12 February 2014
Dear Editor,
We appreciate the thorough review of our manuscript and the helpful comments provided by the
reviewers. We have tried to address all issues raised in the extensive review below. Please find a
copy of each of the reviewers’ comments, along with a point-by-point response in bold font:
Reviewers Comments:
Reviewer #1: Reitze Rodseth
This is a nice, well conducted study. It has been performed in a homogeneous population of
orthopaedic patients undergoing elective joint replacement surgery (hip or knee). The question
posed if well defined and clearly addressed. The reporting of patient eligibility and recruitment
is clearly provided. The findings seem robust and are in agreement with the currently literature.
I think the paper provides confirmation of previous findings demonstrating the weakness of the
RCRI and the ASA scoring system, as well as providing confirmation for preoperative and
postoperative BNP thresholds that predict MACE.
There are a few aspects that are not clear in the manuscript.
1. It is not clear as to how MACE was defined. Currently, and this may be function of the way
the sentence is written, it seems as if “... other non-cardiac complications ...’ have been
included within the MACE definition. If this is the case this should be changed as MACE
should refer only to cardiac events. If this is not the case, then the sentence should be rewritten to address this ambiguity.
Following the reviewer’s suggestion, the phrase regarding the MACE definition in the
methods section was changed to: Perioperative data collection included details of the surgery
and anesthesia and any major adverse cardiac events (MACE: new onset of atrial fibrillation,
flutter, acute heart failure or non-fatal/fatal myocardial infarction) occurring prior to
hospital discharge.
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2. The statistics used in this analysis are appropriate for the questions being addressed.
However, I would like to see what the reclassification statistics would look like for patients
primarily stratified using the RCRI, and then subsequently reclassified with an elevated
preoperative BNP.
Although it was a demanding task, we are grateful to the reviewer for the suggestion of
first stratifying the patients using the RCRI and then reclassifying them for elevated
preoperative BNP, considering a cut-off ≥ 39. The following results were obtained (SAS
program): of the 165 patients classified as RCRI low: 59.4% remained low and 40.6%
became reclassified as medium. Of the 54 patients classified as RCRI average: 37.0%
became low, no patient remained average and 63.0% became very high. Of the 8 patients
originally ranked as RCRI high: 100.0% remained classified as high. These data were
added to the Results section and subsequently commented upon in the discussion section
(table 3).
3. The authors have collected outcome data for non-cardiac events. However, they have not
analysed the ability of an elevated preoperative BNP to predict these events. While preoperative
BNP has repeatedly been shown to predict adverse cardiac events there is supporting evidence
suggesting patients with preoperative BNP elevations may be at a higher risk of non-cardiac
complications such as renal failure, infections – particularly pneumonia, and possibly stroke.
This mechanisms is thought to be linked to reductions in cardiac output and BNP elevations
reflecting reductions in physiological reserve. It would be of great interest to see if BNP is able
to predict these complications in this study population, particularly as these occurred more
frequently than the MACE complications.
We totally agree with the reviewer about the need for the ability of an elevated
preoperative BNP to predict non-cardiac events to be studied.
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The Chi Square test showed that there is no statistically significant association between the
dichotomized preoperative BNP and occurrence of other complications (non-cardiac) p =
0.8782. The following two logistic regressions show that: i) having a preoperative BNP ≥ 39
pg/dL does not increase the risk of further complications (OR = 0.919, 95% CI: 0.312, 2.710);
and ii) an increase in preoperative BNP is not associated with a statistically significant higher
risk of further complications (OR = 0.996 95% CI: 0.991, 1.001).
Minor comments
4. Please define the components of MACE in the abstract
The following description of MACE has been added to the abstract: (MACE): new onset of
atrial fibrillation, flutter, acute heart failure or non-fatal/fatal myocardial infarction.”
5. The authors have done an admirable job in writing the manuscript in a language other than
their first language. However, the entire manuscript would benefit from being edited by an
English first language proof reader.
In accordance to the reviewer’s suggestion, a native English-speaking copy editor has
revised the entire manuscript, including the examples below:
a) the second sentence of the background is long, unwieldy and contains syntax errors. The
sentence has been shortened and corrected.
b) “Only age, from the demographic variables ...” has been replaced with “Of the demographic
variables, only age was…”
c) Results section – line 8 “… showed only marginally association…”, corrected to “showed
only marginal association”
Reviewer: Alisdair D Ryding
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Major Compulsory Revisions (which the author must respond to before a
decision on publication can be reached)
Methods
a. Inclusion / exclusion criteria should state type of anaesthesia
In order to explain this aspect, the following description in the methods section has been
modified: Patients were included if they were >50 years of age and undergoing spinal
anesthesia.
b. Please reference ASA classification.
As the Reviewer requested, the study below has been cited for ASA classification.
Saklad M. Grading of patients for surgical procedures. Anesthesiol. 1941;2:281–4.
c. Define when pre-operative BNP (and other bloods) was measured.
In our clinical practice, patients undergo venous blood sampling on the day of the preanesthesia visit (pre-hospitalization). However, for some cases where this was not possible,
a blood sample to assess pre-operative BNP was drawn on the same day as surgery. For
this reason, the following description in the methods section has been modified:
Patients underwent venous blood sampling in the morning of the pre-anesthesia visit (prehospitalization). However, in cases in which this was not possible, blood samples for
assessing pre-operative BNP were drawn on the same day as surgery. Postoperative BNP was
sampled in the morning of the first day after surgery.
d. State the method of BNP measurement/assay/manufacturer.
The method of BNP measurement/assay/manufacturer was added to the methods: Bayer
ADVIA CentaurTM.
e. State the blood sampling conditions for BNP measurement.
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We know that the accuracy of the test is compromised if subjected to changes in
temperature. Thus sampling, transport to the laboratory and testing are all performed
with great care:
Patients underwent venous blood sampling in the morning of the pre-anesthesia visit (prehospitalization). However, in cases in which this was not possible, blood samples for
assessing pre-operative BNP were drawn on the same day as surgery. Postoperative BNP was
sampled in the morning of the first day after surgery. Blood was collected in EDTA and
lithium heparin vacutainer tubes, and immediately send to the laboratory for analysis (by
means of a specialized transport service for biological materials) where BNP concentrations
were assayed using the Bayer ADVIA CentaurTM.
f. State when post-operative bloods were measured (were these all POD 1?).
In order to address this comment, the following phrase has been modified in the methods
section: Postoperative BNP was sampled in the morning of the first day after surgery.
(Please, consider the difficulty due to real-world limitations).
g. Clearly state the period over which post-operative complications were assessed. This should
also be clearly stated in the abstract and elsewhere in the paper.
The period over which postoperative complications were assessed has been stated in the
abstract and elsewhere in the paper.
h. Was post-operative troponin measured in all patients systematically, or only those with
specific clinical features?
i. Was the diagnosis of post-operative myocardial infarction based purely on troponin
measurement, or were clinical / ECG signs of ischaemia also required?
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In order to address these two comments, troponin was only measured in patients
presenting specific features. The following phrase has been modified in the methods
section:
In particular, postoperative acute myocardial infarction (AMI) was defined for Troponin I
(cTnI) concentrations ≥0.12 ng/mL (3 times the 99th percentile upper reference limit (URL) in
patients presenting specific features (clinical or ECG signs), in accordance with the
definition of myocardial infarction used in previous clinical investigations.
j. The sentence defining MACE is confusing, and needs to be revised. Currently it
suggests that non-cardiac events were also included in the definition. Why was AF / Flutter
included in the definition of MACE?
b. The definition of MACE in the methods section does not include new onset
atrio-ventricular block, but this is reported as a MACE event in the results. Please
revise the MACE definition or results accordingly.
We apologize for that the error; we have separated the MACE description from that for
non cardiac events. As stated above in response to Reviewer 1, the following description of
MACE was added to the abstract, methods and results sections: (MACE: new onset of
atrial fibrillation, flutter, acute heart failure or non-fatal/fatal myocardial infarction).”
We agree with the reviewer that is uncommon to include atrial fibrillation and flutter in
the definition of MACE and have thus decided to discuss this point in the study limitation
as suggested. However, in our clinical practice the new onset of these two events during
the post-op period of these patients requires intervention, with a call being made from the
ward to the Intensive Care Unit.
k. The methodology for determining optimal cut points for BNP from ROC analysis should be
described.
To address this comment, the following description has been added to the methods section:
The optimum cut-off point was determined as the value corresponding to the greatest
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accuracy (i.e. highest sum of sensitivity plus specificity values, with sensitivity and specificity
weighted equally).
l. It is not clear what data/ assumptions were used to calculate the sample size.
The sample size of 206 patients completing the study was calculated on the basis of our
own pilot data, with 90% statistical power at the 5% significance level.
Our own pilot data on vascular surgery patients suggest that the incidence of AMI is around
11%, with these patients presenting a mean preoperative BNP level of 209 pg/mL
(interquartile range, IQR: 84-346) compared to 74 pg/mL (IQR: 28-142) in those who did not.
Thus, we were able to calculate that a sample size of 200 patients completing the study for
preoperative BNP and 206 patients for postoperative BNP would allow us to detect a 30
pg/mL difference in BNP levels between patients who did and did not experience acute
myocardial infarction, with 90% statistical power at the 5% significance level. The software
SAS 9.3 for Windows (SAS Institute Inc., Cary, North Carolina, USA) was used for all
statistical analyses.
Vetrugno L, Costa MG, Pompei L, et al. Prognostic power of pre- and postoperative B-Type
natriuretic peptide levels in patients undergoing abdominal aortic surgery. J Cardiothorac
Vasc Anesth. 2012;26:637-42
And also described by:
Cuthbertson BH, Amiri AR, Croal BL, et al. Utility of B-type natriuretic peptide in predicting
perioperative cardiac events in patients undergoing major non-cardiac surgery. Br J Anaesth
2007;99:170-6
Results
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a.Table 1 should be included in the main body of the paper, rather than as a supplement.
Likewise table 2.
We apologize for that, we will include table 1 in the main test in the resubmitted
manuscript.
b. It would be better to quote the p values with the data as it is reported, rather
than separately.
As the Reviewer requested, p values are now only quoted in the table, rather than
separately.
d. p6 line 7: “Only age, from demographic variable, was associated……”: delete “from
demographic variable” or rewrite (eg Of the demographic variables, only age was associated….)
In accordance to the reviewer’s suggestion, a native English-speaker has edited and
modified the entire manuscript.
e. p6 line 11: delete n=14
In accordance to the reviewer’s suggestion, we have deleted n=14 in the indicated
sentence.
f. Can the authors define the post-operative neurological events? If some of
these were stroke, did BNP levels provide any predictive value, either for stroke
or MACE (ie composite MACE + Stroke)?
As stated above in response to Reviewer 1, we totally agree with the reviewer about the
need to study the ability of an elevated preoperative BNP to predict non-cardiac events.
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The Chi Square test showed that there is no statistically significant association between the
dichotomized preoperative BNP and occurrence of other complications (non-cardiac) p =
0.8782. The following two logistic regressions show that: i) having a preoperative BNP ≥ 39
pg/dL does not increase the risk of further complications (OR = 0.919, 95% CI: 0.312, 2.710);
and ii) an increase in preoperative BNP is not associated with a statistically significant higher
risk of further complications (OR = 0.996 95% CI: 0.991, 1.001).
Discussion
a. Brief discussion about the pathophysiological role of BNP in heart failure and other clinical
conditions would provide a context for the reader to understand why BNP measurement may be
useful in the surgical setting (this could also be considered in the introduction).
A description has been added to the introduction section.
b. p8 line 16-17: should state that this applies to patients with heart failure.
In accordance to the reviewer’s suggestion, we now state that this applies to patients with
heart failure.
c.The authors should state whether they feel pre or post-operative BNP is more useful for
patient management, and why.
d. Please discuss how BNP measurement might be used in routine clinical practice, and how
elevated / normal results would change current practice.
e.*A further limitation of all observational studies such as this is that they do not demonstrate
how BNP measurement should be used in practice. We do not know what changes in
clinical care are required if BNP is elevated, and whether this would make any difference to
outcome. This should be acknowledged.
These two questions are very difficult to reply to.
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As stated in the discussion section: we think that: ...the preoperative BNP cut-off could
provide a more suitable tool for the stratification of preoperative risk; and second, increased
postoperative BNP levels could be used to signal the need for hemodynamic optimization in
the appropriate setting depending on the resources available.
How preoperative BNP might be used to stratify patients who are candidates for
“restricted or liberal” fluid strategies or intraoperative GTD is unknown.
*It is my personal point of view that preoperative BNP with its high NPV could be used to
stratify patients down to
the high risk to moderate or low risk class (RCRI
reclassification) as for reviewer #1.
e. The cost effectiveness discussion is too simplistic and assumes that measurement of BNP
would reduce the duration of hospitalisation. There is no evidence to support this.
To resolve this issue, the phrase in the discussion section about cost-effectiveness has been
deleted.
f. The limitations described are valid. It might also be useful to state that the definition of
MACE in this study was very broad. Furthermore, there were no hard endpoints such as fatal
myocardial infarction, and the clinical relevance of incidental rises in troponin is uncertain. A
larger study with higher risk patients would be needed to address these issues.
We agree with the reviewer and we state in discussion about the limitations of the study
that: our definition of MACE was very broad and the clinical relevance of incidental rises in
Troponin is uncertain.
You actually write:
In our population the clinical relevance of incidental rises in postoperative Troponin is
uncertain as well as the data about patients ejection fraction. We also exclude patients with
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impaired renal function and this could represent another limitation of the study because in
clinical practice renal failure is quite common. Last but not least, our definition of MACE
including atrial fibrillation and flutter was very broad.
My revised version is: to add
Figure 1.
a.BNP “dosage” is wrong: consider “level”.
“dosage” has now been changed to “level”.
Reviewer#2: chiara lazzeri
Reviewer's report:
Minor issues: in the limitation study the Authors should underscore that the exclusion of
patients with "impaired renal function" could represent a limitation taking into account the fact
that in clinical practice it is quite common (due to hte progressive increase of elderly patients).
We agree with the reviewer that in clinical practice impaired renal function is quite
common and that this could be a limitation of the study. This is now stated in the
discussion.
Data on left ventricular function (known to affect BNP levels) should be added, if available.
Otherwise it should be added in the limitation section.
We agree with the reviewer that data about left ventricular function should be added if
available, but in this setting (orthopedic surgery) only few patients underwent
echocardiography prior to surgery, namely those with known cardiac disease. We now
state this in the discussion of the study’s limitations.
In closing, we hope that our revised manuscript addresses all the issues raised in the
informative and thorough review of our paper. We would be glad to make further changes
upon request. On behalf of the other authors, I extend my gratitude for your time and
assistance with our review and we look forward to hearing your response.
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Kind regards,
Luigi Vetrugno, MD
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