Blood Volume Deficit in POTS Assessed by Semi-Automated Carbon Monoxide Rebreathing, 2024, Kulapatana et al

Now published - link here

Preprint
Blood Volume Deficit in Postural Orthostatic Tachycardia Syndrome Assessed by Semi-Automated Carbon Monoxide Rebreathing

Kulapatana, Urechie, Rigo, Mohr, Vance, Okamoto, Gambao, Shibao, Biaggioni, Furlan, Diedrich

Abstract

Purpose: Semi-automated carbon monoxide (CO) rebreathing method has been introduced as a non-invasive and radioactive-free blood volume estimation method. We tested whether the semi-automated CO rebreathing method can detect the blood volume deficit in postural orthostatic tachycardia syndrome (POTS). In addition, we explored the relationship between blood volume estimated from the CO rebreathing and body impedance.

Methods: We recruited 53 subjects (21 POTS females, 19 healthy females, 13 healthy males) to record blood volumes and hemodynamic data. Blood volumes were measured by the CO rebreathing and the segmental body impedance. Linear regression models to predict normal volume of red blood cell volume(RBCV), plasma volume (PV), and blood volume (BV) were developed. Percentage deviations from the predicted normal volumes were calculated.

Results: POTS had lower RBCV (25.18±3.95 vs. 28.57±3.68 mL/kg, p=0.010, POTS vs. healthy females), BV (64.53±10.02 vs. 76.78±10.00, p<0.001), and BV deviation (-13.92±10.38% vs. -0.02±10.18%,p<0.001). POTS had higher supine heart rate (HR) (84±14 vs. 69±11 bpm, p<0.001) and upright HR (123±23 vs.89±22 bpm, p<0.001). We found a correlation between BV deviation and upright HR in POTS (r=-0.608, p=0.003), but not in healthy [controls]. Volumes from the CO rebreathing and body impedance were well correlated (r=0.629, p<0.001).

Conclusion: The CO rebreathing method can detect BV decit, as well as the RBCV deficit in POTS. The negative correlation between BV deviation and upright HR indicates that hypovolemia is one of POTS’ pathophysiological causes. Correlations between body impedance and CO rebreathing volume suggest the usefulness for measurements of volume changes.

https://assets-eu.researchsquare.co...xQvYFzb8qhCLREAgKQ_aem_rLreawDPMoRc2-4eKBGXGw

Edited to add missing word (their typo) in square brackets.

 

Haven’t read the paper but is it not slightly problematic to have a very different proportion of sexes in control vs test group?

 

The device used in the study:
https://detalo-health.com/

Carbon monoxide rebreathing is not a brand new testing method, has been used at NASA for instance, but I believe the "off the shelf" version being sold by this company is the first of its type.

Research version, as used in above study, is available to anyone worldwide. Medical version has been approved for use in Europe.

Cheaper to buy and run, and safer, than radioactive tracer method. Only requires phlebotomist, technician, cylinder of carbon monoxide, and blood gas analysis (standard test already done in hospital labs).

Can be used to help with various conditions, such as kidney and heart failure and polycythemia vera.

 

The researchers also used a technique called segmental body impedance, which I don't know much about. Would be interested to hear people's comments on it.

 

It is touched on in the paper at several points – I am not scientifically literate enough to comment on what is said about it.

They compare "female subjects to female controls" as well as "all subjects to all controls".

Perhaps they did the best they could with the available patient population.

 

This is a recent preprint — 2021 in the thread title should be 2024.

 

It's probably on purpose, given they had almost enough healthy females to match the POTS group.

 

I don't think that's a problem here. If the paper compares female POTS patients to female healthy controls (which they appear to be doing) then that is a sufficiently good control already. The male controls can then be viewed as an additional variable to gain further understanding (and it seems that here male controls and female controls do differ quite a bit showing how bad the POTS literature in general is where controls tend to not exist sufficiently). That is of course if everything is well thoughtout and the statistics are done well (it seems they mainly did a regression analysis here). If I remember the discussion by @ME/CFS Skeptic well enough the POTS literature generally has massive problems with matching controls. Things here appear to be somewhat decently matched at first look between HC females and POTS females, but there is also quite a small descepancy in weight and I cannot tell whether that would have influenced any results. Other than that the descriptions appear to be rather vague.

What is once again quite prominent here at a first look is that once again many healthy controls would seem to meet the POTS diagnostic criteria of a 30BPM heart rate increase with the average increase in healthy females being 20BPM and the variance being rather large (it seems that the authors didn't clarify how exactly these measurements were taken).

If anything the baseline heart rate in POTS patients here seems to be an as good discriminator between HC and POTS as an increase in heart rate upon standing. Perhaps one would have to perform an additional analysis whether that is a general feature in humans (i.e. higher heart rate causes a statistically higher difference in standing heart rate) rather than this being a feature of POTS specifically. Is this accounted for in the regression analysis? Which of the results have anything to do with POTS or can they be explained by a generally higher heart rate?

If an increase in change of heart rate is not a defining feature of POTS, which is what most studies seem to suggest (at least in ME/CFS), I don't know how far one will get in understanding POTS by analysis different things by comparing them to an increase in heart rate...

 

I don't think there is any good data on the male/female make-up of POTS patients, but this survey (which obviously suffers from being a survey, and being in English only), found the following:

Total valid survey participants = 4835
Female = 4539 (94%)
Male = 296 (6%)

Edited: Forgot to put details of survey.

The face of postural tachycardia syndrome – insights from a large cross‐sectional online community‐based survey
https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30861229/

(Also from Vanderbilt, with some of the same researchers involved)

 

Complete guess on my part: The researchers included male controls even though there weren't any male subjects because they were interested in seeing the differences in the CO rebreathing and impedance data between the male and female controls and comparing the formulae for estimating blood volume (which they talk about a bit in the article).

I imagine they are all excited about the CO rebreathing technology and want to try it out on as many people as possible. I would be!

My daughter and I have been watching Detalo Health with great interest and waiting with bated breath for studies using its CO rebreathing device to come out in the OI, ME/CFS, FM area.

 

This is why the 30BPM increase is only one part of the diagnostic criteria. The patient also has to be symptomatic: chronic OI symptoms of more than 3 or more than 6 months (varies between guidelines/authors).

The selection criteria for Vanderbilt POTS studies are here (only in basic form):
https://www.vumc.org/autonomic-dysfunction-center/postural-orthostatic-tachycardia-syndrome-research

Autonomic specialists and researchers do not like the 30BPM criterion, and are vocal critics of it. However, they have been stuck with it (perhaps their own fault) because "ya gotta measure something".

In future, if all goes well, the 30BPM criterion will probably be replaced (when possible) by a certain measured drop in cerebral blood flow during orthostatic testing. Dr Novak and colleagues did some research on this recently, discussed in this thread:
https://www.s4me.info/threads/cereb...ith-orthostatic-intolerance-2024-novak.39321/

 

Apologies. Have fixed this. Thank you for pointing it out.

 

Article about CO rebreathing:

Validation of a clinically applicable device for fast and accurate quantification of blood volume
https://pmc.ncbi.nlm.nih.gov/articles/PMC10388222/

Note that one of the authors, Carsten Lundby, is from Detalo Health, the manufacturer of the device (this is declared in the article).

 

The problem is however, that the guidelines are not particularly specific, everybody is brewing their own cuppa and that previous research has appeared to be rather arbitrary and not particularly well matched and that the studies often lack data to asses them. In the analysis here the comparison is directly towards uprate heart rate, if that is not supposed to be a meaningful measure, then why compare BV deviation to it in the first place?

I'm not sure whether they are stuck with it because "ya gotta measure something", I think they have found something that they believe can be meaningful in someway, patients like being showed an "abnormality" and so do MDs so they hang on to it, after all it let's them publish results even if research hasn't progressed at all. Arguably having the 30BPM replaced by something that currently suffers from even more problems (studies of only small sample sizes, problems with matching, HC's also having a decrease in cerebral blood flow without orthostatic symptoms) probably doesn't make sense either. I suspect there might be a reason why there has been a lack of interest in the results that van Campen et al have obtained.

I suspect someone will really have to invent what a wheel even is in this field before any progress will be made...

 

@EndME , the first (?) article describing POTS in what you might call the modern era was focused on idiopathic hypovolemia rather than orthostatic tachycardia as the hallmark of the condition (although the authors certainly also took note of the tachycardia).

Idiopathic hypovolemia

https://pubmed.ncbi.nlm.nih.gov/3511818/

(I think you can get the full article via Sci Hub. Several articles by POTS experts have described this article as being about POTS, although the name did not exist yet when it was written.)

If history had taken a different turn in terms of the availability of blood volume measurement, or these authors had gone so far as to name their discovery, it may never have been called POTS.

 

Hmm, I thought that the recent articles that I have read found that healthy controls had a decrease in cerebral blood flow of less than 10%, and the subjects with OI had a decrease of more than that. I don't remember reading about healthy controls having equivalent decreases, but perhaps I edited that out with confirmation bias. I will have to do some re-reading.

I dare say this has all been discussed very thoroughly in other threads by people who know a lot more about it than me.

To be honest, my main interest in this article is the re-emergence of blood volume measurement as an accessible research tool, not only for POTS or ME/CFS but for many other medical conditions. I have been cheering on the Detalo Health chaps for several years (had a nice email exchange with them a while ago).

I am also interested in the impedance measurements, as that is new to me.

 

Different angle of dicussion:

We know that blood volume decreases when activity levels decrease.

How could researchers distinguish between hypovolemia related to loss of ability to exercise and hypovolemia caused by (or associated with) the disease processes of POTS or ME/CFS?

Would using sedentary controls help? What about controls with different illnesses that cause inactivity but haven't been associated with hypovolemia?

 

This 2024 study looked at three methods of CO rebreathing and found discrepancies:

Duplicate measures of hemoglobin mass within an hour: feasibility, reliability, and comparison of three devices in supine position
https://pubmed.ncbi.nlm.nih.gov/38265850/

(I believe the "semi-automated electromechanical device" that is referred to in the abstract is the Detalo Health device, but the article is behind a paywall so I am unable to verify this.)

The authors looked at haemoglobin mass, one measurement parameter, and found a difference between the semi-automated device and the two other methods of approximately 13%.

"Hemoglobin mass is comparable between the glass-spirometer and the three-way plastic valve, but higher for the semi-automated device. The differences are amplified if the device-specific recommendations of CO-loss corrections are followed."

Measuring blood volume seems to be rather difficult. Would it be easier to measure a change in blood volume, rather than trying to measure blood volume itself? Would that be useful information?

 

It's been discussed for more than 20 years, though I can't always vouch for the bit about knowledge.

The most plausible conclusion I've seen is that ME/CFS is what's behind OI, not a separate condition like hypovolemia.
That it's a common symptom of the syndrome, and it tends to improve with the other symptoms when people with fluctuating ME/CFS are a bit better, and get worse when they're on a downhill slope. It's also worse in PEM, so it varies over very short periods as well as fluctuations that may take place over months or years.

If you look at it from that point of view, it doesn't really need explaining. It's a downstream effect of whatever process is causing all the other delightful shenanigans we have to put up with.