Reviewer's report
Title: Increased global end-diastolic volume is pivotal to maintain fluid responsiveness in sepsis-induced systolic dysfunction.
Version: 2 Date: 17 August 2012
Reviewer: Daniel Reuter
Reviewer's report:
The aim of the article reviewed was evaluate and compare cardiac filling volumes to pressure in determining cardiac response to fluid loading in sepsis induced hypotension. Patients were divided in two groups according to evaluation of GEF from thermodilution. The experimental setting, methods applied, measurements and calculations are presented comprehensible. Authors demonstrated that maintaining cardiac dilation is essential for maintaining fluid responsiveness.
Limitations of the method itself and its informative value are also presented and discussed in detail. Literature available on the issue is also taken into consideration.
Major Compulsory Revisions
(1) The definition chosen to determine hypovolemia was “systolic blood pressure
<110 mmHg and relatively low CVP”. There is excellent evidence in literature that
CVP does not adequately reflect the patients volume status and is influenced by many factors. Maybe you could comment on this
We agree with this reviewer that CVP does not adequately reflect patients true volume status nor whether the patient is fluid responsive and in fact our data confirm this. In our previous publications we also used hypotension/filling pressure criteria for defining clinical hypovolemia (vd
Heijden CCM 2009;37:1275, Verheij ICM 2006;32:1030), as the trigger for fluid infusion and evaluated the predictive values afterwards (to avoid confounding of predictive values by giving fluids only on the basis of assumed predictors!).
(2) The fluid loading protocol is based on CVP, which is one of the parameters investigated. Why was this chosen? Again there is evidence that guiding fluid therapy by CVP seems not to be appropriate.
Clinical hypovolemia as a trigger for fluid infusion was defined above, in line with all our other published papers.
Particularly delta filling pressures, rather than absolute values, as indicated by the (modified) Weil algorithm (see paper) may still be helpful to guide fluid administration in the absence of any other, admittedly, superior predictors.
(2) The authors describe reproducibility of measurement by thermodilution to be within 10%. Why was a cutoff for detecting volume responsiveness set at 10%?
The authors also report that the definition of an increase of CI >15% was calculated, however results are not reported. What impact had this on the described findings? Did results differ?
The cutoff of 10% is in line with other reports in literature.
We introduced a table for a 15% cutoff to define fluid

responsiveness and the conclusions of the paper did not change.
(3) The statiscs section describes that ROC analysis were performed. However results are not presented.
We removed this since baseline values of GEDVI/CVP did not predict in this cohort.
(4) The main conclusion is that volume responsiveness appears to be dependent on the ability of myocardial dilation. This is an interesting finding, however in the present setting it can only be hypothesized. Detailed Evaluation of diastolic function as well as differentiated measurements of left- and right-ventricular cardiac function are lacking.
We agree with this statement. Indeed we found that in septic hearts with systolic dysfunction and subsequent dilatation, higher GEDVI are still indicative and pivotal for maintaining fluid responsiveness as in hearts with (near-)normal systolic function. Inability to dilate (diastolic dysfunction ?) was associated with non-responsiveness. In future studies the results should be confirmed by simultaneously performing echocardiography. We also added this in the revision.
Discretionary Revisions
(5) Division of patients in groups with normal and impaired cardiac function is carried out according to GEF derived from TCPTD. Though this does not influence the main finding of this study that maintaining the ability for cardiac dilation is essential for maintaining fluid responsiveness, GEF itself also is affected by preload.
We agree with this reviewer that GEF itself is also affected by preload (at least in part). However, the change in GEF
(15±2 versus 16±4)in the low GEF group after 90 minutes of fluid loading was not significant (P=0.09). The division according to GEF coincided with differences in better, relatively load-independent indicators of cardiac function like the preload-recruitable stroke work.
Level of interest: An article whose findings are important to those with closely related research interests
Quality of written English: Acceptable
Statistical review: Yes, and I have assessed the statistics in my report.
Declaration of competing interests:
Consultancy, scientific collaboration and lecturing for Pulsion Medical Systems,
Edwards Lifesciences, Draeger Medical

Reviewer's report
Title: Increased global end-diastolic volume is pivotal to maintain fluid responsiveness in sepsis-induced systolic dysfunction.
Version: 2 Date: 16 August 2012
Reviewer: Daniel De Backer
Reviewer's report:
Major compulsory revisions
1/ An important part of the manuscript is based on evaluation of changes in
GEDV and changes in CVP during fluid loading. While it is quite obvious that changes in GEDVI occurred only during responding fluid loading, the changes in
CVP were very similar (1 or 2 mmHg). Even if some statistical significance in the differences in changes in CVP could be detected, the clinical significance of 1 mmHg in CVP can really be questioned. There is also a risk of mathematical coupling between changes in CI and GEDV. This is nicely illustrated in the linear relationship reported in figure 1 which is of course non compatible with the curvilinear shape of the Starling relationship. Given theses methodological limitations (minimal changes and/or risk of spurious relationships), it is probably fair to tune down all this part. The remaining and important information is that
GEDVI is somewhat higher in responding than in non responding fluid administrations which occurred in patients with low GEF.
The relationship between preload-volumes and CI/SV (preloadrecruitable cardiac output or stroke work) is, normally linear, not curvilinear (!), since the pressure/volume curve at the end of diastole is curvilinear (too, as the classical
Starling curve). We agree with the small changes in CVP per fluid loading step, and that this may explain in part their relatively poor predictive value. Conversely, we have extensively discussed the mathematical coupling issue. We fully agree with the important observation that (using cutoffs
>10-15%) responders do not (!) have a low GEDVI at baseline when cardiac systolic function is impaired.
2/ You stated that this was a substudy of ref 16/28. However, it seems that you included only 16 patients (this number is only mentioned in table 2) while ref
16/28 included 24 septic patients. Please explain why 8 pts (one third of the original study) were excluded.
In reference 16/28 both saline loaded en colloid loaded patients were included. In this study we excluded saline loaded patients. These were 6 patients, remaining 18 (24-6).
In two of the colloid loaded patients, some data were missing.
We excluded these patient from analysis, as indicated in the text.
3/ Myocardial depression is a changing condition. You investigated multiple fluid administrations per patients. You stated “We divided patients in groups according to a low GEF (<20%) and nearnormal GEF (#20%).” Do you mean that patients

were divided according to their initial GEF (and this may thus have changed in subsequent fluid administrations) or did you categorize according to GEF at time of fluid administration?
Patients were divided to GEF at t=0, thus before fluid loading. However, the change in GEF in both GEF groups after
90 minutes of fluid loading was not significant. Near-normal
GEF group P=0.938, low GEF group P=0.06
4/ You should have access to a newer/larger database of patients reported from your group (Trof et al CCM 2012). As the number of patients in the current trial is quite low and as you have access to data from 72 other septic patients (several of these received fluids), you should also include these data in the current manuscript, which certainly would strengthen the findings.
The study this reviewer refers to (Volume-limited versus pressure-limited hemodynamic management in septic and nonseptic shock, Crit Care Med. 2012 Apr;40(4):1177-85)was rather a safety study than a resuscitation study.
In this study we did not investigate the change of hemodynamic parameters upon fluid loading. So we also did not record hemodynamic data after each fluid loading event. We also did not divide patients according to cardiac function. So we cannot include these data in the current manuscript.
Minor compulsory revsions
1/ Some sentences, especially in the abstract, are long and complex requiring a lot of attention of the reader to be understood (“Prior to fluid loading, CVP did not differ between responding and non-responding steps and levels attained were higher in the former, regardless of GEF (P=0.004)”-need to think twice to understand that CVP increased in responders / ”During dysfunction, cardiac dilation with a high baseline GEDVI maintains fluid responsiveness by further dilatation (increase in GEDVI rather than of CVP) as in patients without dysfunction.”
We adapted this.
2/ Table 3: p values posted right after changes (cvp/gedvi) seems to rather refer to values “after”. Otherwize, I do not understand why some p values were significant (i.e. change in cvp with low GEF)
The p values are correctly posted. For Patients in the low GEF group for example, the change in CVP was greater in nonresponders compared to responders suggesting right ventricular dysfunction or diastolic dysfunction as explained in the discussion.

Level of interest: An article of importance in its field
Quality of written English: Needs some language corrections before being published
Statistical review: No, the manuscript does not need to be seen by a statistician.
Declaration of competing interests: honoraria for lectures from Edwards Lifesciences, Pulsion, LiDCO.
Grant and material for studies from Edwards Lifesciences, Vytech.

Reviewer's report
Title: Increased global end-diastolic volume is pivotal to maintain fluid responsiveness in sepsis-induced systolic dysfunction.
Version: 2 Date: 23 August 2012
Reviewer: Jochen Renner
Reviewer's report:
“Increased global end-diastolic volume is pivotal to maintain fluid responsiveness in sepsisinduced systolic dysfunction”
Comments to the Author
The question of preload optimization is still a clinically relevant issue and a lot of work is needed to more precisely define indications and limitations of both, dynamic variables and static variables like global end-diastolic volume (GEDV).
The recent literature regarding GEDV as a valid measure of preload and a predictor of fluid responsiveness is inconsistent. Consequently, the hypothesis the authors investigated in the presented clinically study on septic patients on the
ICU is of some interest. Especially the question whether normal ranges of GEDV differ due to global cardiac dysfunction on the basis of ischemia and/or sepsis-induced cardiac dysfunction. We already know that GEDV shows a large inter-individual variance and dependency on age and gender and of cardiac comorbidities such as myocardial infarction. However, there are some points, which have to be clarified to more precisely accentuate the message for the interested reader and clinician.
First of all, the manuscript, especially the introduction and the discussion are too long and not straight to the point.
We have rewritten the paper in order to improve the message it contains.
Major revisions:
INTRODUCTION:
Please change the following sentence: …
These abnormalities may include depression of biventricular or predominantly right ventricular systolic function and/or diastolic dysfunction, as estimated from echocardiography or radionuclide-determined cardiac dimensions and other features and are usually reversible and return to normal in 7 to 10 days in survivors (4-6).
Do the authors mean that right ventricular systolic function is depressed and/or diastolic dysfunction is present? Is it also right ventricular diastolic dysfunction or left ventricular diastolic dysfunction. It is confusing. Delete …other features… or clearly define.
We have adapted this part.
Next sentence; please add whether you talk about right or left ventricular systolic dysfunction
It concerns left ventricular systolic dysfunction and dilatation as measured by radionuclide cineangiography.

Please avoid to list some facts regarding haemodynamic monitoring independently of the main hypothesis you are going to develop by the means of a focussed introduction.
Delete echocardiography.
It might be a problem to state that central venous pressure is recommended to guide fluid loading in sepsis-induced hypotension, although its value to predict fluid responsiveness has not been established, on the one hand. And to follow a fluid challenge protocol that is based solely on changes of CVP, adjusted by the
PEEP value applied (this protocol is also a matter of debate). Please clarify this issue.
The statement that fluid responsiveness was found to be associated with biventricular dilatation (please stay consistent with the spelling of dilation or dilatation, not both) by nuclear angiography, and non-responsiveness appeared attributable to right ventricular systolic dysfunction following mild pulmonary hypertension, needs also some clarification, since for the moment it is just another listing.
Use transpulmonary dilution consistently (see conclusion of the discussion).
Again, in the last section of the introduction please more clearly define what exact you mean: right heart systolic function or left heart or biventricular function
(dys-function).
We have adapted the introduction part.
Methods:
I have some problems regarding the inclusion criteria: the definition of hypovolaemia is q uite diffuse:…presumed hypovolemia, defined as a systolic blood pressure <110 mmHg and a relatively low CVP taking positive endexpiratory pressure into account…..strictly speaking this definition is like flipping a coin. Please try to clarify.
We agree with this reviewer that CVP does not adequately reflect patients true volume status nor whether the patient is fluid responsive and in fact our data confirm this. In our previous publications we also used hypotension/filling pressure criteria for defining clinical hypovolemia (vd
Heijden CCM 2009;37:1275, Verheij ICM 2006;32:1030), as the trigger for fluid infusion and evaluated the predictive values afterwards (to avoid confounding of predictive values by giving fluids only on the basis of assumed predictors!).
A major point of criticism is the definition of a relevant increase in cardiac index #
10% to discriminate between responder and non-responder due to fluid loading and to justify this cutoff value with 2 references. You will find a bunch of studies which use as a cutoff value an increase in CI/SVI #15%, which seems to me and most of the investigators working on this issue much more differentiated. On the next page of the Methods section the following statement could be red:
Reproducibility of measurements is typically within 10%. Can you please

comment on that regarding the issue cutoff values!
The cutoff of 10% is in line with other reports in literature.
We introduced a table for a 15% cutoff to define fluid responsiveness and the conclusions of the paper did not change.
It is quite interesting how much parameters can be generated using transpulmonary thermodilution. Please provide the correct formulars for each calculation; do not put it the text.
GEF:…….
LVSWI:……
CFI:………
Preload-recruitable stroke work
…and all together were used to assess cardiac (e.g. left ventricular) systolic function.
We do not quite understand this comment and retained the formulas in the text for reasons of clarity, to improve understanding..
Statistics:
That the cutoff of 20% approximately reflects a cutoff of 40% EF measured by echocardiography is not an information for this section but for the methods section.
We moved this part to the methods section.
Regarding the power of the study the number of 16 patients is very low, especially to discriminate between responder and non-responder. Please comment on that.
We agree that 16 patients is very low, but we included 48 fluid loading steps ! Hence, statistical analysis revealed a significant difference between NR and R in both low and nearnormal GEF groups, in this proof of principle study. We have to emphasize that we retrospectively analysed the data of the original study.
Results:
The following sentence is very diffuse, please more clearly show the results: In the low GEF group, other function indices also pointed to systolic cardiac dysfunction, prior to and after fluid loading, even though the CI attained with fluid loading did not differ among the groups.
….but the increase in CI decreased with increasing fluid loading steps only when
GEF was low….
At the end of the results section: When fluid responsiveness was defined as an increase in CI#15%, changes in CO were also directly associated with changes in GEDVI (data not shown). To me, it seems more reasonable to show these data rather than the presented data.

The cutoff of 10% is in line with other reports in literature.
We introduced a table for a 15% cutoff to define fluid responsiveness and the conclusions of the paper did not change.
Discussion.
The first sentence of the discussion must be changed from….that fluid responsiveness is maintained by cardiac dilatation to…fluid responsiveness can be present even in patients with global cardiac dilation, as indicated by high
GEDVI.
We have now changed this.
It would have been much better to underline the presented data with some echocardiography derived variables regarding right and left ventricular function
(systolic and diastolic), and some data regarding diameters for example.
We agree with this point. Unfortunately we did not perform echocardiograms simulataneously.
…..possibly caused by systolic right ventricular or diastolic dysfunction, in view of the increase in CVP. This is a hypothesis, which is not provided by the data, since the increase in CVP was highest 1mmHg due to fluid loading. To presume a right ventricular dysfunction on the basis of a mean increase in CVP of 1mmHg is very hazardous.
We cannot exclude that right ventricular dysfunction may have been (at least in part) the cause of fluid unresponsiveness at low GEDVI since the increase in CVP was higher in these non responding steps. We agree that this 1 mm Hg difference may insufficiently reflect right ventricular dysfunction, however it may be suggested as well. Since we did not perform echocardiography, we cannot differentiate between right and left. Therefore, we have weakened the suggestion of right ventricular dysfunction to be more a hypothesis than a convincing explanation.
Moreover, the increase in GEDVI is less than 10% even in the responder group with a preserved GEF (Table 3). Maybe the amount of fluid given in this patient population was not high enough (please comment on that).
Fluid loading occurred as described in table 1. This protocol was applied to all patients, based on the (increase of) CVP prior to and during fluid loading. Fluid responsiveness per step was defined by a cutoff >10 and >15 %, and a considerable number of steps proved responsive (in accordance with other studies).
To summarize:

Although the main hypothesis of this manuscript seems quite interesting, that we probably have to consider that due to cardiac dilation the normal reference values of (any?!) volumetric variables are increased, consequently, even in case of a high GEDVI >1000ml/m2 fluid responsiveness is not excluded per se
(although I believe it is still common clinical practise to challenge these septic patients with fluid boluses), the way the data are presented in this manuscript is somehow confusing. There is a lot of work needed to carve out the main points and to discuss these points and to focus on the main issue.
Level of interest: An article whose findings are important to those with closely related research interests
Quality of written English: Needs some language corrections before being published
Statistical review: Yes, but I do not feel adequately qualified to assess the statistics.
Declaration of competing interests:
I declare that I have no competing interests