Serum amylase and lipase and urinary trypsinogen and amylase for diagnosis of acute pancreatitis and serum C-reactive protein, procalcitonin and lactate dehydrogenase for the diagnosis of pancreatic necrosis

  • Protocol
  • Diagnostic

Authors


Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

To compare the diagnostic accuracy of serum amylase, serum lipase, urinary trypsinogen-2, and urinary amylase, either alone or in combination, in the diagnosis of acute pancreatitis in patients with acute onset of a persistent, severe, epigastric pain or diffuse abdominal pain.

Diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis

To compare the diagnostic accuracy of CRP, procalcitonin, or LDH, either alone or in combination, in the diagnosis of necrotising pancreatitis in patients with acute pancreatitis and without organ failure.

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

If we identify heterogeneity, we plan to explore the following potential sources of heterogeneity: risk of bias, prospective or retrospective studies, publication status, previous history of acute pancreatitis, different aetiology for acute pancreatitis, presence of organ failure, average time to performance of the test, and different test manufacturers.

Diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis

If we identify heterogeneity, we plan to explore the following potential sources of heterogeneity: risk of bias, prospective or retrospective studies, publication status, previous history of acute pancreatitis, different aetiology for acute pancreatitis, presence or absence of infection, pancreatic versus peripancreatic necrosis, average time to performance of the test, and different test manufacturers.

Background

The pancreas is an abdominal organ that secretes several digestive enzymes into the pancreatic ductal system that empties into the small bowel. It also houses the Islets of Langerhans, which secrete several hormones including insulin (NCBI 2014a). Acute pancreatitis is a sudden inflammatory process in the pancreas, with variable involvement of adjacent organs or other organ systems (Bradley 1993). The annual incidence of acute pancreatitis ranges from 5 to 30 per 100,000 population (Roberts 2013; Yadav 2006). There is an increase in the incidence of acute pancreatitis in the last one to two decades in the United Kingdom (UK) and the United States (US) (Roberts 2013; Yang 2008). Acute pancreatitis is the most common gastrointestinal (digestive tract) cause of hospital admission in the US (Peery 2012). Gallstones and alcohol are the two main causes of acute pancreatitis. Approximately 50% to 70% of acute pancreatitis is caused by gallstones (Roberts 2013; Yadav 2006). Increasing age, male gender and lower socioeconomic class are associated with a higher incidence of acute pancreatitis (Roberts 2013).

According to a consensus conference on the classification of acute pancreatitis, the diagnosis of acute pancreatitis is generally made when at least two of the following three features are present (Banks 2013):

  1. Acute onset of a persistent, severe, epigastric pain often radiating to the back.

  2. Serum lipase activity (or amylase activity) at least three times greater than the upper limit of normal.

  3. Characteristic findings of acute pancreatitis on contrast-enhanced computed tomography (CECT) and, less commonly, magnetic resonance imaging (MRI) or transabdominal ultrasonography.

Depending upon the type of inflammation, acute pancreatitis can be classified into interstitial oedematous pancreatitis (diffuse or occasionally localised enlargement of the pancreas due to inflammatory oedema as seen on CECT) or necrotising pancreatitis (necrosis involving either the pancreas or peripancreatic tissues or both) (Banks 2013). Approximately 90% to 95% of people with acute pancreatitis have interstitial oedematous pancreatitis, while the remainder have necrotising pancreatitis (Banks 2013). Necrotising pancreatitis may be sterile or infected (Banks 2013). Various theories exist as to how pancreatic and peripancreatic tissues become infected. These include spread from blood circulation, lymphatics, bile, from the small bowel (duodenum) through the pancreatic duct, and migration through the large bowel wall (translocation) (Schmid 1999).

Local complications of acute pancreatitis include acute peripancreatic fluid collection, pancreatic pseudocyst, acute necrotic collection and walled-off necrosis (Banks 2013). The systemic complications of acute pancreatitis include worsening of pre-existing illnesses, such as heart or chronic lung disease (Banks 2013). The mortality rate following an attack of acute pancreatitis is between 6% and 20% (Roberts 2013; Yadav 2006). The mortality rate depends upon the severity of acute pancreatitis and the presence of infection. Acute pancreatitis can be classified as mild, moderate, or severe depending upon the presence of local or systemic complications, transient organ failure involving one of more of lungs, kidneys, and cardiovascular system (heart and blood vessels) lasting up to 48 hours, or persistent failure of the same organs mentioned above, lasting beyond 48 hours. In mild pancreatitis, there are no local or systemic complications or organ failure. In moderately severe acute pancreatitis, there may be local or systemic complications or transient organ failure. In severe acute pancreatitis, there is persistent organ failure (Banks 2013). This is summarised in Table 1. Acute severe pancreatitis carries the worst prognosis in terms of mortality, while mild pancreatitis has the best prognosis (Banks 2013). Infected necrotising pancreatitis carries a significantly worse prognosis than sterile necrotising pancreatitis, with an average in-hospital mortality of more than 30% for people with infected necrotising pancreatitis, which increases to more than 40% in the subgroup of people with organ failure in addition to infection (Petrov 2010).

Table 1. Acute pancreatitis classification
Mild acute pancreatitis Moderate acute pancreatitisSevere acute pancreatitis
  • No local or systemic complications.

  • No organ failure.

  • Interstitial oedematous pancreatitis.

  • Local or systemic complications (peripancreatic fluid collection, pancreatic pseudocyst, necrosis) may be present.

  • Transient organ failure (up to 48 hrs) may be present

  • May be interstitial oedematous pancreatitis or necrotising pancreatitis.

  • Necrotising pancreatitis may be infected or sterile.

  • Local or systemic complications may be present

  • Persistent organ failure (> 48 hrs) present

  • May be interstitial oedematous pancreatitis or necrotising pancreatitis.

  • Necrotising pancreatitis may be infected or sterile.

See Appendix 1 for a glossary of terms.

Target condition being diagnosed

Acute pancreatitis in people with acute epigastric pain or diffuse abdominal pain, and acute necrotising pancreatitis in people with an established diagnosis of acute pancreatitis.

Index test(s)

All the index tests evaluated in this review are performed by the laboratory technician and interpreted by the clinician.

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

Serum amylase

Amylase is an enzyme secreted by the pancreas. Various other tissues including salivary glands, small intestines, ovaries, adipose tissue, and skeletal muscles secrete amylase. There are two major isoforms of amylase - pancreatic amylase and salivary amylase. The normal range of amylase varies between laboratories but is usually between 100 international units (IU)/L to 300 IU/L (Vissers 1999). Acute pancreatitis is one of the causes of increased amylase (hyperamylasaemia). The reason for this elevation is not clear although capillary leakage due to obstruction to venous and lymphatic drainage of pancreatic and peripancreatic tissues, and transperitoneal absorption of amylase may be responsible for the hyperamylasaemia (Vissers 1999). In acute pancreatitis, serum amylase levels usually rise within 6 to 24 hours, peak in 48 hours, and decrease to normal or near normal levels over the next 5 to 7 days (Vissers 1999). A common threshold used is three times the normal limit.

Serum lipase

Lipase is another enzyme secreted by the pancreas. Acute pancreatitis is the main reason for an increase in lipase, although a number of other conditions such as chronic pancreatitis, acute cholecystitis, and bowel obstruction can cause an increase in lipase activity (Vissers 1999). In acute pancreatitis, serum lipase levels usually rise within 4 to 8 hours, peak in 24 hours, and decrease to normal or near normal levels over the next 8 to 14 days. Serum lipase remains elevated for a longer period of time compared to the period of elevation of serum amylase after acute pancreatitis (Vissers 1999). A common threshold used is three times the normal limit.

Urinary trypsinogen level

Autodigestion because of trypsinogen activation is one of the mechanisms believed to cause acute pancreatitis. Since trypsinogen levels are elevated in acute pancreatitis, measurement of urinary trypsinogen-2 (an isoenzyme of trypsinogen) has been proposed as a test for diagnosing pancreatitis (Hedstrom 1994; Hedstrom 1996a; Hedstrom 1996b). In acute pancreatitis, urinary trypsinogen levels usually rise to high levels within a few hours and decrease in three days (Matull 2006). A common threshold used is 50 mcg/L (Chang 2012).

Urinary amylase

Urinary amylase above 2000 IU/L is considered abnormal. Measurement of urinary amylase has been proposed as a test for diagnosis of pancreatitis (Hedstrom 1996a; Kemppainen 1997).

Diagnosis of necrotising pancreatitis in people with an established diagnosis of acute pancreatitis

Serum C-reactive protein (CRP)

CRP is a plasma protein that increases during inflammation and after tissue damage (NCBI 2014b). Inflammation and tissue damage occur in patients with pancreatic necrosis. However, activation of inflammatory pathways is considered to be one of the reasons for the clinical manifestation of acute pancreatitis (Banks 2013) and hence serum CRP may be elevated even in oedematous pancreatitis. One of the thresholds proposed for distinguishing oedematous pancreatitis and necrotising pancreatitis is 140 mg/L (Rau 1998). An increasing trend in the values of the test may also be used for the triage of patients who require radiological examination.

Serum procalcitonin

Procalcitonin is the precursor of the hormone calcitonin found in the thyroid C cells and the pulmonary endocrine cells. However, all the tissues have the potential to produce procalcitonin. In patients with sepsis and severe inflammation, procalcitonin is elevated (Becker 2010). Since pancreatic necrosis is associated with severe inflammation, serum procalcitonin may distinguish between oedematous pancreatitis and necrotising pancreatitis. Procalcitonin levels are undetectable in healthy adults. Hence, any detectable levels of serum procalcitonin can be considered abnormal. An increasing trend in the values of the test may also be used for the triage of patients who require radiological examination.

Serum lactate dehydrogenase (LDH)

LDH is an indicator of cell death. Since pancreatic necrosis is associated with cell death, LDH may distinguish between oedematous pancreatitis and pancreatic necrosis. Normal LDH levels range from 140 units/L to 280 units/L. One of the thresholds proposed for distinguishing oedematous pancreatitis and necrotising pancreatitis is 290 units/L (Rau 1998). An increasing trend in the values of the test may also be used for the triage of patients who require radiological examination.

Clinical pathway

For patients with acute onset of a persistent, severe, epigastric pain or patients with diffuse abdominal pain which started in the epigastric region (or if the patient is unsure about the region in which diffuse abdominal pain began), clinical examination including recording of blood pressure, pulse rate, and oxygen saturations (when available) are performed. Routine blood tests such as full blood count, urea, creatinine, and electrolytes are also performed. Blood tests such as amylase and lipase (index tests being evaluated in this review) are performed to confirm (or rule out) the diagnosis of acute pancreatitis. Radiological findings of acute pancreatitis evolve over a few days and the radiological features examined may not demonstrate characteristic features in the early stages, or may even be normal (Banks 2013; Vissers 1999). Thus, one cannot rely entirely on radiological tests to diagnose acute pancreatitis, at least in the early stages. Radiological examination with computed tomography (CT scan) or MRI scan are not routinely performed if diagnosis of acute pancreatitis is suspected. If acute pancreatitis can be ruled out, other causes of acute epigastric pain should be considered. Peptic ulcer, functional dyspepsia, and gallstones can present with acute epigastric pain (Gurusamy 2014; Moayyedi 2006). All of these alternative causes of epigastric pain are generally investigated and treated after discharge of the patient unless there is a strong suspicion of perforated peptic ulcer, usually because of features of peritonitis or because pain control could not be achieved. In such instances, either a plain X-ray of the abdomen or emergency CT scan or both may be performed to identify the presence of free-intraperitoneal gas (Ghekiere 2007; Grassi 2004). The usual treatment for perforated peptic ulcer is emergency surgical closure, which can be performed by open or laparoscopic surgery (Sanabria 2013).

If the diagnosis of acute pancreatitis can be established, usually based on the consensus criteria, the patients are admitted to hospital and the severity of pancreatitis assessed, irrespective of whether symptomatic control of pain can be achieved. The treatment of acute pancreatitis is generally supportive treatment, i.e. maintenance of fluid and electrolyte imbalance. Despite various pharmacological interventions being evaluated in acute pancreatitis, none is currently being recommended as treatment. Ultrasound and magnetic resonance cholangio pancreatography or endoscopic ultrasound may be performed to investigate the aetiology of acute pancreatitis. In the presence of gallstones, cholecystectomy is performed. The timing of cholecystectomy in acute pancreatitis is controversial and different factors have to be considered depending upon the severity of acute pancreatitis (Gurusamy 2013). Endoscopic sphincterotomy or common bile duct exploration may have to be performed in the presence of common bile duct stones (Ayub 2004; Larson 2006). In the absence of gallstones, investigation of other causes of acute pancreatitis and appropriate treatment is provided. Patients are generally monitored clinically. If the patient improves clinically with supportive treatment, the patient is discharged after cholecystectomy or after scheduling a cholecystectomy as a separate admission. If the patient deteriorates clinically, they undergo a CT scan and may require high dependency care or intensive care unit care in the presence of organ failure or in the presence of infected pancreatic necrosis.

In the presence of organ failure, patients undergo a CT scan or MRI to identify any local complications. CRP, procalcitonin, and LDH might distinguish between oedematous and necrotising pancreatitis (Alfonso 2003; Khanna 2013; Rau 1998) and could potentially be used as a triage test to identify patients who need further radiological tests (Alfonso 2003) in those without organ failure. Some centres use CRP routinely to determine whether patients require radiological investigations to diagnose necrotising pancreatitis. Frequently, rising trend in CRP, procalcitonin, or LDH rather than a single test may be used to determine whether patients require radiological investigations to diagnose necrotising pancreatitis. It has to be noted that CT scan or MRI are not routinely performed during the initial stages of acute pancreatitis but are usually performed in the presence of organ failure or because of the results of the serum CRP. The various treatment strategies in acute necrotising pancreatitis include early surgical debridement (necrosectomy, which can performed by open surgery or by minimally invasive retroperitoneal debridement), delayed necrosectomy (delaying the surgery by about four weeks), percutaneous drainage, endoscopic transluminal drainage, a step-up approach which consists of endoscopic or percutaneous drainage followed by laparoscopic necrosectomy if required, and non-surgical (conservative) treatment (Bakker 2012; Mouli 2013; Tenner 2013; van Brunschot 2014; van Santvoort 2010; van Santvoort 2011). All of these treatments are supported by appropriate fluid treatment and appropriate nutritional treatment. This is in comparison with acute oedematous pancreatitis, where the main treatment is supportive treatment for systemic complications including organ failure and treatment of local complications such as pseudocyst if symptomatic (Cannon 2009; Cheruvu 2003; Johnson 2009; Varadarajulu 2008; Varadarajulu 2013). If patients have infected pancreatic necrosis, appropriate antibiotics are administered in addition to the treatment outlined above for non-infected pancreatic necrosis. If patients have acute peripancreatic collections or pseudocysts on the radiological tests, they patients are treated conservatively and require clinical follow-up and radiological follow-up to ensure resolution of these collections.

If the diagnosis of acute pancreatitis cannot be ruled out on the basis of the clinical presentation and serum amylase or lipase, the patients are admitted to hospital and the evolution of signs and symptoms is noted. Serum amylase and lipase may be repeated or radiological examinations may be performed to establish or rule out acute pancreatitis with a reasonable amount of certainty. Tests for organ failure (for example, urea and creatinine for identifying renal failure, blood pressure, pulse rate, respiratory rate, urine output, and arterial blood gases) may also be performed to ensure that patients do not have moderately severe or severe pancreatitis irrespective of the results of serum amylase and lipase. The possible clinical pathway in the diagnosis and management of acute pancreatitis is shown in Figure 1.

Figure 1.

Clinical pathway

Footnotes:

  1. Acute pancreatitis is usually confirmed by consensus criteria (Banks 2013).

  2. Irrespective of the CT scan findings and presence or absence of necrosis, patients with organ failure will require organ support and will receive a CT scan.

  3. CT scan may also be performed in people without organ failure if there is clinical deterioration (not amounting to organ failure) or in some centres based on an elevated CRP.

  4. Necrotising pancreatitis is usually confirmed by the findings on the CT scan and by histopathological examination of the biopsy obtained during necrosectomy if early necrosectomy is performed.

  5. Infected necrotising pancreatitis is usually confirmed by the findings on the CT scan and by microbiological examination of fluid aspirated under radiological guidance or from the tissue biopsy obtained during necrosectomy if early necrosectomy is performed.

  6. Organ failure is diagnosed on the basis of clinical examination and blood tests (urea, creatinine, blood pressure, pulse rate, respiratory rate, arterial blood gas analysis).

Abbreviations:

CRP = C-reactive protein;

CT = computed tomography;

EUS = endoscopic ultrasound;

MRCP = magnetic resonance cholangio pancreatography

Prior test(s)

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

The minimum prior test that is performed before these tests are performed are clinical history and clinical examination which includes obtaining the body temperature, heart rate, blood pressure, respiratory rate, and pulse oximetry (when available).

Diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis

The tests that are performed before the index tests are those performed to establish the diagnosis of acute pancreatitis such as serum lipase, serum amylase, or radiological tests such as CECT, MRI, or transabdominal ultrasonography, and clinical examination and blood tests to rule out organ failure (for example, urea and creatinine for identifying renal failure, blood pressure, pulse rate, respiratory rate, urine output, and arterial blood gases). Of these tests, serum tests for the diagnosis of acute pancreatitis,clinical examination and blood tests to rule out organ failure are routinely performed, while CT scan is not routinely performed for diagnosis of acute pancreatitis. Thus, the minimum prior tests are serum lipase, serum amylase, clinical examination and blood tests to rule out organ failure.

Role of index test(s)

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

The index tests are used for the diagnosis of acute pancreatitis in patients with acute onset of a persistent, severe, epigastric pain, or patients with diffuse abdominal pain which started in the epigastric region (or if the patient is unsure about the region in which diffuse abdominal pain began). Serum amylase and serum lipase are the tests that are used at present. Urinary trypsinogen and urinary amylase are being evaluated as replacement tests for serum amylase and serum lipase.

Diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis

Currently, if necrotising pancreatitis is suspected in patients without organ failure, radiological investigations are performed directly, although some units may use CRP (in particular an increasing trend in CRP values) to identify patients who require radiological investigations. In patients in whom the diagnosis of acute pancreatitis was based on CT scan, it is quite possible that the radiological features of necrosis are not manifest as there may be a delay in the appearance of these features (Banks 2013). In such patients, CRP may be used to identify patients who require additional radiological investigations. The index tests (CRP, procalcitonin, and LDH) are being evaluated as triage tests for detecting pancreatic necrosis in patients with acute pancreatitis in whom the diagnosis of pancreatic necrosis has not been made. Further radiological tests such as CECT will be necessary for confirming pancreatic necrosis, and the location and extent of pancreatic necrosis, before treatment can be planned. We will not evaluate the role of these tests in monitoring necrotising pancreatitis once the diagnosis of necrotising pancreatitis is made.

Alternative test(s)

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

Other tests used in the diagnosis of acute pancreatitis include serum trypsinogen-2 (Hedstrom 1994), and radiological tests such as contrast-enhanced computed tomography (CECT), magnetic resonance imaging (MRI) or transabdominal ultrasonography (Banks 2013). Other biomarkers such as serum trypsin 2 - alpha 1 antitrypsin complex, carboxypeptidase B activation peptide (CAPAP), and urinary trypsinogen activation peptide (TAP) have been evaluated as diagnostic tests for acute pancreatitis (Hedstrom 1996c; Saez 2005) but these are not in routine use for the diagnosis of this condition.

Diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis

Other tests used in the diagnosis of pancreatic necrosis include CECT, MRI, or transabdominal ultrasonography (Banks 2013). Various other blood tests such as blood haematocrit, blood urea, serum creatinine, and procarboxypeptidase B have been evaluated as diagnostic tests for pancreatic necrosis, but these are not in routine use (Muddana 2009; Rau 1998) for the diagnosis of pancreatic necrosis.

Rationale

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

In addition to acute pancreatitis, there are several other causes of epigastric pain including peptic ulcer, functional dyspepsia, and gallstones (Gurusamy 2014; Moayyedi 2006). Of these various causes, patients with acute pancreatitis and perforated peptic ulcer need emergency admission and treatment, while others may be discharged if pain control can be achieved. Thus, it is important to make a diagnosis of acute pancreatitis. Radiological findings of acute pancreatitis evolve over a few days and the radiological features examination may not demonstrate characteristic features in the early stages, or may even be normal (Banks 2013; Vissers 1999). Thus, radiological tests are not routinely performed for diagnosing this condition. In addition, acute pancreatitis can mimic perforated peptic ulcer (Kuzmich 2012), which is usually treated by surgery. Correct diagnosis of acute pancreatitis can avoid unnecessary surgery. Hence, a diagnosis of acute pancreatitis is essential in patients with suspected acute pancreatitis. Serum amylase and lipase are the most common tests used in the diagnosis of acute pancreatitis. It is important to understand the diagnostic accuracy of these tests. Urinary trypsinogen and amylase have been investigated as alternate tests, and it is important to understand whether they can replace serum amylase and lipase in the diagnosis of acute pancreatitis. If one or more of the tests being assessed has a high degree of accuracy, patients with acute pancreatitis can be identified and managed appropriately. At the same time, unnecessary hospital admission for observation can be avoided in patients without acute pancreatitis, resulting in considerable resource savings. There has been no systematic review and meta-analysis of the diagnostic accuracy of serum lipase and amylase activity or urinary amylase in the diagnosis of acute pancreatitis. There have been two systematic reviews on the diagnostic test accuracy of urinary trypsinogen-2 in the diagnosis of acute pancreatitis (Chang 2012; Jin 2013). In both reviews, language restrictions (English and Chinese) were present. The searches were performed to 2011 and 2012 respectively. Only one of the reviews used appropriate statistical analysis (Chang 2012). There has been no Cochrane review on the role of urinary trypsinogen-2 in the diagnosis of acute pancreatitis. The change in diagnostic accuracy of these tests with different time intervals from presentation has not been assessed in a systematic review before. A Cochrane systematic review of the diagnostic test accuracy of serum and urine tests in the diagnosis of acute pancreatitis is, therefore, necessary.

Diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis

The treatment of patients with acute pancreatitis is different in patients with and without pancreatic necrosis, as mentioned in the Clinical pathway. Patients with organ failure undergo radiological investigations routinely, while other patients do not receive CT scan routinely. Some units already use CRP as a triage test to identify patients without organ failure who require radiological investigations, while others do not. Thus the role of CRP, procalcitonin, and LDH as triage tests is not clear. There is no currently no systematic review of the diagnostic test accuracy of CRP, procalcitonin, or LDH in the diagnosis of pancreatic necrosis. A Cochrane systematic review of the diagnostic test accuracy of CRP, procalcitonin, or LDH in the diagnosis of pancreatic necrosis is necessary, to understand the value of these tests as triage tests to identify patients who require radiological investigation.

Objectives

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

To compare the diagnostic accuracy of serum amylase, serum lipase, urinary trypsinogen-2, and urinary amylase, either alone or in combination, in the diagnosis of acute pancreatitis in patients with acute onset of a persistent, severe, epigastric pain or diffuse abdominal pain.

Diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis

To compare the diagnostic accuracy of CRP, procalcitonin, or LDH, either alone or in combination, in the diagnosis of necrotising pancreatitis in patients with acute pancreatitis and without organ failure.

Secondary objectives

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

If we identify heterogeneity, we plan to explore the following potential sources of heterogeneity: risk of bias, prospective or retrospective studies, publication status, previous history of acute pancreatitis, different aetiology for acute pancreatitis, presence of organ failure, average time to performance of the test, and different test manufacturers.

Diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis

If we identify heterogeneity, we plan to explore the following potential sources of heterogeneity: risk of bias, prospective or retrospective studies, publication status, previous history of acute pancreatitis, different aetiology for acute pancreatitis, presence or absence of infection, pancreatic versus peripancreatic necrosis, average time to performance of the test, and different test manufacturers.

Methods

Criteria for considering studies for this review

Types of studies

We will include studies that evaluate the accuracy of the index tests mentioned above in the appropriate patient population (see below). We will include relevant studies irrespective of language or publication status, whether the data were collected prospectively or retrospectively, and whether there was a comparison between the tests. However, we will exclude case reports (that describe how the diagnosis of acute pancreatitis or acute necrotising pancreatitis was made on an individual patient or a group of patients and which do not provide sufficient diagnostic test accuracy data, i.e. true positive, false positive, false negative, and true negative). We will also exclude case-control studies because they are prone to bias (Whiting 2011).

Participants

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

Adult patients with acute epigastric or diffuse abdominal pain (with or without previous history of acute pancreatitis and with or without systemic signs and symptoms of acute pancreatitis), presenting within three days of the onset of symptoms, irrespective of the interval between onset of symptoms and the time at which the test was performed.

Diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis

Adult patients with acute pancreatitis within 14 days of the onset of symptoms, irrespective of the interval between the onset of symptoms and the time at which the test was performed. The diagnosis of acute pancreatitis should have been made on the basis of the consensus conference definition (Banks 2013). Patients who have organ failure will be excluded, since all such patients undergo radiological investigations. We will also exclude patients in whom pancreatic necrosis has been diagnosed in the CT scan carried out to make a diagnosis of acute pancreatitis.

Index tests

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

Serum amylase, serum lipase, urinary trypsinogen, and urinary amylase either alone or in combination. A variety of kits are available for measuring these tests. We will include the kits from all of the manufacturers, and will include studies irrespective of the threshold used. We will not include repeat tests (i.e. we will include the first test performed on initial assessment only).

Diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis

Serum CRP, procalcitonin, and LDH either alone or in combination immediately prior to radiological investigation. A variety of kits are available for measuring these tests. We will include the kits from all of the manufacturers, and will include studies irrespective of the threshold used. We will include studies that report a single test and sequential tests of serum CRP, procalcitonin, and LDH. If the study reports sequential testing, we will consider progressive increase as positive index test irrespective of the degree of increase, and stationary or decrease in the levels as negative test.

Target conditions

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

Acute pancreatitis (mild, moderately severe, or severe)

Diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis

Pancreatic or peripancreatic necrosis (infected or sterile)

Reference standards

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

While inflammation of the pancreas confirmed by biopsy can be considered the gold standard for the diagnosis of acute pancreatitis, for ethical reasons it is unlikely to be performed in any patient. As a result, different study authors may use different reference standards such as radiological features of acute pancreatitis or the presence of organ failure. However, such reference standards may miss some of the mild acute pancreatitis. This will result in underestimation of diagnostic test accuracy of the index tests. We will also accept the consensus conference definition of acute pancreatitis, i.e. when at least two of the following three features are present (Banks 2013):

  1. Acute onset of a persistent, severe, epigastric pain often radiating to the back.

  2. Serum lipase activity (or amylase activity) at least three times greater than the upper limit of normal.

  3. Characteristic findings of acute pancreatitis on CECT and less commonly MRI or transabdominal ultrasonography.

We will accept any of the following reference standards, used alone or in combination: biopsy, radiological features of acute pancreatitis (CT or MRI), organ failure, or the consensus conference definition (including or excluding the index test being evaluated). In terms of ranking the reference standards, we will consider biopsy as the best reference standard (although for ethical reasons it is unlikely to be performed in any patient) followed by consensus definition of acute pancreatitis, radiological features of acute pancreatitis, or the presence of organ failure, in that order. We anticipate that the authors will exclude the test being assessed to be incorporated into the reference standard; for example, if serum amylase was being evaluated, the final diagnosis of acute pancreatitis will not depend upon the levels of serum amylase. However, if the test being assessed was incorporated into the reference standard, the diagnostic accuracy of the test will be overestimated.

Diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis

While necrosis confirmed by biopsy can be considered the gold standard, it may not be performed in all patients because it may not be ethical to perform an invasive treatment (during which biopsy is taken) for those without a diagnosis of pancreatic necrosis. As a result, study authors may use radiological features of pancreatic necrosis (an area of impairment enhancement or non-enhancing area of pancreatic parenchyma on CECT or contrast-enhanced MRI). However, this reference standard may miss some of the patients with pancreatic necrosis. This will result in underestimation of diagnostic test accuracy of the index tests. In addition, using radiological features of pancreatitis might introduce an intrinsic threshold effect because of inter-observer variation between radiologists. We will accept any of the following reference standards, used alone or in combination: radiological features of pancreatic necrosis (CECT or contrast-enhanced MRI) or histological confirmation of pancreatic necrosis. In terms of ranking the reference standards, we will consider biopsy in all patients as the best reference standard (although it is unlikely to be performed in patients with negative test for pancreatic necrosis) followed by biopsy in patients with positive test and radiological features of pancreatic necrosis in patients with negative test, and radiological tests alone as the reference standard, in that order.

Search methods for identification of studies

We will include all studies irrespective of the language of publication, and publication status. If non-English language articles are found, we will obtain translations.

Electronic searches

We will search the following databases.

  1. MEDLINE (In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R)) via OvidSP (January 1946 to present) (Appendix 2).

  2. EMBASE via OvidSP (January 1947 to present) (Appendix 3).

  3. Science Citation Index Expanded via Web of Knowledge (January 1980 to present) (Appendix 4).

  4. Conference Proceedings Citation Index- Science (CPCI-S) via Web of Knowledge (January 1990 to present) (Appendix 4)

  5. National Insitute for Health Research (NIHR HTA and DARE) via Centre for Reviews and Dissemination (at present date) (Appendix 5).

  6. Zetoc via British Library (at present date) (Appendix 6).

  7. World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (Appendix 7).

  8. ClinicalTrials.gov (Appendix 8).

We will use the same strategy for both elements of this review (diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain, and diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis).

Searching other resources

We will search the references of the included studies to identify additional studies. We will also search for articles related to the included studies by performing the 'related search' function in MEDLINE (OvidSP) and EMBASE (OvidSP) and a 'citing reference' search (by searching the articles which cite the included articles) (Sampson 2008) in these databases.

Data collection and analysis

Selection of studies

Two review authors (research assistants to KG) will independently search the references to identify relevant studies. We will obtain the full texts of references that are considered relevant by at least one of the authors. Two authors will independently screen the full text papers against the inclusion criteria. Any differences in study selection will be arbitrated by KG. We will contact the study authors if there are any doubts about the study eligibility.

Data extraction and management

Two review authors will independently extract the following data from each included study using a data extraction form designed and piloted by KG, and any differences will be resolved by discussion with KG.

  1. First author.

  2. Year of publication.

  3. Study design (prospective or retrospective cohort studies; cross-sectional studies or randomised controlled trials).

  4. Inclusion and exclusion criteria for individual studies.

  5. Total number of patients.

  6. Number of females.

  7. Average age of the participants.

  8. Average time between onset of symptoms and index test.

  9. Aetiology of acute pancreatitis.

  10. Proportion of patients with organ failure (for the review on diagnosis of acute pancreatitis only).

  11. Proportion of patients with infected pancreatic necrosis.

  12. Description of the index test.

  13. Threshold used for index test.

  14. Reference standard.

  15. Number of true positives, false positives, false negatives, and true negatives.

If the same study reports multiple index tests, we will extract the number of true positives, false positives, false negatives, and true negatives for each index test at each threshold. If the same study reports the number of true positives, false positives, false negatives, and true negatives for each index test at different thresholds, we will extract this information for each threshold. If the study reports the results for a combination of tests, we will extract the number of true positives, false positives, false negatives, and true negatives for each different combination of tests.

A common way that the diagnostic accuracy of a combination of tests is assessed is at least one test positive versus all tests positive. We will extract the number of true positives, false positives, false negatives, and true negatives for both the scenarios. If the study reports the test at multiple time points, we will use the results of the first test in the diagnosis of acute pancreatitis review to calculate the true positives, false positives, false negatives, and true negatives, since the aim of this review is to assess the diagnostic accuracy in patients with acute epigastric pain and abdominal pain who have not undergone any prior tests other than routine clinical examination. With regard to the diagnosis of necrotising pancreatitis, we will obtain the trend in sequential testing of CRP, procalcitonin, or LDH if the author uses progressively increasing trend in index test values for distinguishing acute necrotising pancreatitis and oedematous pancreatitis. For this purpose, we will consider increasing trend as positive index test irrespective of the degree of increase, and consider stationary levels or decrease in the levels as negative test in order to calculate the number of true positives, false positives, false negatives, and true negatives. If the authors provide the final values of these index tests prior to radiological examination, we will obtain these values for calculating the true positives, false positives, false negatives, and true negatives. This is because we want to evaluate the role of these index tests used as a test with a pre-specified threshold, and the role of an increasing trend in the values of these index tests for distinguishing acute necrotising pancreatitis and oedematous pancreatitis. Patients may receive treatment for organ failure if they develop organ failure between the index test and reference standard. We anticipate that a radiological investigation would have been performed within 24 hours of diagnosis of organ failure. Pancreatic necrosis does not resolve in 24 hours and there will be no alteration of the final diagnosis by the treatment in patients with pancreatic necrosis. People with oedematous pancreatitis and organ failure may develop pancreatic necrosis in the absence of appropriate treatment. Consequently, there is a possible interaction between inadequate treatment and the final diagnosis. The final values, which have the shortest time interval between the index test and reference standard, are the least likely to be affected by inappropriate treatment and are likely to provide the best estimates of diagnostic test accuracy.

We will exclude patients with uninterpretable index test results (no matter the reason given for lack of interpretation) since in clinical practice, uninterpretable index test results will result in additional tests for the diagnosis of acute pancreatitis. However, we will record the number of uninterpretable index test results as this will provide information on the applicability of the test in clinical practice and may affect the cost-effectiveness of a test. (Although cost-effectiveness is outside the scope of this review, cost-effectiveness studies may use data from this review). If there is an overlap of participants between multiple reports, as suggested by common authors and centres, we will attempt to contact the study authors to seek clarification about the overlap. If we are unable to contact the authors, we will extract the maximum possible information from all of the reports. Further information will be sought from study authors if necessary.

Assessment of methodological quality

Two authors will independently assess study quality using the QUADAS-2 assessment tool (Whiting 2006; Whiting 2011). Any differences will be resolved by KG. The criteria that will be used to classify the different studies are shown in Table 2 and Table 3. We will consider studies which are classified as 'low risk of bias' and 'low concern' in all the domains (except for the reference standard domain, where we will accept a 'No' for the signalling question 'Is the reference standard likely to correctly classify the target condition?') as studies with high methodological quality. The results will be presented in a'Risk of bias' summary and graphs in addition to a narrative summary.

Table 2. QUADAS-2 classification (acute pancreatitis)
Domain 1: Patient selectionPatient samplingAdult patients with acute epigastric or diffuse abdominal pain
Was a consecutive or random sample of patients enrolled?Yes: If a consecutive sample or a random sample of patients with acute epigastric or diffuse abdominal pain was included in the study.
No: If a consecutive sample or a random sample of patients with acute epigastric or diffuse abdominal pain was not included in the study.
Unclear: If this information was not available.
  
Did the study avoid inappropriate exclusions?Yes: If all patients with acute epigastric or diffuse abdominal pain suspected to be acute pancreatitis were included.
No: If the study excluded patients based on high or low probability of acute pancreatitis (for example, those with organ failure).
Unclear: If this information was not available.
Could the selection of patients have introduced bias?

Low risk of bias: If 'yes' classification for all the above two questions.

High risk of bias: if 'no' classification for any of the above two questions. Unclear risk of bias: if 'unclear' classification for any of the above two questions but without a 'no' classification for either of the above two questions.

Patient characteristics and settingYes: If all patients with acute epigastric or diffuse abdominal pain suspected to be acute pancreatitis were included.
No: If a proportion of patients with acute epigastric or diffuse abdominal pain were excluded on the basis of the results of another diagnostic test (for example, an arterial blood gas analysis performed after the index test).
Unclear: If it is not clear whether the patients have been included on the basis of the results of another diagnostic test (for example, an arterial blood gas analysis performed after the index test).
Are there concerns that the included patients and setting do not match the review question?

Low concern: if the patient characteristics and setting is classified as 'yes'. Unclear concern: if the patient characteristics and setting is classified as 'unclear'.

High concern: if the patient characteristics and setting is classified as 'no'.

Domain 2: Index testIndex test(s)Serum amylase, serum lipase, urinary trypsinogen-2, urinary amylase
Were the index test results interpreted without knowledge of the results of the reference standard?

The index test would always be conducted though not interpreted before the reference standard.

Yes: If the index test is conducted and interpreted without the knowledge of the results of the reference standard.
No: If the index test is interpreted with the knowledge of the results of the reference standard.
Unclear: If it is not clear whether the index test was interpreted without the knowledge of the results of the reference standard.

If a threshold was used, was it pre-specified?

Yes: if a pre-specified threshold was used.

No: if a pre-specified threshold was not used.

Unclear: if it was not clear whether the threshold used was pre-specified.

Could the conduct or interpretation of the index test have introduced bias?

Low risk of bias: If 'yes' classification for both the questions.

High risk of bias: if 'no' classification for either of the above two questions. unclear risk of bias: if 'unclear' classification for either of the above two questions but without a 'no' classification for either of the above two questions.

Are there concerns that the index test, its conduct, or interpretation differ from the review question?Low concern: If the criteria for positive index test is clearly stated. High concern: if the criteria for positive index test is not stated.
Domain 3: Target condition and reference standardTarget condition and reference standard(s)

Target condition: acute pancreatitis (mild, moderately severe, or severe).

While inflammation of the pancreas confirmed by biopsy can be considered the gold standard for the diagnosis of acute pancreatitis, for ethical reasons it is unlikely to performed in any patient. As a result, different study authors may use different reference standards such as radiological features of acute pancreatitis or the presence of organ failure. However, such reference standards may miss some of the mild acute pancreatitis. This will result in underestimation of diagnostic test accuracy of the index tests. We also accepted the consensus conference definition of acute pancreatitis, i.e. when at least two of the following three features are present (Banks 2013):

  1. Acute onset of persistent, severe, epigastric pain often radiating to the back.

  2. Serum lipase activity (or amylase activity) at least three times greater than the upper limit of normal.

  3. Characteristic findings of acute pancreatitis on CECT and less commonly MRI or transabdominal ultrasonography.

We will accept any of the following reference standards used alone or in combination as reference standards: biopsy, radiological features of acute pancreatitis, organ failure, or the consensus conference definition (including or excluding the index test being evaluated). In terms of ranking the reference standards, we will consider biopsy as the best reference standard (although for ethical reasons it is unlikely to be performed in any patient) followed by the consensus definition of acute pancreatitis, radiological features of acute pancreatitis, or the presence of organ failure, in that order. We anticipate that the authors will exclude the test being assessed to be incorporated into the reference standard, for example, if serum amylase was being evaluated, the final diagnosis of acute pancreatitis will not depend upon the levels of serum amylase. However, if the test being assessed was incorporated into the reference standard, the diagnostic accuracy of the test will be overestimated.

Is the reference standard likely to correctly classify the target condition?Yes: If histological confirmation of acute pancreatitis is obtained or the consensus definition of acute pancreatitis is used.
No: If the reference standard is radiological confirmation or organ failure.
Unclear: If the reference standard was not described adequately.
Is the reference standard independent of the index test?Yes: If the index test is not part of the reference standard.
No: If the index test is part of the reference standard.
Unclear: If it was not clear whether the index test was part of the reference standard. We anticipate that there will be no difficulty in assessing whether the index test was part of the reference standard, so we anticipate that all studies included in the review will be classified as 'yes' or 'no' for this item.
Were the reference standard results interpreted without knowledge of the results of the index tests?Yes: If the reference standard is interpreted without the knowledge of the results of the index test.
No: If the reference standard is interpreted with the knowledge of the results of the index test.
Unclear: It is not clear if the reference standard is interpreted without the knowledge of the results of the index test.
Could the reference standard, its conduct, or its interpretation have introduced bias?

Low risk of bias: If 'yes' classification for all the three questions.

High risk of bias: if 'no' classification for any of the above three questions. Unclear risk of bias: if 'unclear' classification for any of the above three questions but without a 'no' classification for any of the above three questions.

Are there concerns that the target condition as defined by the reference standard does not match the question?Considering the inclusion criteria for this review, we anticipate that all of the included studies will be classified as 'low concern'
Domain 4: Flow and timingFlow and timingPatients may have complete resolution of acute pancreatitis if they had acute pancreatitis, or may have an episode of acute pancreatitis if they did not have acute pancreatitis if the interval between the index test and reference standard is long.
Was there an appropriate interval between index test and reference standard?Yes: If the time interval between index test and reference standard was less than one week.
No: If the time interval between index test and reference standard was more than one week.
Unclear: If the time interval between index test and reference standard was unclear.
Did all patients receive a reference standard?Yes: If all patients receive a reference standard.
No: If some of the patients did not receive a reference standard. Such studies will be excluded.
Unclear: If it was not clear whether all patients received a reference standard. Such studies will be excluded. We anticipate that all studies included in the review will be classified as 'yes' for this item.
Did all patients receive the same reference standard?

Yes: If all the patients received the same reference standards (we anticipate that all the studies are classified as 'yes').
No: If different patients received different reference standards.

Unclear: If this information was not clear.

Were all patients included in the analysis?Yes: If all the patients are included in the analysis irrespective of whether the results were interpretable.
No: If some patients are excluded from the analysis because of uninterpretable results.
Unclear: If this information is not clear.
Could the patient flow have introduced bias?

Low risk of bias: If 'yes' classification for all the above four questions.

High risk of bias: if 'no' classification for any of the above four questions. Unclear risk of bias: if 'unclear' classification for any of the above four questions but without a 'no' classification for any of the above four questions.

Table 3. QUADAS-2 classification (acute necrotising pancreatitis)
Domain 1: Patient selectionPatient samplingAdult patients with acute pancreatitis and without organ failure.
Was a consecutive or random sample of patients enrolled?Yes: If a consecutive sample or a random sample of patients with acute pancreatitis and without organ failure were included in the study.
No: If a consecutive sample or a random sample of patients with acute pancreatitis and without organ failure was not included in the study.
Unclear: If this information was not available.
  
Did the study avoid inappropriate exclusions?Yes: If all patients with acute pancreatitis and without organ failure were included.
No: If the study excluded patients based on high or low probability of pancreatic necrosis (for example, those with normal white cell count were excluded).
Unclear: If this information was not available.
Could the selection of patients have introduced bias?Low risk of bias: If 'yes' classification for both of the above two questions. High risk of bias: if 'no' classification for either of the above two questions.Unclear risk of bias: if 'unclear' classification for either of the above two questions but without a 'no' classification for either of the above two questions
Patient characteristics and settingYes: If all patients with acute pancreatitis and without organ failure were included.
No: If a proportion of patients with acute pancreatitis was excluded on the basis of the results of another diagnostic test (for example, white cell count).
Unclear: If it is not clear whether the patients have been included on the basis of the results of another diagnostic test (for example, white cell count).
Are there concerns that the included patients and setting do not match the review question?

Low concern: if the patient characteristics and setting is classified as 'yes'. Unclear concern: if the patient characteristics and setting is classified as 'unclear'.

High concern: if the patient characteristics and setting is classified as 'no'.

Domain 2: Index testIndex test(s)Serum C-reactive protein, procalcitonin, lactate dehydrogenase
Were the index test results interpreted without knowledge of the results of the reference standard?

The index test would always be conducted though not interpreted before the reference standard.

Yes: If the index test is conducted and interpreted without the knowledge of the results of the reference standard.
No: If the index test is interpreted with the knowledge of the results of the reference standard.
Unclear: If it is not clear whether the index test was interpreted without the knowledge of the results of the reference standard.

If a threshold was used, was it pre-specified?

Yes: if a pre-specified threshold was used.

No: if a pre-specified threshold was not used.

Unclear: if it was not clear whether the threshold used was pre-specified.

Could the conduct or interpretation of the index test have introduced bias?

Low risk of bias: If 'yes' classification for both of the above two questions.

High risk of bias: if 'no' classification for either of the above two questions.

Unclear risk of bias: if 'unclear' classification for either of the above two questions but without a 'no' classification for either of the above two questions

Are there concerns that the index test, its conduct, or interpretation differ from the review question?

Low concern: If the criteria for positive index test is clearly stated.

High concern: if the criteria for positive index test is not stated.

Domain 3: Target condition and reference standardTarget condition and reference standard(s)

Target condition: pancreatic or peripancreatic necrosis (infected or sterile).

While necrosis confirmed by biopsy can be considered the gold standard, it may not be performed in all patients because it may not be ethical to perform an invasive treatment (during which biopsy is taken) for those without a diagnosis of pancreatic necrosis. As a result, study authors may use radiological features of pancreatic necrosis (an area of impairment enhancement or non-enhancing area of pancreatic parenchyma on CECT). However, this reference standard may miss some of the patients with pancreatic necrosis.

In terms of ranking the reference standards, we will consider biopsy in all patients as the best reference standard (although it is unlikely to be performed in patients with negative test for pancreatic necrosis) followed by biopsy in patients with positive test and radiological features of pancreatic necrosis in patients with negative test, and radiological tests alone as the reference standard, in that order.

Is the reference standard likely to correctly classify the target condition?

Yes: If histological confirmation of pancreatic necrosis is obtained in all patients or at least in all patients with positive test.
No: If the reference standard is CECT in all patients.

Unclear: If the reference standard was not described adequately.

Were the reference standard results interpreted without knowledge of the results of the index tests?Yes: If the reference standard is interpreted without the knowledge of the results of the index test.
No: If the reference standard is interpreted with the knowledge of the results of the index test.
Unclear: It is not clear if the reference standard is interpreted without the knowledge of the results of the index test.
Could the reference standard, its conduct, or its interpretation have introduced bias?

Low risk of bias: If 'yes' classification for both of the above two questions. High risk of bias: if 'no' classification for any of the above two questions. Unclear risk of bias: if 'unclear' classification for any of the above two questions but without a 'no' classification for any of the above two questions.

We anticipate that most studies will be classified as high risk of bias as most studies will be classified as 'no' for the question "Is the reference standard likely to correctly classify the target condition?".

Are there concerns that the target condition as defined by the reference standard does not match the question?Considering the inclusion criteria for this review, we anticipate that all the included studies will be classified as 'low concern'.
Domain 4: Flow and timingFlow and timingPatients may have progression or regression of pancreatic necrosis if there is a long delay between index test and reference standard. In addition, patients may receive treatment for organ failure if they develop organ failure between the index test and reference standard. We anticipate that a radiological investigation would have been performed within 24 hours of diagnosis of organ failure. Pancreatic necrosis does not resolve in 24 hours and there will be no alteration of the final diagnosis by the treatment in patients with pancreatic necrosis. People with oedematous pancreatitis and organ failure may develop pancreatic necrosis in the absence of appropriate treatment. Therefore there is a possible interaction between inadequate treatment and the final diagnosis. We have minimised this misclassification error because of the final diagnosis being altered by inappropriate treatment, by choosing 24 hours as acceptable delay between index test and reference standard.
Was there an appropriate interval between index test and reference standard?Yes: If the time interval between index test and reference standard was less than 24 hours.
No: If the time interval between index test and reference standard was more than 24 hours.
Unclear: If the time interval between index test and reference standard was unclear.
Did all patients receive a reference standard?Yes: If all patients receive a reference standard.
No: If some of the patients did not receive a reference standard. Such studies will be excluded.
Unclear: If it was not clear whether all patients received a reference standard. Such studies will be excluded. As a result, we anticipate that all studies included in the review to be classified as 'yes' for this item.
Did all patients receive the same reference standard?

Yes: If all the patients received the same reference standard.
No: If different patients received different reference standards.

Unclear: If this information was not clear.

Were all patients included in the analysis?Yes: If all the patients are included in the analysis irrespective of whether the results were interpretable.
No: If some patients are excluded from the analysis because of uninterpretable results.
Unclear: If this information is not clear.
Could the patient flow have introduced bias?

Low risk of bias: If 'yes' classification for all the above four questions.

High risk of bias: if 'no' classification for any of the above four questions.

Unclear risk of bias: if 'unclear' classification for any of the above four questions but without a 'no' classification for any of the above four questions.

Statistical analysis and data synthesis

We will stratify the analysis by the test thresholds and different reference standards (i.e. tests at different thresholds and using different reference standards will be considered as different index tests). If the study uses increasing trend in the values of the CRP, procalcitonin, or LDH as the diagnostic criteria for distinguishing necrotising pancreatitis from oedematous pancreatitis, we will consider this as the 'threshold' for the purpose of this review. We will plot study estimates of sensitivity and specificity on forest plots and in receiver operating characteristic (ROC) space to explore between-study variation in the performance of each test stratified by the threshold and reference standard. To estimate the summary sensitivity and specificity of each test at each threshold level and each reference standard, we will perform the meta-analysis by fitting the bivariate model (Chu 2006; Reitsma 2005).This model accounts for between-study variability in estimates of sensitivity and specificity through the inclusion of random effects for the logit sensitivity and logit specificity parameters of the bivariate model. If sparse data resulted in unreliable estimation of the covariance matrix of the random effects as indicated by very large variance of logit sensitivity and specificity, we will simplify the model by assuming an exchangeable covariance structure (i.e. common variances for the random effects and one common pairwise covariance) instead of the more complex unstructured covariance matrix that allows for separate variances for each random effect and distinct covariances. Other alternate models that we will try include the random-effects model ignoring the inverse correlation between sensitivities and specificities in the different studies due to intrinsic threshold effect, and the fixed-effect model for either sensitivity or specificity or both. The choice between the different models will be based on the distribution of sensitivities and specificities as noted in the forest plots or ROC space (Takwoingi 2015). .

We will compare the diagnostic accuracy of the different tests by including a single covariate term for test type in the bivariate model to estimate differences in the sensitivity and specificity of the tests. We will consider a combination of tests for each of the scenarios (any test positive or all tests positive) as different index tests. We will allow the variances of the random effects and their covariance to also depend on test type, thus allowing the variances to differ between tests. We will use the hierarchical summary receiver operating characteristics curve (HSROC) (Rutter 2001) to test hypotheses about whether one test is superior to another and to investigate heterogeneity. For this purpose, we will combine tests irrespective of the thresholds and reference standards. In case the study reports results at multiple thresholds, we will use the threshold used for primary analysis by the authors for inclusion in the HSROC model. We will use likelihood ratio tests to compare the model with and without covariate (test type). A P value of < 0.05 for the likelihood ratio test will indicate differences in diagnostic accuracy between the tests. We will also compare the estimates of sensitivity and specificity between models to check the robustness of our assumptions about the variances of the random effects. If studies that evaluate different tests in the same study population are available (for example, in studies that perform more than one index test in all the participants, individual index tests and combination of index tests in all the participants, or randomised controlled trials in which participants have been randomised to the different index tests) from at least four studies, we will perform a direct head-to-head comparison by limiting the test comparison to such studies. We will also present the relative sensitivities and relative specificities of the index tests from the direct comparisons in a table.

We will perform the meta-analysis using the NLMixed command in SAS version 9.3 (SAS Institute Inc, Cary, North Carolina, USA). We will create a graph of pre-test probabilities (using the observed median and range of prevalence from the included studies) against post-test probabilities for each test stratified by different thresholds and reference standards. The post-test probabilities will be calculated using these pre-test probabilities and the summary positive and negative likelihood ratios. The summary likelihood ratios and their confidence intervals will be calculated from the functions of the parameter estimates from the bivariate model that we will fit to estimate the summary sensitivities and specificities. Post-test probability associated with positive test is the probability of having the target condition (acute pancreatitis or acute necrotising pancreatitis) on the basis of a positive test result, and is the same as the term 'positive predictive value' used in a single diagnostic accuracy study. Post-test probability associated with a negative test is the probability of having the target condition (acute pancreatitis or acute necrotising pancreatitis) on the basis of a negative test result and is 1 - 'negative predictive value'. Negative predictive value is the term used in a single diagnostic accuracy study to indicate the chance that the patient has no target condition when the test is negative. We will report the summary sensitivity, specificity, positive and negative likelihood ratios, and post-test probabilities for the median, lower quartile, and upper quartile of the pre-test probabilities.

Investigations of heterogeneity

Diagnosis of acute pancreatitis in people with acute epigastric or diffuse abdominal pain

We plan to explore heterogeneity by using the following sources of heterogeneity as covariate(s) in the regression model.

  1. Studies at low risk of bias in all the domains (except for reference standard domain, where we will accept a 'No' for the signalling question 'Is the reference standards likely to correctly classify the target condition?') versus those at unclear or high risk of bias (as assessed by the QUADAS-2 tool, recommended by the Cochrane Diagnostic Test Accuracy Group) (Whiting 2006; Whiting 2011).

  2. Prospective studies versus retrospective studies (this can give an idea about whether there is a difference in diagnostic accuracy between prospective and retrospective studies).

  3. Full text publications versus abstracts (this can give an idea about publication bias since there may be an association between the results of the study and the study reaching full publication status) (Eloubeidi 2001).

  4. Previous history of acute pancreatitis.

  5. Different aetiology for acute pancreatitis (gallstone versus alcohol versus other aetiology). The accuracy of the test may depend upon the aetiology of the acute pancreatitis.

  6. Presence of organ failure: The accuracy of the test may depend upon the presence of organ failure.

  7. Average time to performance of the test. The accuracy of the test may depend upon the interval between the onset of clinical symptoms and the performance of the test.

  8. Different test manufacturers.

Of the eight sources of heterogeneity mentioned in the section 'Secondary objectives', risk of bias, publication status, prospective or retrospective studies, and different test manufacturers will be used as categorical covariates; while the proportion of patients with a previous history of acute pancreatitis, proportion of participants with different aetiologies, proportion of participants with organ failure, and the average time to performance of the test will be used as continuous covariates in the regression model. We will include one covariate at a time in the regression model. We will use the likelihood ratio test to determine whether the covariate is statistically significant.

Diagnosis of necrotising pancreatitis in people with established diagnosis of acute pancreatitis

We plan to explore heterogeneity by using the following sources of heterogeneity as covariate(s) in the regression model.

  1. Studies at low risk of bias (except for the reference standard domain, where we will accept a 'No' for the signalling question 'Is the reference standard likely to correctly classify the target condition?') versus those at unclear or high risk of bias (as assessed by the QUADAS-2 tool, recommended by the Cochrane Diagnostic Test Accuracy Group) (Whiting 2006; Whiting 2011).

  2. Prospective studies versus retrospective studies (this can give an idea about whether there is a difference in diagnostic accuracy between prospective and retrospective studies).

  3. Full text publications versus abstracts (this can give an idea about publication bias, since there may be an association between the results of the study and the study reaching full publication status) (Eloubeidi 2001).

  4. Previous history of acute pancreatitis.

  5. Different aetiology for acute pancreatitis (gallstone versus alcohol versus other aetiology). The accuracy of the test may depend upon the aetiology of the acute pancreatitis.

  6. Presence or absence of infection. The accuracy of the test may depend upon the presence or absence of infection.

  7. Pancreatic versus peripancreatic necrosis.

  8. Average time to performance of the test. The accuracy of the test may depend upon the interval between the onset of clinical symptoms and the performance of the test.

  9. Different test manufacturers.

Of the nine sources of heterogeneity mentioned above, risk of bias, prospective or retrospective studies, publication status, presence or absence of infection, and different test manufacturers will be used as categorical covariates; while the proportion of patients with a previous history of acute pancreatitis, the proportion of participants with different aetiologies, the proportion of participants with pancreatic necrosis and peripancreatic necrosis, and the average time to performance of the test will be used as continuous covariates in the regression model. As before, we will include one covariate at a time in the regression model and use the likelihood ratio test to determine whether the covariate is statistically significant.

Sensitivity analyses

We do not plan any sensitivity analyses except when the data available from the studies are ambiguous (for example, the numbers in the text are different from the numbers in the figures), in which case, we will assess the impact of different data used by a sensitivity analysis.

Assessment of reporting bias

We plan to investigate whether the summary sensitivity and specificity are different between studies that are published as full texts and those that are available only as abstracts (at least two years prior to the search date) using the methods described in the section on Investigations of heterogeneity.

Acknowledgements

We thank the Cochrane Upper Gastrointestinal and Pancreatic Diseases (UGPD) Group, the United Kingdom Support Unit for Diagnostic Test Accuracy (DTA) Reviews, and the DTA editorial team for their advice in the preparation of this review.

Appendices

Appendix 1. Glossary of terms

Adipose: fat.

Autodigestion: breaking-down of the same organ that secretes the substance.

Debridement: surgical removal of damaged, dead or infected tissue; in this context, identical with necrosectomy.

Epigastric: upper central abdomen.

Heterogeneity: differences between studies.

Histological: by examination of the tissue under a microscope.

Hyperamylasaemia: increase amylase in circulation.

Interstitial: small, narrow spaces between tissues or parts of an organ.

Necrosectomy: removal of dead tissue.

Necrosis: death and decomposition of living tissue usually caused by lack of blood supply but can be caused by other pathological insult.

Necrotising: presence of necrosis.

Oedematous: tissue with an excess of interstitial fluid.

Parenchyma: functional parts of an organ.

Percutaneous drainage: drainage carried out by insertion of drain from the external surface of the body, usually guided by an ultrasound or computed tomography (CT) scan.

Peripancreatic tissues: tissues surrounding the pancreas.

Pancreatic pseudocysts: fluid collections in the pancreas or the tissues surrounding the pancreas, surrounded by a well-defined wall and containing only fluid with little or no solid material.

Retroperitoneal: behind the abdominal cavity.

Sphincterotomy: partial division of the sphincter of Oddi, a circular band of muscle at the junction of the biliary tree (tubes that conduct bile from liver to the small intestine) and pancreatic duct (tubes that conduct pancreatic juice into the second part of the duodenum).

Transperitoneal: through the abdominal cavity.

Appendix 2. MEDLINE search strategy

1. Pancreatitis, Acute Necrotizing/

2. Pancreatitis/et

3. Pancreas/ab, pa, pp

4. (acute adj3 pancrea*).mp.

5. (necro* adj3 pancrea*).mp.

6. (inflam* adj3 pancrea*).mp.

7. ((interstitial or edema* or oedema*) adj2 pancrea*).mp.

8. 1 or 2 or 3 or 4 or 5 or 6 or 7

9. exp Amylases/ or exp Lipase/ or exp Trypsinogen/

10. (amylase or lipase or trypsinogen or hyperamylasaemia or hyperamylasemia).mp.

11. exp C-Reactive Protein/

12. ("c-reactive protein" or "c reactive protein" or CRP).mp.

13. procalcitonin.mp.

14. exp L-Lactate Dehydrogenase/

15. ("lactate dehydrogenase" or LDH).mp.

16. 9 or 10 or 11 or 12 or 13 or 14 or 15

17. 8 and 16

Appendix 3. EMBASE search strategy

1. acute hemorrhagic pancreatitis/

2. Pancreatitis/et

3. acute pancreatitis/

4. (acute adj3 pancrea*).mp.

5. (necro* adj3 pancrea*).mp.

6. (inflam* adj3 pancrea*).mp.

7. ((interstitial or edema* or oedema*) adj2 pancrea*).mp.

8. 1 or 2 or 3 or 4 or 5 or 6 or 7

9. exp amylase/

10. exp triacylglycerol lipase/

11. exp trypsinogen/

12. (amylase or lipase or trypsinogen or hyperamylasaemia or hyperamylasemia).mp.

13. exp C reactive protein/

14. ("c-reactive protein" or "c reactive protein" or CRP).mp.

15. exp procalcitonin/

16. procalcitonin.mp.

17. exp lactate dehydrogenase/

18. ("lactate dehydrogenase" or LDH).mp.

19. 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18

20. 8 and 19

Appendix 4. Science Citation Index and Conference Proceedings Citation Index- Science search strategy

# 1 TS=((acute or necro* or inflam* or interstitial or edema* or oedema*) near/3 pancrea*)

# 2 TS=(amylase or lipase or trypsinogen or hyperamylasaemia or hyperamylasemia or "c-reactive protein" or "c reactive protein" or CRP or procalcitonin or "lactate dehydrogenase" or LDH)

# 3 #2 AND #1

Appendix 5. National Institute for Health Research - HTA and DARE search strategy

acute pancreatitis

Appendix 6. Zetoc search strategy

Each of the following lines will be searched separately. since the Boolean operator 'or' is not available for searching Zetoc database.

1. acute pancreatitis amylase

2. acute pancreatitis lipase

3. acute pancreatitis trypsinogen

4. acute pancreatitis hyperamylasaemia

5. acute pancreatitis hyperamylasemia

6. acute pancreatitis "c-reactive protein"

7. acute pancreatitis "c reactive protein"

8. acute pancreatitis CRP

9. acute pancreatitis procalcitonin

10. acute pancreatitis "lactate dehydrogenase"

11. acute pancreatitis LDH

Appendix 7. WHO ICTRP search strategy

Title: (amylase or lipase or trypsinogen or hyperamylasaemia or hyperamylasemia or "c-reactive protein" or "c reactive protein" or CRP or procalcitonin or "lactate dehydrogenase" or LDH)

Condition: acute pancreatitis

Appendix 8. ClinicalTrials.gov search strategy

amylase OR lipase OR trypsinogen OR hyperamylasaemia OR hyperamylasemia OR "c-reactive protein" OR "c reactive protein" OR CRP OR procalcitonin OR "lactate dehydrogenase" OR LDH | acute pancreatitis

Contributions of authors

KS Gurusamy wrote the protocol.

BR Davidson advised on the protocol and will critically comment on the review.

Declarations of interest

This report is independent research funded by the National Institute for Health Research (NIHR Cochrane Programme Grants, 13/89/03 - Evidence-based diagnosis and management of upper digestive, hepato-biliary, and pancreatic disorders). The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the NIHR or the Department of Health.

KSG: none known.

BD: none known.

Sources of support

Internal sources

  • University College London, UK.

    The source supports salary, consumables (including printing, photocopying), and equipment (including laptop, scanner, printer, and any other equipment) necessary to complete the review.

External sources

  • National Institute for Health Research, UK.

    The source supports salary, consumables (including printing, photocopying), and equipment (including laptop, scanner, printer, and any other equipment) necessary to complete the review in addition to payment for editorial support.

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