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Metabolic Acidosis

The renal system is responsible for eliminating the daily load of non-volatile acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance, which is approximately 70 millimoles per day. This daily load comes primarily from anaerobic metabolism, absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance, and excretion of bases Bases Usually a hydroxide of lithium, sodium, potassium, rubidium or cesium, but also the carbonates of these metals, ammonia, and the amines. Acid-Base Balance from the GI system. Metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis occurs when there is an increase in the levels of new non-volatile acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Respiratory compensation Compensation Respiratory Acidosis occurs very quickly (within minutes) and mitigates changes in pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance. In the acute period, metabolic disorders can cause severe symptoms. Management is aimed at correcting the underlying etiology.

Last updated: Dec 12, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Definition

Metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis is the process that results in the gain of hydrogen ions (H+) or the loss of HCO3. In primary metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis, arterial blood gas Arterial blood gas Respiratory Alkalosis will show:

  • pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance < 7.4
  • HCO3 < 24 mEq/L
  • Partial pressure Partial pressure The pressure that would be exerted by one component of a mixture of gases if it were present alone in a container. Gas Exchange of arterial CO2 (PCO2) < 40 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma Hg

Etiology

  • Ketoacidosis
  • Lactic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease
  • Renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
  • Toxic alcohols: methanol, ethylene glycol Ethylene glycol A colorless, odorless, viscous dihydroxy alcohol. It has a sweet taste, but is poisonous if ingested. Ethylene glycol is the most important glycol commercially available and is manufactured on a large scale in the United States. It is used as an antifreeze and coolant, in hydraulic fluids, and in the manufacture of low-freezing dynamites and resins. Nephrolithiasis
  • Medications:
    • Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) poisoning
    • Chronic acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen use
    • Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors (CAIs) block the carbonic anhydrase enzymes in the proximal convoluted tubule, inhibiting the reabsorption of sodium bicarbonate (NaHCO3), which results in diuresis and metabolic acidosis. Carbonic Anhydrase Inhibitors
  • Dilutional acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis

Acid-base Review

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

Identifying the primary disturbance

Consider pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance, PCO2, and HCO3 to determine the primary disturbance. 

  • Normal values:
    • pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance: 7.35–7.45
    • PCO2: 35–45 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma Hg
    • HCO3: 22–28 mEq/L
  • Difference between “-emia” and “-osis”:
  • Primary (uncompensated) respiratory disorders:
    • Disorders caused by abnormalities in PCO2
    • Both pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance and PCO2 are abnormal, in opposite directions
    • Primary respiratory acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance < 7.35 and PCO2 > 45
    • Primary respiratory alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis: pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance > 7.45 and PCO2 < 35
  • Primary (uncompensated) metabolic disorders:
    • Disorders caused by abnormalities in HCO3 
    • Both pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance and PCO2 are abnormal, in same direction
    • Primary uncompensated metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis:
      • pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance < 7.35 and PCO2 < 40 
      • Think: “So the acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis is not due to ↑ CO2; it must be due to ↓ serum HCO3” → metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
      • Confirm by looking at HCO3: will be low (< 22 mEq/L)
    • Primary uncompensated metabolic alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis
      • pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance > 7.45 and PCO2 > 40
      • Think: “So the alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis is not due to ↓ CO2; it must be due to ↑ serum HCO3” → metabolic alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory 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 Compensation Respiratory Acidosis
    • Respiratory disorders are compensated by renal mechanisms.
    • Metabolic disorders are compensated by respiratory mechanisms.
  • Mixed disorders: presence of 2 primary disorders

Compensation Compensation Respiratory Acidosis

When a patient develops acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis or alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis, the body will try to compensate. Oftentimes, compensation Compensation Respiratory Acidosis will result in normal pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance.

  • In primary metabolic acid-base disorders, the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy may try to compensate in an attempt to normalize the pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance.
    • Lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy respond to metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis by ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing
    • Lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy respond to metabolic alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis by ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing
  • Interpreting serum HCO3 levels:
    • Normal range: 22–28 mEq/L
    • ↑ HCO3 is due to either:
      • Metabolic alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis, or
      • Compensated chronic respiratory acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
    • ↓ HCO3 is due to either:
      • Metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis, or
      • Compensated chronic respiratory alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis

Pathophysiology

Pathophysiology

Metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory 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 Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
      • Tissue hypoxia Tissue hypoxia Sub-optimal oxygen levels in the ambient air of living organisms. Gas Exchange causes a shift from aerobic to anaerobic metabolism → lactic acid produced from glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis
      • Usually due to shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock or sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock
    • Ketoacidosis:
      • Abnormal glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance metabolism → reliance on ketosis Ketosis A condition characterized by an abnormally elevated concentration of ketone bodies in the blood (acetonemia) or urine (acetonuria). It is a sign of diabetes complication, starvation, alcoholism or a mitochondrial metabolic disturbance (e.g., maple syrup urine disease). Hyperglycemic Crises for energy
      • Due to uncontrolled diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, alcohol abuse, and/or starvation
    • Toxic alcohols:
      • Methanol (found in improperly made alcohol, “moonshine”) → converted to formic acid in the body (leads to blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity)
      • Ethylene glycol Ethylene glycol A colorless, odorless, viscous dihydroxy alcohol. It has a sweet taste, but is poisonous if ingested. Ethylene glycol is the most important glycol commercially available and is manufactured on a large scale in the United States. It is used as an antifreeze and coolant, in hydraulic fluids, and in the manufacture of low-freezing dynamites and resins. Nephrolithiasis (a component of antifreeze) → converted to glycolic and oxalic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance in the body (leads to AKI AKI Acute kidney injury refers to sudden and often reversible loss of renal function, which develops over days or weeks. Azotemia refers to elevated levels of nitrogen-containing substances in the blood that accompany AKI, which include BUN and creatinine. Acute Kidney Injury)
    • Medications:
      • Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) overdose
      • Chronic acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen use
  • Impaired H+ excretion:
    • Renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis type 1 Type 1 Spinal Muscular Atrophy
    • Renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis type 4 Type 4 Spinal Muscular Atrophy 
    • Renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome/ ↓ glomerular filtration Glomerular filtration The kidneys are primarily in charge of the maintenance of water and solute homeostasis through the processes of filtration, reabsorption, secretion, and excretion. Glomerular filtration is the process of converting the systemic blood supply into a filtrate, which will ultimately become the urine. Glomerular Filtration: leads to a build-up of multiple acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance
  • Loss of HCO3:
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. 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 Ureters One of a pair of thick-walled tubes that transports urine from the kidney pelvis to the urinary bladder. Urinary Tract: Anatomy and GI tract, creation of a replacement urinary bladder Bladder A musculomembranous sac along the urinary tract. Urine flows from the kidneys into the bladder via the ureters, and is held there until urination. Pyelonephritis and Perinephric Abscess 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 Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis type 2 Type 2 Spinal Muscular Atrophy:
      • Impaired proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System HCO3 reabsorption → HCO3 lost in urine
      • Also known as proximal renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
    • Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors (CAIs) block the carbonic anhydrase enzymes in the proximal convoluted tubule, inhibiting the reabsorption of sodium bicarbonate (NaHCO3), which results in diuresis and metabolic acidosis. Carbonic Anhydrase Inhibitors:
      • Impairs proximal tubule Proximal tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Tubular System HCO3 reabsorption → HCO3 lost in urine
      • Examples: acetazolamide Acetazolamide One of the carbonic anhydrase inhibitors that is sometimes effective against absence seizures. It is sometimes useful also as an adjunct in the treatment of tonic-clonic, myoclonic, and atonic seizures, particularly in women whose seizures occur or are exacerbated at specific times in the menstrual cycle. However, its usefulness is transient often because of rapid development of tolerance. Its antiepileptic effect may be due to its inhibitory effect on brain carbonic anhydrase, which leads to an increased transneuronal chloride gradient, increased chloride current, and increased inhibition. Carbonic Anhydrase Inhibitors, topiramate Topiramate A sulfamate-substituted fructose analog that was originally identified as a hypoglycemic agent. It is used for the treatment of epilepsy and migraine disorders, and may also promote weight loss. Second-Generation Anticonvulsant Drugs 
  • Dilutional acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis:
    • Due to excessive administration of 0.9% NaCl
    • 0.9% NaCl has a pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance 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 Compensation Respiratory Acidosis

Compensatory respiratory alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis occurs in response to metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis.

  • Hyperventilation Hyperventilation A pulmonary ventilation rate faster than is metabolically necessary for the exchange of gases. It is the result of an increased frequency of breathing, an increased tidal volume, or a combination of both. It causes an excess intake of oxygen and the blowing off of carbon dioxide. Respiratory Alkalosis → ↑ alveolar ventilation Ventilation The total volume of gas inspired or expired per unit of time, usually measured in liters per minute. Ventilation: Mechanics of Breathing→ ↓ PCO2 → ↑ pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance
  • Process is relatively fast:
    • Begins within minutes
    • Full effect is seen within 24 hours.
    • Due to the speed of compensation Compensation Respiratory Acidosis, the degree of compensation Compensation Respiratory Acidosis is not used to differentiate acute versus chronic metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis.
  • Change in PaCO2 can be estimated by the following:
    • PCO2 = serum HCO3 + 15
    • PCO2 = decimal portion of pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance (e.g., pH pH The quantitative measurement of the acidity or basicity of a solution. Acid-Base Balance 7.3 would predict a PCO2 pCO2 Respiratory Acidosis of 30)
    • The lowest possible PCO2 from respiratory compensation Compensation Respiratory Acidosis is 8–12 mm MM Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma 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 Kussmaul respirations Rapid, deep respirations. Hyperglycemic Crises (slow, deep breathing)
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Ketoacidosis:
  • Renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome:
    • Nocturia Nocturia Frequent urination at night that interrupts sleep. It is often associated with outflow obstruction, diabetes mellitus, or bladder inflammation (cystitis). Diabetes Insipidus
    • Polyuria Polyuria Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes. Renal Potassium Regulation
    • Pruritis
  • Methanol poisoning Methanol poisoning Alcohol Use Disorder: visual symptoms ( photophobia Photophobia Abnormal sensitivity to light. This may occur as a manifestation of eye diseases; migraine; subarachnoid hemorrhage; meningitis; and other disorders. Photophobia may also occur in association with depression and other mental disorders. Migraine Headache, scotomata, blindness Blindness The inability to see or the loss or absence of perception of visual stimuli. This condition may be the result of eye diseases; optic nerve diseases; optic chiasm diseases; or brain diseases affecting the visual pathways or occipital lobe. Retinopathy of Prematurity)
  • Salicylate overdose:
    • Tinnitus Tinnitus A nonspecific symptom of hearing disorder characterized by the sensation of buzzing, ringing, clicking, pulsations, and other noises in the ear. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. Cranial Nerve Palsies
    • Blurred vision Vision Ophthalmic Exam
    • Vertigo Vertigo Vertigo is defined as the perceived sensation of rotational motion while remaining still. A very common complaint in primary care and the ER, vertigo is more frequently experienced by women and its prevalence increases with age. Vertigo is classified into peripheral or central based on its etiology. Vertigo

Diagnosis and Management

Metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory 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 Cations Positively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. Electrolytes = total anions Anions Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. Electrolytes
    • Major cations Cations Positively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. Electrolytes: Na+ and K+ (others are negligible)
    • Major anions Anions Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. Electrolytes: Cl and HCO3; however:
      • Other anions Anions Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. Electrolytes are also significant (primarily albumin Albumin Serum albumin from humans. It is an essential carrier of both endogenous substances, such as fatty acids and bilirubin, and of xenobiotics in the blood. Liver Function Tests).
      • These “unmeasured anions Anions Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. Electrolytes” 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 Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
    • No change in AG acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
    • Compensatory rise in Cl in non-AG acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
      • ↑ Cl keeps AG within normal range
      • Also known as “hyperchloremic metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory 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 Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis according to anion gap
Increased anion gap
  • Ketoacidosis:
    • Diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus
    • Starvation
  • Lactic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
  • Severe CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease ( GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests < 15–20 mL/min)
  • Toxic alcohols (methanol, ethylene glycol Ethylene glycol A colorless, odorless, viscous dihydroxy alcohol. It has a sweet taste, but is poisonous if ingested. Ethylene glycol is the most important glycol commercially available and is manufactured on a large scale in the United States. It is used as an antifreeze and coolant, in hydraulic fluids, and in the manufacture of low-freezing dynamites and resins. Nephrolithiasis)
  • Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) poisoning
  • Chronic acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen use
Normal anion gap (hyperchloremic)
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis (all types)
  • Moderate CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease ( GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests 20–50 mL/min)
  • Addison’s disease ( adrenal insufficiency Adrenal Insufficiency Conditions in which the production of adrenal corticosteroids falls below the requirement of the body. Adrenal insufficiency can be caused by defects in the adrenal glands, the pituitary gland, or the hypothalamus. Adrenal Insufficiency and Addison’s Disease)
  • Dilutional acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis
  • Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors Carbonic anhydrase inhibitors (CAIs) block the carbonic anhydrase enzymes in the proximal convoluted tubule, inhibiting the reabsorption of sodium bicarbonate (NaHCO3), which results in diuresis and metabolic acidosis. Carbonic Anhydrase Inhibitors

Osmolal gap

  • Used to determine if AG acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis is due to toxic alcohols:
    • Only necessary to calculate if AG is elevated
    • Toxic alcohols increase plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation significantly.
  • Osmolal gap = calculated plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation – measured plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation:
    • Plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation = 2(Na+) + (BUN/2.8) + ( glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance/18) + ( ethanol Ethanol A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. Ethanol Metabolism/4.6)
    • Ethanol Ethanol A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. Ethanol Metabolism is often included due to common concurrent intoxication. 
  • The normal osmolal gap is ≤ 10.
  • Osmolal gap > 25 is very specific for toxic alcohol poisoning.

Management

  • Directed at correcting the underlying etiology (e.g., give insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin and correct fluid and electrolyte abnormalities in ketoacidosis)
  • Consider giving HCO3 if:
    • Acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis is severe (e.g., < 7.1).
    • The patient has severe kidney injury.

Clinical Relevance

  • Diabetic ketoacidosis Diabetic ketoacidosis A life-threatening complication of diabetes mellitus, primarily of type 1 diabetes mellitus with severe insulin deficiency and extreme hyperglycemia. It is characterized by ketosis; dehydration; and depressed consciousness leading to coma. Hyperglycemic Crises ( DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises): a complication of uncontrolled diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus, which follows a characteristic pattern of metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis. Initially, the AG rises as ketoacids accumulate. Ketoacids are a source of potential HCO3 and are lost in the urine during DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises. Treatment with insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. 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 Ketonuria Hyperglycemic Crises. Large volumes of 0.9% NaCl are routinely given during the treatment of DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises, which also contributes to non-AG metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis.
  • Chronic renal failure Renal failure Conditions in which the kidneys perform below the normal level in the ability to remove wastes, concentrate urine, and maintain electrolyte balance; blood pressure; and calcium metabolism. Renal insufficiency can be classified by the degree of kidney damage (as measured by the level of proteinuria) and reduction in glomerular filtration rate. Crush Syndrome: metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis is a characteristic feature of CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease. Non-AG metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis occurs when the GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests is < 50 mL/min, and changes to elevated AG acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis when the GFR GFR The volume of water filtered out of plasma through glomerular capillary walls into Bowman’s capsules per unit of time. It is considered to be equivalent to inulin clearance. Kidney Function Tests is < 20 mL/min. The underlying mechanisms are incompletely understood; however, the increased AG in severe CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease is in part due to the accumulation of titratable acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance (e.g., phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes, urate).
  • Aspirin toxicity Aspirin Toxicity Nonsteroidal Antiinflammatory Drugs (NSAIDs): a relatively common poisoning with a characteristic mixed acid-base disorder, including respiratory alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis and metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis. Aspirin Aspirin The prototypical analgesic used in the treatment of mild to moderate pain. It has anti-inflammatory and antipyretic properties and acts as an inhibitor of cyclooxygenase which results in the inhibition of the biosynthesis of prostaglandins. Aspirin also inhibits platelet aggregation and is used in the prevention of arterial and venous thrombosis. Nonsteroidal Antiinflammatory Drugs (NSAIDs) causes direct stimulation of the respiratory drive, which results in primary respiratory alkalosis Alkalosis A pathological condition that removes acid or adds base to the body fluids. Respiratory Alkalosis. Salicylic acid causes the accumulation of lactic acid and a primary increase in AG metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis.
  • Renal tubular acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis: a type of non-AG metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory Acidosis caused by the inability of the renal tubules to excrete H+ due to impaired acid secretion Secretion Coagulation Studies in the distal tubules (type I), impaired HCO3 reabsorption in the proximal tubules (type II), or impaired aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia release or response (type IV).

References

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

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