Metabolic acidosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

In medicine, metabolic acidosis is an acid-base imbalance in which the blood pH is low (less than 7.35) due to increased production of H⁺ by the body or the inability of the body to form bicarbonate (HCO₃^–) in the kidney. Its causes are diverse, and its consequences can be serious, including diarrhea, coma and death. Together with respiratory acidosis, it is one of the two general types of acidosis, the other being respiratory acidosis.

A pH under 7.1 is an emergency, due to the risk of cardiac arrhythmias, and may warrant treatment with intravenous bicarbonate. Bicarbonate is given at 50-100 mmol at a time under scrupulous monitoring of the arterial blood gas readings. This intervention however, is not effective in case of lactic acidosis. If the acidosis is particularly severe and/or there may be intoxication, consultation with the nephrology team is considered useful, as dialysis may clear both the intoxication and the acidosis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Metabolic acidosis can be classified as:

• Low anion gap metabolic acidosis
• Normal anion gap metabolic acidosis (Hyperchloremic Acidosis)
• High anion gap metabolic acidosis

Usually the HCO₃^– lost is replaced by a chloride anion, and thus there is a normal anion gap. In normal anion gap acidosis, the increased anion is chloride, which is measured, so the anion gap does not increase. Thus, normal anion gap acidosis is also known as hyperchloremic acidosis. Urine anion gap is useful in evaluating a patient with a normal anion gap.

• An elevated anion gap can coexist with a normal anion gap metabolic acidosis.
• In a single acid-base disorder of elevated anion gap metabolic acidosis, serum bicarbonate (HCO3) will decrease by the same amount that the anion gap increases.
• However, a situation in which the anion gap increases less and serum bicarbonate decreases significantly indicates that there is another metabolic acidosis present, which is decreasing the the serum bicarbonate, but not affecting the anion gap i.e. normal anion gap metabolic acidosis is also present.
• Thus, it is advised to compare the changes in the anion gap with the changes in the serum bicarbonate.
• This is often referred as the delta-delta equation, or the corrected bicarbonate equation.
• Delta-Delta equation: Change in anion gap = Change in bicarbonate

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Metabolic acidosis is the state of low blood pH that can result from:

• Failure of the kidneys to excrete H+
• Increased H+ load
• Loss of bicarbonate

Shown below is a table summarizing the mechanisms of metabolic acidosis.

High anion gap metabolic acidosis can be caused by one of the following:

• Lactic acidodis
• Ketoacidosis
• Renal failure
• Ingestions

Metabolic acidosis is either due to increased generation of acid or an inability to generate sufficient bicarbonate. The body regulates the acidity of the blood by four buffering mechanisms.

• Bicarbonate buffering system
• Intracellular buffering by absorption of hydrogen atoms by various molecules, including proteins, phosphates and carbonate in bone.
• Respiratory compensation
• Renal compensation

• For 1 meq/L fall of serum HCO3 levels there is a 1.2 mmHg fall in arterial pCO2.
• The respiratory compensation of metabolic acidosis is fast and begins within half an hour of metabolic acidosis.
• In cases where the metabolic acidosis develops slowly, the respiratory compensation occurs simultaneously with the metabolic acidosis.
• The respiratory compensation usually completes within 12 to 24 hours
• A failure to develop adequate respiratory response indicates an acute underlying respiratory disease, neurologic disease or a very acute development of metabolic acidosis.
• Formula for checking appropriate respiratory compensation to metabolic acidosis include:
  • Arterial pCO2 = 1.5 x serum HCO3^– + 8 ± 2 (Winters’ formula)
  • Arterial pCO2 = Serum HCO3 + 15

• A urine anion gap helps to differentiate renal tubular acidosis (specifically a Type 1 or Type 4 RTA) from other causes of normal anion gap acidosis.
• The urine anion gap is calculated as the urine sodium plus urine potassium, minus the urine chloride
• Urine anion gap = (Urine Na + Urine K) – Urine Cl
• The pathophysiology behind this is:
  • When the kidney is exposed to acidosis, the normal response of the kidney is to excrete acid.
  • Kidney excretes the excess acid in the form of ammonium, NH4+.
  • To maintain neutrality, Cl- is excreted along with ammonium, NH4+.
  • Thus, urine chloride acts as a surrogate marker for urine ammonium (acidosis)
  • In Types 1 and 4 renal tubular acidosis, the kidney’s function of acid excretion is compromised (decreased excretion of NH4+ and Cl).
  • Thus, in renal tubular acidosis (specifically a Type 1 or Type 4 RTA) urine anion gap will be high (> than zero).
  • A urine anion gap less than zero in the normal anion gap metabolic acidosis suggests the kidney is excreting acid, making renal tubular acidosis less likely.

• Methanol, ethylene glycol, isopropyl alcohol, toluene are osmotically active substances.
• The estimated serum osmolality should be close to the actual, measured serum osmolality (within 10 points).
• If the measured serum osmolality is much higher (i.e. >10 points) than the estimated serum osmolality then presence of osmotically active substances should be suspected.
• They can be differentiated because of these following characteristics:
  • Methanol
    • Also called wood alcohol
    • Used in antifreeze and solvents
    • Presentation: Delirium, papilledema, and retinal hemorrhages
    • Elevated anion gap metabolic acidosis
  • Ethylene Glycol
    • Used in antifreeze and solvents
    • Presentation: Delirium
    • Elevated anion gap metabolic acidosis
    • Presence of oxalate crystals in urine
  • Isopropyl Alcohol
    • Also called rubbing alcohol
    • No acid-base disorder
    • Metabolism causes increase acetone in the blood
    • Other conditions with elevated acetones in blood are: diabetes, starvation, and isopropyl alcohol.
  • Toluene
    • Initial elevated anion gap followed with normal anion gap
• Estimated serum osmolality = (2 * serum sodium + BUN/2.8 + Glucose/18)

• The decreased bicarbonate that distinguishes metabolic acidosis is therefore due to two separate processes: the buffer (from water and carbon dioxide) and additional renal generation. The buffer reactions are: :H⁺ + HCO₃^– <–> H₂CO₃ <–> CO₂ + H₂O
• The Henderson-Hasselbalch equation mathematically describes the relationship between blood pH and the components of the bicarbonate buffering system:

pH=pKa + log [HCO₃^–]/[CO₂]

Using Henry’s Law, we can say that [CO₂]=0.03xPaCO₂

(PaCO₂ is the pressure of CO₂ in arterial blood)

Adding the other normal values, we get

pH = 6.1 + log (24/0.03×40)

= 6.1 + 1.3

= 7.4

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ogheneochuko Ajari, MB.BS, MS [2]

Metabolic acidosis is a state in which the blood pH is low (less than 7.35) due to an increased blood concentration of H+.

• Diabetic ketoacidosis
• Ethylene Glycol poisoning
• Lactic acidosis
• Methanol

The mnemonic for the most common causes of a normal-anion gap metabolic acidosis is “DURHAM.”

• D– Diarrhea

• U– Ureteral diversion

• R– Renal tubular acidosis

• H– Hyperalimentation

• A– Addison’s disease, acetazolamide, ammonium chloride

• M– Miscellaneous (congenital chloride diarrhea, amphotericin B, toluene

The mnemonic “MUDPILES” is used to remember the causes of a high anion gap.

• M – Methanol/Metformin
  
• U – Uremia
  
• D – Diabetic ketoacidosis
  
• P – Paraldehyde/Propylene glycol
  
• I – Infection/Ischemia/Isoniazid
  
• L – Lactate
  
• E – Ethylene glycol/Ethanol
  
• S – Salicylates/Starvation

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]

Metabolic acidosis is occured in different situations such as poisoning, ketoacidosis, renal, gastrointestinal, cardiac, endocrine, and systemic diseases. 

Differential diagnosis of metabolic acidosis is as follow:^[1][2][3][4]

To review differential diagnosis of high anion gap metabolic acidosis, click here.

To review differential diagnosis of high osmolar gap metabolic acidosis, click here.

To review differential diagnosis of metabolic acidosis and lactic acidosis, click here.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Most studies only had serum bicarbonate concentrations available and defined metabolic acidosis using the bicarbonate levels as standard. At time no meaningful contribution of respiratory system was considered in metabolic acidosis. Most epidemiologic studies have measured serum bicarbonate using an autoanalyzer using either an electrode-based or enzymatic method. The specimens are often shipped to a central laboratory by air to minimize assay variability. Scientists found that there was a difference in the bicarbonate levels between measurement of blood at a local laboratory and those shipped to a central laboratory. Bicarbonate measured at a central laboratory was always lower than that measured at a local laboratory. Then it was hypothesized that it is due to potential gas leak from a different atmospheric pressure during air travel. The time that samples were exposed to air in commercial laboratories also contributed to the variability in bicarbonate values. There are few studies that measured arterialized venous blood gas. For sampling, The patient’s hand or wrist have been placed in a warmer set to 42°C for a minimum of 15 minutes for Arterialized venous blood gas samples. As it provides a full assessment of acid-base status and is usually measured at the point of care, thus eliminating the errors that might have occurred during specimen transport. Due to cumbersome method of obtaining arterial blood gas sample, arterialized venous blood gas is often used for research purpose.^[1][2][3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Prognosis and recovery of Metabolic Acidosis is dependent on the causative factor. Appropriate and timely treatment takes time but help in recovery. Some people totally recover from Metabolic Acidosis whereas others may develop

• Cardiovascular System: Decrease contractility, Arterial vasodilatation, Decrease Mean Arterial Pressure, Decrease Cardiac Output, Decrease response to Catecholamine, Increase risk of arrhythmias
• Respiratory System: Hyperventilation(compensatory), Decrease Respiratory Muscle Strength, Metabolic Acidosis Increase Potassium(Due to H+/K+ pump exchanging excess H+ with Intracellular K+)
• Neurological: Altered Mental Status, lethargy

• Multiple organ dysfunction
• Renal System: Renal failure, Kidney stones
• Musculoskeletal: Bone disease, delayed growth
• severe acidosis can also result in shock and rarely death
• Glucose tolerance can be impaired because of interference with the actions of insulin
• predisposes patients to amyloidosis because of production Beta 2 micro globulins.

COMPLICATIONS FROM USE OF BICARBONATES:

Caution with bicarbonate therapy is indicated because of its potential complications, including the following:

• Volume overload
• Hypokalemia
• CNS acidosis
• Hypercapnia
• Tissue hypoxia via leftward shift of hemoglobin-oxygen dissociation curve
• Alkali stimulation of organic acidosis (lactate)
• Overshoot alkalosis

PROGNOSIS:

The prognosis is directly related to the underlying etiology and the ability to treat or correct that particular disorder.

• A study in 2016 indicated that in patients undergoing renal replacement therapy, an association exists between uncorrected severe metabolic acidosis (serum bicarbonate concentrations of below 20 mmol/L) and a 10-year risk for coronary heart disease of over 20%, as well as a high overall mortality rate.^[1]
• A study in 2017 indicated that a high rate of metabolic acidosis occurs in kidney transplant recipients; a low serum total CO₂ concentration (< 22 mmol/L) was found in about 30-70% of such patients with an estimated glomerular filtration rate of under 30 mL/min per 1.73 m². The study also found evidence that metabolic acidosis may increase the likelihood of mortality in kidney transplant recipients^[2] and graft failure.
• In a study of emergency department patients with acute kidney injury, metabolic acidosis is independently associated with mortality, along with sex, age over 60 years, blood urea nitrogen (BUN) concentration, hyperkalemia, cause of renal failure, and type of renal failure. ^[3]

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