Metabolic Acidosis

The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. This daily load comes primarily from anaerobic metabolism, absorption of acids, and excretion of bases from the GI system. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3, or ingestion of toxic alcohols. Respiratory compensation occurs very quickly (within minutes) and mitigates changes in pH. In the acute period, metabolic disorders can cause severe symptoms. Management is aimed at correcting the underlying etiology.

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Metabolic acidosis is the process that results in the gain of hydrogen ions (H+) or the loss of HCO3. In primary metabolic acidosis, arterial blood gas will show:

  • pH < 7.4
  • HCO3 < 24 mEq/L
  • Partial pressure of arterial CO2 (PCO2) < 40 mm Hg


  • Ketoacidosis
  • Lactic acidosis
  • Diarrhea
  • CKD
  • Renal tubular acidosis
  • Toxic alcohols: methanol, ethylene glycol
  • Medications:
    • Aspirin poisoning
    • Chronic acetaminophen use
    • Carbonic anhydrase inhibitors
  • Dilutional acidosis

Acid-base Review

Acid-base disorders are classified according to the primary disturbance (respiratory or metabolic) and the presence or absence of compensation.

Identifying the primary disturbance

Consider pH, PCO2, and HCO3 to determine the primary disturbance. 

  • Normal values:
    • pH: 7.35–7.45
    • PCO2: 35–45 mm Hg
    • HCO3: 22–28 mEq/L
  • Difference between “-emia” and “-osis”:
    • The suffix “-emia” refers to “in the blood”:
      • Acidemia: more H+ in the blood = pH < 7.35
      • Alkalemia: more hydroxide ions (OH) in the blood = pH > 7.45 
    • The suffix “-osis” refers to a process:
      • Acidosis and alkalosis refer to the processes that cause acidemia and alkalemia, respectively. 
      • Blood pH may be normal in acidosis and alkalosis.
  • Primary (uncompensated) respiratory disorders: 
    • Disorders caused by abnormalities in PCO2
    • Both pH and PCO2 are abnormal, in opposite directions
    • Primary respiratory acidosis: pH < 7.35 and PCO2 > 45
    • Primary respiratory alkalosis: pH > 7.45 and PCO2 < 35
  • Primary (uncompensated) metabolic disorders: 
    • Disorders caused by abnormalities in HCO3 
    • Both pH and PCO2 are abnormal, in same direction
    • Primary uncompensated metabolic acidosis:
      • pH < 7.35 and PCO2 < 40 
      • Think: “So the acidosis is not due to ↑ CO2; it must be due to ↓ serum HCO3” → metabolic acidosis
      • Confirm by looking at HCO3: will be low (< 22 mEq/L)
    • Primary uncompensated metabolic alkalosis: 
      • pH > 7.45 and PCO2 > 40
      • Think: “So the alkalosis is not due to ↓ CO2; it must be due to ↑ serum HCO3” → metabolic alkalosis
      • Confirm by looking at HCO3: will be high (> 28 mEq/L)
  • Simple disorders:
    • Presence of any 1 of the above disorders with appropriate compensation
    • Respiratory disorders are compensated by renal mechanisms.
    • Metabolic disorders are compensated by respiratory mechanisms.
  • Mixed disorders: presence of 2 primary disorders


When a patient develops acidosis or alkalosis, the body will try to compensate. Oftentimes, compensation will result in normal pH.

  • In primary metabolic acid-base disorders, the lungs may try to compensate in an attempt to normalize the pH.
    • Lungs respond to metabolic acidosis by ↑ ventilation
    • Lungs respond to metabolic alkalosis by ↓ ventilation
  • Interpreting serum HCO3 levels:
    • Normal range: 22–28 mEq/L
    • ↑ HCO3 is due to either:
      • Metabolic alkalosis, or
      • Compensated chronic respiratory acidosis
    • ↓ HCO3 is due to either:
      • Metabolic acidosis, or
      • Compensated chronic respiratory alkalosis



Metabolic acidosis is caused by 1 of 3 primary processes, namely, an increase in acid production, a loss of base, or impaired acid excretion.

  • ↑ Acid production:
    • Lactic acidosis: 
      • Tissue hypoxia causes a shift from aerobic to anaerobic metabolism → lactic acid produced from glycolysis
      • Usually due to shock or sepsis
    • Ketoacidosis:
      • Abnormal glucose metabolism → reliance on ketosis for energy
      • Due to uncontrolled diabetes, alcohol abuse, and/or starvation
    • Toxic alcohols:
      • Methanol (found in improperly made alcohol, “moonshine”) → converted to formic acid in the body (leads to blindness)
      • Ethylene glycol (a component of antifreeze) → converted to glycolic and oxalic acids in the body (leads to AKI)
    • Medications:
      • Aspirin overdose
      • Chronic acetaminophen use
  • Impaired H+ excretion:
    • Renal tubular acidosis type 1
    • Renal tubular acidosis type 4 
    • Renal failure/ ↓ glomerular filtration: leads to a build-up of multiple acids
  • Loss of HCO3:
    • Diarrhea: 
      • Direct loss of HCO3 in stool
      • Direct loss of potential HCO3 (e.g., propionate, butyrate) in stool
    • Urine exposure to GI mucosa:
      • Examples: surgical connection between ureters and GI tract, creation of a replacement urinary bladder using GI mucosa 
      • H+ in urine is reabsorbed by the GI mucosa.
      • HCO3 is not reabsorbed by GI mucosa → lost in stool
    • Renal tubular acidosis type 2:
      • Impaired proximal tubule HCO3 reabsorption → HCO3 lost in urine
      • Also known as proximal renal tubular acidosis
    • Carbonic anhydrase inhibitors:
      • Impairs proximal tubule HCO3 reabsorption → HCO3 lost in urine
      • Examples: acetazolamide, topiramate 
  • Dilutional acidosis:
    • Due to excessive administration of 0.9% NaCl
    • 0.9% NaCl has a pH of 5.5, Cl concentration of 154 mmol/L, and no HCO3.
    • Does not occur with balanced crystalloids (e.g., lactated Ringer’s solution or Plasma-Lyte)
Relationship between plasma pH and plasma HCO3- in uncompensated metabolic acidosis

Relationship between plasma pH and plasma HCO3in uncompensated metabolic acidosis (1):
Notice how the decrease in HCO3moves along the PCO2.

Image by Lecturio.

Respiratory compensation

Compensatory respiratory alkalosis occurs in response to metabolic acidosis.

  • Hyperventilation → ↑ alveolar ventilation→ ↓ PCO2 → ↑ pH
  • Process is relatively fast:
    • Begins within minutes
    • Full effect is seen within 24 hours.
    • Due to the speed of compensation, the degree of compensation is not used to differentiate acute versus chronic metabolic acidosis.
  • Change in PaCO2 can be estimated by the following:
    • PCO2 = serum HCO3 + 15
    • PCO2 = decimal portion of pH (e.g., pH 7.3 would predict a PCO2 of 30)
    • The lowest possible PCO2 from respiratory compensation is 8–12 mm Hg.
Respiratory compensation of metabolic acidosis

Respiratory compensation of metabolic acidosis:
As PCO2 decreases, the curve shifts down and to the right along the “blood-buffer line” (2). As the curve shifts, the pH increases toward normal.

Image by Lecturio.

Clinical Presentation

The clinical presentation depends on the underlying etiology. Symptoms may include:

  • Kussmaul respirations (slow, deep breathing)
  • Diarrhea
  • Ketoacidosis:
    • Polyuria
    • Polydipsia
    • Epigastric pain
    • Vomiting
  • Renal failure:
    • Nocturia
    • Polyuria
    • Pruritis
  • Methanol poisoning: visual symptoms (photophobia, scotomata, blindness)
  • Salicylate overdose: 
    • Tinnitus
    • Blurred vision
    • Vertigo

Diagnosis and Management

Metabolic acidosis has a long list of potential etiologies, many of which can be present concurrently. The concepts of anion gap (AG) and osmolal gap are helpful when the diagnosis is not evident from history alone. 

Anion gap

The AG can be used to narrow the differential diagnosis.

  • Under normal conditions in the blood: total cations = total anions
    • Major cations: Na+ and K+ (others are negligible)
    • Major anions: Cl and HCO3; however:
      • Other anions are also significant (primarily albumin).
      • These “unmeasured anions” account for the AG.
  • AG = (Na+ + K+) – (HCO3 + Cl)
    • Some sources will omit the K+ (i.e., AG = Na+ – (HCO3 + Cl)).
    • Normal AG: 8–16 mEq/L: 
      • The normal range is 4–12 mEq/L if K+ is not included.
      • Either may differ slightly depending on the lab’s reference range.
  • Cl levels: differ between AG and non-AG acidosis
    • No change in AG acidosis
    • Compensatory rise in Cl in non-AG acidosis 
      • ↑ Cl keeps AG within normal range
      • Also known as “hyperchloremic metabolic acidosis
  • AG is useful for categorizing (and assisting in the diagnosis of) common etiologies.
Components of the anion gap

Components of the anion gap

Image by Lecturio.
Table: Differential diagnosis of metabolic acidosis according to anion gap
Increased anion gap
  • Ketoacidosis:
    • Diabetes mellitus
    • Starvation
  • Lactic acidosis
  • Severe CKD (GFR < 15–20 mL/min)
  • Toxic alcohols (methanol, ethylene glycol)
  • Aspirin poisoning
  • Chronic acetaminophen use
Normal anion gap (hyperchloremic)
  • Diarrhea
  • Renal tubular acidosis (all types)
  • Moderate CKD (GFR 20–50 mL/min)
  • Addison’s disease (adrenal insufficiency)
  • Dilutional acidosis
  • Carbonic anhydrase inhibitors

Osmolal gap

  • Used to determine if AG acidosis is due to toxic alcohols:
    • Only necessary to calculate if AG is elevated
    • Toxic alcohols increase plasma osmolality significantly.
  • Osmolal gap = calculated plasma osmolality – measured plasma osmolality:
    • Plasma osmolality = 2(Na+) + (BUN/2.8) + (glucose/18) + (ethanol/4.6)
    • Ethanol is often included due to common concurrent intoxication. 
  • The normal osmolal gap is ≤ 10.
  • Osmolal gap > 25 is very specific for toxic alcohol poisoning.


  • Directed at correcting the underlying etiology (e.g., give insulin and correct fluid and electrolyte abnormalities in ketoacidosis)
  • Consider giving HCO3 if:
    • Acidosis is severe (e.g., < 7.1).
    • The patient has severe kidney injury.

Clinical Relevance

  • Diabetic ketoacidosis (DKA): a complication of uncontrolled diabetes mellitus, which follows a characteristic pattern of metabolic acidosis. Initially, the AG rises as ketoacids accumulate. Ketoacids are a source of potential HCO3 and are lost in the urine during DKA. Treatment with insulin results in the conversion of the remaining ketoacids back into HCO3. The AG normalizes as the ketoacids are no longer present; however, there is a total deficit in HCO3 due to the previous ketonuria. Large volumes of 0.9% NaCl are routinely given during the treatment of DKA, which also contributes to non-AG metabolic acidosis.
  • Chronic renal failure: metabolic acidosis is a characteristic feature of CKD. Non-AG metabolic acidosis occurs when the GFR is < 50 mL/min, and changes to elevated AG acidosis when the GFR is < 20 mL/min. The underlying mechanisms are incompletely understood; however, the increased AG in severe CKD is in part due to the accumulation of titratable acids (e.g., phosphate, urate).
  • Aspirin toxicity: a relatively common poisoning with a characteristic mixed acid-base disorder, including respiratory alkalosis and metabolic acidosis. Aspirin causes direct stimulation of the respiratory drive, which results in primary respiratory alkalosis. Salicylic acid causes the accumulation of lactic acid and a primary increase in AG metabolic acidosis.
  • Licorice acidosis: ingestion of significant amounts of licorice can result in metabolic alkalosis due to excessive mineralocorticoid activity. Glycyrrhetinic acid in licorice inhibits 11-beta-hydroxysteroid dehydrogenase-2, which converts cortisol to cortisone. Cortisol, which can also bind to mineralocorticoid receptors, accumulates and is responsible for metabolic alkalosis, hypokalemia, and hypertension.
  • Renal tubular acidosis: a type of non-AG metabolic acidosis caused by the inability of the renal tubules to excrete H+ due to impaired acid secretion in the distal tubules (type I), impaired HCO3 reabsorption in the proximal tubules (type II), or impaired aldosterone release or response (type IV).


  1. Boyer, E.W., Weibrecht, K.W. (2020). Salicylate (aspirin) poisoning in adults. UpToDate. Retrieved April 2, 2021, from
  2. Emmett, M., Palmer, B.F. (2020). Acid-base and electrolyte abnormalities with diarrhea. UpToDate. Retrieved April 2, 2021, from
  3. Emmett, M., Szerlip, H. (2020). Approach to the adult with metabolic acidosis. UpToDate. Retrieved April 2, 2021, from 
  4. Sivilotti, M.L.A. (2020). Methanol and ethylene glycol poisoning: Pharmacology, clinical manifestations, and diagnosis. UpToDate. Retrieved April 2, 2021, from

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