Reviewer’s report
Title:  Extracorporeal liver support: trending epidemiology and mortality - A nationwide database  
analysis 2007-2015
Version: 0 Date: 05 Apr 2019
Reviewer: G. Auzinger
Reviewer's report:
Dr Wiesmann and colleagues report in this manuscript on Extracorporeal Liver Support (ELS) device  
use in Germany during a 9 year observation period.
This is an area of practice where there is paucity of RCT data for clinicians to take guidance from. It is  
an observational descriptive study which utilises nationwide data from the Federal Statistical Office  
which is a strength, as well as a weakness of the study. ELS use in Germany is not regulated per se but  
remunerated through a specific procedures code, therefore the authors were able to provide in detail  
information as to the exact number of device interventions undertaken during the observation period; at  
the same time there are major drawbacks relating to the descriptive nature of the investigation and  
paucity  of  detail  in  relation  to  diagnostic  coding,  as  the  indications  and  timing  of  device  use  
particularly in relation to Liver Failure bridge to or use after Liver transplantation are far from clear.
The paper is reasonably well written but would benefit from critical appraisal by a native English  
speaking reviewer. There are expression / phraseology errors  such as "ELS utilization and case-
concomitant..." on page 3 or "provisioning of ELS" page 13, "was only a minor aspect in clinical  
practice" Discussion 2nd paragraph.
Major revision points:
2015 incidence rates of ELS quoted in the abstract don't match percentage figures given in the Results  
section of the manuscript or the Table.
The authors describe ALF in the Introduction however mix decompensated chronic liver disease and or  
AoCLF patients into this group. In fact most of the patients appear to have suffered from acute  
decompensation of CLD as in cirrhosis, rather than ALF. Preexisting chronic liver disease is in fact an  
exclusion criteria for ALF - Trey and Davidson Progress in liver disease 1970; Bernal and Wendon  
NEJM 2014. 
The ALF definition given in the 2nd sentence of the Introduction is wrong (see above publications).
It maybe worthwhile grouping patients into hyperacute, acute and subacute LF (O'Grady Lancet 1993)  
depending on jaundice to HE interval to better risk stratify, which is of particular importance in relation  
to any attempts made to utilise ELS as "bridge to recovery".
The authors should attempt to not only group patients into primary liver support or secondary i.e. post  
CTS use of ELS, but also provide separate data for ALF as per internationally recognised definitions vs  
acute decompensation of CLD cases. This is particularly important when reporting on  bridge to Liver  
Transplantation for HU cases or Emergency Liver Transplantation (ELT) as commonly referred to in  
the Anglo American literature.
ELS is not an established therapy as a "bridge to transplant" in ALF - Introduction page 5 - as the only  
RCT to that effect did not show a benefit of using MARS in that indication - FULMAR trial Saliba Ann  
Int Med.
The authors only talk about detoxifying devices, there are many cell based devices usually combined  
with  detoxifying  columns  or  modalities;  although  not  really  used  outside  RCT's  this  should  be  
commented on in the Introduction and Discussion parts of the paper.
When talking about the use of detoxifying methods of ELS, high volume TPE should be mentioned as  
it is the only modality that has shown an outcome benefit in ALF patients in a RCT setting Larsen et al  
J Hepatology 2016. Is TPE used in Germany, or is there an OPS code for it?
The term "ischemic liver failure" or hepatitis has been superseded by "Hypoxic hepatitis" the authors  
should change terminology throughout the manuscript accordingly. 
Are all the cases of secondary liver failure due to "hypoxic hepatitis" or are there patients with a  
predominant refractory hyperbilirubinemia phenotype? Presumably there is not enough granularity in  
the data available for interrogation to access this information; this should however be commented on in  
the Discussion. Hypoxic hepatitis is commonly reversible after restoration of flow and relief of right  
ventricular failure/dysfunction; there are however subsets of patients who develop refractory jaundice;  
this is a poorly understood pathology often multifactorial in etiology. Septic bile transporter defects, co  
factors such as ongoing congestion of the liver, drugs etc possibly playing a role. 
Outcome section Results: Apart from comparing "Primary vs secondary etiologies" it would be helpful  
to compare outcomes in the ALF vs decompensated CLD groups within the "Primary Liver failure"  
cohort. The authors document on the difficulties of getting information as to when ELS was used in the  
context of Liver Tx i.e. bridge to transplant vs postoperative support for graft dysfunction. This would  
have been very valuable as larger scale information regarding outcome of graft dysfunction treated with  
ELS is lacking.  
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.
Not relevant to this manuscript
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
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.
I declare that I have no competing interests
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:  Extracorporeal liver support: trending epidemiology and mortality - A nationwide database  
analysis 2007-2015
Version: 0 Date: 05 Apr 2019
Reviewer: G. Auzinger
Reviewer's report:
Dr Wiesmann and colleagues report in this manuscript on Extracorporeal Liver Support (ELS) device  
use in Germany during a 9 year observation period.
This is an area of practice where there is paucity of RCT data for clinicians to take guidance from. It is  
an observational descriptive study which utilises nationwide data from the Federal Statistical Office  
which is a strength, as well as a weakness of the study. ELS use in Germany is not regulated per se but  
remunerated through a specific procedures code, therefore the authors were able to provide in detail  
information as to the exact number of device interventions undertaken during the observation period; at  
the same time there are major drawbacks relating to the descriptive nature of the investigation and  
paucity  of  detail  in  relation  to  diagnostic  coding,  as  the  indications  and  timing  of  device  use  
particularly in relation to Liver Failure bridge to or use after Liver transplantation are far from clear.
The paper is reasonably well written but would benefit from critical appraisal by a native English  
speaking reviewer. There are expression / phraseology errors  such as "ELS utilization and case-
concomitant..." on page 3 or "provisioning of ELS" page 13, "was only a minor aspect in clinical  
practice" Discussion 2nd paragraph.
Major revision points:
2015 incidence rates of ELS quoted in the abstract don't match percentage figures given in the Results  
section of the manuscript or the Table.
The authors describe ALF in the Introduction however mix decompensated chronic liver disease and or  
AoCLF patients into this group. In fact most of the patients appear to have suffered from acute  
decompensation of CLD as in cirrhosis, rather than ALF. Preexisting chronic liver disease is in fact an  
exclusion criteria for ALF - Trey and Davidson Progress in liver disease 1970; Bernal and Wendon  
NEJM 2014. 
The ALF definition given in the 2nd sentence of the Introduction is wrong (see above publications).
It maybe worthwhile grouping patients into hyperacute, acute and subacute LF (O'Grady Lancet 1993)  
depending on jaundice to HE interval to better risk stratify, which is of particular importance in relation  
to any attempts made to utilise ELS as "bridge to recovery".
The authors should attempt to not only group patients into primary liver support or secondary i.e. post  
CTS use of ELS, but also provide separate data for ALF as per internationally recognised definitions vs  
acute decompensation of CLD cases. This is particularly important when reporting on  bridge to Liver  
Transplantation for HU cases or Emergency Liver Transplantation (ELT) as commonly referred to in  
the Anglo American literature.
ELS is not an established therapy as a "bridge to transplant" in ALF - Introduction page 5 - as the only  
RCT to that effect did not show a benefit of using MARS in that indication - FULMAR trial Saliba Ann  
Int Med.
The authors only talk about detoxifying devices, there are many cell based devices usually combined  
with  detoxifying  columns  or  modalities;  although  not  really  used  outside  RCT's  this  should  be  
commented on in the Introduction and Discussion parts of the paper.
When talking about the use of detoxifying methods of ELS, high volume TPE should be mentioned as  
it is the only modality that has shown an outcome benefit in ALF patients in a RCT setting Larsen et al  
J Hepatology 2016. Is TPE used in Germany, or is there an OPS code for it?
The term "ischemic liver failure" or hepatitis has been superseded by "Hypoxic hepatitis" the authors  
should change terminology throughout the manuscript accordingly. 
Are all the cases of secondary liver failure due to "hypoxic hepatitis" or are there patients with a  
predominant refractory hyperbilirubinemia phenotype? Presumably there is not enough granularity in  
the data available for interrogation to access this information; this should however be commented on in  
the Discussion. Hypoxic hepatitis is commonly reversible after restoration of flow and relief of right  
ventricular failure/dysfunction; there are however subsets of patients who develop refractory jaundice;  
this is a poorly understood pathology often multifactorial in etiology. Septic bile transporter defects, co  
factors such as ongoing congestion of the liver, drugs etc possibly playing a role. 
Outcome section Results: Apart from comparing "Primary vs secondary etiologies" it would be helpful  
to compare outcomes in the ALF vs decompensated CLD groups within the "Primary Liver failure"  
cohort. The authors document on the difficulties of getting information as to when ELS was used in the  
context of Liver Tx i.e. bridge to transplant vs postoperative support for graft dysfunction. This would  
have been very valuable as larger scale information regarding outcome of graft dysfunction treated with  
ELS is lacking.  
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.
Not relevant to this manuscript
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
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.
I declare that I have no competing interests
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:  Extracorporeal liver support: trending epidemiology and mortality - A nationwide database  
analysis 2007-2015
Version: 0 Date: 05 Apr 2019
Reviewer: G. Auzinger
Reviewer's report:
Dr Wiesmann and colleagues report in this manuscript on Extracorporeal Liver Support (ELS) device  
use in Germany during a 9 year observation period.
This is an area of practice where there is paucity of RCT data for clinicians to take guidance from. It is  
an observational descriptive study which utilises nationwide data from the Federal Statistical Office  
which is a strength, as well as a weakness of the study. ELS use in Germany is not regulated per se but  
remunerated through a specific procedures code, therefore the authors were able to provide in detail  
information as to the exact number of device interventions undertaken during the observation period; at  
the same time there are major drawbacks relating to the descriptive nature of the investigation and  
paucity  of  detail  in  relation  to  diagnostic  coding,  as  the  indications  and  timing  of  device  use  
particularly in relation to Liver Failure bridge to or use after Liver transplantation are far from clear.
The paper is reasonably well written but would benefit from critical appraisal by a native English  
speaking reviewer. There are expression / phraseology errors  such as "ELS utilization and case-
concomitant..." on page 3 or "provisioning of ELS" page 13, "was only a minor aspect in clinical  
practice" Discussion 2nd paragraph.
Major revision points:
2015 incidence rates of ELS quoted in the abstract don't match percentage figures given in the Results  
section of the manuscript or the Table.
The authors describe ALF in the Introduction however mix decompensated chronic liver disease and or  
AoCLF patients into this group. In fact most of the patients appear to have suffered from acute  
decompensation of CLD as in cirrhosis, rather than ALF. Preexisting chronic liver disease is in fact an  
exclusion criteria for ALF - Trey and Davidson Progress in liver disease 1970; Bernal and Wendon  
NEJM 2014. 
The ALF definition given in the 2nd sentence of the Introduction is wrong (see above publications).
It maybe worthwhile grouping patients into hyperacute, acute and subacute LF (O'Grady Lancet 1993)  
depending on jaundice to HE interval to better risk stratify, which is of particular importance in relation  
to any attempts made to utilise ELS as "bridge to recovery".
The authors should attempt to not only group patients into primary liver support or secondary i.e. post  
CTS use of ELS, but also provide separate data for ALF as per internationally recognised definitions vs  
acute decompensation of CLD cases. This is particularly important when reporting on  bridge to Liver  
Transplantation for HU cases or Emergency Liver Transplantation (ELT) as commonly referred to in  
the Anglo American literature.
ELS is not an established therapy as a "bridge to transplant" in ALF - Introduction page 5 - as the only  
RCT to that effect did not show a benefit of using MARS in that indication - FULMAR trial Saliba Ann  
Int Med.
The authors only talk about detoxifying devices, there are many cell based devices usually combined  
with  detoxifying  columns  or  modalities;  although  not  really  used  outside  RCT's  this  should  be  
commented on in the Introduction and Discussion parts of the paper.
When talking about the use of detoxifying methods of ELS, high volume TPE should be mentioned as  
it is the only modality that has shown an outcome benefit in ALF patients in a RCT setting Larsen et al  
J Hepatology 2016. Is TPE used in Germany, or is there an OPS code for it?
The term "ischemic liver failure" or hepatitis has been superseded by "Hypoxic hepatitis" the authors  
should change terminology throughout the manuscript accordingly. 
Are all the cases of secondary liver failure due to "hypoxic hepatitis" or are there patients with a  
predominant refractory hyperbilirubinemia phenotype? Presumably there is not enough granularity in  
the data available for interrogation to access this information; this should however be commented on in  
the Discussion. Hypoxic hepatitis is commonly reversible after restoration of flow and relief of right  
ventricular failure/dysfunction; there are however subsets of patients who develop refractory jaundice;  
this is a poorly understood pathology often multifactorial in etiology. Septic bile transporter defects, co  
factors such as ongoing congestion of the liver, drugs etc possibly playing a role. 
Outcome section Results: Apart from comparing "Primary vs secondary etiologies" it would be helpful  
to compare outcomes in the ALF vs decompensated CLD groups within the "Primary Liver failure"  
cohort. The authors document on the difficulties of getting information as to when ELS was used in the  
context of Liver Tx i.e. bridge to transplant vs postoperative support for graft dysfunction. This would  
have been very valuable as larger scale information regarding outcome of graft dysfunction treated with  
ELS is lacking.  
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.
Not relevant to this manuscript
Quality of written English
Please indicate the quality of language in the manuscript:
Needs some language corrections before being published
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.
I declare that I have no competing interests
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