Saturday, December 12, 2015

Acetoacetate and arterial oxygen tension

This is very exciting. Remi forwarded it to me. He understands.

Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats

It’s from D'Agostino’s ketone group. Unless you are in to hyperbaric medicine you can ignore the bulk of the paper. Instead look at Fig. 3:

We're interested in the grey line in graph A with the triangle data points. How does enforced ketosis with an exogenous acetoacetate/betahydroxybutyrate precursor (but not when using a pure beta hydroxybutyrate precursor) raise arterial pO2 from the normal of 100mmHg to the rather spectacular high of 130mmHg?

This is fascinating and of genuine physiological significance. Not the raised arterial pO2 per se, more what it says about AcAc and metabolism. But never the less, how do you get a sustained increase in arterial pO2 by gavaging a with substance which is an AcAc precursor anyway? This is from the discussion:

“An unexpected finding was that BD-AcAc2 [the acetoacetate precursor] caused a significant and sustained increase in blood pO2 levels of ∼30%. It’s conceivable that these changes in PO2 result from BD-AcAc2-induced alterations in the neural control of autonomic regulation, including cardiorespiratory function (38). Further studies are needed to determine the specific contribution of BD-AcAc2 on brain O2 consumption, ventilatory drive, systemic blood pressure, and brain blood flow preceding CNS-OT.”

The finding was unexpected. There is no obvious explanation. It needs further study.

I love this. I’ll put on my anaesthetist’s hat and speculate.

The rats are breathing room air and there is nothing to suggest there has been any change in minute volume of breathing following treatment with the AcAc precursor. I think the effect possibly comes down to a decrease in tissue oxygen consumption under this drug derived ketone.

Aside: pO2 here is the partial pressure of oxygen in the arterial blood. This is only linked to oxygen content via the the oxygen-haemoglobin dissociation curve which is highly non linear. A change in pO2 from 100mmHg to 130mmHg is on the flat section of the curve and adds almost no oxygen carriage/delivery via haemoglobin. But it tells us things. End aside.

If you have a manoeuvre which decreases tissue oxygen consumption but leaves all else unchanged you will raise the partial pressure of oxygen in the alveoli within the lungs closer to the inspired concentration. This is because less is being taken up in to the blood, so more is left in those alveoli. Arterial blood leaving the lungs (in equilibrium with the alveolar pO2) will, therefore, have a higher partial pressure of oxygen too.

Equally, if you have lower oxygen consumption then the partial pressure of oxygen in the venous blood will be raised compared to normal tissue extraction, all other factors being unchanged. Again, it's because less is extracted, more is left. So there will be a higher venous oxygen partial pressure. Now, lungs are not 100% efficient. Some venous blood gets through and lowers the oxygen partial pressure in arterial blood. Higher oxygen partial pressure in venous blood means less effect on arterial blood pO2 through this lung inefficiency.

These are gross simplifications. John Nunn's Applied Respiratory Physiology, chapter 10 p242 onwards, "The oxygen cascade" has a little more detail. OK, a hell of a lot more, caveats included. Especially Fig 10.7.

Is this enough to explain D'Agostino's results? I don’t know. But an idea of whether I am correct would be given by taking a venous blood sample and measuring the venous pO2. The measured effect on arterial pO2 is large so you could possibly see a raised venous pO2 on a simple jugular vein sample without needing to try and get a pulmonary artery sample from a rat. That would give a “back of an envelope” assessment in little more time than it takes time to stick the sample through their blood gas analyser.

Equally, just stick a rat in respiratory chamber, gavage it with the acetoacetate precursor and measure its decrease in O2 uptake.

This finding has huge implications for managing any condition where oxygen delivery is compromised. Not the carotid pO2 of 130mmHg per se, this will have put very little more O2 on to haemoglobin than a pO2 of 100mmHg as stated. It's that decreased need for oxygen by the tissues which it signifies. Acetoacetate appears to allow tissues to function with a significantly reduced need for oxygen; that I find exciting. OK, I'm a bit strange but, well, that's me!


Summary: People climbing Everest should be in ketosis. With acetoacetate predominating.


bill said...

"Summary:..." Ha! Love it.

Larcana said...

I work in hyperbaric medicine and we have Blood Glucose parameters for diabetic patients. They tend to drop their BG 50-100 points during their treatments (2.4ATA for 90 minutes) . There is much discussion about why. The thought is that increased metabolic demand is causing it. Possibly. The other interesting parameter is increased BP. This is thought to be because of O2 increase in cerebral tissue and the rebound vasoconstrictive effect.
Interesting paper. Thanks. Lauren Romeo, MD

Peter said...

Lauren, has anyone looked at hepatic glucose output? The increased metabolism idea looks a little simplistic.... But very interesting when you start to think about what might be happening when superoxide might be being formed from electrons which would never normally get near an oxygen molecule at 100mmHg. Sorry about these quaint pressure units, the initial paper is in these antiquated units and my brain is so old that I think in them still too!


Judd said...

I have read that people with copd should go on a low carb diet to reduce Co2 production. Not sure if that is relavent.

Tucker Goodrich said...

Darn it all, I was just about to go out on a run (fasted, of course) and I saw this.

Tim Ferriss did a three-hour (!) interview w/ D'Agostino in which they discussed this paper in the context of his other experiments and the implications for human metabolism. It was fascinating, and I highly recommend it.

"Summary: People climbing Everest should be in ketosis. With acetoacetate predominating."

He used acetoacetate because beta-hydroxybutyrate gets converted to it in order to be used. So acetoacetate doesn't need to "predominate", as that's what's used physiologically, anyway.

The impetus for the research was Navy SEALs who use rebreathers underwater. Turns out the rats can survive significantly longer underwater before they start seizures.

As far as your comment about Everest goes, one of the most amazing athletes in the world right now is Killian Journet. While he eats a pretty high-carb diet, he trains in the fasted state, for eight-plus hours, at altitude—think he might be in ketosis doing that?. He's the top mountain-runner and ski mountaineer in the world.

He recently set the record for climbing up/skiing down Denali in Alaska.

"Fat is your friend. He was one of the first ultra-runners to reduce his calorie intake on long outings, relying instead on body fat for a more dependable, nearly inexhaustible fuel source. During his almost 12-hour Denali circuit, he consumed a half-liter of water and a single energy gel."

That's a few hundred calories of carbs. He climbed 13,000 feet to the ~20k summit. Again, think he was in ketosis? He knocked five hours off the previous time getting up and down in just under 12 hours.

His next big project?

"Expect the growing FKT movement to shed its scrappy, unpublicized existence next spring. That’s when Jornet will head to Mount Everest without oxygen, carrying only the slimmest survivalist’s pack of food, water, and protective gear, and attempt to lay down a new record on the world’s most scrutinized peak. Jornet hasn’t settled on his precise route or starting point yet, but he does have a time in mind: 20-some hours up, 35-ish back down. Bottom to top to bottom in one weekend."

God speed.

valerie said...

Hi Peter,

First of all, I have to tell you that I don't know much about biology. That caveat aside, here is my question: could it all be about balancing blood ph?

Ketone bodies are acidic. Oxygen in the blood is alkaline, CO2 is acidic. The body will compensate a (slight) metabolic acidosis by inducing a (slight) respiratory alkalosis.

At least, that's how I interpreted my blood test results when I happened to get tested after 7 days of fasting a few years ago (long story). My anion gap was off (sorry, I don't remember the details), and my venous gases were weird (high O2, low CO2). The doctor never said anything about it, as usual (I don't know if he even looked at my results) but my Wikipedia searches led me to believe I was in respiratory alkalosis to compensate a metabolic acidosis.

If it is any indication, I felt crappy the whole time I fasted. I definitely did not feel super-oxygenated (I imagine that would feel pretty good, right?).

Morris said...

Would you expect the increased oxygen partial pressure in venous blood tend to visibly distend human veins? This has happened to me (6 year experiment) and my veins have become quite prominent, particularly on waking. A lesser effect has been a small reduction in quantity/size of broken veins, although broken veins were minor to begin with. I am an ancient male. I have asked medical people (in the abstract) whether vein distension is a useful medical marker, but they have no idea.

John U said...

Recently while swiming in a pool after not doing so for over a year, I noticed that I could swim under water for a greater time than I remember doing in the past. I am not in a ketogenic state most of the time, but I do follow a low carb diet and I do know that I generate some ketone bodies. I was surprised at how long I could stay under water without any feeling of distress. I guess I was not imagining the experience. There may be a plausible explanation for it. BTW, I am 70.

JohnN said...

"People climbing Everest should be in ketosis"
That's right. I came across conclusion while researching high altitude training and decided this summer to hike above 14K ft in ketosis. Noticeably easier.

JohnN said...

"..similar conclusion" I mean.
Less oxygen consumed if you draw from fat reserve or burning ketones.

Larcana said...

Well yes, I sort of increased ROS and depletion of SOD as you treat with longer tables. That can happen say in decompression sickness and recompression. Metabolic acidosis as well. Vasoconstriction...lactic acidosis.
Its' a complex picture because of the meds people are on. Let's say it's just Metformin...well then you have decreased BG due to liver effect, as well as risk for lactic acidosis.
Just insulin...lower BG and effects of circulating insulin due to decreased kidney clearance.
Any other combo of drugs....? Who knows there are so many now and they are placed in various combinations. !!
I wish I could take them off meds and just use a low carb diet..then we could see a clearer picture. That won't happen unless some university decides to take that on. Sadly.

Peter said...

Judd, yes, it’s relevant. Drive to breathe is driven by high CO2 rather than O2 at sea level. Low O2 takes over as partial pressure drops as you climb. The same applies to swimming under water as John U comments. I have noted that swimming a length under water is much easier under LC eating than it ever used to be. But this is CO2 being the main drive to breathe here, not O2, which is the drive at the top of Everest.

Morris, no, I doubt it is pO2 related. The combined venous gas pressure is always below venous blood pressure, so the gasses stay in solution and don’t form bubbles, but they don’t apply a wall pressure per se.

Hi valerie, the change in pO2 does not help oxygen delivery because most O2 is carried on haemoglobin. Mind you, it may well blunt the hypoxic drive to the aortic body chemoreceptors so limit the CO2 wash out that comes from over hypoxia induced hyperventilation. At a pO2 of 100mmHg (normal) Hb is almost completely saturated and increasing the pO2 to 130mmHg will not add any extra to the Hb. The amount in solution is tiny and will increase with the rise in pO2 to an amount slightly more than the usual tiny amount… What does matter is that as the blood goes through the tissue capillaries they only need to take a small amount of O2 out. This shows as there being more left in the venous blood. The pH change is real but in the paper the pH change was identical between ketone types but the rise in arterial pO2 only occurred when the precursor drug generated AcAc. With BHB only there was no rise in arterial (nor presumable venous) pO2. This asks deep questions about AcAc vs BHB and what difference an NADH molecule makes to O2 consumption… BHB is just AcAc carrying an NADH, nicely pointed out by George in previous comments or on BTW the rise in venous pO2 on fasting is rather nice dollop of confirmation bias.

Of course you have to ask questions next about exogenous ketones, fasting generated ketones and oxygen consumption, simple chemistry and ETC efficiency etc etc etc.

JohnN, very nice to hear…


nfkb0 said...
This comment has been removed by the author.
nfkb0 said...

The jugular vein might be THE right spot to find a bigger PvO2 :-D

Next secret study to come lactate+AcAc in cardiogenic shock state (I.e. after cardiopulmonary bypass)
About lactate :

- Rémi

Peter said...

Very interesting Rémi. I guess in the jugular you are looking with a bias towards the brain.... Also I suppose it's not surprising the body produces lactate in perfusion crisis. Evolution would hardly favour something which was positively bad!


Betsy said...

@Morris, nitric oxide is a powerful vasodilator, do you have any symptoms of orthostatic intolerance? It's common in people with bacterial and viral pathogens as the pathogens somehow cause increased nitric oxide levels (iNOS).

Morris said...

No such symptoms. Strangely I have been (very) slowly recovering from a persistent microbial infection (periodontal gum disease) which appears to have spread systemically. At times my blood pressure falls to 100/65 but I have no adverse symptoms. The change in BP is part of the recovery as my BP had been slowly rising (130/90) in my early 70's. My experience is strange indeed; 2 simultaneous processes, one a decades long degeneration (aging) and the other a slow recovery but without obvious overlap.

Peter said...

Hi Tucker, finally got to listen to the D’Agostino interview. Fits in well with the rest of the discussion here. The extended free diving ability seems to be quite generic, lots of n = 1 anecdote which seems to be approaching transformation in to data. Very interesting. Not sure I’m quite as enthusiastic about exogenous ketones but I certainly can see where he’s coming from…

Thanks for the link. For anyone wanting to listen to the section on on the study it’s about 1 hour to 1 hour 20 minutes.


Tucker Goodrich said...

"Not sure I’m quite as enthusiastic about exogenous ketones but I certainly can see where he’s coming from…"

Agreed. I think taking ketones on a higher carb diet is probably a bad idea. If your body doesn't do it on purpose, there just might be a reason.

But for therapeutic or case-specific applications like the SEALs, it makes sense.

altavista said...

Merry Xmas, Peter.
Thanks for writing this blog.

Peter said...

Best wishes altavista, Solstice and New Year too!


Betsy said...

@Morris, microbial infections seem to complicate the process, aging seems to not help either. I have my microbe issues, too, your mention of periodontal disease made me get more diligent with a few things. Do you know the specific microbe? Are you doing anything besides LCHF for it?

Also, I just read Peter's post that had information about endotoxins causing all sorts of problems, which helped me refocus on a few other things, too, such as trying to keep the endotoxin from spreading to the bloodstream.

Take care,

Morris said...

@ Betsy
Perio disease is caused by biofilms of commensal bacteria and some archaea and is totally refractive to antibiotics. The disease remains totally idiopathic and now the blame seems to be shifting blaming the patient’s too active immune system. Interestingly I have experienced noticeable improvements not just to gums but also to neighboring tissue i.e. skin, hair follicles, cheek muscle, eyes, throat mucous membrane. I have raised the healing question (totally in the abstract) with people in the medical field and they claim no knowledge how such a thing can be possible. I find that telling as even high school biology might suggest some common causes. As far as my experiment I have not found anyone even remotely interested or knowledgeable. I started with the notion that our bodies are eco-systems , home to other species which compete for energy and performed experiment which might disfavour the “other”. It has been a very slow process and somewhat like a Russian doll; changing contexts (health states) sometimes produce different results (markers). The experiment goes beyond nutrient ratios but I don’t want to expand. I don’t know how it will turn out in the end but in the mean time I have tried and ruled out a lot of commonly held beliefs.

Tucker Goodrich said...

"Perio disease is caused by biofilms of commensal bacteria and some archaea and is totally refractive to antibiotics. The disease remains totally idiopathic and now the blame seems to be shifting blaming the patient’s too active immune system."

It's caused by excessive consumption of carbohydrates, combined, sometimes, with malnutrition—although that's sort of redundant. Without the sucrose and glucose the bacteria cannot create the biofilms to the same extent, and do not create the lactic acid that dissolves the teeth. I don't think it's been considered "idiopathic" for a very long time, the cause is well known in all the literature I've ever seen on the subject.

I covered a bunch of the academic discussions about carbohydrates and periodontal disease in a post I'd previously shared here:

"Yes Virginia, The Paleo Diet Was Low-Carb"

Morris said...

You could review published literature on NCBI or dental journals re chronic disease, periodontal disease and treatment outcomes but I doubt any of that would alter your opinion as you “know” the answer. Why did you bother to respond?

Betsy said...
This comment has been removed by the author.
Tucker Goodrich said...

"You could review published literature on NCBI or dental journals re chronic disease, periodontal disease and treatment outcomes..."

For the audience, you can start here:

"Microbiology of Dental Decay and Periodontal Disease"

"Dental decay is due to the dissolution of tooth mineral (primarily hydroxyapatite, Ca10 (P04)6(0H)2) by acids derived from bacterial fermentation of sucrose and other dietary carbohydrates."