We are undergoing a revolution in the way we clinically assess acid-base status. For almost 100 years, the Holy Grail for clinicians has been to accurately determine the mechanism for an acid-base disturbance. Landmark advancements in the clinical diagnosis and treatment of acid-base disturbances have included the Henderson-Hasselbalch equation (1916) ^{(1)}, base excess (1960) ^{(2)}, anion gap (1970s) ^{(3)}, and the strong ion approach (1983) ^{(4)}. In this issue of *Anesthesia & Analgesia*, Rehm and Finsterer ^{(5)} investigate the treatment of hyperchloremic acidosis, a frequently observed response to IV crystalloid fluid administration ^{(6–10)}. The mechanism for the development of hyperchloremic acidosis cannot be satisfactorily explained using the traditional approach to acid-base balance.

We are all familiar with the Henderson-Hasselbalch equation ^{(1)}, which describes how plasma CO_{2} tension (Pco_{2}), plasma bicarbonate concentration ([HCO_{3}^{−}]), the negative logarithm of the apparent dissociation constant (pK_{1’}) for plasma carbonic acid (H_{2}CO_{3}), and the solubility (*S*) of CO_{2} in plasma interact to determine plasma pH. This relationship is most often expressed in the following form:

The evaluation of acid-base status using the Henderson-Hasselbalch equation (Equation 1) has traditionally used the pH value as an overall measure of acid-base status, Pco_{2} as an independent measure of the respiratory component of acid-base balance, base excess, actual bicarbonate concentration, or standard bicarbonate as a measure of the metabolic (also called nonrespiratory) component of acid-base balance, and calculation of the anion gap to facilitate identification of unmeasured anions or cations in plasma.

So what is wrong with this proven and widely used approach? Simply stated, using the Henderson-Hasselbalch equation to calculate base excess, actual bicarbonate concentration, or standard bicarbonate provides an estimate of the magnitude of a metabolic acidosis and not the mechanism for its development. Thus, the Henderson-Hasselbalch equation cannot satisfactorily explain the mechanism for many acid-base disturbances; hyperchloremic acidosis is one of many clinical conditions that have no rational explanation. It is well recognized that the rapid infusion of large quantities of 0.9% NaCl induces acidemia (hyperchloremic acidosis) and decreases plasma bicarbonate concentration ^{(6–10)}. The Henderson-Hasselbalch equation indicates that hyperchloremic acidosis should be treated by administering bicarbonate in the form of an isotonic solution of sodium bicarbonate: or the bicarbonate donor tris-hydroxymethyl aminomethane (THAM): where R-NH_{2} is THAM, and R-NH_{3}^{+} is the protonated form of THAM. As shown by Rehm and Finsterer ^{(5)}, both treatments are effective in restoring bicarbonate concentration and pH to normal. But how does the rapid IV administration of 0.9% NaCl decrease plasma pH and bicarbonate concentration? Is there more to this story?

Our understanding of acid-base balance was revolutionized in 1983 by Stewart’s development of strong ion theory ^{(4)}. The strong ion approach has two novel aspects: acid-base balance is examined using a systems approach, and a clear conceptual distinction is made between dependent and independent variables. Independent variables influence a system from the outside and cannot be affected by changes within the system or by changes in other independent variables. In contrast, dependent variables are influenced directly and predictably by changes in the independent variables. Therefore, the strong ion approach offers a clear mechanistic explanation for changes in acid-base balance.

Stewart proposed that plasma pH was determined by three independent factors; Pco_{2}, the strong ion difference (SID), which is the difference between the charge of plasma strong cations (sodium, potassium, calcium, and magnesium) and anions (chloride, lactate, sulfate, ketoacids, nonesterified fatty acids, and many others), in which strong cations and anions are fully dissociated at physiologic pH, and Atot, which is the total plasma concentration of nonvolatile buffers (albumin, globulins, and inorganic phosphate) ^{(4)}. In this context, pH value and bicarbonate concentration are dependent variables. From the three independent factors (Pco_{2}, SID, and Atot), Stewart developed a complicated polynomial equation that expressed pH value (he erroneously used H^{+} concentration) as a function of eight factors, consisting of three independent factors and five constants ^{(4)}. It was subsequently shown, algebraically ^{(11)} and graphically ^{(12)}, that changes in two of Stewart’s eight factors had no quantitative effect on pH value, leading to the development of the six-factor simplified strong ion equation in 1997 ^{(11)}. Currently, the six-factor simplified strong ion equation is the preferred form for applying the strong ion approach ^{(11–14)}. The equation states that the pH value is a function of three independent factors (Pco_{2}, SID, and Atot) and three constants (*S*, the apparent dissociation constant for plasma carbonic acid [K_{1’}], and K_{a}, the effective dissociation constant for nonvolatile buffers in plasma), such that:

For those readers that dislike complicated equations, Equation 4 can be expressed in an algebraically simpler but equivalent form as:

Equation 5 simplifies to the Henderson-Hasselbalch equation (Equation 1) in solutions that do not contain protein or phosphate (because Atot = 0 and SID = [HCO_{3}^{−}]).

A number of clinical ramifications arise from the simplified strong ion equation (Equation 4). Because clinically important acid-base derangements result from changes in Pco_{2}, SID, or concentrations of individual nonvolatile plasma buffers (Atot; albumin, globulins, and phosphate), the strong ion approach distinguishes six primary acid-base disturbances (respiratory, strong ion, or nonvolatile buffer ion acidosis and alkalosis) instead of the four primary acid-base disturbances (respiratory or metabolic acidosis and alkalosis) differentiated by the traditional Henderson-Hasselbalch equation ^{(11–14)}. Acidemia results from an increase in Pco_{2} and nonvolatile buffer concentrations (albumin, globulin, and phosphate) or from a decrease in SID. Alkalemia results from a decrease in Pco_{2} and nonvolatile buffer concentration or from an increase in SID.

The strong ion approach provides an explanation for the development of hyperchloremic acidosis and therefore a rational treatment for this condition. Normal human plasma SID is 42 mEq/L ^{(15)}, whereas the SID of 0.9% NaCl is 0 mEq/L because sodium and chloride are both strong ions ^{(11)}. IV administration of 0.9% NaCl must, therefore, decrease plasma SID, which will create a strong ion acidosis (assuming that infusion does not cause a change in Pco_{2} or plasma albumin, globulin, or phosphate concentrations). The magnitude of the decrease in plasma SID when 0.9% NaCl is administered is dependent upon the relative volumes of the extracellular space and 0.9% NaCl and the speed of the 0.9% NaCl administration. Therefore, hyperchloremic acidosis is easier to detect when large volumes of 0.9% NaCl are rapidly administered, as in the study by Rehm and Finsterer ^{(5)}.

The following rules of thumb for the clinical assessment of acid-base disturbances in humans have been developed from the simplified strong ion approach: ΔpH = ΔSID × 0.016, ΔpH = −ΔPco_{2} × 0.009, and ΔpH = −Δ(g total protein/dL) × 0.04 ^{(12)}. These rules of thumb are approximate, because they simplify a complex curvilinear relationship; however, the clinical guidelines indicate that at a normal pH value (7.40), a 1-mEq/L decrease in SID will decrease the pH value by 0.016, a 1-mm Hg increase in Pco_{2} will decrease the pH value by 0.009, and a 1-g/dL increase in total protein concentration will decrease the pH value by 0.039. Because the ΔSID from its normal value is equivalent to the base excess value ^{(13,14)}, assuming a normal nonvolatile buffer ion concentration (normal albumin, globulins, and phosphate concentration), we can readily determine the mechanism for the metabolic acidosis in patients receiving large volume 0.9% NaCl solutions. In the patients studied by Rehm and Finsterer ^{(5)}, mean base excess was approximately −7 mEq/L, which would decrease the pH value by 0.11 U (−7 × 0.016) if SID were the only independent variable to change. Because the measured pH value (7.28) was decreased 0.12 U from normal values (7.40), and because values for Pco_{2} (40 mm Hg) and Atot approximated normal, the acidemia induced by rapid administration of large volume 0.9% NaCl was caused by a strong ion acidosis. Accordingly, the specific treatment for hyperchloremic acidosis is to increase SID by administering a solution where the strong cation concentration exceeds the strong anion concentration by >42 mEq/L (42 mEq/L is the normal SID for human plasma). Two solutions with a high effective SID were therefore administered by Rehm and Finsterer ^{(5)} and are 130 mmol of sodium bicarbonate (effective SID, 130 mEq because bicarbonate is volatile buffer ion and not a strong anion; see Equation 2) or 128 mmol of THAM (effective SID, 128 × 70% = 90 mEq because 70% of the neutral compound R-NH_{2} in THAM is immediately protonated to the strong cation R-NH_{3}^{+} in plasma; see Equation 3). Therefore, the strong ion approach predicts that sodium bicarbonate would more effectively correct the induced hyperchloremic acidosis than an equivalent number of moles of THAM, and this prediction is supported by the results reported by Rehm and Finsterer ^{(5)}.

Equation 2 Image Tools |
Equation 3 Image Tools |

So what new information has application of the strong ion approach provided? Remember that the traditional Henderson-Hasselbalch equation did not describe the mechanism for the development of hyperchloremic acidosis but indicated that hyperchloremic acidosis should be treated with sodium bicarbonate or the bicarbonate donor THAM because bicarbonate concentration was decreased. In contrast, the strong ion approach indicated that hyperchloremic acidosis was caused by the decrease in plasma SID after rapid infusion of large quantities of 0.9% NaCl and that the resultant strong ion acidosis would be best treated by administering a solution with a high effective SID, such as sodium bicarbonate or THAM. For hyperchloremic acidosis, application of the Henderson-Hasselbalch equation and strong ion approaches produced the same treatment (sodium bicarbonate or THAM) but completely different reasons for the response.

Finally, a comment on the method used by Rehm and Finsterer ^{(5)} to quantify the unmeasured strong cation concentration in patients receiving THAM, because THAM (R-NH_{2}) is protonated in plasma to R-NH_{3}^{+}, which is a strong cation (see Equation 3). A clinically important problem in sick patients is identifying and quantifying the presence of strong anions or cations in plasma that are not routinely measured including anions such as lactate, β-hydroxybutyrate, acetoacetate, and anions associated with uremia and cations such as protonated THAM (R-NH_{3}^{+}). Unmeasured strong anion or cation concentrations can be quantified by calculating the anion gap ^{(3)}, applying the Fencl base excess method ^{(16)}, calculating the strong ion gap (SIG) using the Figge unmeasured anion method ^{(17,18)}, or calculating the SIG using an equation derived from the simplified strong ion equation ^{(19)}. This equation requires measurement of six variables (pH value, Pco_{2}, [Na], [K], [Cl], and [total protein]) and known species-specific values for Atot and K_{a} (pKa is the negative logarithm to the base 10 of Ka):

Rehm and Finsterer ^{(5)} calculated SIG using the Figge unmeasured anion method ^{(17,18)}. It would have been interesting had they calculated SIG using Equation 6 and estimated Atot and pKa values for human plasma ^{(12,19)}, whereby:

In Equation 7, SIG and ANION GAP ({[Na^{+}] + [K^{+}]}−{[CI^{−}] + [HCO_{3}^{−}]}) are in units of milliequivalent per liter, and total protein concentration is in units of grams per deciliter. Two milliequivalents per liter was subtracted from the right hand side of Equation 7 because the unmeasured strong cation concentration exceeds the unmeasured strong anion concentration by 2–3 mEq/L in horse ^{(19)} and cattle ^{(20)} plasma and presumably by a similar amount in human plasma, although this has not been confirmed. For normal values of pH (7.40), total protein concentration (7.0 g/dL), and anion gap (16 mEq/L when [K^{+}] is included in the calculation, as in Equation 7), Equation 7 calculates that SIG ≈ 0 mEq/L. Because calculating SIG using Equation 6 and species-specific values for Atot and K_{a} more accurately predicted unmeasured strong anion concentration in sick cattle than calculating SIG using the Figge unmeasured anion method ^{(20)}, it is possible that Equation 7 may have more accurately described the increase in SIG after administration of THAM.

In summary, the strong ion approach provides the clinician with an improved understanding of complex acid-base disturbances and the mechanisms for their development. Because increased understanding will lead to more targeted treatments of acid-base and electrolyte disorders, we are at the dawn of a new era in the treatment of critically ill patients. Exciting times are ahead. Studies by Wilkes ^{(21)} in 1998 and Rehm and Finsterer (this journal) are among the first to use the strong ion approach in humans to determine the mechanism for an acid-base disturbance and identify the most appropriate treatment. For hyperchloremic acidosis in healthy patients with normal renal function and hydration status, the most appropriate treatment is to discontinue the IV administration of crystalloid solutions with a low effective SID, such as 0.9%NaCl. For hyperchloremic acidosis in critically ill patients, the most appropriate treatment is to commence the IV administration of a crystalloid solution with a high effective SID, such as sodium bicarbonate or THAM.