Amylase in drain fluid for the diagnosis of pancreatic leak in post‐pancreatic resection

Tsetsegdemberel Bat‐Ulzii Davidson; Mohammad Yaghoobi; Brian R Davidson; Kurinchi Selvan Gurusamy

doi:10.1002/14651858.CD012009.pub2

引流液中的淀粉酶含量用于诊断胰腺切除术后胰瘘

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Referencias

References to studies included in this review

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estudios excluidos
otras referencias

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References to studies excluded from this review

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estudios incluidos
otras referencias

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Characteristics of studies

Characteristics of included studies [ordered by study ID]

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estudios excluidos

Araki 2012

Study characteristics
Patient sampling	Type of study: retrospective study. Consecutive or random sample: unclear.
Patient characteristics and setting	Sample size: 182. Females: not stated. Age: not stated. Presentation: people who underwent pancreaticoduodenectomy in a single center in Japan between April 2003 and May 2012 were included. Setting: secondary care, Japan.
Index tests	Index test: postoperative day 3 drain fluid amylase. Further details: Technical specifications: not stated. Performed by: not stated. Criteria for positive diagnosis: > 600 IU/L.
Target condition and reference standard(s)	Target condition: clinically significant pancreatic leak. Reference standard: ISGPF grade B or C. Further details: Technical specifications: not applicable. Performed by: clinicians. Criteria for positive diagnosis: ISGPF definitions.
Flow and timing	Number of indeterminates for whom the results of reference standard was available: 0 (0%). Number of patients who were excluded from the analysis: not stated.
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Unclear
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Unclear
		Unclear	Unclear
DOMAIN 2: Index Test All tests
Were the index test results interpreted without knowledge of the results of the reference standard?	Unclear
If a threshold was used, was it pre‐specified?	No
		High	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Unclear
Were the reference standard results interpreted without knowledge of the results of the index tests?	Unclear
Did all patients receive a reference standard?	Yes
		Unclear	High
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Unclear
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	Unclear
		Unclear

El Nakeeb 2013

Study characteristics
Patient sampling	Type of study: retrospective study. Consecutive or random sample: consecutive sample.
Patient characteristics and setting	Sample size: 471. Females: 193 (41.0%). Age: 53 years. Presentation: people who underwent pancreaticoduodenectomy from January 2001 to June 2012 were included. Setting: secondary care, Egypt.
Index tests	Index test: postoperative day 5 drain fluid amylase. Further details: Technical specifications: not stated. Performed by: not stated. Criteria for positive diagnosis: > 4000 U/L.
Target condition and reference standard(s)	Target condition: clinically significant pancreatic leak. Reference standard: ISGPF grade B or C. Further details: Technical specifications: not applicable. Performed by: clinicians. Criteria for positive diagnosis: ISGPF definitions.
Flow and timing	Number of indeterminates for whom the results of reference standard was available: 0 (0%). Number of patients who were excluded from the analysis: 0 (0%).
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Yes
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Yes
		Low	Low
DOMAIN 2: Index Test All tests
Were the index test results interpreted without knowledge of the results of the reference standard?	Unclear
If a threshold was used, was it pre‐specified?	No
		High	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Unclear
Were the reference standard results interpreted without knowledge of the results of the index tests?	Unclear
Did all patients receive a reference standard?	Yes
		Unclear	High
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Unclear
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	Yes
		Unclear

Facy 2012

Study characteristics
Patient sampling	Type of study: prospective study. Consecutive or random sample: neither.
Patient characteristics and setting	Sample size: 65. Females: 31 (47.69%). Age: 62 years. Presentation: people who underwent pancreatic resection between 2008 and 2010 and had the concentration of amylase and lipase measured in abdominal drains were included. People who underwent total pancreatectomy were not included. People in whom the lipase concentration was not measured were excluded from analysis. Setting: tertiary care, France.
Index tests	Index test: post operative day 3 to 5 drain fluid amylase. Further details: Technical specifications: Dimension Vista Colorimetric Analyser. Performed by: Dr David Masson. Criteria for positive diagnosis: 3 times normal limit.
Target condition and reference standard(s)	Target condition: clinically significant pancreatic leak. Reference standard: ISGPF grade B or C. Further details: Technical specifications: not applicable. Performed by: clinicians. Criteria for positive diagnosis: ISGPF definitions.
Flow and timing	Number of indeterminates for whom the results of reference standard was available: 0 (0%). Number of participants who were excluded from the analysis: not stated.
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	No
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Unclear
		High	Unclear
DOMAIN 2: Index Test All tests
Were the index test results interpreted without knowledge of the results of the reference standard?	Unclear
If a threshold was used, was it pre‐specified?	Yes
		Unclear	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Unclear
Were the reference standard results interpreted without knowledge of the results of the index tests?	Unclear
Did all patients receive a reference standard?	Yes
		Unclear	High
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Unclear
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	Unclear
		Unclear

Kong 2008

Study characteristics
Patient sampling	Type of study: prospective study.. Consecutive or random sample: consecutive patients.
Patient characteristics and setting	Sample size: 50. Females: 15 (30%). Age: 67 years. Presentation: people who underwent modified extended pancreaticoduodenectomy for a periampullary tumour between April 2004 and August 2006 at two hospitals in Australia were included. Setting: secondary and tertiary care, Australia.
Index tests	Index test: postoperative day 5 drain fluid amylase. Further details: Technical specifications: Roche Modular System and Roche Reagent Assays. Performed by: not stated. Criteria for positive diagnosis: > 125 u/ml (3 times serum amylase and 50 mls/24 h on D5).
Target condition and reference standard(s)	Target condition: clinically significant pancreatic leak. Reference standard: ISGPF grade B or C. Further details: Technical specifications: not applicable. Performed by: clinicians. Criteria for positive diagnosis: ISGPF definitions.
Flow and timing	Number of indeterminates for whom the results of reference standard was available: 0 (0%). Number of patients who were excluded from the analysis: 0 (0%).
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Yes
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Yes
		Low	Low
DOMAIN 2: Index Test All tests
Were the index test results interpreted without knowledge of the results of the reference standard?	Unclear
If a threshold was used, was it pre‐specified?	Unclear
		Unclear	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Unclear
Were the reference standard results interpreted without knowledge of the results of the index tests?	Unclear
Did all patients receive a reference standard?	Yes
		Unclear	High
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Unclear
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	Yes
		Unclear

Kosaka 2014

Study characteristics
Patient sampling	Type of study: retrospective study. Consecutive or random sample: consecutive patients.
Patient characteristics and setting	Sample size: 100. Females: 36 (36%). Age: 67 years. Presentation: people who underwent pancreaticoduodenectomy between January 2009 and October 2012 were included. Setting: secondary care, Japan.
Index tests	Index test: postoperative day 4 drain fluid amylase Further details: Technical specifications: not stated. Performed by: not stated. Criteria for positive diagnosis: 647 U/L.
Target condition and reference standard(s)	Target condition: clinically significant pancreatic leak. Reference standard: ISGPF grade B or C. Further details: Technical specifications: not applicable. Performed by: clinicians. Criteria for positive diagnosis: ISGPF definitions
Flow and timing	Number of indeterminates for whom the results of reference standard was available: 0 (0%). Number of patients who were excluded from the analysis: 0 (0%).
Comparative
Notes
Methodological quality
Item	Authors' judgement	Risk of bias	Applicability concerns
DOMAIN 1: Patient Selection
Was a consecutive or random sample of patients enrolled?	Yes
Was a case‐control design avoided?	Yes
Did the study avoid inappropriate exclusions?	Yes
		Low	Low
DOMAIN 2: Index Test All tests
Were the index test results interpreted without knowledge of the results of the reference standard?	Unclear
If a threshold was used, was it pre‐specified?	No
		High	Low
DOMAIN 3: Reference Standard
Is the reference standards likely to correctly classify the target condition?	Unclear
Were the reference standard results interpreted without knowledge of the results of the index tests?	Unclear
Did all patients receive a reference standard?	Yes
		Unclear	High
DOMAIN 4: Flow and Timing
Was there an appropriate interval between index test and reference standard?	Unclear
Did all patients receive the same reference standard?	Yes
Were all patients included in the analysis?	Yes
		Unclear

ISGPF = International Study Group on Pancreatic Fistula

Characteristics of excluded studies [ordered by study ID]

Ir a:

estudios incluidos

Study	Reason for exclusion
Ansorge 2014	No diagnostic test accuracy data using appropriate reference standard
Burdy 1999	No diagnostic test accuracy data using appropriate reference standard
Ceroni 2014	No diagnostic test accuracy data using appropriate reference standard
Chen 2015	No diagnostic test accuracy data using appropriate reference standard
Cherian 2010	Inappropriate target condition (target condition not defined adequately)
Chhabra 2011	No diagnostic test accuracy data using appropriate reference standard
Cirocchi 2015	Inappropriate target condition
Dugalic 2014	No diagnostic test accuracy data using appropriate reference standard
Fong 2016	Not a diagnostic test accuracy study.
Furukawa 2015	No diagnostic test accuracy data using appropriate reference standard
Gebauer 2012	No diagnostic test accuracy data using appropriate reference standard
Graham 2013	No diagnostic test accuracy data using appropriate reference standard
Hashimoto 2003	No diagnostic test accuracy data using appropriate reference standard
Hashimoto 2014	No diagnostic test accuracy data using appropriate reference standard
Hiyoshi 2013	No diagnostic test accuracy data using appropriate reference standard
Ho 2014	No diagnostic test accuracy data using appropriate reference standard
Israel 2014	Inappropriate target condition
Kanda 2014	Inappropriate population (patients without pancreatic fistula were excluded from the study)
Kawai 2011	Inappropriate index test (drain fluid amylase was measured on post‐operative day 1 only)
Kim 2014	No diagnostic test accuracy data using appropriate reference standard
Kobayashi 2015	Inappropriate population (not in patients undergoing pancreatic resection)
Kosaka 2013	Inappropriate index test (not on drain fluid amylase)
Kosaka 2014a	Inappropriate index test
Kumar 2013	Inappropriate target condition
Kurahara 2011	No diagnostic test accuracy data using appropriate reference standard
Lee 2014	Inappropriate target condition
Malleo 2014	Inappropriate target condition
Mcmillan 2015	Inappropriate population (people with amylase > 5000 IU were initially excluded; in addition, people with low unvalidated fistula risk score were excluded from the analysis)
Menon 2012	Inappropriate target condition
Mimura 2012	No diagnostic test accuracy data using appropriate reference standard
Molinari 2007	Inappropriate target condition
Moskovic 2010	No diagnostic test accuracy data using appropriate reference standard
Musiewicz 2010	No diagnostic test accuracy data using appropriate reference standard
Nissen 2012	Inappropriate target condition
Noji 2012	No diagnostic test accuracy data using appropriate reference standard
Okano 2011	No diagnostic test accuracy data using appropriate reference standard
Palani Velu 2015	Not a diagnostic test accuracy study
Partelli 2014	Inappropriate target condition
Prakash 2011	Inappropriate index test
Raja 2015	Inappropriate target condition
Ramesh 2006	Not a diagnostic test accuracy study
Robinson 2010	No diagnostic test accuracy data using appropriate reference standard
Sanchez Acedo 2013	Inappropriate target condition
Saxena 2014	Inappropriate target condition
Shi 2009	Inappropriate target condition
Shimizu 2015	No diagnostic test accuracy data using appropriate reference standard
Shinchi 2006	Inappropriate target condition
Shyr 2003	Inappropriate target condition
Srivastava 2016	Inappropriate target condition.
Sugimoto 2013	No diagnostic test accuracy data using appropriate reference standard
Sutcliffe 2012	Inappropriate target condition
Sutcliffe 2014	Inappropriate target condition
Sutcliffe 2015	Not a diagnostic test accuracy study
Tang 2015	No diagnostic test accuracy data using appropriate reference standard
Teixeira 2016	Not a diagnostic test accuracy study
Tsujie 2012	No diagnostic test accuracy data using appropriate reference standard
Uemura 2011	No diagnostic test accuracy data using appropriate reference standard
Uemura 2014	No diagnostic test accuracy data using appropriate reference standard
Veillette 2010	No diagnostic test accuracy data using appropriate reference standard
Ven Fong 2015	No diagnostic test accuracy data using appropriate reference standard
Yamaguchi 2003	No diagnostic test accuracy data using appropriate reference standard
Yang 2015	Not a diagnostic test accuracy study (systematic review)
Zelga 2015	Inappropriate target condition

Data

Presented below are all the data for all of the tests entered into the review.

Open in table viewer

Tests. Data tables by test

Test	No. of studies	No. of participants
1 POD:3 DFA > 600 IU/L Show forest plot	1	182
Open in figure viewer Test 1 POD:3 DFA > 600 IU/L.
2 POD:3 to 5 DFA > 3 times serum amylase Show forest plot	1	65
Open in figure viewer Test 2 POD:3 to 5 DFA > 3 times serum amylase.
3 POD:4 DFA > 647 U/L Show forest plot	1	100
Open in figure viewer Test 3 POD:4 DFA > 647 U/L.
4 POD:5 DFA > 3 times serum amylase Show forest plot	1	50
Open in figure viewer Test 4 POD:5 DFA > 3 times serum amylase.
5 POD:5 DFA > 4000 U/L Show forest plot	1	471
Open in figure viewer Test 5 POD:5 DFA > 4000 U/L.

Figure 1

Clinical pathway

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Figure 2

Study flow diagram.

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Figure 3

Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study

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Figure 4

Forest plot of tests: The numbers following POD (postoperative day) indicate the number of the postoperative day. The numbers or text following DFA (drain fluid amylase) indicate the threshold. The drain fluid amylase measured on 5th postoperative day using a threshold of more than three times serum amylase provides the best sensitivity with high specificity. However, this is based on a single study with small sample size. Another study which used the same threshold between 3 days and 5 days has much less diagnostic test accuracy introducing significant uncertainty in the findings.

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Figure 5

Plot of sensitivity and specificity in the ROC (receiver operating characteristics) space: The numbers following POD (postoperative day) indicate the number of the postoperative day. The numbers or text following DFA (drain fluid amylase) indicate the threshold. The drain fluid amylase measured on 5^th postoperative day using a threshold of more than three times serum amylase provides the best sensitivity with high specificity. However, this is based on a single study with small sample size. Another study which used the same threshold between 3 days and 5 days has much less diagnostic test accuracy introducing significant uncertainty in the findings.

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Test 1

POD:3 DFA > 600 IU/L.

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Test 2

POD:3 to 5 DFA > 3 times serum amylase.

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Test 3

POD:4 DFA > 647 U/L.

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Test 4

POD:5 DFA > 3 times serum amylase.

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Test 5

POD:5 DFA > 4000 U/L.

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Summary of findings Summary of findings table

Population	People undergoing pancreatic resection
Setting	Secondary care in various countries
Target condition	Clinically significant pancreatic leak
Reference standard	International Study Group on Pancreatic Fistula (ISGPF) grade B or C
Median prevalence of pancreatic leak	15.9%
Index test¹	Sensitivity	Specificity	Post‐test probability of a positive test²	Post‐test probability of a negative test²	Number of studies	Number of participants	Risk of bias	Applicability concerns	Plain language interpretation
POD:3 DFA > 600 IU/L	0.86 (95% CI 0.68 to 0.96)	0.73 (95% CI 0.65 to 0.80)	37.9% (95% CI 31.1% to 45.1%)	3.4% (95% CI 1.4% to 8.2%)	1	182	Unclear	High	At the median pre‐test probability of 16%, out of 100 people with positive test, 38 people (95% CI 31 to 45) have clinically significant pancreatic leak. At the same pre‐test probability, out of 100 people with negative test, 3 people (95% CI 1 to 8) have clinically significant pancreatic leak.
POD:3 to 5 DFA > 3 times serum amylase	0.79 (95% CI 0.49 to 0.95)	0.78 (95% CI 0.65 to 0.89)	40.8% (95% CI 27.7% to 55.5%)	4.9% (1.8% to 12.5%)	1	65	High	High	At the median pre‐test probability of 16%, out of 100 people with positive test, 41 people (95% CI 28 to 56) have clinically significant pancreatic leak. At the same pre‐test probability, out of 100 people with negative test, 5 people (95% CI 2 to 13) have clinically significant pancreatic leak.
POD:4 DFA > 647 U/L	0.72 (95% CI 0.53 to 0.86)	0.91 (95% CI 0.82 to 0.97)	60.7% (95% CI 41.1% to 77.4%)	5.5% (95% CI 3.2% to 9.3%)	1	100	High	High	At the median pre‐test probability of 16%, out of 100 people with positive test, 61 people (95% CI 41 to 77) have clinically significant pancreatic leak. At the same pre‐test probability, out of 100 people with negative test, 6 people (95% CI 3 to 9) have clinically significant pancreatic leak.
POD:5 DFA > 3 times serum amylase	1.00 (95% CI 0.29 to 1.00)	0.94 (95% CI 0.82 to 0.99)	74.8% (95% CI 49.8% to 89.9%)	0% (95% CI not estimable)	1	50	Unclear	High	At the median pre‐test probability of 16%, out of 100 people with positive test, 75 people (95% CI 50 to 90) have clinically significant pancreatic leak. It was not possible to estimate the number of people with clinically significant pancreatic leak when the test was negative.
POD:5 DFA > 4000 U/L	0.75 (95% CI 0.58 to 0.88)	0.99 (95% CI 0.98 to 1.00)	95.4% (95% CI 86.8% to 98.5%)	4.6% (95% CI 2.6% to 7.8%)	1	471	High	High	At the median pre‐test probability of 16%, out of 100 people with positive test, 95 people (95% CI 87 to 99) have clinically significant pancreatic leak. At the same pre‐test probability, out of 100 people with negative test, 5 people (95% CI 3 to 8) have clinically significant pancreatic leak.
Interpretation	The drain fluid amylase measured on 5th postoperative day using a threshold of more than three times serum amylase provides the best sensitivity with high specificity. A negative test more or less rules out pancreatic leak. However, this is based on a single study with small sample size. Another study which used the same threshold between 3 days and 5 days has much less diagnostic test accuracy introducing significant uncertainty in the findings.
¹The numbers following POD (postoperative day) indicate the number of the postoperative day. The numbers or text following DFA (drain fluid amylase) indicate the threshold. ²All post‐test probabilities were calculated at the median prevalence (pre‐test probability) of pancreatic leak in the studies. At the lower quartile of the prevalence of 7.6%, the post‐test probabilities of pancreatic leak of positive POD:3 DFA > 600 IU/L, POD:3 to 5 DFA > 3 times serum amylase, POD:4 DFA > 647 U/L, POD:5 DFA > 3 times serum amylase, and POD:5 DFA > 4000 U/L were 21.0% (95% CI 16.5% to 26.4%), 23.2% (95% CI 14.3% to 35.2%), 40.3% (95% CI 23.4% to 59.9%), 56.5% (95% CI 30.3% to 79.5%), and 90.0% (95% CI 74.2% to 96.6%) respectively. At the same pre‐test probability, the post‐test probabilities of pancreatic leak of negative POD:3 DFA > 600 IU/L, POD:3 to 5 DFA > 3 times serum amylase, POD:4 DFA > 647 U/L, POD:5 DFA > 3 times serum amylase, and POD:5 DFA > 4000 U/L were 1.5% (95% CI 0.6% to 3.7%), 2.2% (95% CI 0.8% to 5.9%), 2.5% (95% CI 1.4% to 4.3%), 0% (95% CI not estimable), and 2.0% (95% CI 1.2% to 3.5%) respectively. At the upper quartile of the prevalence of 21.5%, the post‐test probabilities of pancreatic leak of positive POD:3 DFA > 600 IU/L, POD:3 to 5 DFA > 3 times serum amylase, POD:4 DFA > 647 U/L, POD:5 DFA > 3 times serum amylase, and POD:5 DFA > 4000 U/L were 46.9% (95% CI 39.6% to 54.4%), 50.0% (95% CI 35.7% to 64.3%), 69.1% (95% CI 50.3% to 83.2%), 81.1% (95% CI 59.0% to 92.8%), and 96.8% (95% CI 90.5% to 98.9%) respectively. At the same pre‐test probability, the post‐test probabilities of pancreatic leak of negative POD:3 DFA > 600 IU/L, POD:3 to 5 DFA > 3 times serum amylase, POD:4 DFA > 647 U/L, POD:5 DFA > 3 times serum amylase, and POD:5 DFA > 4000 U/L were 4.9% (95% CI 2.0% to 11.4%), 7.0% (95% CI 2.7% to 17.1%), 7.8% (95% CI 4.6% to 12.9%), 0% (95% CI not estimable), and 6.5% (95% CI 3.8% to 10.8%) respectively. CI = confidence intervals

Summary of findings Summary of findings table

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Table 1. International study group postoperative pancreatic fistula

Grade	A	B	C
Clinical conditions	Well	Often well	Usually ill
Ultrasound/CT (computed tomogram) (if obtained)	Negative	Negative/positive	Positive
Persistent drainage (after 3 weeks)	No	Usually yes	Yes
Reoperation	No	No	Yes
Death related to postoperative pancreatic fistula	No	No	Possibly yes
Signs of infections	No	Yes	Yes
Sepsis	No	No	Yes
Readmission	No	Yes/no	Yes/no
Modified from Bassi 2005.

Table 1. International study group postoperative pancreatic fistula

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Table 2. QUADAS‐2 classification

Domain 1: Patient selection	Patient sampling	Patients 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). We planned to exclude such studies. Unclear: as anticipated, we were able to determine whether the design was case‐control. There were no case‐control studies. Hence, as anticipated, all studies included in the review were 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 setting	Yes: 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 was not clear whether the patients had 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 were classified as 'yes'. Unclear concern: if the patient characteristics and setting were classified as 'unclear'. High concern: if the patient characteristics and setting were classified as 'no'.
Domain 2: Index test	Index test(s)	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 was conducted and interpreted without the knowledge of the results of the reference standard. No: if the index test was interpreted with the knowledge of the results of the reference standard. Unclear: if it was 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 was clearly stated. High concern: if the criteria for positive index test was not stated.
Domain 3: Target condition and reference standard	Target condition and reference standard(s)	Target condition: clinically significant pancreatic leak (requiring clinical intervention). Planned reference standards (see below). Pancreatic leak confirmed at surgery. 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 was confirmed at reoperation. No: if the reference standard was 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: although we planned to exclude studies if the reference standard was not described adequately or was not one of the above planned reference standards, this would have meant that there would have been no studies included in the review. So, we accepted the ISGPF grades B and C as an appropriate references standard and classified the answer to this signalling question as unclear.
	Were the reference standard results interpreted without knowledge of the results of the index tests?	Yes: if the reference standard was interpreted without the knowledge of the results of the index test. No: if the reference standard was interpreted with the knowledge of the results of the index test. Unclear: it is not clear if the reference standard was 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?	Although we anticipated that all of the included studies would be classified as 'low concern' because of the reference standards we planned to use, we have classified all the studies as 'high concern' because of the reference standards that we accepted.
Domain 4: Flow and timing	Flow and timing	Patients 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 received a reference standard. No: if some of the patients did not receive a reference standard. Such studies were excluded. Unclear: if it was not clear whether all patients received a reference standard. Such studies were excluded. As anticipated, all studies included in the review were 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 were 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.
ISGPF = International Study Group on Pancreatic Fistula

Table 2. QUADAS‐2 classification

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Table Tests. Data tables by test

Test	No. of studies	No. of participants
1 POD:3 DFA > 600 IU/L Show forest plot	1	182

2 POD:3 to 5 DFA > 3 times serum amylase Show forest plot	1	65

3 POD:4 DFA > 647 U/L Show forest plot	1	100

4 POD:5 DFA > 3 times serum amylase Show forest plot	1	50

5 POD:5 DFA > 4000 U/L Show forest plot	1	471

Table Tests. Data tables by test

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Referencias

References to studies included in this review

Araki 2012 {published data only}

El Nakeeb 2013 {published data only}

Facy 2012 {published data only}

Kong 2008 {published data only}

Kosaka 2014 {published data only}

References to studies excluded from this review

Ansorge 2014 {published data only}

Burdy 1999 {published data only}

Ceroni 2014 {published data only}

Chen 2015 {published data only}

Cherian 2010 {published data only}

Chhabra 2011 {published data only}

Cirocchi 2015 {published data only}

Dugalic 2014 {published data only}

Fong 2016 {published data only}

Furukawa 2015 {published data only}

Gebauer 2012 {published data only}

Graham 2013 {published data only}

Hashimoto 2003 {published data only}

Hashimoto 2014 {published data only}

Hiyoshi 2013 {published data only}

Ho 2014 {published data only}

Israel 2014 {published data only}

Kanda 2014 {published data only}

Kawai 2011 {published data only}

Kim 2014 {published data only}

Kobayashi 2015 {published data only}

Kosaka 2013 {published data only}

Kosaka 2014a {published data only}

Kumar 2013 {published data only}

Kurahara 2011 {published data only}

Lee 2014 {published data only}

Malleo 2014 {published data only}

Mcmillan 2015 {published data only}

Menon 2012 {published data only}

Mimura 2012 {published data only}

Molinari 2007 {published data only}

Moskovic 2010 {published data only}

Musiewicz 2010 {published data only}

Nissen 2012 {published data only}

Noji 2012 {published data only}

Okano 2011 {published data only}

Palani Velu 2015 {published data only}

Partelli 2014 {published data only}

Prakash 2011 {published data only}

Raja 2015 {published data only}

Ramesh 2006 {published data only}

Robinson 2010 {published data only}

Sanchez Acedo 2013 {published data only}

Saxena 2014 {published data only}

Shi 2009 {published data only}

Shimizu 2015 {published data only}

Shinchi 2006 {published data only}

Shyr 2003 {published data only}

Srivastava 2016 {published data only}

Sugimoto 2013 {published data only}

Sutcliffe 2012 {published data only}

Sutcliffe 2014 {published data only}

Sutcliffe 2015 {published data only}

Tang 2015 {published data only}

Teixeira 2016 {published data only}

Tsujie 2012 {published data only}

Uemura 2011 {published data only}

Uemura 2014 {published data only}

Veillette 2010 {published data only}

Ven Fong 2015 {published data only}

Yamaguchi 2003 {published data only}

Yang 2015 {published data only}

Zelga 2015 {published data only}

Additional references

Bassi 2005

Buscemi 2006

Chu 2006

Diener 2011

Doust 2005

Eloubeidi 2001