Physiological assessment of orthostatic intolerance in chronic fatigue syndrome, 2022, Natelson et al

Discussion in 'ME/CFS research' started by Hutan, Feb 18, 2022.

  1. Hutan

    Hutan Moderator Staff Member

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    https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-022-03289-8

    Benjamin H. Natelson
    Jin-Mann S. Lin
    Michelle Blate
    Sarah Khan
    Yang Chen
    Elizabeth R. Unger

    Open access

    Background
    Orthostatic intolerance-OI is common in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-ME/CFS. We used a 10-min passive vertical lean test as orthostatic challenge-OC and measured changes in vitals and end tidal CO2(eTCO2). An abnormal physiologic response to OC was identified in 60% of the 63 patients evaluated from one to three times over several years. Hypocapnia, either resting or induced by OC, was the most frequent abnormality, followed by postural orthostatic tachycardia.

    Objective
    Evaluate the physiologic response of patients with ME/CFS to a standardized OC.

    Design
    Respiratory and heart rate, blood pressure and eTCO2 were recorded twice at the end of 10-min supine rest and then every minute during the 10-min lean. Hypocapnia was eTCO2 ≤ 32 mmHg. Orthostatic tachycardia was heart rate increase ≥ 30 beats per minute compared with resting or ≥ 120 BPM. Orthostatic hypotension was decreased systolic pressure ≥ 20 mmHg from baseline. Tachypnea was respiratory rate of  ≥ 20 breaths per minute—either supine or leaning. Questionnaire data on symptom severity, quality of life and mood were collected at visit #2.

    Patients
    63 consecutive patients fulfilling the 1994 case definition for CFS underwent lean testing at first visit and then annually at visit 2 (n = 48) and 3 (n = 29).

    Measures
    Supine hypocapnia; orthostatic tachycardia, hypocapnia or hypotension.

    Results
    The majority of ME/CFS patients (60.3%, 38/63) had an abnormality detected during a lean test at any visit (51%, 50% and 45% at visits 1, 2 and 3, respectively). Hypocapnia at rest or induced by OC was more common and more likely to persist than postural orthostatic tachycardia. Anxiety scores did not differ between those with and without hypocapnia.

    Conclusions
    The 10-min lean test is useful in evaluation of OI in patients with ME/CFS. The most frequent abnormality, hypocapnia, would be missed without capnography.
     
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  2. Andy

    Andy Committee Member

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    Fukuda yet again.
     
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  3. Keela Too

    Keela Too Senior Member (Voting Rights)

    Hypocapnia - I had to look it up. It’s reduced carbon dioxide in the blood.

    Maybe that could also contribute to our inability to ramp up aerobic energy production, as increasing CO2 is one way the body detects exertion that requires more O2 delivery to muscles etc.
     
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  4. Hutan

    Hutan Moderator Staff Member

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    Last edited: Feb 18, 2022
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  5. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    As far as I know the only explanation for Hypocapnia during a lean test would be over breathing.
    Over breathing during a lean test as part of a diagnostic work up does not seem particularly surprising to me. There needs to be a control group of people similarly likely to be stressed by a diagnostic procedure. There is no need to invoke 'anxiety'.

    If this was really thought to be of interest it ought to have been studied prospectively and with attention to basic methodology. This just seems to be checking over some old patient records.
     
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  6. Medfeb

    Medfeb Senior Member (Voting Rights)

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    Natelson was one of the doctors in CDC's Multi-site Clinical Assessment of CFS that started in 2011-2012 and saw patients over a few years. Other doctors included Klimas, Bateman, Kogelnik, Peterson, Podell, and Lapp. They used a common core set of assessments across centers but AFAIK, Natelson is the only one of those docs who added in capnography.

    About Fukuda - CDC did not specify what definition to use with the idea that these were experts and it would help clarify what the criteria should be. It didn't. The IOM did.

    AFAIK, very few papers have been published yet from CDC's multisite study although I understand more are in process - years later. It's been a frustrating experience and a missed opportunity IMO
     
    Last edited: Feb 18, 2022
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  7. Hutan

    Hutan Moderator Staff Member

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    (Apologies, I'm thinking aloud here, in writing. Just trying to understand. I think there have been a number of studies related to hypocapnia in ME/CFS but I'm not sure what we should make of them yet.)

    So the measurement was CO2 in the breath. Hypocapnia is actually low CO2 in the blood, so I guess the assumption is that there is a direct and unperturbable correlation between CO2 in the blood and in the breath. I don't think that that is accurate. I think it's better, when studying people with ME/CFS with an end tidal CO2 test to talk about low levels of end tidal CO2 than to assume it's hypocapnia.

    End tidal CO2 level
    https://www.ems1.com/ems-products/c...s-to-know-about-capnography-Hr5ETRdXzCoU3fLH/
    Just on that comment that "low ETCO2 with other signs of shock indicates poor systemic perfusion". I've posted before about 'shock index'. Shock index is heart rate/systolic blood pressure. During the times when I monitored my blood pressure and heart rate (at rest first thing in the morning and in the evening), a high shock index (and there were times when I had a shock index of 1 or more) was definitely correlated with worse ME/CFS symptoms and PEM. To me, it seems possible that the people with ME/CFS symptoms and a low ETCO2 could have poor systemic perfusion.



    So of the 11 patients (out of the 63) that this study found had low end tidal CO2 at rest, only one was tachypneic (breathing fast). And having a psychiatric diagnosis or being anxious didn't make a difference in terms of whether the person had low end tidal CO2 at rest.
     
    Last edited: Feb 19, 2022
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  8. Hutan

    Hutan Moderator Staff Member

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    Another thing that struck me about the results was the inconsistency. Abnormalities of any sort were only found in 60% of the patients. But, of course, that does not necessarily mean that patients aren't experiencing the abnormalities when they have PEM. Three of the 29 patents who came in for a third visit were found to have an abnormality only at the third visit. With the drop out rates on the subsequent visits reported here, I wonder if 'having a bad day' i.e. having PEM might have contributed to a person not coming along for the test. Certainly, if I had my doubts about the usefulness of going along to see a doctor who hadn't helped me a year ago, feeling awful on the day might tip me towards not going to the appointment.


    There's that of course - with no controls we don't really know if what is reported here is completely normal - maybe you could find abnormalities in healthy people if you look hard and often enough.

    I am certain, from the monitoring that I did at home, that issues with blood pressure and heart rate are correlated with PEM for me. So, I think for this sort of study to be of any use, researchers need to go to the person, at their home, on a bad day. And also test healthy controls.
     
  9. Hutan

    Hutan Moderator Staff Member

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    Yeah, just thinking this over, it's hard to feel as though anyone involved in this study is approaching the problem of ME/CFS with any sense of urgency. See this, from the paper:

    So, it's not like it is some early exploratory work. (I checked a couple of times to make sure that I had the right year on it, as it feels like a paper that could have come out 10 years ago). The authors explicitly refer to this being a replication, and an extension, of 'earlier important work'. If it was that important, why did it not deserve a decent study design? Sure, a lack of money might have been an issue, but one of the authors is Elizabeth Unger - and if she can't find some money for a study if she thinks it's really important, then I don't know who can.

    Ugh. And, the takeaway from this study, if people aren't looking at it closely and tend towards dismissing ME/CFS is just 'oh, those people with ME/CFS, they are just over-breathing. They just need to learn to breathe better and do some mindfulness training to calm down.'

    That's pretty much what this study concludes:

    They didn't find people were breathing abnormally fast. So, they decided the low levels of end tidal CO2 must therefore be due to them breathing abnormally deeply. They know this because 'the people weren't breathing abnormally fast'. Are those two possibilities (breathing too fast, breathing too deep) really the only options? Surely we'd be aware if we were breathing abnormally deeply? Following a lung infection when I was younger my lung capacity is half of what it should be - this idea of breathing too deeply being the problem doesn't make sense to me.

    Maybe a key to understanding ME/CFS is considering that there is another reason? Maybe during PEM usual levels of CO2 aren't being produced? Maybe during PEM the CO2 isn't getting moved out of the body efficiently?

    There is a bit of consideration of the possibility of causes other than inappropriate breathing caused by anxiety in the paper. But, they certainly leave it there as an option.
     
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  10. bobbler

    bobbler Senior Member (Voting Rights)

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    I think you are on the right track talking PEM/needing to understand the 'phase/stage' the body is in before they interpret anything. My next bit is I'm afraid a bit of a ramble focused on mainly the thinking out loud on the overbreathing, what it is and how it could be miscontrued but how my experience has been it relates to exertion and 'coping' physically ie to keep standing or going or talking.

    They've got some big issues looking into the physiology without accounting for and being aware of PEM and anaerobic threshold. I think that this needs to be the next standard developed - as I note that Workwell for example seem to be getting to the point where they are able to identify these thresholds and other experiments with HR over time might then be able to 'plot' what can cause it.

    I personally got identified as an overbreather with alkaline blood as I exhaled too much CO2 in 2012. No idea if it was total tosh and me being as usual played around with by a consultant or real and still have or real and less relevant as a few things were present then that aren't now.

    One of these things turned out to be not being able to breath through my nose, literally (I know it seems strange to others that you wouldn't realise this until it is fixed). The ending was that I ended up at ENT who discovered my nose was blocked by polyps and inflammation from rhinosinusitis.

    The other was that exertion/PEM - I was also on arriving at all these appointments doing a full time job, a big one for someone with then moderate 'CFS' (as it was diagnosed then). And was at the 'peak time' of year where I couldn't work from home and it was long v hectic intense days. And it was a rush through heavy traffic to get to the appointments. At the end of the day (when I'd normally be collapsed into bed). PS I don't think it's a spoiler to say I 'used' adrenaline, caffeine, every (well the mundane ones - not meds of any kind) trick in the book to push through.

    I've been told overbreathing is common in athletes and musicians (to be able to e.g. sing long notes), having spoken to a physio (socially) who doesn't see it as abnormal or as extreme as I'd been led to believe by other medics/physios - so who knows. At that point it did make more sense, and I did notice (having been an athlete) that I probably did use it in order to keep on 'exerting' past my body's limits e.g. in workplace. I noticed (having been used to it since I was an athlete when a teenager so most of my life) it being something I naturally used to be able to continue 'that phone call', 'that spreadsheet', keep going to the end of the day. Same breathing you use when you kick for the line at the end of a long x-country race, or when training in 2 sets of 10 x 200m - not anxiety but keeping your body going/pushing/functioning beyond normal points to try and get oxygen coming in and lactic acid down or whatever it does.

    I guess we need someone like Workwell to study/take their various measures for people who do day-to-day tasks that happen to take them near enough to their exertion threshold - I suspect they'd knock that one on the head for us which would be highly useful. Like eliciting 'athlete's breathing levels' to get through talking on a phone or looking at a spreadsheet, or from walking to get a tea then being grabbed with a question while you are still standing etc.

    So maybe 'PEM' (the amount of 'cumulative' I've just had to live with continually would have been unmeasurable but always there) but also 'live' exerting into the 'above baseline zone' - and pushing through and holding it together/on the line. It's weird that medics interpret so many things that are 'symptoms' or 'necessary coping changes' that kick in e.g. to keep yourself standing as 'causes' and 'from the mind' - to me it takes a v strange pair of eyes to see the latter over the former. But that is the point of BPS etc spending so much time 'priming' I guess - it changes what/how people see
     
    Last edited: Feb 20, 2022
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  11. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I think they probably are the only two options. CO2 physiology is fairly simple. If production is reduced respiratory drive is reduced so no hypocapnia. And it is not going to be reduced during a lean test. I don't think we necessary realise our breathing changes when in stressful situations.

    As I see it they are measuring a response to a stress test, not PEM. I think it highly likely that ill people who are worried because they are in the middle of diagnostic tests - which would be normal - may breath more deeply.
     
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  12. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I can't see how the CO2 sensor actually works but having that put on may be stressful in itself - and more stressful for patients than for 'healthy controls' so you need a comparator group of people at the point of being diagnosed with some other condition.
     
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  13. Hutan

    Hutan Moderator Staff Member

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    There are various versions, generally involving a mask and some with 'nasal prongs' which sound anxiety inducing but are, I think soft plastic that goes just inside the nostrils. The fact that some people didn't have low end tidal CO2 on their first two visits, but did have on their third visit* (by which time they must have been quite familiar with what is going on) argues a bit against the idea that low CO2 levels are a product of being stressed about the procedure. (*and some people just had abnormal levels on the second visit).

    I don't think people who have had ME/CFS for years would be particularly stressed about being diagnosed, especially on the followup visits. But sure, it would be good to have patients with some other illness to compare with. Perhaps people for whom it is also an effort to get to the clinic.
     
  14. Hutan

    Hutan Moderator Staff Member

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    Yes. And I'm saying that that is a problem. They found some people had low end tidal Co2 levels when lying down, before doing the lean test. Yes, it's possible that the whole getting to the clinic and just being there is stressful, but why the variability between visits, with levels being low on some visits and not on others?

    So, I'm hypothesising that the presence of PEM, or not, might account for the variability. And so it would be good to see a study that took into account whether the person with ME/CFS has PEM, or not.
     
  15. Keela Too

    Keela Too Senior Member (Voting Rights)

    So what if low CO2 is a thing for ME peeps (and not just an artefact of the stress of the test)?

    AND What if that low CO2 in the blood then dampens the releases of oxygen to the tissues?

    As I understand, it the Bohr Effect causes haemoglobin molecules to release more O2 in situations of high CO2, so maybe we can’t avail of that effect easily, because it will take extra CO2 production to happen before we can even hit normal CO2 levels, let alone the high CO2 that encourages haemoglobin to dump more of it’s O2 to the tissues.

    Also, if our aerobic energy production doesn’t ramp up well, and we end up producing energy anaerobically, that type of energy production (which results in the formation of lactic acid) doesn’t increase our CO2 levels, and so we are stuck!

    Could this account for our rapid fatiguability?

    Of course it wouldn’t be as black/white as this, but it might be a part of our problem.

    And (speculating wildly now) might other cellular reactions also be altered by an unusually low baseline CO2 level, and might that result in the production of unexpected metabolites as we try to exercise? Then might PEM, be our immune system treating those metabolites as foreign bodies, and so we experience the whole horrible flu sensation a couple of days later?

    Edit to add - this is all me playing “what if”, why our CO2 levels might end up chronically low (if in fact they do) is another question altogether!
     
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  16. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I don't think this will work. If you have low CO2 all you need to do is breath a bit more slowly or less deeply and it will come up. (Unless of course the low CO2 is associated with a metabolic acidosis, but that would show up on pH.)
     
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  17. Keela Too

    Keela Too Senior Member (Voting Rights)

    Though if some homeostatic check was altered within ME metabolism, that made our bodies correct to the “wrong” level of CO2, then it might be possible that the rest could follow.

    Let’s face it most breathing is done below conscious control, so the real question should perhaps be why does our breathing apparently not correctly self regulate?

    You suggest it is the stress of the measuring, that causes us to over breathe and so lower CO2, but what if that isn’t the case? What if the lowered CO2 is a new homeostatic balance that our bodies have been tipped into?

    It’s easy to say - breathe better - but that is almost like saying - do better, don’t be ill - it doesn’t help ME folk if they actually do have an underlying metabolic flaw in CO2/O2 balance.

    I don’t really know the answers but breathing training does not sound to me like one that will help me.
     
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  18. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    So this might be yet another intolerance, like exertion intolerance and light intolerance - CO2 intolerance!

    It is conceivable. I am a bit sceptical that PWME actually have low CO2 levels though - other than maybe in some test situations or during episodes of distress. I also doubt that it would cause the other symptoms.
     
  19. Keela Too

    Keela Too Senior Member (Voting Rights)

    CO2 intolerance! Sure what’s another intolerance amongst the many others! :rofl:

    It’s hard to know what’s what with ME. As you say the low CO2 could be an artefact of measuring, and if that the case then the other speculations that follow aren’t much use either.

    The experience I had, of having a sudden improvement from severe to a much better level, makes me think the idea of some sort of trapped but reversible state (or series of states) is likely with ME. But what causes them, and how to reverse them is another matter.

    Answers cannot come too soon.
     
  20. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    The Bohr effect of CO2 doesn't actually have that much impact at physiological pressures in most tissue in humans at close to sea-level atmospheric pressures.

    Example from exercise trials:
    "We conclude that although hypocapnia promotes a decrease in MCAvmean and cerebral oxygenation, this does not limit maximal O2-uptake. Furthermore, hypocapnia does not restrict ventilation during maximal hypoxic exercise."

    (There was a slight reduction in cerebral oxygenation in the hypocapnic group - the results were −4.7 ± 0.9% vs −5.4 ± 0.9% - so there was an overlapping distribution)
    https://www.sciencedirect.com/science/article/abs/pii/S1569904812002339
     
    Last edited: Feb 19, 2022
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