Acid-base disorders — Medicine Library

Summary

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.

Definitions

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)

Pathophysiology

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

Pathophysiology of acid-base disorders [2]
	Respiratory acidosis	Respiratory alkalosis	Metabolic acidosis	Metabolic alkalosis
pH	↓	↑	↓	↑
PCO₂	↑	↓	Expected compensatory response: ↓	Expected compensatory response: ↑
HCO₃^-	Expected compensatory response: ↑	Expected compensatory response: ↓	↓	↑
Mechanism	Alveolar hypoventilation → CO₂ retention	↑ Respiratory rate and/or tidal volume → alveolar hyperventilation → CO₂ washout	↑ Production and/or ingestion of H⁺ or loss of HCO₃^-	Loss of H⁺ or ↑ production/ingestion of HCO₃^-
Compensation mechanisms in acid-base disorders	Acute compensation: buffers in blood Chronic compensation ↓ Arterial pH (with ↑ PCO₂) → ↑ HCO₃^- via: ↑ Reabsorption of HCO₃^- by the proximal convoluted tubule ↑ Excretion of H⁺ as H₂PO₄^- and NH₄⁺ from the distal convoluted tubule and collecting duct	Acute compensation: buffers in blood Chronic compensation: ↑ Arterial pH (with ↓ PCO₂) → ↓ HCO₃^- via: ↓ Reabsorption of HCO₃^- by the proximal convoluted tubule ↓ Renal excretion of H⁺	↓ Arterial and CSF pH (with ↓ HCO₃^-) → ↑ stimulation of the medullary chemoreceptors → ↑ respiratory rate and/or tidal volume (hyperventilation) → ↑ CO₂ washout → ↓ PCO₂	↑ Arterial and CSF pH (with ↑ HCO₃^-) → ↓ stimulation of the medullary chemoreceptors → ↓ respiratory rate and/or tidal volume (hypoventilation) → ↑ CO₂ retention → ↑ PCO₂ The compensatory process in metabolic alkalosis is not as efficient as the process in metabolic acidosis because hypoventilation-induced hypoxia blunts the decrease in ventilatory drive.

Henderson-Hasselbalch equation Acid-base nomogram

Diagnosis

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.

Arterial blood gas analysis Acid-base nomogram

Initial blood gas analysis

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

Suggested approach

Evaluate blood pH (reference range: 7.35–7.45).
Evaluate HCO₃^- (reference range: 22–28 mEq/L).
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

Calculation of compensatory response
Primary acid-base disturbance		Expected compensation [1][9]
Metabolic acidosis		Winter formula: expected PCO₂ (mm Hg) = (1.5 × HCO₃^-) + 8 ± 2 OR (rule of thumb) expected PCO₂ (mm Hg) = last two digits of the pH value
Metabolic alkalosis		Expected PCO₂ (mm Hg) = [0.7 × (HCO₃^- - 24)] + 40 ± 2 OR expected PCO₂ (mm Hg) = HCO₃^- + 15
Respiratory acidosis	Acute	Expected HCO₃^- (mEq/L) = 24 + [0.1 × (PCO₂ - 40)] OR expected HCO₃^- (mEq/L): HCO₃^- increases by 1 mEq/L for every 10 mm Hg increase in PCO₂ above 40 mm Hg.
Respiratory acidosis	Chronic	Expected HCO₃^- (mEq/L) = 24 + [0.35 × (PCO₂ - 40)] OR expected HCO₃^- (mEq/L): HCO₃^- increases by 4–5 mEq/L for every 10 mm Hg increase in PCO₂ above 40 mm Hg.
Respiratory alkalosis	Acute	Expected HCO₃^- (mEq/L) = 24 - [0.2 × (40 - PCO₂)] OR expected HCO₃^- (mEq/L): HCO₃^- decreases by 2 mEq/L for every 10 mm Hg decrease in PCO₂ below 40 mm Hg.
	Chronic	Expected HCO₃^- (mEq/L) = 24 - [0.4 × (40 - PCO₂)] OR expected HCO₃^- (mEq/L): HCO₃^- decreases by 4–5 mEq/L for every 10 mm Hg decrease in PCO₂ below 40 mm Hg.

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.

**Arterial blood gas analysis**
This algorithm does not account for mixed acid-base disorders.

Cl^-: chloride
HCO₃^-: bicarbonate
Na⁺: sodium
PCO₂: partial pressure of carbon dioxide

© AMBOSS

Metabolic acidosis

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).

Metabolic acidosis formulas [1][10][11]
Anion gap	Serum anion gap	[Na⁺] - ([Cl^-] + [HCO₃^-]) Reference range: 6–12 mEq/L Correction for hypoalbuminemia: Increase the anion gap by 2.5 mEq/L for every 1 g/dL reduction in serum albumin. If potassium levels are taken into consideration: ([Na⁺] + [K⁺]) - ([Cl^-] + [HCO3^-]) (reference range: 10–16 mmol/L)
Anion gap	Urine anion gap	[Urine Na⁺] + [urine K⁺] - [urine Cl^-]
Osmolal gap	Serum osmolal gap	Measured serum osmolality - calculated serum osmolality Calculated serum osmolality = (2 × [Na⁺]) + ([glucose in mg/dL]/18) + ([BUN in mg/dL]/2.8)
Osmolal gap	Urine osmolal gap	Measured urine osmolality - calculated urine osmolality Calculated urine osmolality = (2 × [urine Na⁺ + urine K⁺]) + ([urine urea in mg/dL]/2.8) + ([urine glucose in mg/dL]/18)
Delta gap		∆ Anion gap/∆ bicarbonate ∆ Anion gap = measured anion gap - 12 ∆ Bicarbonate = 24 - measured HCO3^-
Anion gap: the difference between the concentration of measured cations and measured anions Osmolal gap: the difference between the measured osmolality and the calculated osmolality Delta gap: a ratio of the change in anion gap to the change in bicarbonate

Anion gap Urine Anion Gap Osmolal Gap

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.

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.
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.
Calculate the delta gap: to exclude concomitant acid-base disturbances

Etiology of high anion gap metabolic acidosis
Mechanism	Causes
Accumulation of endogenous organic acids	Ketoacidosis (e.g., diabetic ketoacidosis, starvation ketoacidosis, alcoholic ketoacidosis) Lactic acidosis Type A lactic acidosis (related to hypoxia): e.g., caused by septic shock, hypovolemic shock, hypoxemia, carbon monoxide poisoning Type B lactic acidosis (not related to hypoxia): e.g., caused by liver failure , seizures, intoxication with methanol or toxic alcohols, toluene, medications such as isoniazid and metformin D-lactic acidosis: e.g., caused by short bowel syndrome (can also occur in other forms of malabsorption) Renal insufficiency, uremia Massive rhabdomyolysis
Accumulation of exogenous organic acids	Ingestion of methanol → ↑ formic acid Ingestion of ethylene glycol (a component of antifreeze products) → ↑ oxalic acid Ingestion of propylene glycol → ↑ lactic acid Toluene [12] Long-term acetaminophen use → ↑ 5-oxoproline (pyroglutamic acid) Salicylate toxicity Iron overdose Isoniazid (INH) overdose Djenkol bean poisoning Use of penicillin-derived antibiotics

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]

Etiology of normal anion gap metabolic acidosis
Mechanism	Causes
Loss of bicarbonate (negative urine anion gap)	Diarrhea GI fistulas (e.g., biliary or pancreatic fistula) Toluene ingestion Medications (e.g., carbonic anhydrase inhibitors such as acetazolamide, spironolactone) Type 2 renal tubular acidosis
Decreased renal acid excretion (positive urine anion gap)	Hyperchloremia (e.g., due to excess saline infusion, ammonium chloride) Renal failure (early uremic acidosis) Addison disease Renal tubular acidoses: type 1 renal tubular acidosis, type 4 renal tubular acidosis

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

**Urine Anion Gap**
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**Osmolal Gap**
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Created by: QxMD.

Metabolic alkalosis

Approach to metabolic alkalosis [1]

Assess the patient's blood pressure and volume status.
Evaluate for ingestions (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.

Differential diagnosis of metabolic alkalosis

Etiology

Etiology of metabolic alkalosis [1][17]
Mechanism	Causes
Chloride-responsive metabolic alkalosis (urine chloride < 25 mEq/L)	Hypovolemia (e.g., contraction alkalosis ) Gastrointestinal losses: due to vomiting, nasogastric suction, or diarrhea Other: hemorrhage Renal losses: due to loop or thiazide diuretics Cystic fibrosis Dietary chloride deficiency with a high alkali dietary load
Chloride-resistant metabolic alkalosis (urine chloride > 40 mEq/L)	Severe magnesium deficiency Extreme hypercalcemia, hypokalemia High alkali load (e.g., due to antacid use, alkalization therapy) Loop or thiazide diuretics Other (less common causes) Associated with low or normal blood pressure Bartter syndrome Gitelman syndrome Associated with high blood pressure Hyperaldosteronism Cushing syndrome Liddle syndrome Licorice ingestion [18] Ingestions or drugs [17] Laxative abuse Clay ingestion Carbenicillin, ampicillin, penicillin Recovery from starvation Hypoalbuminemia

**Differential diagnosis of metabolic alkalosis**
ABG: arterial blood gas
BMP: basic metabolic panel

© AMBOSS

Respiratory disorders

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).”

Etiology of respiratory acidosis [1]
Mechanism	Causes
Acute respiratory acidosis	Acute lung disease (e.g., pneumonia , pulmonary edema) Acute exacerbation of chronic obstructive airway disease (e.g., COPD, asthma) CNS depression due to: Head trauma Postictal state Drug toxicity (e.g., from opiates, barbiturates, benzodiazepines) Central sleep apnea
Chronic respiratory acidosis	Airway obstruction (e.g., COPD, asthma) Respiratory muscle weakness, e.g., due to: Myasthenia gravis ALS Guillain-Barré syndrome Poliomyelitis Multiple sclerosis Severe hypokalemia

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).”

Etiology of respiratory alkalosis [19]
Mechanism	Causes
Acute respiratory alkalosis	Pulmonary disease (e.g., pneumonia, pulmonary embolism, pulmonary edema, aspiration pneumonitis), interstitial fibrosis Pain, anxiety, panic attacks Fever Drug toxicity (e.g., from salicylate , theophylline, progesterone) CNS infections (e.g., meningitis, encephalitis) Stroke Severe anemia Congestive heart failure Sepsis Hypoxemia (e.g., upon arrival at high altitude) Hyperventilation while on mechanical ventilation
Chronic respiratory alkalosis	Pulmonary embolism during pregnancy Liver failure Hyperthyroidism Brainstem tumor (may cause central neurogenic hyperventilation) Hypoxemia (e.g., after a few days at high altitude)

Gastrointestinal disorders

Acid-base disturbances associated with GI disorders [20][21]
GI disturbance	Acid-base disturbance	Cl^-	K⁺	Na⁺
Severe diarrhea or laxative use	Metabolic acidosis	↑	↓	↑
Prolonged vomiting or nasogastric suctioning	Metabolic alkalosis	↓	↓	↑

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

Treatment

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.”

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