Revie wer’s report  
 
Title: Dexmedetomidine is safe and reduces the additional  dose of midazolam for sedation 
during Endoscopic retrograde cholangiopancreatography in very elderly patients  
 
Version: 1 Date: 13 Aug 2018  
 
Reviewer: Taira Kuro da 
 
Reviewer's report:  
 
GENERAL COMMENTS  
 
Inatomi O, et al. reported the efficacy and safety of midazolam for sedation during ERCP among 
140 elderly patients greater than 80 years of age. They retrospectively compared two groups, one 
is the intermittent use of midazolam alone (conventional group, N=78) and the other is 
combination with dexmedetomidine and intermittent use of midazolam (DEX group, N=62), and 
concluded that DEX group resulted in a reduction of midazolam use and decreased the incidence 
of respiratory complications. Respiratory complic ation is a major concern while sedating patients 
undergoing ERCP, elderly patients in particular. In this regard, this is an interesting report. 
However, the authors need to consider revising the following points to give a conclusion.  
 
 
 
MAJOR COMMENTS  
 
1) Given dose of midazolam (pp.5 -6): The authors need to clearly explain why they gave 
2mg of midazolam, which is considered to add another 1mg only when the initial dose of 
1mg was not effective. Administration of 2mg seems to be overdose for elderly patients  
and one might argue this being the main reason of respiratory complication.  
 
 
2) Setting of endpoints (p.6): The authors set the amount of midazolam as a main endpoint, 
which seems a bit queer. In this study, the frequency of respiratory depression associa ted 
with sedation should be the main endpoint, whereas the amount of midazolam as a 
surrogate endpoint.  
 
 
3) Patient's background (Table 1): Sedatives may cause adverse events followed by 
exacerbation of general physical condition. Therefore, general condit ions such as vital 
signs and severity of comorbidities prior to sedation between the two groups should be 
compared ． 
 
 
4) Reasons for discontinuation of examination (p.7): The authors mentioned "In the two 
patients of the conventional group we could not conti nue the examination due to 
respiratory insufficiency". What were the reasons for this? Couldn't they overcome this 
issue by increasing oxygen inhalation, keeping the airway, etc.? Details of these two 
cases including vital signs and severity of comorbiditi es prior to sedation should be 
described.  
 
 
5) Adverse events in DEX group (p.8): There were two patients and one patient who 
required atropine and dopamine, respectively. Depression of cardiac function directly 
may lead to cardiac arrest, much more serious  than respiratory depression. Therefore, 
even the authors conclude the merit of DEX use, this should not be ignored. Indeed, they 
discussed this as clinically accepted matter since these patients recovered right after 
halting the use of DEX and did not res ult in a severe cardiac complication (p.11). 
However, these statements are not enough to convince the readers. One may compare 
with respiratory depression after midazolam use that it may be also clinically accepted 
when oxygen is given or airway is kept.  
 
 
 
MINOR COMMENTS  
 
6) Sedation -related complication (Table 2): Considering the few number of events, Fisher's 
test should be applied instead of chi -square test in this analysis.  
 
 
7) Post sedation information: Time to awake and minor events such as dizziness, vertigo, 
turnover, etc. should be added and compared between the two groups.  
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
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.  
 
No 
 
 
Are you able to assess any statistics in the manuscript or would you re commend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indic ate 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 fro m an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation t hat 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 understan d that my na me will be included 
on my repo rt to the authors and, if the manuscript is accepted f or 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 a n Open Access Creati ve 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 in cluded as confidential comments 
to the editor s, which will not be published.  
 
I agree to th e open peer review policy of the journal  
 
Revie wer’s report  
 
Title: Dexmedetomidine is safe and reduces the additional  dose of midazolam for sedation 
during Endoscopic retrograde cholangiopancreatography in very elderly patients  
 
Version: 1 Date: 13 Aug 2018  
 
Reviewer: Taira Kuro da 
 
Reviewer's report:  
 
GENERAL COMMENTS  
 
Inatomi O, et al. reported the efficacy and safety of midazolam for sedation during ERCP among 
140 elderly patients greater than 80 years of age. They retrospectively compared two groups, one 
is the intermittent use of midazolam alone (conventional group, N=78) and the other is 
combination with dexmedetomidine and intermittent use of midazolam (DEX group, N=62), and 
concluded that DEX group resulted in a reduction of midazolam use and decreased the incidence 
of respiratory complications. Respiratory complic ation is a major concern while sedating patients 
undergoing ERCP, elderly patients in particular. In this regard, this is an interesting report. 
However, the authors need to consider revising the following points to give a conclusion.  
 
 
 
MAJOR COMMENTS  
 
1) Given dose of midazolam (pp.5 -6): The authors need to clearly explain why they gave 
2mg of midazolam, which is considered to add another 1mg only when the initial dose of 
1mg was not effective. Administration of 2mg seems to be overdose for elderly patients  
and one might argue this being the main reason of respiratory complication.  
 
 
2) Setting of endpoints (p.6): The authors set the amount of midazolam as a main endpoint, 
which seems a bit queer. In this study, the frequency of respiratory depression associa ted 
with sedation should be the main endpoint, whereas the amount of midazolam as a 
surrogate endpoint.  
 
 
3) Patient's background (Table 1): Sedatives may cause adverse events followed by 
exacerbation of general physical condition. Therefore, general condit ions such as vital 
signs and severity of comorbidities prior to sedation between the two groups should be 
compared ． 
 
 
4) Reasons for discontinuation of examination (p.7): The authors mentioned "In the two 
patients of the conventional group we could not conti nue the examination due to 
respiratory insufficiency". What were the reasons for this? Couldn't they overcome this 
issue by increasing oxygen inhalation, keeping the airway, etc.? Details of these two 
cases including vital signs and severity of comorbiditi es prior to sedation should be 
described.  
 
 
5) Adverse events in DEX group (p.8): There were two patients and one patient who 
required atropine and dopamine, respectively. Depression of cardiac function directly 
may lead to cardiac arrest, much more serious  than respiratory depression. Therefore, 
even the authors conclude the merit of DEX use, this should not be ignored. Indeed, they 
discussed this as clinically accepted matter since these patients recovered right after 
halting the use of DEX and did not res ult in a severe cardiac complication (p.11). 
However, these statements are not enough to convince the readers. One may compare 
with respiratory depression after midazolam use that it may be also clinically accepted 
when oxygen is given or airway is kept.  
 
 
 
MINOR COMMENTS  
 
6) Sedation -related complication (Table 2): Considering the few number of events, Fisher's 
test should be applied instead of chi -square test in this analysis.  
 
 
7) Post sedation information: Time to awake and minor events such as dizziness, vertigo, 
turnover, etc. should be added and compared between the two groups.  
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
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.  
 
No 
 
 
Are you able to assess any statistics in the manuscript or would you re commend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indic ate 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 fro m an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation t hat 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 understan d that my na me will be included 
on my repo rt to the authors and, if the manuscript is accepted f or 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 a n Open Access Creati ve 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 in cluded as confidential comments 
to the editor s, which will not be published.  
 
I agree to th e open peer review policy of the journal  
 
Please review this paper.
user
Revie wer’s report  
 
Title: Dexmedetomidine is safe and reduces the additional  dose of midazolam for sedation 
during Endoscopic retrograde cholangiopancreatography in very elderly patients  
 
Version: 1 Date: 13 Aug 2018  
 
Reviewer: Taira Kuro da 
 
Reviewer's report:  
 
GENERAL COMMENTS  
 
Inatomi O, et al. reported the efficacy and safety of midazolam for sedation during ERCP among 
140 elderly patients greater than 80 years of age. They retrospectively compared two groups, one 
is the intermittent use of midazolam alone (conventional group, N=78) and the other is 
combination with dexmedetomidine and intermittent use of midazolam (DEX group, N=62), and 
concluded that DEX group resulted in a reduction of midazolam use and decreased the incidence 
of respiratory complications. Respiratory complic ation is a major concern while sedating patients 
undergoing ERCP, elderly patients in particular. In this regard, this is an interesting report. 
However, the authors need to consider revising the following points to give a conclusion.  
 
 
 
MAJOR COMMENTS  
 
1) Given dose of midazolam (pp.5 -6): The authors need to clearly explain why they gave 
2mg of midazolam, which is considered to add another 1mg only when the initial dose of 
1mg was not effective. Administration of 2mg seems to be overdose for elderly patients  
and one might argue this being the main reason of respiratory complication.  
 
 
2) Setting of endpoints (p.6): The authors set the amount of midazolam as a main endpoint, 
which seems a bit queer. In this study, the frequency of respiratory depression associa ted 
with sedation should be the main endpoint, whereas the amount of midazolam as a 
surrogate endpoint.  
 
 
3) Patient's background (Table 1): Sedatives may cause adverse events followed by 
exacerbation of general physical condition. Therefore, general condit ions such as vital 
signs and severity of comorbidities prior to sedation between the two groups should be 
compared ． 
 
 
4) Reasons for discontinuation of examination (p.7): The authors mentioned "In the two 
patients of the conventional group we could not conti nue the examination due to 
respiratory insufficiency". What were the reasons for this? Couldn't they overcome this 
issue by increasing oxygen inhalation, keeping the airway, etc.? Details of these two 
cases including vital signs and severity of comorbiditi es prior to sedation should be 
described.  
 
 
5) Adverse events in DEX group (p.8): There were two patients and one patient who 
required atropine and dopamine, respectively. Depression of cardiac function directly 
may lead to cardiac arrest, much more serious  than respiratory depression. Therefore, 
even the authors conclude the merit of DEX use, this should not be ignored. Indeed, they 
discussed this as clinically accepted matter since these patients recovered right after 
halting the use of DEX and did not res ult in a severe cardiac complication (p.11). 
However, these statements are not enough to convince the readers. One may compare 
with respiratory depression after midazolam use that it may be also clinically accepted 
when oxygen is given or airway is kept.  
 
 
 
MINOR COMMENTS  
 
6) Sedation -related complication (Table 2): Considering the few number of events, Fisher's 
test should be applied instead of chi -square test in this analysis.  
 
 
7) Post sedation information: Time to awake and minor events such as dizziness, vertigo, 
turnover, etc. should be added and compared between the two groups.  
 
 
 
Are the methods appropriate and well described?  
If not, please specify what is required in your comments to the authors.  
 
No 
 
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.  
 
No 
 
 
Are you able to assess any statistics in the manuscript or would you re commend an 
additional statistical review?  
If an additional statistical review is recommended, please speci fy what aspects require further 
assessment in your comments to the editors.  
 
I recommend additional statistical review  
 
Quality of written English  
Please indic ate 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 fro m an 
organisation that may in any way gain or lose financial ly from the publication of this 
manuscript, either now or in the future?  
 
2. Do you hold any stocks or shares in an organisation t hat 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 understan d that my na me will be included 
on my repo rt to the authors and, if the manuscript is accepted f or 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 a n Open Access Creati ve 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 in cluded as confidential comments 
to the editor s, which will not be published.  
 
I agree to th e open peer review policy of the journal  
 
assistant