Elements such as Na⁺, K⁺, Ca²⁺, Mg²⁺, and Cl^- exist in body fluids as completely ionized entities. At physiologic pH this can also be said of anions with pKa values of 4 or less, for example sulphate, lactate, and β-hydroxybutyrate. Stewart described all such compounds as 'strong ions'. In body fluids there is a surfeit of strong cations, quantified by SID. In other words, SID = [strong cations] - [strong anions]. Being a 'charge' space, SID is expressed in mEq/l. SID calculated from measured strong ion concentrations in normal plasma is 42 mEq/l.

Arterial PCO₂ (PaCO₂) is an equilibrium value determined by the balance between CO₂ production (15,000 mmol/day) and CO₂ elimination via the lungs. In areas where PCO₂ is less directly controlled by alveolar ventilation (e.g. venous blood and interstitial fluid during low flow states), the total CO₂ concentration (CO_2TOT) becomes the independent variable.

Body fluid compartments have varying concentrations of nonvolatile (i.e. non-CO₂) weak acids. In plasma these consist of albumin and inorganic phosphate. The same applies to interstitial fluid, although total concentrations here are very small. In red cells the predominant source is haemoglobin.

Nonvolatile weak acids dissociate in body fluids as follows:

HA ↔ H⁺ + A^-

The group of ions summarized as A^- are weak anions (pKa approximately 6.8). Unlike strong ions, weak ions in body fluids vary their concentrations with pH by dissociation/association of their respective parent molecules. The total concentration of nonvolatile weak acid in any compartment is termed A_TOT, where A_TOT = [HA] + [A^-]. Although [A^-] varies with pH, A_TOT does not, and as such it is an independent variable.

The SID space is filled by weak ions, one of which is A^-. The only other quantitatively important weak ion is HCO₃ ^-, but there are also minute concentrations of CO₃ ^2-, OH^-, and H⁺. To preserve electrical neutrality, their net charge must always equal the SID.

Stewart set out six simultaneous equations primarily describing the behaviour of weak ions occupying the SID space (Table 1). They are applications of the Law of Mass Action to the dissociation of water, H₂CO₃, HCO₃ ^-, and nonvolatile weak acids, coupled with the expression for A_TOT and a statement of electrical neutrality. If P CO₂, SID and A_TOT are known, then the equations in Table 1 can be solved for the remaining six unknowns – [A^-], [HCO₃ ^-], [OH^-], [CO₃ ^2-], [HA] and, most importantly, [H⁺].

From Stewart's equations, four simple rules can be derived concerning isolated abnormalities in SID and A_TOT (Table 2). These can be verified by in vitro experimentation 7.

The rules in Table 2 illustrate an important Stewart principle. Metabolic acid–base disturbances arise from abnormalities in SID and A_TOT, either or both. However, to quantify metabolic acid–base status at the bedside, neither SID nor A_TOT needs individual measurement. For this the standard base excess (SBE) is sufficient. The SBE concept was developed by Siggaard-Andersen and the Copenhagen group 89. It is calculated from buffer base offsets by assuming a mean extracellular haemoglobin concentration of 50 g/l. A useful formula is as follows (with SBE and [HCO₃ ^-] values expressed in mEq/l):

SBE = 0.93 × {[HCO₃ ^-] + 14.84 × (pH - 7.4) - 24.4}

SBE supplements the Stewart approach as a practical tool 101112. A typical reference range is -3.0 to +3.0 mEq/l. The SBE deviation from zero is the change in extracellular SID needed to normalize metabolic acid–base status without changing A_TOT. If the SBE is below -3.0 mEq/l then there is metabolic acidosis, either primary or compensatory. The deviation below zero is the increase in extracellular SID needed to correct the acidosis. Although this value should also equate to the dose (in mmol) of NaHCO₃ required per litre of extracellular fluid, in practice more is usually needed – a dose corresponding to an extracellular space of 30% body weight rather than 20%. Similarly, if the SBE is greater than 3.0 mEq/l then there is metabolic alkalosis. The positive offset from zero represents a theoretical dose calculation for HCl rather than for NaHCO₃.

No crystalloid contains A_TOT. Crystalloid loading therefore dilutes plasma A_TOT, causing a metabolic alkalosis (Table 2). Simultaneously, plasma and extracellular SID are forced toward the SID of the infused crystalloid, primarily by differential alteration in [Na⁺] and [Cl^-]. If these changes increase SID then the effects of A_TOT dilution are enhanced, and if they decrease SID then they oppose them (Table 2).

It has been reported on many occasions that large-scale saline infusions can cause a metabolic acidosis 192021. Although best documented during repletion of extracellular fluid deficits, acute normovolaemic haemodilution 2223 and cardiopulmonary bypass 23242526 have similar potential. The mechanism is not bicarbonate dilution, as is commonly supposed 27. Bicarbonate is a dependent variable. The key fact is that the SID of saline is zero, simply because the strong cation concentration ([Na⁺]) is exactly the same as the strong anion concentration ([Cl^-]). Large volumes of saline therefore reduce plasma and extracellular SID. This easily overwhelms the concurrent A_TOT dilutional alkalosis. A normal (in fact reduced) anion gap metabolic acidosis is the end result 2829, albeit less severe than if A_TOT had remained constant.

The critical care practitioner should be alert to this possibility when confronted with a patient who has a metabolic acidosis and a normal anion gap. It is wise to check that the corrected anion gap 3031 and perhaps the strong ion gap 3233 are also normal. These are thought to be more reliable screening tools for unmeasured anions 3435. (For a more detailed discussion of the anion gap, corrected anion gap and strong ion gap, see other reviews in this issue.) A history of recent large volume saline infusion (e.g. > 2 l in < 24 hours) in such a patient is highly suggestive of infusion related metabolic acidosis. Even if there is an alternative explanation, such as renal tubular acidosis or enteric fluid loss, saline infusions will perpetuate and exacerbate the problem.

The phenomenon is not confined to 0.9% saline, and the resultant metabolic acidosis may or may not be hyperchloraemic. Hypotonic NaCl solutions also have a zero SID. Even fluids with no strong ions at all, such as dextrose solutions, mannitol and water, have a zero SID. Infusion of any of these fluids reduces plasma and extracellular SID by the same equilibration mechanism, irrespective of whether plasma [Cl^-] rises or falls, forcing acid–base in the direction of metabolic acidosis 36. For a theoretical illustration of dilutional SID effects, imagine adding 1 l of either saline or water to a sealed 3 l mock 'extracellular' compartment with a SID of 40 mEq/l, as illustrated in Table 3. In either case the SID is reduced to 30 mEq/l, but with a fall in [Cl^-] after water dilution.

Interestingly, hypertonicity makes solutions more acidifying 36. In this case the reduction in extracellular SID is magnified by an added dilution effect, because water is drawn by osmosis from the intracellular space. An unproven corollary is that hypotonic solutions are less acidifying. The important message here is that the intracellular space is a participant in the final equilibrium, and can contribute significantly to fluid induced acid–base effects.

Patients categorized as suffering from 'contraction alkalosis' or 'diminished functional extracellular fluid volume' are said to be 'saline responsive', and complex hormonal and renal tubular mechanisms are often invoked 373839. In fact, from the perspective of physical chemistry, any metabolic alkalosis is 'saline responsive', provided sufficient saline (or any zero SID fluid) can be administered. Unfortunately, in the absence of hypovolaemia the amount of saline required introduces a risk for overload.

Hence, a diagnosis of volume depletion should be established before treating metabolic alkalosis in this way. Signs of extracellular volume depletion include reduced skin turgor, postural hypotension, and systolic pressure variability 40. There may also be a prerenal plasma biochemical pattern (high urea:creatinine ratio), and if tubular function is preserved then urinary [Na^-] is normally under 20 mmol/l 41.

Some types of metabolic alkalosis are associated with hypokalaemia and total body potassium deficits 3742. When dealing with these categories, correcting the deficit with KCl is a particularly effective way to reverse the alkalosis. From the Stewart perspective, this practice has similarities to infusing HCl, minus the pH disadvantages of a negative SID. This is because potassium and potassium deficits are predominantly intracellular, and so all but a small fraction of retained potassium ends up within the cells during correction. The net effect of KCl administration is that the retained strong anion (Cl^-) stays extracellullar, whereas most of the retained strong cation disappears into the intracellular space. This is a potent stimulus for reducing plasma and extracellular SID.

To give another rough illustration, imagine the repletion of a 200 mmol total body potassium deficit using KCl. If the extracellular [K⁺] is increased by 3 mmol/l during the process, then approximately 50 mmol of K⁺ has been retained in the 17 l extracellular space and about 150 mmol has crossed into the cells. This means that 150 mmol Cl^- is left behind in the extracellular space, now unaccompanied by a strong cation. This lowers extracellular SID and thus SBE by about 9 mEq/l.

To avoid crystalloid induced acid–base disturbances, plasma SID must fall just enough during rapid infusion to counteract the progressive A_TOTdilutional alkalosis. Balanced crystalloids thus must have a SID lower than plasma SID but higher than zero. Experimentally, this value is 24 mEq/l 2343. In other words, saline can be 'balanced' by replacing 24 mEq/l of Cl^- with OH^-, HCO₃ ^- or CO₃ ^2-. From this perspective, and for now ignoring pH, solutions 1 and 3 in Table 4 are 'balanced'. However, it is noteworthy that, unless stored in glass, solutions 1 and 3 both become solution 2 by gradual equilibration with atmospheric CO₂ (Table 4). Solution 2 is also 'balanced'.

To eliminate the issue of atmospheric equilibration, commercial suppliers have substituted various organic anions such as L-lactate, acetate, gluconate and citrate as weak ion surrogates. Solution 4 (Table 4) is a generic example of this approach (for actual examples, see Table 5). L-lactate is a strong anion, and the in vitro SID of solution 4 is zero. However, solution 4 can also be regarded as 'balanced', provided L-lactate is metabolized rapidly after infusion. In fact, in the absence of severe liver dysfunction, L-lactate can be metabolized at rates of 100 mmol/hour or more 4445, which is equivalent to nearly 4 l/hour of solution 4. The in vivo or 'effective' SID of solution 4 can be calculated from the L-lactate component subject to metabolic 'disappearance'. If the plasma [lactate] stays at 2 mmol/l during infusion, then solution 4 has an effective SID of 24 mEq/l.

Hence, despite wide variation in pH, solutions 1–4 in Table 4 have identical effective SID values. They are all 'balanced', with identical systemic acid–base effects. However, other attributes must be considered. Solution 1 (pH 12.38) is too alkaline for peripheral or rapid central administration. The situation for solution 2 is less clear. Atmospheric equilibration has brought the pH to 9.35, which is less than that of sodium thiopentone (pH 10.4) 46 – a drug that is normally free of venous irritation. Similarly Carbicarb, a low CO_2TOT alternative to NaHCO₃ preparations 47, has a pH of 9.6 48. Thus, the pH of solution 2 may not preclude peripheral or more rapid central administration. On the downside, and like Carbicarb, solution 2 contains significant concentrations of carbonate, which precipitates if traces of Ca²⁺ or Mg²⁺ are present. A chelating agent such as sodium edetate may be required.

Hartmann's solution (Table 5) is the best known commercial 'balanced' preparation. It contains 29 mmol/l of L-lactate. In the absence of severe liver dysfunction, the effective SID is therefore approximately 27 mEq/l. Although this should make it slightly alkalinizing, much as Hartmann originally intended 49, it is close to the ideal from an acid–base perspective. Slight alkalinization is difficult to demonstrate in laboratory and especially in clinical studies, but the available evidence shows that Hartmann's solution reduces or eliminates infusion related metabolic acidosis 5051525354.

The acid–base status of a patient before resuscitation is a consideration. If it is normal to start with, then higher SID fluids such as Plasma-Lyte 148 (effective SID 50 mEq/l; Table 5) are likely to cause a progressive metabolic alkalosis from the outset. Again, evidence is limited, but in support of this statement Plasma-Lyte 148 priming cardiopulmonary bypass pumps has been shown to increase arterial base excess by the end of bypass 25. On the other hand, if there is a pre-existing metabolic acidosis, caused by diabetic ketoacidosis or hypovolaemic shock for example, then fluids with higher effective SID such as Isolyte E or Plasma-Lyte 148 will correct the acidosis more rapidly (provided their organic anions are metabolized with efficiency) while counteracting ongoing generation of acidosis. The problem with high SID fluids is the potential for over-correction and 'break through' metabolic alkalosis, particularly when the cause of the acidosis is accumulation of organic strong anions such as ketoacids and lactate, which disappear as the illness resolves.

Unfortunately, available commercial 'balanced' preparations have unresolved problems. Many contain either calcium or magnesium (or sometimes both; Table 5). Calcium neutralizes the anticoagulant effect of citrate, and both can precipitate in the presence of HCO₃ ^- and CO₂ ^2-. This restricts their range of ex vivo compatibilities (e.g. there are incompatibilities with stored blood and sodium bicarbonate preparations) and makes them poor drug delivery vehicles. Another disadvantage is that they all require an intermediary metabolic step, often at times of severe metabolic stress, to achieve their effective SID.

Hartmann's solution is also hypotonic relative to extracellular fluid. Although a potential disadvantage in traumatic brain injury 55, this was not borne out in a comparison with hypertonic saline given prehospital to hypotensive brain-injured patients 56. Diabetic ketoacidosis is another scenario that predisposes to brain swelling during fluid loading 57, but here Hartmann's solution and other mildly hypotonic preparations seem safe for a least part of the repletion process 58596061. If used from the beginning, the slightly alkalinizing Hartmann's SID of 27 mEq/l is probably sufficient to ameliorate or even prevent the late-appearing normal anion gap metabolic acidosis to which these patients are prone 57, although this remains to be demonstrated.

Given the limitations of commercially available solutions and assuming that infusion-related acidosis causes harm, as seems likely 62, then an argument could be put for new 'balanced' resuscitation solutions. Ideally, these should be normotonic and free of organic anion surrogates and divalent cations. The design could be along the lines of solution 3 in Table 4. However, because solution 3 requires CO₂-impermeable storage, solution 2 might be preferable, provided its higher pH does not preclude rapid peripheral administration. Such a fluid could become the first line crystalloid in all large volume infusion scenarios, including intraoperative fluid replacement, acute normovolaemic haemodilution and cardiopulmonary bypass, as well as resuscitation of hypovolaemic and distributive shock, diabetic ketoacidosis and hyperosmolar nonketotic coma. Refinements would include a selection of [Na⁺] and corresponding [Cl^-] values to cater for varying osmolality requirements. The standard SID for neutral acid–base effects would be 24 mEq/l, perhaps with variations above or below to correct pre-existing acid–base disturbances.