What is metabolic alkalosis?

Metabolic alkalosis is an abnormal increase in the pH of tissues in the body. Among these tissues, the blood and – consequently – the urine are particularly affected.

Note: If specifically referred to the blood, the excessive increase in pH is better defined as alkalemia (blood pH > 7.40).
Metabolic alkalosis is an acid-base disorder frequently encountered in hospitalized patients, especially those in critical care, and is often complicated by mixed acid-base disorders (we will better understand what this is later).

This disorder can have serious clinical consequences, particularly on the cardiovascular and central nervous systems. The level of severity is in part determined by the effectiveness/efficiency of the body’s compensation system.
Underlying metabolic alkalosis is a complex hydro-saline disturbance, upon which the onset of the acid-base disorder depends.

Metabolic alkalosis may have different etiologic causes, which feed off each other and worsen the condition. Since the resolution of the acid-base disorder depends on the correction of these factors, it is essential to know the specific mechanisms in order to undertake the most appropriate therapeutic action.

Symptoms

Symptoms of metabolic alkalosis

The main symptoms of metabolic alkalosis, mainly related to alkalemia, are:

  • incoercible vomiting
  • Dehydration
  • Confusion
  • Astenia

Cause

Primary causes
The direct mechanism of metabolic alkalosis is the alteration of blood pH; this occurs primarily by:

  • Loss of hydrogen ions (H+), which exert an acidic function, and consequent increase of bicarbonate [hydrogenobicarbonate ions (HCO3-)], which exert an alkaline function
  • Independent increase in bicarbonate

The causes of these imbalances can be divided into two categories, depending on the level of measurable chloride in the urine.

Chloride-responsive (chloride in the urine.

  • Loss of hydrogen ions: occurs predominantly through two mechanisms, vomiting and renal filtration.
  • Vomiting causes loss of hydrochloric acid (hydrogen and chloride ions) contained in the stomach.
  • Severe vomiting also causes loss of potassium (hypokalemia) and sodium (hyponatremia). The kidneys compensate for these losses by keeping sodium in the collecting ducts at the expense of hydrogen ions (sparing the sodium/potassium pumps to prevent further potassium loss), however, leading to metabolic alkalosis.
  • Congenital chloride diarrhea: a very rare cause, because diarrhea is more likely to cause acidosis instead of alkalosis.
  • Contraction alkalosis: caused by loss of water in extracellular spaces, such as due to systemic dehydration. The reduction in extracellular volumes triggers the renin-angiotensin-aldosterone system, and aldosterone subsequently stimulates sodium (hence water) reabsorption within the nephron of the kidney. However, aldosterone is also responsible for stimulating the renal excretion of hydrogen ions (by retaining bicarbonate), and it is this loss that raises the pH of the blood.
  • Diuretic therapy: loop diuretics and thiazide drugs may initially cause chloride to rise, but once deposits are depleted, urine excretion will be lower
  • Post-hypercapnia: hypoventilation (decreased respiratory rate) causes hypercapnia (increased CO2), which consequently causes respiratory acidosis. Renal compensation, which involves the release of large amounts of bicarbonate, is necessary to reduce the effect of acidosis. Once carbon dioxide levels return to normal, excess bicarbonate persists, inducing what is known as metabolic alkalosis.
  • Cystic fibrosis: excessive loss of sodium chloride with sweat leads to contraction of extracellular volumes (analogous to contraction alkalosis) and chloride depletion.

Chloride-resistant (chloride in urine > 20 mEq/L)

  • Bicarbonate retention: bicarbonate retention can result in alkalosis.
  • Displacement of hydrogen ions into the intracellular space: this is the same process described in hypokalemia. Because of the low concentration in the extracellular space, potassium moves into the cells. In order to maintain electrical neutrality, hydrogen also follows the same path, consequently increasing the pH of the blood.
  • Alkalizing agents: alkalizing agents, such as bicarbonate (given in cases of peptic ulcer or hyperacidity) and antacids, in excessive doses can lead to alkalosis.
  • Hyperaldosteronism: an excess of aldosterone (typical of Conn’s syndrome – adrenal adenoma) results in the loss of hydrogen ions in the urine by increasing the activity of the sodium-hydrogen exchange protein in the kidney. This increases the retention of sodium ions as hydrogen ions are pumped into the renal tubule. Excess sodium increases extracellular volume and the loss of hydrogen ions creates metabolic alkalosis. Subsequently, the kidney responds by excreting aldosterone in order to excrete sodium and chloride in the urine.
  • Excessive consumption of Glycyrrhizin (active ingredient of licorice extract)
  • Bartter syndrome and Gitelman syndrome, two diseases with similar treatments consisting of the coupling of diuretics even in normotensive patients.
  • Liddle syndrome: a function mutation in the genes encoding for the epithelial sodium channel (ENaC) characterized by hypertension and hypoaldosteronism.
  • 11β-hydroxylase and 17α-hydroxylase deficiency: both characterized by hypertension.
  • Aminoglycoside toxicity can induce hypokalemic metabolic alkalosis through activation of the receptor for calcium in the ascending tract of the nephron, inactivating the NKCC2 cotransporter, in a manner similar to Bartter’s.

Clinical Causes

NaCl-sensitive (with volume contraction)

  • Vomiting
  • Nose-gastric probe
  • Diuretic therapy
  • Post-ipercapnia
  • Chlorine-dispersant hysteropathies

NaCl-resistant (with volume expansion)

  • Primary hyperaldosteronism
  • Cushing’s Syndrome
  • Exogenous steroids or drugs with mineralocorticoid activity
  • Secondary hyperaldosteronism (renal artery stenosis, accelerated hypertension, renin-secreting tumors)
  • Adrenal 11- or 12-hydroxylase deficiency
  • Liddle Syndrome

Alkaline administration or ingestion

  • Milk Alkaline Syndrome
  • Oral or parenteral HCO3- in renal failure
  • Conversion of HCO3- precursors after organic acidosis

Diverse

  • Rialimentation after fasting
  • Hypercalcemia with secondary hyperparathyroidism
  • High-dose penicillins
  • Severe K+ or Mg++ deficiency
  • Bartter’s disease

Compensation

Physiological compensation of metabolic alkalosis

In its pure form, metabolic alkalosis manifests as alkalemia and subsequent alveolar hypoventilation (reduction in respiratory rate). This is aimed at increasing the carbon dioxide pressure (PaCO2) in the arteries, which in turn is required for the formation of carbonic acid, which is essential to control pH change. Normally, arterial PaCO2 increases by 0.5-0.7 mmHg for every 1 mEq/L of plasma bicarbonate and is very rapid.
Respiratory compensation, however, is an incomplete reaction. Hydrogen reduction suppresses peripheral chemoreceptors sensitive to pH change. Increased pCO2 (caused by hypoventilation) can stimulate compensatory action by central chemoreceptors, which are very sensitive to the change in partial pressure of carbon dioxide in the cerebrospinal fluid. Precisely because of this reaction, the respiratory rate may increase again.
Renal compensation of metabolic alkalosis is less effective than respiratory compensation and consists of increased excretion of bicarbonate, exceeding the ability of the renal tubule to reabsorb it.

Diagnosis

Diagnosis of metabolic alkalosis

Blood test: electrolyte and gas dosage

Once the typical symptoms of metabolic alkalosis are recognized, the actual diagnosis is made by measuring the concentration of electrolytes and gases dissolved in arterial blood. Among these, the level of HCO3- is particularly important, as it tends to increase significantly. However, it is necessary to remember that the increase in blood bicarbonate is not a prerogative of metabolic alkalosis; on the contrary, it also occurs in the compensatory response to primary respiratory acidosis.

We might define that if the HCO3- concentration reaches or exceeds 35 mEq/L, there is a very high probability that it is metabolic alkalosis.

Differential diagnosis: urinalysis

When the etiology of metabolic alkalosis is uncertain and drug use or hypertension are suspected, other tests may be necessary. First of all the dosage of chloride ions (Cl-) in urine and the calculation of the gap referred to the concentration of serum anions. This last parameter is fundamental to differentiate primary metabolic alkalosis from the compensation of respiratory acidosis.

Consequences

Clinical Consequences

The clinical consequences of metabolic alkalosis are:

  • Cardiovascular
  • Arterial constriction
  • Diminution of coronary flow
  • Lowering of anginal threshold
  • Superventricular and ventricular arrhythmias
  • Respiratory
  • Hypoventilation, hypercapnia, hypoxemia
  • Metabolic
  • Stimulation of anaerobic glycolysis
  • Hypokalemia
  • Diminution of the ionized fraction of calcemia
  • Hypomagnesemia and hypophosphatemia
  • Central Nervous System
  • Diminished cerebral flow
  • Tetany, seizures, lethargy, delirium, stuporous state.

Complications

If, for the reasons we will see below, the physiological reactions are not effective or efficient enough, the risk of so-called mixed acid-base disorders increases. For example, if the increase in arterial PaCO2 is greater than 0.7 per 1 mEq/L of plasma bicarbonate, the condition of metabolic alkalosis may arise in association with primary respiratory acidosis. Similarly, if the increase in PaCO2 is less, primary respiratory alkalosis occurs in addition to metabolic alkalosis.

Therapy

The management of metabolic alkalosis depends primarily on the etiology and condition of the individual. In some cases, it is necessary to intervene directly on the alkalosis by injecting an intravenous solution with an acid pH into the blood.