Asidosis hiperkloremik: Contoh Klasik dari Asidosis Ion Kuat

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EDITORIAL

Hyperchloremic Acidosis: The Classic Example of Strong

Ion Acidosis

Peter D. Constable, BVS, PhD

Department of Veterinary Clinical Medicine, University of Illinois, Urbana

We are undergoing a revolution in the way weclinically assess acid-base status. For almost100 years, the Holy Grail for clinicians has

been to accurately determine the mechanism for anacid-base disturbance. Landmark advancements in theclinical diagnosis and treatment of acid-base distur-

bances have included the Henderson-Hasselbalchequation (1916) (1), base excess (1960) (2), anion gap(1970s) (3), and the strong ion approach (1983) (4). Inthis issue of Anesthesia & Analgesia, Rehm and Fin-sterer (5) investigate the treatment of hyperchloremicacidosis, a frequently observed response to IV crystal-loid fluid administration (6–10). The mechanism forthe development of hyperchloremic acidosis cannot besatisfactorily explained using the traditional approachto acid-base balance.

We are all familiar with the Henderson-Hasselbalchequation (1), which describes how plasma CO2 tension

(Pco

2), plasma bicarbonate concentration ([HCO3

]),the negative logarithm of the apparent dissociationconstant (pK1’) for plasma carbonic acid (H2CO3), andthe solubility (S) of CO2 in plasma interact to deter-mine plasma pH. This relationship is most often ex-pressed in the following form:

pH pK1 logHCO3

]

S Pco2

(1)

The evaluation of acid-base status using theHenderson-Hasselbalch equation (Equation 1) has tra-

ditionally used the pH value as an overall measure of acid-base status, Pco2 as an independent measure of the respiratory component of acid-base balance, baseexcess, actual bicarbonate concentration, or standard

bicarbonate as a measure of the metabolic (also callednonrespiratory) component of acid-base balance, and

calculation of the anion gap to facilitate identificationof unmeasured anions or cations in plasma.

So what is wrong with this proven and widely usedapproach? 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 metabolicacidosis and not the mechanism for its development.Thus, the Henderson-Hasselbalch equation cannot sat-isfactorily explain the mechanism for many acid-basedisturbances; hyperchloremic acidosis is one of manyclinical conditions that have no rational explanation. Itis well recognized that the rapid infusion of largequantities of 0.9% NaCl induces acidemia (hyperchlo-remic acidosis) and decreases plasma bicarbonate con-centration (6–10). The Henderson-Hasselbalch equa-tion indicates that hyperchloremic acidosis should betreated by administering bicarbonate in the form of an

isotonic solution of sodium bicarbonate:

NaHCO3 7 Na HCO3

(2)

or the bicarbonate donor tris-hydroxymethyl amin-omethane (THAM):

R-NH2 H2O CO2 7 R-NH3 HCO3

(3)

where R-NH2 is THAM, and R-NH3

is the proton-ated form of THAM. As shown by Rehm and Finsterer(5), both treatments are effective in restoring bicarbon-ate concentration and pH to normal. But how does therapid IV administration of 0.9% NaCl decrease plasmapH and bicarbonate concentration? Is there more tothis story?

Our understanding of acid-base balance was revo-lutionized in 1983 by Stewart’s development of strongion theory (4). The strong ion approach has two novelaspects: acid-base balance is examined using a systemsapproach, and a clear conceptual distinction is made

between dependent and independent variables. Inde-pendent variables influence a system from the outsideand cannot be affected by changes within the system

Accepted for publication December 5, 2002.Address correspondence and reprint requests to Peter D. Constable,

PhD, Department of Veterinary Clinical Medicine, University of Illi-nois, 1008 W Hazelwood Dr., Urbana, IL 60102. Address e-mail [email protected].

DOI: 10.1213/01.ANE.0000053256.77500.9D

©2003 by the International Anesthesia Research Society0003-2999/03 Anesth Analg 2003;96:919–22 919



or by changes in other independent variables. In con-trast, dependent variables are influenced directly andpredictably by changes in the independent variables.Therefore, the strong ion approach offers a clear mech-anistic explanation for changes in acid-base balance.

Stewart proposed that plasma pH was determined by three independent factors; Pco2, the strong iondifference (SID), which is the difference between thecharge of plasma strong cations (sodium, potassium,calcium, and magnesium) and anions (chloride, lac-tate, sulfate, ketoacids, nonesterified fatty acids, andmany others), in which strong cations and anions arefully dissociated at physiologic pH, and Atot, which isthe total plasma concentration of nonvolatile buffers(albumin, globulins, and inorganic phosphate) (4). Inthis context, pH value and bicarbonate concentrationare dependent variables. From the three independentfactors (Pco2, SID, and Atot), Stewart developed a

complicated polynomial equation that expressed pHvalue (he erroneously used H concentration) as afunction of eight factors, consisting of three indepen-dent factors and five constants (4). It was subsequentlyshown, algebraically (11) and graphically (12), thatchanges in two of Stewart’s eight factors had no quan-titative effect on pH value, leading to the developmentof the six-factor simplified strong ion equation in 1997(11). Currently, the six-factor simplified strong ionequation is the preferred form for applying the strongion approach (11–14). The equation states that the pHvalue is a function of three independent factors (Pco2,SID, and Atot) and three constants (S, the apparent

dissociation constant for plasma carbonic acid [K1’],and Ka, the effective dissociation constant for nonvol-atile buffers in plasma), such that:

pH

log10

2SID

K1S Pco2 KaAtot KaSID K1S Pco2

KaSID KaAtot)2 4Ka

2SIDAtot}

(4)

For those readers that dislike complicated equa-

tions, Equation 4 can be expressed in an algebraicallysimpler but equivalent form as:

pH pK1 logSID Atot/1 10 pKapH

S Pco2(5)

Equation 5 simplifies to the Henderson-Hasselbalchequation (Equation 1) in solutions that do not containprotein 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 resultfrom changes in Pco2, SID, or concentrations of indi-vidual nonvolatile plasma buffers (Atot; albumin,globulins, and phosphate), the strong ion approachdistinguishes six primary acid-base disturbances (re-

spiratory, strong ion, or nonvolatile buffer ion acidosisand alkalosis) instead of the four primary acid-basedisturbances (respiratory or metabolic acidosis andalkalosis) differentiated by the traditional Henderson-Hasselbalch equation (11–14). Acidemia results froman increase in Pco2 and nonvolatile buffer concentra-tions (albumin, globulin, and phosphate) or from adecrease in SID. Alkalemia results from a decrease inPco2 and nonvolatile buffer concentration or from anincrease in SID.

The strong ion approach provides an explanationfor the development of hyperchloremic acidosis andtherefore a rational treatment for this condition. Nor-

mal human plasma SID is 42 mEq/L (15), whereas theSID of 0.9% NaCl is 0 mEq/L because sodium andchloride are both strong ions (11). IV administration of 0.9% NaCl must, therefore, decrease plasma SID,which will create a strong ion acidosis (assuming thatinfusion does not cause a change in Pco2 or plasmaalbumin, globulin, or phosphate concentrations). Themagnitude of the decrease in plasma SID when 0.9%NaCl is administered is dependent upon the relativevolumes of the extracellular space and 0.9% NaCl andthe 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 inthe study by Rehm and Finsterer (5).The following rules of thumb for the clinical assess-

ment of acid-base disturbances in humans have beendeveloped from the simplified strong ion approach:pH SID 0.016, pH Pco2 0.009, andpH (g total protein/dL) 0.04 (12). These rulesof thumb are approximate, because they simplify acomplex curvilinear relationship; however, the clinicalguidelines indicate that at a normal pH value (7.40), a1-mEq/L decrease in SID will decrease the pH value

by 0.016, a 1-mm Hg increase in Pco2 will decrease thepH value by 0.009, and a 1-g/dL increase in total

protein concentration will decrease the pH value by0.039. Because the SID from its normal value isequivalent to the base excess value (13,14), assuming anormal nonvolatile buffer ion concentration (normalalbumin, globulins, and phosphate concentration), wecan readily determine the mechanism for the meta-

bolic acidosis in patients receiving large volume 0.9%NaCl solutions. In the patients studied by Rehm andFinsterer (5), mean base excess was approximately 7mEq/L, which would decrease the pH value by 0.11 U(7 0.016) if SID were the only independent vari-able to change. Because the measured pH value (7.28)

was decreased 0.12 U from normal values (7.40), and

920 EDITORIAL ANESTH ANALG2003;96:919 –22



because values for Pco2 (40 mm Hg) and Atot approx-imated normal, the acidemia induced by rapid admin-istration of large volume 0.9% NaCl was caused by astrong ion acidosis. Accordingly, the specific treat-ment for hyperchloremic acidosis is to increase SID by

administering a solution where the strong cation con-centration exceeds the strong anion concentration by42 mEq/L (42 mEq/L is the normal SID for humanplasma). Two solutions with a high effective SID weretherefore administered by Rehm and Finsterer (5) andare 130 mmol of sodium bicarbonate (effective SID,130 mEq because bicarbonate is volatile buffer ion andnot a strong anion; see Equation 2) or 128 mmol of THAM (effective SID, 128 70% 90 mEq because70% of the neutral compound R-NH

2 in THAM is

immediately protonated to the strong cation R-NH3

in plasma; see Equation 3). Therefore, the strong ionapproach predicts that sodium bicarbonate would

more effectively correct the induced hyperchloremicacidosis than an equivalent number of moles of THAM, and this prediction is supported by the resultsreported by Rehm and Finsterer (5).

So what new information has application of thestrong ion approach provided? Remember that thetraditional Henderson-Hasselbalch equation did notdescribe the mechanism for the development of hyperchloremic acidosis but indicated that hyperchlo-remic acidosis should be treated with sodium bicar-

bonate or the bicarbonate donor THAM because bi-carbonate concentration was decreased. In contrast,the strong ion approach indicated that hyperchloremic

acidosis was caused by the decrease in plasma SIDafter rapid infusion of large quantities of 0.9% NaCland that the resultant strong ion acidosis would be

best treated by administering a solution with a higheffective SID, such as sodium bicarbonate or THAM.For hyperchloremic acidosis, application of theHenderson-Hasselbalch equation and strong ion ap-proaches produced the same treatment (sodium bicar-

bonate or THAM) but completely different reasons forthe response.

Finally, a comment on the method used by Rehmand Finsterer (5) to quantify the unmeasured strongcation concentration in patients receiving THAM, be-cause THAM (R-NH2) is protonated in plasma toR-NH

3

, which is a strong cation (see Equation 3). Aclinically important problem in sick patients is identi-fying and quantifying the presence of strong anions orcations in plasma that are not routinely measuredincluding anions such as lactate, -hydroxybutyrate,acetoacetate, and anions associated with uremia andcations such as protonated THAM (R-NH

3

). Unmea-sured strong anion or cation concentrations can bequantified by calculating the anion gap (3), applyingthe Fencl base excess method (16), calculating thestrong ion gap (SIG) using the Figge unmeasured an-

ion method (17,18), or calculating the SIG using an

equation derived from the simplified strong ion equa-tion (19). This equation requires measurement of sixvariables (pH value, Pco2, [Na], [K], [Cl], and [totalprotein]) and known species-specific values for Atotand K

a (pKa is the negative logarithm to the base 10 of

Ka):

SIG Atot/1 10 pKapH ANION GAP

(6)

Rehm and Finsterer (5) calculated SIG using theFigge unmeasured anion method (17,18). It wouldhave been interesting had they calculated SIG usingEquation 6 and estimated Atot and pKa values forhuman plasma (12,19), whereby:

SIG 3.44 total protein/1 10 6.98pH 2

ANION GAP (7)

In Equation 7, SIG and ANION GAP ({[Na] [K]}{[CI] [HCO

3

]}) are in units of milliequiv-alent per liter, and total protein concentration is inunits of grams per deciliter. Two milliequivalents perliter was subtracted from the right hand side of Equa-tion 7 because the unmeasured strong cation concen-tration exceeds the unmeasured strong anion concen-tration by 2–3 mEq/L in horse (19) and cattle (20)plasma and presumably by a similar amount in hu-man plasma, although this has not been confirmed.For normal values of pH (7.40), total protein concen-

tration (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. Becausecalculating SIG using Equation 6 and species-specificvalues for Atot and Ka more accurately predicted un-measured strong anion concentration in sick cattlethan calculating SIG using the Figge unmeasured an-ion method (20), it is possible that Equation 7 mayhave more accurately described the increase in SIGafter administration of THAM.

In summary, the strong ion approach provides theclinician with an improved understanding of complexacid-base disturbances and the mechanisms for theirdevelopment. Because increased understanding willlead to more targeted treatments of acid-base andelectrolyte disorders, we are at the dawn of a new erain the treatment of critically ill patients. Exciting timesare ahead. Studies by Wilkes (21) in 1998 and Rehmand Finsterer (this journal) are among the first to usethe strong ion approach in humans to determine themechanism for an acid-base disturbance and identifythe most appropriate treatment. For hyperchloremicacidosis in healthy patients with normal renal functionand hydration status, the most appropriate treatmentis to discontinue the IV administration of crystalloid

solutions with a low effective SID, such as 0.9%NaCl.

ANESTH ANALG EDITORIAL 9212003;96:919 –22



For hyperchloremic acidosis in critically ill patients,the most appropriate treatment is to commence the IVadministration of a crystalloid solution with a higheffective SID, such as sodium bicarbonate or THAM.

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4. Stewart PA. Modern quantitative acid-base chemistry. Can J Physiol Pharmacol 1983;61:1444 – 61.

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sociation constant of nonvolatile buffers in human plasma. J Appl Physiol 2001;91:1364–71.

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14. Constable PD. Clinical assessment of acid-base status: compar-ison of the Henderson-Hasselbalch and strong ion approaches.Vet Clin Pathol 2000;29:115–28.

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blood. Med 1948;27:223– 42.16. Gilfix BM, Bique M, Magder S. A physical chemical approach to

the analysis of acid-base balance in the clinical setting. J CritCare 1993;8:187–97.

17. Figge J, Mydosh T, Fencl V. Serum proteins and acid-baseequilibria: a follow-up. J Lab Clin Med 1992;120:713–9.

18. Kellum JA, Kramer DJ, Pinsky MR. Strong ion gap: a method-ology for exploring unexplained anions. J Crit Care 1995;10:51–5.

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Asidosis hiperkloremik: Contoh Klasik dari Asidosis Ion Kuat

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