Acute pancreatitis. Epidemiology. Keywords acute pancreatitis; organ failure; ERCP; nutritional support; antibiotics; necrosectomy.

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1 Acute pancreatitis A Peter Wysocki C Ross Carter Abstract Acute pancreatitis is one of the more common reasons for surgical admission. Most patients have mild disease and settle quickly with intravenous fluids and analgesia; the major consideration is prevention of further attacks. In 20% of patients, local inflammation initiates a systemic inflammatory response that results in a variable degree of respiratory, cardiac and renal compromise, leading to the development of multiorgan dysfunction syndrome in some patients. Fifty percent of deaths occur within the first week due to overwhelming organ failure, for which there is no specific therapy. This contribution discusses the aetiology, pathophysiology and definitions used in acute pancreatitis; the diagnosis of acute pancreatitis and the initial generic management are also discussed. This is followed by a review of evidence for specific interventions (endoscopic retrograde cholangiopancreatography, nutritional support, antibiotics, radiological imaging) and the role and indications for intervention, which are aimed primarily at the management of secondary complications. Keywords acute pancreatitis; organ failure; ERCP; nutritional support; antibiotics; necrosectomy viral infection (e.g. HIV, mumps) medications (e.g. angiotensin-converting enzyme inhibitors, corticosteroids, diuretics, azathioprine) hypercalcaemia (e.g. hyperparathyroidism), hypetriglyceridaemia (>1000 mg/dl) autoimmune pancreatitis. 1 Several risk factors for post-ercp pancreatitis have been identified: therapeutic ERCP pancreatic duct injection female sex dysfunction of the sphincter of Oddi previous pancreatitis. 3 A prophylactic agent has not been identified. 4 Epidemiology The annual incidence of acute pancreatitis is 5 80 per 100,000 population, depending on the region. 1 About four out of five patients have mild disease. 5 At least 40% of those with severe acute pancreatitis (or about 1 in 10 of all patients with pancreatitis) develop infected pancreatic necrosis; the mortality rate approaches 40%. 6,7 The leading independent predictor of mortality is organ failure lasting >48 hours during the first week of illness. 8,9 Up to 50% of deaths in patients with severe pancreatitis occur within the first week due to organ failure in the absence of local complications. 10 Eighty percent of patients who die do so within three days of hospital admission despite ongoing improvements in supportive care. 11 Some patients may never reach a specialist Pancreatic Unit, while others may be unfit for intervention or transfer. 12 Late mortality is often due to infective complications. 8 Pathophysiology Aetiology Gallstones and alcohol are the commonest (80%) causes of acute pancreatitis. Consumption of >100 g of alcohol in 24 hours and low intake of fat are significant risk factors. 1 Gallstones <5 mm in diameter are more likely to cause pancreatitis than larger stones. 1 Overall, <5% of patients with gallstones present with pancreatitis. 1 The third-largest group of patients (20%) do not have a cause identified after clinical assessment, biochemistry, ultrasound and CT. Further evaluation in this idiopathic group usually identifies: microlithiasis (calculi <3 mm) or sludge (crystals) chronic pancreatitis pancreas divisum. 2 Most of the other cases are due to: structural lesions (e.g. tumour, stricture in pancreatic duct) trauma (e.g. endoscopic retrograde cholangiopancreatography (ERCP), surgery, trauma (blunt or penetrating)) A Peter Wysocki FRACS is a General Surgeon at Logan Hospital, Logan, Queensland, Australia. Conflicts of interest: none declared. C Ross Carter FRCS is a Consultant General Surgeon at Glasgow Royal Infirmary, Glasgow, Scotland, UK. Conflicts of interest: none declared. Trypsin is the pivotal pancreatic enzyme because it activates itself and other proenzymes. 7 The specific trigger of trypsinogen activation ultimately resulting in autodigestion and pancreatitis is unknown, but various mechanisms have been proposed: cytoskeletal disruption ph reduction activation of hydrolases and apical enzymes. 7 The initiating molecular steps of biliary- and alcohol-induced pancreatitis are probably different. 7 Typically, acinar cell injury is followed by sequestration of acute inflammatory cells within the gland. 7 This complicated second phase is a balance between pro- and anti-inflammatory cytokines. 7 Nitric oxide and other mediators are produced and may spill over into the systemic circulation, provoking a systemic inflammatory response syndrome (SIRS). 7 Organ dysfunction probably begins within hours of the onset of pancreatitis. 8 Further systemic stimulation may result from the activation of inflammatory cells via extracellular matrix components released from necrotic tissue. 13 These stimulate monocytes to secrete tumour necrosis factor-α, which results in a cascade of release of pro-inflammatory cytokines. 14 The extent of pancreatic necrosis correlates with the development of organ failure and later with the development of infection, but SIRS may occur without significant necrosis and infection. 5,15 A gallstone may initiate an episode of pancreatitis, but stone impaction is not thought to cause disease progression: in the first two days SURGERY 25: Elsevier Ltd. 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2 of illness, choledocholithiasis was present in 61% of patients whereas, by 4 10 days, an impacted common bile duct calculus was present in only 5% of patients at open surgery. 16 Diagnosis At least 95% of patients present with acute moderate-to-severe pain in the upper abdomen, often radiating to the back (50%) and vomiting (70%). 17 The pain is often eased by sitting forward and reaches its peak within one hour. Mild pyrexia, epigastric tenderness and guarding are typical. Eponymous signs of retroperitoneal haemorrhage (Cullen s, Grey Turner s and Fox s signs) are rare, non-specific and occur late (48 hours). 17 At three times the upper normal limit, the specificity of serum amylase is up to 95%, but sensitivity may be as low as 61%. 18 Serum lipase may remain elevated for more than one week, giving greater sensitivity with longer delays to presentation. 18 Specificity of lipase at four times normal exceeds 95% and sensitivity is %. 18 Both enzymes may be measured in the urine, which is particularly useful if presentation is late. The following features are suspicious of gallstone aetiology on admission: female sex age >50 years amylase of >4000 IU/l bilirubin of >25 μmol/l aspartate aminotransferase or alanine aminotransferase of >100 IU/l alkaline phosphatase >300 IU/l. 19 A serum alanine aminotransferase value of >150 IU/l alone has a positive predictive value of 95%, but this is found in only half of the patients with this cause. 18 Serum amylase may not be elevated in acute pancreatitis due to hypertriglyceridaemia or in patients with underlying chronic pancreatitis. 18 Conditions that do not involve the pancreas may also result in hyperamylasaemia (e.g. perforated peptic ulcer). 18 Ultrasound identifies cholelithiasis with a sensitivity of up to 95%, but may need to be repeated once the pancreatitis-related ileus has resolved. 18 It is poor at diagnosing acute pancreatitis and, if there is diagnostic uncertainty, an early CT of the abdomen may be required to exclude mesenteric ischaemia or abdominal aortic aneurysm. 17 Definitions The reader is initially directed to a summary of the Atlanta definitions, but a number of entities must be distinguished. 20 Acute pancreatitis is termed severe if local complications or organ failure is present, otherwise the episode is termed mild. A major criticism of the Atlanta definitions is that transient (<48 hours) minor organ failure is common (patients are termed severe ) and not associated with a complicated course; the morbidity and mortality is concentrated in those with persistent organ failure. 8 Prognostically, severe acute pancreatitis may be considered if: Imrie or Ranson score is 3 Acute Physiology and Chronic Health Examination (APACHE) II score is >8 C-reactive peptide at 48 hours is >150 mg/dl. Pancreatic necrosis is a histological diagnosis but, radiologically, pancreatic tissue measuring <50 Hounsfield units (HU) on intravenous contrast-enhanced CT is considered to be non-perfused and thus necrotic if it is >3 cm in diameter or occupies at least 30% of the gland. 21,22 Enhancement in the HU range strongly suggests necrosis, but may represent tissue oedema or fat. 23 CT alone may be unable to reliably distinguish between three components of pancreatic necrosis that are readily diagnosed with gadolinium-enhanced MRI: non-perfused/necrotic pancreatic parenchyma or peripancreatic fat collection of perinecrotic fluid foci of haemorrhage. 24 Acute fluid collection (see below) refers to peripancreatic fluid diagnosed within the first four weeks of illness that lacks a defined wall. It may represent liquefied fat or oedema fluid within the lesser sac. Post-acute pseudocyst arises due to disruption of the main duct such that enzyme-rich fluid elicits an inflammatory or fibrous capsule. 25 This can be diagnosed only after four weeks. The internal density is not >10 HU on CT. 26 Pancreatic abscess is an uncommon late sequel of acute pancreatitis where limited necrosis is followed by liquefaction and infection. 20,27 29 Organized pancreatic necrosis or necroma is a more recent concept: this under-appreciated entity represents a postpancreatitic area of necrotic tissue often confused with a postacute pseudocyst. 26,30 It is the end-product of liquefaction of pancreatic necrosis, which takes 1 3 months to form. 25 The necrosum is well demarcated from the retroperitoneum and is easily removed at surgery. This has also been described as a pseudocyst with debris. 25 CT density of this ovoid lesion is >20 HU and thus distinguishes it from post-acute pseudocyst. 26 Assessment and initial management Aggressive fluid resuscitation is the key element of initial resuscitation well over three litres of additional crystalloid, in addition to measured losses, may be required in the first 24 hours. One must also consider: analgesia supplemental oxygen nasogastric suction in the event of gastroparesis or ileus prophylaxis against deep venous thrombosis. Analgesia for mild pancreatitis consists of paracetamol and/ or NSAIDs (e.g. ibuprofen); opiates are required for severe disease. Regular monitoring of electrolytes as well as temperature, renal (urine output, urea and creatinine), respiratory (blood gas, chest radiograph) and cardiovascular (pulse, blood pressure) systems is essential. Patients with organ compromise are cared for in an HDU or ICU depending on resources; others may be transferred to these wards within hours. Frequent re-evaluation is vital because clinical signs are time-dependent. SURGERY 25: Elsevier Ltd. All rights reserved.

3 Early discussion with a specialist unit is recommended, but transfer may be unnecessary. Criteria for discussion include: requirement for intervention multiple fluid collections necrosis of >50% infected necrosis multiple organ failure C-reactive protein of >150 mg/l. 31 Predicting disease severity Some authors consider it desirable to anticipate the onset of multiorgan failure because the outcome of severe pancreatitis is poor even though specific therapy for pancreatitis does not exist. 32,33 Clinical assessment at admission identifies only half of patients who subsequently follow a severe course. 10 The overall accuracy of the three often-quoted multivariable scores (Glasgow or Imrie (Table 1), Ranson (Table 1), APACHE II) is about 70%, which reflects their limited clinical use. 10,19,34,35 A readily available test in most institutions is C-reactive protein at 48 hours: the negative predictive value for necrosis of C-reactive protein of <150 mg/l is 90%, but the positive predictive value of a result >150mg/dl is <40%. 10 Body Mass Index of >30 is also a major adverse prognostic factor. 31 Organ dysfunction must be present before these factors become positive and the predictive systems help in recognizing developing organ dysfunction. Nutrition Patients with mild acute pancreatitis resume normal oral intake within a few days and supplemental nutrition is usually not required. Some authors consider ad libitum patient-controlled oral intake from time of admission with mild acute pancreatitis Comparison of Imrie and Ranson prognostic scores Glasgow criteria* Age >55 years White blood cell count > /l Blood glucose >10 mmol/l (excluding diabetic patients) Lactate dehydrogenase >600 IU/l Aspartate transaminase >200 IU/l Albumin <32 g/l Calcium <2 mmol/l Urea >16 mmol/l * During initial 48 hours. Table 1 Ranson criteria Age >55 years White blood cell count > /l Blood glucose >11.1 mmol/l Lactate dehydrogenase >350 IU/l Aspartate transaminase >250 IU/l Calcium <2 mmol/l* Urea >1.8 mmol/l increase* Fall haematocrit >10%* Base deficit >4 mmol/l* Arterial PO 2 <60 mmhg* Fluid sequestration >6000 ml* as speculation but, in the absence of adverse clinical evidence to the contrary, the West of Scotland Pancreatic Unit does not limit oral intake if the patient is not vomiting. 36 Relapse of pain has been reported in up to 25% of patients on refeeding. 37 In patients unable to resume normal intake within a few days, peptide-based enteral nutrition is started promptly because most patients are catabolic. 38 Nasogastric tube feeding is well tolerated in about 90% of patients, otherwise endoscopic placement of a nasojejunal tube for enteral nutrition is required. 39 If enteral nutrition is not tolerated, a double-lumen tube to allow gastric decompression and nasojejunal feeding or dual feeding with additional parenteral nutrition may be required. 40 Insulin may be needed to achieve tight glycaemic control. Routine gastric acid suppression or nasogastric tube drainage are not indicated. 36 Prophylactic antibiotics Two randomized double-blind studies have addressed prophylactic antibiotics in patients with acute pancreatitis with prognostically severe and severe pancreatitis on imaging. 41,42 No difference was found in the rate of pancreatic sepsis and mortality despite previous smaller non-randomized studies suggesting a benefit. 43 Antibiotic overuse has been associated with up to 30% of patients developing necrosis superinfection with Candida species which may confer a poorer prognosis If antimicrobials are prescribed, the duration should to be limited to 14 days. The West of Scotland Pancreatic Unit does not routinely give prophylactic antibiotics to patients with acute pancreatitis but, if started before referral, will complete the course. A subsequent sepsis episode is treated with a short course of sensitivity-directed antibiotic therapy. ERCP During the open surgery era, clearance of the common bile duct early in severe acute pancreatitis was not advocated due to higher mortality than conventional management. 16 Five randomized trials of early endoscopic sphincterotomy in acute pancreatitis were published recently (Table 2) The only trial to show a statistically significant survival advantage appears in abstract form from Poland. 49 The Cochrane meta-analysis of the first three published trials indicates the only benefit of early ERCP is a reduction in complication rate in patients with predicted severe acute pancreatitis, but there is no documented mortality reduction in predicted mild or severe disease. 52 Jaundice and fever are not presentating features of acute pancreatitis. Their presence should raise the suspicion of hyperamylasaemia associated with cholangitis where the organ dysfunction is driven by biliary sepsis, and the associated pancreatic inflammation is mild; ERCP and ductal clearance is essential in these patients. Early ERCP is not recommended for severe acute pancreatitis but is useful in cholangitis or obstructive jaundice. 5 If ERCP sphincterectomy is done, interval cholecystectomy is recommended because otherwise there is a high incidence of further biliary symptoms, including recurrent pancreatitis. 53 Clinical course Most patients recover within 4 5 days and those with cholecystolithiasis undergo cholecystectomy with cholangiography during SURGERY 25: Elsevier Ltd. All rights reserved.

4 ERCP trials in pancreatitis Author, year Number Timing (hours) Indication Primary endpoint Outcome Study conclusion Neoptolemos, Suspected gallstone pancreatitis Reduction in complication or death rate Fan, Pancreatitis Reduction in complication rate Nowak, Aim 24 but some >72 Suspected gallstone pancreatitis Folsch, Suspected gallstone pancreatitis without jaundice Oria, Gallstone pancreatitis with biliary dilation and hyperbilirubinaemia without cholangitis Fewer local complications in patients with Imrie-predicted SAP (p <0.05) but not systemic complications or mortality Same local and systemic complications and mortality Fewer complications and mortality (p <0.05 for each) Reduction in mortality Reduction in organ failure during first week Higher mortality in early ERCP group and study terminated Equivalent organ failure rates, CT severity index, morbidity and mortality Improved outcome in patients with predicted severe attack Lower rate of biliary sepsis with early ERCP S; ERCP indicated in patients with pancreatitis within 24 hours regardless of cause or predicted severity ERCP S in every patient with biliary pancreatitis within 24 hours regardless of predicted severity Only indication for early ERCP S is biliary obstruction If cholangitis can be excluded; early ERCP is not a standard indication ERCP: Endoscopic retrograde cholangiopancreatography; S: Sphincterotomy; SAP: Severe acute pancreatitis. Table 2 the same hospital admission to minimize recurrence. 1 Recurrence is expected in 32 61% of patients if cholecystectomy is not done during the index admission. 1 Patients with alcohol-induced pancreatitis are provided with a coping strategy and support networks. Patients who do not have a cause identified after clinical assessment, biochemistry, ultrasound and CT undergo MRI to exclude a structural lesion. ERCP has the advantage of excluding an ampullary lesion and allows bile sampling for crystal analysis. Endoscopic ultrasound may be more sensitive than ERCP/ MRI for the diagnosis of early-stage alcohol-induced chronic pancreatitis. 54 Managing severe acute pancreatitis is resource intensive. The two phases of illness are SIRS (early, toxic, hypovolaemic or vasoactive) and multiorgan dysfunction syndrome (MODS), also termed late or septic phase. 21,44,55,56 These often overlap, but the transition usually occurs at the end of the second week of illness. 55,57 Early organ failure (i.e. within the first week) is transient (usually respiratory alone) in >40% of patients (i.e. recovery occurs within 48 hours). 9 Death due to the complications of necrotizing pancreatitis without persistent MODS during the first week is unusual. 9 With persistent organ failure (i.e. longer than 48 hours), the mortality is at least 35%. 8,9 It is exceptional to develop a significant local complication without organ failure in the first week of illness. 12 The significance of intra-abdominal hypertension is unclear. 58 MODS may progress or, with ICU support, improve. Follow-up imaging every 7 10 days may be appropriate. Secondary infection of (peri)pancreatic necrosis must be considered if, after a period of stability or improvement, typically in week 2 4 of illness, there is a significant deterioration (e.g. clinical pyrexia, tachycardia; or haematological C-reactive protein, white blood cell count, blood cultures) without evidence of pulmonary, urinary or line sepsis. 12 This is rare in the first week. 59 The patient is investigated with contrast-enhanced CT and radiological drainage of a collection done. Many authors recommend fine-needle aspiration under image guidance to confirm infection before intervention. 5 The complication rate of this procedure is low and sensitivity and specificity are 90%. 5 The investigation may need to be repeated because the development of infection is time-dependent. 28 Routine fine-needle aspiration biopsy should be avoided because of the risk of iatrogenic infection of the necrosum. 28 Gram-positive bacteria predominate in alcoholic necrotizing pancreatitis; Gram-negative bacteria are more frequently found with a gallstone cause. 45 SURGERY 25: Elsevier Ltd. All rights reserved.

5 Contrast-enhanced CT Contrast-enhanced CT is the principal method of imaging during the acute phase of illness. A recent meta-analysis showed that intravenous contrast does not exacerbate the necrotizing process in humans. 60 Necrosis occurs early in the disease process and is complete by four days and, unless there is diagnostic uncertainty, imaging should be deferred for at least 72 hours because the zones of liquefaction are easier to recognize. 12,61 The amount of necrosis remains stable during a particular episode of acute pancreatitis. 61 This may represent <30%, 30 50% or >50% of the pancreas and be diffuse or patchy, deep or superficial. Images are obtained in the early portal venous phase after giving contrast intravenously. Depending on bolus volume, speed of injection and timing of acquisition, normally enhancing pancreas density is HU. 61 Non-enhancing pancreas measures HU. 61 Minor variations in enhancement occur due to oedema and necrosis should not be diagnosed unless a change in the texture of the gland is shown. 61 Peripancreatic gas ( soap bubbles, Figure 1) occurs in up to 50% of patients with subsequent aspirate-proven infected necrosis, and is considered a pathognomonic CT finding There are two components to Balthazar s CT severity index (Table 3), the: appearance of the pancreas (his original CT studies were without contrast) degree of necrosis (can be determined only from contrastenhanced CT). The total score reflects the severity of disease and predicts mortality. 61 Acute fluid collection Acute fluid collection is an immature collection of enzyme-rich fluid, typically found in the periphery of the gland, which occurs within 48 hours and settles spontaneously in 50% of patients. 65 These patients are rarely symptomatic; the collection is immature and acute drainage is not recommended. 65 Necrosis Surgical intervention for necrosis within the first two weeks of illness carries a high mortality and should be avoided. 32,59 To Figure 1 CT (coronal view) shows mid-body necrosis and gas bubbles (arrow), indicating infection. minimize intraoperative haemorrhage, necrosectomy should ideally be done during the third or fourth week of illness because the necrosum becomes more demarcated. Surgical intervention for acute pancreatitis should be limited predominantly to infected pancreatic necrosis. 32 Intervention in patients with sterile necrosis is becoming the exception rather than the rule. 66 The subgroup of patients with sterile necrosis who fail to thrive is a heterogeneous mix in whom intervention may be appropriate. The difficulty arises in how this subgroup is defined: some authors suggest failure to improve with maximal support over 3 5 days, while others adopt a policy of 3 4 weeks of maximal conservative treatment. 55,56 It seems there is little additional benefit from waiting >4 weeks before intervention if this is thought to be indicated. 67 The accepted management of patients with infected pancreatic necrosis is by laparotomy. Necrosectomy with closed lavage by Beger from the Ulm group. 68 Necrosectomy and closed packing with Penrose drains by Warshaw s group. 69 Traditional open drainage with scheduled re-explorations as described by Bradley. 70 Balthazar CT severity index 61 Grade CT finding Points Morbidity (%) Mortality (%) A Normal 0 B Pancreatic enlargement C Pancreatic/peripancreatic inflammation 2 D Single peripancreatic fluid collection 3 E Two or more fluid collections or peripancreatic gas Necrosis 0% <30% % >50% Table 3 SURGERY 25: Elsevier Ltd. All rights reserved.

6 In high-volume institutions, the mortality in all patients with necrosis is >6.2 15%, but may be as high as 30% New techniques have been employed due to the recent explosion of interventional radiology and minimal-access surgery. Simple percutaneous aspiration and drainage alone predictably fail in the management of infected pancreatic necrosis because solid necrotic tissue prevents drainage of pus. 59 What is not known is whether endoscopic or radiological management can reliably stabilize the unwell patient for a period of weeks while the necrotic tissue matures. 28 Further encouragement is gained from the realization that non-laparotomy techniques minimize the physiological insult. 55 At the West of Scotland Pancreatic Unit, carrying out percutaneous necrosectomy in place of open surgery has reduced the requirement for intensive care. 72 In a retrospective nonrandomized series, Connor et al. found a halving of the mortality rate when comparing retroperitoneoscopic necrosectomy with laparotomy (19% versus 39%, respectively) but this difference was not statistically significant (p=0.06). 55 Additional techniques of necrosectomy are laparoscopic, endoscopic and via lumbotomy A number of patients with infected necrosis diagnosed by fine-needle aspiration or retroperitoneal gas bubbles on CT have been treated with prolonged focused antibiotics alone These are a highly selected group of patients without organ failure and are exceptional. 76,79 There may be an increasing role for antibiotics in delaying intervention to a time where organ failure has improved, the collection organized, and the morbidity and mortality associated with early intervention avoided. Regardless of the method of initial management, a significant proportion of patients develop a pancreatic fistula or communicating pseudocyst because pancreatic necrosis and disruption of the pancreatic duct are intricately related. 80 Haemorrhage Haemorrhage usually occurs in patients undergoing early necrosectomy, but may be de novo. 81 Bleeding may be slow and intermittent or sudden. Almost all reported cases of sudden massive blood loss in this setting are fatal within minutes to hours. 81 Overall, the mortality is >30%. 81 Arterial bleeding typically occurs in the early phase of necrotizing pancreatitis, but may occur weeks or months later. 82 It is typically from a left gastric, splenic or gastroduodenal artery pseudoaneurysm. 82 Venous bleeding is uncommon and may account for a non-diagnostic angiogram. 81,82 Embolization of an arterial bleeder provides the best chance of survival. 81 Venous haemorrhage is difficult to manage, and emergency distal pancreatectomy may be required. 81 References 1 Sekimoto M, Takada T, Kawarada Y, et al. JPN Guidelines for the management of acute pancreatitis: epidemiology, etiology, natural history, and outcome predictors in acute pancreatitis. J Hepatobiliary Pancreat Surg 2006; 13: Wilcox CM, Varadarajulu S, Eloubeidi M. Role of endoscopic evaluation in idiopathic pancreatitis: a systematic review. 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