Alpha-stat and pH-stat models of blood gas interpretation

The alpha-stat hypothesis suggests we always interpret our blood gases as corrected to the same temperature (normal body temperature) irrespective of what the body temperature actually is. The pH-stat hypothesis instead recommends that we always correct the temperature to the core body temperature. Each approach has its merits and demerits.  In order to maintain one's appearance as an intelligent interpreter of blood gas data, one should decide on which approach to use, and come up with some well-articulated arguments as to why one is using it.

There are several eminent resources for this subject matter:

The "Alpha" and it's meaning

The ‘Alpha’ is the ratio of protonated to total imidazole of histidine residues among the protein molecules. It is expressed as a ratio or percentage. It At 37°C, at the normal intracellular pH of 6.8, alpha is approximately 0.55; that is to say approximately half of the imidazole and histidine residues are protonated. T.J. Morgan from Oh's Manual reports to us that this 0.55 alpha value is optimal for intracellular enzyme structure and function, and that maintaining this optimal value should be a goal of therapy.

Rationale for the routine application of the alpha-stat approach

Correcting pH for temperature makes no physiological sense, as the pH of neutrality also changes with temperature.

pH changes with temperature, and this relationship is almost linear. The linked article addresses this concept with diligence, brevity and a heaping serving of complicated maths. For the calculus-averse, Kerry Brandis has gone through this with patience and passion. For those who do not appreciate brief and lucid explanations, a rambling series of digressions is also available as a part of the ABG Interpretation chapter:

Briefly, the reason for the change in pH associated with changes in temperature is explained by the fact that dissociation is an endothermic reaction - i.e. for a given acid HA, with more energy available in the system more HA molecules will dissociate into their components, H+ and A-. The balance of HA and its dissociation products will therefore trend left (towards HA) if energy is subtracted from the system, eg. by a big cooling blanket. With less H+ activity in the system, the pH will increase (because it is a negative logarithm of H+ activity). Thus, the apparent alkalosis of hypothermia is observed.

Now, blood gases are measured at 37°, which is usually close enough to our patients actual temperature. However, if our patient is not normothermic, we have the option of correcting the ABG results for their actual body temperature. This will give very different results.

Say you correct the pH for 20° or 30°, whatever the patients temperature is. You get a number. But you have no normal reference ranges for pH at that temperature - only for 37°. If you start using the normal values for pH and pCO2 at 37° to interpret the gas at 20°, you will run into all sorts of trouble. For one, the patient will appear to have a respiratory alkalosis, and you will be tempted to play with the ventilator.

But in actual fact, at all temperatures intracellular pH remains at pN- the normal pH of neutrality, required for cellular function. The reason for this is that protein buffering of intracellular pH (via imidazole residues on histidine moeties ) is also temperature dependent, and changes in parallel with body temperature. Not only that, but as intracellular pH increases (obeying the linear relationship) so must the extracellular pH increase, in order to maintain the normal pH gradient (from pH 7.4 to pH 6.8, at 37°). Thus, if the cellular machinery is already functioning under ideal conditions for that temperature, the introduction of a respiratory acidosis (by changing ventilator settings) will result in a deterioration of this function, by decreasing the transmembrane pH gradient.

Lastly, and most importantly, behold the definition of neutrality (going back to Arrhenius)- it is not "a pH of 7.0", but rather the presence of equal numbers of H+ and OH- ions. Because temperature has an equal effects on the concentration of each of them, neutrality is preserved no matter the temperature.

The lower the temperature, the lower the corrected pCO2.

Solubility of CO2 is increased in hypothermia; it is a temperature-dependent property. The PCO2 of your hypothermic patient, if interpreted at the actual body temperature, will appear abnormally low (even if you already expect it to be low, given the decreased metabolic rate).

The lower the temperature, the lower the corrected PaO2.
Changes in temperature do not significantly alter the oxygen content of blood.

Solubility of O2 is also increased in hypothermia. In fact, total blood oxygen content is increased in hypothermia. Now, the solubility of oxygen in water increases only by 100% from 37° to 0°, but the affinity of hemoglobin for O2 increases by a whopping factor of 22. The hemoglobin hungrily absorbs the dissolved oxygen, decreasing the PO2 - thus increasing the concentration gradient and enticing more O2 into the blood from the alveolar gas. (this doesn't mean that the oxygen-carrying capacity of the blood is dramatically increase, of course- there is still 1.37ml of oxygen per 1g of hemoglobin).

Now, you put this cooled sample into the blood gas machine, and the electrode will measure its PO2 at 37°. The increase in temperature at the electrode will force the hemoglobin to give up a lot of its oxygen, and some of the dissolved oxygen will also come out of solution. The result is a slightly raised PaO2.

However, this is not a realistic way of looking at the sample. Who cares what the available oxygen content of blood is at 37°? At a low temperature, all that oxygen is trapped in high-affinity bonds with hemoglobin, and is unavailable to the mitochondria.

How much oxygen is available to these cold mitochondria? There are numerous complex formulae to arrive at the corrected PO2 value. However, a simple method is to subtract 5mmHg for every 1°C from the measured PaO2 - thus, at 32° with a measured PaO2 of 100mmHg the actual PaO2 is 70mmHg.

So what do you do? Does PaO2 need to be corrected at the bedside?

In short, no.
Ashwood and colleagues present us with an excellent table (see Table 5 in their article) which demonstrates that for any given hemoglobin saturation, oxygen content of blood (in mls of gas per ml of blood) is not significantly altered, even though the calculation of PaO2 gives vastly different values.

For example, at 95% SaO2 the hypothermic patient (at 22°) would have a PaO2 of 95mmHg when measured at 37°, and 27mmHg when measured at 22° - that difference is massive. But the calculated oxygen content of blood varies very little - from 0.1920 to 0.1933 mls/ml.

Thus, there is little point in correcting PaO2for temperature. The American Association for Respiratory Care recommended against the routine correction of blood gas samples for temperature, quoting the analysis by Shapiro (1995) as their main reference for this recommendation.


Device-specific information in all these ABG pages refers to the ABG machine used in my home unit.

Other machines may have different reference ranges and different symbols.

For my ABG analyser, one can examine this handy operations manual.

There is also an even more handy reference manual, but one needs to be an owner of this equipment before one can get hold of it. Its called the "989-963I ABL800 Reference Manual" and can occasionally be browsed accidentally.

Covington, Arthur K., R. G. Bates, and R. A. Durst. "Definition of pH scales, standard reference values, measurement of pH and related terminology (Recommendations 1984)." Pure and Applied Chemistry 57.3 (1985): 531-542.

Reed, Christopher A. "Myths about the Proton. The Nature of H+ in Condensed Media." Accounts of chemical research 46.11 (2013): 2567-2575.

Palascak, Matthew W., and George C. Shields. "Accurate experimental values for the free energies of hydration of H+, OH-, and H3O+." The Journal of Physical Chemistry A 108.16 (2004): 3692-3694.

Franks, Felix. Water: a matrix of life. Vol. 22. Royal Society of Chemistry, 2000.

Yagasaki, Takuma, et al. "A theoretical study on anomalous temperature dependence of pKw of water." The Journal of chemical physics 122.14 (2005): 144504.

Ohtaki, Hitoshi. "Effects of temperature and pressure on hydrogen bonds in water and in formamide." Journal of molecular liquids 103 (2003): 3-13.

Bandura, Andrei V., and Serguei N. Lvov. "The ionization constant of water over wide ranges of temperature and density." Journal of Physical and Chemical Reference Data 35.1 (2006): 15-30.

Moon, Richard B., and John H. Richards. "Determination of intracellular pH by 31P magnetic resonance." Journal of Biological Chemistry 248.20 (1973): 7276-7278.

Roos, Albert, and Walter F. Boron. Intracellular pH. American Physiological Society, 1981.'

Davis, Michael D., et al. "AARC clinical practice guideline: blood gas analysis and hemoximetry: 2013." Respiratory care 58.10 (2013): 1694-1703.

Shapiro B.  Temperature correction of blood gas values. Respir Clin N Am 1995;1(1):69–76