Section Editor: Knott, Jonathan
Comments to the Author:
Thank-you for submitting this paper to EMA for publication. The response
from peer review is that whilst there is merit in this study and the data
acquired, the paper as it stands is not ready for publication. Each one of
the individual comments will need to be addressed (see below).
All 3 reviewers (each with substantial experience in this field) found the
paper difficult to read, thus I would anticipate too that our EMA readers
would also struggle with this manuscript, as it stands.
Please do resubmit this paper, but it will require a significant rewrite in
terms of clarity, as well as needing to address all the individual points
that have been raised by the reviewers.
EMA woill be happy to re-evaluate that submission as soon as it is received
back.
Reviewers' Comments to Author:
Prof. Anne-Maree Kelly, Dr. Anthony Cross, Dr. Grant Cave
Reviewer: 1
Comments to the Author
Thankyou for asking me to review this interesting manuscript. I like the
scientific basis and approach and there are interesting results here.
However, there are some factors that seriously threaten the validity/
publishability of this paper.
1.
Inclusion of cardiac arrest and intubated patients [see below]
2.
Inconsistencies between stated objectives, methods, outcomes of
interest and results.
It should possible to make a grid where each specific objective lines up
with a specific method, outcome of interest and result. It is not
acceptable to report results that ‘work’ if they are not defined outcomes
of interest.
I would strongly suggest:
1. Re-analysis, but excluding cardiac arrest and intubated patients.
2. Better definition of the outcomes of interest, and reporting against
these.
3. Attention to overall consistency as described above. This means
reporting against all stated outcomes of interest, not just those that have
significant or interesting results.
General comments:
There are minor grammatical issues throughout the manuscript.
Specific comments:
1.
Abstract:
The usual format is Aim/ objective, methods, results and conclusion. The
Objective can include a brief statement regarding background or relevance.
As presented, some of the material in Objective belongs in Methods.
I would like a bit more detail in methods. Eg convenience sample?
data were collected and from where? Define outcomes of interest.
What
State
how analyses were performed. There appears to be a training and validation
set, but this is not well described.
In Results, I prefer the term ‘defined outcomes’ rather than ‘worse
outcomes’, even though this may be semantic.
There should be a p value related to the AUC comparison.
I would like 95% CI around the reported sensitivity and the inclusion of
specificity.
2.
Introduction
Page 4, last paragraph, line 2. There are a lot of brackets here that make
readability difficult. This should be stated more clearly in words / prose
without resorting to brackets.
VD/VT ratio should be defined again.
The Introduction is too long and most of it belongs in the Discussion. I
would prefer the abstract to concentrate on why is this area of study
important, what is the current state of knowledge and where are the gaps
followed by a statement of your aim.
Page 5, para 1, 4th last line: do you mean physiological or alveolar dead
space rather than anatomical?
3. Methods:
•
Was this a consecutive or convenience sample?
•
Who decided SOB was the primary reason for ABG? Were they blinded
to the study hypothesis?
•
Were treated doctors blinded to the CO2 gap?
•
The outcomes could be better defined. At what point after ED
attendance was outcome defined. eg assisted anytime during admission a
defined outcome, or just within 24 hours or just within ED? Same for
death. I would like more justification for the admission to CCU/HDU/ICU
endpoints. These are ‘softer’ and most subject to local practice
differences.
•
I would have preferred hard outcomes [death and assisted
ventilation within eg 24 hours] as the primary analysis and with the softer
endpoints included as a secondary analysis.
4. Results:
With an ED mortality of 4% and an assisted ventilation rate of 30%, this is
clearly a very high risk SOB cohort rather than a broad SOB cohort. Is
this due to local practices re use/ non-use of ABG? This should be
addressed in the discussion section.
I note that a significant proportion of your sample were in cardiac or
respiratory arrest. This is a serious threat to your findings as most
people would NOT consider this to be ‘shortness of breath’.
Your results compare performance of CO2 GAP, a-A gradient, VD/VT but you do
not describe this in your methods. This should be listed as an outcome of
interest.
C statistics [AUC] numbers with 95% CI are required for each comparison,
along with p value for comparison of AUCs.
Looking at the ROC curves, there is not a statistically significant
difference between CO2 gap, CO2 gradient and VD/VT. This should be
reported in the text, preferably with p values for the comparison.
Suggested diagnostic cut-offs are chosen from the training set and this
should be described in the body of the paper. These cut-offs are then
tested on the validation set and performance reported.
Table 1 is not needed, but I would like a table summarising demographics,
clinical features [RR, BP, pulse, O2 sat] and diagnosis in training and
validation sets. This would also replace table 2.
In methods you say you will analyse against a composite outcome [assisted
ventilation, ICU admission, death] and then in results you report a
different analysis. You need to be consistent.
Inclusion of ventilated patients also challenges your findings as one of
the outcomes was need for assisted ventilation. I would have excluded this
group.
Discussion
See comments above in Introduction.
Reviewer: 2
Comments to the Author
P5 line 20: glossary not clearly set out - suggest tabulate
No definition for PETCO2
A new abbreviation (AAG) for A-a gradient is really not
needed or helpful.
P6 line28: should be "when cardiovascular and metabolic parameters are
stable"
p6 line30: "the (a-ET) PCO2 (CO2 GAP)" what is this? Is this a typesetting
error?
p7 line27: correct bracket position
p8 line16-18: correct sentence construction
P9: Equipment - 2 devices to measure ABG's and 3 to measure ETCO2 leads to
concern that any findings are influenced by difference in device
measurement of CO2
p11 line29: change "and onto" to "or"
P12 line25: Age and gender are the only baseline demographics given. How
"sick" were the patients (in terms of vital signs, ABG's or APACHE etc)?
p17 line 13: given the aim of the study is to "predict need for assisted
ventilation" you cannot include 27 intubated patients - the analysis should
be repeated with those patients excluded.
Reviewer: 3
Comments to the Author
The authors present the perfomance of a relatively novel marker of the
function of the cardiorespiratory axis, the CO2 gap, as a predictor of the
need for assisted ventilation and mortality.
Based on the initial and subsequent validation datasets at a CO2 gap of
10.5% had 100% sensitivity with acceptable specificity.
This is a methodologically sound and intellectually stimulating paper. The
dataset could make a valuable contribution to the literature, which could
potentially translate into clinical practice.
My main concern is that, as presented, the paper leans towards increased
alveolar dead space secondary to reduced cardiac output as being the main
cause of increased CO2 gap. This will be the case for the trauma cohort in
the cited paper, but is less likely to be so for all of those in this
study.
As I am sure the authors are aware, in settings of reduced ventilation
with normal perfusion, less ventilated alveoli contribute proportionately
less and later in the expiratory phase to the expired gas flow - this being
the explanation for the capnography "ramping" seen in asthma and COPD
exacerbations. Inspiration begins before equilibration of these less
ventilated alveolar units - thus it will give rise to a CO2 gap.
In these settings A-a gradient is a less important variable, and clinical
decisions on assisted ventilation are often based on arterial pCO2 along
with clinical assessment. For me, in this subgroup (asthma, CAL and
possibly pulmonary oedema) the performance of CO2 gap vs PaCO2 to predict
assisted ventilation and mortality would be of particular interest.
Minor points:
I have had a moderate amount of statistical education but I do not
understand the power sentence in the methods at all. This needs to be fixed
up. Suggest get advice if you can not express this coherently.
What were the characteristics of the 275 potentially enrollable but not
included - were there any systematic differences that could have led to a
biased study?
I think the first paragraph of the discussion is the place to make your
point rather than build towards an argument - I'd restate the main results
with some expansion on potential application.
p10, line 32 "the overall mortality was 17" needs to be fixed.