Abnormal blood lactate accumulation during repeated exercise testing in ME/CFS, 2019, Lien et al

Physiological Reports Abnormal blood lactate accumulation during repeated exercise testing in myalgic encephalomyelitis/chronic fatigue syndrome by Katarina Lien et al

Abstract
Post‐exertional malaise and delayed recovery are hallmark symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Studies on repeated cardiopulmonary exercise testing (CPET) show that previous exercise negatively affects oxygen uptake (VO2) and power output (PO) in ME/CFS. Whether this affects arterial lactate concentrations ([Laa]) is unknown.

We studied 18 female patients (18–50 years) fulfilling the Canadian Consensus Criteria for ME/CFS and 15 healthy females (18–50 years) who underwent repeated CPETs 24 h apart (CPET1 and CPET2) with [Laa] measured every 30th second. VO2 at peak exercise (VO2peak) was lower in patients than in controls on CPET1 (P < 0.001) and decreased in patients on CPET2 (P < 0.001).

However, the difference in VO2peak between CPETs did not differ significantly between groups. [Laa] per PO was higher in patients during both CPETs (Pinteraction < 0.001), but increased in patients and decreased in controls from CPET1 to CPET2 (Pinteraction < 0.001).

Patients had lower VO2 (P = 0.02) and PO (P = 0.002) at the gas exchange threshold (GET, the point where CO2production increases relative to VO2), but relative intensity (%VO2peak) and [Laa] at GET did not differ significantly from controls on CPET1. Patients had a reduction in VO2 (P = 0.02) and PO (P = 0.01) at GET on CPET2, but no significant differences in %VO2peak and [Laa] at GET between CPETs.

Controls had no significant differences in VO2, PO or %VO2peak at GET between CPETs, but [Laa] at GET was reduced on CPET2 (P = 0.008).

In conclusion, previous exercise deteriorates physical performance and increases [Laa] during exercise in patients with ME/CFS while it lowers [Laa] in healthy subjects.

 

Discussion section excerpts. Why is repeatability in ME so hard!

 

For easier reading:

Post‐exertional malaise and delayed recovery are hallmark symptoms of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Studies on repeated cardiopulmonary exercise testing (CPET) show that previous exercise negatively affects oxygen uptake (VO2) and power output (PO) in ME/CFS.

Whether this affects arterial lactate concentrations ([Laa]) is unknown.

We studied 18 female patients (18–50 years) fulfilling the Canadian Consensus Criteria for ME/CFS and 15 healthy females (18–50 years) who underwent repeated CPETs 24 h apart (CPET1 and CPET2) with [Laa] measured every 30th second.

VO2 at peak exercise (VO2peak) was lower in patients than in controls on CPET1 (P < 0.001) and decreased in patients on CPET2 (P < 0.001).

However, the difference in VO2peak between CPETs did not differ significantly between groups.
[Laa] per PO was higher in patients during both CPETs (Pinteraction < 0.001), but increased in patients and decreased in controls from CPET1 to CPET2 (Pinteraction < 0.001).

Patients had lower VO2 (P = 0.02) and PO (P = 0.002) at the gas exchange threshold (GET, the point where CO2production increases relative to VO2), but relative intensity (%VO2peak) and [Laa] at GET did not differ significantly from controls on CPET1.

Patients had a reduction in VO2 (P = 0.02) and PO (P = 0.01) at GET on CPET2, but no significant differences in %VO2peak and [Laa] at GET between CPETs.

Controls had no significant differences in VO2, PO or %VO2peak at GET between CPETs, but [Laa] at GET was reduced on CPET2 (P = 0.008).

In conclusion, previous exercise deteriorates physical performance and increases [Laa] during exercise in patients with ME/CFS while it lowers [Laa] in healthy subjects.

 

Happy to finally see it published.

Seems to me to indicate that we lack the ability to recover from day 1 and increase our physical performance, as fast as healthy controls?

What do u think @Jonathan Edwards ?

 

This is significant isn't it? Saying there was an increase at the 2nd CPET for pwME compared to the 1st, whereas for controls it dropped.

 

This study did reproduce the major consistent finding so far: reduced performance at the ventilatory threshold. The 8th study so far if we include the study based on a single pair of twins.

The VO2Peak findings have been inconsistent because patients have not been consistently exercising to their true VO2Max across studies.

No, it was the same on both days for ME patients. This clearly shows that differences in lactate accumulation is not the cause of the reduced performance at the ventilatory threshold on the 2nd day.

 

This is interesting. I think we previously discussed how the ventilatory threshold is often used as a proxy of the turning point to anaerobic energy production and thus lactate accumulation in CPET studies, but that it would be interesting to measure the actual lactate in the blood as some of the old studies did. It seems that this group has done just that and found some interesting results.

Yes, Snow Leopard is correct, the most consistent finding of previous studies (workload at VT) was confirmed in this study. See:


(I should probably recalculate those figures to check they are correct, but the bold figures indicate statistically significant results compared to controls.)

The peak heart rate did not differ between patients and controls so no indication of chronotropic intolerance.

 

Could you explain what you mean by this: did the studies that did not push patients to their VO2max had smaller differences between patients and controls at the VT of the 2day CPET procedure?

What about the current study: patients had lower VO2peak values at both exercise tests but reached similar RER and heart rates. Do you think patients were exercised enough to reach their true VO2max? Or is that exactly your point: that ME/CFS patients have to be pushed harder (higher RER and heart rates) than controls to come close to their VO2max and since this isn't always possible (or ethical) the results do not consistently show a reduction of VO2peak at VT?

 

There’s something not right if your controls are having a “significant reduction in VO2 peak between CPET1 and CPET2”. There is plenty of literature out there that says this does not happen. It’s the whole basis of it being a reliably reproducible test.

 

Many patients in these studies were not exercised enough to reach true VO2Max. RER=1.1, age predicted HR etc are merely suggestive.

Patients have to be pushed harder in terms of perceived exertion (which is basically central drive) to achieve VO2Max and the level of encouragement etc is inconsistent across studies. It requires a great deal of motivation to exercise to a true VO2Max.

Patients are not highly trained athletes who want a high VO2Max to brag about to their mates.

I am basing this on discussions I had with one of the researchers who has published a 2 day CPET study and my own experience doing the 2 day CPET. I was on the bike for about a minute and a half past the point that I reached RER~1.1 and age predicted heart rate. My true peak heart rate was about 8% higher than the age predicted (either 220-age or 208-0.7*age) with a noticeably higher VO2Peak as well. The main difference between me and most participants is two fold: I was comfortable riding a bicycle and I literally rode until I was about to pass out - dizzy and issues with my vision. Most people are probably smarter than me and would stop earlier.

It shows the level of motivation provided by the exercise physiologists to keep going (their job is to encourage participants until they reach their true VO2Max) is quite inconsistent.

 

The ventilatory threshold is much more interesting than merely the turning point to anerobic energy production. So much more is going on at that point, including increased neural drive from the brain, recruitment of substantially more muscle fibres and there is also an autonomic response - deeper breathing, which in turn stimulates the heart (which also leads to the so-called Vt2 or second ventilatory threshold).

There is much discussion in the exercise physiology literature about which comes first. Is it the drop off of force by the (currently recruited) muscle fibres, leading to increased neural drive, leading to more muscle fibres being recruited, leading to metabolic issues, leading to anerobic metabolism. Or is it metabolic factors that limit the force? Or is it accumulation of solutes past a certain point that start inhibiting the force generation of the muscle fibres? There is some evidence that the pattern in trained athletes differs from sedentary participants. Or perhaps the order doesn't matter because feedback loops between all of these variables inevitably drives the other. But that doesn't much help us as we want to work out why performance is specifically inhibited on the 2nd day in patients but not controls.

 

I’m not sure what Snow Leopard is referring to but not all of the studies have been exercising their subjects to VO2peak. In those that have, patients have consistently given their all and this is reflected in their RER. They don’t need a higher RER than controls.

 

Yes, an RER of 1 or 1.1 or whatever does not indicate that participants have necessarily reached a true VO2Max.

To clarify my view, I do believe that the true VO2Max on the second day in patients will be lower than the first day, but methodological constraints means this is hard to capture, since it is very hard for patients to exercise to a true VO2Max.

 

But in this study the controls’ performance also dropped, just not enough to be significant. Because the controls’ performance dropped as well the difference between the groups was not significant. Perhaps in this case the blood sampling which resulted in a lower base hemoglobin level on day 2 explains the different results.

“As opposed to what others have found, the ability to reproduce VO2peak did not differ significantly between the two study groups. Although VO2peak decreased significantly in patients, the absolute change was too small, in our opinion, to indicate any major change in exercise tolerance or explain PEM. Furthermore, the decrease in resting hemoglobin concentration of 0.7 g/dL in both study groups from CPET1 to CPET2 should be taken into consideration.”

That is true, and is why most studies say VO2peak rather than VO2max. VO2peak is enough to make the necessary comparisons. Nonetheless, it does not explain the difference here. If patients in this study reached VO2max on day 1 but didn’t in other studies, then you would expect to see a bigger drop in performance on day 2 than in the studies where they weren’t pushed as hard on day 1.

 

I was specifically referring to the performance at the ventilatory threshold, not VO2Peak.

The conclusions that the authors are making about VO2Peak are assuming that patients and controls actually achieved their VO2Max, something which I am sceptical about.

Why would we assume that patients reached VO2max on day 1 of this study? Also, check figure 2 - patients peak heart rate increased on the 2nd day but controls peak heart rate dropped on the 2nd day. This provides doubt as to whether true VO2Max was consistently reached in both patients and controls.

 

Yay! :-D It's finally published! We've been waiting for this one for a while.

Have other exercise studies done this?

If not, could this explaine some of the difference vs other studies...?

 

So it looks like the results are sort of all over the place on these CPET studies?

 

I am still worried that tests like this feel us about the symptom of PEM, which is present even before trying to exercise. What @Snow Leopard says sounds like a good detailed analysis but I am not familiar enough with the practicalities to be sure I fully understand the implications.

 

Good that it is finally published.

Not read it yet. I guess you will find significant differences between day 1 and 2 among patients and controls. Maybe this is the only practical way to go about such study (2 days), but the weakness of such a study, is that you often won’t be able to catch the real PEM, the most devastating PEM that often “arrives”(much) later than 24 hours after.

After listening once again, I would also stress the important point touched over by J Edwards, that many (probably most) patients are in different states of PEM, often great, even before starting cycling. That need to be clarified when Lien says that patients don’t get it (get bad) before long after and almost giving the impression that patients starts out “just fine”. Sure Liens aware that it’s not like this, that there are no “baseline”, and she would nuance this if time, but the radio format doesn’t always allow great precision.

These kind of exercise-studies can measure differences in patients and controls from day 1 to day 2. What you miss out is the no baseline starting point for many/most patients, even if housing them close to test-place prior to cycling. And again: the longer effect on the delayed PEM is «lost». You will have PEM day 2, but very often to a greater extent day 3, 4 and 5.

EDIT, added two paragraphs.