Reviewer’s report
Title:  Stress ulcer prophylaxis with proton pump inhibitors or histamine 2 receptor antagonists in
critically ill adults - A meta-analysis of randomized controlled trials with trial sequential analysis.
Version: 0 Date: 01 Oct 2019
Reviewer: Angelo Zullo
Reviewer's report:
Please include all comments  for the authors in this  box rather than uploading your report as an
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, supporting
materials or other aspects of your report which cannot be included in a text format.
Please overwrite this text when adding your comments to the authors.
This  meta-analysis of randomized controlled studies aimed to assess the role of therapy with PPI or
H2-antagonist for stress ulcers prophylaxis (SUP). In detail, data of 29 studies (4 at low risk of biases)
were evaluated.  Basically, data found that SUP has benefits on the overt GI bleeding - but not
clinically relevant bleeding - in critically ill patients who did not receive enteral nutrition. The Authors
cautelatively concluded there is need of more evidences. 
The analysis is comprehensive, data was well analyzed, and interpretation is correct. Therefore, I have
not major criticisms to do. As a comment, I would suggest that PPI dose, route of administration, and
therapy duration are highly different among trials, so that it could be a mattern for concern. In other
words, a certain therapy could be more effective than another so that considering all therapy regimens
as "PPI therapy" could be misleading. These considerations could be briefly discussed.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
Yes
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
Yes
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
Yes
Are you able to assess any statistics in the manuscript or would you recommend an additional
statistical review?
If  an  additional  statistical  review  is  recommended,  please  specify  what  aspects  require  further
assessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Acceptable
Declaration of competing interests
Please complete a declaration of competing interests, considering the following questions:
1. Have you in the past five years received reimbursements, fees, funding, or salary from an
organisation that may in any way gain or lose financially from the publication of this
manuscript, either now or in the future?
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose
financially from the publication of this manuscript, either now or in the future?
3. Do you hold or are you currently applying for any patents relating to the content of the
manuscript?
4. Have you received reimbursements, fees, funding, or salary from an organization that holds
or has applied for patents relating to the content of the manuscript?
5. Do you have any other financial competing interests?
6. Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If
your reply is yes to any, please give details below.
None
I agree to the open peer review policy of the journal. I understand that my name will be included on my
report to the authors and, if the manuscript is accepted for publication, my named report including any 
attachments I upload will be posted on the website along with the authors' responses. I agree for my 
report to be made available under an Open Access Creative Commons CC-BY license 
(http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments which I do not wish to 
be included in my named report can be included as confidential comments to the editors, which will not
be published.
I agree to the open peer review policy of the journal
Reviewer’s report
Title:  Stress ulcer prophylaxis with proton pump inhibitors or histamine 2 receptor antagonists in
critically ill adults - A meta-analysis of randomized controlled trials with trial sequential analysis.
Version: 0 Date: 01 Oct 2019
Reviewer: Angelo Zullo
Reviewer's report:
Please include all comments  for the authors in this  box rather than uploading your report as an
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, supporting
materials or other aspects of your report which cannot be included in a text format.
Please overwrite this text when adding your comments to the authors.
This  meta-analysis of randomized controlled studies aimed to assess the role of therapy with PPI or
H2-antagonist for stress ulcers prophylaxis (SUP). In detail, data of 29 studies (4 at low risk of biases)
were evaluated.  Basically, data found that SUP has benefits on the overt GI bleeding - but not
clinically relevant bleeding - in critically ill patients who did not receive enteral nutrition. The Authors
cautelatively concluded there is need of more evidences. 
The analysis is comprehensive, data was well analyzed, and interpretation is correct. Therefore, I have
not major criticisms to do. As a comment, I would suggest that PPI dose, route of administration, and
therapy duration are highly different among trials, so that it could be a mattern for concern. In other
words, a certain therapy could be more effective than another so that considering all therapy regimens
as "PPI therapy" could be misleading. These considerations could be briefly discussed.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
Yes
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
Yes
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
Yes
Are you able to assess any statistics in the manuscript or would you recommend an additional
statistical review?
If  an  additional  statistical  review  is  recommended,  please  specify  what  aspects  require  further
assessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Acceptable
Declaration of competing interests
Please complete a declaration of competing interests, considering the following questions:
1. Have you in the past five years received reimbursements, fees, funding, or salary from an
organisation that may in any way gain or lose financially from the publication of this
manuscript, either now or in the future?
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose
financially from the publication of this manuscript, either now or in the future?
3. Do you hold or are you currently applying for any patents relating to the content of the
manuscript?
4. Have you received reimbursements, fees, funding, or salary from an organization that holds
or has applied for patents relating to the content of the manuscript?
5. Do you have any other financial competing interests?
6. Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If
your reply is yes to any, please give details below.
None
I agree to the open peer review policy of the journal. I understand that my name will be included on my
report to the authors and, if the manuscript is accepted for publication, my named report including any 
attachments I upload will be posted on the website along with the authors' responses. I agree for my 
report to be made available under an Open Access Creative Commons CC-BY license 
(http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments which I do not wish to 
be included in my named report can be included as confidential comments to the editors, which will not
be published.
I agree to the open peer review policy of the journal
Please review this paper.
user
Reviewer’s report
Title:  Stress ulcer prophylaxis with proton pump inhibitors or histamine 2 receptor antagonists in
critically ill adults - A meta-analysis of randomized controlled trials with trial sequential analysis.
Version: 0 Date: 01 Oct 2019
Reviewer: Angelo Zullo
Reviewer's report:
Please include all comments  for the authors in this  box rather than uploading your report as an
attachment. Please only upload as attachments annotated versions of manuscripts, graphs, supporting
materials or other aspects of your report which cannot be included in a text format.
Please overwrite this text when adding your comments to the authors.
This  meta-analysis of randomized controlled studies aimed to assess the role of therapy with PPI or
H2-antagonist for stress ulcers prophylaxis (SUP). In detail, data of 29 studies (4 at low risk of biases)
were evaluated.  Basically, data found that SUP has benefits on the overt GI bleeding - but not
clinically relevant bleeding - in critically ill patients who did not receive enteral nutrition. The Authors
cautelatively concluded there is need of more evidences. 
The analysis is comprehensive, data was well analyzed, and interpretation is correct. Therefore, I have
not major criticisms to do. As a comment, I would suggest that PPI dose, route of administration, and
therapy duration are highly different among trials, so that it could be a mattern for concern. In other
words, a certain therapy could be more effective than another so that considering all therapy regimens
as "PPI therapy" could be misleading. These considerations could be briefly discussed.
Are the methods appropriate and well described?
If not, please specify what is required in your comments to the authors.
Yes
Does the work include the necessary controls?
If not, please specify which controls are required in your comments to the authors.
Yes
Are the conclusions drawn adequately supported by the data shown?
If not, please explain in your comments to the authors.
Yes
Are you able to assess any statistics in the manuscript or would you recommend an additional
statistical review?
If  an  additional  statistical  review  is  recommended,  please  specify  what  aspects  require  further
assessment in your comments to the editors.
I am able to assess the statistics
Quality of written English
Please indicate the quality of language in the manuscript:
Acceptable
Declaration of competing interests
Please complete a declaration of competing interests, considering the following questions:
1. Have you in the past five years received reimbursements, fees, funding, or salary from an
organisation that may in any way gain or lose financially from the publication of this
manuscript, either now or in the future?
2. Do you hold any stocks or shares in an organisation that may in any way gain or lose
financially from the publication of this manuscript, either now or in the future?
3. Do you hold or are you currently applying for any patents relating to the content of the
manuscript?
4. Have you received reimbursements, fees, funding, or salary from an organization that holds
or has applied for patents relating to the content of the manuscript?
5. Do you have any other financial competing interests?
6. Do you have any non-financial competing interests in relation to this paper?
If you can answer no to all of the above, write 'I declare that I have no competing interests' below. If
your reply is yes to any, please give details below.
None
I agree to the open peer review policy of the journal. I understand that my name will be included on my
report to the authors and, if the manuscript is accepted for publication, my named report including any 
attachments I upload will be posted on the website along with the authors' responses. I agree for my 
report to be made available under an Open Access Creative Commons CC-BY license 
(http://creativecommons.org/licenses/by/4.0/ ). I understand that any comments which I do not wish to 
be included in my named report can be included as confidential comments to the editors, which will not
be published.
I agree to the open peer review policy of the journal
assistant