Unexplained exertional intolerance associated with impaired systemic oxygen extraction - 2019, by Melamed, Systrom et al

[Kalliope]

European Journal of Applied Physiology:
Unexplained exertional intolerance associated with impaired systemic oxygen extraction
by Kathryn H. Melamed, Mário Santos, Rudolf K. F. Oliveira, Mariana Faria Urbina, Donna Felsenstein, Alexander R. Opotowsky, Aaron B. Waxman, David M. Systrom

Abstract
Purpose

The clinical investigation of exertional intolerance generally focuses on cardiopulmonary diseases, while peripheral factors are often overlooked. We hypothesize that a subset of patients exists whose predominant exercise limitation is due to abnormal systemic oxygen extraction (SOE).

Methods
We reviewed invasive cardiopulmonary exercise test (iCPET) results of 313 consecutive patients presenting with unexplained exertional intolerance. An exercise limit due to poor SOE was defined as peak exercise (Ca-vO2)/[Hb] ≤ 0.8 and VO2max < 80% predicted in the absence of a cardiac or pulmonary mechanical limit. Those with peak (Ca-vO2)/[Hb] > 0.8, VO2max ≥ 80%, and no cardiac or pulmonary limit were considered otherwise normal. The otherwise normal group was divided into hyperventilators (HV) and normals (NL). Hyperventilation was defined as peak PaCO2 < [1.5 × HCO3 + 6].

Results
Prevalence of impaired SOE as the sole cause of exertional intolerance was 12.5% (32/257). At peak exercise, poor SOE and HV had less acidemic arterial blood compared to NL (pHa = 7.39 ± 0.05 vs. 7.38 ± 0.05 vs. 7.32 ± 0.02, p < 0.001), which was explained by relative hypocapnia (PaCO2 = 29.9 ± 5.4 mmHg vs. 31.6 ± 5.4 vs. 37.5 ± 3.4, p < 0.001). For a subset of poor SOE, this relative alkalemia, also seen in mixed venous blood, was associated with a normal PvO2nadir (28 ± 2 mmHg vs. 26 ± 4, p = 0.627) but increased SvO2 at peak exercise (44.1 ± 5.2% vs. 31.4 ± 7.0, p < 0.001).

Conclusions
We identified a cohort of patients whose exercise limitation is due only to systemic oxygen extraction, due to either an intrinsic abnormality of skeletal muscle mitochondrion, limb muscle microcirculatory dysregulation, or hyperventilation and left shift the oxyhemoglobin dissociation curve.

 

[Kalliope]

Seems all patients included had ME/CFS? I didn't catch that from the abstract.

 

[Kitty]

Odd, isn't it, @Kalliope? It was funded by Solve, so I guess we can assume they did.

 

[Mithriel]

Exertional intolerance is not the same as PEM. It sounds like a symptom of PEM.

I wonder how this fits in with all the other findings like deformed red blood cells and increased anaerobic respiration.

I have a prejudice about talk of hyperventilation because it was used as a way of dismissing the seriousness of ME years ago.

 

[Andy]

The nature of our database is a clinical referral system whereby many of the patients came from outside of BWH, and as a result, systematic follow-up of their clinical course was not available for all cases. All of our cohort with poor SOE carried a clinical diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (Bested and Marshall 2015). We were additionally able to identify three general disease categories: MM [Mitochondrial myopathies], dysautonomia, and connective tissue disease. Although about two-thirds were referred with suspected MM, most did not hold a confirmed diagnosis by muscle biopsy or blood mutation screens at the time of iCPET.

Sci hub link, https://sci-hub.se/10.1007/s00421-019-04222-6

Conclusion
Using direct measurements of the Fick principle variables, we have identified a cohort of patients whose exertional intolerance is caused solely by poor systemic oxygen extraction. These patients demonstrate a hyperventilatory and hypercirculatory pattern, which may be driven by an exaggerated muscle metaborefex. While for some, there appears to be a primary defect in skeletal muscle mitochondrial oxygen uptake (PvO2 at maximum exercise is high), for others, the predominant pathophysiology appears to be hyperventilation that causes a left shift of the oxyhemoglobin dissociation curve and impaired oxygen of-loading in the systemic capillary.

Impaired systemic oxygen extraction should be added to the differential diagnosis of unexplained exertional intolerance. In addition, exercise hyperventilation should be recognized for its deleterious effects on oxygen transport, rather than being dismissed as inconsequential or psychosomatic.

 

[borko2100]

Impaired systemic oxygen extraction should be added to the differential diagnosis of unexplained exertional intolerance.

So if this is a differential diagnosis how does one get tested for it?

 

[Peter T]

Is this then saying ‘impaired oxygen extraction’ is a feature of ME or at least a factor in some people with ME, or are they implying that this is a distinct disorder mistaken as ME?

 

[WillowJ]

I have a prejudice about talk of hyperventilation because it was used as a way of dismissing the seriousness of ME years ago.

Yes, that’s reasonable coming from people who suspect anxiety as a cause.

But when they’re people who are talking about acid-base balance, they would know the hyperventilation would be a physiological mechanism. It’s a type of respiratory compensation for metabolic causes of acidosis. Theoretically, if the kidneys are not causing the acidosis they could compensate, too (or instead).

 

[Ryan31337]

Yes, that’s reasonable coming from people who suspect anxiety as a cause.

But when they’re people who are talking about acid-base balance, they would know the hyperventilation would be a physiological mechanism. It’s a type of respiratory compensation for metabolic causes of acidosis. Theoretically, if the kidneys are not causing the acidosis they could compensate, too (or instead).

Agreed. The layperson's interpretation of hyperventilation is unfortunate, using the word scientifically does not infer anything about the cause being related to anxiety.

The paper offers several physiological explanations for hyperventilation and the conclusion explicitly states it should not be "dismissed as inconsequential or psychosomatic".

 

[Ryan31337]

Is this then saying ‘impaired oxygen extraction’ is a feature of ME or at least a factor in some people with ME, or are they implying that this is a distinct disorder mistaken as ME?

This paper uses an ME/CFS cohort, but seems to only really consider them as being patients with unexplained exertional intolerance. There is no attempt that I could see to make any conclusions as to the pathophysiology of ME/CFS based on these results, merely that in patients with unexplained extertional intolerance you need to consider abnormal systemic oxygen extraction (SOE) as a cause.

Perhaps this implies something about how these researchers see ME/CFS, or at least the poor diagnosis and categorisation of ME/CFS patients? Systrom talks about seeing similar abnormal SOE across many syndromic patients, ME/CFS/Fibro/POTS etc. Their focus is of course on physiology but I wonder if they see the exertional intolerance as simply downstream effects to another disease, in the same way many see POTS as a downstream effect and not a disease in itself. The paper does consider a clinical diagnosis in their ME/CFS cohort, with the vast majority sorted into mitochondrial myopathy, dysautonomia or connective tissue disease.

What they establish here is that there's a significant prevalence of poor SOE (VO2max < 80%) in ME/CFS patients as the only identifiable cause explaining the exertion intolerance, i.e. the heart and/or lungs were not limiting them. Though it was fairly small number at 12% of patients.

They suggest that three mechanisms contribute to impaired peripheral oxygen extraction: (1) primary dysfunction of the skeletal muscle mitochondrion, (2) hyperventilation and a left shift of the oxyhemoglobin dissociation curve, and (3) limb muscle microcirculatory dysregulation.

- (1) relates to mitochondrial myopathy (MM), which they consider as both primary (genetic) AND secondary (acquired from infection or autoimmunity). Oxygen is available but not taken up by the muscle.

- (2) is excess minute ventilation, which they note has established physiological origins in MM (and I know is present in POTS too from other research) and is not necessarily psychosomatic. Oxygen is less freely 'given up' by the blood.

- (3) relates to the neuropathic changes associated with POTS/dysautonomia, whereby microcirculation is impaired and systemic vascular resistance is increased. Oxygen is less freely available to the muscle due to impaired circulation.

Furthermore, they suggest: These mechanisms are likely interrelated, each exacerbating the effect of the other with the end result of poor SOE.

This all tends to fit quite sensibly with my own experience of CPETs, ME/CFS, POTS, SFN, Autoimmunity & suspected but unconfirmed MM.

 

[Ryan31337]

Exertional intolerance is not the same as PEM. It sounds like a symptom of PEM.

The exertional intolerance (defined by SOE) here is essentially a measurement of peripheral oxygen extraction. It could be that PEM is a downstream symptom of abnormal SOE.

I expect its a lot more nuanced than either of those explanations though!

 

[Snow Leopard]

All of our cohort with poor SOE carried a clinical diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (Bested and Marshall 2015). We were additionally able to identify three general disease categories: Mitochondrial myopathies, dysautonomia, and connective tissue disease

Notably, 185 of the 257 patients were excluded due to high blood pressure or heart failure...

The hyperventilation explanation doesn't make much sense to me, I'm wondering if there is a bit of Pulmonologist bias? When you're a hammer, everything looks like a nail...

They noted the following of their hyperventilatory group:

It is reasonable to ask why our HV group did not have a statistically significant impairment of systemic oxygen extraction. This is because our study design first dictated normal oxygen extraction in this group.

It is important, to note that exercise past the ventilatory threshold is always 'hypervenitalory', this is the normal physiological response. So hyperventilation in this sense is simply relative over the overall exercise test.

Secondly, untrained or deconditioned individuals perform less efficiently and can have stronger autonomic responses (eg hyperpnea, baroreflex responses) at an earlier stage as a result. Notably, they did not use a consistent ramping protocol, stating "Work was then continuously increased using a ramp protocol by 5, 10, 15, or 20 watts per minute based on historic exercise tolerance in the field". This is definitely going to result in differences in the ramping of (minute) ventilation between participants, particularly for untrained individuals who are not used to exercising hard.

It is also difficult to prove that the patients consistently exercised to their VO2Max, there is no discussion in the method on how patients were strongly encouraged to exercise to their true limits for example. The authors do mention "Subjects were excluded if they had submaximal exercise testing (defined by RER < 1.0 and peak HR < 80% of predicted)" but this is a weak criterion for exclusion.

They state

We do not believe lower HR and arterial lactate at peak exercise suggested a submaximum effort in SOEL, since Qtmax percent predicted was the same and the PvO2 nadir was no different from normal.

But I find this unconvincing. Lower heart rate necessarily suggests a lower Qtmax. The SOE groups achieved far lower VO2Max than was predicted yet the difference in Hb was not statistically significant. (they state: predicted Qtmax was calculated from predicted VO2max ***(from a 1984 study)*** and an assumed maximal Ca-vO2 equivalent to a normal [Hb] (14 g/dL) for healthy subjects).

I think if the goal is to investigate ventilatory parameters, this should be done so at a more consistently physiological state, namely the first ventilatory threshold.

Yet:

Furthermore, in our specific subgroup of patients who hyperventilate at submaximal exercise, we are not able to reliably detect either the ventilatory anaerobic threshold or the respiratory compensation point due to the burden of hyperventilation during submaximum exercise.

I'm not convinced that the thresholds cannot be determined and I'd like to see strong evidence as to why they claim they were unable to do this. The fact that the authors refer to a "ventilatory anaerobic threshold" is a little concerning, suggesting a lack of understanding of exercise physiology, as those two thresholds are not strictly synonymous. Likewise they mention "However, for centres investigating undifferentiated dyspnea with noninvasive CPET, it is important to note ventilatory inefficiency is a nonspecific finding." but this is irrelevant because the ventilatory threshold is not determined by shortness of breath or ventilatory inefficiency of the lungs.

Notably there was a large age difference between the 'hyperventilatory' group and the other groups. Likewise, the 'poor SOE' group were overwhelmingly female (84%) compared to the 'normal' group (36%). 38% of the 'poor SOE' group were taking beta blockers compared to 17% of the 'hyperventilatory' group and 0% of the 'normal' group. They also discuss potential issues with their sampling methods - aterial and mixed venous sampling compared to hypothetical sampling of the local capillary which is more directly relevant to metabolism in the muscle.

The discussion of microcirculatory dysfunction was interesting, though just as speculative as the rest of the discussion... The hypothesis is an altered muscle metaborefex, namely restriction of blood flow in the limbs in lieu of central blood flow.

Overall this study is quite frustrating with the results being less informative than they could have been if there were less methodological issues. I think they would have been better served to first do a pilot study and perhaps then the major methodological issues (ramping, encouragement, lack of healthy deconditioned controls) would have been ironed out. Repeating the test (with the invasive testing only conducted on the second occasion) may also have helped otherwise untrained participants to perform more consistently, since they know what to expect.

Lastly, the lack of reference to other ME/CFS findings is odd - namely the 2 day CPETs, and novel research by other exercise physiology groups such as those led by Alan Light and Yves Jammes.

 

[Ryan31337]

Some interesting points raised @Snow Leopard.

I think some of the confusion/disappointment might stem from this not really being a CFS study? Not much of a structured study at all really. I don't think it was reported correctly by ME/CFS News (above), my interpretation after reading comments elsewhere is that it's just an analysis of several hundred consecutive referrals for unexplained exertion intolerance. It looks like the funding came from a CFS charity, so they also retrospectively established which of their SOE patients would also meet a CFS diagnosis and that was that...

With regards to the hyperventilation explanation: If the patients were chronic hyperventilators, with resting hypocapnia, would this not lead to reduced oxygen extraction? Oxygen disassociation curve and all that.

Ryan

 

[ME/CFS Skeptic]

my interpretation after reading comments elsewhere is that it's just an analysis of several hundred consecutive referrals for unexplained exertion intolerance.

Yes. It seems that the subjects were patients referred to the Brigham and Women’s Hospital because they had unexplained exertional intolerance. In some, a mitochondrial disease was suspected. As Snow Leopard pointed out most of these patients were excluded from the analyses because pulmonary hypertension or heart failure was found and the authors wanted to do the analysis without these factors obscuring things. The remaining 72 patients were divided into two groups: those with poor systemic oxygen extraction or SOE (n = 32), hyperventilators (n = 29) and normals (n = 11). All of the 32 patients with poor SOE turned out to carry a clinical diagnosis of ME/CFS, so I think that's ME/CFS news was referring to on twitter.

The fact that there's a group of patients with no evidence explanation for their exercise intolerance but with a poor SOE, seems to be the main conclusion of the study.

These data support the hypothesis that a subset of patients with “unexplained” exertional intolerance has dysfunction at the level of skeletal muscle resulting in limited oxygen extraction, in the absence of heart failure, pulmonary hypertension, or primary pulmonary mechanical limitation.

I thought this was rather interesting, though I don't have the knowledge to judge the more technical aspects of the study. Perhaps they could do the same test on a ME/CFS sample to see what % has this poor SOE compared to controls.

 

[Snow Leopard]

Some interesting points raised @Snow Leopard.

I think some of the confusion/disappointment might stem from this not really being a CFS study?

The problem is that they are comparing apples with oranges. The ramping and encouragement matters a great deal if they claim to be measuring maximal exertion.

The "hyperventilation" group did not have the same effect on performance as the SOEL and SOEH groups and the SOE groups were split 50/50 suggesting any effect of hyperventilation was not a specific predictor of SOE.

With regards to the hyperventilation explanation: If the patients were chronic hyperventilators, with resting hypocapnia, would this not lead to reduced oxygen extraction? Oxygen disassociation curve and all that.

Yes, but it doesn't really matter. What happens at rest and what happens at maximal exertion are two different cases. Peak exertion has two rate limiting factors - one primarily on the supply side, which is typically determined by blood volume pumped by the heart along with the capacity of the blood itself. The second, namely the demand side, related to the capacity of the peripheral muscle to utilise oxygen (this is not merely limited to aerobic respiration, but all consumption of oxygen...). Notably, the former (supply) is the major rate limiting factor in highly trained muscles of athletes. The latter, while it could be simplified as a physiological oxygen–hemoglobin dissociation curve, is determined by a lot of physiological and biochemical factors, rather than simply the relative concentrations of oxygen and carbon dioxide in the capillaries serving the muscle.

 

[Hoopoe]

I think some of the confusion/disappointment might stem from this not really being a CFS study? Not much of a structured study at all really. I don't think it was reported correctly by ME/CFS News (above), my interpretation after reading comments elsewhere is that it's just an analysis of several hundred consecutive referrals for unexplained exertion intolerance. It looks like the funding came from a CFS charity, so they also retrospectively established which of their SOE patients would also meet a CFS diagnosis and that was that...

It says in the paper that the SOE patients had a clinical diagnosis of ME/CFS.

Maybe I missed it but I don't believe the paper says that a ME/CFS diagnosis was retrospectively established.

 

[Ryan31337]

It says in the paper that the SOE patients had a clinical diagnosis of ME/CFS.

Maybe I missed it but I don't believe the paper says that a ME/CFS diagnosis was retrospectively established.

It didn't make it clear either way I don't think.

The reason I leaned towards the assumption it was retrospective was because of the review type and funding. It's unclear but they cite a CFS diagnostic guideline after saying the patients had diagnosed CFS, then in the next sentence say: 'we were additionally able to identify three general disease categories' and give further clinical diagnoses.

I guess it also strikes me as a bit strange/unhelpful/convenient that ALL the abormal SOE patients had CFS, but there's no mention of CFS patients that did not have SOE. Surely this would be useful when trying to establish relevance to CFS...especially given <80% VO2Max (aka SOE) is far from a universal finding in previous single CPET investigations.

 

[Ryan31337]

The "hyperventilation" group did not have the same effect on performance as the SOEL and SOEH groups and the SOE groups were split 50/50 suggesting any effect of hyperventilation was not a specific predictor of SOE.

Were they not suggesting that it was the combined effect of 1x or more poor performance causes (HV, Mito, Neuropathy) that gave you the different groups? I.e. HV with no Mito/Neuropathy was sub-normal but not SOE. HV+Mito or Mito+Neuropathy etc. was SOE?

Yes, but it doesn't really matter. What happens at rest and what happens at maximal exertion are two different cases.

I understood from other work that the effects of HV on oxygen transfer are quite far reaching, this paper mentions blunted acidemia and the Bohr effect, as well as a blood flow “steal” phenomenon from hyperpnea - I'm not sure why these don't matter?

 

[Snow Leopard]

Were they not suggesting that it was the combined effect of 1x or more poor performance causes (HV, Mito, Neuropathy) that gave you the different groups? I.e. HV with no Mito/Neuropathy was sub-normal but not SOE. HV+Mito or Mito+Neuropathy etc. was SOE?

If you want to claim that, you have to test it with a model - how much of the variance does it predict? How sensitive and specific is the predictor?

I understood from other work that the effects of HV on oxygen transfer are quite far reaching, this paper mentions blunted acidemia and the Bohr effect, as well as a blood flow “steal” phenomenon from hyperpnea - I'm not sure why these don't matter?

They do matter, but they aren't necessarily the most important factor at peak exertion. Keep in mind that the body tries to buffer the effects of these sorts of biochemical events and has responses to it.

 

[Snow Leopard]

Upon further reading, I'm further frustrated by this study. Sex is a particular confounding factor and there are substantial differences in age, peak heart rate, peak VO2 and peak power between the groups. Peak heart rates at 140-150 show that many of these participants did not reach maximal exertion.

The authors discuss the Bohr effect and Hyperventilation and the oxyhemoglobin dissociation curve, despite the fact that the study they cited (which they claimed had similar effects), actually concluded:

It thus is still unclear whether O2diffusion increased by the Bohr effect with hypercapnia affects the V˙o2 response in humans.

There has not been a convincing argument for O2 diffusion as a “rate-limiting” step of V˙o2 kinetics. We did not observe accelerated V˙O2kinetics with hypercapnia with a small change in PaCO2

The reason why should be obvious if we actually look at the math of the Bohr effect. The delta P50 for a delta of 0.05 to 0.1 pH is approximately 1 Torr, which is small and explains why the studies did not find a clear effect.
The authors seem to have ignored the coupling of the muscle structure with neurology as an explanation - earlier recruitment of larger motor units with lower O2 diffusion (due to lower capillary density) can also cause the effect... Of course poor microcirculation will exacerbate this effect.