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.