician to investigate this possible cause when all others have been eliminated. Acute pancreatitis was discovered early on as a potential risk from undergoing endoscopic retrograde cholangiopancreatography (ERCP) [28]. A series of studies showed that pancreatitis results from 1% and 40% of procedures; however, a rate of less than 5% is more realistic at most centers [2931]. As expected, the rate of pancreatitis from an ERCP usually is lower when the procedure is performed by an experienced gastroenterologist and when fewer intraprocedure manipulations are used. A

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Box 1. Common Causes of Acute Pancreatitis Gall stones, biliary sludge, microlithiasis ([50% of cases) Ethyl alcohol ingestion (approximately 30% of cases) Remaining causes (approximately 15% of cases) a-1-Antitrypsin deciency Anatomic anomalies in the area of the ampulla of Vater with possible obstruction (Crohns disease, pancreas divisum, sphincter of Oddi dysfunction, choledochal cysts and duodenal diverticula) Hereditary pancreatitis Hypercalcemia/hyperparathyroidism Hypertriglyceridemia (greater than 1000 mg/dL) Iatrogenic (ie, endoscopic retrograde cholangiopancreatography [ERCP]) Idiopathic Infection (eg, viral, bacterial, parasitic, co-infections) Medications Aminosalicylates Angiotensin-converting enzyme inhibitors Angiotensin-2 receptor antagonists Antibiotics (eg, tetracycline, metronidazole, sulfonamides, pentamidine, isoniazid, rifampin) Antipsychotics (eg, clozapine, olanzapine, resperidone) Antiretrovirals Corticosteroids Diuretics (eg, lasix, thiazides) Estrogens Immunosuppressants (eg, cyclosporine, azathioprine) Organophosphate insecticides Valproic acid Mucin-producing tumors Penetrating peptic ulcers Pregnancy Renal failure/renal transplantation Sequelae of instrumentation (ie, ERCP and sphincter of Oddi manometry) Scorpion venom Trauma Vasculitis
Adapted from Levitt MD. Pancreatitis. In: Sleisinger MH, editor. Cecil textbook of medicine, 18th edition. Philadelphia: WB Saunders; 1988. p. 77480.

transient increase in serum amylase is observed more frequently during an ERCP; this generally reects manipulation of the pancreatic duct system rather than frank inammation of the pancreas itself. The ERCP presents the ideal setting in which to test potential cytoprotective agents for the management of acute pancreatitis. Somatostatin analogs and protease inhibitors [3239] have been tried in the clinical setting, but the results have been mixed and a recent meta-analysis failed to show a superior benet for any individual agent [37]. The most promising cytoprotective agents are gabexate (a protease inhibitor) [33,34]

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and octreotide [38], but no conclusive evidence supports the broad use of either drug for post-ERCP pancreatitis or during the rst hours of an acute attack. One study showed no signicant clinical benet to octreotide [39], whereas recent experimental work suggests that octreotide may be deleterious for the management of acute pancreatitis [40]. Infection always has been considered to be a rare potential cause of acute pancreatitis. Recognized viral pathogens include cytomegalovirus, mumps, coxsackie, varicella, herpes simplex, and hepatitis B viruses. Potential bacterial pathogens include leptospira, mycoplasma, salmonella, and Legionella [41]. Ascaris lumbricoides, harbored in the digestive tract of up to 1 billion people across the world, seems to equal gallstones as a potential cause of biliary disease, of which 15% of patients present with acute pancreatitis [42]. In the developed world, this pathogen is more rare but needs to be considered in recent immigrants from endemic areas in southern Asia and Latin America [43]. The ever-increasing prevalence of HIV infection is another potential cause of acute pancreatitis. A combination of factors seems to place the HIV-infected individual at a higher risk for developing acute pancreatitis [44]. In addition to the HIV virus itself as a suspected cause [45,46], the extensive use of antiretrovirals, such as diadanosine, alone [47,48] and in combination with other antiviral agents for the treatment of HIV disease or hepatitis C coinfection, dramatically increases the risks of developing pancreatitis. Pentamidine, which is used commonly in the treatment of Pneumocystis carinii pneumonia, sulfonamides, and rifampin also increase the risk of development of acute pancreatitis. Opportunistic infections, including toxoplasmosis, mycobacterium avium intracellulare, and, possibly, Cryptosporidium, are all suspected as causes of acute pancreatitis as well [44,49].

SIGNS, SYMPTOMS, AND INDICATORS The most common presenting symptom in acute pancreatitis is abdominal pain; it is observed in approximately 95% of affected individuals. The location usually is epigastric and the pain radiates to the back in approximately half of the presenting cases. Typically, the pain is described as being constant and can last from several hours to days. Nausea and vomiting often accompany the pain and an ileus may develop in association with the inammatory process. Additional physical examination ndings also may be present and may correlate with the stage and severity at which the patient presents; these include hemodynamic instability, fever, metabolic derangements, acute renal failure, and ascites. The classically described Cullens sign, a peri-umbilical bluish discoloration, and GrayTurners sign, a bluish discoloration of the anks, are not specic for pancreatitis and are uncommon manifestations [50]. When these physical signs are apparent, it usually has been longer than 48 hours since the acute event and they do not presage any additional mortality risk [50,51].

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Determination of serum pancreatic enzyme measurements is the usual next step when acute pancreatitis is suspected. The most common enzymes that are assayed, amylase and lipase, are released at approximately the same time after the initial insult to the pancreas but are cleared from the bloodstream at different rates. Therefore, relying on total serum amylase alone to make an accurate diagnosis of acute pancreatitis is errorprone, because it is cleared almost totally from the blood within 48 to 72 hours. The sensitivity of pancreatic amylase for the diagnosis of acute pancreatitis decreases to less than 30% between the second and fourth day after the onset of the acute episode [8]. Amylase levels may be elevated in a variety of nonpancreatic conditions; a small bowel obstruction is the most relevant of these when abdominal pain is of an unclear etiology [52,53]. The clearance of pancreatic amylase is diminished with a decline in renal function, and, thus, may cloud the clinical picture even further. By contrast, an elevated serum lipase level can be detected as distant as 14 days after the acute event and has a sensitivity of greater than 90% for acute pancreatitis [8,54,55]. Of the numerous other pancreatic enzymes, proenzymes, activation peptides, and serum markers studied, C-reactive protein (CRP) and urinary trypsinogen activation peptide (uTAP) seem to hold the greatest promise as prognosticators of severe disease [5661]. The CRP assay is inexpensive, readily available, and has at least an 86% sensitivity for acute pancreatitis at 48 hours after presentation; this approximates the Advanced Physiology and Chronic Health Evaluation score, system II (APACHE II) in reliability [51]. A CRP value of 150 mg/L seems to be the pivotal point in the differentiation of mild and severe pancreatitis. A uTAP level at 48 hours of greater than 35 nmol/L provides a similar result to the CRP, but its greatest value may be in its negative predictive value for severe acute pancreatitis at 24 hours [51,62]. Procalcitonin is a newly-recognized marker that indirectly reects pancreatitisassociated endotoxemia and increased gut mucosal permeability [59,60]. DIAGNOSTIC IMAGING Contrast-enhanced CT (CECT) is the most extensively studied modality for the conrmation of acute pancreatitis and provides the highest level of certainty among existing imaging technologies. CECT may not be as readily available to the clinician as ultrasonography, which has the advantages of low-cost, rapid result that requires minimal preparation, and can be performed without the administration of potentially harmful contrast media. Additionally, innovations in technique, hardware, and software (eg, compression scanning, tissue harmonic imaging, Doppler studies of adjoining vessels) provide the experienced radiologist with far more information than the earlier iterations that were used in often-quoted studies that date from the mid 1980s [63]. Limitations in these newer techniques do persist however, including overlying gas (often seen with pancreatitis-related ileus), excessive abdominal fat, and distortions of the skin from scarring or ostomies that can make visualization of the underlying organs less reliable [64]. Pancreatic

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necrosis, intra-abdominal gas, and acute hemorrhage also are poorly visualized with these newer techniques [65]. With this caveat in mind, ultrasonography should be a routine part of the initial evaluation of most patients who have suspected acute pancreatitis because it can provide time-critical information about the biliary tree and its neighboring structures. Studies that used ultrasonography for the evaluation of cholelithiasis and choledocholithiasis reported sensitivities of greater than 95% and 55% to 85%, respectively [63]. CECT may have a lower detection rate for gallstones than ultrasonography because of their isoattenuation with the bile in which they are immersed [66]. Overall, sensitivities using ultrasonography for the diagnosis of acute pancreatitis ranged between 62% and 95% [65] and probably reect the failure to visualize the organ as frequently as 30% of the time in this setting [67,68]. When the pancreas is visualized in the setting of acute disease, tissue abnormalities are detected in 90% of those studied [67,68]. The latest computerized axial tomography technology boasts multidetector scanners that can image the abdomen in less than a minute, provide ultrathin sagittal sections of the abdomen, perform three-dimensional digital image reconstruction, require 30% less contrast medium than scanners of the last decade, and virtually eliminate any potential motion or breathing artifact. With this technology, visualization of the pancreas is assured and the sensitivity for detecting pancreatic necrosis is greater than 90% [65,69,70]. The degree to which the pancreas enhances with contrast seems to be related inversely to the severity of the acute event. Therefore, the absence of enhancement of more than 50% of the pancreas (hence, necrosis) on the arterial phase of the bolus contrast infusion correlates well with a severe case of acute pancreatitis [11], whereas failure to enhance less than 30% of the pancreas correlates well with mild cases of pancreatitis [71]. The sensitivity for detecting severe pancreatitis over several studies exceeds 94%, but decreases to 80% for moderately severe acute pancreatitis. The milder the disease presentation, the less likely it is that abnormalities will manifest that are detectable on CT examination. The qualitative improvement in CT scanning led a group of investigators at the New York University Medical Center to formulate a severity grading system that is based on imaging alone; this is known as the CT Severity Index (CTSI) [72] (Table 1). Some concern has been raised about the potential deleterious effect of intravenous (IV) contrast on an evolving case of acute pancreatitis through its impairment of pancreatic microcirculation that was described rst in animal studies in the early 1990s [73]. Since then, retrospective human studies have shown conicting results; although the acute setting should not preclude its use, it does raise a cautionary note against haphazard imaging, particularly in suspected mild cases [7476]. MRI and magnetic resonance cholangiopancreatography (MRCP) are two newer modalities that have their specic, yet limited, place in diagnosing acute pancreatitis. In contrast to CT imaging, MRI is more likely to uncover mild disease but the technology has serious limitations [77]. MRI requires longer scanning times that necessitate breath-holding for often

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TABLE 1. Computerized Tomography Severity Index Grade Normal pancreas Pancreatic enlargement Inammation of the pancreas or peripancreatic fat Single peripancreatic uid collection Two or more uid collections or retroperitoneal air To which the following scores are added: Degree of Pancreatic Necrosis None <30% 3050% >50% A B C D E Score 0 1 2 3 4

0 2 4 6

Adapted from Balthazar EJ, Robinson DL, Megibow AJ, et al. Acute pancreatitis: value of CT in establishing prognosis. Radiology 1990;174:297306.

uncomfortable periods of time within cramped spaces; this limits its applicability in critically ill individuals. This modality is of particular use in patients who have allergic reactions to iodinated IV contrast, impaired renal function or are pregnant and in others who wish to avoid ionizing radiation. It is superior at detecting gallstone disease [78] and detailing anatomic anomalies, including pancreas divisum [77,79], complex pseudocysts, and neoplasms than conventional CT imaging. Ultimately, MRCP may supplant ERCP as the primary diagnostic modality of the biliary tree because of its superior precision in revealing irregularities of the pancreatic duct system. A recent innovation, secretin infusion, further enhances the smallest branches of the pancreatic ductal system by stimulating secretion into the network and will have applicability in the evaluation of chronic pancreatitis [77]. MRI should be reserved for individuals in whom CT scanning is contraindicated and when mild acute pancreatitis is suspected. GAUGING SEVERITY Since the nineteenth century, clinicians have sought to identify markers of severity as early as possible after the onset of recognizable pancreatic disease [80]. The reasons for this are self- evident; with an overall mortality rate in the hospital setting of approximately 10%, a mortality rate of up to 25% in older patients, and an average hospital stay that ranged from 40 to 226 days in one United Kingdom study [12], the direct and indirect costs of acute pancreatitis are staggering. Over the past

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quarter-century, several grading schemes have been devised with the hope of identifying the most vulnerable patients in the rst 48 hours of disease. These paradigms include the Ransons criteria (Box 2) the modied Glasgow criteria (Table 2), and the APACHE II scoring system (Table 3). Ranson and colleagues [81] rst proposed a system to determine prognosis in acute pancreatitis that relied on 5 initial prognosticators at initial evaluation and 13 factors at re-evaluation 48 hours later. This scoring system only proved useful at identifying the patients at the margins. Fewer than three positive signs at 48 hours predicted a mortality of less than 1%, whereas more than six positive signs corresponded with a 100% mortality rate [82]. Less denitive at an accurate diagnosis and prognosis were scores of 4, which reected a mortality rate of 15%, and scores of 5 to 6, which reected a mortality rate of 40% [82]. Years later, the modied Glasgow criteria [82] aimed to reduce the total number of measured values of the Ranson scale, yet the end result was the same; useful predictions of mortality only could be arrived at after a period of 48 hours, not at admission, and at a positive predictive value averaged approximately 50% [51]. Again, this diagnostic paradigm was of little value in predicting outcomes in intermediate-scoring cases. The APACHE and subsequent APACHE II scoring criteria were developed in the early 1980s as a physiologically-based grading system for

Box 2. Ransons Criteria At initial presentation: Age older than 55 years White blood cell (WBC) count greater than 16,000/mm3 Lactase dehydrogenase (LDH) greater than 350 IU/L Aspartate aminotransferase (AST) greater than 250 IU/L Glucose greater than 200 mg/dL (no diabetic history) At 48 hours: Age older than 55 years WBC count greater than 15,000/mm3 Glucose greater than 180 mg/dL (with no diabetic history) Blood urea nitrogen (BUN) greater than 16 mmol/L (no response to IV uids) BUN increase of more than 5 mg/dL PaO2 less than 60 mm Hg Calcium less than 8 mg/dL Hematocrit decrease of more than 10% Base decit of greater than 4 mEq/L Fluid sequestration of more than 6 L Albumin less than 3.2 gm/dL LDH greater than 600 units/L AST or alanine aminotransferase greater than 200 units/L
Adapted from Ranson JH, Rifkind KM, Roses DF, et al. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynaecol Obstet 1974;139: 6981.

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TABLE 2. Modied Glasgow Scoring System (at 48 Hours) Laboratory Test WBC count AST LDH Albumin Glucose BUN Serum calcium PaO2 Measurement > > > < > > < < 15,000/mm3 200 lm/L 600 U/L 3.2 g/dL 10 mmol/L 16 mmol/L 2.0 mmol/L 60 mm Hg

Adapted from Ranson JH. Etiologic and prognostic factors in human acute pancreatitis: a review. Am J Gastroenterol 1982;77:6338; with permission.

general disease assessment upon hospital admission; later they were applied to the case of acute pancreatitis [83]. The APACHE II scoring system relies on 12 variables; each is graded from 0 to 4 depending upon its variation from a mean normal value. When prospectively studied, the APACHE II criteria could predict the severity of pancreatitis accurately at admission in only 60% of cases [84] and had a negative predictive value of greater than 90% [51]; thus, it was better at identifying mild disease at admission. The advantage of this grading scheme is fact that assessments can be made at 24-hour intervals and used as an indicator of worsening severity, which proves to be helpful in deciding whether intensive care monitoring is appropriate. With all of these carefully measured efforts, the overall success at prediction of mortality from acute pancreatitis at hospital admission remains at 40%, and even at 48 hours it is no better than 80% when all of the above diagnostic strategies are compared [12]. In 1990, Balthazar and colleagues [72] formulated a grading system for diagnosing acute pancreatitis based on CT ndings that incorporate the absence, presence, and extent of uid collection (original Balthazars classication) and the degree of pancreatic necrosis [72]. This system, the CTSI, is graded from 0 to 10 (Table 1). In the initial study, a CTSI grade of 3 or less was associated with morbidity (dened as distal organ dysfunction or failure)/mortality rates of 8% and 3% respectively, whereas a grade of 7 or greater was associated with morbidity/mortality rates of 92% and 17%, respectively. INDEPENDENT RISK FACTORS Clinical assessment alone has proven to be wholly unreliable as a prognostic strategy for the diagnosis of acute pancreatitis. Although the aforementioned scoring systems have their appeal and are most reliable when applied to groups, rather than individual patients, they are most useful in predicting outcomes only after 48 hours. Despite this fact, three

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TABLE 3. APACHE II Scoring System Variables Score Temperature(C) Mean arterial pressure (mm Hg) Heart rate Respiratory rate Oxygenationa Arterial pH (if none, use bicarbonate) Serum sodium Serum creatinine Hematocrit (%) White blood cell count Glasgow coma scaleb Bicarbonate (use if no arterial pH) 4 41 160 180 50 500 7.7 180 7 60 40 15-GCS <52 3 3940.9 130159 140179 3549 350499 7.67.69 160179 6.06.9 2 110129 110139 2534 200349 7.57.59 155159 5059.9 2039.9 4151.9 150154 5.55.9 4649.9 1519.9 3240.9 1 38.538.9 0 36.038.4 70109 70109 12 to 24 <200 7.337.49 130149 3.55.4 3045.9 3.014.9 2231.9 1 34.035.9 2 32.033.9 5069 5569 6 to 9 7.257.32 3.03.4 120129 2.52.9 2029.9 1.02.9 1821.9 3 30.031.9 4054 7.157.24 111119 4 29.9 49 39 5 <7.15 110 2.5 <20 <1
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10 to 11

1517.9

<15

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Total of above 12 parameters = A Age (B) is factored in as follows: Age (y) Points < 44 0 4554 2 5564 3 6574 5 > 75 6 Chronic Health Points (C) are calculated as follows: Liver Cirrhosis or encephalopathy Cardiovascular Class IV angina Pulmonary Chronic hypoxemia, CO2 retention Renal Dialysis dependence Immune status Immune-compromised state If any of one these is present, 5 points are awarded. Sum of A + B + C is the total APACHE II score.
a b

Refers to A-aDO2 or PaO2: If FIO2 > 0.5, use A-aDO2; if FIO2 < 0.5, use PaO2. Score based on Glasgow Coma Scale (GCS) parameter is derived from the formula 15 minus the GCS total (eg, 15 GCS score of 12 = 3 points). Abbreviations: A-aDO2, alveolar-to-arterial gradient; FIO2, fraction of inspired oxygen.

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clinical ndings have been identied as showing good correlation to the severity of disease. The presence of a pleural effusion or pulmonary inltrate and elevation of serum creatinine to greater than 2 gm/dL within the rst 24 hours after the diagnosis of acute pancreatitis suggest a more vigorous inammatory response that presages a less favorable outcome [85]. Secondly, obesity has emerged as an independent risk factor that correlates to the severity of acute pancreatitis [86,87]. A body mass index (BMI) of at least 30 kg/m2 seems to impart a greater risk for the development of local and systemic complications independent of other concurrent illnesses. It is postulated that the presence of large fat deposits in the peri-pancreatic and retroperitoneal spaces presents an opportunity for local disease extension and necrosis. Bolstering this idea is a recent study that suggested that android fat distribution, that is characterized by an increased waist-to-hip ratio, is of greater risk for severity of disease in men and women [88]. Aside from the richer reservoir for potential necrosis, the obese state is accompanied by a proinammatory condition that is reected in elevated TNF-a levels in men and women and IL-6 levels in men; an enhanced inammatory response may lead to severe acute pancreatitis [89]. Lastly, hemoconcentration on presentation is another recognized risk factor to be considered in the assessment of severity of acute pancreatitis. A hematocrit of at least 44% was associated with a greater likelihood of progression to distal organ dysfunction and pancreatic necrosis [90]. A subsequent study disputed its predictive value; however, it was shown that its absence had a signicant negative predictive value for severe acute pancreatitis and may serve as a tool with which to decide if a costly (and potentially risk-laden) CECT is warranted [91].

RISK ASSESSMENT AND MANAGEMENT The appropriate management of acute pancreatitis requires much more than an algorithm followed to a denable conclusion, simply because no algorithm exists. Survival, therefore, depends on a multi-disciplinary approach, fastidious monitoring, and exibility in reassessment of the patient. The most comprehensive work on the subject to date, The Guidelines of the Management of Acute Pancreatitis [8], compiled at the behest of the World Congress of Gastroenterology, presents an excellent strategy for the care of these patients. The approach that was recommended by the investigators for the initial assessment and triage for severity of disease depends on many of the indicators that were discussed earlier: Evidence of distal organ compromise (eg, renal, pulmonary, hepatic, or cardiovascular) Evidence of a pleural effusion or pulmonary inltrate BMI greater than 30 kg/m2 Failure to visualize more than 30% of the pancreas on CECT

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APACHE II score that is greater than 8 First or second episode of acute pancreatitis If a preponderance of these indicators is present at the initial evaluation (an APACHE II score of 8 or greater at admission or at 48 hours may alone sufce [51]), management in an intensive care setting is the prudent course. Even in apparently mild cases (approximately 80% of all patients who are diagnosed with acute pancreatitis), close monitoring is recommended for the rst 48 hours because the full extent of severity may be late to manifest. Reassessment at 24 and 48 hours should include a careful clinical assessment, the use of Ransons criteria, the modied Glasgow scoring system, or the APACHE II scoring system, as well as serum amylase, lipase, and CRP assays. After an accurate diagnosis of acute pancreatitis has been established, the immediate concerns of necessary uid resuscitation and the correction of electrolyte and glycemic derangements take priority. Considerable third-spacing of uids can ensue with profound, life-threatening intravascular volume depletion that is not necessarily reective of the severity of the pancreatitis. Evidence suggests that although uid resuscitation may not forestall progression to greater severity, persistent hemoconcentration at 24 hours is associated with progression to pancreatic necrosis [92]. Oxygen saturation also must be monitored carefully; although respiratory involvement of acute pancreatitis is common, few cases progress to the acute respiratory distress syndrome. Obtaining a chest radiograph is recommended as a part of the initial evaluation, as is an arterial blood gas when hypoxemia is suspected. An adynamic ileus may present with signicant abdominal distention and a conrmatory plain radiograph abdominal series should be performed with placement of a nasogastric tube for decompression as indicated. Urine output should be followed and is an early indicator of declining renal function. Oral alimentation and hydration customarily is withheld for at least the rst 48 to 72 hours until objective clinical improvement is realized and abdominal pain has dissipated. Pain control is addressed best early in the course of acute pancreatitis, generally with the use of narcotic analgesia, and, often, in the form of a patient-controlled anesthesia pump [8]. Meperidine (demerol) is the narcotic agent of choice for pain control in the management of acute pancreatitis. Conventional wisdom holds that morphine is to be avoided because it can precipitate sphincter of Oddi spasm and can worsen the pancreatitis. In its place, demerol was recommended initially [93], but because of common adverse side effects, other costlier options for narcotic analgesia are becoming more widely used, including hydromorphone (dilaudid). No actual data exist to show that morphine or its derivatives may precipitate sphincter of Oddi spasm, except for animal studies that demonstrated delayed bile ow after administration of morphine [93,94]. Manometric studies have shown that all opiates, including meperidine, increase the amplitude and frequency of phasic waves measured at the sphincter of Oddi. This nding has failed to correlate with any statistically

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signicant increase in sphincter of Oddi mean basal pressure [95]. Furthermore, meperidine holds a greater risk for lowering the seizure threshold along with an increased likelihood for development of dependence when administered in higher dosages, whereas morphine is a longerlasting preparation [93]. Radiographic imaging is the next course of action in the risk assessment of acute pancreatitis. The use of ultrasound radiography, particularly when biliary disease is suspected, can direct intervention or suggest other imaging modalities in a timely fashion. If this modality proves to be inconclusive, CECT should be the next step in risk assessment, but only if rapid clinical improvement is not observed within the rst 72 hours after presentation or initial improvement is followed by a rapid deterioration. Follow-up imaging 7 days after the initial study generally is reserved for patients who score higher than 3 on the CTSI scale [72]. A second scan always should be performed in these instances because pseudocyst or pseudoaneurysm formation can occur independently of the objectively improved clinical scenario. The use of MRI and MRCP in the setting of acute pancreatitis is evolving; the latter ultimately may have a greater role in the diagnosis of cases of acute biliary pancreatitis (ABP) [8]. If ABP is established or seriously suspected, despite equivocal radiologic ndings, the physician can avail himself of two denitive therapeutic options: ERCP and cholecystectomy. If the pancreatitis is of mild severity, the gallstones are identied readily; if the patient is of a low surgical risk, an early cholecystectomy is the procedure of choice. In more severe cases of acute pancreatitis, it is preferable to defer surgery until the inammatory response signicantly subsides and the patients hemodynamic and nutritional status improves [9699]. Whether the surgery should be performed immediately after an ERCP or with intraoperative biliary imaging remains a point of contention. Early ERCP with endoscopic sphincterotomy is recommended when demonstrable biliary obstruction or dilatation is found, when cholangitis is suspected, or in patients in whom the surgical risks are deemed unacceptable, as in the elderly or individuals who have serious comorbidities [8]. Endoscopic sphincterotomy at the time of ERCP dramatically reduces the risk of further episodes of pancreatitis and may be an acceptable therapeutic end-point in the elderly and other patients in whom cholecystectomy is not feasible [100102]. This procedure does not, however, eliminate the chances of acute cholecystitis; therefore, cholecystectomy should be advised when the patient is hemodynamically stable enough to tolerate the procedure [8,102]. A small subset of patients who has acute pancreatitis fails to demonstrate complete clinical resolution weeks after the acute attack despite careful observation and supportive care. Known as smoldering pancreatitis [103], this condition is characterized by chronically elevated serum amylase and lipase and recurrent abdominal pain after oral feeding is reintroduced. Frequently, the cause is elusive but it is believed to relate to persistent local inammation within the pancreas that prevents adequate drainage of the pancreatic duct system. In this setting, deployment

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of a pancreatic duct stent by way of ERCP left intact for up to 4 weeks often results in the rapid resolution of symptoms and may reduce the likelihood of progression to irreversible pancreatic parenchymal damage and chronic pancreatitis.

MANAGEMENT CONSIDERATIONS IN SEVERE ACUTE PANCREATITIS Severe acute pancreatitis accounts for approximately 20% of all cases. In this group, the mortality rate is in excess of 20% [8] and can reach 40 to 70% if infected necrosis supervenes [68,104,105]. Acute pancreatitis may progress to two additional conditions in the continuum of severity. The rst, systemic inammatory response syndrome (SIRS), is recognized by the presence of at least two of the following criteria [8,106]: Temperature less than 36C or greater than 38C Heart rate greater than 90 beats/min Respiratory rate greater than 20 breaths/min PaCO2 less than 32 White blood cell (WBC) count less than 4000 or greater than 12,000/mm3 Immature neutrophil count greater than 10% The second condition, known as multiorgan dysfunction syndrome (MODS), is most often is the proximate cause death during the early course of events, typically during the 7 to 14 days after diagnosis. This syndrome includes the criteria for SIRS and more than one distal organ dysfunction or failure (typically renal, pulmonary, adrenal, or hepatic) and may include disseminated intravascular coagulation, hypotension, and encephalopathy [6,68]. Patients who have severely dened pancreatitis and MODS have a mortality rate that approaches 50%, despite the best intensive care. Treatment of these patients consists of supportive measures; experimental therapeutics, including secretory inhibitors, platelet activation factor inhibitors, and antiproteases have yet to demonstrate proven benet in large-scale studies [8]. Adequate and proper nutrition is integral toward moderating and improving survival in severe cases of acute pancreatitis. The intense inammatory state that is associated with pancreatitis imposes a taxing catabolic state upon the patient and must be addressed by nutritional support no later than 4 days after diagnosis [8]. In mild cases of acute pancreatitis, oral alimentation usually can begin within 2 to 3 days after presentation, presuming the resolution of pain. Care must be taken, even in mild cases, to observe for deterioration that is related to the premature restarting of oral feeds that usually manifests as a recurrence of epigastric abdominal pain or vomiting. In cases of moderate to severe pancreatitis, the options for management include an endoscopically-placed nasojejunal tube, a laparoscopically-placed jejunal tube, and total parenteral nutrition (TPN). The goal of each option is to provide the patient with necessary

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caloric requirements reecting a moderate to severely stressed physiologic state without stimulating the pancreas. Enteral feeding carries the advantage of lower overall cost and helps to maintain gut mucosal integrity by direct delivery of nutrients. Despite long-held beliefs to the contrary, early enteral feeding that uses a jejunal feeding tube can be initiated with few untoward effects [107,108] and may reduce objectively-measured markers of pancreatic inammation [109]. Fewer infectious complications, metabolic derangements, and lower morbidity and mortality rates also are reported with the use of enteral nutrition as compared with TPN [68]. The primary disadvantages of using the nasojejunal tubes are potential for proximal migration of the tube and the potential for pancreatic stimulation. Both enteral feeding options are contraindicated when a severe ileus is present, thus necessitating TPN. Antibiotic prophylaxis was proven to reduce dramatically the likelihood of infected pancreatic necrosisthe most common cause of death in the later phase of the necro-inammatory process; typically, it occurs in the second to third week after diagnosis. Broad-spectrum antibiotics with good penetration into pancreatic tissue should be started after pancreatic necrosis is demonstrated on CT evaluation. Imipenem is the agent of choice for prophylaxis, but cefuroxime and the quinolones also are used widely [110113]. If evidence of infection is seen on the initial CT evaluation or follow-up scan a week later, a ne needle aspiration (FNA) under CT guidance should be performed for conrmation of infection, followed by surgical debridement. Surgical therapy comes into play for a variety of sequelae of acute pancreatitis, but initially is important in the management of pancreatic necrosis. Much information has been written about sterile necrosis [68]. With the accepted use of broad-spectrum antibiotics early in the course of the inammatory process, there has been a greater willingness to manage this complication conservatively [114116]. There is some evidence to suggest that attempts at debridement of the areas of necrosis may convert a sterile area to an infected necrosis [117]. Therefore, surgical debridement of sterile necrosis should be performed only when absolutely necessary, such as in cases of intractable pain or MODS and sepsis despite the sterile FNA, and only if the collection becomes more organized, generally up to 4 weeks after the acute presentation [102]. In the most straightforward situations, organized necrosis is debrided and the capsule is anastomosed to the stomach or the jejunum. Often, more extensive surgery may be required because of widespread necrosis that extends to the bowel, its mesentery, and retroperitoneal fat. Infected necrosis is seen in approximately one third of patients in whom necrosis is detected on CECT. Usually a later event, infected necrosis typically is observed after the second week following diagnosis. Escherichia coli, Klebsiella pneumonia, and Enterococcus spp are identied as the offending organisms in 75% of cases; usually, the remainder is attributable to Staphylococcus spp, Pseudomonas spp, Streptococcus spp, Proteus mirabilis, and various anaerobes [118]. Fungal infections have been observed with increasing frequency as the use of broad-spectrum

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antibiotics for prophylaxis has become the standard of therapy. Limiting prophylaxis to no more than 7 to 10 days may reduce the likelihood for secondary fungal infections [68]. Surgery, namely an organ-preserving necrosectomy with a cholecystectomy, is performed laparoscopically or by way of an open abdominal approach, depending upon the expertise that is available at the facility and the patients body habitus [102]. This procedure may not sufce for adequate therapy and a right hemicolectomy may be necessary when the transverse colon is compromised. Daily peritoneal lavage through indwelling drains is routine for as long as 1 month after the initial procedure; re-exploration of the abdomen is required frequently. Mortality rates associated with this procedure are reported to be as high as 20% [68]. A recent proposal for conservative management with long-term antibiotics of a select few patients who develop infected necrosis and remain otherwise stable is provocative, but requires further study [116]. For the primary care physician, several late complications of acute pancreatitis must be surveyed closely because they may present weeks after recovery from the initial presentation. These potential complications include: Pseudocyst formation Fistula formation between pseudocysts and the gut Persistent pancreatic ascites because of a disrupted pancreatic duct system Communication with the peritoneal cavity Pancreatic abscess formation Mesenteric venous thrombosis Arterial pseudoaneurysm Pseudocysts form in approximately 5% of cases of acute pancreatitis [8,12], communicate with the pancreatic duct in 80% of cases, can take up to 6 weeks to completely mature, and have a wall that is devoid of an epithelial layer. After they develop, serial imaging studies are performed to follow them because up to 50% spontaneously regress and require no further intervention [119]. Of the remainder of the pseudocysts, drainage becomes an issue only when the enlarging pseudocyst compresses adjoining structures or causes abdominal pain. Therapeutic options include the stenting of a leaking pancreatic duct that feeds the collection (if one is detected) and internal drainage by stenting or a surgical anastomosis to the stomach or jejunum. Pancreatic duct stenting was shown to help resolve late-occurring pancreatic ascites [120,121], whereas treatment of a pancreatic abscess can be accomplished by internal or external drainage. SUMMARY In maximizing the odds for surviving acute pancreatitis, the clinician needs to be cognizant of the shortcomings of existing diagnostic tools and paradigms while appreciating the dynamic nature of the illness. With that

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in mind, several management points should be considered when confronted with a case of suspected pancreatitis. Physical examination and measurement of serum amylase and lipase are notoriously unreliable and represent a mere snapshot in time. The use of newer serum markers at the time of suspected diagnosis, such as uTAP, CRP, and procalcitonin, may add to the task of severity stratication, but are not universally available or of fully proven value. Judicious use of imaging, when indicated, can point quickly to a readily correctable cause of acute pancreatitis, but often has risks and limitations. Various grading schemes have improved severity assessment, but at best, are reliable only 48 hours after diagnosis. Vigilance is essential after the diagnosis of acute pancreatitis is made and must be accompanied by a readiness to transfer the patient to an intensive care setting when parameters change adversely. The use of the APACHE II scoring system often meets with resistance because of its complexity, but in truth, the variables that make up the system are ones that are measured readily. The availability of therapeutic ERCP has reduced the dependence on emergency surgery in cases of acute biliary pancreatitis and a better understanding of the natural history of sterile necrosis, combined with the use of antibiotic prophylaxis, has decreased this reliance further. The appreciation that nutrition plays a greater role than was understood previously in the survival of this profoundly catabolic state led to its reintroduction earlier in the course of illness. The safety of enteral nutrition by way of a jejunal feeding tube (bypassing potential pancreatic stimulation) seems to be established and carries a lower complication rate and cost compared with TPN.

Key Points Serum markers of acute pancreatitis have high sensitivities and specicities, but have no usefulness in predicting the severity or course of diseaseEvidence Level B. Various imaging techniques, including CECT, MRI, and MRCP help to aid in the diagnosis of acute pancreatitis, but each has signicant limitations, risks, and costsEvidence Level B. The overall success at prediction of mortality from acute pancreatitis at hospital admission remains at 40%, and even at 48 hours is no better than 80% when all diagnostic strategies of morbidity and mortality prediction are comparedEvidence Level B. Referral to a gastroenterologist or surgeon in a severe case of acute pancreatitis should be considered early in the course of disease to minimize the risk of potential complicationsEvidence Level C. Nutritional status and maintenance should be considered early in the course of acute pancreatitis to minimize morbidity and mortality riskEvidence Level B.

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