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

[Dolphin]

https://journals.physiology.org/doi/abs/10.1152/ajpregu.00071.2024

Research Article
Phenylephrine Alters Phase Synchronization between Cerebral Blood Velocity and Blood Pressure in Chronic Fatigue Syndrome with Orthostatic Intolerance

Marvin S. Medow* and Julian M. Stewart
29 APR 2024https://doi.org/10.1152/ajpregu.00071.2024

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Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neuro-cognitive deficits perhaps related to upright hypocapnia and loss of cerebral autoregulation (CA).

We performed N-back neurocognition testing and calculated the phase synchronization index (PhSI) between Arterial Pressure (AP) and cerebral blood velocity (CBV) as a time-dependent measurement of cerebral autoregulation in 11 control (mean age=24.1 years) and 15 ME/CFS patients (mean age=21.8 years).

All ME/CFS patients had postural tachycardia syndrome (POTS).

A 10-minute 60⁰ head-up tilt (HUT) significantly increased heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P <0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decreased end-tidal CO2 (ETCO2; 33.9 ± 1.1 vs. 42.8 ± 1.2 Torr, P < 0.05) in ME/CFS vs. control.

In ME/CFS, HUT significantly decreased CBV compared to control (-22.5% vs -8.7%, p<0.005).

To mitigate the orthostatic CBV reduction, we administered supplemental CO2, phenylephrine and acetazolamide and performed N-back testing supine and during HUT.

Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct n=4 N-back during HUT in ME/CFS similar to control (ME/CFS=38.5±5.5 vs. ME/CFS+PE= 65.6±5.7 vs. Control 56.9±7.5).

HUT in ME/CFS resulted in increased PhSI values indicating decreased CA.

While CO2 and Acetazolamide had no effect on PhSI in ME/CFS, PE caused a significant reduction in PhSI (ME/CFS=0.80±0.03 vs ME/CFS+PE= 0.69±0.04, p< 0.05) and improved cerebral autoregulation.

Thus, PE improved neurocognitive function in ME/CFS patients, perhaps related to improved neurovascular coupling, cerebral autoregulation and maintenance of CBV.

Citation:
Phenylephrine Alters Phase Synchronization between Cerebral Blood Velocity and Blood Pressure in Chronic Fatigue Syndrome with Orthostatic Intolerance
Marvin S. Medow and Julian M. Stewart
American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 0 0:0

Grants and funding

• RO1 HL 112736/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
• RO1 HL 074873/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
• 1R56HL162752/HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
• Solve ME/CFS Initiative (SMCI)

https://twitter.com/user/status/1784938896146534689

 

[rvallee]

Phenylephrine is a decongestant commonly found in some over-the-counter cold medication like Sudafed. Usually it's to reduce swelling and congestion in the sinuses, but apparently it works rather poorly for that when taken in pill form.

Also apparently in some hemorrhoid medication, again to reduce swelling.

 

[Hutan]

HUT in ME/CFS resulted in increased PhSI values indicating decreased CA.

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?

Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct n=4 N-back during HUT in ME/CFS similar to control (ME/CFS=38.5±5.5 vs. ME/CFS+PE= 65.6±5.7 vs. Control 56.9±7.5).

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

While CO2 and Acetazolamide had no effect on PhSI in ME/CFS, PE caused a significant reduction in PhSI (ME/CFS=0.80±0.03 vs ME/CFS+PE= 0.69±0.04, p< 0.05) and improved cerebral autoregulation.

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

• What is the suggested mechanism for the improved cognition?

Phenylephrine is an alpha-1 adrenergic receptor agonist used to treat hypotension,6,8 dilate the pupil,7 and induce local vasoconstriction.1

 

[Hutan]

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.

Neurocognitive impairment in ME/CFS, subjectively described as mental fog or cloudiness, causes impaired working memory, concentration, and difficulty processing complex information (1, 15, 16). ME/CFS patients often exhibit working memory deficits during demanding tasks that require attention and switching between mental processing routines (16–19), and experience impaired information processing speed (17). While a cause for this neurocognitive impairment has not been established, it is likely related to decreased cerebral blood flow (16, 20), due to decreased CO2 reducing cerebrovascular flow, reduced cerebrovascular regulation or a combination of these (16, 21, 22), but can be mitigated in part by phenylephrine, as previously shown (23).

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:

We hypothesize that cerebral autoregulation is decreased with OI and that improvement of cerebral autoregulation through maintenance of CO2 corrects this deficit determined by measurement of phase synchronization and N-Back performance.

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.

 

[Hutan]

We recruited ME/CFS subjects all with reported neurocognitive impairment and hyperventilation/ hypocapnea (n=15), and healthy controls (n=11).

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

Once identified, ME/CFS subjects with OI and hyperventilation/ hypocapnea were asked to continue with N-back testing of their neurocognitive function.

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"

 

[Hutan]

1. Supine Cardiorespiratory Characteristics

... although control subjects had a significantly lower heart rate while supine compared to ME/CFS patients, there were no differences while supine in mean blood pressure, ETCO2 or respiratory rate comparing control subjects to ME/CFS patients, respectively.

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.

 

[SNT Gatchaman]

Cerebral autoregulation I assume is the ability to maintain blood flow regardless of posture.

Posture is one variable to account for. More generally it's the mechanism to maintain relatively constant cerebral perfusion despite changes in mean arterial pressure, recognising that the brain a) has no local fuel reserve and needs energy via constant oxygen and glucose (and removal of metabolic waste); b) lives in a closed box, so can't accomodate significant changes in blood pressure and blood volume. There's little room to move with brain tissue and CSF.

 

[Eddie]

Posture is one variable to account for. More generally it's the mechanism to maintain relatively constant cerebral perfusion despite changes in mean arterial pressure, recognising that the brain a) has no local fuel reserve and needs energy via constant oxygen and glucose (and removal of metabolic waste); b) lives in a closed box, so can't accomodate significant changes in blood pressure and blood volume. There's little room to move with brain tissue and CSF.

I assume it also regulates brain temperature as heat can't effectively radiate through the skull

 

[SNT Gatchaman]

Cerebral blood flow is key for deep brain structures - I think superficial can exchange with the environment a little more easily. I assume as long as the heart is pumping then heat can be cleared from the brain. I'm not sure how much cerebral autoregulation plays in finessing, but certainly hyperthermia impairs autoregulation.

 

[Jonathan Edwards]

If POTS was due to hyper ventilatory hpocapnia then solving it would be easy - just stop over-breathing. I doubt anyone here thinks that is realistic.

 

[Hutan]

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.

 

[Jonathan Edwards]

I haven't read in detail but it seems very confusing. If people with ME/CFS did not show auto regulation and had fixed phase synchrony that presumably means that they were not constricting brain blood vessels - which would seem likely to increase blood flow. Maybe it indicates a normal response to poor arterial perfusion but that should show up as BP drop. I can't make much sense of any of it.

 

[Hutan]

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:

The effect of phenylephrine may therefore simply be an effect of blood pressure elevation since elevating blood pressure during orthostasis using another α-1 adrenergic agonist, midodrine, improved aspects of neurocognitive function in some subjects with spinal cord injury (53).

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.

 

[Hutan]

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.

 

[Jonathan Edwards]

So, with phenylepinephrine, there is a lower PSI and so possibly better cerebral auto regulation in ME/CFS and better cognitive performance.

What I don't understand is if there is a problem with adequate cerebral blood flow what you want is no autoregulation - just open up the tubes and let the blood run - with maximal phase synchrony.

I would worry about anything purporting to show that giving people phenylephrine was good for them. These things were largely abandoned in the 1970s because of adverse effects.

 

[Hutan]

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:

In the present study it is possible that phenylephrine vasoconstricts the cerebral vasculature via an elevation in perfusion pressure, which is one determinant of cerebral reactivity (60). Since phenylephrine does not cross the blood-brain barrier (61, 62), cerebral vasoconstriction may be a myogenic response to an increase in cerebral perfusion pressure.

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

 

[SNT Gatchaman]

Published today is a very detailed discussion of time-domain models of dynamic cerebral autoregulation. Time-domain methods for quantifying dynamic cerebral blood flow autoregulation: Review and recommendations. A white paper from the Cerebrovascular Research Network CARNet (2024, Journal of Cerebral Blood Flow & Metabolism)

Its introduction says —

Cerebral autoregulation (CA) describes the intrinsic ability of the brain to protect itself against potential damage caused by large changes in cerebral perfusion pressure (CPP). CPP is defined as the difference between arterial blood pressure (ABP) and intracranial pressure (ICP). In most cases, ICP is presumed to be stable and ABP changes are assumed to reflect CPP changes. However, this assumption is not valid under pathophysiological conditions, e.g., in traumatic brain injury or intracranial hemorrhage. Through adaptation of cerebrovascular resistance by vasodilation or vasoconstriction via arteriolar vascular muscle relaxation or contraction, CA regulates cerebral blood flow (CBF) responses to CPP (or ABP) changes. These changes include both changes in mean CPP or ABP that occur over long periods of time (static CA; sCA), as well as faster, more transient CPP or ABP changes that happen in seconds or minutes (dynamic CA; dCA). Impaired CA increases the risk of cerebral hypoperfusion/hyperemia, neuronal damage, and cerebral bleeding. Accurate CA assessment and monitoring can provide clinical guidance for patient management and treatment.

 

[Hutan]

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.

 

[Hutan]

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

Phenylephrine is a sympathomimetic drug, which means that it mimics the actions of epinephrine (commonly known as adrenaline) or norepinephrine. Phenylephrine selectively binds to α1-adrenergic receptors which causes venous and arterial vasoconstriction.

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

According to the Endocrine Society, “adrenaline causes a noticeable increase in strength and performance, as well as heightened awareness, in stressful times.”

For runners, adrenaline is a nifty little hormone that does a lot. “This molecule helps increase force of contraction of the heart muscle, increase blood flow to working muscle—to a point—and reduce blood flow to non-working muscle and it activates the mobilization of substrate molecules to be used by those tissues,” says Allan Goldfarb, kinesiology professor at the University of North Carolina Greensboro. He adds that epinephrine also works with norepinephrine to “provide greater blood flow and control blood pressure.”

In general, it makes your body more efficient. A recent Harvard Medical School study, for example, found that epinephrine exposure, among other hormones, increased proteasome activity, a marker that the body is breaking down and eliminating ‘misfolded’ proteins that can cause disease if they accumulate.

 

[Mij]