2 Day CPET discussion - is it evidence that GET is harmful, and is it a biomarker?

There is a particular difficulty if a potential side effect of a treatment is exacerbation of the pre-existing problem. For most drug side effects the effect is something rather rarely encountered in the treated population. Most people with a cough do not have a widespread itchy rash suddenly appear so it is relatively easy to suspect that an antibiotic was the cause. It is even easier if the side effect is rare, like bone marrow failure.

If the unwanted effect is an exacerbation of a fluctuating condition then the only way to gather evidence is to show that the pattern of the worsening is different in a treated population from a non-treated population, using statistical analysis. That need not be confined to mean levels. A different pattern of variance would be important. Thus a scatter plot of the untreated group might show after a certain period of time that the individuals' levels had wandered around but the spread of levels was the same. For the treated group after a period of time there might be a slight upward trend as whole but 10% of cases might dip way below the previous range.

That is why we really need scatter plots for all these studies, to see changes in variance patterns. Maybe the data for PACE exist somewhere on a computer, but drop outs would need to be addressed too.

 

The "training effect" is becoming more comfortable with the testing procedure and your level of performance. You don't expect to do it perfect first time right? It is the VO2peak that is often improved slightly (1-2%), the ventilatory threshold etc. is normally unchanged.

 

When discussing GET, I've generally referred to it as "possibly harmful" or something along those lines. And I've also indicated that it is contra-indicated if the cardinal symptom, per IOM and others, is PEM or "exertion intolerance" or whatever it's called. I have also cited the surveys that more people report harms than improvements. In other words, I've tried to find ways to suggest that there is a risk of long-term harm, based on all the data, without stating declaratively that this is the case. It's possible one could find places where I wasn't so careful, but that's how I've tried to approach it when reporting on it.

 

Interesting and important. At first, the layman in me really calls for solid distinctions and accuracy. What is GET and what is PACE style GET? These terms need to be defined. If being the devils Advocate, I think we have to acknowledge that the long-term harmful effect of GET not is well documented- here defining GET as the very mildest form of physical activity. At the same time - GET is of little use and benefit, may come out as pretty neutral. The problematic part then, is overselling GET as some kind of treatment, that is just not right.

Then there is “activity/training”, something that for pedagogical purposes, simply can be defined as a step above GET. What we are sure of; there are a vast number of testimonies and experiences of how activity/training harms. If you gather such testimonies and systemize them, they become something else and of some sort of value. You have patient surveys. Unfortunately they won’t count much in a the hierarchy of the medical world, which in general and here very specific, must be said to have a somewhat vulgar cochranised approach.

It is a fact that many patients have experienced long-term harm of exercise/training early on. That could be seen as a wild speculation, one could argue that it wouldn’t play any difference long-term. I personally think it has great influence on an anecdotal level, and then again, if the anecdotes are many, it is something else. Maybe not an authoritative source, but knowledge of value. With all reasonable and relevant reservations, I’m quite sure that many have ruined their prognosis the described way. But how to pin down the connection in a scientific way? We need really clever scientists with good ideas on studies. But to prove in retrospect the connection of to much activity/training early on and long-term harm, may be, in its nature and without a clear marker, almost impossible?

But if we can’t argue very strong against the long-time harm of GET, we can, and it may be even more important, highlight the real danger of activity/training early on and the impact it often has on long-term prognosis.

Interesting but difficult.

 

Depends what we is meant by ‘training effect’.
For aerobic exercise, “training effect” sounds like aerobic conditioning, meaning that your capacity to do it increases after doing it for a period of time. This takes place over a period of weeks with the shortest time to observe a change being maybe about five days.

The increase in Endurance actually happens while you are resting, the exercise triggers the body to adapt to it. For people in normal health the difference can be dramatic; one can go from being winded and sore after running a mile to being able to continue for 10

But you may have meant something entirely different.

 

The point of discussion was the variance in performance in healthy people between the first day and the second day of a 2 day CPET.

 

OK, that suggests that, as one might suspect, results can be affected by factors other than the inherent biochemical capacity of muscle tissue. That is why I wonder if the change in 2 day CPET in ME is actually measuring a metabolic change or is reflecting a signalling event that both generates PEM (before exercising) and curtails performance irrespective of muscle chemistry.

 

isn't the change on day 2 measured in gas output? that doesn't reflect a change in muscle chemistry?

 

There's a new paper on CPET and PEM, focusing on methodology.

https://www.frontiersin.org/articles/10.3389/fped.2018.00242/full

 

The VO2Peak can easily be affected through motivation, experience doing the test etc. I don't believe that a true VO2Max has been achieved by many of the ME CFS participants in both the 1 day and 2 day cardiopulmonary tests reported in the literature, due to inconsistent motivation and other biases.

That is why reductions of VO2Peak haven't been replicated in ME CFS studies. It is the performance at the ventilatory threshold (reflecting an alteration of efficiency if you look at the exchange ratios) that is hard to bias by the participant and that is the effect that is replicated between the studies in ME CFS studies.

 

The gas comes from the muscle (or goes to it) so yes it does reflect muscle chemistry!

 

Yes, I see that. But I am not concerned with 'bias by the participant' so much as influence on the metabolic pattern by signals such as cytokines that have nothing to do with the inherent metabolic capacity of the muscle or mitochondria. CPET is being used as a marker of lack of metabolic capacity of pathways in muscle or mitochondria. I wonder if the shift in ME is a shift due to a signalling mechanism that alters pathway usage, and also makes PWME feel ill even before they try.

 

What signaling mechanisms can you name that do just one single thing and interfere with nothing else? Evolution guides biology and drives pathways to be used for related functions when it confers a biological advantage. This leads to a hypothesis:

The likely answer is the hypothetical signalling mechanism likely signals to the cells to alter their metabolic functioning in addition to contributing to the sensation of fatigue.

This is what I have been looking at in particular for the last few years. But few seem to be exploring this line of research, at least from a hypothesis driven science perspective, apart from Alan Light and his colleagues. My perspective is that a large majority of the interesting research in the ME CFS field has come from exercise physiologists.

Aside from that, I think the suggestions that some people make of a demarcation between peripheral and central sensation of fatigue is a mistake leading to insufficiently justified hypotheses that the defect of sensation in patients is primarily in the brain.

 

Yes, that is what I was meaning.

 

I thought that the experimenters measured the gas exchange ratios to confirm peak effort?

 

From a purely logical point of view I still think investigation into whatever mechanism causes Delayed Onset Muscle Soreness could turn out to be useful to us.

In no way do I think it's the same thing as PEM but for me it shares enough similarities to suggest that the two things at least share a pathway, unless nature has come up with two separate pathways to do two pretty similar things.

From https://en.m.wikipedia.org/wiki/Delayed_onset_muscle_soreness

 

Yes, I'd not really twigged that aspect, but it makes sense. A bit like pain killers making a condition more painful.

 

I think we are arguing the wrong issue. I am preparing a further comment, it will take some time, but I think the crux of this issue is this - what constitutes unjustifiable harm?

 

That is one of the indicators of peak effort, but is not the sole indicator. My RER peaked above 1.1 more than a minute before I reached the final VO2Peak during my testing (on the first day).

The ventilatory threshold is the knee in the curve when you plot total ventilation vs oxygen consumption. There are some practical examples in the figures here:
https://www.researchgate.net/public..._Fatigue_During_Incremental_Treadmill_Running

Hodges 2018 noted a 11% drop in performance (wattage) despite a modest increase in oxygen consumption at the ventilatory threshold:
https://www.ncbi.nlm.nih.gov/pubmed/28782878

My own experience with the 2 day CPET was similar, a 7% drop in performance from 140w to 130w at the ventilatory threshold, despite occurring at near identical VO2VT of 22.5 mL/kg/min on both days. But unlike the subjects in Hodges, I simply couldn't reproduce my VO2Peak of 44 mL/kg/min on the second day since my legs simply could not put out the same level of force.

 

For what it's worth, inspired by this discussion, I've posted a speculative model for PEM and the 2 day CPET results based on previous musings and discussion on another forum.

Here : https://www.s4me.info/threads/speculative-schema-for-pem-and-the-2-day-cpet-results.5626/