- Email: [email protected]
Acute pancreatitis
GI EMERGENCIES
Acute pancreatitis
What’s new?
Robin NB Baddeley C
James RA Skipworth Stephen P Pereira
C
C
Abstract Acute pancreatitis is an inflammatory condition with a variable clinical course. Diagnosis is based upon clinical presentation, laboratory indices and imaging studies, whilst illness severity can be assessed by clinical scoring systems, such as the Ranson, Glasgow or APACHE II criteria, or by radiological assessments such as the CT severity index. Most patients develop self-limiting disease. However, a minority progress to a severe form with both local and systemic complications. Management is usually non-operative with interventional therapy reserved for those with common bile duct stones or complications such as pancreatic abscess and pseudocyst formation. This article will review the pathophysiology, assessment and treatment of acute pancreatitis, the evidence for nutritional support and the use of antibiotics, and the indications for and timing of interventional therapy.
Antibiotic use e antibiotics should be reserved for patients with confirmed infected pancreatic necrosis Nutrition strategies e early enteral feeding is preferred over total parental nutrition as it results in a reduced incidence of infection, length of hospital stay and mortality Minimally-invasive surgical approaches are emerging as an effective treatment for infected pancreatic necrosis
necrosis. Acute pancreatitis remains a challenging condition to manage, with a significant burden of morbidity, mortality and financial cost.
Pathophysiology The pathophysiology of acute pancreatitis remains poorly understood. A predisposing insult (e.g. gallstones, alcohol, trauma) (Table 1) results in premature and inappropriate activation of pancreatic enzymes. The initial step is thought to occur within the pancreatic acinar cells where trypsinogen is converted to active trypsin, triggering a cascade of further digestive enzyme activation
Keywords acute; antibiotics; complications; management; nutrition; pancreatitis; severity
Causes of acute pancreatitis C
Acute pancreatitis is an inflammatory condition with a clinical course that varies from mild to severe. Mild disease is often selflimiting and inflammation resolves with simple medical management. However, a minority of patients (up to 20%) will develop severe disease that carries substantial morbidity and mortality. The incidence of acute pancreatitis continues to increase and has doubled since the 1960s,1 rising noticeably in women under 35 years of age in line with changing patterns of alcohol consumption.2 In the UK, there are 150e420 clinically diagnosed cases of acute pancreatitis per million population per year.1 The mortality resulting from acute pancreatitis has remained largely unchanged (approximately 10%) since the 1970s.1 Acute pancreatitis is associated with two distinct phases of mortality e early, secondary to organ failure resulting from the systemic inflammatory response syndrome (SIRS); and late, related to super-infection of pancreatic
C C C C C
C C C
C C
Drugs Common Azathioprine 6-Mercaptopurine Didanosine Valproic acid Oestrogens Furosemide Pentamidine Sulphonamides Tetracycline Tamoxifen
Robin NB Baddeley BSc(Hons) is a final year medical student at the University of Sheffield, Sheffield, UK. Competing interests: none declared. James RA Skipworth MBBS BSc(Hons) MRCS is the inaugural ‘Jason Boas’ Hepatopancreaticobiliary Fellow at the UCL Division of Surgery and Interventional Science, University College London, London, UK. Competing interests: none declared. Stephen P Pereira MBBS BSc(Hons) PhD FRCP is a Reader in Hepatology and Gastroenterology at University College London, London, UK. Competing interests: none declared.
MEDICINE 39:2
Alcohol Cholelithiasis, microlithiasis, choledocholithiasis Post-endoscopic retrograde cholangiopancreatography Hypertriglyceridaemia, Hypercalcaemia Autoimmune pancreatitis Pancreatic ductal obstruction: pancreatic cancer, sphincter of Oddi dysfunction, pancreas divisum, periampullary tumours, ascariasis Genetic: hereditary pancreatitis, cystic fibrosis Viral infection: coxsackie, mumps, HIV, adenovirus Ischaemia: intra-abdominal surgery, coronary artery bypass surgery, embolism, vasculitis Venom: spider, scorpion Idiopathic (<10%)
Less common Corticosteroids Aminosalicylates Metronidazole l-asparaginase ACE* inhibitors
*
Angiotensin-converting enzyme.
Table 1
108
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
Mild acute pancreatitis Pancreatitis without the presence of SIRS, organ failure, parenchymal necrosis or other acute complications can be classified as mild disease. It is often referred to as interstitial or oedematous pancreatitis and generally improves within 48e72 h following institution of conservative measures.
and resulting in cellular damage with consequent gland autodigestion (Figure 1). Damaged cells leak activated enzymes into the surrounding tissues, propagating the autodigestive process, as well as releasing inflammatory mediators, such as cytokines and macrophages, into the systemic circulation. The ensuing SIRS is characterized by hypovolaemia, hyperdynamic circulation, capillary leak and fluid loss into the third space. The pancreatic vascular changes that follow are disproportionate to reductions in cardiac output as each anatomic lobule is supplied by a single, end vessel;3 these lead to pancreatic ischaemic damage, and ultimately necrosis, if the disease is severe or prolonged. Alcohol can amplify the inflammatory response independently.4 Early in the course of disease (1e14 days), SIRS may lead to failure of the primary organs, including the lungs (acute respiratory distress syndrome), kidneys (acute renal failure) and liver (hepatic decompensation). The presence of persistent SIRS, or SIRS coupled with infection (sepsis), may lead in turn to the multiple organ dysfunction syndrome (MODS). MODS typically occurs 3e4 weeks after the onset of severe acute pancreatitis and accounts for some of the late deaths.
Severe acute pancreatitis Early disease: the revised Atlanta Classification (2008) suggests that severity during the early phase of the disease should be based upon clinical evaluations, with radiological assessments of severity becoming more crucial later in the course of the disease.6 The development of severe acute pancreatitis can be predicted in the first 48 h of the disease, using the following criteria: 1. a score of 3 or more on Ranson’s criteria (Table 2) 2. a score of 8 or more on APACHE II (acute physiology and chronic health evaluation II) 3. the presence of SIRS 4. developing organ failure. Patients are classified as having severe, early disease upon the development of organ failure that persists for over 48 h duration. The revised Atlanta classification suggests that standardized assessments of organ dysfunction, such as the Marshall scoring system or sequential organ failure assessment (SOFA) score (see Tables 3a and 3b), be used for this purpose, as they are universally applicable and can be repeated on a daily basis for evaluation of progress.
Definition and classification The Atlanta classification system defines acute pancreatitis as an acute inflammatory process of the pancreas, with variable involvement of regional tissues or remote organ systems.5 The system categorizes acute pancreatitis into mild and severe disease, as outlined below.
Late disease: during the later phase of acute pancreatitis, radiological evaluation can aid assessment of severity, with severe disease based upon: 1. the presence of pancreatic peripancreatic necrosis 2. local complications of pseudocyst or abscess.
Pathogenesis of acute pancreatitis
Diagnosis
Trypsinogen → Trypsin
A diagnosis of acute pancreatitis is based upon the presence of two of the following three features (as per the revised Atlanta Classification, 2008)6: abdominal pain characteristic of acute pancreatitis serum amylase and/or lipase 3 times the upper limit of normal characteristic findings of acute pancreatitis on ultrasonography or on computed tomography (CT) for those patients in whom it is clinically indicated (Figure 2).
Positive feedback loop Cascade of enzyme activation
Pancreatic damage/ autodigestion
Clinical presentation
Systemic inflammatory response syndrome
The condition is characterized by the presence of acute and constant pain in the upper abdomen7 (Table 4). Pain may last for several days, radiate to the back, and be associated with nausea and vomiting. Jaundice (resulting from biliary obstruction), tachycardia, fever, hypovolaemia (due to vomiting and third space fluid losses) and small bowel ileus, may also be present. In mild disease, tenderness in the upper abdomen on palpation may be the only finding. In severe disease, exudates from pancreatic necrotic areas tracking along the falciform ligament and into the retroperitoneum can be seen as ecchymosis in the periumbilical region (Cullen’s sign) and the flanks (Grey-Turner’s
Fluid loss and vascular alterations
MODS, multiple organ dysfunction syndrome.
Organ failure and MODS
Figure 1
MEDICINE 39:2
109
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
Table 2
sign).8 Extension of inflammatory exudates from the peripancreatic region to the diaphragm may result in shallow respiration.
insufficiency (e.g. chronic pancreatitis, cystic fibrosis and diabetes mellitus), falsely low in the context of hypertriglyceridaemia, and raised in those with impaired renal clearance.10
Laboratory markers of diagnosis Clinical presentation can vary widely, and enzymes derived from pancreatic acinar cells have therefore been used as biochemical markers to confirm a diagnosis of acute pancreatitis.
Serum lipase Serum lipase has been reported to have a higher sensitivity and specificity for the diagnosis of acute pancreatitis than serum amylase. In a prospective study of 253 patients with acute abdominal pain, a serum lipase of twice the upper limit of the reference range had a sensitivity of 94% and a specificity of 95% for the diagnosis of acute pancreatitis one day after pain onset, compared to 71% and 98% for a serum amylase of twice the upper limit of the reference range.11 Serum lipase may remain elevated
Serum amylase A raised concentration of serum amylase, at least three times the upper limit of the reference range, supports a diagnosis of acute pancreatitis. The concentration usually rises within the first 12 h after the onset of symptoms and returns to normal within 3e5 days.9 However, it may be normal in patients with pancreatic
The Marshall scoring system for evaluation of organ failure Score System Respiratory PO2/FIO2 Renal serum creatinine (mmol/l) Cardiovascular systolic BP (mmHg)
0
1
2
3
4
>400 134 >90
301e400 134e169 <90 Fluid responsive
201e300 170e310 <90 Not fluid responsive
101e200 311e439 <90 pH <7.3
101 >439 <90 pH <7.2
Table 3a
MEDICINE 39:2
110
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
The SOFA scoring system for evaluation of organ failure SOFA score Respiration PaO2/FIO2 Coagulation: Plts (103/mm3) Hepatic: Bilirubin (mmol/L) Cardiovascular: BP
0 >400 >150 20 No hypotension
1 400 150 20e32 MAP <70 mmHg
2 300 100 33e101 Dopamine 5 or dobutamine (any)
CNS: Glasgow coma score Renal: Creatinine (mmol/L) or urine output
15
13e14
10e12
110
110e170
171e299
3 200 50 102e204 Dopamine >5 or norepinephrine 0.1 or epinephrine 0.1 6e9
4 100 20 204 Dopamine >15 or norepinephrine >0.1 or epinephrine >0.1 <6
300e400 or UO<500 ml/day
>440 or UO <200 ml/day
Table 3b
and detectable for up to 14 days, thereby giving greater sensitivity than serum amylase in patients with a delayed presentation. Falsely high concentrations are seen in intra-abdominal pathology and renal insufficiency. Where available, lipase is preferred over amylase for the diagnosis of acute pancreatitis.12
patients with severe acute pancreatitis reported that a CRP >81 mg/l and white cell count (WCC) >13 109/l were markers for super-infection of pancreatic necrosis; if both indices were below these thresholds, the predicted infection risk was only 1.4%.16
Serum trypsinogen-2 Trypsinogen-2 is a pro-enzyme that can be released in high quantities during acute pancreatitis and is measured using a simple serum immunofluorometric assay or urine dipstick at the bedside. It has a reported sensitivity and specificity of 86e100% for the diagnosis of acute pancreatitis.13
Haematocrit Reduction of intravascular volume owing to extravasation of fluid into the third space can lead to a raised serum haematocrit. In a meta-analysis of 399 patients presenting with acute pancreatitis, a serum haematocrit above 44 mg/dl was one of the three most sensitive predictors of overall severity in acute pancreatitis (the other two being raised body mass index and pleural effusion).17
Serum ALT In the context of a clinical diagnosis of acute pancreatitis, a serum alanine aminotransferase (ALT) activity of >150 IU/l has a positive predictive value of 95% for gallstone aetiology, although only half of the patients with gallstone-induced acute pancreatitis will present with high ALT values.14
Other potential markers A number of other potential laboratory markers of severity of acute pancreatitis or predictors of pancreatic necrosis are under investigation but are not yet established in clinical practice. These include IL-6 and IL-8;18 serum procalcitonin;19 and polymorphonuclear elastase.20
Laboratory markers of severity C-reactive protein (CRP) Serum CRP is useful in predicting acute pancreatitis severity and infection: in a study of 50 patients, a CRP of 150 mg/l at 36 h had a sensitivity of 86% and a specificity of 87% for the development of severe acute pancreatitis.15 Another study of 90
Assessment of disease severity Identification of patients at risk for severe disease early in the course of acute pancreatitis is an important step to guiding management and improving outcome. A number of prognostic
CT appearances of: a a normal pancreatic head; b mild oedematous acute pancreatitis, and c severe acute pancreatitis, with non-enhancing pancreatic parenchyma and acute fluid collection. Figure 2
MEDICINE 39:2
111
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
Body mass index Obesity adversely influences the severity of acute pancreatitis, although the pathogenic mechanisms remain poorly understood. A meta-analysis of 739 patients showed that the risk of severe acute pancreatitis, local and systemic complications, and mortality were significantly more common in obese patients with a body mass index >30 kg/m2.23
Differential diagnosis of acute pancreatitis C C C C C C C
Inferior myocardial ischaemia Peptic ulcer disease Symptomatic gallbladder stones Mesenteric ischaemia Small bowel obstruction Dissecting aortic aneurysm Macroamylasaemia
Imaging studies Ultrasonography (US): transabdominal US can be used as an early test to document the presence of gallbladder stones and bile duct dilatation, with a false negative rate of 20e40% for the detection of common bile duct stones, particularly in patients with a high body mass index or those with overlying air-filled bowel loops.24
Table 4
scoring systems have been developed (Table 3), including Ranson’s criteria and the Glasgow (Imrie) score. APACHE II assesses 12 physiologic a variables, age and chronic health status at admission and at 48 h. A systematic review of 13 studies showed APACHE II to have a sensitivity of 65e81% and specificity of 77e91% for the prediction of mortality from acute pancreatitis.21 Scoring systems to assess multiple organ dysfunction, such as the SOFA score and Marshall scoring system (see Tables 3a and 3b), have also been developed.
Computed tomography: contrast-enhanced CT is the imaging procedure of choice if clinical and biochemical findings are inconclusive, or to investigate the possibility of an alternative abdominal emergency.12 It is also used to document the extent of pancreatic and extrapancreatic acute fluid collections, and to detect pancreatic necrosis. However, in a prospective multi-centre study of 166 patients with a clinically established diagnosis of acute pancreatitis, the yield of early CT (within 4 days of symptom onset) was low and did not lead to changes in clinical management.25
BISAP (Bedside index for severity in acute pancreatitis) The BISAP score is a simple prognostic tool where a composite score of 0e5 is assigned within 24 h of presentation, based on five variables (Table 5). A prospective study of 185 patients demonstrated that BISAP was equivalent to other scoring systems in the classification of patients with acute pancreatitis into mild and severe groups (AUC ¼ 81), with the advantage of early assessment.22
CT severity index: (CTSI; score 0e10) is based upon the presence and degree of pancreatic inflammation and necrosis seen at CT (Table 6). In a prospective study of 185 patients with acute pancreatitis, a CTSI <2 was associated with severe disease or death in 7% and 0%, respectively, whereas in patients with a CTSI >3, these figures rose to 51% and 9% respectively.22 Magnetic resonance imaging (MRI) accurately depicts pancreatic and biliary duct disruption, and avoids the risks associated with
The bedside index for severity in acute pancreatitis (BISAP) scoring system Point
CT severity index
Individual components of the BISAP scoring system BUN >25 mg/dl Impaired mental status (Glasgow coma scale score <15) SIRS defined as two or more of the following: C Temperature <36 or >38 C C Respiratory rate >20 breaths/min or P CO a 2 <32 mmHg C Pulse >90 beats/min 3 C WBC <4,000 or >12,000 cells/mm or >10% immature bands Age >60 years Pleural effusion detected on imaging
CT severity index (time not specified) (A) Normal pancreas (B) Pancreatic enlargement (oedema) (C) Pancreatic inflammation and/or peripancreatic changes (D) Single peripancreatic fluid collection (E) Two or more fluid collections and/or retroperitoneal air (AeE are exclusive) Plus Necrosis (% of pancreatic parenchyma) 0% <30% 30e50% >50% Total Minimum score 0, Maximum Score 10
A prognostic scoring system for early identification of patients at risk for in-hospital mortality. One point is assigned for each variable within 24h of presentation and added for a composite score of 0e5. BISAP, bedside index for severity in acute pancreatitis; BUN, blood urea nitrogen; SIRS, systemic inflammatory response syndrome. Adapted from Papachristou et al 2010.22
3 4 Add 0 2 4 6
Modified from Papachristou et al, 2010.22
Table 5
MEDICINE 39:2
Points 0 1 2
Table 6
112
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
radiation exposure. It has been shown to be comparable to CT in the assessment of disease severity: in one study of 101 patients with acute pancreatitis, non-enhanced MRI had a sensitivity of 79% and a specificity of 92% for the development of severe disease, using contrast-enhanced CT as the gold standard.26 However, MRI was superior to CT in the detection of pancreatic haemorrhage, which was a poor prognostic sign in this cohort.
Complications of severe acute pancreatitis Local Pancreatic necrosis C Sterile C Infected Pancreatic pseudocyst Pancreatic abscess Pancreatic haemorrhage Retroperitoneal/localized fat necrosis
Clinical course The majority (around 85%) of patients develop a self-limiting, mild, oedematous-interstitial pancreatitis. This mild disease is associated with minimal organ dysfunction, and usually resolves with conservative management.27 However, around 15% of patients will develop severe disease, characterized by pancreatic necrosis, distant organ failure, acute fluid collections and later pseudocyst formation (Tables 7 and 8). Approximately one-third of these patients develop super-infection of pancreatic tissue, which carries a 30% mortality rate (compared with 12% in sterile necrosis).27 Early deaths (within the first 2 weeks) are usually a result of organ failure; deaths after this interval are generally caused by sepsis associated with infected necrosis or other complications of sterile necrosis.
Systemic Paralytic ileus Pulmonary effusions and ascites Adult respiratory distress syndrome Shock Acute renal failure Hypocalcaemia Disseminated intravascular coagulation
Table 8
present, early endoscopic retrograde cholangiopancreatography (ERCP) sphincterotomy or duct drainage with stenting, should be considered.12,29 The diagnosis of gallstone-induced acute pancreatitis should prompt cholecystectomy in the recovery phase of pancreatitis, ideally before hospital discharge.30 If severe disease is present, this intervention should be delayed until signs of lung injury and systemic disturbance have resolved.12
Management
Nutrition Nutritional deterioration is common in acute pancreatitis, and occurs secondary to reduced intake in combination with systemic catabolism resulting from SIRS. Enteral nutrition can be administered via nasojejunal or nasogastric catheters and should be instituted as early as safely possible to provide nutritional support and reduce the risk of infective complications, length of hospital stay and mortality.31 However, in certain circumstances, such as duodenal outlet obstruction or paralytic ileus, parenteral nutrition may be required. Currently, there is little evidence to support the use of probiotics, prokinetics, immunonutrition or anti-oxidant supplementation in acute pancreatitis.32 In a trial of probiotic prophylaxis in 296 patients with predicted severe acute pancreatitis, the use of probiotics increased mortality within the first 90 days (6% vs. 16%, p ¼ 0.01), predominantly as a result of bowel ischaemia.33
Mild acute pancreatitis Mild acute pancreatitis usually resolves with supportive care: oxygen administration, ensuring adequate hydration and pain control, and the investigation and treatment of any reversible or treatable aetiology. Severe acute pancreatitis The management of severe acute pancreatitis requires a multidisciplinary approach (Table 9). Patients with severe acute pancreatitis should be managed in a high dependency unit or intensive therapy unit.12 Priorities include stabilization of haemodynamic status sufficient to maintain a mean blood pressure of 65 mmHg and a urine volume of 0.5 mL/kg/h; oxygen therapy; clear fluids only (initially); and adequate pain control.28 If cholestasis is
Predictors of a severe attack of acute pancreatitis Initial assessment
24 h after admission
48 h after admission
Clinical impression of severity Body mass index >30 kg/m2 Pleural effusion on chest radiograph APACHE II score 8 Haematocrit >44 mg/dl Clinical impression of severity APACHE II score 8 BISAP score 3 Clinical impression of severity Glasgow score 3 Ranson score 3 C-reactive protein >150 mg/dl Multiple or progressive organ failure
Treatment strategies for a successful outcome in severe acute pancreatitis 1. Resuscitation 2. Assessment of disease severity with the aid of scoring systems 3. Identification and early triage of severe acute pancreatitis patients to HDU/ITU for closer monitoring 4. Early imaging in patients where disease has been prolonged before presentation, or risk of pancreatic/peripancreatic complications 5. Identification and treatment of aetiology 6. Early introduction of enteral nutrition 7. Anticipation of complications with appropriate interventions Table 9
Table 7
MEDICINE 39:2
113
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
Antibiotics Infectious complications account for 80% of deaths from severe acute pancreatitis, as well as the majority of late complications. However, there remains little evidence to support the use of prophylactic antibiotics in the prevention of infected necrosis, either at presentation or once necrosis is confirmed. Carbapenems remain the antibiotics of choice, but whereas prophylactic imipenem may reduce pancreatic infection rates, it has not been shown to alter mortality.31 Thus, antibiotics should be reserved for treatment of confirmed, infected necrosis.12
consisting of percutaneous drainage followed, if necessary, by minimally-invasive retroperitoneal necrosectomy may reduce the rate of major complications, as compared to primary open necrosectomy.45
Novel therapies There are few specific therapeutic strategies for the treatment of acute pancreatitis. Various novel therapies are under investigation although studies to date remain limited. A systematic review of 22 studies found insufficient data to support using anti-oxidants alone or in combination with conventional therapy in the management of acute pancreatitis or post-ERCP pancreatitis.46A
Specific therapies Chemoprevention of post-ERCP pancreatitis The potential role of various chemopreventative agents in the prevention of acute pancreatitis, the most common complication following ERCP, has been evaluated in a number of welldesigned clinical trials. A meta-analysis of six randomized controlled trials concluded that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the rate of post-ERCP pancreatitis.34 Somatostatin, a suppressor of pancreatic secretion, administered for 12 h (starting from 30 min before ERCP) may reduce rates of post-ERCP pancreatitis,35 although these results were not corroborated by meta-analysis.36 Similarly, meta-analyses of the protease inhibitors, gabexate36 and octreotide,37 did not reveal convincing results as to their efficacy and there also remains limited evidence for the use of allopurinol,38 corticosteroids,39 N-acetylcysteine40 and mitogen-activated protein kinase inhibitor.41
REFERENCES 1 Goldacre MJ, Roberts SE. Hospital admission for acute pancreatitis in an English population, 1963e98: database study of incidence and mortality. BMJ 2004; 328: 1466e9. 2 Roberts SE, Williams JG, Meddings D, Goldacre MJ. Incidence and case fatality for acute pancreatitis in England: geographical variation, social deprivation, alcohol consumption and aetiology e a record linkage study. Aliment Pharmacol Ther 2008; 28: 931e41. 3 Juvonen PO, Tenhunen JJ, Heino AA, et al. Splanchnic tissue perfusion in acute experimental pancreatitis. Scand J Gastroenterol 1999; 34: 308e14. 4 Szabo G, Mandrekar P, Oak S, Mayerle J. Effect of ethanol on inflammatory responses. Implications for pancreatitis. Pancreatology 2007; 7: 115e23. 5 Bradley EL. A clinically based classification-system for acutepancreatitis e summary of the international-symposium on acutepancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg 1993; 128: 586e90. 6 Acute Pancreatitis Classification Working Group: revision of the Atlanta Classification of Acute Pancreatitis (3rd revision based on worldwide review/suggestions). 2008. 7 Kemppainen E, Puolakkainen P, Leppaniemi A, Hietaranta A, Gronroos J, Haapiainen R. Diagnosis of acute pancreatitis. Ann Chir Gynaecol 1998; 87: 191e4. 8 Frossard JL, Steer ML, Pastor CM. Acute pancreatitis. Lancet 2008; 371: 143e52. 9 Smotkin J, Tenner S. Laboratory diagnostic tests in acute pancreatitis. J Clin Gastroenterol 2002; 34: 459e62. 10 Yadav D, Agarwal N, Pitchumoni CS. A critical evaluation of laboratory tests in acute pancreatitis. Am J Gastroenterol 2002; 97: 1309e18. 11 Keim V, Teich N, Fiedler F, Hartig W, Thiele G, Mossner J. A comparison of lipase and amylase in the diagnosis of acute pancreatitis in patients with abdominal pain. Pancreas 1998; 16: 45e9. 12 UK guidelines for the management of acute pancreatitis. Gut 2005; 54(suppl 3): iii1e9. 13 Andersen AM, Novovic S, Ersboll AK, Jorgensen LN, Hansen MB. Urinary trypsinogen-2 dipstick in acute pancreatitis. Pancreas 2010; 39: 26e30. 14 Johnson CD. ABC of the upper gastrointestinal tract. Upper abdominal pain: gall bladder. BMJ 2001; 323: 1170e3. 15 Pongprasobchai S, Jianjaroonwong V, Charatcharoenwitthaya P, et al. Erythrocyte sedimentation rate and c-reactive protein for the prediction of severity of acute pancreatitis. Pancreas 2010; 39: 1226e30.
Treatment of complications Pancreatic necrosis is characterized by focal or diffuse areas of non-viable or dead pancreatic parenchyma, often associated with peripancreatic fat necrosis. In severe pancreatitis, bacteria can translocate from the gut to infect necrotic pancreatic tissue, often during the second or third week following initial diagnosis. Sterile necrosis: the distinction between sterile and infected necrosis is crucial as patients with infected necrosis often follow a different natural history and prognosis, but can be clinically difficult as the presence of SIRS in sterile necrosis can closely mimic sepsis. Patients with sterile necrosis are best managed conservatively, as mortality rates are significantly higher in patients who undergo surgical intervention.42 Infected necrosis: patients with infected pancreatic necrosis can be managed with the appropriate use of antibiotics and radiological drains42 but surgical intervention should be considered in those who develop worsening sepsis syndrome or fail to improve following institution of these simpler measures. Ideally, surgical debridement of necrotic tissue (necrosectomy), should be delayed until the necrosis has demarcated:43 a carefullyplanned single laparotomy, with postoperative lavage, has been associated with lower rates of mortality, bleeding and fistula development as compared to procedures incorporating openpacking techniques.42 Other studies have demonstrated that peritoneal lavage, with or without anti-proteases, has no significant benefit.44 However, the results of a large multi-centre study demonstrated that a minimally-invasive, step-up approach,
MEDICINE 39:2
114
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
16 Dambrauskas Z, Gulbinas A, Pundzius J, Barauskas G. Value of routine clinical tests in predicting the development of infected pancreatic necrosis in severe acute pancreatitis. Scand J Gastroenterol 2007; 42: 1256e64. 17 Brown A, James-Stevenson T, Dyson T, Grunkenmeier D. The panc 3 score: a rapid and accurate test for predicting severity on presentation in acute pancreatitis. J Clin Gastroenterol 2007; 41: 855e8. 18 Aoun E, Chen J, Reighard D, Gleeson FC, Whitcomb DC, Papachristou GI. Diagnostic accuracy of interleukin-6 and interleukin8 in predicting severe acute pancreatitis: a meta-analysis. Pancreatology 2009; 9: 777e85. 19 Mofidi R, Suttie SA, Patil PV, Ogston S, Parks RW. The value of procalcitonin at predicting the severity of acute pancreatitis and development of infected pancreatic necrosis: systematic review. Surgery 2009; 146: 72e81. 20 Dominguez-Munoz JE, Villanueva A, Larino J, et al. Accuracy of plasma levels of polymorphonuclear elastase as early prognostic marker of acute pancreatitis in routine clinical conditions. Eur J Gastroenterol Hepatol 2006; 18: 79e83. 21 Gravante G, Garcea G, Ong SL, et al. Prediction of mortality in acute pancreatitis: a systematic review of the published evidence. Pancreatology 2009; 9: 601e14. 22 Papachristou GI, Muddana V, Yadav D, et al. Comparison of BISAP, Ranson’s, APACHE-II, and CTSI scores in predicting organ failure, complications, and mortality in acute pancreatitis. Am J Gastroenterol 2010; 105: 435e41. quiz 42. 23 Martinez J, Johnson CD, Sanchez-Paya J, de Madaria E, Robles-Diaz G, Perez-Mateo M. Obesity is a definitive risk factor of severity and mortality in acute pancreatitis: an updated meta-analysis. Pancreatology 2006; 6: 206e9. 24 Dong B, Chen M. Improved sonographic visualization of choledocholithiasis. J Clin Ultrasound 1987; 15: 185e90. 25 Spanier BW, Nio Y, van der Hulst RW, Tuynman HA, Dijkgraaf MG, Bruno MJ. Practice and yield of early CT scan in acute pancreatitis: a Dutch observational multicenter study. Pancreatology 2010; 10: 222e8. 26 Stimac D, Miletic D, Radic M, et al. The role of nonenhanced magnetic resonance imaging in the early assessment of acute pancreatitis. Am J Gastroenterol 2007; 102: 997e1004. 27 Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006; 101: 2379e400. 28 Wada K, Takada T, Hirata K, et al. Treatment strategy for acute pancreatitis. J Hepato-Bil-Pan Sci 2010; 17: 79e86. 29 van Santvoort HC, Besselink MG, de Vries AC, et al. Early endoscopic retrograde cholangiopancreatography in predicted severe acute biliary pancreatitis: a prospective multicenter study. Ann Surg 2009; 250: 68e75. 30 Kimura Y, Arata S, Takada T, et al. Gallstone-induced acute pancreatitis. J Hepato-Bil-Pan Sci 2010; 17: 60e9. 31 NICE. Alcohol-use disorders: diagnosis and clinical management of alcohol-related physical complications [Clinical guideline CG100]. London: National Institute for Health and Clinical Excellence, 2010.
MEDICINE 39:2
32 Al Samaraee A, McCallum IJ, Coyne PE, Seymour K. Nutritional strategies in severe acute pancreatitis: a systematic review of the evidence. Surgeon 2010; 8: 105e10. 33 Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371: 651e9. 34 Dai HF, Wang XW, Zhao K. Role of nonsteroidal anti-inflammatory drugs in the prevention of post-ERCP pancreatitis: a meta-analysis. Hepatobiliary Pancreat Dis Int 2009; 8: 11e16. 35 Lee KT, Lee DH, Yoo BM. The prophylactic effect of somatostatin on post-therapeutic endoscopic retrograde cholangiopancreatography pancreatitis: a randomized, multicenter controlled trial. Pancreas 2008; 37: 445e8. 36 Andriulli A, Leandro G, Federici T, et al. Prophylactic administration of somatostatin or gabexate does not prevent pancreatitis after ERCP: an updated meta-analysis. Gastrointest Endosc 2007; 65: 624e32. 37 Bai Y, Gao J, Zou DW, Li ZS. Prophylactic octreotide administration does not prevent post-endoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis of randomized controlled trials. Pancreas 2008; 37: 241e6. 38 Bai Y, Gao J, Zhang W, Zou D, Li Z. Meta-analysis: allopurinol in the prevention of postendoscopic retrograde cholangiopancreatography pancreatitis. Aliment Pharmacol Ther 2008; 28: 557e64. 39 Zheng MH, Bai JL, Yuan BS, et al. Meta-analysis of prophylactic corticosteroid use in post-ERCP pancreatitis. BMC Gastroenterol 2008; 8. 40 Milewski J, Rydzewska G, Degowska M, Kierzkiewicz M, Rydzewski A. N-acetylcysteine does not prevent post-endoscopic retrograde cholangiopancreatography hyperamylasemia and acute pancreatitis. World J Gastroenterol 2006; 12: 3751e5. 41 van Westerloo DJ, Rauws EA, Hommes D, et al. Pre-ERCP infusion of semapimod, a mitogen-activated protein kinases inhibitor, lowers post-ERCP hyperamylasemia but not pancreatitis incidence. Gastrointest Endosc 2008; 68: 246e54. 42 Heinrich S, Schafer M, Rousson V, Clavien PA. Evidence-based treatment of acute pancreatitis: a look at established paradigms. Ann Surg 2006; 243: 154e68. 43 Rodriguez JR, Razo AS, Targarona J, et al. Debridement and closed packing for sterile or infected necrotizing pancreatitis e insights into indications and outcomes in 167 patients. Ann Surg 2008; 247: 294e9. 44 Dong Z, Petrov MS, Xu J, Shanbhag S, Windsor JA, Pang S. Peritoneal lavage for severe acute pancreatitis: a systematic review of randomised trials. World J Surg 2010; 34: 2103e8. 45 van Santvoort HC, Besselink MG, Bakker OJ, et al. A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med 2010; 362: 1491e502. 46 Mohseni Salehi Monfared SS, Vahidi H, Abdolghaffari AH, Nikfar S, Abdollahi M. Antioxidant therapy in the management of acute, chronic and post-ERCP pancreatitis: a systematic review. World J Gastroenterol 2009; 15: 4481e90.
115
Ó 2010 Elsevier Ltd. All rights reserved.
Acute pancreatitis
What’s new?
Robin NB Baddeley C
James RA Skipworth Stephen P Pereira
C
C
Abstract Acute pancreatitis is an inflammatory condition with a variable clinical course. Diagnosis is based upon clinical presentation, laboratory indices and imaging studies, whilst illness severity can be assessed by clinical scoring systems, such as the Ranson, Glasgow or APACHE II criteria, or by radiological assessments such as the CT severity index. Most patients develop self-limiting disease. However, a minority progress to a severe form with both local and systemic complications. Management is usually non-operative with interventional therapy reserved for those with common bile duct stones or complications such as pancreatic abscess and pseudocyst formation. This article will review the pathophysiology, assessment and treatment of acute pancreatitis, the evidence for nutritional support and the use of antibiotics, and the indications for and timing of interventional therapy.
Antibiotic use e antibiotics should be reserved for patients with confirmed infected pancreatic necrosis Nutrition strategies e early enteral feeding is preferred over total parental nutrition as it results in a reduced incidence of infection, length of hospital stay and mortality Minimally-invasive surgical approaches are emerging as an effective treatment for infected pancreatic necrosis
necrosis. Acute pancreatitis remains a challenging condition to manage, with a significant burden of morbidity, mortality and financial cost.
Pathophysiology The pathophysiology of acute pancreatitis remains poorly understood. A predisposing insult (e.g. gallstones, alcohol, trauma) (Table 1) results in premature and inappropriate activation of pancreatic enzymes. The initial step is thought to occur within the pancreatic acinar cells where trypsinogen is converted to active trypsin, triggering a cascade of further digestive enzyme activation
Keywords acute; antibiotics; complications; management; nutrition; pancreatitis; severity
Causes of acute pancreatitis C
Acute pancreatitis is an inflammatory condition with a clinical course that varies from mild to severe. Mild disease is often selflimiting and inflammation resolves with simple medical management. However, a minority of patients (up to 20%) will develop severe disease that carries substantial morbidity and mortality. The incidence of acute pancreatitis continues to increase and has doubled since the 1960s,1 rising noticeably in women under 35 years of age in line with changing patterns of alcohol consumption.2 In the UK, there are 150e420 clinically diagnosed cases of acute pancreatitis per million population per year.1 The mortality resulting from acute pancreatitis has remained largely unchanged (approximately 10%) since the 1970s.1 Acute pancreatitis is associated with two distinct phases of mortality e early, secondary to organ failure resulting from the systemic inflammatory response syndrome (SIRS); and late, related to super-infection of pancreatic
C C C C C
C C C
C C
Drugs Common Azathioprine 6-Mercaptopurine Didanosine Valproic acid Oestrogens Furosemide Pentamidine Sulphonamides Tetracycline Tamoxifen
Robin NB Baddeley BSc(Hons) is a final year medical student at the University of Sheffield, Sheffield, UK. Competing interests: none declared. James RA Skipworth MBBS BSc(Hons) MRCS is the inaugural ‘Jason Boas’ Hepatopancreaticobiliary Fellow at the UCL Division of Surgery and Interventional Science, University College London, London, UK. Competing interests: none declared. Stephen P Pereira MBBS BSc(Hons) PhD FRCP is a Reader in Hepatology and Gastroenterology at University College London, London, UK. Competing interests: none declared.
MEDICINE 39:2
Alcohol Cholelithiasis, microlithiasis, choledocholithiasis Post-endoscopic retrograde cholangiopancreatography Hypertriglyceridaemia, Hypercalcaemia Autoimmune pancreatitis Pancreatic ductal obstruction: pancreatic cancer, sphincter of Oddi dysfunction, pancreas divisum, periampullary tumours, ascariasis Genetic: hereditary pancreatitis, cystic fibrosis Viral infection: coxsackie, mumps, HIV, adenovirus Ischaemia: intra-abdominal surgery, coronary artery bypass surgery, embolism, vasculitis Venom: spider, scorpion Idiopathic (<10%)
Less common Corticosteroids Aminosalicylates Metronidazole l-asparaginase ACE* inhibitors
*
Angiotensin-converting enzyme.
Table 1
108
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
Mild acute pancreatitis Pancreatitis without the presence of SIRS, organ failure, parenchymal necrosis or other acute complications can be classified as mild disease. It is often referred to as interstitial or oedematous pancreatitis and generally improves within 48e72 h following institution of conservative measures.
and resulting in cellular damage with consequent gland autodigestion (Figure 1). Damaged cells leak activated enzymes into the surrounding tissues, propagating the autodigestive process, as well as releasing inflammatory mediators, such as cytokines and macrophages, into the systemic circulation. The ensuing SIRS is characterized by hypovolaemia, hyperdynamic circulation, capillary leak and fluid loss into the third space. The pancreatic vascular changes that follow are disproportionate to reductions in cardiac output as each anatomic lobule is supplied by a single, end vessel;3 these lead to pancreatic ischaemic damage, and ultimately necrosis, if the disease is severe or prolonged. Alcohol can amplify the inflammatory response independently.4 Early in the course of disease (1e14 days), SIRS may lead to failure of the primary organs, including the lungs (acute respiratory distress syndrome), kidneys (acute renal failure) and liver (hepatic decompensation). The presence of persistent SIRS, or SIRS coupled with infection (sepsis), may lead in turn to the multiple organ dysfunction syndrome (MODS). MODS typically occurs 3e4 weeks after the onset of severe acute pancreatitis and accounts for some of the late deaths.
Severe acute pancreatitis Early disease: the revised Atlanta Classification (2008) suggests that severity during the early phase of the disease should be based upon clinical evaluations, with radiological assessments of severity becoming more crucial later in the course of the disease.6 The development of severe acute pancreatitis can be predicted in the first 48 h of the disease, using the following criteria: 1. a score of 3 or more on Ranson’s criteria (Table 2) 2. a score of 8 or more on APACHE II (acute physiology and chronic health evaluation II) 3. the presence of SIRS 4. developing organ failure. Patients are classified as having severe, early disease upon the development of organ failure that persists for over 48 h duration. The revised Atlanta classification suggests that standardized assessments of organ dysfunction, such as the Marshall scoring system or sequential organ failure assessment (SOFA) score (see Tables 3a and 3b), be used for this purpose, as they are universally applicable and can be repeated on a daily basis for evaluation of progress.
Definition and classification The Atlanta classification system defines acute pancreatitis as an acute inflammatory process of the pancreas, with variable involvement of regional tissues or remote organ systems.5 The system categorizes acute pancreatitis into mild and severe disease, as outlined below.
Late disease: during the later phase of acute pancreatitis, radiological evaluation can aid assessment of severity, with severe disease based upon: 1. the presence of pancreatic peripancreatic necrosis 2. local complications of pseudocyst or abscess.
Pathogenesis of acute pancreatitis
Diagnosis
Trypsinogen → Trypsin
A diagnosis of acute pancreatitis is based upon the presence of two of the following three features (as per the revised Atlanta Classification, 2008)6: abdominal pain characteristic of acute pancreatitis serum amylase and/or lipase 3 times the upper limit of normal characteristic findings of acute pancreatitis on ultrasonography or on computed tomography (CT) for those patients in whom it is clinically indicated (Figure 2).
Positive feedback loop Cascade of enzyme activation
Pancreatic damage/ autodigestion
Clinical presentation
Systemic inflammatory response syndrome
The condition is characterized by the presence of acute and constant pain in the upper abdomen7 (Table 4). Pain may last for several days, radiate to the back, and be associated with nausea and vomiting. Jaundice (resulting from biliary obstruction), tachycardia, fever, hypovolaemia (due to vomiting and third space fluid losses) and small bowel ileus, may also be present. In mild disease, tenderness in the upper abdomen on palpation may be the only finding. In severe disease, exudates from pancreatic necrotic areas tracking along the falciform ligament and into the retroperitoneum can be seen as ecchymosis in the periumbilical region (Cullen’s sign) and the flanks (Grey-Turner’s
Fluid loss and vascular alterations
MODS, multiple organ dysfunction syndrome.
Organ failure and MODS
Figure 1
MEDICINE 39:2
109
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
Table 2
sign).8 Extension of inflammatory exudates from the peripancreatic region to the diaphragm may result in shallow respiration.
insufficiency (e.g. chronic pancreatitis, cystic fibrosis and diabetes mellitus), falsely low in the context of hypertriglyceridaemia, and raised in those with impaired renal clearance.10
Laboratory markers of diagnosis Clinical presentation can vary widely, and enzymes derived from pancreatic acinar cells have therefore been used as biochemical markers to confirm a diagnosis of acute pancreatitis.
Serum lipase Serum lipase has been reported to have a higher sensitivity and specificity for the diagnosis of acute pancreatitis than serum amylase. In a prospective study of 253 patients with acute abdominal pain, a serum lipase of twice the upper limit of the reference range had a sensitivity of 94% and a specificity of 95% for the diagnosis of acute pancreatitis one day after pain onset, compared to 71% and 98% for a serum amylase of twice the upper limit of the reference range.11 Serum lipase may remain elevated
Serum amylase A raised concentration of serum amylase, at least three times the upper limit of the reference range, supports a diagnosis of acute pancreatitis. The concentration usually rises within the first 12 h after the onset of symptoms and returns to normal within 3e5 days.9 However, it may be normal in patients with pancreatic
The Marshall scoring system for evaluation of organ failure Score System Respiratory PO2/FIO2 Renal serum creatinine (mmol/l) Cardiovascular systolic BP (mmHg)
0
1
2
3
4
>400 134 >90
301e400 134e169 <90 Fluid responsive
201e300 170e310 <90 Not fluid responsive
101e200 311e439 <90 pH <7.3
101 >439 <90 pH <7.2
Table 3a
MEDICINE 39:2
110
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
The SOFA scoring system for evaluation of organ failure SOFA score Respiration PaO2/FIO2 Coagulation: Plts (103/mm3) Hepatic: Bilirubin (mmol/L) Cardiovascular: BP
0 >400 >150 20 No hypotension
1 400 150 20e32 MAP <70 mmHg
2 300 100 33e101 Dopamine 5 or dobutamine (any)
CNS: Glasgow coma score Renal: Creatinine (mmol/L) or urine output
15
13e14
10e12
110
110e170
171e299
3 200 50 102e204 Dopamine >5 or norepinephrine 0.1 or epinephrine 0.1 6e9
4 100 20 204 Dopamine >15 or norepinephrine >0.1 or epinephrine >0.1 <6
300e400 or UO<500 ml/day
>440 or UO <200 ml/day
Table 3b
and detectable for up to 14 days, thereby giving greater sensitivity than serum amylase in patients with a delayed presentation. Falsely high concentrations are seen in intra-abdominal pathology and renal insufficiency. Where available, lipase is preferred over amylase for the diagnosis of acute pancreatitis.12
patients with severe acute pancreatitis reported that a CRP >81 mg/l and white cell count (WCC) >13 109/l were markers for super-infection of pancreatic necrosis; if both indices were below these thresholds, the predicted infection risk was only 1.4%.16
Serum trypsinogen-2 Trypsinogen-2 is a pro-enzyme that can be released in high quantities during acute pancreatitis and is measured using a simple serum immunofluorometric assay or urine dipstick at the bedside. It has a reported sensitivity and specificity of 86e100% for the diagnosis of acute pancreatitis.13
Haematocrit Reduction of intravascular volume owing to extravasation of fluid into the third space can lead to a raised serum haematocrit. In a meta-analysis of 399 patients presenting with acute pancreatitis, a serum haematocrit above 44 mg/dl was one of the three most sensitive predictors of overall severity in acute pancreatitis (the other two being raised body mass index and pleural effusion).17
Serum ALT In the context of a clinical diagnosis of acute pancreatitis, a serum alanine aminotransferase (ALT) activity of >150 IU/l has a positive predictive value of 95% for gallstone aetiology, although only half of the patients with gallstone-induced acute pancreatitis will present with high ALT values.14
Other potential markers A number of other potential laboratory markers of severity of acute pancreatitis or predictors of pancreatic necrosis are under investigation but are not yet established in clinical practice. These include IL-6 and IL-8;18 serum procalcitonin;19 and polymorphonuclear elastase.20
Laboratory markers of severity C-reactive protein (CRP) Serum CRP is useful in predicting acute pancreatitis severity and infection: in a study of 50 patients, a CRP of 150 mg/l at 36 h had a sensitivity of 86% and a specificity of 87% for the development of severe acute pancreatitis.15 Another study of 90
Assessment of disease severity Identification of patients at risk for severe disease early in the course of acute pancreatitis is an important step to guiding management and improving outcome. A number of prognostic
CT appearances of: a a normal pancreatic head; b mild oedematous acute pancreatitis, and c severe acute pancreatitis, with non-enhancing pancreatic parenchyma and acute fluid collection. Figure 2
MEDICINE 39:2
111
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
Body mass index Obesity adversely influences the severity of acute pancreatitis, although the pathogenic mechanisms remain poorly understood. A meta-analysis of 739 patients showed that the risk of severe acute pancreatitis, local and systemic complications, and mortality were significantly more common in obese patients with a body mass index >30 kg/m2.23
Differential diagnosis of acute pancreatitis C C C C C C C
Inferior myocardial ischaemia Peptic ulcer disease Symptomatic gallbladder stones Mesenteric ischaemia Small bowel obstruction Dissecting aortic aneurysm Macroamylasaemia
Imaging studies Ultrasonography (US): transabdominal US can be used as an early test to document the presence of gallbladder stones and bile duct dilatation, with a false negative rate of 20e40% for the detection of common bile duct stones, particularly in patients with a high body mass index or those with overlying air-filled bowel loops.24
Table 4
scoring systems have been developed (Table 3), including Ranson’s criteria and the Glasgow (Imrie) score. APACHE II assesses 12 physiologic a variables, age and chronic health status at admission and at 48 h. A systematic review of 13 studies showed APACHE II to have a sensitivity of 65e81% and specificity of 77e91% for the prediction of mortality from acute pancreatitis.21 Scoring systems to assess multiple organ dysfunction, such as the SOFA score and Marshall scoring system (see Tables 3a and 3b), have also been developed.
Computed tomography: contrast-enhanced CT is the imaging procedure of choice if clinical and biochemical findings are inconclusive, or to investigate the possibility of an alternative abdominal emergency.12 It is also used to document the extent of pancreatic and extrapancreatic acute fluid collections, and to detect pancreatic necrosis. However, in a prospective multi-centre study of 166 patients with a clinically established diagnosis of acute pancreatitis, the yield of early CT (within 4 days of symptom onset) was low and did not lead to changes in clinical management.25
BISAP (Bedside index for severity in acute pancreatitis) The BISAP score is a simple prognostic tool where a composite score of 0e5 is assigned within 24 h of presentation, based on five variables (Table 5). A prospective study of 185 patients demonstrated that BISAP was equivalent to other scoring systems in the classification of patients with acute pancreatitis into mild and severe groups (AUC ¼ 81), with the advantage of early assessment.22
CT severity index: (CTSI; score 0e10) is based upon the presence and degree of pancreatic inflammation and necrosis seen at CT (Table 6). In a prospective study of 185 patients with acute pancreatitis, a CTSI <2 was associated with severe disease or death in 7% and 0%, respectively, whereas in patients with a CTSI >3, these figures rose to 51% and 9% respectively.22 Magnetic resonance imaging (MRI) accurately depicts pancreatic and biliary duct disruption, and avoids the risks associated with
The bedside index for severity in acute pancreatitis (BISAP) scoring system Point
CT severity index
Individual components of the BISAP scoring system BUN >25 mg/dl Impaired mental status (Glasgow coma scale score <15) SIRS defined as two or more of the following: C Temperature <36 or >38 C C Respiratory rate >20 breaths/min or P CO a 2 <32 mmHg C Pulse >90 beats/min 3 C WBC <4,000 or >12,000 cells/mm or >10% immature bands Age >60 years Pleural effusion detected on imaging
CT severity index (time not specified) (A) Normal pancreas (B) Pancreatic enlargement (oedema) (C) Pancreatic inflammation and/or peripancreatic changes (D) Single peripancreatic fluid collection (E) Two or more fluid collections and/or retroperitoneal air (AeE are exclusive) Plus Necrosis (% of pancreatic parenchyma) 0% <30% 30e50% >50% Total Minimum score 0, Maximum Score 10
A prognostic scoring system for early identification of patients at risk for in-hospital mortality. One point is assigned for each variable within 24h of presentation and added for a composite score of 0e5. BISAP, bedside index for severity in acute pancreatitis; BUN, blood urea nitrogen; SIRS, systemic inflammatory response syndrome. Adapted from Papachristou et al 2010.22
3 4 Add 0 2 4 6
Modified from Papachristou et al, 2010.22
Table 5
MEDICINE 39:2
Points 0 1 2
Table 6
112
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
radiation exposure. It has been shown to be comparable to CT in the assessment of disease severity: in one study of 101 patients with acute pancreatitis, non-enhanced MRI had a sensitivity of 79% and a specificity of 92% for the development of severe disease, using contrast-enhanced CT as the gold standard.26 However, MRI was superior to CT in the detection of pancreatic haemorrhage, which was a poor prognostic sign in this cohort.
Complications of severe acute pancreatitis Local Pancreatic necrosis C Sterile C Infected Pancreatic pseudocyst Pancreatic abscess Pancreatic haemorrhage Retroperitoneal/localized fat necrosis
Clinical course The majority (around 85%) of patients develop a self-limiting, mild, oedematous-interstitial pancreatitis. This mild disease is associated with minimal organ dysfunction, and usually resolves with conservative management.27 However, around 15% of patients will develop severe disease, characterized by pancreatic necrosis, distant organ failure, acute fluid collections and later pseudocyst formation (Tables 7 and 8). Approximately one-third of these patients develop super-infection of pancreatic tissue, which carries a 30% mortality rate (compared with 12% in sterile necrosis).27 Early deaths (within the first 2 weeks) are usually a result of organ failure; deaths after this interval are generally caused by sepsis associated with infected necrosis or other complications of sterile necrosis.
Systemic Paralytic ileus Pulmonary effusions and ascites Adult respiratory distress syndrome Shock Acute renal failure Hypocalcaemia Disseminated intravascular coagulation
Table 8
present, early endoscopic retrograde cholangiopancreatography (ERCP) sphincterotomy or duct drainage with stenting, should be considered.12,29 The diagnosis of gallstone-induced acute pancreatitis should prompt cholecystectomy in the recovery phase of pancreatitis, ideally before hospital discharge.30 If severe disease is present, this intervention should be delayed until signs of lung injury and systemic disturbance have resolved.12
Management
Nutrition Nutritional deterioration is common in acute pancreatitis, and occurs secondary to reduced intake in combination with systemic catabolism resulting from SIRS. Enteral nutrition can be administered via nasojejunal or nasogastric catheters and should be instituted as early as safely possible to provide nutritional support and reduce the risk of infective complications, length of hospital stay and mortality.31 However, in certain circumstances, such as duodenal outlet obstruction or paralytic ileus, parenteral nutrition may be required. Currently, there is little evidence to support the use of probiotics, prokinetics, immunonutrition or anti-oxidant supplementation in acute pancreatitis.32 In a trial of probiotic prophylaxis in 296 patients with predicted severe acute pancreatitis, the use of probiotics increased mortality within the first 90 days (6% vs. 16%, p ¼ 0.01), predominantly as a result of bowel ischaemia.33
Mild acute pancreatitis Mild acute pancreatitis usually resolves with supportive care: oxygen administration, ensuring adequate hydration and pain control, and the investigation and treatment of any reversible or treatable aetiology. Severe acute pancreatitis The management of severe acute pancreatitis requires a multidisciplinary approach (Table 9). Patients with severe acute pancreatitis should be managed in a high dependency unit or intensive therapy unit.12 Priorities include stabilization of haemodynamic status sufficient to maintain a mean blood pressure of 65 mmHg and a urine volume of 0.5 mL/kg/h; oxygen therapy; clear fluids only (initially); and adequate pain control.28 If cholestasis is
Predictors of a severe attack of acute pancreatitis Initial assessment
24 h after admission
48 h after admission
Clinical impression of severity Body mass index >30 kg/m2 Pleural effusion on chest radiograph APACHE II score 8 Haematocrit >44 mg/dl Clinical impression of severity APACHE II score 8 BISAP score 3 Clinical impression of severity Glasgow score 3 Ranson score 3 C-reactive protein >150 mg/dl Multiple or progressive organ failure
Treatment strategies for a successful outcome in severe acute pancreatitis 1. Resuscitation 2. Assessment of disease severity with the aid of scoring systems 3. Identification and early triage of severe acute pancreatitis patients to HDU/ITU for closer monitoring 4. Early imaging in patients where disease has been prolonged before presentation, or risk of pancreatic/peripancreatic complications 5. Identification and treatment of aetiology 6. Early introduction of enteral nutrition 7. Anticipation of complications with appropriate interventions Table 9
Table 7
MEDICINE 39:2
113
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
Antibiotics Infectious complications account for 80% of deaths from severe acute pancreatitis, as well as the majority of late complications. However, there remains little evidence to support the use of prophylactic antibiotics in the prevention of infected necrosis, either at presentation or once necrosis is confirmed. Carbapenems remain the antibiotics of choice, but whereas prophylactic imipenem may reduce pancreatic infection rates, it has not been shown to alter mortality.31 Thus, antibiotics should be reserved for treatment of confirmed, infected necrosis.12
consisting of percutaneous drainage followed, if necessary, by minimally-invasive retroperitoneal necrosectomy may reduce the rate of major complications, as compared to primary open necrosectomy.45
Novel therapies There are few specific therapeutic strategies for the treatment of acute pancreatitis. Various novel therapies are under investigation although studies to date remain limited. A systematic review of 22 studies found insufficient data to support using anti-oxidants alone or in combination with conventional therapy in the management of acute pancreatitis or post-ERCP pancreatitis.46A
Specific therapies Chemoprevention of post-ERCP pancreatitis The potential role of various chemopreventative agents in the prevention of acute pancreatitis, the most common complication following ERCP, has been evaluated in a number of welldesigned clinical trials. A meta-analysis of six randomized controlled trials concluded that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the rate of post-ERCP pancreatitis.34 Somatostatin, a suppressor of pancreatic secretion, administered for 12 h (starting from 30 min before ERCP) may reduce rates of post-ERCP pancreatitis,35 although these results were not corroborated by meta-analysis.36 Similarly, meta-analyses of the protease inhibitors, gabexate36 and octreotide,37 did not reveal convincing results as to their efficacy and there also remains limited evidence for the use of allopurinol,38 corticosteroids,39 N-acetylcysteine40 and mitogen-activated protein kinase inhibitor.41
REFERENCES 1 Goldacre MJ, Roberts SE. Hospital admission for acute pancreatitis in an English population, 1963e98: database study of incidence and mortality. BMJ 2004; 328: 1466e9. 2 Roberts SE, Williams JG, Meddings D, Goldacre MJ. Incidence and case fatality for acute pancreatitis in England: geographical variation, social deprivation, alcohol consumption and aetiology e a record linkage study. Aliment Pharmacol Ther 2008; 28: 931e41. 3 Juvonen PO, Tenhunen JJ, Heino AA, et al. Splanchnic tissue perfusion in acute experimental pancreatitis. Scand J Gastroenterol 1999; 34: 308e14. 4 Szabo G, Mandrekar P, Oak S, Mayerle J. Effect of ethanol on inflammatory responses. Implications for pancreatitis. Pancreatology 2007; 7: 115e23. 5 Bradley EL. A clinically based classification-system for acutepancreatitis e summary of the international-symposium on acutepancreatitis, Atlanta, Ga, September 11 through 13, 1992. Arch Surg 1993; 128: 586e90. 6 Acute Pancreatitis Classification Working Group: revision of the Atlanta Classification of Acute Pancreatitis (3rd revision based on worldwide review/suggestions). 2008. 7 Kemppainen E, Puolakkainen P, Leppaniemi A, Hietaranta A, Gronroos J, Haapiainen R. Diagnosis of acute pancreatitis. Ann Chir Gynaecol 1998; 87: 191e4. 8 Frossard JL, Steer ML, Pastor CM. Acute pancreatitis. Lancet 2008; 371: 143e52. 9 Smotkin J, Tenner S. Laboratory diagnostic tests in acute pancreatitis. J Clin Gastroenterol 2002; 34: 459e62. 10 Yadav D, Agarwal N, Pitchumoni CS. A critical evaluation of laboratory tests in acute pancreatitis. Am J Gastroenterol 2002; 97: 1309e18. 11 Keim V, Teich N, Fiedler F, Hartig W, Thiele G, Mossner J. A comparison of lipase and amylase in the diagnosis of acute pancreatitis in patients with abdominal pain. Pancreas 1998; 16: 45e9. 12 UK guidelines for the management of acute pancreatitis. Gut 2005; 54(suppl 3): iii1e9. 13 Andersen AM, Novovic S, Ersboll AK, Jorgensen LN, Hansen MB. Urinary trypsinogen-2 dipstick in acute pancreatitis. Pancreas 2010; 39: 26e30. 14 Johnson CD. ABC of the upper gastrointestinal tract. Upper abdominal pain: gall bladder. BMJ 2001; 323: 1170e3. 15 Pongprasobchai S, Jianjaroonwong V, Charatcharoenwitthaya P, et al. Erythrocyte sedimentation rate and c-reactive protein for the prediction of severity of acute pancreatitis. Pancreas 2010; 39: 1226e30.
Treatment of complications Pancreatic necrosis is characterized by focal or diffuse areas of non-viable or dead pancreatic parenchyma, often associated with peripancreatic fat necrosis. In severe pancreatitis, bacteria can translocate from the gut to infect necrotic pancreatic tissue, often during the second or third week following initial diagnosis. Sterile necrosis: the distinction between sterile and infected necrosis is crucial as patients with infected necrosis often follow a different natural history and prognosis, but can be clinically difficult as the presence of SIRS in sterile necrosis can closely mimic sepsis. Patients with sterile necrosis are best managed conservatively, as mortality rates are significantly higher in patients who undergo surgical intervention.42 Infected necrosis: patients with infected pancreatic necrosis can be managed with the appropriate use of antibiotics and radiological drains42 but surgical intervention should be considered in those who develop worsening sepsis syndrome or fail to improve following institution of these simpler measures. Ideally, surgical debridement of necrotic tissue (necrosectomy), should be delayed until the necrosis has demarcated:43 a carefullyplanned single laparotomy, with postoperative lavage, has been associated with lower rates of mortality, bleeding and fistula development as compared to procedures incorporating openpacking techniques.42 Other studies have demonstrated that peritoneal lavage, with or without anti-proteases, has no significant benefit.44 However, the results of a large multi-centre study demonstrated that a minimally-invasive, step-up approach,
MEDICINE 39:2
114
Ó 2010 Elsevier Ltd. All rights reserved.
GI EMERGENCIES
16 Dambrauskas Z, Gulbinas A, Pundzius J, Barauskas G. Value of routine clinical tests in predicting the development of infected pancreatic necrosis in severe acute pancreatitis. Scand J Gastroenterol 2007; 42: 1256e64. 17 Brown A, James-Stevenson T, Dyson T, Grunkenmeier D. The panc 3 score: a rapid and accurate test for predicting severity on presentation in acute pancreatitis. J Clin Gastroenterol 2007; 41: 855e8. 18 Aoun E, Chen J, Reighard D, Gleeson FC, Whitcomb DC, Papachristou GI. Diagnostic accuracy of interleukin-6 and interleukin8 in predicting severe acute pancreatitis: a meta-analysis. Pancreatology 2009; 9: 777e85. 19 Mofidi R, Suttie SA, Patil PV, Ogston S, Parks RW. The value of procalcitonin at predicting the severity of acute pancreatitis and development of infected pancreatic necrosis: systematic review. Surgery 2009; 146: 72e81. 20 Dominguez-Munoz JE, Villanueva A, Larino J, et al. Accuracy of plasma levels of polymorphonuclear elastase as early prognostic marker of acute pancreatitis in routine clinical conditions. Eur J Gastroenterol Hepatol 2006; 18: 79e83. 21 Gravante G, Garcea G, Ong SL, et al. Prediction of mortality in acute pancreatitis: a systematic review of the published evidence. Pancreatology 2009; 9: 601e14. 22 Papachristou GI, Muddana V, Yadav D, et al. Comparison of BISAP, Ranson’s, APACHE-II, and CTSI scores in predicting organ failure, complications, and mortality in acute pancreatitis. Am J Gastroenterol 2010; 105: 435e41. quiz 42. 23 Martinez J, Johnson CD, Sanchez-Paya J, de Madaria E, Robles-Diaz G, Perez-Mateo M. Obesity is a definitive risk factor of severity and mortality in acute pancreatitis: an updated meta-analysis. Pancreatology 2006; 6: 206e9. 24 Dong B, Chen M. Improved sonographic visualization of choledocholithiasis. J Clin Ultrasound 1987; 15: 185e90. 25 Spanier BW, Nio Y, van der Hulst RW, Tuynman HA, Dijkgraaf MG, Bruno MJ. Practice and yield of early CT scan in acute pancreatitis: a Dutch observational multicenter study. Pancreatology 2010; 10: 222e8. 26 Stimac D, Miletic D, Radic M, et al. The role of nonenhanced magnetic resonance imaging in the early assessment of acute pancreatitis. Am J Gastroenterol 2007; 102: 997e1004. 27 Banks PA, Freeman ML. Practice guidelines in acute pancreatitis. Am J Gastroenterol 2006; 101: 2379e400. 28 Wada K, Takada T, Hirata K, et al. Treatment strategy for acute pancreatitis. J Hepato-Bil-Pan Sci 2010; 17: 79e86. 29 van Santvoort HC, Besselink MG, de Vries AC, et al. Early endoscopic retrograde cholangiopancreatography in predicted severe acute biliary pancreatitis: a prospective multicenter study. Ann Surg 2009; 250: 68e75. 30 Kimura Y, Arata S, Takada T, et al. Gallstone-induced acute pancreatitis. J Hepato-Bil-Pan Sci 2010; 17: 60e9. 31 NICE. Alcohol-use disorders: diagnosis and clinical management of alcohol-related physical complications [Clinical guideline CG100]. London: National Institute for Health and Clinical Excellence, 2010.
MEDICINE 39:2
32 Al Samaraee A, McCallum IJ, Coyne PE, Seymour K. Nutritional strategies in severe acute pancreatitis: a systematic review of the evidence. Surgeon 2010; 8: 105e10. 33 Besselink MG, van Santvoort HC, Buskens E, et al. Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial. Lancet 2008; 371: 651e9. 34 Dai HF, Wang XW, Zhao K. Role of nonsteroidal anti-inflammatory drugs in the prevention of post-ERCP pancreatitis: a meta-analysis. Hepatobiliary Pancreat Dis Int 2009; 8: 11e16. 35 Lee KT, Lee DH, Yoo BM. The prophylactic effect of somatostatin on post-therapeutic endoscopic retrograde cholangiopancreatography pancreatitis: a randomized, multicenter controlled trial. Pancreas 2008; 37: 445e8. 36 Andriulli A, Leandro G, Federici T, et al. Prophylactic administration of somatostatin or gabexate does not prevent pancreatitis after ERCP: an updated meta-analysis. Gastrointest Endosc 2007; 65: 624e32. 37 Bai Y, Gao J, Zou DW, Li ZS. Prophylactic octreotide administration does not prevent post-endoscopic retrograde cholangiopancreatography pancreatitis: a meta-analysis of randomized controlled trials. Pancreas 2008; 37: 241e6. 38 Bai Y, Gao J, Zhang W, Zou D, Li Z. Meta-analysis: allopurinol in the prevention of postendoscopic retrograde cholangiopancreatography pancreatitis. Aliment Pharmacol Ther 2008; 28: 557e64. 39 Zheng MH, Bai JL, Yuan BS, et al. Meta-analysis of prophylactic corticosteroid use in post-ERCP pancreatitis. BMC Gastroenterol 2008; 8. 40 Milewski J, Rydzewska G, Degowska M, Kierzkiewicz M, Rydzewski A. N-acetylcysteine does not prevent post-endoscopic retrograde cholangiopancreatography hyperamylasemia and acute pancreatitis. World J Gastroenterol 2006; 12: 3751e5. 41 van Westerloo DJ, Rauws EA, Hommes D, et al. Pre-ERCP infusion of semapimod, a mitogen-activated protein kinases inhibitor, lowers post-ERCP hyperamylasemia but not pancreatitis incidence. Gastrointest Endosc 2008; 68: 246e54. 42 Heinrich S, Schafer M, Rousson V, Clavien PA. Evidence-based treatment of acute pancreatitis: a look at established paradigms. Ann Surg 2006; 243: 154e68. 43 Rodriguez JR, Razo AS, Targarona J, et al. Debridement and closed packing for sterile or infected necrotizing pancreatitis e insights into indications and outcomes in 167 patients. Ann Surg 2008; 247: 294e9. 44 Dong Z, Petrov MS, Xu J, Shanbhag S, Windsor JA, Pang S. Peritoneal lavage for severe acute pancreatitis: a systematic review of randomised trials. World J Surg 2010; 34: 2103e8. 45 van Santvoort HC, Besselink MG, Bakker OJ, et al. A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med 2010; 362: 1491e502. 46 Mohseni Salehi Monfared SS, Vahidi H, Abdolghaffari AH, Nikfar S, Abdollahi M. Antioxidant therapy in the management of acute, chronic and post-ERCP pancreatitis: a systematic review. World J Gastroenterol 2009; 15: 4481e90.
115
Ó 2010 Elsevier Ltd. All rights reserved.