Trial Report Phenylephrine Alters Phase Synchronization between Cerebral Blood Velocity and Blood Pressure in CFS with Orthostatic Intolerance,2024,Medow & Stewart

I wish abstract writers wouldn't use so many acronyms. It saves what, a line or two or words, at best while greatly reducing readability.

The study looks worth reading though.

Some questions I have include:

• The cohort is young and all had POTS. Is this more to do with POTS than ME/CFS?

• What did phenylephrine do to controls, or did they not get treated? Did the ME/CFS group get more practice at the task?

• What was the PhSI (Phase Synchronisation Index) in the controls?

• What is the suggested mechanism for the improved cognition?

 

They say that they and others have shown that, in ME/CFS, being upright changes CO2, resulting is hypocapnia (not enough CO2) and hyperventilation. They suggest that the phenylepiphrine stops hyperventilation and increases CO2.

Reference 23 is a 2014 paper by these same authors:
Medow MS, Sood S, Messer Z, Dzogbeta S, Terilli C, Stewart JM. Phenylephrine alteration of cerebral blood flow during orthostasis: effect on n-back performance in chronic fatigue syndrome. J Appl Physiol (1985) 117: 1157–1164, 2014.
These authors actually seem to have been working on this idea in CFS and POTS for some time - the reference list is full of their papers, many from the 1990's and 2000's.

In this paper, which relates to that same 2014 study, they are hypothesising that:

Cerebral autoregulation I assume is the ability to maintain blood flow regardless of posture. The measure they use of cerebral autoregulation is how closely the arterial pressure (AP) and the cerebral blood velocity (CBV) match, with that making a 'phase synchronisation index' (variably PSI or PhSI - I'll use PSI). The more closely the arterial pressure and the cerebral blood velocity match (the higher the phase synchronisation index), the worse the cerebral autoregulation. I'm not sure I am fully understanding this yet, but it seems that you want to be able to maintain cerebral blood velocity according to the cognitive demands (so that the blood is delivering enough oxygen to the brain for the work it is doing), regardless of posture (and hence arterial pressure).

So, cerebral blood velocity should not change in lock step with arterial pressure, but in ME/CFS it is seeming to. And therefore the orthostatic intolerance, and the improvement in cognition when lying down.

 

Aside from the small size of the study, there is this screening problem.

So, it is looking as though the participants had to not only have ME/CFS but they had to test positive to orthostatic intolerance (with a 10 minute upright tilt) and hyperventilation/hypocapnea. We aren't told how many people they had to screen in order to get the 15 participants. So, the results may only be relevant to a subset of people with ME/CFS, although that can still be useful. The subjects met Fukuda criteria.

This was the method:
1. Supine
The participants lay down for 30 minutes, during which time they had a practice and an actual n-back test, counting backwards, subtracting various numbers each time. So, I assume, 100, 99, 98 etc, then 100, 98, 96, 94, etc, then 100, 97, 94...

2. Tilted at 60 degrees for 10 minutes
Again they did the n-back test.

3. Three repeat visits with various modifying agents
The participants came back on other days to test what changed when they were given one of the following:
a. breathing supplemental CO2
b. intravenous phenylephrine infused until BP was elevated by about 10mmHg
c.1 gram of acetazolamide as an IV bolus prior to tilt/N-back testing. "Acetazolamide is a carbonic anhydrase inhibitor that acts as a potent cerebral vasculature vasodilator thus increasing cerebral blood flow velocity"

 

1. Supine Cardiorespiratory Characteristics

The finding of a higher resting heart rate in ME/CFS seems pretty solid. Of course, perhaps it's hard to know if that is just deconditioning, but I think the way the resting heart rate changes from day to day, and in line with symptoms suggests otherwise.

2. Cardiorespiratory Effects of 60° Head-Up Tilt (HUT)

There was a significant increase in heart rate in the ME/CFS group during the head up tilt, relative to both the heart rate when supine and the heart rate of the controls when also head up tilted. Although, as the authors note, this is to be expected because the ME/CFS group was selected on a criteria including POTS. There are differences that look interesting but fail to reach significance. e.g. upon tilt, the mean respiratory rate, which was already higher than the controls, increases in the ME/CFS group whereas it decreases in the control group. Upon tilt, End tidal carbon dioxide significantly reduces in the ME/CFS group whereas it does not in the control group.

 

I ran out of energy to finish writing the paper up. But, the two treatments they tried that didn't work are interesting. Just breathing CO2 didn't fix the problem.

 

Yeah, I was struggling to make a clear story which is why I stopped. There might be one, not sure.

Here's the benefit from the phenylephrine on the cognitive performance during tilt - % of numbers correct at each task difficulty. 'n=4' is the hardest task difficulty and is the one to focus on. PE lifts the ME/CFS performance from well below that of the controls to better than the controls. It looks quite marked.



There's this comment:

And maybe that's right, but the increase in blood pressure was only 10mmHg, which doesn't seem like it would be enough to account for the substantial lift in performance. And both the groups had the same increase in blood pressure - that was how the phenylephrine was titrated.

 

So, a clear improvement on cognitive performance in the ME/CFS after PE. (I don't think we have data for the cognitive performance in the controls after PE - there is just one line in the figures which I assume is cognitive performance without PE. - I don't know if there is an explanation)

Then there's the Phase Synchronisation Index - how well the cerebral blood velocity matches with arterial pressure:

When supine, both ME/CFS and controls had a PSI of around 0.60.
When tilted without treatment, ME/CFS had a PSI of around 0.80; controls had a PSI of around 0.70
When tilted with phenylephrine, ME/CFS had a PSI of around 0.70; controls had a PSI of around 0.60

So, with phenylephrine, there is a lower PSI and so possibly better cerebral auto regulation in ME/CFS and better cognitive performance. The ME/CFS people with the treatment look like the controls without treatment.

 

The changes in the PSI seem to match with the changes in the Cerebral Blood Velocity.

When supine, the blood velocity of the ME/CFS and control groups is the same.
When tilted, the blood velocity of the controls drops by 8.7%; the blood velocity of the ME/CFS drops by a remarkable 22.5%
When tilted with phenylephrine, the control blood velocity was the same as when supine and untreated. The ME/CFS blood velocity was lower than the untreated supine by 8.1%.




The authors suggest:

Yeah, I don't know. That's me done for the day. Time for a lie down.

 

I've just seen my son with one wax-white hand and one purple hand. The other day, part of my hand was so blue I actually wiped it with a cloth to see if I had touched something that transferred dye to it. But no, it was just blue. I often wake with a numb arm. I can't hold a steering wheel for more than 20 minutes without my arms going numb.

It seems to me that vascular regulation is a core feature of the disease my son and I have, and the orthostatic intolerance, if caused by cerebral hypoperfusion, is just another manifestation of that. Without doubt, I am more productive on extended cognitive work when lying down. Perhaps the limb weakness and rapid fatiguability is part of the vascular dysregulation too. We just need some biomarkers that actually fit with that idea.

 

I was posting on another thread about how adrenalin can delay or avoid PEM, and I remembered this thread.

I posted the following on the other thread, but I think it's interesting to join the dots on this thread.