This is the third in a series of blogs following the work of Workwell and allied exercise physiologists who are aiming to do nothing less than revolutionize the way chronic fatigue syndrome / myalgic encephalomyelitis (ME/CFS) is viewed.

The first word in the first sentence of the paper says it all:

Concise methodological directions for administration of serial cardiopulmonary exercise testing (CPET) are needed for testing of patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Why concise? Because Workwell asserts that in the universe of diseases known to man, ME/CFS is so different when it comes to exercise that it needs a place all its own. It needs its own concise methodology, and above all it needs to be understood differently.

This methodology paper, then, is an attempt by the exercise physiologists at Workwell (Staci Stevens, Mark Van Ness, Chris Snell, Jared Stevens) and Betsy Keller to spread the word that something very different, something perhaps even unique in the annals of medicine, is occurring in people with chronic fatigue syndrome when they exercise.

Very Popular Paper (!)

Someone, it seems, is listening. This dry, seemingly obscure methodology paper (“Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome“) has proven to be a surprise hit. In the two months since its publication it’s been viewed by over 7,400 people spread across the globe.  More than two months after its publication, Frontiers reports the paper is still receiving more views than 91% of the articles published in the Frontiers journals. (Add to the total by viewing the paper here.)


Two and a half months later, the Workwell CPET paper has been viewed more than 91% of other articles.

Much of the interest has probably been driven by the 194 tweeters (!) that Altmetrics states have linked to the article. People in Ecuador, Saudi Arabia and Malaysia have read this paper. (Check out the demographics here.)

The paper’s focus is on cardiopulmonary exercise testing (CPET). In heart disease, CPETs are used to assess disease severity and functionality and can even predict mortality outcomes. In ME/CFS, they’re used to assess functionality and energy production as an objective way to stress ME/CFS patients’ bodies and provide guidelines for safe exercise.

For people who need objective evidence of impaired functionality for disability, these tests can make all the difference. Their ability to provide physiologically based assessments of functionality in ME/CFS and FM destroys any ideas about malingering.

The Deconditioning Dilemma

When done correctly, CPET tests can cut through the mistaken idea that malaise and malingering cause this disease, something the biopsychosocial field has shrouded the ME/CFS field in for decades.

There’s a danger, though. The same tests done incorrectly or used for the wrong purpose can produce more trouble than help. While one-day CPET tests provide an excellent way to objectively stress one’s system, they have also been used as evidence that deconditioning causes ME/CFS and that people with the disease are malingerers.

exercise energy chronic fatigue

It’s a remarkable fact that even people with disabling diseases can exercise to exhaustion two days in a row without affecting their ability to produce energy.

That’s because the reduced peak oxygen levels that often show up in ME/CFS during one-day CPETs can be taken as a sign of deconditioning. That finding – which makes sense in other diseases but not ME/CFS – has given the biopsychosocial crowd a reason to emphasize graded exercise therapy (GET) and cognitive behavioral therapy (CBT) as treatments.

Not so fast, Betsy Keller and the exercise physiologists from Workwell say. It’s impossible, they assert, to say anything about deconditioning in ME/CFS without doing a two-day exercise test. The reason is simple: ME/CFS is so different from other diseases that the traditional rules do not apply.

Studies indicated that people with all sorts of disabling diseases can exercise to exhaustion two days in a row, and, surprisingly, generate the same amount of energy on the second day as they did on the first.

Take pulmonary hypertension (PH),  a very serious disease (about 50% of patients die within five years) which can cause exercise intolerance. PH causes a narrowing of the blood vessels in the lungs that makes it difficult for the heart to push blood through them.  Yet people with PH can hop on a bike, exercise until they can go no further, and then the next day do the same, with no diminishment of their ability to exercise.

The same is true for people with heart failure, end-stage renal disease, cystic fibrosis, COPD and/or stroke. The fact that they can do so is a testament to the incredible robustness of our energy production systems.

Those people don’t need a 2-day test to demonstrate their functional status: a one-day test works just fine – for them. It only makes sense to assume that people with chronic fatigue syndrome would be able to do the same. But they can’t.

A Unique Disease?

Cardiopulmonary exercise testing can provide helpful insights into this disease by better characterizing the unique post-exertional pathology of the illness. The authors

The ME/CFS community lucked out when an exercise physiologist named Staci Stevens got ill.  She realized that exercise was making her symptoms worse (post-exertional malaise or PEM) and making her weaker to boot.  When she tested herself on a metabolic cart two days in a row she found that the first exercise bout had indeed inhibited her ability to produce energy.  She had gotten ”pemmed”.

chronic fatigue syndrome exercise

Thus far, studies suggest that people with ME/CFS are uniquely affected by exercise.

The finding intuitively made sense, but intellectually it was an astonishing moment. Her mentors, after all, had ground into her that anyone – even people with serious illnesses – can reproduce their exercise test results. She was an anomaly and so are many of the hundreds of ME/CFS patients that she and the exercise physiology group at Workwell have tested over the past 20 years. Their findings indicate that as exercise greatly exacerbates patients’ symptoms, it’s also whacking away at their ability to aerobically produce energy.

The protracted symptom flare following exertion (post-exertional malaise) is such a dramatic feature of ME/CFS that a term new to medicine, “post-exertional malaise or PEM”, was created to explain it.

The Somatic Hypervigilance / Deconditioning Trap

ME/CFS is not alone in its struggle to get past the deconditioning issue. Because deconditioning occurs in any disease that severely limits movement, it is, of course, present in diseases like ME/CFS and POTS.  The difference between the deconditioning that results from disease and the deconditioning that causes disease is critical, though.  The consequences of not convincing the medical profession that the deconditioning found in ME/CFS and POTS is caused by the disease has been immense.

For one thing, it’s enabled biopsychosocial researchers to attempt to explain ME/CFS by throwing deconditioning together with something called “somatic hypervigilance”. That hypothesis has caught many POTS, ME/CFS and fibromyalgia patients in its snare.

We can get an excellent view of what’s going on by looking at other diseases such as orthostatic intolerance (POTS), in which exercise seem to indicate that deconditioning plays a major role. One exercise study concluded that 90% of people with orthostatic intolerance had some form of deconditioning.

One lecture (“POTS versus deconditioning: the same or different?”) concluded, using the results of a one-day exercise test, that what people with POTS and ME/CFS really need to do is exercise.

“In this context, the physiological responses to exercise appear remarkably normal in many patients with chronic fatigue syndrome, but there is a mismatch between the perception of effort and objective measures of the physiological stress. These results seem analogous to the somatic hypervigilance seen in patients with POTS. In other words, normal physiological responses are perceived very differently in these patients.


“It is important that the medical community retain their empathy for patients with unusual conditions, but at the same time perhaps we should send a firm but empowering message about physical activity to them.” Joyner and Mazuki

There’s no doubt that exercise, when properly done in POTS, can often times be helpful.  A 2015 review flatly stated that, “the tachycardia (increased heart rate upon standing) seen in POTS is due to reduced stroke volume, which can be ameliorated or even eliminated by exercise”. A three month graded exercise program, which started off with supine exercise, found that after 3 months about 50% of the participants no longer met the criteria for POTS.

That was clearly a positive finding, but then again, 50% of the study participants still met the criteria for POTS, those who didn’t meet the criteria weren’t necessarily cured, and the physiological results – blood volume increases of 6%, end-diastolic volume increases of 8% – weren’t exactly staggering. In fact, despite all the exercise – which by the end of the study was being done several times a week and included weight-lifting – neither the heart rate nor stroke volume of the POTS patients reached the normal levels found in sedentary, healthy individuals.

Two researchers who had clearly tired of what they believed was an over-emphasis on deconditioning in POTS recently penned an editorial.  They acknowledged that deconditioning is present in POTS while asserting it is not primary. Noting that 60% of POTS patients fail to complete graded exercise studies, they bemoaned the emphasis the medical profession now places on deconditioning in POTS.

“Most (POTS) patients undergo extensive, noninvasive cardiac testing and are often told that their symptoms are secondary to deconditioning, given a common finding of poor exercise tolerance on an exercise stress test.”

Of course, people with ME/CFS have been dealing with this scenario for decades. The entire graded exercise therapy (GET) edifice is built upon the idea of deconditioning, false beliefs and somatic hypervigilance. If you can just get people with ME/CFS moving again, the original GET proponents felt, the disease should resolve itself.  That hasn’t proven to be true, but the idea has burrowed into many doctors’ heads.

The Antidote to the Deconditioning Dilemma

There is an antidote, though, to the deconditioning/somatic hypervigilance issue and it’s called a two-day exercise test.

dogma head in sand

Overturning decades of dogma is never easy.

Staci Stevens and Workwell have tried to get the need for two-day CPETs in ME/CFS across for over a decade. It’s a measure of the strength belief systems (i.e dogma) can have that the idea has received considerable pushback. It’s really no surprise; Workwell is, after all, trying to overturn decades of perceived wisdom, and they’re using a controversial disease to do it.

Rather than believe their results, some exercise physiologists simply assume Workwell’s metabolic cart is not working properly. Workwell’s response to that is to do the most rigorous calibrations possible, including using a technique called biological validation which many exercise physiologists probably haven’t even heard of.

Research Studies

The two-day exercise test occupies an important and even unique position in ME/CFS’s research armory: not only does it make clear, in a way that no other test can do, that too much exertion reduces functioning in ME/CFS – the core issue in this disease – but it does so in a way that demonstrates how unique this disease is.  It comes as no surprise that a test which objectively demonstrates the energy problems in ME/CFS is going to overturn accepted dogma.

The opportunities the two-day exercise test provides have made it all the more puzzling to me, at least, why two-day studies have been rather rare in ME/CFS. The tests, of course, aren’t easy on patients. Most recover within a week but others can take much longer.

A large two-day exercise study could, though, at one stroke both legitimize this disease, demonstrate its uniqueness, and point a finger straight at energy production problems and arouse tremendous interest in that vital area of research.

I asked Staci which, if any, studies employing this test were underway.

The most exciting for us is the Cornell’s ENID NIH CRC 2 day CPET study. Workwell will be providing testing as the west coast arm of the study. I’m thrilled when I hear of any study using 1 or 2 day CPET. There are several groups – the NIH Intramural Study, Columbia ME/CFS CRC, Nova, Cortene and Mike VanElzakker come to mind – who have opted for a 1 day CPET instead of submaximal testing and this is huge progress for the field.

Workwell has been giving two-day CPETs for years. I asked Staci if the drop in energy production seen in an exercise test given one day after a previous test was really unique in ME/CFS. Her answer demonstrated just how much we have to learn.

Clinically we have seen patients with more than 30 different fatiguing conditions including POTS and fibromyalgia. ME/CFS is unique but more research is needed to determine ME/CFS CPET subsets and if other conditions have abnormal test 2 responses.. Our clinical patients often have comorbid conditions, so this makes it more difficult to sort out. That said, several distinct subsets of abnormal responses are emerging. We have a case series on this very topic comparing fatiguing conditions with ME/CFS which will be published soon.

I asked Staci what was next for Workwell. She reported that research will be ramping up and several publications are in the works including the CPET case report series, heart rate responses in ME/CFS and more on PEM. Plus, Workwell will be producing a continuing education program on ME/CFS in partnership with MedBridge, which will be aimed at health care providers, including physical and occupational therapists, nurses and athletic trainers, and is expected to launch in 2019. Her hope is to educate health care providers and provide resources for patients.

A Guide to Giving a Two-Day Exercise Test in ME/CFS – The Methodology Section

The methodology section of the paper gives exacting instructions on how to give a two-day exercise test. Some are given below.

The pre-test preparations should begin as early as 2-3 weeks prior to the test and basically include ways to minimize stress on the patient. Alcohol, caffeine, exercise and food restrictions prior to CPET are given. Physician consent and a completed cardiovascular disease risk questionnaire is required. If a plane trip is required, resting after the flight for a day or two is suggested. The patient should not drive after either exercise test.

Workwell - two -day exercise test

Workwell and Betsy Keller provide the first how-to guide on doing a two-day exercise test in ME/CFS.

Following 5 min. of supine rest at the facility, baseline measurements (resting heart rate, blood pressure, O2 saturation, body temperature, and monitor electrocardiogram) are taken. Water should be provided throughout the testing and after the second exercise test electrolyte replacement drinks may be helpful. A saline infusion at that time can also be helpful.

The test should be devised so that the patient is on the bike (treadmills are not recommended) at least 8 min. but no more than 12 min. Depending on the physical condition of the patients, Workwell gives different workload increments that can be used. (The pressure on the pedals starts off at basically zero and then is ramped up (workload increments) over time.)

The protocol is as follows:

  • START: 3 min seated rest on cycle—monitor ECG, VO2, and record BP and O2saturation at min 2.
  • EXERCISE PROTOCOL: first minute exercise stage—begin at 0 watts (no prior warm-up) and increase 10–15 watts per min, or as appropriate.
  • DURING EXERCISE: Measure BP/O2saturation/RPE every 2 min (e.g., @ 15W, 45W, 75W, etc.).
  • PEAK EXERCISE: Obtain RPE, HR, BP at peak or immediate post exercise.
  • POST EXERCISE: Recovery measures of BP, HR/ECG, O2 sat @ minutes 1, 3, 5, etc. until recovery when HR is within 20 bpm above pretest HR, close to pretest BP, normal ECG, asymptomatic.

Special emphasis is placed on ensuring that the exercise physiologist accurately report that a maximal effort has been given.

Biological Validation

“Even when automated system calibration appears accurate, results may be erroneous.”

Workwell has long emphasized the need to ensure that the twitchy metabolic carts are properly calibrated. They assert that it’s essential to calibrate the machine prior to and following each CPET and then go beyond normal guidelines to assert that monthly “biological validation” of the metabolic cart is essential as well.

That includes having a human being (usually a staff member) with known values test the machine monthly. Biological validation can identify errors not detected by the automatic calibration of the machine.

Biological validation of the metabolic cart is particularly important for ME/CFS patients because the carts tend to read high; i.e. make the patient appear healthier than they are, when biological validation is not done.

The group also provides recommendations for software, frequency of sampling, data display, etc.  Finally, the group asserts that one-day CPETs should only be used as stressors in studies seeking to understand how exercise impacts the immune system, gene expression, etc. Because they provide an objective measure of effort, they’re ideal for this purpose.

One-day CPETs should never be used, however, to assess aerobic capacity, functionality, etc. Two CPETs are needed to assess functionality and the impact of exercise on energy production.


A two-day maximal exercise (CPET) is not an easy test for someone with ME/CFS to take but it can be stunningly effective in demonstrating the apparently unique effect exercise has on energy production in this disease.  The fact that one-day maximal exercise tests do accurately assess functioning in people with other serious disabling diseases unfortunately has had negative consequences for ME/CFS. This is because the low values people with ME/CFS often post on one-day tests suggest deconditioning is present. Two-day exercise tests reveal, however, that the low values are primarily due to problems with energy production.

Few fields are receptive to findings that overturn dogma and the exercise physiology field has proven to be no exception. The field, in general, has resisted Workwell’s and other’s findings indicating that exercise affects people with ME/CFS differently than people with other diseases.

The evidence, though, is starting to add up, and Workwell’s recent CPET methodology paper will make it harder for exercise physiologists and others to keep ignoring the obvious. Not only do studies suggest that exercise affects people with ME/CFS far differently than people with other diseases, but it also asserts that a rigorous methodology unique to ME/CFS is needed to successfully do these tests. That by itself should open some exercise physiologists’ eyes, change some minds, and hopefully spark more interest.

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