Respiratory Alkalosis

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Background

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.

Pathophysiology

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:

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]

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.[6]

Epidemiology

Frequency

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.[5]

Mortality/Morbidity

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.[7]

Sex

Respiratory alkalosis is equally prevalent in males and females.

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.[10]

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:

Physical

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:

Causes

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 causes are as follows:

Hypoxia-related causes are as follows:

Drug-related causes are as follows:

Endocrine-related causes are as follows:

Pulmonary causes are as follows:

Miscellaneous causes are as follows:

Laboratory Studies

An essential laboratory analysis is as follows:

The following laboratory studies may be helpful:

Imaging Studies

Consider the following imaging studies:

Other Tests

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.

Procedures

Perform a lumbar puncture if the history and physical examination findings are suggestive of a CNS infectious process.

Medical Care

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.

Consultations

Based on the 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.

What is respiratory alkalosis?How are acute and chronic respiratory alkalosis characterized?Which patients are at highest risk for respiratory alkalosis?What is the pathophysiology of respiratory alkalosis?What is the role of hyperventilation in the pathophysiology of respiratory alkalosis?What is the role of acute hypocapnia in the pathophysiology of respiratory alkalosis?What is the role of serum bicarbonate concentration in the pathophysiology of respiratory alkalosis?What is the expected change in pH with respiratory alkalosis?How does respiratory alkalosis affect venous-arterial difference in CO2?What is the frequency of respiratory alkalosis in the US?What is the mortality and morbidity of respiratory alkalosis, and is there a sex predilection?What is the prognosis of respiratory alkalosis?Which patients with respiratory alkalosis benefit from breathing technique instruction?What are the signs and symptoms of respiratory alkalosis?What are the physical findings characteristic of respiratory alkalosis?What can help limit the differential diagnoses of respiratory alkalosis?What are the central nervous system causes of respiratory alkalosis?What are the hypoxia-related causes of respiratory alkalosis?What are drug-related causes of respiratory alkalosis?What are endocrine-related causes of respiratory alkalosis?What are the pulmonary causes of respiratory alkalosis?What are miscellaneous causes of respiratory alkalosis?Why is hyperthyroidism included in the differential diagnosis of respiratory alkalosis?Why is pregnancy a risk factor for respiratory alkalosis?How does congestive heart failure cause respiratory alkalosis?How does chronic or severe liver disease cause respiratory alkalosis?How is salicylate overdose-related respiratory alkalosis diagnosed?How do fever and sepsis lead to respiratory alkalosis?What is characteristic of gram-negative sepsis-caused respiratory alkalosis?How does pain lead to respiratory alkalosis?How is hyperventilation syndrome diagnosed?What are the differential diagnoses for Respiratory Alkalosis?How is respiratory alkalosis diagnosed?What is the role of lab studies in the diagnosis of respiratory alkalosis?What is the role of imaging studies in the diagnosis of respiratory alkalosis?What is the role of echocardiography in the diagnosis of respiratory alkalosis?What is the role of lumbar puncture in the diagnosis of respiratory alkalosis?What is the focus of treatment for respiratory alkalosis?How is respiratory alkalosis treated in patients on mechanical ventilators?How is hyperventilation syndrome treated?Why is a systemic approach initially needed in the treatment of respiratory alkalosis?Which specialist consultations are needed for the treatment of respiratory alkalosis?

Author

Ranjodh Singh Gill, MD, FACP, CCD, Associate Professor of Medicine, Division of Endocrinology, Virginia Commonwealth University School of Medicine and McGuire Veterans Administration Medical Center; Consulting Staff, Department of Internal Medicine, Virginia Commonwealth University Health System

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Zab Mosenifar, MD, FACP, FCCP, Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Ryland P Byrd, Jr, MD, Professor of Medicine, Division of Pulmonary Disease and Critical Care Medicine, James H Quillen College of Medicine, East Tennessee State University

Disclosure: Nothing to disclose.

Acknowledgements

Gregg T Anders, DO Medical Director, Great Plains Regional Medical Command , Brooke Army Medical Center; Clinical Associate Professor, Department of Internal Medicine, Division of Pulmonary Disease, University of Texas Health Science Center at San Antonio

Disclosure: Nothing to disclose.

Jackie A Hayes, MD, FCCP Clinical Assistant Professor of Medicine, University of Texas Health Science Center at San Antonio; Chief, Pulmonary and Critical Care Medicine, Department of Medicine, Brooke Army Medical Center

Jackie A Hayes is a member of the following medical societies: Alpha Omega Alpha, American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

Oleh Wasyl Hnatiuk, MD Program Director, National Capital Consortium, Pulmonary and Critical Care, Walter Reed Army Medical Center; Associate Professor, Department of Medicine, Uniformed Services University of Health Sciences

Oleh Wasyl Hnatiuk, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society

Disclosure: Nothing to disclose.

April Lambert-Drwiega, DO Fellow, Department of Pulmonology and Critical Care Medicine, East Tennessee State University

April Lambert-Drwiega is a member of the following medical societies: American College of Physicians, American Medical Association, American Osteopathic Association, and Southern Medical Association

Disclosure: Nothing to disclose.

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