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 (HCO3-) concentration to PaCO2, thereby increasing 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.
The hyperventilation syndrome can mimic many conditions that are more serious. Symptoms may include paresthesia, circumoral numbness, chest pain or tightness, dyspnea, and tetany.[3]
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.[4]
Respiratory alkalosis may impair vitamin D metabolism, which may lead to vitamin D deficiency and cause symptoms such as fibromyalgia.[5]
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:
Imaging studies
These include the following:
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.
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 more easily 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,[6] 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 partial pressure of carbon dioxide (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.[7] 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.[4] After 2-6 hours, renal compensation begins via a decrease in bicarbonate reabsorption. The kidneys respond more to the decreased PaCO2 rather than to the increased pH. Complete kidney compensation may take several days and requires normal kidney function and intravascular volume status.[4] The expected change in serum bicarbonate concentration can be estimated as follows:
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).[7]
The expected change in pH with respiratory alkalosis can be estimated with the following equations:
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.[8]
United States
The frequency of respiratory alkalosis varies depending on the etiology. The most common acid-base abnormality observed in critically ill patients is respiratory alkalosis.[4]
Morbidity and mortality of patients with respiratory alkalosis depend on the nature of the underlying cause of the respiratory alkalosis and associated conditions.
An Iranian study, by Hamdi et al, found primary respiratory alkalosis to be one of the mortality risk factors during hospitalization for poisoning, with the other predictors consisting of age, intensive care unit admission, consciousness level, period of hospitalization, and severe metabolic acidosis.[9]
A study by Wu et al suggested that an association exists between respiratory alkalosis and the severity of coronavirus disease 2019 (COVID-19). The investigators reported that after adjusting for age, gender, and the presence of comorbidities (specifically, cardiovascular disease and hypertension), the hazard ratio for the development of severe COVID-19 in patients with respiratory alkalosis was 2.445.[10]
Respiratory alkalosis is equally prevalent in males and females.
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.[11]
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.[12]
A retrospective study by Miró et al reported similar results, finding evidence that alkalosis does not increase the mortality risk in patients with heart failure. The cohort included 676 patients with probable metabolic alkalosis and 937 with probable respiratory alkalosis, with the investigators reporting that the adjusted odds ratio for inhospital mortality was 0.919.[13]
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 ratios for those with respiratory alkalosis or metabolic acidosis, compared with controls, were 1.21 and 1.17, respectively.[14]
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.
Clinical manifestations of respiratory alkalosis depend on its duration, its severity, and the underlying disease process. Note the following:
A retrospective study by de Souza et al found that among the 211 patients in their report with COVID-19, the most common acid-base disorder was respiratory alkalosis. The investigators determined that 149 patients (70.6%) had alkalosis, with this being of respiratory origin in 128 patients (60.7%). The other 21 patients (10.0%) had metabolic alkalosis, while 28 patients (13.3%) had metabolic acidosis, and 34 patients (16.1%) had normal arterial pH.[17]
Physical examination findings in patients with respiratory alkalosis are nonspecific and are typically related to the underlying illness or cause of the respiratory alkalosis. Note the following:
The differential diagnosis of respiratory alkalosis is broad; therefore, a thorough history, physical examination, and laboratory evaluation are helpful in arriving at the true diagnosis.
Central nervous system (CNS) causes are as follows:
CNS effects are secondary to the reduction in cerebral blood flow caused by reduction in PCO2. The cerebral blood flow may decrease by 1-2 mL/100 g/min for each 1 mm Hg fall in PCO2, with maximum reduction in cerebral blood flow of 40-50% achieved with a PCO2 of 20-25 mm Hg. Reduced cerebral blood flow may cause altered mentation, dizziness, and sometimes seizures.
The effects of hyperoxemia and hypoxemia on cerebral blood flow velocity in premature neonates appear to depend on gestational age.[19]
Any condition associated with a fall in the PaO2 below 55 mm Hg or with decreased oxygen delivery to the tissues increases minute ventilation, causing respiratory alkalosis. Hypoxia-related causes are as follows:
Drug-related causes are as follows:
Endocrine-related causes are as follows:
Interstitial, airway, and parenchymal pulmonary diseases affect PO2 more prominently than PCO2, and hyperventilation usually results in hypocapnia.[7] Inflammation of the irritant receptors in the airways and parenchyma also causes hyperventilation, resulting in respiratory alkalosis. Pulmonary causes are as follows:
Miscellaneous causes are as follows:
An essential laboratory analysis is as follows:
Transcutaneous or end-tidal PCO2 may be used in place of arterial PCO2; however, transcutaneous PCO2 requires normal skin perfusion, and end-tidal pCO2 is useful only in the presence of normal lung function and when no other acid-base disturbance is suspected. Furthermore, the noninvasive tests do not measure the pH.
The following laboratory studies may be helpful.
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 takes place 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 alkalosis, 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.
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.
Findings may be abnormal if hepatic failure is the etiology of respiratory alkalosis.
Cultures of blood, sputum, urine, and other sites 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-stimulating hormone and thyroxine levels may be indicated to rule out hyperthyroidism.
Beta-human chorionic hormone levels may be helpful in ruling out pregnancy.
Drug screens and theophylline and salicylate levels may be useful in determining whether drugs or medications are the cause.
Consider the following imaging studies.
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.
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, CNS tumor, and CNS trauma.
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.
If a central cause of hyperventilation and respiratory alkalosis is suggested and the initial brain CT-scan findings are negative or inconclusive, an MRI scan of the brain can be considered. MRI scans may reveal abnormalities not seen on CT scans, particularly lesions of the brain stem. Possible etiologies based on MRI scans include cerebrovascular accident, CNS tumor, and CNS trauma.
Echocardiography can be performed to assess myocardial and valvular function. A "bubble" study is helpful when assessing patients for unexplained hypoxemia and right-to-left shunting of blood.
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 to control the manifestations of the hyperadrenergic state that can lead to hyperventilation syndrome in some patients.[7]
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.
Based on findings from the history, physical examination, laboratory studies, and imaging modalities, the necessity for assistance from consultants such as pulmonologists, neurologists, or nephrologists can be determined.