1
Fluid and Electrolytes
Respiratory acidosis
Respiratory acidosis is a condition that occurs when the
lungs cannot remove all of the carbon dioxide the body
produces. This causes body fluids, especially the blood, to
become too acidic.
Respiratory acidosis is an acid-base balance disturbance
due to alveolar hypoventilation. Production of carbon dioxide
occurs rapidly and failure of ventilation promptly increases
the partial pressure of arterial carbon dioxide (PaCO2). [1] The
normal reference range for PaCO2 is 35-45 mm Hg.
Alveolar hypoventilation leads to an increased PaCO2 (ie,
hypercapnia). The increase in PaCO2, in turn, decreases the
bicarbonate (HCO3–)/PaCO2 ratio, thereby decreasing the
pH. Hypercapnia and respiratory acidosis ensue when
impairment in ventilation occurs and the removal of carbon
dioxide by the respiratory system is less than the production
of carbon dioxide in the tissues.
Lung diseases that cause abnormalities in alveolar gas
exchange do not typically result in alveolar hypoventilation.
Often these diseases stimulate ventilation and hypocapnia
due to reflex receptors and hypoxia. Hypercapnia typically
occurs late in the disease process with severe pulmonary
disease or when respiratory muscles fatigue.
Acute vs chronic respiratory acidosis
Respiratory acidosis can be acute or chronic. In acute
respiratory acidosis, the PaCO2 is elevated above the upper
limit of the reference range (ie, >45 mm Hg) with an
accompanying acidemia (ie, pH < 7.35). In chronic
respiratory acidosis, the PaCO2 is elevated above the upper
limit of the reference range, with a normal or near-normal pH
secondary to renal compensation and an elevated serum
bicarbonate levels (ie, >30 mEq/L).
Acute respiratory acidosis is present when an abrupt failure
of ventilation occurs. This failure in ventilation may result
from depression of the central respiratory center by one or
another of the following:
● Central nervous system disease or
drug-induced respiratory depression
● Inability to ventilate adequately, due to a
neuromuscular disease or paralysis (eg,
myasthenia gravis, amyotrophic lateral
sclerosis [ALS], Guillain-Barré syndrome,
muscular dystrophy)
● Airway obstruction, usually related to asthma
or chronic obstructive pulmonary disease
(COPD)
Chronic respiratory acidosis may be secondary to many
disorders, including COPD. Hypoventilation in COPD
involves multiple mechanisms, including the following:
● Decreased responsiveness to hypoxia and
hypercapnia
● Increased ventilation-perfusion mismatch
leading to increased dead space ventilation
● Decreased diaphragmatic function due to
fatigue and hyperinflation
Chronic respiratory acidosis also may be secondary to
obesity hypoventilation syndrome (OHS—ie, Pickwickian
syndrome), neuromuscular disorders such as ALS, and
severe restrictive ventilatory defects such as are observed in
interstitial fibrosis and thoracic skeletal deformities.
Causes
Causes of respiratory acidosis include:
● Diseases of the airways, such as asthma and
COPD
● Diseases of the lung tissue, such as pulmonary
fibrosis, which causes scarring and thickening of
the lungs
● Diseases that can affect the chest, such as
scoliosis
● Diseases affecting the nerves and muscles that
signal the lungs to inflate or deflate
● Medicines that suppress breathing, including
powerful pain medicines, such as narcotics
(opioids), and "downers," such as benzodiazepines,
often when combined with alcohol
● Severe obesity, which restricts how much the lungs
can expand
● Obstructive sleep apnea
●
Chronic respiratory acidosis occurs over a long time. This
leads to a stable situation, because the kidneys increase
body chemicals, such as bicarbonate, that help restore the
body's acid-base balance.
Acute respiratory acidosis is a condition in which carbon
dioxide builds up very quickly, before the kidneys can return
the body to a state of balance.
Some people with chronic respiratory acidosis get acute
respiratory acidosis because an acute illness makes their
condition worse and disrupts their body's acid-base balance.
● COPD – Emphysema, chronic bronchitis,
severe asthma [5, 6]
● Neuromuscular diseases – ALS, diaphragm
dysfunction and paralysis, Guillain-Barré
syndrome, myasthenia gravis, muscular
dystrophy, botulism
● Chest wall disorders – Severe
kyphoscoliosis, status post thoracoplasty,
flail chest, and, less commonly, ankylosing
spondylitis, pectus excavatum, [7] or pectus
carinatum
● Obesity-hypoventilation syndrome
● Obstructive sleep apnea (OSA)
● Central nervous system (CNS) depression –
Drugs (eg, narcotics, barbiturates,
benzodiazepines, and other CNS
depressants), neurologic disorders (eg,
encephalitis, brainstem disease, and
trauma), primary alveolar hypoventilation, or
congenital central alveolar hypoventilation
syndrome (Ondine curse)
● Other lung and airway diseases – Laryngeal
and tracheal stenosis, interstitial lung
disease

● Lung-protective mechanical ventilation with
permissive hypercapnia in the treatment of
acute respiratory distress syndrome (ARDS);
these patients typically are heavily sedated
and may require paralytic agents
● Acute respiratory acidosis may develop
rapidly during bronchoscopy-guided
percutaneous dilation tracheostomy from a
reduced minute ventilation (aimed at
lung-protective ventilation) [8]
● Hypermetabolic states such as sepsis,
malignant hyperthermia, thyroid crisis, fever,
and overfeeding can elevate carbon dioxide
levels; similarly, administration of
bicarbonate to buffer acidosis or
citrate-containing anticoagulants used in
dialysis may lead to elevated partial arterial
pressure of carbon dioxide (PaCO2) levels;
these may result in the development of acute
respiratory acidosis in the critically ill patient
Alveolar ventilation
Alveolar ventilation is under the control of the central
respiratory centers, which are located in the pons and the
medulla. Ventilation is influenced and regulated by
chemoreceptors for PaCO2, partial pressure of arterial
oxygen (PaO2), and pH located in the brainstem, as well as
by neural impulses from lung-stretch receptors and impulses
from the cerebral cortex. Failure of ventilation quickly results
in an increase in the PaCO2.
Physiologic compensation
In acute respiratory acidosis, the body’s compensation
occurs in 2 steps. The initial response is cellular buffering
that takes place over minutes to hours. Cellular buffering
elevates plasma bicarbonate values, but only slightly
(approximately 1 mEq/L for each 10-mm Hg increase in
PaCO2). The second step is renal compensation that occurs
over 3-5 days. With renal compensation, renal excretion of
carbonic acid is increased, and bicarbonate reabsorption is
increased.
The expected change in serum bicarbonate concentration in
respiratory acidosis can be estimated as follows:
● Acute respiratory acidosis – Bicarbonate
increases by 1 mEq/L for each 10-mm Hg
rise in PaCO2.The acute change in
bicarbonate is, therefore, relatively modest
and is generated by the blood, extracellular
fluid, and cellular buffering system.
● Chronic respiratory acidosis – Bicarbonate
increases by 3.5 mEq/L for each 10-mm Hg
rise in PaCO2. The greater change in
bicarbonate in chronic respiratory acidosis is
accomplished by the kidneys. The response
begins soon after the onset of respiratory
acidosis but requires 3-5 days to become
complete.
The expected change in pH with respiratory acidosis can be
estimated with the following equations:
● Acute respiratory acidosis – Change in pH =
0.008 × (40 – PaCO2)
● Chronic respiratory acidosis – Change in pH
= 0.003 × (40 – PaCO2)
● patients.
Respiratory acidosis does not have a great effect on serum
electrolyte levels. Some small effects occur in calcium and
potassium levels. Acidosis decreases binding of calcium to
albumin and tends to increase serum ionized calcium levels.
2
In addition, acidemia causes an extracellular shift of
potassium.
Symptoms
Symptoms may include:
● Confusion
● Anxiety
● Easy fatigue
● Lethargy
● Shortness of breath
● Sleepiness
● Tremors (shaking)
● Warm and flushed skin
● Sweating
Exams and Tests
The health care provider will perform a physical exam and
ask about symptoms.
Tests that may be done include:
● Arterial blood gas, which measures oxygen and
carbon dioxide levels in the blood
● Basic metabolic panel
● Chest x-ray
● CT scan of the chest
● Pulmonary function test to measure breathing and
how well the lungs are functioning
Workup in respiratory acidosis
Arterial blood gas (ABG) analysis is necessary in the
evaluation of a patient with suspected respiratory acidosis or
other acid-base disorders. [4] The bicarbonate level reported
on the blood gas analysis is calculated from the
Henderson-Hasselbalch equation. Thus, a measured serum
bicarbonate level must also be obtained. Other tests that
may be helpful include serum electrolytes and
biochemistries, thyroid studies, a complete blood count
(CBC), and drug and toxicology screens.
Acidemia is documented by the presence of a decreased pH
(< 7.35) on ABG analysis. The presence of an increased
partial pressure of arterial carbon dioxide (PaCO2) (>45 mm
Hg) indicates a respiratory etiology of the acidemia.
Hypoxemia may be present and is frequently associated with
pulmonary diseases that cause respiratory acidosis.
The most common abnormal serum electrolyte finding in
chronic respiratory acidosis is the presence of a
compensatory increase in serum bicarbonate concentration.
Some patients with hypothyroidism hypoventilate. In
addition, hypothyroidism may cause obesity, leading to
obstructive sleep apnea (OSA) and sleep apnea–related
hypoventilation. Obesity hypoventilation syndrome (OHS)
also leads to chronic respiratory acidosis. A thyrotropin and
a free T4 level should, therefore, be considered in selected
Many patients with chronic hypercapnia and respiratory
acidosis are also hypoxemic. These patients may have
secondary polycythemia, as demonstrated by elevated
hemoglobin and hematocrit values.

Drug and toxicology screens should be performed in patients
presenting with unexplained hypercapnia and respiratory
acidosis. Screening for specific drugs, including opiates,
barbiturates, and benzodiazepines, should be performed.
A study by Sadot et al found alveolar hypoventilation to be
frequent among children undergoing flexible bronchoscopy.
The investigators stated, therefore, that during the procedure
children, especially those susceptible to complications from
respiratory acidosis or who are expected to need a large
amount of sedation, should be monitored for a rise in
transcutaneous carbon dioxide, an indicator of alveolar
hypoventilation. The study included 95 children.
A thyrotropin and a free T4 level should be considered in
selected patients, since hypothyroidism may cause obesity,
leading to obstructive sleep apnea (OSA) and sleep
apnea–related hypoventilation.
Many patients with chronic hypercapnia and respiratory
acidosis are also hypoxemic. These patients may have
secondary polycythemia, as demonstrated by elevated
hemoglobin and hematocrit values.
In patients without an obvious source of hypoventilation and
respiratory acidosis, a drug screen should be performed.
The effects of sedating drugs such as narcotics and
benzodiazepines in depressing the central ventilatory drive
and causing respiratory acidosis should be considered.
These sedative drugs should be avoided, if possible, in
patients with respiratory acidosis.
Radiography, computed tomography (CT) scanning, and
fluoroscopy of the chest may provide helpful information in
determining causes of respiratory acidosis. Radiologic
studies (CT scanning and magnetic resonance imaging
[MRI]) of the brain should be considered if a central cause of
hypoventilation and respiratory acidosis is suspected.
Plain Radiography and Fluoroscopy
Chest radiography should be performed to help rule out
pulmonary disease as a cause of hypercapnia and
respiratory acidosis. Findings on chest radiographs that may
help determine an etiology of respiratory acidosis include the
following:
● Hyperinflation and diaphragmatic flattening
due to severe obstructive airway disease
● Infiltrates secondary to pneumonias
● Elevated diaphragm related to diaphragmatic
weakness or paralysis
● Pneumothorax
● Atelectasis
● Thoracic skeletal deformities
If complicating pulmonary hypertension is present, the hilar
vascular shadows may be prominent and the cardiac
silhouette may show evidence of right ventricular
enlargement.
A fluoroscopic “sniff test,” in which paradoxical elevation of
the paralyzed diaphragm is observed with inspiration, can
confirm diaphragmatic paralysis, even in the presence of a
normal appearance on chest radiographs. However, this test
is not as useful in bilateral diaphragmatic paralysis as it is in
unilateral diaphragmatic paralysis.
CT and MRI
A CT scan of the chest may be obtained if the results of
chest radiography are inconclusive or if a pulmonary
disorder remains high on the differential diagnosis. CT
scanning is more sensitive than plain radiography for
detecting pulmonary diseases and may reveal abnormalities
not observed on chest radiographs.
3
Specific etiologies that may be diagnosed by using brain CT
scanning include stroke, central nervous system (CNS)
tumor, and CNS trauma. Pay particular attention to the
brainstem for lesions in the pons and medulla.
If a central cause of hypoventilation and respiratory acidosis
is suspected and after initial findings brain CT imaging is
negative or inconclusive, a MRI of the brain should be
perfromed. MRI may disclose abnormalities not observed on
CT scans, particularly in the brainstem.
Pulmonary function test measurements are required for the
diagnosis of obstructive lung disease and for assessment of
the severity of disease. Forced expiratory volume in 1
second (FEV1.0) is the most commonly used index of airflow
obstruction.
Pulmonary Function Testing
Pulmonary function test measurements are required for the
diagnosis of obstructive lung disease and for assessment of
the severity of disease. Forced expiratory volume in 1
second (FEV1.0) is the most commonly used index of airflow
obstruction. The ratio of FEV1.0 to forced vital capacity (FVC)
(ie, FEV1.0/FVC), is reduced and is the diagnostic variable in
airflow obstruction.
Lung volume measurements may document an increase in
total lung capacity (TLC), functional residual capacity (FRC),
and residual volume (RV) in obstructive airway diseases.
TLC is decreased in restrictive lung diseases. Measurement
of maximal inspiratory and expiratory pressures may be
useful in screening for respiratory muscle weakness.
Electromyography (EMG) and measurement of nerve
conduction velocity (NCV) are useful in diagnosing
neuromuscular disorders (eg, myasthenia gravis,
Guillain-Barré syndrome, and amyotrophic lateral sclerosis
[ALS]), which can cause ventilatory muscle weakness.
MG and Nerve Conduction Velocity
Electromyography (EMG) and measurement of nerve
conduction velocity (NCV) are useful in diagnosing
neuromuscular disorders (eg, myasthenia gravis,
Guillain-Barré syndrome, and amyotrophic lateral sclerosis
[ALS]), which can cause ventilatory muscle weakness.
These studies may reveal a neuropathic pattern or a
myopathic pattern, depending on the etiology of the
diaphragmatic and respiratory muscle dysfunction. Some
centers can perform phrenic nerve conduction studies and
diaphragmatic EMG in the workup of diaphragmatic
dysfunction.
The clinical manifestations of respiratory acidosis are often
those of the underlying disorder. Manifestations vary,
depending on the severity of the disorder and on the rate of
development of hypercapnia. Mild to moderate hypercapnia
that develops slowly typically has minimal symptoms.
Measurement of Transdiaphragmatic Pressure
Measurement of transdiaphragmatic pressure is a useful
diagnostic test for documenting respiratory muscle
weakness. However, it is difficult to perform, and it is usually
performed only in specialized pulmonary function
laboratories.
The test is performed by placing an esophageal catheter
with an esophageal balloon and a gastric balloon. The
difference between the pressures measured at the 2
balloons is the transdiaphragmatic pressure. Patients with
diaphragmatic dysfunction and paralysis have a decrease in
maximal transdiaphragmatic pressure.

Capnography, or end-tidal carbon dioxide monitoring
Capnography is a noninvasive bedside diagnostic tool for
measurement of the partial pressure of carbon dioxide in
exhaled breath, especially in the operating room, endoscopy
suite settings, and the emergency department (ED) setting.
A meta-analysis of 13 randomized, controlled trials showed
that with capnography monitoring, employed in combination
with visual assessment and pulse oximetry, there was a
reduction in respiratory compromise during procedural
sedation and analgesia administered for ambulatory surgery,
in comparison with the use of visual assessment and pulse
oximetry alone.
Patients may be anxious and may complain of dyspnea.
Some patients may have disturbed sleep and daytime
hypersomnolence. As the partial arterial pressure of carbon
dioxide (PaCO2) increases, the anxiety may progress to
delirium, and patients become progressively more confused,
somnolent, and obtunded. This condition is sometimes
referred to as carbon dioxide narcosis.
Physical Examination
Physical examination findings in patients with respiratory
acidosis are usually nonspecific and are related to the
underlying illness or the cause of the respiratory acidosis.
Thoracic examination of patients with obstructive lung
disease may demonstrate diffuse wheezing, hyperinflation
(ie, barrel chest), decreased breath sounds, hyperresonance
on percussion, and prolonged expiration. Rhonchi may also
be heard.
Cyanosis may be noted if accompanying hypoxemia is
present. Digital clubbing may indicate the presence of a
chronic respiratory disease or other organ system disorders.
The patient’s mental status may be depressed if severe
elevations of PaCO2 are present. Patients may have
asterixis, myoclonus, and seizures.
Papilledema may be found during the retinal examination.
Conjunctival and superficial facial blood vessels may also be
dilated.
A study by Zorrilla-Riveiro et al of 212 patients indicated that
in persons with dyspnea, nasal flaring is a sign of respiratory
acidosis.
Treatment
Treatment is aimed at the underlying disease, and may
include:
● Bronchodilator medicines and corticosteroids to
reverse some types of airway obstruction
● Noninvasive positive-pressure ventilation
(sometimes called CPAP or BiPAP) or a breathing
machine, if needed
● Oxygen if the blood oxygen level is low
● Treatment to stop smoking
● For severe cases, a breathing machine (ventilator)
might be needed
● Changing medicines when appropriate
Management of respiratory acidosis
Pharmacologic therapies are generally used as treatment for
the underlying disease process. Oxygen therapy is
4
employed to prevent the sequelae of long-standing
hypoxemia.
Therapeutic measures that may be lifesaving in severe
hypercapnia and respiratory acidosis include endotracheal
intubation with mechanical ventilation and noninvasive
positive pressure ventilation (NIPPV) techniques such as
nasal continuous positive-pressure ventilation (NCPAP) and
nasal bilevel ventilation. The latter techniques of NIPPV are
preferred treatment for obesity hypoventilation syndrome
(OHS) and neuromuscular disorders, because they help to
improve partial pressure of arterial oxygen (PaO2) and
decrease the partial pressure of arterial carbon dioxide
(PaCO2).
Noninvasive external negative-pressure ventilation devices
are also available for the treatment of selected patients with
chronic respiratory failure.
Rapid correction of the hypercapnia by the application of
external noninvasive positive-pressure ventilation or invasive
mechanical ventilation can result in alkalemia. Accordingly,
these techniques should be used with caution.
Treatment of respiratory acidosis is primarily directed at the
underlying disorder or pathophysiologic process. Caution
should be exercised in the correction of chronic hypercapnia:
too-rapid correction of the hypercapnia can result in
metabolic alkalemia. Alkalization of the cerebrospinal fluid
(CSF) can result in seizures.
The criteria for admission to the intensive care unit (ICU)
vary from institution to institution but may include patient
confusion, lethargy, respiratory muscle fatigue, and a low pH
(< 7.25). All patients who require tracheal intubation and
mechanical ventilation must be admitted to the ICU. Most
acute care facilities require that all patients being treated
acutely with noninvasive positive-pressure ventilation
(NIPPV) be admitted to the ICU.
Consider consultation with pulmonologists and neurologists
for assistance with the evaluation and treatment of
respiratory acidosis. Results from the history, physical
examination, and available laboratory studies should guide
the selection of the subspecialty consultants.
Pharmacologic Therapy
Pharmacologic therapies are generally used as treatment for
the underlying disease process.
Bronchodilators
Bronchodilators such as beta agonists (eg, albuterol and
salmeterol), anticholinergic agents (eg, ipratropium bromide
and tiotropium), and methylxanthines (eg, theophylline) are
helpful in treating patients with obstructive airway disease
and severe bronchospasm. Theophylline may improve
diaphragm muscle contractility and may stimulate the
respiratory center.
Respiratory stimulants
Respiratory stimulants have been used but have limited
efficacy in respiratory acidosis caused by disease.
Medroxyprogesterone increases central respiratory drive and
may be effective in treating obesity-hypoventilation
syndrome (OHS). Medroxyprogesterone has also been
shown to stimulate ventilation is some patients with COPD
and alveolar hypoventilation. This medication does not
improve apnea frequency or sleepiness symptoms in
patients with sleep apnea.
There is an increased risk of thromboembolism with
progestational agents. Many experts do not recommend the
use of medroxyprogesterone as a means to increase
alveolar ventilation.
Acetazolamide is a diuretic that increases bicarbonate
excretion and induces a metabolic acidosis, which

subsequently stimulates ventilation. However, acetazolamide
must be used with caution in this setting. Inducing a
metabolic acidosis in a patient with a respiratory acidosis
could result in a severely low pH. If the patient's respiratory
system cannot compensate for the metabolic acidosis it
induces, the patient may suffer hyperkalemia and potentially
a life-threatening cardiac arrhythmia.
Theophylline increases diaphragm muscle strength and
stimulates the central ventilatory drive. In addition,
theophylline is a bronchodilator.
Drug antagonists
Drug therapy aimed at reversing the effects of certain
sedative drugs may be helpful in the event of an accidental
or intentional overdosage. Naloxone may be used to reverse
the effects of narcotics. Flumazenil may be used to reverse
the effects of benzodiazepines. However, care must be taken
in reversing the effects of benzodiazepines because patients
may have seizures if benzodiazepine reversal is
accomplished too vigorously.
Bicarbonate
Infusion of sodium bicarbonate is rarely indicated. This
measure may be considered after cardiopulmonary arrest
with an extremely low pH (< 7.0-7.1). In most other
situations, sodium bicarbonate has no role in the treatment
of respiratory acidosis.
Oxygen Therapy
Because many patients with hypercapnia are also
hypoxemic, oxygen therapy may be indicated. Oxygen
therapy is employed to prevent the sequelae of
long-standing hypoxemia. Patients with COPD who meet the
criteria for oxygen therapy have been shown to have
decreased mortality when treated with continuous oxygen
therapy. Oxygen therapy has also been shown to reduce
pulmonary hypertension in some patients.
Oxygen therapy should be used with caution because it may
worsen hypercapnia in some situations. For example,
patients with COPD may experience exacerbation of
hypercapnia during oxygen therapy. This observation is
thought by many to be primarily a consequence of
ventilation-perfusion mismatching, in opposition to the
commonly accepted concept of a reduction in hypoxic
ventilatory drive. The exact pathophysiology, however,
remains controversial.
Hypercapnia is best avoided by titrating oxygen delivery to
maintain oxygen saturation in the low 90% range and partial
arterial pressure of oxygen (PaO2) in the range of 60-65 mm
Hg.
Ventilatory Support
Therapeutic measures that may be lifesaving in severe
hypercapnia and respiratory acidosis include endotracheal
intubation with mechanical ventilation and noninvasive
positive pressure ventilation (NIPPV) techniques such as
nasal continuous positive-pressure ventilation (NCPAP) and
nasal bilevel ventilation. The latter techniques of NIPPV are
preferred treatment for OHS and neuromuscular disorders,
because they help to improve PaO2 and decrease the partial
pressure of arterial carbon dioxide (PaCO2).
Noninvasive external negative-pressure ventilation devices
are also available for the treatment of selected patients with
chronic respiratory failure.
5
Rapid correction of the hypercapnia by the application of
external noninvasive positive-pressure ventilation or invasive
mechanical ventilation can result in alkalemia. Accordingly,
these techniques should be used with caution.
A study comparing noninvasive techniques with invasive
ventilation in myasthenic crisis found that patients who
underwent noninvasive ventilation had better outcomes than
patients who underwent invasive ventilation. [24]
A 4-year retrospective study reported that NIPPV was highly
beneficial in the treatment of COPD with hypercapnia (type
II) respiratory failure. [25] NIPPV led to a decreased length of
stay and a reduced cost of hospitalization.
Based on a literature review, Fielding-Singh et al
recommended that in refractory respiratory acidosis resulting
from ARDS, patients be treated with “initial modest
liberalization of tidal volumes, followed by neuromuscular
blockade and prone positioning.” [26]
A study by Nentwich et al indicated that in patients with
hypercapnia and concomitant renal failure, respiratory
acidosis can be decreased and ventilation requirements
reduced through the use of low-flow extracorporeal CO2
removal in combination with renal replacement therapy. [27]
Investigational therapy
Extracorporeal carbon dioxide removal (ECCO2 R) is a
newer technique for removing carbon dioxide via
venovenous bypass without affecting oxygenation. ECCO2 R
is being evaluated in the treatment of respiratory acidosis as
a complication of the low tidal volume lung-protective
ventilation with permissive hypercapnia. However, this
technique has been associated with serious complications
and requires more investigation.
Beta2 Agonists
Class Summary
Beta2 agonists, by decreasing muscle tone in both small and
large airways in the lungs, increase ventilation. Beta2
agonists activate the beta2 -adrenergic receptors on the
surface of smooth muscle cells of the bronchial airways,
thereby increasing intracellular cyclic adenosine
monophosphate (cAMP). This interaction results in smooth
muscle relaxation.
The short-acting beta2 agonists (albuterol, levalbuterol,
metaproterenol, and pirbuterol) are used for the treatment or
prevention of bronchospasm. These medications are
typically delivered to the bronchial smooth muscles through
inhalation of aerosolized or nebulized preparations of these
medications. Oral preparations of albuterol and
metaproterenol are available but are less effective and more
prone to complications.
The long-acting beta2 agonists (arformoterol, formoterol,
indacaterol, and salmeterol) are typically used in patients
with more persistent symptoms. The bronchodilating effects
of these drugs last more than 12 hours. Each requires
twice-daily dosing, except for indacaterol, which is
administered once daily.
Albuterol (Proventil HFA, Ventolin HFA, AccuNeb, ProAir
HFA)
Albuterol is a beta agonist for bronchospasm that is
refractory to epinephrine. This agent relaxes bronchial
smooth muscle through its action on beta2 receptors; it has
little effect on cardiac muscle contractility.
Salmeterol (Serevent Diskus)
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By relaxing the smooth muscles of the bronchioles in
conditions associated with bronchitis, emphysema, asthma,
or bronchiectasis, salmeterol can relieve bronchospasms. It
also may facilitate expectoration. The long-acting
bronchodilating effect of salmeterol lasts for more than 12

hours. This agent is used on a fixed schedule, in addition to
regular use of anticholinergic agents. When salmeterol is
administered at higher or more frequent doses than
recommended, the incidence of adverse effects is higher.
Metaproterenol
Metaproterenol is a beta2-adrenergic agonist that relaxes
bronchial smooth muscle, with little effect on heart rate.
Levalbuterol (Xopenex, Xopenex HFA)
Levalbuterol acts on beta2 receptors, causing relaxation of
bronchial smooth muscle, with little effect on heart rate.
Pirbuterol (Maxair)
Pirbuterol is a beta2-adrenergic agonist with a structure
similar to that of albuterol. Binding to beta2-adrenergic
receptors causes relaxation of bronchial smooth muscle.
Formoterol (Foradil, Perforomist)
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Formoterol acts on beta2 receptors, with little effect on the
cardiovascular system. It is long acting and relaxes the
smooth muscles of the bronchioles, with little effect on heart
rate.
Indacaterol (Arcapta Neohaler)
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Indacaterol acts on beta2 receptors, with little effect on the
cardiovascular system. It is long acting and relaxes the
smooth muscles of the bronchioles, with little effect on heart
rate.
Arformoterol (Brovana)
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Arformoterol acts on beta2 receptors, with little effect on the
cardiovascular system. It is long acting and relaxes the
smooth muscles of the bronchioles, with little effect on heart
rate.
Anticholinergics, Respiratory
Class Summary
The anticholinergic medications compete with acetylcholine
for postganglionic muscarinic receptors, thereby inhibiting
cholinergically mediated bronchomotor tone and resulting in
bronchodilatation. These agents effectively block vagally
mediated reflex arcs that cause bronchoconstriction. When
inhaled, these medications are poorly absorbed systemically
and are, therefore, relatively safe.
Compared with beta2-adrenergic agents, the inhaled
short-acting anticholinergic medication ipratropium has
equivalent-to-superior bronchodilator activity in stable
chronic obstructive pulmonary disease (COPD) patients.
When ipratropium is used in combination with
beta2-adrenergic agonists, a synergistic effect on
bronchodilatation occurs. This medication has a slower
onset of action than the beta2-adrenergic agents and is,
therefore, less suitable for use on an as-needed basis.
Ipratropium (Atrovent HFA)
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Ipratropium is an anticholinergic bronchodilator that is
chemically related to atropine. It inhibits serous and
seromucous gland secretions.
Tiotropium (Spiriva)
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Tiotropium is a quaternary ammonium compound that elicits
anticholinergic and antimuscarinic effects with inhibitory
effects on M3 receptors on airway smooth muscles, leading
to bronchodilation. This agent is available in a capsule form
that contains a dry powder for oral inhalation via the
HandiHaler inhalation device. Tiotropium helps patients by
6
dilating narrowed airways and keeping them open for 24
hours. It is given once daily.
anthine Derivatives
Class Summary
Xanthine derivatives such as theophylline inhibit
phosphodiesterase, resulting in an increase in cAMP. The
increase in cAMP causes relaxation of bronchial smooth
muscle. Theophylline is dosed orally. Its analogue,
aminophylline, can be given intravenously (IV). In addition,
theophylline may improve diaphragmatic muscle contractility
and stimulate the central nervous system (CNS) respiratory
center.
Theophylline (Theo-24, Elixophyllin)
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Theophylline potentiates exogenous catecholamines by
stimulating endogenous catecholamine release and
diaphragmatic muscular relaxation, which, in turn, stimulates
bronchodilation. The popularity of this agent has decreased
because of its narrow therapeutic range and its toxicities.
Theophylline's therapeutic range is relatively narrow,
between 8-15 mg/dL. Unfortunately, bronchodilation may
require near-toxic levels (>20 mg/dL). The clinical efficacy of
this agent is controversial, especially in the acute setting.
Corticosteroids
Class Summary
Inflammation plays a significant role in the pathogenesis of
asthma. Although the inflammatory pathway mediators differ,
inflammation is also important in the pathogenesis of COPD.
Accordingly, glucocorticosteroids are used to temper the
inflammation in these diseases.
The inhaled glucocorticoids (budesonide, fluticasone, and
mometasone) have a direct route to the airways. They are
only minimally absorbed systemically and thus have fewer
adverse side effects than systemic glucocorticoids do.
Inhaled glucocorticoids improve airflow in asthmatic patients
by reducing inflammation and, in the long-term, preventing
airway remodeling. These medications are less effective in
COPD patients. They may slow the rate of progression in
patients with COPD.
The systemic glucocorticoids (methylprednisolone,
prednisone, and prednisolone) are highly efficacious in the
treatment of acute exacerbations of asthma. They are also
widely accepted and recommended in the treatment of
COPD exacerbations. For long-term use of these
medications, the adverse effect profile must be weighed
against the potential benefits.
Budesonide inhaled (Pulmicort Flexhaler, Pulmicort
Respules)
● View full drug information
Budesonide reduces inflammation in airways by inhibiting
multiple types of inflammatory cells and decreasing the
production of cytokines and other mediators involved in
bronchospasm. This agent is available as Pulmicort
Flexhaler powder for inhalation (90 µg/actuation and 180
µg/actuation; each actuation delivers 80 µg and 160 µg,
respectively) or Pulmicort Respules.
Fluticasone inhaled (Flovent Diskus, Flovent HFA)
● View full drug information
Fluticasone may decrease the number and activity of
inflammatory cells, in turn decreasing airway
hyperresponsiveness. It also has vasoconstrictive activity.
Mometasone (Asmanex Twisthaler)
Mometasone reduces inflammation in airways by inhibiting
multiple types of inflammatory cells and decreasing the

production of cytokines and other mediators involved in
bronchospasm.
Methylprednisolone (A-Methapred, Medrol, Solu-Medrol)
● View full drug information
Methylprednisolone decreases inflammation by suppressing
the migration of polymorphonuclear leukocytes (PMNs) and
reversing increased capillary permeability.
Prednisone
● View full drug information
The immunosuppressant prednisone is a first-line therapy
administered for the treatment of autoimmune disorders. It
may decrease inflammation by reversing increased capillary
permeability and suppressing PMN activity and CD4 counts.
Prednisolone (Pediapred, Flo-Pred, Orapred)
● View full drug information
Prednisolone may reduce inflammation by reversing
increased capillary permeability and suppressing PMN
activity and CD4 counts.
Opioid Antagonists
Class Summary
Opioid abuse, toxicity, and overdose are potential etiologies
of hypoventilation and respiratory acidosis. Opioid
antagonists can be used to reverse the effects of opiates and
to improve ventilation.
Naloxone
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Naloxone is a pure opioid antagonist that prevents or
reverses opioid effects (eg, hypotension, respiratory
depression, and sedation), possibly by displacing opiates
from their receptors. This agent is used to reverse opioid
intoxication.
Naltrexone (Vivitrol, ReVia)
● View full drug information
Naltrexone is an opioid antagonist that prevents or reverses
opioid effects (eg, hypotension, respiratory depression, and
sedation), possibly by displacing opiates from their
receptors. It shows a higher affinity for mu receptors. This
agent may be used to reverse opioid intoxication.
Outlook (Prognosis)
How well you do depends on the disease causing the
respiratory acidosis.
Possible Complications
Complications that may result include:
● Poor organ function
● Respiratory failure
● Shock
Patients with chronic respiratory acidosis, by definition, have
a component of alveolar hypoventilation. Partial arterial
pressure of carbon dioxide (PaCO2) and bicarbonate levels
are increased, and obligatory decreases in partial pressure
of arterial oxygen (PaO2) also occur.
7
Complications are often related to the chronic hypoxemia,
which can result in increased erythropoiesis, leading to
secondary polycythemia.
Chronic hypoxia is a cause of pulmonary vasoconstriction.
This physiologic response can, in the long term, lead to
pulmonary hypertension, right ventricular failure, and cor
pulmonale.
Hypopneas and apneas during sleep lead to impaired sleep
quality and cerebral vasodilation, causing morning
headaches, daytime fatigue, and somnolence.
High levels of CO2 can lead to confusion, often referred to as
carbon dioxide narcosis. As a late complication of cerebral
vasodilation, patients may have papilledema. [16]
A study by Lun et al indicated that in patients with acute
exacerbation of COPD, those with either compensated or
decompensated respiratory acidosis tend to have poorer
lung function and a greater risk for future life-threatening
events than do normocapnic patients. [17]
A study by de Miguel-Díez et al indicated that respiratory
acidosis is one factor increasing the risk of rehospitalization
for patients within 30 days of initial hospitalization for acute
exacerbation of COPD and is also a risk factor for inhospital
mortality in these readmitted patients. Other factors
associated with rehospitalization and inhospital mortality
included older age, malnutrition, nonobesity, and treatment
with noninvasive ventilation. [18]
Similarly, a study by Fazekas et al indicated that in patients
with COPD who survive a first episode of acute hypercapnic
respiratory failure requiring noninvasive ventilation, severe
respiratory acidosis predicts decreased long-term survival,
as do chronic respiratory failure and lower body mass index.
In addition, a prospective study by Crisafulli et al indicated
that in patients who have been hospitalized for acute
exacerbation of COPD, a modified Medical Research
Council dyspnea score of 2 or greater and acute respiratory
acidosis are independent risk factors, if present at
admission, for a hospital stay of more than 7 days (odds
ratios of 2.24 and 2.75, respectively). [20]
A study by Mochizuki et al indicated that in intensive care
unit (ICU) patients, mortality rates from acidemia differ by
subtype. Of over 640,000 ICU patients, 57.8% were found to
have acidemia. Metabolic, combined, and respiratory
acidemia had prevalences of 42.9%, 30.3%, and 25.9%,
respectively. Combined acidemia had the highest mortality
rate (12.7%), followed by metabolic (11%) and respiratory
(5.5%) acidemia. Hospital mortality in respiratory acidemia
was best predicted by PaCO2.
When to Contact a Medical Professional
Severe respiratory acidosis is a medical emergency. Seek
medical help right away if you have symptoms of this
condition.
Call your provider if you have symptoms of lung disease that
suddenly get worse.
Prevention
DO NOT smoke. Smoking leads to the development of many
severe lung diseases that can cause respiratory acidosis.
Losing weight may help prevent respiratory acidosis due to
obesity (obesity-hypoventilation syndrome).
Be careful about taking sedating medicines, and never
combine these medicines with alcohol.

Use your CPAP device regularly if it has been prescribed for
you.
Alternative Names
Ventilatory failure; Respiratory failure; Acidosis - respiratory
Respiratory acidosis typically occurs due to failure of ventilation
and accumulation of carbon dioxide. The primary disturbance is an
elevated arterial partial pressure of carbon dioxide (pCO2) and a
decreased ratio of arterial bicarbonate to arterial pCO2, which
results in a decrease in the pH of the blood.
To compensate for the disturbance in the balance between carbon
dioxide and bicarbonate (HCO3-), the kidneys begin to excrete
more acid in the forms of hydrogen and ammonium and reabsorb
more base in the form of bicarbonate.
Etiology
Chemoreceptors for PCO2, PO2, and pH regulate ventilation.
Central chemoreceptors in the medulla are sensitive to changes in
the pH level. A decreased pH level influences the mechanics of
ventilation and maintains proper levels of carbon dioxide and
oxygen. When ventilation is disrupted, arterial PCO2 increases and
an acid-base disorder develop. Another pathophysiological
mechanism may be due to ventilation/perfusion mismatch of dead
space.
In acute respiratory acidosis, there is a sudden elevation of PCO2
because of failure of ventilation. This may be due to
cerebrovascular accidents, use of central nervous system (CNS)
depressants such as opioids, or inability to use muscles of
respiration because of disorders like myasthenia gravis, muscular
dystrophy or Guillain-Barre Syndrome.
a slight compensation occurring minutes after the incidence
chronic respiratory acidosis may be caused by COPD where there
is a decreased responsiveness of the reflexes to states of hypoxia
and hypercapnia. Other individuals who develop chronic
respiratory acidosis may have fatigue of the diaphragm resulting
from a muscular disorder.
Respiratory acidosis may cause slight elevations in ionized calcium
and an extracellular shift of potassium. However, hyperkalemia is
usually mild. In chronic respiratory acidosis, renal compensation
occurs gradually over the course of days
Pathophysiology
In a state of hypoventilation, the body produces more CO2 than it
can eliminate, causing a net retention of CO2. The increased CO2
is what leads to an increase in hydrogen ions and a slight increase
in bicarbonate, as seen by a right shift in the following equilibrium
reaction of carbon dioxide:
● CO2 + H2O -> H2CO3- -> HCO3- + H+
The buffer system created by carbon dioxide consists of the
following three molecules in equilibrium: CO2, H2CO3-, and
HCO3-. When H+ is high, HCO3- buffers the low pH. When OH-
is high, H2CO3 buffers the high pH. In respiratory acidosis, the
8
slight increase in bicarbonate serves as a buffer for the increase in
H+ ions, which helps minimize the drop in pH. The increase in
hydrogen ions inevitably causes a decrease in pH, which is the
mechanism behind respiratory acidosis
History and Physical
Patients can present with dyspnea, anxiety, wheezing, and sleep
disturbances. In some cases, patients may present with cyanosis
due to hypoxemia. If the respiratory acidosis is severe and
accompanied by prolonged hypoventilation, the patient may have
additional symptoms such as altered mental status, myoclonus, and
possibly even seizures.
Respiratory acidosis leads to hypercapnia, which induces cerebral
vasodilation. If severe enough, increased intracranial pressure and
papilledema may ensue, increasing the risk of herniation and
possibly even death. Cases of chronic respiratory acidosis may
cause memory loss, impaired coordination, polycythemia,
pulmonary hypertension, and heart failure. Persistence of apnea
during sleep can lead to daytime somnolence and headaches. In
patients with an obvious source of respiratory acidosis, the
offending agent needs to be removed or reversed.
Treatment / Management
The hypercapnia should be corrected gradually because rapid
alkalization of the cerebrospinal fluid (CSF) may lead to seizures.
Pharmacologic therapy can also be used to help improve
ventilation. Bronchodilators like beta-agonists, anticholinergic
drugs, and methylxanthines can be used in treating patients with
obstructive airway diseases. Naloxone can be used in patients who
overdose on opioid use.
Respiratory Alkalosis
Respiratory alkalosis is 1 of the 4 basic classifications of blood pH
imbalances. Normal human physiological pH is 7.35 to 7.45. A
decrease in pH below this range is acidosis, an increase above this
range is alkalosis. Respiratory alkalosis is by definition a disease
state where the body’s pH is elevated to greater than 7.45
secondary to some respiratory or pulmonary process.
Practice Essentials
Respiratory alkalosis is a disturbance in acid and base
balance due to alveolar hyperventilation. Alveolar
hyperventilation leads to a decreased partial pressure of
arterial carbon dioxide (PaCO2). In turn, the decrease in
PaCO2 increases the ratio of bicarbonate concentration to
PaCO2 and, thereby, increases the pH level; thus the
descriptive term respiratory alkalosis. The decrease in
PaCO2 (hypocapnia) develops when a strong respiratory
stimulus causes the respiratory system to remove more
carbon dioxide than is produced metabolically in the tissues.
[1, 2]
Respiratory alkalosis can be acute or chronic. In acute
respiratory alkalosis, the PaCO2 level is below the lower limit
of normal and the serum pH is alkalemic. In chronic
respiratory alkalosis, the PaCO2 level is below the lower limit
of normal, but the pH level is relatively normal or near
normal due to compensatory mechanisms.
Respiratory alkalosis is the most common acid-base
abnormality observed in patients who are critically ill. It is
associated with numerous illnesses and is a common finding
in patients on mechanical ventilation. Many cardiac and
pulmonary disorders can manifest with respiratory alkalosis
as an early or intermediate finding. When respiratory
alkalosis is present, the cause may be a minor,

non–life-threatening disorder. However, more serious
disease processes should also be considered in the
differential diagnosis.
Etiology
Before going into details about pathology and this disease process,
some background information about the physiological pH
buffering process is important. The primary pH buffer system in
the human body is the HCO3/CO2 chemical equilibrium system.
Where:
● H + HCO3 <----> H2CO3 <----> CO2 + H2O
HCO3 functions as an alkalotic substance. CO2 (carbon dioxide)
functions as an acidic substance. Therefore, Increases in HCO3
(bicarbonate) or decreases in CO2 will make blood more alkalotic.
The opposite is also true where decreases in HCO3 or an increase
in CO2 will make blood more acidic. CO2 levels are
physiologically regulated by the pulmonary system through
respiration, whereas the HCO3 levels are regulated through the
renal system with reabsorption rates. Therefore, respiratory
alkalosis is a decrease in serum CO2. While it is theoretically
possible to have decreased CO2 production, in every scenario this
illness is a result of hyperventilation where CO2 is breathed away.
Signs and symptoms of respiratory alkalosis
The hyperventilation syndrome can mimic many conditions
that are more serious. Symptoms may include paresthesia,
circumoral numbness, chest pain or tightness, dyspnea, and
tetany. [11]
Acute onset of hypocapnia can cause cerebral
vasoconstriction. An acute decrease in PaCO2 reduces
cerebral blood flow and can cause neurologic symptoms,
including dizziness, mental confusion, syncope, and
seizures. Hypoxemia need not be present for the patient to
experience these symptoms. [5]
Respiratory alkalosis may impair vitamin D metabolism,
which may lead to vitamin D deficiency and cause symptoms
such as fibromyalgia. [14]
Workup in respiratory alkalosis
Laboratory tests
Alkalemia is documented by the presence of an increased
pH level (>7.45) on arterial blood gas determinations. The
presence of a decreased PaCO2 level (< 35 mm Hg)
indicates a respiratory etiology of the alkalemia.
The following laboratory studies may be helpful:
● Serum chemistries
● Complete blood count (CBC)
● Liver function test
● Cultures of blood, sputum, urine, and other
sites
● Thyroid testing
● Beta-human chorionic hormone levels
● Drug screens and theophylline and salicylate
levels
Imaging studies
9
These include the following:
● Chest radiography - Should be performed to
help rule out pulmonary disease as a cause
of hypocapnia and respiratory alkalosis
● Computerized tomography (CT) scanning of
the chest - May be performed if chest
radiography findings are inconclusive or a
pulmonary disorder is strongly considered as
a differential diagnosis
● Ventilation perfusion scanning - Can be
considered in patients who are unable to
undergo an intravenous contrast injection
associated with CT scanning to assess the
patient for pulmonary embolism
● Brain magnetic resonance imaging (MRI) -
Can be considered if a central cause of
hyperventilation and respiratory alkalosis is
suggested and the initial brain CT scan
findings are negative or inconclusive
Management of respiratory alkalosis
The treatment of respiratory alkalosis is primarily directed at
correcting the underlying disorder. Respiratory alkalosis itself
is rarely life threatening. Therefore, emergent treatment is
usually not indicated unless the pH level is greater than 7.5.
Because respiratory alkalosis usually occurs in response to
some stimulus, treatment is usually unsuccessful unless the
stimulus is controlled. If the PaCO2 is corrected rapidly in
patients with chronic respiratory alkalosis, metabolic acidosis
may develop due to the renal compensatory drop in serum
bicarbonate.
Pathophysiology
In almost every scenario, respiratory alkalosis is induced by a
process involving hyperventilation. These include central causes,
hypoxemic causes, pulmonary causes, and iatrogenic causes.
Central sources are a head injury, stroke, hyperthyroidism,
anxiety-hyperventilation, pain, fear, stress, drugs, medications such
as salicylates, and various toxins. Hypoxic stimulation leads to
hyperventilation in an attempt to correct hypoxia at the expense of
a CO2 loss. Pulmonary causes include pulmonary embolisms,
pneumothorax, pneumonia, and acute asthma or COPD
exacerbations. Iatrogenic causes are primarily due to
hyperventilation in intubated patients on mechanical
ventilation.[6][7]
Respiratory alkalosis may be an acute process or a chronic process.
These are determined based on the level of metabolic
compensation for the respiratory disease. Excess HCO3 levels are
buffered to reduce levels and maintain a physiological pH through
the renal decrease of H secretion and increasing HCO3 secretion;
however, this metabolic process occurs over the course of days
whereas respiratory disease can adjust CO2 levels in minutes to
hours. Therefore, acute respiratory alkalosis is associated with high
bicarbonate levels since there has not been sufficient time to lower
the HCO3 levels and chronic respiratory alkalosis is associated
with low to normal HCO3 levels.
Breathing or alveolar ventilation is the body’s method of
providing adequate amounts of oxygen for metabolism while
removing carbon dioxide produced in the tissues. By sensing
the body’s partial pressure of arterial oxygen (PaO2) and
partial pressure of arterial carbon dioxide (PaCO2), the
respiratory system adjusts pulmonary ventilation so that
oxygen uptake and carbon dioxide elimination at the lungs

are balanced with the amount used and produced by the
tissues.
The PaCO2 must be maintained at a level that ensures that
hydrogen ion concentrations remain in the narrow limits
required for optimal protein and enzymatic function. PaO2 is
not as closely regulated as the PaCO2. Adequate
hemoglobin saturation can be achieved over a wide range of
PaO2 levels. The movement of oxygen from the alveoli to the
vascular system is dependent on pressure gradients. On the
other hand, carbon dioxide diffuses much easier through an
aqueous environment.
Metabolism generates a large quantity of volatile acid
(carbonic acid excreted as carbon dioxide by the lungs) and
nonvolatile acid. The metabolism of fats and carbohydrates
leads to the formation of a large amount of carbon dioxide, [3]
which combines with water to form carbonic acid. The lungs
excrete the volatile fraction through ventilation so that acid
accumulation does not occur. Significant alterations in
ventilation can affect the elimination of carbon dioxide and
lead to a respiratory acid-base disorder.
PaCO2 is normally maintained in the range of 35-45 mm Hg.
Chemoreceptors in the brain (central chemoreceptors) and
in the carotid bodies (peripheral chemoreceptors) sense
hydrogen concentrations and influence ventilation to adjust
the PCO2 and pH. This feedback regulator is how the PaCO2
is maintained within its narrow normal range. When these
receptors sense an increase in hydrogen ions, breathing is
increased to “blow off” carbon dioxide and subsequently
reduce the amount of hydrogen ions. Various disease
processes may cause stimulation of ventilation with
subsequent hyperventilation. If hyperventilation is persistent,
it leads to hypocapnia.
Hyperventilation refers to an increase in alveolar ventilation
that is disproportionate to the rate of metabolic carbon
dioxide production, leading to a PaCO2 level below the
normal range, or hypocapnia. Hyperventilation is often
associated with dyspnea, but not all patients who are
hyperventilating complain of shortness of breath. Conversely,
patients with dyspnea need not be hyperventilating.
Acute hypocapnia causes a reduction of serum levels of
potassium and phosphate secondary to increased
intracellular shifts of these ions. A reduction in free serum
calcium also occurs. Calcium reduction is secondary to
increased binding of calcium to serum albumin due to the
change in pH. Many of the symptoms present in persons
with respiratory alkalosis are related to hypocalcemia. [4]
Hyponatremia and hypochloremia may also be present.
Acute hyperventilation with hypocapnia causes a small, early
reduction in serum bicarbonate levels resulting from cellular
shift of bicarbonate. Acutely, plasma pH and bicarbonate
concentration vary proportionately with the PaCO2 along a
range of 15-40 mm Hg. The relationship of PaCO2 to arterial
hydrogen and bicarbonate is 0.7 mmol/L per mm Hg and 0.2
mmol/L per mm Hg, respectively. [5] After 2-6 hours, renal
compensation begins via a decrease in bicarbonate
reabsorption. The kidneys respond more to the decreased
PaCO2 rather than the increased pH. Complete kidney
compensation may take several days and requires normal
kidney function and intravascular volume status. [5] The
expected change in serum bicarbonate concentration can be
estimated as follows:
● Acute - Bicarbonate (HCO3-) falls 2 mEq/L for
each decrease of 10 mm Hg in the PCO2;
that is, ΔHCO3 = 0.2(ΔPCO2); maximum
compensation: HCO3- = 12-20 mEq/L
● Chronic - Bicarbonate (HCO3-) falls 5 mEq/L
for each decrease of 10 mm Hg in the PCO2;
that is, ΔHCO3 = 0.5(ΔPCO2); maximum
compensation: HCO3- = 12-20 mEq/L
Note that a plasma bicarbonate concentration of less than 12
mmol/L is unusual in pure respiratory alkalosis alone and
should prompt the consideration of a metabolic acidosis as
well (ie, the presence of a mixed acid-base disorder). [4]
10
The expected change in pH with respiratory alkalosis can be
estimated with the following equations:
● Acute respiratory alkalosis: Change in pH =
0.008 X (40 – PCO2)
● Chronic respiratory alkalosis: Change in pH
= 0.017 X (40 – PCO2)
A study by Morel et al suggested that when respiratory
alkalosis is present, caution be used in the employment of
venous-arterial difference in CO2 (ΔCO2) as an indicator of
the adequacy of tissue perfusion (as has been proposed for
shock states). Using healthy volunteers in whom either
hypocapnia or hypercapnia was induced, the investigators
found a significant increase in ΔCO2 in the hypocapnic
subjects, who also had a significant decrease in skin
microcirculatory blood flow.
Prognosis
The prognosis of respiratory alkalosis is variable and
depends on the underlying cause and the severity of the
underlying illness.
Lewis et al hypothesized that respiratory alkalosis may
interfere with vitamin D production, contributing to the
development of fibromyalgia. The investigators suggested
that, possibly by suppressing the kidneys’ ability to release
phosphate into the urine, alkalotic pH disrupts endogenous
1,25-dihydroxyvitamin D formation.[8]
A study by Park et al indicated that in patients with high-risk
acute heart failure, respiratory alkalosis is the most frequent
acid-base imbalance. However, while acidosis was found to
be a significant risk factor for mortality in acute heart failure
patients, this was not true for alkalosis. [9]
A study by Raphael et al indicated that in healthy older
adults, low serum bicarbonate levels can be linked to a
higher mortality rate no matter whether respiratory alkalosis
or metabolic acidosis is responsible for the bicarbonate
reduction. Among the study’s patients (mean age 76 y), the
mortality hazard ratio for those with respiratory alkalosis or
metabolic acidosis, compared with controls, was 1.21 or
1.17, respectively.
Patient Education
Patients with hyperventilation syndrome as the etiology of
their respiratory alkalosis may particularly benefit from
patient education. The underlying pathophysiology should be
explained in simple terms, and patients should be instructed
in breathing techniques that may be used to relieve the
hyperventilation. Reassurance is key for these patients.
History
Clinical manifestations of respiratory alkalosis depend on its
duration, its severity, and the underlying disease process.
Note the following:
● The hyperventilation syndrome can mimic
many conditions that are more serious.
Symptoms may include paresthesia,
circumoral numbness, chest pain or
tightness, dyspnea, and tetany. [11]
● Acute onset of hypocapnia can cause
cerebral vasoconstriction. An acute decrease
in PaCO2 reduces cerebral blood flow and
can cause neurologic symptoms, including
dizziness, mental confusion, syncope, and
seizures. Hypoxemia need not be present for
the patient to experience these symptoms.[5]
● The first cases of spontaneous
hyperventilation with dizziness and tingling
leading to tetany were described in 1922 in
patients with cholecystitis, abdominal
distention, and hysteria. [12]
● Haldane and Poulton described painful
tingling in the hands and feet, numbness and
 11
sweating of the hands, and cerebral ● Fever
symptoms following voluntary ● Cerebrovascular accident
hyperventilation. [13] ● Meningitis
● Respiratory alkalosis may impair vitamin D ● Encephalitis
metabolism, which may lead to vitamin D ● Tumor
deficiency and cause symptoms such as ● Trauma
fibromyalgia. Hypoxia-related causes are as follows:
Physical
Physical examination findings in patients with respiratory ● High altitude
alkalosis are nonspecific and are typically related to the ● Right-to-left shunts
underlying illness or cause of the respiratory alkalosis. Note
Drug-related causes are as follows:
the following:
● Progesterone
● Many patients with hyperventilation
● Methylxanthine toxicity
syndrome appear anxious and are frequently
● Salicylate toxicity
tachycardic. Understandably, tachypnea is a
● Catecholamines
frequent finding.
● Nicotine
● In acute hyperventilation, chest wall
movement and breathing rate increase. In Endocrine-related causes are as follows:
patients with chronic hyperventilation, these
physical findings may not be as obvious. ● Pregnancy
● Positive Chvostek and Trousseau signs may ● Hyperthyroidism
be elicited. [4]
Pulmonary causes are as follows:
● Patients with underlying pulmonary disease
may have signs suggestive of pulmonary
disease, such as crackles, wheezes, or ● Pneumothorax/hemothorax
rhonchi. Cyanosis may be present if the ● Pneumonia
patient is hypoxic. ● Pulmonary edema
● If the underlying pathology is neurologic, the ● Pulmonary embolism
patient may have focal neurologic signs or a ● Aspiration
depressed level of consciousness. [15] ● Interstitial lung disease
● Cardiovascular effects of hypocapnia in ● Asthma
healthy and alert patients are minimal, but in ● Emphysema
patients who are anesthetized, critically ill, or ● Chronic bronchitis
receiving mechanical ventilation, the effects Miscellaneous causes are as follows:
can be more significant. Cardiac output and
systemic blood pressure may fall as a result ● Sepsis
of the effects of sedation and ● Severe anemia
positive-pressure ventilation on venous ● Hepatic failure
return, systemic vascular resistance, and ● Mechanical ventilation
heart rate. [5] ● Heat exhaustion
● Cardiac rhythm disturbances may occur ● Recovery phase of metabolic acidosis
because of increased tissue hypoxia related ● Congestive heart failure
to the leftward shift of the
Hyperthyroidism: Hyperthyroidism increases the ventilation
hemoglobin-oxygen dissociation curve. [5]
chemoreflexes, thereby causing hyperventilation. These
Since the primary cause of all respiratory alkalosis etiologies is hyperventilation, many patients present with
chemoreflexes return to normal with treatment of the
complain to shortness of breath. The exact history and physical exam findings are highly variable as there are
hyperthyroidism.
many pathologies that induce the pH disturbance. These may include acute onset dyspnea, fever, chills,
Pregnancy: Progesterone levels are increased during
peripheral edema, orthopnea, weakness, confusion, light-headedness, dizziness, anxiety, chest pain, wheezing,
pregnancy. Progesterone causes stimulation of the
hemoptysis, trauma, history of central line catheter, recent surgery, history of thromboembolic disease, history
respiratory center, which can lead to respiratory alkalosis.
of asthma, history of COPD, acute focal neurological signs, numbness, paresthesia, abdominal pain, nausea,
Chronic respiratory alkalosis is a common finding in
vomiting, tinnitus, or weight loss.
pregnant women. [5]
Congestive heart failure: Patients with congestive heart
Physical exam findings may be just as varied depending on etiology to include fever, tachycardia, tachypnea, failure (and other low cardiac-output states) hyperventilate at
diaphoresis, hyper or hypotension, altered mental status, productive or non-productive cough, wheezing, rales, rest, during exercise, and during sleep. Owing to pulmonary
crackles, cardiac murmur or arrhythmia, jugular venous distension, meningeal signs, focal neurological loss, congestion, pulmonary vascular and interstitial receptors are
Trousseau sign, Chvostek sign, jaundice, melena, hematochezia, hepatosplenomegaly, or there may be no stimulated. Additionally, the low cardiac-output state and
definitive signs at all. hypotension stimulate breathing via the arterial
baroreceptors.
Chronic/severe liver disease: Several mechanisms have
been hypothesized to explain the hyperventilation associated
Causes with liver disease. Increased levels of progesterone,
The differential diagnosis of respiratory alkalosis is broad; ammonia, vasoactive intestinal peptide, and glutamine can
therefore, a thorough history, physical examination, and stimulate respiration. Patients with severe disease or portal
laboratory evaluation are helpful in arriving at the true hypertension may have small pulmonary arteriovenous
diagnosis. anastomoses in the lungs or portal-pulmonary shunts, which
Central nervous system causes are as follows: result in hypoxemia. This stimulates the peripheral
chemoreceptors and leads to hyperventilation. The degree of
● Pain respiratory alkalosis correlates with the severity of hepatic
● Hyperventilation syndrome insufficiency. [5]
● Anxiety Salicylate overdose: Initially, a respiratory alkalosis occurs,
● Panic disorders which is followed by a metabolic acidosis that induces
● Psychosis secondary hyperventilation.

Fever and sepsis: Fever and sepsis may manifest as
hyperventilation, even before hypotension develops. The
exact mechanism is not known but is thought to be due to
carotid body or hypothalamic stimulation by the increased
temperature.
Gram-negative sepsis: Before fever, hypoxemia, or
hypotension develops, acute respiratory alkalosis may be
the only early finding. [5]
Pain: Hyperventilation may be due to stimulation of the
peripheral and central chemoreceptors, as well as the
behavioral control system.
Hyperventilation syndrome: This is also known as
psychogenic hyperventilation and was first described in
1935. [16] It is due to stress and anxiety, both of which act on
the behavioral respiratory control system. The
hyperventilation ceases during sleep, when the behavioral
control system is inactive and only the metabolic system is
controlling breathing. The diagnosis of hyperventilation
syndrome should be a diagnosis of exclusion. [4] Rule out all
organic medical conditions, including pulmonary embolism,
cardiac ischemia, and hyperthyroidism, before establishing a
diagnosis of hyperventilation syndrome.
Laboratory Studies
An essential laboratory analysis is as follows:
● Arterial blood gas determination: Alkalemia
is documented by the presence of an
increased pH level (>7.45) on arterial blood
gas determinations. The presence of a
decreased PaCO2 level (< 35 mm Hg)
indicates a respiratory etiology of the
alkalemia.
The following laboratory studies may be helpful:
● Serum chemistries: Acute respiratory
alkalosis causes small changes in electrolyte
balances. Minor intracellular shifts of sodium,
potassium, and phosphate levels occur. A
minor reduction in free calcium occurs due to
an increased protein-bound fraction.
Compensation for respiratory alkalosis is by
increased renal excretion of bicarbonate. In
acute respiratory alkalosis, the bicarbonate
concentration level decreases by 2 mEq/L
for each decrease of 10 mm Hg in the
PaCO2 level. In chronic respiratory acidosis,
the bicarbonate concentration level
decreases by 5 mEq/L for each decrease of
10 mm Hg in the PaCO2 level. Plasma
bicarbonate levels rarely drop below 12 mm
Hg secondary to compensation for primary
respiratory alkalosis.
● Complete blood count (CBC): An elevation of
the white blood cell (WBC) count may
indicate early sepsis as a possible etiology of
respiratory alkalosis. A reduced hematocrit
value may indicate severe anemia as the
potential cause of respiratory alkalosis.
● Liver function test: Findings may be
abnormal if hepatic failure is the etiology of
the respiratory alkalosis.
● Cultures of blood, sputum, urine, and other
sites: These should be considered,
depending on information obtained from the
history and physical examination and if
sepsis or bacteremia are thought to be the
cause of the respiratory alkalosis.
● Thyroid testing: Thyroid-stimulating hormone
and thyroxine levels may be indicated to rule
out hyperthyroidism.
● Beta-human chorionic hormone levels may
be helpful in ruling out pregnancy.
12
● Drug screens and theophylline and salicylate
levels may be useful to determine whether
drugs or medications are the cause.
Imaging Studies
Consider the following imaging studies:
● Chest radiography: Chest radiography
should be performed to help rule out
pulmonary disease as a cause of
hypocapnia and respiratory alkalosis.
Potential etiologies that may be confirmed
based on chest radiography findings include
pneumonia, pulmonary edema, aspiration
pneumonitis, pneumothorax, and interstitial
lung disease.
● Computerized tomography (CT) scanning:
CT scanning of the chest may be performed
if chest radiography findings are inconclusive
or a pulmonary disorder is strongly
considered as a differential diagnosis. CT
scanning is more sensitive for helping detect
disease, and findings may reveal
abnormalities not seen on the chest
radiograph. Consider spiral CT angiography
of the chest if pulmonary embolism is
suggested. Consider CT scanning of the
brain if a central cause of hyperventilation
and respiratory alkalosis is suspected.
Specific etiologies that may be diagnosed
based on brain CT scan findings include
cerebrovascular accident, central nervous
system tumor, and central nervous system
trauma.
● Ventilation perfusion scanning: Consider this
scan in patients who are unable to undergo
an intravenous contrast injection associated
with CT scanning to assess the patient for
pulmonary embolism.
● Brain magnetic resonance imaging (MRI): If
a central cause of hyperventilation and
respiratory alkalosis is suggested and the
initial brain CT scan findings are negative or
inconclusive, an MRI of the brain can be
considered. MRIs may reveal abnormalities
not seen on CT scans, particularly lesions of
the brain stem. Possible etiologies based on
MRIs include cerebrovascular accident,
central nervous system tumor, and central
nervous system trauma.
Perform a lumbar puncture if the history and physical
examination findings are suggestive of a CNS infectious
process.
The treatment of respiratory alkalosis is primarily directed at
correcting the underlying disorder. Respiratory alkalosis itself
is rarely life threatening. Therefore, emergent treatment is
usually not indicated unless the pH level is greater than 7.5.
Because respiratory alkalosis usually occurs in response to
some stimulus, treatment is usually unsuccessful unless the
stimulus is controlled. If the PaCO2 is corrected rapidly in
patients with chronic respiratory alkalosis, metabolic acidosis
may develop due to the renal compensatory drop in serum
bicarbonate.
In mechanically ventilated patients who have respiratory
alkalosis, the tidal volume and/or respiratory rate may need
to be decreased. Inadequate sedation and pain control may
contribute to respiratory alkalosis in patients breathing over
the set ventilator rate.
In hyperventilation syndrome, patients benefit from
reassurance, rebreathing into a paper bag during acute
episodes, and treatment for underlying psychological stress.
Sedatives and/or antidepressants should be reserved for
patients who have not responded to conservative treatment.

Beta-adrenergic blockers may help control the
manifestations of the hyperadrenergic state that can lead to
hyperventilation syndrome in some patients. [4]
In patients presenting with hyperventilation, a systematic
approach should be used to rule out potentially
life-threatening, organic causes first before considering less
serious disorders.
Treatment of metabolic alkalosis is targeted at treating the
underlying pathology. In anxious patients, anxiolytics may be
necessary. In infectious disease, antibiotics targeting sputum or
blood cultures are appropriate. In embolic disease, anticoagulation
is necessary. Ventilator support may be necessary for patients with
acute respiratory failure, acute asthma, or acute, chronic
obstructive pulmonary disease (COPD) exacerbation if they show
signs of respiratory fatigue. In ventilator controlled patients, it may
be necessary to reevaluate their ventilator settings to reduce
respiratory rate. If hyperventilation is intentional, monitor the
arterial or venous blood gas values closely. In severe cases, pH
may be directly reduced using acidic agents. However, this is not
routinely done.
Prognosis
Respiratory alkalosis in itself is not a life-threatening diagnosis.
However, the prognosis is variable depending on etiology.
Go to:
Pearls and Other Issues
Respiratory alkalosis is a pathology that is secondary to
hyperventilation.
Hyperventilation typically occurs in response to an insult such as
hypoxia, metabolic acidosis, pain, anxiety, or increased metabolic
demand.
Respiratory alkalosis in itself is not life-threatening; however, the
underlying etiology may be. Always look for and treat the source
of the illness. Interventions to reduce pH directly are typically not
necessary as there is no mortality benefit to this therapy.
Respiratory alkalosis is a pathology that is secondary to
hyperventilation.
Hyperventilation typically occurs in response to an insult such as
hypoxia, metabolic acidosis, pain, anxiety, or increased metabolic
demand.
Respiratory alkalosis in itself is not life-threatening; however, the
underlying etiology may be. Always look for and treat the source
of the illness. Interventions to reduce pH directly are typically not
necessary as there is no mortality benefit to this therapy.
Go to:
Enhancing Healthcare Team Outcomes
Respiratory alkalosis is easy to diagnose but its management can
be difficult; the key is to find the cause. Because there are many
causes of respiratory alkalosis, the condition is best managed by an
interprofessional team that includes an internist, primary care
provider, nurse practitioner, pulmonologist, mental health nurse
and a pain specialist.
Treatment of metabolic alkalosis is targeted at treating the
underlying pathology. If hyperventilation is intentional, monitor
the arterial or venous blood gas values closely. In severe cases, pH
13
may be directly reduced using acidic agents. However, this is not
routinely done. Hyperventilation typically occurs in response to an
insult such as hypoxia, metabolic acidosis, pain, anxiety, or
increased metabolic demand.
Respiratory alkalosis in itself is not life-threatening; however, the
underlying etiology may be. Always look for and treat the source
of the illness. Interventions to reduce pH directly are typically not
necessary as there is no mortality benefit to this therapy.
—--------------------------
Metabolic Acidosis
Practice Essentials
Metabolic acidosis is a clinical disturbance characterized by
an increase in plasma acidity. [1] Metabolic acidosis should be
considered a sign of an underlying disease process.
Identification of this underlying condition is essential to
initiate appropriate therapy.
Understanding the regulation of acid-base balance requires
appreciation of the fundamental definitions and principles
underlying this complex physiologic process.
Acid-base disorders are disturbances in the homeostasis of
hydrogen ion concentration in the plasma. Any process that
increases the serum hydrogen ion concentration is an acidotic
process. The term acidemia is used to describe serum that is
abnormally acidic, and this can be due to a respiratory acidosis,
which involves changes in carbon dioxide, or a metabolic acidosis
which is influenced by decreased bicarbonate. Metabolic acidosis
is characterized by an increase in the hydrogen ion concentration in
the systemic circulation that results in an abnormally low serum
bicarbonate level. Metabolic acidosis signifies an underlying
disorder that needs to be corrected to minimize morbidity and
mortality. This activity describes the risk factors, evaluation, and
management of metabolic acidosis and highlights the role of the
interprofessional team in enhancing care delivery for affected
patients.
Acid-base disorders, including metabolic acidosis, are disturbances
in the homeostasis of plasma acidity. Any process that increases
the serum hydrogen ion concentration is a distinct acidosis. The
term acidemia is used to define the total acid-base status of the
serum pH. For example, a patient can have multiple acidoses
contributing to a net acidemia. Its origin classifies acidosis as
either a respiratory acidosis which involves changes in carbon
dioxide, or metabolic acidosis which is influenced by bicarbonate
(HCO3).[1][2][3]
Metabolic acidosis is characterized by an increase in the hydrogen
ion concentration in the systemic circulation resulting in a serum
HCO3 less than 24 mEq/L. Metabolic acidosis is not a benign
condition and signifies an underlying disorder that needs to be
corrected to minimize morbidity and mortality. The many
etiologies of metabolic acidosis are classified into 4 main
mechanisms: increased production of acid, decreased excretion of
acid, acid ingestion, and renal or gastrointestinal (GI) bicarbonate
losses.
Etiology
Determining the type of metabolic acidosis can help clinicians
narrow down the cause of the disturbance. Acidemia refers to a pH
less than the normal range of 7.35 to 7.45. In addition, metabolic
acidosis requires a bicarbonate value less than 24 mEq/L. Further
classification of metabolic acidosis is based on the presence or
absence of an anion gap, or concentration of unmeasured serum
anions. Plasma neutrality dictates that anions must balance cations
to maintain a neutral charge. Therefore, sodium (Na), the primary
plasma cation, is balanced by the sum of the anions bicarbonate

and chloride in addition to the unmeasured anions, which represent
the anion gap. Unmeasured anions include lactate and acetoacetate,
and these are often some of the main contributors to metabolic
acidosis.[7][8][9]
● Anion gap (AG) = [Na] –([Cl] + [HCO3])
Anion gap metabolic acidosis is frequently due to anaerobic
metabolism and lactic acid accumulation. While lactate is part of
many mnemonics for metabolic acidosis, it is important to
distinguish it is not a separate etiology, but rather a consequence of
a condition.
Mnemonic for anion gap metabolic acidosis differential: CAT
MUDPILES
● C: Cyanide and carbon monoxide poisoning
● A: Arsenic
● T: Toluene
● M: Methanol, Metformin
● U: Uremia
● D: DKA
● P: Paraldehyde
● I: Iron, INH
● L: Lactate
● E: Ethylene glycol
● S: Salicylates
Non-gap metabolic acidosis is primarily due to the loss of
bicarbonate, and the main causes of this condition are diarrhea and
renal tubular acidosis. Additional and rarer etiologies include
Addison’s disease, ureterosigmoid or pancreatic fistulas,
acetazolamide use, and hyperalimentation through TPN initiation.
GI and renal losses of bicarbonate can be distinguished via urine
anion gap analysis:
● Urine AG = Urine Na + Urine K – Urine Cl
A positive value is indicative of renal bicarbonate loss, such as
renal tubular acidosis. Negative values are found with non-renal
bicarbonate losses, such as diarrhea.
A focused history can elicit potential causes of acid-base
disturbances such as vomiting, diarrhea, medications, possible
overdoses and chronic conditions with a predisposition to acidosis
including diabetes mellitus.
The physical exam reveals signs unique to each cause such as dry
mucous membranes in the patient with diabetic ketoacidosis.
Hyperventilation may also be present as a compensatory
respiratory alkalosis to assist with PCO2 elimination and
correction of the acidemia. Compensatory reactions do not
completely correct a disturbance to the normal pH range, however.
Background
Basic definitions
14
+
An acid is a substance that can donate hydrogen ions (H ). A
base is a substance that can accept H+ ions. The ion
exchange occurs regardless of the substance's charge.
Strong acids are those that are completely ionized in body
fluids, and weak acids are those that are incompletely
ionized in body fluids. Hydrochloric acid (HCl) is considered
a strong acid because it is present only in a completely
ionized form in the body, whereas carbonic acid (H2 CO3) is a
weak acid because it is ionized incompletely, and, at
equilibrium, all three reactants are present in body fluids.
See the reactions below.
H2 CO3 (acid)↔H+ + HCO3- (base)
HCl↔H+ + Cl-
The law of mass action states that the velocity of a reaction
is proportional to the product of the reactant concentrations.
On the basis of this law, the addition of H+or bicarbonate
(HCO3-) drives the reaction shown below to the left.
H2 CO3 (acid)↔H+ + HCO3- (base)
In body fluids, the concentration of hydrogen ions ([H+]) is
maintained within very narrow limits, with the normal
physiologic concentration being 40 nEq/L. The concentration
of HCO3- (24 mEq/L) is 600,000 times that of [H+]. The tight
regulation of [H+] at this low concentration is crucial for
normal cellular activities because H+ at higher concentrations
can bind strongly to negatively charged proteins, including
enzymes, and impair their function.
Under normal conditions, acids and, to a lesser extent,
bases are being added constantly to the extracellular fluid
compartment, and for the body to maintain a physiologic [H+]
of 40 nEq/L, the following three processes must take place:
● Buffering by extracellular and intracellular
buffers
● Alveolar ventilation, which controls PaCO 2
● Renal H + excretion, which controls plasma
HCO 3 -
Buffers
Buffers are weak acids or bases that are able to minimize
changes in pH by taking up or releasing H+. Phosphate is an
example of an effective buffer, as in the following reaction:
HPO42- + (H+)↔H2 PO4-
Upon addition of an H+ to extracellular fluids, the
monohydrogen phosphate binds H+ to form dihydrogen
phosphate, minimizing the change in pH. Similarly, when [H+]
is decreased, the reaction is shifted to the left. Thus, buffers
work as a first-line of defense to blunt the changes in pH that
would otherwise result from the constant daily addition of
acids and bases to body fluids.
The major extracellular buffering system is HCO3-/H2 CO3; its
function is illustrated by the following reactions:
H2 O + CO2 ↔ H2CO3 ↔ H+ + HCO3-
One of the major factors that makes this system very
effective is the ability to control PaCO2 by changes in
ventilation. As can be noted from this reaction, increased
carbon dioxide (CO2) concentration drives the reaction to the
right, whereas a decrease in CO2 concentration drives it to
the left. Put simply, adding an acid load to the body fluids
results in consumption of HCO3- by the added H+, and the
formation of carbonic acid; the carbonic acid, in turn, forms
water and CO2. CO2concentration is maintained within a
narrow range via the respiratory drive, which eliminates
accumulating CO2. The kidneys regenerate the HCO3-
consumed during this reaction.
This reaction continues to move to the left as long as CO2 is
constantly eliminated or until HCO3- is significantly depleted,
making less HCO3- available to bind H+. That HCO3- and
PaCO2 can be managed independently (by kidneys and
lungs, respectively) makes this a very effective buffering
system. At equilibrium, the relationship between the 3
reactants in the reaction is expressed by the
Henderson-Hasselbalch equation, which relates the

concentration of dissolved CO2 (ie, H2CO3) to the partial
pressure of CO2 (0.03 × PaCO2) in the following way:
pH = 6.10 + log ([HCO3-]/0.03 × PaCO2)
Alternatively, [H+] = 24 × PaCO2/[HCO3-]
Note that changes in pH or [H+] are a result of relative
changes in the ratio of PaCO2 to [HCO3-] rather than to
absolute change in either one. In other words, if both PaCO2
and [HCO3-] change in the same direction, the ratio stays the
same and the pH or [H+] remains relatively stable. To
diminish the alteration in pH that occurs when either HCO3-
or PaCO2 changes, the body, within certain limits, changes
the other variable in the same direction.
In chronic metabolic acidosis, intracellular buffers (eg,
hemoglobin, bone) may be more important than HCO3- when
the extracellular HCO3- level is low.
Renal acid handling
Acids are added daily to the body fluids. These include
volatile (eg, carbonic) and nonvolatile (eg, sulfuric,
phosphoric) acids. The metabolism of dietary carbohydrates
and fat produces approximately 15,000 mmol of CO2 per
day, which is excreted by the lungs. Failure to do so results
in respiratory acidosis.
The metabolism of proteins (ie, sulfur-containing amino
acids) and dietary phosphate results in the formation of
nonvolatile acids, H2 SO4 and H3 PO4. These acids first are
buffered by the HCO3-/H2 CO3 system as follows:
H2SO4 + 2NaHCO3 ↔ Na2SO4 + 2H2CO3 ↔ 2H2O + CO2
The net result is buffering of a strong acid (H2 SO4) by 2
molecules of HCO3- and production of a weak acid (H2 CO3),
which minimizes the change in pH. The lungs excrete the
CO2 produced, and the kidneys, to prevent progressive
HCO3- loss and metabolic acidosis, replace the consumed
HCO3- (principally by H+ secretion in the collecting duct).
Some amino acids (ie, glutamate, aspartate) result in the
formation of citrate and lactate, which, in turn, will be
converted to HCO3-. The net result, in a typical American
diet, is an acid load in the range of 50-100 mEq of H+ per
day.
To maintain normal pH, the kidneys must perform two
physiologic functions. The first is to reabsorb all the filtered
HCO3- (any loss of HCO3- is equal to the addition of an
equimolar amount of H+), a function principally of the
proximal tubule. The second is to excrete the daily H+ load
(loss of H+ is equal to addition of an equimolar amount of
HCO3-), a function of the collecting duct.
Bicarbonate reabsorption
With a serum HCO3- concentration of 24 mEq/L, the daily
glomerular ultrafiltrate of 180 L, in a healthy subject, contains
4300 mEq of HCO3-, all of which has to be reabsorbed.
Approximately 90% of the filtered HCO3- is reabsorbed in the
proximal tubule, and the remainder is reabsorbed in the thick
ascending limb and the medullary collecting duct.
The 3Na+ -2K+/ATPase (sodium-potassium/adenosine
triphosphatase) provides the energy for this process, which
maintains a low intracellular Na+ concentration and a relative
negative intracellular potential. The low Na+ concentration
indirectly provides energy for the apical Na+/H+ exchanger,
NHE3 (gene symbol SLC9A3), which transports H+ into the
tubular lumen. H+ in the tubular lumen combines with filtered
HCO3- in the following reaction:
HCO3- + H+ ↔ H2CO3 ↔H2O + CO2
Carbonic anhydrase (CA IV isoform) present in the brush
border of the first 2 segments of the proximal tubule
accelerates the dissociation of H2 CO3 into H2O + CO2, which
shifts the reaction shown above to the right and keeps the
luminal concentration of H+ low. CO2 diffuses into the
proximal tubular cell perhaps via the aquaporin-1 water
channel, where carbonic anhydrase (CA II isoform)
combines CO2 and water to form HCO3- and H+. The HCO3-
formed intracellularly returns to the pericellular space and
15
then to the circulation via the basolateral
Na+/3HCO3-cotransporter, NBCe1-A (gene symbol SLC4A4).
In essence, the filtered HCO3- is converted to CO2 in the
lumen, which diffuses into the proximal tubular cell and is
then converted back to HCO3- to be returned to the systemic
circulation, thus reclaiming the filtered HCO3-.
Acid excretion
Excretion of the daily acid load (50-100 mEq of H+) occurs
principally through H+secretion by the apical H+/ATPase in
α-intercalated cells of the collecting duct.
HCO3- formed intracellularly is returned to the systemic
circulation via the basolateral Cl-/HCO3- exchanger, AE1
(gene symbol SLC4A1), and H+ enters the tubular lumen via
1 of 2 apical proton pumps, H+/ATPase or H+ -K+/ATPase.
The secretion of H+ in these segments is influenced by Na+
reabsorption in the adjacent principal cells of the collecting
duct. The reabsorbed Na+ creates a relative lumen
negativity, which decreases the amount of secreted H+ that
back-diffuses from the lumen.
Hydrogen ions secreted by the kidneys can be excreted as
free ions but, at the lowest achievable urine pH of 5.0 (equal
to free H+ concentration of 10 µEq/L), would require
excretion of 5000-10,000 L of urine a day. Urine pH cannot
be lowered much below 5.0 because the gradient against
which H+/ATPase has to pump protons (intracellular pH 7.5
to luminal pH 5) becomes too steep. A maximally acidified
urine, even with a volume of 3 L, would thus contain a mere
30 µEq of free H+. Instead, more than 99.9% of the H+ load is
excreted buffered by the weak bases NH3 or phosphate.
Titratable acidity
The amount of secreted H+ that is buffered by filtered weak
acids is called titratable acidity. Phosphate as HPO42- is the
main buffer in this system, but other urine buffers include uric
acid and creatinine.
H2PO4 ↔ H+ + HPO42-
The amount of phosphate filtered is limited and relatively
fixed, and only a fraction of the secreted H+ can be buffered
by HPO42-.
Ammonia
A more important urine-buffering system for secreted H + than
phosphate, ammonia (NH3) buffering occurs via the following
reaction:
NH3 + H+ ↔ NH4+
Ammonia is produced in the proximal tubule from the amino
acid glutamine, and this reaction is enhanced by an acid
load and by hypokalemia. Ammonia is converted to
ammonium (NH4+) by intracellular H+ and is secreted into the
proximal tubular lumen by the apical Na+/H+ (NH4+)
antiporter.
The apical Na+/K+ (NH4+)/2Cl- cotransporter in the thick
ascending limb of the loop of Henle then transports NH4+ into
the medullary interstitium, where it dissociates back into NH3
and H+. The NH3 enters the collecting duct epithelial cells via
the basolateral ammonia transporters, RhBG and RhCG,
and then is transported into the lumen of the collecting duct
via apical RhCG, where it is available to buffer H+ions and
becomes NH4+. NH4+ is trapped in the lumen and excreted as
the Cl salt, and every H+ ion buffered is an HCO3- gained to
the systemic circulation.
The increased secretion of H+ in the collecting duct shifts the
equation to the right and decreases the NH3 concentration,
facilitating continued diffusion of NH3 from the interstitium
down its concentration gradient into the collecting duct
lumen, allowing more H+ to be buffered. The kidneys can
adjust the amount of NH3synthesized to meet demand,
making this a powerful system to buffer secreted H+in the
urine. [2]

Acidosis and alkalosis
In healthy people, blood pH is maintained at 7.39-7.41, and
because pH is the negative logarithm of [H+] (pH = - log10
[H+]), an increase in pH indicates a decrease in [H+] and vice
versa. An increase in [H +] and a fall in pH are termed
acidemia, and a decrease in [H+] and an increase in pH are
termed alkalemia. The underlying disorders that lead to
acidemia and alkalemia are acidosis and alkalosis,
respectively. Metabolic acidosis is a primary decrease in
serum HCO3 - concentration and, in its pure form, manifests
as acidemia (pH < 7.40).
Rarely, metabolic acidosis can be part of a mixed or complex
acid-base disturbance in which two or more separate
metabolic or respiratory derangements occur together. In
these instances, pH may not be reduced or the HCO3-
concentration may not be low.
As a compensatory mechanism, metabolic acidosis leads to
alveolar hyperventilation with a fall in PaCO2. Normally,
PaCO2 falls by 1-1.3 mm Hg for every 1-mEq/L fall in serum
HCO3- concentration, a compensatory response that can
occur fairly quickly. If the change in PaCO2 is not within this
range, then a mixed acid-base disturbance is present. For
example, if the decrease in PaCO2 is less than the expected
change, then a primary respiratory acidosis also is present.
The only definitive way to diagnose metabolic acidosis is by
simultaneous measurement of serum electrolytes and
arterial blood gases (ABGs) that shows both pH and PaCO2
to be low; calculated HCO3- also is low. (See Metabolic
Alkalosis for a discussion of the difference between
measured and calculated HCO3- concentrations.)
A normal serum HCO 3- level does not rule out the presence
of metabolic acidosis, because a drop in HCO3- from a high
baseline (ie, preexisting metabolic alkalosis) can result in a
serum HCO3- level that is within the reference range,
concealing the metabolic acidosis.
In general, patients with kidney failure tend to have a serum
HCO3- level greater than 12 mEq/L, and buffering by the
skeleton prevents further decline in serum HCO3-. Note that
patients with hypobicarbonatemia from kidney failure cannot
compensate for additional HCO3- loss from an extrarenal
source (eg, diarrhea), and severe metabolic acidosis can
develop rapidly.
In persons with chronic uremic acidosis, bone salts
contribute to buffering, and the serum HCO3- level usually
remains greater than 12 mEq/L. This bone buffering can lead
to significant loss of bone calcium, with resulting osteopenia
and osteomalacia.
Anion gap
Plasma, like any other body fluid compartment, is neutral;
total anions match total cations. The major plasma cation is
Na+, and major plasma anions are Cl- and HCO3-.
Extracellular anions present in lower concentrations include
phosphate, sulfate, and some organic anions, while other
cations present include K+, Mg2+, and Ca2+. The anion gap
(AG) is the difference between the concentration of the major
measured cation Na+ and the major measured anions Cl-
and HCO3-.
An increase in the AG can result from either a decrease in
unmeasured cations (eg, hypokalemia, hypocalcemia,
hypomagnesemia) or an increase in unmeasured anions (eg,
hyperphosphatemia, high albumin levels). In certain forms of
metabolic acidosis, other anions accumulate; by recognizing
the increasing AG, the clinician can formulate a differential
diagnosis for the cause of that acidosis. [3]
The reaction below indicates that the addition of an acid (HA,
where H+ is combined with an unmeasured anion A -) results
in the consumption of HCO3- with an addition of anions that
will account for the increase in the AG. Metabolic acidosis is
classified on the basis of AG into normal- (also called
16
[4]
non-AG or hyperchloremic metabolic acidosis ) and
high-AG metabolic acidosis.
HA + NaHCO 3 ↔ NaA + H 2CO3 ↔ CO2 + H2O
Urinary AG
Calculating the urine AG is helpful in evaluating some cases
of non-AG metabolic acidosis. The major measured urinary
cations are Na+ and K+, and the major measured urinary
anion is Cl-.
Urine AG = ([Na +] + [K+]) - [Cl-]
The major unmeasured urinary anions and cations are
HCO3- and NH4+, respectively. HCO3- excretion in healthy
subjects is usually negligible, and average daily excretion of
NH4+ is approximately 40 mEq/L, which results in a positive
or near-zero gap. In the face of metabolic acidosis, the
kidneys increase the amount of NH3 synthesized to buffer
the excess H+ and NH4 Cl excretion increases. The
increased unmeasured NH4+ thus increases the measured
anion Cl- in the urine, and the net effect is a negative AG,
representing a normal response to systemic acidification.
Thus, the finding of a positive urine AG in the face of non-AG
metabolic acidosis points toward a renal acidification defect
(eg, renal tubular acidosis [RTA]).
Caveats to urinary anion gap testing
The presence of ketonuria makes this test unreliable
because the negatively charged ketones are unmeasured
and urine AG will be positive or zero despite the fact that
renal acidification and NH4+ levels are increased. Moreover,
severe volume depletion from extrarenal NaHCO3 loss
causes avid proximal Na+ reabsorption, with little Na+
reaching the lumen of the collecting duct to be reabsorbed in
exchange for H+. Limiting H+ excretion reduces NH4+
excretion and may make the urine AG become positive.
Potassium and renal acid secretion
Renal acid secretion is influenced by serum K+ and may
result from the transcellular shift of K+ when intracellular K+ is
exchanged for extracellular H+ or vice versa. In hypokalemia,
an intracellular acidosis can develop; in hyperkalemia, an
intracellular alkalosis can develop. HCO3- reabsorption is
increased secondary to relative intracellular acidosis. The
increase in intracellular H+ concentration promotes the
activity of the apical Na+/H+ exchanger.
Renal production of NH3 is increased in hypokalemia,
resulting in an increase in renal acid excretion. The increase
in NH3 production by the kidneys may be significant enough
to precipitate hepatic encephalopathy in patients who have
advanced liver disease. Correcting the hypokalemia can
reverse this process.
Patients with hypokalemia may have relatively alkaline urine
because hypokalemia increases renal ammoniagenesis.
Excess NH3 then binds more H+ in the lumen of the distal
nephron and urine pH increases, which may suggest RTA as
an etiology for non-AG acidosis. However, these conditions
can be distinguished by measuring urine AG, which will be
negative in patients who have normal NH4+ excretion and
positive in patients with RTA. The most common cause for
hypokalemia and metabolic acidosis is GI loss (eg, diarrhea,
laxative use). Other less common etiologies include renal
loss of potassium secondary to RTA or salt-wasting
nephropathy. The urine pH, the urine AG, and the urinary K +
concentration can distinguish these conditions.
Hyperkalemia has an effect on acid-base regulation opposite
to that observed in hypokalemia. Hyperkalemia impairs NH4+
excretion through reduction of NH3synthesis in the proximal
tubule and reduction of NH4+ reabsorption in the thick
ascending limb, resulting in reduced medullary interstitial
NH3 concentration. This leads to a decrease in net renal acid

secretion and is a classic feature of primary or secondary
hypoaldosteronism. Consistent with the central role of
hyperkalemia in the generation of the acidosis, lowering the
serum K+ concentration can correct the associated metabolic
acidosis.
Etiology
Causes and diagnostic considerations
Metabolic acidosis is typically classified according to whether
the anion gap (AG) is normal (ie, non-AG) or high. Non-AG
metabolic acidosis is also characterized by hyperchloremia
and is sometimes referred to as hyperchloremic acidosis.
Calculation of the AG is thus helpful in the differential
diagnosis of metabolic acidosis. [3, 5]
Normal anion gap metabolic acidosis
Hyperchloremic or non-AG metabolic acidosis occurs
principally when HCO3- is lost from either the GI tract or the
kidneys or because of a renal acidification defect. Some of
the mechanisms that result in a non-AG metabolic acidosis
are the following:
● Addition of HCl to body fluids: H + buffers
HCO 3 - and the added Cl - results in a
normal AG.
● Loss of HCO 3 - from the kidneys or the GI
tract: The kidneys reabsorb sodium chloride
to maintain volume.
● Rapid volume expansion with normal saline:
This results in an increase in the chloride
load that exceeds the renal capacity to
generate equal amounts of HCO 3 -.
Causes of non-AG metabolic acidosis can be remembered
with the mnemonic ACCRUED:
● Acid load
● Chronic kidney disease (CKD)
● Carbonic anhydrase inhibitors
● Renal tubular acidosis (RTA)
● Ureteroenterostomy
● Expansion/extra-alimentation
● Diarrhea
Conditions that may cause a non-AG metabolic acidosis are
as follows:
● GI loss of HCO 3 - - Diarrhea
● Enterocutaneous fistula (eg, pancreatic) -
Enteric diversion of urine (eg, ileal loop
bladder), pancreas transplantation with
bladder drainage
● Renal loss of HCO 3 - - Proximal RTA (type
2), carbonic anhydrase inhibitor therapy
(including topiramate [6] )
● Failure of renal H + secretion - Distal RTA
(type 1), hyperkalemic RTA (type 4), kidney
failure
● Acid infusion - Ammonium chloride,
hyperalimentation
● Other - Rapid volume expansion with normal
saline
Causes of non-AG metabolic acidosis are discussed in more
detail below.
High anion gap metabolic acidosis
High AG metabolic acidosis warrants consideration of the
following:
● Lactic acidosis – L-lactate, D-lactate
● Ketoacidosis - Beta-hydroxybutyrate,
acetoacetate
● CKD - High-AG chronic metabolic acidosis is
seen in later stages of CKD, as a result of
17
loss of nephron mass and impaired
glomerular elimination of organic acid
residues [7]
● Ingestions - Salicylate, methanol,
formaldehyde (formate), ethylene glycol
(glycolate, oxalate), paraldehyde (organic
anions), phenformin/metformin [8]
● Infusions - Propylene glycol (D-lactate,
L-lactate)
● Pyroglutamic acid (5-oxoprolinemia) -
Typically seen in malnourished, chronically ill
women with a history of long-term
acetaminophen ingestion [9]
● Massive rhabdomyolysis (release of H + and
organic anions from damaged muscle)
Several mnemonics are used to help recall of the differential
diagnosis of high anion gap acidosis. Three are as follows:
● MUDPILES: Methanol; Uremia; Diabetic
ketoacidosis (DKA); Paraldehyde,
phenformin; Iron, isoniazid; Lactic (ie, carbon
monoxide [CO], cyanide); Ethylene glycol;
Salicylates
● DR. MAPLES: DKA; Renal; Methanol;
Alcoholic ketoacidosis; Paraldehyde,
phenformin; Lactic (ie, CO, HCN); Ethylene
glycol; Salicylates
● SLUMPED: Salicylate, Lactate, Uremia,
Methanol, Paraldehyde, Ethylene glycol,
Diabetes)
A more current mnemonic is GOLD MARK, which
incorporates newly recognized forms of metabolic acidosis
and eliminates P for paraldehyde as that is now rarely seen.
[10]
● GOLD MARK: Glycols (ethylene and
propylene), Oxoproline, Lactate, D-lactate,
Methanol, Aspirin, Renal failure,
Ketoacidosis
Plasma osmolality and the osmolar gap can be helpful in
determining the cause of high AG acidosis. Plasma
osmolality can be calculated using the following equation:
Posm = [2 × Na+]+[glucose in mg/dL]/18+[BUN in mg/dL]/2.8
Posm can also be measured in the laboratory, and because
other solutes normally contribute minimally to serum
osmolality, the difference between the measured and the
calculated value (osmolar gap) is no more than 10-15
mOsm/kg. In certain situations, unmeasured osmotically
active solutes in the plasma can raise the osmolar gap (eg,
mannitol, radiocontrast agents).
The osmolar gap can also be a clue to the nature of the
anion in high-AG acidosis because some osmotically active
toxins also cause a high-AG acidosis. Methanol, ethylene
glycol, and acetone are classic poisons that increase the
osmolar gap and AG; measuring the osmolar gap can help
narrow the differential diagnosis of high-AG acidosis.
Causes of AG metabolic acidosis are discussed in more
detail below.
Specific causes of hyperchloremic or non-AG metabolic
acidosis
Loss of HCO3- via the GI tract
The secretions of the GI tract, with the exception of the
stomach, are relatively alkaline, with high concentrations of
base (50-70 mEq/L). Significant loss of lower GI secretions
results in metabolic acidosis, especially when the kidneys
are unable to adapt to the loss by increasing net renal acid
excretion.
Such losses can occur in diarrheal states, fistula with
drainage from the pancreas or the lower GI tract, and
sometimes vomiting if it occurs as a result of intestinal

obstruction. When pancreatic transplantation is performed,
the pancreatic duct is sometimes diverted into the recipient
bladder, from where exocrine pancreatic secretions are lost
in the final urine. Significant loss also occurs in patients who
abuse laxatives, which should be suspected when the
etiology for non-AG metabolic acidosis is not clear.
Urine pH will be less than 5.3, with a negative urine AG
reflecting normal urine acidification and increased NH4+
excretion. However, if distal Na+ delivery is limited because
of volume depletion, theurine pH cannot be lowered
maximally.
Replacing the lost HCO3- on a daily basis can treat this form
of metabolic acidosis.
Distal RTA (type 1) (see the Table below)
The defect in this type of RTA is a decrease in net H +
secreted by the A-type intercalated cells of the collecting
duct. As mentioned previously, H + is secreted by the apical
H+–ATPase and, to a lesser extent, by the apical
K+/H+–ATPase. The K+/H+–ATPase seems to be more
important in K+ regulation than in H+ secretion. The secreted
H+ is then excreted as free ions (reflected by urine pH value)
or titrated by urinary buffers, phosphate, and NH3. A
decrease in the amount of H+secreted results in a reduction
in its urinary concentration (ie, increase in urine pH) and a
reduction in total H+ buffered by urinary phosphate or NH3.
Type 1 RTA should be suspected in any patient with non-AG
metabolic acidosis and a urine pH greater than 5.0. Patients
have a reduction in serum HCO3- to various degrees, in
some cases to less than 10 mEq/L. They are able to
reabsorb HCO3-normally, and their fractional excretion (FE)
of HCO3- is less than 3%. The disorder has been classified
into 4 types—secretory, rate dependent, gradient, and
voltage dependent—based on the nature of the defect.
Several different mechanisms are implicated in the
development of distal RTA. These include a defect in 1 of the
2 proton pumps, H+–ATPase or K+/H+–ATPase, that can be
acquired or congenital. This may lead to loss of function (ie,
secretory defect) or a reduction in the rate of H+ secretion
(ie, rate-dependent defect).
Another mechanism is a defect in the basolateral Cl-/HCO3-
exchanger, AE1, or the intracellular carbonic anhydrase that
can be acquired or congenital. This also causes a secretory
defect.
Back-diffusion of the H+ from the lumen via the paracellular
or transcellular space is another mechanism; this occurs if
the integrity of the tight junctions is lost or permeability of the
apical membrane is increased (ie, permeability or gradient
defect). With a urine pH of 5.0 and an interstitial fluid pH of
7.4, the concentration gradient facilitating back-diffusion of
free H+, under conditions of increased permeability of the
collecting duct epithelia, is approximately 250-fold.
A defect in Na + reabsorption in the collecting duct would
decrease the electrical gradient favoring the secretion of H+
into the tubular lumen (ie, voltage-dependent defect). This
can occur, for instance, in severe volume depletion with
decreased luminal Na+ delivery to this site.
The serum potassium level typically is low in patients with
distal RTA because defects in H + secretion or back-diffusion
of H+ tend to increase urinary K+ wasting. Potassium wasting
occurs from one or more of the following factors:
● Decreased net H+ secretion results in more
Na+ reabsorption in exchange for K+
secretion.
● The drop in serum HCO3- and, therefore,
filtered HCO3-, reduces the amount of Na+
reabsorbed by the Na+/H+ exchanger in the
proximal tubule, leading to mild volume
depletion. The associated activation of the
renin-angiotensin-aldosterone system
increases K+ secretion in the collecting duct.
● A possible defect in K +/H+–ATPase results in
decreased H+ secretion and decreased K+
reabsorption.
18
+
The serum K level can be high if the distal RTA is secondary
to decreased luminal Na+ in the distal nephron. Na+
reabsorption in the principal cells of the collecting duct
serves as the driving force for K+ secretion. In this case, the
patient has hyperkalemia and acidosis; the disorder is also
called voltage-dependent or hyperkalemic type 1 acidosis.
Urine AG is positive and urine pH is high secondary to the
renal acid secretion defect. Urine pH also can be high in
patients with type 2 RTA if their serum HCO 3-level is higher
than the renal threshold for reabsorption, typically when a
patient with type 2 RTA is on HCO 3- replacement therapy.
Administration of an HCO3- load leads to a marked increase
in urine pH in those who have type 2 RTA, while those with
type 1 RTA have a constant urine pH unless their acidosis is
overcorrected.
Patients with type 1 RTA may develop nephrocalcinosis and
nephrolithiasis. This is thought to occur for the following
reasons:
● Patients have a constant release of calcium
phosphate from bones to buffer the
extracellular H +.
● Patients have decreased reabsorption of
calcium and phosphate, leading to
hypercalciuria and hyperphosphaturia.
● Patients have relatively alkaline urine, which
promotes calcium phosphate precipitation.
● Metabolic acidosis and hypokalemia lead to
hypocitraturia, a risk factor for stones. Citrate
in the urine complexes calcium and inhibits
stone formation.
The causes of distal RTA are shown as follows. Type 1 RTA
occurs sporadically, although genetic forms have been
reported.
● Primary - Genetic or sporadic
● Drug-related - Amphotericin B, lithium,
analgesics, ifosfamide, topiramate, toluene
● Autoimmune disease - Systemic lupus
erythematosus, chronic active hepatitis,
Sjögren syndrome, rheumatoid arthritis,
primary biliary cirrhosis
● Related to other systemic disease - Sickle
cell disease, hyperparathyroidism, light chain
disease, cryoglobulinemia, Wilson disease,
Fabry disease
● Tubulointerstitial disease - Obstructive
uropathy, transplant rejection, medullary
cystic kidney disease, hypercalciuria
The genetic forms of type 1 RTA are the following:
● Autosomal dominant: Heterozygous
mutations in the basolateral
Cl-/HCO3-exchanger, AE1 (gene symbol
SLC4A1), cause a dominant form of distal
RTA with nephrocalcinosis and
osteomalacia. Some patients with this
disorder can be relatively asymptomatic and
present in later years, while others present
with severe disease in childhood. The
disorder is allelic with one form of hereditary
spherocytosis, but each disease is caused
by distinct mutations in the same gene.
● Autosomal recessive: This form of the
disease may occur with or without
sensorineural deafness. The type that occurs
with deafness involves homozygous
mutations in the B subunit of H+ –ATPase
(gene symbol ATP6B1) in the A-type
intercalated cells. The type that occurs
without deafness involves homozygous
mutations in the accessory N1 subunit of H+
–ATPase (gene symbol ATP6N1B).

Homozygous or compound heterozygous
mutations in AE1also cause a recessive form
of distal RTA that manifests in childhood with
growth retardation and nephrocalcinosis that
may lead to renal insufficiency.
Heterozygous carriers have autosomal
dominant ovalocytosis but normal renal
acidification.
Proximal (type 2) RTA
The hallmark of type 2 RTA is impairment in proximal tubular
HCO3- reabsorption. In the euvolemic state and in the
absence of elevated levels of serum HCO3-, all filtered HCO3-
is reabsorbed, 90% of which is in the proximal tubule.
Normally, HCO3- excretion occurs only when serum HCO3-
exceeds 24-28 mEq/L. Patients with type 2 RTA, however,
have a lower threshold for excretion of HCO3-, leading to a
loss of filtered HCO3- until the serum HCO3- concentration
reaches the lower threshold. At this point, bicarbonaturia
ceases and the urine appears appropriately acidified. Serum
HCO3- typically does not fall below 15 mEq/L because of the
ability of the collecting duct to reabsorb some HCO3-.
Type 2 RTA can be found as a solitary proximal tubular
defect, in which reabsorption of HCO3- is the only
abnormality (rare) such as with homozygous mutations in
SLC4A4. More commonly, it is part of a more generalized
defect of the proximal tubule characterized by glucosuria,
aminoaciduria, and phosphaturia, also called Fanconi
syndrome.
Dent disease or X-linked hypercalciuric nephrolithiasis is one
example of a generalized proximal tubular disorder
characterized by an acidification defect, hypophosphatemia,
and hypercalciuria and arises from mutations in the renal
chloride channel gene (CLCN5). Homozygous mutations in
SCL34A1 also cause a genetic form of Fanconi syndrome.
The proximal tubule is the site where bulk reabsorption of
ultrafiltrate occurs, driven by the basolateral Na+/K+
–ATPase. Any disorder that leads to decreased ATP
production or a disorder involving Na+ -K+ –ATPase can
result in Fanconi syndrome. In principle, loss of function of
the apical Na+/H+ antiporter or the basolateral Na+/3HCO3-
cotransporter or the intracellular carbonic anhydrase results
in selective reduction in HCO3- reabsorption.
Patients with type 2 RTA typically have hypokalemia and
increased urinary K+wasting. This is thought, in part, to be
due to an increased rate of urine flow to the distal nephron
caused by the reduced proximal HCO3- reabsorption and, in
part, to be due to activation of the
renin-angiotensin-aldosterone axis with increased collecting
duct Na+ reabsorption from the mild hypovolemia induced by
bicarbonaturia. Administration of alkali in those patients
leads to more HCO3-wasting and can worsen hypokalemia
unless K+ is replaced simultaneously.
The diagnosis of type 2 RTA should be suspected in patients
who have a normal-AG metabolic acidosis with a serum
HCO3- level usually greater than 15 mEq/L and acidic urine
(pH < 5.0). Those patients have an FEHCO3- less than 3%
when their serum HCO3- is low. However, raising serum
HCO3- above their lower threshold and closer to normal
levels results in significant HCO3- wasting and an
FEHCO3exceeding 15%.
FEHCO3- = (urine [HCO3-] X plasma [creatinine] / plasma
[HCO3-]) X urine [creatinine] X 100
Some patients with type 2 RTA tend to have osteomalacia, a
condition that can be observed in any chronic acidemic
state, although it is more common in persons with type 2
RTA. The traditional explanation is that the proximal tubular
conversion of 25(OH)-cholecalciferol to the active
1,25(OH)2-cholecalciferol is impaired. Patients with more
generalized defects in proximal tubular function (as in
Fanconi syndrome) may have phosphaturia and
hypophosphatemia, which also predispose to osteomalacia.
The following are causes of proximal RTA:
● Primary - Genetic or sporadic
19
● Inherited systemic disease - Wilson disease,
glycogen storage disease, tyrosinemia, Lowe
syndrome, cystinosis, fructose intolerance
● Related to other systemic disease - Multiple
myeloma, amyloidosis, hyperparathyroidism,
Sjögren syndrome
● Drug- and toxin-related - Carbonic
anhydrase inhibitors, ifosfamide, gentamicin,
valproic acid, lead, mercury, streptozotocin
Isolated proximal RTA occurs sporadically, although an
inherited form has recently been described. Homozygous
mutations in the apical Na+/3HCO3- cotransporter have been
found in 2 kindred with proximal RTA, band keratopathy,
glaucoma, and cataracts. A form of autosomal recessive
osteopetrosis with mental retardation is associated with a
mixed RTA with features of both proximal and distal disease
(called type 3). The mixed defect is related to the deficiency
of carbonic anhydrase (CA II isoform) normally found in the
cytosol of the proximal tubular cells and the intercalated cells
of the collecting duct. The most common cause of acquired
proximal RTA in adults follows the use of carbonic anhydrase
inhibitors.
Type 4 RTA
This is the most common form of RTA in adults and results
from aldosterone deficiency or resistance. The collecting
duct is a major site of aldosterone action; there it stimulates
Na+ reabsorption and K+ secretion in the principal cells and
stimulates H+ secretion in the A-type intercalated cells.
Hypoaldosteronism, therefore, is associated with decreased
collecting duct Na+ reabsorption, hyperkalemia, and
metabolic acidosis.
Hyperkalemia also reduces proximal tubular NH4+ production
and decreases NH4+absorption by the thick ascending limb,
leading to a reduction in medullary interstitial NH3
concentration. This diminishes the ability of the kidneys to
excrete an acid load and worsens the acidosis.
Because the function of H+ –ATPase is normal, the urine is
appropriately acidic in this form of RTA. Correction of
hyperkalemia leads to correction of metabolic acidosis in
many patients, pointing to the central role of hyperkalemia in
the pathogenesis of this acidosis.
Almost all patients with type 4 RTA manifest varying degrees
of hyperkalemia, which commonly is asymptomatic. The
etiology of hyperkalemia is multifactorial and related to the
presence of hypoaldosteronism in conjunction with a degree
of renal insufficiency. The acidosis and hyperkalemia,
however, are out of proportion to the degree of renal failure.
The following findings are typical of type 4 RTA:
● Mild-to-moderate chronic kidney disease
(stages 2-3) in most patients, with a
creatinine clearance of 30-60 mL/min
● Hyperkalemia
● Hypoaldosteronism
● Diabetes mellitus (in approximately 50% of
patients)
Type 4 RTA should be suspected in any patient with a mild
non-AG metabolic acidosis and hyperkalemia. The serum
HCO3- level is usually greater than 15 mEq/L, and the urine
pH is less than 5.0 because these patients have a normal
ability to secrete H+. The primary problem is hyperkalemia
from aldosterone deficiency or end organ (collecting duct)
resistance to the action of aldosterone. This can be
diagnosed by measuring the transtubular potassium gradient
(TTKG).
TTKG = urine K+ X serum osmolality/serum K+ X urine
osmolality
A TTKG greater than 8 indicates that aldosterone is present
and the collecting duct is responsive to it. A TTKG less than
5 in the presence of hyperkalemia indicates aldosterone
deficiency or resistance. For the test to be interpretable, the
urine Na+level should be greater than 10 mEq/L and the

urine osmolality should be greater than or equal to serum
osmolality.
The hyperkalemia suppresses renal ammoniagenesis,
leading to a lack of urinary buffers to excrete the total H+
load. The urine AG will be positive. Note that patients with
hyperkalemic type 1 RTA have a urine pH greater than 5.5
and a low urine Na+.
The following are causes of type 4 RTA:
● Hypoaldosteronism (low renin) -
Hyporeninemic hypoaldosteronism (diabetes
mellitus/mild renal impairment, chronic
interstitial nephritis, nonsteroidal
anti-inflammatory drugs, beta-blockers)
● Hypoaldosteronism (high renin) - Primary
adrenal defect (isolated: congenital
hypoaldosteronism; generalized: Addison
disease, adrenalectomy, AIDS), inhibition of
aldosterone secretion (heparin, ACE
inhibitors, AT1 receptor blockers)
● Aldosterone resistance (drugs) - Diuretics
(amiloride, triamterene, spironolactone),
calcineurin inhibitors (cyclosporine,
tacrolimus), antibiotics (trimethoprim,
pentamidine)
● Aldosterone resistance (genetic) -
Pseudohypoaldosteronism (PHA) types I and
II
Although type 4 RTA occurs sporadically, familial forms have
been reported. The genetic forms are called PHA; PHA type
1 is characterized by hypotension with hyperkalemia and
acidosis and includes an autosomal recessive and
autosomal dominant form. PHA type 2 is characterized by
hypertension with hyperkalemia and acidosis and is also
known as Gordon syndrome and familial hyperkalemic
hypertension. Note the following:
● Autosomal recessive PHA type 1:
Homozygous mutations in the alpha, beta, or
gamma subunits (gene symbols SCNN1A,
SCNN1B, and SCNN1G) of the collecting
duct epithelial sodium channel cause a
syndrome that manifests in infancy with
severe salt wasting, hypotension,
hyperkalemia, and acidosis. A pulmonary
syndrome characterized by recurrent
respiratory infections, chronic cough, and
increased respiratory secretions has also
been noted in some individuals.
● Autosomal dominant PHA type 1:
Heterozygous mutations in the
mineralocorticoid receptor lead to a milder
phenotype that is restricted to the kidneys.
Unlike the autosomal recessive form, the
clinical symptoms improve with age.
● Gordon syndrome (PHA type 2): This
disorder is characterized by hypertension
and hyperkalemia with variable degrees of
metabolic acidosis. There are at least 5
genetic loci associated with this disease.
Heterozygous mutations in 1 of 2 kinases,
WNK1 or WNK4, or in the CUL3 gene cause
this syndrome. Heterozygous or
homozygous mutations in the KLHL3
genecause an autosomal dominant or
recessive form of this syndrome. A fifth locus
on band 1q has been described, but the
genetic defect at this locus has not yet been
identified.
Early renal failure
Metabolic acidosis is usual in patients with renal failure, and,
in early to moderate stages of chronic kidney disease
(glomerular filtration rate of 20-50 mL/min), it is associated
20
with a normal AG (hyperchloremic). In more advanced renal
failure, the acidosis is associated with a high AG.
In hyperchloremic acidosis, reduced ammoniagenesis
(secondary to loss of functioning renal mass) is the primary
defect, leading to an inability of the kidneys to excrete the
normal daily acid load. In addition, NH3 reabsorption and
recycling may be impaired, leading to reduced medullary
interstitial NH3 concentration.
In general, patients tend to have a serum HCO3- level greater
than 12 mEq/L, and buffering by the skeleton prevents
further decline in serum HCO3-.
Note that patients with hypobicarbonatemia from renal failure
cannot compensate for additional HCO3- loss from an
extrarenal source (eg, diarrhea) and severe metabolic
acidosis can develop rapidly.
Urinary diversion
Hyperchloremic metabolic acidosis can develop in patients
who undergo a urinary diversion procedure, such as a
sigmoid bladder or an ileal conduit.
This occurs through 1 of the following 2 mechanisms:
The first is the intestinal mucosa has an apical Cl-/HCO3-
exchanger. When urine is diverted to a loop of bowel (as in
patients with obstructive uropathy), the chloride in the urine
is exchanged for HCO3-. Significant loss of HCO3- can occur,
with a concurrent increase in serum Cl- concentration.
The second is intestinal mucosa reabsorbs urinary NH4+, and
the latter is metabolized in the liver to NH3 and H+. This is
particularly likely to occur if urine contact time with the
intestinal mucosa is prolonged, as when a long loop of bowel
is used or when the stoma is obstructed and when sigmoid
rather than ileal loop is used. Presumably, the creation of a
continent bladder also increases HCO3- loss. This disorder is
not observed very frequently anymore because short-loop
incontinent ureteroileostomies are used now.
Infusion of acids
The addition of an acid that contains Cl- as an ion (eg, NH4
Cl) can result in a normal-AG acidosis because the drop in
HCO3- is accompanied by an increase in Cl-.
The use of arginine or lysine hydrochloride as amino acids
during hyperalimentation can have the same result.
Specific causes of high-AG metabolic acidosis
Lactic acidosis
Briefly, L-lactate is a product of pyruvic acid metabolism in a
reaction catalyzed by lactate dehydrogenase that also
involves the conversion of nicotinamide adenine dinucleotide
(NADH) to the oxidized form of nicotinamide adenine
dinucleotide (NAD+). This is an equilibrium reaction that is
bidirectional, and the amount of lactate produced is related
to the reactant concentration in the cytosol (pyruvate,
NADH/NAD+).
Daily lactate production in a healthy person is substantial
(approximately 20 mEq/kg/d), and this is usually metabolized
to pyruvate in the liver, the kidneys, and, to a lesser degree,
in the heart. Thus, production and use of lactate (ie, Cori
cycle) is constant, keeping plasma lactate low.
The major metabolic pathway for pyruvate is to acetyl
coenzyme A, which then enters the citric acid cycle. In the
presence of mitochondrial dysfunction, pyruvate
accumulates in the cytosol and more lactate is produced.
Lactic acid accumulates in blood whenever production is
increased or use is decreased. A value greater than 4-5
mEq/L is considered diagnostic of lactic acidosis.
Type A lactic acidosis occurs in hypoxic states, while type B
occurs without associated tissue hypoxia.
D-lactic acidosis is a form of lactic acidosis that occurs from
overproduction of D-lactate by intestinal bacteria. It is
observed in association with intestinal bacterial overgrowth
syndromes. D-lactate is not measured routinely when lactate
levels are ordered and must be requested specifically when
such cases are suspected.
Metformin-associated lactic acidosis has been reported. [11, 12]

Ketoacidosis
Free fatty acids released from adipose tissue have 2
principal fates. In the major pathway, triglycerides are
synthesized in the cytosol of the liver. In the less common
pathway, fatty acids enter mitochondria and are metabolized
to ketoacids (acetoacetic acid and beta-hydroxybutyric acid)
by the beta-oxidation pathway. Ketoacidosis occurs when
delivery of free fatty acids to the liver or preferential
conversion of fatty acids to ketoacids is increased.
This pathway is favored when insulin is absent (as in the
fasting state), in certain forms of diabetes, and when
glucagon action is enhanced.
Alcoholic ketoacidosis occurs when excess alcohol intake is
accompanied by poor nutrition. Alcohol inhibits
gluconeogenesis, and the fasting state leads to low insulin
and high glucagon levels. These patients tend to have a mild
degree of lactic acidosis. This diagnosis should be
suspected in alcoholic patients who have an unexplained AG
acidosis, and detection of beta-hydroxybutyric acid in the
serum in the absence of hyperglycemia is highly suggestive.
Patients may have more than one metabolic disturbance (eg,
mild lactic acidosis, metabolic alkalosis secondary to
vomiting).
Starvation ketoacidosis can occur after prolonged fasting
and may be exacerbated by exercise.
DKA is usually precipitated in patients with type 1 diabetes
by stressful conditions (eg, infection, surgery, emotional
trauma), but it can also occur in patients with type 2
diabetes. Hyperglycemia, metabolic acidosis, and elevated
beta-hydroxybutyrate confirm the diagnosis. The metabolic
acidosis in DKA is commonly a high-AG acidosis secondary
to the presence of ketones in the blood. However, after
initiation of treatment with insulin, ketone production ceases,
the liver uses ketones, and the acidosis becomes a non-AG
type that resolves in a few days (ie, time necessary for
kidneys to regenerate HCO3-, which was consumed during
the acidosis).
Advanced renal failure
Patients with advanced chronic kidney disease (glomerular
filtration rate of less than 20 mL/min) present with a high-AG
acidosis. The acidosis occurs from reduced
ammoniagenesis leading to a decrease in the amount of H+
buffered in the urine. The increase in AG is thought to occur
because of the accumulation of sulfates, urates and
phosphates from a reduction in glomerular filtration and from
diminished tubular function.
In persons with chronic uremic acidosis, bone salts
contribute to buffering, and the serum HCO3- level usually
remains greater than 12 mEq/L. This bone buffering can lead
to significant loss of bone calcium with resulting osteopenia
and osteomalacia.
Salicylate overdose
Deliberate or accidental ingestion of salicylates can produce
a high-AG acidosis, although respiratory alkalosis is usually
the more pronounced acid-base disorder.
The increase in AG is only partly from the unmeasured
salicylate anion. Increased ketoacid and lactic acid levels
have been reported in persons with salicylate overdose and
are thought to account for the remainder of the AG.
Salicylic acid ionizes to salicylate and H+ ion with increasing
pH; at a pH of 7.4, only 0.004% of salicylic acid is
nonionized, as follows:
Salicylic acid (HS)↔salicylate (S) + H+ (H+)
HS is lipid soluble and can diffuse into the CNS; with a fall in
pH, more HS is formed. The metabolic acidosis thus
increases salicylate entry to the CNS, leading to respiratory
alkalosis and CNS toxicity.
Methanol poisoning
Methanol ingestion is associated with the development of a
high-AG metabolic acidosis. Methanol is metabolized by
alcohol dehydrogenase to formaldehyde and then to formic
acid.
21
Formaldehyde is responsible for the optic nerve and CNS
toxicity, while the increase in AG is from formic acid and from
lactic acid and ketoacid accumulation.
Clinical manifestations include optic nerve injury that can be
appreciated by funduscopic examination as retinal edema,
CNS depression, and unexplained metabolic acidosis with
high anion and osmolar gaps.
Ethylene glycol poisoning
Ingestion of ethylene glycol, a component of antifreeze and
engine coolants, leads to a high-AG acidosis. Ethylene
glycol is converted by alcohol dehydrogenase first to
glycoaldehyde and then to glycolic and glyoxylic acids.
Glyoxylic acid then is degraded to several compounds,
including oxalic acid, which is toxic, and glycine, which is
relatively innocuous.
The high AG is primarily from the accumulation of these
acids, although a mild lactic acidosis also may be present.
Patients present with CNS symptoms, including slurred
speech, confusion, stupor or coma, myocardial depression,
and renal failure with flank pain.
Oxalate crystals are usually observed in the urine and are an
important clue to the diagnosis, as is an elevated osmolar
gap.
Prognosis
Morbidity and mortality in metabolic acidosis are primarily
related to the underlying condition.
In a prospective, observational, cohort study, Maciel and
Park looked at differences between survivors and
nonsurvivors within a group of 107 patients suffering from
metabolic acidosis on admission to an intensive care unit
(ICU). [13] The authors found that although acidosis was more
severe in nonsurvivors than in survivors, the proportion of
acidifying variables was similar on admission between the 2
groups (with hyperchloremia being the primary cause of the
acidosis).
The investigators also found that in nonsurviving patients,
the degree of metabolic acidosis was similar on the day of
death to the level measured when they were admitted to the
ICU, but that the proportion of anions had changed.
Specifically, the chloride levels in the patients had
decreased, and the lactate levels had increased.
History
Symptoms of metabolic acidosis are not specific. The
respiratory center in the brainstem is stimulated, and
hyperventilation develops in an effort to compensate for the
acidosis. As a result, patients may report varying degrees of
dyspnea. Patients may also report chest pain, palpitations,
headache, confusion, generalized weakness, and bone pain.
Patients, especially children, also may present with nausea,
vomiting, and decreased appetite.
The clinical history in metabolic acidosis is helpful in
establishing the etiology when symptoms relate to the
underlying disorder. The age of onset and a family history of
acidosis may point to inherited disorders, which usually start
during childhood. Important points in the history include the
following:
● Diarrhea - Gastrointestinal (GI) losses of
HCO 3 -
● History of diabetes mellitus, alcoholism, or
prolonged starvation - Accumulation of
ketoacids
● Polyuria, increased thirst, epigastric pain,
vomiting - Diabetic ketoacidosis(DKA)
● Nocturia, polyuria, pruritus, and anorexia -
Kidney failure [14]
● Ingestion of drugs or toxins - Salicylates,
acetazolamide, cyclosporine, ethylene
glycol, methanol, metformin, topiramate

● Visual symptoms, including dimming,
photophobia, scotomata - Methanol ingestion
● Renal stones - Renal tubular acidosis (RTA)
or chronic diarrhea
● Tinnitus, blurred vision, and vertigo -
Salicylate overdose
Physical Examination
The best recognized sign of metabolic acidosis is Kussmaul
respirations, a form of hyperventilation that serves to
increase minute ventilatory volume. This is characterized by
an increase in tidal volume rather than respiratory rate and is
appreciated as deliberate, slow, deep breathing.
Chronic metabolic acidosis in children may be associated
with stunted growth and rickets.
Coma and hypotension have been reported with acute
severe metabolic acidosis.
Other physical signs of metabolic acidosis are not specific
and depend on the underlying cause. Some examples
include xerosis, scratch marks on the skin, pallor,
drowsiness, fetor, asterixis, and pericardial rub for kidney
failure, as well as reduced skin turgor, dry mucous
membranes, and fruity breath odor for DKA.
Laboratory Evaluation
The diagnosis is made by evaluating serum electrolytes and
ABGs. A low serum HCO 3- and a pH of less than 7.40 upon
ABG analysis confirm metabolic acidosis. The anion gap
(AG) should be calculated to help with the differential
diagnosis of the metabolic acidosis and to diagnose mixed
disorders. In general, a high-AG acidosis is present if the AG
is greater than 10-12 mEq/L, and a non-AG acidosis is
present if the AG is less than or equal to 10-12 mEq/L. It is
important to note that the AG decreases by 2.5 mEq for
every 1 g/dL decrease in serum albumin.
If the AG is elevated, the osmolar gap should be calculated
by subtracting the calculated serum osmolality from the
measured serum osmolality. Ethylene glycol and methanol
poisoning increase the AG and the osmolar gap. Acetone,
produced by decarboxylation of acetoacetate, can also raise
serum osmolality. Other tests can be performed, including a
screen for toxins (eg, ethylene glycol, salicylate) and tests
for metabolic disorders (eg, ketoacidosis, lactic acidosis),
that are known to elevate the AG.
If the AG is not elevated, then a urinalysis should be
performed and a urine pH obtained with a pH electrode on a
fresh sample of urine collected under oil or in a capped
syringe. A urine AG is calculated from the measurement of
urine Na+, K+, and Cl-. This helps to differentiate between GI
and renal losses of HCO3- in non-AG metabolic acidosis.
The change in AG (delta AG) helps in detecting the
presence of a second acid-base disorder in patients with an
elevated AG. It is calculated by the following equation:
(AG - 10)/(24 - HCO3-)
A value less than 1 indicates that the drop in serum HCO 3- is
not accompanied by a corresponding increase in the AG.
This suggests that a portion of the H+ load is not
accompanied by an unmeasured anion and indicates the
presence of a mixed metabolic acidosis (eg, a non-AG
acidosis and a high-AG acidosis).
A value greater than 1.6 indicates that the drop in serum
HCO3- is associated with a larger-than-expected increase in
the AG. This would occur if the serum HCO 3- level was
higher than normal prior to the onset of the metabolic
acidosis and then dropped below normal with the addition of
H+ coupled to an unmeasured anion. This indicates the
presence of a mixed metabolic acidosis and metabolic
alkalosis.
22
Evaluation
Interpretation Steps
Acid-base interpretation is crucial to identify and correct
disturbances in acid-base equilibrium that have profound
consequences on patient health. The following steps use lab values
and equations to determine if a patient has metabolic acidosis and
any additional acid-base disturbances.
Step 1: pH, determine if the acid-base status is acidemia or
alkalemia
Blood pH is maintained within a narrow range for optimization of
physiological functions. Acid-base equilibrium is achieved within
a pH range of 7.35 to 7.45. Blood pH distinguishes between
acidemia (pH less than 7.35) and alkalemia (pH greater than 7.45)
Step 2: CO2, determine if the disturbance is metabolic or
respiratory
The pCO2 determines whether an acidosis is respiratory or
metabolic in origin. For a respiratory acidosis, the pCO2 is greater
than 40 to 45 due to decreased ventilation. Metabolic acidosis is
due to alterations in bicarbonate, so the pCO2 is less than 40 since
it is not the cause of the primary acid-base disturbance. In
metabolic acidosis, the distinguishing lab value is a decreased
bicarbonate (normal range 21 to 28 mEq/L).
Step 3: Determine if there is anion gap or non-anion gap metabolic
acidosis
● AG= Na – (Cl + HCO3)
The normal anion gap is 12. Therefore, values greater than 12
define an anion gap metabolic acidosis.
Step 4: CO2, assess if respiratory compensation is appropriate
Respiratory compensation is the physiologic mechanism to help
normalize a metabolic acidosis, however, compensation never
completely corrects an acidemia. It is important to determine if
there is adequate respiratory compensation or if there is another
underlying respiratory acid-base disturbance. Winter's formula is
the equation used to determine the expected CO2 for adequate
compensation.
● Winter’s formula: Expected CO2 = (Bicarbonate x 1.5) +
8 +/- 2
If the patient’s pCO2 is within the predicted range, then there is no
additional respiratory disturbance. If the pCO2 is greater than
expected, this indicates an additional respiratory acidosis. If the
pCO2 is less than expected, there is an additional respiratory
alkalosis occurring.
Step 5: Evaluate for additional metabolic disturbances
A delta gap must be determined if an anion gap is present.
● Delta gap = Delta AG – Delta HCO3 = (AG-12) –
(24-bicarbonate)

If the gap is less than -6, then a NAGMA is present.
If the gap is greater than 6, then an underlying metabolic alkalosis
is present.
If the gap is between -6 and 6 then only an anion gap acidosis
exists.
Special tests
Measuring the transtubular potassium gradient (TTKG) is
useful in determining the etiology of hyperkalemia or
hypokalemia associated with metabolic acidosis.
Plasma renin activity and plasma aldosterone levels are
useful in determining the etiology of the hyperkalemia and
hypokalemia that accompany metabolic acidosis.
Calculation of fractional excretion (FE) of HCO3- is useful in
the diagnosis of proximal renal tubular acidosis (RTA).
The NH4Cl loading test is useful in patients with
nephrocalcinosis and/or nephrolithiasis, who may have an
incomplete form of distal RTA. These patients may not have
a pH less than 7.35 or a drop in serum HCO3-; metabolic
acidosis can be induced by administration of NH4Cl (0.1 g/kg
for 3 d). Under these circumstances of induced acidemia, a
urine pH greater than 5.3 indicates distal RTA.
An alternative to the NH4Cl loading test involves the
simultaneous oral administration of furosemide to increase
distal Na+ delivery and fludrocortisone to increase collecting
duct Na+ absorption and proton secretion. [15] Under these
circumstances, a urine pH greater than 5.3 indicates distal
RTA.
Measuring the urine-blood PaCO2 gradient following an
HCO3- load is useful in some patients with classic distal RTA
to differentiate a permeability defect from other defects. This
test is useful in patients with nephrocalcinosis in whom distal
RTA is suspected but urine is acidified appropriately in the
face of metabolic acidosis. Some of these patients have a
rate-dependent defect in proton secretion, revealed by a low
urine-blood PaCO2 gradient following HCO3- loading.
Abdominal radiographs (eg, kidneys, ureters, bladder), CT
scans, and/or renal ultrasound images may show renal
stones or nephrocalcinosis in patients with distal RTA.
Base excess/base deficit
ABGs also measure base excess/base deficit (BE/BD),
which is the best indicator of the degree of
acidosis/alkalosis. BE/BD is measured by gauging the
amount of acid or base that is required to titrate the patient's
blood sample to a pH of 7.40, given a PCO2 level of 40 mm
Hg at 37°C.
Complete Blood Count
An elevation of the white blood cell (WBC) count is a
nonspecific finding, but it should prompt consideration of
septicemia, which causes lactic acidosis.
Severe anemia with compromised oxygen delivery may
cause lactic acidosis.
Urinalysis
Urine pH is normally acidic, at less than 5.0. In acidemia, the
urine normally becomes more acidic. If the urine pH is above
5.5 in the face of acidemia, this finding is consistent with a
type I RTA. Alkaline urine is typical in salicylate toxicity.
Patients with ethylene glycol toxicity may present with
calcium oxalate crystals, which appear needle shaped, in the
urine.
23
Urine Anion Gap
Calculating the urine AG is helpful in evaluating some cases
of non-AG metabolic acidosis. The major measured urinary
cations are Na+ and K+, and the major measured urinary
anion is Cl-:
Urine AG = ([Na +] + [K+]) - [Cl-]
In the face of metabolic acidosis, the kidneys increase the
amount of NH3synthesized to buffer the excess H+ and NH4
Cl excretion increases. The increased unmeasured NH4+
thus increases the measured anion Cl- in the urine, and the
net effect is a negative AG, representing a normal response
to systemic acidification. The finding of a positive urine AG in
the face of non-AG metabolic acidosis points toward a renal
acidification defect (eg, RTA [16] ). See earlier section on urine
anion gap.
Ketone Level
Elevations of ketones indicate diabetic, alcoholic, and
starvation ketoacidosis.
The nitroprusside test is used to detect the presence of
ketoacids in the blood and the urine. This test measures only
acetoacetate and acetone; therefore, it may underestimate
the degree of ketonemia and ketonuria, because it will not
detect the presence of beta-hydroxybutyrate (BOH). This
limitation of the test can be especially problematic in patients
with ketoacidosis who cannot convert BOH to acetoacetate
because of severe shock or liver failure.
An assay for BOH is unavailable in some hospitals. An
indirect method to circumvent this problem is to add a few
drops of hydrogen peroxide to a urine specimen. This
enzymatically will convert BOH into acetoacetate, which will
be detected by the nitroprusside test.
Serum Lactate level
The normal plasma lactate concentration is 0.5-1.5 mEq/L.
Lactic acidosis is considered present if the plasma lactate
level exceeds 4-5 mEq/L in an acidemic patient.
Most cases of lactic acidosis are due to tissue hypoxia (eg,
from shock). Less commonly, underlying disease (eg,
diabetic ketoacidosis), drugs, or toxins may be the cause.
Salicylate levels and Iron levels
Therapeutic salicylate levels range up to 20-35 mg/dL.
Plasma levels exceeding 40-50 mg/dL are in the toxic range.
Plasma levels provide some information as to the severity of
intoxication: 40-60 mg/dL is considered mild; 60-100 mg/dL
is moderate; and greater than 100 mg/dL is considered
severe.
Iron toxicity is associated with lactic acidosis. Iron levels
greater than 300 mg/dL are considered toxic.
Transtubular Potassium Gradient
Measuring the transtubular potassium gradient (TTKG; see
the calculation below) is useful in determining the etiology of
hyperkalemia or hypokalemia associated with metabolic
acidosis.
TTKG = urine K+ × serum osmolality/serum K+ × urine
osmolality
A TTKG of greater than 8 indicates that aldosterone is
present and that the collecting duct is responsive to it. A
TTKG of less than 5 in the presence of hyperkalemia
indicates aldosterone deficiency or resistance. For the test to
be interpretable, the urine Na+ level should be greater than
10 mEq/L and the urine osmolality should be greater than or
equal to serum osmolality.

Plasma Renin Activity, Plasma Aldosterone levels, and
FEHCO3-
Plasma renin activity and plasma aldosterone levels are
useful in determining the etiology of the hyperkalemia and
hypokalemia that accompany metabolic acidosis.
Measurement of the fractional excretion of bicarbonate
(FEHCO3-) is useful in the diagnosis of proximal RTA.
Ammonium Chloride Loading Test
The ammonium chloride (NH4 Cl) loading test is useful in
patients with nephrocalcinosis and/or nephrolithiasis, who
may have an incomplete form of distal RTA. These patients
may not have a pH of less than 7.35 or a drop in serum
HCO3-; metabolic acidosis can be induced by administration
of NH4 Cl (0.1 g/kg for 3 d). Under these circumstances of
induced acidemia, a urine pH of greater than 5.3 indicates
distal RTA.
An alternative to the NH4 Cl loading test involves the
simultaneous oral administration of furosemide to increase
distal Na+ delivery and fludrocortisone to increase collecting
duct Na+ absorption and proton secretion. [15] Under these
circumstances, a urine pH greater than 5.3 indicates distal
RTA.
Urine-Blood PaCO2 Gradient Following HCO3- Loading
Measuring the urine-blood PaCO2 gradient following an
HCO3- load is useful in some patients with classic distal RTA
to differentiate a permeability defect from other defects. This
test is useful in patients with nephrocalcinosis in whom distal
RTA is suspected but urine is acidified appropriately in the
face of metabolic acidosis. Some of these patients have a
rate-dependent defect in proton secretion, revealed by a low
urine-blood PaCO2 gradient following HCO3- loading.
Imaging Studies and Electrocardiography
Abdominal radiographs (eg, kidneys, ureters, bladder),
computed tomography (CT) scans, and/or renal
ultrasonographic images may show renal stones or
nephrocalcinosis in patients with distal RTA.
If iron ingestion is suspected, perform imaging studies on the
abdominal area, including the kidneys, ureters, and bladder.
An electrocardiogram (ECG) may be used to detect
abnormalities that result from the effects of electrolyte
imbalances (eg, hyperkalemia).
Treatment / Management
The management of metabolic acidosis should address the cause of
the underlying acid-base derangement. For example, adequate fluid
resuscitation and correction of electrolyte abnormalities are
necessary for sepsis and diabetic ketoacidosis. Other therapies to
consider include antidotes for poisoning, dialysis, antibiotics, and
bicarbonate administration in certain situations.
Refer to the specific conditions for a thorough explanation of the
appropriate treatment.
Approach Considerations
Treatment of acute metabolic acidosis with alkali therapy is
usually indicated to raise and maintain the plasma pH to
greater than 7.20. In the following two circumstances this is
particularly important.
When the serum pH is below 7.20, a continued fall in the
serum HCO3- level may result in a significant drop in pH. This
is especially true when the PCO2 is close to the lower limit of
24
compensation, which in an otherwise healthy young
individual is approximately 15 mm Hg. With increasing age
and other complicating illnesses, the limit of compensation is
likely to be less. A further small drop in HCO 3- at this point
thus is not matched by a corresponding fall in PaCO2, and
rapid decompensation can occur. For example, in a patient
with metabolic acidosis with a serum HCO3-level of 9 mEq/L
and a maximally compensated PCO2 of 20 mm Hg, a drop in
the serum HCO3- level to 7 mEq/L results in a change in pH
from 7.28 to 7.16.
A second situation in which HCO 3- correction should be
considered is in well-compensated metabolic acidosis with
impending respiratory failure. As metabolic acidosis
continues in some patients, the increased ventilatory drive to
lower the PaCO2 may not be sustainable because of
respiratory muscle fatigue. In this situation, a PaCO2 that
starts to rise may change the plasma pH dramatically even
without a significant further fall in HCO3-. For example, in a
patient with metabolic acidosis with a serum HCO3- level of
15 and a compensated PaCO2 of 27 mm Hg, a rise in PaCO2
to 37 mm Hg results in a change in pH from 7.33 to 7.20. A
further rise of the PaCO2 to 43 mm Hg drops the pH to 7.14.
All of this would have occurred while the serum HCO3- level
remained at 15 mEq/L.
In lactic acidosis and diabetic ketoacidosis, the organic anion
can regenerate bicarbonate when the underlying disorder is
corrected, and caution must be exercised in trying to correct
the acidosis with bicarbonate therapy, unless the pH is less
than 7.0-7.1.
Sodium bicarbonate (NaHCO3) is the agent most commonly
used to correct metabolic acidosis. The HCO3- deficit can be
calculated by using the following equation:
HCO3- deficit = deficit/L (desired serum HCO 3- - measured
HCO3-) × 0.5 × body weight (volume of distribution for HCO3-)
This provides a crude estimate of the amount of HCO3- that
must be administered to correct the metabolic acidosis; the
serum HCO3- level or pH should be reassessed frequently.
HCO3- can be administered intravenously to raise the serum
HCO3- level adequately to increase the pH to greater than
7.20. Further correction depends on the individual situation
and may not be indicated if the underlying process is
treatable or the patient is asymptomatic.
This is especially true in certain forms of metabolic acidosis.
For example, in high anion gap acidosis secondary to
accumulation of organic acids, lactate, and ketones, these
anions are eventually metabolized to HCO3-. When the
underlying disorder is treated, the serum pH corrects; thus,
caution should be exercised in these patients when providing
alkali to raise the pH much higher than 7.20, because an
overshoot alkalosis may occur.
To minimize the risk of hypernatremia and hyperosmolality,
two 50-mL ampules of 8.4% NaHCO 3 (containing 50 mEq
each) are added to 1 L of 0.25 normal saline or three
ampules are added to 1 L of 5% dextrose in water.
Volume overload can be a consequence of alkali therapy.
Loop diuretics can be used in these circumstances.
Another consequence of treatment with NaHCO3 is a rise in
PaCO2. This can become a very important factor in patients
who have reduced ventilatory reserve.
In high anion gap acidosis secondary to accumulation of
organic acids, lactate, and ketones, these anions are
eventually metabolized to HCO3-. When the underlying
disorder is treated, the serum pH corrects; thus, caution
should be exercised in these patients when providing alkali
to raise the pH much higher than 7.20, because an
overshoot alkalosis may occur.
Potassium citrate can be useful when the acidosis is
accompanied by hypokalemia but should be used cautiously
in the presence of kidnery impairment and must be avoided
in the presence of hyperkalemia.
Oral NaHCO3 can be administered in some acute metabolic
acidemic states in which correction of metabolic acidosis is
unlikely to occur without exogenous alkali administration.

Oral alkali administration is the preferred route of therapy in
persons with chronic metabolic acidosis. The most common
alkali forms for oral therapy include NaHCO3tablets. These
are available in 325 and 650 mg strengths (1 g of NaHCO3 is
equal to 11.5 mEq of HCO3-).
Citrate salts are available in a variety of formulations, as
mixtures of citric acid with sodium citrate and/or potassium
citrate. These solutions generally contain 1-2 mEq of HCO3-
per mL. Potassium citrate is useful when the acidosis is
accompanied by hypokalemia but should be used cautiously
in persons with renal impairment and must be avoided in
those with hyperkalemia.
In a 12-month controlled, randomized, interventional trial that
included 30 kidney transplant patients with metabolic
acidosis, correction of metabolic acidosis with potassium
citrate was found to be effective and well tolerated, and was
associated with improvements in bone quality, suggesting a
beneficial effect of both alkali treatment and restoration of
acid/base balance. The researchers concluded that
potassium citrate may be superior to sodium bicarbonate,
because it lacks volume effects and the obligatory calcium
excretion associated with sodium administration.
Type 1 Renal Tubular Acidosis
Administration of an alkali is the mainstay of treatment for
type 1 renal tubular acidosis (RTA). Adult patients should be
given the amount required to buffer the daily acid load from
the diet. This is usually approximately 1-3 mEq/kg/d and can
be administered in any form, although the preferred form is
as potassium citrate. Correction of acidosis usually corrects
the hypokalemia, but K+ supplements may be necessary.
Type 2 Renal Tubular Acidosis
Correcting this form of acidosis with alkali is difficult because
a substantial proportion of the administered HCO3- is
excreted in the urine, and large amounts are needed to
correct the acidosis (10-30 mEq/kg/d). Potassium is also
required when administering HCO3-. Correction is essential
in children for normal growth, while in adults aggressive
correction to a normal level may not be required. Thiazide
diuretics can be administered to induce diuresis and mild
volume depletion, which, in turn, raises the proximal tubule
threshold for HCO3- wasting.
Patients with type 2 RTA typically have hypokalemia and
increased urinary K+wasting. Administration of alkali in those
patients leads to more HCO3- wasting and can worsen
hypokalemia unless K+ is replaced simultaneously.
Type 4 Renal Tubular Acidosis
Because hyperkalemia is central to the etiology of this
disorder, [19] a major treatment goal is to lower the serum K+
level. This can be achieved by placing the patient on a
low-K+ diet (1 mEq/kg K+/d) and by withdrawal of drugs that
can cause hyperkalemia (eg, angiotensin-converting enzyme
[ACE] inhibitors, nonsteroidal anti-inflammatory drugs). Loop
diuretics can be helpful in reducing serum potassium levels
as long as the patient is not hypovolemic.
In resistant cases, fludrocortisone, a synthetic
mineralocorticoid, can be used to increase K+ secretion, but
this may increase Na+ retention. Alkali therapy is not usually
required, because, in many patients, the mild degree of
acidosis is corrected by achieving normokalemia.
Hyperkalemia and acidosis worsen as kidney function
declines further; eventually, the patient develops a high
anion gap renal acidosis. Renal replacement therapy should
be considered once the measures described fail to control
hyperkalemia or acidosis.
Chronic Kidney Disease
25
Treatment of chronic metabolic acidosis in persons with
chronic kidney disease (CKD) is indicated because it can
help to prevent bone loss that can progress to osteopenia or
osteoporosis. In children, growth retardation can occur. In
addition, treatment slows the progression of
hyperparathyroidism and helps to reduce the high-protein
catabolic state associated with uremic acidosis, which leads
to loss of muscle mass and malnutrition.
Alkali treatment is suggested when the serum bicarbonate
concentration falls below 22 mEq/L, as treatment may
decrease muscle wasting, improve bone disease, and slow
the progression of CKD. [20] In patients with stages 3b and 4
CKD, treatment of metabolic acidosis with sodium
bicarbonate has also been shown to significantly improve
vascular endothelial function. [21] The target serum
bicarbonate concentration is unclear, however;
concentrations above 24 mEq/L have been tentatively linked
with worsening of cardiovascular disease, which complicates
treatment decisions. [22]
NaHCO3 is the most frequently used agent. It is administered
in an amount necessary to keep the serum HCO3- level
greater than 20 mEq/L. The average requirement is
approximately 1-2 mEq/kg/d. Sodium citrate should be
avoided if the patient is taking aluminum as a phosphate
binder, because citrate increases aluminum absorption and,
hence, the risk for aluminum toxicity.
The choice of sodium bicarbonate dose remains unclear,
and there are concerns over adverse effects, most notably
fluid retention, especially with higher doses. Consequently,
Abramowitz and colleagues conducted a single-blinded pilot
study in 20 adults with stages 3 and 4 CKD and mild
metabolic acidosis. Participants were treated during
successive 2-week periods with placebo followed by
escalating doses of oral sodium bicarbonate at 2-week
intervals (0.3, 0.6, and 1.0 mEq/d per kg ideal body weight).
[23]
Sodium bicarbonate was well tolerated, even at high doses;
produced a dose-dependent increase in serum bicarbonate;
and was associated with an improvement in lower extremity
muscle strength and reduced urinary nitrogen excretion. The
authors caution, however, that the results require further
study and confirmation from a large randomized
placebo-controlled study. [23]
In older persons with CKD, existing evidence is insufficient to
show whether any benefits of sodium bicarbonate therapy
outweigh the adverse effects and treatment burden in this
population, which may include fluid retention and blood
pressure from the additional sodium load, as well as
gastrointestinal side effects. Trials of bicarbonate therapy for
older persons with CKD are currently in progress. [24]
Metabolic acidosis in patients with CKD can also be treated
with dietary modification. Dietary acid reduction can be
accomplished by limiting the intake of acid-producing foods
such as animal protein and emphasizing base-producing
foods such as fruits and vegetables. [25]
In a year-long randomized study of 71 patients with stage 4
CKD, Goroya et al compared the effectiveness of daily oral
sodium bicarbonate with that of base-producing fruits and
vegetables for reduction of kidney injury and improvement of
metabolic acidosis. Patients consuming fruits and vegetables
dosed to reduce dietary acid by half had a reduction in
kidney injury and improvement in metabolic acidosis
comparable to that in the sodium bicarbonate group and did
not experience hyperkalemia. [26]
The investigators note that study patients were selected to
be at low risk for hyperkalemia and advise that caution
should be exercised in prescribing fruits and vegetables in
patients with very low estimated glomerular filtration rates.
Nevertheless, Goroya et al concluded that treating metabolic
acidosis in individuals with stage 4 CKD due to hypertensive
nephropathy with fruits and vegetables appeared to be an
effective kidney-protective adjunct.
Ketoacidosis

Starvation and alcohol use resulting in acidosis is treated
with intravenous glucose, which is administered to stimulate
insulin secretion and stop lipolysis and ketosis.
For diabetic ketoacidosis (DKA), insulin is administered,
usually intravenously, to facilitate cellular uptake of glucose,
reduce gluconeogenesis, and halt lipolysis and production of
ketone bodies. In addition, normal saline is administered to
restore extracellular volume; potassium and phosphate
replacement also may be necessary. The acidosis is
corrected partly by the metabolism of ketones to HCO3-,
partly by increased H+ secretion by the collecting duct, and
partly by H+ excretion as NH4+.
Lactic Acidosis
Correction of the underlying disorder is the mainstay of
therapy. [27] In patients with tissue hypoxia, restoration of
tissue perfusion is essential.
The role of alkali therapy is controversial; some authors
recommend raising the serum pH to 7.20 when possible.
Some evidence suggests, however, that HCO3-therapy
produces only a transient increase in the serum HCO3- level
and that this can lead to intracellular acidosis and worsening
of lactic acidosis. Furthermore, large amounts of NaHCO3
are commonly required, and volume overload and
hypernatremia can occur. In such situations, hemodialysis or
continuous venovenous hemofiltration can be used to correct
the metabolic abnormalities.
If the process leading to lactic acidosis is corrected, lactic
acid can be used again by the liver to produce HCO3- on an
equimolar basis. This is important, because rebound
alkalosis can occur if the patient has received an excessive
amount of alkali during the acidemia.
Metformin-associated lactic acidosis (MALA) is treated with
hemodialysis, bicarbonate therapy, and continuous renal
replacement therapy (CRRT).
Salicylate Poisoning
Alkali therapy is an important component of therapy in
salicylate overdose for several reasons. Correcting the
acidemia decreases the amount of salicylate crossing the
blood-brain barrier. Care should be exercised to avoid
inducing or worsening the alkalosis that may be present.
Increasing urine pH increases the excreted salicylate.
Alkaline diuresis can be initiated by intravenous NaHCO3
administration or by acetazolamide therapy. The goal is to
maintain the urine pH at greater than 7.5 until the salicylate
level falls below 30-50 mg/dL.
Multiple dosing of activated charcoal at 0.25-1 g/kg every 2-4
hours can also be used to increase the excretion of
salicylate.
In acute intoxication, hemodialysis should be considered
when the blood level is greater than 80 mg/dL or when acute
kidney injury or severe central nervous system (CNS)
depression is present.
Methanol or Ethylene Glycol Poisoning
Treatment should be started promptly to prevent any
neurologic sequelae.
Fomepizole (4-methylpyrazole; Antizol) is a potent inhibitor
of alcohol dehydrogenase and is now the preferred therapy,
although it is much more expensive than ethanol.
Fomepizole is given as a loading dose and continued over
several doses until toxin levels decline substantially.
Fomepizole levels do not need to be monitored.
Ethanol competes for alcohol dehydrogenase and can be
used as an alternative to fomepizole. It is administered orally
or intravenously to saturate alcohol dehydrogenase, to which
it has a higher affinity, thus inhibiting metabolism of methanol
or ethylene glycol to its toxic metabolites. The blood ethanol
level should be maintained at 100-150 mg/dL.
26
-
HCO therapy can be administered to correct severe
3
acidosis, but large amounts of HCO3- may be required and
fluid overload can compromise therapy.
Patients with methanol overdose should receive folate to
enhance the metabolism of formic acid. Patients with
ethylene glycol overdose should receive thiamine and
pyridoxine.
Hemodialysis should be considered in any patient with
significant metabolic acidosis, acute kidney injury, visual
symptoms, a high blood toxin level, or a suspected large
overdose. Hemodialysis is effective in clearing methanol and
ethylene glycol, as well as their toxic metabolites; in
correcting the acidosis; and in restoring extracellular volume.
A study by Zakarov et al of 31 patients involved in a mass
outbreak of methanol poisoning determined that correction of
acidemia was accomplished more rapidly with intermittent
hemodialysis (IHD) than with continuous renal replacement
therapy (CRRT). HCO3- increased by 1 mmol/L in a mean of
12 ± 2 min with IHD versus 34 ± 8 min withr CRRT (P <
 0.001), while arterial blood pH increased 0.01 in a mean of
7 ± 1 mins with IHD versus 11 ± 4 min with CRRT (p = 0.024).
[28]
Medication Summary
Sodium bicarbonate (NaHCO3) is the agent most commonly
used to correct metabolic acidosis. However, the role of
alkali therapy is controversial in the treatment of lactic
acidosis, with some evidence suggesting that HCO3- therapy
produces only a transient increase in the serum HCO3- level
and that this can lead to intracellular acidosis and worsening
of lactic acidosis. Other agents may be indicated in patients
with metabolic acidosis due to certain underlying disease
processes (eg, carbonic anhydrase inhibitors in salicylate
toxicity, insulin in diabetic ketoacidosis).
Alkalinizing Agents
Class Summary
Acute metabolic acidosis is usually treated with alkali
therapy to raise plasma pH and to maintain it at greater than
7.20.
Sodium bicarbonate
● View full drug information
Sodium bicarbonate is a systemic and urinary alkalinizer
used to increase serum or urinary HCO3- concentration and
raise pH. Dosing is based on the clinical setting, blood pH,
serum HCO3- level, and PaCO2.
Tromethamine (THAM)
● View full drug information
THAM combines with hydrogen ions to form a bicarbonate
buffer. It is used to prevent and correct systemic acidosis. It
is available as 0.3-mol/L IV solution containing 18 g (150
mEq) per 500 mL (0.3 mEq/mL).
Carbonic Anhydrase Inhibitors
Class Summary
Agents in this class may be used to induce alkaline diuresis.
Acetazolamide (Diamox)
● View full drug information
This agent is used in the treatment of salicylate poisoning. It
reduces the reduction of hydrogen ion secretion at the renal
tubule and increases excretion of sodium, potassium,
bicarbonate, and water. The goal is to maintain the urine pH
at greater than 7.5 until the salicylate level falls below 30-50
mg/dL.

Antidiabetic Agents
Class Summary
These agents are used for the treatment of ketoacidosis.
Insulin
Insulin is administered, to facilitate cellular uptake of
glucose, reduce gluconeogenesis, and halt lipolysis and
production of ketone bodies. In addition, normal saline is
administered to restore extracellular volume; potassium and
phosphate replacement also may be necessary.
Detoxification Agents
Class Summary
These agents may be used in methanol or ethylene glycol
poisoning.
Fomepizole (Antizol)
● View full drug information
Begin fomepizole treatment immediately upon suspicion of
ethylene glycol ingestion based on patient history or anion
gap metabolic acidosis, increased osmolar gap, oxalate
crystals in urine, or documented serum methanol level.
Activated charcoal (Actidose-Aqua, Requa Activated
Charcoal)
● View full drug information
This agent can be used to increase the excretion of
salicylate. It is used in the emergency treatment of poisoning
caused by drugs and chemicals. The network of pores
present in activated charcoal absorbs 100-1000 mg of drug
per gram of charcoal. It prevents absorption by adsorbing
the drug in the intestine. Multidose charcoal may interrupt
enterohepatic recirculation and enhance elimination by
enterocapillary exsorption. Theoretically, by constantly
bathing the GI tract with charcoal, the intestinal lumen
serves as a dialysis membrane for reverse absorption of the
drug from intestinal villous capillary blood into the intestine. It
does not dissolve in water.
Pearls and Other Issues
Metabolic acidosis is a clinical disturbance defined by a pH less
than 7.35 and a low HCO3 level.
The anion gap helps determine the cause of the metabolic acidosis.
An elevated anion gap metabolic acidosis can be caused by
salicylate toxicity, diabetic ketoacidosis, and uremia
(MUDPILES). Non-Gap metabolic acidosis is due to GI loss of
bicarbonate (diarrhea) or a failure of kidneys to excrete acid.
Lab tests that help evaluate metabolic acidosis are those that assess
renal and lung function including electrolytes, venous or arterial
blood gas, and toxin levels such as salicylate if an overdose is
suspected.
Treatment of metabolic acidosis is case-dependent.
Go to:
Enhancing Healthcare Team Outcomes
The management of metabolic acidosis should address the cause of
the underlying acid-base derangement. Because there are many
causes, the electrolyte disorder is best managed by an
interprofessional teamt that also includes nurses and pharmacists.
For example, adequate fluid resuscitation and correction of
27
electrolyte abnormalities are necessary for sepsis and diabetic
ketoacidosis. Other therapies to consider include antidotes for
poisoning, dialysis, antibiotics, and bicarbonate administration in
certain situations.
The outcomes depend on the cause, patient morbidity and response
to treatment.
—-------
Metabolic Alkalosis
Normal human physiological pH is 7.35 to 7.45. A decrease in pH
below this range is acidosis, an increase over this range is
alkalosis. Metabolic alkalosis is defined as a disease state where
the body’s pH is elevated to greater than 7.45 secondary to some
metabolic process. Before going into details about pathology and
this disease process, some background information about the
physiological pH buffering process is important. The primary pH
buffer system in the human body is the bicarbonate
(HCO3)/carbon dioxide (CO2) chemical equilibrium system.
Where:
● H + HCO3 <--> H2CO3 <--> CO2 + H2O
HCO3 functions as an alkalotic substance. CO2 functions as an
acidic substance. Therefore, increases in HCO3 or decreases in
CO2 will make blood more alkalotic. The opposite is also true
where decreases in HCO3 or an increase in CO2 will make blood
more acidic. CO2 levels are physiologically regulated by the
pulmonary system through respiration, whereas the HCO3 levels
are regulated through the renal system with reabsorption rates.
Therefore, metabolic alkalosis is an increase in serum HCO3.
Practice Essentials
Metabolic alkalosis is defined as elevation of the body's pH
above 7.45. [1] Metabolic alkalosis involves a primary
increase in serum bicarbonate (HCO3-) concentration, due to
a loss of H+ from the body or a gain in HCO3-. As a
compensatory mechanism, metabolic alkalosis leads to
alveolar hypoventilation with a rise in arterial carbon dioxide
tension (PaCO2), which diminishes the change in pH that
would otherwise occur.
Normally, arterial PaCO2 increases by 0.5-0.7 mm Hg for
every 1 mEq/L increase in plasma bicarbonate
concentration, a compensatory response that is very quick. If
the change in PaCO2 is not within this range, then a mixed
acid-base disturbance occurs. For example, if the increase in
PaCO2 is more than 0.7 times the increase in bicarbonate,
then metabolic alkalosis coexists with primary respiratory
acidosis. Likewise, if the increase in PaCO2 is less than the
expected change, then a primary respiratory alkalosis is also
present.
The first clue to metabolic alkalosis is often an elevated
bicarbonate concentration that is observed when serum
electrolyte measurements are obtained. Remember that an
elevated serum bicarbonate concentration may also be
observed as a compensatory response to primary respiratory
acidosis. However, a bicarbonate concentration greater than
35 mEq/L is almost always caused by metabolic alkalosis.
Metabolic alkalosis is diagnosed by measuring serum
electrolytes and arterial blood gases. If the etiology of
metabolic alkalosis is not clear from the clinical history and
physical examination, including drug use and the presence
of hypertension, then a urine chloride ion concentration can
be obtained. Calculation of the serum anion gap may also
help to differentiate between primary metabolic alkalosis and
metabolic compensation for respiratory acidosis. (See
Workup.)

The management of metabolic alkalosis depends primarily
on the underlying etiology and on the patient’s volume
status. Direct treatment of the alkalosis itself (eg,
administration of acidic intravenous solutions) may be
indicated in some cases
Pathophysiology
Pathophysiology
There is a multitude of disease states that induce metabolic
alkalosis. In general, the causes can be narrowed down to an
intracellular shift of hydrogen ions, gastrointestinal (GI) loss of
hydrogen ions, excessive renal hydrogen ion loss, retention or
addition of bicarbonate ions, or volume contraction around a
constant amount of extracellular bicarbonate known as contraction
alkalosis. All of which leads to the net result of increased levels of
bicarbonate in the blood. As long as renal function is maintained,
excess bicarbonate is excreted in the urine fairly rapidly. As a
result, metabolic alkalosis will persevere if the ability to eliminate
bicarbonate is impaired due to one of the following causes:
hypovolemia, reduced effective arterial blood volume, chloride
depletion, hypokalemia, reduced glomerular filtration rate, and/or
hyperaldosteronism.
Intracellular Shift of Hydrogen
Anytime that hydrogen ions are shifted intracellularly, this
imbalance in the buffer system has a relative increase in
bicarbonate. Processes that drive hydrogen intracellularly include
hypokalemia.
Gastrointestinal Loss of Hydrogen
Stomach fluids are highly acidic at a pH of approximately 1.5 to
3.5. Hydrogen secretion is accomplished via parietal cells in the
gastric mucosa. Therefore, the large volume loss of gastric
secretions will correlate as a loss of hydrogen chloride, an acidic
substance, leading to a relative increase in bicarbonate in the
blood, thus driving alkalosis. Losses can occur pathologically via
vomitus or nasogastric suctioning.
Renal Loss of Hydrogen
Hydrogen is used within the kidneys are an antiporter energy
gradient to retain a multitude of other elements. Of interest here,
sodium is reabsorbed through an exchange for hydrogen in the
renal collecting ducts under the influence of aldosterone.
Therefore, pathologies that increase the levels of
mineralocorticoids or increase the effect of aldosterone, such as
Conn syndrome will lead to hypernatremia, hypokalemia, and
hydrogen loss in the urine. In a similar vein of thought, loop and
thiazide diuretics are capable of inducing secondary
hyperaldosteronism by increasing sodium and fluid load to the
distal nephron, which encourages the
renin-angiotensin-aldosterone system. Genetic defects that lead to
decreased expression of ion transporters in the Loop of Henle are
possible but less common. These syndromes are known as Bartter
and Gitelman disease. The net effect of these genetic defects is
akin to the action of loop diuretics.
Retention/Addition of Bicarbonate
Several etiologies lead to increases in bicarbonate within the blood.
The simplest of which is an overdose of exogenous sodium
bicarbonate in a medical setting. Milk-alkali syndrome is a
pathology where the patient consumes excessive quantities of oral
28
calcium antacids, which leads to hypercalcemia and varying
degrees of renal failure. Additionally, since antacids are
neutralizing agents, they add alkaline substances to the body while
reducing acid levels thus increasing pH. A pathology that is in line
with normal physiology is the body’s natural compensation
mechanism for hypercarbia. When a patient hypoventilates, CO2
retention occurs in the lungs and subsequently reduces pH. Over
time, the renal system compensates by retaining bicarbonate to
balance pH. This is a slower process. Once the hypoventilation is
corrected, such as with a ventilator-assisted respiratory failure
patient CO2 levels will quickly decrease, but bicarbonate levels
will lag in reducing. This causes post-hypercapnia metabolic
alkalosis, which is self-correcting. It is possible to calculate the
expected pCO2 in the setting of metabolic alkalosis to determine if
it is a compensatory increase in bicarbonate, or if there is an
underlying pathology driving alkalosis using the following
equation:
● Expected pCO2 = 0.7 (HCO3) + 20 mmHg +/- 5
If the expected pCO2 does not match the measured value, an
underlying metabolic alkalosis is a likely present.
Contraction Alkalosis
This phenomenon occurs when a large volume of sodium-rich,
bicarbonate low fluid is lost from the body. This occurs with
diuretic use, cystic fibrosis, congenital chloride diarrhea, among
others. The net concentration of bicarbonate increases as a result.
This pathology is easily offset by the release of hydrogen from
intracellular space to balance the pH in most incidences.
The exact etiology, if unknown or not obvious, can be elucidated in
part by evaluation of urinary chloride. Metabolic alkalosis is split
into 2 main categories: Chloride responsive with urine chloride
less than 10 mEq/L and chloride resistant with urine chloride
greater than 20 mEq/L. Chloride responsive etiologies include loss
of hydrogen via the gastrointestinal tract, congenital chloride
diarrhea syndrome, contraction alkalosis, diuretic therapy,
post-hypercapnia syndrome, cystic fibrosis, and exogenous
alkalotic agent use. Chloride-resistant etiologies include retention
of bicarbonate, the shift of hydrogen into intracellular spaces,
hyperaldosteronism, Bartter syndrome, and Gitelman syndrome.
The organ systems involved in metabolic alkalosis are
mainly the kidneys and GI tract. The pathogenesis involves
two processes, the generation of metabolic alkalosis and the
maintenance of metabolic alkalosis, which usually overlap.
Generation of metabolic alkalosis
Metabolic alkalosis may be generated by one of the following
mechanisms:
● Loss of hydrogen ions
● Shift of hydrogen ions into the intracellular
space
● Alkali administration
● Contraction alkalosis
Hydrogen ions may be lost through the kidneys or the GI
tract. Vomiting or nasogastric (NG) suction generates
metabolic alkalosis by the loss of gastric secretions, which
are rich in hydrochloric acid (HCl). Whenever a hydrogen ion
is excreted, a bicarbonate ion is gained in the extracellular
space.

Renal losses of hydrogen ions occur whenever the distal
delivery of sodium increases in the presence of excess
aldosterone, which stimulates the electrogenic epithelial
sodium channel (ENaC) in the collecting duct. As this
channel reabsorbs sodium ions, the tubular lumen becomes
more negative, leading to the secretion of hydrogen ions and
potassium ions into the lumen.
Shift of hydrogen ions into the intracellular space mainly
develops with hypokalemia. As the extracellular potassium
concentration decreases, potassium ions move out of the
cells. To maintain neutrality, hydrogen ions move into the
intracellular space.
Administration of sodium bicarbonate in amounts that
exceed the capacity of the kidneys to excrete this excess
bicarbonate may cause metabolic alkalosis. This capacity is
reduced when a reduction in filtered bicarbonate occurs, as
observed in renal failure, or when enhanced tubular
reabsorption of bicarbonate occurs, as observed in volume
depletion (see Maintenance of metabolic alkalosis).
Loss of bicarbonate-poor, chloride-rich extracellular fluid, as
observed with thiazide diuretic or loop diuretic therapy or
chloride diarrhea, leads to contraction of extracellular fluid
volume. Because the original bicarbonate mass is now
dissolved in a smaller volume of fluid, an increase in
bicarbonate concentration occurs. This increase in
bicarbonate causes, at most, a 2- to 4-mEq/L rise in
bicarbonate concentration.
Maintenance of metabolic alkalosis
Decreased perfusion to the kidneys, caused by either
volume depletion or a reduction in effective circulating blood
volume (eg, edematous states such as heart failure or
cirrhosis) stimulates the renin-angiotensin-aldosterone
system. This increases renal sodium ion reabsorption
throughout the nephron, including the principal cells of the
collecting duct, and results in enhanced hydrogen ion
secretion via the apical proton pump H+ adenosine
triphosphatase (ATPase) in the adjacent A-type intercalated
cells.
Aldosterone may also independently increase the activity of
the apical proton pump in the collecting duct. Whenever a
hydrogen ion is secreted into the tubular lumen, a
bicarbonate ion is gained into the systemic circulation via the
basolateral Cl-/HCO3- exchanger.
Chloride depletion may occur through the GI tract by loss of
gastric secretions, which are rich in chloride ions, or through
the kidneys with loop diuretics or thiazides. Chloride
depletion, even without volume depletion, enhances
bicarbonate reabsorption by different mechanisms as
discussed below.
In the late thick ascending limb (TAL) and early distal tubule,
specialized cells called the macula densa are present. These
cells have an Na+/K+/2Cl- cotransporter in the apical
membrane, which is mainly regulated by chloride ions. When
fewer chloride ions reach this transporter (eg, chloride
depletion), the macula densa signals the juxtaglomerular
apparatus (ie, specialized cells in the wall of the adjacent
afferent arteriole) to secrete renin, which increases
aldosterone secretion via angiotensin II.
In alkalemia, the kidneys secrete the excess bicarbonate via
the apical chloride/bicarbonate exchanger, pendrin, in the
B-type intercalated cells of the collecting duct. In this way,
protons are gained to the systemic circulation via the
basolateral H+ ATPase. In chloride depletion, fewer chloride
ions are available to be exchanged with bicarbonate, and the
ability of the kidneys to excrete the excess bicarbonate is
impaired.
Many of the causes of metabolic alkalosis are also
associated with hypokalemia. In turn, hypokalemia maintains
metabolic alkalosis by five different mechanisms.
29
First, hypokalemia results in the shift of hydrogen ions
intracellularly. The resulting intracellular acidosis enhances
bicarbonate reabsorption in the collecting duct.
Second, hypokalemia stimulates the apical H+/K+ ATPase in
the collecting duct. Increased activity of this ATPase leads to
teleologically appropriate potassium ion reabsorption but a
corresponding hydrogen ion secretion. This leads to a net
gain of bicarbonate, maintaining systemic alkalosis.
Third, hypokalemia stimulates renal ammonia genesis,
reabsorption, and secretion. Ammonium ions (NH 4+) are
produced in the proximal tubule from the metabolism of
glutamine. During this process, alpha-ketoglutarate is
produced, the metabolism of which generates bicarbonate
that is returned to the systemic circulation. Hypokalemia
stimulates NH4+ uptake via the Na+/K+/2Cl- cotransporter of
TAL because NH 4+ competes with K+ for the transporter.
Hypokalemia increases the expression of the ammonia
transporter RhBG, which increases NH3 excretion in the
collecting duct.
Fourth, it leads to impaired chloride ion reabsorption in the
distal nephron. This results in an increase in luminal
electronegativity, with subsequent enhancement of hydrogen
ion secretion.
Fifth, it reduces the glomerular filtration rate (GFR). Animal
studies have shown that hypokalemia, by unknown
mechanisms, decreases GFR, which decreases the filtered
load of bicarbonate. In the presence of volume depletion,
this impairs renal excretion of the excess bicarbonate.
Etiology
The most common causes of metabolic alkalosis are the use
of diuretics and the external loss of gastric secretions.
Causes of metabolic alkalosis can be divided into
chloride-responsive alkalosis (urine chloride < 20 mEq/L),
chloride-resistant alkalosis (urine chloride > 20 mEq/L), and
other causes, including alkali-loading alkalosis.
Chloride-responsive alkalosis
The principal causes of chloride-responsive alkalosis are the
loss of gastric secretions, ingestion of large doses of
nonabsorbable antacids, and use of thiazide or loop
diuretics. [2] Miscellaneous causes account for the remainder
of cases. [3]
Gastric secretions are rich in hydrochloric acid (HCl). The
secretion of HCl by the stomach usually stimulates
bicarbonate secretion by the pancreas once the 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 HCl is lost through vomiting (including purging, in
persons with eating disorders [4] ) or nasogastric suction,
pancreatic secretions are not stimulated and a net gain of
bicarbonate into the systemic circulation occurs, generating
a metabolic alkalosis. 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 nonabsorbable 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.
Volume depletion also stimulates aldosterone secretion,
which enhances sodium ion reabsorption in the collecting
duct and increases hydrogen ion and potassium secretion in
this segment. Urine chloride is low after discontinuation of
diuretic therapy, while it is high during active diuretic use.
Miscellaneous causes of metabolic alkalosis include villous
adenomas, which are a rare cause of diarrhea. Villous
adenomas usually lead to metabolic acidosis from loss of
colonic secretions that are rich in bicarbonate, but
occasionally these tumors cause metabolic alkalosis. The
mechanism is not well understood. Some authors opine that
hypokalemia from these tumors is the etiology of the
metabolic alkalosis.
Congenital chloridorrhea (see Chloride Diarrhea, Familial.
Online Mendelian Inheritance in Man [OMIM]) is a rare form
of severe secretory diarrhea that is inherited as an
autosomal recessive trait. Mutations in the down-regulated
adenoma gene result in defective function of the
chloride/bicarbonate exchange in the colon and ileum,
leading to increased secretion of chloride and reabsorption
of bicarbonate.
During respiratory acidosis, the kidneys reabsorb
bicarbonate and secrete chloride to compensate for the
acidosis. In the posthypercapnic state, urine chloride is high
and can lead to chloride depletion. Once the respiratory
acidosis is corrected, the kidneys cannot excrete the excess
bicarbonate because of the low luminal chloride.
Infants with cystic fibrosis may develop metabolic alkalosis
because of loss of chloride in sweat. These infants are also
prone to volume depletion.
Chloride-resistant alkalosis
Causes of chloride-resistant alkalosis can be divided into
those associated with hypertension and those associated
with hypotension or normotension. The former may result
from primary hyperaldosteronism, as well as a variety of
acquired and hereditary disorders. An adrenal adenoma
(most common), bilateral adrenal hyperplasia, or an adrenal
carcinoma may cause primary hyperaldosteronism. [5]
Another cause of primary hyperaldosteronism is
glucocorticoid-remediable aldosteronism (see
Hyperaldosteronism, Familial, Type 1 [OMIM]), an autosomal
dominant disorder, in which ectopic production of
aldosterone in the zona fasciculata of the adrenal cortex
occurs. In this case, aldosterone production is controlled by
adrenocorticotropic hormone (ACTH) rather than angiotensin
II and potassium, its principal regulators. This type of primary
hyperaldosteronism responds to glucocorticoid therapy,
which inhibits aldosterone secretion by suppressing ACTH.
The mineralocorticoid receptor (MR) in the collecting duct
usually is responsive to both aldosterone and cortisol.
Cortisol has a higher affinity for the MR and circulates at a
higher concentration than aldosterone. Under physiological
conditions, however, the enzyme 11-beta-hydroxysteroid
dehydrogenase type 2 (11B-HSD2) inactivates cortisol to
cortisone in the collecting duct, allowing aldosterone free
access to its receptor.
Deficiency of this enzyme leads to occupation and activation
of the MR by cortisol, which, like aldosterone, then
stimulates the ENaC. Cortisol behaves as a
mineralocorticoid under these circumstances.
11B-HSD2 deficiency may be inherited as an autosomal
recessive trait (see Cortisol 11-Beta-Ketoreductase
Deficiency [OMIM]), manifesting as syndrome of apparent
30
mineralocorticoid excess (AME). The enzyme may be
inhibited by glycyrrhizic acid, which is found in licorice and
chewing tobacco, or carbenoxolone, which is a synthetic
derivative of glycyrrhizinic acid. Deficiency or inhibition of
11B-HSD2 causes hypertension with low renin and low
aldosterone, hypokalemia, and metabolic alkalosis. Serum
cortisol is within the reference range because the negative
feedback of cortisol on adrenocorticotropic hormone (ACTH)
is intact.
Active use of thiazides or loop diuretics in hypertension is
the most common cause of metabolic alkalosis in
hypertensive patients. The mechanism of alkalosis is
discussed above.
The enhanced mineralocorticoid effect in Cushing syndrome
is caused by occupation of the MR by the high concentration
of cortisol. Hypokalemia and metabolic alkalosis are more
common in Cushing syndrome caused by ectopic ACTH
production (90%) than in other causes of Cushing syndrome
(10%). This difference is related to the higher concentration
of plasma cortisol and the defective 11B-HSD activity found
in ectopic ACTH production.
Liddle syndrome (see Liddle Syndrome [OMIM]) is a rare
autosomal dominant disorder arising from a gain-of-function
mutation in the beta (SCNN1B) or gamma subunit
(SCNN1G) of the ENaC in the collecting duct. The channel
behaves as if it is permanently open, and unregulated
reabsorption of Na+ occurs, leading to volume expansion and
hypertension. This unregulated Na+ reabsorption is
responsible for secondary renal hydrogen ion and potassium
ion losses and persists despite suppression of aldosterone.
Significant unilateral or bilateral renal artery stenosis
stimulates the renin-angiotensin-aldosterone system, leading
to hypertension and hypokalemic metabolic alkalosis.
Renin- or deoxycorticosterone-secreting tumors are rare. In
renin-secreting tumors, excessive amounts of renin are
secreted by tumors in the juxtaglomerular apparatus,
stimulating aldosterone secretion. In the latter,
deoxycorticosterone (DOC), rather than aldosterone, is
secreted by some adrenal tumors and has mineralocorticoid
effects.
Mutation in mineralocorticoid receptor (see Hypertension,
Early-Onset, Autosomal Dominant, with Severe
Exacerbation in Pregnancy [OMIM]) is a form of early-onset
hypertension with autosomal dominant inheritance that has
now been linked to a specific mutation of the MR. This
mutation results in constitutive activation of the MR, making
the MR responsive to progesterone.
Activation of MR leads to unregulated sodium ion
reabsorption via the collecting duct sodium ion channel, with
accompanying hypokalemia and alkalosis. The disease is
characterized by severe exacerbations of hypertension
during pregnancy, and spironolactone can exacerbate
hypertension.
Congenital adrenal hyperplasia (CAH; see Adrenal
Hyperplasia, Congenital, Due to 11-Beta-Hydroxylase
Deficiency [OMIM] and Adrenal Hyperplasia, Congenital,
Due to 17-Alpha-Hydroxylase Deficiency [OMIM]) can be
caused by deficiency of either 11-beta-hydroxylase or
17-alpha-hydroxylase. Both enzymes are involved in the
synthesis of adrenal steroids.
Deficiency of either enzyme leads to increased levels of the
mineralocorticoid 11-deoxycortisol, while cortisol and
aldosterone production is impaired. 11-Hydroxylase
deficiency differs from 17-hydroxylase deficiency by the
presence of virilization.
Chloride-resistant alkalosis (urine chloride >20 mEq/L) with
hypotension or normotension may be a manifestation of
Bartter syndrome (see Hypokalemic Alkalosis with
Hypercalciuria [OMIM]), an inherited autosomal recessive
disorder. In Bartter syndrome, impaired reabsorption of
sodium ions and chloride ions in the thick ascending loop of
Henle leads to their increased delivery to the distal nephron.
The impaired reabsorption of sodium chloride in the loop of
Henle is secondary to loss of function mutations of 1 of

several transporters in this site of the nephron: (1) the
furosemide-sensitive Na+/K+/2Cl- cotransporter (NKCC2); (2)
the basolateral chloride ion channel (CLCNKB); (3) the
inwardly rectifying apical potassium ion channel (ROMK1);
(4) barttin (BSND), the beta-subunit of the chloride channels,
CLC-Ka and CLC-Kb; and (5) the calcium sensing receptor
(CaSR).
Mutations of CLCNKB cause classic Bartter syndrome, while
mutations of the other 2 transporters manifest with the
antenatal form of Bartter syndrome. [6] Edema and
hypertension are absent, and hypercalciuria is common
because the impaired reabsorption of sodium chloride
inhibits the paracellular reabsorption of calcium. Because
loop diuretics inhibit the Na+/K+/2Cl- transporter, the
electrolyte abnormalities observed in Bartter syndrome and
with loop diuretic use are similar.
Gitelman syndrome (see Potassium and Magnesium
Depletion [OMIM]) is an inherited autosomal recessive
disorder in which loss of function of the thiazide-sensitive
sodium/chloride transporter (NCCT) in the distal convoluted
tubule occurs. The subsequent increased distal solute
delivery and salt wasting with stimulation of the
renin-angiotensin-aldosterone system lead to hypokalemic
metabolic alkalosis. Other features of the syndrome are
hypocalciuria and hypomagnesemia. The electrolyte
abnormalities resemble those caused by thiazide diuretics.
Pure hypokalemia (ie, severe potassium ion depletion)
causes mild metabolic alkalosis, but, in combination with
hyperaldosteronism, the alkalosis is more severe. Possible
mechanisms of alkalosis in hypokalemia are enhanced
proximal bicarbonate reabsorption, stimulated renal
ammonia genesis, impaired renal chloride reabsorption,
reduced GFR (in animals), and intracellular acidosis in the
distal nephron with subsequent enhanced hydrogen
secretion.
Magnesium depletion (ie, hypomagnesemia) may lead to
metabolic alkalosis. The mechanism probably involves
hypokalemia, which is usually caused by or associated with
magnesium depletion.
Other causes
The kidneys are able to excrete any excess alkali load,
whether it is exogenous (eg, infusion of sodium bicarbonate)
or endogenous (eg, metabolism of lactate to bicarbonate in
lactic acidosis). However, in renal failure or in any condition
that maintains the alkalosis, this natural ability of the kidneys
to excrete the excess bicarbonate is impaired. Examples
include the following:
● Alkali-loading alkalosis
● Hypercalcemia
● Intravenous penicillin
● Hypoproteinemic alkalosis
Milk-alkali syndrome comprises hypercalcemia, renal
insufficiency, and metabolic alkalosis. Before the advent of
H2-receptor antagonists, milk-alkali syndrome was observed
in patients who ingested large amounts of milk and antacids
as treatment for peptic ulcers. Currently, the syndrome is
observed mainly in people who chronically ingest large
doses of calcium carbonate, with or without vitamin D
(typically for osteoporosis prevention). [7]
The hypercalcemia that develops in some of these persons
increases renal bicarbonate reabsorption. Renal insufficiency
can occur secondary to nephrocalcinosis or hypercalcemia
and contributes to maintaining the metabolic alkalosis.
Patients with end-stage renal disease (ESRD) are dialyzed
with a high concentration of bicarbonate in the dialysate to
reverse metabolic acidosis (ie, hemodialysis using high
bicarbonate dialysate). Sometimes, this high bicarbonate
exceeds the amount needed to buffer the acidosis. Because
the ability of the kidneys to excrete the excess bicarbonate is
absent or severely diminished, the alkalosis persists
31
temporarily. The degree of alkalosis might be severe if the
patient also has vomiting.
Metabolic alkalosis has been reported after regional citrate
anticoagulation in hemodialysis or in continuous renal
replacement therapies. Citrate is infused in the blood inflow
line in the hemodialysis circuit, where it prevents clotting by
binding calcium. Because the dialyzer does not remove
citrate completely, a fraction of the infused citrate might
reach the systemic circulation. Citrate in the blood is
metabolized to bicarbonate in the liver. The accumulated
bicarbonate may lead to metabolic alkalosis.
In an international prospective cohort study involving 17,031
patients receiving thrice-weekly hemodialysis, high dialysate
bicarbonate, especially in patients with prolonged exposure,
contributed to higher mortality, most likely through
development of post-dialysis metabolic alkalosis. The
positive association between dialysate bicarbonate
concentration and mortality (adjusted hazard ratio, 1.08 per
4 mEq/L higher; 95% confidence index [CI], 1.01–1.15;
adjusted hazard ratio for dialysate bicarbonate ≥38 vs.
33–37 mEq/L, 1.07 [95% CI, 0.97–1.19]) was consistent
across pre-dialysis session serum bicarbonate levels and
between facilities that used one dialysate bicarbonate
concentration and those that prescribed different
concentrations for each patient. [8]
Metabolic alkalosis may be a potential complication of
plasmapheresis in patients with renal failure. The source of
alkali is the citrate that is used to prevent clotting in the
extracorporeal circuit and in the stored blood from which the
fresh frozen plasma is prepared. Using heparin as the
anticoagulant and using albumin instead of fresh frozen
plasma as the replacement solution can prevent the
metabolic alkalosis.
Recovery from lactic or ketoacidosis in the presence of
volume depletion or renal failure typically occurs when
exogenous bicarbonate is administered to correct the
acidosis. When the patient recovers, the
beta-hydroxybutyrate and lactate are metabolized to
bicarbonate and the original bicarbonate deficit is recovered.
The administered bicarbonate now becomes a surplus.
Refeeding with a carbohydrate-rich diet after prolonged
fasting results in mild metabolic alkalosis because of
enhanced metabolism of ketoacids to bicarbonate.
Massive blood transfusion results in mild metabolic alkalosis
as the citrate in the transfused blood is converted to
bicarbonate. Metabolic alkalosis is more likely to develop in
the presence of renal insufficiency.
Hypercalcemia may cause metabolic alkalosis by volume
depletion and enhanced bicarbonate reabsorption in the
proximal tubule. However, hypercalcemia from primary
hyperparathyroidism is usually associated with a metabolic
acidosis.
The intravenous administration of penicillin, carbenicillin, or
other semisynthetic penicillins may cause hypokalemic
metabolic alkalosis. This occurs because of distal delivery of
nonreabsorbable anions with an absorbable cation such as
Na+.
Metabolic alkalosis has been reported in patients with
hypoproteinemia. The mechanism of alkalosis is not clear,
but it may be related to loss of negative charges of albumin.
A decrease in plasma albumin of 1 g/dL is associated with
an increase in plasma bicarbonate of 3.4 mEq/L.
High rates of acid-base disorders have been reported in
patients hospitalized with COVID-19. In one retrospective
series of 211 patients, pH variations occurred in 79.7% of
patients, with the most common finding being metabolic
alkalosis, in a third of patients. [9] A similar rate of metabolic
alkalosis was reported in an observational study of 104
hospitalized COVID-19 patients with acute respiratory
distress syndrome (ARDS). [10]
Summary of causes of metabolic alkalosis

Causes of chloride-responsive alkalosis (urine chloride < 20
mEq/L) include the following:
● Loss of gastric secretions - Vomiting,
nasogastric suction
● Loss of colonic secretions - Congenital
chloridorrhea, villous adenoma
● Thiazides and loop diuretics (after
discontinuation)
● Posthypercapnia
● Cystic fibrosis
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
● 11B-HSD2 - Genetic, licorice, chewing
tobacco, carbenoxolone
● 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
● 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
History
Symptoms of metabolic alkalosis are not specific. Because
hypokalemia is usually present, the patient may experience
weakness, myalgia, polyuria, and cardiac arrhythmias.
Hypoventilation develops because of inhibition of the
respiratory center in the medulla. Symptoms of
hypocalcemia (eg, jitteriness, perioral tingling, muscle
spasms) may be present.
The clinical history is helpful in establishing the etiology.
Important points in the history include the following:
● Vomiting or diarrhea - Gastrointestinal (GI)
losses of hydrochloric acid (HCl)
● Age of onset and family history of alkalosis -
Familial disorders (eg, Bartter syndrome,
which starts during childhood)
● Renal failure - Alkali-loading alkalosis
develops only when impairment of renal
function occurs
● Drug use (eg, loop or thiazide diuretics;
licorice; tobacco chewing; carbenoxolone;
fludrocortisone; glucocorticoids; antacids [eg,
magnesium hydroxide]; calcium carbonate)
● Previous GI surgery [11] (eg, ileostomy [12] )
Physical Examination
32
The physical signs of metabolic alkalosis are not specific and
depend on the severity of the alkalosis. Because metabolic
alkalosis decreases ionized calcium concentration, signs of
hypocalcemia (eg, tetany, Chvostek sign, Trousseau sign),
change in mental status, or seizures may be present.
Physical examination is helpful to establish the cause of
metabolic alkalosis. Important aspects of the physical
examination include the evaluation of hypertension and of
volume status.
Hypertension accompanies several causes of metabolic
alkalosis (see Etiology). Volume status assessment includes
evaluation of orthostatic changes in blood pressure and
heart rate, mucous membranes, presence or absence of
edema, skin turgor, weight change, and urine output. Volume
depletion usually accompanies chloride-responsive alkalosis,
while volume expansion accompanies chloride-resistant
alkalosis.
Bulimia
Because patients with bulimia frequently self-induce
vomiting, they may have erosions of teeth enamel and dental
caries because of repeatedly exposing their teeth to gastric
acid.
Cushing syndrome
Findings associated with Cushing syndrome include the
following:
● Obesity
● Moon face
● Buffalo hump
● Hirsutism
● Violaceous skin striae
● Acne
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia (CAH): Infants with CAH
secondary to 11-hydroxylase deficiency have hypertension
and growth retardation. Male infants have premature sexual
development, while female infants develop virilization. In
17-hydroxylase deficiency, males develop sexual ambiguity,
while females have sexual infantilism.
Complications
Alkalosis may lead to tetany, seizures, and decreased
mental status. Metabolic alkalosis also decreases coronary
blood flow and predisposes persons to refractory
arrhythmias. Metabolic alkalosis causes hypoventilation,
which may cause hypoxemia, especially in patients with poor
respiratory reserve, and it may impair weaning from
mechanical ventilation. By increasing ammonia production, it
can precipitate hepatic encephalopathy in susceptible
individuals.
Diagnostic Considerations
Severe metabolic alkalosis is a life-threatening condition;
recognizing and treating the condition appropriately is
important. The diagnosis of metabolic alkalosis is difficult to
miss in patients in the intensive care unit (ICU) because
arterial blood gases (ABGs) are measured routinely in most
of these patients.
In non-ICU patients, metabolic alkalosis is suspected if
electrolytes show an elevated carbon dioxide level. An
elevated carbon dioxide level may also be secondary to
respiratory acidosis. Because treatments for the 2 conditions
differ, differentiating between them by reviewing the clinical
condition of the patient and performing ABGs if the elevation

in carbon dioxide is severe is important. In addition, check
serum K+ and ionized Ca2+ because metabolic alkalosis is
often associated with hypokalemia and decreased serum
ionized Ca2+ levels.
Serum Anion Gap
Calculation of the serum anion gap may help to differentiate
between primary metabolic alkalosis and metabolic
compensation for respiratory acidosis. The anion gap is
frequently elevated to a modest degree in metabolic
alkalosis because of the increase in the negative charge of
albumin and the enhanced production of lactate.
Normal values for the anion gap vary in different laboratories
and between individual patients, however, so it is important
to know the range of normal for the particular clinical
laboratory and the prevailing baseline value for a particular
patient. [13] In any event, the only definitive way to diagnose
metabolic alkalosis is with a simultaneous blood gases
analysis that shows elevation of both pH and PaCO2 and
increased calculated bicarbonate.
Serum bicarbonate concentration can be calculated from a
blood gas sample using the Henderson-Hasselbalch
equation, as follows:
pH = 6.10 + log (HCO3- ÷ 0.03 × PaCO2)
Alternatively, HCO3- = 24 × PaCO2 ÷ [H+]
Because pH and PaCO2 are directly measured, bicarbonate
can be calculated.
Another means of assessing serum bicarbonate
concentration is with the total carbon dioxide content in
serum, which is routinely measured with serum electrolytes
obtained from venous blood. In this method, a strong acid is
added to serum, which interacts with bicarbonate in the
serum sample, forming carbonic acid. Carbonic acid
dissociates to carbon dioxide and water; then, carbon
dioxide is measured.
Note that the carbon dioxide measured includes bicarbonate
and dissolved carbon dioxide. The contribution of dissolved
carbon dioxide is quite small (0.03 × PaCO2) and is usually
ignored, although it accounts for a difference of 1-3 mEq/L
between the measured total carbon dioxide content in
venous blood and the calculated bicarbonate in arterial
blood. Thus, at a PaCO2 of 40, a total carbon dioxide content
of 25 means a true bicarbonate concentration of 23.8 (ie, 25
- 0.03 × 40).
The Henderson-Hasselbalch equation may fail to account for
acid-base findings in critically ill patients. An alternative
method of acid-base analysis, known as the quantitative, or
strong ion, approach, [14] determines pH on the basis of the
following 3 independent variables (see Metabolic Acidosis):
● Strong ion difference (SID): Ions almost
completely dissociated at physiologic pH (the
cations Na+, K+, Ca+, and Mg+, and the
anions Cl- and lactate)
● Total weak acid concentration: Ions that can
be dissociated or associated at physiologic
pH (albumin and phosphate)
● pCO2 (mm Hg)
In a study that compared the conventional
Henderson-Hasselbalch equation with the strong ion
approach, carried out in 100 patients with trauma who were
admitted to a surgical intensive care unit, the investigators
concluded that the strong ion approach provides a more
accurate means of diagnosing acid-base disorders, including
metabolic alkalosis and tertiary disorders.
Urine Sodium Ion Concentration
Measurement of urine sodium ion concentration is used in
many conditions to determine volume status, especially in
patients with oliguria. However, volume depletion in
metabolic alkalosis may not lead to low urine sodium. In the
first few days of vomiting, the loss of acidic gastric secretions
leads to an increase in serum bicarbonate concentration.
The kidneys try to excrete the excess bicarbonate as the
33
sodium or potassium salt. Therefore, despite volume
depletion, the urine sodium level may be inappropriately
high.
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
Evaluations for Primary Hyperaldosteronism, Cushing
Syndrome, and Apparent Mineralocorticoid Excess
Measure aldosterone levels in a 24-hour urine collection
after salt loading to diagnose primary hyperaldosteronism.
To test for Cushing syndrome, measure plasma cortisol at
midnight during sleep or free cortisol in a 24-hour urine
study, or perform a dexamethasone suppression test.
Measurement of urine cortisol metabolites is used to
diagnose the syndrome of apparent mineralocorticoid excess
(AME). In AME and other conditions of 11B-HSD deficiency,
the proportion of cortisol to cortisone metabolites is
increased (ie, ratio of tetrahydrocortisol and
5-alpha-tetrahydrocortisol to tetrahydrocortisone).
Evaluation for Congenital Adrenal Hyperplasia Variants
In 11-hydroxylase deficiency, plasma and urine levels of
DOC and 11-deoxycortisolare high. In 17-hydroxylase
deficiency, DOC is elevated while 11-deoxycortisol is low.
Another important difference between the 2 conditions is the
impaired adrenal androgen synthesis in the latter and
enhanced synthesis in the former. Therefore, measuring
plasma or urine adrenal androgens (eg,
dehydroepiandrosterone[DHEA], testosterone) may help to
differentiate between the 2 conditions.
Diuretic Screen, Adrenal Imaging, and Renovascular
Hypertension Imaging
Obtain a urine diuretics screen to exclude surreptitious
diuretic use in patients having unexplained hypokalemic
metabolic alkalosis.
Perform adrenal imaging studies (eg, CT scan, MRI) to find
the etiology of primary hyperaldosteronism, Cushing
syndrome, and DOC excess.
Renal Doppler ultrasound, captopril renogram, MRI, and
renal angiography are helpful in diagnosing renovascular
hypertension (ie, significant renal artery stenosis). The
preferred imaging method is controversial.
Gene Analysis
Gene analysis is helpful to diagnose inherited causes of
hypokalemic alkalosis. Examples are Liddle syndrome,

glucocorticoid-remediable hypertension, Bartter syndrome,
Gitelman syndrome, syndrome of AME, and CAH.
Approach Considerations
The management of metabolic alkalosis depends primarily
on the underlying etiology and on the patient’s volume
status. 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). [16, 17] 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. [18]
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. [19]
Chloride-Responsive Alkalosis
If chloride-responsive 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
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
34
Metabolic alkalosis in the syndrome of 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. [20]
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.
Specialized Therapies in All Types of Metabolic Alkalosis
Hydrochloric acid
Intravenous 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. HCl may also be indicated if rapid correction of
severe metabolic alkalosis is warranted (eg, cardiac
arrhythmias, hepatic encephalopathy, digoxin cardiotoxicity).
[21]
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.
Medication Summary

The choice of therapy in metabolic alkalosis varies with the
underlying cause. Depending on the may be used in specific
situation, the following may be used [22] :
● Carbonic anhydrase inhibitors (eg,
acetazolamide)
● Hydrochloric acid (HCl)
● Potassium-sparing diuretics
● Angiotensin-converting enzyme (ACE)
inhibitors
● Potassium supplements
● Fluid replacement
● Nonsteroidal anti-inflammatory drugs
(NSAIDs)
Carbonic Anhydrase Inhibitors
Class Summary
Diuretics may be used to treat severe metabolic alkalosis in
edematous states (eg, from congestive heart failure (CHF),
chronic obstructive pulmonary disease (COPD), or right
heart failure).
Acetazolamide (Diamox)
● View full drug information
This agent inhibits carbonic anhydrase, the enzyme that
catalyzes the hydration of CO2 and dehydration of carbonic
acid. Inhibition reduces reabsorption of NaHCO3 in the
proximal tubule, leading to natriuresis, bicarbonate, diuresis,
and a decreased serum bicarbonate level. As NaHCO3
delivery to the collecting duct increases, potassium secretion
enhances, resulting in hypokalemia.
Acids
Class Summary
Acidic IV solutions are used to treat severe metabolic
alkalosis. Seek the advice of nephrologist in severe alkalosis
when HCl therapy or dialysis is contemplated.
Hydrochloric acid
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. This approach
may also be indicated if rapid correction of severe metabolic
alkalosis is warranted (eg, in cases of cardiac arrhythmia,
hepatic encephalopathy, digoxin toxicity). HCl is available in
preparations of 0.1 and 0.2 M, which contain 100 mmol H+/L
and 200 mmol H+/L, respectively.
Ammonium chloride (NH4Cl)
● View full drug information
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 tablets and a 26.75%
parenteral formulation for intravenous use. The parenteral
formulation contains 5 mEq/mL (267.5 mg/mL).
Potassium-Sparing Diuretics
Class Summary
These agents may be used to correct potassium deficiency
or fluid/electrolyte imbalance.
Triamterene (Dyrenium)
● View full drug information
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.
Spironolactone (Aldactone)
35
● View full drug information
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 acid-base balance.
Amiloride
● View full drug information
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.
Angiotensin-Converting Enzyme Inhibitors
Class Summary
ACE inhibitors block conversion of angiotensin I to
angiotensin II and prevent secretion of aldosterone from the
adrenal cortex. These agents are indicated in metabolic
alkalosis due to hyperaldosteronism.
Captopril
● View full drug information
Captopril prevents conversion of angiotensin I to angiotensin
II, a potent vasoconstrictor, resulting in lower aldosterone
secretion.
Enalapril (Vasotec)
● View full drug information
A competitive inhibitor of ACE, enalapril reduces angiotensin
II levels, decreasing aldosterone secretion.
Lisinopril (Prinivil, Zestril)
● View full drug information
Lisinopril prevents conversion of angiotensin I to angiotensin
II, a potent vasoconstrictor, resulting in lower aldosterone
secretion.
Potassium Supplements
Class Summary
Potassium supplements may be used to correct metabolic
alkalosis, which is often associated with hypokalemia.
Potassium chloride (Epiklor, MicroK, Klor-Con)
● View full drug information
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.
Fluid Replacements
Class Summary
Fluid replacement is used in chloride-responsive alkalosis
with volume depletion.
Sodium chloride hypertonic, ophthalmic
● View full drug information
This volume expander solution is used to correct metabolic
imbalances.
Corticosteroids
Class Summary
Corticosteroids are used in glucocorticoid-remediable
hyperaldosteronism, metabolic alkalosis, and hypertension.
Dexamethasone (Baycadron, Maxidex, Ozurdex)
● View full drug information
 36
Dexamethasone suppresses cortisol production by inhibiting
ACTH. It does not activate the mineralocorticoid receptor.

Nonsteroidal Anti-inflammatory Agents

Class Summary
NSAIDs may partially correct metabolic alkalosis in Bartter
syndrome and Gitelman syndrome.

Ibuprofen (Motrin, Advil, NeoProfen)

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Ibuprofen inhibits inflammatory reactions and decreases
prostaglandin synthesis.

Indomethacin (Indocin)
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Indomethacin is a rapidly absorbed NSAID. Metabolism
occurs in liver by demethylation, deacetylation, and
glucuronide conjugation. This agent inhibits prostaglandin
synthesis.

Clinical Significance

Metabolic alkalosis is a relatively common diagnosis in medicine.

The biological effects of metabolic alkalosis are directly resultant
to associated problems such as hypovolemia and potassium and
chloride depletion. These changes lead to decreased myocardial
contractility, arrhythmias, decreased cerebral blood flow,
confusion, increased neuromuscular excitability, and impaired
peripheral oxygen unloading secondary to the shift of the oxygen
dissociation curve to left. Additionally, there is a compensatory
increase in arterial pCO through hypoventilation. Overall there is a
net effect on the body resulting in hypoxia.

Clinically it is important to understand the relationships between carbo

dioxide and bicarbonate in the buffering system and to understand the
interactions of how these components are regulated. Additionally, it is
essential to understand the mechanism through which sodium,
potassium, and hydrogen function to modulate pH when these ion
channels are altered with medications. Therefore, the treatment of
chloride resistant metabolic alkalosis is focused on treating the
underlying condition that triggered the alkalotic event. Since many of
these pathologies are resultant to the effect on the
renin-angiotensin-aldosterone system, treatment includes inhibiting th
effect of aldosterone on the nephron using potassium-sparing diuretics
such as amiloride and triamterene. Additionally, an investigation for a
malignant source should be considered, such as with primary
hyperaldosteronism and Conn syndrome. In chloride responsive
metabolic alkalosis, this includes repletion of electrolytes, specifically
chloride and potassium along with the replenishment of fluid. In
scenarios, such as congestive heart failure (CHF) or edematous states,
diuresis is essential using potassium-sparing diuretics.[