Approach

A systematic evaluation of acid-base status of the patient provides insight into the underlying medical problem. The differential diagnosis of these disorders can be narrowed down with the help of the patient's clinical information and some laboratory data. These clinical conditions with acid-base disorders can be effectively evaluated by a stepwise pathophysiologic approach.[15][16][17]

Arterial blood gas (ABG) analysis and a comprehensive metabolic panel (CMP) should be requested. The laboratory data required to approach a suspected acid-base disorder are obtained from the ABG, which provides information about pH, PaO₂, PaCO₂, and calculated HCO₃- values, and venous serum CMP, which provides Na+, K+, Cl-, and total CO₂ content (TCO₂). TCO₂ represents total carbon dioxide concentration in the serum including dissolved CO₂, bicarbonate, carbonate, and carbonic acid. Dissolved CO₂ is a small fraction of TCO₂. TCO₂ on the serum electrolyte panel mainly represents the plasma bicarbonate concentration.

The following steps are required to interpret the data and determine the cause of metabolic acidosis

1. Determine the disturbance in pH

  • Arterial pH indicates the ongoing disturbance - acidosis versus alkalosis.

  • At sea level the normal pH is 7.42 ± 0.02, with a range of 7.35 to 7.45.

  • Decrease in arterial pH <7.35 suggests that the major ongoing disturbance is acidosis.

2. Identify the primary disorder

  • To determine the primary disorder, the directional changes of serum HCO₃- and arterial PaCO₂ from the normal and their relation with change in arterial pH are examined.

  • If the pH is low and HCO₃- is low, then the primary disorder is metabolic acidosis.

3. Assess compensation in response to the primary disorder

  • With simple metabolic acidosis, the normal adaptive respiratory response will decrease the arterial PaCO₂ 1 to 1.5 times the decrease in serum HCO₃-.[18][19]

4. Calculate the serum anion gap (AG)

  • Serum AG = Na+ - (Cl- + HCO₃-).

  • In serum, measured cations + unmeasured cations = measured anions + unmeasured anions. Serum AG, which is calculated as measured cation (Na+) - measured anion (Cl- + HCO₃-), is actually an indicator of whether unmeasured anions have accumulated in the serum. Therefore, any metabolic process that contributes to accumulation of unmeasured anions will increase the anion gap.

  • The concept is that in an organic acidosis, the anions accumulate in a 1:1 relationship with the consumption of HCO₃-. Therefore, the increase in the serum AG should be roughly equal to the decrease in HCO₃- in organic acidosis.

  • In contrast, acidosis without accumulation of anions would not be expected to have any change in the serum AG; these types of acidosis are known as normal AG or hyperchloremic metabolic acidosis, reflecting the compensatory increase in serum Cl, which maintains the serum AG at 6 to 12 mEq/L.[20]

  • Values <12 mEq/L imply normal AG metabolic acidosis, whereas values >12 mEq/L imply increased AG metabolic acidosis.[20]

5. Compare the change in the serum AG with the decrease in HCO₃-

  • In increased AG metabolic acidosis, the increase in the serum AG should equal the decrease in HCO₃-.

  • When the increase in serum AG is greater than the decrease in HCO₃-, combined metabolic acidosis and alkalosis can be inferred.

  • Conversely, when the decrease in HCO₃- is greater than the increase in serum AG (and the serum AG is significantly increased), simultaneous normal AG and increased AG metabolic acidosis are present.

  • If increased AG metabolic acidosis is present, calculate serum osmolar gap.[9] 

    • Serum osmolar gap = measured serum osmolality - calculated serum osmolarity.

    • Calculated serum osmolality = 2 x serum Na+ + glucose/18 + BUN/2.8 (normal <10).

    • Serum osmolality is due to solutes normally present in the serum. Addition of substances such as alcohols, proteins, lipids, and mannitol increases the measured osmolality and thus increases the serum osmolar gap. Increased serum osmolar gap in the presence of increased AG metabolic acidosis can be an indirect indication of ethanol intoxication, or methanol and ethylene glycol ingestion.

6. If a normal AG (hyperchloremic) metabolic acidosis is present, the urine AG should be measured[9][21]

  • Urine AG = (Na+ + K+) - Cl (urinary ions).

  • In the setting of normal AG metabolic acidosis, the urine AG distinguishes between most renal tubular acidosis and nonrenal causes.[21]

  • Substantially negative values (<0 mEq/L) favor nonrenal causes.

  • As urinary ammonium is not usually measured in clinical situations, the urine AG is used to make inferences about whether substantial amounts of ammonium are present (negative urine AG) or absent (positive urine AG).

  • Mostly useful in differentiating renal (mainly renal tubular acidosis) causes, which are often characterized by a failure of ammonium production or secretion, from nonrenal causes of normal AG metabolic acidosis (e.g., diarrhea).

7. Identify the underlying disease

  • This is the main purpose of analyzing the acid-base disorder and can be achieved with the help of clinical presentation and the steps listed above.

  • Further tests for lactate levels and ketones, and toxicology screening (ethanol, methanol, ethylene glycol, propylene glycol, 5-oxoproline, and salicylate levels) should be performed where indicated by the history.

  • If a patient has diabetes, review their medication for any drugs that can cause hyperglycemia. Hyperglycemia, if untreated, may progress to diabetic ketoacidosis (DKA). Drugs that can cause hyperglycemia include:[22]  

    • Fluoroquinolone antibiotics

    • Atypical antipsychotics, particularly clozapine and olanzapine

    • Corticosteroids

    • Atenolol, propranolol, and metoprolol

    • Thiazide and thiazide-like diuretics

    • Protease inhibitors

    • Calcineurin inhibitors

    Diabetic ketoacidosis is a rare adverse effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors, which are licensed to treat type 2 diabetes mellitus. If diabetic ketoacidosis is suspected, discontinue the SGLT2 inhibitor immediately.[23][24] Serum glucose may not be significantly elevated. 

8. The classic diagnostic approach mentioned above may not be applicable in patients who are critically ill. In critically ill patients, various cations such as Ca2+ and Mg2+, and anions such as albumin and PO₄-, may not remain unchanged as assumed in the classic approach.[1]

  • AG needs to be corrected for abnormal albumin concentration.[9]

  • Corrected AG = observed AG + 2.5 x (normal serum albumin - measured serum albumin).

  • Strong ion approach (developed by Dr Peter Stewart) accounts for all the ions dissolved in plasma.

  • Apparent strong ion difference (SID) = (Na+ + K+ + Ca2+ + Mg2+) - Cl-.

  • Effective SID = HCO₃- + measured albumin x (0.123 x pH - 0.631) + inorganic phosphate x (0.309 x pH - 0.469).

  • Strong ion gap = apparent SID - effective SID.

9. Initiate appropriate therapy

  • The fundamental principle of therapy of metabolic acidosis is identifying and treating the underlying disease state.

  • Direct therapy of metabolic acidosis may sometimes be required.

  • Normal AG metabolic acidosis is effectively treated by gradually giving bicarbonate, whereas even gradual treatment of increased AG metabolic acidosis with bicarbonate is controversial.[9]

  • Acute treatment of any metabolic acidosis with boluses of intravenous sodium bicarbonate should be avoided.[25]

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