Hypochloremic Alkalosis 

Updated: Aug 30, 2018
Author: Jagdish Desai, MD, MPH; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Practice Essentials

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. Diarrhea, when watery (see the image below), is highly suggestive of chloride-losing diarrhea.

Watery stool from an infant with congenital chlori Watery stool from an infant with congenital chloride-losing diarrhea. Chloride level was 205 mmol/L.

Signs and symptoms

Hypochloremia itself often has no signs or symptoms. Instead, associated signs and symptoms result from electrolyte imbalance or underlying causes of the hypochloremia.

Symptoms that may be noted in fetuses and neonates include the following:

  • Prenatal polyhydramnios
  • Lack of meconium or delayed meconium
  • Abdominal distension of unknown etiology
  • Prolonged neonatal jaundice
  • Hypotonia and lethargy without sepsis

Symptoms that may be noted in infants include the following:

  • Repeated vomiting
  • Failure to thrive
  • Constipation
  • Watery diarrhea
  • Polyuria
  • Salty taste upon being kissed
  • Central nervous system (CNS) dysfunctions (eg, lethargy, confusion, or seizure)
  • Neuromuscular symptoms (eg, weakness and muscle cramps)
  • Other symptoms (eg, abdominal distention, dry skin, apathy, loss of interests, and frequent hospital admissions for recurrent dehydration)

General physical findings may include the following:

  • Small size for age
  • Signs of chronic dehydration (eg, skin tenting and poor peripheral perfusion)

CNS manifestations may include the following:

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

Abdominal manifestations may include the following:

  • Scaphoid or distended abdomen (depending on the cause of the hypochloremic alkalosis)
  • Peristaltic waves in children with chloride-losing diarrhea (CLD)
  • Exacerbated bowel sounds in patients with CLD
  • 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.

See Presentation for more detail.

Diagnosis

Laboratory studies that may be helpful include the following:

  • Amniocentesis
  • Blood workup - Serum electrolyte levels; pH; serum bicarbonate, uric acid, hemoglobin, renin, and aldosterone levels
  • Urine and stool studies - Urine chloride, sodium, and potassium concentrations; urine calcium-to-creatinine and uric acid–to–creatinine ratios; stool electrolytes (when measurable)
  • Kidney and liver function tests
  • Genetic studies

Ultrasonography may be useful for the following purposes:

  • Prenatal - Detection of minimal prenatal polyhydramnios and assessment of intestinal fluid content
  • Postnatal - Evaluation of a fluid-filled bowel, renal echogenicity, nephrocalcinosis, medullary or diffuse calcinosis, and renal growth

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

Additional studies that may be considered include the following:

  • Wrist radiography
  • Upper gastrointestinal (GI) series
  • Computed tomography (CT) of the brain
  • Magnetic resonance imaging (MRI) of the brain
  • Electroencephalography (EEG)
  • Renal nuclear scanning
  • Renal biopsy

See Workup for more detail.

Management

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

Initial management (≤6 hours) includes the following:

  • Assessment of dehydration status and severity of hypochloremia, hypokalemia, hyponatremia, and metabolic alkalosis
  • In cases of shock, aggressive resuscitation with isotonic fluid, preferably normal saline
  • Drawing of blood and urine samples for testing of electrolytes

Maintenance therapy (7-72 hours) depends on how much improvement occurred after initial management. The aim is to increase the serum potassium concentration very slowly as the serum bicarbonate level drops.

Long-term management (>72 hours) includes the following:

  • Discontinuance of intravenous (IV) fluids
  • Oral administration (q6-8h) of calculated daily amounts of chloride, sodium, and potassium required to correct serum electrolyte levels
  • Other management procedures as appropriate for the condition determined to be the primary cause of hypochloremic alkalosis

Surgical or endoscopic intervention is unnecessary except in particular circumstances (eg, when the cause of hypochloremic alkalosis is an upper GI tract abnormality)

Dietary measures that may be considered include the following:

  • Kilojoule intake appropriate for the patient’s catabolic status
  • Additional protein to prevent malnutrition
  • Additional fat, depending on the individual patient’s requirements
  • Multivitamins and hematinic agents as required
  • Supplemental trace elements (eg, zinc) as necessary
  • High-sodium and high-potassium diets for patients with Bartter syndrome or CLD

See Treatment and Medication for more detail.

Background

Hypochloremic alkalosis is common in hospitalized children and is rare in outpatient settings. In the neonatal intensive care unit (ICU), this form of alkalosis frequently results from diuretic therapy for bronchopulmonary dysplasia. Hypochloremic alkalosis due to loss of gastric acid via nasogastric tube suctioning is also common in pediatric ICUs.

Other rare but potentially serious causes must be considered in any child presenting with failure to thrive, poor development, and a family history of neonatal demise and metabolic alkalosis in the absence of diuretic or laxative abuse. Repeated vomiting may be a clue that the patient has severe gastroesophageal reflux or pyloric stenosis.

A history of polyhydramnios is helpful; polyhydramnios may result from polyuria or congenital diarrhea. A lack of both symptoms may help identify cystic fibrosis. Severe hypochloremic metabolic alkalosis may be the presenting metabolic derangement for multiple conditions. Molecular diagnostic procedures sometimes help resolve differential diagnoses. Severe brain damage and psychomotor retardation may occur in children when diagnosis and treatment are delayed.

Etiology

Hypochloremia is defined as a serum chloride level of less than 95 mEq/L. Hypochloremia results from either low chloride intake or excessive chloride wasting. Low chloride intake is very uncommon. Excessive chloride wasting often occurs in hospitalized children, usually as a consequence of diuretic therapy or nasogastric tube suctioning. Chloride-wasting syndromes, including Bartter syndrome, congenital chloride-losing diarrhea (CLD), and cystic fibrosis, result from renal tubular loss, defective electrolyte transport across intestinal epithelia, and chloride loss via the skin, respectively.[1] There have been reports of dietary deficiencies or formula lacking chloride causing metabolic alkalosis and severe neurological consequences.[2, 3, 4] However, these causes are now rare since the introduction of standard nutritional guidelines for formulas and dietary requirements.

Causes of hypochloremic alkalosis in children. Causes of hypochloremic alkalosis in children.

Hypochloremic alkalosis can be classified into two categories: chloride-responsive and chloride-resistant. Causes of chloride-responsive alkalosis (extrarenal chloride loss) include recurrent vomiting, gastric acid loss, diuretic-induced alkalosis (loop or thiazide diuretics), and posthypercapnic metabolic alkalosis. CLD, cystic fibrosis, and laxative abuse are also potential causes.

With respect to chloride-resistant alkalosis (with either euvolemia or hypovolemia), renal chloride wasting, as well as severe potassium and magnesium depletion, may occur in patients with Bartter syndrome and, rarely, in patients with Gitelman syndrome.[5] Chloride-resistant alkalosis may result from acute administration of exogenous alkali, as in milk-alkali syndrome or after massive blood transfusion. Rare causes include hypercalcemia due to vitamin D toxicity and hyperparathyroidism and nonreabsorbable anions.

Pathophysiology

The renal collecting duct plays an important role in acid-base balance by maintaining bicarbonate (HCO3-) reabsorption and secretion.[6] Abundant evidence now supports pendrin as an important regulatory transporter in the cortical collecting ducts, which responds briskly[7] in vivo and in vitro[8] to alterations in chloride intake and to acid-base perturbations, including metabolic alkalosis and acidosis and respiratory acidosis. The figure below depicts a detailed explanation of ion exchange at collecting duct cells in a hypochloremic condition.

Explanation of ion exchange at  collecting duct ce Explanation of ion exchange at collecting duct cells in a hypochloremic condition.

The collecting duct plays the main role in acid-base balance by maintaining HCO3- reabsorption and secretion. In type-B intercalated cells of the cortical collecting duct, pendrin channel (Pn) activity is increased because of a low Cl- concentration in that segment (due to low chloride levels in ultrafiltrate from hypochloremia), but secretion of HCO3- is inhibited by insufficient Cl- for anion exchange. HCO3- reabsorption is continued by Na+/H+ exchange in the principal cell and in the type-A intercalated cells. In the medullary collecting duct, HCO3- reabsorption is continued because a decreased HCO3- concentration in that segment enhances H+ secretion in type-A cells.[9] Rat studies have shown that, after Cl- delivery to the cortical collecting ducts increases, HCO3- secretion occurs and medullary HCO3- reabsorption diminishes, allowing correction of the hypochloremic alkalosis. In these studies, bicarbonaturia occurred within minutes of Cl- administration intravenously, and Cl- did not increase in the urine until correction of serum Cl- was nearly complete.[8]

Chloride-losing diarrhea

Chloride-losing diarrhea (CLD) is caused by a defective anion exchange protein, an epithelial chloride/bicarbonate (Cl-/HCO3-) exchanger located in the brush border of the ileum and colon, resulting in defective intestinal chloride absorption and secretion of HCO3-, with a secondary defect in sodium/hydrogen (Na+/H+) transport, altogether leading to intestinal losses of both sodium and water, hypochloremia, hyponatremia, and metabolic alkalosis.

Epidemiology

The frequency of hypochloremic alkalosis is unknown, both in the United States and worldwide. However, there is some reason to think that this condition may be more common worldwide than was previously accepted. Many cases of CLD have emerged from Eastern Europe and Middle Eastern Arab countries; indeed, the largest purported series is from Saudi Arabia.[10] Fewer cases in the English language literature have been reported in the Far East and North America, perhaps because of cultural and academic barriers.

CLD can manifest before birth as severe midtrimester polyhydramnios. Metabolic derangements may manifest as early as the first few days of life. Bartter syndrome may present at any age but primarily occurs in infants younger than 1 year. Hypochloremic alkalosis resulting from cystic fibrosis is infrequent in infancy but can become more severe in summer because of excessive chloride loss from sweating. Drug-related hypochloremic alkalosis is observed at all ages. Males and females are affected in equal numbers.

Prognosis

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 CLD, renal failure and 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.

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 sequelae.

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.

Patient Education

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 (CLD).

Educate the caregiver regarding the primary disease and how to identify signs of dehydration and to prevent it.

Ask the clinical pharmacist to discuss the importance and methods of drug administration, timing, and adverse effects with the caregiver, in addition to storage of medications at home.

 

Presentation

History

Prenatal and neonatal history

Prenatal polyhydramnios is present in most patients with congenital forms of metabolic alkalosis, especially chloride-losing diarrhea (CLD). Premature birth resulting from polyhydramnios is common in patients with Bartter syndrome and CLD. 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.

Infant history

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 CLD.

Watery stool from an infant with congenital chlori Watery stool from an infant with congenital chloride-losing diarrhea. Chloride level was 205 mmol/L.

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).[11] Central nervous system (CNS) dysfunctions (eg, lethargy, confusion, or seizure) are observed in patients with severe alkalosis. Neuromuscular symptoms include weakness and muscle cramps.

Other symptoms (eg, abdominal distention, dry skin, apathy, loss of interests, growth retardation,[12] 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.[13]

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 CLD.[10]

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

Depending on the cause of the hypochloremic alkalosis, the abdomen may be scaphoid (in Bartter syndrome) or distended (in CLD). (See the images below.)

Infant with severe metabolic alkalosis resulting f Infant with severe metabolic alkalosis resulting from congenital chloride-losing diarrhea.
Visible bowel loops in an infant with congenital c Visible bowel loops in an infant with congenital chloride-losing diarrhea.

Additional abdominal findings that may be present are as follows:

  • Peristaltic waves in children with CLD

  • Exacerbated bowel sounds in patients with CLD

  • 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.

Complications

Disease-related complications of hypochloremic alkalosis include the following:

  • Nephrocalcinosis and nephrolithiasis in patients with Bartter syndrome and in those with CLD
  • 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 CLD
 

DDx

Diagnostic Considerations

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

  • Enteric anendocrinosis or dysendocrinosis

  • Gitelman syndrome

  • Laxative abuse

  • Loop or thiazide diuretic abuse

  • Pyloric stenosis

Differential Diagnoses

 

Workup

Approach Considerations

The flowchart below depicts a workup approach to hypochloremic alkalosis.

Approach to hypochloremic alkalosis. 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 (CLD). 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:

  • Fex sodium concentration >1%

  • Fex potassium concentration >35%

  • Fex chloride concentration >2.5% (2.7% ± 1.1%)

In patients with CLD, 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 CLD.

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 CLD 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 CLD, the CLD (SLC26A3) locus is on band 7q22-q31.1.[14, 15] Bartter syndrome is identified by NKCC2, ROMK, and CLCNKB[16] ; 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 CLD.

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

Sonogram depicting severe nephrocalcinosis in a 2- Sonogram depicting severe nephrocalcinosis in a 2-year-old child with Bartter syndrome.
Renal sonogram of an infant with congenital chlori Renal sonogram of an infant with congenital chloride-losing diarrhea showing diffuse sclerosis.

Physiologic Study of Tubule

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[17]

  • 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

 

Treatment

Approach Considerations

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.

Medical Correction of Hypochloremic Alkalosis

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 (CLD). High sodium and potassium diets are required for all children with chronic metabolic alkalosis secondary to Bartter syndrome or CLD.

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.

Prevention

In patients with CLD, 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.

Consultations

The following may be consulted as necessary:

  • Pediatric nephrologist (in all cases)

  • Pediatric gastroenterologist

  • Genetic counselor

  • Social workers

  • Pediatric nutritionist

  • Pediatric endocrinologist (to exclude other causes of growth failure)

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 (CLD), 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.

 

Medication

Medication Summary

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.

Electrolytes

Class Summary

Electrolytes are administered to correct disturbances in fluid and electrolyte homoeostasis or acid-base balance. They are also given to reestablish osmotic equilibrium of specific ions.

Potassium chloride (K-Lor, Klor-Con, Micro-K, K-Vescent)

Potassium is essential for transmission of nerve impulses, contraction of cardiac muscle, maintenance of intracellular tonicity, skeletal and smooth muscles, and maintenance of normal renal function. Gradual potassium depletion occurs via renal excretion or gastrointestinal (GI) loss or because of low intake.

Depletion usually results from diuretic therapy, primary or secondary hyperaldosteronism, diabetic ketoacidosis, severe diarrhea (if associated with vomiting), or inadequate replacement during prolonged parenteral nutrition. Potassium depletion sufficient to cause a 1 mEq/L drop in the serum potassium level requires a loss of approximately 100-200 mEq of potassium from the total body store.

Sodium chloride hypertonic

Hypertonic sodium chloride is given to restore sodium ions in patients with restricted oral intake, especially those with hyponatremia states or salt-wasting syndromes.

Nonsteroidal Anti-inflammatory Drugs

Class Summary

NSIADs have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is unknown but may involve inhibition of cyclooxygenase activity and prostaglandin synthesis. Other mechanisms may also play a role, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

Indomethacin (Indocin)

Indomethacin inhibits prostaglandin synthesis. It is rapidly absorbed and is metabolized in liver via demethylation, deacetylation, and glucuronide conjugation.

Ibuprofen (Motrin, Advil)

Ibuprofen is usually the drug of choice for mild to moderate pain, if no contraindications exist. This drug inhibits inflammatory reactions and pain, probably by decreasing the activity of the enzyme cyclooxygenase, which results in decreased prostaglandin synthesis.

Ketoprofen

Ketoprofen is used to relieve mild to moderate pain and inflammation. Small dosages are initially indicated in small and elderly patients and in those with renal or liver disease. Doses of more than 75 mg do not increase therapeutic effects; therefore, administer high doses with caution, and closely observe patient response.

Naproxen (Anaprox, Naprelan, Naprosyn)

Naproxen is indicated for the relief of mild to moderate pain. This agent acts by inhibiting inflammatory reactions and pain via decreasing the activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Carbonic Anhydrase Inhibitors

Class Summary

The major pharmacologic action of agents in this class is noncompetitive inhibition of the enzyme carbonic anhydrase. Carbonic anhydrase is located at the luminal border of cells of the proximal tubule. Urine volume increases with enzyme inhibition (proximal tubule reabsorption of water is reduced by approximately one third), which promotes an alkaline pH. This results in a subsequent decrease in the excretion of titratable acid and ammonia. Increases in urinary excretion of bicarbonate and sodium lead to metabolic acidosis.

Acetazolamide (Diamox Sequels)

Acetazolamide may be used in loop or thiazide diuretic−induced metabolic alkalosis, especially in edematous states.

Acidifying Agents

Class Summary

Consequences of severe metabolic alkalosis include increased susceptibility to ventricular arrhythmia and a left shift of the oxyhemoglobin dissociation curve. HCl is particularly useful in patients with hepatic or renal impairment, which often precludes more standard treatments.

Hydrochloric acid

Intravenous administration of HCl may be indicated in severe metabolic alkalosis (pH >7.55) or when sodium chloride or potassium chloride cannot be administered because of volume overload or advanced renal failure. It may also be indicated if rapid correction of severe metabolic alkalosis is warranted (eg, in cardiac arrhythmia, hepatic encephalopathy, or digoxin toxicity). HCl for IV use is not commercially available and must be extemporaneously compounded from concentrated HCl solution.

Dosing is based on the chloride deficit and base excess. Typically, concentration ranges from 0.1N to 0.15N (ie, H+ concentration of 100-150 mmol/L). Concentrations greater than 0.2N may be associated with an increased risk of hemolysis.

Xanthine Oxidase Inhibitors

Class Summary

Xanthine oxidase inhibitors are effective for treating diuretic-induced hyperuricemia and renal complications resulting in hyperuricemia.

Allopurinol (Zyloprim, Aloprim)

Allopurinol inhibits xanthine oxidase, the enzyme that synthesizes uric acid from hypoxanthine. It reduces synthesis of uric acid without disrupting biosynthesis of vital purines.