Metabolic alkalosis is an acid-base disturbance caused by an elevation in the plasma bicarbonate (HCO3) concentration. This condition is not a disease; it is a sign or state encountered in certain disease processes. Although metabolic alkalosis may not be referred to as often as metabolic acidosis, it is the most common acid-base abnormality in hospitalized adults,[1] particularly those in the intensive care unit (ICU).[2] Alkalosis refers to a loss of acid or gain of base in the extracellular fluid (ECF); alkalemia refers to a change in blood pH. Alkalosis is not necessarily accompanied by alkalemia.
The two types of metabolic alkalosis (ie, chloride-responsive, chloride-resistant) are classified based on the amount of chloride in the urine.
Chloride-responsive metabolic alkalosis involves urine chloride levels of less than 20 mEq/L, is typically found to be below 10 mEq/L, and is characterized by decreased ECF volume and low serum chloride levels, such as occurs with vomiting. This type responds to administration of chloride salt.
Chloride-resistant metabolic alkalosis involves urine chloride levels above 20 mEq/L and is characterized by increased ECF volume. As the name implies, this type resists administration of chloride salt. Primary aldosteronism is an example of chloride-resistant metabolic alkalosis.
For a review of metabolic alkalosis in patients of all ages, see Metabolic Alkalosis.
Causes of metabolic alkalosis include the following:
Loss of hydrogen ions (eg, due to vomiting or renal acid losses that exceed acid production from cellular metabolism) (Loss of hydrochloric acid due to vomiting is an especially common cause.)
Disproportionate chloride loss compared with bicarbonate (HCO3) loss (ie, the plasma concentration of HCO3 increases upon restriction to a smaller space of distribution)
HCO3 administration (unusual, because additional HCO3 is very quickly eliminated by the kidneys)
The consequences of metabolic alkalosis on organ systems depend on the severity of the alkalemia and the degree of respiratory compensation. Mild to moderate metabolic alkalosis is rarely clinically significant in isolation. If the elevated plasma HCO3 concentration is not accompanied by a rise in the partial pressure of carbon dioxide (PCO2), the elevation of pH is much more severe.
Effects of severe alkalemia
The respiratory effects of metabolic alkalosis are two-fold. An increase in blood pH shifts the oxygen-hemoglobin dissociation curve to the left. This creates a tighter bond between hemoglobin and oxygen, causing decreased oxygen delivery to tissues. Hypoxemia may be worsened by a compensatory hypoventilation to elevate PCO2. Hypoventilation may be severe enough to cause apnea and respiratory arrest.
Cardiovascular effects often result from the association of hypokalemia with metabolic alkalosis. Life-threatening arrhythmias are the most significant adverse effect of metabolic alkalosis. Direct arteriolar constriction is further worsened by electrolyte disturbances. Ventricular and supraventricular arrhythmias that are often unresponsive to antiarrhythmic agents can occur.
Neuromuscular effects of severe metabolic alkalosis may include headache, seizures, and obtundation, as well as marked muscle weakness. These resolve only with correction of the pH.
Electrolyte imbalances in metabolic alkalosis include a decrease in ionized calcium levels due to the increased binding of calcium to plasma proteins; consequences include tetany and seizures. Total-body potassium loss may contribute to alkalemia, in which serum potassium is intracellularly shifted. Weakness and cardiac arrhythmias may result from severe hypokalemia.
Compensation mechanisms
The body compensates for metabolic alkalosis through buffering of excess HCO3 and hypoventilation. Intracellular buffering occurs through sodium/hydrogen and potassium/hydrogen ion exchange, with eventual formation of CO2 and water from HCO3.
Within several hours, elevated levels of HCO3 and metabolic alkalosis stimulate a chemoreceptor inhibition of the respiratory center, resulting in hypoventilation and increased PCO2 levels. This mechanism produces a rise in PCO2 of as much as 0.7 mm Hg for each 1-mEq/L increase in HCO3.[3] Hypoventilation may cause hypoxemia.
Milk-alkali syndrome (excess calcium plus bicarbonate intake and vomiting)
Regarding gastric losses (eg, vomiting, NG drainage), bicarbonate (HCO3) produced by the pancreas normally neutralizes the hydrochloric acid (HCl) produced by the gastric mucosa, so that no net gain or loss of hydrogen ions or bicarbonate occurs. When gastric acid is lost through vomiting or removed by suction, plasma HCO3 levels increase. In addition, the loss of potassium and volume contraction due to vomiting potentiate metabolic alkalosis.
Diuretics produce increased renal losses of sodium, which is followed by excretion of chlorides. To maintain electrical neutrality in the extracellular fluid (ECF), HCO3 reabsorption in the renal tubules increases. Additionally, increased sodium levels in the distal tubules increases sodium-potassium exchange. The loss of potassium, in turn, leads to intracellular accumulation of hydrogen ions and their secretion in the distal tubules. Diuretics also promote the loss of magnesium in the urine, which further lowers potassium levels through an unknown mechanism.
Volume contraction concentrates the existing levels of HCO3 in the ECF. In addition, it stimulates release of renin-angiotensin, which causes increased potassium and hydrogen ion losses in the kidney.
Regarding posthypercapnia syndrome, chronic carbon dioxide (CO2) retention causes a compensatory increase in HCO3 levels. When a patient with chronic CO2 retention receives treatment that abruptly drops the CO2 level, metabolic alkalosis becomes evident.
Because metabolic alkalosis is a manifestation of a disease process rather than a disease itself, the true incidence is unknown. In a review of 2000 hospitalized adults, Hodgkin et al noted that metabolic alkalosis was the most common acid-base disorder.[6] It has been estimated that metabolic alkalosis comprises about half of all acid-base disorders in hospitalized patients.[1]
No racial or sexual differences in incidence have been noted, and metabolic alkalosis can occur in people of any age. However, a higher incidence of metabolic alkalosis after cardiac surgery in younger children has been reported.[7, 8, 9]
The overall prognosis in patients with metabolic alkalosis depends on the underlying etiology. Chloride-responsive metabolic alkalosis responds to volume resuscitation and chloride repletion. Chloride-resistant metabolic alkalosis may be more difficult to control. The prognosis is good with prompt treatment and avoidance of hypoxemia.
Severe metabolic alkalosis is associated with increased morbidity and mortality, probably because of its profound influences on multiple organ systems and, more importantly, because of tissue anoxia caused by hypoventilation and shift of the oxygen-dissociation curve to the left.[10]
Complications
Severe metabolic alkalosis can lead to hypoventilation; as noted above, the resultant hypoxemia is compounded by a shift of the oxygen-hemoglobin dissociation curve to the left. In extreme cases, hypoventilation may be severe enough to require mechanical ventilation or to interfere with weaning from current mechanical ventilation.
Intracellular shift of potassium in severe alkalemia may lead to life-threatening arrhythmias or cardiac arrest.
Obtain clinical historical data to pinpoint the nature of the disease causing the patient's metabolic alkalosis. Symptoms usually relate to the specific disease process that caused the acid-base disorder. Ask about vomiting, other gastric fluid loss, and diuretic use. Loss of gastric fluid and hydrochloric acid (HCl) due to vomiting is the most common cause of metabolic alkalosis. Vomiting may be caused by pyloric stenosis or ulcers. Occasionally, it may be self-induced. Significant gastric fluid loss can occur via long-term nasogastric (NG) tube drainage.
Diuretic use may lead to increased chloride losses. It may also result in potassium loss, and hypokalemia may lead to metabolic alkalosis.
Obtain information about specific disease states such as primary hyperaldosteronism, reninism, hyperglucocorticoidism, Bartter syndrome, and deoxycorticosterone (DOC) excess syndromes.[11, 12]
Signs observed with metabolic alkalosis usually relate to the specific disease process that caused the acid-base disorder. Increased neuromuscular excitability (eg, from hypocalcemia) sometimes causes tetany or seizures. Generalized weakness may be noted if the patient also has hypokalemia.
Patients who develop metabolic alkalosis from vomiting can have symptoms related to severe volume contraction, with signs of dehydration that include tachycardia, dry mucous membranes, decreased skin turgor, postural hypotension, poor peripheral perfusion, and weight loss.
Although diarrhea typically produces a hyperchloremic metabolic acidosis, diarrheal stools may rarely contain significant amounts of chloride, as in the case of congenital chloride diarrhea. Children with this condition present at birth with watery diarrhea, metabolic alkalosis, and hypovolemia.
Weight gain and hypertension may accompany metabolic alkalosis that results from a hypermineralocorticoid state.
Blood Gas, Serum Electrolytes, and Spot Urine Chloride Measurements
Measurements of blood gas and serum electrolyte levels, including calcium, are the essential laboratory studies necessary for the initial evaluation of metabolic alkalosis. An algorithm for metabolic alkalosis is shown in the image below.
View Image
Algorithm for metabolic alkalosis.
Blood gas measurement typically shows elevated pH with a high bicarbonate (HCO3) level. With compensation, the partial pressure of carbon dioxide (PCO2) may also be near the reference range or elevated.
Serum electrolyte levels may show evidence of hypokalemia, hypercalcemia, hypochloremia, or hyponatremia.
A urine chloride level below 20 mEq/L indicates chloride-responsive metabolic alkalosis. A urine chloride level over 20 mEq/L indicates chloride-resistant metabolic alkalosis.
Patients with primary aldosteronism have metabolic alkalosis, hypokalemia, a urine chloride level above 20 mEq/L, and persistently elevated aldosterone levels despite a controlled sodium chloride (NaCl) intake of 12-15 g daily for 5 days.
Cushing syndrome is marked by hypersecretion of cortisol.
Primary reninism usually results from renovascular disease with hypertension.
Bartter syndrome manifests as hypokalemic metabolic alkalosis with secondary hyperaldosteronism and with renal potassium and chloride wasting.
Milk-alkali syndrome results from excessive oral intake of calcium, vitamin D metabolites, and absorbable alkali. Metabolic alkalosis in affected patients is usually accompanied by hypercalcemia.
Pyloric stenosis causes marked hypochloremia (due to loss of hydrochloric acid in gastric contents) and metabolic alkalosis. It is generally observed in male infants aged approximately 6-12 weeks. These patients present with protracted vomiting and frequently have significant dehydration and cachexia.
Mild or moderate metabolic alkalosis or alkalemia rarely requires correction. For severe metabolic alkalosis, therapy should address the underlying disease state, in addition to moderating the alkalemia. As with correction of any electrolyte or acid-base imbalance, the goal is to prevent life-threatening complications with the least amount of correction. The initial target pH and bicarbonate levels in correcting severe alkalemia are approximately 7.55 mmol/L and 40 mmol/L, respectively—which are not values within the reference range.
Consider the severity of the hypovolemia or hypokalemia and the degree of alkalosis when managing metabolic alkalosis due to chloride loss from vomiting or other gastrointestinal (GI) losses. Children with protracted vomiting, whether due to pyloric stenosis or other causes, may develop hypovolemic shock. Intravascular volume expansion with isotonic crystalloid solution is needed, and monitoring of the central venous pressure to determine adequacy of volume resuscitation may be indicated.
Administer potassium as a chloride salt to patients with hypokalemia to help replenish chloride losses. However, remember that using potassium chloride (KCl) alone to correct hypochloremia has limited utility, because the KCl infusion rate cannot exceed prescribed safe levels.
For persistent severe metabolic alkalosis, administration of HCl or ammonium chloride (NH4Cl) may be considered, but each must be administered with care.[13] Although uncommon, fatality from extravasated HCl has been reported.[14]
Acetazolamide may help patients with chloride-resistant metabolic alkalosis. It has been safely used for treatment of diuretic-induced metabolic alkalosis in pediatric cardiac patients.[15, 16, 17] Acetazolamide also appears to be as effective as arginine hydrochloride in correcting metabolic alkalosis in critically ill pediatric patients.[18]
However, the efficacy of acetazolamide appears to be mixed in pediatric cardiac surgery patients. Bar et al found that although acetazolamide had an overall effect in reducing plasma bicarbonate (HCO3) levels in 63 critically ill children on mechanical ventilation, this agent had no effect in the pediatric cardiac patients in their study; the reason for the difference in response was unclear.[8] The investigators indicated their findings did not support the use of acetazolamide for metabolic alkalosis in critically ill children with congenital heart disease.[8] In contrast, Lopez et al reported a reduction in levels of serum HCO3 and partial pressure of carbon dioxide (PCO2) in pediatric intensive care unit (PICU) cardiac patients with metabolic alkalosis secondary to diuretic therapy, as well as a significant increase in urine output in cardiac postoperative patients following administration of acetazolamide.[9]
Correction of metabolic alkalosis in patients with renal failure may require hemodialysis or continuous renal replacement therapy with a dialysate that contains high levels of chloride and low levels of HCO3. Note that use of the chelating agent sodium polystyrene sulfonate (SPS) for the treatment of hyperkalemia in children with chronic kidney disease may precipitate acute hypocalcemia and increased metabolic alkalosis.[19] Oral calcium supplementation and cessation of SPS therapy corrected the hypocalcemia in two affected children.[19]
Temporary discontinuation of chloruretic diuretics (eg, furosemide, bumetanide, ethacrynic acid) may help patients with metabolic alkalosis due to long-term diuretic use. Potassium-sparing diuretics and carbonic anhydrase inhibitors may be used in patients who require continued diuretic therapy. Patients with accompanying extracellular fluid (ECF) volume contraction occasionally require sodium and potassium administration. If continued diuretic use is indicated, administration of potassium salt supplements may help avoid metabolic alkalosis.
Severe metabolic alkalemia should be monitored in an ICU setting with full noninvasive cardiopulmonary monitoring. Invasive monitoring and specialized vascular access may be necessary, depending on the overall clinical picture.
Monitor serum electrolyte levels and acid-base status when providing treatment for metabolic alkalosis, particularly when using chloride salts. Provide follow-up care specific to the disease that caused metabolic alkalosis.
Children with pyloric stenosis require surgical intervention (pyloromyotomy) following intravascular fluid expansion and correction of metabolic abnormalities.
Tailor dietary changes to the underlying disease.
Metabolic alkalosis may be avoided by judicious use of long-term diuretics with appropriate monitoring.
Transfer considerations and consultations
The role of a pediatric tertiary care center where appropriate subspecialists are available in the care of a child with metabolic alkalosis cannot be overemphasized. If the patient requires dialysis or has a renal disease, such as Bartter syndrome, transfer the patient to a nephrologist. An endocrinologist should manage primary aldosteronism and mineralocorticoid excess states. Children who develop hypovolemic shock or those with persistent severe and symptomatic metabolic alkalosis are best monitored in a critical care setting.
Severe alkalemia should be initially managed in an ICU setting under the direction of a pediatric intensivist. Subsequent consultations should be obtained with specific specialists (eg, endocrinologist, nephrologist) to manage the underlying etiology responsible for the metabolic alkalosis.
Other considerations
Respiratory status and oxygenation must be monitored. Failure to realize that severe metabolic alkalosis can lead to hypoventilation and consequent hypoxemia could delay treatment and result in hypoxic damage.
Hydrochloric acid (HCl) can cause severe tissue necrosis if the solution extravasates into the tissues. In addition, use of high concentrations (ie, >0.1 N) of HCl can corrode central veins and venous catheters.
Physicians must be familiar with the complications associated with the use of chloride salts to treat severe metabolic alkalosis. Use of NH4Cl can result in hyperammonemia and encephalopathy. Carefully weigh use of chloride salts against risks. Use chloride salts only when absolutely necessary.
Patient education
Educate parents and, if age-appropriate, children placed on long-term diuretic therapy and those with diseases that can lead to metabolic alkalosis to recognize the symptoms of moderate to severe alkalosis. This knowledge allows them to promptly seek medical care.
Metabolic alkalosis that results from chloride depletion and volume contraction can often be corrected with volume replacement. Persistent severe metabolic alkalosis may require more specific therapy directed at moderating the alkalemia.
Clinical Context:
IV HCl may be indicated in severe metabolic alkalosis (pH >7.55) or when NaCl or KCl 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, cardiac arrhythmia, hepatic encephalopathy, digoxin toxicity).
The amount of HCl required to correct metabolic alkalosis is determined by estimating the amount of pH deficit, the volume, and the infusion rate of HCl solution. The typical HCl preparation contains 0.1 N solution (ie, 100 mmol H+/L [mEq/L]) in D5W or 0.9% NaCl).
Clinical Context:
Ammonium chloride is administered to correct severe metabolic alkalosis related to chloride deficiency. NH4Cl is converted to ammonia and HCl by the liver. By releasing HCl, NH4Cl may help correct metabolic alkalosis.
This agent is available as 500-mg tabs and 26.75% parenteral formulation for IV use. The parenteral formulation contains 5 mEq/mL (267.5 mg/mL).
Clinical Context:
Potassium is essential for transmission of nerve impulses, contraction of cardiac muscle, and maintenance of intracellular tonicity, skeletal and smooth muscles, and normal renal function. Metabolic alkalosis is often associated with hypokalemia.
These solutions are the recommended therapeutic agents for rapid correction of severe metabolic alkalosis, especially metabolic alkalosis due to gastric losses of chloride.
Clinical Context:
Captopril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.
Clinical Context:
Lisinopril prevents the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor, resulting in lower aldosterone secretion.
ACE inhibitors block the conversion of angiotensin I to angiotensin II and prevent the secretion of aldosterone from the adrenal cortex. These agents are indicated in metabolic alkalosis due to hyperaldosteronism.
Clinical Context:
Acetazolamide is a carbonic anhydrase inhibitor that blocks HCO3 reabsorption in the proximal renal tubules. It causes increased renal excretion of sodium vs chloride, causing a net increase in serum chloride. Acetazolamide is also a diuretic and, therefore, may help decrease extracellular fluid (ECF) volume that frequently accompanies chloride-resistant metabolic alkalosis.
Clinical Context:
Triamterene interferes with potassium/sodium exchange (active transport) in the distal tubule, cortical collecting tubule, and collecting duct by inhibiting sodium/potassium adenosine triphosphatase (ATPase). This agent decreases calcium excretion and increases magnesium loss.
Clinical Context:
Spironolactone is an aldosterone antagonist that competitively inhibits binding to the aldosterone receptor. It competes for receptor sites in distal renal tubules and increases water excretion while retaining potassium and hydrogen ions needed to restore the acid-base balance.
Clinical Context:
Amiloride is a pyrazine-carbonyl-guanidine that is unrelated chemically to other known potassium-conserving (antikaliuretic) or diuretic agents. It is an antikaliuretic drug, which, compared with thiazide diuretics, possesses weak natriuretic, diuretic, and antihypertensive activity.
Lennox H Huang, MD, FAAP, Chief Medical Officer, The Hospital for Sick Children; Associate Professor of Pediatrics, University of Toronto Faculty of Medicine; Associate Clinical Professor of Pediatrics, McMaster University School of Medicine, Canada
Disclosure: Nothing to disclose.
Coauthor(s)
Jonathan Sniderman, MD, Fellow in Pediatric Intensive Care, Department of Pediatrics, University of Toronto Faculty of Medicine, Canada
Disclosure: Nothing to disclose.
Margaret A Priestley, MD, Associate Professor of Clinical Anesthesiology and Critical Care, Perelman School of Medicine at the University of Pennsylvania; Clinical Director, Pediatric Intensive Care Unit, The Children's Hospital of Philadelphia
Disclosure: Nothing to disclose.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Barry J Evans, MD, Assistant Professor of Pediatrics, Temple University Medical School; Director of Pediatric Critical Care and Pulmonology, Associate Chair for Pediatric Education, Temple University Children's Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Timothy E Corden, MD, Associate Professor of Pediatrics, Co-Director, Policy Core, Injury Research Center, Medical College of Wisconsin; Associate Director, PICU, Children's Hospital of Wisconsin
Disclosure: Nothing to disclose.
Additional Contributors
G Patricia Cantwell, MD, FCCM, Professor of Clinical Pediatrics, Chief, Division of Pediatric Critical Care Medicine, University of Miami Leonard M Miller School of Medicine/ Holtz Children's Hospital, Jackson Memorial Medical Center; Medical Director, Palliative Care Team, Holtz Children's Hospital; Medical Manager, FEMA, South Florida Urban Search and Rescue, Task Force 2
Disclosure: Nothing to disclose.
References
Singh AK. Metabolic alkalosis. In: Mushlin SB, Greene HL II, eds. Decision Making in Medicine: An Algorithmic Approach. 3rd ed. Philadelphia, PA: Mosby Elsevier; 2010. 374-5.
){kind=link}