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The ME/CFS 2-day exercise test results are unique.

Every once in a while in the chronic fatigue syndrome (ME/CFS) world, we get a really big study, and this is one. For one, it validates and expands upon the findings of past, smaller 2-day exercise studies, and that’s a big deal. The 2-day exercise studies, after all, occupy a unique place not only in ME/CFS but in the medical research world – and that means trouble.

It’s tough overturning paradigms, but that’s what the 2-day exercise studies that the Workwell Foundation initiated in ME/CFS over two decades ago aimed to do.

THE GIST

  • Every once in a while in the chronic fatigue syndrome (ME/CFS) world, we get a really big study, and this is one. For one, it validates and expands upon the findings of past, smaller 2-day exercise studies and that’s a big deal. The 2-day exercise studies, after all, occupy a unique place not only in ME/CFS but in the medical research world.
  • These types of studies were largely abandoned decades ago after researchers concluded that even people with serious medical conditions were able to duplicate the results of their first day on the second day. It seems that human beings, even when they are very ill, can produce the same amount of energy from one day to the next.
  • At least that was the thinking until Staci Stevens and the Workwell Foundation showed, in a landmark study, that was not true for ME/CFS. The results were so shocking that the exercise physiology world essentially ignored them. Since then smaller studies have been done, but what we really needed was a NICE, BIG STUDY, and that’s what we have.
  • Thanks to Maureen Hanson and her NIH-funded ME/CFS research center, we have a nice big, well-funded (NIH funded), rigorously produced 2-day CPET study.
  • These 2-day CPET studies are crucial because they are the only studies that have definitively shown that intense exercise one day somehow knocks down energy production the next day in people with ME/CFS; i.e. they validate the post-exertional malaise symptom in ME/CFS.
  • The study comes at a good time. Another exercise physiologist, Dane Cook, found that after controlling for aerobic fitness, all the problems with energy production that the other studies found disappeared – potentially giving a death blow to a core understanding of ME/CFS.
  • This study, which used sedentary healthy controls, took up Cook’s challenge, but after controlling for aerobic fitness, it found the same energy production problems that the studies Cook dismissed found. That is, when asked to engage in an intense but short exercise bout, people with ME/CFS couldn’t produce as much energy, use as much oxygen, last as long, nor do as much work as the sedentary healthy controls.
  • The authors also proposed that Cook’s study, which matched some of his female with male participants, underestimated the energy production problems that were present.
  • The “pulse pressure” findings suggested that impaired blood flows and oxygen delivery to the muscles probably play a major role in the exercise problems in ME/CFS.
  • The findings from the second CPET exercise test followed on the findings from the first. It indicated that the first exercise test had indeed damaged ME/CFS patients’ ability to produce energy in a number of ways. Contrast that with the sedentary but healthy controls who displayed a normal recovery from the exercise and no change in energy production (peak oxygen consumption or peak work).
  • The study also found that the first exercise session damaged the ability of the hearts of ME/CFS patients to respond normally during the second exercise session; i.e. the ME/CFS patients (but not the healthy controls) demonstrated chronotropic incompetence.
  • The authors also took a shot at the conclusions of the Nath Intramural study, stating that the effort preference findings should not have been applied to the exercise test results and that muscle problems in ME/CFS (rather than the brain) could have contributed to the low exercise results.
  • This large study validated, hopefully for the last time, the findings of all the 2-day CPET studies that have gone before. I still remember being gobsmacked at the implications of Workwell’s 2009 2-day CPET finding. As I wrote the blog, “A Crack in the Foundation”, I thought this will change everything. It has been changing everything but much more slowly than I would have thought.
  • Now that we have a big, rigorous study whose results cannot be denied, thanks so much to the pioneers who have led the way over the past 25 years. They are courageous people who have bucked the system, perhaps at a cost to themselves. So, thank you so much Staci and Jared Stevens, Chris Snell, Mark Van Ness and Todd Davenport (Workwell), thank you Betsy Keller and her Ithaca group, and Maureen Hanson (Cornell), thank you to the Van Campen, Rowe and Visser team, thank you Ruud Vermeulen and your group, and thanks, more recently, to Jong-Han Leem and his Korean group.
  • Thanks as well to over 250 people who have brought Health Rising about 80% of the way to its goal as we look to wrap up the drive shortly!
Look up 2-day CPET on PubMed and you’ll find a lot of ME/CFS studies and not much else. There’s a reason for that: the 2-day exercise studies were largely abandoned decades ago after researchers concluded that even people with serious medical conditions were able to duplicate the results of their first day on the second day. It seems that human beings, even when they are very ill, can produce the same amount of energy from one day to the next.

At least that was the thinking until Staci Stevens and the Workwell Foundation showed, in a landmark study, that was not true for ME/CFS. The results were so shocking that the exercise physiology world essentially ignored them.

Since then, though, ME/CFS researchers have, in mostly small studies, been working at validating Workwell’s initial findings, although one has the sense they’ve really never taken hold outside of ME/CFS. Then again, we’ve never had a big, really rigorously produced 2-day CPET study that’s seemed guaranteed to turn heads. That is, until now.

The Study

The “Cardiopulmonary and metabolic responses during a 2-day CPET in myalgic encephalomyelitis/chronic fatigue syndrome: translating reduced oxygen consumption to impairment status to treatment considerations” study, led by exercise physiologist Betsy Keller, is easily the biggest (and best) 2-day ME/CFS cardiopulmonary exercise study done to date.

The 2-day CPET test is unique in that, while 1-day CPET and invasive cardiopulmonary exercise studies can tell us what happens during exercise, the 2-day CPET studies have been able to show us how exercise one day impacts the ability to produce energy the next day, i.e. it validates postexertional malaise at a core level.

These studies – which require that patients to exercise to exhaustion twice over two days – must be amongst the most difficult to pull off. Not only does the patient have to engage in two short but intense exercise sessions over two days – a big commitment for a person with ME/CFS – but if they’ve traveled, they’ll probably have to book some rest days before they can leave.

Those restrictions made the size and scope of this study (n=151 over 3 locations – Ithaca College (Gerald Moore MD), Weill Cornell Medicine (Susan Levine MD), and Dr. John Chia – unusual. The reason this complex study – which took place over four years – was able to get so large was simple: it got some very nice NIH funding via Maureen Hanson’s Cornell ME/CFS Collaborative Research Center.

Maureen Hanson’s decision to regularly employ exercise stressors in her NIH-funded Center has paid off in spades with this study and others that have moved the ME/CFS field forward considerably. Once again, we see how valuable the NIH-funded research centers and NIH-funded studies can be. Few groups fund studies of the size and complexity that the NIH regularly funds.

Rigorous Effort

checklist

Canadian criteria – check; sedentary healthy controls – check; CPET calibration – check.

The authors went to great lengths to dot their i’s and cross their t’s. The patients met the Canadian Criteria for ME/CFS and, importantly, the healthy controls were sedentary. The lead author, Betsy Keller, met with the exercise technicians to “practice the test protocol, confirm calibration and long-term quality control and assurance with biocalibration of metabolic measurement systems.”

This is important as CPET machines can be touchy. AI CoPilot reported that CPET machines require “careful handling and proper calibration” and can be sensitive to things like “patient movement, improper sensor placement, and environmental conditions”. CPET machines, for instance, have to be calibrated for altitude. For Betsy Keller and the exercise physiologists at Workwell (Staci and Jared Stevens in this study), calibration usually requires having the machines tested using a human subject with known readings to make sure they are reading accurately.

In short, we can assume that the ME/CFS patients were real ME/CFS patients and that the cardiopulmonary exercise test was done properly.

A Little Controversy

The two main ME/CFS exercise groups in the U.S. – the Workwell/Keller group working with Maureen Hanson, and Dane Cook’s group that’s been working with the CDC – have been at loggerheads for years.

Early on, Workwell asserted that Cook’s submaximal testing procedure was: a) ineffective at uncovering the aerobic impairments found in ME/CFS; and b) exposed ME/CFS patients to increased levels of stress. For his part, for almost 20 years, Cook has asserted that Workwell, Keller, Vermoulen, (everyone except him, actually) have been assessing their exercise results incorrectly. Their results, Cook asserted, needed to be matched for aerobic fitness.

Cook got similar results to the other studies until he controlled for aerobic fitness. Once he did that – most notably in a recent large CDC exercise study- all the problems with energy production disappeared…

Cook had an explanation for exercise problems in ME/CFS, but it was markedly different. He proposed that metabolic problems at the cellular level were throwing ME/CFS patients’ breathing patterns off. His assertion that the early entry into the anaerobic energy production, the reduced oxygen consumption, the reduced ability to do work, etc., seen during exercise were all incorrect struck at the heart of what we thought we knew about ME/CFS.

On both a physiological and personal level, these findings seemed to make so much sense, but here we were with an issue that needed to be addressed – and which this study finally did by controlling for aerobic fitness.

A Gas Exchange Disease? Huge CDC Exercise Study Puts New Slant on ME/CFS

Were the energy impairment findings during exercise findings a statistical fluke, or were they real?

Results

The First CPET

This study found they were real after all. Even after controlling for aerobic fitness, the Keller group found that during exercise ME/CFS patients overall had a lower capacity to do work, took a shorter time to reach peak effort, had reduced ventilatory function, O2 consumption, CO2 production, and oxygen pulse compared to the healthy controls.

In other words, in contrast to Cook’s results, this study found that ME/CFS patients couldn’t produce as much energy, use as much oxygen, last as long, or do as much work as the sedentary healthy controls.

What gives? Keller et. Al proposed that Cook had his own matching problem. Noting that about 10% of Cook’s samples matched males with females, they proposed that sex differences in oxygen-carrying capacity, blood flows, blood volume, etc., could have caused Cook to miss the reduced levels of oxygenation and energy production that were present.

Pulse Pressure
blood vessels

Decreased blood flows appear to be a major problem.

Next, the Keller group focused on pulse pressure: the difference between the diastolic and systolic blood pressures during peak load; i.e. the point at which the participants’ systems were most stressed. Pulse pressure is an important indicator of cardiovascular health. While an increased pulse pressure can reflect hardening of the arteries, a narrowed pulse pressure can indicate problems with blood flows.

The narrowed pulse pressure found in the ME/CFS patients suggested that “total peripheral resistance” (i.e. resistance in the blood vessels to blood flows) was present. A variety of past findings could help explain why that might be so in ME/CFS. Hypoperfusion (the inability to provide adequate blood flows), endothelial dysfunction (blood vessel problems), reduced stroke volume (blood outflows from the heart), preload failure (inability to load the heart with enough blood), and smaller heart size could all be contributing to problems with blood flows.

This suggested that impaired blood flows and oxygen delivery are contributing to the reduced energy production during exercise they found in the ME/CFS patients. With the focus on energy metabolism and blood flows, we’re right back where we started prior to the publication of the Cook study.

Effort Preference?

With the Cook study apparently out of the way, they took on Nath’s Intramural study next. Noting that the results of the small CPET portion of the study were in line with others, they agreed with the author’s conclusion that autonomic nervous system problems contributed to the results, but there the similarities ended.

Keller et. Al. called the use of the Effort Preference Reward Test (EPRT) used, and the conclusion that reduced “effort preference” contributed to the CPET findings, “misguided”. Noting that the EPRIT test was developed for depression, and that the findings have never been highly associated with oxygen, they also asserted that the small CPET study (n=19) suffered from its own patient matching problems (!).

The jump from the Effort Preference findings to the study’s conclusion that the problem lay in broken pathways in the brain and that nothing was wrong with the muscles was one of the more dicey parts of the study. It seemed to fly in the face of several studies that have found muscle problems in ME/CFS.

Keller et. Al. proposed that problems in the muscles (poor signaling due to vagus nerve problems, accumulation of muscle metabolites, damage to the brainstem) could also explain the reduced muscle activation the Nath study found. Looking at things more systemically, they proposed that both low blood volume and blood vessel dysfunction could signal the brainstem to put the brakes on exercise in ME/CFS.

Plus, their CPET studies don’t show reductions in peak effort. Instead, they propose that ME/CFS patients’ early entry into anaerobic energy production during exercise naturally makes things more effortful for them.

2nd CPET Exercise Test

energy depletion

The sedentary but healthy controls were not affected by the short, intense exercise session; the ME/CFS patients were.

The findings from the second CPET exercise test followed on the findings from the first. From the already low 1st exercise test, the results (further reductions in peak Work (− 5.5%), time to peak exercise (− 6.6%), ventilatory measures (− 4.9% to − 7.8%), heart rate (− 2.6%), O2 pulse (− 4.0%), and rate-pressure product (− 3.4%) indicated that the first exercise test had indeed damaged ME/CFS patients’ ability to produce energy.

Contrast that with the sedentary but healthy controls who displayed a normal recovery from the exercise and no change in energy production (peak oxygen consumption or peak work).

The study also found that the first exercise session damaged the ability of the hearts of ME/CFS patients to respond normally during the second exercise session; i.e. the ME/CFS patients (but not the healthy controls) demonstrated chronotropic incompetence.

In contrast to Cook’s focus on peak VO2 – which assesses the maximum aerobic capacity present (or one’s peak ability to produce energy) – Workwell and Keller have always emphasized the importance of assessing ME/CFS patients at their ventilatory/anaerobic threshold. This is the point at which a person relies more and more on anaerobic energy production. It’s also the point at which toxic by-products from anaerobic energy production start producing pain, fatigue and other symptoms. In other words, it’s the point at which people stop exerting themselves. In their study, ME/CFS patients reached that point at lower levels of energy production, workload, and heartrate.

Cook has been more focused on peak aerobic capacity – the point in the test where someone produces their peak energy levels. That focus makes some sense with healthy controls but ignores the possibility that some people with ME/CFS can produce normal or even high peak levels of energy at some point in the test but can’t maintain them. I know an ME/CFS patient who had abnormally high peak aerobic capacity but who is very low functioning. She can temporarily produce high amounts of energy, but her aerobic window fades quickly – leaving her very impaired.

Conclusion

The largest and most rigorous 2-day cardiopulmonary exercise done to date did a couple of significant things. For one, it validated, hopefully once and for all, the highly unusual problem with exercise that afflicts people with ME/CFS. Exercise almost always makes people stronger, but in people with ME/CFS, intense exercise, in particular, does not. Instead, it damages them. In no other disease to date has a short but intense bout of exercise knocked a person’s energy production system for a loop.

This finding, of course, potentially explains so much about a disease that’s been characterized as a “systemic exertion intolerance disorder”. It helps explain why studies have indicated that people with ME/CFS are significantly less functional than people with other serious illnesses.

I still remember being gobsmacked by Workwell’s first 2-day CPET study way back in 2009. It is still probably my most exciting ME/CFS moment and I vividly remember the title of the blog I wrote “A Crack in the Foundation“.  I thought, my god, this is it! Everything is going to change after this study. Legitimacy was just around the corner and we were going to see massive studies to learn about this strange finding – and that didn’t happen. The rest of the world did not sit up and take notice.

Things have been changing, though. ME/CFS researchers took it upon themselves to do more 2-days studies and now we finally have the big study to lay all the objections to rest. Will it change things? I’m sure it will. How quickly? I have no idea.

I think it’s time, though, to say thank you to all the pioneers who plugged away for so many years at resurrecting these difficult tests, and in doing so, paved the way for this study to happen. They are courageous people who have bucked the system, perhaps at a cost to themselves. So, thank you so much Staci and Jared Stevens, Chris Snell, Mark VanNess and Todd Davenport (Workwell), thank you Betsy Keller and her Ithaca group, and Maureen Hanson (Cornell), thank you to the Van Campen, Rowe and Visser team, thank you Ruud Vermeulen and your group, and thanks, more recently, to Jong-Han Leem and his Korean group. (Thanks also to Yvette to alerting me about this study and so many more…)

We’ll see what happens from here.

  • Coming up Pt. II – the authors’ treatment recommendations given the low energy state people with ME/CFS find themselves in.

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