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Physiology of dyspnea

Physiology of dyspnea
Author:
Richard M Schwartzstein, MD
Section Editor:
Meredith C McCormack, MD, MHS
Deputy Editor:
Paul Dieffenbach, MD
Literature review current through: Dec 2022. | This topic last updated: Dec 09, 2022.

INTRODUCTION — Breathing discomfort is one of the most common and distressing symptoms experienced by patients. While there are no symptom-specific data about the prevalence of this problem in ambulatory patients, the epidemiology of cardiac and pulmonary diseases indicates that the magnitude of the problem is large. Cardiac disease is the leading cause of death in the United States, and individuals with angina or myocardial infarction often experience breathlessness as the major (and sometimes sole) indicator that they are ill [1]. In addition, asthma and chronic obstructive pulmonary disease (COPD) afflict approximately 34 million people in the United States, many of whom are unaware of their diagnosis, and they typically seek help from clinicians for relief of breathlessness [2,3]. Data from patients admitted to the hospital suggest that 16 percent of patients suffer from dyspnea within 24 hours of admission [4] and that the presence of dyspnea during the hospitalization is associated with a higher mortality [5].

The pathophysiology of dyspnea will be reviewed here. Factors affecting the control of ventilation and disorders of ventilation, and an approach to a patient with dyspnea, are presented separately. (See "Control of ventilation" and "Disorders of ventilatory control" and "Approach to the patient with dyspnea".)

DESCRIPTIONS OF DYSPNEA — Investigations of the descriptors used by patients, or the "language" of dyspnea, suggest that this symptom represents a number of qualitatively distinct sensations, and that the words utilized by patients to describe their breathing discomfort may provide insights into the underlying pathophysiology of the disease [6-9]. Furthermore, there is a growing recognition that one must distinguish between a "sensation" (the neural activation resulting from the stimulation of a receptor) and a "perception" (the reaction of the individual to that sensation) [10-12] and that healthcare providers are relatively poor at estimating the intensity of dyspnea by observing patients [13,14]. In addition, for a given intensity of a breathing sensation, the unpleasantness of the sensation may vary with the stimulus [15].

A consensus statement of the American Thoracic Society (ATS) has defined dyspnea as "a term used to characterize a subjective experience of breathing discomfort that comprises qualitatively distinct sensations that vary in intensity. The experience derives from interactions among multiple physiological, psychological, social, and environmental factors, and may induce secondary physiological and behavioral responses" [10].

The respiratory system is designed to maintain homeostasis with respect to gas exchange (adequate oxygenation) and the acid-base status of the organism (adjust arterial tension of carbon dioxide [PaCO2] to maintain normal pH). Derangements in oxygenation as well as acidemia lead to breathing discomfort. However, the development of dyspnea is a complex phenomenon which, in many patients, is the result of stimulation of a variety of mechanoreceptors throughout the upper airway, lungs, and chest wall, and which must also account for the sensations that arise when there is a mechanical load on the system (eg, increased airway resistance or decreased lung and/or chest wall compliance). Failure to achieve the expected flow of air into the lungs and/or displacement of the lungs and chest wall for a given output from respiratory centers (ie, the drive to breathe) may intensify dyspnea associated with many pathologic abnormalities. The origins of dyspnea associated with the inadequate delivery of oxygen to, or utilization by, peripheral muscles are less well understood, but are felt to be related to stimulation of metaboreceptors and deserve consideration as well.

INCREASED OUTPUT FROM THE RESPIRATORY CENTERS — Most conditions that are associated with respiratory discomfort are characterized by increases in ventilation in response to derangements in ventilation-perfusion matching, increases in dead space, the presence of metabolic acidosis, or stimulation of pulmonary or chest wall receptors. For many years it was believed that this increase in stimulation of the respiratory centers and the resultant augmentation of activity of the ventilatory muscles was responsible for dyspnea. However, subsequent data suggest that the intensity of respiratory discomfort for a given level of ventilation may vary considerably depending upon the nature of the stimulus giving rise to the hyperpnea, and that stimulation of chemoreceptors can produce dyspnea even in the absence of activation of the respiratory muscles (figure 1).

Chemoreceptors — The peripheral chemoreceptors, located in the carotid bodies and aortic arch, sense changes in the partial pressure of oxygen in arterial blood and are also stimulated by acidosis and hypercapnia. The central chemoreceptors, located in the medulla, respond to changes in pH and arterial tension of carbon dioxide (PaCO2). Acute hypercapnia is generally a much stronger stimulus for respiratory discomfort than is acute hypoxemia. (See "Control of ventilation".)

Acute hypercapnia — While acute hypercapnia typically leads to brisk increases in ventilation, dyspnea can result from hypercapnia among ventilator-dependent C1-2 quadriplegics who lack functioning respiratory muscles and in normal subjects paralyzed with neuromuscular blocking agents [16,17]. In a different experimental model, normal subjects maintaining a targeted ventilation experienced greater dyspnea when made hypercapnic than when eucapnic conditions were maintained [18]. These results are consistent with the notion that there are direct projections from the brainstem chemoreceptors to the sensory cortex, ie, there is a "corollary discharge" or neural discharge to the sensory cortex that is generated simultaneously with and in proportion to the brainstem neural output to the respiratory muscles [19].

Evidence that one can experience some form of dyspnea in the absence of functioning central chemoreceptors is provided by studies of individuals with congenital central hypoventilation syndrome [20]. Many of these individuals breathe relatively normally when awake but have cessation of breathing and respiratory arrest when they are asleep and must be maintained on mechanical ventilation while sleeping. Although they do not increase ventilation or become dyspneic with acute hypercapnia, exercise hyperpnea and breathing discomfort with exercise persist. (See 'Impaired oxygen delivery or utilization' below.)

Acute hypoxemia — Acute hypoxemia is also associated with increases in ventilation and respiratory discomfort. While the data supporting a direct role for hypoxic stimulation of chemoreceptors in the production of dyspnea are less clear than with hypercapnia, it seems likely that hypoxemia can produce breathing discomfort independently of changes in ventilation. As examples:

Subjects exercising under hypoxic conditions experience more dyspnea than when performing the same activity while breathing room air, and less dyspnea when breathing 100 percent oxygen [21].

Similar results have been obtained in patients with chronic obstructive pulmonary disease (COPD) who exercise with varying degrees of hypoxia [22].

Progressive hypoxemia in normal subjects is associated with greater breathing discomfort than comparable degrees of ventilation resulting from exercise [23], demonstrating an effect of hypoxemia on dyspnea that is independent of minute ventilation.

Nonetheless, hypoxemia alone or in the setting of minimal underlying cardiopulmonary abnormalities is a relatively weak stimulus for dyspnea, particularly if compensatory hyperventilation with resulting hypocapnia ensues; misunderstanding of this phenomenon may explain the notion of the "happy hypoxemic" patient with mild coronavirus disease 2019 (COVID-19) [24]. Consequently, it is common that patients with hypoxemia and severe lung disease may experience little improvement of dyspnea despite administration of supplemental oxygen.

STIMULATION OF MECHANORECEPTORS — Throughout the airways, lungs, and chest wall are a variety of receptors that assist the body in monitoring changes in pressure, flow, and volume in the respiratory system. Information from these receptors is integrated by the central nervous system in a manner that modulates the intensity of dyspnea. However, in some cases, most notably the "chest tightness" associated with bronchoconstriction, the receptors may be the primary source of the sensation [25,26].

Upper airway receptors — Stimulation of receptors in the face and upper airway, which are largely innervated by the trigeminal nerve, can reduce the intensity of dyspnea. As examples, cold air directed against the face increases breathholding time and reduces the respiratory discomfort associated with breathing against an inspiratory load [27,28]. Presumed stimulation of flow or temperature receptors by the inhalation of cold air reduces exertional dyspnea and ventilation in patients with chronic obstructive pulmonary disease (COPD), while reductions in upper airway receptor stimulation achieved with topical lidocaine or by the inhalation of warm, humidified air worsen respiratory discomfort in normal subjects [29,30]. High-flow nasal oxygen has been shown to reduce dyspnea to a greater degree than standard supplemental oxygen therapy [31], presumably because of greater stimulation of nasal receptors.

Pulmonary receptors — The lung is populated by three major categories of receptors that transmit information relevant to respiratory sensation to the central nervous system via the vagus nerve:

Slowly adapting receptors, also known as pulmonary stretch receptors, are activated by an increase in tension in the walls of airways, thereby providing information about increases in lung volume.

Rapidly adapting receptors or irritant receptors are stimulated by rapid changes in lung volume, direct mechanical stimuli, or inhalation of irritant particulate matter or chemicals such as histamine.

C-fibers are unmyelinated afferent nerve fibers that originate in J-receptors located in small airways and near alveolar capillaries; they are stimulated by mechanical and chemical factors.

The configuration of these receptors is such that limitations of the movement of the respiratory system exacerbate dyspnea in a variety of experimental conditions, including breathholding and acute hypercapnia [32-34]. Restriction of tidal volume associated with hyperinflation may also contribute to the discomfort experienced by patients with emphysema [35] and by mechanically ventilated patients receiving low tidal volumes [36].

Inhaled furosemide is hypothesized to stimulate pulmonary stretch receptors. It has been shown to reduce dyspnea in healthy subjects in whom dyspnea was induced using a large resistive load plus hypercapnia [37]. Similarly, dyspnea associated with acute hypercapnia and a restricted tidal volume, as well as the breathlessness associated with exercise, is ameliorated by inhaled furosemide [38,39]. More controlled administration of inhaled furosemide with a similar model of producing dyspnea with hypercapnia and restricted tidal volume, however, resulted in a highly variable response among individuals and group differences compared with placebo are not significant [40,41].

Stimulation of pulmonary receptors may provoke the dyspnea of asthma. While the work of breathing is increased in patients with acute bronchoconstriction due to changes in airways resistance and hyperinflation, the intensity of dyspnea is greater with acute bronchoconstriction than with external resistive loads at comparable degrees of airway resistance [25,26], and the quality of the discomfort is different [6,7,25,26,42]. Breathing against an external load leads to a sensation of increased "effort" or "work" of breathing, while acute bronchospasm is associated with a sensation of "chest tightness or constriction." Furthermore, the inhalation of lidocaine appears to blunt the dyspnea of bronchoconstriction, consistent with the hypothesis that stimulation of pulmonary receptors is contributing to the breathing discomfort [25]. Activation of pulmonary receptors may also play a role in the dyspnea of acute pulmonary embolism [43].

Chest wall receptors — Information from muscle spindles and tendon organs within the chest wall is also important to the perception of dyspnea. Muscle spindles function as length or stretch receptors, while tendon organs monitor force generation. As noted above, constrained chest wall movement exacerbates dyspnea associated with acute hypercapnia, although the relative roles of pulmonary and chest wall receptors are difficult to ascertain [33,34].

Investigators have studied the importance of chest wall receptors on dyspnea by applying mechanical vibrators to the intercostal space, resulting in stimulation of muscle spindles. In-phase vibration, ie, vibration applied to the inspiratory muscles during inspiration, reduces dyspnea in normal subjects made breathless with hypercapnia and an external resistive load [44]. Similar results were obtained in patients with COPD at rest [45] and while breathing carbon dioxide [46], although vibration appeared to have little effect at higher degrees of discomfort associated with exercise on a cycle ergometer [46]. Timing of the stimulation also appears to be important because out-of-phase vibration, ie, vibration of inspiratory muscles during expiration, heightens the intensity of dyspnea [47]. It is important to note that the vibration used in these studies might also have stimulated pulmonary receptors.

While stimulation of chest wall receptors likely plays a role in the detection of changes in thoracic expansion, pulmonary receptors are sufficient to monitor lung volume. Patients with cervical spinal cord injury, for example, in whom information from chest wall receptors is interrupted before reaching the brain, can detect small changes in tidal volume and experience respiratory discomfort when tidal volumes are reduced [48,49].

MECHANICAL LOADING OF THE RESPIRATORY SYSTEM — A wide variety of cardiopulmonary diseases are associated with an increased mechanical load due to changes in airways resistance (eg, asthma, chronic obstructive pulmonary disease [COPD]) or pulmonary or chest wall compliance (eg, idiopathic pulmonary fibrosis, kyphoscoliosis). To achieve a given tidal volume under these conditions, the brain must generate a greater neural output to the ventilatory muscles [50].

Outgoing motor commands to the ventilatory muscles probably are associated with a corollary discharge to the sensory cortex, which is perceived as a "sense of effort" [51]. The sense of effort appears to be a function of the ratio of the pressure generated by the ventilatory muscles on a given breath to the maximal pressure achievable by the muscles [52]. Thus, the sense of effort may increase because there is an obstruction to flow and the intrathoracic pressure generated on each breath is high, or because the pressure-generating capacity of the muscles is reduced, as is seen in the presence of muscle fatigue, myopathy, or hyperinflation.

Normal subjects maintaining a constant ventilatory target experience less effort but more dyspnea when hypercapnic than eucapnic [18], suggesting that ventilation arising from "automatic" or reflexive mechanisms (ie, stimulation of chemoreceptors by hypercapnia) results in a lesser sense of effort than voluntary increases in ventilation. While mechanical loading and the effort to breathe are common features of dyspnea in many disease states, they do not explain respiratory discomfort in all settings.

NEUROMECHANICAL DISSOCIATION — Efferent neural impulses exit the brain and proceed to the ventilatory muscles, where they trigger contraction, generation of negative pressure within the thorax, and inspiratory air flow with expansion of the lungs and chest wall. If there is a mechanical load suddenly imposed on the respiratory system with no change in the neurologic command to the ventilatory muscles, the muscles will not shorten appropriately for the tension being generated, intrathoracic pressures will be less negative than normal, inspiratory flow will be reduced, and tidal volume will be diminished.

Although the exact means by which the body makes the comparison between what is expected under normal conditions for a given efferent message and the actual outcome of that message remains unclear, the mismatch between the two (termed "efferent-reafferent dissociation" [53] or "neuromechanical dissociation" [54]) appears to worsen the intensity of dyspnea. This mechanism may in part explain the dyspnea associated with experimentally constrained ventilation [33,34], hyperinflation in COPD [35,54,55], hyperinflation in asthma [56], and in some patients on mechanical ventilators [36,57], particularly those receiving low tidal volume ventilation as a strategy to avoid acute lung injury. It may also explain the amelioration of dyspnea with chest wall vibration [44-46] or a flow of air on the face [28].

In these last two examples, receptors in the chest wall and in the distribution of the trigeminal nerve are stimulated exogenously. It is believed that such stimulation, by conveying to the brain information that would indicate the respiratory system had achieved greater flows or volume displacement than actually had occurred, would lead to reduced discrepancy between the efferent neural command and the "apparent" mechanical response, thereby diminishing the intensity of dyspnea.

With the advent of low tidal volume ventilation for patients with acute respiratory distress syndrome [58], there is increasing concern about the dyspnea that may accompany this treatment strategy. The contribution of restricted tidal volume and associated dyspnea to the development of emotional problems, including posttraumatic stress disorder, in patients surviving acute respiratory failure has been postulated as a concern during the coronavirus disease 2019 (COVID-19) pandemic [59].

IMPAIRED OXYGEN DELIVERY OR UTILIZATION — Anemia and cardiovascular deconditioning are two common clinical conditions that are associated with exertional dyspnea and do not readily fit into the categories outlined above.

Anemia — Patients with moderate to severe anemia typically experience breathing discomfort with light exercise despite the absence of a gas exchange abnormality or mechanical loading of the respiratory system. The response of the body to the reduced oxygen-carrying capacity of the blood is to increase cardiac output. This may necessitate an increase in left ventricular end-diastolic pressure with consequent increases in pulmonary venous pressures, the development of interstitial edema, and stimulation of C-fibers. However, tachycardia, rather than increased stroke volume, is often the first response of the cardiovascular system, and it is unclear to what extent intracardiac and pulmonary vascular pressures rise in this setting.

An alternative explanation is that the reduced delivery of oxygen to the metabolically active muscles may lead to the development of a localized metabolic acidosis and the stimulation of "ergoreceptors" or "metaboreceptors" in the peripheral muscles [60,61]. Another possibility is that the ventilatory muscles are impaired by inadequate oxygen delivery during exercise, which could lead to muscle fatigue under conditions of sustained hyperpnea.

Deconditioning — An individual's fitness is determined by the ability of the cardiovascular system to deliver oxygenated blood to the muscles and by the capability of the muscles to utilize that oxygen via aerobic metabolism to engage in mechanical work. Exercise programs improve fitness by training the heart to generate a greater cardiac output and by inducing capillary growth and enzyme changes in skeletal muscle to improve the delivery of oxygen and efficiency of oxygen use. (See "Exercise physiology".)

Many patients with chronic lung disease assume a sedentary lifestyle and become deconditioned; functional capabilities may be determined more by their level of fitness than by their underlying respiratory illness [62]. Dyspnea on exertion in these individuals may result primarily from reliance on anaerobic metabolism at low levels of exercise, development of a metabolic acidosis, and increased neural output from the respiratory centers. Whether the development of localized acidosis and stimulation of ergoreceptors also play a role in this situation remains uncertain. In addition, for some patients with chronic diseases that impair their functional capacity leading to a very limited lifestyle, normal increases in ventilation with exercise may be perceived as pathologic, ie, they become sensitized to dyspneic stimuli.

NEURAL ACTIVATION ASSOCIATED WITH BREATHING DISCOMFORT — Investigators have begun to employ positron emission tomography and magnetic resonance imaging as tools to localize regions of the brain that are activated when breathing discomfort is induced experimentally. Acute hypercapnia [63], restriction of tidal volume [64], and imposition of external resistive loads [65,66] have all led to activation of areas within the limbic system and, to a lesser degree, within the brainstem. These areas of the brain also are likely to be involved in the perception of uncomfortable sensations such as pain and hunger. Whether future studies utilizing this technique will identify clearly delineated neural pathways for different types of dyspnea remains to be seen.

The affective dimension of dyspnea — There is growing evidence that the emotional response to a stimulus that produces dyspnea varies and may be responsible, in part, for the different experiences and reports of the severity of dyspnea by patients [15,67,68]. Higher degrees of dyspnea-related fear in patients with chronic obstructive pulmonary disease (COPD) may predict salutary response to pulmonary rehabilitation programs, which emphasize reassurance that the sensation of dyspnea with a particular activity is not harmful [69]. For the same degree of sensory discomfort, air hunger results in greater fear and anxiety than increased work of breathing [15].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dyspnea".)

SUMMARY

Descriptions of dyspnea – Breathing discomfort is a complex set of sensations which clinicians group under the term dyspnea. The physiologic mechanisms underlying these sensations are varied, and multiple mechanisms may be present in a given patient (figure 1). (See 'Descriptions of dyspnea' above.)

Common mechanisms of dyspnea – Most conditions that are associated with respiratory discomfort are characterized by increases in ventilation in response to derangements in ventilation-perfusion matching, increases in dead space, the presence of metabolic acidosis, or stimulation of pulmonary or chest wall receptors. (See 'Increased output from the respiratory centers' above.)

While mechanical loading and the effort to breathe are common features of dyspnea in many disease states, they do not completely explain respiratory discomfort in all settings; stimulation of receptors throughout the respiratory system, changes in oxygen delivery to tissues, and arterial tensions of oxygen and carbon dioxide also contribute. (See 'Increased output from the respiratory centers' above and 'Impaired oxygen delivery or utilization' above.)

Respiratory system efferents

Chemoreceptors – The peripheral chemoreceptors, located in the carotid bodies and aortic arch, sense changes in the partial pressure of oxygen in arterial blood and are also stimulated by acidosis and hypercapnia. The central chemoreceptors, located in the medulla, respond to changes in pH and arterial tension of carbon dioxide (PaCO2). (See 'Chemoreceptors' above.)

Mechanoreceptors – A variety of mechanoreceptors that assist the body in monitoring changes in pressure, flow, and volume in the respiratory system are located in the airways, lungs, and chest wall. Airway mechanoreceptors may be the primary source of the sensation of "chest tightness" associated with bronchoconstriction. (See 'Stimulation of mechanoreceptors' above.)

A wide variety of cardiopulmonary diseases are associated with an increased mechanical load due to changes in airways resistance (eg, asthma, chronic obstructive pulmonary disease [COPD]) or pulmonary or chest wall compliance (eg, idiopathic pulmonary fibrosis, kyphoscoliosis). (See 'Stimulation of mechanoreceptors' above.)

Neuromechanical dissociation – A mismatch between what is "expected" under normal conditions for a given efferent message to the respiratory muscles and the actual outcome of that message (eg, increased tidal volume, flow, and ventilation) may contribute to the sensation of dyspnea and is called "efferent-reafferent dissociation" or "neuromechanical dissociation." The exact means by which the body makes the comparison between the expected and actual outcome of a neural message to the respiratory muscles remains unclear. (See 'Neuromechanical dissociation' above.)

Multifactorial dyspnea – The sensation of dyspnea is often due to a combination of multiple factors. Individuals with COPD, for example, may experience breathlessness because of hypoxemia (increased neural input from peripheral chemoreceptors and output from the respiratory centers), increased airways resistance and hyperinflation (mechanical loading), and neuromechanical dissociation (associated with dynamic hyperinflation). In the presence of an acute respiratory infection or volume overload, stimulation of pulmonary receptors may also play a role.

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Topic 1427 Version 16.0

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