When a strong acid is added to plasma, one expects a quantitativerelationship between excess anion gap (AG) and bicarbonate deficit(HCO3–) with the AG/HCO3– ratio close to unity.If true, then this ratio could be used to diagnose mixed acid-basedisorders in patients with metabolic acidosis. Although themean ratio in selected patients is close to unity, this ratioalso has a wide range, making its use in individual patientsproblematic. The ratio should therefore be used cautiously inmaking a diagnosis of mixed acid-base disorders.
The anion gap (AG) is the difference between the concentrationof selected positive and negative ions in the plasma. By convention,the AG is usually calculated as [Na – (Cl + HCO3–)],ignoring the concentration of potassium; in this commentary,HCO3– is also used synonymously for total CO2 (TCO2).Because the total concentration of anions and cations in plasmais equal, the AG reflects the difference between the concentrationof unmeasured anions and cations.1 A normal AG primarily reflectsthe concentration of nonbicarbonate buffers including albumin,phosphate, sulfate, and organic acids. Albumin is the main componentof the normal AG with each gram per deciliter contributing 2.5mEq/L to the gap calculation.2 This contribution is pH dependentand increases with a rise in ambient pH. The elevated AG seenin metabolic alkalosis is due primarily to an increase in albuminconcentration and a lesser extent to alkaline pH.3 The normalrange for the AG varies from 3 to 11 to 8 to 16 mEq/L, dependingon the instrument used to measure serum electrolytes, especiallychloride.4 The range, however, is wide, regardless of the instrumentused. To evaluate the AG in a patient, it is therefore importantto know the normal range in your laboratory and compare thepresent AG with baseline AG, both corrected for albumin concentrationand, if indicated, serum pH. Sometimes the baseline AG has tobe estimated on the basis of the albumin concentration at thetime of evaluation.
When a strong acid (HA) is added to the plasma, it dissociatesto its base (A–) and H+ ion. Hydrogen is then neutralizedby both bicarbonate and nonbicarbonate buffers present in extra-and intracellular compartments, resulting in a drop in serumbicarbonate (Figure 1). The accumulated A–, an unmeasuredanion, then raises the AG. The resultant excess AG (AG), therefore,serves as a footprint for the accumulation of a strong acidin plasma. AG, of course, often contains more than a singleanion. Gabow et al.,5 studying an unselected population withAG metabolic acidosis (AGMA), could not account for 23% (8.7mEq/L) of the gap. Forni et al.,6 in a group of intensive careunit patients with lactic acidosis, diabetic ketoacidosis (DKA),and acidosis of unknown cause, noted the presence of significantamounts (3 to 5 mEq/L) of Kreb cycle intermediates, includingcitrate, isocitrate, -ketoglutarate, and d-lactate. These metabolitesaccounted for some but not all of the unknown anions.
Figure 1. Factors affecting AG/HCO3– ratio. I, distribution space for A– and H+; II, metabolism of A–; III, renal handling of A– and H+; ECF, extracellular fluid; ICF, intracellular fluid.
Metabolic acidosis is due to either loss of bicarbonate or netaddition of strong acid(s). In the former, no new anion is addedand the AG does not change, resulting in hyperchloremic metabolicacidosis (HCMA). In this disorder, there is a lack of correlationbetween the AG and HCO3–, with the ratio of AG/HCO3–falling below unity (1.0) and sometimes approaching zero. Whena strong acid (HA) is added to plasma either as a result ofa decrease in excretion, such as in renal failure, or as a resultof addition, such as in DKA or in methanol poisoning, AGMA develops.In this disorder, one expects a direct quantitative relationshipbetween AG and HCO3– with a ratio close to unity. If true,then a mixed disturbance is suspected when the ratio deviatesfrom unity. If the ratio is significantly lower than 1, thenan underlying HCMA or respiratory alkalosis can be inferred;if greater than 1, then an underlying metabolic alkalosis orrespiratory acidosis may be present. One could also calculatethe so-called —the difference between AG and HCO3–.In pure AGMA, the would be zero. If the AG is greater thanthe HCO3–, then the would be positive. This is plausibleonly if the initial bicarbonate is higher than normal, reflectingthe presence of a hidden metabolic alkalosis or respiratoryacidosis. If the is a negative number because the AG is lessthan the HCO3–, then the initial bicarbonate must be lowerthan normal, reflecting the presence of a HCMA or respiratoryalkalosis. Use of either the AG/HCO3– ratio or the alsorequires that A– and H+ have a similar distribution spaceand renal and nonrenal clearance and that the overall contributionof albumin and other nonbicarbonate buffers to the AG remainstable (Figure 1). However, as summarized in Figure 1, the ratioor would change if these conditions were not met.
The utility of the AG/HCO3– ratio is best studied in DKA,in which production of ketoacids is associated with an acutedrop in serum bicarbonate and a rise in AG. Patients with DKAoften present with vomiting, volume depletion, and/or infection,conditions that could affect acid-base status. Adroguéet al.7 recently summarized seven studies in patients with DKAand noted that the mean rise in AG was similar to the mean decreasein bicarbonate, resulting in a AG/HCO3– ratio close to1.0. In the largest study involving 242 patients, although themeanAG/HCO3– ratio was close to unity, there was no relationshipbetween AG and HCO3–, and the ratio varied from 0 to 2.8Similar variations in this ratio have been noted in patientswith ESRD.9 In a carefully done study of 100 admissions forDKA, Paulson,10 after a careful review of clinical data, selected20 admissions with simple metabolic acidosis. Slope of regressionlines between AG to HCO3– in this group and 43 normalcontrol subjects was close to unity but with a wide 95% confidenceinterval of ±8 mEq/L. Given this wide interval, two conclusionscan be drawn: (1) The AG in itself is often a poor predictorof severity of metabolic acidosis, and (2) the AG/HCO3–ratio should be used cautiously in diagnosing a mixed acid-basedisturbances.
When this ratio was further evaluated in light of volume status(blood urea nitrogen [BUN] used as a surrogate for volume status),there was a direct relationship between BUN and this ratio aswell as among BUN, serum albumin, and the AG.8,10 This relationshipis primarily due to the effect of volume status on renal clearanceof keto-anions. Lower renal clearance of keto-anion in hypovolemiaalso explains two other observations: (1) That volume expansionis associated with the development of HCMA,8,11 and (2) thatpatients with higher AG/HCO3– ratios on admission havea more rapid rise in bicarbonate generated by metabolism ofketo-anions.8 In summary, the expected stoichiometric relationshipseems true only of the mean data, with a wide range for individualpatients. In addition, volume depletion, by changing the renalexcretion of keto-anions, has a major impact on this ratio.
Given this complex relationship, how should the AG/HCO3–ratio be used to diagnose mixed disturbance? Some authors, usingthe data from Adrogué et al.,12 suggested that mixeddisturbances should be considered if the ratio is <0.8 or>1.2. Paulson, applying this rule to a group of normal controlsubjects and patients with simple metabolic acidosis, notedthat the formula erroneously categorized 56% of this group asmixed disturbances. Use of the 95% confidence interval of ±8mEq/L increased the specificity to 97% but with a poor sensitivityof only 27%.13 In addition, one should be cautious in applyingthese rules developed in DKA to patients with other types ofmetabolic acidosis. Oh et al.11 found a mean ratio close tounity in a group of patients with DKA but as high as 1.6 inpatients with phenformin-induced lactic acidosis. This is probablydue to the lower renal clearance of lactate compared with keto-anions.It is interesting that in exercise-induced lactic acidosis,the ratio remains close to unity up to a serum lactate of 15mEq/L but increases significantly as the lactate level risesfurther and serum pH drops below 7.15.14 This finding may bedue to better buffering at lower pH by nonbicarbonate buffers,including hemoglobin. The difference between DKA and lacticacidosis, however, is multifactorial and reflects the differencesin distribution space, renal clearance, duration, and severityof acidosis as well as volume status.
Given the complexity in the relationship between AG and HCO3–,how, then, should clinicians use this ratio? I think we shouldabandon diagnosing mixed disturbance solely on the basis ofthe use of AG/HCO3– ratio of <0.8 or >1.2. Althoughthe confidence interval derived by Paulson provides greaterspecificity, it has poor sensitivity and should therefore beused cautiously.15 To diagnose a mixed acid-base disorder, wetherefore need to use all available data and not depend on asingle formula. I therefore suggest the following:
Know thenormal AG range for your laboratory.
Correct the AG for serumalbumin concentration, and always usecorrected AG.
Comparethe AG with the baseline AG in your patient rather thanwitha normal range.
Use all clinical information, including historicaland laboratorydata, in making a diagnosis of mixed acid-basedisturbance.
Follow patients with a complex presentation carefullybecausethe diagnosis of a hidden disorder(s) may become apparentbyevaluating response to therapy.
Use theAG/HCO3– ratioor as one piece of evidence amongmany in making your finaldiagnosis. Be aware of its limitationsas discussed here.
Emmett M, Narins R: Clinical use of the anion gap.
Medicine (Baltimore) 56
: 38
–54, 1977[Medline]
Figge J, Jabor A, Kazda A, Fencl V: Anion gap and hypoalbuminemia.
Crit Care Med 26
: 1807
–1810, 1998[Medline]
Adrogue HJ, Brensilver J, Madias NE: Changes in the plasma anion gap during chronic metabolic acid-base disturbances.
Am J Physiol 4
: F291
–F291, 1978
Lolekha PH, Vanavanan S, Teerakarnjana N, Chaichanajarenkukl U: Reference ranges of electrolytes and anion gap on the Beckman, E4A, Beckman Synchron CX5, Nova CRT, and Nova Stat Profile Ultra.
Clin Chim Acta 307
: 87
–93, 2001[CrossRef][Medline]
Gabow PA, Kaehny WD, Fennessey PV, Goodman SL, Gross PA, Schrier RW: Diagnostic importance of an increased anion gap.
N Engl J Med 303
: 854
–858, 1980[Medline]
Forni LG, McKinnon,W, Lord GA, Treacher DF, Peron JM, Hilton PJ: Circulating anion usually associated with the Kreb cycle in pa-tients with metabolic acidosis.
Crit Care 9
: R591
–R595, 2005[CrossRef][Medline]
Adrogue HJ, Madias NE: Diabetic and other forms of ketoacidosis. In:
Acid-Base Disorders and Their Treatment, edited by Gennari FJ, Adrouge HJ, Galla JH, Madias NE, London, Taylor & Francis, 2005
, pp 313
–351
Adrogué HJ, Wilson H, Boyd AE, Suki WN, Eknoyan G: Plasma acid-base patterns in diabetic ketoacidosis.
N Engl J Med 307
: 1603
–1610, 1982[Abstract]
Wallia R, Greenberg A, Piraino B, Mitro R, Puschett JB: Serum electrolyte pattern in end-stage renal disease.
Am J Kidney Dis 8
: 98
–104, 1986[Medline]
Paulson WD: Anion gap-bicarbonate relation in diabetic ketoacidosis.
Am J Med 81
: 995
–1000, 1986[CrossRef][Medline]
Oh MS, Carroll HJ, Goldstein DA, Fein IA: Hyperchloremic acidosis during the recovery phase of diabetic keto acidosis.
Ann Intern Med 89
: 925
–927, 1978[CrossRef][Medline]
Elisaf M, Tsatsoulis AA, Katopodis KP, Siamopolous KC: Acid-base and electrolyte disturbances in patients with diabetic ketoacidosis.
Diabetes Res Clin Pract 34
: 23
–27, 1966[CrossRef]
Paulson WD, Gadallah MF: Diagnosis of mixed acid-base disorders in diabetic ketoacidosis.
Am J Med Sci 306
: 295
–300, 1993[Medline]
Osnes JB, Hermansen L: Acid-base balance after maximal exercise of short duration.
J Appl Physiol 32
: 59
–62, 1972[Free Full Text]
DiNubile MJ: The increment in the anion gap; overextension of a concept?
Lancet 2
: 951
–953, 1988[Medline]
AG/
Top
Abstract
Introduction
AG) and bicarbonate deficit (
-ketoglutarate, and d-lactate. These metabolites accounted for some but not all of the unknown anions. 
