PONE-D-20-29529

Use of non-invasive intracranial pressure pulse waveform to monitor patients with End-Stage Renal Disease (ESRD)

PLOS ONE

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•    CR declares no competing interests/ has nothing to disclose.

•    LDC declares no competing interests/ has nothing to disclose.

•    FAS declares no competing interests/ has nothing to disclose.

•    GHF declares personal fees as employee (Research Coordinator) from Braincare Desenvolvimento e Inovação Tecnológica S.A., during the conduct of the study; In addition, GHF has a patent US9826934B2 issued, and a patent US9993170B1 issued.

•    NNR declares personal fees as medical consultant from Braincare Desenvolvimento e Inovação Tecnológica S.A., during the conduct of the study

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•    SM declares he has a patent US9826934B2 issued, and a patent US9993170B1 issued.

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Additional Editor Comments:

This is an interesting paper highlighting a novel technique for monitoring intracranial pressure in dialysis. Overall I thought it was well done and whilst there was some divergence of opinion in the reviewers, I thought it would merit revision and look forward to have a looking at another version.

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: No

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: No

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: In the manuscript, authors present data from a study assessing the “Use of non-invasive intracranial pressure pulse waveform to monitor patients with End-Stage Renal Disease”. The study is in general of interest and provides some new insights, especially concerning the application of a non-invasive device for ICP measurement. Nevertheless, there are some open questions and thus will not provide full impact for the readership:

Minor issues:

• The data are nicely presented and, I guess, “behave” as expected. Seen differences are like data known for "normal" blood pressure. So, it may reflect just the same phenomenon (removal of fluid) as well? Blood pressure is increasing from end of dialysis session till next start (thus higher at beginning of week). This is all nicely described in the discussion as well. Do you have data on ultrafiltration volume and intradialytic weight gain? These data would be of interest to be included in your analyses. Rate of change from pre- to post-dialytic session could be directly related to UFV and IDWG. Do you have blood pressure data as well? Would be interesting to see the “same” behaviour in these data as well. Please comment.

• Methods for normality testing: Have you checked normality using QQ-plots (or other means to visualize data) or used any formal tests? Just reporting checking of skewness and kurtosis is in my opinion not common in the medical domain (although might be correct).

• Table 1: Are you sure all data are normally distributed? E.g. Are you sure mean HD session length is normally distributed, if 52.4% of the sessions are longer than 240 minutes and the mean is 220 mins? What about the mean HD time? If looking at the SD, I assume they are not normally distributed, thus use of mean and SD are not correct.

• Figure 2 and Figure 3: Are you sure the captions are correct? In Figure 2, I cannot see any comparison of sessions. In Figure 3, I cannot see any data “over the six months of FU”. Furthermore, in Figure 3 it says, “ANOVA is used for comparing data over six months” Please comment.

• Figure 3B, is it correct that for post-dialysis, there are no significant differences? Especially between session 1 and session 2, the difference seems to be “large”.

• In the discussion, you mention that TTP and P2/P1 ratio were higher in the first session compared to the second and third. You argue that it “may happen as a function of the time gap between the last and the first session of the week.” I guess it is not the time, but the fluid overload, thus IDWG.

Reviewer #2: In this study the authors non-invasively recorded intracranial pressure in patients with end-stage renal disease (ESRD) receiving hemodialysis by using the Brain4care device. The authors concluded that intracranial pressure parameters (time to peak and P1/P2) were higher before dialysis compared to after dialysis and that these differences were significantly elevated in the first session relative to the subsequent dialysis sessions. The authors indicated that the rationale for doing this study is based on the fact that some ESRD patients on dialysis may progress into dialysis disequilibrium syndrome suffering of cerebral edema and high intracranial pressure. Although this phenomenon is rare in clinical practice, the authors suggest that the presence of cramps, headaches, fatigue and inability to concentrate after dialysis may be mild manifestations of the dialysis disequilibrium syndrome.

This reviewer has several concerns and comments with this investigation:

1) Although the concept of this work is interesting, I am concerned with the validation of the non-invasive device (Brain4care®) used for measuring intracranial pressure in humans. The authors report that this device measures volumetric changes of the skull in adults by simply applying the sensor through a plastic band around the head and apparently, there is no need for calibration. This appears to be a very simple device in its utilization, but its validation is a concern, particularly when most studies of validation were performed in animal models. Moreover, it seems that the two studies that have addressed validation have been performed by the same group and it appears that there has not been any further independent validation. In addition, data on the device reliability and accuracy in humans is not provided and in consequence, extrapolating a relationship between this device and any gold standard from animals into humans without a complete assessment of reliability may be an important source of study bias.

2) The description of the methodology is succinct and there is no information on the technical details of the measurements. Also, it is not clear what the 4881 data-points from the 42 subjects represent. From this number, I speculate that 116 data points were obtained per subject along the 6-month period at a rate of 3 times sessions per week. Then, we should expect that only 1.61 data-points per patient and session were accomplished. Is the rate of these data points per patient and session sufficient and reliable to provide confidence in these measurements? Unfortunately, without any clear assessment of the reproducibility of the technique any interpretation becomes speculative.

3) It is not clear to this reviewer what would be the contribution of extracranial sources to these measurements and whether this could be a source of artifacts to the readings.

4) Few investigations have used transcranial Doppler from the middle cerebral artery to determine the effects of dialysis on the cerebral circulation. These studies have reported that mean flow velocities remain high before dialysis, decline significantly during dialysis, and stay lower in the post-dialysis period. What is interesting from these studies is that the reduction in flow velocity negatively correlates with the ultrafiltrate volumes, amount of fluid removed and the loss of weight after hemodialysis. Moreover, the post-dialysis reduction in mean flow velocity after 12 months of continued dialysis correlated significantly with the patients’ lower global and executive functions and with progression of their white matter hyperintensities with MRI. It seems then, that these studies are opposite the conclusions achieved by the current study which indicates that intracranial pressure remains high before dialysis. In my opinion, these hemodynamic changes of cerebral blood flow before, during and after dialysis should be discussed in the context of the authors’ findings. [See Stroke 1994;25:408-412; J Am Soc Nephrol 2019;30:147-158.

5) Figure 2 shows the statistical significance of 18 paired comparisons between pre-dialysis and post-dialysis through the use of individual paired student t-tests. In my opinion, these multiple comparisons require an adjustment in the alpha value due to the number of comparisons. Statistical advice is suggested. In addition, Figure 3 displays the comparisons of all measurements through the 6-month period and the authors conclude that session 1 was significantly higher than 2 and 3. Unfortunately, with the large standard deviations and without information on the variability of the measurements, it is difficult to believe that there was a significant difference.

6) An important parameter that would help to understand these changes is systemic blood pressure. However, there was no attempt to document this information. Data on blood pressure may be particularly important as they reported that 64% of the patients were classified with systemic arterial hypertension.

7) In my opinion, most of these hemodynamic changes occur during the dialysis session. If such device is demonstrated to be a valid surrogate of the intracranial pressure, intra-dialytic recordings would be more interesting in order to determine the impact of dialysis on the brain dynamics.

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Reviewer #1: No

Reviewer #2: No

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Use of non-invasive intracranial pressure pulse waveform to monitor patients with End-Stage Renal Disease (ESRD)

PONE-D-20-29529R1

Dear Dr. Vellosa,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Patrick Barry Mark

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thank you for revising this interesting study

Reviewers' comments: