Scolaris Content Display Scolaris Content Display

Clinical pathway
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Figure 1

Clinical pathway

Study flow diagram.
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Figure 2

Study flow diagram.

Risk of bias and applicability concerns summary: review authors' judgements about each domain for each included study
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Figure 3

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

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 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.

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 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 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.

POD:3 DFA > 600 IU/L.
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Test 1

POD:3 DFA > 600 IU/L.

POD:3 to 5 DFA > 3 times serum amylase.
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Test 2

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

POD:4 DFA > 647 U/L.
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Test 3

POD:4 DFA > 647 U/L.

POD:5 DFA > 3 times serum amylase.
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Test 4

POD:5 DFA > 3 times serum amylase.

POD:5 DFA > 4000 U/L.
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Test 5

POD:5 DFA > 4000 U/L.

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

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Summary of findings Summary of findings table
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.

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Table 1. International study group postoperative pancreatic fistula
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).

  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 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

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Table 2. QUADAS‐2 classification
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

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Table Tests. Data tables by test