The next in an ongoing series of blogs on hypotheses by professionals associated with ME/CFS focuses on Dr. David Bell’s 2007 intriguing idea that ME/CFS patients could be stuck in a mild form of chronic septic shock.
In the ten years since Bell put forth his hypothesis, the hypothesis, has seemed, at least in this laymen’s accounting, to only gain currency. Find out why Dr. Bell believes that sepsis – one of the most dangerous and expensive to treat diseases – could have its counterpart in ME/CFS in this Simmaron Research Foundation supported blog:
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Very interesting. Especially the core problem bloodflow, low oxygen in the tissue and vascular problems! This is ME/CFS/POTS. So, oxygen delivery is the cause of our symptoms. Hyperventilation -Not due to psychogial issues- can also be a major player. Brainstem?
Hi Gijs,
The recent discussion going with you, Merida and others lately ended with a “if so much effort is done to breath plenty and oxygen would not be short, then CO2 must be low for a reason” hypothesis from my side. Somehow however it still felt wrong. When it comes to the breathing paradox I often felt I had to chose between either observation and coherence between many elements but ignoring the Bohr effect as “something that will be overwhelmed by something really big” on one side and the Bohr effect on the other side. It just had no common ground. Maybe until now.
I’ll break this post up for readability, hoping that it’ll spark discusion. If a few things would be backed up by facts I feel it could lead to more then a dent in ME’s armor: I still see some small inconsistencies and gaps in my idea’s about breathing and might mis some really big ones. But if there ain’t and those facts would end up more or less correct it could circle really close near one of the core problems. So please all discuss, add facts or counterfacts…
PART 1:
A few things came together in my mind:
– My body and brain seem to do combined an enormous amount of effort to breath more. With such depleted body and mind I have a hard time to believe it’s a “faulty function” of the brain or ANS/CNS.
– The recent blog talked about RBC membrame damage by H202 and the resulting reduced elasticity of RBC reducing flow in caplillars as a result.
– I had quite a few times H202 in the croshairs but I never could make a meaningful enough case for it to be a breathing problem next to a blood flow problem as well. Numbers or arguments always seemed to fall short.
– I had doubts more then once if it was breathing in, breathing out or both that drove this huge urge to breathe.
– A lot of things that helped my ongoing breakout of the viscious circle have the combination breathing-bloodflow at the centre.
– The last two months I began more and more to think of the remaining problems at night, after eliminating side effects gave me a bit clearer feel of it, as being “sleep poisoning”. It felt an awful lot like some kind of poisoning begining at about 1.5 hours after first sleep and increasing till the morning.
– A few days ago I cut myself at about 3am by accident and never had seen that kind of blood color. It was closer to black then to red. It was obviously with artificial light so it isn’t very color true but dark remains dark. And I had seen blood under artificial light before. I tried and looked under both CFL and LED light to have a better idea of the effect of artificial light but the color remained black-ish.
correction: psychological
PART 2:
I decided that I had to delve deeper into that enoying Bohr effect that always countered my observations and ideas so far. I found some wonderful information that opend my eyes:
– http://www.gmch.gov.in/e-study/e%20lectures/Anaesthesia/O2_AND_CO2.pdf
The whole document is a marvel, but a bit difficult unfortunately. Slide 24 and some of the text in the PPT convinced me not to chose to drop the Bohr effect as a nuisance to be solved later. The graph explains well what’s governing oxygen uptake by the lungs and release to the tissues. I needed such clear info. Then slide 31 hit me: factors that effect dissociation. Low body temperature isn’t helping release of oxygen to the tissues, but CO2 and lactic acid is. That seemed more then reasonable. Slide 32 conviced me that breathing out too much CO2 is an actual good candidate for poor oxygen release to tissue even in ME. So why breathe so much? The graphs indicated that O2 shortage in blood wasn’t a likely candidate.
I looked into slide 39 and 40 for a candidate but couldn’t get it work.
Slide 43 got me thinking: we haven’t got Anemia, but could there exist something likewise? That would make a good candidate.
Slide 44 and 45 made the link between ME and FM: if myoglobine is more affected? more tendency to FM. if hemoglobine is more affected? more tendency to ME. It’s a big jump but I felt the need to Google myoglobine. BHAM: https://www.ncbi.nlm.nih.gov/pubmed/7071598 “Hydrogen peroxide converted intracellular myoglobin to products incapable of combination with oxygen, but had no deleterious effect on neuromuscular transmission or on mitochondrial oxidative phosphorylation.” in the abstract. That was perfect in line with the fact that H202 bonds well with hemoglobin when anti-oxidants fails as a last line of defence. I earlier considered a drop of an estimated 5 to 10% in usable RBC due to H202 occupation not significant enough to cause that much trouble we are in. But here were two parallell mechanisms, hemoglobine for ME and myoglobine for FM that can spill problems over in each other and act like the Anemia curve of slide 32. Add to that the recent discovery that RBC lose elasticity when subject to high concentrations of H202 and Naviaux’s strong Dauer hypothesis that cells churn out massive amounts of H202 in a cell defence reaction. On plus anti-oxidants and gluthathione are often depleted.
Numbers didn’t add up; even if I combined both effects they fell short of the onslaught we experience. But hey, if CO2 effects dissociation curves by the Bohr effect, couldn’t a chemcial with far stronger affinity to hemoglobin not have it’s own Bohr effect?
A few searches later I ended up with https://en.wikipedia.org/wiki/Methemoglobinemia:
“Methemoglobin is a form of hemoglobin that contains the ferric [Fe3+] form of iron. The affinity for oxygen of ferric iron is impaired. The binding of oxygen to methemoglobin results in an increased affinity for oxygen in the remaining heme sites that are in ferrous state within the same tetrameric hemoglobin unit.[1] This leads to an overall reduced ability of the red blood cell to release oxygen to tissues, with the associated oxygen–hemoglobin dissociation curve therefore shifted to the left. When methemoglobin concentration is elevated in red blood cells, tissue hypoxia may occur.”
“Normally, methemoglobin levels are H202 does not only reduce the amount of available RBC to carry oxygen, it also works in concert with low levels of CO2 to make the reduced amount of 02 near inaccesable. And it discolors blood (but maybe more to secondairy cyanosis due to hypoxia then to methemoglobin intoxication, more on that later).
“Signs and symptoms of methemoglobinemia (methemoglobin level above 10%) include shortness of breath, cyanosis, mental status changes (~50%), headache, fatigue, EXERCISE INTOLLERANCE, dizziness and loss of hairlines” (note, methemoglobine acts a lot like CO or cyanide poisonning so 10% is a *lot*)
Myoglobine is also effected: H202 breaks it down and one of the waste products is NO. NO is the unlikely chemical that is a very strong blood vessel dilator. The combination of both sentence makes NO a good indicator of dangerously low levels of myoglobine and thus it finally makes sense that this NO chemical is used as such a strong signal to increase blood supply to get sufficient oxygen.
But why breath so much that low CO2 levels would make things even worse when there is (somewhat) sufficient O2 in the blood? That is a clear one: natural detoxification of methemoglobin is done in the same way as CO poisoning and cyanide poisoning is done by the body: MASSIVE BREATHING to replace the poisonous component by oxygen, FAR beyond the oxygen needs to fuel the body.
=> That is what I now feel is the reason why we breath like a horse till we drop even if the low levels of CO2 are supposed to make us suffocate. As we likely produce copious amounts of H202 that broke long ago through the defence of anti-oxidant capacity we MUST prioritise continous rapid removal of the poison to prevent a cyanide poison like death. As us producing so much and so often H202 we could improve short times by breathing less, but soon RBC poisoning would strike back in double force.
That may also explain why many people claim improvements with “odd” breathing related things like:
– COPD: surgery or a tool can maximise breathing capacity
– nightly breathers: same
– increased oxygen Merida talked about: increased detoxification
– hyperbaric chambers: increased oxygen supply and once more increased detoxifaction
(warning: increased oxygen by itself can be dangerous and even lethal when used wrong, don’t just go experimenting!)
– alternate nostral breathing, holding breath as long as possible: are variants of deeper and slower breathing I learned. It increases used lung area a lot increasing O2 takeup and detoxification speed a lot while allowing for same or lower CO2 breathing out speed (levelling out to higher amounts of CO2 in blood shifting the Bohr effect into our favour)
This may also provide a solid link to air pollution, !air borne mold!, my continous colds due to inherited weakness, chemical sensitivities. All easily end up in the same natural reaction: constrict the lungs to expose them to less of the bad stuff. Unfortunately that hampers/criples methemoglobinn detoxification a lot too.
So why most patients breath undeep and fast? Because breathing slow and deep is damn hard on the brain and muscles. And both are already weakened a lot. It requires training, building up muscle strength, increase endurance of the brain pushing the muscles so hard… all while not causing PEM or “breathing system” exhaustion. Really hard!
Hi Dejurgen, I’ve been following your posts on this blog and see that you’re in on all the science and research. Could I connect with you on email to go over some theories? Thanks, Gaurav
PART 3:
About hypoxia, CO poisoning and why not diagnosed?
Symptoms of hypoxia according to https://en.wikipedia.org/wiki/Hypoxia_(medical) overlap with our disease:
“The symptoms of generalized hypoxia depend on its severity and acceleration of onset.
In the case of altitude sickness, where hypoxia develops gradually, the symptoms include fatigue, numbness / tingling of extremities, nausea, and anoxia.[5][6] In severe hypoxia, or hypoxia of very rapid onset, ataxia, confusion / disorientation / hallucinations / behavioral change, severe headaches / reduced level of consciousness, papilloedema, breathlessness,[5] pallor,[7] tachycardia, and pulmonary hypertension eventually leading to the late signs cyanosis, slow heart rate / cor pulmonale, and low blood pressure followed by death.”
The sysmptoms of CO posioning show quite an overlap with our disease according to https://en.wikipedia.org/wiki/Carbon_monoxide_poisoning:
“The main manifestations of carbon monoxide poisoning develop in the organ systems most dependent on oxygen use, the central nervous system and the heart.[15] The initial symptoms of acute carbon monoxide poisoning include headache, nausea, malaise, and fatigue.[24] These symptoms are often mistaken for a virus such as influenza or other illnesses such as food poisoning or gastroenteritis.[25] Headache is the most common symptom of acute carbon monoxide poisoning; it is often described as dull, frontal, and continuous.[26] Increasing exposure produces cardiac abnormalities including fast heart rate, low blood pressure, and cardiac arrhythmia;[27][28] central nervous system symptoms include delirium, hallucinations, dizziness, unsteady gait, confusion, seizures, central nervous system depression, unconsciousness, respiratory arrest, and death.[29][30] Less common symptoms of acute carbon monoxide poisoning include myocardial ischemia, atrial fibrillation, pneumonia, pulmonary edema, high blood sugar, lactic acidosis, muscle necrosis, acute kidney failure, skin lesions, and visual and auditory problems.[27][31][32][33]
One of the major concerns following acute carbon monoxide poisoning is the severe delayed neurological manifestations that may occur. Problems may include difficulty with higher intellectual functions, short-term memory loss, dementia, amnesia, psychosis, irritability, a strange gait, speech disturbances, Parkinson’s disease-like syndromes, cortical blindness, and a depressed mood.[25][34] Depression may occur in those who did not have pre-existing depression.”
Note http://scuba-doc.com/carbonmon.html: classic treatments of CO poisoning include 100% oxygen treatment and hyperbaric oxygen for *accute poisoning* => can be highly dangerous or lethal on permanent basis!
Why would methemoglobine poisoning be so often overlooked (if the hypothesis is correct)?
=> short answer: Too low oxygen levels, CO poisoning, cyanide poisoning and the less common H2S poisoning all show up as a DESoxy state or as iron lacking oxygen. methemoglobine is a SUPERoxy state or a superoxide, a different form of oxidated iron or iron having oxygen. Many standard test look for the DESoxy state and methoxyglobine poisoning may falsly show up as good oxygen saturation. Many hemical based lab test convert all hemoglobine having (or not having dependend on the test) to the same thing so methemoglobin often ends up in the “plenty of oxygen” category with chemical tests.
In addition, DESoxy states have a clearly different purple/brownish color compared to oxygenated red blood. Methoxyglobine has a different color compared to normal oxygenated blood but the difference is more subtle. If it is “only” 5 to 10% diluted in likewise cloured red blood it can easily get unnoticed. It requires an accurate sensor that looks at three different avelenghts and has sufficient accuracy. 5 to 10% may sound few, but 5 to 10% CO-bound-hemoglobine on a permanent basis would not be that little. If methemoglobine acts similar… Also, this low percentage can only be kept that low by vigorously and continously overbreathing. Here is a paper on the difficulty of measuring methemoglobine posioning http://www.jbc.org/content/148/1/173.full.pdf and https://acutecaretesting.org/en/articles/hemoglobin-and-its-measurement discusses several different methods to measure blood oxygenation with its pro’s and con’s.
=> HiCN is called the international standard; but among the contras of this methods: “Does not distinguish those hemoglobin derivatives which have no oxygen-carrying capacity (MetHb, COHb, SHb). Thus may overestimate the oxygen-carrying capacity of blood if these are present in abnormal (more than trace) amounts.”
If a 50 dollar finger gizmo could do better then the above (and nonfunctional for us) test would not be an international standard I guess. It seems that methemoglobin poisoning is not considerd “a thing” as it hasn’t got a separate name ore measurment protocol. The belief seems to be that it occurs as a result of certain medications or in specific accute conditions.
Another thought on non-diagnosis: the worst moments with me are after exercising and during sleep. Those moments are not the typical ones when you see a doctor. I suspect the amount of methemoglobine to swing wildy between acceptable or more then acceptable to terrible at the worst of onslaughts. At rest the body could work very hard to minimise the remaining waste as it knows a new overload is due soon.
PART 4:
Fitting methemoglobin into the bigger picture of our disease.
My believes/ideas are the following:
An initial onslaught can simultaniously derail blood flow and overwhelm anti-oxidation capacity. This can be due to a short but strong burst, surgery (anastesia increase chances of methemoglobin poisoning for the mid term), infection causing blood thickening by provoking imune stuff (too fatigued to remember/search the name of these signal molecules) and provoking strong H202 generation as countermeasure and sometimes creating plenty of nitrous components creating mild cyanide poisoning lowering the bar for methemoglobin poisoning and messing with body temperature shifting dissociation curves for the better or worse. It can also be due to more long lasting sorts of stress (including working or exercising too hard on a daily basis), due to (auto)-immune problems especially if they attack blood vessel walls, severe gut disfunctionning starving the body and poisonning the blood, parasites entering the blood flow… and strenghtend by missing key enzymes, genetic deffects or having a pre-existing breathing problem like my combined very strong weakness to the common cold constricting the lungs and filling airways with slime and me being born quite preterm often leading to weak lungs… …and plenty more causes or a combination thereof.
The RBC (and myoglobine?) act as a last line of defence against oxidants when other lines like glutathione and anti-oxidants are overwhelmed. They only carry H202 but don’t break it down. Part can be expeled through the lungs but I estimate that is a minority of it. Doing so generates increased hypoxia from combined increased methemoglobine poisoning and decreased blood C02. This in turn increases H202 production…
Another route of “disposal” of H202 is to move H202 from the source (sick body part) to the rest of the body in the hope it’s dilluted up there and can be processed in a timely matter. If the problem is body wide like for example EBV or spread Borelia (tick bacteria) that seems to be an idle hope.
If the transported H202 can’t be processed in a timely matter the risk arises that new sites get “started” as H202 acts as a messanger molecule: if local concentration increase above a threshold then nearby molecules could start a cell defense reaction… …producing more H202 that has to be transported by RBCs througout the body (as anti-oxidant capacity is even more overhelmed). And so we edge near a dangerous vicious circle. As a bonus prolonged H202 levels in the blood now appear to damage the RBCs themselves making them more fragile and bend less to get trough capilars. And H202 kills local NO. This is a triple effect that decreases global blood flow through cappilars increasing hypoxia producing more H202 and reducing imune systems performance further…
The special “negative” RBC gene Merida repported beiing very frequent observed in her ME support group decreases CO2 permeability through RBC. The most likely path here seems to be simple: if CO2 gets slower into the RBC than H202 then H202 outcompetes CO2 in occupying the RBC and the slower increase in CO2 in the RBC as the RBC pass by the exercising tissue lower the amount of CO2 where and when it matters: near the hemoglobine at the exact moment the hemoglobine has to give up here O2. But this local lower concentration of CO2 is now seen as a reduced Bohr effect at the time it is least desired clinging on to O2 when and where tissue most needs it.
The reduced blood flow makes things worse when the “low pressure” venous side is reached. Even minimal blood pooling gives localy generated H202 the change to “saturate” the very slow moving RBCs at these sites while uptake of CO2 slows down.
It may also hold the answer to the question I lately posed: If hypoxia/mild septic state/imune trouble/anaerobic functionning are so rampant in our bodies then the liver should run double or triple shifts while the rest of the body can’t even do half or quarter shifts? How does that make sense?
Well, the liver is at the core of the body giving it better temperature near optimal, increasing oxygen delivery. Increased adrenaline helps the liver a lot as well. But most and for all: the liver is the storage warehouse and main recycler of antioxidants like gluthathione. If “new” blood enters the liver from somewhere else it gets showered in locally produced, stored and recycled anti-oxidants killing of H202 at highly increased rate. So this “HO2O Bohr like effect” is likely a lot milder near/in the liver, increasig oxygen release. Killing local H202 would give NO a decent chance to do it’s thing: dilating blood vessels in the liver. The liver also turns a high portion of fructose to lactic accid locally. While this may seem bad, if it is controlled it *could* “help modulate/improve” oxygen release. It’s a tricky one but it might work in an otherwise aerobe liver environment.
It is a very early idea that I release now. Text quality is low as producing this demanded the utmost of me. It can contain huge gaps or things that will be rejected, but even then I feel it starts to get near !part! of a key disease mechanism that is common (in those with decreased body temperature). It is not finished so I’d be pleased people improve it to become a blow in the face of ME.
Kind Regards,
Dejurgen
Dear Dejurgen
I am very sick with infection and ME and have a lot of problems with my heart and breathing.
An last time I was on the hospital my carbon monoxide was high but no smoke.
I Denmark there is no one to help me except one infection doctor who gives me antibiotics and after stop it get worser.
Will you please contact me on trine.mortensen@hotmail.com