Total blood volume and red blood cell volume are not associated with orthostatic intolerance in adults with [ME/CFS], 2026, Yamazaki+

[SNT Gatchaman]

Total blood volume and red blood cell volume are not associated with orthostatic intolerance in adults with myalgic encephalomyelitis/chronic fatigue syndrome

Spoiler: Authors

Tadahiro Yamazaki; Donna M Mancini; Michelle Blate; Patrick Quan; Anna Norweg; Dane B Cook; Benjamin H Natelson

Orthostatic intolerance is common in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and may worsen daily functioning. Although hypovolemia has been proposed as a contributor, its relationship to objective orthostatic abnormalities remains uncertain. We examined whether measured blood-volume abnormalities were associated with standardized lean-test outcomes.

Adults meeting the 1994 ME/CFS criteria and reporting substantial post-exertional malaise underwent a 10-min lean test with capnography, followed 8 days later by total blood volume (TBV) measurement using the Daxor BVA-100. Supine hypocapnia was defined as baseline end-tidal CO2 (eTCO2) <34 mmHg; postural orthostatic syndrome of hypocapnia (POSH) as normal supine eTCO2 with any leaning value <34 mmHg; and postural orthostatic tachycardia syndrome (POTS) as a heart-rate increase ≥30 beats/min or absolute heart rate ≥120 beats/min.

Among 49 participants, TBV was hypovolemic in 35%, normovolemic in 43%, and hypervolemic in 22%; red blood cell volume was deficient in 49%. Overall, 55.1% had at least one lean-test abnormality, most commonly POSH (40.8%). Abnormalities did not differ by TBV or red blood cell volume category.

Static blood-volume categories were not associated with lean-test-defined orthostatic abnormalities in ME/CFS, suggesting contributions from autonomic, vascular, respiratory, or cerebrovascular mechanisms.

Web | DOI | PDF | Physiological Reports | Open Access

 

[Utsikt]

Edit: I missed that they did not look at symptoms, so we don’t actually know if the various measurements would have been correlated with actual OI, i.e. feeling unwell when upright. This was a missed opportunity, and not the nail in the coffin that I first believed it was.

Spoiler: My initial comment

It’s about time someone looked at this properly. Due to being a single center and subgrouping an already small sample size there might be some nuances that were missed, but the clear lack of correlation between any of the measurements probably means that it’s not worth pursuing this particular angle further if the aim is to figure out the main contributor(s) to OI.

 

[ChronicallyOverIt]

Holy shit, someone actually TRIED instead of repeating rhetoric.

How does this model with the salt helping “blood volumes lol my gut reaction is it’s point against this as well

 

[Utsikt]

How does this model with the salt helping “blood volumes lol my gut reaction is it’s point against this as well

The purpose is the increase blood volume, so this is a strong argument against salt or IV. Not that it had much legs to stand on anyways, the effect of IVs are far too short lived and the body is pretty persistent when it comes to keeping blood volume at the target level (even if the target level is «low»).

 

[DHagen]

Forty-nine participants with ME/CFS (40 women and
9 men) completed both the lean test and blood volume
analysis. The median age was 36 years [29–46]. Seventeen
participants (35%) were classified as hypovolemic, 21
(43%) as normovolemic, and 11 (22%) as hypervolemic.
Age and sex did not differ significantly across the three
TBV groups (Table 1). Twenty-four participants (49%) had
an RBCV deficit, 20 (41%) had normal RBCV, and 5 (10%)
had RBCV excess. Age and sex did not differ significantly
across the three RBCV groups (Table 2). The RBCV defi-
cits indicated reduced circulating red cell mass by BVA
and were compatible with occult anemia if routine hemo-
globin and hematocrit values were normal.

Am I wrong in thinking that 35% with hypovolemia and 49% with an RBCV deficit seem notable numbers (regardless of whether there are other noteworthy aspects of this study)? Obviously they don't constitute majorities and don't correspond specifically to anything being measured with the NASA lean test, but, at the same time, this doesn't sound like what one would expect from a healthy cohort, no?

 

[Felis Catus]

I haven't read the paper, just the abstract here. Given that
1) the correlation between orthostatic intolerance and HR seems weak (based on research so far)
2) the NASA lean test captures only HR and BP
3) they say "Static blood-volume categories were not associated with lean-test-defined orthostatic abnormalities in ME/CFS"

I'm not sure what this actually tells us about orthostatic intolerance.


*edits to make it less confusing

 

[DHagen]

I haven't read the paper, just the abstract here. Given that
1) the correlation between orthostatic intolerance and HR seems weak (based on research so far)
2) the NASA lean test captures only HR and BP
3) they say "Static blood-volume categories were not associated with lean-test-defined orthostatic abnormalities in ME/CFS"

I'm not sure what this actually tells us about orthostatic intolerance.


*edits to make it less confusing

This stood out to me, too, and a quick read-through of the paper doesn't really suggest anything further. In discussing what could be responsible for OI symptoms, they list, among others, "Impaired venous constriction and increased venous capacitance... Autonomic dysregulation, with reduced vagal modulation and altered heart rate variability... Upright posture [that] can substantially reduce cerebral blood flow even when heart rate and blood pressure remain within conventional limits...Neurohumoral and neural abnormalities, including arenin–aldosterone mismatch and small-fiber neuropathy..." etc., so, pretty much all of the usual ideas, significantly including blood not getting where it needs to be, which leaves the door open for blood volume being a factor somewhere in there. I am sure others will have more insight and be better equipped to evaluate the methods and findings than I.

 

[Formerhuman]

Definitions of orthostatic outcomes​

Supine hypocapnia was diagnosed when any baseline eTCO2 measurement was <34 mmHg. POSH was defined as all supine eTCO2 values ≥34 mmHg with at least one leaning eTCO2 value <34 mmHg. POTS was defined as a ≥30 beats/min increase in heart rate or an absolute heart rate ≥120 beats/min at any time during leaning. “Any lean-test abnormality” denoted the presence of at least one of these three findings (supine hypocapnia, POSH, or POTS); “no lean-test abnormality” indicated that none occurred.

DISCUSSION​

In this single-center cohort of adults with ME/CFS, quantitatively measured TBV category was not associated with orthostatic outcomes on a standardized 10-min lean test, including supine hypocapnia, POSH, or POTS. More than half of participants exhibited at least one orthostatic abnormality, yet the distribution of these abnormalities was similar across hypovolemic, normovolemic, and hypervolemic groups. These findings suggest that static blood volume deficits alone are unlikely to be the principal determinant of OI in ME/CFS.

The authors do not report assessing presence of OI and its severity in patients. Besides, it is known that neither a ≥30-bpm HR increase nor hypocapnia is necessary to experience OI.

The conclusion "These findings suggest that static blood volume deficits alone are unlikely to be the principal determinant of OI in ME/CFS" is not applicable to this data and the title of the paper is misleading.

 

[Turtle]

Natelson still using Fukuda, A Nasa-lean-test only finding POTS and dOH not the mixed group with normal BP.
What's wrong with this researcher, trying to find "something ", but nothing helpful, just muddying the waters, like the CPET paper.

 

[InitialConditions]

Why would they measure blood volume 8 days later?

 

[obeat]

It would be interesting to know if blood volume actually fluctuates over time. Why do people have high blood volumes? Is there just a wider range than previously realized?

If you have chronic hypovolemia with normal kidney function and normal blood pressure does that suggest that the system is fully compensated( unlike acute hypovolemia).

They could now do blood t volume measurements, before and after Iv saline. I think what I'm trying to say is if low blood volume is not causing OI , does it need to be treated?

 

[Evergreen]

Am I wrong in thinking that 35% with hypovolemia and 49% with an RBCV deficit seem notable numbers (regardless of whether there are other noteworthy aspects of this study)? Obviously they don't constitute majorities and don't correspond specifically to anything being measured with the NASA lean test, but, at the same time, this doesn't sound like what one would expect from a healthy cohort, no?

It's a shame they didn't have a healthy control group.

 

[Utsikt]

I haven't read the paper, just the abstract here. Given that
1) the correlation between orthostatic intolerance and HR seems weak (based on research so far)
2) the NASA lean test captures only HR and BP
3) they say "Static blood-volume categories were not associated with lean-test-defined orthostatic abnormalities in ME/CFS"

I'm not sure what this actually tells us about orthostatic intolerance.

*edits to make it less confusing

They measured more than just the HR during the NASA lean test.

2.3 Ten-minute lean test​

A standardized 10-min lean test, originally developed by NASA to detect spaceflight-related orthostatic intolerance, was administered to all participants (Bungo et al., 1985). After a minimum 10-min supine rest, baseline physiological parameters—blood pressure, heart rate, respiratory rate, and end-tidal CO2 (eTCO2), measured with a portable capnograph/pulse oximeter (Nellcor N-85 Microstream, Covidien LLC, Mansfield, MA, USA)—were recorded in triplicate at 1-min intervals. Participants then stood with their feet together approximately 6–8 inches from a wall and leaned against the wall without moving for 10 min, during which the same parameters were measured at 1-min intervals.

2.5 Definitions of orthostatic outcomes​

Supine hypocapnia was diagnosed when any baseline eTCO2 measurement was <34 mmHg. POSH was defined as all supine eTCO2 values ≥34 mmHg with at least one leaning eTCO2 value <34 mmHg. POTS was defined as a ≥30 beats/min increase in heart rate or an absolute heart rate ≥120 beats/min at any time during leaning. “Any lean-test abnormality” denoted the presence of at least one of these three findings (supine hypocapnia, POSH, or POTS); “no lean-test abnormality” indicated that none occurred. In our protocol, supine hypocapnia was treated as a resting abnormality identified during the orthostatic testing sequence, based on prior work linking low supine eTCO2 to orthostatic intolerance (Natelson et al., 2007).

Why would they measure blood volume 8 days later?

It was part of a larger study looking at 2- CPETs so there are probably logistical reasons for that.

This study was a cross-sectional analysis of prospectively collected pre-intervention data from a prospective, single-center NIH-funded parent study designed to determine the relationship between performance on two successive cardiopulmonary exercise tests (CPETs) and PEM, the sine qua non of ME/CFS.

All participants completed a 10-min lean test 8 days before the quantitative blood volume assessment, and both assessments were completed before CPETs.

Natelson still using Fukuda, A Nasa-lean-test only finding POTS and dOH not the mixed group with normal BP.
What's wrong with this researcher, trying to find "something ", but nothing helpful, just muddying the waters, like the CPET paper.

They used Fukuda to be able to compare to their previous work, but they required PEM:

Adults aged 25–60 years fulfilled the 1994 case definition for ME/CFS (Fukuda et al., 1994). To ensure a substantial current symptom burden at intake, participants were additionally required to report a score of ≥3 on a 0–5 Likert scale for at least three of the following seven non-PEM symptoms: sore throat; tender cervical or axillary lymph nodes; headache; myalgia; arthralgia; problems with attention or concentration; and unrefreshing sleep. They were also required to report a score of ≥3 for PEM.

What is dOH? There is no mention of «doh» in the entire paper.

The authors do not report assessing presence of OI and its severity in patients. Besides, it is known that neither a ≥30-bpm HR increase nor hypocapnia is necessary to experience OI.

The conclusion "These findings suggest that static blood volume deficits alone are unlikely to be the principal determinant of OI in ME/CFS" is not applicable to this data and the title of the paper is misleading.

I completely missed that they did not measure symptoms. It seems like they are aware that they created a new definition of «physiologically defined OI», but that nuance is lost in many parts of the text, including the very next sentences:

We therefore examined whether quantitatively defined hypovolemia was associated with physiologically defined OI during a standardized 10-min lean test in adults with ME/CFS. We further evaluated RBCV in addition to TBV to explore whether RBCV was related to OI. We hypothesized that OI would be more common in hypovolemic participants than in normovolemic or hypervolemic participants.

 

[Evergreen]

What is dOH?

Delayed orthostatic hypotension. I can demonstrate it if you like.

 

[Turtle]

dOH = delayed Orthostatic Hypotension, after a while blood pressure drops
POTS an immediate raise in heart rate, up 30 beats or more.
The mixed group a smaller raise in heart beat and a smaller drop in blood pressure

 

[Felis Catus]

They measured more than just the HR during the NASA lean test.

Thanks. The point is still the same - they used measurements for which we either know are weakly correlated with OI or we don't know anything/much about their correlation with OI, and based on that made a conclusion about OI.

I see you mention their definition of "physiologically defined OI". Perhaps the title of the paper should've been:

A newly defined OI, which is not what its name implies, is not associated with total blood volume and red blood cell volume

 

[Yann04]

Am I wrong in thinking that 35% with hypovolemia and 49% with an RBCV deficit seem notable numbers (regardless of whether there are other noteworthy aspects of this study)? Obviously they don't constitute majorities and don't correspond specifically to anything being measured with the NASA lean test, but, at the same time, this doesn't sound like what one would expect from a healthy cohort, no?

I wonder if they correlated it with activity levels/severity/time spent upright or laying down.

I feel like hypovolemia and RBCV might be substantially associated with bedrest.

Also, I’d never heard of postural orthostatic syndrome of hypocapnia (POSH) before. Do people think it’s relevant?