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.[2, 3]
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. (See also Pediatric Respiratory Acidosis, Metabolic Acidosis, and Pediatric Metabolic 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:
Chronic respiratory acidosis may be secondary to many disorders, including COPD. Hypoventilation in COPD involves multiple mechanisms, including the following:
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.
Arterial blood gas (ABG) analysis is necessary in the evaluation of a patient with suspected respiratory acidosis or other acid-base disorders.[4]
The most common abnormal serum electrolyte finding in chronic respiratory acidosis is the presence of a compensatory increase in serum bicarbonate concentration.
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.
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.
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.
Measurement of transdiaphragmatic pressure is a useful diagnostic test for documenting respiratory muscle weakness. However, it is difficult to perform and is usually carried out only in specialized pulmonary function laboratories.
Pharmacologic therapies are generally used as treatment for the underlying disease process. Oxygen therapy is 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.
As noted (see Background), respiratory acidosis may have a variety of different causes, including the following:
Metabolism rapidly generates a large quantity of volatile acid (carbon dioxide) and nonvolatile acid. The metabolism of fats and carbohydrates leads to the formation of a large amount of carbon dioxide. The carbon dioxide combines with water to form carbonic acid (H2 CO3). The lungs excrete the volatile fraction through ventilation, and normally acid accumulation does not occur.[8]
A significant alteration in ventilation that affects elimination of carbon dioxide can cause a respiratory acid-base disorder. The partial arterial pressure of carbon dioxide (PaCO2) is normally maintained within the range of 35-45 mm Hg.[9, 10]
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.
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:
The expected change in pH with respiratory acidosis can be estimated with the following equations:
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. In addition, acidemia causes an extracellular shift of potassium.[11] Respiratory acidosis, however, rarely causes clinically significant hyperkalemia.
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.
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 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.[12]
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.
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.[13]
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.[14]
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.[15]
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.[16]
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).[17]
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. Tests for pulmonary function, nerve function, and transdiaphragmatic pressure (when available), may also be helpful.
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 patients.
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.[18]
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:
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.
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.
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. 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. 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.
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.
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 therapies are generally used as treatment for the underlying disease process.
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 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 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.
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.
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.
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.
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.[19]
A 4-year retrospective study reported that NIPPV was highly beneficial in the treatment of COPD with hypercapnia (type II) respiratory failure.[20] 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.”[21]
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.[22]
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.[23]
No drugs are used specifically to treat respiratory acidosis. Medical therapies are directed at the underlying disease or disorder causing hypoventilation and, therefore, respiratory acidosis. The drugs for these various conditions are included in this review.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: Metaproterenol is a beta2-adrenergic agonist that relaxes bronchial smooth muscle, with little effect on heart rate.
Clinical Context: Levalbuterol acts on beta2 receptors, causing relaxation of bronchial smooth muscle, with little effect on heart rate.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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.
Clinical Context: 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.
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.
Clinical Context: Ipratropium is an anticholinergic bronchodilator that is chemically related to atropine. It inhibits serous and seromucous gland secretions.
Clinical Context: 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 dilating narrowed airways and keeping them open for 24 hours. It is given once daily.
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.
Clinical Context: 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.
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.
Clinical Context: 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.
Clinical Context: Fluticasone may decrease the number and activity of inflammatory cells, in turn decreasing airway hyperresponsiveness. It also has vasoconstrictive activity.
Clinical Context: Mometasone reduces inflammation in airways by inhibiting multiple types of inflammatory cells and decreasing the production of cytokines and other mediators involved in bronchospasm.
Clinical Context: Methylprednisolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes (PMNs) and reversing increased capillary permeability.
Clinical Context: 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.
Clinical Context: Prednisolone may reduce inflammation by reversing increased capillary permeability and suppressing PMN activity and CD4 counts.
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.
Clinical Context: Flumazenil reverses the effects of benzodiazepines in an overdose by selectively antagonizing the gamma-aminobutyric acid (GABA)–benzodiazepine receptor complex. If an overdosed patient has not responded after 5 minutes of administration of flumazenil to a cumulative dose of 5 mg, the cause of the sedation is unlikely to be a benzodiazepine.
Flumazenil is a short-acting agent, with a half-life of 0.7-1.3 hours; however, because most benzodiazepines have longer half-lives, multiple doses should be administered so that patients do not relapse into a sedative state.
Benzodiazepine antagonists are used in reversing the CNS-depressing effects of benzodiazepine overdoses. However, these agents’ ability to reverse the benzodiazepine-induced respiratory depression is less predictable. Care must be taken in reversing the effects of benzodiazepines because patients may have seizures if benzodiazepine reversal is accomplished too vigorously.
Clinical Context: 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.
Clinical Context: 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.
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.