Reviewer's report
Title:"Treatment of acute pancreatitis with protease inhibitors: an updated
systematic review and meta-analysis."
Version:1Date:28 October 2013
Reviewer: Rupjyoti Talukdar
Reviewer's report:
In this meta-analysis, the authors have evaluated the role of protease inhibitors in
ameliorating severity of acute pancreatitis. This is an extension of a previous
meta-analysis by the same authors from 2006. Results from both the
meta-analyses showed lack of any benefit from protease inhibitor. The rationale
for use of protease inhibitors have probably stemmed from experimental
evidence that there is intra-acinar activation of protease (trypsinogen to trypsin
followed by activation of other proenzymes) after an acute insult to the pancreas.
Intra-acinar activation of proteases after acute insult to the pancreas occurs very
early on in the natural history of the disease; and by the time the patient reaches
the hospital these intracellular activities would have already occurred. The
morbidity and mortality of the patients is a result of the inflammatory response
and local complication resulting from the initial events. Therefore, it is not
surprising that protease inhibitors won’t have any plausible role in ameliorating
the severity of the disease, except for specific predictable situations like
post-ERCP pancreatitis. Nevertheless, this has to be backed by clinical evidence
for which trials and meta-analysis (like the current one) becomes important. Even
though the study appears sound from a statistical standpoint, the authors need to
address certain issues.
General comment:
There is a need for language and grammatical corrections.
Specific comments (Major compulsory revisions):
INTRODUCTION:
1. Please provide some more detail on the previous meta-analysis, for eg. total
no. of studies included, sample sizes in the control and intervention groups, study
outcomes, etc.
MEHODS:
1. How was severity defined? How was the CMR calculated?
2. Why was post-ERCP pancreatitis excluded? Conceptually this is an ideal
group where protease inhibitors might have some beneficial role. A subgroup
analysis could have addressed this issue.
3. Inclusion criteria were described separately in two places. All of these can be
written together.
4. The authors seem to have evaluated too many outcomes. Authors should
divide the outcomes into one primary and the other related ones should be
described under secondary outcomes. Pain relief and paralytic small bowel
obstruction can be removed as outcomes since these do not necessarily depend
upon the severity of disease.
5. How was 'other major complications' defined?
6. How was low, moderate and high heterogeneity among the studies defined?
RESULTS:
1. The text in the section of Selection and features of trials may be shortened and
only the salient features be written, since the same are expressed in Figure 1
and Table 1.
2. Mention the exact I2 values wherever mild, moderate and high heterogeneity
is mentioned.
3. Figure 2: I guess outcome presented in this Forrest plot is mortality. Add this in
the legend. What does -.44329 and .443297 indicate? Add the heterogeneity (I2)
and the 'p' value in the Forrest plot.
DISCUSSION:
1. The results from the current and the authors' previous meta-analysis (2004)
are similar. Therefore, describe clearly the salient differences between the two
studies, and the rationale why this meta-analysis was taken up.
2. The last paragraph in the discussion lacks clarity.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I declare that I have no competing interests
Reviewer's report
Title:"Treatment of acute pancreatitis with protease inhibitors: an updated
systematic review and meta-analysis."
Version:1Date:28 October 2013
Reviewer: Rupjyoti Talukdar
Reviewer's report:
In this meta-analysis, the authors have evaluated the role of protease inhibitors in
ameliorating severity of acute pancreatitis. This is an extension of a previous
meta-analysis by the same authors from 2006. Results from both the
meta-analyses showed lack of any benefit from protease inhibitor. The rationale
for use of protease inhibitors have probably stemmed from experimental
evidence that there is intra-acinar activation of protease (trypsinogen to trypsin
followed by activation of other proenzymes) after an acute insult to the pancreas.
Intra-acinar activation of proteases after acute insult to the pancreas occurs very
early on in the natural history of the disease; and by the time the patient reaches
the hospital these intracellular activities would have already occurred. The
morbidity and mortality of the patients is a result of the inflammatory response
and local complication resulting from the initial events. Therefore, it is not
surprising that protease inhibitors won’t have any plausible role in ameliorating
the severity of the disease, except for specific predictable situations like
post-ERCP pancreatitis. Nevertheless, this has to be backed by clinical evidence
for which trials and meta-analysis (like the current one) becomes important. Even
though the study appears sound from a statistical standpoint, the authors need to
address certain issues.
General comment:
There is a need for language and grammatical corrections.
Specific comments (Major compulsory revisions):
INTRODUCTION:
1. Please provide some more detail on the previous meta-analysis, for eg. total
no. of studies included, sample sizes in the control and intervention groups, study
outcomes, etc.
MEHODS:
1. How was severity defined? How was the CMR calculated?
2. Why was post-ERCP pancreatitis excluded? Conceptually this is an ideal
group where protease inhibitors might have some beneficial role. A subgroup
analysis could have addressed this issue.
3. Inclusion criteria were described separately in two places. All of these can be
written together.
4. The authors seem to have evaluated too many outcomes. Authors should
divide the outcomes into one primary and the other related ones should be
described under secondary outcomes. Pain relief and paralytic small bowel
obstruction can be removed as outcomes since these do not necessarily depend
upon the severity of disease.
5. How was 'other major complications' defined?
6. How was low, moderate and high heterogeneity among the studies defined?
RESULTS:
1. The text in the section of Selection and features of trials may be shortened and
only the salient features be written, since the same are expressed in Figure 1
and Table 1.
2. Mention the exact I2 values wherever mild, moderate and high heterogeneity
is mentioned.
3. Figure 2: I guess outcome presented in this Forrest plot is mortality. Add this in
the legend. What does -.44329 and .443297 indicate? Add the heterogeneity (I2)
and the 'p' value in the Forrest plot.
DISCUSSION:
1. The results from the current and the authors' previous meta-analysis (2004)
are similar. Therefore, describe clearly the salient differences between the two
studies, and the rationale why this meta-analysis was taken up.
2. The last paragraph in the discussion lacks clarity.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I declare that I have no competing interests
Please review this paper.
user
Reviewer's report
Title:"Treatment of acute pancreatitis with protease inhibitors: an updated
systematic review and meta-analysis."
Version:1Date:28 October 2013
Reviewer: Rupjyoti Talukdar
Reviewer's report:
In this meta-analysis, the authors have evaluated the role of protease inhibitors in
ameliorating severity of acute pancreatitis. This is an extension of a previous
meta-analysis by the same authors from 2006. Results from both the
meta-analyses showed lack of any benefit from protease inhibitor. The rationale
for use of protease inhibitors have probably stemmed from experimental
evidence that there is intra-acinar activation of protease (trypsinogen to trypsin
followed by activation of other proenzymes) after an acute insult to the pancreas.
Intra-acinar activation of proteases after acute insult to the pancreas occurs very
early on in the natural history of the disease; and by the time the patient reaches
the hospital these intracellular activities would have already occurred. The
morbidity and mortality of the patients is a result of the inflammatory response
and local complication resulting from the initial events. Therefore, it is not
surprising that protease inhibitors won’t have any plausible role in ameliorating
the severity of the disease, except for specific predictable situations like
post-ERCP pancreatitis. Nevertheless, this has to be backed by clinical evidence
for which trials and meta-analysis (like the current one) becomes important. Even
though the study appears sound from a statistical standpoint, the authors need to
address certain issues.
General comment:
There is a need for language and grammatical corrections.
Specific comments (Major compulsory revisions):
INTRODUCTION:
1. Please provide some more detail on the previous meta-analysis, for eg. total
no. of studies included, sample sizes in the control and intervention groups, study
outcomes, etc.
MEHODS:
1. How was severity defined? How was the CMR calculated?
2. Why was post-ERCP pancreatitis excluded? Conceptually this is an ideal
group where protease inhibitors might have some beneficial role. A subgroup
analysis could have addressed this issue.
3. Inclusion criteria were described separately in two places. All of these can be
written together.
4. The authors seem to have evaluated too many outcomes. Authors should
divide the outcomes into one primary and the other related ones should be
described under secondary outcomes. Pain relief and paralytic small bowel
obstruction can be removed as outcomes since these do not necessarily depend
upon the severity of disease.
5. How was 'other major complications' defined?
6. How was low, moderate and high heterogeneity among the studies defined?
RESULTS:
1. The text in the section of Selection and features of trials may be shortened and
only the salient features be written, since the same are expressed in Figure 1
and Table 1.
2. Mention the exact I2 values wherever mild, moderate and high heterogeneity
is mentioned.
3. Figure 2: I guess outcome presented in this Forrest plot is mortality. Add this in
the legend. What does -.44329 and .443297 indicate? Add the heterogeneity (I2)
and the 'p' value in the Forrest plot.
DISCUSSION:
1. The results from the current and the authors' previous meta-analysis (2004)
are similar. Therefore, describe clearly the salient differences between the two
studies, and the rationale why this meta-analysis was taken up.
2. The last paragraph in the discussion lacks clarity.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Needs some language corrections before being
published
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I declare that I have no competing interests
assistant