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Pathophysiology of Dyspnea

Article  in  New England Journal of Medicine · January 1996

DOI: 10.1056/NEJM199512073332307 · Source: PubMed


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Monaldi Arch Chest Dis
2001; 56: 4, 325–330 REVIEW

Pathophysiology of dyspnea
H.L. Manning, D.A. Mahler

ABSTRACT: Pathophysiology of dyspnea. H.L. Manning, to a combination of mechanisms. For example, in asthma,
D.A. Mahler. a heightened sense of effort, neuroventilatory dissociation,
Dyspnea may be defined as an uncomfortable sensa- and vagal stimuli arising from bronchoconstriction and
tion of breathing. The sense of respiratory effort, chemore- airway inflammation may all play a role. Patients with dif-
ceptor stimulation, mechanical stimuli arising in lung and ferent disorders and different mechanisms of dyspnea use
chest wall receptors, and neuroventilatory dissociation different phrases to describe their breathing discomfort.
may all contribute to the sensation of dyspnea. Different Hence, the language patients use to describe their dyspnea
mechanisms likely give rise to qualitatively different sensa- may provide clues to the etiology of their symptoms.
tions of dyspnea. In most patients, dyspnea is probably due Monaldi Arch Chest Dis 2001; 56: 4, 323–328.

Keywords: Dyspnea, hypoxia, hypercapnia, COPD, asthma.

Pulmonary Section, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.

Correspondence: Harold L. Manning, MD; Pulmonary Section; Dartmouth-Hitchcock Medical Center; One Medical Center
Drive; Lebanon, NH 03756; e-mail:

Introduction pacity of the muscles (Pimax), i.e. Pbreath/Pimax [1].

Thus, the sense of effort increases whenever the
Dyspnea, defined here as an uncomfortable or inspiratory muscles must generate greater pres-
unpleasant sensation of breathing, is a common sure, such as when they face an added elastic, re-
symptom in patients with cardiopulmonary disor- sistive or threshold load, or when the pressure gen-
ders. Few symptoms are more distressing to pa- erating capacity of the respiratory muscles is re-
tients than dyspnea. Unfortunately, in all too many duced, such as when the muscles are weakened, fa-
patients, treatment of the underlying condition tigued or mechanically disadvantaged by an in-
causing dyspnea is ineffective, or only partially ef- crease in lung volume.
fective. Until further research leads to more effec-
tive treatment of such conditions, our best hope for Chemoreceptors
decreasing the breathlessness experienced by these
patients is through an improved understanding of Stimulation of either the peripheral or the cen-
the mechanisms that give rise to the sensation of tral chemoreceptors increases ventilation. These
dyspnea. same receptors also contribute to the sensation of
In this article, we will review the different breathlessness. Hypoxia stimulates respiration
pathophysiological mechanisms that produce dys- through its effects on the peripheral chemorecep-
pnea and modify its intensity. We will then focus tors, and may cause or contribute to the sensation
on a number of clinical scenarios in which dyspnea of breathlessness in patients with lung disease
plays a role and demonstrate how one can apply [2–4]. However, many dyspneic patients are not
these pathophysiological mechanisms to clinical hypoxic, and those that are hypoxic often have on-
disorders. ly modest improvement in their symptoms after
the hypoxia is corrected.
Mechanisms of dyspnea Normal subjects and patients with pulmonary
disease also experience breathlessness while
The sense of respiratory effort breathing CO2 [5, 6]. Despite that, the clinical rele-
vance of such experimental observations is uncer-
The sense of muscular effort refers to con- tain because there are many clinical settings, such
scious awareness of voluntary activation of skele- as interstitial lung disease and pulmonary vascular
tal muscles. We are all familiar with the sense of disease, in which hypercapnia is rare, yet such pa-
muscular effort: a heavy object requires great ef- tients often experience significant breathlessness.
fort to move, whereas little effort is needed to Conversely, many patients with COPD and hyper-
move a light object. What feels “heavy” or “light” capnia experience little or no dyspnea at rest.
depends not only on the weight of the object but
also on one’s strength. Similarly, the sense of res- Mechanoreceptors
piratory muscle effort is related to the ratio of the
pressure generated by the respiratory muscles There are a number of receptors distributed
(Pbreath) to the maximum pressure generating ca- throughout the respiratory system that respond to

mechanical stimuli (some, such as irritant recep- corporate the general concept of mismatch be-
tors, also respond to chemical stimuli); these re- tween the outgoing motor command to the respira-
ceptors are collectively referred to as “mechanore- tory muscles and incoming afferent information. In
ceptors”. essence, this revised theory of “afferent mismatch”
or “neuroventilatory dissociation” suggests that
Upper airway receptors. Clinical observations under a given set of conditions, the brain ‘expects’
suggest that upper airway and facial receptors a certain pattern of ventilation and associated af-
modify the sensation of dyspnea. Patients some- ferent feedback. Deviations from that pattern
times report a decrease in the intensity of their cause and/or intensify the sensation of dyspnea.
breathlessness when sitting by a fan or open win-
dow. Conversely, some patients report worsening Dyspnea in common clinical disorders
dyspnea when breathing through a mouthpiece
during pulmonary function testing. Studies involv- There is accumulating evidence that in many
ing dyspnea induced in normal subjects indicate patients, dyspnea is multifactorial in etiology, and
that receptors in the trigeminal nerve distribution that in most patients, there is no single, all-en-
influence the intensity of breathlessness [7]. compassing explanation for dyspnea. Some fea-
tures leading to dyspnea are shared by patients
Chest wall receptors. The brain receives projec- with a variety of disorders, whereas others are
tions from a variety of receptors in the joints, ten- unique to a particular clinical situation. Moreover,
dons, and muscles of the chest that influence ven- most conditions associated with dyspnea are char-
tilation and affect the sensation of breathlessness. acterized by more than one mechanism that may
Mechanical stimuli, such as vibration, are known produce respiratory discomfort. Unfortunately,
to activate these receptors, and may affect the sen- our understanding of dyspnea has not generally
sation of breathlessness. For example, MANNING et reached the point where we can conclusively link
al. found that inspiratory vibration of the paraster- a specific disease with a specific mechanism (or
nal intercostal muscles reduced breathlessness in- mechanisms) of dyspnea. However, knowledge of
duced in normal volunteers [8], and subsequent the pathophysiology of a disorder sometimes al-
studies by other investigators have shown that lows us to formulate rational hypotheses about the
chest wall vibration may reduce dyspnea in pa- underlying mechanisms of dyspnea (table 1). In
tients with COPD [9–10]. this section, we review the evidence for potential
mechanisms of dyspnea in some of the more com-
Lung receptors. The lung contains several types of mon conditions and disorders associated with dys-
receptors that transmit information to the central pnea.
nervous system. Pulmonary stretch receptors in the
airways respond to lung inflation; irritant receptors Asthma
in the airway epithelium respond to a variety of
mechanical and chemical stimuli and mediate Asthma is an inflammatory disorder of the air-
bronchoconstriction; and C-fibers (unmyelinated ways that is characterized by increased airways re-
nerve endings) located in the alveolar wall and sistance and airway closure at abnormally high
blood vessels respond to interstitial congestion. lung volumes. These pathological and physiologi-
Numerous studies suggest that information from cal abnormalities give rise to dyspnea in patients
these vagal receptors also plays a role in dyspnea with asthma.
[11–13]. The effect of vagally transmitted afferent Although physicians often gauge the severity
information from the lungs on dyspnea likely de- of asthma in terms of its effects on expiratory air-
pends upon which receptors are stimulated. Stimu- flow (e.g. FEV1 and peak expiratory flow rate are
lation of vagal irritant receptors appears to intensi- standard measures of asthma severity), the most
fy the sensation of breathlessness and may impart important mechanical abnormalities in asthma that
a sense of chest tightness or constriction [14], contribute to dyspnea are related to the inspiratory
whereas stimulation of pulmonary stretch recep- muscles. The inspiratory muscles must generate
tors likely decreases the sensation of breathless- greater tension to overcome the increase in airflow
ness [11]. resistance that accompanies bronchoconstriction.
When asthma is accompanied by hyperinflation,
Integration of Sensory Information. The many sen- the inspiratory muscles become shorter and there-
sory inputs related to breathing must reach the fore operate at a less optimal length for developing
cerebral cortex in order to be experienced as dysp- tension. Hyperinflation may change the radius of
nea, and thus the processing of respiratory-related curvature of the diaphragm, thereby placing it at a
afferent information is an important step in the mechanical disadvantage; and hyperinflation rep-
pathogenesis of dyspnea. Campbell and Howell resents an additional threshold load for the inspira-
proposed the concept of length-tension inappropri- tory muscles to overcome. As a result of these fac-
ateness as the cause of breathlessness [15]. Ac- tors, respiratory motor output increases, and the
cording to their theory, dyspnea arose from a dis- accompanying increased sense of respiratory mus-
turbance in the relationship between the force or cle effort likely contributes to dyspnea in asthma.
tension generated by the respiratory muscles and Moreover, the inspiratory threshold load, (so-
the resulting change in muscle length and lung called “auto-PEEP” or “intrinsic PEEP”) repre-
volume. Their theory has since been refined to in- sents the ultimate example of afferent mismatch


Table 1. – Mechanism(s) of dyspnea in selected disorders. Presence of mechanism(s) is indicated by “x” Although
the mechanism(s) listed for each disorder are to some degree speculative, the question mark indicates an even
greater degree of uncertainty about the contribution of that mechanism. The sign ± indicates that the mechanism
likely plays a minor role in the dyspnea experienced by most patients with the disorder

Asthma COPD LV dysfunction ILD Neuromuscular Disease Pulmonary Embolism

Sense of effort xa x x x x
Hypoxia ± ± ± ±
Hypercapnia ± ±
Irritant receptor x
C-fiber ? ? ?
Afferent mismatch x x x x x
a the sense of effort probably plays a significant role in moderate and severe asthma and a lesser role in mild asthma.
COPD = chronic obstructive pulmonary disease;
LV dysfunction = left ventricular dysfunction;
ILD = interstitial lung disease.

(neuroventilatory dissociation). During the initial COPD

contraction of the inspiratory muscles, there is no
volume change; airflow only occurs once the in- In patients with chronic obstructive pulmonary
spiratory muscles have generated sufficient pres- disease (COPD), the respiratory muscles face
sure to overcome the elastic recoil (auto-PEEP) of many of the same loads outlined above in the dis-
the respiratory system. cussion of asthma. Furthermore, the increased
Experimental evidence indicates that hyperin- dead space ventilation requires that for any given
flation likely plays an important role in the patho- workload (and level of CO2 production), minute
genesis of dyspnea in asthma. In a group of 21 ventilation will be greater in patients with COPD
mild asthmatics given methacholine to induce than in normal individuals. Just as with asthma,
bronchoconstriction, Lougheed and colleagues these factors necessitate an increase in respiratory
found that an increase in end-expiratory lung vol- motor output and lead to an increased sense of ef-
ume was the single greatest contributor to sub- fort.
jects’ breathlessness [16]. Similarly, the best phys- Other factors may also contribute to breath-
iologic correlate of relief of breathlessness after lessness in patients with COPD. For example, dy-
the administration of salbutamol was a return of namic airway compression occurs in some patients
end-expiratory lung volume to baseline. with COPD and may be a factor in their breath-
However, there is also evidence that hyperin- lessness. One mechanism by which dynamic air-
flation is not the sole mechanism of dyspnea in way compression might cause breathlessness is
asthma. Some patients with chronic asthma have through simple mechanical distortion of the air-
minimal increases in lung volumes, but are quite ways during exhalation. It is interesting that some
symptomatic. The work of TAGUCHI et al. may patients with COPD spontaneously purse their lips
shed light on the dyspnea experienced by these during exhalation, and others report improvement
patients [13]. TAGUCHI et al. used an external re- in their breathlessness after they are taught to
sistive load and histamine aerosol to induce dysp- adopt such a breathing strategy. Although pursed
nea in a group of normal subjects. Subjects expe- lips breathing may influence lung function in sev-
rienced greater breathlessness during histamine- eral ways, its effects on respiratory sensation may
induced bronchoconstriction than when breathing be mediated in part through transmural pressure
through an external resistance of comparable changes along the intrathoracic airways. O’DON-
magnitude, even though end-expiratory lung vol- NELL et al. demonstrated that when a negative
ume was similar in the two conditions. Inhaled li- pressure is applied at the mouth in patients with se-
docaine ameliorated the sensation of breathless- vere COPD, breathlessness increases when the
ness associated with bronchoconstriction, but had added pressure leads to dynamic compression of
no effect on the discomfort associated with the ex- the airways [17]. Presumably, receptors in the air-
ternal resistive load. Moreover, the inhaled lido- ways that are sensitive to airway compression or to
caine provided relief of dyspnea in the absence of transmural pressure changes across the airway
any change in end-expiratory lung volume. This wall modulate the sensation of breathlessness.
study suggests that vagal irritant receptors con- Chemoreceptor stimulation probably plays a
tribute to dyspnea during bronchoconstriction. In modest role in the dyspnea experienced by many
particular, vagal receptors may impart the sensa- patients with COPD. Although patients with
tion of chest tightness experienced by many asth- COPD may be acutely or chronically hypoxemic,
matic patients [14]. virtually all have persistent dyspnea after their hy-


poxemia is corrected. Many chronically hypercap- tal pneumonitis (similar to the abnormal breathing
nic patients are not dyspneic at rest, thereby rais- pattern in ILD) is vagally mediated [24].
ing doubts about the contribution of chronic hy-
percapnia to dyspnea. During acute exacerbations Neuromuscular disease
of COPD, patients may develop new or worsening
hypercapnia (accompanied by new or worsening In patients with disorders such as amyotrophic
respiratory acidosis), which may be a more potent lateral sclerosis or myasthenia gravis, the mechan-
stimulus for breathlessness than chronic, compen- ical properties of the respiratory system may be
sated hypercapnia. normal, but the weakened respiratory muscles (i.e.
decreased Pimax) require greater neural drive for
Chronic left ventricular dysfunction activation. For example, Spinelli and colleagues
found that in patients with myasthenia gravis
Many patients with chronic left ventricular breathing room air at rest, there was a trend to-
(LV) dysfunction complain of dyspnea even in the wards greater P0.1 (pressure measured 0.1 sec after
absence of overt heart failure. Several mechanisms the airway is occluded) values in the patients with
may contribute to dyspnea in these patients. myasthenia than in the control group [25]. The pa-
Changes in the mechanical properties of the tients with myasthenia also manifested greater
lungs sometimes accompany chronic heart disease, fractional electromyograph (EMG) activity (ratio
as patients may manifest a decrease in lung com- of EMG activity during breathing to EMG activity
pliance and an increase in airway resistance [18]. during maximal volitional effort) of both the di-
Most patients with severe chronic LV dysfunction aphragm and intercostal muscles. This heightened
also have an excessive ventilatory response to ex- neuromotor output is sensed as increased respira-
ercise resulting from increased dead space ventila- tory muscle effort, and is likely the principle
tion [19]. These abnormal demands on the ventila- mechanism of breathlessness in patients with un-
tory muscles occur on a background of reduced complicated (i.e. without superimposed respirato-
respiratory muscle function. Several studies have ry complications such as pneumonia, atelectasis,
shown a substantial decrement in inspiratory mus- etc.) neuromuscular disease.
cle strength [20, 21]. Furthermore, there is also
some evidence to suggest that such patients expe- Pulmonary embolism
rience respiratory muscle ischemia during exercise
[22]. Together, these factors create a situation in Although dyspnea is the most common
which Pbreath represents a large fraction of Pimax, symptom in patients with pulmonary embolism,
leading to an increased sense of breathing effort. there has been virtually no systematic study of
Some patients with chronic LV dysfunction dyspnea in this disorder. Pulmonary embolism
have an elevated pulmonary artery wedge pressure may be associated with a variety of pathophysi-
at rest, which usually increases further with exer- ological abnormalities, but the dyspnea experi-
cise. Since pulmonary venous hypertension is a enced by patients with pulmonary embolism
potent stimulus to C-fibers, it is tempting to spec- may be out of proportion to any derangement in
ulate that these receptors contribute to exertional respiratory mechanics or gas exchange, particu-
dyspnea in chronic heart failure (CHF) [23]. Most larly in those patients who have not had massive
patients with chronic LV dysfunction are not hy- embolism. Anecdotal reports of patients under-
percapnic and do not develop significant arterial going thrombolysis indicate that dyspnea may
oxygen desaturation during exercise; thus, it is un- be rapidly relieved by clot lysis. Such observa-
likely that the chemoreceptors play a significant tions suggest that the receptors causing the sen-
role in the dyspnea experienced by this patient sation of dyspnea lie within the pulmonary vas-
population. culature and respond to changes in pressure. The
receptor most likely to sense these changes is
Interstitial lung disease the pulmonary C-fiber. In animal studies, C-
fibers increase their firing in response to eleva-
In patients with interstitial lung disease (ILD), tions in pulmonary artery pressure [26] or pul-
lung compliance is diminished and, because of an monary embolism [27], though irritant and
increase in dead space, there is an increase in rest- stretch receptors may be stimulated by emboli as
ing ventilation and an exaggerated ventilatory re- well. It seems reasonable to postulate that C-
sponse to exercise. These factors necessitate an in- fibers cause, or at least contribute to, the sensa-
crease in respiratory motor output, resulting in an tion of dyspnea in patients with pulmonary em-
increased sense of effort. However, some patients bolism.
with ILD are dyspneic at rest, when ventilation and
the work of breathing are increased, but not to a Qualitative aspects of dyspnea
level that seems sufficient to account for their dys-
pnea. Since many interstitial disorders involve a In the preceding sections, we have described
component of alveolitis at some stage in the dis- our current understanding of the different mecha-
ease process, one possibility is that vagal receptors nisms contributing to the pathogenesis of dyspnea.
stimulated by the inflammatory process also con- Given the existence of several distinct mechanisms
tribute to patients’ breathlessness. That possibility of dyspnea, it is logical to ask whether these dif-
is consistent with animal studies demonstrating ferent mechanisms translate into distinct sensory
that the abnormal breathing pattern in experimen- experiences.


Several recent studies indicate that the answer

to that question is “yes”: different respiratory stim-
uli produce different respiratory sensations, and
patients with different disorders use different
phrases to describe their breathlessness (table 2)
[28, 29]. The sense of air hunger appears to arise
out of an increased brain stem “drive” to breathe
[30]. Patients with conditions in which there is ei-
ther an increased mechanical load on the respirato-
ry system or neuromuscular weakness or fatigue
often report an increased sense of “effort” or in-
creased “work” of breathing [28]. In patients with
moderate to severe obstructive lung disease, the
respiratory system may be characterized by
marked hyperinflation, and tidal volume, especial-
ly during exercise, may be limited by the en-
croachment of end-expiratory lung volume on to-
tal lung capacity. Under these conditions, individ-
uals may report a sense of an “inability to get a
deep breath” as the dominant feature of their
breathing discomfort [31]. Finally, questionnaire
studies demonstrate that chest tightness is a promi-
nent feature of the dyspnea of asthma, and may be
present even when there is little or no airflow ob-
struction [14].

Dyspnea is the product of a complex interac-

tion of signals arising within the brain stem and in
a variety of receptors in the upper airway, lungs,
and chest wall (figure 1). The cortical processing Fig. 1. – Pathways involved in the pathophysiology of dyspnea. For
of these afferent signals determines the intensity simplicity, receptors in the lungs, chest wall, and upper airways are
and quality of breathlessness. Various studies sug- shown schematically projecting directly to the sensory cortex, but the
gest that that although different disease states pathways likely reach the cortex via the brainstem.
share common mechanisms of dyspnea, most
pathologic conditions produce breathlessness by
more than one mechanism, and each disorder prob- References
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