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