Response to 1L of Hartmann's compound sodium lactate

This chapter is relevant to Section I2(i) of the 2023 CICM Primary Syllabus, which expects the exam candidates to "understand the pharmacology of colloids and crystalloids". After decades of being ignored by the CICM exams, Hartmann's solution came up as part of Question 18 from the second paper of 2023, where it was being compared with normal saline, which means this ancient chapter (dating back to the very origins of Deranged Physiology) had to be taken apart and renovated.

In summary:

Name Normal saline Hartmann's solution
Class Crystalloid fluid Crystalloid fluid
Chemistry Monovalent cation salt:
0.9% sodium chloride (8.77g/L, or 150 mmol/L)
- pH around 4.6
- calculated osmolality 300 mOsm/kg
- measured osmolality 286 mOsm/kg
"Balanced" crystalloid solution composed of several cation salts:
- Sodium chloride (105 mmol/L)
- Sodium lactate (29 mmol/L)
- Potassium chloride (5 mmol/L)
- calcium chloride (2 mmol/L)
So, in total;, 131 mmol/L sodium, 112 mmol/L chloride, 5 mmol/L potassium and 2mmol/Lcalcium
- pH 5.0
- Calculated osmolality 278 mOsm/kg
- Measured osmolality 260 mOsm/kg
Routes of administration IV, subcutaneously, orally, or as a neb (plus multople others) IV only
Absorption 100% oral bioavailability; well absorbed 100% oral bioavailability; well absorbed
Solubility pKa 3.09; good water solubility pKa of sodium lactate is 3.78; all components have excellent water solubility.
Distribution VOD=0.2L/kg, basically confined to the extracellular fluid
(thus: 25% remains intravascular, 75% becomes interstitial)
VOD=0.2L/kg, basically confined to the extracellular fluid
(thus: 25% remains intravascular, 75% becomes interstitial)
Target receptor As a resuscitation fluid, you could say that the target receptor is the baroreceptor As a resuscitation fluid, you could say that the target receptor is the baroreceptor
Metabolism Not metabolised Only the lactate is metabolised, producing H2O and CO2
Elimination Eliminated renally, where specific reabsorption mechanisms in the renal tubule regulate the rate of sodium and chloride excretion Eliminated renally, where specific reabsorption mechanisms in the renal tubule regulate the rate of sodium and chloride excretion
Time course of action Half life is 20-40 minutes in healthy volunteers, longer in shock states and in mechanically ventilated patients (up to 8 hours) Half life is 20-40 minutes in healthy volunteers, longer in shock states and in mechanically ventilated patients (up to 8 hours)
Mechanism of action Expands the extracellular fluid volume and changes the biochemistry of the body fluids Expands the extracellular fluid volume and changes the biochemistry of the body fluids
Clinical effects Volume expansion:
- by 25% of the infused volume, after 25-30 minutes
- below the circulatory reflex activation threshold
- effect is greater during the infusion (prior to redistribution)
Change in osmolality:
- minimal; unnoticed by osmoreceptors
Change in biochemistry:
- trivial sodium elevation (~0.5-.0 mmol/L)
- nontrivial chloride elevation (up to 3 mmol/L)
- decrease in bicarbonate and base excess (also up to 3 mmol/L)
Volume expansion:
- by 25% of the infused volume, after 25-30 minutes
- below the circulatory reflex activation threshold
- effect is greater during the infusion (prior to redistribution)
Change in osmolality:
- minimal; unnoticed by osmoreceptors
Change in biochemistry:
- trivial sodium depression (~0.5-1.0 mmol/L)
- trivial chloride elevation (up by 1.5 mmol/L for every litre of Hartmanns)
- increase in bicarbonate and base excess (up by 2-3 mmol/L)
Single best reference for further information Griffel and Kaufman (1992) White & Goldhill (2010)

The best references to describe Haertmann's solution would have to be McLoughlin & Bell (2010) or 

White & Godlhill (1997), of which the latter is sufficiently awesome to have their images used by the LITFL Hartmann's page. Alexis Hartmann's original 1932 articles are also worth reading for mainly symbolic reasons.

Chemical class of Hartmann's solution

Hartmann Compound Sodium Lactate is what the bag reads. If one were forced to compose a opening motherhood statement for an SAQ answer, would have to call it a "balanced" crystalloid, or an isotonic salt solution, or a something similar. Weirdly, MIMS lists this as a pregnancy category C substance, which demonstrates the usefulness of that ranking. Hartmanns is still essentially normal saline, garnished with small amounts of calcium and potassium. The key difference is the sodium compound. Of the 9 or so grams, 3.17g is contributed by sodium lactate, a slightly salty-tasting substance which Wikipedia introduces as a meat preservative.

Sodium lactate is only one sodium compound among many which could be safely infused without causing major problems, and other such compounds already find use in medicine, of which probably the best known are sodium acetate and sodium gluconate (components of Plasmalyte). Yet more such compounds are available but are not used routinely. For example, in order to test one of the central assertions of Peter Stewart's physicochemical interpretation of acid-base balance, Ke et al (2013) had infused animals with sodium octanoate. In short, there are plenty of high-SID alternatives to sodium lactate.

Pharmacokinetics of Hartmann's solution

Weirdly, MIMS lists this as a pregnancy category C substance, which demonstrates the usefulness of that ranking. Hartmanns is still essentially normal saline, garnished with small amounts of calcium and potassium. The key difference is the sodium compound. Of the 9 or so grams, 3.17g is contributed by sodium lactate, a slightly salty-tasting substance which Wikipedia introduces as a meat preservative. 

Presentation of Hartmann's solution

Hartmann Compound Sodium Lactate is what the bag reads. 

Contents of Hartmanns compound sodium lactate

Administration of Hartmann's solution

Unlike saline, which is used to irrigate wounds and moisten eyeballs, Hartmann's is mostly infused intravenously. In fact if you do irrgiate eyes with it, Harmann's can cause reversible clouding, which would be annoying. Interestingly, whereas saline is recommended for wound irrigation in humans, it appears that veterinary literature recommends Hartmanns for wound irrigation, a trend apparently based on a single paper from Buffa et al (1997). Considering that millions of people now own pets who were irrigated with Hartmann's, and that tap water appears to be non-inferior to either, there is probably no reason not to list wound irrigation alongside intravenous infusion in the list of administration methods

Bioavailability and  absorption of Hartmann's solution

Like saline, Hartmann's is basically water, and is therefore rapidly and completely absorbed if consumed orally. It does, however, taste odd, salty with and one would not be reduced to drinking it outside of some kind of bizarre dare during internship, or if one were a sick child in the late 1940s in England

Distribution of Hartmann's solution

Like saline, Hartmanns distributes rapidly from the intravascular to the interstitial compartment. About 225ml of Hartmanns will remain to expand the circulating volume.

Metabolism of Hartmann's solution

Sodium will hang around in the extracellular fluid and its presence there will fatten up your intravascular volume. The excess chloride in contrast is worse than useless. So, one can give the sodium complexed with lactate instead. The lactate is in equilibrium with pyruvate; its metabolic fate is to be incorporated into the citric acid cycle. Yes, the metabolism of lactate is "nutrition", of a sort.
One litre of Hartmanns will provide you with 9 calories, roughly equivalent to 200g of raw bok choy.

Elimination of Hartmann's solution

Water, sodium and chloride are all eliminated via the kidneys by mechanisms which are tightly regulated by the combined effects of vasopressin and angiotensin/aldosterone systems. In short, the elimination of the litre of Hartmanns will typically be rather rapid in the euvolaemic patient, as their homeostatic mechanisms will not perceive any need to hang on to the volume. The half-life of normal saline under these circumstances is usually described as 20-40 minutes (Hahn, 2016), though it is approximated as 2-4 hours for critically ill patients, and up to 8 hours in mechanically ventilated or shocked patients. 

Pharmacodynamics of Hartmann's solution

The water distributes rapidly (within about 15 minutes) from the intravascular to the interstitial compartment, and becomes trapped there. All the electrolytes in it (except for the lactate, which doesn’t count) end up trapped in the extracellular space, and the water has nowhere to go. The lactate disappears into the cells (specifically, a good healthy liver can metabolise amazing amounts of it).
Hartmanns is not particularly isoosmotic. Its osmolality (sans lactate) is 248, which is lower than that of the body fluids, and so some of the water shifts into the cells:

The infusion of 1000ml Hartmanns compound sodium lactate

 So. Let us ignore the lactate for now. 248 mOsm of electrolytes join the total pool of body electrolytes;
(1015 + 3045 + 8120 + 248) = 12428

1 litre of water joins the total pool of body water.
(1 + 42) = 43

At equilibrium (where the osmolality of the compartments is the same) the mOsm/L concentration will be
12428 / 43 = 289 mOsm/L

But; the osmoles are distributed unequally. Practically none of the 248 mOsm will enter the cells. Thus, more water will be distributed to the extracellular compartment in order to maintain an osmolality of 289 Osm/L.

How much more water will be distributed there? Extracellular water volume= (1015 + 3045 + 248) / 289 = 14.9L

Thus, of the 1 litre of Hartmanns, 900ml will distribute to the extracellular compartment and 100ml into the intracellular compartment. Following the 25:75 ratio of intravascular to extravascular spaces, this means about 225ml of Hartmanns will remain to expand the circulating volume.

Changes in compartment volumes and osmolality in response to the infusion of 1000ml Hartmanns compound sodium lactate

Distribution of the major electrolytes in Hartmann's solution

62 mOsm of the electrolytes end up in the intravascular fluid, and 186 in the extravascular. If we consider that the sodium concentration is initially 140, then it will rise by 0.3 mmol/L. As for chloride – though its concentration in Hartmanns is still higher than in human blood, it will not rise as fast as it would in the case of normal saline.. For every litre of Hartmanns, chloride will rise by 1.5 mmol/L. Thus, a hyperchloremic metabolic acidosis could slowly develop, as the strong ion difference decreases and more hydrogen ions invade the body fluid. This is remedied to some extent by the fact that for every 112 mmol of chloride, 28 mmol of lactate is also infused, the metabolism of which consumes 28 mmol of hydrogen ions.

Circulatory effects of infusing 1L of Hartmann's solution

The intravascular compartment volume increases by 225ml – from 5000ml to 5225ml. The increase in intravascular volume is 4.5% - outside the volume receptor sensitivity threshold.  Since the osmolality of the compartments decreases by only 1 mmol/L, there is also no appreciable osmoreceptor response. 

Glomerulotubular balance

This is explained in detail elsewhere. Essentially, its the response to extra body water which occurs even if there is no response from the osmoreceptors and baroreceptors, and is purely due to the fact that intravascular protein dilution results in diminished water resorption from the proximal tubule.

Where does the potassium and calcium go?

Well; one can expect that the calcium will remain in the extracellular fluid, because it is a forbidden cation inside cells. The 2mmol of calcium will distribute into the extracellular compartments, and the total concentration will not change dramatically. If it was 2.4 mol/L before, it will become 2.38mmol/L after. This is unlikely to exert a physiological effect.

As for the potassium: this is more complex. The extracellular concentration is tightly controlled, as there is only about 50-60 mmol of extracellular potassium. The body's responsiveness to sudden changes to this potassium occurs via the rapid large-scale movement of potassium into the cells, specifically the muscle cells (which contribute the bulk of your extracellular fluid. This happens within a minute, and is mediated by the activity of Na+/K+ ATPase. Furthermore, this uptake activity is inversely proportional to the extracellular concentration: the more extracellular potassium the less intracellular uptake.

Essentially, the less extracellular potassium there is, the more uptake there will be by cells. A hypokalemic patient will have about 10% of the potassium remain extracellular; a hyperkalemic patient will have about 30% remain extracellular, i.e potassium will distribute more equally into all body fluid compartments. And then the kidneys will control the total body potassium by selectively excreting an appropriate amount.

One may argue that this has greater relevance when it comes to the act of infusing huge amounts of potassium into people. The humble bag of Hartmanns only has 5mmol of potassium to contribute. Even in a hyperkalemic anephric patient, working on the premise that it distributes into all body fluid compartments equally, when divided among the 43 litres of body fluid this gives us a potassium concentration increase of 0.1 mmol/L after 15 minutes. Of course, in any patient with a normal serum potassium and normal kidneys a piddly 0.5mmol will end up in the extracellular fluid - which gives a rise of 0.035mmol/L, well outside the laboratory error ranges.

Lobo et al (2003) compared saline to Hartmanns in a randomised blinded trial; of specific interest is page 21 where the graphs demonstrate changes in electrolyte concentration and osmolality over the hours following the 2 litre infusion. The serum potassium rises transiently in the Hartmanns group, and then falls as diuresis carries it out with sodium and the extra fluid. So in fact Hartmanns has the potential to induce hypokalemia (by increasing sodium delivery to the distal nephron) 

Will the serum lactate rise appreciably?

Well, actually... yes. Briefly.

The bag of Hartmanns has bold writing on it which recommends we never use it for the treatment of lactic acidosis.

But let us be clear. The administration of Hartmanns will never cause a lactic acidosis. The lactate in Hartmanns is a conjugate base, the anionic part of lactic acid, in which the role of the hydrogen ion is played by sodium. Such a substance, when infused, will not increase the total body acid content, because no extra hydrogen ions are added (to use the classical interpretation of acid-base balance). Yes, under special conditions the lactate anion will "buffer" hydrogen ions and become an acid - but this happens at and below a pH of 3.86 or so. However. The lactate anion is what the ABG machine measures. So, the rapid infusion of Hartmanns will cause a transient increase in the serum lactate levels, without causing a drop in pH. And, it will confuse your serial lactate measurements.

From the perspective of a Stewart quantitative acid-base analysis, the Hartmanns will actually act as an alkalinising solution, because it has an SID of 29 mEq/L: if the lactate (a strong ion) is completely and rapidly metabolised, it will disappear from the equation, leaving behind volatile CO2 and water. Thus, the only situation in which Hartmanns can cause an acidosis is the total absence of liver function. In patients who have no working liver cells, the lactate cannot be metabolised any more than chloride. Hartmanns will thus not exert any positive alkalinising effect. It will just add to the total body pool of under-metabolised lactate. Indeed, in such a situation - in a totally anhepatic patient - the Hartmanns would act as a fluid with an effective strong ion difference of zero. The effects of infusing it on the acid-base balance would be similar to the effects of other SID=0 fluids, such as normal saline. Unfortunately, a quick lazy search does not reveal any literature in support of this; it does not appear as if anybody has ever performed an experimental Hartmanns infusion during the anhepatic phase of a liver transplant.

References

Reid F, Lobo DN, Williams RN, Rowlands BJ, Allison SP.(Ab)normal saline and physiological Hartmann's solution: a randomized double-blind crossover study.Clin Sci (Lond). 2003 Jan;104(1):17-24.

Winklet A.W, Smith P.K. The apparent volume of distribution of potassium injected intravenously.J. Biol. Chem. 1938 124: 589-598.

Richard H Sterns, Peter U Feig, Martin Pring, Joseph Guzzo and Irwin Singer Disposition of intravenous potassium in anuric man: A kinetic analysis Kidney International (1979) 15, 651–660; doi:10.1038/ki.1979.85

Raghunathan, Karthik, et al. "Association Between the Choice of IV Crystalloid and In-Hospital Mortality Among Critically Ill Adults With Sepsis." Critical care medicine (2014).

From MIMS online, via CIAP; using Baxter Full PI data sheets. Those PI documents are word for word what you will find on the bags.  Additionally, the anaesthesiauk website has this page, with a summary of the relevant details. To find out more about the pH of intravenous solutions, you could pay JAMA for this article.

Ke, Lu, et al. "Acid–base changes after fluid bolus: sodium chloride vs. sodium octanoate." Intensive Care Medicine Experimental 1.1 (2013): 1-11.

Hartmann, Alexis F., and Milton JE Senn. "studies in the metabolism of sodium R-lactate. I. Response of normal human subjects to the intravenous injection of sodium R-lactate." The Journal of Clinical Investigation 11.2 (1932): 327-335.

Hartmann, Alexis F., and Milton JE Senn. "Studies in the metabolism of sodium r-lactate. II. Response of human subjects with acidosis to the intravenous injection of sodium r-lactate." The Journal of Clinical Investigation 11.2 (1932): 337-344.

BUFFA, EUGENE A., et al. "The effects of wound lavage solutions on canine fibroblasts: an in vitro study." Veterinary surgery 26.6 (1997): 460-466.

Beam, Joel W. "Wound cleansing: water or saline?." Journal of athletic training 41.2 (2006): 196.

Lawson, D. "Management of gastroenteritis at the Hospital for Sick Children, Great Ormond Street 1948–49." Great Ormond Street J 2 (1951): 110-114.

And if you have a couple of spare hours, reading Dileep N. Lobo's thesis on fluid physiology will be an ideal way to spend them. It contains beautiful digressions. To wit, when discussing the effects of starvation and injury on fluid balance, Lobo muses "Life began in the sea and the intracellular environment of early life forms was isotonic with the external environment, as these unicellular organisms had no means of regulating the internal osmotic pressure"... and so on.