Published ahead of print on March 27, 2008, doi:10.1164/rccm.200711-1675OC
© 2008 American Thoracic Society doi: 10.1164/rccm.200711-1675OC
The Affective Dimension of Laboratory DyspneaAir Hunger Is More Unpleasant than Work/Effort1 Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts; 2 Department of Medicine, Harvard Medical School, Boston, Massachusetts; and 3 Physiology Program, Harvard School of Public Health, Boston, Massachusetts Correspondence and requests for reprints should be addressed to Robert B. Banzett, Ph.D., Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215 E-mail: rbanzett{at}bidmc.harvard.edu
Rationale: It is hypothesized that the affective dimension of dyspnea (unpleasantness, emotional response) is not strictly dependent on the intensity of dyspnea. Objectives: We tested the hypothesis that the ratio of immediate unpleasantness (A1) to sensory intensity (SI) varies depending on the type of dyspnea. Methods: Twelve healthy subjects experienced three stimuli: stimulus 1: maximal eucapnic voluntary hyperpnea against inspiratory resistance, requiring 15 times the work of resting breathing; stimulus 2: PETCO2 6.1 mm Hg above resting with ventilation restricted to less than spontaneous breathing; stimulus 3: PETCO2 7.7 mm Hg above resting with ventilation further restricted. After each trial, subjects rated SI, A1, and qualities of dyspnea on the Multidimensional Dyspnea Profile (MDP), a comprehensive instrument tested here for the first time. Measurements and Main Results: Stimulus 1 was always limited by subjects failing to meet a higher ventilation target; none signaled severe discomfort. This evoked work and effort sensations, with relatively low unpleasantness (mean A1/SI = 0.64). Stimulus 2, titrated to produce dyspnea ratings similar to those subjects gave during stimulus 1, evoked air hunger and produced significantly greater unpleasantness (mean A1/SI = 0.95). Stimulus 3, increased until air hunger was intolerable, evoked the highest intensity and unpleasantness ratings and high unpleasantness ratio (mean A1/SI = 1.09). When asked which they would prefer to repeat, all subjects chose stimulus 1. Conclusions: (1) Maximal respiratory work is less unpleasant than moderately intense air hunger in this brief test; (2) unpleasantness of dyspnea can vary independently from perceived intensity, consistent with the prevailing model of pain; (3) separate dimensions of dyspnea can be measured with the MDP.
Key Words: dyspnea • signs and symptoms, respiratory • pain • psychophysiology
Two of the most common and troubling symptoms experienced by patients are dyspnea, defined as "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity" (1), and pain, defined as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" (2). Progress in understanding and treatment of pain leads progress in dyspnea by two decades (3). In part, this is the result of more complete knowledge of how pain is perceived in both laboratory and clinical situations. The recognition that different qualities and dimensions of pain exist, and the development over the past three decades of measuring instruments that can reveal these dimensions, has led to a better understanding of the neurophysiological mechanisms and treatment of pain. Pain is understood as having a "sensory dimension" and an "affective dimension" (4, 5). The sensory dimension comprises components such as intensity (SI), quality (SQ), and time course (ST); the affective dimension comprises stages of immediate unpleasantness (A1) and evaluative and emotional response (A2). These components of pain are indeed linked, but they also have substantial independence, and are processed at different sites in the brain. Although SI is a strong predictor of A1, it is not the only factor that determines A1, nor is A1 the only determinant of A2. Different kinds of pain vary widely in magnitude of A1 at similar SI. For instance, the ratio of A1 to SI is much higher in esophageal pain than in cutaneous pain (6). Likewise, analgesic drugs, hypnosis, and some brain lesions can reduce the A1/SI ratio (e.g., References 7–9). Thus, comprehensive measurement of pain requires more than a single measure of intensity; we hypothesized that the same is true for dyspnea. Recent functional imaging studies of dyspnea (e.g., Reference 10) have shown that dyspnea activates many of the same limbic brain structures involved in the affective dimension of pain, providing biological evidence that the perceptual model of pain may be appropriate for dyspnea. A few prior studies (reviewed in DISCUSSION) have examined some aspects of affective responses to dyspnea, but none has tested a comprehensive measurement model. We propose a model of dyspnea perception incorporating all major aspects of the multidimensional pain model and present an instrument, the Multidimensional Dyspnea Profile (MDP), that can be used in both laboratory and clinical settings to measure the qualitative, sensory, and affective dimensions of dyspnea. The present study was designed (1) to determine whether different forms of dyspnea differ in provoking an affective response and (2) to test the MDP. We tested the following null hypothesis: The ratio of unpleasantness, A1, to sensory intensity, SI, is the same for all dyspnea stimuli. This is the key aspect of the multidimensional dyspnea model that remains unsettled. To test the hypothesis, we subjected healthy volunteers to different combinations of laboratory dyspnea stimuli as follows: (1) maximal hyperpnea against a moderate inspiratory resistance was designed to evoke predominantly a sense of excessive respiratory work and effort; (2) mildly elevated end-tidal carbon dioxide partial pressure (PETCO2) with an enforced limit to ventilation was designed to evoke predominantly air hunger. We show that, at similar SI, laboratory-induced perception of air hunger has a significantly greater A1 than the induced sense of respiratory work/effort. This finding disproves the null hypothesis under test, demonstrating the face validity of the measurement concept. It also shows the greater potency of air hunger in causing discomfort, which may be important in evaluating causes of patient discomfort. This study has been reported in abstract form (11).
Subjects We studied 12 healthy subjects (Table 1); none was familiar with dyspnea research or the hypothesis under study. The study protocol was approved by internal review boards at the University of Massachusetts Medical Center (Worcester, MA; performance site) and Harvard School of Public Health (Boston, MA; primary grantee institution). All subjects read and signed consent forms that informed them that we were studying shortness of breath, that they would be uncomfortable for periods during the study, and that they could interrupt or stop procedures at any time without penalty.
Measurement of Dyspnea Our primary measure of dyspnea was the MDP, an instrument under development in our laboratory. The MDP incorporates standard measuring techniques of rating scales and descriptor selection and is patterned after a validated multidimensional pain instrument (12, 13) and previous work on the quality of dyspnea sensation (14–17). This instrument is designed to measure sensory intensity (SI), immediate unpleasantness (A1), sensory quality (SQ), and emotional response (A2). Details of this questionnaire are being refined before final validation (persons interested in the current form may contact the authors). We used a scripted "radio analogy" developed by Price and colleagues to explain the difference between SI ("how strong the breathing sensation feels") and A1 ("how uncomfortable or bad it feels") (18). Briefly, we told subjects that SI is analogous to how loud a sound is and A1 is analogous to how unpleasant the sound is, which depends on what sound is heard, and that a sound can be unpleasant even if it's not loud. All subjects averred they understood the concept. Scales comprising all integers from 0 to 10, equally spaced, were presented for rating SI and A1. In addition to the numbers, words descriptive of magnitude and dimension were ranged along each scale to help subjects to distinguish between the dimensions to be rated and to improve consistency among subjects; the words were placed according to their semantic magnitude as determined in published studies (e.g., Reference 19). The upper end of the SI scale was labeled "maximum," whereas the upper end of the A1 scale was labeled "unbearable." Subjects reported SQ using a list of terms derived from previous work (14, 15, 20, 21), narrowed to five categories using information on the internal correlations within longer lists (16). The five categories were as follows: "smothering, suffocating"; "breathing requires work or effort"; "cannot get enough air, hunger for air"; "chest and lungs feel tight, constricted"; "breathing a lot; rapidly, deeply, heavily". A descriptor category not expected to describe dyspnea was added to assess the individual's tendency to agree with every statement; in this instance, we used "crushing or heavy sensation in chest," a symptom of myocardial infarction, but seldom chosen as a dyspnea descriptor. Subjects rated how much of each sensation quality they felt (0 to 10), and chose the most apt single descriptor. Finally, subjects were asked to rate a list of five negative emotions: depression, anxiety, frustration, anger, and fear. Subjects rated how much of each emotion they experienced on a scale ranging from 0 to 10 ("most severe I can imagine"). Subjects were also asked if they had any current pain, and if so, whether it was related to breathing.
Physiological Measurements
Dyspnea Stimuli
Stimulus 1: hyperpnea (maximal). During the hyperpnea stimulus, a moderate resistance was imposed (14 cm H2O at 1 L/s). The subject viewed the anesthesia bag, and was instructed to prevent it from becoming fully distended or collapsed—thus, the amount of gas flowing into the bag determined the target minute ventilation. This target flow began at resting levels and was gradually increased until the subject could no longer keep pace, then decreased slightly to obtain a stimulus sustainable for 30 seconds. Fraction of inspired carbon dioxide (FICO2) was manipulated to hold PETCO2 0 to 7 mm Hg below resting PCO2 throughout the trial. The left side of Figure 2 shows a typical recording of the key variables during the stimulus 1 rating focus period.
Stimulus 2: hypopnea (matched). At the outset of this period, the FICO2 was raised to elevate PETCO2 approximately 6 mm Hg above resting, with ample flow to supply the increased spontaneous breathing. (The bag was not visible to the subject during this task.) The experimenter then began to decrease flow to the bag to limit ventilation, holding PETCO2 constant by simultaneously reducing FICO2. Ventilation was gradually decreased until online ratings of breathing discomfort increased to approximately match the maximum online ratings given near the end of stimulus 1; this required only modest reduction from spontaneous ventilation. The right side of Figure 2 shows a typical recording of the key variables during the stimulus 2 rating focus period.
Stimulus 3: hypopnea (maximal).
Stimulus order and time course. To help us guide the experiment, subjects gave continuous online single-dimension ratings of overall breathing discomfort using an electronic visual analog scale (VAS). We denoted the upper end of this VAS as "intolerable," and informed the subject that the stimulus would be immediately reduced if she or he rated 100% scale. This rating was used only to approximately match the magnitude of sensation produced by stimuli 1 and 2, and to terminate the stimulus if discomfort was intolerable; it was not used as an outcome measure. We administered the MDP immediately after each stimulus, instructing subjects to attend to a "focus period" near the end of the stimulus period during which online ratings had been constant for at least 10 seconds (median, 30 s). In pilot studies, we found it impossible to drive most subjects above midscale ratings using the hyperpnea stimulus; in contrast, all but one subject could be driven to the top of the scale with the hypopnea stimulus. Because of this limitation, stimulus 1 was administered first on Day 2 and the maximal online rating was noted; we then adjusted stimulus 2 to match this rating. After obtaining MDP responses for stimulus 2, we obtained a behavioral measure of the relative unpleasantness experienced by asking whether the subject would rather repeat stimulus 1 or 2, and why. In the third trial, we administered stimulus 3.
We found that air hunger was distinctly more unpleasant than work/effort sensation. The MDP was capable of measuring this difference, and subjects' ratings were consistent with their behavioral choices and qualitative comments. In CHARACTERIZATION OF STIMULI below, we characterize the stimuli (physiological changes and resultant qualities of sensation). In AFFECTIVE DIMENSION, we present evidence that the ratio of unpleasantness (A1) to SI is greater for air hunger than for work/effort, supporting the hypothesis that sensory and affective dimensions are separate, and can be measured. In EVALUATION OF MDP, we present further information on use of the MDP.
Characterization of Stimuli
Stimulus 1. As intended, stimulus 1 entailed much higher  E (0.48 L · min–1 · kg–1 ± 0.19 SD) and lower PETCO2 (1.7 mm Hg ± 2.2 SD below resting) than stimuli 2 and 3. The median external work of breathing at this condition was 1.23 cm H2O · L · s–1 · kg–1 (i.e., more than 10 times the internal respiratory work rate at rest for a typical healthy subject). Although we did not measure pleural pressure to calculate internal work, a conservative estimate is that internal work increased proportionally to ventilation, or about fivefold; thus, total work would have been about 15 times the work of resting breathing. Work of breathing was likely underestimated in some subjects (see DISCUSSION). In no case did the subject terminate stimulus 1 due to discomfort; the stimulus limit was always determined by the subject's failure to meet the target flow. As expected during stimulus 1, ratings of respiratory work/effort and the sense of rapid deep breathing were substantial (mean rating for both was 83% scale). Seven subjects chose "rapid deep breathing," three subjects chose "work/effort," and one chose "chest tightness" as the best descriptor for stimulus 1 (the subject who chose tightness did not have asthma; one subject was not asked for best descriptor).
Stimulus 2. During stimulus 2, ratings of suffocation and air hunger were substantial (mean: 57% and 69% scale, respectively), much higher than during stimulus 1, whereas work/effort and rapid/deep ratings were much lower than during stimulus 1. One subject added the descriptor "unsatisfied inspiration." Seven subjects chose "air hunger" as the best descriptor for this stimulus, two chose "suffocating," and two chose "work/effort."
Stimulus 3.
Other sensations. Subjects BN22 and BN29 reported pain ("side stitch") related to stimulus 1, but both achieved greater than average ventilation; there were no other reports of pain. The presence of pain may have contributed to the A1 ratings of stimulus 1 for these subjects; nonetheless, these subjects rated low A1 for stimulus 1.
Affective Dimension
Mean A1/SI ratio was 0.95 during stimulus 2 (air hunger), significantly greater than the mean of 0.64 during the matched magnitude stimulus 1 (work) (P = 0.039, two-tailed paired t test [Microsoft Excel 2004; Microsoft Corp., Redmond, WA]; Bonferroni corrected for two comparisons, as described by M. Bland, University of York, http://www-users.york.ac.uk/
When asked whether they would prefer to repeat stimulus 1 or stimulus 2, all subjects immediately and emphatically chose stimulus 1 (work/effort), and all gave explanations referring to the greater unpleasantness of air hunger (see quotations in Table 2). Another way to match the stimuli is to raise the intensity of each stimulus to the subject's limit. In stimulus 1 and stimulus 3, the two kinds of stimuli were increased until the subject could no longer perform the stimulus task. All subjects rated unpleasantness of stimulus 3 (maximal air hunger) greater than 80% scale (group mean, 93% of scale). No subject rated unpleasantness of stimulus 1 (maximal work of breathing) greater than 80% scale (group mean, 50% of scale).
Emotional response (A2) to laboratory stimuli. Ratings of anxiety and frustration were greater than zero for all stimuli, and appreciable fear emotion was rated during stimuli 2 and 3, even though all subjects intellectually understood that they were safe (see BN23's comment in Table 2). The sample size of the current experiment was not powered for multiple comparisons of all outcome measures, but the data shown in Figure 6 strongly suggest that the emotional response to air hunger is substantially greater than the response to work/effort. These emotions were greatest during stimulus 3. Subjects commented that the frustration in both stimuli arose from their inability to do the task at higher levels. Depression and anger were not evoked by these brief laboratory tests in normal subjects.
Evaluation of MDP
We conclude the following: (1) moderate air hunger is more unpleasant than maximal respiratory work, and maximal air hunger is far more unpleasant; (2) unpleasantness of dyspnea (A1) can vary independently from perceived intensity (SI), suggesting that dyspnea conforms to the multidimensional pain model; (3) the MDP instrument is convenient to use, and can distinguish differences in affective responses among kinds of dyspnea.
Affective Dimension of Dyspnea
Emotional response.
Relationship of present findings to prior studies. In several studies of dyspnea, subjects were asked to rate both the intensity of dyspnea and some aspect of affective response, described in terms such as "distress" or "anxiety" (28–31). Subjects gave separate ratings, and different subjects assigned different relative values to intensity and affect. There were, however, no interventions designed to alter the relationship between intensity and affective response, so it could not be concluded that the dimensions are independent. The first series of experiments to strongly suggest that affective response can be independent of dyspnea intensity examined the effect of pulmonary rehabilitation in patients with chronic obstructive pulmonary disease (29, 32). Dyspnea-related anxiety (a component of A2 in our model) fell by 25% relative to dyspnea intensity. We calculated an A/SI ratio using published mean data; statistical testing was not possible without paired individual data.
More recent studies have measured SI and unpleasantness (A1) while attempting to alter their relationship by acutely altering psychological state (33, 34). These studies were performed on healthy subjects in whom moderate respiratory discomfort was produced with inspiratory resistive loads. The results obtained support the multidimensional model proposed here: modest (15–25%) changes in A1/SI were seen with interventions altering attentional state or emotional state. The strength of this support is limited because the investigators did not measure or control the physiological variables pertinent to respiratory sensation (VT,
Implications of Air Hunger Unpleasantness
Critique of Physiological Methods We chose to use a mask rather than a mouthpiece, and pilot studies showed no difference in air hunger sensation stimulus response with a mask compared with a mouthpiece. Although mask fit was carefully tested before each experiment, examination of inspiratory and expiratory flow tracings suggested leaks at the mask face seal in several subjects during the strenuous high ventilation of stimulus 1. These leaks would cause our ventilation and work measures to underestimate those actually achieved by those subjects; nonetheless, subjects breathed hard enough to produce work ratings of at least 60% of scale and SI ratings of at least 60% of scale in every subject (PETCO2 measures would be unaffected by the leak).
MDP Measurement Performance Our impression from verbal debriefings is that the true difference in unpleasantness may be even greater than our quantitative results indicate. This is not surprising, because 5 to 10% of normal subjects cannot give ratings that correlate with changes in respiratory stimuli (40, 41), and the semantic distinction between intensity and unpleasantness is more subtle than subjects are ordinarily called on to make. We did not attempt to exclude such subjects from this study, as they will occur in a clinical population, but such subjects can be screened using pretests of rating correlation with repeated known stimuli (40, 42). Even with these limitations, the MDP was capable of showing a clear difference in affective response between kinds of dyspnea. Subjects rated the MDP highly for clarity, helpfulness, and ease of use. Initial use of the questionnaire, including explanations, was usually accomplished in less than 5 minutes, and subsequent use of the questionnaire required 1 to 2 minutes for most subjects. We spent only 1 to 2 minutes explaining the concept of separate scales for intensity and unpleasantness, and all subjects professed to understand the explanation, although three said the distinction was difficult to make in practice.
Comparison with established dyspnea instruments.
Conclusions If the global rating of dyspnea comprises both sensory and affective components, a multidimensional measurement such as the MDP may help the clinician. Assessment of SQ can help distinguish disease states that cause dyspnea (44, 45). Determining whether a change in dyspnea primarily reflects a change in the primary sensation or the affective response may inform us about the role of the psychological state of the patient in ratings of respiratory discomfort and guide therapies such as psychological interventions or psychoactive drugs, that reduce the A1/SI ratio to reduce discomfort and enhance function. Existing measurement instruments have not been adequate to address these problems. Although the individual concepts underlying the MDP have appeared in other instruments, the MDP integrates these concepts into one instrument. We believe that the MDP will be of value in studies of dyspnea mechanisms, as well as in clinical trials evaluating treatment.
The authors thank Richard Gracely for many enlightening discussions that were fundamental in helping us to understand pain, and to develop this line of inquiry. Paula Meek and Mark Parshall were instrumental in developing the MDP. Jeanette Hoit was extremely helpful in designing and performing preliminary experiments. The authors are deeply indebted to David Paydarfar of the University of Massachusetts Medical School for generous logistical support as well as probing discussion. Lily Nguyen provided valuable logistical help. The authors thank members of the community at UMass Medical Center for volunteering for these studies.
Supported by National Institutes of Health grants HL46690 and NR10006 to R.B.B. Originally Published in Press as DOI: 10.1164/rccm.200711-1675OC on March 27, 2008 Conflict of Interest Statement: R.B.B. received $30,000 from Boehringer Ingelheim as an unrestricted grant in support of a 2005 symposium. S.H.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. R.W.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. Received in original form November 13, 2007; accepted in final form March 25, 2008
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