Few healthy people give any thought at all to standing up, but for a subset of people with chronic fatigue syndrome standing up is an act that’s fraught with peril.  Whether their hearts start racing (postural orthostatic tachycardia syndrome (POTS) and/or their breathing does (postural hyperventilation) standing often leaves them fatigued, loopy, cognitively impaired and out of it.

Dizziness-orthostatic-intolIf your heart beats too fast it doesn’t have time to fill with enough blood to feed the brain. If you breathe too fast your CO2 levels tank producing hypocapnia.

Hypocapnia causes the blood vessels in your brain to narrow (vasoconstrict), impeding blood flows to the brain causing dizziness, anxiety and other symptoms. It also causes alkalosis, muscle cramps and pins and needles sensations.

Either way your brain – the recipient of 20 to 25% of the blood in your body – gets hammered by a lack of blood.

I find blood flow regulation to be one of the most intriguing and complex areas in ME/CFS.  (Hopefully, this overview is correct!)

Low Rates of Neuronal Activation In ME/CFS

orthostatic intolerance

Particularly when being tilted or standing it’s just not all happening in the brains of some people with ME/CFS

Medical technology is now so precise that it can pick up small changes in blood flows to the brain. If you are searching your environment for something, for instance, your visual neurons should become activated. If you are trying to remember something the neurons involved in memory capture should become activated. Any mental activity that you engage in should result in the corresponding neurons becoming activated and that means increased blood flows flowing to them. Studies have shown, though, that when CFS/POTS patients are tilted and given a cognitive test their neurons simply don’t become activated. It’s no wonder they can’t think well when they’re standing.

Marvin Medow and Julian Stewart have been studying why standing poses such problems for people with chronic fatigue syndrome (ME/CFS) and POTS for quite a while now.  In over a dozen papers they’ve dug deeper and deeper into the physiological causes of orthostatic dysregulation in these disorders.  In this paper, though, they’ve taken on big challenge – trying, at least in the lab, to fix it.

System Regulation Off

Dysregulation or the inability of systems to communicate properly with each other has become something of a theme in chronic fatigue syndrome and it’s dysregulation – not organ failure – that appears to be driving the problems with orthostatic intolerance.

When less blood (and oxygen) starts reaching your brain and/or your CO2 blood levels go squirrelly, chemoreflex receptors in your blood vessels attempt to fix the problem by sending messages to your brainstem to alter your breathing rate. They fix the low blood oxygen levels by increasing your breathing rate. They fix high blood CO2 levels by decreasing your breathing rate.

The systems seem to be consistently missing their targets

The systems seem to be consistently missing their targets

Studies suggest that both these auto correction processes are off in some people with ME/CFS/POTS.  In a pattern reminiscent of the “system on” situation found with the sympathetic nervous system, the chemoreflex system in ME/CFS appears to increase breathing rates too much when brain blood oxygen levels drop and fails to reduce breathing rates enough when CO2 levels start to tank.

These problems are evident when people with CFS/POTS are lying supine and worsen when they stand.

Fixing the Problem

phenylephrine chronic fatigue syndrome

As Phenylephrine increased blood flows to the brain the symptoms during TILT disappeared…

In this small NIH and Solve ME/CFS Initiative funded study the Medow/Stewart team used a drug called phenylephrine to increase blood flows to the brain.  Phenylephrine stimulates α-adrenergic receptors leading increased in blood pressure, baroreflex stimulation, and a deep vagal stimulation with a reduction in heart rate.  Many studies suggest that the main regulator of the sympathetic nervous system – the vagal branch of the autonomic nervous system – is not doing its job.

First they measured their blood flows to the brain and cognitive performance (N-back test) while the participants were lying supine and then tilted on a tilt table.  Then they injected them with the phenylephrine to increase brain blood flows and prevent hyperventilation, tilted them again and  repeated the cognitive testing.

J Appl Physiol (1985). 2014 Nov 15;117(10):1157-64. doi: 10.1152/japplphysiol.00527.2014. Epub 2014 Oct 2. Phenylephrine alteration of cerebral blood flow during orthostasis: effect on n-back performance in chronic fatigue syndrome.Medow MS1, Sood S2, Messer Z2, Dzogbeta S2, Terilli C2, Stewart JM3.

Most Results Normal at Rest

While lying supine the chronic fatigue syndrome patients, with one exception, looked very much like the healthy controls. While their heart rates were demonstrably much faster, their breathing rates, the oxygen delivery to their brains, their end-tidal CO2 volumes and their reaction times during the N-back cognitive tests were all similar to healthy controls.

ME/CFS Patients Wilt Under the Stress of Tilting …

Once they tilted the ME/CFS patients up, however, their cardiovascular system started to go haywire. Their heart and breathing rates increased significantly more than the controls (HR -109 vs 77; BR – 21 vs 14) and their end-tidal CO2 levels dropped (34 vs 43). The velocity of the blood flows to ME/CFS patients brains was significantly less (58-69), and they experienced double the drop in  blood flows to the brain (20%-10%).

downwward-trendsNot surprisingly, their performance on the cognitive test took a huge hit. While lying supine their reaction time to the questions was similar to the healthy controls (106-98) but once they were tilted it was a remarkable fifty percent (148-97) slower (higher numbers equal increased reaction times).

This study, like others, indicates how important stressing ME/CFS patients systems is  uncovering the problems present. Some differences were present at baseline (increased heart rate – ME/CFS), but most (ETCO2, breathing rate, cognitive tests) were not.

But Then Bounce Back !

“In CFS subjects, phenylephrine reversed the orthostasis-induced decrease in neurocognitive performance as measured by N-Back testing” Medow et. al.


Even the cognitive issues resolved with phenylephrine adminstration

Once the ME/CFS group got phenylephrine everything changed. Every physiological feature that had gone bonkers during the Tilt table test – their heart and breathing rates and their end-tidal CO2 levels and blood flows to the brain – normalized. Even more impressively, their performance on the cognitive test was now similar to the healthy controls. Their brain fog was gone.

Phenylephrine had effectively wiped out their problems with standing. Nobody to my knowledge has ever done that before. This group is clearly getting at some core issues in ME/CFS.


Phenylephrine causes the blood vessels to narrow (vasoconstriction) through its promotion of alpha-adrenergic1 receptor activity. These receptors are present in the skin, the gut, the kidney and the brain.

Phenylephrine does not increase heart rate or the strength of heart contractions, or release noradrenaline – none of which you would want to happen to people with ME/CFS. Phenylephrine can, however, cause something called “reflex bradycardia” or a drop in heart rate that sometimes occurs in response to increased blood pressure increase.  That would be clearly helpful in those patients with POTS.

If I understood this difficult paper right, the authors believe phenylephrine probably constricted the blood vessels in the brain via something called “perfusion pressure”. As phenylephrine increased the perfusion pressure in the blood vessels they clamped down driving more blood to the neurons in the brain.

blood vessels chronic fatigue syndrome

The drug apparently provided enough perfusion pressure for the lax blood vessels to clamp down and send the blood on its way

It was a tricky situation. The researchers wanted to increase blood flows to the brain. Constricting the blood vessels can either enhance or stop blood flows. If the blood vessels are constricted too much they’ll shut down blood flows. If they’re too dilated they  lack the pressure to drive the blood deeper into the body.

Their findings suggested two problems may be present; not enough blood is flowing to the brain to maintain enough perfusion pressure, and the blood vessels are too dilated (opened up) to drive the blood through them deeper into the brain.

Newton has found some evidence of reduced blood pressure in ME/CFS. One wonders, as well if given the blood vessel problems in the disorder, higher blood pressure than normal is needed to drive the blood sufficiently.

Phenylephrine, interestingly enough, increased the blood flows to the ME/CFS patient’s brains without ever actually entering the brain; it cannot cross the blood-brain barrier. Either it’s altering the baroreflex set point – or it’s vasoconstricting blood vessels in the body and increasing blood pressure across the body – and in the brain.  Stewart believed that phenylephrine was also reducing blood pooling in the abdomen and legs – two common contributors to orthostatic  intolerance in ME/CFS.


What might be causing the blood vessels to swell up like little balloons? Numerous things can with a prominent candidate being inflammation. Phenylephrine is often used in hospitals to increase blood pressure and reduce the vasodilating (blood vessel opening) effects of systemic inflammation and sepsis. Glial cells called astrocytes can emit substances that open or close the blood vessels.


Inflammation could be contributing to the blood vessels problems in ME/CFS

I asked Stewart if inflammation could be driving the vasodilation he saw in the study and he said yes.

Problems with ion channels found on the smooth muscles lining them (Alzheimers and hypertension) can also affect blood flows through the blood vessels.  Damaged neurons that result in an explosion of astrocytes and damage to the smooth muscles lining the blood vessels during aging can cause vasodilation as well.

Fluge and Mella believe the blood vessel problems may play a key role in ME/CFS and are examining blood vessel functioning in their Rituximab study.

Exercise Connection?

“We found that the acceleration of baroreflex function in the presence of blood pressure decrements can lead to insufficient exercise tolerance and easy sympathetic activation during low-intensity exercise, and it is possible to predict the chronotropic incompetence and poor prognosis in patients with heart disease. “ Fukuma et. al.

Baroreflex problems could also be causing the blood flow problems. Baroreceptors in the major blood vessels monitor blood pressure and cause the heart to slow down when blood pressure gets too high. If the baroreflex is not set right or the brainstem is not interpreting the signals correctly the system will not respond to the stress of exercise  or standing correctly.

Newton has found some evidence of reduced blood pressure and reduced blood pressure variability in ME/CFS. It may be possible, as well, that given the blood vessel problems in the disorder, higher blood pressure than normal is needed to drive the blood sufficiently.

exercise chronic fatigue

Baroreflex problems could also be contributing to the exercise problems

Baroreflex problems have been associated with poor exercise tolerance, increased sympathetic nervous system during exercise and “chronotropic incompetence” – three issues found in chronic fatigue syndrome. Chronotropic incompetence refers to the inability of the heart rate to increase normally during exercise.

People with ME/CFS can display two seemingly paradoxical heart rate patterns; their heart rates are increased during rest relative to healthy controls, but then poop out when exercise is applied.

I asked Stewart if the same baroreflex problems that may be occurring during tilting could be happening during exercise as well? He said he wasn’t sure.

Who Does This Research Apply to?

I asked Dr. Stewart what percentage of people with ME/CFS have these problems? He said about a third of his younger group (up to age 29) do, but that the problem may be intermittent. My gut-level feeling is that, at least at some level, the problems are much more frequently found.

Treatment Implications

I asked Stewart what the treatment implications, if any, are at this point and whether phenylephrine (in some form) is available to be used? Stewart said he was “Not sure.” They injected phenylephrine in the study but found that taking it nasally or orally had little effect. He does believe that “forcing” or increasing blood pressure to get blood flows to the brain is probably going to be necessary but that that option may pose problems for some.

Next up on these researchers agenda is figuring which of these is happening so that they can target therapies directly to the problem.


While there’s still much to learn it’s clear that enormous progress has been made in understanding the standing problems present in ME/CFS and POTS. While clear treatment options are not known, this study indicated that insufficient blood flows are  causing the distress found while standing and perhaps during exercise in a significant number of ME/CFS patients.

Next up for them is figuring out precisely where system goes wrong. Is it the baroreflex response or the receptors in the blood vessels or something else?

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