Car Wreck on ME/CFS Patients ‘Oxygen Highway’…
Clean vs Dirty Energy Production
Keep your eyes on the oxygen molecule. Your body thrives on it. It’s at the heart of your aerobic energy production system. When it’s working correctly you’re filled with clean, abundant energy. When its not you’re in trouble.
Multiple systems explode into action in order to get that oxygen to your muscles when you exercise. You breath more deeply and your heart pumps harder and faster to transport it just as quickly as it can to your cells. That heart/lung/muscle connection is the oxygen highway.
You have a second (mostly backup) energy production system but it’s a dirty, inefficient and even painful system to use. Called anaerobic glycolysis it mostly kicks in only after your aerobic (oxygen-using) energy production system has pooped out. If you exercise long and hard enough (or if you have ME/CFS – not very long and not very hard) the pain and fatigue you experience when you switch to anaerobic system is unmistakeable.
As soon as you make that switch – at what researchers call your ‘anaerobic threshold’ – toxins are going to start building up in your muscles and you’re probably not going to be exercising that much longer. ( ‘Aerobic threshold’ might be a better name for a switch point that represents the end of clean (ie aerobic) energy production, and a dependence on anaerobic metabolism.)
At that point things get complicated quickly. With anaerobic glycolysis comes lactic acid, and with lactic acid comes lactate, and with lactate comes CO2, and with CO2 comes a big problem. CO2 displaces oxygen – the life blood of our system – so it’s got to be removed fast, and so into the blood and out the lungs it goes. As the CO2 levels in your blood rise your breathing rate speeds up automatically just to get it out of your system.
A ‘Beautiful’ Test
The beauty of the VO2 max test is that it documents all of that. As you exercise it’s measuring your heart rate, how your lungs are doing, the amount of oxygen in your blood, the amount of CO2 you’re getting rid of, etc. It can precisely tell when your aerobic oxygen system poops out and your anaerobic system clicks in (and CO2 starts pouring out of your lungs.) It’s hand-made to detect energy metabolism problems.
A low VO2 max (or anaerobic threshold) test result means you’ve quickly sped through your aerobic energy cycle and slammed into your anaerobic threshold way ahead of schedule. That walk to the store now seems like a marathon and those bike trips you used to enjoy – don’t even think about them. Somewhere on your oxygen highway you’ve got a wreck…
There’s a big proviso to this. The VO2 max test is very revealing but only if you do it the right way. The energy production systems of most ME/CFS patients will ‘rise to the occasion’ in a one-off exercise test and produce normal results. That turned researchers off to exercise tests until Workwell (Pacific Fatigue Lab back then) showed that these seemingly ‘normal tests’ were leaving big potholes in ME/CFS patients ‘oxygen highways’. The next day most of them people were not able to get back up to speed on an exercise test.
According to Workwell investigators, that’s an unheard of finding in the medical world. Heart, kidney and even lung disease patients can jump on the bike and produce the same amount of energy the next day….but ME/CFS patients couldn’t.
That, of course, means the test-retest protocol could prove that post-exertional malaise – a term introduced to the medical lexicon by ME/CFS researchers – is biologically based. Exertion, after all, is a function of energy; no energy – no exertion
In this two-day test-retest study Workwell investigators were looking to validate their findings from that earlier study.
Let’s see what they found.
A team of exercise physiologists from the Workwell Foundation had 51 people with ME/CFS and 10 healthy, sedentary controls exercise to exhaustion on a bike two days in a row. They measured their heart rates, blood pressure, oxygen consumption, oxygen levels in the blood, lung functioning, CO2 levels ,etc.
The chronic fatigue syndrome patients and the healthy controls were similar age, height, weight and had similar BMI’s. (The controls were actually quite a bit fatter but not ‘significantly so’ statistically :))
Couch Potatoes Crush ME’/CFS Patients
First Day – On the first test the two groups looked the same. (The people with ME/CFS had consistently lower results but not low enough to be statistically significant. That probably indicated a number of ME/CFS patients did have significantly lower test results but that the group as a whole did not. )
Second Day – the second day was a different story. Placing in the lower 10 percentile in fitness, the healthy controls were certified couch potato’s, but they looked like Olympic athletes compared to the people with ME/CFS. Flabby muscles and all, they were able to jump on the bike the second day and repeat their results.
The ME/CFS group, on the other hand, dropped a full 40% in the amount of energy they were able to produce at their ‘ventilatory threshold’. (If you’re into physics that was about 8 watts of energy).
(Your ventilatory threshold occurs when you’ve exhausted your aerobic energy stores and have begun pumping out lactic acid. VO2 max, the better known test in ME/CFS, measures the amount of energy you produce at your peak level of oxygen consumption. Ventilatory threshold is probably a more accurate measurement of post-exertional malaise because it clearly identifies that you’ve entered into your ‘dirty energy’ production phase.
Workwell’s first study found more evidence of VO2 max issues; this one found more evidence of ventilatory threshold issues; both findings suggest an abnormal metabolic problem is present. It will take time and larger studies to determine which is more prevalent in ME/CFS.)
Deconditioning Not A Factor
Deconditioning was not the cause of the ME/CFS patients declining ability to exercise. If it was, the deconditioned healthy controls would have met the same fate. Nor was lack of effort. An important facet of the full cardiopulmonary (heart/lung) maximal exercise test is that it (and it alone) physiologically determines whether you’re giving your all or not…
Their CPET scores (RER) showed the ME/CFS patients gave it their all on the first test, and when they came back for the second day, they gave it their all on the second test. That’s no surprise; people with ME/CFS are rabid for answers, and they’re willing to go through some pain to get them. Anyone who thinks otherwise (aka a skeptical research community) doesn’t know this group.
(The problem, by the way, is not finding ME/CFS patients who are willing to put themselves through a second test but finding sedentary controls who will.)
High, High Accuracy Rates At Determining Who’s Who
Remarkably, all the ME/CFS patients and 9/10’s of the healthy controls were identified correctly simply by looking at the test results.
That suggests two things; one – a) this test is very robust; and b), at least for me, it starts to erode the idea of an illness permeated with subsets.
This was, after all, a pretty heterogeneous group – both newbies (just 6 months in) and oldies (30 years with ME/CFS) participated – and both demonstrated what appears to be a unique metabolic problem. Yes, there is heterogeneity; some people with ME/CFS have lower VO2 max scores, and some have lower ventilator threshold scores, but the key is that most people with ME/CFS appear to have an unusual metabolic abnormality that keeps them from being able to exercise much.
Too Harsh? Maximal vs Submaximal Effort Test
Questions have been raised, however, whether two-day test-retest trials are ethical because of the temporary pain they cause. That is a question probably best answered by the patients who choose to participate in these trials.
Staci Stevens reports, however, that Workwell rarely sees ‘adverse events’ in these tests, and that people needing heart and kidney transplants routinely do them. In fact, patients want so strongly to contribute that Workwell ‘frequently’ advises severely ill patients who want to do the second test, not to. Dr. Peterson and Dr. Lapp have been doing CPET testing for years without safety issues. This is not to say ME/CFS patients aren’t in pain after the test but they’re not irreparably harmed; they simply require more time off (from days to weeks) to get back to baseline.
Staci noted that recovery time in submaximal and maximal effort tests is about the same, and that patients actually exercise longer on the submaximal test. (In VO2 max tests you’re on the bike pedaling about 8 minutes).
While submaximal exercise tests can provide useful information, substitutes for the Stevens protocol (2-day test-retest maximal exercise study) simply don’t exist. For one thing, the submaximal test results have not been validated in ME/CFS. For another, a skeptical research community being presented with highly unusual results – needs to have all the T’s crossed and I’s dotted to accept them. The test-retest protocol does that. The submaximal test does not.
ME/CFS patients inability to reach age associated heart rates, etc. during exercise (‘chronotropic intolerance’ ) means they’re at risk of being accused of not providing full effort in submaximal exercise tests. Because maximal exercise with CPET actually validate a state of physiological exhaustion has been reached, they do away with this concern. All that’s left at that point is for exercise physiologists to gulp and try to figure out what’s going on. (A favorite fall-back thus far has been “your instruments must not be calibrated right”. )
Under normal circumstances most activities of daily living require energy below ventilator threshold. However, if VT occurs at very low levels of oxygen consumption and/or a very low workloads then activities of daily living may exceed VT….Snell et. al.
This study involved an exercise test but we’re not really talking about exercise with ME/CFS – we’re talking about daily activity levels. In this brief passage Snell et. al bring home the point that in ME/CFS it’s more about being able to engage in the day-to-day activities of normal life than going jogging.
I imagine that’s a very hard message for researchers who dismiss ‘chronic fatigue syndrome’ to get. I suspect many researchers shy away when they hear of the really disabled people with ME/CFS because it just doesn’t fit in their reality. Not many disorders, after all, cause that kind of debility.
That will take time to get across – and more studies like this.
Foundations Not Cracked Yet
There’s no denying Workwell’s influence; exercise and stress tests are now commonly used in ME/CFS studies but the foundational shift that I thought (and I think they thought) we were on the cusp of when I wrote “Cracking the Foundations’ five years ago, hasn’t happened. Neither the ME/CFS or the outside research community have embraced the full 2-day test-retest protocol. Aside from this one, just one study in the past five years has attempted to validate Workwell’s original study (it succeeded).
(No studies, furthermore, have appeared in Science or Nature on the bizarre metabolic abnormalities present in ME/CFS; yes,-I was dreaming big when I thought that would happen, but if these metabolic problems really are unique to this disorder, why not? :))
This means that instead of getting at the cause of the metabolic abnormalities present in ME/CFS Workwell is still trying to prove they exist. It means that GET has not been reinterpreted within an understanding of the metabolic problems present in ME/CFS. It means that exercise programs that fit ME/CFS patients physiology are not the norm. It means that worries about ‘effort’ still exist. It means this disease still gets a psychiatric slant in many quarters. It means that a core aspect of ME/CFS is not getting fully researched.
It’s astonishing to me that an easily validated, readily available and non-controversial technology that appears to explain post-exertional malaise – the key symptom in ME/CFS – has not been embraced. I’m shocked that we’re not further than we are but we are moving forward.
Three test-retest studies have had similar results and Betsy Keller at Ithaca in New York is publishing a fourth. An exercise test (type undetermined) appears to be on the boards of the CDC big multi-center study. A test-retest study by the CDC that finally pushed these findings into the bigger journals and into the news would be a huge win.
To reiterate the CPET maximal exercise test-retest
- smashes the deconditioning argument to bits
- provides a metabolic basis for the exertion problems in ME/CFS
- relies on commonly used equipment that has been used to validate dysfunction in many disorders (unlike much cutting-edge research in ME/CFS).
- provides the best evidence for disability possible.
- appears to identify a core issue that many people with ME/CFS, young and old, highly disabled, and more functional share.
- can differentiate between people with ME/CFS who have metabolic issues and people who are equally low functioning but don’t have them. Thus it’s an excellent way to subset patients prior to studies.
This study provides further validation that something has gone very wrong in ME/CFS patients energy production pathway. In my opinion if anything deserves more study in ME/CFS…it’s this…
After years of work it’s time to attempt what we’ve never been able to do before – get Congress to force the NIH to double its funding for ME/CFS. Support the historic bill to increase research funding, add new ME/CFS research centers, require the development of a strategic plan, etc.. It will take less than 5 minutes.