Open (Palmerston North, New Zealand) Effects of exercise at anaerobic threshold on post exertional malaise in individuals with ME/CFS

[obeat]

I think this group were going to include metabolomics in their next study which would give us more information. Are there any UK CPET experts who would be willing to comment? What about the MRC labs @ Nottingham and Birmingham that are collaborating with Harvard?

 

[BruceInOz]

Myss is that the lactic acid feeling is not necessarily due to lactate.

I have often wondered this. The aspect that I want to see explained in a working model is why do I get this achy leg muscle feeling from purely too much cognitive effort.

 

[pteropus]

@SnowLeopard - the studies you mentioned, re effects of glycogen depletion during exercise ...

did anyone check for altered / lowered glycogens in the brain, that might wobble the CNS, and/or trigger a whole-body danger signal ?

it might help explain why both physical exertion and mental / emotional exertion can contribute to PEM ...

 

[Snow Leopard]

@SnowLeopard - the studies you mentioned, re effects of glycogen depletion during exercise ...

did anyone check for altered / lowered glycogens in the brain, that might wobble the CNS, and/or trigger a whole-body danger signal ?

it might help explain why both physical exertion and mental / emotional exertion can contribute to PEM ...

Not specifically. But I personally have not observed cognitive exertion leading to PEM issues in the rest of my body. (example, exams at uni). Whereas PEM induced through exercise does induce cognitive issues. (and increased cognitive exertion does lead to cognitive issues the next day)

 

[Hutan]

Here's my data from the last trial this Massey University group did.

At ventilatory threshold (the proxy for anaerobic threshold):
Test 1:
Watts 90
Heart rate 165
VO2 (ml/kg/min) 19.5

Test 2 - 48 hours later (no feeling of PEM)
Watts 75
Heart rate 148
VO2 (ml/kg/min) 14.7

% drop
Watts 17%
Heart rate 10%
VO2. 25%

Normative VO2 for my age 17.8

So, this suggests that I'm not less fit than the average woman of my age, but some activity (which is not enough to cause any prolonged feeling of PEM) can markedly lower my ventilatory threshold. As far as I can see, that isn't normal, even if the result was confounded by activity done outside of the actual test.

I bought a lactate monitor and have checked my blood levels a few times before and after exercise. My lactate levels seem to be the same as what would be expected in a healthy person.

It would not be hard to monitor the ventilatory threshold of severely ill PwME - at least monitoring what happens when they get up to go to walk to another room or whatever to see if they get to the ventilatory threshold. I wonder if this has been done. It would also be interesting to compare ventilatory thresholds when people with mild ME feel that they are in a crash to those when they are not.

I can't find anything on what happens to ventilatory thresholds when people have viral or bacterial infections. Exercise physiologists must surely know this.

@Jonathan Edwards, I'm quite open to the possibility of this CPET stuff being a red herring. But I'm not understanding yet why you seem to give the 2 day CPET little credence as a biomarker.

 

[Jonathan Edwards]

@Jonathan Edwards, I'm quite open to the possibility of this CPET stuff being a red herring. But I'm not understanding yet why you seem to give the 2 day CPET little credence as a biomarker.

I think if I was sure the result was reproducible and not due to confounding factors it would be of interest as a biomarker, but rather impractical. My main concern here is that it being a biomarker for diagnosis should not be confused with it have any direct significance in terms of generation of symptoms.

 

[Hutan]

1. Is the quantification of ventilatory threshold reliable?
From a quick bit of googling, it looks as though there is a good level of confidence in the measurement of ventilatory thresholds. I.e. they seem to be reproducible, objective and any issues with lack of effort from the trial participant can be identified. But I don't really know. Are there questions about the reliability of CPET measurements?

2. Is the finding of a lowered ventilatory threshold on the second CPET in PwME reliable?
I thought that the finding had been replicated by at least a few researchers, but I haven't looked at this in any structured way. Is this not right? Yes, more care probably needs to be taken to get unconfounded data.

3. If the finding of a lowered ventilatory threshold on the second CPET in PwME is reliable, is this not useful? Isn't the finding telling us that PwME are less good at using oxygen 24 to 48 hours after exercise whereas healthy people are not? If so, doesn't that give us clues as to part of what is going on?

4. Does exceeding the ventilatory threshold (or a certain heart rate) cause PEM? (and so can keeping below the ventilatory threshold or a certain heart rate allow for safe activity?)

The hope is to understand how much those with ME/CFS can increase their heart rate without exhibiting symptoms of PEM, which will ideally provide individuals with a safe intensity for exercise. From this research we are hoping to discover a way in which symptoms of PEM can be reduced and therefore lead to individuals with CFS/ME to manage their condition better and have a greater quality of life.

There is a lot of confidently delivered advice to PwME out there saying 'keep your heart rate below x% of your heart rate at anaerobic threshold' or variations on this idea.

e.g.

A target heart rate range should be set to avoid overexertion, generally <100 beats per minute.

And there is little to no evidence to support this kind of advice. So it's good that the Hodges team wants to explore the question. But, as @Ravn said, there's so much variability that I doubt that one paired non-maximal CPET per trial participant in a trial with only 20 participants is going to tell us much, even if they do take steps to ensure the exertion of travel and other non-test activity doesn't confound things. Things like menstrual cycle, and infections, and the timing and composition of meals, and the time of day the testing is done could all potentially confuse the result.

Also, there is no account made of the possible cumulative effect of exertion. Exertion that doesn't cause PEM when done once, or even twice perhaps may cause PEM if it's done for three days in a row.

If the Massey team really want to achieve their hope,

The hope is to understand how much those with ME/CFS can increase their heart rate without exhibiting symptoms of PEM

they would do better to issue participants with fitness trackers with step monitoring and an alarm set to go off at a specified heart rate, with an electronic symptom diary to be completed daily over the course of a few months.

If instead the Massey team really just want to use the CPET machine for something, then I'm sure that we could think of something better. Even just replicating the standard 2xCPETS but working hard to reduce confounding could help us answer 'yes' more confidently to the question of whether the reduction in ventilatory threshold is a reliable finding.

 

[Sean]

Also, there is no account made of the possible cumulative effect of exertion. Exertion that doesn't cause PEM when done once, or even twice perhaps may cause PEM if it's done for three days in a row.

important point.

 

[Jonathan Edwards]

they would do better to issue participants with fitness trackers with step monitoring and an alarm set to go off at a specified heart rate, with an electronic symptom diary to be completed daily over the course of a few months.

This is rather my feeling.

 

[Snow Leopard]

I think if I was sure the result was reproducible and not due to confounding factors it would be of interest as a biomarker, but rather impractical. My main concern here is that it being a biomarker for diagnosis should not be confused with it have any direct significance in terms of generation of symptoms.

I suggest it has central significance as the ventilatory threshold correlates with the increase in perception of effort across almost all patient groups and healthy controls where the test is limited by muscle fatigue, rather than ventilation difficulties (for example, COPD is limited by ventilation issues).

Experiments involving the ventilatory threshold has been of clear interest to exercise physiologists who seek to uncover the basis for effort perception, fatigue and to improve performance of endurance athletes.

Note: I have noticed that many people seem to assume the ventilatory threshold and the anaerobic threshold are the same thing. They are not. The transitions are indeed associated in healthy people, but it is important to note it is not merely a change in metabolism that is important and it has been shown that increase in 'lactate' on its own does not cause this transition, nor is it singularly associated with the perception of fatigue.

The ventilatory threshold that is of central importance (not the anaerobic threshold) as it signifies a complex physiological transition point, involving shifts not only in peripheral metabolism, but shifts in nociceptive sensory factors, a changes in nerve conduction velocity (age and temperature are factors related to this too), a change in neural drive of the muscles (frequency and amplitudes), shifts in activation of muscle fibre subtypes, a change in neural drive of the heart and so on. So far, what I have learned of the relationships and potential directional relationships/feedback between each of these factors has been surprising.

Lastly, performance at the ventilatory threshold is the most reproducible finding during a CPET (regardless of who the subject is) - unlike VO2peak is is not influenced by motivation (read: giving up early). The fact that all studies in CFS have noted lower performance at the ventilatory threshold means that it is the most reproduced and noteworthy physiological finding found in CFS patients so far.

Lastly, I can tell you what it feels like as a patient - the power that I am used to from my legs, the power I remember from yesterday is simply not there. Lo and behold, I've hit the ventilatory threshold early. What is the cause of this loss of power I wonder? That is why the aforementioned research is important.

 

[Snow Leopard]

If the Massey team really want to achieve their hope,

they would do better to issue participants with fitness trackers with step monitoring and an alarm set to go off at a specified heart rate, with an electronic symptom diary to be completed daily over the course of a few months.

If instead the Massey team really just want to use the CPET machine for something, then I'm sure that we could think of something better. Even just replicating the standard 2xCPETS but working hard to reduce confounding could help us answer 'yes' more confidently to the question of whether the reduction in ventilatory threshold is a reliable finding.

I agree, but I don't believe limiting heartrate on its own is a magic strategy to prevent PEM. Quite frankly, it just sounds like a recipe for deconditioning, since patients will learn to specifically avoid even brief moments of intense activity.

 

[Jonathan Edwards]

I agree that the physiology is complex and that the various thresholds and levels interrelate in subtle ways. But I am still stuck with the idea that studying PWME under athletic training conditions misses the point. The problem for PWME is not that they have trouble with exercise that makes them out of breath (something I do once a month much of the time without missing anything). They have trouble with exertion at a much lower level in daily activities. Rather than constantly thinking the solution is to find a way to make these people athletes without pain it seems what we need is a way of understanding why ordinary daily activity is troublesome. That to my mind means learning how to study what is going on in muscle or other tissues at those ordinary levels, well below any thresholds.

 

[Dolphin]

Not specifically. But I personally have not observed cognitive exertion leading to PEM issues in the rest of my body. (example, exams at uni). Whereas PEM induced through exercise does induce cognitive issues. (and increased cognitive exertion does lead to cognitive issues the next day)

I haven’t followed this thread. But cognitive exertion of an exam caused a big relapse for me in college including physical symptoms. I had realised I needed to do less exercise during the exam period (had been swimming 1000 metres or cycling 6 miles/ 9 km virtually every second day for over a year). So I was doing less physically than usual. After an intense three-hour exam (we were told to answer as many questions as possible but there was not enough time to answer them all), my glands swelled up and I had a very sore throat making it painful to swallow. It was summertime so unlikely to have been an infection. I hadn’t cut down on sleep.

 

[Snow Leopard]

I haven’t followed this thread. But cognitive exertion of an exam caused a big relapse for me in college including physical symptoms. I had realised I needed to do less exercise during the exam period (had been swimming 1000 metres or cycling 6 miles/ 9 km virtually every second day for over a year). So I was doing less physically than usual. After an intense three-hour exam (we were told to answer as many questions as possible but there was not enough time to answer them all), my glands swelled up and I had a very sore throat making it painful to swallow. It was summertime so unlikely to have been an infection. I hadn’t cut down on sleep.

I had an experience like that too, developing symptoms pretty much straight after my last exam and it was summertime - but it ended up being an actual infection and lasted quite some time - 3 weeks then the virus seemed to come back for another round. (I get ill just as often in summer as winter)

The PEM I'm talking about is that drained/loss of power feeling, sometimes with some more pain than usual if muscles were used on the previous days. Exams did cause "post exertional" cognitive issues, worse headache etc on subsequent days.

¯\_(ツ)_/¯

 

[alex3619]

There are a few issues in this thread I would like to address, mostly from comments by @Jonathan Edwards .

Yes, its a problem that CPET involves investigations at the high end of performance. The reason this is being focused on is its a more reliable test, the gold standard in determining dysfunction. Its used in a number of illnesses.

Invasive CPET is getting much more data. Like high venous oxygen return, and low heart preload.

However these problems are not, in ME, at the athletic level of performance. The measured changes are found in patients at the anaerobic threshold. For patients still well enough to be ambulatory this can sometimes be found with a heart rate of eighty something. That is not an athletic range. Athletic consequences are often found for us at very low activity levels. I suspect this is tied to severity, but we lack that data.

We do however have very little idea of how this gets worse with more severe patients. I have suggested that another path would be to use metabolic rate testing. When I was a mild patient my metabolic rate was always quite low. My brain metabolism was also measured (tagged glucose I think) and found quite low. Since then I have gotten much worse, but have not had these tests again.

 

[Inara]

Can anyone help explain this paradox?

a) There's another process going on in you?
b) Could instant muscle burning happen due to neuropathies (of whatever kind)?
c) They're not measuring the right things? (Whatever right is....)
d) Many other things?

Is there some way to experience a lactic acid feeling without reaching the anaerobic

Yes? See mitochondriopathies. Or is the production of ATP via glycolysis always defined as "anaerobic threshold"?

 

[Snow Leopard]

I agree that the physiology is complex and that the various thresholds and levels interrelate in subtle ways. But I am still stuck with the idea that studying PWME under athletic training conditions misses the point. The problem for PWME is not that they have trouble with exercise that makes them out of breath (something I do once a month much of the time without missing anything). They have trouble with exertion at a much lower level in daily activities. Rather than constantly thinking the solution is to find a way to make these people athletes without pain it seems what we need is a way of understanding why ordinary daily activity is troublesome. That to my mind means learning how to study what is going on in muscle or other tissues at those ordinary levels, well below any thresholds.

(note the following is not directly related to the Palmerston study, which is not directly studying what I am proposing)

I thought I made it clear that the ventilatory threshold is not due to people being "out of breath" at all, it is achieved much sooner than that.

The ventilatory threshold is reached substantially before VO2Max (which some people can reach without feeling like they're completely "out of breath") and is specifically associated with a sudden and specific increase in perceived exertion (typically measured using the Borg scale - the interesting part is everyone, regardless of if you are healthy or not, follows the same pattern).

The reason why it is of particular note is because it is a reproducible control point in a study - otherwise it is difficult to control for all the other variables/biases when you want to consider the relationship between what is going on in terms of cellular metabolism, neuromuscular drive and their relationship with perceived exertion and so on. Sure you can try and study them separately, but focusing on the ventilatory threshold ties them up into a neat bundle. I don't really see any other way of uncovering what the specific signals are that lead us to perceive fatigue, the specific issues that lead to early fatiguability (less leg power on my bike for example) during PEM.

The way I see it, the idea is to obtain clues for old-fashioned hypothesis driven research, clues which will also explain why daily activity is troublesome. The alternative is hoping to find a needle in another omics haystack with the usual difficulties, like poor signal to noise due to lack of funding/sample size.

 

[Jonathan Edwards]

I thought I made it clear that the ventilatory threshold is not due to people being "out of breath" at all, it is achieved much sooner than that.

I understood what you meant but I am using out of breath in the popular sense of noticing an increase in respiratory rate, not complete exhaustion. Thus my wife teases me for big out of breath having walked up an escalator when she is not.

PWME tell me that they get PEM without being out of breath and I am pretty sure it is in this sense. They get PEM from doing exams and from travelling in trains, which do not increase respiratory rate.

For patients still well enough to be ambulatory this can sometimes be found with a heart rate of eighty something.

I was under the impression that thresholds for PWME were not that different on the first CPET testing from sedentary controls. If people are not even noticing breathing a bit harder I doubt they are at the level of anaerobic threshold. Do we actually have evidence for PWME going into high level anaerobic respiration during normal daily activities?

 

[alex3619]

Do we actually have evidence for PWME going into high level anaerobic respiration during normal daily activities?

Numerous patients have reported their target heart rate and anaerobic threshold. I am still waiting for a published paper that focuses on this. I suspect, its not proven, that very severe patients may have an anaerobic threshold in the 70s or even 60s, but how do you test them? I could be wrong about this of course, we need better studies, and this area is problematic as how do you test very severe patients? From recollection most of these accounts are anecdotal, but it does raise a question about where these thresholds are. Its also possible patients are misunderstanding what they have been told, but I tend to doubt this except maybe for a few isolated cases. Heck, I could be misunderstanding what they have said. We do need better studies.

 

[Jonathan Edwards]

Numerous patients have reported their target heart rate and anaerobic threshold.

I don't understand the terminology here fully but as you say how do you test them? I am not clear how you can reach an anaerobic threshold without increasing your respiratory rate because anaerobic threshold is surely the point where despite breathing harder you still cannot supply enough oxygen to muscle to maintain aerobic demand? I wonder if this is where confusion with the 'early anaerobic' phase comes in. I guess that if I run a 60 metre sprint without even taking a breath anaerobic metabolism might kick in but my understanding is that when anaerobic thresholds are being measured it is more of a steady state situation where anaerobic metabolism is needed despite maximum ventilation.