Acid-base homeostasis is vital to life. Disruptions in the balance of Hydrogen ions within the body, and within the cell cause problems that are often the symptoms of disease. Understanding how these mechanisms work gives us two valuable insights, firstly it aids in diagnosis, and second it can guide treatment.
Everything begins with water.
We are all approximately 60% water (though I have evidence that some ED Registrars are made entirely from gin). Water dissociates as follows
H2O <–> H+ + OH–
The dissociation of water is constant, and is dependent on temperature, at high temperatures you get more dissociation, this means you get more liberated Hydrogen ions, and so the acidity goes up.
If we are 60% water, that’s a lot of available, easily liberated hydrogen. We don’t measure hydrogen ion concentration, we measure the negative logarithm of proton concentration (because some bright spark thought that was easier).
Normal mean INTRACELLULAR pH = 6.8
ECF [pH usually aprx > 7.3] – Contains cells, particles, dissolved gases, fully and partially dissociated ions
Normal mean ARTERIAL pH = 7.4
So it’s important to realise that what we are measuring and what we really care about, are again, different things. We should care about the intracellular pH, but we can’t measure that, so we measure the arterial (or venous) pH of blood, and use that as a surrogate for extracellular fluid (ECF) which is, in itself, a surrogate for intracellular pH.
Determinants of pH
Numero uno; CO2
We make a lot of CO2 each day from aerobic metabolism and the trusty Krebs cycle (12 500 mEq/day). It goes from the cell to the ECF, to the blood, to the lungs where it follows it’s partial pressure gradient out into the atmosphere. For us to understand CO2’s effect on plasma pH we have to plug it into our formula.
CO2 + H2O <–> H2CO3 <–> H+ + HCO3–
Using this, and the formula for pH we can derive the following formula
pH = 6.1 + log10([HCO3–]/αPCO2)
This equation is the Henderson Hasselbach equation (not the top one!) and it is how we derive the bicarbonate in a blood gas readout. 6.1 is the pKa (another time), and α is the solubility coefficient of CO2. (which is 0.3, but we all knew that right?)
Important point: HCO3– is a derived value. It is not a measurement.
Numero Dos; Non-volatile weak acid dissociation
Fluid compartments have a soup of molecules that don’t generate CO2. Some of these have acidic properties. They predominantly have a negative charge, and this charge alters in parallel with pH. The main constituents are albumin, and inorganic phosphate (haemoglobin is also a weak acid and does the same thing inside the red cell). This gets expressed with the incredibly complex formula
HA <–> H+ + A–
Now one of the laws of physics comes into play here. That law is conservation of mass
We can define the total amount of non-volatile weak acids in a fluid compartment ATOT,.
ATOT = HA + A–
KEY POINT: ATOT is a constant, it cannot vary with pH, because you would have to convert some of the mass to energy, which would cause your fluid compartment to EXPLODE [e=mc2]. A change in pH signals a shift in the balance between HA and A–.
Numero trois; Electrical Neutrality – and strong ions.
The balance of charge of cations and anions must equal eachother in a dissolved fluid. This is another one of the laws of physics, takes precedence over any desire for pH neutrality.
K+, Na+, Ca2+, Mg2+, Cl– exist as ions dissolved in fluid. We also have lactate, sulphate, and β-hydroxybutyrate acting as strong cations in the plasma compartment.
In human plasma we do not have a balance of cations and anions, this “gap” or “difference” is the Strong Ion Difference [SID], which is expressed mEq/L (because it’s an expression of CHARGE, not concentration).
SID = [strong cations] – [strong anions]
And because of the law of electrical neutrality we can re-arrange that formula to state:
SID + [H+] –[HCO3–] – [CO2-3] – [A–] – [OH–] = 0
Number “whats spanish for four?” – crazy voodoo – aka Gibbs Donnon forces.
This is the name given to the forces that compel dissolved ions to alter their equilibria across semi-permeable membranes (if you want to draw some circles with a dotted line across the middle and talk about concentration gradients…you can, I won’t stop you). The 3 fluid compartments that we are concerned about in this model are the ones inside red blood cells, as well in the plasma, and the ECF. Each compartment contains big molecules which have a charge, and will not diffuse (haemoglobin and albumin I’m looking at you). Red blood cells harbour a lot of negative charge (as they’re packed with Hb) so they attract Na+ and K+, if it wasn’t for the Na/K+ ATPase working against that electrochemical gradient, they’d swell up, pop, and we would all die. Chloride is the major anion, and it is shuttled around by this affect a lot.
Putting this all together.
There are 6 equations that govern, and predict how much H+ there is in the plasma. They are as follows.
Water dissociation equilibrium [H+] x [OH–] = Kw
Weak acid dissociation equilibrium [H+] x [A–] = Ka x [HA]
Conservation of mass for weak acids [HA] + [A–] = [ATOT]
Bicarbonate Ion formation equilibrium [H+] x [HCO3–] = Kc x PCO2
Carbonate ion formation equilibrium [H+] x [CO32-] = K3 x [HCO3–]
Electrical neutrality SID + [H+] –[HCO3–] – [CO2-3] – [A–] – [OH–] = 0
Stewart proved (using sexy maths) that 6 of the variables in these equations (HA, A, HCO3–, CO32-, OH– and H+) are reliant on just 3 independent variables: SID, ATOT and PCO2
The Strong Ion Difference.
SID is the gap between anions and cations on this bar chart. It is a ‘charge space’ – that is filled by weak ions dissociating in varying combinations to keep the charge in solution equal. The majority of this work is completed by just 2 components, the weak acids (A–) and the HCO3– . If we add more cations to the mix, the buffer base has to get larger to obey the law of electrical neutrality. If we add more anions, the buffer base has to get smaller to obey the same law.
The pH of human plasma is based on 3 things:
- ATOT – the concentration of non volatile weak acids
- PCO2 – the partial pressure of CO2
- SID – the charge space between cations and anions dissolved in the plasma.
Next week – we’ll talk about “apparent SID” Vs “effective SID”, anion gaps, and what clinical applications all this has!
For more on SID – have a look at this youtube lecture, it really helped me understand this.