Metabolic alkalosis

Metabolic alkalosis is defined as a disease state that increases the serum bicarbonate concentration (HCO₃^–) above 30 meq/L causing the arterial blood pH to rise into the alkaline range greater than 7.45 secondary to some metabolic process ¹, ². Metabolic alkalosis is a very common disorder in hospitalized patients, especially in ICU settings ³. The incidence of metabolic alkalosis has shown to be 22.5% to 44.7% in inpatient studies in the United States ⁴, ⁵. The pH is a number that shows how acidic or alkaline a substance is. A pH of less than 7 is acidic, and greater than 7 is alkaline. The pH of blood is about 7.4 (a slightly alkaline range of 7.35 to 7.45). Your blood pH is highly stable within a normal range of pH 7.35 to 7.45 and it’s tightly regulated by your kidneys and respiratory system. The primary pH buffering system in the human body is the bicarbonate (HCO₃^–) and carbon dioxide (CO₂). Bicarbonate (HCO₃^–) functions as an alkalotic substance. Carbon dioxide (CO₂) functions as an acidic substance. Therefore, an increase in serum bicarbonate (HCO₃^–) or a decrease in CO₂ (carbon dioxide) will make blood more alkaline. The opposite is also true where decreases in bicarbonate (HCO₃^–) or an increase in carbon dioxide (CO₂) will make blood more acidic. The carbon dioxide (CO₂) levels are physiologically regulated by the pulmonary system through respiration, whereas the serum bicarbonate (HCO₃^–) levels are regulated through your kidneys by two mechanisms: bicarbonate [HCO₃^–] (a base) reclamation mainly in the proximal tubule and bicarbonate [HCO₃^–] (a base) generation predominantly in the distal nephron. Elevated pH above 7.45 and elevated plasma bicarbonate (HCO₃^–) level above 30 meq/L characterize metabolic alkalosis. When bicarbonate (HCO₃^–) is elevated the arterial partial pressure of carbon dioxide (PaCO₂) must also be elevated to maintain pH to its normal range. Therefore with metabolic alkalosis, the compensation is to decrease alveolar ventilation (hypoventilation) in order to increase the arterial partial pressure of carbon dioxide (PaCO₂).

To understand acid-base buffering system, it is important to recall that pH is governed by the ratio bicarbonate [HCO₃^–] (a base)/arterial partial pressure of carbon dioxide (PaCO₂) (an acid). So long as the ratio is normal, pH will be normal.

Normal body functions and metabolism generate large quantities of acids that must be neutralized and/or eliminated to maintain blood pH balance. Most of the acid is carbonic acid (H₂CO₃), which is created from carbon dioxide (CO₂) and water (H₂O). Carbon dioxide (CO₂) is produced as the body uses glucose (sugar) or fat for energy. In its normal state, the body maintains carbon dioxide (arterial partial pressure of carbon dioxide [PaCO₂]) in a well-controlled range from 35 to 45 mm Hg by balancing its production and elimination. Lesser quantities of lactic acid, ketoacids, and other organic acids are also produced.

• Carbon dioxide (CO₂) + water (H₂O) -> H₂CO₃ (carbonic acid) -> HCO₃^– + H⁺

According to the Henderson-Hasselbalch equation (Figure 2), maintaining physiological pH depends on arterial partial pressure of carbon dioxide (PaCO₂), which in turn depends on alveolar ventilation (hypoventilation causes acidosis and hyperventilation causes alkalosis). The kidneys participate in maintaining the stable pH by reabsorption of bicarbonate (3,600 mmol of bicarbonate is filtrated in glomeruli during 24 hour) and excretion of hydrogen ions from nonvolatile acids (including sulfur and phosphate) as titratable acidity (0.3 mmol hydrogen ions/kg/day) and in the form of ammonium ion (0.7 mmol hydrogen ions/kg/day) ⁶, ⁷.

The lungs and kidneys are the major organs involved in regulating blood pH. And to compensate for the metabolic alkalosis, you decrease your breathing rate (hypoventilation) to produce more carbon dioxide (CO₂) ⁸, ⁹.

1. The lungs flush acid out of your body by exhaling carbon dioxide (CO₂). Raising and lowering the respiratory rate alters the amount of carbon dioxide (CO₂) that is breathed out, and this can affect blood pH within minutes ¹⁰.
2. The kidneys excrete acids in the urine, and they regulate the concentration of bicarbonate (HCO3^–, a base) in blood. Acid-base changes due to increases or decreases in bicarbonate [HCO3^–] concentration occur more slowly than changes in carbon dioxide (CO₂), taking hours or days. Bicarbonate (HCO₃^–) reabsorption occurs in the kidneys in every part of the tubules. About 85–90% of the filtered bicarbonate is reabsorbed in the proximal tubules, 10% in the ascending arms of the Henle loop, 6% in the distal tubules, and 4% in the collecting tubules ⁶, ⁷.

Both of these processes are always at work, and they keep the blood pH in healthy people tightly controlled. The absolute quantities of acids or bases are less important than the balance between the two and its effect on blood pH.

Buffering systems that resist changes in pH also contribute to the regulation of acid and base concentrations. The main buffers in blood are hemoglobin (in red blood cells), plasma proteins, carbon dioxide (CO₂), bicarbonate (HCO₃^–) and phosphates.

Carbon dioxide (CO₂) plays a remarkable role in the human body mainly through pH regulation of the blood. The pH is the primary stimulus to initiate ventilation. In its normal state, the body maintains carbon dioxide (CO₂) in a well-controlled range from 38 to 42 mm Hg by balancing its production and elimination. In a state of hypoventilation (breathing that is too shallow or too slow to meet the needs of the body), the body produces more carbon dioxide (CO₂) than it can eliminate, causing a net retention of carbon dioxide (CO₂). The increased carbon dioxide (CO₂) is what leads to an increase in hydrogen ions (H⁺) and a slight increase in bicarbonate (HCO₃^–), as seen by a right shift in the following equilibrium reaction of carbon dioxide:

• Carbon dioxide (CO₂) + water (H₂O) -> H₂CO₃ (carbonic acid) -> HCO₃^– + H⁺

The buffer system created by carbon dioxide consists of the following three molecules in equilibrium: carbon dioxide (CO₂), H₂CO₃ (carbonic acid), and bicarbonate (HCO₃^–). When hydrogen ions (H⁺) is high, bicarbonate (HCO₃^–) buffers the low pH. When hydroxide (OH^–) is high, H₂CO₃ (carbonic acid) buffers the high pH.

Usually metabolic alkalosis indicates an accumulation of “excess” bicarbonate (HCO₃^–). The source of excess bicarbonate (HCO₃^–) can be exogenous, endogenous, or both ¹¹.

Metabolic alkalosis the mechanisms of excess bicarbonate (HCO₃^–) generation ¹¹, ¹², ¹³:

• Increased bicarbonate in the extracellular compartment via ingestion and absorption or infusion of  bicarbonate (HCO₃^–) or alkali (milk-alkali syndrome) or increased parenteral intake of sodium bicarbonate [NaHCO3] or NaHCO3 precursors (i.e., sodium acetate, sodium citrate, sodium gluconate)
• Distal renal tubule bicarbonate (HCO₃^–) generation through enhanced hydrogen ions (H⁺) secretion
  • Diuretic-induced alkalosis—diuretics (loop diuretic and thiazide diuretic) that block sodium and chloride [NaCl] reabsorption or other sodium salts such as sodium sulfate [Na2SO4] or sodium penicillin can cause increased bicarbonate absorption at the proximal tubule leading to increased serum bicarbonate concentration, also called contraction alkalosis.
• Increased renal reabsorption of bicarbonate (HCO₃^–) can also cause metabolic alkalosis (severe hypokalemia or potassium (K⁺) depletion [shifting H⁺ into cells], primary hyperaldosteronism, Cushing syndrome, Bartter syndrome, Gitelman syndrome, toxic ingestion of licorice, excessive chloruretic diuretic use) ¹⁴, ¹⁵, ¹⁶, ¹⁷.
• Excess loss of hydrogen ions (H⁺) via the removal of hydrochloric acid (HCl) from body this occurs primarily due to gastric losses due to prolonged and severe gastric aspiration, nasogastric suction, excessive vomiting of gastric contents as in pyloric stenosis and congenital chloride-rich diarrhea ¹⁸, ¹⁹

Exogenous sources are sodium (Na⁺) or potassium (K⁺) bicarbonate (HCO₃^–) salts (e.g., Sodium bicarbonate [NaHCO3] and Potassium bicarbonate [KHCO3]) or salts of precursors (organic anions such as lactate, acetate or citrate, which generate bicarbonate [HCO₃^–] when completely oxidized). These salts can be ingested/absorbed or infused.

The two potential endogenous sources of large amounts of bicarbonate (HCO₃^–) are:

1. The stomach and
2. The kidneys.

Net endogenous bicarbonate (HCO₃^–) generation requires hydrogen ions (H⁺) removal from the body. Bicarbonate (HCO₃^–) is generated when hydrochloric acid (HCl) is secreted into gastric lumen, but net bicarbonate (HCO₃^–) accumulation in the extracellular fluid (ECF) requires the hydrochloric acid (HCl) to be lost externally, usually as a result of vomiting and/or suction.

Normally, kidney hydrogen ions (H⁺) excretion into the urine (as ammonium [NH4⁺] and/or titratable acid) generates bicarbonate (HCO₃^–) to replace the quantity decomposed by nonvolatile hydrogen ions (H⁺) derived from dietary intake and metabolism and any bicarbonate (HCO₃^–) lost in alkaline stool. To the extent kidney bicarbonate (HCO₃^–) generation exceeds this requirement, “excess” bicarbonate (HCO₃^–) is generated. This generally occurs when the following conditions coexist: (1) the kidney tubules/ducts beyond the early distal tubule are avidly reabsorbing Na+ (for example, aldosterone activity is high), and (2) the delivery of salt and volume to these sites is relatively large.

Urine chloride is a direct measurement of chloride being excreted into urine. This test is useful to help determine the cause of metabolic alkalosis ²⁰, ²¹, ²².

The most common causes of metabolic alkalosis are the use of diuretics (water pills tha help rid your body of sodium and water) and the external loss of gastric hydrochloric acid (HCl) secretions ²³.

Metabolic alkalosis is further divided into 2 main categories ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ²³:

1. Chloride-responsive alkalosis with urine chloride less than 20 mEq/L. Chloride-responsive alkalosis causes include loss of hydrogen via the gastrointestinal tract (vomiting, nasogastric suction), congenital chloride diarrhea syndrome (congenital chloridorrhea), loss of colonic secretions via villous adenoma, contraction alkalosis, diuretic therapy (thiazides and loop diuretics [after discontinuation]), post-hypercapnia syndrome, cystic fibrosis, exogenous alkalotic agent use and laxative abuse are also potential causes.
2. Chloride-resistant alkalosis with urine chloride greater than 20 mEq/L.
   • Causes of chloride-resistant alkalosis (urine chloride > 20 mEq/L) with hypertension include the following:
     • Primary hyperaldosteronism: adrenal adenoma, bilateral adrenal hyperplasia, adrenal carcinoma, glucocorticoid-remediable hyperaldosteronism
     • 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2): 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) normally converts active cortisol to inactive cortisone and protects mineralocorticoid receptor (MR) occupied by cortisol. The Apparent Mineralocorticoid Excess syndrome is an ultrarare autosomal recessive disorder caused by 11β-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) resulting in impairment of the enzyme 11β-HSD2 leading to excessive cortisol that is able to activate mineralocorticoid receptor (MR). The Apparent Mineralocorticoid Excess syndrome is typically characterized by hypertension with hypokalemia, metabolic alkalosis, low renin activity, and low aldosterone level. The cause is inherited in autosomal recessive form, mutations in 11β-HSD2 gene or acquired form by ingestion of competitive inhibitors of 11β-HSD2 such as liquorice, chewing tobacco or carbenoxolone. Uncontrolled hypertension and prolong hypokalemia are the leading causes of end organ damages and cardiovascular mortality ³⁰.
     • Congenital adrenal hyperplasia (CAH) 11-hydroxylase or 17-hydroxylase deficiency
     • Current use of diuretics in hypertension
     • Cushing syndrome
     • Exogenous mineralocorticoids or glucocorticoids
     • Liddle syndrome
     • Renovascular hypertension
   • Causes of chloride-resistant alkalosis (urine chloride >20 mEq/L) without hypertension include the following:
     • Bartter syndrome
     • Gitelman syndrome
     • Severe potassium depletion (hypokalemia)
     • Current use of thiazides and loop diuretics
     • Hypomagnesemia

Other causes include the following:

• Exogenous alkali administration – Sodium bicarbonate therapy in the presence of renal failure, metabolism of lactic acid or ketoacids
• Milk-alkali syndrome
• Hypercalcemia
• Intravenous penicillin
• Refeeding alkalosis
• Massive blood transfusion

The management of metabolic alkalosis depends primarily on the underlying cause and on the patient’s volume status. Managing alkalosis requires an interprofessional team of healthcare professionals, including several physicians in different specialties, laboratory technologists and pharmacists.

Figure 1. Abnormal acid-base compensation

Figure 2. Henderson-Hasselbalch equation

Figure 3. Acid-base buffering system

Hypochloremic metabolic alkalosis

Hypochloremia is defined as a serum chloride level of less than 95 mEq/L. Hypochloremic alkalosis results from either low chloride intake or excessive chloride wasting. Whereas low chloride intake is very uncommon, excessive chloride wasting often occurs in hospitalized children, usually as a result of diuretic therapy or nasogastric tube suctioning ³². Hypochloremic alkalosis is also seen in hypertrophic pyloric stenosis where it occurs in only about half the patients ³³. Diarrhea, when watery is also highly suggestive of chloride-losing diarrhea.

Hypochloremic alkalosis can be classified into two categories ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ²³:

1. Chloride-responsive alkalosis with urine chloride less than 20 mEq/L. Chloride-responsive alkalosis causes include loss of hydrogen via the gastrointestinal tract (vomiting, nasogastric suction), congenital chloride diarrhea syndrome (congenital chloridorrhea), loss of colonic secretions via villous adenoma, contraction alkalosis, diuretic therapy (thiazides and loop diuretics [after discontinuation]), post-hypercapnia syndrome, cystic fibrosis, exogenous alkalotic agent use and laxative abuse are also potential causes.
2. Chloride-resistant alkalosis with urine chloride greater than 20 mEq/L.
   • Causes of chloride-resistant alkalosis (urine chloride > 20 mEq/L) with hypertension include the following:
     • Primary hyperaldosteronism: adrenal adenoma, bilateral adrenal hyperplasia, adrenal carcinoma, glucocorticoid-remediable hyperaldosteronism
     • 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2): 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) normally converts active cortisol to inactive cortisone and protects mineralocorticoid receptor (MR) occupied by cortisol. The Apparent Mineralocorticoid Excess syndrome is an ultrarare autosomal recessive disorder caused by 11β-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) resulting in impairment of the enzyme 11β-HSD2 leading to excessive cortisol that is able to activate mineralocorticoid receptor (MR). The Apparent Mineralocorticoid Excess syndrome is typically characterized by hypertension with hypokalemia, metabolic alkalosis, low renin activity, and low aldosterone level. The cause is inherited in autosomal recessive form, mutations in 11β-HSD2 gene or acquired form by ingestion of competitive inhibitors of 11β-HSD2 such as liquorice, chewing tobacco or carbenoxolone. Uncontrolled hypertension and prolong hypokalemia are the leading causes of end organ damages and cardiovascular mortality ³⁰.
     • Congenital adrenal hyperplasia (CAH) 11-hydroxylase or 17-hydroxylase deficiency
     • Current use of diuretics in hypertension
     • Cushing syndrome
     • Exogenous mineralocorticoids or glucocorticoids
     • Liddle syndrome
     • Renovascular hypertension
   • Causes of chloride-resistant alkalosis (urine chloride >20 mEq/L) without hypertension include the following:
     • Bartter syndrome
     • Gitelman syndrome
     • Severe potassium depletion (hypokalemia)
     • Current use of thiazides and loop diuretics
     • Hypomagnesemia

Replacement of electrolytes with chloride salts is the most important mode of therapy for hypochloremic alkalosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used in patients with Bartter syndrome. Hydrochloric acid (HCl) and carbonic anhydrase inhibitors may be used in some acute situations.

In patients with chloride-losing diarrhea, fluid intake should be encouraged so as to prevent renal damage resulting from recurrent dehydration. Patients or caregivers should be instructed to avoid long periods of exposure to hot climates, which may exacerbate dehydration episodes.

Constipation must be treated in patients with Bartter syndrome. Any intercurrent febrile illnesses, especially urinary tract infections, must be treated to prevent further renal damage.

Figure 3. Hypochloremic metabolic alkalosis diagnostic algorithm

Hypochloremic alkalosis signs and symptoms

Prenatal polyhydramnios is present in most patients with congenital forms of metabolic alkalosis, especially chloride-losing diarrhea. Premature birth resulting from polyhydramnios is common in patients with Bartter syndrome and chloride-losing diarrhea. Lack of meconium is highly suggestive of intrauterine diarrhea. Prolonged neonatal jaundice may be present. A history of hypotonia and lethargy without sepsis is significant in patients with early-onset hypochloremia and hypokalemia.

In infants, a history of repeated vomiting may be suggestive of severe gastroesophageal reflux or pyloric stenosis. Failure to thrive is common. Constipation is very common in patients with Bartter syndrome. Diarrhea, when watery (see the image below), is highly suggestive of Chloride-losing diarrhea.

A salty taste upon being kissed may help identify patients with cystic fibrosis. Guidelines for newborn screening for cystic fibrosis have been established by the Centers of Disease Control and Prevention (CDC) ³⁴. Central nervous system (CNS) dysfunctions (eg, lethargy, confusion, or seizure) are observed in patients with severe alkalosis. Neuromuscular symptoms include weakness and muscle cramps.

Central nervous system (CNS) manifestations range from mild to severe, depending on the severity of alkalosis, and may include the following:

• Confusion
• Apathy
• Disorientation
• Excessive sleeping
• Seizure
• Stupor

Other symptoms (eg, abdominal distention, dry skin, apathy, loss of interests, growth retardation ³⁵ and frequent hospital admissions because of recurrent dehydration) are significant diagnostic clues during childhood.

Other history

A family history may be suggestive. Consanguinity, recurrent prematurity, neonatal demise, and psychomotor retardation are helpful clues to familial conditions.

A psychosocial history may reveal loss of interests and behavioral problems, which were reported in patients with chronic hypochloremic alkalosis. Difficulty in school performance may be a consequence of the disorder.

In hospitalized patients with hypochloremic metabolic alkalosis, the physician should always ask about nasogastric tube suctioning and oral secretions. Overzealous use of loop or thiazide diuretics, especially in the intensive care unit (ICU), is another important factor.

Physical examination

Patients with hypochloremic alkalosis commonly are small for their age, lethargic, or apathetic. Signs of chronic dehydration (eg, skin tenting and poor peripheral perfusion) may be evident upon presentation. One study reported that cystic fibrosis was diagnosed in an infant who presented with dehydration and metabolic alkalosis ³⁶.

Weight and height usually fall below the reference range in patients with chronic disease but are not affected in patients with acute disease. In one series, both weight and height were in the lowest 3% in more than 60% of patients with chloride-losing diarrhea ³⁷.

Depending on the cause of the hypochloremic alkalosis, the abdomen may be scaphoid (in Bartter syndrome) or distended (in chloride-losing diarrhea).

Additional abdominal findings that may be present are as follows:

• Peristaltic waves in children with chloride-losing diarrhea
• Exacerbated bowel sounds in patients with chloride-losing diarrhea
• Hard stools in patients with Bartter syndrome
• Hepatomegaly (suggesting cystic fibrosis)

Musculoskeletal findings include muscle wasting, atrophy, and hypotonia. Respiratory findings include shallow breathing and hypopnea in severely affected children.

Hypochloremic metabolic alkalosis complications

Disease-related complications of hypochloremic alkalosis include the following:

• Nephrocalcinosis and nephrolithiasis in patients with Bartter syndrome and in those with chloride-losing diarrhea
• Coexisting electrolyte abnormalities such as hypokalemia, hyponatremia, and hypercalcemia may be present
• Liver damage and recurrent chest infection leading to hepatic and pulmonary failure, respectively, in patients with cystic fibrosis
• End-stage renal disease (ESRD) in patients with poor compliance; ESRD can occur in all conditions mentioned, including Bartter syndrome and chloride-losing diarrhea

Hypochloremic alkalosis diagnosis

The flowchart in Figure 3 depicts a workup approach to hypochloremic alkalosis.

Laboratory studies

Amniocentesis

Amniotic fluid sodium and chloride concentrations may reflect fetal values; these are high in fetuses with chloride-losing diarrhea. Levels may also be elevated in patients with Bartter syndrome. Although testing for alpha1 -fetoprotein is not routine, levels may be elevated.

Blood workup

Serum electrolyte levels may be within the reference range, especially in neonates and treated patients. However, typical findings include low concentrations of serum chloride, sodium, and potassium. Attention must be paid in interpreting the serum potassium level in relation to the state of metabolic alkalosis. For example, the potassium shift from serum into the intracellular compartment increases as the serum pH rises; thus, the potassium level is less than normal by 0.6 mmol/L when measured at a serum pH of 7.5.

Serum pH and bicarbonate, calcium, uric acid, hemoglobin (if patient is not anemic), renin, and aldosterone levels may be elevated. The serum renin level is exponentially high, in line with secondary hyperaldosteronism due to chronic volume depletion, and this finding is supported by low or normal blood pressure measurements.

Urine and stool studies

In patients with Bartter syndrome, urine chloride, sodium, and potassium concentrations are usually measured. Urine calcium-to-creatinine and uric acid–to–creatinine ratios are usually high. Stool electrolytes cannot be measured because of well-formed or hard stool. Fractional excretion (Fex) studies are more reliable than absolute values. Usually, results are higher than reference range values, as follows:

• Fractional excretion (Fex) sodium concentration >1%
• Fractional excretion (Fex) potassium concentration >35%
• Fractional excretion (Fex) chloride concentration >2.5% (2.7% ± 1.1%)

In patients with chloride-losing diarrhea, urine chloride concentration is very low or undetectable (< 10 mmol/L). Stool is usually watery, and electrolyte studies are very helpful and diagnostic, as follows:

• Stool chloride concentration >100 mmol/L
• Stool sodium and potassium concentrations are elevated
• Stool chloride concentration is greater than stool sodium plus potassium concentrations, which is normally less than either; chloride concentrations are lowest in colonic secretions (usually < 35 mmol/L)
• The ratio of stool chloride to combined sodium and potassium concentrations is greater than 0.6

Patients with cystic fibrosis typically demonstrate high sweat chloride and sodium concentrations. Urine chloride concentration is usually very low, and stools are usually not watery, as they are in patients with chloride-losing diarrhea.

Kidney and liver function tests

• Renal function is usually normal. The glomerular filtration rate (GFR) may be low in patients with severe disease.
• Liver function test results are usually within the reference range in patients with chloride-losing diarrhea and Bartter syndrome but may be deranged in patients with cystic fibrosis.

Genetic studies

DNA diagnosis is available for most congenital disorders that cause hypochloremic metabolic alkalosis. For chloride-losing diarrhea, the chloride-losing diarrhea (SLC26A3) locus is on band 7q22-q31.1 ³⁸. Bartter syndrome is identified by NKCC2, ROMK, and CLCNKB ³⁹; Bartter syndrome with deafness is identified by BSND; and Bartter syndrome with autosomal dominant hypocalcemia is identified by CASR. For cystic fibrosis, the CFTR locus is on band 7q31.2. For Gitelman syndrome, the NCCT locus is on 16q.

Ultrasonography

Prenatal ultrasonography may be useful in the detection of minimal polyhydramnios and assessment of intestinal fluid content, which is increased in patients with chloride-losing diarrhea.

Postnatal ultrasonography (see the images below) may be useful in the evaluation of a fluid-filled bowel, which is characteristically increased in patients with chloride-losing diarrhea. Ultrasonography may also assist in the evaluation of renal echogenicity, nephrocalcinosis, medullary or diffuse calcinosis, and renal growth.

Physiologic study of renal tubules

Physiologic study of renal tubules by performing maximal free water clearance during hypotonic saline diuresis is indicated.

Oral administration of water 20 mL/kg over 30 minutes is followed by administration of a one-half isotonic sodium chloride solution at a rate of 600 mL/m²/h for 2-3 hours. During this time, urine is collected in aliquots over 30-minute periods for 4-6 aliquots.

These samples are sent for evaluation of creatinine, sodium, potassium, and chloride levels, as well as for osmolality, pH, and volume. Usually, urine is diluted by oral administration of water. Halfway through each collection, a blood sample is obtained for evaluation of creatinine, sodium, potassium, and chloride levels, and for pH and osmolality. The clearance of each substance is calculated, and a ratio is derived by means of the following formula:

• Water clearance/(chloride clearance + water clearance)

Usually, the result of this formula reflects the percentage of distal tubule sodium and chloride reabsorption. Normal values are up to 85-90%, which means that the percentage of chloride and sodium excreted should be 10-15% (corrected to a GFR of 100 mL/min/1.73 m²). In patients with Bartter syndrome, the percentage of chloride and sodium excreted can reach 35% or more.

Other studies

Additional studies that may be considered include the following:

• Wrist radiography – This may be performed to determine bone age in infants with growth failure; it may also help assess bone density and the presence of rickets
• Upper gastrointestinal (GI) series – This helps detect gastroesophageal reflux and pyloric stenosis, which are case-dependent conditions ⁴⁰
• Computed tomography (CT) of the brain – This is useful for evaluation of brain growth and calcifications
• Magnetic resonance imaging (MRI) of the brain – This is helpful in patients who present with seizures
• Electroencephalography (EEG) – This is also helpful in patients who present with seizures
• Renal nuclear scanning – This may facilitate assessment of renal function but is not useful in all patients
• Renal biopsy – This is not usually indicated, but if it is performed, it may reveal interstitial fibrosis and calcium/urate crystal deposition

Hypochloremic metabolic alkalosis treatment

Hydration status and electrolyte levels must be assessed. Replacement of electrolytes with chloride salts is the most important mode of therapy for hypochloremic alkalosis. A full nutritional assessment should be obtained, energy intake calculated, and adequate energy intake ensured through oral or nasogastric methods.

Nonsteroidal anti-inflammatory drugs (NSAIDs; eg, indomethacin) are used in patients with Bartter syndrome. Hydrochloric acid (HCl) and carbonic anhydrase inhibitors (eg, acetazolamide) may be used in some acute situations. Potential complications of pharmacotherapy include the following:

• Indomethacin-induced nephrotoxicity
• Acetazolamide treatment compromising respiratory function in children with lung disease

Discharge medication instructions should be clearly written, and a supply sufficiently large to last until the patient is seen in the outpatient clinic should be prescribed.

Acute emergency management (6 hours or less)

Initial management includes assessment of dehydration status and severity of hypochloremia, hypokalemia, hyponatremia, and metabolic alkalosis. If the patient is in shock, treatment should be directed toward aggressive resuscitation with isotonic fluid, preferably normal saline. Blood and urine samples for testing of electrolytes should always be obtained before any form of therapy is initiated; this is of great help in differentiating etiologic factors in new cases.

Chronic acid-base disturbances must not be treated too rapidly; more serious complications may be prevented by meticulous and slow correction. For example, consider the case of a child whose initial blood work shows the following results:

• Sodium 120 mmol/L
• Potassium 2 mmol/L
• Chloride 80 mmol/L
• Bicarbonate 40 mmol/L
• pH 7.5

In this child, assessment of cardiac function is indicated. If there is no dysrhythmia, rapid correction of this severe hypokalemia is unnecessary. Administration of 5% dextrose in 0.9 isotonic sodium chloride solution plus potassium chloride 20 mEq/L at a maintenance rate can be a safe measure.

Maintenance management (7-72 hours)

Maintenance therapy depends on how much improvement occurred after 6 hours of initial fluid and electrolyte administration. The aim is to increase the serum potassium concentration very slowly as the serum bicarbonate level drops. This helps prevent a sharp increase in serum potassium concentration and its subsequent detrimental effects on cardiac conductivity.

Long-term management (after 72 hours)

For long-term management, intravenous (IV) fluids can be discontinued. The physician should calculate the average daily amounts of chloride, sodium, and potassium that were required to correct the serum electrolyte levels. The total amounts can then be administered orally in 3-4 divided doses per day. In most patients, the average chloride dose required is 4-10 mEq/kg/day in the form of sodium and potassium salts.

Other management procedures depend on the primary cause of hypochloremic alkalosis.

Surgical or endoscopic intervention

Surgical intervention is usually unnecessary. If ileus is suspected in a child with severe hypokalemia, the appropriate treatment is administration of potassium chloride, not surgical intervention. However, if the cause of hypochloremic alkalosis is an upper gastrointestinal (GI) tract abnormality, such as gastroesophageal reflux or pyloric stenosis, surgical or endoscopic intervention is indicated.

Diet

Kilojoule intake should be appropriate for the patient’s catabolic status, usually 100-150% of the recommended daily allowance (RDA). Additional protein should be ingested to prevent malnutrition. Fat requirements depend on the individual patient. For example, patients with cystic fibrosis have special dietary needs that should be met.

Multivitamins and hematinic agents should be provided as required. Supplemental trace elements (eg, zinc) should be provided to patients with a trace-element deficiency, such as some patients with chloride-losing diarrhea (chloride-losing diarrhea). High sodium and potassium diets are required for all children with chronic metabolic alkalosis secondary to Bartter syndrome or chloride-losing diarrhea.

Activity

Normal activity should be recommended for children with hypochloremic alkalosis unless central nervous system (CNS) damage is severe, in which case special restrictions are required.

Children with refractory severe hypokalemia should avoid extended exposure to heat, especially in hot climates. Exposure to heat may cause dehydration and may exacerbate the condition.

Genetic counseling

Genetic counseling should be considered when prenatal diagnosis is offered to mothers with familial diseases, such as cystic fibrosis, Bartter syndrome, or chloride-losing diarrhea.

Long-term monitoring

Patients should receive regular follow-up examinations by a physician and nurse clinician. Such examinations should take place at least once every month in infants but may be less frequent in older children and children who are more stable.

The preclinic laboratory workup includes a biochemical profile and monitoring of urine electrolytes. The pharmacotherapeutic regimen should be reviewed at each visit. Medications should be refilled and dosages adjusted in accordance with the patient’s clinical status and laboratory results.

Diagnostic imaging studies should be repeated as necessary. For example, kidney ultrasonography may be needed to assess the degree of nephrocalcinosis in children with Bartter syndrome.

Growth parameters should be assessed, and the question of whether growth hormone therapy is needed should be evaluated in consultation with a pediatric endocrinologist. Renal function should be assessed, and every effort should be made to minimize the use of nephrotoxic agents if possible.

Patients with chronic diseases, such as Bartter syndrome, chloride-losing diarrhea and cystic fibrosis, should have lifelong follow-up care.

Future pregnancies in women with a child with hypochloremic alkalosis should be monitored in a tertiary care center so that early diagnosis and intervention are available at delivery.

Hypochloremic metabolic alkalosis prognosis

Hypochloremic alkalosis prognosis is usually good for patients with Bartter syndrome, provided the patient complies well with treatment. Children who receive effective treatment have minimal risk of severe renal damage.

In patients with chloride-losing diarrhea, renal failure and end-stage renal disease (ESRD) may complicate the picture if diagnosis and treatment are delayed.

In patients with cystic fibrosis, prognosis depends on the severity of lung and liver involvement.

Anorexia and polyuria eventually lead to malnutrition and growth failure. Chronic dehydration frequently causes constipation. A small muscle mass and muscle wasting are frequently seen in patients following a late diagnosis or in untreated patients.

Central nervous system (CNS) effects include cerebral dysfunction and defective cognitive function resulting from chronic hypoperfusion in moderate-to-severe metabolic alkalosis due to hypokalemic and hypochloremic states. Hypopnea is due to depression of respiratory drive. CNS calcification occurs in some patients for unclear reasons. Seizure disorder, brain atrophy, and mental retardation are other known complications.

Depending on the renal disorder, complications may include nephrocalcinosis, interstitial nephropathy, hypercalcemia, hyperuricemia, hypertension during the late stages of renal damage, and renal failure. Children with end-stage renal disease require renal replacement therapy in the form of hemodialysis or peritoneal dialysis. Kidney transplantation with the consequences of graft loss due to metabolic derangements adds more morbidity in these patients.

Metabolic alkalosis causes

The most common causes of metabolic alkalosis are the use of diuretics (water pills tha help rid your body of sodium and water) and the external loss of gastric hydrochloric acid (HCl) secretions ²³.

Other causes include the following:

• Exogenous alkali administration – Sodium bicarbonate therapy in the presence of renal failure, metabolism of lactic acid or ketoacids
• Milk-alkali syndrome
• Hypercalcemia
• Intravenous penicillin
• Refeeding alkalosis
• Massive blood transfusion

Metabolic alkalosis is further divided into 2 main categories ²⁴, ²⁵, ²⁶, ²⁷, ²⁸, ²⁹, ²³:

1. Chloride-responsive alkalosis with urine chloride less than 20 mEq/L. Chloride-responsive alkalosis causes include loss of hydrogen via the gastrointestinal tract (vomiting, nasogastric suction), congenital chloride diarrhea syndrome (congenital chloridorrhea), loss of colonic secretions via villous adenoma, contraction alkalosis, diuretic therapy (thiazides and loop diuretics [after discontinuation]), post-hypercapnia syndrome, cystic fibrosis, exogenous alkalotic agent use and laxative abuse are also potential causes.
2. Chloride-resistant alkalosis with urine chloride greater than 20 mEq/L.
   • Causes of chloride-resistant alkalosis (urine chloride > 20 mEq/L) with hypertension include the following:
     • Primary hyperaldosteronism: adrenal adenoma, bilateral adrenal hyperplasia, adrenal carcinoma, glucocorticoid-remediable hyperaldosteronism
     • 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2): 11 β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) normally converts active cortisol to inactive cortisone and protects mineralocorticoid receptor (MR) occupied by cortisol. The Apparent Mineralocorticoid Excess syndrome is an ultrarare autosomal recessive disorder caused by 11β-hydroxysteroid dehydrogenase type 2 gene (HSD11B2) resulting in impairment of the enzyme 11β-HSD2 leading to excessive cortisol that is able to activate mineralocorticoid receptor (MR). The Apparent Mineralocorticoid Excess syndrome is typically characterized by hypertension with hypokalemia, metabolic alkalosis, low renin activity, and low aldosterone level. The cause is inherited in autosomal recessive form, mutations in 11β-HSD2 gene or acquired form by ingestion of competitive inhibitors of 11β-HSD2 such as liquorice, chewing tobacco or carbenoxolone. Uncontrolled hypertension and prolong hypokalemia are the leading causes of end organ damages and cardiovascular mortality ³⁰.
     • Congenital adrenal hyperplasia (CAH) 11-hydroxylase or 17-hydroxylase deficiency
     • Current use of diuretics in hypertension
     • Cushing syndrome
     • Exogenous mineralocorticoids or glucocorticoids
     • Liddle syndrome
     • Renovascular hypertension
   • Causes of chloride-resistant alkalosis (urine chloride >20 mEq/L) without hypertension include the following:
     • Bartter syndrome
     • Gitelman syndrome
     • Severe potassium depletion (hypokalemia)
     • Current use of thiazides and loop diuretics
     • Hypomagnesemia

Chloride-responsive metabolic alkalosis

The principal causes of chloride-responsive metabolic alkalosis are the loss of gastric secretions, ingestion of large doses of nonabsorbable antacids, and use of thiazide or loop diuretics ⁴¹. Miscellaneous causes account for the remainder of cases ¹¹.

Gastric secretions are rich in hydrochloric acid (HCl). The secretion of hydrochloric acid (HCl) by the stomach usually stimulates bicarbonate secretion by the pancreas once the hydrochloric acid (HCl) reaches the duodenum. Ordinarily, these pancreatic secretions neutralize the gastric secretions, and no net gain or loss of hydrogen ions or bicarbonate occurs.

When hydrochloric acid (HCl) is lost through vomiting (including purging, in persons with eating disorders) or nasogastric suction, pancreatic secretions are not stimulated and a net gain of bicarbonate into the systemic circulation occurs, generating a metabolic alkalosis ⁴². Volume depletion maintains alkalosis. In this case, the hypokalemia is secondary to the alkalosis itself and to renal loss of potassium ions from the stimulation of aldosterone secretion.

Ingestion of large doses of non-absorbable antacids (eg, magnesium hydroxide) may generate metabolic alkalosis by a rather complicated mechanism. Upon ingestion of magnesium hydroxide, calcium, or aluminum with base hydroxide or carbonate, the hydroxide anion buffers hydrogen ions in the stomach. The cation binds to bicarbonate secreted by the pancreas, leading to loss of bicarbonate with stools. In this process, both hydrogen ions and bicarbonate are lost, and, usually, no acid-base disturbance occurs. Sometimes, however, not all the bicarbonate binds to the ingested cation, which means that some bicarbonate is reabsorbed in excess of the lost hydrogen ions. This occurs primarily when antacids are administered with a cation-exchange resin (eg, sodium polystyrene sulfonate [Kayexalate]); the resin binds the cation, leaving bicarbonate unbound.

Thiazides and loop diuretics enhance sodium chloride excretion in the distal convoluted tubule and the thick ascending loop, respectively. These agents cause metabolic alkalosis by chloride depletion and by increased delivery of sodium ions to the collecting duct, which enhances potassium ion and hydrogen ion secretion.

Plasma renin activity and aldosterone level

Measuring the plasma renin activity and aldosterone level may help in finding the etiology of metabolic alkalosis, especially in patients with hypertension, hypokalemic metabolic alkalosis, and renal potassium wasting without diuretic use. Low renin activity and high plasma aldosterone levels are found in primary hyperaldosteronism, including glucocorticoid-remediable hyperaldosteronism.

Low plasma renin activity and aldosterone levels are found in the following circumstances:

• Cushing syndrome
• Exogenous steroid use
• Congenital adrenal hyperplasia (CAH)
• 11-beta-hydroxysteroid dehydrogenase (11B-HSD) deficiency
• Deoxycorticosterone (DOC)-secreting tumors
• Liddle syndrome

High plasma renin activity and aldosterone levels are found in the following circumstances:

• Renal artery stenosis
• Diuretic use
• Renin-secreting tumors
• Bartter syndrome
• Gitelman syndrome

Amniocentesis

Amniotic fluid sodium and chloride concentrations may reflect fetal values; these are high in fetuses with chloride-losing diarrhea. Levels may also be elevated in patients with Bartter syndrome. Although testing for alpha1 -fetoprotein is not routine, levels may be elevated.

Blood workup

Serum electrolyte levels may be within the reference range, especially in neonates and treated patients. However, typical findings include low concentrations of serum chloride, sodium, and potassium. Attention must be paid in interpreting the serum potassium level in relation to the state of metabolic alkalosis. For example, the potassium shift from serum into the intracellular compartment increases as the serum pH rises; thus, the potassium level is less than normal by 0.6 mmol/L when measured at a serum pH of 7.5.

Serum pH and bicarbonate, calcium, uric acid, hemoglobin (if patient is not anemic), renin, and aldosterone levels may be elevated. The serum renin level is exponentially high, in line with secondary hyperaldosteronism due to chronic volume depletion, and this finding is supported by low or normal blood pressure measurements.

Urine and stool studies

In patients with Bartter syndrome, urine chloride, sodium, and potassium concentrations are usually measured. Urine calcium-to-creatinine and uric acid–to–creatinine ratios are usually high. Stool electrolytes cannot be measured because of well-formed or hard stool. Fractional excretion (Fex) studies are more reliable than absolute values. Usually, results are higher than reference range values, as follows:

• Fractional excretion (Fex) sodium concentration >1%
• Fractional excretion (Fex) potassium concentration >35%
• Fractional excretion (Fex) chloride concentration >2.5% (2.7% ± 1.1%)

In patients with chloride-losing diarrhea, urine chloride concentration is very low or undetectable (< 10 mmol/L). Stool is usually watery, and electrolyte studies are very helpful and diagnostic, as follows:

• Stool chloride concentration >100 mmol/L
• Stool sodium and potassium concentrations are elevated
• Stool chloride concentration is greater than stool sodium plus potassium concentrations, which is normally less than either; chloride concentrations are lowest in colonic secretions (usually < 35 mmol/L)
• The ratio of stool chloride to combined sodium and potassium concentrations is greater than 0.6

Patients with cystic fibrosis typically demonstrate high sweat chloride and sodium concentrations. Urine chloride concentration is usually very low, and stools are usually not watery, as they are in patients with chloride-losing diarrhea.

Kidney and liver function tests

• Renal function is usually normal. The glomerular filtration rate (GFR) may be low in patients with severe disease.
• Liver function test results are usually within the reference range in patients with chloride-losing diarrhea and Bartter syndrome but may be deranged in patients with cystic fibrosis.

Genetic studies

DNA diagnosis is available for most congenital disorders that cause hypochloremic metabolic alkalosis. For chloride-losing diarrhea, the chloride-losing diarrhea (SLC26A3) locus is on band 7q22-q31.1 ³⁸. Bartter syndrome is identified by NKCC2, ROMK, and CLCNKB ³⁹; Bartter syndrome with deafness is identified by BSND; and Bartter syndrome with autosomal dominant hypocalcemia is identified by CASR. For cystic fibrosis, the CFTR locus is on band 7q31.2. For Gitelman syndrome, the NCCT locus is on 16q.

Ultrasonography

Prenatal ultrasonography may be useful in the detection of minimal polyhydramnios and assessment of intestinal fluid content, which is increased in patients with chloride-losing diarrhea.

Postnatal ultrasonography (see the images below) may be useful in the evaluation of a fluid-filled bowel, which is characteristically increased in patients with chloride-losing diarrhea. Ultrasonography may also assist in the evaluation of renal echogenicity, nephrocalcinosis, medullary or diffuse calcinosis, and renal growth.

Physiologic study of renal tubules

Physiologic study of renal tubules by performing maximal free water clearance during hypotonic saline diuresis is indicated.

Oral administration of water 20 mL/kg over 30 minutes is followed by administration of a one-half isotonic sodium chloride solution at a rate of 600 mL/m²/h for 2-3 hours. During this time, urine is collected in aliquots over 30-minute periods for 4-6 aliquots.

These samples are sent for evaluation of creatinine, sodium, potassium, and chloride levels, as well as for osmolality, pH, and volume. Usually, urine is diluted by oral administration of water. Halfway through each collection, a blood sample is obtained for evaluation of creatinine, sodium, potassium, and chloride levels, and for pH and osmolality. The clearance of each substance is calculated, and a ratio is derived by means of the following formula:

• Water clearance/(chloride clearance + water clearance)

Usually, the result of this formula reflects the percentage of distal tubule sodium and chloride reabsorption. Normal values are up to 85-90%, which means that the percentage of chloride and sodium excreted should be 10-15% (corrected to a GFR of 100 mL/min/1.73 m²). In patients with Bartter syndrome, the percentage of chloride and sodium excreted can reach 35% or more.

Other studies

Additional studies that may be considered include the following:

• Wrist radiography – This may be performed to determine bone age in infants with growth failure; it may also help assess bone density and the presence of rickets
• Upper gastrointestinal (GI) series – This helps detect gastroesophageal reflux and pyloric stenosis, which are case-dependent conditions ⁴⁰
• Computed tomography (CT) of the brain – This is useful for evaluation of brain growth and calcifications
• Magnetic resonance imaging (MRI) of the brain – This is helpful in patients who present with seizures
• Electroencephalography (EEG) – This is also helpful in patients who present with seizures
• Renal nuclear scanning – This may facilitate assessment of renal function but is not useful in all patients
• Renal biopsy – This is not usually indicated, but if it is performed, it may reveal interstitial fibrosis and calcium/urate crystal deposition

Metabolic alkalosis treatment

The management of metabolic alkalosis depends primarily on the underlying etiology and on the patient’s volume status ⁶². In the case of vomiting, administer antiemetics, if possible. If continuous gastric suction is necessary, gastric acid secretion can be reduced with H2-blockers or more efficiently with proton pump inhibitors. In patients who are on thiazide or loop diuretics, the dose can be reduced or the drug can be stopped if appropriate. Alternatively, a potassium-sparing diuretic or acetazolamide can be added.

Acetazolamide also appears safe and effective in patients with metabolic alkalosis following treatment of respiratory acidosis from exacerbations of chronic obstructive pulmonary disease (COPD) ⁶³, ⁶⁴. One randomized trial found that the duration of mechanical ventilation in patients with COPD or obesity-hypoventilation syndrome with metabolic alkalosis was not significantly reduced in patients who received early administration of acetazolamide, compared with placebo ⁶⁵.

However, a systematic review and meta-analysis of that trial and five other randomized controlled studies concluded that in patients with respiratory failure and metabolic alkalosis, therapy with acetazolamide or other carbonic anhydrase inhibitors may have favorable effects on blood gas parameters. In mechanically ventilated patients, carbonic anhydrase inhibitor therapy may decrease the duration of mechanical ventilation ⁶⁶.

Hydrochloric acid

Intravenous hydrochloric acid (HCl) is indicated in severe metabolic alkalosis (pH >7.55) or when sodium or potassium chloride cannot be administered because of volume overload or advanced renal failure. Hydrochloric acid (HCl) may also be indicated if rapid correction of severe metabolic alkalosis is warranted (eg, cardiac arrhythmias, hepatic encephalopathy, digoxin cardiotoxicity) ⁶⁷. Seek the advice of a nephrologist when severe alkalosis is present and HCl therapy or dialysis is contemplated.

Dialysis

Both peritoneal dialysis and hemodialysis can be used with certain modifications of the dialysate to correct metabolic alkalosis. The main indication of dialysis in metabolic alkalosis is in patients with advanced renal failure, who usually have volume overload and are resistant to acetazolamide.

With hemodialysis, metabolic alkalosis may be corrected by using a low-bicarbonate dialysate (bicarbonate can be as low as 18 mmol/L). Otherwise, acetate-free biofiltration (buffer-free dialysate), in which bicarbonate is not present in the dialysate but is infused separately as needed, may be used. In peritoneal dialysis, dialysis can be performed using isotonic sodium chloride solution as the dialysate.

Chloride-responsive metabolic alkalosis treatment

If chloride-responsive metabolic alkalosis occurs with volume depletion, treat the alkalosis with an intravenous infusion of isotonic sodium chloride solution. Because this type of alkalosis is usually associated with hypokalemia, also use potassium chloride to correct the hypokalemia.

If chloride-responsive alkalosis occurs in the setting of edematous states (eg, congestive heart failure [CHF]), use potassium chloride instead of sodium chloride to correct the alkalosis and avoid volume overload. If diuresis is needed, a carbonic anhydrase inhibitor (eg, acetazolamide) or a potassium-sparing diuretic (eg, spironolactone, amiloride, triamterene) can be used to correct the alkalosis.

Chloride-resistant metabolic alkalosis treatment

Management of chloride-resistant metabolic alkalosis is based on the specific cause.

Primary hyperaldosteronism

Metabolic alkalosis is corrected with the aldosterone antagonist spironolactone or with other potassium-sparing diuretics (eg, amiloride, triamterene). If the cause of primary hyperaldosteronism is an adrenal adenoma or carcinoma, surgical removal of the tumor should correct the alkalosis. In glucocorticoid-remediable hyperaldosteronism, metabolic alkalosis and hypertension are responsive to dexamethasone.

Cushing syndrome

Potassium-sparing diuretics should correct the alkalosis until surgical therapy is performed. Definitive therapy includes transsphenoidal microresection of adrenocorticotropic hormone (ACTH)–producing pituitary adenomas and adrenalectomy for adrenal tumors.

Syndrome of apparent mineralocorticoid excess

Metabolic alkalosis in the syndrome of apparent mineralocorticoid excess (AME) may be treated with potassium-sparing diuretics. On the other hand, dexamethasone may be used to suppress cortisol production by inhibiting ACTH. Unlike cortisol and some synthetic glucocorticoids, dexamethasone does not activate the mineralocorticoid receptor.

Licorice ingestion

Discontinuation of licorice ingestion corrects the alkalosis; however, because full recovery of the enzyme 11B-HSD may take as long as 2 weeks following long-term licorice use, potassium-sparing diuretics can be used during this interval.

Bartter syndrome and Gitelman syndrome

Metabolic alkalosis can be corrected partially with the following:

• Potassium supplementation
• Potassium-sparing diuretics
• Nonsteroidal anti-inflammatory drugs
• ACE inhibitors

Indomethacin is the most prescribed NSAID for the treatment of Bartter syndrome; in patients with Gitelman synrome it has shown to be more effective than eplerenone or amiloride for treating associated hypokalemia ⁶⁸.

Liddle syndrome

Metabolic alkalosis can be treated with amiloride or triamterene but not with spironolactone. Both amiloride and triamterene inhibit the apical sodium ion channel in the collecting duct. Spironolactone, which is a mineralocorticoid receptor antagonist that works upstream of the defective sodium ion channel, does not correct the alkalosis or the hypertension.

Metabolic alkalosis prognosis

Metabolic alkalosis prognosis depends on associated problems of volume depletion, electrolyte, and hormonal disturbances and varies based on the primary cause of the alkalosis. Patients with metabolic alkalosis have been found to have increased ICU duration of stay, more days on mechanical ventilation, and higher hospital mortality. An increase of 5-mEq/L in the serum bicarbonate level over 30 mEq/L correlated with an odds ratio of 1.21 for hospital mortality. The association between metabolic alkalosis and mortality occurs independently of the etiology of alkalosis ⁶⁷.

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