Mechanisms and Measurement of Dyspnea in Chronic Obstructive Pulmonary Disease Donald A. Mahler Dartmouth Medical School, Lebanon, New Hampshire

Patients with chronic obstructive pulmonary disease (COPD) describe their breathlessness as related to the work and effort associated with breathing. Current evidence suggests that the perception of dyspnea is due to a “mismatch” between the outgoing motor command from the central nervous system and the corresponding afferent information from chemoreceptors and/or mechanoreceptors. To measure the severity of dyspnea the principles of psychophysics (stimulus → response relationship) can be applied. One approach is to consider activities of daily living as a putative stimulus. Although this method relies on patient recall and description of daily tasks, ability to function, as well as time and effort to complete an activity, select clinical instruments have demonstrated appropriate measurement criteria in randomized clinical trials involving patients with COPD. Another approach is for a patient to report the intensity of dyspnea during exercise, and current practice is to provide ratings each minute “on cue” during the exercise test. A computerized system has been developed whereby the person can report ratings spontaneously and continuously by moving a computer mouse that adjusts a vertical bar adjacent to 0–10 category-ratio scale positioned on a monitor. With this continuous method the patient reports twice the number of dyspnea ratings during exercise compared with discrete ratings each minute. Patient-reported dyspnea based on activities of daily living and exercise testing provides distinct but complimentary information. Keywords: descriptors of breathlessness; clinical dyspnea instruments; exercise testing; neuroventilatory dissociation

Breathing difficulty is the major reason that patients with chronic obstructive pulmonary disease (COPD) seek medical attention. More than 50% of respondents to a telephone survey reported that dyspnea limited sports and recreation activities as well as normal physical exertion (1). About 40% indicated that their breathing affected their ability to perform household chores (1). Unfortunately, many patients with COPD ignore this complaint and mistakenly attribute breathlessness to “getting old” or “being out of shape.” Typically, the person decides to be evaluated when dyspnea interferes with work and/or activities of daily living.

MECHANISMS OF DYSPNEA IN COPD Descriptors of Dyspnea

Dyspnea has been defined as a subjective experience comprised of distinct qualitative sensations which can vary in intensity (2). A variety of studies have demonstrated that patients with different respiratory diseases report unique descriptors of their dyspnea. In particular, those with COPD select statements that relate to

(Received in original form September 21, 2005; accepted in final form December 16, 2005 ) Correspondence and requests for reprints should be addressed to Donald A. Mahler, M.D., Section of Pulmonary & Critical Care Medicine, DartmouthHitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756-0001. E-mail: [email protected] Proc Am Thorac Soc Vol 3. pp 234–238, 2006 DOI: 10.1513/pats.200509-103SF Internet address: www.atsjournals.org

the work and/or effort associated with breathing. As an example, the three most common phrases chosen from a list of 15 items by 85 patients with COPD to describe their “uncomfortable awareness of breathing with activities” were (3): • “My breathing requires effort”—85% • “I feel out of breath”—49% • “I can not get enough air in”—38% Using cluster analysis, Mahler and coworkers (3) found that the “work/effort” cluster was common in different groups of patients who had various cardiorespiratory disorders. Each diagnosis was associated with a unique set of clusters (e.g., asthma with “work/effort” and “tight”; interstitial lung disease with “work/effort” and “rapid” breathing) (3). In addition, patients with COPD responded that their breathing difficulty was perceived more frequently during inspiration rather than during expiration (3). In a study by O’Donnell and colleagues (4), the following descriptors of breathlessness were most frequently selected from a list of 16 phrases by patients with COPD immediately after cycle ergometry: • increased inspiratory difficulty—75% • unsatisfactory inspiratory effort—75% • shallow breathing—50% The descriptors of breathlessness chosen by patients with COPD support the concept that inspiratory muscles play an important role in the experience of dyspnea. Neurophysiologic Model of Dyspnea

Dyspnea may be due to a variety of mechanisms in patients with COPD (Table 1). These different mechanisms may be considered based on a neurophysiological model (5): receptor → afferent impulse → integration/processing in the central nervous system (CNS) → efferent impulse → dyspnea. Receptors. Ventilatory demand may be increased due to hypoxemia, which stimulates carotid bodies, as well as hypercapnia and/or acidosis, which stimulate the medulla. However, many patients with COPD have an adequate oxygen saturation (⭓ 90%) and normal or low carbon dioxide levels (⭐ 40 mm Hg), but still experience dyspnea. In these patients, other mechanisms play a role in their breathing difficulty. Upper airway and facial mechanoreceptors can modify the perception of breathlessness as evidenced by the observation that some patients prefer to sit by a fan or an open window to allow air movement (6). Dynamic compression of airways during exhalation can stimulate receptors to initiate vagal afferent impulses that contribute to dyspnea in patients with COPD (7). Breathing with pursed lips can modify dyspnea by preventing airway collapse and by providing a sense of control over “the struggle to breathe.” Airway stretch receptors respond to lung inflation. In patients with COPD expiratory airflow limitation can cause hyperinflation at rest and/or during activities that could stimulate stretch receptors. The consequences of hyperinflation include mechanical limitation to increase tidal volume, an increase in the elastic

Mahler: Understanding and Measuring Dyspnea in COPD TABLE 1. MECHANISMS OF DYSPNEA IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE 1. Increased ventilatory demand A. Physiologic dead space (↑ VD/VT) B. Hypoxemia C. Hypercapnia D. Early onset of lactic acidosis E. Limb muscle weakness due to: 1) Deconditioning 2) Systemic effects 3) Poor nutrition 2. Dynamic airway compression 3. Hyperinflation, at rest or with exertion (dynamic) 4. Respiratory muscle weakness

recoil, and shortening of the vertical muscle fibers of the diaphragm (8). The enhanced elastic recoil places an inspiratory “load” on the diaphragm which has functional weakness due to the shorter muscle length resulting from hyperinflation. O’Donnell and coworkers (9) showed that exertional breathlessness (⌬Borg at isotime) was significantly correlated (r ⫽ 0.50; p ⫽ 0.0001) with ⌬ inspiratory capacity at isotime, a measure of dynamic hyperinflation, during constant work exercise on the cycle ergometer in patients with COPD. However, the modest correlation indicates that other factors also contribute to exertional breathlessness. Both vagal-mediated receptors and nerve fibers located in the airway epithelium and/or alveolar wall respond to a variety of mechanical and chemical stimuli. The improvement in dyspnea reported with inhaled corticosteroids, as well as monoclonal antibody targeting interleukin-8 in patients with COPD, may result from a direct effect of these medications on airway receptors and/ or nerve fibers (10–12). Afferent impulse. Various nerve pathways can transmit the information after stimulation of the receptor site(s) to the CNS. For example, the vagal nerve transmits afferent information from lung receptors, whereas spinal and supraspinal reflexes are involved in afferent activity from respiratory muscle spindles (2, 5). Integration/processing in the central nervous system. Although afferent signals associated with breathlessness are received, integrated, and processed in the CNS, little is actually known about these neural activities. It is believed that motor cortex or brainstem respiratory neurons transmit a signal to the sensory cortex (i.e., corollary discharge), which may contribute to a “sense of effort” to breathe (13). This sensation increases whenever central motor command is increased. Efferent impulse. In response to afferent information the CNS sends efferent impulses via the phrenic nerve to the diaphragm and via other motor nerve discharges to the respiratory muscles in order to increase respiration. O’Donnell and colleagues (14) proposed the phrase “neuroventilatory dissociation” to reflect a “mismatch” between afferent information to the CNS and the outgoing motor command to the respiratory muscles. Based on this concept the brain anticipates or expects a certain ventilatory response according to the associated afferent information. Banzett and coworkers (15) termed this process “efferentreafferent dissociation.” This “mismatch theory” of neural activity and subsequent ventilatory outputs appears to contribute to dyspnea under various experimental conditions. Perception of dyspnea. Perception of dyspnea is highly variable among individuals with COPD (16–19). For example, patients with COPD exhibit a wide range for magnitude estimation of added resistive loads (17). However, comparison of groups shows that the exponents of the psychophysical power function were similar between patients with COPD and age-matched healthy

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subjects (17). Noseda and colleagues (16) classified 16 patients with COPD into either “high perceivers” or “low perceivers” based on their ratings of the “change in shortness of breath” after inhalation of saline and after terbutaline. Patients with COPD demonstrate a range of dyspnea responses during exercise testing that are not directly related to the severity of disease (18, 19). Certainly, psychological factors, such as anxiety, anger, and depression, can increase the severity of breathlessness out of proportion to the physiologic impairment (2). For example, Lavietes and colleagues (20) found that subjects who reported higher ratings of dyspnea while breathing through an inspiratory resistive load had higher depression scores compared with those who had lower ratings of dyspnea. Thus, the psychological profile of patients may contribute to the amplification or exaggeration of the intensity of a symptom such as breathlessness (20). In addition, affective components (i.e., distress associated with breathing difficulty) are common in patients with COPD and can influence any breathing discomfort (21).

MEASUREMENT OF DYSPNEA IN COPD The two purposes of measuring dyspnea are: to differentiate between patients who have less dyspnea and those who have more dyspnea (discriminate), and to determine whether dyspnea has changed over time and/or as a result of treatment (evaluate). The principles of psychophysics have been applied to develop instruments to quantify the severity of dyspnea (22). Key requirements of the instruments used to measure dyspnea are listed in Table 2. Clinical Instruments

One approach has been to consider that activities of daily living impact the experience of breathlessness. Over the past 40 years, numerous questionnaires have been developed to quantify the severity of breathlessness based on daily activities (23–36) (Table 3). This approach depends on a patient’s recall and description of daily tasks, ability to function, and the time and effort to complete an activity. One of the original questionnaires is the fivepoint Medical Research Council (MRC) scale developed by Fletcher and coworkers (24). This scale considers a single dimension (i.e., physical tasks such as walking) that provokes breathlessness. The MRC scale has proven to be an excellent discriminative instrument for categorizing patients according to the severity of their breathlessness. In addition, initial scores on the MRC scale have been shown to predict survival in patients with COPD (37, 38). However, the MRC scale is limited as an evaluative instrument because its broad grades make it difficult to detect small but important changes with an intervention (34). Consequently, multidimensional clinical instruments were developed in order to provide a more comprehensive assessment of the severity of dyspnea. The most widely used multidimensional instruments include the Baseline (BDI) and Transition (TDI) Dyspnea Indices (30), which consider three components (functional impairment, magnitude of task, and magnitude of effort), and the dyspnea component of the Chronic Respiratory Disease Questionnaire (CRQ) (31), which incorporates five physical

TABLE 2. KEY REQUIREMENTS OF INSTRUMENTS USED TO MEASURE DYSPNEA 1. 2. 3. 4.

Patient-reported outcome Multidimensional, but simple to use Responsive to therapy—ability to detect change Established minimal clinical important difference

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TABLE 3. CLINICAL INSTRUMENTS DEVELOPED FOR MEASURING THE SEVERITY OF DYSPNEA

Unidimensional Instruments Pneumoconiosis Dyspnea Questionnaire MRC Breathlessness scale Visual analog scale Oxygen-cost diagram WHO Dyspnoea Questionnaire ATS Dyspnea scale Breathlessness component of BCSS scale Multidimensional Instruments Baseline Dyspnea Index (BDI) Transition Dyspnea Index (TDI) Dyspnea component of CRQ UCSD shortness of breath questionnaire Self-administered computerized BDI/TDI Self-administered CRQ

Exercise Testing

Grades

Year of Publication

Ref. No.

1–4 1–5 0–10 cm mm on a line 1–4 0–4

1952 1959 1969 1978 1982 1982

23 24 25 26 27 28

0–4

2003

29

0–12 ⫺9 to ⫹9 1–5

1984 1984 1987

30 30 31

0–120

1998

32

2004 2004 2003 2005

33, 34 33, 34 35 36

0–12 BDI ⫺9 to ⫹9 TDI* 1–5

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Definition of abbreviations: ATS ⫽ American Thoracic Society; BCSS ⫽ breathlessness, couth, sputum scale; CRQ ⫽ Chronic Respiratory Questionnaire; MRC ⫽ medical research council; UCSD ⫽ University of California San Diego; WHO ⫽ World Health Organization. * Continuous scale from ⫺9 to ⫹9

activities that are specific for the individual patient. These instruments have been shown to be valid, reliable, and responsive (39). The responsiveness of the TDI and the dyspnea component of the CRQ have been demonstrated in numerous multicenter randomized clinical trials (i.e., improvements in breathlessness) with pharmacotherapy, pulmonary rehabilitation, and inspiratory muscle training in patients with COPD (9, 11, 40–46). There has been interest, particularly by regulatory agencies, in determining whether an observed change in a dyspnea score in a randomized clinical trial is meaningful to the patient group. The concept of minimal clinically important difference (MCID) has developed to examine the smallest improvement in an outcome that is considered meaningful to the individual patient. Based on different methods (expert preference; anchor approach; and distribution estimates), the MCID has been determined to be one unit for the TDI (47, 48) and 0.5 unit for the dyspnea component of the CRQ (49). An important characteristic for measuring dyspnea is that the score or grade be patient reported. Both the original BDI/ TDI and the dyspnea component of the CRQ were developed so that a physician, nurse, or technician could interview an individual patient in order to inquire about how various aspects of the person’s life might affect his/her breathlessness. According to the patient’s answers, the interviewer would then select (for the BDI/TDI), or help the patient select (for the CRQ), a grade for breathlessness for each dimension or activity. Recently, both instruments have been developed into self-administered versions so that the dyspnea grades represent direct patient-reported measures rather than be influenced by possible bias or interpretation by the interviewer (33–36). These self-administered instruments represent a standardized approach for obtaining a patient’s report of the severity of breathlessness based on specific questions or activities.

Another approach for measuring dyspnea is for the patient to rate the intensity of dyspnea on a scale while exercising on a cycle ergometer or on a treadmill (18, 50). This method attempts to simulate the person’s experience while performing physical activities. Although the precise stimulus for exertional breathlessness is not completely understood, for measurement purposes it is reasonable to consider power production (watts) and/ or oxygen consumption (ml/kg/min) as putative “stimuli” for provoking dyspnea during exertion (18, 50). Typically, subjects provide ratings of dyspnea during exercise on the 0–10 categoryratio scale (CR-10) developed by Borg (51) or on a visual analog scale (VAS) (52). The CR-10 scale has two major advantages for measuring dyspnea during exercise testing. The presence of descriptors on the CR-10 scale permits comparisons between individuals based on the assumption that the verbal descriptors on the scale have similar meaning to different subjects (51). In addition, a value on the CR-10 scale may be used as a dyspnea “target” for patients to monitor the intensity of their exercise training (53). Initial investigations had subjects rate dyspnea at the end of the exercise test (i.e., peak values). In general, both healthy individuals and patients with cardiorespiratory disease reported peak ratings between 5 and 8 on the CR-10 scale (54). These findings led to the standard practice of instructing patients to give ratings at each minute “on cue” during the exercise test (18, 50). By combining the physiologic variables (e.g., power production or oxygen consumption) with these discrete dyspnea ratings, it is possible to calculate a slope and an intercept of the stimulus → response relationship (18, 19, 50). In general, the slope of the regression between power production and dyspnea ratings is higher in patients with respiratory disease compared with healthy individuals (18, 19). The majority of exercise studies involving patients with COPD have used the cycle ergometer for diagnostic testing to evaluate breathlessness and for assessing response to therapy. The rationale for using the cycle ergometer is that the work load can be quantified and older patients may feel safer during exertion because their weight is supported. However, the majority of patients are more familiar with walking rather than cycling. Man and coworkers (55) showed that patients with COPD selected higher ratings for dyspnea while walking, but generally reported higher ratings for leg discomfort while cycling. Additional testing will be required to examine which mode of exercise is preferable to evaluate the patient’s experience of dyspnea. In 1993 Harty and colleagues (56) described the methodology and results of the continuous measurement of breathlessness during exercise in six healthy subjects who used a potentiometer to give their ratings on a VAS displayed on a monitor. In 2001 Mahler and coworkers (57) reported on a continuous method in which subjects moved a computer mouse that controlled the length of a bar (i.e., a VAS) whose lower edge coincided with a value along the CR-10 scale to represent the current level of perceived dyspnea throughout exercise. This approach allows the subject to provide ratings spontaneously and continuously while exercising without waiting for a cue or request from the physician. In general, subjects report about twice the number of dyspnea ratings during exercise while using the continuous method compared with the discrete method (i.e., ratings each minute) (19, 57). There are three important advantages of the continuous method for measuring dyspnea. First, the perception of breathlessness may change throughout the course of exercise rather than at arbitrary one-minute time intervals. Thus, the standard

Mahler: Understanding and Measuring Dyspnea in COPD

approach obtaining discrete ratings each minute may not accurately reflect the perceptual changes in dyspnea. Second, the continuous method enables subjects to provide, on average, about twice the number of dyspnea ratings compared with the discrete method. This may be important because some patients with respiratory disease may only be able to exercise for three or four minutes; consequently, only a few dyspnea ratings may be obtained with the discrete method (19, 57). Certainly, statistical analyses may be difficult when trying to fit a quantitative function to only a few data points. Third, this system incorporates a VAS positioned adjacent to the CR-10 scale that provides a continuous measure for patients to rate breathlessness, whereas the discrete method provides only integer choices on the CR-10 scale. The validity of the continuous system for subjects to report the intensity of dyspnea during exercise has been established in healthy young and old adults as well as in patients with COPD (19, 57). In addition, this methodology has demonstrated responsiveness to acute interventions such as breathing through an inspiratory resistive load (57) and administration of short-acting bronchodilator therapy (58). CONCLUSIONS

Various pathophysiologic mechanisms can contribute to dyspnea in patients with COPD. Current understanding suggests that a “mismatch” between neural activity from the brain and consequent ventilatory output from the respiratory muscles contributes to the perception of breathlessness. To quantify the intensity of dyspnea, various questionnaires/scales have been developed that have demonstrated validity, reliability, and responsiveness. Recently, two widely used clinical instruments, the BDI/TDI and the dyspnea component of the CRQ, have been modified into self-administered versions so that the patient can report directly the impact of activities of daily living on dyspnea. These questionnaires are appropriate for randomized clinical trials involving large numbers of subjects, as dyspnea scores can be obtained easily with minimal equipment and cost. Another approach uses exercise testing whereby the patient reports discrete (e.g., each minute) or continuous (e.g., whenever there is a change) ratings of dyspnea while exercising. Both the discrete and continuous methods can be used during cardiopulmonary exercise testing for clinical and research purposes. Conflict of Interest Statement : D.A.M. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

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