Therefore many patients without tachycardia remain undiagnosed by the tilt test if the end tidal CO2 and CBFv are not measured. Novak – author

Orthostatic intolerance just got a bit more complex.  That was actually good news. Hopefully chronic fatigue syndrome (ME/CFS) will soon get more complex in the same way.

Usually when we think of problems standing or orthostatic intolerance (OI) we think about postural orthostatic tachycardia syndrome (POTS), which is characterized by a greatly increased heart rate upon standing.  There’s also, less commonly, orthostatic hypotension (low blood pressure upon standing).

Missing hypocapnic group

Several types of orthostatic intolerance had been identified but at least one was still missing.

Both disorders produce similar symptoms (lightheadedness, dizziness, headache, nausea, fatigue, shortness of breath) upon standing that are relieved by lying down.  Both also feature sympathetic nervous system hyperactivity and reduced blood flow to the brain (cerebral hypoperfusion).

But neither condition describes everyone. Dr. Peter Novak, Chief of the Autonomic Neurology Division within the Department of Neurology at Brigham and Women’s Hospital in Boston knew there was more to the OI story than was meeting the eye. He had plenty of patients with orthostatic intolerance (problems standing without having symptoms), which didn’t fit into either of those categories.  He decided to dig deeper, and when he did, he uncovered what appears to be a new kind of OI.

Novak P (2018) Hypocapnic cerebral hypoperfusion: A biomarker of orthostatic intolerance. PLoS ONE 13(9): e0204419. https://doi.org/10.1371/journal.pone.0204419

Novak found this group by putting patients with orthostatic intolerance but without POTS or blood pressure problems (or ME/CFS or fibromyalgia for that matter) through tilt table tests while measuring their CO2 levels and blood flow to the brain.

He discovered that these mystery patients had something called hypocapnic cerebral hypoperfusion; i.e., upon being tilted they were emitting abnormally low levels of carbon dioxide (CO2) and had disturbingly low blood flow to the brain.

Hypocapnia or low CO2 levels are not new to orthostatic intolerance; low CO2 levels appear to be common in POTS, for instance, but no one had uncovered a group of OI patients who only had hypocapnia.

Low CO2 levels are often associated with deep breathing or hyperventilation syndrome – a tricky diagnosis. Hyperventilation is divided into two types – secondary (caused by physiological factors) or primary (caused by psychological factors such as anxiety). The MERCK Manual focuses almost entirely on primary hyperventilation.

CO2 hypocapnia

The new group had low levels of CO2 and low blood flows to the brain but no increases in heart rate or drops in blood pressure.

Novak did everything he could to knock out the physiological factors group by preventing anyone with a disorder/problem that could cause hyperventilation (lung disorders, low blood pressure, severe metabolic abnormalities, central nervous system disorders (FM, ME/CFS), drugs and high amounts of pain) from participating in the study.

That would seem to leave anxiety as the only remaining cause of OI for this group, but that wasn’t the case.  The field is so unexplored that Novak couldn’t come to any conclusions about what caused the low CO2 levels he’d seen.

He did, however, come up with a rather long list of possibilities, including baroreceptor problems interfering with “respiratory drive” compensation for metabolic acidosis, orthostatic ventilation-perfusion mismatch, problems with the respiratory centers in the brain and others…

Under the Radar No More

This group of patients, which appears to be fairly common, has apparently gone under the radar for years.  Novak noted that more than 80% of the patients in this study had been referred to him as suspected POTS patients. Most doctors would have likely given them a tilt table test, found no evidence of POTS, and sent them on their way.

dizziness hyopapnia

If you experience problems standing – and don’t have POTS or OH – you may have HCH.

Novak reminds me of his colleague, pulmonologist David Systrom, who, while working at the same hospital, gave patients with idiopathic (i.e. unexplained) exercise intolerance (including people with ME/CFS, POTS) a deeper look.  These people, also not uncommon, had passed fruitlessly through the medical system for years.  Systrom decided to use his invasive cardiopulmonary testing to examine them in detail, and uncovered a fascinating group of patients.

Next, Novak will try to differentiate these groups further and determine if hypocapnic cerebral hypoperfusion is commonly found in POTS, and whether it is an entirely different disease or exists on a spectrum of orthostatic intolerance disorders.

The central takeaway from this study is that if you have problems standing, and have been tested for OI and been found wanting because you didn’t display a high heart rate or a drop in blood pressure, an end-tidal CO2 test might be the test for you.

If that’s so, you should tell your doctor that low CO2 levels have been linked to low blood flow to the brain in OI. Low CO2 levels have been found in ME/CFS and FM dating back to 2007 and 2010. In fact, ME/CFS and FM were two of the three diseases that Novak reported exhibited hypocapnic hypoperfusion in his paper.

Core Feature Identified

Novak noted that the “spectrum of orthostatic intolerance is broad, complicated, and includes several overlapping presentations”, but one factor, thus far, links them together. So far, every form of OI, including hypocapnic cerebral hypoperfusion, has had one thing in common – a decrease in blood flow to the brain while standing.  Problems getting proper blood flow to the brain may be the core feature of all these forms of orthostatic intolerance.

That, interestingly, was the same conclusion Dr. David Bell came to almost twenty years ago in chronic fatigue syndrome (ME/CFS).

The Brain Blood Flow Problem in ME/CFS #1: Maggie’s Story

Her panic was organic in nature; it came on as a result of physiologic, not psychiatric, factors.  Dr. David Bell

Almost twenty years ago Dr. Bell concluded that people with ME/CFS were having trouble getting blood to the brain. He explained his thinking in a vivid example, republished on Health Rising as “When Panic Isn’t: Dr. Bell on Maggie’s ME/CFS and Fibromyalgia Story“.

Maggie had been doggedly looking for an answer to health problems for ten years when she met up with Dr. Bell. She’d repeatedly been diagnosed with panic disorder, but the exhaustion she felt, her cognitive problems, her leaden feeling legs, etc. didn’t signal panic to him at all. They signaled ME/CFS.

Bell blood flows brain me/cfs

Twenty years ago Dr. Bell asserted problems getting blood to the brain was a key feature in ME/CFS.

Blood volume and standing tests revealed real physiological abnormalities. Maggie was fine until about the ten-minute mark of her standing test when she began experiencing fatigue, pain, lightheadedness and a feeling of panic. At that point her heart rate, blood pressure and epinephrine (adrenaline) levels shot up.  She was diagnosed with hyperadrenergic POTS, low blood volume, orthostatic diastolic hypertension, as well as ME/CFS and FM.

“Whatever else this disease does to the human brain, it includes agitation in its repertoire.” Dr. David Bell

We don’t know if Maggie also had hypocapnia, but it doesn’t matter. Her panicked feeling was probably the result of her epinephrine levels going bananas in an attempt to get more blood to her brain.  In the end, Bell felt that some form of panic or agitation was a core part of ME/CFS, but it was not a psychological problem – it was the result of low brain blood levels – the same core problem Novak found in his hypocapnic patients who did not have ME/CFS or FM.

The Brain Blood Flow Problem in ME/CFS Fixed – Temporarily…

A fascinating study also suggested that reduced blood flows to the brain is perhaps the key issue for one group of ME/CFS patients. When researchers were able to temporarily fix that issue their symptoms completely disappeared.

This group of younger ME/CFS patients looked quite normal lying down, but tilting them up sent their systems haywire. Relative to the healthy controls, their heart and breathing rates increased by about 50%, their CO2 levels dropped by 25%, and they experienced a 50% drop in blood flow to the brain.  Not surprisingly, their cognitive performance also dropped dramatically.


Remarkably, phenylephrine, a blood vessel constrictor, returned brain blood flows to normal and removed the symptoms of one group of ME/CFS patients.

Remarkably, all those symptoms were reversed with the administration of phenylephrine.  The ME/CFS patients’ cardiovascular and cognitive test results normalized leaving them looking like healthy controls.  The authors believed phenylephrine fixed the central problem in this group of patients – reduced blood flow to the brain.

Phenylephrine causes the blood vessels, interestingly, to narrow (vasoconstrict).  Its success suggested that either not enough blood was flowing to the brain and/or inflammation was dilating the blood vessels. Either way the pressure needed to move their blood into smaller blood vessels was missing.

Phenylephrine, interestingly, is often used in hospitals to increase blood pressure and reduce the vasodilating (blood vessel opening) effects of systemic inflammation and sepsis. That’s an interesting finding, given the possibility that ME/CFS may be an atypical form of sepsis – something Dr. David Bell also suggested years ago.

Dr. Stewart, the author of that study, believed that finding ways to get more blood into the brain was going to be key in this group of patients. (Unfortunately the inhaled form of phenylephrine does not work.)


Novak’s identification of new kind of orthostatic intolerance suggests that the deeper researchers dig the more there is to find. They also, suggest, though, that all kinds of OI may link back to one central problem – the inability to get sufficient amounts of blood to the brain. Stewart’s study suggests that the same core problem is afflicting at least one subset of ME/CFS patients.

They also suggest that some of the problems found in ME/CFS/FM are not unique to it. Novak’s experience was similar to David Systrom who found that a whole raft of patients (ME/CFS, FM, POTS and others) had problems with preload or  mitochondrial functioning which impaired their ability to exercise.

Interestingly, by reducing blood flows to the heart, the preload problems Systrom found could conceivably affect blood flows to the brain. Dr. Shungu’s brain lactate findings, the reduced blood volume in ME/CFS, and Ron Davis’s red blood cell studies are adding other blood flow elements into the picture.

Standing Clear: Drug Stops Orthostatic Intolerance in ME/CFS In Lab – Next Steps

Since those studies have not been done in Novak’s or Systrom’s patients, we don’t know if those findings apply to them, but it’s looking more and more like some of the core issues involving blood flows and blood vessels occurring in ME/CFS are probably occurring in other diseases. Given how terribly debilitating ME/CFS, in particular, can be, it makes sense that it’s impacting very basic physiological processes. Ron Davis has repeatedly stated that he believes understanding ME/CFS will accelerate our understanding of other diseases.

So did Dr. Bell almost twenty years ago.

CFS, and the patients who suffer from it, have a great deal to teach those of us who have made medicine our life. Once researchers unravel the physiologic mechanisms of this illness, the discoveries will help unravel basic mechanisms of unnumbered other diseases.


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