Sensory Receptors

Activation of sensory receptors provides afferent information to several brain areas that are perceived as respiratory sensations. Blood gas abnormalities (hypoxemia and hypercapnia), mechanical respiratory loads (increased airway resistance and elastance), disturbances in airway epithelium (e.g., edema, inflammation), and hyperinflation are stimuli that activate sensory receptors. For example, neurons in the carotid bodies (peripheral chemoreceptors) are more sensitive to arterial hypoxemia than are neurons in the aortic bodies, although both contribute to hypoxemic ventilatory responsiveness. Central chemoreceptors located in the ventral medulla respond to changes in bloodstream H⁺-CO₂ equilibrium.

Mechanoreceptors are distributed throughout the lung and the chest wall. Parenchymal stretch receptors transmit information about airway caliber and lung volume to the somatosensory cortex through unmyelinated vagal nerve fibers. C-fibers relay information about airway irritation, which can be demonstrated using various chemical mediators. J-fibers are stimulated by interstitial pressure increases, especially pulmonary edema. The chest wall muscles are innervated by Golgi tendon organs and spindle fibers that project to anterior horn cells of spinal neurons. These structures transduce information on length-tension and spatial relationships to the somatosensory cortex.

Afferent Impulses

Afferent information from sensory receptors are transmitted to brain stem respiratory centers that automatically adjust breathing and also may project to higher brain areas for direct assessment of the status of various stimuli. Well-characterized examples include the following: The glossopharyngeal nerve transmits impulses for peripheral chemoreceptors; the vagus nerve transmits information for rapidly adapting, slowly adapting, and C-fiber lung mechanoreceptors; and cervical spinal nerves 3 to 5 (C3 to C5) transmit sensory information accrued by mechanoreceptors from the diaphragm.

Two different pathways have been proposed to process respiratory sensations to the cerebral cortex. One pathway reflects discriminative processing—that is, awareness of the spatial, temporal, and intensity components (e.g., how bad is it?). With activation of respiratory muscle receptors, afferent information is relayed into the brain stem medulla and is then projected to the ventroposterior thalamus area; from here, projections ascend to the primary and secondary somatosensory cortex. These structures are thought to process the intensity component of dyspnea.

A second pathway reflects affective processing (e.g., how does it feel?). With activation of airway and lung receptors, afferent information is relayed by the vagal nerve to the brain stem medulla and is then projected to the amygdala and medial dorsal areas of the thalamus; from here, projections ascend to the insular and cingulate cortex. These structures are part of the limbic system, which forms the inner border of the cortex and contains rich interconnections among the cerebral cortex, thalamus, and brain stem, and are thought to process the affective component of dyspnea.

Central Nervous System

The central nervous system integrates and processes the sensory information into a combined output carried by the phrenic nerve to the respiratory muscles. Neuroimaging studies demonstrate that the anterior cingulate cortex, amygdala, and thalamus are consistently activated in response to various respiratory perturbations. Activation of cortical neural processes appears to require a gating mechanism that can receive changes in respiratory afferent neural activity and distribute this sensory information to specific cortical areas for cognitive processing. It is believed that the thalamus and hippocampus are critical neural areas for the gating of respiratory sensory input to the cerebral cortex.

The experience of dyspnea is thought to result from a mismatch between incoming afferent information (from one or more activated sensory receptors) and the outgoing central respiratory motor activity.

Neuromodulation by Endogenous Opioids

Endogenous opioids and their receptors are expressed broadly throughout the peripheral and central nervous systems, as well as the respiratory system. Beta-endorphins are one of five groups of naturally occurring opioid peptides that modulate pain and dyspnea. In response to noxious and stressful stimuli, the pituitary gland releases beta-endorphins into the circulation, whereas the brain elaborates endogenous opioids into the cerebrospinal fluid.

Naloxone, an opioid antagonist that readily crosses the blood-brain barrier, has been used to uncover the putative effects of endogenous opioids on modulating dyspnea. Studies using methacholine-induced bronchoconstriction, high-intensity treadmill exercise, and inspiratory resistive breathing (as stimuli to provoke breathlessness) have shown that patients with asthma or COPD report higher ratings of dyspnea after receiving naloxone than after receiving normal saline. These observations support the role of endogenous opioids as neuromodulators of the perception of dyspnea.

Initial Evaluation

The rapidity with which dyspnea develops is clinically important. Although a standard definition of acute dyspnea does not exist, potentially life-threatening cardiopulmonary processes often are heralded by unprecedented, severe dyspnea minutes to hours in duration. Whenever possible, details should be sought about the circumstances under which dyspnea began, whether it is associated with other symptoms, and how it has progressed. Knowledge of medications and comorbid conditions also is helpful. Dyspnea in the prehospital environment independently predicts a nearly seven-fold likelihood of hospital admission from the emergency department. Studies have shown that delays in seeking clinical attention for acute exacerbations of asthma, COPD, and congestive heart failure (CHF) are associated with a higher frequency of hospital admissions and worse outcomes.

With any clinical encounter, the focus of the initial assessment is on whether or not the patient is stable (Figure 19-3). If this evaluation reveals evidence of hemodynamic insult or lability, hypotension may need to be treated promptly with intravenous fluids, vasopressors, and/or vasodilators. Airway patency and adequacy may be threatened by a depressed level of consciousness, aspiration, or trauma. Endotracheal intubation may become necessary in such instances and when gas exchange derangements cannot be rectified by supplemental oxygen or noninvasive positive-pressure ventilation. Once these basic support elements are addressed, diagnostic testing can safely proceed.

Figure 19-3 Initial evaluation of acute dyspnea.

Differential Diagnosis

One approach to the differential diagnosis for acute dyspnea is to consider how processes in certain anatomic regions contribute to this symptom (Table 19-1). Obstruction is the most common mechanism for dyspnea arising from upper airway problems. Stridor, a variably high-pitched, harsh inspiratory noise caused by turbulent airflow, often can be heard in the context of an aspirated foreign body and edema of the epiglottis and laryngeal soft tissues. Prompt evaluation and management of upper airway blockage are critical, because the airway is endangered. Exacerbations of asthma and COPD typically are manifested as bronchospasm, wheeze, and cough. Sputum production is common to exacerbations of COPD associated with acute bronchitis and pneumonia, but its physical characteristics alone are not useful in predicting a causative pathogen. Pleuritic chest pain is sharp, incisive, breath-taking discomfort caused by irritation of the parietal pleural nerve supply along the thoracic cavity. This type of pain can accompany pulmonary embolism, pneumonia with or without pleural effusion, and pneumothorax.

In an acute coronary syndrome (ACS) or CHF, dyspnea is caused by pulmonary venous hypertension and interstitial fluid accumulation. Sudden dyspnea without chest discomfort is the presenting feature of myocardial infarction in 4% to 14% of events. Papillary muscle rupture with mitral valve incompetence, florid pulmonary edema, and shock complicates myocardial infarction in approximately 7% of affected patients. Neuromuscular diseases more commonly cause chronic, progressive dyspnea, but ventilatory failure can develop over just a few hours in acute idiopathic demyelinating polyneuropathy (AIDP). Dyspnea is a frequent consequence of severe abdominal distention, such as that seen with bowel obstruction. The increased pressure of the abdominal cavity restricts diaphragm excursion, thereby decreasing functional residual capacity. Abdominal pain restricts ventilation as a consequence of muscle splinting, which also can cause atelectasis.

Physical Examination

Inspection of the patient in respiratory distress may be quite revealing. Stigmata of adrenergic excess commonly are present, including hypervigilance, diaphoresis, and tachycardia. The breathing pattern frequently is rapid and shallow, which foreshortens responses to clinical questioning. An exception is the deep and sometimes bradypneic pattern of Kussmaul respirations seen with severe metabolic acidosis, typical of diabetic ketoacidosis. Engagement of accessory inspiratory muscles (e.g., scalenes, intercostals, and sternocleidomastoids) often signals respiratory failure. This finding alone is associated with a nearly three-fold risk of death and a roughly doubled requirement for posthospital care in patients admitted through the emergency department for COPD exacerbation. Among adult asthmatics who were noted to use accessory breathing muscles at the time of hospitalization, percent-predicted FEV₁ values were lower than in patients who were not activating these muscles. Pursed-lip breathing (exhaling against partially occluded lips) can be seen in persons with airflow obstruction. In patients with moderate to severe COPD, pursed-lip breathing facilitates the recruitment of accessory muscles, decreases the electromyographic propensity for diaphragm fatigue, and improves tidal volume and arterial oxyhemoglobin saturation. Dyspnea observed in the context of altered mental status and cyanosis is worrisome, because taken together, these findings attest to profound gas exchange problems.

Biomarkers

Thoracic Imaging

Treatment

Further details on the treatment of acute dyspnea caused by the aforementioned processes are presented elsewhere in this book. Two interventions, oxygen therapy and noninvasive positive-pressure ventilation (NIPPV), merit a brief discussion here because of their application to several of these processes. Table 19-2 presents a list of processes that cause acute dyspnea and their specific therapies.

Table 19-2 Specific Therapies for Acute Dyspnea by Etiologic Condition

COPD, chronic obstructive pulmonary disease; MDI, metered dose inhaler.

Differential Diagnosis

Causes of chronic dyspnea are listed in Table 19-3. Conditions such as COPD and CHF (see Table 19-1) may have both acute and chronic phases. Relatively few studies have tried to identify those diseases that most commonly underlie chronic dyspnea in the outpatient setting. A prospective evaluation of 85 patients at a university-based pulmonary clinic showed that asthma (29%), COPD (14%), interstitial lung disease (14%), and cardiomyopathy (10%) explained two thirds of cases. Although the study investigators emphasized a rational diagnostic approach that incorporated the responses to disease-specific therapies, an average of 6.2 tests were conducted per patient, and no participants had pulmonary vascular disease or muscle weakness. Another investigation of 72 consecutive patients with chronic dyspnea and unrevealing history, physical examination, chest radiograph, and spirometry data found that 36% had pulmonary disease, 14% had cardiac disease, and 19% had primary hyperventilation. Only 3% had an extrathoracic reason for their breathlessness.

Table 19-3 Differential Diagnosis of Chronic Dyspnea

ANCA, antineutrophil cytoplasmic antibodies; COPD, chronic obstructive pulmonary disease.

Dyspnea often affects patients without obvious heart or lung disease; therefore, the clinician must consider various etiologic conditions. Some of these processes, listed in Table 19-3, warrant further discussion, because dyspnea could be overlooked as a presenting symptom. Moderate to severe anemia can limit tissue oxygen delivery but does not lead to oxyhemoglobin desaturation. Thus, the mechanism by which a low hemoglobin concentration provokes dyspnea probably is related to impaired muscle energetics and a compensatory increase in ventilation and cardiac output. Patients with many forms of advanced cancer indeed experience significant, albeit temporary, dyspnea relief from blood transfusions and erythropoietic growth factor support. Respiratory muscle weakness has been implicated as the cause of chronic dyspnea in patients with hypothyroidism and thyrotoxicosis, on the basis of responses to specific medical therapy. Limited data are available regarding the prevalence of dyspnea among patients with selected neuromuscular diseases. Roughly 40% of patients with amyotrophic lateral sclerosis, 23% of patients with post-poliomyelitis, and 12% of patients with multiple sclerosis complain of dyspnea. Both weight gain and a sedentary lifestyle are common causes of exertional dyspnea in those residing in developed countries.

Medical History

Processes that cause chronic breathlessness are likely to have evolved to some extent before a patient presents for evaluation. Accordingly, it is incumbent on the clinician to ask about the ways in which the patient’s dyspnea has changed. Questions might focus on how frequently dyspnea occurs, how long each episode lasts, how intense each episode is, and defining factors that both trigger and relieve it. Eliciting which activities of daily living provoke dyspnea can facilitate longitudinal assessment. This determination also sheds light on whether the patient is modifying behaviors as dyspnea worsens. Unless the clinician specifically asks about activities that the patient has stopped because of breathing difficulty, it can appear that breathlessness only modestly affects that patient’s functional status. Perspectives on the patient’s dyspnea from spouses, relatives, and friends frequently are useful and should be sought.

As discussed earlier, the correct diagnosis may be suggested by patient-selected descriptors of dyspnea, but it also can be substantiated by the presence or absence of associated symptoms. For example, asthmatic persons generally experience episodes of wheezing, chest tightness, and dyspnea with or without antecedent exposure to a discrete trigger such as an aeroallergen or cold air. A report of wheezing is nonspecific for asthma, however, because it can signify COPD, upper airway obstruction, or CHF. Many asthmatics also cough during bronchospasm periods, but asthma explains a chronic cough only about 25% of the time. The elderly asthmatic patient may describe exertional dyspnea and no other respiratory symptoms—a possible correlate of nonreversible airflow obstruction.

Paroxysmal nocturnal dyspnea and orthopnea may suggest CHF. A systematic review of studies investigating emergency department diagnosis of CHF found that a history of paroxysmal nocturnal dyspnea increased the pretest probability of CHF in the dyspneic patient by a factor of 2.6. Data from the Cardiovascular Health Study suggest that orthopnea and paroxysmal nocturnal dyspnea are relatively specific (87.5% and 89.8%, respectively) but somewhat insensitive (42.8% and 37.6%, respectively) indicators of CHF. Orthopnea also may be due to respiratory muscle weakness and abdominal “loading,” as with ascites and obesity.

Physical Examination

A focused physical examination frequently yields sufficient clues about the origin of chronic breathlessness. The investigation should begin with an appraisal of the patient’s voice. Someone with “breathy” dysphonia whose voice tends to wane during prolonged speech could have vocal cord dysfunction. In the setting of chronic dyspnea, stridor most commonly is caused by the development of benign or malignant lesions or focal stenoses. The diagnostic utility of jugular venous pressure elevation for detection of decompensated CHF has been extensively studied. The sensitivity and specificity of this finding for high pulmonary capillary occlusion pressure (i.e., pulmonary venous hypertension) are 70% and 79%, respectively. The jugular venous pressure can be difficult to measure in persons with an obese habitus and can be elevated as a consequence of pulmonary arterial hypertension, tricuspid regurgitation, pericardial constriction, or occlusion of the superior vena cava. Examination of the neck also should involve palpation for thyroidomegaly and lymphadenopathy, because dyspnea can result from tracheal compression.

Inspection of the spine and thorax can provide a clear reason for why a patient experiences persistent dyspnea. Severe kyphosis reduces total lung capacity, limits alveolar ventilation, and eventually impairs gas exchange. The anteroposterior dimension of the thorax can be exaggerated in patients with COPD, but this adaptation to lung hyperinflation lacks sensitivity for this diagnosis. Central adiposity in the morbidly obese patient reduces functional residual capacity (FRC) and reserve volume, thereby increasing resistance to airflow and decreasing lung compliance. Collapse of small peripheral airways in the lung bases of obese patients can lead to ventilation-perfusion mismatch and breathlessness.

Crackles on lung auscultation can reflect several pathologic processes, all of which should be considered along with other aspects of the examination. The negative predictive value of crackles for interstitial lung disease and CHF has been reported as 98% and 89%, respectively, indicating that a majority of patients without crackles will not have these conditions. The sensitivity of crackles for CHF can be as low as 29%, even when echocardiography is used to affirm or refute presence of left ventricular dysfunction. In one study of 57 patients with pleural effusions, 49 of whom were dyspneic, dullness to percussion and decreased breath sounds were individually more suggestive of pleural fluid than crackles. Wheezes similarly are useful in diagnosing asthma and COPD, but their absence cannot exclude airflow obstruction. Emphysema is suggested by diminished breath sounds in the upper lung fields, sometimes associated with indistinct heart tones. The S3 gallop on heart auscultation is highly specific for elevated left ventricular end-diastolic pressure.

Diagnostic Testing

Details from the history and physical examination should inform the selection of diagnostic tests that further refine decision-making. One approach involves categorizing these modalities according to their ability to investigate relevant anatomy and physiology (Table 19-4). Various guidelines on management of COPD recommend that the diagnosis be determined by a value of 70% or less for the ratio of postbronchodilator forced expiratory volume in 1 second (FEV₁) to forced vital capacity (FVC). However, the FEV₁/FVC ratio declines with aging, and the use of a “fixed” ratio may lead to overdiagnosis of COPD among patients older than 60 years of age. We concur with the American Thoracic Society–European Respiratory Society recommendation that airflow obstruction be diagnosed by a FEV₁/FVC value below the lower limit of normal for the specific patient.

Table 19-4 Diagnostic Testing for Chronic Dyspnea

A low FVC may be due to air trapping in a patient with airflow obstruction or may point to a restrictive lung process that can be confirmed by measurement of lung volumes. Analysis of the flow-volume loop can demonstrate evidence of upper airway obstruction (Figure 19-4). In cases of suspected asthma, a negative result on direct bronchoprovocation testing essentially rules out this diagnosis. However, false-positive results can be seen in normal persons as well as those with sarcoidosis or vocal cord dysfunction. Measurement of maximal inspiratory mouth pressure is sensitive for detection of respiratory muscle weakness.

Figure 19-4 Flow-volume loop and spirometry data for a patient with intrathoracic upper airway obstruction. Note plateau of expiratory flow.

Many cardiac causes of chronic breathlessness can be identified by echocardiography. In addition to quantifying left ventricular systolic function, this procedure provides information about peak systolic pulmonary artery pressure, pericardial structure, and valvular function. Intravenous administration of agitated saline solution coupled with echocardiography (i.e., contrast echocardiography) is more than 98% sensitive for detecting pulmonary arteriovenous malformations. In a study of nearly 18,000 patients without established coronary artery disease who were referred for radionuclide myocardial perfusion testing, evidence of inducible ischemia was similar for patients with self-reported dyspnea and for those with typical angina pectoris, prompting the investigators to conclude that a more systematic appraisal of dyspnea should occur at the time of stress testing referral.

The etiology of chronic dyspnea will sometimes remain elusive despite a careful history and physical examination and multiple diagnostic endeavors. Then, cardiopulmonary exercise testing should be considered to provoke the patient’s dyspnea with comprehensive assessment of the oxygen transport system on an integrated level. Pulmonary gas exchange, cardiac function, and metabolic activity can be measured noninvasively (Table 19-5). Patients also are asked to rate dyspnea and leg discomfort throughout the exercise test. The results of cardiopulmonary exercise testing usually are able to distinguish cardiac dysfunction and ventilatory limitation but cannot always discriminate between cardiac disease and deconditioning.

Treatment

Disease-specific therapies generally are successful in mitigating chronic dyspnea, although this may not be the case with multiple concurrent processes or disease progression. Dyspnea is a prominent feature of CHF, yet most studies of various interventions for CHF consider death or utilization of health care resources as outcome metrics. Good-quality evidence supports exercise training to improve functional status in patients with CHF. Diuretics, inotropes, and vasodilators are mainstays of a management strategy of regulating volume status and controlling symptoms in CHF.

For patients with COPD, the combination of an inhaled corticosteroid and a long-acting β-agonist has been shown to improve lung function, relieve respiratory symptoms, and modestly reduce risk of death. Large trials of inhaled long-acting anticholinergic drugs also show a positive impact on dyspnea associated with COPD. Supplemental oxygen is indicated for patients with COPD who have resting hypoxemia, although its effect on mortality and symptoms in patients who display only exertional oxyhemoglobin desaturation is currently being investigated. Specific criteria to select patients with emphysema who could benefit from lung volume reduction surgery are well established. Pulmonary rehabilitation has been shown to have multiple benefits, including decreasing the severity of dyspnea, enhancing exercise tolerance, reducing the frequency of exacerbations, and improving quality of life. Interstitial lung disease is a broad category of infiltrative pulmonary disorders for which disease-modifying and symptom-relieving treatments are needed.