The clinical benefits of subspecialisation in pancreaticobiliary surgery are now widely accepted and are supported by a considerable body of evidence.1 However, the nature of surgical service provision often demands that pancreaticobiliary emergencies be treated by surgeons with principal specialist interests lying outside upper gastrointestinal surgery. The aim of this chapter is to provide an overview of current evidence relating to the treatment of the more commonly encountered pancreaticobiliary emergencies, including the management of acute cholecystitis, acute cholangitis, acute pancreatitis, and pancreaticobiliary disease in pregnancy, for the emergency general surgeon.
Biliary colic and acute cholecystitis
The majority of acute gallbladder disorders are due to gallstones and have a range of clinical presentations.
In the emergency setting, biliary colic or acute cholecystitis are the most common presentations of symptomatic cholelithiasis and it is often difficult at the initial assessment to distinguish between the two conditions as they form part of a continuum. Biliary colic is thought to occur following the impaction of a gallstone within the cystic duct or gallbladder infundibulum, leading to gallbladder obstruction. In a functioning gallbladder, obstruction results in marked gallbladder contraction with the perception of pain. Following disimpaction of the stone, the pain subsides. Disimpacted gallstones may either fall back into the gallbladder or pass into the common bile duct (CBD).
Persistent gallbladder obstruction leads to acute mural inflammation, although there is often a poor correlation between the clinical presentation and the histopathological features of acute and chronic inflammation in the gallbladder wall. Initially, in acute cholecystitis, the inflammatory process within the gallbladder is sterile; however, bacterial colonisation of the obstructed bile and inflamed tissue occurs and may result in an empyema of the gallbladder. Further, if the inflammatory process is particularly severe, gallbladder ischaemia and necrosis can occur, with the risk of gallbladder perforation and subsequent biliary peritonitis.
Biliary colic presents with severe upper abdominal pain in the epigastric and right upper quadrant regions, commonly with radiation to the back or shoulders. Although termed ‘colic’, the pain is usually constant when present, but remits after a period of minutes to hours. Pain may be provoked by eating, and the patients frequently describe an association with ingestion of fatty foods. A history of previous similar episodes may be obtained. Palpation of the abdomen may reveal epigastric/right upper quadrant tenderness but no evidence of peritoneal irritation. Blood investigations are usually normal.
In acute cholecystitis the pain is localised to the right upper quadrant, and also may radiate to the back or right shoulder tip. Because of peritoneal irritation the pain is exacerbated by movement and breathing. Commonly, the patient is nauseated and may have vomited. Systemic signs of inflammation including tachycardia and pyrexia may be present and abdominal examination will typically reveal right upper quadrant tenderness with signs of localised peritonitis. Classically, Murphy's sign (acute tenderness during palpation below the tip of the right ninth rib elicited on inspiration) can be observed in patients with acute cholecystitis. A tender gallbladder may occasionally be palpable in the right upper quadrant, particularly in the presence of an empyema. Haematological investigations typically demonstrate a leucocytosis and liver function tests (LFTs) may be mildly deranged. An obstructive picture to the LFTs may be a consequence of choledocholithiasis, but may also be a consequence of impacted gallstones in Hartmann's pouch pressing on or eroding into the common hepatic duct (Mirizzi syndrome) or contiguous inflammation affecting the biliary tree or adjacent hepatic parenchyma.
Initial Radiological Imaging
Transabdominal ultrasound is the initial investigation of choice in both biliary colic and acute cholecystitis and has a sensitivity of greater than 95% for detecting gallstones (see alsoChapter 5). In addition, ultrasound (US) can demonstrate signs of acute inflammation such as gallbladder wall thickening, pericholecystic fluid and a positive sonographic Murphy's sign (Fig. 8.1). US may also demonstrate gas in the gallbladder wall in patients with emphysematous cholecystitis. Newer techniques of colour velocity imaging and power Doppler ultrasound can provide additional information, and may therefore be helpful in distinguishing patients with true acute cholecystitis from those with upper abdominal pain and incidental cholelithiasis. In addition, transabdominal ultrasound can detect the presence of biliary tree dilatation, which may indicate choledocholithiasis, although the sensitivity for choledocholithiasis may be significantly impaired by obesity or gas within overlying bowel. In patients where US is equivocal either computed tomography (CT) or magnetic resonance imaging (MRI) can be helpful (Fig. 8.1).
FIGURE 8.1 (a) Ultrasound features of acute cholecystitis. Note the thickened gallbladder wall. The gallbladder contains stone and debris. This patient was also tender on pressing the transducer on to the gallbladder (sonographic Murphy's sign). (b) Addition of colour Doppler to help identify associated anatomy. (c) Axial CT image demonstrates cholecystitis with gallbladder wall thickening and adjacent parenchymal inflammatory changes in the liver. (d) Coronal MRCP reconstruction with a single calculus in the gallbladder and normal biliary tree.
Radionucleotide scintigraphy has historically been reported to have greater accuracy in diagnosing acute cholecystitis than standard US techniques. However, these techniques are time-consuming, involve the use of radiopharmaceuticals, and their use is now generally restricted to individuals who are clinically suspected of having abnormal gallbladder function in the presence of a normal ultrasound scan (gallbladder dyskinesia).
Management Of Patients With Acute Gallbladder Disease And Suspected Bile Duct Stones
Concomitant choledocholithiasis may be indicated by obstructive LFTs or US evidence of biliary dilatation and/or evidence of ductal calculi. In the acute setting several additional factors may complicate the decision-making process. Most importantly, if there are signs of generalised peritonitis, operative intervention cannot be deferred and investigation for CBD calculi becomes of secondary importance. In this situation, any ductal stones can be looked for at operation. It is also important to bear in mind the clinical overlap between acute cholangitis and acute cholecystitis, and patients with cholangitis due to CBD calculi may have upper abdominal tenderness and guarding. An appropriate index of suspicion together with findings on US should result in such individuals being appropriately treated for their ductal calculi.
In the majority of patients with acute biliary colic or cholecystitis who have deranged LFTs there will be an opportunity to assess the CBD preoperatively. The management options include endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP). MRCP has the advantage that it is non-invasive and is as accurate as ERCP in detecting bile duct stones (Fig. 8.2),2 as well as providing valuable additional information about more complex presentations, e.g. Mirizzi syndrome (Fig. 8.3). Nowadays, ERCP is reserved for therapeutic intervention, e.g. sphincterotomy and stone removal or stenting, rather than for diagnosis (Fig. 8.4).
FIGURE 8.2 MRCP demonstrating gallbladder stones and extensive choledocholithiasis extending into the intrahepatic biliary tree. The patient underwent laparoscopic cholecystectomy and bile duct exploration.
FIGURE 8.3 Coronal MRCP reconstruction demonstrates Mirizzi syndrome.
FIGURE 8.4 (a) EUS demonstrates a distal common bile duct stone. (b) The stone was removed at ERCP (endoscopic retrograde cholangiopancreatography). With thanks to Dr Ian Penman, Consultant Gastroenterologist, Royal Infirmary of Edinburgh, UK.
Guidelines on the management of CBD stones published by the British Society of Gastroenterology recommend that where initial assessment, based on clinical features, liver function tests and ultrasound findings, suggests a high probability of CBD calculi, then it is reasonable to proceed directly to ERCP if this is considered the treatment of choice.3 Where initial assessment suggests a low or uncertain index of suspicion for CBD calculi, then it is recommended that patients undergo MRCP or endoscopic ultrasound (EUS), with ERCP reserved for those with abnormal or equivocal results.
An alternative management strategy is to undertake intraoperative cholangiography during acute cholecystectomy (Fig. 8.5). If a ductal stone is demonstrated on intraoperative cholangiography, the options are to undertake laparoscopic CBD exploration, convert to an open procedure with exploration of the CBD or to perform a postoperative ERCP or, in some cases, intraoperative ERCP. The potential risk with adoption of a postoperative ERCP strategy is failure to cannulate at endoscopy; however, in practice, success rates are high with experienced endoscopists and few patients require further surgery.
FIGURE 8.5 Intraoperative cholangiograms obtained during laparoscopic cholecystectomy demonstrating a non-obstructing calculus in the cystic duct (a) and distal common bile duct (b).
Systematic reviews of studies reporting the outcome of laparoscopic CBD exploration report morbidity rates of between 2% and 17% and mortality rates of 1–5%.4 This is comparable to ERCP, with a Cochrane review of randomised controlled trials concluding that there was no clear difference in primary success rates, morbidity or mortality between the two approaches.5 However, it is important to note that the majority of these studies involved elective as well as emergency patients.
Although laparoscopic CBD exploration is a logical extension to laparoscopic cholecystectomy and is now becoming much more widely practised, the associated inflammation around Calot's triangle and the CBD in patients with acute cholecystitis may make laparoscopic exploration difficult and/or hazardous. A suggested algorithm for the management of patients with suspected biliary colic/acute cholecystitis and suspected CBD stones is described in Fig. 8.6.
FIGURE 8.6 Investigation and management of patients with biliary colic or acute cholecystitis and suspected bile duct stones. ERCP, endoscopic retrograde cholangiopancreatography; LFT, liver function tests; MRCP, magnetic resonance cholangiopancreatography.
The initial treatment for biliary colic consists of adequate analgesia and antiemetics. Although opiate analgesia is widely prescribed, non-steroidal anti-inflammatory drugs (NSAIDs) are also effective in relieving pain. Moreover, studies have suggested that NSAIDs can reduce the number of patients progressing from biliary colic to acute cholecystitis. Early laparoscopic cholecystectomy should be offered.
Initial therapy in acute cholecystitis includes intravenous fluid resuscitation, analgesia, a nil-by-mouth regimen and administration of intravenous antibiotics. Although the initial inflammation is sterile, secondary infection with aerobic Gram-negative organisms, enterococci and anaerobes occurs. Clostridium perfringens infection of the necrotic gallbladder may be a particular complication in the diabetic patient. Few data exist to support the optimum antibiotic regimen and local microbiology recommendations should be followed, although a second- or third-generation cephalosporin combined with metronidazole is frequently prescribed.
Urgent surgical intervention is indicated in those patients with generalised peritonitis arising from a gallbladder perforation or in those with emphysematous cholecystitis (Fig. 8.7). Outwith these circumstances, the therapeutic options are to remove the gallbladder, either during the index admission or, electively, at a later admission. Early operation has the advantage of prompt definitive therapy but surgical intervention may be technically more difficult. The rationale for deferred surgery is to allow for resolution of inflammation, but the patient remains at risk of exacerbations during the ‘waiting’ period, leading to readmission and increased healthcare-associated costs. In addition, as many surgeons can attest, subsequent ‘delayed’ surgery may still be technically very demanding. Several randomised trials over the last 15 years comparing early versus late laparoscopic cholecystectomy for acute cholecystitis have now confirmed that early laparoscopic cholecystectomy is both safe and has significant benefits for patients. Conversion rate, hospital stay and complications are all significantly lower in the early surgery group.6–8 A meta-analysis of five randomised clinical trials comparing early versus delayed laparoscopic cholecystectomy for acute cholecystitis has demonstrated that there is no difference in conversion rate or incidence of bile duct injury and the total hospital stay is shorter.9
FIGURE 8.7 CT image of emphysematous cholecystitis demonstrating gas in the gallbladder wall with extension into the hepatoduodenal ligament.
The benefits of early laparoscopic cholecystectomy over early open cholecystectomy have also been assessed.10 A total of 63 patients with acute cholecystitis were randomised to either early laparoscopic cholecystectomy (n = 32) or early open cholecystectomy (n = 31). Conversion to the open procedure was required in five patients randomised to laparoscopic cholecystectomy. Although there were no deaths or bile duct injuries in either group, the postoperative complication rate was significantly higher in the open group (P = 0.0048): seven patients (23%) had major and six (19%) had minor complications after open cholecystectomy, whereas only one (3%) minor complication occurred after the laparoscopic procedure. Both the postoperative hospital stay (median 4 days vs. 6 days; P = 0.0063) and duration of sick leave (mean 13.9 days vs. 30.1 days; P < 0.0001) were significantly shorter in the laparoscopic group.
Early laparoscopic cholecystectomy should be attempted in all patients with acute cholecystitis who are fit for surgery, recognising that there will be some in whom the acute inflammation prevents adequate visualisation of the anatomy and conversion will be required.6–10
It therefore follows that patients admitted to hospital as an emergency with acute biliary colic should also be offered early laparosocpic cholecystectomy.
Antibiotic Cover For Urgent Cholecystectomy:
Antibiotic therapy following successful early cholecystectomy for acute non-gangrenous cholecystitis does not need to be continued beyond 12 hours.11
Non-Surgical Options For Decompressing The Gallbladder In Acute Cholecystitis: Although early laparoscopic cholecystectomy is optimal management for acute cholecystitis, surgery may not be feasible in some patients because of comorbid conditions. In these patients US-guided percutaneous cholecystostomy is a useful alternative (Fig. 8.8). If the diagnosis is in doubt, such as might be the case in the critically ill patient on the intensive care unit, percutaneous cholecystostomy can also be diagnostic,12 with successful drainage of the gallbladder possible in up to 90% of patients.13 Although cannulation of the gallbladder may be achieved through a transperitoneal approach, a transhepatic approach is to be preferred because of the lower risk of biliary peritonitis and the earlier maturation of the cholecystostomy tract. Following insertion of the drainage tube into the gallbladder, free drainage is established. On occasions, simple aspiration of the gallbladder may be effective; however, a recent randomised trial concluded that placement of a percutaneous cholecystostomy drain was associated with a superior clinical response rate.14 With effective intervention, clinical improvement usually occurs within 24–48 hours; therefore, in those in whom rapid improvement does not occur, a complication, either of the original acute cholecystitis (gallbladder necrosis and/or perforation) or of the cholecystostomy tube placement (bile leak, visceral perforation, bleeding, etc.), should be suspected and surgical intervention should be reconsidered. The cholecystostomy tube should be maintained until a mature fistula tract is achieved, which usually forms within 3 weeks. Contrast radiology in the form of a ‘tubogram’ may be undertaken in order to confirm drain position, cystic and common bile duct patency, as well as the presence and site of any calculi.
FIGURE 8.8 Ultrasound of a patient with acute cholecystitis. (a) Before treatment; note the microabscesses within the thickened gallbladder wall. (b) After successful percutaneous transhepatic drainage. With thanks to Dr Paul Allan, Consultant Radiologist, Royal Infirmary of Edinburgh, UK.
A randomised clinical trial assessing the role of percutaneous cholecystostomy in patients with acute cholecystitis who are high-risk surgical candidates included 123 patients with acute cholecystitis and an Acute Physiological and Chronic Health Evaluation (APACHE) II score of 12 or greater.15 Patients were randomised to either percutaneous cholecystostomy (PC; n = 60) or to conservative therapy (C; n = 63). Percutaneous cholecystostomy was associated with a number of major complications in the initial stages of the trial, although this appeared to be due to the use of non-locking drains inserted under CT guidance. A change in technique to US transhepatic placement of locking drains helped to lower procedure-related complications. Nevertheless, in this trial rates of clinical resolution (PC 86% vs. C 87%) and mortality (PC 17.5% vs. C 13%) were similar between the two groups.
Percutaneous cholecystostomy should only be used in those patients not fit for surgery whose symptoms do not improve rapidly on standard non-operative therapy.15
The results of the current multicentre randomised controlled (CHOCOLATE) trial, comparing percutaneous cholecystostomy with laparoscopic cholecystectomy, are awaited.16
In patients who have not been offered early cholecystectomy for their acute cholecystitis, including those who have undergone cholecystostomy, following disease resolution, definitive therapy directed towards the gallbladder needs to be considered. Recurrent symptoms will occur in approximately one-third of patients who have previously had acute calculous cholecystitis and have not undergone definitive treatment.17 Therefore, interval cholecystectomy following optimisation of any comorbid disease should be considered. In those patients in whom surgical intervention is absolutely contraindicated, the cholecystostomy tube may be left in situ for a more prolonged period. Cholelithiasis may then be treated by percutaneous extraction of the gallstones or, less commonly, by direct dissolution with a solvent such as methyl-tert-butyl ether. However, recurrence of gallstones following these therapies is common, with studies suggesting that 10–20% of all patients treated by these methods develop further symptoms.18–20 As a result of these limitations, such approaches are not widely employed.
Management Of Acute Gallstone Disease In Pregnancy
Non-obstetric acute abdominal pain is relatively common in pregnancy, causes being similar to those in non-pregnant patients, and transabdominal US and MRI are the primary imaging modalities. Laparoscopic cholecystectomy is generally a safe therapeutic option in pregnancy.21 Although traditionally invasive approaches during the first trimester have been avoided, more recent data indicate that minimally invasive surgery can be conducted with relative safety in the first trimester.22,23 Biliary imaging may be performed with intraoperative ultrasound, or with limited exposure fluoroscopy and foetal shielding. Management decisions must be based on the efficacy or otherwise of non-operative measures, fully informed consent and with foetal–maternal benefits being considered on an individual basis.
Torsion of the gallbladder is rare, may be partial or complete and can result in gallbladder necrosis. It can present with clinical and radiological features of acute cholecystitis without gallstones. Treatment is by cholecystectomy.
Acute acalculous cholecystitis
Acute inflammation of the gallbladder can occur in the absence of gallstones and is termed acute acalculous cholecystitis (AAC). Although AAC may present as a complication of a number of clinical conditions, it occurs most frequently in the critically ill or postoperative patient. Despite the fact that AAC is an uncommon entity, it does appears to be increasing in frequency.24 Observational studies have suggested that AAC occurs in 0.004–0.05% of patients undergoing surgery.25,26 Although much less common than gallstone-induced acute cholecystitis, the mortality rate of AAC is significantly higher, in part reflecting the patient population affected.24
The pathogenetic mechanisms in AAC are not clear. Most recent evidence suggests that AAC is a consequence of microvascular ischaemia resulting in gallbladder inflammation. Studies have demonstrated that the gallbladder arterial and capillary network is reduced and irregular in AAC compared with that in acute cholecystitis.27 Furthermore, in animal models, the induction of a vasculitic process through the activation of factor XII causes AAC. As indirect evidence, AAC can occur as a consequence of systemic lupus erythematosus, polyarteritis nodosa and antiphospholipid syndrome. In critical illness states, gallbladder microvascular ischaemia probably occurs as a manifestation of the systemic inflammatory response syndrome.
The diagnosis of AAC is often difficult. Because it occurs principally in critically ill patients and in those who have recently had abdominal surgery, the symptoms and signs may be masked by coexisting problems. The critically ill patient may be sedated and/or ventilated, limiting the availability of historical information, and abdominal signs may be masked by sedation or drug-induced paralysis in the critical care setting. In the postoperative patient, abdominal signs may be limited by wound pain, and other more operation-specific complications may be considered as a cause for changes in the clinical condition.
Unfortunately, diagnostic imaging may also be unhelpful. Although US signs of AAC have been described (dilated gallbladder, gallbladder wall thickening, pericholecystic fluid and gallbladder sludge), these are not diagnostic. In a prospective series of 21 critically ill patients, all study subjects had gallbladder abnormalities on at least one occasion during serial US examinations; however, only four patients required intervention for AAC.28 Similarly, although CT may demonstrate gallbladder abnormalities, these signs may again be non-diagnostic. Cholescintigraphy may be the most accurate method of identifying AAC. In a retrospective study of 27 patients with AAC, cholescintigraphy detected AAC in 9 of 10 patients (90%), whereas CT detected AAC in 8 of 12 (67%) and US detected AAC in 2 of 7 (29%).29 However, these results must be viewed cautiously as every patient did not undergo all investigations. Moreover, other series have suggested a high incidence of false-positive cholescintigraphy scans in critically ill patients.30 Because of the inaccuracy of imaging studies, the definitive diagnosis of AAC may only be made at laparotomy or diagnostic laparoscopy.31 AAC must therefore be considered in all critically ill or postoperative patients with right upper quadrant pain, deranged LFTs or unexplained sepsis. With the difficulty of diagnosis in mind, one prospective study assessed the benefit of percutaneous cholecystostomy in 82 critically ill patients with unexplained sepsis.32 In 48 patients (59%) there was rapid improvement in the clinical condition within 48 hours but ultrasound did not predict which patients would respond to cholecystostomy.
The optimal therapeutic strategy in AAC is not clear. In all patients, broad-spectrum antibiotic therapy should be instituted as 65% of bile cultures will be positive, with Escherichia colithe most common organism. Therapeutic interventions include cholecystostomy with or without interval cholecystectomy, or early cholecystectomy. Several series have demonstrated that percutaneous cholecystostomy is not only an effective immediate intervention but may also constitute definitive treatment as the likelihood of recurrent episodes is small.33,34However, early cholecystectomy has been advocated because necrosis of the gallbladder may occur in up to 63% of cases,29,35 with perforation occurring in approximately 15%. It would therefore appear reasonable to manage AAC in critically ill patients with initial percutaneous cholecystostomy, but in the absence of rapid clinical improvement a complication should be presumed and cholecystectomy carried out. In those patients managed successfully by percutaneous cholecystostomy there does not appear to be an absolute requirement for interval cholecystectomy.
A high index of suspicion is required for the diagnosis of AAC in critically ill patients.32 Percutaneous cholecystostomy under either US or CT guidance is the primary treatment unless there are signs of overt peritonitis when cholecystectomy is indicated. Failure to improve after cholecystostomy is also an indication for cholecystectomy.
Acute cholangitis may be defined as an acute pyogenic infection within the biliary tree. Because of the possibility of rapid disease progression, acute cholangitis is a potentially life-threatening condition that requires urgent therapeutic intervention.
Acute cholangitis arises as a consequence of biliary stasis with subsequent bacterial infection. Although a number of pathological processes may lead to biliary stasis, the most common underlying causes of acute cholangitis are bile duct calculi, malignant bile duct obstruction and biliary stent occlusion. Biliary obstruction need not be complete as acute cholangitis can arise in a partially obstructed biliary system. Under normal conditions bile is sterile; however, in 58% of individuals with asymptomatic ductal calculi, bile cultures will be positive, indicating bacterial colonisation.36 In those progressing to acute cholangitis, cholangiovenous reflux of bacteria and bacterial products occurs because of increasing hydrostatic pressure within the biliary tree. This cholangiovenous reflux results in bacteraemia and the induction of a systemic inflammatory response, and it is this response, leading to organ dysfunction, that is responsible for the morbidity and mortality in acute cholangitis. Decompression of the biliary tree removes the inflammatory insult.
Aerobic Gram-negative bacilli (E. coli, Klebsiella, Pseudomonas species), enterococcus and anaerobes are the most common organisms cultured from the bile of patients with acute cholangitis.36 In up to 50% of patients, anaerobic organisms may be associated with aerobic organisms. In the elderly, polymicrobial infection is more common than monomicrobial infection, and again concomitant anaerobic infection occurs in the majority. In approximately 35% of patients, blood cultures will be positive for the same organisms that are found in the bile.37 The route of bacterial biliary colonisation is not clear; however, the types of bacteria involved suggest that they are derived from the intestinal tract.
The presentation of acute cholangitis can be variable, ranging from mild symptoms and signs to overwhelming septic shock. Classically, patients with acute cholangitis present with the symptoms and signs that constitute Charcot's triad: upper abdominal pain, jaundice and pyrexia. However, the complete triad may be present in as few as 22% of patients.38 In the elderly patient, the presentation may be subtle, with signs of an acute confusional state being common and deranged LFTs being the only pointer to the diagnosis. Similarly, acute cholangitis must be included in the differential diagnosis for any patient presenting with rigors. It is not uncommon for patients who have previously had endoscopic biliary stents to present with a rigor as the major feature of an obstructed and infected stent. At the other end of the spectrum, acute cholangitis can present with signs of septic shock and evidence of multiple organ dysfunction. Because the progression to septic shock can be rapid in patients with biliary obstruction, the diagnosis of acute cholangitis must be considered in any patient presenting with jaundice and signs of sepsis.
Cholestatic LFTs are found in the majority of patients with acute cholangitis, demonstrating elevated bilirubin, alkaline phosphatase and γ-glutamyl transferase. However, serum bilirubin may be normal in acute cholangitis arising in a partly obstructed biliary tree because the remaining unobstructed liver is able to compensate. A neutrophilia is typical and serum amylase may also be raised. Deranged coagulation tests can occur, either as a consequence of prolonged biliary obstruction resulting in vitamin K deficiency, or due to disseminated intravascular coagulation. Blood cultures must be obtained as soon as possible.
The initial radiological investigation of choice is transabdominal US. This may demonstrate signs of bile duct obstruction, although false-negative scans can occur. Ultrasound may also determine the underlying pathology. CT can identify biliary dilatation in 78% of patients with acute cholangitis as well as the level of obstruction in 65% and the cause of the obstruction in 61%;39 however, the initial information obtained is no greater than with US.
Although the determination of the exact site and nature of the bile duct obstruction may require direct visualisation with either ERCP or percutaneous transhepatic cholangiography (PTC), the true value of these procedures is their potential for therapeutic intervention. For this reason, although MRCP has recently been reported to be accurate in identifying biliary obstruction and the underlying obstructing lesion, it does not have an early role in managing patients with acute cholangitis.
Initial resuscitation aims to achieve adequate oxygen delivery, administration of an appropriate volume of intravenous fluid and appropriate analgesia. Efficacy of therapy is assessed by close monitoring of vital signs and, because of the potential for rapid decompensation, management of the patient in a high-dependency unit is usually required (see also Chapter 16).
Aerobic Gram-negative bacilli are the most common organisms in acute cholangitis and therefore empirical therapy with antibiotics covering these bacteria should be commenced. In addition, because anaerobic bacteria, although rarely cultured from blood, are frequently found in bile cultures in association with aerobic bacteria, antibiotic regimens should also have anaerobic activity. Piperacillin is an extended-spectrum penicillin with activity against aerobic Gram-negative bacilli, enterococcus and anaerobes. The addition of the β-lactamase inhibitor tazobactam increases the spectrum of activity.
In a randomised clinical trial involving 96 patients with acute cholangitis, piperacillin had similar efficacy to combination therapy with ampicillin and tobramycin, achieving clinical cure or significant improvement in 70% of patients.40 Another randomised trial assessing single antibiotic therapy37 demonstrated that intravenous ciprofloxacin alone improved the clinical condition in 85% of cases and had similar efficacy to a combination of ceftazidime, ampicillin and metronidazole.
Although appropriate antibiotic therapy is important, relief of biliary obstruction is crucial to successful disease resolution. Emergency operative intervention is associated with significant risk, with a reported mortality of 20% and a 50% complication rate for patients with severe acute cholangitis.41 As a result, the mainstay of treatment now is endoscopic bile duct drainage, with improved results compared with surgical intervention.42
The benefits of endoscopic therapy over surgery in patients with acute cholangitis were confirmed several years ago in a randomised controlled trial, with significantly fewer complications and lower mortality in those undergoing endoscopic drainage.42,43
The method used to achieve non-surgical biliary drainage would appear to be less important than simply achieving adequate drainage. Within the confines of a randomised trial, one study44 demonstrated that biliary decompression in acute cholangitis with a biliary stent inserted without a sphincterotomy was as efficacious as insertion of a nasobiliary drain. In patients in whom ERCP is unsuccessful, drainage by PTC should be undertaken in the acute situation, even in patients who do not have a dilated intrahepatic biliary tree.45 Once external drainage has been achieved in the first instance, the placement of a biliary stent can be organised as a staged procedure.
In the case of gallstone-related acute cholangitis, following resolution of the episode of acute cholangitis, adequate clearance of the bile duct should be confirmed by direct cholangiography, ERCP, high-quality MRCP or operative cholangiography. Cholecystectomy should be undertaken if there are no contraindications in order to reduce the risk of further gallstone-related problems.46,47
Acute pancreatitis is defined as an acute inflammatory process of the pancreas, with variable involvement of other regional or remote organ systems.48 It is a common acute illness, with epidemiological data from the Health Service Statistics Division in Scotland reporting an annual incidence of 318 cases per million (365 cases per million in men, 275 cases per million for women).49 Analysis of patterns of incidence in this particular population (which has remained relatively constant over the past decade) suggests an increase in the incidence of acute pancreatitis, particularly in those over 40 years of age. Similar increases in the incidence of acute pancreatitis have also been observed in Germany, Finland and Denmark. The factors giving rise to the observed increased incidences are not clear; however, at least in Finland, the increase in the incidence of acute pancreatitis is strongly correlated with an increase in alcohol consumption.
In practical terms the management of acute pancreatitis can be divided into two broad phases. The first phase includes the establishment of diagnosis, severity stratification, initial resuscitation and the choice of appropriate disease-specific initial therapy. The second phase relates to those with severe disease who will usually require further intervention for intra-abdominal complications or support for ongoing multiple organ failure. Guidelines50–52 suggest that patients with complications arising from severe acute pancreatitis are most appropriately managed in a unit with specialist expertise and therefore this chapter only focuses on the initial phase of management.
Within this chapter the terminology used to describe patients with acute pancreatitis is in keeping with definitions agreed by the 1992 Atlanta consensus conference (Box 8.1).48 The Atlanta classification attempted to introduce uniformity in the description of clinical severity and the various complications of the disease; however, with increasing understanding of the pathophysiology of pancreatitis, improved imaging techniques and newer therapeutic strategies, steps are being taken to revise the classification of acute pancreatitis. Alternative classfication techniques have already been proposed53 but still suffer from significant limitations as prognostic or predictive tools. A revision of the Atlanta criteria and management guidelines is anticipated.
Box 8.1 Terminology relating to acute pancreatitis as defined by the Atlanta consensus conference
Mild acute pancreatitis
Minimal organ dysfunction and an uneventful recovery
Severe acute pancreatitis
Associated with organ failure and/or local complications such as necrosis, abscess or pseudocyst
Acute fluid collections
Occur early in the course of acute pancreatitis, are situated in or near the pancreas, and always lack a wall of granulation or fibrous tissue
Diffuse or focal areas of non-viable pancreatic parenchyma, typically associated with peripancreatic fat necrosis
Collection of pancreatic juice surrounded by a wall of fibrous or granulation tissue
Circumscribed intra-abdominal collection of pus arising in close proximity to the pancreas, but containing little or no pancreatic necrosis, which arises as a consequence of acute pancreatitis
Acute pancreatitis may be caused by a wide variety of aetiological agents (Box 8.2), although the majority of cases are due to either gallstones or alcohol excess. Recent epidemiological studies have demonstrated that alcohol excess is an increasingly frequent cause of acute pancreatitis. The prevalence of idiopathic acute pancreatitis varies between reported series and is probably a function of the degree of investigation undertaken to identify a cause. Recent UK guidelines state that no more than 20% of patients should be labelled as having idiopathic acute pancreatitis.51
Box 8.2 Aetiological agents in acute pancreatitis
Endoscopic retrograde cholangiopancreatography
Pancreatic duct obstruction
Ampulla of Vater neoplasia
The mechanisms through which each aetiological agent causes pancreatic acinar cell injury are not clear. However, after the initial pancreatic insult, it is believed that regardless of the aetiological agent the pathogenetic mechanisms of disease progression in acute pancreatitis are similar. Following pancreatic acinar cell injury, local pancreatic inflammation occurs. Although the inflammatory process may remain confined to the pancreas and peripancreatic tissues, a systemic inflammatory response may be triggered. This systemic inflammatory response is characterised by the systemic activation of leucocytes and endothelial cells and the secretion of proinflammatory cytokines, and is responsible for the development of the organ dysfunction that characterises severe acute pancreatitis. It is not clear why some patients develop severe acute pancreatitis whilst others with similar aetiological agents develop mild acute pancreatitis; however, there is evidence to implicate both excessive proinflammatory mediators and decreased anti-inflammatory mechanisms.
Presenting symptoms may range from mild discomfort to overwhelming abdominal pain. Typically, patients present with increasing epigastric/central abdominal pain radiating through to the back. This pain may be eased by sitting forward. Nausea is a predominant early symptom, with associated vomiting or retching. Before presenting with gallstone-induced acute pancreatitis, patients may have had symptoms consistent with biliary colic. Likewise, in alcohol-induced acute pancreatitis, patients will often have a long history of alcohol ingestion and/or recent binge drinking.
Signs of cardiovascular and respiratory dysfunction may be present. Examination may reveal abdominal signs ranging from localised epigastric tenderness to generalised peritonitis. More specific signs of severe acute pancreatitis include periumbilical bruising (Cullen's sign) and flank bruising (Grey Turner's sign; Fig. 8.9).
FIGURE 8.9 Grey Turner's sign in severe acute pancreatitis. Reproduced from Powell JJ, Parks RW. Diagnosis and early management of acute pancreatitis. Hosp Med 2003; 64:150–5. With permission from the BJHM.
Diagnosis (See Also Chapter 5)
Traditionally, the diagnosis of acute pancreatitis has depended on the detection of a serum amylase concentration more than three times the upper limit of normal. However, hyperamylasaemia may occur in several other conditions (Box 8.3), and a serum amylase concentration above the ‘diagnostic’ threshold does not definitely indicate acute pancreatitis. Conversely, acute pancreatitis may exist with serum amylase concentrations below this threshold. In those patients with a prolonged history prior to admission to hospital, serum amylase concentrations may have normalised. Amylase measurement therefore needs to be timely. Serum amylase levels do not provide prognostic information, nor can they be followed in order to monitor the early disease process. However, very high levels of serum amylase on admission are often suggestive of a gallstone aetiology.
Box 8.3 Main differential diagnoses of hyperamylasaemia
Because of the limitations of the serum amylase test, other markers have been used to diagnose acute pancreatitis. Serum lipase is perhaps the most common and is more sensitive and specific than serum amylase. Moreover, because of its longer half-life, serum lipase is more accurate if there has been a delay in obtaining the initial sample.50 However, as with serum amylase, serum lipase concentrations do not correlate with disease severity. In contrast, newer markers such as urinary trypsinogen activation peptide and serum carboxypeptide B activation peptide provide both diagnostic and prognostic information, although these are not assayed routinely in most units.
Although the vast majority of cases of acute pancreatitis can be diagnosed either clinically or biochemically, contrast-enhanced CT may be required in equivocal cases (Fig. 8.10).
FIGURE 8.10 (a) Contrast-enhanced CT image of severe acute pancreatitis demonstrating extensive necrosis with gas. (b) A radiologically guided drain has been placed. (c) Minimally invasive necrosectomy was performed to remove solid debris.
Finally, in a few patients, laparotomy may be required to confirm the diagnosis of acute pancreatitis while refuting other potential diagnoses such as acute mesenteric ischaemia or a perforated peptic ulcer. The decision to undertake diagnostic laparotomy should not be made lightly as there is evidence that early operation has an adverse effect on outcome in acute pancreatitis.54 In contrast, patients with acute intestinal ischaemia may present with abdominal pain and hyperamylasaemia and diagnostic delay may be critical. If the pancreas appears normal on CT, and in the absence of a firm diagnosis, laparoscopy or laparotomy should be considered if there are ongoing signs of peritonitis. Clearly, access to CT on a 24-hour basis is a prerequisite for this strategy.
Establishment Of Aetiology
Following diagnosis, usually confirmed biochemically, transabdominal US should be undertaken in all patients with acute pancreatitis within 24 hours to determine the presence or absence of gallstones. For those patients in whom alcohol is thought to be the causative agent, an accurate alcohol history must be taken, with corroborative information being obtained from other sources as necessary. In patients where alcohol is effectively excluded as a causative agent and no other biochemical cause is identified, it is reasonable to repeat transabdominal US. Endoscopic ultrasound should be considered for patients without an identified aetiology as this may demonstrate biliary microlithiasis (Fig. 8.11), in which case cholecystectomy should be considered.
FIGURE 8.11 Endoscopic ultrasound detection of gallbladder microlithiasis in a patient with recurrent pancreatitis. Transabdominal ultrasound was normal. Following laparoscopic cholecystectomy there have been no further episodes of pancreatitis. Courtesy of Dr Ian Penman, Edinburgh
Guidelines for the initial management of acute pancreatitis have been published by the 1997 Santorini consensus conference,50 the British Society of Gastroenterology,51 the American College of Gastroenterology,52 the Japanese Society of Abdominal Emergency Medicine55,56 and the International Association of Pancreatology.57 Their recommendations are broadly similar and are described below.
As in other acute abdominal emergencies, initial therapy is aimed at adequate resuscitation (see also Chapter 16). Provision of oxygen to maintain arterial oxygen saturation, intravenous fluid therapy and adequate analgesia constitute the mainstays of therapy. In addition, the correction of metabolic abnormalities such as hyperglycaemia or hypocalcaemia may require administration of intravenous insulin or calcium. Patients with acute pancreatitis should be started on some form of thromboprophylaxis (see also Chapter 14). Antacid therapy with H2antagonists, proton-pump inhibitors or other gastroprotective agents may be commenced as prophylaxis against upper gastrointestinal haemorrhage in those patients with severe disease.
Following resuscitation, patients should be categorised into either prognostically mild or severe disease, allowing decisions to be taken regarding the degree of monitoring, supportive care and intervention appropriate for each patient. Subjective clinical assessment of prognosis is inaccurate and a validated prognostic scoring system should be used. A number of systems currently exist and can be divided as follows:
It should be noted that the Ranson score is based on a North American population with alcohol as the predominant aetiological agent, whereas the Glasgow score is designed for use in a typical British population of gallstone-predominant disease. Furthermore, practical confusion can result from the fact that there are at least three versions of the ‘Glasgow’ score: the original publication in 197858 and subsequent modifications in 198159 and 1984.60 An APACHE II score of 9 or more has been validated for predicting prognostic severity in acute pancreatitis,68 although a number of clinical trials have used lower cut-off points in order to predict severe disease, resulting in lower positive predictive values. Although an APACHE II score can be generated soon after admission, unlike the Ranson and Glasgow systems, it has the disadvantage of requiring collation of a sizeable number of variables. Comparative studies of the commonly used scoring systems have reported that no single system is superior to the others.69 Accuracy to predict prognosis is typically 75–80%; however, a recent modification of the APACHE II system, which includes a clinical assessment of obesity (APACHE-O score), has been suggested to further improve predictive accuracy70 and accuracy rates as high as 95% have been reported using computerised artificial neural networks.71
Finally, it should be noted that the currently used prognostic systems are a one-off or static assessment and serial or dynamic assessment may provide a more accurate determination of outcome. Indeed, it would appear that it is not the presence of organ dysfunction at presentation that is important in determining outcome, rather it is the response to initial resuscitation. Several authors have demonstrated that clinical outcome is worst in patients with persistent organ dysfunction, as manifested by worsening or static organ dysfunction scores following initial resuscitation, compared with patients whose organ dysfunction scores improve.72–74
Imaging in acute pancreatitis
As already mentioned, US should be performed in order to confirm or exclude the presence of gallstones. Following this, all patients with prognostically ‘severe’ acute pancreatitis should undergo contrast-enhanced CT between the third and tenth days of admission to determine the presence of pancreatic necrosis.51
Specific Therapies For Acute Pancreatitis
The majority of patients recover from an episode of acute pancreatitis without complication and require little intervention. However, despite intense biomedical research activity there remains a dearth of effective specific therapies for severe acute pancreatitis. The importance of vigorous volume resuscitation and careful monitoring and treatment for metabolic, respiratory, renal and cardiac complications cannot be overemphasised. However, in addition to this supportive care, the therapeutic options are limited. Several randomised controlled trials have assessed the role of early ERCP and prophylactic antibiotics; however, controversy still persists regarding the relative values of both these therapeutic options. These treatments, together with other potential therapeutic options, are reviewed below.
Early ERCP with endoscopic sphincterotomy (ES) in gallstone-induced acute pancreatitis aims to remove impacted ductal gallstones, thereby eliminating the initiating stimulus and hopefully reducing pancreatic inflammation. Three randomised trials assessing early ERCP have been published. They have produced some conflicting results and so it is worth discussing the results in some detail.
Neoptolemos et al.75 randomised 121 patients with gallstone-induced acute pancreatitis, 53 of whom had prognostically severe disease, to either early ERCP (n = 59) or conventional therapy (n = 62). Although there was no difference in mortality between the two groups (1 for ERCP vs. 5 for conventional therapy; P = 0.23), there was a significant reduction in total complications (17% ERCP vs. 34% conventional; P = 0.03) and duration of hospital stay (median 9.5, range 6–36 days ERCP vs. 17.0, range 4–74 days conventional; P = 0.035) in those patients with prognostically severe disease. Similarly, Fan et al.76 randomised 195 patients with acute pancreatitis, of whom 127 had gallstone-induced disease and 81 had prognostically severe disease, to either early ERCP (n = 97) or conventional therapy (n = 98). Again, there was no significant difference in mortality rates between the two groups (5 for ERCP vs. 9 for conventional therapy; P = 0.276). However, there was a significant reduction in the incidence of biliary sepsis following ERCP in those with prognostically severe acute pancreatitis (0% ERCP vs. 20% conventional; P = 0.008). Moreover, in those patients with gallstones a significant reduction in overall morbidity was observed (16% ERCP vs. 33% conventional; P = 0.003).
In contrast, a multicentre trial undertaken by Folsch et al.77 randomised 238 patients with gallstone-induced acute pancreatitis but without evidence of biliary obstruction to undergo either early ERCP (n = 126) or conventional management (n = 112). In total only 46 patients had prognostically severe disease. In contrast to the previous studies, the mortality rate was higher in the groups undergoing ERCP (10 for ERCP vs. 4 for conventional therapy; odds ratio (OR) 4.57, 95% confidence interval (CI) 0.67–62.7; P = 0.16). Furthermore, ERCP was associated with an increased rate of respiratory failure (15 for ERCP vs. 5 for conventional, OR 5.16, 95% CI 1.63–22.9; P = 0.03). Because of the trend towards increased mortality and the significantly increased rate of respiratory failure in those undergoing ERCP, the trial supervisory committee terminated the study early.
The Dutch Acute Pancreatitis Study Group reported an observational multicentre study in eight university medical centres and seven major teaching hospitals involving 153 patients with predicted severe acute biliary pancreatitis without cholangitis who were enrolled in a randomised multicentre probiotic trial and who were prospectively followed. Conservative treatment or ERCP within 72 hours after symptom onset were compared, management being based on the discretion of the treating physician. Patients without and with cholestasis (bilirubin: > 40 μmol/L and/or common bile duct dilatation) were analysed separately. In the 51% of patients with cholestasis, ERCP was associated with fewer complications than conservative treatment (25% vs. 54%, P = 0.020; multivariate adjusted OR 0.35, 95% CI 0.13–0.99, P = 0.049). Mortality was non-significantly lower after ERCP (6% vs. 15%, P = 0.213, multivariate adjusted OR 0.44; 95% CI 0.08–2.28, P = 0.330). In patients without cholestasis, ERCP was not associated with reduced complications (45% vs. 41%, P = 0.814; multivariate adjusted OR 1.36, 95% CI 0.49–3.76, P = 0.554) or mortality (14% vs. 17%, P = 0.754; multivariate adjusted OR 0.78, 95% CI 0.19–3.12, P = 0.734).78
Rationalisation of the results of the fully reported trials suggests that early ERCP/ES is of benefit in patients with prognostically severe gallstone-induced acute pancreatitis with evidence of cholangitis or biochemical evidence of obstructive liver function tests (serum bilirubin > 90 μmol/L).75–79
The administration of prophylactic antibiotics in acute pancreatitis is based on the hypothesis that the prevention of infected pancreatic necrosis would improve outcome. Numerous studies have been undertaken to investigate this hypothesis and differing results have led to much debate. Early clinical studies did not show any benefit, possibly due to inclusion of patients with a low risk of infection or because antibiotics with poor pancreatic penetration were used. In the light of these conflicting reports and more recent meta-analyses the details of these studies are worth considering further.
In a multicentre trial published in 1993,80 74 patients with CT-proven pancreatic necrosis were randomised to receive either imipenem or no initial antibiotic therapy. Pancreatic infection was significantly reduced in the antibiotic-treated group (30% vs. 12%; P < 0.001). Furthermore, rates of non-pancreatic infection were also significantly reduced; however, antibiotic therapy had no effect on the development of multiple organ failure, the need for operative intervention or on the mortality rate.
A Finnish study81 randomised 60 patients with CT-proven pancreatic necrosis to receive either prophylactic intravenous cefuroxime or antibiotics only when there were clinical indications of infection. Although there was no difference in the rates of pancreatic infections between the two groups (30% cefuroxime vs. 40% control), prophylactic cefuroxime significantly reduced the mean number of infectious complications per patient (1.0 vs. 1.8; P < 0.01), mainly through a marked fall in the number of urinary tract infections. There was also a significant reduction in mortality in patients treated with cefuroxime (23.3% vs. 3.3%; P = 0.028), although this was not associated with any difference in local pancreatic infection.
Another study82 randomised 23 patients with alcohol-induced severe acute pancreatitis to either standard medical therapy or standard medical therapy plus intravenous ceftazidime, amikacin and metronidazole. Antibiotic therapy resulted in a significant reduction in the number of patients with proven infections (0 vs. 7; P < 0.03), but there was no significant reduction in mortality rates. Schwarz et al.83 reported a randomised controlled trial of 26 patients with CT-proven pancreatic necrosis in which the combination of ofloxacin and metronidazole lessened the physiological disturbance found in severe acute pancreatitis, but did not prevent or delay the development of infected pancreatic necrosis.
Subsequently two further studies were published that compared different antibiotic regimens in patients with necrotising pancreatitis. The first of these,84 a multicentre, randomised controlled trial involving 60 patients with pancreatic necrosis, observed that intravenous imipenem was more effective than perfloxacin at reducing rates of both infected pancreatic necrosis (34% vs. 10%; P = 0.034) and extrapancreatic infection (44% vs. 20%; P = 0.059), but had no effect on the mortality rate. The second of these studies again examined the effect of imipenem85 in a randomised trial comparing the prophylactic use of imipenem with the therapeutic use of imipenem in patients with severe acute pancreatitis and CT-proven pancreatic necrosis. Patients enrolled in the prophylactic arm received imipenem from the time of admission, whereas patients in the therapeutic arm only commenced imipenem following the development of signs suggesting the development of infected pancreatic necrosis (pyrexia, leucocytosis, raised CRP, in the absence of another source of infection). There was no significant difference in the number of patients requiring necrosectomy or in the mortality rate between the two groups.
The largest randomised placebo-controlled, double-blind trial on the use of prophylactic antibiotics was published in 2004.86 This multicentre study randomised 114 patients to receive either ciprofloxacin in combination with metronidazole or placebo. Only patients with a predicted severe attack were included, defined either by an elevated serum C-reactive protein above 150 mg/L or by pancreatic necrosis on CT scan. No beneficial effects with regard to reduction of pancreatic infection, systemic complications or hospital mortality were demonstrated; however, a shift to open antibiotic treatment was more frequent in patients receiving placebo, suggesting a subgroup of patients may warrant antibiotic treatment.
Using a different strategy aimed at eliminating the reservoir from which bacteria arise to colonise pancreatic necrosis, Luiten et al.87 evaluated the role of selective gut decontamination. In a multicentre trial, 102 patients with prognostically severe acute pancreatitis were randomised to either conventional therapy or conventional therapy supplemented with selective gut decontamination using oral and rectal colistin, amphotericin and norfloxacin. In addition, patients in the selective gut decontamination group received intravenous cefotaxime until aerobic Gram-negative bacteria were eliminated from the oral cavity and rectum. Selective gut decontamination reduced rates of pancreatic infection compared with the control group (38% vs. 18%; P = 0.03). Although there was a reduction in mortality from 35% in the control group to 22% in the selective decontamination group, it did not reach significance (P = 0.19). However, when allowing for differences in disease severity, multivariate analysis suggested a significant survival benefit following gut decontamination (P = 0.048). Although the results of this trial appear promising, selective gut decontamination is not regarded as a standard for the prevention of pancreatic infection because of the difficulties of drug administration in the intensive care setting.
The inconsistencies among these trials may result from the relatively small number of patients per study and the limited statistical power to detect such differences. There is also considerable heterogeneity in patient selection and the antibiotics used. Other differences include variety in the non-antibiotic treatments, such as fluid resuscitation, enteral nutrition and timing of surgical intervention. Although many published guidelines recommend the use of antibiotics in patients with severe acute pancreatitis, none of the published randomised trials is in itself of sufficient power to mandate antibiotic prophylaxis.
In an attempt to strengthen the evidence regarding the use of antibiotic prophylaxis in acute pancreatitis, several meta-analyses have been performed. In 1998, Golub et al.88 undertook a meta-analysis of all trials that had been published up to that point and reported that in patients with severe disease, the risk of death fell from 18.2% in patients not receiving antibiotic prophylaxis to 5.3% in those receiving prophylaxis (log odds ratio − 0.32 to − 2.44; P = 0.008). Similarly, Sharma and Howden89 undertook a meta-analysis of three of the trials utilising broad-spectrum antibiotics in patients with severe disease. They suggested that antibiotic prophylaxis resulted in a 12.3% (95% CI 2.7–22%) absolute risk reduction in mortality rate, with eight (95% CI 5–37) patients needing treatment to prevent one death.
More recent meta-analyses, however, do not support the use of prophylactic antibiotics in patients with severe acute pancreatitis. In 2006, Mazaki et al.90 analysed six trials and concluded that prophylactic antibiotics were not associated with a statistically significant reduction in infected necrosis (relative risk 0.77, CI 0.54–1.12; P = 0.173), non-pancreatic infections (relative risk 0.71, CI 0.32–1.58), surgical intervention (relative risk 0.78, CI 0.55–1.11) or mortality (relative risk 0.78, CI 0.44–1.39), but were associated with a significant reduction in hospital stay. In 2007, de Vries et al.91 undertook a meta-analysis on six trials and reported that prophylactic antibiotics had no significant effect on infection of pancreatic necrosis (absolute risk reduction 0.055, CI − 0.084 to 0.194) or mortality (absolute risk reduction 0.058, CI − 0.017 to 0.134).
Furthermore, there is concern that the use of potent antibiotics may increase the rate of fungal-associated infected pancreatic necrosis and in turn adversely affect outcome. The use of antibiotic therapy has been shown to alter the organisms involved in the development of infected pancreatic necrosis,92 and it has been suggested that higher rates of fungal infection have been reported in recent studies.93 There is currently debate as to whether fungal-associated infected pancreatic necrosis is associated with increased mortality; however, a recent randomised trial of antifungal therapy in patients with severe acute pancreatitis showed a definite reduction in the incidence of fungal infection in the treatment group.94
In the light of all these conflicting studies, it is clear that further trials are needed to clarify the role of antibiotic and antifungal prophylaxis in acute pancreatitis. At present, a pragmatic approach is that routine administration of prophylactic antibiotics to all patients with predicted severe acute pancreatitis is not indicated, but should be considered in those patients with evidence of pancreatic necrosis who appear septic (with leucocytosis, fever and/or organ failure). If blood and other cultures are subsequently found to be negative and no source of infection is identified, antibiotics should be discontinued. If positive microbiological cultures are obtained, appropriate antibiotics should be continued based on microbiological sensitivities.88–91
Early enteral nutrition
In those patients with severe acute pancreatitis the systemic inflammatory response may be maintained by intestinal dysfunction, leading to bacterial translocation from the intestinal lumen. Intestinal dysfunction may in part be a consequence of the nil-by-mouth regimen, leading to a loss of luminal nutrition in the intestine. The provision of enteral nutrition aims to ameliorate intestinal dysfunction, thereby reducing the systemic inflammatory response and improving outcome.
This hypothesis was assessed in a randomised study of 32 patients with acute pancreatitis who received either early enteral nutrition through an endoscopically placed feeding tube, or parenteral nutrition following central or peripheral venous cannulation.95 Enteral nutrition appeared to be well tolerated, with no patients developing a significant complication from the study intervention. Importantly, enteral nutrition was able to supply a similar caloric intake to parenteral nutrition. However, the patients in the study had relatively mild disease and thus no significant differences in clinical outcome were observed, although enteral nutrition was associated with a significant reduction in the cost of patient care.
A similar study that randomised 34 patients with acute pancreatitis to receive, in addition to standard therapy, either early enteral nutrition or parenteral nutrition demonstrated that the introduction of early enteral nutrition was associated with a significant reduction in CRP and APACHE II scores.96 Furthermore, in those receiving parenteral nutrition, serum anti-endotoxin IgM antibody levels increased, whereas they remained unchanged in those receiving enteral nutrition.
In contrast to the previous two studies, all patients in the randomised controlled trial reported by Kalfarentzos et al.97 had prognostically severe disease. In total, 38 patients were randomised to receive either enteral nutrition or parenteral nutrition. Enteral nutrition was delivered distal to the ligament of Treitz through a radiologically placed feeding tube. Even in this population of patients with severe disease, enteral nutrition was well tolerated, with the protein and caloric intake equalling that administered to the patients receiving parenteral nutrition. This ability to provide adequate nutrition via the enteral route appeared to translate into a clinical benefit. In those patients receiving enteral nutrition there were significantly fewer complications and a significant reduction in the number of infectious episodes. Further, the cost of nutritional support in the enteral feeding group was one-third of that in the parenteral nutrition group.
A slightly different study randomised 27 patients with prognostically severe acute pancreatitis to either enteral nutrition or standard care, where parenteral nutrition was not instituted from the outset.98 Although no major complications arose from the provision of enteral nutrition, it was not possible to meet full nutritional requirements. In contrast to previous studies, enteral nutrition did not appear to affect markers of the inflammatory response (IL-6, tumour necrosis factor receptors and CRP). Moreover, the institution of enteral nutrition was associated with a significant deterioration in gut barrier function.
A large study from China99 randomised 96 patients with severe pancreatitis to parenteral nutrition versus nasojejunal feeding. Measures of inflammation including CRP and IL-6 decreased earlier with enteral nutrition, as did APACHE II scores. Furthermore, mucosal permeability was improved, as inferred by urine endotoxin levels.
In an attempt to determine the efficacy of both enteral nutrition and antibiotic prophylaxis, Olah et al.100 undertook a two-phase study. In the first phase, patients within 72 hours of the onset of prognostically severe acute pancreatitis were ‘randomised’ to either parenteral nutrition or enteral nutrition delivered by a nasojejunal feeding tube. In this phase of the study there was no significant difference in the rates of septic complications between the two treatment groups. The second phase of the study was a prospective cohort study, with all patients being given enteral nutrition and imipenem with prophylactic intent, with subsequent comparison of outcome measures obtained in phase 2 with those obtained in phase 1. Following their analysis, the authors of this study stated that the combination of enteral nutrition and antibiotic prophylaxis significantly reduced the rate of septic complications and the requirement for surgical intervention when compared with parenteral nutrition. However, the results of the study have to be interpreted with caution. The initial phase of the study was not truly ‘randomised’, with patients being allocated to treatment groups according to date of birth, whereas the second phase involved comparison of historical cohorts. Both of these flaws may have resulted in bias.
Another small study randomised 17 patients with prognostically severe acute pancreatitis (APACHE II score = 6) to either enteral nutrition through a nasojejunal tube (n = 8) or parenteral nutrition (n = 9).101 Not surprisingly, given the small numbers enrolled in the trial, there was no significant difference in morbidity between the two treatment groups, although the use of enteral nutrition was associated with an earlier institution of normal diet and resumption of normal bowel opening.
The interpretation of the results of all the published trials assessing the role of enteral nutrition and the subsequent translation of these into evidence-based clinical practice is difficult. Firstly, all the trials have insufficient power to determine the effects of enteral nutrition on the most relevant outcome measures of morbidity and mortality. The conclusions of two meta-analyses, one of which reported on six studies102 and the other on two of the six studies,103 were contradictory. In one, enteral nutrition was favoured;103 in the other, the interpretation was that there were insufficient data upon which to make firm judgments.102 Secondly, all the randomised trials to date have delivered enteral nutrition through a nasojejunal feeding tube requiring either radiological or endoscopic placement. However, a prospective observational study has reported that successful nasogastric feeding can be achieved in patients with severe acute pancreatitis.104 Early nasogastric and nasojejunal feeding appear equivalent in patients with objectively graded severe acute pancreatitis.105 Thirdly, other than the trial conducted by Powell et al.,98 enteral nutrition was compared with early parenteral nutrition. In general, it is not standard practice to commence parenteral nutrition in patients immediately following admission with acute pancreatitis. Furthermore, it is possible that the observed ‘benefits’ from the institution of enteral nutrition, as compared with parenteral nutrition, are in fact due to the induction of deleterious effects by parenteral nutrition. It has been demonstrated that a nil-by-mouth regimen and the institution of parenteral nutrition in normal volunteers is associated with an increased inflammatory response following a stimulus,106 and malnourished patients have an impairment of intestinal function and increased markers of the acute-phase response. Furthermore, the use of parenteral nutrition in acute pancreatitis is associated with a significant increase in line sepsis when compared with standard management.107
The Dutch PYTHON multicentre trial108 plans to recruit 208 patients with predicted severe acute pancreatitis and randomise to a very early (< 24 h) start of enteral nutrition versus introducing oral diet and enteral nutrition if necessary at around 72 hours after admission. The 3-year trial is designed to determine whether very early feeding reduces the combined end-point of mortality or infections.
Although there is no definitive evidence demonstrating that early enteral nutrition improves outcome in severe acute pancreatitis, all published studies demonstrate that enteral nutrition is feasible, safe and does not exacerbate the disease process. Further trials are required to determine the impact of early enteral nutrition in predicted severe acute pancreatitis on infectious complications and disease outcome.102,103
Other potential treatment strategies
Probiotic Therapy: The use of probiotic therapy in acute pancreatitis is based on the hypothesis that colonisation of the proximal gastrointestinal tract by pathogenic bacteria is a precursor to the development of infected pancreatic necrosis. Probiotic therapy therefore aims to establish colonisation of the gastrointestinal tract by non-pathogenic bacteria, thereby reducing the risk of infective complications. This hypothesis was tested by randomising 45 patients with acute pancreatitis, 32 of whom had severe disease, to receive either live Lactobacillus plantarum(n = 22) or killed Lactobacillus plantarum (n = 23) delivered via a nasojejunal feeding tube, along with oat fibre as a bacterial substrate.109 All patients received a standard enteral nutrition formula in addition to the live or killed L. plantarum. Within this trial, probiotic therapy appeared to reduce the risk of developing either infected pancreatic necrosis or abscess. One patient who received live L. plantarum developed pancreatic infection compared with seven patients in the control group (P = 0.023).
The controversial PROPATRIA trial, a multicentre randomised, double-blind, placebo-controlled trial, recruited 298 patients with predicted severe acute pancreatitis (Acute Physiology and Chronic Health Evaluation (APACHE II) score ≥ 8, Imrie score ≥ 3 or CRP > 150 mg/L) within 72 hours of onset of symptoms to receive a multispecies probiotic preparation (n = 153) or placebo (n = 145), via the enteral route twice daily for 28 days. An unexpected more than doubling in mortality in the treatment arm was reported.110 This trial provoked extensive discussion regarding its design, execution, analysis and safety monitoring.
As a result of the current evidence available, the use of probiotics in patients with severe acute pancreatitis cannot be recommended.109,110
Anticytokine Therapy: With increased understanding of the pathogenetic mechanisms in acute pancreatitis, it is hoped that novel therapies will be developed that can perturb these mechanisms and improve outcome. Indeed, a large number of agents that either antagonise the proinflammatory response or augment the anti-inflammatory response have been demonstrated to ameliorate disease severity in animal models of acute pancreatitis. However, it should be noted that in these studies the agent is usually administered before or immediately after the induction of acute pancreatitis, a scenario that does not translate to the clinical situation. One such agent to undergo clinical trials was lexipafant, a high-affinity platelet-activating factor receptor antagonist, which acts as a general down-regulator of the proinflammatory cytokine response. On the basis of encouraging results from initial trials, a large multicentre trial recruiting 1500 patients was undertaken. Although the trial results have not been formally reported, it is widely known that there was no improvement in mortality following the use of lexipafant, and that the manufacturers are now no longer pursuing this drug as a treatment for severe acute pancreatitis.
It is expected that further drugs that perturb the pathogenetic mechanisms of acute pancreatitis will be developed and will undergo clinical trials.
Current UK guidelines provide targets for mortality rates in acute pancreatitis.51 These guidelines state that overall mortality should be less than 10% of patients admitted with acute pancreatitis, with a mortality rate less than 30% in those with prognostically severe disease. Certainly, epidemiological data published in 1999 suggested that there had been a significant reduction in mortality rates between 1984 and 1995.49
Treatment Of Gallstones In Acute Gallstone Pancreatitis
In 1988, before laparoscopic surgery, Kelly and Wagner111 randomised 165 patients with gallstone-induced acute pancreatitis to either early (n = 83) or late (n = 82) biliary surgery, with early surgery being undertaken within 48 hours of admission. In those with mild acute pancreatitis (n = 125) there was no significant difference in outcome between the two groups (morbidity: early 6.7% vs. late 3.3%, P > 0.10; mortality: early 3.1% vs. late 0%, P > 0.10). However, in those with severe acute pancreatitis (n = 40) early biliary surgery resulted in a significant increase in morbidity and mortality (morbidity: early 82.6% vs. late 17.6%, P < 0.001; mortality: early 47.8% vs. late 11%, P < 0.025). A recent prospective study112 randomised 50 patients with mild gallstone pancreatitis to laparoscopic cholecystectomy performed within 48 hours of admission, regardless of the resolution of abdominal pain or serum biochemistry, or performed once pain had resolved and biochemistry was normalising. The primary end-point, hospital length of stay, was significantly shorter in the early surgery group, with no apparent impact on the technical difficulty of the procedure or perioperative complication rate. However, careful patient selection for such early surgery remains important as other considerations may influence decision-making, such as further investigation and/or treatment of abnormal LFTs, persistent fever and so on, which may complicate assessment of the patient after laparoscopic cholecystectomy. As a result most surgeons still prefer to wait a few days until the acute attack has resolved before proceeding (still during the same hospital admission) with removal of the gallbladder.
British Society of Gastroenterology guidelines recommend that patients with gallstone-induced mild acute pancreatitis should undergo cholecystectomy (laparoscopic) during the same hospital admission unless a clear plan for definitive treatment within the following 2 weeks has been made.51 In patients with severe comorbid disease contraindicating cholecystectomy, definitive treatment may be provided by ERCP and ES. In those with gallstone-induced severe disease, cholecystectomy should be delayed until disease resolution or undertaken as an additional procedure during surgery for a complication of the acute pancreatitis.
Managing The Acute Sequelae Of Acute Pancreatitis
Many patients with pancreatic necrosis require minimal if any local intervention.113 In those patients requiring intervention, an individualised approach is required. The interventional approaches to infected necrosis can be viewed as lying along a spectrum of ‘invasiveness’. The optimal therapeutic approach will depend on the patient's condition and the morphology and extent of the pancreatic or peripancreatic necrosis. Many patients with infected necrosis can be managed with radiologically guided percutaneous drainage alone. Minimally invasive necrosectomy techniques, e.g. minimally invasive retroperitoneal pancreatic necrosectomy (MIRP) and videoscopic-assisted retroperitoneal debridement (VARD), as well as radiologically guided limited incision open necrosectomy, have gained popularity and may result in lesser physiological insult than more traditional open necrosectomy. These patients should be managed within a specialist pancreatic unit where appropriate repertoire of interventional techniques is available.
Advances in imaging and endovascular intervention capabilities have increased the options available for patients that develop acute bleeding in association with pancreatic necrosis, often the result of pseudoaneurysm or true aneurysm formation. CT angiography is generally the preferred initial modality to localise the site of haemorrhage. Once the bleeding vessel is localised, directed transarterial embolisation can be attempted and, in many cases, obviates the need for a technically challenging laparotomy in an unwell patient with a ‘hostile abdomen’.
Iatrogenic pancreaticobiliary emergencies
The most common complications of ERCP and ES are pancreatitis, cholangitis, haemorrhage and duodenal perforation. Pancreatitis is managed in the same way as pancreatitis of any other aetiology. Cholangitis will commonly respond to antibiotic treatment, provided biliary drainage has been achieved at ERCP, either by effective stent placement or by clearing the biliary tree. Haemostasis can frequently be achieved endoscopically using local adrenaline injection into the papilla. However, should endoscopic haemostasis be ineffective, an operative approach may be required, particularly in a haemodynamically unstable patient. Generally, haemostasis can be achieved at laparotomy via a duodenotomy. Localisation of the ampulla, placement of the duodenotomy and initial tamponade can be facilitated by insertion of a Fogarty catheter via the cystic duct, through the ampulla. Definitive haemostasis can then achieved by direct suture similar to that carried out during a surgical ‘sphincteroplasty’. Care should be taken to avoid suturing the pancreatic duct and the use of a small cannula or probe can be helpful here.
Perforation may be apparent at the time of ERCP, but should be suspected in patients who develop severe pain or systemic physiological compromise following ERCP. CT is the preferred modality for diagnosis of perforation as the perforation is frequently retroperitoneal (Fig. 8.12). Small perforations may seal spontaneously and can, in some cases, be managed non-operatively by placing the patient nil by mouth, then initiating nasogastric tube drainage and systemic antibiotic treatment. The patient's nutritional status also requires careful attention. Should sepsis develop, a collection should be suspected and actively sought. Percutaneous drainage of the retroperitoneum may be required, although operative debridement should not be delayed if the patient's condition is not improved by percutaneous drainage, or if this approach is ineffective in controlling the collection. Again, referral to a specialist unit may be advisable as these complications can be difficult to treat and have a significant mortality.
FIGURE 8.12 CT image demonstrates retroperitoneal gas in a patient with iatrogenic perforation at ERCP.
This potentially life-threatening complication is fortunately relatively uncommon but may present to the non-pancreatic surgeon. A ‘herald bleed’ may precede major haemorrhage and in most cases following pancreaticoduodenectomy, the bleeding arises from the gastroduodenal artery stump. In patients sufficiently stable for transfer to radiology, CT angiography and endovascular treatment with embolisation may be sufficient to control haemorrhage. In patients requiring emergency laparotomy, mortality rates are significant.