Acid-base disorders

Acid-base disorders are characterized by changes in the concentration of hydrogen ions (H+) in the body. Increased H⁺ concentration (acidosis) can lead to an abnormally low blood pH (acidemia) and decreased H⁺ concentration (alkalosis) can lead to an abnormally high blood pH (alkalemia); however, if compensation occurs, acidosis and/or alkalosis may be present without acidemia or alkalemia. Acidosis and alkalosis may be respiratory or metabolic in origin depending on the cause of the imbalance; they can also coexist as mixed acid-base disorders. Diagnosis is made based on arterial blood gas (ABG) results. In metabolic acidosis, calculation of the anion gap can also help determine the cause and reach a precise diagnosis. In metabolic alkalosis, urine chloride (Cl‑) concentration can help identify the cause. Treatment is based on the underlying cause.

• Acid-base processes ^[1]
  • Acidosis: the processes by which H⁺ concentration is increased
  • Alkalosis: the processes by which H⁺ concentration is decreased
• pH scale
  • A logarithmic scale that expresses the acidity or alkalinity of a solution based on the concentration of H⁺ (pH = -log[H⁺])
  • Neutral pH is 7; lower values are acidic and higher values are alkaline.
• Blood pH abnormalities
  • Acidemia; : abnormally low blood pH (pH < 7.35)
  • Alkalemia; : abnormally high blood pH (pH > 7.45)

• The Henderson-Hasselbalch equation allows for the calculation of pH from HCO₃^- and PCO₂: pH = 6.1 + log([HCO₃^-]/[0.03 × pCO₂])
  • 6.1 = pKa of carbonic acid
  • 0.03 = solubility constant of PCO₂

Approach to acid-base disorders ^[1][3]

• Perform an initial clinical evaluation: to help identify the most likely underlying cause
• Order initial laboratory studies: ABG, BMP ^[4][5]
• Determine the primary acid-base disorder: i.e., using pH, PCO₂, and HCO₃^-
• Calculate the expected compensatory (or secondary) response.
  • Mixed acid-base disorder: The expected compensatory response differs from the laboratory findings.
  • No mixed acid-base disorder: The expected compensatory response aligns with the laboratory findings.
• Perform further diagnostic workup (to determine the mechanism and the cause), e.g.:
  • In metabolic acidosis: anion gap and delta gap
  • In metabolic alkalosis: urinary chloride and potassium levels

Careful clinical evaluation is an important first step in the assessment of acid-base disorders, as it can provide important diagnostic clues that can help determine the underlying cause.

Initial blood gas analysis

There are different methods for the assessment of acid-base status; the following method is just one example.

Suggested approach

1. Evaluate blood pH (reference range: 7.35–7.45).
2. Evaluate HCO₃^- (reference range: 22–28 mEq/L).
3. Evaluate PCO₂ (reference range: 33–45 mm Hg).

Interpretation

• pH < 7.35 (acidemia): Primary disorder is an acidosis.
  • ↓ pH and ↓ HCO₃^-: metabolic acidosis
  • ↓ pH and ↑ PCO₂: respiratory acidosis
• pH > 7.45 (alkalemia): Primary disorder is an alkalosis.
  • ↑ pH and ↑ HCO₃^-: metabolic alkalosis
  • ↑ pH and ↓ PCO₂: respiratory alkalosis

Further considerations

• Evaluate PO₂.
  • High: hyperoxemia
  • Low: hypoxemia
• See also “Respiratory failure.”

SMORE: change in PCO₂ in the Same direction as pH → Metabolic disorder; change in PCO₂ in the Opposite direction to pH → REspiratory disorder

Corrections to central venous blood gas values ^[6][7]

Reference values for venous blood gas (VBG) are different from those for ABG; central VBG results can be corrected to approximate ABG.

• Arterial pH = venous pH + 0.03–0.05 units
• Arterial PCO₂ = venous PCO₂ – 5 mm Hg

Compensation (acid-base) ^[1][8]

• Definition: physiological changes that occur in acid-base disorders in an attempt to maintain normal body pH
• Compensatory changes
  • In metabolic disorders: rapid compensation within minutes through changes in minute ventilation (respiratory compensation)
  • In respiratory disorders: typically slow compensation over several hours to days through changes in urine pH (metabolic compensation)
  • See also “Compensation mechanisms in acid-base disorders.”
• Assessment and interpretation: Calculate the expected compensation; see “Calculation of compensatory response.”
  • Primary respiratory disorders
    • Measured HCO₃^- > expected HCO₃^-: metabolic alkalosis in addition to respiratory disturbance
    • Measured HCO₃^- < expected HCO₃^-: metabolic acidosis in addition to respiratory disturbance
  • Primary metabolic disorders
    • Measured PCO₂ > expected PCO₂: respiratory acidosis in addition to metabolic disturbance
    • Measured PCO₂ < expected PCO₂: respiratory alkalosis addition to metabolic disturbance

Discordance between the measured compensatory response and the expected compensatory response suggests a secondary acid-base disturbance.

In primary metabolic disorders, respiratory compensation develops quickly (within hours), whereas metabolic compensation may take 2–5 days to develop in primary respiratory disorders.

General principles

• Calculation of the anion gap is the first step in the evaluation of metabolic acidosis.
  • Maintenance of electrical neutrality requires that the total concentration of cations approximate that of anions.
  • Anion gap: the difference between the concentration of measured cations and measured anions
  • High anion gap: increased concentration of organic acids such as lactate, ketones (e.g., beta-hydroxybutyrate, acetoacetate), oxalic acid, formic acid, or glycolic acid, with no compensatory increase in Cl^-.
  • Normal anion gap: primary loss of HCO₃^- compensated with ↑ Cl^-
• The measured serum sodium (Na⁺), not the corrected serum Na⁺, should be used in the formulas, even if glucose levels are high.
• Depending on the results, further evaluation and calculations may be needed (see specific subsections below).

High anion gap metabolic acidosis ^[1][11]

Review clinical features and initial studies and follow a stepwise approach to identify the underlying cause of high anion gap metabolic acidosis.

1. Exclude accumulation of endogenous organic acids.
   • Exclude ketoacidosis : Consider measuring ketone levels in urine or serum (e.g., beta-hydroxybutyrate).
   • Exclude lactic acidosis: Measure or review lactate levels.
   • Exclude uremia: Measure or review BUN and creatinine levels.
2. Consider accumulation of exogenous organic acids (ingestion) as the cause: e.g., if the cause remains unclear, or initially if the patient is comatose
   • Consider obtaining serum or urine toxicology screen.
   • Calculate serum osmolal gap: If elevated (≥ 10 mOsm/kg), consider propylene glycol, ethylene glycol, diethylene glycol, methanol, and isopropanol as potential causes.
3. Calculate the delta gap: to exclude concomitant acid-base disturbances

Causes of high anion gap acidosis (MUDPILES): Methanol toxicity, Uremia, Diabetic ketoacidosis, Paraldehyde, Isoniazid or Iron overdose, Inborn error of metabolism, Lactic acidosis, Ethylene glycol toxicity, Salicylate toxicity

Concomitant acid-base disturbances ^[10][11]

Calculation of the delta gap can help determine if another acid-base disturbance is present in addition to a high anion gap metabolic acidosis. Cut-off values may vary depending on the source.

• Delta gap < 1 : Hyperchloremic or normal anion gap metabolic acidosis is present in addition to high anion gap metabolic acidosis. ^[10]
• Delta gap 1–2 : Only high anion gap metabolic acidosis is present.
• Delta gap > 2 : A metabolic alkalosis is present in addition to high anion gap metabolic acidosis. ^[11]

Normal anion gap metabolic acidosis

Review clinical features and initial studies and consider further diagnostic workup to determine the underlying cause of normal anion gap metabolic acidosis.

• Calculate the urine anion gap
  • Negative urine anion gap: Acidosis is likely due to loss of bicarbonate.
  • Positive urine anion gap: Acidosis is likely due to decreased renal acid excretion.
• Consider calculating the urine osmolal gap
  • Preferred over urine anion gap if the urine pH is > 6.5 or urine Na⁺ is < 20 mEq/L
  • ↓ Urine osmolal gap (< 80–100 mOsm/kg) suggests impairment in the excretion of urinary ammonium. ^[13][14]

Causes of normal anion gap acidosis (FUSEDCARS): Fistula (biliary, pancreatic), Ureterogastric conduit, Saline administration, Endocrine (Addison disease, hyperparathyroidism), Diarrhea, Carbonic anhydrase inhibitors, Ammonium chloride, Renal tubular acidosis, Spironolactone

A neGUTive urine anion gap may be due to GI loss of bicarbonate.

Abnormal anion gap without metabolic acidosis ^[15]

• Etiology of low anion gap
  • Hypoalbuminemia → ↓ unmeasured anions → ↓ anion gap
  • Paraproteinemia (e.g., in multiple myeloma), severe hypercalcemia, severe hypermagnesemia, and/or lithium toxicity → ↑ unmeasured cations → ↓ anion gap
• Etiology of high anion gap
  • Severe hyperphosphatemia → ↑ unmeasured anions → ↑ anion gap ^[16]
  • Severe hypocalcemia and/or hypomagnesemia → ↓ unmeasured cations → ↑ anion gap

Approach ^[1]

• Assess the patient's blood pressure and volume status.
• Evaluate for exogenous ingestion (e.g., laxatives, calcium, alkali load, diuretics).
• Obtain BMP and serum calcium, urinary chloride, and urinary potassium levels.
  • Low urine chloride (< 25 mEq/L): chloride-responsive metabolic alkalosis
  • High urine chloride (> 40 mEq/L): chloride-resistant metabolic alkalosis ; check urine potassium.
    • High urine potassium (> 30 mEq/L): Review blood pressure.
      • Elevated blood pressure: Consider mineralocorticoid excess as a potential cause.
      • Low or normal blood pressure: Consider Gitelman syndrome or Bartter syndrome as a potential cause.
    • Low urine potassium (< 20 mEq/L): Consider laxative abuse as a potential cause.

Elevated calcium with renal failure suggests milk-alkali syndrome.

Etiology

Respiratory acidosis

• Seen in alveolar hypoventilation; see also “Respiratory insufficiency.”
• Establish the expected chronicity based on clinical presentation using the following rule:
  • HCO₃^- increases by 1 mEq/L for every 10 mm Hg increase in PCO₂ above 40 mm Hg: suggests acute respiratory acidosis
  • HCO₃^- increases by 4–5 mEq/L for every 10 mm Hg increase in PCO₂ above 40 mm Hg: suggests chronic respiratory acidosis
• Expected and measured HCO₃^- values may differ if additional metabolic disturbances are present; see “Compensation (acid-base).”

Respiratory alkalosis

• Seen in hyperventilation; see also “Respiratory insufficiency.”
• Establish the expected chronicity based on clinical presentation using the following rule:
  • HCO₃^- decreases by 2 mEq/L for every 10 mm Hg decrease in PCO₂ below 40 mm Hg: suggests acute respiratory alkalosis
  • HCO₃^- decreases by 4–5 mEq/L for every 10 mm Hg decrease in PCO₂ below 40 mm Hg: suggests chronic respiratory alkalosis
• Expected and measured values may differ if additional metabolic disturbances are present; see “Compensation (acid-base).”

The loss of bicarbonate-rich fluid in severe diarrhea may cause non-anion gap metabolic acidosis.

General considerations ^[2]

• Treatment of acid-base disorders should target the underlying cause.
• Medications (e.g., sodium bicarbonate, acetazolamide) used to correct acid-base abnormalities should be initiated in consultation with a specialist (e.g., nephrologist).
• Mechanical ventilation may be indicated in severe respiratory disorders and severe metabolic acidosis.
• Optimize ventilation in mechanically ventilated patients as needed.
• Electrolyte imbalances should be corrected: See “Disorders of potassium balance” and “Electrolyte repletion.”

Respiratory acidosis

• Severe acute respiratory acidosis: Consider noninvasive or invasive mechanical ventilation.
• See also “COPD,” “Opioid intoxication,” and “Benzodiazepine overdose.”

Respiratory alkalosis

• Acute respiratory alkalosis accompanied by increased work of breathing: Consider mechanical ventilation.
• See also “Treatment of congestive heart failure,” “Treatment of pulmonary embolism,” and “Salicylate toxicity.”

Metabolic acidosis

• Acute severe metabolic acidosis
  • Consider intravenous sodium bicarbonate and mechanical ventilation (see “High-risk indications for mechanical ventilation”)
  • See also “Diabetic ketoacidosis” and “Salicylate toxicity.” ^[4][22]
• Chronic metabolic acidosis
  • Consider oral sodium bicarbonate
  • See also “Chronic kidney disease,” and “Diarrhea.”

Metabolic alkalosis

• Chloride-responsive metabolic alkalosis
  • Start isotonic saline to increase urinary bicarbonate excretion and correct extracellular volume loss
  • See “Intravenous fluid therapy” and “Treatment” in “Dehydration and hypovolemia.”
• Chloride-resistant metabolic alkalosis
  • Consider bicarbonate excess as a potential cause and administer acetazolamide.
  • See also “Cushing Syndrome” and “Primary hyperaldosteronism.”