Metabolic fate of lactate, acetate, citrate and gluconate

This chapter is a distant vague relation of Section I2(i) from the 2017 CICM Primary Syllabus, which expects the exam candidate to develop "an understanding of the pharmacology of colloids and crystalloids". It is probably also vaguely related to Section J1(i), "describe the chemistry of buffer mechanisms". The main topic of discussion is "bicarbonate precursor" molecules that form the basis of the theoretical benefit of "balanced" crystalloid fluids. What follows should not under any circumstances be regarded as a piece of mandatory exam revision material, as it  has never appeared in any CICM exam paper, not is it ever likely to appear there, largely because it remains contentious even among the uppermost demigods of critical care.  

What is a "bicarbonate precursor"

In common bedside parlance of critical care, the term "bicarbonate precursor" is used as a shorthand to refer to the anion substitute molecules used by crystalloid manufacturers to "balance" their solutions, making their composition more closely resemble the electrolyte milieu of extracellular fluid.  The presence of organic anions and negative charge residues on proteins has lowered the chloride concentration of extracellular fluid, which means the manufactured crystalloid also needs to present a lower chloride concentration - while at the same time retaining enough sodium to ensure the fluid remains in the extracellular compartment. Practically, this is achieved by the addition of various benign anion salts of sodium to the crystalloid - usually acetate, lactate or gluconate salts, but potentially also maleate, citrate, and so on. A crystalloid with this sort of composition is said to have an alkalinising effect on the body fluids, as opposed to the acidifying effect exerted by everybody's favourite pickle juice.

The first time the term "bicarbonate precursor" was used in reference to the alkalinising effects of intravenous fluids was probably by Winfield & Mersheimer (1951), describing the effects of a crystalloid solution developed by Fox et al (1952). Noting that 0.9% saline had about 50% more chloride in it than it really needs, the authors decided to infuse their surgical patients with what they called a "balanced" electrolyte solution. On close inspection, this was some kind of mutant Plasmalyte with a double dose of potassium and 55 mEq of organic anions of which the majority were acetate and citrate (the latter added to "obtain some inhibition of clotting in the needle during slow infusions").

Why not just bicarbonate?

Surely, one might ask, it would be just easier to put sodium bicarbonate in those bags, if bicarbonate and alkalinisation is what one is truly after? Well, reader, this is technically correct, insofar as a solution with 66% sodium chloride and 33% sodium bicarbonate would be "balanced" from the perspective of acid-base, and this sort of concoction could be theoretically infused into a patient for an alkalinising effect. In practice, however, it would be impossible to store such a fluid, except in glass. T.J Morgan (2004) explains that the bicarbonate in the solution would leak (as CO₂) into the atmosphereic gas mixture in the fluid bag, increasing the PCO₂ and depressing the pH of the solution. Organic anions do not have that problem, and are much more attractive because of their extended shelf life.

Common bicarbonate precursors

Sodium acetate: The conjugate base of acetic acid, acetate is mated to a sodium cation instead of hydrogen. If one were to speak like a real scientist one might say that sodium acetate is the sodium salt of acetic acid. Cheap junk food manufacturers occasionally use it in lieu of actual salt and vinegar.

Sodium lactate: The conjugate base of lactic acid, this is present in Hartmann’s solution and Ringer's lactate as a sodium salt. It is found in all kinds of unlikely places.  It is a food additive and apparently when given intravenously it can be used to treat an overdose of Class 1 antiarrhytmics like procainamide and quinidine (mainly by increasing the sodium levels).

Sodium citrate salts come in three flavours: monosodium, disodium and trisodium. As can be plainly seen, there are three positions for sodium to occupy on the citrate anion. The monosodium variety is used to chelate calcium in packed cells to prevent clotting. The disodium species is an acidity-regulating food additive. Trisodium citrate is the hideous-tasting antacid shot you give to pregnant women as a premedication for their elective caesarian.

Sodium gluconate  is the sodium salt of gluconic acid. It is contributed to solutions as a mean of equalizing the cation-anion balance; however as an anion it seems to be physiologically useless, and it has only a theoretical role to play as a "bicarbonate precursor". It is mentioned here because each litre bag of Plasma-Lyte 148 contains 23 mmol of this stuff.

The metabolic fate of bicarbonate precursors

The first authors writing about balanced crystalloids and bicarbonate precursors in the 1950s did not question the biochemistry of their product: the "rapid metabolic conversion to bicarbonate" was an established fact for them. 

The classical view of this is demonstrated by the diagram below:

All these bicarbonate precursors funnel into the citric acid cycle. Among the precursors, it looks like acetate is the better choice because it is metabolised in most tissues, whereas 70% of the lactate needs a working liver, but overall they all end up becoming citrate.  Conventional teaching holds that by being metabolised, these substances consume a proton, and produce water and CO₂, which combine to form bicarbonate (hence "bicarbonate precursor"). The consumption of hydrogen ions is emphasised by some authors, because it is equivalent to the generation of bicarbonate (given the equilibrium between the two). This conversion is said to be 1:1 (i.e. one molecule of lactate consumes one proton and is therefore equivalent to one molecule of bicarbonate). Vághy (1979) was actually able to demonstrate this process of proton consumption in some rabbit mitochondria. 

However, many reasonable people (and readers of Φ) have pointed out that this makes no sense. First of all, they rightly point out that the oxidative dehydrogenase reactions
of the citric acid cycle liberate three protons, instead of consuming them. Those protons consumed by Vághy's rabbit mitochondria? The very same protons. The net  change is zero.  Secondly, CO₂ produced by the metabolism of these substrates dissociates into equal parts of bicarbonate and protons (because CO₂ + H₂O ⇌ H₂CO₃ ⇌ HCO₃^- + H⁺) which means there would be no net change in total body acid-base balance.

How, then, do we explain the alkalinising effects of these "bicarbonate precursors"? Because the effect is undeniable. Without trying to quote every possible study reporting on the acid-base effects of balanced crystalloids, let us behold one classical study by Kirkendol et al (1980), who infused dogs with 0.25mmol/kg/min of sodium acetate, sodium lactate, sodium succinate and sodium gluconate:

Clearly, something is happening here, but it may not be related directly to the effects of "bicarbonate precursor" metabolism, and the "classical" model of acid-base analysis may not be the right mechanism to explain these phenomena. Kowalchuk et al (1989) came to this conclusion trying to explain the effects of trisodium citrate on the performance of athletes:

"The mechanism responsible for the alkalosis is explained using the physico-chemical principles reviewed by Stewart (1983). Sodium citrate does not exist in molecular form in body fluids but dissociates into individual ions, sodium⁺ and citrate^3-. As the citrate anion, but not the sodium cation, is removed from plasma, the plasma [strong ion difference] ([SID] = (sum of the strong cations) - (sum of the strong anions)) increases (Stewart 1983); that is, the ratio of strong cations to strong anions increases and there is an electrical charge imbalance. Electrical neutrality must be maintained and this is met by a fall in [H⁺] and an increase in [HCO₃^- ](Stewart 1983). Thus the fall in [H⁺] (or increase in [HCO₃^-]) induces the state of alkalosis observed in the present study."

The mystery of gluconate

Leaving the most irrelevant digression until last, the reader's time will now be wasted by the following complaints about the lack of medical information for the pharmacology of the gluconate anion.

After some difficulty, the author managed to get a hold of this document, which makes several assertions about gluconate (for instance, that it is a normal metabolic product of glucose metabolism, and that the average human produces 25-30 grams of it per day).  According to this industrial chemistry paper, gluconate is not metabolised particularly well, and about 85% of it is excreted unchanged in the urine. Do physiologists agree?  Perhaps. Why is everything about this subject written in the 1950s? There was passion then; people used to really fall in love with physiology. Not like this cynical age we live in now. The only real study on gluconate metabolism in the electronic literature is this report by Marjorie and DeWitt Stetten, written in 1953. The Stettens administering their radiolabelled sodium gluconate to a number of anaesthetized rats. They also concluded that the majority of the gluconate (something like 57%) was renally excreted in an unchanged form. 14% of the administered C14-labelled gluconate was excreted rapidly as carbon dioxide,and great portion of the C14 isotope was also renally excreted – as glucose. The rat livers also were aglow with C14 radioactivity, presumably because they were bloated with radiolabelled glycogen. This supports the assertion that gluconate is converted to glucose, and incorporated into energy stores.

The same authors investigated this pathway, and concluded that the first carbon (C1) of gluconate ends up turning into CO₂, whereas the rest end up being converted to glucose, god knows how. The enzyme which may be responsible is glucose 1-dehydrogenase. A Swede named Brink found it in his puree of beef liver, and speculated regarding its function (again, in 1953). However, nothing further came of this. So, if you can shed some light on this process, please contact me and I will send you a token gift, likely a T-shirt emblazoned with the pathway you explained.

In the meantime, my confusion is demonstrated in my allusion to a supernatural power as a catalytic influence on the conversion of gluconate to glucose.