Severe hypoxia drive your tissues to anaerobic metabolism even in the context of a normal circulatory system.

Having arrived at a putative figure for the limit of hypoxic tolerance (i.e. minimum rate of oxygen delivery, or about 250ml/minute) one can also try to calculate the lowest arterial oxygen tension which would support aerobic metabolism, for a person with a normal hemoglobin

DO2 equation

Thus, in order to have a DO2 less than 250ml/min, with a Hb of 150, and a cardiac output of 5l/min, one’s oxygen saturation would need to be less than 25%. Perhaps a  more likely scenario is an ICU patient with a Hb of 70g/L, which would give us a “minimal” SaO2 of 50% or so. Is that accurate?  A PaO2 of about 26mmHg would give you this sort of number, but one boggles at the conditions which would give rise to this for long enough that lactate is produced, collected in a blood gas syringe, and measured. One can imagine some sort of nightmarish scenario with an intensive care registrar in front of an alarming monitor, blinking sleepily at the hypoxia alarm for twenty minutes, trying to wake up enough to process this information.

Is this supported by any experimental evidence?

In order to study asphyxia at this level of cruelty, again we turn to dog experiments from the 70s. All efforts were taken to get the circulatory system out of the picture, and the dogs even had PA catheters inserted to make sure their cardiac output did not play a role in the lactic acidosis. The investigators found that the animals had to get down to a PaO2 of around 36mmHg before they started producing excess lactate – an arterial saturation of around 67%. This, though quite low, is not quite the figure my calculations arrived at. The error may be in my crappy calculations, or it may stem from the fact that the authors did not report their dogs haemoglobin concentration (though I doubt that it would be substantially lower than 70g/L)

However, the chloralose-anaesthetised dog is probably a reasonable proxy for a sedated ICU patient. This “lactate threshold” could be a useful number to remember.

But let us forget about the lactate for a second.

 What happens if you keep asphyxiating?

Cardiac output will eventually begin to diminish, presumably because the myocardium no longer has any oxygen to oxidise the  metabolic substrate with.  The dogs in the abovementioned experiment  had a sharp drop-off in their cardiac output at around 15mmHg PaO2. Bradycardic arrest ensued.

The intracellular events:

Recall the  oxygen cascade. Weirdly, mitochondrial oxygen is usually quite low. The minimum partial pressure of oxygen required for mitochondria to carry on aerobic metabolism is thought to be around 1mmHg. However, when we measure venous oxygen content, we find that even in the most vigorously exercising muscle, the PaO2 of venous blood is never much lower than 20mmHg. Such a wide gradient between capillaries and mitochondria can be explained by the heterogenous soupy cytoplasm which interferes with oxygen diffusion.

The anaerobic life

Truly ridiculous exercises have been carried out by intelligent men who carried an ABG machine up Mount Everest and performed  tests on themselves. Why they did this, apart from fun, is difficult to establish, as one can easily be exposed to hypobaric hypoxia without the inconvenience of interacting with crooked Sherpas. Anyway: with maximal hyperventilation (and an alveolar pCO2 of around 7mmHg) they were able to get a PaO2 of around 20mmHg and still perform various tasks. Nunns Respiratory physiology reminds us that the reason thy were able to do this is the physiological compensation for hypoxia. Their cerebral vessels were massively dilated and their cardiac output was greatly increased, to maintain an oxygen delivery rate to their brain, thereby maintaining consciousness. This will not be the experience of a non-mountaineering person. We, the normal humans, will lose consciousness at around 27mmHg PaO2.

But did these hypoxia-resistant supermen have a raised lactate? No they did not. The gas results from these people give a lactate of 2.0 mmol/L, or thereabout. Obviously, anaerobic glycolysis is not a major contributor to body ATP production even at such laughably low PaO2 concentrations. The authors acknowledge this, and suggest that in such conditions there may be increased use of lactate as a fuel. Additionally, the cardiac output in these Everest-climbers was also massively elevated, which means the DO2 would have remained within a normal range.

References

Richardson, Russell S., et al. "Human skeletal muscle intracellular oxygenation: the impact of ambient oxygen availability." The Journal of physiology 571.2 (2006): 415-424.

 

Hobler, K.E.; L.C. Carey (1973). "Effect of acute progressive hypoxemia on cardiac output and plasma excess lactate". Ann Surg 177 (2): 199–202.

 

Gerace, E., et al. "Distribution of Chloralose in a Fatal Intoxication." Journal of analytical toxicology 36.6 (2012): 452-456.

 

Cain, Stephen M. Oxygen Deficit Incurred During Hypoxia and Its Relation to Excess Lactate. No. SAM-TR-66-107. SCHOOL OF AEROSPACE MEDICINE BROOKS AFB TX, 1966.

 

There is also this, though I cannot get a hold of a copy:

Ross Armstrong McFarland, United States. Civil Aeronautics Authority; The Effects of oxygen deprivation (high altitude) on the human organism. (1932)

If you own it, send me a copy! It sounds like a fun read.

 

M.C. Brahimi-Horn, J. Pouysségur Oxygen, a source of life and stress FEBS Lett., 581 (2007), pp. 3582–3589

 

West, John B., et al. "Maximal exercise at extreme altitudes on Mount Everest." Journal of Applied Physiology 55.3 (1983): 688-698.

 

Grocott, Michael PW, et al. "Arterial blood gases and oxygen content in climbers on Mount Everest." New England Journal of Medicine 360.2 (2009): 140-149.

 

Cable GG. In-flight hypoxia incidents in military aircraft: causes and implications for training. Aviat Space Environ Med 2003; 74: 169-172.

 

Sutton JR, Reeves JT, Wagner PD, et al.  Operation Everest II: oxygen transport during exercise at extreme simulated altitude. J Appl Physiol 1988;64:1309-21.