Pancreatic amylase in drain fluid for the diagnosis of pancreatic leak in post pancreatic resection

  • Protocol
  • Diagnostic

Authors


Abstract

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

To determine the diagnostic accuracy of pancreatic amylase in drain fluid for the diagnosis of pancreatic leak in patients who had undergone pancreatic resection.

If we identify heterogeneity, we plan to explore the following potential sources of heterogeneity: risk of bias, publication status, prospective or retrospective studies, type of pancreatic resection (pancreatoduodenectomies versus distal pancreatic resection), different aetiologies, and different reference standards.

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 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)

Index test(s)

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).

Clinical pathway

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.

Figure 1.

Clinical pathway

Prior test(s)

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.

Rationale

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.

Objectives

To determine the diagnostic accuracy of pancreatic amylase in drain fluid for the diagnosis of pancreatic leak in patients who had undergone pancreatic resection.

Secondary objectives

If we identify heterogeneity, we plan to explore the following potential sources of heterogeneity: risk of bias, publication status, prospective or retrospective studies, type of pancreatic resection (pancreatoduodenectomies versus distal pancreatic resection), different aetiologies, and different reference standards.

Methods

Criteria for considering studies for this review

Types of studies

We will include all studies that evaluate the diagnostic test accuracy of pancreatic amylase in the drain fluid for the diagnosis of pancreatic leak in patients who had undergone pancreatic resection. To be included, studies must provide information on the index test and reference standards irrespective of language or publication status, or whether the data is collected prospectively or retrospectively. However, we will exclude case reports that describe how the diagnosis of pancreatic fistula 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 these studies are prone to bias (Whiting 2011).

Participants

Patients who have undergone pancreatic resection with drain fluid at least 48 hours after pancreatic resection irrespective of the volume of the drain fluid.

Index tests

Drain fluid pancreatic amylase.

Target conditions

Clinically significant pancreatic leak (ISGPF Grade B or Grade C fistula).

Reference standards

We will accept one of the following reference standards:

  1. Pancreatic leak confirmed at surgery. This is confirmation of pancreatic leak at surgery, usually on the basis of the presence of partial or complete separation of the anastomosis allowing leakage of contents, abdominal collections, or fistula (a tract between the anastomosis and exterior), and is a subjective decision made by the surgeon. Nevertheless, this is the best reference standard available.

  2. Pancreatic leak confirmed at surgery for patients with elevated amylase and clinical follow-up for a minimum period of six weeks (to ensure that they do not have complications due to pancreatic leak such as abdominal collections requiring drainage, intra-abdominal sepsis, generalised sepsis resulting from intra-abdominal sepsis, or mortality due to intra-abdominal sepsis) in people with negative amylase. The clinical follow-up should include clinical examination of the patient, and may or may not include radiological follow-up done as follow-up of suspected pancreatic leak or routine radiological follow-up to detect the recurrence of cancer. In retrospective studies, we will accept hospital records of physical examination of the patient after a minimum follow-up period of six weeks as an acceptable reference standard. The presence of one or more of complications due to pancreatic leak such as abdominal collections requiring drainage, intra-abdominal sepsis, generalised sepsis resulting from intra-abdominal sepsis, or mortality due to intra-abdominal sepsis will be considered as a positive reference standard.

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

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 two databases.

Data collection and analysis

Selection of studies

Two review authors (research assistants to KG) will independently search the references produced by the search 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 pre-piloted data extraction form, 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. Number of pancreatoduodenectomies and distal pancreatic resections.

  9. Number with cancers.

  10. Average volume of pancreatic fluid.

  11. Description of the index test.

  12. Threshold used for index test.

  13. Reference standard.

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

If the same study reports multiple tests on the same patient, we will extract the number of true positives, false positives, false negatives, and true negatives at each measurement. However, we will include the last measurement prior to CT scan or MRCP or surgery in the analysis. If the study author uses progressively increasing trend in drain fluid amylase levels as the criterion for diagnosing pancreatic leaks, we will consider increasing trend as a positive index test irrespective of the degree of increase and consider stationary levels or decrease in the levels as a negative test in order to calculate the number of true positives, false positives, false negatives, and true negatives. If the same study reports the number of true positives, false positives, false negatives, and true negatives for the index test at different thresholds, we will extract this information for each threshold. We will exclude patients with uninterpretable index test results (no matter the reason given for lack of interpretation, for example, low volume of drain fluid) since in clinical practice, uninterpretable index test results will result in additional tests such as CT scan for diagnosis of pancreatic leak. 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 suspected because of 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 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 1. We will consider studies which are classified as 'low risk of bias' and 'low concern' in all the domains as studies of high methodological quality. The results will be presented in 'Risk of bias' summary and graphs in addition to a narrative summary.

Table 1. QUADAS-2 classification
Domain 1: Patient selectionPatient samplingPatients who have undergone pancreatic resection with drain fluid at least 48 hours after pancreatic resection irrespective of the volume of the drain fluid.
Was a consecutive or random sample of patients enrolled?Yes: If a consecutive sample or a random sample of patients with pancreatic resection with drain fluid at least 48 hours after pancreatic resection was included in the study.
No: If a consecutive sample or a random sample of patients with pancreatic resection with drain fluid at least 48 hours after pancreatic resection was not included in the study.
Unclear: If this information was not available.
Was a case-control design avoided?Yes: If a cohort of patients with pancreatic resection with drain fluid at least 48 hours after pancreatic resection was studied.
No: If patients with pancreatic leak were compared with patients without pancreatic leak (controls). Such studies will be excluded.
Unclear: We anticipate that we will be able to determine whether the design was case-control. Hence we anticipate that all studies included in the review will be classified as 'yes' for this item.
Did the study avoid inappropriate exclusions?Yes: If all patients with pancreatic resection with drain fluid at least 48 hours after pancreatic resection were included.
No: If the study excluded patients based on high or low probability of pancreatic leak (for example, those with high volume in the drain).
Unclear: If this information was not available.
Could the selection of patients have introduced bias?

Low risk of bias: If 'yes' classification for all of the above 3 questions.

High risk of bias: If 'no' classification for any of the above 3 questions.

Unclear risk of bias: if 'unclear' classification for any of the above 3 questions but without a 'no' classification for any of the above 3 questions.

Patient characteristics and settingYes: If all patients with pancreatic resection with drain fluid at least 48 hours after pancreatic resection were included.
No: If some patients with pancreatic resection with drain fluid at least 48 hours after pancreatic resection were excluded on the basis of the results of drain fluid volume.
Unclear: If it is not clear whether the patients have been included on the basis of the results of drain fluid volume.
Are there concerns that the included patients and setting do not match the review question?

Low concern: if the patient characteristics and setting are classified as 'yes'.

Unclear concern: if the patient characteristics and setting are classified as 'unclear'.

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

Domain 2: Index testIndex test(s)Pancreatic amylase in drain fluid.
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 questions.

High risk of bias: if 'no' classification for any of the above 2 questions.

Unclear risk of bias: if 'unclear' classification for any of the above 2 questions but without a 'no' classification for any of the above 2 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: clinically significant pancreatic leak (requiring clinical intervention).

Reference standard:

  1. Pancreatic leak confirmed at surgery.

  2. Pancreatic leak confirmed at surgery for patients with elevated amylase and clinical follow-up for a minimum period of 6 weeks (to ensure that they do not have complications due to pancreatic leak such as abdominal collections requiring drainage, intra-abdominal sepsis, or generalised sepsis) in people with negative amylase.

Is the reference standard(s) likely to correctly classify the target condition?

Yes: If pancreatic leak is confirmed at reoperation.
No: If the reference standard is a combination of pancreatic leak and clinical follow-up for a minimum period of 6 weeks (to ensure that they do not have complications due to pancreatic leak such as abdominal collections requiring drainage, intra-abdominal sepsis, or generalised sepsis) in people with negative amylase.

Unclear: If the reference standard was not described adequately. Such studies will be excluded.

Because of the inclusion criteria, all the studies in this review will be classified as 'yes' for this signalling question.

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 2 questions.

High risk of bias: if 'no' classification for any of the above 2 questions.

Unclear risk of bias: if 'unclear' classification for any of the above 2 questions but without a 'no' classification for any of the above 2 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 progression or resolution of pancreatic leak if there is a long delay between index test and reference standard. An arbitrary 2 weeks was chosen as an 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 2 weeks.
No: If the time interval between index test and reference standard was more than 2 weeks.
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 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.

Because of the inclusion criteria, all the studies in this review will be classified as 'yes' for this signalling question.

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 4 questions.

High risk of bias: if 'no' classification for any of the above 4 questions.

Unclear risk of bias: if 'unclear' classification for any of the above 4 questions but without a 'no' classification for any of the above 4 questions.

Statistical analysis and data synthesis

We plan to perform a separate meta-analysis (i.e. stratify the analysis) for each level of threshold, i.e. tests at different thresholds will be considered as different index tests. If the study uses increasing trend in the values of the drain fluid pancreatic amylase as the diagnostic criteria for diagnosis of pancreatic leak, 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 different thresholds. To estimate the summary sensitivity and specificity of the test at each threshold level, we will perform the meta-analysis by fitting the bivariate model (Reitsma 2005, Chu 2006).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 results 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 pancreatic amylase in drain fluid at different threshold levels by including a single covariate term for threshold level in the bivariate model to estimate differences in the sensitivity and specificity of the test at different thresholds. 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 different thresholds. We will use the hierarchical summary receiver operating characteristics curve (HSROC) (Rutter 2001) to test hypotheses whether one threshold is superior to another and to investigate heterogeneity. For this purpose, we will combine tests irrespective of the thresholds. 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 (threshold levels). A P value of < 0.05 for the likelihood ratio test will indicate differences in the diagnostic accuracy between the threshold levels. 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 thresholds in the same study population are available from at least four studies, we will perform a direct head-to-head comparison by limiting the threshold 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 threshold level. 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 a positive test is the probability of having the target condition (pancreatic leak) 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 (pancreatic leak) 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

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 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. 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).

  3. Prospective studies versus retrospective studies.

  4. Pancreatoduodenectomies versus distal pancreatic resection.

  5. Patients with cancers versus those with benign diseases.

  6. Different reference standards (confirmation by surgical resection in all patients versus a combination of surgical resection and clinical follow-up.

Of the six sources of heterogeneity mentioned above, risk of bias, publication status, prospective or retrospective studies, and different thresholds used in the studies will be used as categorical covariates; while the proportion of patients undergoing pancreatoduodenectomies versus distal pancreatic resection and proportion of patients with different aetiologies 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.

Sensitivity analyses

We do not plan to conduct 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 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 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

Anastomosis: connection of two structures (in this context, connection between pancreas and small bowel).

Enteral: intestinal.

Epithelial surface: a surface lined by epithelium.

Epithelium: membranous tissue composed of one or more layers of cells. It forms the covering of most internal and external surfaces of the body and its organs.

Fistula: an abnormal duct or passage connecting a cavity or hollow organ to the body surface or to another hollow organ.

Heterogeneity: differences in results between studies.

In situ: in its original position in the body.

Pancreatectomy: removal of part of pancreas.

Pancreaticoduodenectomy: removal of part of pancreas and duodenum (first part of the small intestine).

Pancreaticogastrostomy: connecting the pancreatic duct to the stomach.

Pancreaticojejunostomy: connecting the pancreatic duct to the jejunum (second part of the small intestine).

Pancreato-enteric: connecting the pancreatic duct to the intestine.

Parenchymal: functional parts of an organ.

Parenteral: administered into the body in a manner other than through the gut (in this context by a drip).

Peripancreatic: adjacent to the pancreas.

Appendix 2. MEDLINE search strategy

(((ampulla vateri[tiab] OR "Ampulla of Vater" [Mesh] OR ampullovateric[tiab] OR papilla vateri[tiab]  OR vater papilla[tiab] OR vater ampulla[tiab] OR peri-ampull*[tiab] OR periampull*[tiab] OR choledoch*[tiab] OR alcholedoch*[tiab] OR bile duct*[tiab] OR biliary[tiab] OR cholangio*[tiab] OR gall duct[tiab] OR duodenum[tiab] OR duodenal[tiab] OR duoden*[tiab] OR small bowel[tiab] OR small instestin*[tiab] OR enteral[tiab] OR enteric[tiab] OR enter*[tiab] OR pancreatic[tiab] OR pancreato*[tiab] OR pancreas*[tiab]) AND (surger*[tiab] OR operat*[tiab] OR resection*[tiab] OR surgical*[tiab] OR Surgical Procedures, Operative[MeSH] OR General Surgery[MeSH])) OR (pancreatect*[tiab] OR pancreaticojejunost*[tiab] OR pancreaticogastros*[tiab] OR pancreaticoduodenect*[tiab] OR duodenopancreatectom*[tiab] OR Pancreatectomy[MeSH] OR Pancreaticojejunostomy[MeSH] OR Pancreaticoduodenectomy[MeSH])) AND ("Amylases"[Mesh] OR amylase[tiab]) AND ("Drainage"[Mesh] OR drain*[tiab] OR "Anastomotic Leak"[Mesh] OR leak[tiab] OR "Pancreatic Fistula"[Mesh] OR fistula[tiab])

Appendix 3. EMBASE search strategy

1. (ampulla vateri or ampullovateric or papilla vateri or vater papilla or vater ampulla or periampull* or peri-ampull* or choledoch* or alcholedoch* or bile duct* or biliary or cholangio* or gall duct or duoden* or small bowel or small intestin* or enter* or pancrea*).ti,ab.

2. exp duodenum cancer/ or Vater papilla tumor/ or exp pancreas cancer/ or exp bile duct tumor/

3. 1 or 2

4. (surger* or surgical* or operat* or resection*).ti,ab.

5. exp Surgery/

6. 4 or 5

7. 3 and 6

8. (pancreatect* or pancreaticojejunost* or pancreaticogastros* or pancreaticoduodenect* or duodenopancreatectom*).ti,ab.

9. exp pancreas surgery/

10. 7 or 8 or 9

11. amylase.ti,ab.

12. exp amylase/

13. 11 or 12

14. (drain* or leak or fistula).ti,ab.

15. exp drain/

16. exp anastomosis leakage/

17. exp pancreas fistula/

18. 14 or 15 or 16 or 17

19. 10 and 13 and 18

Appendix 4. Science Citation Index search strategy

#1 TS=(ampulla vateri or ampullovateric or papilla vateri or vater papilla or vater ampulla or periampull* or peri-ampull* or choledoch* or alcholedoch* or bile duct* or biliary or cholangio* or gall duct or duoden* or small bowel or small intestin* or enter* or pancrea*)
#2 TS=(operat* OR surger* OR surgical* OR resection*)
#3 #1 AND #2
#4 TS=(pancreatect* OR pancreaticojejunost* OR pancreaticogastros* OR pancreaticoduodenect* OR duodenopancreatectom*)
#5 #3 OR #4
#6 TS=(amylase)
#7 TS=(drain* or leak or fistula)
#8 #5 AND #6 AND #7

Appendix 5. National Institute for Health Research - Health Technology Assessment

pancrea* AND amylase

Contributions of authors

KS Gurusamy wrote the protocol.

M Yaghoobi and BR Davidson critically commented on the protocol.

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.

Sources of support

Internal sources

  • University College London, UK.

    Support 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.

External sources

  • National Institute for Health Research, UK.

    Support 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.

Ancillary