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The Timeline of Post Exertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2018, Nielsen

Discussion in 'ME/CFS research' started by Hutan, Jun 2, 2019.

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  1. Hutan

    Hutan Moderator Staff Member

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    Participating in this trial has made me more skeptical about the results of any study. I'm not suggesting that the people running this study were any less diligent than the average researcher, but here's a few of examples:

    I didn't get a diary to fill in.

    Organising my household to survive in my absence, packing, waiting around in an airport and walking to the gates and taking taxis and flights is not my 'usual activity'. The team knew I was travelling a long way to get to the mobile laboratory. It's possible that some participants were in PEM on day 1.

    The subjective assessments of recovery time were probably just nonsense. I know that I was not at all clear on when I had recovered from the test - or whether any ill-effects were from the whole effort of travelling. And actually I felt ok afterwards, and when I got home and still ok while hosting visitors. It was a while later when I got infections and was generally wrecked.

    I'm not sure about the determination of the VO2Max point. Clearly I'm not an expert in this but the cycling didn't seem that hard, it seemed like there was only a couple of minutes of effortful cycling and I was nowhere near thinking 'I need this to end'. If I did some exercise like that at home once, I wouldn't expect it to give me PEM. Standing waiting for the pickup before the test for 15 minutes was far more physically stressful. It looks like there were a range of ways that a test could be termed maximal. I wonder if there were differences in the criteria used for the ME/CFS and control groups.
    My conclusion is that ME/CFS is bloody hard to study. And there needs to be a lot of effort to manage and record activity levels prior to, during and after a 2xCPET study to avoid confounding.

    I don't know what I think about the 2-day CPET now. Of course this study doesn't disprove the idea that people with ME/CFS show a drop in VO2 and/or workrate at anaerobic threshold 24 hours after an exercise test.
     
    Hutan, Jun 8, 2019
    #21
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  2. Hutan

    Hutan Moderator Staff Member

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    The author seems to be under the impression that current GET protocols involve exercise only once a week or once a fortnight (when my understanding is that the idea is that you are supposed to do some exercise nearly every day). So, seeing that the trial participants weren't showing declining performance (on average, I must note - because my performance did decline), they presumably don't have PEM and can get into some more exercise.

    We may need to make it clearer that activity has a cumulative effect.
     
    Last edited: Jun 8, 2019
    Hutan, Jun 8, 2019
    #22
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  3. ME/CFS Skeptic

    ME/CFS Skeptic Senior Member (Voting Rights)

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    Concerning negative results of the repeated CPET procedure: I don't know if this has been shared on this forum yet but there's a 2018 presentation by Ruud Vermeulen (in Dutch), where he says he did the repeated exercise test on approximately 500 (!) patients but he couldn't see a difference between the first and second test. It's not exactly clear what measure he's talking about - his graph only shows VO2max.
    upload_2019-6-8_11-22-39.png

    But Vermeulen should know what he's talking about because he published a 2 day CPET study in 2010. It too could not find significant reductions at the VT compared to controls. It's hard to know what to make out of this: why didn't he publish those result for example?
     

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    ME/CFS Skeptic, Jun 8, 2019
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  4. Trish

    Trish Moderator Staff Member

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    Thank you @Hutan for that fascinating insight into what it was actually like to participate in this study. I'm not clear - has this been published as a peer reviewed paper anywhere?

    I note it's a Masters' degree thesis, so presumably the author, with an undergraduate degree probably in sport science, had in the space of a year or two to learn what ME is from a zero starting point, design a study, find participants and carry out the study with them, analyse the results and write up the thesis. As well as presumably doing courses on research methods and statistics etc. Unless her supervisor was already very knowledgeable about ME and how to design this sort of study, I can see why she might have floundered and not done it very well.
     
    Trish, Jun 8, 2019
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  5. Hutan

    Hutan Moderator Staff Member

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    Yes indeed. My daughter is in the middle of doing something similar, she's done a year of course work and now has a year for a thesis. It's a big ask, and the author of this study was tackling a difficult subject with a lot of conflicting literature.
     
    Hutan, Jun 8, 2019
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  6. Hutan

    Hutan Moderator Staff Member

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    Along with Tessa Nielsen, the team consisted of Lyn Hodges and a young man. In addition to the CPETs, there were measurements of arterial stiffness and a battery of cognitive tests, repeated after each test. So there may be another Masters thesis to come, and perhaps a comprehensive published paper.
     
    Hutan, Jun 8, 2019
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  7. Hutan

    Hutan Moderator Staff Member

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    Hutan, Jun 8, 2019
    #27
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  8. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    Vermeulen 2010 found significant reductions in VO2Peak, but this has not been found in later studies and the image you quoted clearly shows a plot of VO2Max on day 1 vs VO2Max on day 2. As I have explained previously, we cannot assume VO2Peak = VO2Max and I believe this is the reason for the inconsistent results found. I believe that most patients cannot reproduce their true VO2Max on the second day, but a majority of patients are also not reaching a true VO2Max on either day. Obviously this means focusing on VO2Peak is a poor choice as a marker.

    Also, while I'm at it, I don't like the trend of Vermeulen and Hodges and others calling the Ventilatory or Gas Exchange Threshold an "Anerobic Threshold" you shouldn't call it that unless you're actually measuring several measures of metabolism directly.

    Given the small sample sizes, Vermeulen 2010 may be a false negative due to limited statistical power, particularly as there was a similar trend towards lower performance at VT and O2 Pulse which was significant is strongly associated with VO2, only it is scaled by the heart rate.
     
    Snow Leopard, Jun 10, 2019
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  9. ME/CFS Skeptic

    ME/CFS Skeptic Senior Member (Voting Rights)

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    Just to be clear: in Vermeulen's clinic patients regularly get a repeated CPET, so I think that's the data he's talking about - something different and much bigger than his 2010 paper. From listening to the talk (in Dutch) he gave the impression that he wasn't just talking about the VO2max showed on the slide but that he couldn't find the differences between ME/CFS patients and controls that had been reported in the studies. So I assumed he means other outcomes as well (it's ambiguous though, and if he actually has that data, then why doesn't he publish?). Just wanted to mention this on the forum.
     
    ME/CFS Skeptic, Jun 10, 2019
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  10. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    I don't think Vermeulen can publish the data on that slide, because it is just routine clinical data and was not collected as part of a study with ethics approval.

    There was another Vermeulen study that may be relevant to this discussion too: https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-12-20

    The early focus of the workwell foundation was on the reduction of VO2Peak, which is why they didn't even publish the data at the ventilatory threshold. The discussion of most of the studies tended to focus on VO2Peak and most people didn't start to talk about the findings at the ventilatory threshold being the most important until Hodges 2018, though it was hinted at in 2016 at least by Keller/Giloteaux. I don't think we can simply speculate Vermeulen was refering to all findings. I think this is a question worth asking Vermeulen directly.
     
    Snow Leopard, Jun 10, 2019
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  11. ME/CFS Skeptic

    ME/CFS Skeptic Senior Member (Voting Rights)

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    There was the 2013 publication of the Workwell Foundation - by far the largest publication on the repeated CPET to date - that showed the most spectacular abnormality in workload at VT. But it's true that because the VO2 at VT was also significantly reduced, the emphasis was on failure to reproduce outcomes at VT, rather than workload at VT. At least that's how I understand it. The talk from Vermeulen was from 2018.

    Good idea. I've just tried to send him an email, using the latest email address of him that I could. I'll let you know if he responds.
     
    Last edited: Jun 10, 2019
    ME/CFS Skeptic, Jun 10, 2019
    #31
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  12. Ravn

    Ravn Senior Member (Voting Rights)

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    Not sure if this is just a publication based on the thesis discussed in this thread, without anything new, or if it contains additional data from the same study cohort?

    Translational Sports Medicine: The physiological timeline of post exertional malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

    Accepted article.

    L Hodges T Nielsen D Cochrane D Baken

    First published: 08 January 2020

    https://doi.org/10.1002/tsm2.133

    https://onlinelibrary.wiley.com/doi/abs/10.1002/tsm2.133
    Full text has been shared by ANZMES on FB but I'm still waiting for permission to share outside the group. Haven't read it myself yet.
     
    Ravn, Jan 17, 2020
    #32
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  13. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    Reading the paper now. Frustrating that they did not report the ventilatory threshold data either. Reporting at RER=1 is not equivalent to the VT.

    Sad to say, but it seems most exercise physiologists have no idea about the significance of the ventilatory threshold and what it means neurologically.

    Peak heart rate for the 72h patient group is a bit suspect, at 133 BPM, compared to 160+ for all the other groups including the 48h patient group. At the very least, this demonstrates selection biases between the groups. If research groups are recruiting patients taking beta blockers, can they please stop!!!!

    No they haven't! Several studies have not shown this. (likewise, the slide of 500 participants shown by Vermeulen in this thread previously)

    VO2Max shouldn't drop unless participants have some sort of loss of red blood cells or cardiopulmonary restriction, or participants were unable or unwilling to exercise to their true VO2Max.
     
    Last edited: Jan 17, 2020
    Snow Leopard, Jan 17, 2020
    #33
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  14. Ravn

    Ravn Senior Member (Voting Rights)

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    What to make of this snippet from the paper?
    If I understand correctly they hypothesise that if you induce PEM (day 1 exercise) and then do your:
    • day 2 exercise after 24 hours, recovery will take 21 days (observed in previous study)
    • day 2 exercise after 48 hours, recovery will take 11 days (observed in current study)
    • day 2 exercise after 72 hours, recovery will take 5.5 days (observed in current study)
    • day 2 exercise after 96 hours, recovery will take 2.5 days (hypothesised).
    If that holds true - big fat IF - I hope nobody will interpret this as meaning ME patients can safely exercice every 4th day. Actually I suspect that will exactly be the interpretation... never mind that you'd be spending more than half your life in PEM.

    But it would be interesting to look at. If true - still a big fat IF - that would be a way of shortening any PEM you accidentally got yourself into. Say your PEM normally lasts 14 days and you exercise a little on day 4, your total PEM could be shortened by a week. Worth having.

    Except you'd need to know exactly what type, intensity and duration of exercise would have that beneficial effect rather than plunging you even deeper into PEM. And maybe day 4 isn't right for everyone either since people have different delays for their PEM. All in all rather risky and uncertain. I don't think I'll be volunteering as a guinea pig.
     
    Ravn, Jan 17, 2020
    #34
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  15. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    Yeah, I'm not quite sure what is the value of working out how frequently someone can do maximal exercise testing to maintain constant PEM related symptoms...
     
    Snow Leopard, Jan 17, 2020
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  16. Hutan

    Hutan Moderator Staff Member

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    Well, this is what I wrote about my experience with this trial:
    So, in my view, the hypothesis in the snippet is, well, not well founded. Of course, maybe everyone else on the trial did experience what the researchers are saying, and I am unusual.
     
    Hutan, Jan 17, 2020
    #36
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