Comparing Idiopathic Chronic Fatigue and ME/CFS: Response to 2-day CPET, two papers males & females, 2021, Van Campen & Visser

[Hoopoe]

My RER was 1.4 or something like that when I did a CPET. Does that mean that I put in real effort?

 

[Snow Leopard]

My RER was 1.4 or something like that when I did a CPET. Does that mean that I put in real effort?

Either that, or your body is broken!

 

[Hoopoe]

It's hard to disagree that my body is broken.

 

[ukxmrv]

I'm trying to put this politely, but a the reason why a few patients didn't record a decline is because they didn't work very hard in the first place. I mean for the males, the mean HR peak on the first day was 148 BPM, for women the figure was 156 BPM (the men were about 12% older, partly explaining the difference). Both of these figures are well below the age predicted peak heart rates for people of their age. One point that many people often don't realise is that deconditioning can lead to a higher peak heart rate than a highly conditioned individual - which I think is one of the reasons why my heart rate peaked at 202 BPM on the first CPET.

When you say "work very hard" do you mean that they were not pushing themselves or that their deconditioning stopped them from reaching their peak heart rate?

If they were deconditioned what would they feel on the bike that would stop them pedalling faster do you think? Would it be a feeling of being "puffed" or would their legs just stop moving.

 

[Snow Leopard]

When you say "work very hard" do you mean that they were not pushing themselves or that their deconditioning stopped them from reaching their peak heart rate?

The former. Deconditioning simply means lower performance at a given heart rate.

If they were deconditioned what would they feel on the bike that would stop them pedalling faster do you think? Would it be a feeling of being "puffed" or would their legs just stop moving.

I don't think it is deconditioning. Having ME/CFS means it is more difficult to exercise if you are not used to it, and it will feel like your legs can't work any harder. Some people may think that this is their peak performance and will stop if not strongly encouraged to continue.

 

[Hoopoe]

Could an unusually high RER indicate an unusual adaptation to anaerobic metabolism? (has ME given me superpowers? The ability to keep going even with little oxygen)

Or is it more likely to be due to problems with the equipment?

 

[Snow Leopard]

Could an unusually high RER indicate an unusual adaptation to anaerobic metabolism? (has ME given me superpowers? The ability to keep going even with little oxygen)

Or is it more likely to be due to problems with the equipment?

A very high RER (>1.2) suggests significant hyperventilation. This could be due to a high rate of respiratory compensation.

Unless it was a transient spike, or the equipment is somehow not calibrated properly, it is probably not an equipment problem.

 

[Hutan]

When you say "work very hard" do you mean that they were not pushing themselves or that their deconditioning stopped them from reaching their peak heart rate?

It could be, as in my case I think, that the researchers applied a significant amount of caution with people with ME/CFS and/or were happy when data supportive of their hypothesis was achieved, and stopped ME/CFS participants when they got to RER=1.1, rather than letting them continue on for a while to see if their VO2 increased.

One of the points that Max Nelson made was that there is inconsistent application of 'encouragement' of participants during the tests and it is possible this inconsistency could apply to patients vs. controls in the van campen studies.

In these studies, it's ME/CFS vs ICF. The researchers may have had an unconscious bias to 'prove' their hypothesis (i.e. that the lowering of performance in 2nd CPET in ME/CFS but not in ICF) or to protect people with ME/CFS from doing more than was necessary. And, when people with ME/CFS are doing the paired CPET to support a disability claim, once they have got to RER=1.1 on their second CPET, there's no incentive for either the patient or the researcher to push on past that point in order to possibly achieve a higher VO2Max.

So there may have been different levels of encouragement applied, and effort made that would produce a decrease of recorded VO2max in ME/CFS and not in ICF.

(Against that argument is the fact that in the female van Campen study, the RER for CPET1 was 1.2, but only 1.1 for CPET2. So it appears that there was less effort on the second CPET, but still the VO2max for the ICF cohort increased.)

Anyway, my conclusion from all of that is that the question of encouragement given, effort applied and the researcher's choice of when to stop a test are potential confounders to the VO2max recorded (and work performance at that point). And so it's best to focus on the ventilatory threshold numbers.

Are there any potential biases with the ventilatory threshold?

Edit : Snow Leopard has discussed the ventilatory threshold more here:
Over which physiological abnormalities in ME/CFS is there a scientific consensus about?

 

[Medfeb]

I'm trying to put this politely, but a the reason why a few patients didn't record a decline is because they didn't work very hard in the first place. I mean for the males, the mean HR peak on the first day was 148 BPM, for women the figure was 156 BPM (the men were about 12% older, partly explaining the difference). Both of these figures are well below the age predicted peak heart rates for people of their age. One point that many people often don't realise is that deconditioning can lead to a higher peak heart rate than a highly conditioned individual - which I think is one of the reasons why my heart rate peaked at 202 BPM on the first CPET.

But those age-predicted maximum heart rates are based on healthy normals. I may misunderstand but I thought Workwell was saying that in ME populations, those calculations were not appropriate as they overestimate the target heart rate. Am I missing something?

 

[Hutan]

Are you perhaps thinking of the target training heart rate that Workwell suggest people with ME/CFS routinely keep their heart rate under, so as to avoid PEM? I don't think I've seen any good evidence yet for the idea that keeping your heart rate below a percentage, e.g. 60% of maximum heart rate, stops PEM.

There are safety limits on the blood pressure a clinic doing a CPET will allow their clients to have. The safety limits might vary from clinic to clinic, and depend on the health of the person being tested too. I guess those safety limits might sometimes result in clinics stopping as soon as RER=1.1 is reached, and so contribute to an issue with recorded VO2maxes being less than actual VO2maxes.

 

[Snow Leopard]

But those age-predicted maximum heart rates are based on healthy normals. I may misunderstand but I thought Workwell was saying that in ME populations, those calculations were not appropriate as they overestimate the target heart rate. Am I missing something?

Besides age and sex (and hormonal variances), there is likely some degree of genetic variance (and an effect of fitness, but this can sometimes increase the maximum heart rate in the less conditioned!)

Exercising to one's true maximal heartrate is hard for someone with ME/CFS. It requires pushing beyond VO2Max and this is difficult to do when your body is strongly telling you to stop! Without strong encouragement, most participants will stop early.

I do think that in these studies, many participants got within a fair shout of their maximum (and I suggest these are the participants that recorded clear drops in performance on the second day), however there can be a few outliers where participants stopped earlier.

A maximal CPET is exactly as it sounds - it is hard. If participants don't recall that it was on par with the most difficult exercise they have ever done, then it is unlikely they reached their maximal workrate.

Are there any potential biases with the ventilatory threshold?

I have wondered about the effect of different pedalling cadences between the two days (equivocal results in healthy participants, though usually focusing on VO2Max). Though an increase in cadence may be considered a normal physiological adaptation, rather than a confounding factor, so...

Are you perhaps thinking of the target training heart rate that Workwell suggest people with ME/CFS routinely keep their heart rate under, so as to avoid PEM? I don't think I've seen any good evidence yet for the idea that keeping your heart rate below a percentage, e.g. 60% of maximum heart rate, stops PEM.

I agree, I experience PEM even without reaching high heart rates. The ventilatory threshold itself is an artefact of the ramped increase in workrate, and so cannot be equated to a true 'anerobic threshold heartrate' when doing other forms of exercise. Having said that, high heart rates may indeed increase the likelihood or severity of PEM, but we don't have strong data that quantifies this risk.

 

[Ryan31337]

Could an unusually high RER indicate an unusual adaptation to anaerobic metabolism? (has ME given me superpowers? The ability to keep going even with little oxygen)

A very high RER (>1.2) suggests significant hyperventilation. This could be due to a high rate of respiratory compensation

I had a similar experience in one of my three CPETs. RER @AT was 1.1, RER @VO2max was 1.5! It was a poor result, 50% of expected VO2max.

I was unknowingly hyperventilating with a clear breathing pattern disorder. I confused the heck out of the technicians because my breathing rate was low but excessively deep. They told me I was breathing slower than their resting BR, despite me being on the bike and pedalling during warm-up. They assumed I was previously a professional athlete/swimmer that was doing some sort of pre-exercise breathing technique - I was just breathing comfortably (for me).

Subsequent CPETs were after I started on a number of POTS interventions + a little bit of behavioural modification on the breathing pattern disorder. Though the BPD largely improved on its own once on the POTS treatments, messed up respiratory drive is well recognised as being caused by (and subsequently reinforcing in a vicious circle) other POTS issues.

My RER was more normal on the tests after that. <1 @AT and 1.2 @VO2max. My VO2Max was up to around 80% of predicted too.

 

[cassava7]

It could be, as in my case I think, that the researchers applied a significant amount of caution with people with ME/CFS and/or were happy when data supportive of their hypothesis was achieved, and stopped ME/CFS participants when they got to RER=1.1, rather than letting them continue on for a while to see if their VO2 increased.


In these studies, it's ME/CFS vs ICF. The researchers may have had an unconscious bias to 'prove' their hypothesis (i.e. that the lowering of performance in 2nd CPET in ME/CFS but not in ICF) or to protect people with ME/CFS from doing more than was necessary. And, when people with ME/CFS are doing the paired CPET to support a disability claim, once they have got to RER=1.1 on their second CPET, there's no incentive for either the patient or the researcher to push on past that point in order to possibly achieve a higher VO2Max.

So there may have been different levels of encouragement applied, and effort made that would produce a decrease of recorded VO2max in ME/CFS and not in ICF.

(Against that argument is the fact that in the female van Campen study, the RER for CPET1 was 1.2, but only 1.1 for CPET2. So it appears that there was less effort on the second CPET, but still the VO2max for the ICF cohort increased.)

Anyway, my conclusion from all of that is that the question of encouragement given, effort applied and the researcher's choice of when to stop a test are potential confounders to the VO2max recorded (and work performance at that point). And so it's best to focus on the ventilatory threshold numbers.

Are there any potential biases with the ventilatory threshold?

Edit : Snow Leopard has discussed the ventilatory threshold more here:
Over which physiological abnormalities in ME/CFS is there a scientific consensus about?

The two papers indicate that encouragement was standardized, with all patients being asked to push to their maximum.

Males (Appendix A): "The test was supervised by an experienced cardiologist. Patients were encouraged by standard phrases each minute to perform maximally to the point of exhaustion. (...) Immediately after the test, the attending cardiologist noted the primary reason for termination of the exercise and judged whether motivation and efforts during exercise were optimal for the individual patient."

Females (section 2.2): "Patients were encouraged by standard phrases each minute to perform as maximally as possible."

As for the studies by the Workwell Foundation: "All subjects achieved peak test criteria on both tests according to American Heart Association guidelines [27]."

 

[Hutan]

The two papers indicate that encouragement was standardized, with all patients being asked to push to their maximum.

Yes, but what is planned and what is reported are both not necessarily what actually happened in every instance. And it's difficult to standardise effective encouragement - disinterested encouragement that is delivered according to a schedule in a flat fashion, or ambivalent encouragement when there is some concern that the person may be pushing themselves in an unsafe way, is likely to be a lot less effective than enthusiastic encouragement delivered by someone who really does want you to increase your performance.

I'm not suggesting any intentional effort to bias the results by the people running the tests. I just want us to think through the possible ways the CPET results might not be true - so that any information about ME/CFS is rock-solid.

As for the studies by the Workwell Foundation: "All subjects achieved peak test criteria on both tests according to American Heart Association guidelines [27]."

Yes, but what we've been finding out here is that simply achieving an RER of 1.1 does not mean that VO2max was achieved.

 

[Mithriel]

We have to remember that the beauty of the CPET test is that it is a standard diagnostic test used routinely all over the world. This is not like some of the other testing proposed in ME papers.

The test is administered just once to give a reading that doctors have been taught to interpret. This reading is taken as proof of the state of the heart and lungs. In some diseases such as cystic fibrosis the reading is used to show if the disease is worsening. A change is seen as more damaged tissues because people recover from the test within 24 hours.

Now, after decades of every standard test being normal in people with ME we have found one where we have a different result.

The results were so shocking to medics that Workwell was forced to prove the machines were working on the second day.

At last we have a pointer to which bodily process is damaged in ME. It is not diagnostic, it is too dangerous for that but it is better than anything we have had before.

 

[Peter T]

At last we have a pointer to which bodily process is damaged in ME. It is not diagnostic, it is too dangerous for that but it is better than anything we have had before.

As this is undertaken more routinely with people with ME, it may be that CPET is seen to be necessary for an ME diagnosis, so in that sense it may become part of the diagnostic process, but as it is obviously not sufficient for an ME diagnosis in another sense it is not uniquely diagnostic. Similarly we might see specific results on a tilt table test, some aspect of orthostatic intolerance, become necessary but not sufficient for an ME diagnosis.

It may be that we will end up with a particular pattern of results in several diagnostic tests as both necessary and sufficient for an ME diagnosis rather than any unique individual test. But even without either option, having such tests supporting the possibility an ME diagnosis will hopefully help to change the medical preconceptions about our condition.

 

[Simon M]

Overall, this looks like a really important study because it's a decent size and includes the ideal comparison — not with healthy controls but with those who have other types of unexplained fatigue. Plus, the broad findings are replicated in its female-only sister study.

And thanks for all the great analysis here. I'm here really late.

Anyway, some comments from me, sometimes offering a slightly different perspective .

But to me, it has a serious methodological problem. The sample is of males who have done CPETs as part of a diagnostic process. ...

It is highly likely that a negative response to exercise in the CPET has contributed to the label of ME/CFS being applied to some of people, while a positive response to exercise was assumed to indicate the absence of PEM, and so those other people were labelled 'idiopathic chronic fatigue'.

That's an important point about the potential of a circular argument by diagnosing on the basis of the two-day test. That would mean overriding the results of some kind of symptom check, which would be a bit strange.

I also have a concern that only 26/76 (one third) of ME/CFS-diagnosed patients who undertook no maximal exercise test had the two-day test with the second test the following day. It wasn't clear why some patients had the test used in this study and the majority did not. That's a potential confounding issue as the sample here might not be representative.

It's studies like that that I hope will transform ME research to ensure the old Oxford and Fukuda definitions that don't require PEM, are no longer used in research, and that old studies that used these broad criteria should be recognised as no longer valid. For example all the GET studies based on these old definitions are scuppered because there's no information on what proportion of patients had PEM.

that risks throwing out the baby with the bathwater. The only studies I have seen that measure PEM in Fukuda patients find that over 90% of people have that symptom. Also, I'm pretty sure the first two day maximal studies diagnosed on the basis of Fukuda, and had the same findings. Nobody wanted to throw away those findings.

Also studies like this are so import in developing our understanding and definitions of what PEM is, and to distinguish it from the widespread confusion with increased fatiguability.

it's important to be clear that this study does not measure PEM, which is a symptom.

The notion is that the decline on day two reflects the same biological changes that drive PEM. That's an assumption. The key thing here is that no patient ever has PEM triggered by a maximal exercise test, unless they're in a research study. It can also be triggered by mental exertion — how does that fit? And the exhaustion we experience with PEM happens for many of us way below even the ventilatory threshold. Maybe had a brief chat on this later. Mostly, I don't think you need a mask

So, at least in my book, these studies are really important for indicating pathology that is potentially unique to ME/CFS. But we can't use them to safely draw conclusions about PEM.

This is useful I think. 22% of the ME/CFS females did not qualify as being 'deconditioned' as defined here (i.e. their VO2 peak was at least 85% of that predicted for their age).

In line with @Snow Leopard's comments. for heart rate at least, even in healthy people, studies have found that age-predicted levels are pretty inaccurate.

I can't finish without commenting on the lack of corrections for multiple comparisons – simply using P <0.01 is not sufficient. However, since most of the p values were really very low, the key findings would survive even strict correction.

 

[ME/CFS Skeptic]

Yes, but look at the change in Vo2 at the ventilatory threshold in both males and females:

Male

Female

I agree with Hutan. This looks too good to be true. All the male ME/CFS patients had a reduction in workload while all the male ICF patients had an increase in workload at the second CPET.

Given how arbitrary ME/CFS diagnostic criteria are, this seems extremely unlikely. Even if there was a true and large effect, one would expect that some patients might have been misdiagnosed in either the ME/CFS or ICF group. No overlap is really strange.

 

[Snow Leopard]

I agree with Hutan. This looks too good to be true. All the male ME/CFS patients had a reduction in workload while all the male ICF patients had an increase in workload at the second CPET.

I talked to Max Nelson about this (several years ago). An increase in peak workload on subsequent tests is actually common in healthy people, albeit not necessarily on consecutive days. As people become used to the test, they're likely to push a little bit harder. Keep in mind that peak workload occurs beyond VO2Max and thus is also dependent on motivation.

 

[ME/CFS Skeptic]

I talked to Max Nelson about this (several years ago). An increase in peak workload on subsequent tests is actually common in healthy people, albeit not necessarily on consecutive days. As people become used to the test, they're likely to push a little bit harder. Keep in mind that peak workload occurs beyond VO2Max and thus is also dependent on motivation.

Ok but why the almost perfect separation between those who meet ME/CFS criteria and those who don't?

If one time in the future something significant is found, it would be really weird that ME/CFS diagnostic criteria would have already separated patients into those who have the abnormality and those who don't. I would expect a much more messy result.