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

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!

 

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

 

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.

 

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

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.

 

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.

 

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.

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...

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.

 

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.

 

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]."

 

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.

 

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.

 

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 .

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.

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.

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.

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.

 

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.

 

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.