Reviewer's report
Title:Effects of Cystalloids and Colloids on liver and intestine microcirculation
and function in CLP-induced septic rodents
Version: 2Date:20 August 2012
Reviewer: Nicolai Haase
Reviewer's report:
Thank you very much for this interesting paper on crystalloid vs. colloid
resuscitation in septic rats. The authors compare different fluids given at fixed
doses in CLP-induced septic rats. Outcomes are hepatic and intestinal
microcirculation, inflammatory markers, macro hemodynamic data and blood gas
measurements.
Synthetic colloids are frequently used in critically ill patients, but the safety and
efficacy of colloids are questioned – especially after the publication of yet another
trial showing increased adverse effects (and mortality) of starch (Perner, Haase
et al. NEJM 2012 Jul 12; 367(2):124-34). The present study may contribute to
some extent to this debate.
Fluids in the present study are given at fixed doses. A better approach might
have been to dose blinded fluid according to the hemodynamic status, but I
acknowledge that it may be very difficult to select valid resuscitation targets and
that the method in this paper may be the most appropriate in an animal study like
this. It is a strength that the authors dose at a crystalloid-to-colloid ratio of 1:1,
which is in line with clinical findings in humans in both the newly publish 6S and
the CRYSTMAS-trials (in the former a subgroup of fluid responsive patients
needed a little less fluid, but only in the very initial phase of resuscitation) (Guidet
et al. Crit Care. 2012 May 24;16(3):R94.).
Major Compulsory Revisions:
1. The paper contains lots of analysis of several outcomes and multiple
comparisons. Thus, all p-values are prone to multiple testing. The study results
would have been much stronger if a pre-defined analysis plan were made and
followed. If the authors did not have such a plan, this should be discussed as a
major limitation.
2. Many of the presented analyses are comparisons between intervention groups
and sham. I think that the clinical question (and the question of this study) should
be “is there a difference between crystalloids and colloids”. When comparing the
intervention groups with sham you easier get a significant result giving the reader
a false impression of a difference between two intervention groups. The
comparison between all intervention groups together and sham may tell you
whether or not your sepsis model worked.
3. The increased mortality in the saline, HES and gelatine groups may influence
the results as only a selected group of living animals are analysed (the most sick
animals have died). This must be mentioned as a limitation. Furthermore, I
strongly suggest that you create a CONSORT flow diagram showing how many
rodents that we randomised in each group, the deaths and how many that you
analysed. This could replace the survival curves, which I do not think are of high
importance due to the limited time frame.
4. Sterofundin should be referred to as “Ringer’s acetate” throughout the article.
5. The rats are given a total dose of 24 ml/100 g = 240 ml/kg in the 24 hours
study period. In humans this would be a huge dose, and it is almost 5 times the
total dose given to the patients in 6S-trial during the whole study period. I
acknowledge that dosing in rats and humans may be different which you discuss,
but can you refer to any data which could indicate if this is to be considered a
small or large dose.
6. This model mimics sepsis in its very, very early phase. Patients are often
transferred to the ICU and resuscitated at much later stages. This should be
mentioned as a limitation as well.
7. Abstract, results: Comparator group must be mentioned for each result.
8. Abstract, conclusion: This conclusion must state your conclusions regarding
crystalloids vs. colloids which is what you aim at in the background. Now it only
describes gelatine and Ringer’s acetate.
Minor Essential revisions:
1. Please state the carrier fluids for both colloids.
2. Background: “The volumen replacement strategies...” varies between contries.
Consider referring to Finfer et al. Crit Care. 2010;14(5):R185. Epub 2010 Oct 15.
3. P. 4 line 6 ( “…increased risk of side effects…”): add “mortality” and reference
to Perner, Haase et al. N Engl J Med. 2012 Jul 12; 367(2):124-34
4. Ref 12: This paper has been updated so it now contains HES, gelatine and
crystalloid data. Bayer et al. Crit Care Med. 2011 Jun;39(6):1335-42.
5. The VISEP study was not blinded and may be prone to bias. Refer to 6S and
CRYSTMAS-trials (see above).
6. Ref. 18: Refers to Singleton et al. and not to Guidet et al. To my knowledge
there are no studies on saline vs. balanced fluid with power to show mortality
differences.
7. Discussion: I suggest beginning with a summary of your main findings.
Discuss these first and then discuss protocol issues, colloid-crystalloid ratio etc.
8. I do not think that the statement in the conclusion and figure legend 2 that
gelatine has higher mortality rate is valid.
Level of interest: An article of limited interest
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I was the coordinating investigator of the Scandinavian Starch for Severe Sepsis
/ Septic Shock (6S) Trial. I have no competing financial interests.
Reviewer's report
Title:Effects of Cystalloids and Colloids on liver and intestine microcirculation
and function in CLP-induced septic rodents
Version: 2Date:20 August 2012
Reviewer: Nicolai Haase
Reviewer's report:
Thank you very much for this interesting paper on crystalloid vs. colloid
resuscitation in septic rats. The authors compare different fluids given at fixed
doses in CLP-induced septic rats. Outcomes are hepatic and intestinal
microcirculation, inflammatory markers, macro hemodynamic data and blood gas
measurements.
Synthetic colloids are frequently used in critically ill patients, but the safety and
efficacy of colloids are questioned – especially after the publication of yet another
trial showing increased adverse effects (and mortality) of starch (Perner, Haase
et al. NEJM 2012 Jul 12; 367(2):124-34). The present study may contribute to
some extent to this debate.
Fluids in the present study are given at fixed doses. A better approach might
have been to dose blinded fluid according to the hemodynamic status, but I
acknowledge that it may be very difficult to select valid resuscitation targets and
that the method in this paper may be the most appropriate in an animal study like
this. It is a strength that the authors dose at a crystalloid-to-colloid ratio of 1:1,
which is in line with clinical findings in humans in both the newly publish 6S and
the CRYSTMAS-trials (in the former a subgroup of fluid responsive patients
needed a little less fluid, but only in the very initial phase of resuscitation) (Guidet
et al. Crit Care. 2012 May 24;16(3):R94.).
Major Compulsory Revisions:
1. The paper contains lots of analysis of several outcomes and multiple
comparisons. Thus, all p-values are prone to multiple testing. The study results
would have been much stronger if a pre-defined analysis plan were made and
followed. If the authors did not have such a plan, this should be discussed as a
major limitation.
2. Many of the presented analyses are comparisons between intervention groups
and sham. I think that the clinical question (and the question of this study) should
be “is there a difference between crystalloids and colloids”. When comparing the
intervention groups with sham you easier get a significant result giving the reader
a false impression of a difference between two intervention groups. The
comparison between all intervention groups together and sham may tell you
whether or not your sepsis model worked.
3. The increased mortality in the saline, HES and gelatine groups may influence
the results as only a selected group of living animals are analysed (the most sick
animals have died). This must be mentioned as a limitation. Furthermore, I
strongly suggest that you create a CONSORT flow diagram showing how many
rodents that we randomised in each group, the deaths and how many that you
analysed. This could replace the survival curves, which I do not think are of high
importance due to the limited time frame.
4. Sterofundin should be referred to as “Ringer’s acetate” throughout the article.
5. The rats are given a total dose of 24 ml/100 g = 240 ml/kg in the 24 hours
study period. In humans this would be a huge dose, and it is almost 5 times the
total dose given to the patients in 6S-trial during the whole study period. I
acknowledge that dosing in rats and humans may be different which you discuss,
but can you refer to any data which could indicate if this is to be considered a
small or large dose.
6. This model mimics sepsis in its very, very early phase. Patients are often
transferred to the ICU and resuscitated at much later stages. This should be
mentioned as a limitation as well.
7. Abstract, results: Comparator group must be mentioned for each result.
8. Abstract, conclusion: This conclusion must state your conclusions regarding
crystalloids vs. colloids which is what you aim at in the background. Now it only
describes gelatine and Ringer’s acetate.
Minor Essential revisions:
1. Please state the carrier fluids for both colloids.
2. Background: “The volumen replacement strategies...” varies between contries.
Consider referring to Finfer et al. Crit Care. 2010;14(5):R185. Epub 2010 Oct 15.
3. P. 4 line 6 ( “…increased risk of side effects…”): add “mortality” and reference
to Perner, Haase et al. N Engl J Med. 2012 Jul 12; 367(2):124-34
4. Ref 12: This paper has been updated so it now contains HES, gelatine and
crystalloid data. Bayer et al. Crit Care Med. 2011 Jun;39(6):1335-42.
5. The VISEP study was not blinded and may be prone to bias. Refer to 6S and
CRYSTMAS-trials (see above).
6. Ref. 18: Refers to Singleton et al. and not to Guidet et al. To my knowledge
there are no studies on saline vs. balanced fluid with power to show mortality
differences.
7. Discussion: I suggest beginning with a summary of your main findings.
Discuss these first and then discuss protocol issues, colloid-crystalloid ratio etc.
8. I do not think that the statement in the conclusion and figure legend 2 that
gelatine has higher mortality rate is valid.
Level of interest: An article of limited interest
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I was the coordinating investigator of the Scandinavian Starch for Severe Sepsis
/ Septic Shock (6S) Trial. I have no competing financial interests.
Please review this paper.
user
Reviewer's report
Title:Effects of Cystalloids and Colloids on liver and intestine microcirculation
and function in CLP-induced septic rodents
Version: 2Date:20 August 2012
Reviewer: Nicolai Haase
Reviewer's report:
Thank you very much for this interesting paper on crystalloid vs. colloid
resuscitation in septic rats. The authors compare different fluids given at fixed
doses in CLP-induced septic rats. Outcomes are hepatic and intestinal
microcirculation, inflammatory markers, macro hemodynamic data and blood gas
measurements.
Synthetic colloids are frequently used in critically ill patients, but the safety and
efficacy of colloids are questioned – especially after the publication of yet another
trial showing increased adverse effects (and mortality) of starch (Perner, Haase
et al. NEJM 2012 Jul 12; 367(2):124-34). The present study may contribute to
some extent to this debate.
Fluids in the present study are given at fixed doses. A better approach might
have been to dose blinded fluid according to the hemodynamic status, but I
acknowledge that it may be very difficult to select valid resuscitation targets and
that the method in this paper may be the most appropriate in an animal study like
this. It is a strength that the authors dose at a crystalloid-to-colloid ratio of 1:1,
which is in line with clinical findings in humans in both the newly publish 6S and
the CRYSTMAS-trials (in the former a subgroup of fluid responsive patients
needed a little less fluid, but only in the very initial phase of resuscitation) (Guidet
et al. Crit Care. 2012 May 24;16(3):R94.).
Major Compulsory Revisions:
1. The paper contains lots of analysis of several outcomes and multiple
comparisons. Thus, all p-values are prone to multiple testing. The study results
would have been much stronger if a pre-defined analysis plan were made and
followed. If the authors did not have such a plan, this should be discussed as a
major limitation.
2. Many of the presented analyses are comparisons between intervention groups
and sham. I think that the clinical question (and the question of this study) should
be “is there a difference between crystalloids and colloids”. When comparing the
intervention groups with sham you easier get a significant result giving the reader
a false impression of a difference between two intervention groups. The
comparison between all intervention groups together and sham may tell you
whether or not your sepsis model worked.
3. The increased mortality in the saline, HES and gelatine groups may influence
the results as only a selected group of living animals are analysed (the most sick
animals have died). This must be mentioned as a limitation. Furthermore, I
strongly suggest that you create a CONSORT flow diagram showing how many
rodents that we randomised in each group, the deaths and how many that you
analysed. This could replace the survival curves, which I do not think are of high
importance due to the limited time frame.
4. Sterofundin should be referred to as “Ringer’s acetate” throughout the article.
5. The rats are given a total dose of 24 ml/100 g = 240 ml/kg in the 24 hours
study period. In humans this would be a huge dose, and it is almost 5 times the
total dose given to the patients in 6S-trial during the whole study period. I
acknowledge that dosing in rats and humans may be different which you discuss,
but can you refer to any data which could indicate if this is to be considered a
small or large dose.
6. This model mimics sepsis in its very, very early phase. Patients are often
transferred to the ICU and resuscitated at much later stages. This should be
mentioned as a limitation as well.
7. Abstract, results: Comparator group must be mentioned for each result.
8. Abstract, conclusion: This conclusion must state your conclusions regarding
crystalloids vs. colloids which is what you aim at in the background. Now it only
describes gelatine and Ringer’s acetate.
Minor Essential revisions:
1. Please state the carrier fluids for both colloids.
2. Background: “The volumen replacement strategies...” varies between contries.
Consider referring to Finfer et al. Crit Care. 2010;14(5):R185. Epub 2010 Oct 15.
3. P. 4 line 6 ( “…increased risk of side effects…”): add “mortality” and reference
to Perner, Haase et al. N Engl J Med. 2012 Jul 12; 367(2):124-34
4. Ref 12: This paper has been updated so it now contains HES, gelatine and
crystalloid data. Bayer et al. Crit Care Med. 2011 Jun;39(6):1335-42.
5. The VISEP study was not blinded and may be prone to bias. Refer to 6S and
CRYSTMAS-trials (see above).
6. Ref. 18: Refers to Singleton et al. and not to Guidet et al. To my knowledge
there are no studies on saline vs. balanced fluid with power to show mortality
differences.
7. Discussion: I suggest beginning with a summary of your main findings.
Discuss these first and then discuss protocol issues, colloid-crystalloid ratio etc.
8. I do not think that the statement in the conclusion and figure legend 2 that
gelatine has higher mortality rate is valid.
Level of interest: An article of limited interest
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
I was the coordinating investigator of the Scandinavian Starch for Severe Sepsis
/ Septic Shock (6S) Trial. I have no competing financial interests.
assistant