on 14-Mar-2021 (Sun)

A consensus statement of the American Thoracic Society defines dyspnea in the following way [1]:

"Dyspnea is a term used to characterize a subjective experience of breathing discomfort that is comprised of 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."

Dyspnea is considered acute when it develops over hours to days and chronic when it occurs for more than four to eight weeks.

Most patients with breathing discomfort can be categorized into one of two groups: respiratory system dyspnea or cardiovascular system dyspnea. Respiratory system dyspnea includes discomfort related to disorders of the central controller, the ventilatory pump, and the gas exchanger (table 1), while cardiovascular system dyspnea includes cardiac diseases (eg, acute ischemia, systolic dysfunction, valvular disorders, pericardial diseases), anemia, and deconditioning (figure 1)

Factors that stimulate the respiratory centers in the brainstem lead to increased ventilation and breathing discomfort in a variety of settings; these often are secondary to derangements in other parts of the system, such as hypoxia or hypercapnia due to ventilation/perfusion mismatching in the gas exchanger, or stimulation of pulmonary receptors as occurs with interstitial inflammation or edema

In addition, drugs such as aspirin (at a toxic dose) or progesterone and conditions such as pregnancy or diabetic ketoacidosis can produce dyspnea through central effects independent of problems in the ventilatory pump or gas exchanger.

Typically, dyspnea associated with stimulation of the respiratory controller is described as a sensation of "air hunger" or an "urge or need to breathe" [2-4]

To some degree, the breathing pattern may also reflect what are presumed to be attempts by the controller to reduce breathing discomfort. Thus, patients with severe airflow obstruction generally adapt a relatively slow, deep breathing pattern to minimize the pleural pressures needed to overcome airways resistance. Alternatively, patients with interstitial fibrosis or kyphoscoliosis and reduced lung or chest wall compliance have a characteristic rapid, shallow breathing pattern which minimizes the work needed to expand the thorax

When the respiratory controller is stimulated (eg, by exercise), airflow obstruction may heighten the sensation of air hunger. The increase in respiratory rate during exercise in the setting of expiratory flow limitation can lead to exercise-induced air-trapping, a process known as dynamic hyperinflation. Dynamic hyperinflation is associated with a reduced inspiratory reserve and increased dyspnea. For those in whom hyperinflation is substantial, such that inspiratory capacity at rest or during exercise is limited by total lung capacity, dyspnea is further exacerbated, and patients may also complain of an inability to get a deep breath.

For patients with restrictive lung disease, the adoption of breathing patterns with either an increase or decrease in tidal volume from their average resting tidal volume results in increased dyspnea [5]. Breathing with a rapid, shallow pattern, the patient experiences an increase in the ratio of dead space to tidal volume (since anatomic dead space is relatively fixed), which leads to a need for greater total ventilation (hence, the increase in respiratory rate); this adds to respiratory work-load and may contribute to the development of hypercapnia. In contrast, an increase in tidal volume requires a significant increase in respiratory work due to the stiffness of the lung. Since most patients with restrictive lung disease tend to use a rapid, shallow breathing pattern, we conclude that this pattern, relative to alternatives, must produce less dyspnea

The "ventilatory pump" comprises the ventilatory muscles, the peripheral nerves which transmit signals to them from the controller, the bones of the chest wall to which the respiratory muscles are connected, the pleura which transforms movement of the chest wall to negative pressure inside the thorax, and the airways that serve as a conduit for the flow of gas from the atmosphere to the alveoli and back again. The most common derangements of the ventilatory pump result in a sense of increased "work of breathing" [6-10].

When hyperinflation results in an end-inspiratory volume that approximates total lung capacity, patients often complain of an inability to get a deeper satisfying breath [9]. A sensation of chest tightness may also be present in patients in whom acute bronchoconstriction is the cause of airflow obstruction [6,7,12,13].

Neuromuscular weakness (eg, myasthenia gravis, Guillain-Barré syndrome) leads to a condition in which the patient must exert near maximal inspiratory effort to produce a normal negative pleural pressure [11]. Patients with reduced compliance of the chest wall (eg, kyphoscoliosis) or lungs (eg, interstitial fibrosis) must perform more work than normal to move air into the lungs. Obstructive lung disease is associated with increased resistance to flow and, in patients with significant hyperinflation, reduced compliance as breathing occurs on the stiff portion of the pressure-volume curve of the respiratory system

The "gas exchanger" consists of the alveoli and the pulmonary capillaries across which oxygen and carbon dioxide diffuse. Most of the common cardiopulmonary disorders leading to dyspnea are associated with some derangement of the gas exchanger due either to destruction of the diffusing membrane (eg, emphysema, pulmonary fibrosis) or the addition of fluid or inflammatory material into the lungs such that ventilation to alveoli is reduced regionally. To a lesser degree, the distance for diffusion may also contribute in these conditions or in the greatly dilated pulmonary capillaries seen in some patients with hepatopulmonary syndrome. Diseases affecting the gas exchanger are typically characterized by hypoxemia, either at rest or with exercise, and by chronic hypercapnia in more severe cases

For this system to work optimally and avert breathing discomfort, one must have a pump that functions without generating high pulmonary capillary pressures. There must also be sufficient hemoglobin to carry oxygen and appropriate enzymes to utilize oxygen in the tissues.

Symptoms of heart failure fall into two major classes: those due to a reduction in cardiac output (fatigue, weakness, and dyspnea on exertion) and those due to increased pulmonary or systemic venous pressure and fluid accumulation (dyspnea at rest and exertion, edema, hepatic congestion, and ascites)

When heart failure causes an increase in pulmonary venous pressure, it can lead to dyspnea either by producing hypoxemia or by stimulating pulmonary vascular and/or interstitial receptors (eg, unmyelinated J-receptors, also called C-fibers)

In patients with low cardiac output, oxygen delivery to the tissues is reduced, which may lead to changes in tissue metabolism with associated accumulation of products of anaerobic energy generation leading to stimulation of metabo- or ergoreceptors [14,15], which can lead to dyspnea.

Anemia can severely impair oxygen delivery because the bulk of oxygen carried in the blood is hemoglobin-bound (see "Structure and function of normal hemoglobins"). Nevertheless, the exact mechanism by which anemia produces dyspnea is not known.

Individuals usually complain of respiratory discomfort when they engage in vigorous physical activity, even in the presence of a normal cardiovascular and respiratory system and normal hematocrit. More fit individuals experience less discomfort for any given workload; cardiovascular fitness is determined by the ability of the heart to increase maximal cardiac output and by the ability of the peripheral muscles to utilize oxygen efficiently for aerobic metabolism.

It is common for patients with chronic cardiopulmonary disease to assume a sedentary lifestyle in an effort to avoid breathing discomfort. However, the end result over a span of months to years is that the individual becomes progressively deconditioned (ie, reduced maximal cardiac output, reduced capillary density in the muscles, and reduced mitochondrial capacity to sustain aerobic metabolism) and ultimately may be limited more by poor cardiovascular fitness than by the underlying disease [16].

Dyspnea due to deconditioning is typically described as "heavy breathing" or a sense of "breathing more" [8], and with careful questioning, one can determine that the patient is actually limited by fatigue or leg discomfort rather than breathing discomfort.

While clinical history is often insufficient to make a secure diagnosis, it provides guidance in narrowing the diagnostic possibilities and selecting diagnostic tests. In one study of 85 patients presenting to a pulmonary unit with a complaint of chronic dyspnea, the initial impression of the etiology of dyspnea based upon the patient history alone was correct in only 66 percent of cases [17]. Thus, a systematic diagnostic approach to these patients is necessary.

The temporal pattern of breathlessness and association with certain triggers can provide important clues. Breathing discomfort arising over the course of minutes to hours is due to a relatively limited number of conditions (table 2). These entities typically have associated symptoms and signs that provide clues to the appropriate diagnosis

Chronic exertional dyspnea and paroxysmal nocturnal dyspnea (PND) are both associated with heart failure, although nocturnal dyspnea is more specific to heart failure. Asthma is also associated with exertional and nocturnal dyspnea, but unlike PND does not usually improve with sitting or standing.

Orthopnea, the development of or worsening of dyspnea in the supine position, is also associated with heart failure and increased pulmonary capillary pressure due to the increased venous return to the heart in this position. Central obesity, however, with a large protuberant abdomen, may also lead to orthopnea; increased intra-abdominal pressure associated with large abdominal girth impairs movement of the diaphragm during inhalation. Finally, patients with inspiratory muscle weakness may also complain of orthopnea due to the increased work of breathing associated with moving the diaphragm against high intra-abdominal pressure.

Bendopnea, the worsening of dyspnea when leaning forward, is described in patients with decompensated heart failure [18].

Dyspnea that is not exacerbated by exertion is more often due to a functional or perceptual problem than to cardiopulmonary disease.

Intermittent dyspnea associated with cold air or animal dander exposure suggests asthma; work-related dyspnea may suggest occupational asthma; and dyspnea following upper respiratory infections may be due to asthma or chronic obstructive pulmonary disease (COPD).

In addition to asthma, intermittent symptoms that resolve completely between episodes can be seen with recurrent aspiration; recurrent pulmonary emboli and heart failure can also wax and wane, but generally are characterized by a baseline level of dysfunction. The presence of specific, reproducible inciting events such as exercise or cold air exposure is common with airways hyperreactivity.

The rapidity with which symptoms develop during exercise can also provide useful diagnostic information. For example, patients who develop shortness of breath and wheezing after walking 50 to 100 feet often have acute elevations in pulmonary capillary wedge pressure (usually due to cardiac diastolic dysfunction) or pulmonary hypertension. In contrast, symptoms of exercise-induced asthma usually are precipitated by more intense activity, beginning three minutes into exercise, peaking within 10 to 15 minutes, and resolving by 60 minutes.

Respiratory muscle weakness generally leads to gradually progressive dyspnea, sometimes with an acute worsening at a time of illness, particularly a respiratory infection.

For patients with chronic dyspnea, formal assessment of the severity of dyspnea can help create a baseline for future comparisons [19]. A number of instruments are available to help assess the severity of dyspnea, such as the Baseline Dyspnea Index, the Modified Medical Research Council (mMRC) dyspnea scale (table 3), and the Borg scale (table 4) [20-24]. It is important to note that scales like the mMRC do not measure dyspnea directly; rather, they assess the intensity of exercise that provokes dyspnea and, indirectly, the degree of disability resulting from dyspnea.

Attention to the quality or descriptor that a patient associates with the breathing discomfort often provides clues to the underlying diagnosis [25]. This observation comes from studies in which dyspnea questionnaires (table 5) were presented to patients with breathing discomfort from a variety of cardiopulmonary disorders [6-8,26].

While some clusters of phrases were common to a number of disease categories (eg, increased work or effort of breathing was found with COPD, asthma, and neuromuscular disease), each disease had a relatively unique set of clusters associated with it.

The sensation of "air hunger" has been associated with acute bronchoconstriction and hyperinflation in asthma and COPD, heart failure, pulmonary embolism, and restricted thoracic motion, as well as acute hypercapnia from any cause [3,4,27].

Acute bronchoconstriction leads to a series of sensations as the degree of obstruction worsens, from "chest tightness" to an increased "effort to breathe" to a sensation of "air hunger" [6-9,12,13]. The sensation of "tightness" appears to be independent of the work of breathing [28]. Attention to the use of verbal descriptors of dyspnea may help the clinician avoid underestimation of the severity of airflow limitation when objective measurements of lung function are not possible.

Report of "increased work of breathing" is associated with COPD, moderate to severe asthma, myopathy, and pulmonary fibrosis.

Patients with COPD and dynamic hyperinflation sometimes complain of a sensation of "unsatisfying breaths" or a sense that they "cannot get a deep breath" [9].

● A sensation of rapid, shallow breathing may correspond to interstitial lung disease or reduced chest wall compliance.

● Heart failure is also associated with a sensation of "suffocation" [6].

● A sense of heavy breathing is typical of deconditioning.

The absence of cigarette smoking argues strongly against a diagnosis of COPD, unless the patient has a history of tuberculosis or use of biomass cooking fuels. In one study, a history of smoking cigarettes had a positive predictive value for COPD of 0.4; COPD is uncommon among patients who have never smoked or have smoked less than 10 pack years [37].

A complete physical examination is essential. In particular, attention should be directed at the presence or absence of stridor, wheezing, crackles, tachycardia, arrhythmia, heart murmurs, gallop, peripheral edema, muscle weakness, dysphonia, and evidence of rheumatic disease. However, the absence of physical findings tends to have a greater negative predictive value, than the positive predictive value of any identified signs [17].

Abdominal rounding, the protruding of the central abdomen with diminished transverse diameter during exhalation, has been associated with acute heart failure [38].

Clues to the need for an urgent evaluation include heart rate >120 beats/minute, respiratory rate >30 breaths/minute, pulse oxygen saturation (SpO₂) <90 percent, use of accessory respiratory muscles, difficulty speaking in full sentences, stridor, asymmetric breath sounds or percussion, diffuse crackles, diaphoresis, and cyanosis

The majority of patients with chronic dyspnea of unclear etiology have one of five diagnoses, although the spectrum of potential causes is broad and more than one etiology may be present (table 7) [17,37,39].

The five most common causes of chronic dyspnea are the following:

● Asthma (see 'Respiratory' above)

● Chronic obstructive pulmonary disease (COPD) (see 'Respiratory' above)

● Interstitial lung disease (see 'Respiratory' above)

● Myocardial dysfunction (see 'Cardiovascular' above)

● Obesity/deconditioning (see 'Cardiovascular' above)

The optimal sequence of diagnostic testing for chronic dyspnea has not been determined. We typically follow an algorithm that utilizes three tiers of testing: initial testing (table 8), follow-up testing based on results of initial tests (table 9A and table 9B and table 9C), and advanced testing if the diagnosis remains uncertain (table 10).

One study found that the most informative tests for adults (age 45 to 84) with dyspnea and no known cardiopulmonary disease were the forced expiratory volume in one second (FEV₁) obtained by spirometry, the N-terminal pro-brain natriuretic peptide (NT-proBNP), and percent emphysema on chest computed tomography [40].

If the clinical evaluation doesn’t allow narrowing of the differential we usually obtain the following "initial tests" (table 8):

● Complete blood count (to exclude anemia): The degree of dyspnea associated with anemia may depend on the rapidity of blood loss and the degree of exertion that the patient undertakes. (See 'Cardiovascular' above.)

● Glucose, blood urea nitrogen, creatinine, electrolytes.

● Thyroid stimulating hormone (TSH).

● Spirometry pre and post inhaled bronchodilator OR full pulmonary function tests (PFTs) if the clinical evaluation does not suggest asthma or COPD.

● Pulse oximetry during ambulation at a normal pace over approximately 200 meters and/or up two to three flights of stairs.

● Chest radiograph.

● Electrocardiogram.

● Plasma BNP or NT-pro BNP

Typically in asthma, airflow limitation is reversible, although a large component of airways edema and inflammation may need a course of inhaled or oral glucocorticoid therapy to achieve complete reversibility

Patients with a smoking history longer than 20 years and irreversible airflow limitation on spirometry are usually managed with a presumptive diagnosis of chronic obstructive pulmonary disease (COPD). However, other causes of irreversible airflow limitation (eg, bronchiectasis, bronchiolitis, central airway obstruction) should be considered if the patient does not respond to empiric therapy for asthma or COPD

The second phase of the evaluation of dyspnea is aimed at clarifying abnormalities that were noted on initial testing, but were not diagnostic (table 9A and table 9C and table 9B)

A restrictive pattern may be caused by interstitial lung disease, pleural disease (eg, trapped lung), chest wall disease (eg, kyphoscoliosis), or ventilatory muscle weakness (eg, diffuse or due to diaphragmatic paralysis). Respiratory muscle weakness can be evaluated further with maximal inspiratory and expiratory pressures at the mouth, maximal voluntary ventilation in one minute, and supine spirometry that is compared with sitting spirometry results

Alternatively, if total lung capacity and residual volume are normal or increased, the decrease in vital capacity may be an indicator of reduced elastic recoil or air trapping and the patient may have emphysema or bronchiolitis without airflow limitation that is measurable on spirometry

Bronchoprovocation testing (eg, with methacholine, histamine, or mannitol) is typically obtained in patients with recurrent, episodic dyspnea suggestive of asthma who have normal or near normal spirometry. A trial of therapy for asthma is an alternative, but bronchoprovocation is preferred to enable a precise determination of asthma. Studies have shown that up to 30 percent of patients with a clinical diagnosis of asthma do not have airway reactivity on formal testing [41,42].

Pulmonary vascular disease (eg, pulmonary hypertension, chronic thromboembolic disease, pulmonary veno-occlusive disease) is suggested by the combination of normal spirometry and lung volumes, but abnormal gas transfer manifest by a decrease in DLCO and pulse oxygen saturation on exertion (eg, ≥5 percent).

A low resting oxygen saturation (eg, ≤95 percent) or a significant decline in oxygen saturation during exercise (≥5 percent) warrants further evaluation. The differential diagnosis includes COPD, interstitial lung disease, pulmonary vascular disease, bronchiolitis obliterans, intrapulmonary or intracardiac shunt, and heart failure. Thus, such patients typically need high resolution computed tomography (HRCT) and a transthoracic echocardiogram, possibly with a bubble study

Obesity is associated with reductions in expiratory reserve volume and function residual capacity and, in some patients, a decrease in total lung capacity (restrictive ventilatory defect) [43]. However, the changes in lung volumes do not necessarily correlate with dyspnea and it can be difficult to know whether this pattern of reduced lung volumes is due to obesity or another respiratory disease. In a population study (NHANES III), subjects in the highest quintile of body mass index (BMI), had the lowest risk for significant airflow obstruction, so obesity by itself is less commonly a cause of classical airflow obstruction [44].