15

Respiratory Acidosis
and Alkalosis
Nicolaos E. Madias | Horacio J. Adrogu

RESPIRATORY ACIDOSIS
Respiratory acidosis, or primary hypercapnia, is the acidbase disturbance initiated by an increase in carbon dioxide
tension of body fluids and in whole-body CO2 stores. Hypercapnia acidifies body fluids and elicits an adaptive increment
in the plasma bicarbonate concentration ([HCO3]) that
should be viewed as an integral part of the respiratory acidosis. Arterial CO2 tension (Pco2), measured at rest and at sea
level, is greater than 45 mm Hg in simple respiratory acidosis. Lower values of Pco2 might still signify the presence of
primary hypercapnia in the setting of mixed acid-base disorders (e.g., eucapnia, rather than the expected hypocapnia,
in the presence of metabolic acidosis). Another special case
of respiratory acidosis is the presence of arterial eucapnia,
or even hypocapnia, in association with venous hypercapnia in patients who have an acute severe reduction in cardiac output but relative preservation of respiratory function
(i.e., pseudorespiratory alkalosis).

PATHOPHYSIOLOGY
The ventilatory system is responsible for maintaining Pco2
within normal limits by adjusting minute ventilation ( V E ) to
match the rate of CO2 production. V E consists of two components: ventilation distributed in the gas-exchange units of
the lungs (alveolar ventilation, V A ) and ventilation wasted
in dead space ( V D). Hypercapnia can result from increased
CO2 production, decreased V A , or both. Decreased V A can
result from a reduction in V E , an increase in V D, or a combination of the two. The main elements of the ventilatory
system are the respiratory pump, which generates a pressure
gradient responsible for airflow, and the loads that oppose
such action. The respiratory pump comprises the cerebrum,
brainstem, spinal cord, phrenic and intercostal nerves, and
the muscles of respiration. The respiratory loads include
the ventilatory requirement (CO2 production, O2 consumption), airway resistance, lung elastic recoil, and chest-wall/
abdominal resistance. Most frequently, primary hypercapnia develops from an imbalance between the strength
of the respiratory pump and the weight of the respiratory
loads, thereby resulting in decreased V A . Impairment of the
pump can occur because of depressed central drive, abnormal neuromuscular transmission, or muscle dysfunction.
Causes of augmented respiratory loads include ventilation/
perfusion mismatch (increased V D), augmented airway flow
resistance, lung/pleural/chest-wall stiffness, and increased
ventilatory demand. An increased V D occurs in many clinical conditions, including emphysema, cystic fibrosis, asthma,

144

and other intrinsic lung diseases, as well as chest-wall disorders. A less frequent cause of primary hypercapnia is failure
of CO2 transport caused by decreases in pulmonary perfusion, a condition that occurs in cardiac arrest, circulatory
collapse, and pulmonary embolism (thrombus, fat, air).
Overproduction of CO2 is usually matched by increased
excretion, so that hypercapnia is prevented. However,
patients with marked limitation in pulmonary reserve and
those receiving constant mechanical ventilation might experience respiratory acidosis due to increased CO2 production
caused by increased muscle activity (agitation, myoclonus,
shivering, seizures), sepsis, fever, or hyperthyroidism. Increments in CO2 production might also be imposed by the
administration of large carbohydrate loads (>2000 kcal/day)
to nutritionally bereft, critically ill patients or during the
decomposition of bicarbonate infused in the course of treating metabolic acidosis.
The major threat to life from CO2 retention in patients
who are breathing room air is the associated obligatory
hypoxemia. When the arterial oxygen tension (Po2) falls to
less than 40 to 50 mm Hg, harmful effects can occur, especially if the fall is rapid. In the absence of supplemental
oxygen, patients in respiratory arrest develop critical hypoxemia within a few minutes, long before extreme hypercapnia ensues. Because of the constraints of the alveolar gas
equation, it is not possible for Pco2 to reach values much
higher than 80 mm Hg while the level of Po2 is still compatible with life. Extreme hypercapnia can be seen only during
oxygen administration, and, in fact, it is often the result of
uncontrolled oxygen therapy.

SECONDARY PHYSIOLOGIC RESPONSE

An immediate rise in plasma [HCO3] owing to titration of nonbicarbonate body buffers occurs in response
to acute hypercapnia. This adaptation is complete within
5 to 10 minutes after the increase in Pco2. On average,
plasma [HCO3] increases by about 0.1 mEq/L for each 1
mm Hg acute increment in Pco2; as a result, the plasma
hydrogen ion concentration ([H+]) increases by about 0.75
nEq/L for each 1 mm Hg acute increment in Pco2. Therefore, the overall limit of adaptation of plasma [HCO3] in
acute respiratory acidosis is quite small; even when Pco2
increases to levels of 80 to 90 mm Hg, the increment in
plasma [HCO3] does not exceed 3 to 4 mEq/L. Moderate
hypoxemia does not alter the adaptive response to acute
respiratory acidosis. On the other hand, preexisting hypobicarbonatemia (from metabolic acidosis or chronic respiratory alkalosis) enhances the magnitude of the bicarbonate
response to acute hypercapnia, whereas this response is

CHAPTER 15 RESPIRATORY ACIDOSIS AND ALKALOSIS

diminished in hyperbicarbonatemic states (from metabolic

alkalosis or chronic respiratory acidosis). Other electrolyte
changes observed in acute respiratory acidosis include mild
increases in plasma sodium (1 to 4 mEq/L), potassium (0.1
mEq/L for each 0.1 unit decrease in pH), and phosphorus, as well as small decreases in plasma chloride and lactate
concentrations (the latter effect originating from inhibition
of the activity of 6-phosphofructokinase and, consequently,
glycolysis by intracellular acidosis). A small reduction in the
plasma anion gap is also observed, reflecting the decline in
plasma lactate and the acidic titration of plasma proteins.
Acute respiratory acidosis induces glucose intolerance and
insulin resistance that are not prevented by adrenergic
blockade. These changes are likely mediated by the direct
effects of the low tissue pH on skeletal muscle.
The adaptive increase in plasma [HCO3] observed in
the acute phase of hypercapnia is amplified markedly during chronic hypercapnia as a result of the generation of new
bicarbonate by the kidneys. Both proximal and distal acidification mechanisms contribute to this adaptation, which
requires 3 to 5 days for completion. The renal response
to chronic hypercapnia includes chloruresis and the generation of hypochloremia. On average, plasma [HCO3]
increases by about 0.35 mEq/L for each 1 mm Hg chronic
increment in Pco2; as a result, the plasma [H+] increases by
about 0.3 nEq/L for each 1 mm Hg chronic increase in Pco2.
More recently, a substantially steeper slope for the change
in plasma [HCO3] was reported (0.51 mEq/L for each
1 mm Hg chronic increase in Pco2), but the small number
of blood gas measurements, one for each of 18 patients, calls
into question the validity of this conclusion. Empiric observations indicate a limit of adaptation of plasma [HCO3] on
the order of 45 mEq/L.
The renal response to chronic hypercapnia is not altered
appreciably by dietary sodium or chloride restriction, moderate potassium depletion, alkali loading, or moderate
hypoxemia. To what extent chronic kidney disease of variable severity limits the renal response to chronic hypercapnia is currently unknown. Obviously, patients with end-stage
kidney disease cannot mount a renal response to chronic
hypercapnia, so they are more subject to severe acidemia.
The degree of acidemia is more pronounced in patients who
are receiving hemodialysis rather than peritoneal dialysis,
because the former treatment maintains, on average, a lower
plasma level [HCO3]. Recovery from chronic hypercapnia
is crippled by a chloride-deficient diet. In this circumstance,
despite correction of the level of Pco2, plasma [HCO3]
remains elevated as long as the state of chloride deprivation
persists, thus creating the entity of posthypercapnic metabolic alkalosis. Chronic hypercapnia is not associated with
appreciable changes in the anion gap or in plasma concentrations of sodium, potassium, or phosphorus.

ETIOLOGY
Respiratory acidosis can develop in patients who have normal or abnormal airways and lungs. Tables 15.1 and 15.2
present, respectively, causes of acute and chronic respiratory acidosis. This classification accounts for the usual
mode of onset and duration of the various causes, and it
emphasizes the biphasic time course that characterizes the
secondary physiologic response to hypercapnia. Primary

145

hypercapnia can result from disease or malfunction within

any element of the regulatory system that controls respiration, including the central and peripheral nervous system,
respiratory muscles, thoracic cage, pleural space, airways,
and lung parenchyma. Not infrequently, more than one
cause contributes to the development of respiratory acidosis
in a given patient. Chronic obstructive pulmonary disease
(COPD) is the most common cause of chronic hypercapnia,
a condition that includes emphysema, chronic bronchitis,
and small-airway disease.

CLINICAL MANIFESTATIONS
Because hypercapnia almost always occurs with some degree
of hypoxemia, it is often difficult to determine whether a
specific manifestation is the consequence of the elevated
Pco2 or the reduced Po2. Clinical manifestations of respiratory acidosis arising from the central nervous system are collectively known as hypercapnic encephalopathy and include
irritability, inability to concentrate, headache, anorexia,
mental cloudiness, apathy, confusion, incoherence, combativeness, hallucinations, delirium, and transient psychosis. Progressive narcosis or coma might develop in patients
receiving oxygen therapy, especially those with an acute
exacerbation of chronic respiratory insufficiency in whom
Pco2 levels of 100 mm Hg or even higher can occur. In
addition, frank papilledema (pseudotumor cerebri) and

motor disturbances, including myoclonic jerks, flapping

tremor identical to that observed in liver failure, sustained
myoclonus, and seizures may develop. Focal neurologic
signs (e.g., muscle paresis, abnormal reflexes) might be
observed. The neurologic symptom burden depends on the
magnitude of hypercapnia, the rapidity with which it develops, the severity of acidemia, and the degree of accompanying hypoxemia. Severe hypercapnia often is misdiagnosed as
a cerebral vascular accident or an intracranial tumor.
The hemodynamic consequences of respiratory acidosis
include a direct depressing effect on myocardial contractility. An associated sympathetic surge, sometimes intense,
leads to increases in plasma catecholamines; however, during severe acidemia (blood pH lower than about 7.20),
receptor responsiveness to catecholamines is markedly
blunted. Hypercapnia results in systemic vasodilatation via
a direct action on vascular smooth muscle; this effect is
most obvious in the cerebral circulation, where blood flow
increases in direct relation to the level of Pco2. By contrast,
CO2 retention can produce vasoconstriction in the pulmonary circulation as well as in the kidneys; in the latter
case, the hemodynamic response may be mediated via an
enhanced sympathetic activity. Mild to moderate hypercapnia is usually associated with an increased cardiac output,
normal or increased blood pressure, warm skin, a bounding
pulse, and diaphoresis. However, if hypercapnia is severe or
considerable hypoxemia is present, decreases in both cardiac output and blood pressure may be observed. Concomitant therapy with vasoactive medications (e.g., -adrenergic
receptor blockers) or the presence of congestive heart failure may further impair the hemodynamic response. Cardiac
arrhythmias, particularly supraventricular tachyarrhythmias
not associated with major hemodynamic compromise, are
common, especially in patients receiving digitalis. They do
not result primarily from the hypercapnia, but rather reflect

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SECTION 2 ACID-BASE, FLUID, AND ELECTROLYTE DISORDERS

Table 15.1Causes of Acute Respiratory Acidosis

Normal Airways and Lungs

Abnormal Airways and Lungs

Central Nervous System Depression

General anesthesia
Sedative overdosage
Head trauma
Cerebrovascular accident
Central sleep apnea
Cerebral edema
Brain tumor
Encephalitis

Upper Airway Obstruction

Coma-induced hypopharyngeal obstruction
Aspiration of foreign body or vomitus
Laryngospasm or angioedema
Obstructive sleep apnea
Inadequate laryngeal intubation
Laryngeal obstruction postintubation
Lower Airway Obstruction
Generalized bronchospasm
Severe asthma (statusasthmaticus)
Bronchiolitis of infancy and adults
Disorders involving pulmonary alveoli
Severe bilateral pneumonia
Acute respiratory distress syndrome
Severe pulmonary edema

Neuromuscular Impairment
High spinal-cord injury
Guillain-Barr syndrome
Status epilepticus
Botulism, tetanus
Crisis in myasthenia gravis
Hypokalemic myopathy
Familial hypokalemic periodic paralysis

Pulmonary Perfusion Defect

Cardiac arrest*
Severe circulatory failure*
Massive pulmonary thromboembolism
Fat or air embolus

Ventilatory Restriction
Rib fractures with flail chest
Pneumothorax
Hemothorax
Impaired diaphragmatic function (e.g., peritoneal dialysis, ascites)
Iatrogenic Events
Misplacement or displacement of airway cannula during anesthesia or mechanical
ventilation
Bronchoscopy-associated hypoventilation or respiratory arrest
Increased CO2 production with constant mechanical ventilation (e.g., due to
high-carbohydrate diet or sorbent-regenerative hemodialysis)

From Madias NE, Adrogu HJ: Respiratory alkalosis and acidosis. In Seldin DW, Giebisch G, editors: The kidney: physiology and
pathophysiology. Philadelphia, 2000, Lippincott Williams & Wilkins, pp 2131-2166.
*May produce pseudorespiratory alkalosis.

Table 15.2Causes of Chronic Respiratory Acidosis

Normal Airways and Lungs

Abnormal Airways and Lungs

Central Nervous System Depression

Sedative overdosage
Methadone/heroin addiction
Primary alveolar hypoventilation (Ondines curse)
Obesity-hypoventilation syndrome (Pickwickian syndrome)
Brain tumor
Bulbar poliomyelitis

Upper Airway Obstruction

Tonsillar and peritonsillar hypertrophy
Paralysis of vocal cords
Tumor of the cords or larynx
Airway stenosis after prolonged intubation
Thymoma, aortic aneurysm

Neuromuscular Impairment
Poliomyelitis
Multiple sclerosis
Muscular dystrophy
Amyotrophic lateral sclerosis
Diaphragmatic paralysis
Myxedema
Myopathic disease

Lower Airway Obstruction

Chronic obstructive lung disease (bronchitis, bronchiolitis,
bronchiectasis, emphysema)
Disorders Involving Pulmonary Alveoli
Severe chronic pneumonitis
Diffuse infiltrative disease (e.g., alveolar proteinosis)
Interstitial fibrosis

Ventilatory Restriction
Kyphoscoliosis, spinal arthritis
Obesity
Fibrothorax
Hydrothorax
Impaired diaphragmatic function

From Madias NE, Adrogu HJ: Respiratory alkalosis and acidosis. In Seldin DW, Giebisch G, editors: The kidney: physiology and
pathophysiology. Philadelphia, 2000, Lippincott Williams & Wilkins, pp 2131-2166.

CHAPTER 15 RESPIRATORY ACIDOSIS AND ALKALOSIS

the associated hypoxemia and sympathetic discharge, concomitant medications, other electrolyte abnormalities, and
underlying cardiac disease. Retention of salt and water is
commonly observed in sustained hypercapnia, especially in
the presence of cor pulmonale. In addition to the effects of
heart failure on the kidney, multiple other factors may be
involved, including the prevailing stimulation of the sympathetic nervous system and the renin-angiotensin-aldosterone
axis, increased renal vascular resistance, and elevated levels
of antidiuretic hormone and cortisol.

DIAGNOSIS
Whenever hypoventilation is suspected, arterial blood gases
should be obtained. Alternatively, venous blood gases can be
used to assess acid-base status and obtain information about
tissue oxygenation. If the acid-base profile of the patient
reveals hypercapnia in association with acidemia, at least an
element of respiratory acidosis must be present. However,
hypercapnia can be associated with a normal or an alkaline
pH because of the simultaneous presence of additional
acid-base disorders (see Chapter 12). Information from the
patients history, physical examination, and ancillary laboratory data should be used for an accurate assessment of the
acid-base status.

THERAPEUTIC PRINCIPLES
Treatment of acute respiratory acidosis should focus on
three critical steps: (1) ensuring a patent airway, (2) restoring
adequate oxygenation by delivering an oxygen-rich inspired
mixture, and (3) securing adequate ventilation to repair the
abnormal blood gas composition. Indications for endotracheal intubation/mechanical ventilation include protection
of the airway, relief of respiratory distress, improvement of
pulmonary gas exchange, assistance with airway and lung
healing, and application of appropriate sedation and neuromuscular blockade. As noted, acute respiratory acidosis
poses its major threat to survival, not because of hypercapnia or acidemia, but because of the associated hypoxemia.
The goal of oxygen therapy is to maintain a Po2 of at least
60 mm Hg and oxygen saturation of 90%; yet, a Po2 of 50
to 55 mm Hg might help prevent respiratory depression in
patients with hypercapnia and chronic hypoxemia. Supplemental oxygen can be administered to the spontaneously
breathing patient with nasal cannulas, Venturi masks, or
nonrebreathing masks. Oxygen flow rates 5 L/min can
be used with nasal cannulas, each increment of 1 L/min
increasing the Fio2 by approximately 4%. Venturi masks,
calibrated to deliver Fio2 between 24% and 50%, are most
useful in patients with COPD as they allow the Po2 to be
titrated, thus minimizing the risk of CO2 retention.
If the target Po2 is not achieved with these measures,
and the patient is conscious, cooperative, hemodynamically
stable and able to protect the lower airway, a method of
noninvasive ventilation through a mask can be used (e.g.,
bilevel positive airway pressure [BiPAP]). With BiPAP, the
inspiratory-pressure support decreases the patients work
of breathing, and the expiratory-pressure support improves
gas exchange by preventing alveolar collapse.
Endotracheal intubation with mechanical ventilatory support should be initiated if adequate oxygenation cannot be

147

secured by noninvasive measures, if progressive hypercapnia

or obtundation develops, or if the patient is unable to cough
and clear secretions. Large tidal volumes during mechanical ventilation often lead to alveolar overdistention, which
results in hypotension and barotrauma, two life-threatening
complications. To overcome these complications, prescription of tidal volumes of 6 mL/kg body weight (instead of the
conventional level of 12 mL/kg body weight) to achieve plateau airway pressures of <30 cm H2O, has been proposed.
Because an increase in Pco2 develops (but rarely exceeds
80 mm Hg), this approach is termed permissive hypercapnia
or controlled mechanical hypoventilation. If the resultant hypercapnia reduces the blood pH to less than 7.20, many physicians would prescribe bicarbonate; however, this strategy
is controversial, and others would intervene only for pH
values on the order of 7.00. Several studies indicate that
permissive hypercapnia affords improved clinical outcomes.
Heavy sedation and neuromuscular blockade are frequently
needed with this therapy. After discontinuation of neuromuscular blockade, some patients develop prolonged
weakness or paralysis. Contraindications to permissive
hypercapnia include cerebrovascular disease, brain edema,
increased intracranial pressure, and convulsions; depressed
cardiac function and arrhythmias; and severe pulmonary
hypertension. Notably, most of these entities can develop as
adverse effects of permissive hypercapnia itself, especially if
it is associated with substantial acidemia.
The presence of a concurrent metabolic acidosis is the
primary indication for alkali therapy in patients with acute
respiratory acidosis. Administration of sodium bicarbonate
to a spontaneously breathing patient with simple respiratory
acidosis is not only of questionable efficacy but also involves
considerable risk. Concerns include pH-mediated depression of ventilation, enhanced CO2 production because of
bicarbonate decomposition, and volume expansion; however, alkali therapy may have a role in patients with severe
bronchospasm by restoring the responsiveness of the bronchial musculature to -adrenergic agonists. Successful management of intractable asthma in patients with blood pH
lower than 7.00 by administering sufficient sodium bicarbonate to raise blood pH to greater than 7.20 has been reported.
Patients with chronic respiratory acidosis frequently
develop episodes of acute decompensation that can be serious or life threatening. Common culprits include pulmonary infections, use of narcotics, and uncontrolled oxygen
therapy. In contrast to acute hypercapnia, injudicious use of
oxygen therapy in patients with chronic respiratory acidosis can produce further reductions in alveolar ventilation.
Respiratory decompensation superimposes an acute element of CO2 retention and acidemia on the chronic baseline.
Only rarely can one remove the underlying cause of chronic
respiratory acidosis, but maximizing alveolar ventilation
with relatively simple maneuvers is often successful in the
management of respiratory decompensation. Such maneuvers include treatment with antibiotics, bronchodilators, or
diuretics; avoidance of irritant inhalants, tranquilizers, and
sedatives; elimination of retained secretions; and gradual
reduction of supplemental oxygen, aiming at a Po2 of about
50 to 55 mm Hg. Administration of adequate quantities of
chloride (usually as the potassium salt) prevents or corrects
a complicating element of metabolic alkalosis (commonly
diuretic-induced) that can further dampen the ventilatory

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SECTION 2 ACID-BASE, FLUID, AND ELECTROLYTE DISORDERS

drive. Acetazolamide may be used as an adjunctive measure,

but care must be taken to avoid potassium depletion. Potassium and phosphate depletion should be corrected, as they
can contribute to the development or maintenance of respiratory failure by impairing the function of skeletal muscles.
Restoration of the Pco2 of the patient to near its chronic
baseline should proceed gradually, over a period of many
hours to a few days. Overly rapid reduction in Pco2 in such
patients risks the development of sudden, posthypercapnic
alkalemia with potentially serious consequences, including
reduction in cardiac output and cerebral blood flow, cardiac
arrhythmias (including predisposition to digitalis intoxication), and generalized seizures. In the absence of a complicating element of metabolic acidosis, and with the possible
exception of the severely acidemic patient with intense generalized bronchoconstriction who is undergoing mechanical ventilation, there is no role for alkali administration in
chronic respiratory acidosis.

RESPIRATORY ALKALOSIS
Respiratory alkalosis, or primary hypocapnia, is the acidbase disturbance initiated by a reduction in carbon dioxide
tension of body fluids. Hypocapnia alkalinizes body fluids
and elicits an adaptive decrement in plasma [HCO3] that
should be viewed as an integral part of the respiratory alkalosis. The level of Pco2 measured at rest and at sea level is
lower than 35 mm Hg in simple respiratory alkalosis. Higher
values of Pco2 may still indicate the presence of an element
of primary hypocapnia in the setting of mixed acid-base disorders (e.g., eucapnia, rather than the anticipated hypercapnia, in the presence of metabolic alkalosis).

PATHOPHYSIOLOGY
Primary hypocapnia most commonly reflects pulmonary
hyperventilation caused by increased ventilatory drive. The
latter results from signals arising from the lung, from the
peripheral (carotid and aortic) or brainstem chemoreceptors, or from influences originating in other centers of the
brain. Hypoxemia is a major stimulus of alveolar ventilation,
but Po2 values lower than 60 mm Hg are required to elicit this
effect consistently. Additional mechanisms for the generation of primary hypocapnia include maladjusted mechanical ventilators, the extrapulmonary elimination of CO2 by a
dialysis device or extracorporeal circulation (e.g., heart-lung
machine), and decreased CO2 production (e.g., sedation,
skeletal muscle paralysis, hypothermia, hypothyroidism) in
patients receiving constant mechanical ventilation.
A condition termed pseudorespiratory alkalosis occurs in
patients who have profound depression of cardiac function
and pulmonary perfusion but have relative preservation of
alveolar ventilation, including patients with advanced circulatory failure and those undergoing cardiopulmonary
resuscitation. In such patients, venous (and tissue) hypercapnia is present because of the severely reduced pulmonary blood flow that limits the amount of CO2 delivered
to the lungs for excretion. On the other hand, arterial
blood reveals hypocapnia because of the increased ventilation-to-perfusion ratio, which causes a larger than normal
removal of CO2 per unit of blood traversing the pulmonary

circulation. However, absolute CO2 excretion is decreased,

and the body CO2 balance is positive. Therefore, respiratory
acidosis, rather than respiratory alkalosis, is present. Such
patients may have severe venous acidemia (often resulting
from mixed respiratory and metabolic acidosis) accompanied by an arterial pH that ranges from mild acidemia to
frank alkalemia. In addition, arterial blood may show normoxia or hyperoxia, despite the presence of severe hypoxemia in venous blood. Therefore, both arterial and mixed
(or central) venous blood sampling is needed to assess the
acid-base status and oxygenation of patients with critical
hemodynamic compromise.

SECONDARY PHYSIOLOGIC RESPONSE

Adaptation to acute hypocapnia is characterized by an immediate drop in plasma [HCO3], principally as a result of
titration of nonbicarbonate body buffers. This adaptation is
completed within 5 to 10 minutes after the onset of hypocapnia. Plasma [HCO3] declines, on average, by approximately
0.2 mEq/L for each 1 mm Hg acute decrement in Pco2; consequently, the plasma [H+] decreases by about 0.75 nEq/L for
each 1 mm Hg acute reduction in Pco2. The limit of this adaptation of plasma [HCO3] is on the order of 17 to 18 mEq/L.
Concomitant small increases in plasma chloride, lactate, and
other unmeasured anions balance the decline in plasma
[HCO3]; each of these components accounts for about
one third of the bicarbonate decrement. Small decreases in
plasma sodium (1 to 3 mEq/L) and potassium (0.2 mEq/L
for each 0.1 unit increase in pH) may be observed. Severe
hypophosphatemia can occur in acute hypocapnia because
of the translocation of phosphorus into the cells.
A larger decrement in plasma [HCO3] occurs in chronic
hypocapnia as a result of renal adaptation to the disorder,
which involves suppression of both proximal and distal acidification mechanisms. Completion of this adaptation requires
2 to 3 days. Plasma [HCO3] decreases, on average, by about
0.4 mEq/L for each 1 mm Hg chronic decrement in Pco2; as
a consequence, plasma [H+] decreases by approximately 0.4
nEq/L for each 1 mm Hg chronic reduction in Pco2. The
limit of this adaptation of plasma [HCO3] is on the order of
12 to 15 mEq/L. About two thirds of the decline in plasma
[HCO3] is balanced by an increase in plasma chloride concentration, and the remainder reflects an increase in plasma
unmeasured anions; part of the remainder results from the
alkaline titration of plasma proteins, but most remains undefined. Plasma lactate does not increase in chronic hypocapnia, even in the presence of moderate hypoxemia. Similarly,
no appreciable change in the plasma concentration of
sodium occurs. In sharp contrast with acute hypocapnia,
the plasma concentration of phosphorus remains essentially
unchanged in chronic hypocapnia. Although plasma potassium is in the normal range in patients with chronic hypocapnia at sea level, hypokalemia and renal potassium wasting
have been described in subjects in whom sustained hypocapnia was induced by exposure to high altitude. Patients with
end-stage kidney disease are obviously at risk for development of severe alkalemia in response to chronic hypocapnia, because they cannot mount a renal response. This risk
is higher in patients receiving peritoneal dialysis rather than
hemodialysis, because the former treatment maintains, on
average, a higher plasma level [HCO3].

CHAPTER 15 RESPIRATORY ACIDOSIS AND ALKALOSIS

ETIOLOGY
Primary hypocapnia is the most frequent acid-base disturbance encountered; it occurs in normal pregnancy and with
high-altitude residence. Box 15.1 lists the major causes of
respiratory alkalosis. Most are associated with the abrupt
appearance of hypocapnia, but in many instances the process is sufficiently prolonged to permit full chronic adaptation. Consequently, no attempt has been made to separate
these conditions into acute and chronic categories. Some of
the major causes of respiratory alkalosis are benign, whereas
others are life threatening. Primary hypocapnia is particularly common among the critically ill, occurring either as
the simple disorder or as a component of mixed disturbances. Its presence constitutes an ominous prognostic sign,
with mortality increasing in direct proportion to the severity
of the hypocapnia.

CLINICAL MANIFESTATIONS
Rapid decrements in Pco2 to half the normal values or
lower are typically accompanied by paresthesias of the
extremities, chest discomfort (especially in patients manifesting increased airway resistance), circumoral numbness,

149

lightheadedness, confusion, and, rarely, tetany or generalized seizures. These manifestations are seldom present in
the chronic phase. Acute hypocapnia decreases cerebral
blood flow, which in severe cases may reach values <50%
of normal, resulting in cerebral hypoxia. This hypoperfusion has been implicated in the pathogenesis of the neurologic manifestations of acute respiratory alkalosis along with
other factors, including hypocapnia per se, alkalemia, pHinduced shift of the oxyhemoglobin dissociation curve, and
decrements in the levels of ionized calcium and potassium.
Some evidence indicates that cerebral blood flow returns to
normal in chronic respiratory alkalosis.
Patients who are actively hyperventilating manifest no
appreciable changes in cardiac output or systemic blood
pressure. By contrast, acute hypocapnia in the course of passive hyperventilation, as typically observed during mechanical ventilation in patients with a depressed central nervous
system or receiving general anesthesia, frequently results in
a major reduction in cardiac output and systemic blood pressure, increased peripheral resistance, and substantial hyperlactatemia. This discrepant response probably reflects the
decline in venous return caused by mechanical ventilation
in passive hyperventilation versus the reflex tachycardia consistently observed in active hyperventilation. Although acute

Box 15.1Causes of Respiratory Alkalosis

Hypoxemia or Tissue Hypoxia
Decreased inspired O2 tension
High altitude
Bacterial or viral pneumonia
Aspiration of food, foreign body,
or vomitus
Laryngospasm
Drowning
Cyanotic heart disease
Severe anemia
Left shift deviation of the HbO2 curve
Hypotension*
Severe circulatory failure*
Pulmonary edema
Stimulation of Chest Receptors
Pneumonia
Asthma
Pneumothorax
Hemothorax
Flail chest
Acute respiratory distress syndrome
Cardiac failure
Noncardiogenic pulmonary edema
Pulmonary embolism
Interstitial lung disease
Central Nervous System Stimulation
Voluntary
Pain
Anxiety

Psychosis
Fever
Subarachnoid hemorrhage
Cerebrovascular accident
Meningoencephalitis
Tumor
Trauma
Drugs or Hormones
Nikethamide, ethamivan
Doxapram
Xanthines
Salicylates
Catecholamines
Angiotensin II
Vasopressor agents
Progesterone
Medroxyprogesterone
Dinitrophenol
Nicotine
Miscellaneous
Pregnancy
Sepsis
Hepatic failure
Mechanical hyperventilation
Acetate hemodialysis
Heart-lung machine
Extracorporeal membrane oxygenation (ECMO)
Heat exposure
Recovery from metabolic acidosis

From Madias NE, Adrogu HJ: Respiratory alkalosis and acidosis. In Seldin DW, Giebisch G, editors: The kidney: physiology and pathophysiology.
Philadelphia, 2000, Lippincott Williams & Wilkins, pp 2131-2166.
HbO2, Oxyhemoglobin.
*May produce pseudorespiratory alkalosis.

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SECTION 2 ACID-BASE, FLUID, AND ELECTROLYTE DISORDERS

hypocapnia does not lead to cardiac arrhythmias in normal

volunteers, it appears that it contributes to the generation of
both atrial and ventricular tachyarrhythmias in patients with
ischemic heart disease. Chest pain and ischemic ST-T wave
changes have been observed in acutely hyperventilating
subjects with or without coronary artery disease. Coronary
vasospasm and Prinzmetal angina can be precipitated by
acute hypocapnia in susceptible subjects. The pathogenesis
of these manifestations has been attributed to the same factors that are incriminated in the neurologic manifestations
of acute hypocapnia.

DIAGNOSIS
Careful observation can detect abnormal patterns of breathing in some patients, yet marked hypocapnia may be present without a clinically evident increase in respiratory effort.
Therefore, an arterial blood gas analysis should be obtained
whenever hyperventilation is suspected. In fact, the diagnosis of respiratory alkalosis, especially the chronic form, is frequently missed; physicians often misinterpret the electrolyte
pattern of hyperchloremic hypobicarbonatemia as indicative
of a normal anion gap metabolic acidosis. If the acid-base
profile of the patient reveals hypocapnia in association with
alkalemia, at least an element of respiratory alkalosis must
be present; however, primary hypocapnia may be associated
with a normal or an acidic pH as a result of the concomitant
presence of other acid-base disorders. Notably, mild degrees
of chronic hypocapnia commonly leave blood pH within the
high-normal range. As always, proper evaluation of the acidbase status of the patient requires careful assessment of the
history, physical examination, and ancillary laboratory data
(see Chapter 12). After the diagnosis of respiratory alkalosis has been made, a search for its cause should ensue. The
diagnosis of respiratory alkalosis can have important clinical
implications, often providing a clue to the presence of an
unrecognized, serious disorder (e.g., sepsis) or indicating
the severity of a known underlying disease.

THERAPEUTIC PRINCIPLES
Management of respiratory alkalosis must be directed whenever possible toward correction of the underlying cause.
Respiratory alkalosis resulting from severe hypoxemia
requires oxygen therapy. The widely held view that hypocapnia, even if severe, poses little risk to health is inaccurate. In fact, transient or permanent damage to the brain,
heart, and lungs can result from substantial hypocapnia. In
addition, rapid correction of severe hypocapnia can lead to
reperfusion injury in the brain and lung. Therefore, severe
hypocapnia in hospitalized patients must be prevented
whenever possible, and, if it is present, a slow correction is
most appropriate.
Rebreathing into a closed system (e.g., a paper bag) may
prove helpful for the patient with the anxiety-hyperventilation syndrome because it interrupts the vicious cycle that can
result from the reinforcing effects of the symptoms of hypocapnia. Administration of 250 to 500 mg acetazolamide can
be beneficial in the management of signs and symptoms of

high-altitude sickness, a syndrome characterized by hypoxemia and respiratory alkalosis. Considering the risks of
severe alkalemia, sedation or, in rare cases, skeletal muscle
paralysis and mechanical ventilation may be required temporarily to correct marked respiratory alkalosis. Management
of pseudorespiratory alkalosis must be directed at optimizing
systemic hemodynamics.
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