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When body fluids are exposed to nonvolatile acid, such as in diabetic ketoacidosis, the pH decreases (H+ increases) and the HCO3- concentration decreases. Additionally, the concentration of the anion associated with the nonvolatile acid increases. This change in anion concentration allows for convenient analysis of the cause of metabolic acidosis through the calculation of the anion gap. The anion gap represents the difference between the concentration of the major extracellular fluid cation (Na+) and the major extracellular fluid anions (Cl- and HCO3-). Under normal conditions, the anion gap ranges from 8 to 16 mEq/L. It is important to note that the anion gap does not actually exist; all cations are balanced by anions. The gap simply reflects the parameters that are measured. In reality, if the anion of the nonvolatile acid is Cl-, the anion gap will be normal (i.e., the decrease in HCO3- is matched by an increase in Cl-). Metabolic acidosis associated with diarrhea or renal tubular acidosis (i.e., defect in renal H+ secretion) has a normal anion gap. In contrast, if the anion of the nonvolatile acid is not Cl- (e.g., lactate, β-hydroxybutyrate), the anion gap will increase (i.e., the decrease in HCO3- is not matched by an increase in Cl- but rather by an increase in the concentration of the unmeasured anion). The anion gap is increased in metabolic acidosis-associated ketoacidosis (e.g., diabetes mellitus) with renal failure, lactic acidosis, or ingestion of toxins or certain drugs (e.g., large quantities of aspirin). Thus, the calculation of the anion gap is a useful way of identifying the etiology of metabolic acidosis in the clinical setting. Albumin, a negatively charged macromolecule, contributes significantly to the "unmeasured anions." Therefore, the anion gap must be adjusted in patients with abnormal serum albumin levels. For every 1g/dL change in serum albumin, the anion gap needs to be adjusted in the same direction by 2.5 mEq/L.

ICF. The respiratory centers are inhibited by the increase in pH, resulting in a reduction in the ventilatory rate and elevation of PCO2 (respiratory compensation). The renal compensatory response to metabolic alkalosis is to increase the excretion of HCO3- by reducing its reabsorption along the nephron. This renal response typically occurs rapidly (within minutes to hours) and effectively. Increased renal excretion of HCO3- eventually restores the pH and [HCO3-] to normal, provided the underlying cause of the initial acid-base disturbance is corrected. Once the pH is corrected, the ventilatory rate also returns to normal.

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Whennonvolatileacidisaddedtobodyfluids,asindiabetic ketoacidosis,the[H+]increases(pHdecreases),andthe[HCO3−]decreases.Inadditiontheconcentrationoftheanionassociatedwiththenonvolatileacidincreases.Thischangeinanionconcentrationprovidesaconvenientwayofanalyzingthecauseofametabolicacidosisbycalculatingwhatistermedtheanion gap. TheaniongaprepresentsthedifferencebetweentheconcentrationofthemajorECFcation(Na+)andthemajorECFanions(Cl− andHCO3−):
Undernormalconditionstheaniongaprangesfrom8to16mEq/L.Itisimportanttorecognizethatananiongapdoesnotactuallyexist.Allcationsarebalancedbyanions.Thegapsimplyreflectstheparametersthataremeasured.Inreality:
IftheanionofthenonvolatileacidisCl− ,theaniongapwillbenormal(i.e.,thedecreasein[HCO3−]ismatchedbyanincreasein[Cl−]).Metabolicacidosisassociatedwithdiarrheaorrenaltubularacidosis(i.e.,defectinrenalH+ secretion)hasanormalaniongap.Incontrast,iftheanionofthenonvolatileacidisnotCl− (e.g.,lactate,β-hydroxybutyrate),theaniongapwillincrease(i.e.,thedecreasein[HCO3−]isnotmatchedbyanincreasein[Cl−]butratherbyanincreaseintheconcentrationoftheunmeasuredanion).Theaniongapisincreasedinmetabolicacidosis–associatedketoacidosis(e.g.,diabetesmellitus)withrenalfailure,lacticacidosis,oringestionoftoxinsorcertaindrugs(e.g.,largequantitiesofaspirin).Thuscalculationoftheaniongapisausefulwayofidentifyingtheetiologyofmetabolicacidosisintheclinicalsetting.
Albuminisanegativelychargedmacromolecule,anditmakesaconsiderablecontributionto“unmeasuredanions.”Asaresulttheaniongapmustbeadjustedinpatientswhohaveanabnormalserum[albumin].Foreach1g/dLchangeinserum[albumin],theaniongapneedstobeadjustedinthesamedirectionby2.5mEq/L.
ICF. The increase in the pH inhibits the respiratory centers, which reduces the ventilatory rate, thus the PCO2 is elevated (respiratory compensation).
The renal compensatory response to metabolic alkalosis is to increase excretion of HCO3 − by reducing its reabsorption along the nephron. Normally this occurs quite rapidly (minutes to hours) and effectively. Enhanced renal excretion of HCO3 − eventually returns the pH and [HCO3 −] to normal, provided the underlying cause of the initial acid-base disturbance is corrected. When the pH is corrected, the ventilatory rate also returns to normal.