Interpretation of Metabolic Acid Base Disturbances Using the Routine Serum Biochemical Profile

The routine serum biochemical profile contains several pieces of information useful in the interpretation of metabolic acid base disturbances. The most important of these are the total CO₂, serum sodium, serum potassium, and serum chloride concentrations.

The total CO₂ content is a measure of all potential sources of CO₂ in plasma or serum. When a sample is handled anaerobically, this includes HCO₃ ^– ions, dissolved CO₂, carbamino CO₂ bound to amino groups in haemoglobin, H₂CO₃, and CO₃ ^–2 ions. The total amount of carbamino CO₂, H₂CO₃, and CO₃ ^–2 present is negligible, and total CO₂ usually is defined as HCO₃ ^–+dissolved CO₂ or HCO₃ ^–+0.03×pCO₂, where 0.03 is the solubility coefficient for CO₂ in plasma. In a normal dog with a [HCO₃ ^–] of 21 mEq/l and pCO₂ of 37 mmHg, total CO₂ would be 22.1 mEq/l with HCO₃ ^– representing 95% of the total CO₂ content. Invariably, samples sent to laboratories for routine biochemical profiles are not handled anaerobically. When the sample is handled aerobically, dissolved CO₂ is released to the atmosphere and the total CO₂ measurement is essentially equal to the concentration of HCO₃ ^– in the sample. Thus, in routine clinical practice the total CO₂ determination often is considered synonymous with [HCO₃ ^–].

Determination of total CO₂ does not allow differentiation of metabolic and respiratory acid base disorders. Occurrence of a high total CO₂ indicates either a primary metabolic alkalosis or an increased HCO₃ ^– concentration as an adaptive response to respiratory acidosis. A low total CO₂ indicates either a primary metabolic acidosis or a decreased HCO₃ ^– concentration as an adaptive response to respiratory alkalosis. Evaluation of the clinical setting is necessary to make a judgement about which acid base disturbance is most likely. If there is doubt, blood gas analysis would be indicated for proper management. Metabolic acidosis is the most common acid base disturbance in small animal practice, and most decreased total CO₂ measurements will be the result of this disorder.

The major cations of extracellular fluid are sodium, potassium, calcium, and magnesium whereas the major anions are chloride, bicarbonate, plasma proteins, organic acid anions (including lactate), phosphate, and sulfate.

Automated clinical chemistry analysers provide values for serum sodium, potassium, chloride, and total CO₂ concentrations. The sum of the concentrations of these commonly measured cations exceeds the sum of the concentrations of the commonly measured anions and the difference has been called the anion gap:

$$\left({\text{Na}}^{+}+{\text{K}}^{+}\right)-\left({\text{Cl}}^{-}+{\text{HCO}}_3^{-}\right)$$

The serum concentration of potassium varies little, and its charge contribution is small compared to that of sodium. Therefore, the anion gap sometimes is defined as:

$${\text{Na}}^{+}-\left({\text{Cl}}^{-}+{\text{HCO}}_3^{-}\right)$$

In reality, there is no anion gap because the law of electroneutrality must always be satisfied. This can be indicated by including terms for unmeasured cations (UC) and unmeasured anions (UA) as follows:

$$\begin{array}{c}{\text{Electroneutrality: Na}}^{+}+{\text{K}}^{+}+\text{UC}={\text{Cl}}^{-}+{\text{HCO}}_3^{-}+\text{UA}\\ \text{Anion gap}=\text{UA}-\text{UC}=\left({\text{Na}}^{+}+{\text{K}}^{+}\right)-\left({\text{Cl}}^{-}+{\text{HCO}}_3^{-}\right)\end{array}$$

Thus, the anion gap is the difference between unmeasured anions and unmeasured cations and may be affected by changes in the concentration of either component. Normally, the anion gap is made up of the net negative charge on sulfates, phosphates, plasma proteins, and organic anions (eg, lactate, citrate, ketoacids). The magnitude of change in the concentration of any of the unmeasured cations (eg, calcium, magnesium) necessary to cause an appreciable change in the anion gap would likely be incompatible with life. As a result, discussions of the anion gap usually focus on changes in unmeasured anions.

Increases in anion gap are much more common than decreases, and the concept of anion gap usually is used as an aid in differentiating the causes of metabolic acidosis. When metabolic acidosis is characterised by a high anion gap, it is assumed to have arisen from an acid that does not contain chloride as an anion. Examples include some inorganic acids (eg, phosphates, sulfates) and organic acids (eg, lactate, ketoacids, salicylate, metabolites of ethylene glycol). In this setting, titration of body buffers by the acid results in accumulation of an anion other than chloride. If the observed metabolic acidosis is characterised by a normal anion gap, there is a reciprocal increase in the plasma chloride concentration to balance the decrease in plasma HCO₃ ^– concentration. Hypoalbuminaemia or dilution of plasma proteins by crystalloid infusion can decrease the anion gap by decreasing the concentration of net negative charge attributable to plasma proteins. Hypoalbuminaemia may be the most common cause of a decreased anion gap.

In organic acidoses (eg, diabetic ketoacidosis, lactic acidosis) and certain intoxications (eg, ethylene glycol, salicylate), HCO₃ ^– is titrated by H⁺ ions from organic acids. In uraemia, phosphates and sulfates represent a portion of the accumulated unmeasured anions. Theoretically, extracellular fluid HCO₃ ^– concentration should fall in reciprocal fashion with the increase in concentration of organic acid anions, serum chloride concentration should not change, and the anion gap should be increased proportionately. In practice, however, the decrement in HCO₃ ^– concentration rarely equals the increment in anion gap. The most common causes of a normochloraemic (increased anion gap) in dogs and cats are ethylene glycol intoxication, diabetic ketoacidosis, uraemic acidosis, and lactic acidosis.

The concentration of HCO₃ ^– in intestinal fluid usually is higher than that of plasma, whereas its Cl^– concentration is lower. Severe acute small bowel diarrhoea may cause loss of HCO₃ ^– in excess of Cl^– with resultant hyperchloraemic (normal anion gap) acidosis. In this setting, renal reabsorption of sodium to repair the volume deficit must occur in conjunction more with Cl^– than with HCO₃ ^– due to the HCO₃ ^– deficit created by the diarrhoea and this further contributes to the hyperchloraemia. Carbonic anhydrase inhibitors (eg, acetazolamide) inhibit proximal tubular reabsorption of HCO₃ ^– in the kidney and result in a self-limiting hyperchloraemic metabolic acidosis. Acidosis caused by administration of NH₄Cl causes a decrease in HCO₃ ^– concentration because H⁺ ions are released during ureagenesis. There is a reciprocal increase in serum chloride concentration and, as a result, there is no change in the anion gap. Infusion of cationic amino acids (eg, lysine HCl, arginine HCl) during total parenteral nutrition may result in hyperchloraemic metabolic acidosis because H⁺ ions are released as the ammonia from these amino acids is converted to urea in the liver. During compensation for chronic respiratory alkalosis, renal net acid excretion decreases with consequent reduction in plasma [HCO₃ ^–] and increase in [Cl^–]. When the stimulus for hyperventilation is removed and pCO₂ increases, pH decreases because it requires 1–3 days for the kidneys to increase net acid excretion and increase plasma HCO₃ ^– concentration. This transient phenomenon has been referred to as posthypocapneic metabolic acidosis and it is associated with hypechloraemia. Dilutional acidosis occurs when extracellular volume is expanded using an alkali-free chloride-containing solution (eg, 0.9% NaCl). The high Cl^– concentration of 0.9% NaCl (ie, 154 mEq/l) and the highly resorbable nature of the chloride ion in the renal tubules contributes to decreased plasma HCO₃ ^– concentration and hyperchloraemia in this situation. Renal tubular acidosis (RTA) is characterised by hyperchloraemic metabolic acidosis due either to decreased HCO₃ reabsorption (type II or proximal RTA) or defective acid excretion (type I or distal RTA) in the presence of normal glomerular filtration rate.

Chloride is the most abundant anion in extracellular fluid, and Cl and HCO₃ are the only important resorbable anions in renal tubular fluid. An alteration in the normal relationship between these ions underlies the pathophysiology of acid base disturbances such as hyperchloraemic (normal anion gap) metabolic acidosis and hypochloraemic metabolic alkalosis. The pathophysiology of chloride-responsive metabolic alkalosis can be understood by considering the events associated with vomiting of stomach contents. Loss of fluid and HCl from the stomach is associated with an increase in the concentration of HCO₃ in ECF. Volume depletion due to loss of fluid from the stomach results in renal sodium avidity. Renal sodium avidity contributes to perpetuation of the alkalosis and development of a potassium deficit because the kidney now must reabsorb more sodium in exchange for H⁺ and K⁺ ions because of the chloride deficit that has developed.

A pure water loss will increase serum-sodium and chloride concentrations resulting in contraction alkalosis whereas an excess of free water will decrease serum sodium and chloride concentrations resulting in dilutional acidosis. Consequently, the serum chloride concentration should be corrected for the effects of changes in water balance before drawing any conclusions about the patient's acid base status. Serum chloride concentration is corrected using the following formulas:

$$\begin{array}{ccc}\text{Corrected }\left[{\text{Cl}}^{-}\right]& =& \text{Measured }\left[{\text{Cl}}^{-}\right]\times (146/\left[{\text{Na}}^{+}\right]\left(\text{for dogs}\right)\\ \text{Corrected }\left[{\text{Cl}}^{-}\right]& =& \text{Measured }\left[{\text{Cl}}^{-}\right]\times (156/\left[{\text{Na}}^{+}\right]\left(\text{for cats}\right)\end{array}$$

Normal corrected [Cl^–] for dogs is approximately 107–113 mEq/l and for cats is approximately 117–123 mEq/l.

The anion gap also may be useful in identifying some mixed acid base disturbances. Consider, for example, a mixed disturbance characterised by metabolic alkalosis and lactic acidosis (eg, chronic vomiting severe enough to have caused hypotension and decreased tissue perfusion). The pH in such a setting could be normal if HCl loss from the stomach was exactly counterbalanced by accumulation of lactic acid from anaerobic metabolism. An increased anion gap in a patient with a relatively normal total CO₂ but low serum chloride concentration would suggest such a complicated acid base disorder. A high anion gap in a patient with hyperchloraemia would suggest the possibility of a mixed hyperchloraemic and organic (eg, lactic) acidosis. Such a situation could arise in a patient with severe small bowel diarrhoea that develops decreased tissue perfusion and a complicating lactic acidosis. In assessing patients with these types of mixed disorders, it is important to consider the serum chloride concentration rather than simply calculating the anion gap.

References available on request