Title: Effectiveness of a Thrombin-gelatin Flowable for treating severe liver bleeding: An
experimental study
Version: 2 Date: 14 Aug 2023
Reviewer's report:
Comments, “Effectiveness of a Thrombin-gelatin Flowable for treating severe liver bleeding:
An experimental study”,
Sánchez-del-Valle and collaborators present a report on the efficacy of treating liver lacerations
using a commercially available thrombin-containing gel. They note that the gel is superior to just
packing the wound with surgical pads, both with respect to blood loss and mortality using a pig
model. It is a straight-forward study that provides useful information. My gripes are principally
to do with the reporting of the study, where we are given very little context for the study and not
enough information about the methods to properly be able to judge the quality of the findings
(let alone being able to replicate the authors’ methods). In short, I think this can become a great
paper, but the authors still have some work to do.
I have listed my major issues below, followed by some specific comments for each section of
the manuscript. I hope that the authors can make use of these.
Context:
The manuscript could give more context to the study. Why was the gel compared to simply
packing? There are a number of products on the market (and a number of studies looking
into them) that could be used for hemostasis in a situation like this. Why was the product not
benchmarked with the standard of care in a hospital? I imagine the context given in the cover
letter could be useful here.
There is also a number of studies into the efficacy of FloSeal. What is the novel aspect of this
study? How does this study contrast with these previous investigations? The introduction could
do a better job of explaining to the reader what information this specific study gathered, that
was not known before.
Methods:
The methods section is not nearly informative enough. None of the methods used to gather the
data are fully explained. The primary endpoint, for example, is the blood loss. But how was this
gauged? As the pig bleeds into the abdominal cavity, blood has to be collected - somehow - to
be weighed. How this is done affects the readings. This is why it is crucial that the authors report
how they did this. Also, how was any of the measurements in Table 1 obtained?
The details for the anesthetic regimen are also insufficient. What were the dosages and timings?
Were all of the pigs anesthetized in the same way? Given that 24-h anesthesia is not a picnic,
and given that it can affect many of the experimental readings, the reader would need quite a
bit more details here.
The authors state that their reporting follows the ARRIVE guidelines. It does not. I suggest the
authors look into what the ARRIVE guidelines suggest, and then report accordingly. Sample size
estimations, reporting on randomization and blinding, and information on experimental animals
are all but completely missing.
Finally, the statistical methods are a bit all over the place. The methods section lists a number of
statistical tests, with no details, followed by pointing out that they were used “as needed.” But
some of these tests do not even seem to have been used..? When was Fisher’s exact test used,
for example? This section could be more fitting the report. Moreover, some of the hypothesis
tests that are presented in the results section seem to not really serve any real purpose.
Specific comments, listed by section:
Abstract
“Total blood volume per animal lost” is probably better described as “lost blood volume.”
Material and methods
“Animals in which one of the suprahepatic veins had not been selectively injured were excluded
from the study.” What does this sentence mean? Did the experimental surgery fail in some cases?
If it did – how frequently?
*When* was random assignment to experimental groups done? If it was done pre-operatively,
was the assignment concealed from the surgeon (and how)?
I assume that no readings were made blinded. This should be mentioned nevertheless.
“Analytical determinations included...” Included? Were there other analyses? And what
equipment/methods were used for these analyses?
The timing of the analytical readings is needlessly repeated. “Study variables were measured...”
and “All determinations were performed...”
Giving the formula for density is a bit excessive. Moreover, where the authors use mathematical
formulae, they should make sure to use proper notation. "V100 = (Vx100/Ve)" is more confusing
than it is helpful. Why quotes? Why the parenthesis? “V × 100” not “Vx100” Also, that is not
the correct way to express a percentage.
How was the lost blood weighed? How was this done in a repeatable and accurate way?
“Secondary outcomes included survival rate; time of application; heart rate (beats per minute,
bpm); and hematocrit values.” Included? Were there others? Also, why is heart rate, but not, say,
blood pressure mentioned? Why hematocrits but not, say, hemoglobin? Are the authors only
showing us the values that differed between the groups?
Results
Why on earth were the animals not evenly distributed between the groups?
Primary endpoints: This whole section is better described in the figure and can be deleted for
brevity. Also, the hypothesis tests (Friedman’s test) make no sense.
“...the percentage of the percentage of total blood volume per animal lost was significantly
lower in the Flowable group than in the packing group from minute 12 to minute 60” I do not
understand this sentence.
What is the purpose of the recurring single-cohort Friedman tests?
“At minute 120, hematocrit was significantly higher in the Flowable group...” Post hoc testing
when the omnibus test was not statistically significant is not advisable, particularly when the
authors have no specific hypothesis with respect to hematocrits at 120 minutes.
What happened to the heart rates that were listed as a secondary outcome? Why are they not
shown?
Discussion
“However, in the Flowable group there were four-point measurement: from 0 to minute 3; from
minute 3 to minute 6; from minute 6 to minute 9; and from minute 9 to minute 12.” What is this?
Why was this only done for one group, and why are these data not shown?
“Gelatin-thrombin flowable agents” Why are new results presented in this paragraph, suddenly,
in the middle of the discussion segment?
Declarations
“All methods are reported in accordance with ARRIVE guidelines for the reporting of animal
experiments.” No, they are not. There is not enough information about the animals or methods to
live up to the ARRIVE guidelines. Things like sample size estimations are completely missing.
Figures
Throughout, it would be better to show the individual data points, rather than fairly
uninformative box plots. The authors did not use that many animals and towards the end of the
study, there were only a handful of animals left alive. Reporting these results as a box plot is
speculative.
Why the blood loss is not shown as cumulative measurements is also a bit unclear.
Tables
The statistical tests in Table 1 are unnecessary. The authors may want to Google “Table 1
fallacy” for a thorough explanation on why these are not really needed.
Title: Effectiveness of a Thrombin-gelatin Flowable for treating severe liver bleeding: An
experimental study
Version: 2 Date: 14 Aug 2023
Reviewer's report:
Comments, “Effectiveness of a Thrombin-gelatin Flowable for treating severe liver bleeding:
An experimental study”,
Sánchez-del-Valle and collaborators present a report on the efficacy of treating liver lacerations
using a commercially available thrombin-containing gel. They note that the gel is superior to just
packing the wound with surgical pads, both with respect to blood loss and mortality using a pig
model. It is a straight-forward study that provides useful information. My gripes are principally
to do with the reporting of the study, where we are given very little context for the study and not
enough information about the methods to properly be able to judge the quality of the findings
(let alone being able to replicate the authors’ methods). In short, I think this can become a great
paper, but the authors still have some work to do.
I have listed my major issues below, followed by some specific comments for each section of
the manuscript. I hope that the authors can make use of these.
Context:
The manuscript could give more context to the study. Why was the gel compared to simply
packing? There are a number of products on the market (and a number of studies looking
into them) that could be used for hemostasis in a situation like this. Why was the product not
benchmarked with the standard of care in a hospital? I imagine the context given in the cover
letter could be useful here.
There is also a number of studies into the efficacy of FloSeal. What is the novel aspect of this
study? How does this study contrast with these previous investigations? The introduction could
do a better job of explaining to the reader what information this specific study gathered, that
was not known before.
Methods:
The methods section is not nearly informative enough. None of the methods used to gather the
data are fully explained. The primary endpoint, for example, is the blood loss. But how was this
gauged? As the pig bleeds into the abdominal cavity, blood has to be collected - somehow - to
be weighed. How this is done affects the readings. This is why it is crucial that the authors report
how they did this. Also, how was any of the measurements in Table 1 obtained?
The details for the anesthetic regimen are also insufficient. What were the dosages and timings?
Were all of the pigs anesthetized in the same way? Given that 24-h anesthesia is not a picnic,
and given that it can affect many of the experimental readings, the reader would need quite a
bit more details here.
The authors state that their reporting follows the ARRIVE guidelines. It does not. I suggest the
authors look into what the ARRIVE guidelines suggest, and then report accordingly. Sample size
estimations, reporting on randomization and blinding, and information on experimental animals
are all but completely missing.
Finally, the statistical methods are a bit all over the place. The methods section lists a number of
statistical tests, with no details, followed by pointing out that they were used “as needed.” But
some of these tests do not even seem to have been used..? When was Fisher’s exact test used,
for example? This section could be more fitting the report. Moreover, some of the hypothesis
tests that are presented in the results section seem to not really serve any real purpose.
Specific comments, listed by section:
Abstract
“Total blood volume per animal lost” is probably better described as “lost blood volume.”
Material and methods
“Animals in which one of the suprahepatic veins had not been selectively injured were excluded
from the study.” What does this sentence mean? Did the experimental surgery fail in some cases?
If it did – how frequently?
*When* was random assignment to experimental groups done? If it was done pre-operatively,
was the assignment concealed from the surgeon (and how)?
I assume that no readings were made blinded. This should be mentioned nevertheless.
“Analytical determinations included...” Included? Were there other analyses? And what
equipment/methods were used for these analyses?
The timing of the analytical readings is needlessly repeated. “Study variables were measured...”
and “All determinations were performed...”
Giving the formula for density is a bit excessive. Moreover, where the authors use mathematical
formulae, they should make sure to use proper notation. "V100 = (Vx100/Ve)" is more confusing
than it is helpful. Why quotes? Why the parenthesis? “V × 100” not “Vx100” Also, that is not
the correct way to express a percentage.
How was the lost blood weighed? How was this done in a repeatable and accurate way?
“Secondary outcomes included survival rate; time of application; heart rate (beats per minute,
bpm); and hematocrit values.” Included? Were there others? Also, why is heart rate, but not, say,
blood pressure mentioned? Why hematocrits but not, say, hemoglobin? Are the authors only
showing us the values that differed between the groups?
Results
Why on earth were the animals not evenly distributed between the groups?
Primary endpoints: This whole section is better described in the figure and can be deleted for
brevity. Also, the hypothesis tests (Friedman’s test) make no sense.
“...the percentage of the percentage of total blood volume per animal lost was significantly
lower in the Flowable group than in the packing group from minute 12 to minute 60” I do not
understand this sentence.
What is the purpose of the recurring single-cohort Friedman tests?
“At minute 120, hematocrit was significantly higher in the Flowable group...” Post hoc testing
when the omnibus test was not statistically significant is not advisable, particularly when the
authors have no specific hypothesis with respect to hematocrits at 120 minutes.
What happened to the heart rates that were listed as a secondary outcome? Why are they not
shown?
Discussion
“However, in the Flowable group there were four-point measurement: from 0 to minute 3; from
minute 3 to minute 6; from minute 6 to minute 9; and from minute 9 to minute 12.” What is this?
Why was this only done for one group, and why are these data not shown?
“Gelatin-thrombin flowable agents” Why are new results presented in this paragraph, suddenly,
in the middle of the discussion segment?
Declarations
“All methods are reported in accordance with ARRIVE guidelines for the reporting of animal
experiments.” No, they are not. There is not enough information about the animals or methods to
live up to the ARRIVE guidelines. Things like sample size estimations are completely missing.
Figures
Throughout, it would be better to show the individual data points, rather than fairly
uninformative box plots. The authors did not use that many animals and towards the end of the
study, there were only a handful of animals left alive. Reporting these results as a box plot is
speculative.
Why the blood loss is not shown as cumulative measurements is also a bit unclear.
Tables
The statistical tests in Table 1 are unnecessary. The authors may want to Google “Table 1
fallacy” for a thorough explanation on why these are not really needed.
Please review this paper.
user
Title: Effectiveness of a Thrombin-gelatin Flowable for treating severe liver bleeding: An
experimental study
Version: 2 Date: 14 Aug 2023
Reviewer's report:
Comments, “Effectiveness of a Thrombin-gelatin Flowable for treating severe liver bleeding:
An experimental study”,
Sánchez-del-Valle and collaborators present a report on the efficacy of treating liver lacerations
using a commercially available thrombin-containing gel. They note that the gel is superior to just
packing the wound with surgical pads, both with respect to blood loss and mortality using a pig
model. It is a straight-forward study that provides useful information. My gripes are principally
to do with the reporting of the study, where we are given very little context for the study and not
enough information about the methods to properly be able to judge the quality of the findings
(let alone being able to replicate the authors’ methods). In short, I think this can become a great
paper, but the authors still have some work to do.
I have listed my major issues below, followed by some specific comments for each section of
the manuscript. I hope that the authors can make use of these.
Context:
The manuscript could give more context to the study. Why was the gel compared to simply
packing? There are a number of products on the market (and a number of studies looking
into them) that could be used for hemostasis in a situation like this. Why was the product not
benchmarked with the standard of care in a hospital? I imagine the context given in the cover
letter could be useful here.
There is also a number of studies into the efficacy of FloSeal. What is the novel aspect of this
study? How does this study contrast with these previous investigations? The introduction could
do a better job of explaining to the reader what information this specific study gathered, that
was not known before.
Methods:
The methods section is not nearly informative enough. None of the methods used to gather the
data are fully explained. The primary endpoint, for example, is the blood loss. But how was this
gauged? As the pig bleeds into the abdominal cavity, blood has to be collected - somehow - to
be weighed. How this is done affects the readings. This is why it is crucial that the authors report
how they did this. Also, how was any of the measurements in Table 1 obtained?
The details for the anesthetic regimen are also insufficient. What were the dosages and timings?
Were all of the pigs anesthetized in the same way? Given that 24-h anesthesia is not a picnic,
and given that it can affect many of the experimental readings, the reader would need quite a
bit more details here.
The authors state that their reporting follows the ARRIVE guidelines. It does not. I suggest the
authors look into what the ARRIVE guidelines suggest, and then report accordingly. Sample size
estimations, reporting on randomization and blinding, and information on experimental animals
are all but completely missing.
Finally, the statistical methods are a bit all over the place. The methods section lists a number of
statistical tests, with no details, followed by pointing out that they were used “as needed.” But
some of these tests do not even seem to have been used..? When was Fisher’s exact test used,
for example? This section could be more fitting the report. Moreover, some of the hypothesis
tests that are presented in the results section seem to not really serve any real purpose.
Specific comments, listed by section:
Abstract
“Total blood volume per animal lost” is probably better described as “lost blood volume.”
Material and methods
“Animals in which one of the suprahepatic veins had not been selectively injured were excluded
from the study.” What does this sentence mean? Did the experimental surgery fail in some cases?
If it did – how frequently?
*When* was random assignment to experimental groups done? If it was done pre-operatively,
was the assignment concealed from the surgeon (and how)?
I assume that no readings were made blinded. This should be mentioned nevertheless.
“Analytical determinations included...” Included? Were there other analyses? And what
equipment/methods were used for these analyses?
The timing of the analytical readings is needlessly repeated. “Study variables were measured...”
and “All determinations were performed...”
Giving the formula for density is a bit excessive. Moreover, where the authors use mathematical
formulae, they should make sure to use proper notation. "V100 = (Vx100/Ve)" is more confusing
than it is helpful. Why quotes? Why the parenthesis? “V × 100” not “Vx100” Also, that is not
the correct way to express a percentage.
How was the lost blood weighed? How was this done in a repeatable and accurate way?
“Secondary outcomes included survival rate; time of application; heart rate (beats per minute,
bpm); and hematocrit values.” Included? Were there others? Also, why is heart rate, but not, say,
blood pressure mentioned? Why hematocrits but not, say, hemoglobin? Are the authors only
showing us the values that differed between the groups?
Results
Why on earth were the animals not evenly distributed between the groups?
Primary endpoints: This whole section is better described in the figure and can be deleted for
brevity. Also, the hypothesis tests (Friedman’s test) make no sense.
“...the percentage of the percentage of total blood volume per animal lost was significantly
lower in the Flowable group than in the packing group from minute 12 to minute 60” I do not
understand this sentence.
What is the purpose of the recurring single-cohort Friedman tests?
“At minute 120, hematocrit was significantly higher in the Flowable group...” Post hoc testing
when the omnibus test was not statistically significant is not advisable, particularly when the
authors have no specific hypothesis with respect to hematocrits at 120 minutes.
What happened to the heart rates that were listed as a secondary outcome? Why are they not
shown?
Discussion
“However, in the Flowable group there were four-point measurement: from 0 to minute 3; from
minute 3 to minute 6; from minute 6 to minute 9; and from minute 9 to minute 12.” What is this?
Why was this only done for one group, and why are these data not shown?
“Gelatin-thrombin flowable agents” Why are new results presented in this paragraph, suddenly,
in the middle of the discussion segment?
Declarations
“All methods are reported in accordance with ARRIVE guidelines for the reporting of animal
experiments.” No, they are not. There is not enough information about the animals or methods to
live up to the ARRIVE guidelines. Things like sample size estimations are completely missing.
Figures
Throughout, it would be better to show the individual data points, rather than fairly
uninformative box plots. The authors did not use that many animals and towards the end of the
study, there were only a handful of animals left alive. Reporting these results as a box plot is
speculative.
Why the blood loss is not shown as cumulative measurements is also a bit unclear.
Tables
The statistical tests in Table 1 are unnecessary. The authors may want to Google “Table 1
fallacy” for a thorough explanation on why these are not really needed.
assistant