Symptom Perception during Acute Bronchoconstriction - ATS Journals

Symptom Perception during Acute Bronchoconstriction KIERAN J. KILLIAN, RICHARD WATSON, JOCELINE OTIS, TIMOTHY A. ST. AMAND, and PAUL M. O’BYRNE Department of Medicine, McMaster University Medical Centre, Hamilton, Ontario, Canada

The hypothesis underlying the present study was that some of the variability in symptom intensity seen during acute bronchoconstriction may result from varying intensities of several stimuli yielding several sensations that can be identified by specific descriptive expressions (symptoms). A total of 232 subjects inhaled methacholine in doubling concentrations to a 20% decrease in FEV1, or 64 mg/ml. The study identified the prevalence of dyspnea, nonspecific discomfort associated with the act of breathing, and 10 specific symptom expressions. Each symptom intensity was rated in Borg scale units. The contribution of the specific symptoms to the intensity of dyspnea is illustrated in the following equation (r ⫽ 0.84): Dyspnea ⫽ 0.44 ⫹ 0.19 Difficult breathing ⫹ 0.41 Chest tightness ⫹ 0.20 Breathlessness ⫹ 0.14 Labored breathing ⫹ 0.11 Chest pain. Dyspnea was more intense with bronchoconstriction, baseline pulmonary impairment, weight, and sex (being female). Dyspnea was less intense with age (being older) and as airway responsiveness to methacholine increased (p ⬍ 0.05 for all factors). Chest tightness and chest pain were at polar extremes on the discrimination scale, i.e., easily discriminated; chest tightness, difficult and labored breathing were not easily discriminated.

Asthma affects 9 to 12 million individuals in the United States or 5% of the population (1). The cost of asthma treatment is estimated at $6 billion per year, representing 1% of the national expenditure on health care (2). Physicians rely on reported symptom severity to manage asthma. The inability to adequately perceive asthma symptoms leads to undertreatment and delay in treatment leading to mortality (3). For the past two decades, asthma mortality has been purported to be on the increase (4, 5). Patients use a broad range of expressions to describe asthma symptoms. The relationship between sensory mechanism and its evoked sensation remains unclear. Some expressions may imply different sensations, therefore different sensory mechanisms, whereas other expressions may imply the same sensation, therefore the same sensory mechanism. The hypothesis underlying this study was that acute bronchoconstriction generates several stimuli activating different sensory receptors eliciting several sensations that are described by different expressions (symptoms). Dyspnea, described as any discomfort associated with the act of breathing, was used as a nonspecific and global expression. To narrow the origin of symptoms, 10 expressions were chosen to reflect specific sensations that could contribute to breathing discomfort (see METHODS). Patients undergoing methacholine-induced bronchoconstriction were asked, throughout the test, if dyspnea or any of the 10 specific expressions was present and rated the intensity of all in Borg scale units (6). The aims of this study were: (1) to establish the prevalence and intensity of dyspnea and 10 specific expressions during methacholine-induced bronchoconstriction; (2) to identify objective factors contributing to the intensity of each symptom; (3) to establish the contribution of the specific expressions to the intensity of dyspnea; (4) to establish

(Received in original form May 21, 1999 and in revised form February 2, 2000 ) Correspondence and requests for reprints should be addressed to Kieran J. Killian, Ambrose Cardiorespiratory Unit, McMaster University Medical Centre, 1200 Main Street, West Hamilton, ON, L8N 3Z5 Canada. E-mail: [email protected] Am J Respir Crit Care Med Vol 162. pp 490–496, 2000 Internet address: www.atsjournals.org

which of these specific expressions can be reliably discriminated.

METHODS Subjects A total of 232 consecutive patients were referred, during the calendar year of 1994, to the clinical pulmonary function laboratory at McMaster University Medical Center with suspected asthma. The referring physicians included pulmonary physicians, general internists, and family doctors. No comprehensive clinical details about the individual patients were provided by the referring physicians. Routine medication questionnaire disclosed that 113 were prescribed inhaled steroids and 112 were prescribed inhaled ␤2-agonists for the relief of symptoms. Patients were asked not to use their ␤2-agonists for 12 h before a methacholine challenge test. All subjects (91 males and 141 females) gave informed consent. The mean age (⫾ SD) was 39 ⫾ 16.9 yr; mean weight was 74 ⫾ 17.3 kg; mean height was 168 ⫾ 9.7 cm. FEV1 was 2.9 ⫾ 0.87 L or 94% ⫾ 18.0% of predicted normal value. The mean vital capacity (VC) was 3.5 ⫾ 0.99 L or 87% ⫾ 15.0% of predicted normal value. The FEV1/VC ratio was 85% ⫾ 7.7%. One hundred seventy-nine of the 232 subjects had normal spirometry (7). The study was approved by the ethics committee of McMaster University.

Protocol Methacholine inhalation was carried out as described by Cockcroft and coworkers (8). Aerosols were generated by a Wright nebulizer with an output of 0.13 ml/min. Baseline spirometry was established after the inhalation of 0.9% saline solution followed by doubling concentrations of methacholine ranging from 0.03 to 64 mg/ml. Solutions were inhaled by tidal breathing for 2 min every 5 min until a decrease in FEV1 of 20% below the postsaline value occurred or until the highest dose had been inhaled. Airway responsiveness was expressed as the provocative concentration of methacholine causing a 20% reduction in FEV1 (PC20). After the inhalation of saline and each dose of methacholine, subjects were asked to identify the presence of dyspnea (discomfort experienced with the act of breathing) or any of the 10 specific expressions. If present, the intensity was rated in Borg scale units. The Borg scale is a category scale with ratio properties in which absolute magnitude is semantically defined as “nothing at all,” “just noticeable,” “very slight,” “slight,” “moderate,” “somewhat severe,” “severe,” “very severe,” “very very severe,” and “maximal.” The ratio properties are represented by the accompanying numbers from 0 to 10.

Symptoms The specific expressions, the reasons and background for their selection were as follows: Dyspnea. Dyspnea was described to the patients as nonspecific discomfort associated with the act of breathing. This was chosen as a global expression to embrace all uncomfortable stimuli and their associated sensations. Chest tightness. Chest tightness was chosen because it is frequently reported by asthmatic patients. At the Hering-Breuer Centenary Symposium (9), Petit reported that the sensation of chest tightness induced by acute bronchoconstriction receded after vagal blockade. During acute bronchoconstriction, chest tightness may arise from the stimulation of sensory receptors within the lungs mediated through vagal and autonomic pathways. Sensations mediated through the autonomic pathways have not been well characterized (10, 11). Difficult breathing. Difficult breathing was introduced without further explanation. During acute bronchoconstriction, a compensatory increase in inspiratory motor command is generated by the respira-

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Killian, Watson, Otis, et al.: Bronchoconstriction and Symptoms tory control systems acting in a homeostatic fashion to maintain arterial blood gas values close to normality. The increase in motor command, relayed by interneurons high in the central nervous system to the sensory cortex, can be perceived as a sensation of effort which, as it intensifies, is accompanied by exertional discomfort (12–15). The intensity of the motor command alone and in combination with the generation of force and contraction activating the intramuscular receptors (muscle spindles, joint receptors, and tendon organs) may be consciously appreciated as difficult breathing. The term “effort” was not used to avoid excessive bias because of our long-held belief that exertional discomfort and effort are virtually synonymous. Labored breathing. Labored breathing was introduced without further explanation. During acute bronchoconstriction, the increase in motor command leads to the increase in force (tension) required to drive the inspiratory muscles to overcome positive end-expiratory alveolar pressure and additional resistive and elastic forces (16, 17). Breathing not satisfying. Breathing not satisfying was described to the patients as any dissatisfaction with breathing that might occur in the absence of or out of proportion to, labored or difficult breathing. A conscious awareness of satiation is common to hunger, thirst, thermal comfort, and breathing. During acute bronchoconstriction, breathing satiation may not be achieved when breathing increases or decreases from eucapnic levels (18, 19). Breathlessness. Breathlessness was introduced without further explanation because it is frequently used. With acute asthma, an additional drive to breathe may arise within the lungs and be perceptually expressed as breathlessness. Inability to get air in. Inability to get air in was introduced without further explanation. During acute bronchoconstriction, as the airways narrow, gas is trapped in the lungs resulting in hyperinflation which reduces the ability of the shortened inspiratory muscles to shorten further (20–23). Air hunger. Air hunger was described as an unpleasant urge to breathe. A rise in PaCO2, as in holding one’s breath, results in an urge to breathe (air hunger) and is easily recognized (24, 25). During acute bronchoconstriction, breathing may be insufficient in some subjects, leading to air hunger. Wheeze. Wheeze was introduced without further explanation. This auditory sensation is generated by airway vibration induced by airflow. Obstructed breathing. Obstructed breathing was introduced without further explanation. During acute bronchoconstriction, more effort is required to achieve displacement and may be consciously perceived and recognized as obstructed breathing (inappropriateness). Chest pain. Chest pain was introduced without further explanation. Spasm of smooth muscle in the esophagus, gastrointestinal and genitourinary tracts causes pain. Pain may arise from nociceptive afferent stimulation as a result of airway spasm, airway inflammation, or muscular injury. The expressions, used to describe the symptoms,

were similar in reasoning but not synonymous to those introduced by Simon and coworkers (26, 27).

Analysis of Results Symptom prevalence and intensity after bronchoconstriction. Symptom prevalence, after the maximal decrease in FEV1 from the postsaline value, was compared using chi-square analysis and considered significant with a p value ⬍ 0.05. Symptom intensity, after the maximal decrease in FEV1 from the postsaline value, was compared using repeated measures analysis of variance (ANOVA) and considered significant with a p value ⬍ 0.05. Because the maximal bronchoconstriction varied between subjects, they were further categorized based on the maximal decrease in FEV1 from the postsaline value induced by methacholine: (1) no measurable fall in FEV1, (2) ⬍ 10%, (3) 10 to 20%, (4) 20 to 30%, and (5) ⬎ 30%. Symptom prevalence and symptom intensity were compared across categories. Factors contributing to symptom intensity after acute bronchoconstriction. A forward stepwise linear added model was used to establish the contribution of the ⌬FEV1, %fall (decrease in FEV1 from baseline), FEVbase percentage of predicted, VCbase percentage of predicted, FEV1/VCbase ratio, airway responsiveness based on PC20 category, age (yr), height (cm), weight (kg), and sex (male ⫽ 0 and female ⫽ 1) were included in the maximum model. PC20 categories were: 0 ⫽ ⬎ 64, 1 ⫽ 8 to 64, 2 ⫽ 2 to 8, 3 ⫽ 0.5 to 2, and 4 ⫽ ⬍ 0.5 mg/ml of methacholine. Symptoms contributing to the intensity of dyspnea after acute bronchoconstriction. A forward stepwise linear added model was used to establish the contribution of chest tightness, difficult breathing, labored breathing, breathing not satisfying, breathlessness, inability to get air in, air hunger, wheezing, obstructed breathing, or chest pain to the intensity of dyspnea. Symptom discrimination after acute bronchoconstriction. Symptom discrimination was explored using Thurstone’s law of comparative judgment which is based on a frequency analysis (28). Table 1 shows each symptom listed both horizontally and vertically. Each cell represents the percentage of the population in which the intensity of the horizontally listed symptom is greater than the symptom listed vertically. When two symptoms were rated equally, the established convention is to add half of the subjects to both groups. The mean proportion by which each symptom exceeds all other symptoms is at the bottom of each column. The standard deviation represents the discriminal dispersion from all other symptoms. The sensory distance between any two symptoms is calculated in discriminal dispersion units. The differences between the mean values is divided by the square root of the pooled variance of both symptoms, i.e., Sensory Distance ⫽ STightness ⫺ SChestPainⲐ √␴2Tightness ⫹ ␴2ChestPain.

TABLE 1 FREQUENCY OF PAIRED SYMPTOMS* Satiation Characteristic Symptoms Symptoms

Tightness

Wheezing

Air Hunger

Breathlessness

31.5

37.1 55.4

40.1 59.7 55.2

Mechanical Breathing Not Satisfying

Labored Breathing

Obstructed Breathing

Difficult Breathing

Inability to Get Air in

44.2 62.3 59.3 54.3

42.7 60.9 57.3 53.5 48.7

32.3 49.1 45.9 40.5 35.8 36.9

45.0 65.7 61.6 57.5 52.2 53.7 67.0

35.9 56.3 51.1 46.8 41.4 43.8 55.6 38.2

Chest Pain

Tightness Wheezing Air hunger Breathlessness Breathing not satisfying Labored breathing Obstructed breathing Difficult breathing Inability to get air in Chest pain

68.5 62.9 59.9 55.8 57.3 67.7 54.9 64.0 77.4

44.6 40.3 37.7 39.0 50.9 34.3 43.8 60.1

44.8 40.7 42.7 54.1 38.4 48.9 64.0

45.5 46.6 59.5 42.5 48.9 65.9

51.3 64.2 47.8 58.6 69.6

63.2 46.4 56.3 69.8

32.9 44.4 56.5

61.9 71.8

63.8

Mean SD

63.2 7.25

42.5 8.77

47.3 9.00

51.5 8.87

56.8 8.17

55.4 8.61

41.6 8.09

59.6 8.35

48.1 9.29

35.1 6.79

0.00

1.82

1.38

1.02

0.59

0.69

1.99

0.33

1.28

2.83

Sense distance

22.6 39.9 35.9 34.1 30.4 30.2 43.5 43.5 36.2

* Each cell represents the percentage of the population in which the intensity of the horizontally listed symptom is greater than the symptom listed vertically. The mean of each column represents the proportion by which each symptom exceeds all the others. The standard deviation represents the discriminal dispersion.

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TABLE 2 SYMPTOM PREVALENCE (%) AFTER MAXIMAL BRONCHOCONSTRICTION

Dyspnea Tightness Wheezing Air hunger Breathlessness Breathing not satisfying Labored breathing Obstructed breathing Difficult breathing Inability to get air in Chest pain

(1) ⌬FEV1%fall ⫽ 0

(2) ⌬FEV1%fall ⫽ ⬍ 10

(3) ⌬FEV1%fall ⫽ 10–20

(4) ⌬FEV1%fall ⫽ 20–30

(5) ⌬FEV1%fall ⫽ ⬎ 30

p Value

67 67 17 67 67 67 67 33 67 67 17

57 53 22 33 39 41 45 16 41 39 33

88 90 48 55 61 67 69 51 71 65 41

94 87 59 65 71 71 68 60 76 64 39

97 81 53 66 75 72 81 53 81 66 41

⬍ 0.0001 ⬍ 0.0001 ⬍ 0.001 ⬍ 0.01 ⬍ 0.01 ⬍ 0.01 ⬍ 0.01 ⬍ 0.0001 ⬍ 0.001 ⬍ 0.05 NS

Definition of abbreviation: NS ⫽ not significant.

For example the sensory distance between chest tightness (63.2% ⫾ 7.25) and chest pain (35.1% ⫾ 6.79) is: Sensory Distance ⫽ 63.2 ⫺ 35.1Ⲑ √7.252 ⫹ 6.792 ⫽ 2.82.

RESULTS At baseline, 85 of 232 subjects had an FEV1 ⬎ 100% predicted, 94 of 232 had an FEV1 80 to 100% predicted, 45 of 232 had an FEV1 60 to 80% predicted, and seven of 232 had an FEV1 ⬍ 60% predicted. Symptom prevalence increased significantly as the pulmonary impairment increased with the exception of wheeze and chest pain (p ⬍ 0.05); symptom intensity also increased with the exception of air hunger and chest pain (p ⬍ 0.05). After saline inhalation, 102 of 232 subjects had no decrease in FEV1, 124 of 232 experienced a decrease ⬍ 10%, and six of 232 experienced a decrease ⬎ 10%. Symptom prevalence increased significantly with saline-induced bronchoconstriction with the exception of chest pain (p ⬍ 0.05); symptom intensity also increased with the exception of air hunger and chest pain (p ⬍ 0.05). Before inhaling methacholine, 93 of 232 subjects (40%) reported the presence of one or more symptoms. Symptom Prevalence during Acute Bronchoconstriction

After methacholine inhalation the maximal decrease in FEV1 was 19.2% (SD 10.6), eighty of 232 subjects did not reach a 20% decrease in FEV1. The ⌬FEV1 %fall was: 0 in six of 232; ⬍ 10% in 49 of 232; 10 to 20% in 51 of 232; 20 to 30% in 94 of 232; and ⬎ 30% in 32 of 232. Symptom prevalence increased significantly with bronchoconstriction (Table 2). At maximal bronchoconstriction, 213 of 232 subjects (92%) reported the presence of one or more symptoms whereas 19 of 232 (8%) reported none. These asymptomatic subjects had a maximal decrease in FEV1 of 10% (SD 9.6) compared with 20% (SD 10.3) in the symptomatic subjects. The prevalence of dyspnea, at maximal bronchoconstriction, was 84.2%, chest tightness 78.9%, difficult breathing 67.1%, labored breathing 64.9%, breathing not satisfying 63.2%, breathlessness 62.3%, inability to get air in 58.3%, air hunger 55.3%, wheezing 49.1%, obstructed breathing 47.4%, and chest pain 37.3% (Figure 1).

Factors Contributing to Symptom Intensity during Acute Bronchoconstriction

A total of 860 separate ratings of dyspnea and 10 specific symptoms were made after the inhalation of saline and methacholine. With symptom intensity as the dependent variable, the independent contributors included ⌬FEV1, %fall, FEVbase percentage of predicted, VCbase percentage of predicted, FEV1/ VCbase ratio, airway responsiveness based on methacholine PC20 categories (least responsive ⫽ 0 ⫽ ⬎ 64 mg/ml; most responsive ⫽ 4 ⫽ ⬍ 0.5 mg/ml), age (yr), height (cm), weight (kg), and sex (male ⫽ 0 and female ⫽ 1). The results for all symptoms are given in Table 4. The coefficients listed had standardized ␤ value which was significantly different from zero, and the partial t statistics achieved significance (p ⬍ 0.05). Specific Symptoms Contributing to the Intensity of Dyspnea during Acute Bronchoconstriction

Five of the 10 specific symptoms contributed significantly and independently to the intensity of dyspnea. They were difficult breathing (␤ ⫽ 0.195; t ⫽ 4.94; p ⬍ 0.0001), chest tightness (␤ ⫽ 0.366; t ⫽ 14.66; p ⬍ 0.0001), breathlessness (␤ ⫽ 0.186; t ⫽ 5.35; p ⬍ 0.0001), labored breathing (␤ ⫽ 0.134; t ⫽ 3.77; p ⬍ 0.001) and chest pain (␤ ⫽ 0.070; t ⫽ 3.42; p ⬍ 0.001). Their contribution is described in the following equation (r ⫽ 0.84): Dyspnea ⫽ 0.44 ⫹ 0.19 Difficult breathing ⫹ 0.41 Chest tightness ⫹ 0.20 Breathlessness ⫹ 0.14 Labored breathing ⫹ 0.11 Chest pain. The intensity of each symptom is expressed in Borg scale units.

Symptom Intensity during Acute Bronchoconstriction

Symptom intensity increased significantly with bronchoconstriction (Table 3). At maximal bronchoconstriction, the intensity of dyspnea was 3.0 (SEM 0.16), chest tightness 2.3 (0.15), difficult breathing 2.3 (0.18), labored breathing 2.2 (0.17), breathing not satisfying 2.3 (0.18), breathlessness 2.1 (0.17), inability to get air in 1.9 (0.17), air hunger 1.8 (0.16), wheezing 1.5 (0.15), obstructed breathing 1.7 (0.17), and chest pain 1.0 (0.12) (Figure 2).

Figure 1. Symptom prevalence (%) after acute bronchoconstriction. The inset indicates significant differences between symptom prevalence.

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Killian, Watson, Otis, et al.: Bronchoconstriction and Symptoms TABLE 3 SYMPTOM INTENSITY AFTER MAXIMAL BRONCHOCONSTRICTION* (1) ⌬FEV1%fall ⫽ 0

(2) ⌬FEV1%fall ⫽ ⬍ 10

(3) ⌬FEV1%fall ⫽ 10–20

(4) ⌬FEV1%fall ⫽ 20–30

(5) ⌬FEV1%fall ⫽ ⬎ 30

p Value

3.3 ⫾ 1.24 2.5 ⫾ 1.18 1.3 ⫾ 1.33 2.5 ⫾ 1.26 3.0 ⫾ 1.24 2.7 ⫾ 1.14 3.0 ⫾ 1.00 1.5 ⫾ 1.03 3.2 ⫾ 1.28 3.5 ⫾ 1.56† 1.3 ⫾ 1.25

1.6 ⫾ 0.28‡§ 1.2 ⫾ 0.26 0.6 ⫾ 0.22 0.9 ⫾ 0.29 1.0 ⫾ 0.27 1.3 ⫾ 0.34 1.0 ⫾ 0.27 0.7 ⫾ 0.27 1.1 ⫾ 0.30 1.2 ⫾ 0.32† 0.7 ⫾ 0.22

3.2 ⫾ 0.35‡ 2.6 ⫾ 0.31 1.7 ⫾ 0.31 1.7 ⫾ 0.30 2.0 ⫾ 0.35 2.3 ⫾ 0.36 2.2 ⫾ 0.32 1.8 ⫾ 0.35 2.4 ⫾ 0.34 1.7 ⫾ 0.30 0.9 ⫾ 0.20

3.4 ⫾ 0.23 2.6 ⫾ 0.22 1.7 ⫾ 0.23 2.1 ⫾ 0.26 2.3 ⫾ 0.26 2.5 ⫾ 0.28 2.3 ⫾ 0.27 2.1 ⫾ 0.27 2.6 ⫾ 0.27 2.1 ⫾ 0.27 1.1 ⫾ 0.20

3.9 ⫾ 0.54§ 2.5 ⫾ 0.51 2.0 ⫾ 0.48 2.4 ⫾ 0.50 2.9 ⫾ 0.52 3.1 ⫾ 0.62 3.1 ⫾ 0.59 2.4 ⫾ 0.59 3.1 ⫾ 0.63 2.6 ⫾ 0.56 1.3 ⫾ 0.45

⬍ 0.0001 ⬍ 0.01 ⬍ 0.05 ⬍ 0.05 ⬍ 0.01 ⬍ 0.05 ⬍ 0.01 ⬍ 0.05 ⬍ 0.01 0.06 NS


* Values are mean ⫾ SEM. † Statistical difference between (1) and (2). ‡ Statistical difference between (2) and (3). § Statistical difference between (2) and (5).

Symptom Discrimination after Acute Bronchoconstriction

Discrimination was established using a frequency analysis of the paired comparisons of the intensity of all symptoms. The sensory distances of the 10 specific symptoms are given in the bottom row of Table 1 and represented graphically in Figure 3. Chest tightness was chosen as the arbitrary origin because it was the most prevalent and intense specific symptom.

DISCUSSION During methacholine-induced bronchoconstriction, difficult and labored breathing, chest tightness, breathlessness, and chest pain accounted for 71% of the variability in the overall breathing discomfort experienced. The symptoms intensified with bronchoconstriction and were also dependent on sex, age, weight, baseline pulmonary function, and airway responsiveness. During bronchoconstriction, different stimuli (mechanical or chemical) activate different receptors eliciting different sensations. A symptom is a perception involving the processing of sensations which by their presence, intensity, or context are disturbing. In the present study, we attempted to identify if linguistic expressions, selected to describe different symptoms, could be discriminated during acute bronchoconstriction. There are multiple mechanisms through which discomfort can be generated during the act of breathing. The forcible contraction of the inspiratory muscles has been the most recog-

nized factor in the causation of dyspnea. However, its role in the generation of asthmatic symptoms is less certain. In 1952, Bates noted that asthmatics were often asymptomatic in the presence of severe pulmonary impairment requiring substantial increases in inspiratory muscle force (29). In 1973, McFadden and coworkers (30) reported that “breathlessness at rest” receded when visible contraction of the sternocleidomastoid muscles disappeared in 22 hospitalized asthmatic patients. The apparent contradiction is due to a general property of sensory systems, i.e., sensory adaptation. If forceful contractions are sustained, sensory adaptation will occur as long as the force generated is below the threshold of inspiratory muscle fatigue. Above this threshold, exertional discomfort continues to increase over time (14). However, even with sensory adaptation, dyspnea reappears readily with any further increase in force, particularly with exercise. In 1973, Kinsman and coworkers (31) reported 77 asthma symptoms which were clustered into six easily recognized domains: airway obstruction; hyperventilation–hypocapnia; fatigue; panic–fear; irritability; miscellaneous. Obvious factors stand out. The symptoms associated with airway obstruction can be easily attributed to mechanical events related to inspiratory muscle force and volume displacement. The symptoms associated with hyperventilation, such as dizziness and syncope, are easily attributed to reduced cerebral perfusion. The symptom of fatigue implies weakness. Asthmatics prone to fear report more intense symptoms at a given pulmonary

TABLE 4 CONTRIBUTION OF INDEPENDENT FACTORS TO SYMPTOM INTENSITY*

Symptoms

A Const

B ⌬FEV1 %fall

C D FEVbase VCbase E % pred % pred FEV/VC Ratio

PC20 cat

G Age (yr)


2.59 6.28 2.45 2.28 2.99 4.27 1.89 1.53 5.71 2.05 5.86

0.089 0.059 0.051 0.050 0.063 0.063 0.063 0.052 0.072 0.057 0.031

⫺0.051 ⫺0.013 NS ⫺0.044 ⫺0.024 ⫺0.027 ⫺0.047 ⫺0.035 ⫺0.023 ⫺0.033 ⫺0.014

⫺0.168 NS NS ⫺0.183 ⫺0.200 ⫺0.256 ⫺0.215 NS ⫺0.252 ⫺0.228 ⫺0.153

⫺0.017 ⫺0.017 ⫺0.023 ⫺0.010 ⫺0.017 ⫺0.017 NS ⫺0.009 ⫺0.024 ⫺0.017 ⫺0.012

0.033 NS NS 0.022 NS NS 0.031 0.210 NS 0.020 NS

NS NS ⫺0.021 NS NS NS NS NS ⫺0.032 NS NS

F

H Sex

I Height (cm)

0.518 NS NS ⫺0.029 NS NS 0.665 NS 0.426 NS 0.390 NS 0.504 NS NS NS 0.468 NS 0.422 NS NS ⫺0.021

J Weight (kg)

r

0.017 0.019 0.010 0.013 0.009 NS 0.011 0.012 0.013 0.011 NS

0.49 0.39 0.37 0.36 0.37 0.34 0.35 0.35 0.40 0.34 0.31

Definition of abbreviation: NS ⫽ not significant. * Intensity ⫽ A ⫹ (B ⫻ ⌬FEV1%fall) ⫹ (C ⫻ FEVbase% pred) ⫹ (D ⫻ VCbase% pred) ⫹ (E ⫻ FEV/VC) ⫹ (F ⫻ PC20 cat) ⫹ (G ⫻ Age) ⫹ (H ⫻ Sex) ⫹ (I ⫻ Height) ⫹ (J ⫻ Weight).

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Figure 2. Symptom intensity (Borg units) (means ⫾ SEM) after acute bronchoconstriction. The inset indicates significant differences between symptom intensity.

impairment and resort to more frequent use of ␤2-agonists on an “as needed” basis. Those without fear are prone to underrate symptoms. In 1976, Rubinfeld and Pain (32–35) reported that asthmatics with “just noticeable” dyspnea had highly variable pulmonary impairment during naturally occurring asthma and chemically induced bronchoconstriction. Twelve of 82 (15%) asthmatics failed to experience any distress after a 20% reduction in their baseline FEV1. In 1982, Burdon and coworkers (36) reported that the average intensity of dyspnea experienced after a 20% reduction in the baseline FEV1 was “moderate” (Borg scale 3). There was substantial variability in the magnitude of dyspnea at any given ⌬FEV1 %fall and at any given FEV1 percentage of predicted. Since that time, many investigators have reported the rating of dyspnea during chemically induced bronchoconstriction (37–40) and during allergen-induced asthma (41, 42). In brief, dyspnea intensifies to approximately the same severity during both methacholineand allergen-induced bronchoconstriction with a modest attenuation of symptoms during the late asthmatic response. The severity of bronchoconstriction is the major contributor to asthma symptoms with substantial residual variability perhaps owing to fear of impending harm, sensory adaptation, and intrinsic perceptual impairment. Poor perception has been reported in patients with lifethreatening asthma but whether this is the result of an intrinsic abnormality remains uncertain (43–47). We addressed the possibility of intrinsic perceptual abnormalities in a study with 120 asthmatic subjects rating the intensity of dyspnea, first during methacholine-induced bronchoconstriction and then during incremental exercise (48). After a 20% decrease in FEV1 99 of 120 subjects reported dyspnea between 0.5 “just noticeable” and 4 “somewhat severe” (normal perceivers); 10 of 120 subjects reported no dyspnea (poor perceivers); and 11 of 120 subjects reported dyspnea ⭓ 5 “severe” (extreme perceivers). During exercise, the poor perceivers reported dyspnea of normal intensity whereas the extreme perceivers reported excessive dyspnea. Extreme symptomatic response was attributed to being overly fearful of impending harm. Poor perception might be reasonably attributed to an inappropriately low level of fear and adaptation stemming from a long history of asthma. The perceived intensity of asthma symptoms may be substantially different from one asthmatic to another because of individual variability in the stimuli generated. To measure all

Figure 3. The sensory distance between each symptom calculated in discriminal dispersion units.

the mechanical, chemical, and other potentially sensory events generating discomfort with asthma is not readily feasible. However, specific symptom descriptions can be chosen to describe different mechanisms. In the present study, we hypothesized that acute bronchoconstriction generates several stimuli activating different sensory mechanisms yielding several sensations. A total of 232 patients rated dyspnea, any discomfort associated with the act of breathing, and 10 specific expressions during methacholine-induced bronchoconstriction. Dyspnea was the most prevalent (84.2%) and intense symptom (3 Borg Scale). It was comforting to know that it appeared to be interpreted in the intended manner. This allowed us to analyze dyspnea as a dependent variable and the other specific symptoms as contributing variables using multiple regression. Of the 10 specific expressions, difficult breathing, chest tightness, breathlessness, labored breathing, and chest pain contributed independently to the intensity of dyspnea. Hence, in response to our primary aim it would appear that some of the variability in overall discomfort can be reasonably attributed to variability in the intensity of these specific symptoms. We went on to explore to what extent these symptoms were discriminated using Thurstone’s law of comparative judgment (49). The basic concept underlying this law is simple: a discrete symptom is associated with a specific neural process; different symptoms have different neural processes. Symptoms that can be reliably discriminated imply different neural processes; symptoms that cannot be reliably discriminated imply a similar neural process. Discrimination was established based on the frequency with which the magnitude of any one specific symptom exceeds the magnitude of each of the other symptoms. For example, the intensity of chest tightness exceeded the intensity of wheezing in 68.5% of the population. On average chest tightness exceeded the intensity of all other

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symptoms in 60.1% with a standard deviation of 11.79% across all the other symptoms. The average frequency with which each symptom exceeds all other symptoms is calculated in the same manner with their standard deviations. The discrimination index (“sensory distance”) is simply the difference between any two means divided by the square root of their pooled variances; these values are familiar to most readers as z scores. The discrimination analysis showed that chest tightness and chest pain were easily discriminated whereas breathlessness and air hunger were not. To further support the approach, we performed K-mean cluster analysis which identified five clusters: (1) chest tightness; (2) chest pain; (3) wheeze; (4) air hunger, breathlessness, and inability to get air in; (5) labored, difficult, obstructed breathing and breathing not satisfying. These clusters narrow the range of specific symptoms and imply different mechanisms. Solid proof would require further studies in which the stimuli and the evoked sensations are both measured. Chest tightness was the most prevalent (78.9%) and intense (2.3 Borg scale) specific symptom. Its mechanism of origin remains contentious. Petit observed that chest tightness recedes after vagal blockade (9). Hence, chest tightness is commonly attributed to intrapulmonary receptor stimulation. Difficult (67.1%, 2.3 Borg scale) and labored breathing (64.9%, 2.2 Borg scale) were the next most prevalent and intense symptoms. When the airways narrow, gas is trapped in the lungs resulting in hyperinflation which reduces the capacity of the shortened inspiratory muscles to generate force (20–23). An increase in motor command is now required to drive the shortened inspiratory muscles to overcome the additional resistive and elastic forces (16, 17). This increase in motor command, perceived as a sensation of effort, is accompanied by exertional discomfort (12–15). The increase in effort, the increase in inspiratory muscle tension, the presence of weakened and shortened inspiratory muscles may be perceived as difficult breathing or labored breathing without significant discrimination. Chest tightness was not reliably discriminated from difficult breathing, labored breathing, and breathing not satisfying, which raises the possibility that they share a common sensory mechanism. Breathlessness and air hunger are easily provoked by holding one’s breath or underbreathing due to a rising PaCO2. With acute asthma, the stimulation of free nerve endings in the airways, may cause an additional drive to breathe leading to air hunger and breathlessness in the same way as a rising PaCO2. These symptoms were not discriminated, suggesting a common mechanism as expected. We did expect that breathlessness/air hunger would be reliably discriminated from the exertional symptoms difficult and labored breathing. Under different experimental conditions, these sensations can be clearly discriminated when one or the other is exaggerated. In this study, it is possible that both sensations could have the same magnitude and therefore could not be discriminated. Patients with airflow limitation, and with hyperinflation, commonly report an inability to get air in. This is not surprising because of the inability to shorten the already shortened inspiratory muscles. However, inability to get air in may be confused with the expressions air hunger or breathlessness. For example, it is not uncommon to have a patient report that he cannot get air in even though his vital capacity is normal. Wheezing (49.1%, 1.5 Borg scale) and obstructed breathing (47.4%, 1.7 Borg scale) were less prevalent and intense than expected. The concordance between wheezing and breathing obstruction was 77.2%. Chest pain was the least prevalent (37.3%) and intense symptom (1 Borg scale). The cause of chest pain associated with acute bronchoconstriction remains

unclear. Chest pain is clearly recognized and discriminated by many patients experiencing acute bronchoconstriction. Pain waxes and wanes with the intensity of contraction when smooth muscle acts in a peristaltic mode against an obstruction. The pain with acute bronchoconstriction does not have these features. A possible cause would be the stimulation of free nerve endings, in response to persistent intense smooth muscle contraction in human airways. Chest pain and chest tightness were at polar extremes on the discrimination scale. The mechanism responsible for chest pain and chest tightness cannot be the same. Independent factors contributing significantly to symptom intensity were also successfully identified (Table 4). Dyspnea intensified by 0.89 Borg scale unit for each 10% reduction in FEV1. However, the intensity of dyspnea experienced by subjects with a baseline FEV1 percentage of predicted of 100, 80, 70 and 60% after a 20% fall in FEV1, was 2.45 (80% predicted), 3.43 (64% predicted), 3.92 (56% predicted) and 4.41 (48% predicted). Dyspnea was more intense in the presence of baseline pulmonary impairment. It is important to note that an equivalent decline from a normal FEV1 would be a ⌬FEV1 %fall of 20, 36, 44, and 52%. The intensity of dyspnea experienced would be 2.45 (80% predicted), 3.87 (64% predicted), 4.59 (56% predicted), and 5.30 (48% predicted). The presence of pulmonary impairment at baseline attenuated the symptomatic response by 11% (80% predicted), 15% (70% predicted), and 17% (60% predicted). Females were 13% more dyspneic than males after a 20% decrease in FEV1. Females are more anxious during naturally occurring asthma, suggesting that the fear of impending harm might account for the sex-based difference (31). The mean intensity of dyspnea was 2.6 in a subject weighing 50 kg compared with 3.45 in a subject weighing 100 kg (33% higher) after a 20% decrease in FEV1. A 60-yr-old was 24% less dyspneic than a 20-yr-old. A 33% reduction in symptom intensity in subjects with a mean age of 68 yr compared with subjects with a mean age of 30 yr has been reported (39). The most reactive subjects (PC20 ⬍ 0.5 mg/ml) rated dyspnea 0.8 Borg scale unit lower than the least reactive subjects (PC20 ⬎ 64 mg/ ml). Reducing airway responsiveness and improving baseline pulmonary function with optimal management would predictably improve the perceptual response to bronchoconstriction. After a 20% reduction in FEV1, seven of 126 (6%) subjects did not experience any dyspnea, whereas 30 of 126 (24%) experienced “severe” or greater than “severe” dyspnea. In summary, five specific symptoms, difficult breathing, chest tightness, breathlessness, labored breathing, and chest pain, account for 71% of the variability in the dyspnea experienced during acute bronchoconstriction. The degree and duration of bronchoconstriction, baseline pulmonary function, sex, age, and airway responsiveness play considerable roles in the intensity of these symptoms. Normalizing pulmonary function and airway responsiveness improves the perceptual response to bronchoconstriction. We suspect that the substantial residual variability in symptom intensity, not accounted for, is the result of an inappropriately high or low level of fear. Poor perception or exaggerated perception can be identified during methacholine-induced bronchoconstriction. Reeducation as to an appropriate level of intensity may be helpful in some asthmatics. References 1. Evans, R., D. I. Mullally, R. W. Wilson, P. J. Gergen, H. M. Rosenberg, J. S. Grauman, F. M. Chevarley, and M. Feinleib. 1987. National trends in the morbidity and mortality of asthma in the US: prevalence, hospitalization and death from asthma over two decades: 1965–1984. Chest 91:65–74.

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