Posted on 04/07/2020 11:33:16 AM PDT by COBOL2Java
In the last 3–5 days, a mountain of anecdotal evidence has come out of NYC, Italy, Spain, etc. about COVID-19 and characteristics of patients who get seriously ill. It’s not only piling up but now leading to a general field-level consensus backed up by a few previously little-known studies that we’ve had it all wrong the whole time. Well, a few had some things eerily correct (cough Trump cough), especially with Hydroxychloroquine with Azithromicin, but we’ll get to that in a minute.
There is no ‘pneumonia’ nor ARDS. At least not the ARDS with established treatment protocols and procedures we’re familiar with. Ventilators are not only the wrong solution, but high pressure intubation can actually wind up causing more damage than without, not to mention complications from tracheal scarring and ulcers given the duration of intubation often required… They may still have a use in the immediate future for patients too far to bring back with this newfound knowledge, but moving forward a new treatment protocol needs to be established so we stop treating patients for the wrong disease.
The past 48 hours or so have seen a huge revelation: COVID-19 causes prolonged and progressive hypoxia (starving your body of oxygen) by binding to the heme groups in hemoglobin in your red blood cells. People are simply desaturating (losing o2 in their blood), and that’s what eventually leads to organ failures that kill them, not any form of ARDS or pneumonia. All the damage to the lungs you see in CT scans are from the release of oxidative iron from the hemes, this overwhelms the natural defenses against pulmonary oxidative stress and causes that nice, always-bilateral ground glass opacity in the lungs. Patients returning for re-hospitalization days or weeks after recovery suffering from apparent delayed post-hypoxic leukoencephalopathy strengthen the notion COVID-19 patients are suffering from hypoxia despite no signs of respiratory ‘tire out’ or fatigue.Here’s the breakdown of the whole process, including some ELI5-level cliff notes. Much has been simplified just to keep it digestible and layman-friendly.
Your red blood cells carry oxygen from your lungs to all your organs and the rest of your body. Red blood cells can do this thanks to hemoglobin, which is a protein consisting of four “hemes”. Hemes have a special kind of iron ion, which is normally quite toxic in its free form, locked away in its center with a porphyrin acting as it’s ‘container’. In this way, the iron ion can be ‘caged’ and carried around safely by the hemoglobin, but used to bind to oxygen when it gets to your lungs.
When the red blood cell gets to the alveoli, or the little sacs in your lungs where all the gas exchange happens, that special little iron ion can flip between FE2+ and FE3+ states with electron exchange and bond to some oxygen, then it goes off on its little merry way to deliver o2 elsewhere.
Here’s where COVID-19 comes in. Its glycoproteins bond to the heme, and in doing so that special and toxic oxidative iron ion is “disassociated” (released). It’s basically let out of the cage and now freely roaming around on its own. This is bad for two reasons:
1) Without the iron ion, hemoglobin can no longer bind to oxygen. Once all the hemoglobin is impaired, the red blood cell is essentially turned into a Freightliner truck cab with no trailer and no ability to store its cargo.. it is useless and just running around with COVID-19 virus attached to its porphyrin. All these useless trucks running around not delivering oxygen is what starts to lead to desaturation, or watching the patient’s spo2 levels drop. It is INCORRECT to assume traditional ARDS and in doing so, you’re treating the WRONG DISEASE. Think of it a lot like carbon monoxide poisoning, in which CO is bound to the hemoglobin, making it unable to carry oxygen. In those cases, ventilators aren’t treating the root cause; the patient’s lungs aren’t ‘tiring out’, they’re pumping just fine. The red blood cells just can’t carry o2, end of story. Only in this case, unlike CO poisoning in which eventually the CO can break off, the affected hemoglobin is permanently stripped of its ability to carry o2 because it has lost its iron ion. The body compensates for this lack of o2 carrying capacity and deliveries by having your kidneys release hormones like erythropoietin, which tell your bone marrow factories to ramp up production on new red blood cells with freshly made and fully functioning hemoglobin. This is the reason you find elevated hemoglobin and decreased blood oxygen saturation as one of the 3 primary indicators of whether the shit is about to hit the fan for a particular patient or not.
2) That little iron ion, along with millions of its friends released from other hemes, are now floating through your blood freely. As I mentioned before, this type of iron ion is highly reactive and causes oxidative damage. It turns out that this happens to a limited extent naturally in our bodies and we have cleanup & defense mechanisms to keep the balance. The lungs, in particular, have 3 primary defenses to maintain “iron homeostasis”, 2 of which are in the alveoli, those little sacs in your lungs we talked about earlier. The first of the two are little macrophages that roam around and scavenge up any free radicals like this oxidative iron. The second is a lining on the walls (called the epithelial surface) which has a thin layer of fluid packed with high levels of antioxidant molecules.. things like abscorbic acid (AKA Vitamin C) among others. Well, this is usually good enough for naturally occurring rogue iron ions but with COVID-19 running rampant your body is now basically like a progressive state letting out all the prisoners out of the prisons… it’s just too much iron and it begins to overwhelm your lungs’ countermeasures, and thus begins the process of pulmonary oxidative stress. This leads to damage and inflammation, which leads to all that nasty stuff and damage you see in CT scans of COVID-19 patient lungs. Ever noticed how it’s always bilateral? (both lungs at the same time) Pneumonia rarely ever does that, but COVID-19 does… EVERY. SINGLE. TIME.
— — — — — — — — — — — — -
Once your body is now running out of control, with all your oxygen trucks running around without any freight, and tons of this toxic form of iron floating around in your bloodstream, other defenses kick in. While your lungs are busy with all this oxidative stress they can’t handle, and your organs are being starved of o2 without their constant stream of deliveries from red blood cell’s hemoglobin, and your liver is attempting to do its best to remove the iron and store it in its ‘iron vault’. Only its getting overwhelmed too. It’s starved for oxygen and fighting a losing battle from all your hemoglobin letting its iron free, and starts crying out “help, I’m taking damage!” by releasing an enzyme called alanine aminotransferase (ALT). BOOM, there is your second of 3 primary indicators of whether the shit is about to hit the fan for a particular patient or not.
Eventually, if the patient’s immune system doesn’t fight off the virus in time before their blood oxygen saturation drops too low, ventilator or no ventilator, organs start shutting down. No fuel, no work. The only way to even try to keep them going is max oxygen, even a hyperbaric chamber if one is available on 100% oxygen at multiple atmospheres of pressure, just to give what’s left of their functioning hemoglobin a chance to carry enough o2 to the organs and keep them alive. Yeah we don’t have nearly enough of those chambers, so some fresh red blood cells with normal hemoglobin in the form of a transfusion will have to do.
The core point being, treating patients with the iron ions stripped from their hemoglobin (rendering it abnormally nonfunctional) with ventilator intubation is futile, unless you’re just hoping the patient’s immune system will work its magic in time. The root of the illness needs to be addressed.
Best case scenario? Treatment regimen early, before symptoms progress too far. Hydroxychloroquine (more on that in a minute, I promise) with Azithromicin has shown fantastic, albeit critics keep mentioning ‘anecdotal’ to describe the mountain, promise and I’ll explain why it does so well next. But forget straight-up plasma with antibodies, that might work early but if the patient is too far gone they’ll need more. They’ll need all the blood: antibodies and red blood cells. No help in sending over a detachment of ammunition to a soldier already unconscious and bleeding out on the battlefield, you need to send that ammo along with some hemoglobin-stimulant-magic so that he can wake up and fire those shots at the enemy.
How does chloroquine work? Same way as it does for malaria. You see, malaria is this little parasite that enters the red blood cells and starts eating hemoglobin as its food source. The reason chloroquine works for malaria is the same reason it works for COVID-19 — while not fully understood, it is suspected to bind to DNA and interfere with the ability to work magic on hemoglobin. The same mechanism that stops malaria from getting its hands on hemoglobin and gobbling it up seems to do the same to COVID-19 (essentially little snippets of DNA in an envelope) from binding to it. On top of that, Hydroxychloroquine (an advanced descendant of regular old chloroquine) lowers the pH which can interfere with the replication of the virus. Again, while the full details are not known, the entire premise of this potentially ‘game changing’ treatment is to prevent hemoglobin from being interfered with, whether due to malaria or COVID-19.
No longer can the media and armchair pseudo-physicians sit in their little ivory towers, proclaiming “DUR so stoopid, malaria is bacteria, COVID-19 is virus, anti-bacteria drug no work on virus!”. They never got the memo that a drug doesn’t need to directly act on the pathogen to be effective. Sometimes it’s enough just to stop it from doing what it does to hemoglobin, regardless of the means it uses to do so.
Anyway, enough of the rant. What’s the end result here? First, the ventilator emergency needs to be re-examined. If you’re putting a patient on a ventilator because they’re going into a coma and need mechanical breathing to stay alive, okay we get it. Give ’em time for their immune systems to pull through. But if they’re conscious, alert, compliant — keep them on O2. Max it if you have to. If you HAVE to inevitably ventilate, do it at low pressure but max O2. Don’t tear up their lungs with max PEEP, you’re doing more harm to the patient because you’re treating the wrong disease.
Ideally, some form of treatment needs to happen to:
Lay people filling in details.
I assume you are asking the medical community, as opposed to the news. The news readers wouldn’t report good news on this front if they were to die from it themselves.
>>why is every nation striving to preserve and expand their supply?<<
I certainly hope it’s because it’s working, but feel there’s still the possibility that people are jumping on the bandwagon before convincing evidence is available. That’s why I asked how many you’ve seen turned around and what the timing is. It’s also why the NBC host should have asked the same question. Big difference between three and three hundred.
If we had a functional media today (we don’t) they would be interviewing people like yourself all over the country and the world and a pattern would quickly evolve. For example, there was the New Orleans doctor who dismissed both HCQ and the Z-Pack, separately or together, as I recall) saying simply that he wasn’t seeing them making a difference.
Decent reporting would get at the discrepancy: why is one doctor seeing results and another not? What are they doing differently, or what is the difference in their patients, or is one of them outright lying due to a severe case of TDS, etc.?
So the initial thought is, the people are hypoxic, crank up the O2 pressure. But that causes further damage to the non-intact alveoli.
This paper is consistent with the clinical findings, that the malaria drugs don't work if the disease has progressed too far: it doesn't combat cytokine storm, but the hydroxychloroquine acts as an ionophore to get the zinc into the cell, where it inhibits viral replication: so if the disease is too far gone, cutting the viral count is a fool's errand.
The idea of red blood infusion *with* hydroxychloroquine /zinc (to prevent the new blood cells from getting infected) is a novel treatment. Won't necessarily repair the lungs though.
1. I am using the combination of HCQ and Azithromycin, no zinc because its a routing issue
2. I have seen all my patient turn around (>20)
3. I see an improvement in ABG PaO@ as soon as 12 hours.
Thanks for the info
Multiple mechanisms of action, many things going on. I read a couple of months ago, or saw on a YouTube, clinical studies on early cases that having the patient prone on a bed with the head slightly downhill, improved survival by helping the junk to drain out of the alveoli. As far as increasing O2 delivery, if you have both the air sacs filled with mucus, and some % of the blood cells out of commission, then a higher O2 % would help the few remaining blood cells, when they *do* make it to somewhere they can pick up O2, load up with more oxygen. Osmosis, diffusion, mole fraction, yada yada.
Precisely. Truth filtered through a layperson.
Blood transfusions are universally a horrid idea. Blood transfusions modulate and key up the immune system (Gives a SIRS response) which is exactly what we are trying to avoid. All gold standard studies in critical care point that a restrictive transfusion practice has a higher survivability at 30 days and one year.
Its not that the alveoli are filled they are not, its that there is increased thickening of the tissues (inflammation) causing diffusion gradient related hypoxemia and additionally probably a surfactant loss from type II pneumocytes. It is ARDS pure and simple from what I am seeing.
Finally all viral PNA are bilateral — there is the subtext coming that most PNA is limited to a lobe — bacterial tends to be lobar, but viral PNA tends to be bilateral.
Higher O2 is not always a good thing. >60% is hyperoxemic tx and promotes fibrosis via free radical injury. Proning does not improve 30 day survivability, although it does transiently improve oxygenation, so maybe its just enough to get someone on the fence through. Head down is a bad idea in prone or supine ventilation as it causes an increase in WEST Zone three via a restrictive mechanism (abdominal contents reducing thoracic volume). So the notion of draining is not founded.
What are the normal modes of hemoglobin? Do they change when it is carrying oxygen?
I said the same thing and was told i had the comprehension of a first grader.... i’m glad you picked up on as well
1st time I’ve seen it too! You know, some of us don’t live on FR all day because we work, have lives, etc so we don’t see every article that is posted, when it’s posted!
I didn’t say nothing seems to work just be someone else. I did say there is no one magic bullet. We are also not seeing an 80% death rate on vents. people are coming off, but some rather slowly
I posted the part right below about the bacteria. Who has reading comprehension problems?
1) thank you for the correction on all viral PNAs being bilateral, vs. bacterial being lobar. Is that due to the smaller size of the virions affecting how they are transported through the body?
2) The alveoli being filled, is from an MD-sponsored YouTube presentation early in the epidemic: they found a higher survival rate on severe cases, when the patient was prone, and with the head lower than the feet. Somewhere along the way (maybe not that same video) was a clinician saying they saw improved results from pounding / massaging on the back of the lungs to keep things loosened up.
3) Any proposed mechanism for follow-on cardiac injury? I've seen but didn't bookmark a medical journal article in the last 36 hours detailing this as a delayed result of Sars2-2019 (or whatever they're calling it *this* afternoon) infection.
4) All gold standard studies in critical care point that a restrictive transfusion practice has a higher survivability at 30 days and one year.
Can't be talking about this virus then, there haven't been any patients around for a year yet.
Therefore, in that particular instance, you're the one talking through your hat based on approximate data. Not anecdotal, but of the kind "why are you looking for your wallet over here if you lost it down the street?" / "Well, there's a streetlight over here" sense.
i realize that but it was the first part of the article i saw. I also posted several other problems with the article right after
The oxygen dissociation curve is unbelievably complex. Its been a while, but there are a few things that influence it...
1. Acidemia tends to promote oxygen dissociation from the HGB molecule (thats why you would rather be a little academic when there is tissue level hypoperfusion in the shock state than alkalemic)
2. The amount of 2,3 DPG available (an enzyme that promotes dissociation). Banked blood is bad (transfusion practices) for a lot of reason, one of the reasons is there is a significant depletion of 2,3 DPG, so oxygen remains bound to the HGB in transfused blood
3. There are other factors, but the main story is that when saturation drops 92% of less there is a very steep decrease in oxygen saturation over a small range of O2 partial pressures.
There are a lot of graphs and I am pretty technically poor at copying graphs in HTML, so I am sure you can find them somewhere on line
As for the conformation of the molecule, If memory serves the reduced state of Iron (Fe2+) is the state of the iron molecule in normal Hgb, and this is what unloads and attracts O2 in normal physiology. If the oxygen reads with the iron itself and oxidizes it to the 3+ state, you get free radical injury with the creation of O2- ion.
If Fe becomes carboxylated or methylated (Carboxyhgb and methemoglobin) it irreversibly binds oxygen and does not permit it to be released at the normal oxygen tension of the proximal and distal capillary.
Ok, I have promises to only say what I know and what I dont know...the above biochemistry is off the top of my head and there may be errors, but the principles are correct. As for CoVID causing a conformation or electrochemical chage in the reduction state of Fe ions on Hgb, we have ways to measure it — it is part of the normal ABG. I am NOT seeing it. I know there has been a question of measuring ferritin in these patients — so then my next question would be has a patient with hemochromatosis ever had CoVID.
There is a lot of conjecture, and it is scientifically interesting, but what this article suggests are practices at the bench that we know at bedside would be dangerous, and I am not seeing these lab results in patients I am treating.
I am enjoying the scientific discussion with you despite some of our differences FWIW.
I will certainly accept any corrections to my biochemistry recall...
If you like a lot of fairy tales misinformation and unsourced statements
Experts are often too enamoured of their own chosen paradigm. And the medical field is especially bad, eh, Dr. Semmelweis? See also the Nobel in medicine for ulcers...
Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.