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 2014). Pancreatic resection is performed to treat pancreatic diseases, including pancreatic cancer, pre-cancerous pancreatic lesions, and chronic pancreatitis. Pancreatic resection is in the form of pancreaticoduodenectomy for lesions and disease of the head of the pancreas, and distal pancreatectomy for lesions in the body and tail of the pancreas (Park 2013). After pancreaticoduodenectomy, pancreato-enteric anastomosis is performed to allow the drainage of pancreatic fluid into the small bowel. After distal pancreatectomy, the cut surface of the pancreatic remnant (pancreatic stump) is closed using staples or sutures (Diener 2011). Generally, an abdominal drain is placed after pancreatic resection, although this practice has been questioned (van der Wilt 2013).
Pancreatic resection is a surgical procedure with high morbidity. It carries a post-operative mortality of around 4.5% (Gurusamy 2013). Approximately 30% of patients develop one or more post-operative complications (Gurusamy 2013). Approximately 18% of patients develop post-operative pancreatic leak or post-operative pancreatic fistula (POPF) making it one of the common complications of pancreatic resection (Gurusamy 2013). Post-operative pancreatic fistula is an abnormal communication between the pancreatic ductal epithelium and another epithelial surface containing enzyme-rich pancreatic fluid. It represents a failure of healing or sealing of the pancreato-enteric anastomosis, or it may represent a parenchymal leak not directly related to an anastomosis, such as a leak from the raw pancreatic surface after distal pancreatectomy (Bassi 2005). Clinically, POPF can be defined as an output via an operatively placed drain (or a subsequently placed, percutaneous drain) of any measurable volume of drain fluid on or after postoperative day 3, with an amylase content greater than 3 times the upper normal serum value according to the definition by the International Study Group on Pancreatic Fistula (ISGPF) (Bassi 2005). Various other definitions exist (Bassi 2005). ISGPF has graded post-operative fistulas as Grade A, Grade B, and Grade C based on their respective clinical impact, as shown below (Bassi 2005).
Grade A: This grade of fistula has no clinical impact and requires little change in management or deviation from the normal clinical pathway.
Grade B: This grade of fistula requires a change in management or adjustment in the clinical pathway. Many patients with this grade of fistula can be discharged with drains in situ and observed in the outpatient setting. However, there is no requirement for an invasive procedure.
Grade C: This grade of fistula requires a major change in clinical management or deviation from the normal clinical pathway. The patients with this grade of fistula typically require an extended hospital stay with a major delay in hospital discharge. There may be a need for invasive procedures.
Various interventions to decrease post-operative fistulas include pancreaticogastrostomy rather than pancreaticojejunostomy after pancreatic resections (McKay 2006), somatostatin analogues to decrease pancreatic fluid secretion (Gurusamy 2013), and fibrin sealants (in the form of glue (Suzuki 1995) or patches (Montorsi 2012)) to seal the pancreatic stump. Despite one or more of these measures, approximately 14% of patients develop pancreatic fistula (Gurusamy 2013).
We provide a glossary of terms in Appendix 1.
Target condition being diagnosed
Clinically significant post-operative pancreatic leak or fistula (ISGPF Grade B or Grade C fistula)
Pancreatic amylase in drain fluid
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 (Vissers 1999). High pancreatic amylase in the drain fluid indicates pancreatic leak since the pancreas is the source of pancreatic amylase and without a leak, the pancreatic fluid drains into the small intestine. Pancreatic amylase can be measured by immunochemical assays, usually with monoclonal antibodies (Maeda 2008; Mifflin 1985). The test is conducted by the laboratory technicians and interpreted by the clinicians managing the patient. Drain fluid pancreatic amylase content greater than 3 times the upper normal serum value is considered to be abnormal (Bassi 2005). Serum amylase can vary between laboratories but is usually between 100 IU/L to 300 IU/L (Vissers 1999).
When there is a high suspicion of pancreatic fistula, usually based on high amylase content of drain fluid, further radiological investigations such as computed tomography (CT) scan are performed. Grade A POPF is not associated with any peripancreatic fluid collections and the patient is clinically well. The major difference in management of people with Grade A POPF and those without pancreatic fistula is the delayed removal of drains. Grade B POPF may be associated with peripancreatic collections on CT scan. The patient may require repositioning of the drain if there is a peripancreatic collection, and usually requires enteral or parenteral nutritional support. Depending upon the clinical signs and symptoms such as abdominal pain, fever, and elevated white cell count, antibiotics and somatostatin analogues may be required. Grade C POPF is usually associated with peripancreatic fluid collections on CT scan and these often require percutaneous drainage. Patients with grade C POPF usually require enteral or parenteral nutritional support, intravenous antibiotics, and somatostatin analogues, and are usually managed in an intensive therapy unit setting. If there is clinical deterioration and development of sepsis and organ dysfunction, reoperation with a view to repair the site of leakage, conversion to an alternative means of pancreato-enteric anastomosis (e.g., conversion of pancreaticojejunostomy to pancreaticogastrostomy), or performing a complete pancreatectomy may be necessary. Thus, the presence and grade of POPF alters the treatment pathway. This is shown in Figure 1. If there is a high suspicion of pancreatic leak because of the presence of peritonitis or sepsis, patients may undergo further radiological investigations directly without the pancreatic amylase.
Pancreatic amylase in the drain fluid (the index test) is usually the first investigation performed in people with suspected pancreatic leak.
Role of index test(s)
The index test is used for the screening of pancreatic leak in patients who had undergone pancreatic resection. It is usually followed by CT scan or magnetic resonance cholangiopancreatography (MRCP) to confirm the presence or absence of peripancreatic collection and pancreatic leak. Thus, pancreatic amylase can be considered as a triage test prior to CT scan or MRCP in the diagnosis of pancreatic leak.
The treatment of patients with clinically significant POPF is different from those with clinically insignificant POPF. It is important to know the true diagnostic accuracy of pancreatic amylase as a screening test for the detection of clinically significant pancreatic leaks, so that an informed decision can be made as to whether the patient with a suspected pancreatic leak needs further investigations. There is no currently no systematic review of the diagnostic test accuracy of pancreatic amylase in the drain fluid for the diagnosis of pancreatic leak. Hence, a Cochrane systematic review of this subject is necessary.