Effect of Controlled Expiratory Pressures on Cerebrovascular Changes During Valsalva Maneuver
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsSummary
Jung, Lee and Kang investigated the haemodynamic response to the Valsalva manoeuvre. Two Valsalva manoeuvre intensities were selected – mouth pressures of 30- and 40-mm Hg. Heart rate, blood pressure, NIRS metrics and ultrasound derived measurements of arterial characteristics were measured at selected time points. Whilst the data is interesting, I have some concerns about the methods and interpretation of the data that limits the impact of this work. Please see my comments below.
General comments
Further clarification on how the Valsalva manoeuvre can improve vascular function is required. For example, on lines 59-63 this discussion could be expanded as it appears integral to underpinning the justification of the study. How can constriction and relaxation improve vascular function? Are you referring to the ability to respond to stimuli, such as shear stress? Again, on lines and 67-69 and 73-74 it is mentioned that the Valsalva manoeuvre can improve vascular function, yet no data is presented to support this statement. Furthermore, it is unclear if the authors are referring to a single Valsalva manoeuvre or multiple/repeated strains. Other authors have reported faint and an increase in PWV following the VM, so these statements require additional discussion.
Generally, the timing of the data collection is unclear. More detail is required throughout to indicate the exact timing, particularly following the release of the strain as phases III and IV are typified by dynamic perturbations in blood pressure. As such, phrases such as “post Valsalva manoeuvre” are potentially misleading. I have provided examples in the specific comments below. Furthermore, in the discussion of the paper the phases of the Valsalva manoeuvre are mentioned, and the data collected by the authors is extrapolated to represent a given phase of the manoeuvre. This is misleading as the post1 data likely encompasses both phase III and IV – especially in the supine position where the phase III haemodynamic response is mitigated and likely short lived compared to the standing position.
Averaging the post Valsalva manoeuvre data over 15s will obfuscate the dynamic blood pressure and cerebral blood flow responses during phase III and IV. Greater strain pressures would generate a more pronounced and sustained phase III and phase IV, meaning that the averaging the data over an arbitrary period of 15s makes interpretation of the current data difficult. I suggest using smaller “bins” to adequately represent this dynamic response and/or extracting data at the specified phases of the Valsalva manoeuvre that the authors identify in the introduction. Similarly, averaging the NIRS data during the VM strain produces the same problem, the haemodynamics within the strain change in a time and intensity dependent manner.
Section 3.2, lines 255 and 323– Blood flow is mentioned, yet blood velocity is reported. Please change to blood velocity. Furthermore “blood flow velocity” is mentioned elsewhere, this should also be blood velocity. Two further points 1) what is the significance of the peak systolic blood velocity and why is mean blood velocity not reported? and 2) if CCA blood velocity and diameter is measured, then absolute blood flow could be reported.
Continuing with CCA blood flow – the authors extrapolate CCA blood velocity as a metric for cerebral blood flow. This is problematic as the CCA bifurcates, with the external carotid artery supplying extracranial structures. Internal carotid artery blood flow would need to be measured to more accurately inform intracranial (cerebral) haemodynamic. The above is further complicated by the increase in intracranial pressure that accompanies the Valsalva manoeuvre. Intracranial pressure should be discussed in the context of the Valsalva manoeuvre and cerebral perfusion pressure.
The key regulators of cerebral blood flow are not discussed, including arterial carbon dioxide content and cerebral autoregulation. Please discuss as appropriate. For example – the discussion on lines 300-308 largely ignores the role of cerebral autoregulation (and potential cerebral sympathetic tone) that would be active during phase IV to counteract the rapid restoration of cerebral perfusion pressure.
The pre- values for the experimental trials appear to have occurred after the participants has already performed several practice Valsalva manoeuvres and thus the compounding effect of multiple Valsalva manoeuvres cannot be ignored. It is also unclear how many practice Valsalva manoeuvres were completed.
Specific comments
Intrathoracic pressure was not measured, I suggest changing to controlled mouth pressure.
Lines 18-19 Please clarify where “regional oxygen saturation” is – what organ specifically?
Abstract – Some clarification is needed to identify 1) when the reported values were measured (e.g. before, during, or following the Valsalva manoeuvre). This is done on lines 25-26, but the specific timeframe is required e.g. X minutes following and 2) when statistically significant differences are noted, does this indicate different to baseline or between mouth pressures?
Line 64-66 My understanding would be that in this acute setting, the increase in arterial pressure would drive the increase in cerebral blood velocity, not the other way around. Please consider rewording this section.
What is the resistance index and how was it calculated? Was this the resistance in the CCA?
Table 1 – are these values mean and standard deviations? Please clarify.
Link 124 – Some clarification required here to explain the closure of the glottis at strain onset. Is this a typo? Are participants asked to close their Glottis at strain onset and then rapidly open to increase mouth pressure?
Line 158 – vascular measures were taken before and after the Valsalva manoeuvre – Please provide more detail. For example, how long after the Valsalva were these measures taken.
Line 149 Has the use of blood pressure data from the specific smartwatch been validated against a gold-standard?
Section 2.4 line 168 – Why have VCD and VDD been used instead of diastolic diameter and systolic diameter? The reference cited (16) has used the latter terms.
Traditional measurement of PWV requires ECG gating – has the method used herein been validated against a two-point method gated to an ECG?
Figure 3 is confusing as the Valsalva manoeuvre appears to span the inhalation period. Please clarify.
Line 267-268 – phase III is typified by an acute reduction in cerebral blood velocity, are the authors referring to the rapid increase in phase IV? Please correct.
Line 280-281 – Can the authors please clarify what is meant by “excessive baroreflex activation”.
Line 291-291 – The results appear to be overstated. The P value for the reduction in CCA stiffness is 0.056 – suggesting that the study is underpowered rather than supporting a definitive statement like that made here.
Line 303 – 304 – the results are again overstated. The NIRS derived metrics (including tissue oxygenation) within the brain are dependent on strain intensity, body position and Valsalva manoeuvre phase. I suggest rewording.
Comments on the Quality of English LanguageSome minor clarification required in places.
Author Response
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Author Response File: 
Author Response.docx
Reviewer 2 Report
Comments and Suggestions for AuthorsDear Editor and Authors,
It was my pleasure to review this work titled "Effect of controlled intrathoracic pressures on cerebrovascular changes during Valsalva maneuver" from Gachon University in Incheon, Republic of Korea.
This is a very interesting and well set up methodologically prospective, randomised experimental study! The authors have performed a sample size calculation prior to study commencement, have utilized appropriate selection criteria and procedures and have obtained all required permisions.
Overall this is a good manuscript which can be improved further. Specifically:
1. The introduction is a bit too long and does not set-up the basic premise of the study well!! The aims/hypothesis need to be better explained - listed.
2. No statistical analysis or comparisons are made between the variables meassured and listed in table 1. Please do.
3. Table 4 needs to be fixed/formated better. This is probably due to a change in processing software!!
4. The manuscript's language is good, only needs minor editing.
5. The discussion is good, concise and to the point.
Thank you, kind regards.
Comments on the Quality of English LanguageMinor language editing is needed.
Author Response
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Author Response File: Author Response.docx
Reviewer 3 Report
Comments and Suggestions for AuthorsInteresting idea of ​​the study with the title: Effect of controlled intrathoracic pressures on cerebrovascular changes during Valsalva maneuver, my recommendations are the following:
Abstract - mentioning the average age and standard deviation of the subjects included in the study. I recommend rewriting the conclusions in accordance with the age of the subjects, according to the demographic data, they are healthy young people.
In Table 2, I recommend that T be added to the descriptive mention. I also recommend that column 3 be called Testing and not Variables, so as not to create confusion. Ditto table 3.
I recommend that the practical implications of this study be mentioned at the end of the Discussion section. I recommend expanding the aspects regarding future research directions, from the end of the Limitations section. I recommend renaming the Limitation section taking into account future research directions.
Author Response
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Reviewer 4 Report
Comments and Suggestions for AuthorsI have received for review an article entitled ,,Effect of controlled intrathoracic pressures on cerebrovascular changes during Valsalva maneuver” which is being processed by the journal Applied Sciences.
The proposed manuscript is one with therapeutic and prognostic impact, but I encourage authors to address the following issues to improve its quality:
Abstract - briefly presents the main aims of the study and the results obtained. Being clearly and concisely written, it increases the interest of the readers - I suggest including a final sentence in the form of a conclusion
Introduction - presents the problems of the theme, makes a detailed review and motivates the chosen research topic. Mentions the purpose of the study in the context of the topic.
Materials and method
- Table 1 should be included in the results section
- quantification of anthropometric parameters should be detailed in the section
- how the vital parameters were assessed should be explained
- ethical issues should be mentioned in a separate section
Results
- presents the main aspects highlighted systematized
Discussion
- presents a comparative analysis of the data obtained with similar data from the literature, but needs to be extended
Conclusions – in accordance with the results, emphasizes the main aspects.
In conclusion, the proposed manuscript brings to attention an extremely interesting topic, presenting scientific information with therapeutic and prognostic value, but needs revision in order to be considered for publication.
Author Response
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Author Response File: Author Response.docx
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsGeneral comments
The measurement of CCA remains an issue. During the Valsalva manoeuvre the increased intracranial pressure and subsequent rise in downstream resistance could potentially shunt blood to the external carotid artery. The authors also allude to this issue elsewhere in their responses by indicating a minimal increase in MCAv during phase I of the Valsalva manoeuvre, evidence of the potential confounding influence of elevations in intracranial pressure. This is a major shortcoming of the study.
“As the reviewer pointed out, Post1 includes both phases III and IV of the VM. To clarify, PWV was measured during phase III (within 5 seconds after the VM stopped), while PSV and RI were measured in the period spanning phases III and IV.” This is still problematic as the authors have captured data across several phases of the manoeuvre where haemodynamics are rapidly changing. As the authors mention, it is possible for blood pressure to stabilise AFTER 15s, yet the measures of PWV are being measured before the stabilisation of blood pressure occurred. More importantly, the authors imply that the 30 mm Hg Valsalva manoeuvre can reduce vascular stiffness. However, PWV has been measured during a rapid reduction in blood pressure. Thus, it is unclear how the results of the current study apply to resting conditions or when a participant is haemodynamically stable. The timing of the measurement of PWV in the current study is not appropriate to inform such a broad statement. Furthermore, the cohort is also young and healthy, and those with “abnormal” vital signs excluded. Thus, statements such as (line 353-355) “The VM can be widely applied to prevent and improve arterial stiffness, as it can be performed by anyone with proper training, without limitations of time, space, or cost” are inappropriate, and conflicts with the statement made on line 370-372.
The authors should also discuss the following paper and why the current results may differ.
K. S. Heffernan, S. Y. Jae, D. G. Edwards, E. E. Kelly and B. Fernhall. Arterial stiffness following repeated Valsalva maneuvers and resistance exercise in young men Applied Physiology, Nutrition, and Metabolism 2007 Vol. 32 Issue 2 Pages 257-264
Regarding the use of bins – I understand the aim of the current study was to assess the vascular responses pre and post. However, given the “post1” period encompasses Phase III and Phase IV, the Valsalva manoeuvre phases cannot be ignored. It is unclear what this POST1 time point actually represent physiologically. Furthermore, in the discussion said Valsalva manoeuvre phases are discussed at length, although the data does not directly align with these phases. The current data is therefore difficult to interpret.
Specific comments
Abstract line 21-22 – what POST time point is this? POST 1 and POST 2 are defined earlier and then only post is mentioned here. Please clarify. Furthermore, in table 2 only POST is mentioned. Please be consistent with the use of POST as defined on lines 213 and 214.
Line 31-32 and line 350– can the authors please clarify what a “stable effect” is.
Line 52-53 – Please be directional. Can both constriction and dilation improve elasticity?
Lines 54-57 – This is a broad overarching statement that does not account for the phases of the Valsalva manoeuvre. Cerebral blood velocity and blood pressure change dynamically during the Valsalva manoeuvre with phase dependent perturbations. Please rectify. Furthermore, yes, vascular tone will change throughout the Valsalva manoeuvre to counter the reduction in blood pressure during phase IIa.
Lines 72-73 – the cerebrovascular response to graded Valsalva manoeuvres is known. Please cite the appropriate research (see below). Furthermore, the authors are assuming that the Valsalva manoeuvre improves cerebrovascular function, however, there are no cerebrovascular function metrics reported in the current study, the cerebrovascular response to the Valsalva manoeuvre is reported.
B. G. Perry, J. D. Cotter, G. Mejuto, T. Mündel and S. J. Lucas Cerebral hemodynamics during graded Valsalva maneuvers Frontiers in physiology 2014 Vol. 5 Pages 1-7
Line 98 – please clarify what abnormal vital signs are by stating the exclusion criteria.
Line 137-138 – Participants inhaled with a closed glottis – this would be a Muller manoeuvre. The glottis would be open during inhalation.
Tabel 2 – please clarify why standard error is reported in some instances and standard deviation in others.
Lines 296-298 - please clarify this statement regarding vessel radius and blood pressure, it appears to be the opposite of the vascular arm of the baroreflex whereby an increase in blood pressure would result in a systemic reduction in sympathetic tone and reduced systemic vascular resistance. A reduction in blood pressure would produce systemic vasoconstriction, and the Phase IV response is underpinned by the vasoconstriction of phase IIb and Phase III persisting, and when cardiac output is restored, the blood is ejected into a constricted arterial tree, resulting in a rapid increase in blood pressure. Furthermore, the differentiation between systemic and (potential) cerebral sympathetic responses must be made. This is highlighted in lines 340-341 as sympathetic regulation of the cerebral circulation is controversial and may be active to limit hyperperfusion during high CPPs, and appears to be active during phase IV to reduce cerebral blood flow (see Zhang paper below). Are the authors referring to systemic sympathetic nervous system activation from previous phases here driving the increase in blood pressure?
R. Zhang, C. G. Crandall and B. D. Levine Cerebral Hemodynamics During the Valsalva Maneuver Insights From Ganglionic Blockade Stroke 2004 Vol. 35 Issue 4 Pages 843-847
Lines 338-340 Further to the above – “Subsequently, from Phase IIb onwards, sympathetic activation results in increased cerebral blood velocity, and this increase persists up to Phase IV”. This is not correct as cerebral blood velocity declines during phase III, particularly when standing. Please clarify.
Comments on the Quality of English Language
Some minor corrections required.
Author Response
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Author Response File: Author Response.docx
Reviewer 4 Report
Comments and Suggestions for AuthorsThe proposed manuscript has been improved and can be considered for publication. The authors have responded to the requirements.
Author Response
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Author Response File: Author Response.docx
